Select Page


Back Clinic Cannabinoids. Plants are medicine, and as research continues with these alternative medicines, more information is available when it comes to medical options for various ailments, conditions, diseases, disorders, etc… Chiropractor Dr. Alex Jimenez investigates and brings insight into these developing medicines, how they can help patients, what they can do, and what they cannot do.

The marijuana plant is how most know about cannabinoids. It is the most recognized cannabinoid tetrahydrocannabinol (THC), which is the compound that causes feelings of euphoria.

Scientists identified cannabinoids only in cannabis. However, new research has found these same medicinal qualities in many plants, including black pepper, broccoli, carrots, clove, echinacea, and ginseng.

These vegetables or spices won’t get you high, but understanding how these different plants affect the human body can lead to vital health discoveries.

A Deeper Look Into Metabolic Syndrome | El Paso, TX (2021)

A Deeper Look Into Metabolic Syndrome | El Paso, TX (2021)

In today’s podcast, Dr. Alex Jimenez, health coach Kenna Vaughn, chief editor Astrid Ornelas discuss about metabolic syndrome from a different point of view as well as, different nutraceuticals to combat inflammation.


Dr. Alex Jimenez DC*: Welcome, guys, welcome to the podcast for Dr. Jimenez and crew. We’re discussing today’s metabolic syndrome, and we’re going to be discussing it from a different point of view. We will give you excellent, useful tips that can make sense and are easily doable at home. Metabolic syndrome is a very vast concept. It contains five major issues. It has high blood glucose, it has belly fat measurements, it has triglycerides, it has HDL issues, and it pretty much has a whole conglomeration of dynamics that have to be measured in the whole reason we discuss metabolic syndrome because it affects our community very much. So, we’re going to be discussing these particular issues and how we can fix them. And give you the ability to adapt your lifestyle so that you don’t end up having. It’s one of the most important disorders affecting modern medicine today, let alone once we understand it. Everywhere you go, you’re going to see a lot of people having metabolic syndrome. And it’s part of a society, and that’s something you see in Europe as much. But in America, because we do have a lot of foods and our plates are usually bigger, we have the ability to adapt our bodies differently by just what we eat. No disorder will change so quickly and fast as a good mechanism and a good protocol to help you with metabolic disorders and metabolic syndrome. So having said that, today, we have a group of individuals. We have Astrid Ornelas and Kenna Vaughn, who will discuss and add information to help us through the process. Now, Kenna Vaughn is our health coach. She’s the one who works in our office; when I’m a practicing physician on physical medicine and when I’m working with people one on one, we have other people working with dietary issues and dietary needs. My team here is very, very good. We also have our top clinical researcher and the individual who curates much of our technology and is at the cutting edge of what we do and our sciences. It’s Mrs. Ornelas. Mrs. Ornelas or Astrid, as we call her, she’s ghetto with the knowledge. She gets nasty with science. And it’s really, really where we are. Today, we live in a world where research is coming and spitting out of the NCBI, which is the repository or PubMed, which people can see we use this information and we use what works and what does it. Not all information is accurate in PubMed because you have different points of view, but it’s almost like a finger on a pulse when we have our finger in. We can see the things that affect it. With certain keywords and certain alerts, we get notified of changes for, let’s say, dietary sugar issues or triglyceride issues with fat issues, anything about metabolic disorders. We can kind of come up with a treatment protocol that is live adapted from doctors and researchers and PhDs around the world almost instantaneously, literally even before they’re published. For example, today happens to be February 1st. It’s not, but we’ll be getting results and studies presented by the National Journal of Cardiology that will come out in March if that makes sense. So that information is early hot off the press, and Astrid helps us figure these things out and sees, “Hey, you know, we found something really hot and something to help our patients” and brings the N equals one, which is patient-doctor equals one. A patient and therapist equal one that we don’t do specific protocols for everyone in general. We do specific protocols for each person as we go through the process. So as we do this, the journey of understanding metabolic syndrome is very dynamic and very deep. We can start from just looking at someone to the bloodwork, all the way to dietary changes, to metabolic changes, all the way down to the cellular activity that it’s actively working. We measure issues with BIAs and BMI, which we have done with previous podcasts. But we can also get into the level, the genomics and the changing of the chromosomes and the telomeres in the chromosomes, which we can affect by our diet. OK. All roads lead to diets. And what I say in some weird way, all roads lead to smoothies, OK, smoothies. Because when we look at smoothies, we look at the components of smoothies and come up with dynamics that are abilities to change now. What I look for is when I look for treatments, I look at things that make people’s lives better, and how can we do this? And for all those mothers, they understand that they may not realize that they do this, but a mom doesn’t wake up saying, I’m going to give my kid food. No, she’s kind of doing a mental lavage of bringing the whole kitchen because she wants to infuse the best nutrition for their child and offer their best kind of options for their baby to go through the world or daycare or elementary school, through middle school, through high school so that the child can develop well. Nobody goes out thinking that I’m going to give my kid just junk and. And if that’s the case, well, that’s probably not good parenting. But we won’t talk about that well; we will talk about good nutrition and adapting those things. So I’d like to introduce Kenna right now. And she’s going to be discussing a little bit of what we do when we see someone with metabolic disorders and our approach to it. So as she goes through that, she’s going to be able to understand how we evaluate and assess a patient and bring it in so that we can start getting a little bit of control for that individual. Kenna, it’s all yours.


Kenna Vaughn: All right. So first, I just want to talk about the smoothies a little bit more. I am a mom, so in the morning time, things get crazy. You never have as much time as you think you do, but you need those nutrient nutrients and so do your kids. So I love smoothies. They’re super fast. You get everything you need. And most people think that when you’re eating, you’re eating to fill your stomach, but you’re eating to fill your cells. Your cells are what need those nutrients. That’s what carries you on with the energy, the metabolism, all of that. So those smoothies are a super great option, which we give our patients. We even have a book with 150 smoothie recipes that are great for anti-aging, helping diabetes, lowering cholesterol, controlling inflammation, and things like that. So it’s one resource we give to our patients. But we do have multiple other options for the patients who come in with metabolic disease.


Dr. Alex Jimenez DC*:  Before you go in there, Kenna. Let me just kind of add that what I’ve learned is that we have to make it simple. We got to take homes or takeaways. And what we’re trying to do is we’re trying to give you the tools that can help you in that process. And we’re going to take you to the kitchen. We’re going to grab you by the ear, so to speak, and we’re going to show you the areas where we need to look at. So Kenna is about to give us the information in terms of smoothies that will assist us with dietary changes that we can provide our families and change its metabolic disaster that affects so many people called metabolic syndrome. Go ahead.


Kenna Vaughn: OK, so like he was saying with those smoothies. One thing that you should add to your smoothie is, which what I love to add in mine is spinach. Spinach is an excellent choice because it gives your body more nutrients. You are getting an extra serving of vegetables, but you can’t taste it, especially when it gets covered up by the natural sweetness that you find in fruits. So that’s a great option when it comes to the smoothies. But another thing that Dr. Jiménez was mentioning is other things in the kitchen. So there are other substitutes that we’re kind of wanting our patients to use and implement. You can start small, and it’ll make a huge difference just by switching out the oils you’re cooking with. And you’ll begin to see an improvement in your joints, your kids, and everyone will just improve immensely. So one thing we want to get our patients into using is those oils, such as avocado oil, coconut oil, and… Olive oil? Olive oil. Yes, thank you, Astrid.


Dr. Alex Jimenez DC*: That was olive oil. That was Astrid in the background. We’re getting the facts out excellent and continue.


Kenna Vaughn: When you switch those out, your body breaks things down differently with those unsaturated fats. So that’s just another option that you have in that kitchen besides making those smoothies. But like I said before, I’m all about quick, easy, simple. It’s way easier to change your lifestyle when you have a whole team around you. And when it’s easy, you don’t. You don’t want to go out and make everything super difficult because the chances of you sticking to it aren’t very high. So one thing we want to do is make sure that everything that we’re giving our patients is easy to do and it’s attainable for everyday life.


Dr. Alex Jimenez DC*: I’m very visual. So when I go to the kitchen, I like making my kitchen look like the cocina or whatever they call it in Italy, the cucina and I have three bottles there, and I have an avocado oil one. I have the coconut oil one, and I have the olive oil right there. There are big bottles there. They make them pretty, and they look Tuscan. And, you know, I don’t care if it’s an egg, I don’t care. Sometimes, even when I’m having my coffee, I grab the coconut oil one, and I pour that one in and make myself a java with coconut oil in it. So, yeah, go ahead.


Kenna Vaughn: I was going to say that’s a great option too. So I drink green tea, and I also add coconut oil in that green tea to help boost everything and give my body another dose of those fatty acids that we want.


Dr. Alex Jimenez DC*: I got a question for you when you have your coffee like that; when you have the oil in it, does it kind of lubricate your lips.


Kenna Vaughn: It does a little bit. So it’s also like chapstick.


Dr. Alex Jimenez DC*: Yeah, it does. It’s like, Oh, I love it. OK, go ahead.


Kenna Vaughn: Yeah, I also have to stir a little bit more just to make sure everything gets it right. Yeah. And then another thing just talking about something our patients can do when it comes to at home, there are tons of different options with eating fish. Increasing your good fish intake throughout the week, that’s going to help also. And just because fish provides so many great things like omegas, I know Astrid also has some more information on omegas.


Dr. Alex Jimenez DC*: I got a question before Astrid gets in there. You know, look, when we talk about carbohydrates, people, is it what a carbohydrate is? Oh, people say an apple, banana, candy bars, and all kinds of stuff people can rattle off carbohydrates or proteins. Chicken, beef, whatever they can rile up. But one of the things I found that people have a difficult time with is what good fats are? I want five. Give me ten good fats for a million dollars. Give me ten good fats like lard, like meat. No, this is what we’re talking about. Because the simple fact that we use and we’re going to add more to it relative bad is going to be avocado oil. Olive oil. Is it coconut oil? We can use things like butter oils, different types of margins, and not margins, but kinds of butter that are from, you know, grass-fed cows. We basically can run out of creamers, you know, non-nondairy creams, very specific creamers, those we run out of it, right? Real fast. So it’s like, what else is fat, right? And then we search for it. So one of the best ways to do it is that we’re not going to always put creamer on top or our butter on top, which by the way, some coffees they have, they put butter in it and blend it, and they make a fantastic little java hit. And everyone comes with their little ginger and oils and their coffee and makes espresso from heaven, right? So what else can we do?


Kenna Vaughn: We can, like I said, adding those fish in, which is going to help to give our bodies more of those omegas. And then we can also do more purple vegetables, and those are going to provide your body with more antioxidants. So that’s a good option when it comes to the grocery store. A rule of thumb that I love and heard a long time ago is to not shop in the aisles is to try to shop on the edges because the edges are where you’re going to find all that fresh produce and all those lean meats. It’s when you start to get into those aisles, and that’s where you’re going to start finding, you know, the cereal, those bad carbohydrates, those simple carbohydrates that the American diet has come to love but does not necessarily need. The Oreos?


Kenna Vaughn: Yes.


Dr. Alex Jimenez DC*: The candy aisle that every kid knows. OK, yes. 


Kenna Vaughn: So that’s just another great point there. So when you come into our office, if you’re suffering from metabolic syndrome or just anything in general, we make your plans super personalized and give you so many tips. We listen to your lifestyle because what works for one person might not work for another. So we make sure that we provide you with information that we know you’ll be successful with and provide education because that’s another huge part of it.


Dr. Alex Jimenez DC*: All roads lead to the kitchen, huh? Right? Yes, they do. OK, so let’s zoom on precisely for the fat and the nutraceuticals. I want to give you an idea as to what type of nutraceuticals are appropriate for us because we want to bust down these five issues affecting metabolic syndrome that we discussed. What are the five guys? Let’s go ahead and start them up. It’s high blood sugar, right?


Kenna Vaughn: High blood glucose, low HDLs, which will be that good cholesterol everyone needs. Yes. And it’s going to be the high blood pressure, which is not considered high from a doctor’s standard, but it is deemed to be elevated. So that’s another thing; we want to ensure that this is metabolic syndrome, not a metabolic disease. So if you go to the doctor and your blood pressure is 130 over eighty-five, that’s an indicator. But yet your provider might not necessarily say your blood pressure is super high. 


Dr. Alex Jimenez DC*: None of these disorders here by themselves are clinical states, and, individually, they’re pretty much just things. But if you combine all these five, you have metabolic syndrome and feel like not too good, right?


Astrid Ornelas: Yeah, yeah.


Kenna Vaughn: Another one is going to be the excess weight around the belly and the higher triglycerides.


Dr. Alex Jimenez DC*: Easy to see. You can see when someone has a belly that’s hanging over like a fountain, right? So we can see that you can go to it sometimes Italian restaurants and see the great cook. And he sometimes I got to tell you, sometimes it’s just, you know, we talked to Chef Boyardee wasn’t a thin guy. I think that Chef Boyardee, you know what? And the Pillsbury guy, right? Well, it wasn’t very healthy, right? Both of them suffer from metabolic syndrome just from the outset. So that’s an easy one to see. So these are the things we’re going to be reflecting on. Astrid will go over some nutraceuticals, vitamins, and some foods that we can improve things. So here’s Astrid, and here’s our science curator. But here’s Astrid, go ahead.


Astrid Ornelas: Yeah, I guess before we get into the nutraceuticals, I want to make something clear. Like we were talking about metabolic syndrome. Metabolic syndrome is not a, and I guess per se, a disease or a health issue itself. Metabolic syndrome is a cluster of conditions that can increase the risk of developing other health issues like diabetes, stroke, and heart disease. Because metabolic syndrome is not, you know, an actual health issue itself, it’s more so this group, this collection of other conditions, of other problems that can develop into much worse health issues. Just because of that fact, metabolic syndrome has no apparent symptoms itself. But of course, like we were talking about, five risk factors are pretty much the ones we discussed: excess waist fat, high blood pressure, high blood sugar, high triglycerides, low HDL, and according to health care professionals. To doctors and researchers, you know you have metabolic syndrome if you have three out of these five risk factors.


Dr. Alex Jimenez DC*: Yes. Three. Now, that doesn’t mean that if you have it, you have symptoms. As I see it was evident on. But I got to tell you in my experience when someone has more than three or three. They’re starting to feel crummy. They don’t feel right. They just feel like, you know, life’s not good. They have just an overall. They don’t look it right. So and I don’t know them, maybe. But their family knows that they don’t look good. Like mom doesn’t look good. Dad does look good.


Astrid Ornelas: Yeah, yeah. And metabolic syndrome, as I said, it has no apparent symptoms. But you know, I was kind of going with one of the risk factors with waist fat, and this is where you will see people with what you call the apple or pear-shaped body, so they have excess fat around their abdomen. And although that’s not technically considered a symptom, it is a factor that can; I guess it can give an idea to doctors or other health care professionals that this person who is, you know, they have prediabetes or have diabetes. And, you know, they have excess weight and obesity. They could have an increased risk of metabolic syndrome and therefore developing, you know, if it’s left untreated, developing other health issues like heart disease and stroke. I guess with that being said; then we’ll get into the nutraceutical.


Dr. Alex Jimenez DC*: I love this, I love this. We’re getting some good stuff, and we’re getting some information.


Astrid Ornelas: And I guess with that being said, we’ll get into the nutraceuticals. Kind of like, how Kenna was talking about what’s the takeaway? You know, we’re here talking about these health issues, and we’re here talking about metabolic syndrome today. But what’s the takeaway? What can we tell people? What can they take home about our talk? What can they do at home? So here we have several nutraceuticals, which I’ve written several articles in our blog and looked at. 


Dr. Alex Jimenez DC*:  You think, Astrid? If you look at 100 articles written in El Paso, at least in our area, they were all curated by somebody. Yes. All right.


Astrid Ornelas: Yes. So we have several nutraceuticals here that have been researched. Researchers have read all these research studies and found that they can help in some way and some form improve, you know, metabolic syndrome and these associated diseases. So the first one I want to discuss is the B vitamins. So what are the B vitamins? These are the ones that you can usually find them together. You can find them in the store. You’ll see them as B-complex vitamins. You’ll see like a little jar, and then it comes with several of the B vitamins. Now, why do I bring up B vitamins for metabolic syndrome? So one of the reasons like researchers has found that one of them, I guess, one of the causes of metabolic syndrome could be stress. So with that being said, we need to have B vitamins because when we get stressed when we have a hard day at work when we have, I guess a lot of you know, a lot of stressful things at home or with family, our nervous system will use these B vitamins to support our nerve function. So when we have a lot of stress, we will use up these vitamins, which increases stress; you know, our body will produce cortisol. You know, which serves a function. But we all know that too much cortisol, too much stress can actually. It can be harmful to us. It can increase our risk of heart disease.


Dr. Alex Jimenez DC*: You know, as I remember when we did this, all roads lead to the kitchen in terms of getting the food back in your body. All roads lead to the mitochondria when it comes to the area of the breakdown. The world of ATP energy production is surrounded and wrapped around with nicotinamide, NADH, HDP, ATPS, ADP. All these things have a connection with vitamin B of all sorts. So the vitamin B’s are at the engine in the turbine of the things that help us. So it makes sense that this was the top of the vitamin and the most important one. And then she’s got some other endpoints here on niacin. What is with niacin? What have you noticed there?


Astrid Ornelas: Well, niacin is another B vitamin, you know, there are several B vitamins. That’s why I have it there under its plural and niacin or vitamin B3, as it’s more well known. A lot of several are so clever. Many research studies have found that taking vitamin B3 can help lower LDL or bad cholesterol, help lower triglycerides, and increase HDL. And several research studies have found that niacin, specifically vitamin B3, can help increase HDL by 30 percent.


Dr. Alex Jimenez DC*: Incredible. When you look at NADP and NADH, These are the N is the niacin, the nicotinamide. So in the biochemical compound, niacin is the one that people have known that when you take it the good one or the one that’s supposed to be, you get this flushing feeling and it makes you scratch all your part of your body, and it feels good when you scratch because it makes you feel that way. Right, so lovely. And this huge.


Astrid Ornelas: Yes. Yes, and also, I just want to highlight a point about B vitamins. B vitamins are essential because they can help support our metabolism when we eat, you know, carbohydrates and fats, good fats, of course, and proteins. When the body goes through the metabolism process, it converts these carbohydrates, fats, and protein. The proteins turn into energy, and B vitamins are the main components in charge of doing that.


Dr. Alex Jimenez DC*: Latinos, in our general population, know that we have always heard of the nurse or the person who gives vitamin B injection. So you heard of those things. Right. Because you’re depressed, you’re sad, what would they do? Well, you know what would inject them with B12, right? Which are the B vitamins, right? And the person would come out like, Yeah, and they’d be excited, right? So we’ve known this, and this is the elixir of the past. Those traveling salesmen, who had the potions and lotions, made a living off of giving B vitamin complex. The first energy drinks were first designed with a B complex, you know, packing of them. Now here’s the deal. Now that we’ve learned that energy drinks cause so many issues, that we’re heading back to the B complexes to help people better. So the following vitamin we have there is that one that we have the D, we have the vitamin D.


Astrid Ornelas: Yeah, the next one I wanted to talk about is vitamin D. So there are several research studies on vitamin D and the benefits, the benefits of vitamin D for metabolic syndrome, and just how I discussed how B vitamins are beneficial for our metabolism. Vitamin D is also helpful for our metabolism, and it can help regulate our blood sugar, essentially our glucose. And that in itself is very important because, like one of the predisposing factors of metabolic syndrome, high blood sugar. And you know, if you have uncontrolled high blood sugar, it can lead to, you know, it can lead to prediabetes. And if that is left untreated, it can lead to diabetes. So research studies have also found that vitamin D itself can also improve insulin resistance, which is pretty much one that can lead to diabetes.


Dr. Alex Jimenez DC*:  You know, I just wanted to put out the vitamin D is not even a vitamin; it’s a hormone. It was discovered after C by Linus Pauling. When they found it, they just kept on naming the following letter. OK, so since it is a hormone, you just have to look at it. This particular vitamin D or this hormone tocopherol. It basically can change so many metabolism issues in your body. I’m talking about literally four to five hundred different processes that we’re finding. Last year was 400. We’re now almost 500 other biochemical processes that are affected directly. Well, it makes kind of sense. Look, our most significant organ in the body is our skin, and most of the time, we ran around in some sort of skimpy clothes, and we were in the sun a lot. Well, we didn’t stand to reason that that particular organ can produce a tremendous amount of healing energies, and vitamin D does that. It is produced by the sunlight and activated. But today’s world, whether we’re Armenian, Iranian, different cultures in the north, like Chicago, people don’t get as much light. So depending on cultural changes and closed people living and working in these fluorescent lights, we lose the essence of vitamin D and get very sick. The person who takes vitamin D is much healthier, and our goal is to raise the vitamin D is a fat-soluble vitamin and one that embeds itself by it and is saved in the liver along with the fat in the body. So you can raise it slowly as you take it, and it’s tough to get toxic levels, but those are at about one hundred twenty-five nanograms per deciliter that are too high. But most of us run around with 10 to 20, which is low. So, in essence, by raising that, you’re going to see that the blood sugar changes are going to happen that Astrid is speaking about. What are some of the things that we notice about, particularly vitamin D? Anything?


Astrid Ornelas: I mean, I’ll get back to vitamin D in a bit; I want to discuss some of the other nutraceuticals first. OK. But pretty much vitamin D is beneficial because it helps improve your metabolism, and it helps improve your insulin resistance, at least towards metabolic syndrome.


Dr. Alex Jimenez DC*: How about calcium?


Astrid Ornelas: So calcium goes hand-in-hand with vitamin D, and the thing that I wanted to talk about with vitamin D and calcium together. We often think about these five factors that we mentioned before that could cause a metabolic syndrome. Still, there’s, you know, if you want to think about it, like what are the underlying causes for a lot of these risk factors? And like, you know, obesity, a sedentary lifestyle, people who don’t engage in an exercise or physical activity. One of the things that can predispose a person or increase their risk of metabolic syndrome. Let me put the scenario. What if a person has a chronic pain disease? What if they have something like fibromyalgia? They’re constantly in pain. They don’t want to move, so they don’t want to exercise. They don’t want to aggravate these symptoms. Sometimes, some people have chronic pain or things like fibromyalgia. Let’s go a little bit more basic. Some people just have chronic back pain, and you don’t want to work out. So just you’re not choosing like some of these people aren’t choosing to be inactive because they want to. Some of these people are legitimately in pain, and there are several research studies, and this is what I was going to tie in vitamin D and calcium with that vitamin D and calcium. You know, we can you can take them together. They can help improve chronic pain in some people.


Dr. Alex Jimenez DC*: Incredible. And we all know that calcium is one of the causes of muscle spasms and relaxers. Tons of reasons. We’re going to go into each one of these. We’re going to have a podcast on just vitamin D and the issues in calcium because we can go deep. We’re going to go deep, and we’re going to go all the way to the genome. The genome is genomics, which is the science of understanding how nutrition and the genes dance together. So we’re going to go there, but we’re kind of like we’re penetrating slowly in this process because we have to take the story slowly. What’s up next?


Astrid Ornelas: So next, we have omega 3s, and I want to specifically highlight that we’re talking about omega 3s with EPA, not DHA. So these are EPA, which is the one that’s listed up there, and DHA. They are two essential types of omega 3s. Essentially, they’re both very important, but several research studies and I’ve done articles on this as well have found that I guess taking omega 3s specifically with EPA, it’s just more superior in its benefits than DHA. And when we talk about the omega 3s, these can be found in fish. Most of the time, you want to take omega 3s; you see them in the form of fish oils. And this is going back to what Kenna discussed before, like following a Mediterranean diet, which mainly focuses on eating a lot of fish. This is where you get your intake of omega 3s, and research studies have found that omega 3s themselves can help promote heart health, and they can help lower bad cholesterol to your LDL. And these can also improve our metabolism, just like vitamin D.


Dr. Alex Jimenez DC*: Want to go ahead and blanket all these things under the fact that we’re also looking, and when we’re dealing with metabolic syndrome, we’re dealing with inflammation. Inflammation and omegas have been known. So what we need to do is to bring out the fact that omegas have been in the American diet, even in a grandma’s diet. And then, like again, we hear back in the day when grandma or great-grandma would give you cod liver oil. Well, the highest omega-carrying fish is the herring, which is at about 800 milligrams per serving. The cod is next when it’s around 600. But because of the availability, the card’s much more available in certain cultures. So everybody would have cod liver oil, and they’d make you close your nose and drink it, and they knew that it correlated. They would think it’s a good lubricant. Still, it was an anti-inflammatory specifically with people, and usually, grandmothers who knew about this right helps with the intestines, helps the inflammation, helps with the joints. They knew the whole story behind that. So we’ll go deep into the Omegas in our later podcast. We have another one that’s here. It’s called berberine, right? What’s the story on berberine?


Astrid Ornelas: Well, pretty much the next set of nutraceuticals that are listed here, berberine, glucosamine, chondroitin, acetyl L-carnitine, alpha-lipoic acid, ashwagandha, pretty much all of these have been tied into what I talked before about chronic pain and all of these health issues. I listed them up here because I’ve done several articles. I’ve read various research studies that have covered these in different trials and across multiple research studies with numerous participants. And these have pretty much found, you know, this group of nutraceuticals here that are listed; these have also been tied in to help reduce chronic pain. You know, and as I discussed before, like chronic pain, you know, people who have fibromyalgia or even like, you know, let’s go a little bit simpler people who have back pain, you know, these inactive people who have sedentary lifestyles simply because of their pain and they can be at risk of metabolic syndrome. A lot of these research studies have found these nutraceuticals themselves can also help reduce chronic pain.


Dr. Alex Jimenez DC*: I think the new one is called alpha-lipoic acid. I see acetyl L-carnitine. We’re going to have our resident biochemist on the following podcast to go deep into these. Ashwagandha is a fascinating name. Ashwagandha. Say it. Repeat it. Kenna, can you tell me a bit about ashwagandha and what we’ve been able to discover about ashwagandha? Because it is a unique name and a component that we look at, we will talk about it more. We’re going to get back to Astrid in a second, but I’m going to give her a little break and kind of like, let Kenna tell me a bit of ashwagandha.


Kenna Vaughn: I was going to add in something about that berberine.


Dr. Alex Jimenez DC*: Oh, well, let’s go back to berberine. These are berberine and ashwagandha.


Kenna Vaughn: OK, so that berberine has also been shown to help decrease the HB A1C in patients with blood sugar dysregulation, which will come back to the whole prediabetes and type two diabetes situations that can occur in the body. So that one is also has been shown to decrease that number to stabilize the blood sugar.


Dr. Alex Jimenez DC*:  There’s a whole thing we’re going to have on berberine. But one of the things that we did in terms of metabolic syndrome definitely made the top list here for the process. So there’s ashwagandha and berberine. So tell us all about ashwagandha. Also, ashwagandha is the one. So in terms of blood sugar, the A1C is the blood sugar calculation that tells you exactly what the blood sugar does over about three months. The glycosylation of the hemoglobin can be measured by the molecular changes that happen within the hemoglobin. That’s why the Hemoglobin A1C is our marker to determine. So when ashwagandha and berberine come together and use those things, we can alter the A1C, which is the three-month kind of like the historical background of what is going on. We’ve seen changes on that. And that’s one of the things that we do now in terms of the dosages and what we do. We’re going to go over that, but not today because that’s a little bit more complex. Soluble fibers have also been a component of things. So now, when we deal with soluble fibers, why are we talking about soluble fibers? First of all, it is food for our bugs, so we have to remember that the probiotic world is something we cannot forget. People need to understand that, though, that probiotics, whether it’s the Lactobacillus or Bifidobacterium strains, whether it’s a small intestine, large intestine, early on the small intestine, there are different bacteria to the very end to see come to the back end. So let’s call that the place that things come out. There are bacteria everywhere at different levels, and each one has a purpose of discovering that. There’s vitamin E and green tea. So tell me, Astrid, about these dynamics in terms of green tea. What do we notice as it pertains to metabolic syndrome?


Astrid Ornelas: OK. So green tea has a lot of benefits, you know? But, you know, some people don’t like tea, and some are more into coffee, you know? But if you want to get into drinking tea, you know, definitely because of its health benefits. Green tea is an excellent place to start and in terms of metabolic syndrome. Green tea has been demonstrated to help improve heart health, and it can help lower these risk factors that pertain to metabolic syndrome. It can help, you know, several research studies that have found that green tea can help lower cholesterol, bad cholesterol, LDLs.


Dr. Alex Jimenez DC*: Does green tea help us with our belly fat?


Astrid Ornelas: Yeah. There’s one of the benefits of green tea that I’ve read about. Pretty much one of the ones that probably that it’s most well known for is that green tea can help with weight loss.


Dr. Alex Jimenez DC*: Oh my gosh. So basically water and green tea. That’s it, guys. That’s all. We limit our lives that are also, I mean, we forgot even the most powerful thing. It takes care of those ROSs, which are reactive oxygen species, our antioxidants, or oxidants in our blood. So it just basically squelch them and takes them out and cools their cool and prevents even the normal deterioration that happens or the excessive deterioration that occurs in the breakdown of normal metabolism, which is a byproduct which is ROS, reactive oxygen species are wild, crazy oxidants, which we have a neat name for the things that squashes them and calms them and puts them in the order they call antioxidants. So the vitamins that are antioxidants are A, E, and C are antioxidants, too. So those are potent tools that we deal with as we lower body weight. We free up a lot of toxins. And as the green tea goes into squirt, squelch them, cools them, and gets them out of gear. Guess where the other organ that helps with the whole insulin production is, which is the kidneys. The kidneys are flushed out with green tea and then also helps. I notice that one thing that you haven’t done, Astrid, is done articles on turmeric, right?


Astrid Ornelas: Oh, I’ve done a lot of articles on turmeric. I know because, from the list that’s up there, turmeric and curcumin are probably like one of my favorite nutraceuticals to talk about.


Dr. Alex Jimenez DC*: Yeah, she’s like gnawing on a root and a couple of times.


Astrid Ornelas: Yeah, I have some in my fridge right now.


Dr. Alex Jimenez DC*: Yeah, you touch that turmeric, and you can lose a finger. What happened to my finger? Did you get near my turmeric? The root, right? So. So tell us a bit about the properties of turmeric and curcumin in terms of metabolic syndrome.


Astrid Ornelas: OK. I’ve done several, you know, a lot of articles on turmeric and curcumin. And we’ve also discussed that before, and several of our past podcasts and turmeric is that it’s that yellow yellowish could look orange to some people, but it’s usually referred to as a yellow root. And it’s very popular in Indian cuisine. It’s what it’s one of the main ingredients that you’ll find in curry. And curcumin, pretty sure some of you people have heard of curcumin or turmeric, you know? What’s the difference? Well, turmeric is the flowering plant, and it’s the root. We eat the root of turmeric, and curcumin is just the active ingredient in turmeric that gives it a yellow color.


Dr. Alex Jimenez DC*: Guys, I will not let anything but the top type of curcumin and turmeric products be available to their patients because there’s a difference. Certain ones are produced with literally, I mean, we got solvents, and with the way we get things out and of curcumin and turmeric or even stuff like cocaine, you have to use a distillate. OK? And whether it’s water, acetone, benzene, OK, or some sort of a byproduct, we know today that benzene is used to process many types of supplements, and certain companies use benzene to get the best out of turmeric. The problem is benzene is cancer-producing. So we’ve got to be very careful which companies we use. Acetone, imagine that. So there are processes that are in place to extract the turmeric properly and that are beneficial. So finding suitable turmeric, all turmerics are not the same. And that’s one of the things that we have to assess since it has so many products in the world is running real crazy to try to process turmeric and precisely, even if it’s the last thing that we’re discussing today on our subject matter. But it’s one of the most important things today. We don’t even understand aspirin. We know it works, but the total magnitude of it is yet to be told. However, turmeric is in the same boat. We’re learning so much about it that every day, every month, studies are being produced on the value of turmeric into the natural diet, so Astris is in tune in on the target on that. So I’m sure she’s going to bring more of that to us, right?


Astrid Ornelas: Yes, of course. 


Dr. Alex Jimenez DC*: So I think what we can do today is when we look at this, I’d like to ask Kenna, when we look at a metabolic syndrome from the presentations of symptoms or even from laboratory studies. The confidence of knowing that N equals one is one of the essential components that we have now in functional medicine and functional wellness practices that a lot of physical medicine doctors are doing in their scope of practice. Because in metabolic issues, you can’t take metabolic away from the body. Does the metabolism happen in a back problem? We notice a correlation with back injuries, back pain, back issues, chronic knee disorders, chronic joint musculoskeletal disorders, and metabolic syndrome. So we can’t tease it. So tell us a bit, Kenna, as we close out today a bit of what a patient can expect when they come to our office, and they get kind of put in the “Oops, you got metabolic syndrome.” So boom, how do we handle it?


Kenna Vaughn: We want to know their background because, as you said, everything is connected; everything is in-depth. There are details we want to get to know all so we can make that personalized plan. So one of the first things we do is a very lengthy questionnaire by Living Matrix, and it’s a great tool. It does take a little while, but it gives us so much insight into the patient, which is great because it allows us to, like I said, dig deep and figure out, you know, traumas that might have happened that are leading to inflammation, which how Astrid was saying then leads that sedentary lifestyle, which then leads to this metabolic syndrome or just kind of down that road. So one of the first things we do is do that lengthy questionnaire, and then we sit down and talk to you one on one. We build a team and make you part of our family because this stuff isn’t easy to go through alone, so the most success is when you have that close-knit family, and you have that support, and we try to be that for you.


Dr. Alex Jimenez DC*: We have taken this information and realized it was very complex five years ago. It was challenging. 300 300-page questionnaire. Today we have software that we can figure out. It is backed by the IFM, the Institute of Functional Medicine. The Institute of Functional Medicine had its origin over the last decade and became very popular, understanding the whole person as an individual. You can’t separate an eyeball from kind of the body as you can’t separate the metabolism from all effects that it has. Once that that body and that food, that nutraceutical that nutrient enters our body. On the other side of our mouth is these little weighting things called chromosomes. They’re spinning, and they’re churning, and they’re creating enzymes and proteins based on what we feed them. To find out what’s going on, we have to do an elaborate questionnaire about mental body spirituality. It brings in the mechanics of normal digestion, how the entanglement works, and how the overall living experience happens in the individual. So when we take into consideration Astrid and Kenna together, we kind of figure out the best approach, and we have a tailor-made process for each person. We call it the IFM one, two, and three, which are complex questions that allow us to give you a detailed assessment and an accurate breakdown of where the cause can be and the nutraceuticals the nutrient nutrients that we focus on. We push you right direction to the place where it matters into the kitchen. We end up teaching you and your family members how to feed so that you can be good to those genetic genomes, which you’re, as I always say, ontogeny, recapitulates phylogeny. We are who we are from the past to the people, and those people have a thread between us and my past, and everyone here’s past. And that is our genetics, and our genetics responds to the environment. So whether it goes in the south fast or exposed or predisposed, we’re going to discuss those, and we’re going to enter the world of genomics soon in this process as we go deeper into the metabolic syndrome process. So I thank you all for listening in on us and know that we can be contacted here, and they’re going to leave you the number. But we have Astrid here that’s doing research. We have a team established by many individuals who can give you the best information that applies to you; N equals one. We got Kenna here that there’s always available and we’re here taking care of people in our beautiful little town of El Paso. So thank you again, and look forward to the following podcast, which will probably be within the next couple of hours. Just kidding. All right, bye, guys. 

Functional Endocrinology: The Endocrine System and CBD

Functional Endocrinology: The Endocrine System and CBD

Do you feel:

  • Unpredictable abdominal swelling?
  • Inflammation?
  • Acne and unhealthy skin?
  • Hormone imbalance?
  • Shaky, jittery, or have tremors?

If you are experiencing any of these situations, then you might be having problems with your endocrine system. How about trying some CBD oils to help calm down your system.

Making the headlines since 2018, the usage of cannabis or even CBD oil to treat ailments have been gaining popularity. Even though some states don’t legalize this plant yet, it has been sweeping through the U.S. with pop-up vendors, smoke shops, and even just selling the product on its own or with other products that contain it. When it comes to the body, however, the effects of cannabinoids, CBD oil, and cannabis itself can help dampen the chronic effects of inflammation, pain, anxiety disorders, neurological symptoms, and endocrine disorders that the body may have encounter. By figuring out how this plant and its oil affect the endocrine system, it will give people a better understanding of the beneficial effects it provides.

The Endocrine System

Lets first take a look at the endocrine system and how it functions. The endocrine system is a network of glands and organs that are located throughout the body. This system helps with the production of hormones that are sent out to the specifically targeted organs and tissues that the body not only needs but function properly. Research shows that when hormone levels are too high or even too low, it can indicate a problem with the endocrine system and the entire body as well. When the body does not respond to hormones in the appropriate ways, dysfunction in the body tends to come.

Many factors can cause hormonal change, and some of the most commonly known ones are the ones that happen to anyone daily. Stress, infections, changes in the bloodstream, and even diabetes can influence the hormonal levels and can lead to many chronic illnesses. So making sure that the hormone levels are functioning correctly is key to making sure that the endocrine system is healthy as well.

Cannabis and Its Products

Everyone throughout their childhood has heard that cannabis (marijuana) is an illicit drug and should stay away from it. The plant itself comes from the Cannabis sativa plant and has been harvested by humans for hundreds of years and been used in various cultures. Some evidence shows that the plant itself or some of its components like CBD can be useful to relieve severe pain, inflammation, nausea, and other chronic conditions.


With the rise of CBD oil in recent years, there is still some confusion and controversy of what it is and how does it affect the human body, mainly affecting the endocrine system. CBD is one of the compounds in marijuana that has a different effect than delta-9 THC (tetrahydrocannabinol), which is the most active constituent of marijuana. THC creates a mind-altering “high” for the person, while CBD does not change the person’s state of mind at all when it is used. What is interesting is that the human body itself produces certain cannabinoids on its own. The two receptors for the cannabinoids are CB1 receptors and CB2 receptors that are in the body to function.

CB1 receptors are mainly in the brain, providing neurological coordination, movement, and other functions that make the body respond. While with CB2 receptors are more common in the immune system, and these receptors are affecting inflammation and pain. When it comes to CBD oil or the CBD compound itself, it does not attach to the CB receptors but can direct the body to use more of its cannabinoids and has beneficial properties for a person’s health in a variety of ways.

The Benefits of CBD Oil

Since CBD is one of the compounds in the cannabis plant, researchers have been looking at the many possible therapeutic uses and benefits of CBD. Since CBD oils are a concentrated form of CBD, the uses can help the symptoms that the body may encounter, including:

  • Being a natural pain reliever
  • Treating epilepsy
  • Treat neurological disorders
  • Delay the development of type 1 diabetes
  • Slow the progress of Alzheimer�s disease

The Effects of CBD and the Endocrine System

In the endocrine system, there is a complex cell-signaling system known as an endocannabinoid system. What this system does is that its endocannabinoid molecules and receptors in the body and help signal any dysfunction. Studies have found that the endocannabinoid system’s ability is that it can control a person’s appetite in the hypothalamus by attaching itself to CB1 receptors. While another study stated that the CB1 receptor could activate and inhibit the release of GnRH through the effects in the hypothalamus as well.

With more upcoming studies about the usage of cannabinoids, it is incredible how the participation of the endocannabinoids system can help with the secretion of the pituitary hormones that have been documented. Surprisingly, cannabinoids can affect the function of the hypothalamus and pituitary glands in multiple directions.


With more and more people using CBD oils to help alleviate their ailments and more information that has been surrounding this oil. It is essential to know that it is better to not be in pain than to suffer in pain. Using CBD oils can help not only the body system but also helps the endocrine system as well. Some products are used to help alleviate the pain that the body may encounter as well as providing the body a chance to relax and have a good night�s sleep.

The scope of our information is limited to chiropractic, musculoskeletal, and nervous health issues or functional medicine articles, topics, and discussions. We use functional health protocols to treat injuries or disorders of the musculoskeletal system. Our office has made a reasonable attempt to provide supportive citations and has identified the relevant research study or studies supporting our posts. We also make copies of supporting research studies available to the board and or the public upon request. To further discuss the subject matter above, please feel free to ask Dr. Alex Jimenez or contact us at 915-850-0900.


Borowska, Magdalena, et al. �The Effects of Cannabinoids on the Endocrine System.� Endokrynologia Polska, 20 Dec. 2018,

Hillard, Cecilia J. �Endocannabinoids and the Endocrine System in Health and Disease.� Handbook of Experimental Pharmacology, U.S. National Library of Medicine, 2015,

Johnson, Jon. �CBD Oil: Uses, Health Benefits, and Risks.� Medical News Today, MediLexicon International, 27 July 2018,

Kathleen Davis, FNP. �Marijuana (Cannabis): Facts, Effects, and Hazards.� Medical News Today, MediLexicon International, 1 Aug. 2018,

Raypole, Crystal. �A Simple Guide to the Endocannabinoid System.� Healthline, 17 May, 2019,

Seladi-Schulman, Jill. �Endocrine System Overview.� Healthline, 22 Apr. 2019,

Zimmermann, Kim Ann. �Endocrine System: Facts, Functions and Diseases.� LiveScience, Purch, 16 Feb. 2018,




CBD – Cannabidiol’s Life Changing Properties

CBD – Cannabidiol’s Life Changing Properties

CBD�research currently being conducted is showing its medical potential. This has opened doors for antipsychotic, anticancer and anti-inflammatory�treatment options among a variety of others. Scientists from all over are publishing studies that are proving CBD is one of the most effective and favorable cannabinoids that promotes proper function of the body’s systems.

Five Properties Of CBD

CBD Medical Benefits

cbd - cannabidiol el paso tx.

1. Inhibits Cancer Cell Growth

Studies have supported this claim. By way of Proapoptotic action or apoptosis, Cannabidiol, Tetrahydrocannabinol, Cannabigerol and Cannabichromene�in this order are extremely effective in tumor growth reduction in rats and cancerous human prostate cells. Research is still ongoing, but understanding that these cannabinoids stimulate the body�s process of killing cells that no longer function properly or at their optimal level. In traditional chemotherapy both�healthy and cancerous cells�are destroyed and only works when the cancer cells are replicating more frequently than healthy cells. CBD treatment promotes the body�s natural immune response to cells that are not functioning properly, which eradicates tumors.

2. Pain Reducer

The most common reason people start using marijuana despite its psychoactive affects, is that it also functions, as a pain reliever! People with chronic pain that are tired of taking pain killing opiates, rely on cannabinoid products to deal with pain and eliminate its source, commonly inflammation. Inflammation is the body�s natural response to injury, which floods the injured area with blood and nutrients to aid in rehabilitation. But inflammation creates secondary problems, among them�pain and discomfort. Through stimulation of nutrients in the area that is injured, CBD creates negative feedback to inflammatory reactions, as the nutrients that came with the inflammation are already there.

cbd - cannabidiol el paso tx.

3. Treats Anxiety

Anxiety along with PTSD affects over 40 million adults in the U.S. Valium and Xanax is what is normally used to treat these conditions. However, CBD products are becoming the preferred treatment, as they have none of the side effects or dependency issues. The effects of CBD have been observed thoroughly by experts and studies have proved its effectiveness, as a dependable alternative for mental disorders. Two receptors in the human brain responsible for sending out Adrenaline and Serotonin are the�?2-adrenergic receptor agonist and 5-HT1A receptor antagonist. These receptors both are related to anxiety, depression, insomnia, and other mental disorders when imbalanced.

4. Strengthens The Immune System

Phytocannabinoids are able to balance, reinforce and strengthen the immune system. Cannabinoid products taken daily, work in regulating the immune system. This increases the body�s detection of foreign and potentially dangerous organisms, which include cancer cells.

5. Prevents Muscle Spasms

CBD contains�chemically antispasmodic properties. Athletes from all sports love CBD and what it can do. It is a preferred supplement and these oils have proven to prevent muscle spasms and soreness. This is done through�lubricating the potassium and calcium pumps within the muscle tissue.

CBD is finding its place, slowly, but surely. It is one of natures own medicines and it is our job to discover and figure how to utilize these properties. Consult a doctor before beginning any treatment of diagnosed or undiagnosed diseases with CBD. For the more severe diseases like diabetes, schizophrenia, epilepsy, which, CBD can treat, but only when used properly.

Medical Benefits

cbd - cannabidiol el paso tx.

Endocannabinoid System And The Human Body

Endocannabinoid System And The Human Body

The endocannabinoid system’s discovery has created debate on its conclusions on human health. Because of its capability to target various therapeutic agents that are in different states of disease has piqued interest for researchers.

Some researchers suggest the endocannabinoid system plays a vital role in cellular homeostasis. This could mean that the health of this system could affect the health of the whole body.

What is the endocannabinoid system and why is it important?

This article reviews the basics of the endocannabinoid system and its role in cardiovascular and neurological health and specifically, endocannabinoid system deficiency and the adverse effects on the other body’s systems.

Endocannabinoid System & What It Consists Of

The endocannabinoid system is comprised of two receptors and a series of internally produced compounds. The two main receptors in the endocannabinoid system are the CB1 and CB2 receptors.

endocannabinoid el paso tx.

endocannabinoid el paso tx.

Endocannabinoid comes from the fact that cannabinoids from the cannabis plant interact with receptors in the endocannabinoid system.�There are many endocannabinoids, the most widely known and studied is;

N-arachidonoylethanolamine (AEA).

AEA increases in times of oxidative stress, inflammation or cell death. Researchers believe that it may be produced as a response to injury when counteracting inflammatory activity. This activity could be the evidence of the systems role in cellular homeostasis.

CB1 and CB2 receptors are found throughout the body. CB1 receptors are primarily found in the nervous system, while CB2 receptors are primarily found in intestinal epithelium cells and immune system cells.

CB1 receptors predominantly interact with THC and other psychoactive compounds from the cannabis plant. This is a logical find because the CB1 receptors are found primarily in the nervous system. This interaction of CB1 receptors and THC could cause certain changes in brain chemistry, which leads to the euphoric feeling produced from cannabis use.

CB2 receptors interact with cannabidiol (CBD) which is a secondary major compound in cannabis. This does not mean that CBD does not interact with CB1 receptors ever, but because these interactions are quite uncommon they are considered unimportant. Because CBD does not have compelling interaction with CB1 receptors, the psychoactive effects from THC are not present.

Both cannabinoid compounds have therapeutic potential. Studies have found these compounds help control chronic inflammation in conditions like�IBS (irritable bowel syndrome).

endocannabinoid el paso tx.

THC use in modulating endocannabinoid system deficiency has been very limited because of its psychoactive properties. Because of this, THC has become rejected in many U.S. states, the U.S federal government, and in conservative countries around the world. Researchers refrain from investigating its therapeutic properties or recommending it, as an alternative medicine.

Cannabinoid Research Marches On Despite THC Affects

CBD contains the same therapeutic properties as THC, without the psychoactive effects. CBD is under extensive research, as a compound that can help with various diseases and their progression. This has led researchers to create synthetic compounds that mimic CBD and its interaction with CB2 receptors.

The endocannabinoid systems role in cardiovascular health and disease.

Depending on the receptors involved cardiovascular health, and the endocannabinoid system’s activation could lead to beneficial or conflicting effects.

CB1 receptors have been linked to an increase of cardiovascular disease or cardiovascular incidents.� Incidents include heart attack, atherosclerosis (plaque inside the blood vessels ), stroke, kidney dysfunction and liver problems. Animal models and epidemiological studies have shown these findings.

endocannabinoid el paso tx.

However, activation of the endocannabinoid system’s CB2 receptors may have cardioprotective properties. Certain animal studies show how the use of synthetic cannabinoids interacting with CB2 receptors could beneficial for heart attacks. This comes from their ability to limit infiltration of cells that cause inflammation by CB2 activation.

The Clinical Significance

The difference between CBD and THC:

THC use, as a therapeutic agent could increase risk of cardiovascular incidents from interaction with CB1 receptors. But CBD also interacts with CB2 receptors and is possible that administration of CBD could lead to cardioprotective effects.

Adult neurogenesis, brain health and the endocannabinoid system

Various research reports show�neural-progenitor cells�produce endocannabinoids in time of injury and stress. This stimulates cell division in the brain, especially in areas like the hippocampus and sub-ventricles.�This division is believed to be produced through interaction of endocannabinoids and CB1 receptors.

endocannabinoid el paso tx.

Other reports have shown CB1 deficient mice have a decreased ability in neural progenitor cell division when a nervous system injury occurs. This could mean CB1 deficient mice have less of a chance to recover from stroke or other type of brain injury compared to mice with CB1 at normal levels.

AEA, for example, induces astroglial proliferation in mice. Astroglia are star-shaped neurons thought to be extremely important for brain structure and protection. These are found in various areas like the blood brain barrier. Pharmacological stimulation of CB1 using synthetic cannabinoids has lead to neurogenesis�or new growth of nervous tissue.

Can Synthetic Cannabinoids Be Beneficial For Brain Health

Synthetic cannabinoids could be beneficial not just for brain injuries, but could also be utilized as an antidepressant. The synthetic cannabinoid HU210 has been used for this purpose from its ability to modulate the endocannabinoid system and increase neural growth.

Recent studies show that CB1-deficient mice tend to suffer from early age related cognitive impairment or�a noticeable and measurable�decline�in�cognitive abilities, which include memory and thinking skills. This could be because CB1 deficient mice cannot regenerate cells in the nervous system, making them succumb faster to age related cellular death. But this is a perfect example of endocannabinoid system deficiencies, which could lead to detrimental effects in humans.

Injury Medical Clinic: Stress Management Care & Treatments

Hemp, What Is It Exactly?

Hemp, What Is It Exactly?

Hemp, is one of the oldest cultivated crops, which was grown thousands of years ago in Asia as a food source. Ancient civilizations wove the strong and durable fibers into clothing and rope.1

It helped Christopher Columbus with the ships he sailed, both the sails and ropes were made of hemp and it was also placed between the planks to help the ships remain watertight.2

Two Plants With Completely Different Uses

hemp el paso, tx.

Hemp (Cannabis Sativa)

In this form is cultivated outside the United States (however, the U.S. Government has allowed it to be grown for research purposes) for clothing, paper, dietary supplements, cosmetics, foods, biofuels, and bioplastics. European hemp has less than 0.3% of the psychoactive compound�tetrahydrocannabinol (THC),�as measured in dried flower tops.3

Marijuana (Cannabis Sativa)

This cannabis sativa is cultivated to maximize the THC content, which is focused in the United States, and used exclusively for recreational and medicinal purposes.

How Hemp Helps The Body

Foods made from the plant are processed from the plant’s seeds and are quite common. Common foods include granola, roasted seeds, milk, and butter. These foods do not appear on drug tests when consumed.

The European strain offers a variety of health benefits without the side effects of the THC.


Powder is made from the oil the of the seeds and then processed into powder. The result is a complete protein that contains all nine essential amino acids plus omega fatty acids and fiber4. When compared to whey or animal protein, hemp powder is low in lysine and leucine.

Can’t Stand Fish?

For essential fatty acids, seeds are rich in healthy fats, which include omega-3,6, and 9 fatty acids. It also contains linoleic acid, and gamma-linolenic acid (GLA).5

Health Benefits Of Phytocannabinoids

The stalk of the plant contains natural compounds called phytocannabinoids. When eaten, they interact with the body’s endocannabinoid system (ECS) and help with stress, as well as, relieve aches, pains, and discomfort. Phytocannabinoids also support brain, bone, digestive health, and promote immune and metabolic function.

The plant contains over 80 different phytocannabinoids that help supplement the cannabinoids in your body makes naturally and support the ECS.6 Legally stalk extracts that are imported from outside of the United States must have less than 0.3% THC.

hemp el paso, tx.


Since 1970, cultivation of cannabis sativa from both the hemp and marijuana plants have been illegal in the U.S. under the federal Controlled Substances Act. Even though some States have legalized marijuana and the federal Farm Bill of 2014 allows States to issue licenses for limited and experimental growth, federal law still prohibits the domestic cultivation, sale, and distribution.8

Hemp products such as, paper, rope, clothing, and bioplastics, have always been available in the United States. Federal law never banned the importation of these products, as long as, the THC content is less than or equal to 0.3 percent.8

Now with people interested in plant nutrition there is a larger availability of hemp-derived foods. These foods are made from sources outside of the U.S. These sources only contain a minimal amount of THC, and are completely legal.

When Buying Hemp Products

When buying a hemp products, make sure that it is made from imported industrial hemp. Buy brands that manufacture with�Good Manufacturing Practice (GMP) standards and test their products purity and quality.

  • Food purchases should be from major brands and reputable sources. It’s best to go with organic products, which do not contain pesticides.
  • Hemp oil products should be organic and cold processed. These oils should be refrigerated to avoid rancidity.
  • When buying hemp protein, find brands, which list amino acid content. There should be no additives, i.e. a lot of sugar.

Cannabidiol (CBD) & Phytocannabinoids


  1. [Accessed March 19, 2018]
  2. [Accessed March 19, 2018]
  3. Johnson R. Hemp as an agricultural commodity. Washington, D.C. Library of Congress Congressional Research Service, 2014.
  4. Callaway J. Hempseed as a nutritional resource: An overview. Euphytica 2004;140(1-2):65-72.
  5. Leizer C, Ribnicky D, Poulev A, et al. The composition of hemp seed oil and its potential as an important source of nutrition. J Nutraceut Func Med Foods 2002;2(4):35-53.
  6. Borgelt L, Franson K, Nussbaum A, Wang G. The pharmacologic and clinical effects of medical cannabis. Pharmacotherapy 2013;33(2):195-209.
  7. Cherney J, Small E. Industrial hemp in North America: production, politics and potential. Agronomy 2016;6(4):58.
  8. Mead A. The legal status of cannabis (marijuana) and cannabidiol (CBD) under U.S. law. Epilepsy Behav 2017;70(Pt B):149-153.
Cannabidiol for Neurodegenerative Disorders

Cannabidiol for Neurodegenerative Disorders

Neurodegenerative disorders are on the rise worldwide. In the USA alone nearly 5.4 million individuals suffer from Alzheimer’s disease, while roughly 500,000 suffer from Parkinson’s disease. As the American population ages, these numbers are just likely to increase. A large proportion of individuals have direct experience with neurodegenerative disorders either on their own or through their loved ones. Brain disorders like Parkinson’s, Huntington’s or Alzheimer’s, have some of the maximum disease burdens.


Illness burden, according to the World Health Organization, or WHO, characterizes the amount of healthy years that are influenced by disability. Neurodegenerative disorders are more burdensome because they not only affect the person, but also have an enormous financial, emotional and physical effect on households. The disease burden for neurodegenerative disorders has been calculated to be more significant than that of cancers. As scientific research expands into the realm of medical marijuana, and its various beneficial elements, there’s beginning to be significant excitement surrounding the treatment possibilities for neurodegenerative ailments with CBD, or cannabidiol, oil.


Research studies into CBD for neurodegenerative diseases, including Huntington’s, Parkinson’s and Alzheimer’s, appears to be overwhelmingly positive. Not only does CBD, or cannabidiol, treatment target some of the most painful symptoms of these diseases but CBD also seems to indicate little to no side effect risk. For a lot of people managing their symptoms, CBD is offering a ray of hope for an assortment of progressively severe neurological diseases. The purpose of the following article is to demonstrate as well as discuss the effects of cannabidiol for the treatment and prevention of neurodegenerative disorders.


Cannabidiol for Neurodegenerative Disorders: Important New Clinical Applications for this Phytocannabinoid?




Cannabidiol (CBD) is a phytocannabinoid with therapeutic properties for numerous disorders exerted through molecular mechanisms that are yet to be completely identified. CBD acts in some experimental models as an anti-inflammatory, anticonvulsant, anti-oxidant, anti-emetic, anxiolytic and antipsychotic agent, and is therefore a potential medicine for the treatment of neuroinflammation, epilepsy, oxidative injury, vomiting and nausea, anxiety and schizophrenia, respectively. The neuroprotective potential of CBD, based on the combination of its anti-inflammatory and anti-oxidant properties, is of particular interest and is presently under intense preclinical research in numerous neurodegenerative disorders. In fact, CBD combined with ?9-tetrahydrocannabinol is already under clinical evaluation in patients with Huntington’s disease to determine its potential as a disease-modifying therapy. The neuroprotective properties of CBD do not appear to be exerted by the activation of key targets within the endocannabinoid system for plant-derived cannabinoids like ?9-tetrahydrocannabinol, i.e. CB1 and CB2 receptors, as CBD has negligible activity at these cannabinoid receptors, although certain activity at the CB2 receptor has been documented in specific pathological conditions (i.e. damage of immature brain). Within the endocannabinoid system, CBD has been shown to have an inhibitory effect on the inactivation of endocannabinoids (i.e. inhibition of FAAH enzyme), thereby enhancing the action of these endogenous molecules on cannabinoid receptors, which is also noted in certain pathological conditions. CBD acts not only through the endocannabinoid system, but also causes direct or indirect activation of metabotropic receptors for serotonin or adenosine, and can target nuclear receptors of the PPAR family and also ion channels.


Keywords: cannabidiol, cannabinoid signalling system, Huntington’s disease, neonatal ischaemia, neuroprotection, Parkinson’s disease


Overview on the Therapeutic Properties of CBD


Cannabidiol (CBD) is one of the key cannabinoid constituents in the plant Cannabis sativa in which it may represent up to 40% of cannabis extracts [1]. However, contrarily to ?9-tetrahydrocannabinol (?9-THC), the major psychoactive plant-derived cannabinoid, which combines therapeutic properties with some important adverse effects, CBD is not psychoactive (it does not activate CB1 receptors [2]), it is well-tolerated and exhibits a broad spectrum of therapeutic properties [3]. Even, combined with ?9-THC in the cannabis-based medicine Sativex� (GW Pharmaceuticals Ltd, Kent, UK), CBD is able to enhance the beneficial properties of ?9-THC while reducing its negative effects [4]. Based on this relatively low toxicity, CBD has been studied, even at the clinical level, alone or combined with other phytocannabinoids, to determine its therapeutic efficacy in different central nervous system (CNS) and peripheral disorders [3]. In the CNS, CBD has been reported to have anti-inflammatory properties, thus being useful for neuroinflammatory disorders [5], including multiple sclerosis for which CBD combined with ?9-THC (Sativex�) has been recently licenced as a symptom-relieving agent for the treatment of spasticity and pain [6]. Based on its anticonvulsant properties, CBD has been proposed for the treatment of epilepsy [7�9], and also for the treatment of sleep disorders based on its capability to induce sleep [10]. CBD is also anti-emetic, as are most of the cannabinoid agonists, but its effects are independent of CB1 receptors and are possibly related to its capability to modulate serotonin transmission (see [11] and below). CBD has antitumoural properties that explain its potential against various types of cancer [12, 13]. Moreover, CBD has recently shown an interesting profile for psychiatric disorders, for example, it may serve as an antipsychotic and be a promising compound for the treatment of schizophrenia [14�17], but it also has potential as an anxiolytic [18] and antidepressant [19], thus being also effective for other psychiatric disorders. Lastly, based on the combination of its anti-inflammatory and anti-oxidant properties, CBD has been demonstrated to have an interesting neuroprotective profile as indicated by results obtained through intense preclinical research into numerous neurodegenerative disorders, in particular the three disorders addressed in this review, neonatal ischaemia (CBD alone) [20], Huntington’s disease (HD) (CBD combined with ?9-THC as in Sativex�) [21�23] or Parkinson’s disease (PD) (CBD probably combined with the phytocannabinoid ?9-tetrahydrocannabivarin, ?9-THCV) [24, 25], work that has recently progressed to the clinical area in some specific cases [26]. The neuroprotective potential of CBD for the management of certain other neurodegenerative disorders, e.g. Alzheimer’s disease, stroke and multiple sclerosis, has also been investigated in studies that have yielded some positive results [27�33]. However, these data will be considered here only very briefly.


Overview on the Mechanisms of Action of CBD


The therapeutic properties of CBD do not appear to be exerted by the activation of key targets within the endocannabinoid system for plant-derived cannabinoids like ?9-THC, i.e. CB1 and CB2 receptors. CBD has in general negligible activity at these cannabinoid receptors [2], so it has been generally assumed that most of its pharmacological effects are not a priori pharmacodynamic in nature and related to the activation of specific signalling pathways, but related to its innate chemical properties, in particular with the presence of two hydroxyl groups (see below) that enables CBD to have an important anti-oxidant action [2]. However, in certain pathological conditions (i.e. damage of immature brain), CBD has shown some activity at the CB2 receptor exerted directly ([20], see also Table 1) or indirectly through an inhibitory effect on the mechanisms of inactivation (i.e. transporter, FAAH enzyme) of endocannabinoids [34, 35], enhancing the action of these endogenous molecules at the CB2 receptor but also at the CB1 and at other receptors for endocannabinoids, i.e. TRPV1 [35] and TRPV2 [36] receptors.


Table 1 CBD Reported Functions


However, the anti-oxidant profile of CBD, as well as the few effects it exerts through targets within the endocannabinoid system in certain pathophysiological conditions, cannot completely explain all of the many pharmacological effects of CBD, prompting a need to seek out possible targets for this phytocannabinoid outside the endocannabinoid system. There is, indeed, already evidence that CBD can affect serotonin receptors (i.e. 5HT1A) [18, 19, 28], adenosine uptake [37], nuclear receptors of the PPAR family (i.e. PPAR-?) [38, 39] and many other pharmacological targets (see Table 1 including references [40�56]). In part, this information derives from numerous studies directed at identifying the pharmacological actions that CBD produces in vitro. This phytocannabinoid has been found to display a wide range of actions in vitro some at concentrations in the submicromolar range, and others at concentrations between 1 and 10 �m or above 10 �m. Its pharmacological targets include a number of receptors, ion channels, enzymes and cellular uptake processes (summarized in Table 1). There is evidence too that CBD can inhibit delayed rectifier K+ and L-type Ca2+ currents and evoked human neutrophil migration, activate basal microglial cell migration, and increase membrane fluidity, all at submicromolar concentrations, and that at concentrations between 1 and 10 �m it can inhibit the proliferation of human keratinocytes and of certain cancer cells (reviewed in [44]). At concentrations between 1 and 10 �m, CBD has also been reported to be neuroprotective, to reduce signs of oxidative stress, to modulate cytokine release and to increase calcium release from neuronal and glial intracellular stores (reviewed in [44]), and at 15 �M to induce mRNA expression of several phosphatases in prostate and colon cancer cells [57].


As will be discussed in the following section, the question of which of these many actions contributes most towards the beneficial effects that CBD displays in vivo in animal models of neurodegenerative disorders such as PD and HD remains to be fully investigated. Also still to be explored is the possibility that CBD may ameliorate signs and symptoms of such disorders and others (i.e. psychiatric disorders), at least in part, by potentiating activation of 5-HT1A receptors by endogenously released serotonin. Thus, although CBD only activates the 5-HT1A receptor at concentrations above 10 �m (Table 1), it can, at the much lower concentration of 100 nm enhance the ability of the 5-HT1A receptor agonist, 8-hydroxy-2-(di-n-propylamino)tetralin to stimulate [35S]-GTP?S binding to rat brainstem membranes [58]. Furthermore, there is evidence first, that activation of 5-HT1A receptors can ameliorate specific symptoms in PD [59, 60] and second, that beneficial effects displayed by CBD in vivo in animal models of ischaemic injury [27, 28], hepatic encephalopathy [61], anxiety, stress and panic [18, 62�64], depression [19], pain [65] and nausea and vomiting [66] are all mediated by increased activation of the 5-HT1A receptor. Importantly, the dose�response curve of CBD for the production of its effects in several of these models has been found to be bell-shaped [19, 28, 62, 65, 67, 68]. This is a significant observation since it strengthens the hypothesis that CBD can act in vivo to potentiate 5-HT-induced activation of 5-HT1A receptors. Thus, the concentration�response curve of CBD for its enhancement of 8-hydroxy-2-(di-n-propylamino)tetralin-induced stimulation of [35S]-GTP?S binding to rat brainstem membranes is also bell-shaped [58].


CBD as a Neuroprotective Agent


In contrast to the neuroprotective properties of cannabinoid receptor agonists [69, 70], those of CBD do not seem to be attributable to the control of excitotoxicity via the activation of CB1 receptors and/or to the control of microglial toxicity via the activation of CB2 receptors. Thus, except in preclinical models of neonatal ischaemia (see below and [20]), CBD has been found not to display any signs of CB1 or CB2 receptor activation, and yet is no less active than cannabinoid receptor agonists against the brain damage produced by different types of cytotoxic insults ([71�75], reviewed in [76]). What then are the cannabinoid receptor-independent mechanisms by which CBD acts as a neuroprotective agent? Finding the correct answer to this question is not easy, although data obtained in numerous investigations into different pathological conditions associated with brain damage indicate that CBD does normalize glutamate homeostasis [71, 72], reduce oxidative stress [73, 77] and attenuate glial activation and the occurrence of local inflammatory events [74, 78]. Furthermore, a recent study by Juknat et al. [79] has strongly demonstrated the existence of notable differences in the genes that were altered by CBD (not active at CB1 or CB2 receptors) and those altered by ?9-THC (active at both these receptors) in inflammatory conditions in an in vitro model. These authors found a greater influence of CBD on genes controlled by nuclear factors known to be involved in the regulation of stress responses (including oxidative stress) and inflammation [79]. This agrees with the idea that there may be two key processes underlying the neuroprotective effects of CBD. The first and the most classic mechanism is the capability of CBD to restore the normal balance between oxidative events and anti-oxidant endogenous mechanisms [69] that is frequently disrupted in neurodegenerative disorders, thereby enhancing neuronal survival. As has been mentioned above [73, 77], this capability seems to be inherent to CBD and structurally-similar compounds, i.e. ?9-THC, cannabinol, nabilone, levonantradol and dexanabinol, as it would depend on the innate anti-oxidant properties of these compounds and be cannabinoid receptor-independent. Alternatively, or in addition, the anti-oxidant effect of CBD may involve intracellular mechanisms that enhance the ability of endogenous anti-oxidant enzymes to control oxidative stress, in particular the signaling triggered by the transcription factor nuclear factor-erythroid 2-related Factor 2 (nrf-2), as has been found in the case of other classic anti-oxidants. According to this idea, CBD may bind to an intracellular target capable of regulating this transcription factor which plays a major role in the control of anti-oxidant-response elements located in genes encoding for different anti-oxidant enzymes of the so-called phase II-anti-oxidant response (see proposed mechanism in Figure 1). This possibility is presently under investigation (reviewed in [69]).


Figure 1 Mechanisms Exerted by CBD


The second key mechanism for CBD as a neuroprotective compound involves its anti-inflammatory activity that is exerted by mechanisms other than the activation of CB2 receptors, the canonic pathway for the anti-inflammatory effects of most of cannabinoid agonists [70]. Anti-inflammatory effects of CBD have been related to the control of microglial cell migration [80] and the toxicity exerted by these cells, i.e. production of pro-inflammatory mediators [81], similarly with the case of cannabinoid compounds targeting the CB2 receptor [70]. However, a key element in this CBD effect is the inhibitory control of NF?B signalling activity and the control of those genes regulated by this transcription factor (i.e. iNOS) [31, 81]. This inhibitory control of NF?B signalling may be exerted by reducing the phosphorylation of specific kinases (i.e. p38 MAP kinase) involved in the control of this transcription factor and by preventing its translocation to the nucleus to induce the expression of pro-inflammatory genes [31]. However, it has been recently proposed that CBD may bind the nuclear receptors of the PPAR family, in particular the PPAR-?[38, 39] (Table 1) and it is well known that these receptors antagonize the action of NF?B, reducing the expression of pro-inflammatory enzymes (i.e. iNOS, COX-2), pro-inflammatory cytokines and metalloproteases, effects that are elicited by different cannabinoids including CBD (reviewed in [9, 39]). Therefore, it could well be that CBD may produce its anti-inflammatory effects by the activation of these nuclear receptors and the regulation of their downstream signals although various aspects of this mechanism are pending further research and confirmation (see proposed mechanism in Figure 1).


Other mechanisms proposed for the neuroprotective effects of CBD include: (i) the contribution of 5HT1A receptors, e.g. in stroke [27, 28], (ii) the inhibition of adenosine uptake [37], e.g. in neonatal ischaemia ([20], see below) and (iii) specific signalling pathways (e.g. WNT/?-catenin signaling) that play a role in ?-amyloid-induced GSK-3? activation and tau hyperphosphorylation in Alzheimer’s disease [82].


CBD in Specific Neurodegenerative Disorders: from Basic to Clinical Studies


Although the neuroprotective properties of CBD have been already examined in numerous acute or chronic neurodegenerative disorders, we will address here only three disorders, i.e. neonatal ischaemia, HD and PD, in which a clinical evaluation of CBD, as monotherapy or in combination with other phytocannabinoids, is already in progress or may be developed soon. CBD has demonstrated significant effects in preclinical models of these three disorders, but, in some cases, its combination with other phytocannabinoids (i.e. ?9-THC for HD, ?9-THCV for PD) revealed some interesting synergies that may be extremely useful at the clinical level.


CBD and Neonatal Ischaemia


Brain damage by hypoxia-ischaemia (HI) affects 0.3% subjects over 65 years old in developed countries leading to more than 150 000 deaths per year in the USA (for review see [83]). Although less prevalent, newborn hypoxic-ischaemic brain damage (NHIBD) is of great importance too. Approximately 0.1�0.2% live term births experience perinatal asphyxia with one third of them developing a severe neurological syndrome. About 25% of severe NHIBD leads to lasting sequelae and about 20% to death. Energy failure during ischaemia provokes the dysfunction of ionic pumps in neurons, leading to accumulation of ions and excitotoxic substances such as glutamate. The consequent increase in intracellular calcium content aggravates the neuron dysfunction and activates different enzymes, starting different processes of immediate and programmed cell death. During post ischaemic reperfusion, inflammation and oxidative stress aggravate and amplify such responses, increasing and spreading neuron and glial cell damage. Excitotoxicity, inflammation and oxidative stress play, therefore, a particularly relevant role in HI-induced brain cell death in newborns [83].


Unfortunately, the therapeutic outcome in NHIBD is still very limited and there is a strong need for novel strategies. We have solid evidence that CBD may be a good candidate to be tested in NHIBD at the clinical level. Using forebrain slices from newborn mice subjected to glucose-oxygen deprivation, a well-known in vitro model of NHIBD, we have already reported that CBD is able to reduce necrotic and apoptotic damage [20]. This neuroprotective effect is related to the modulation of excitotoxicity, oxidative stress and inflammation, as CBD normalizes the release of glutamate and cytokines as well as the induction of iNOS and COX-2 [20]. Surprisingly, we found that co-incubation of CBD with the CB2 receptor antagonist AM-630 abolished all these protective effects, suggesting that CB2 receptors are somehow involved in neuroprotective effects of CBD in immature brain [20]. In addition, adenosine receptors, in particular A2A receptors, seem to be also involved in these neuroprotective effects of CBD in the immature brain as revealed by the fact that the effect of CBD in this model was abolished by co-incubation with the A2A receptor antagonist SCH58261 [20]. CBD has been tested further in an in vivo model of NHIBD in newborn pigs, which closely resembles the actual human condition. In this model, the administration of CBD after the HI insult also reduces immediate brain damage by modulating cerebral haemodynamic impairment and brain metabolic derangement, and preventing the appearance of brain oedema and seizures. These neuroprotective effects are not only free from side effects but also associated with some beneficial cardiac, haemodynamic and ventilatory effects [84]. These protective effects restore neurobehavioural performance in the following 72 h post HI [85].


CBD and Huntington’s Disease


HD is an inherited neurodegenerative disorder caused by a mutation in the gene encoding the protein huntingtin. The mutation consists of a CAG triplet repeat expansion translated into an abnormal polyglutamine tract in the amino-terminal portion of huntingtin, which due to a gain of function becomes toxic for specific striatal and cortical neuronal subpopulations, although a loss of function in mutant huntingtin has been also related to HD pathogenesis (see [86] for review). Major symptoms include hyperkinesia (chorea) and cognitive deficits (see [87] for review). At present, there is no specific pharmacotherapy to alleviate motor and cognitive symptoms and/or to arrest/delay disease progression in HD. Thus, even though a few compounds have produced encouraging effects in preclinical studies (i.e. minocycline, coenzyme Q10, unsaturated fatty acids, inhibitors of histone deacetylases) none of the findings obtained in these studies have yet led on to the development of an effective medicine [88]. Importantly, therefore, following on from an extensive preclinical evaluation using different experimental models of HD, clinical tests are now being performed with cannabinoids, and this includes the use of CBD combined with ?9-THC [26]. To get here, CBD was first studied in rats lesioned with 3-nitropropionic acid, a mitochondrial toxin that replicates the complex II deficiency characteristic of HD patients and that provokes striatal injury by mechanisms that mainly involve the Ca++-regulated protein calpain and generation of ROS. Neuroprotective effects in this experimental model were found with CBD alone [21] or combined with ?9-THC as in Sativex�[22], and in both cases, these effects were not blocked by selective antagonists of either CB1 or CB2 receptors, thus supporting the idea that these effects are caused by the anti-oxidant and cannabinoid receptor-independent properties of these phytocannabinoids. It is possible, however, that this anti-oxidant/neuroprotective effect of phytocannabinoids involves the activation of signalling pathways implicated in the control of redox balance (i.e. nrf-2/ARE), as mentioned before. CBD has also been studied in rats lesioned with malonate, a model of striatal atrophy that involves mainly glial activation, inflammatory events and activation of apoptotic machinery. CBD alone did not provide protection in this model as only CB2 receptor agonists were effective [89], but the combination of CBD with ?9-THC used in Sativex� was highly effective in this model, by preserving striatal neurons, and this protective effect involved both CB1 and CB2 receptors [23]. It is interesting to note that ?9-THC alone produced biphasic effects in this model whereas CB1 receptor blockade aggravated the striatal damage [90]. We are presently studying the efficacy of this phytocannabinoid combination in a transgenic murine model of HD, i.e. R6/2 mice, in which the activation of both CB1 and CB2 receptors has already been found to induce beneficial effects [91, 92]. This solid preclinical evidence has provided substantial support for the evaluation of Sativex�, or equivalent cannabinoid-based medicines, as a new disease-modifying therapy in HD patients. Previous clinical studies had already used CBD, but they concentrated on symptom relief (i.e. chorea) rather than on disease progression and they did not show any significant improvement [93, 94]. We are presently engaged in a novel phase II-clinical trial with Sativex� as a disease-modifying agent in presymptomatic and early symptomatic patients [26], the outcome of which will be known soon.


CBD and Parkinson’s Disease


PD is also a progressive neurodegenerative disorder whose aetiology has been, however, associated with environmental insults, genetic susceptibility or interactions between both causes [95]. The major clinical symptoms in PD are tremor, bradykinesia, postural instability and rigidity, symptoms that result from the severe dopaminergic denervation of the striatum caused by the progressive death of dopaminergic neurons of the substantia nigra pars compacta[96]. CBD has also been found to be highly effective as a neuroprotective compound in experimental models of parkinsonism, i.e. 6-hydroxydopamine-lesioned rats, by acting through anti-oxidant mechanisms that seem to be independent of CB1 or CB2 receptors [24, 25, 97]. This observation is particularly important in the case of PD due to the relevance of oxidative injury to this disease, and because the hypokinetic profile of cannabinoids that activate CB1 receptors represents a disadvantage for this disease because such compounds can acutely enhance rather than reduce motor disability, as a few clinical data have already revealed (reviewed in [98]). Therefore, major efforts are being directed at finding cannabinoid molecules that may provide neuroprotection through their anti-oxidant properties and that may also activate CB2 receptors, but not CB1 receptors, or that may even block CB1 receptors, actions which may provide additional benefits, for example by relieving symptoms such as bradykinesia. One interesting example of a compound with this profile is the phytocannabinoid ?9-THCV, which is presently under investigation in preclinical models of PD [25]. Thus, there could well be clinical advantages to administering ?9-THCV together with CBD as this might induce symptomatic relief (due to the blockade of CB1 by ?9-THCV) and neuroprotection (due to the anti-oxidant and anti-inflammatory properties of both CBD and ?9-THCV). The combination of CBD with ?9-THCV (rather than with ?9-THC) would merit investigation in parkinsonian patients (reviewed in [9, 99]), as previous data obtained in clinical studies have indicated that CBD was effective in the relief of some PD-related symptoms such as dystonia, although not in others like tremor [100], but its combination with ?9-THC, which can activate CB1 receptors, failed to improve parkinsoniam symptoms or to attenuate levodopa-induced dyskinesias [101].



Dr. Alex Jimenez’s Insight

Because the number of neurodegenerative diseases are likely to continue to grow as time passes, the race is on to discover effective treatment options for these debilitating conditions. The choices available today are restricted in scope, and therefore are typically costly. They also have side effects which should be carefully considered. Many of the most common drugs and/or medications used for Parkinson’s disease and Alzheimer’s disease cause nausea, vomiting, digestive issues, and decreased appetite, just to mention a couple. However, the use of cannabidiol, or CBD, is demonstrated to provide many health benefits without the harmful side-effects of many of these drugs and/or medications. It’s essential for healthcare professionals and researchers to continue in the search for evidence regarding the use of CBD for neurodegenerative diseases.


Concluding Remarks and Futures Perspectives


The experimental evidence presented in this review supports the idea that, from a pharmaceutical point of view, CBD is an unusually interesting molecule. As presented above, its actions are channeled through several biochemical mechanisms and yet it causes essentially no undesirable side effects and its toxicity is negligible [2]. It has shown valuable activities in numerous pharmaceutically important areas: (i) it is a potent anti-oxidant [73], which may partly explain its neuroprotective effects in PD [24, 25], and possibly in cerebral ischaemia-reperfusion (reviewed in [83]), (ii) it has been evaluated in human epileptic patients with very positive results [7�9], (iii) it has shown activity in mice with several autoimmune diseases, i.e. type-1 diabetes [102] and rheumatoid arthritis [103], (iv) it lowers the effects of myocardial ischaemic-reperfusion injury in mice [104], (v) it reduces microglial activation in mice and hence may slow the progression of Alzheimer’s disease [78], (vi) it protects against hepatic ischaemia/reperfusion injury in animals [105] and has shown considerable activity in an animal model of hepatic encephalopathy [106], (vii) it even lowers anxiety (in humans) [107] and (viii) it is already in use, together with ?9-THC, in a buccal spray (Sativex�) to lower symptoms of multiple sclerosis [6]. The presence of CBD in Sativex� enhances the positive effects of ?9-THC whilst reducing its adverse effects, in concordance with previous data that indicated that CBD alters some of the effects of ?9-THC, i.e. it lowers the acute memory-impairing effects and anxiety produced by ?9-THC [108]. In addition, cannabis with high CBD content presumably leads to fewer psychotic experiences than cannabis with a highest proportion of ?9-THC [17].


It is possible that CBD has not become a licensed medicine (except in Sativex�) because of patenting problems. However, commercial issues apart, CBD has tremendous potential as a new medicine. Thus, because the mechanisms that underlie its anti-inflammatory effects are different from those of prescribed drugs, it could well prove to be of considerable benefit to a large number of patients, who for various reasons are not sufficiently helped by existing drugs. In type 1-diabetes, we have shown that in mice CBD very significantly lowers the number of insulin-producing cells that are affected even after the disease has advanced [102]. Its neuroprotective effects are extremely valuable as no drugs exist that have similar properties. Surprisingly very few CBD derivatives have been evaluated and compared with CBD. At least one of them, CBD-dimethylheptyl-7-oic acid, is more potent than CBD as an anti-inflammatory agent [109]. Aren’t we missing a valuable new pathway to a family of very promising new therapeutic agents?




The experimental work carried out by our group and that has been mentioned in this review article, has been supported during the last years by grants from CIBERNED (CB06/05/0089), MICINN (SAF2009-11847), CAM (S2011/BMD-2308) and GW Pharmaceuticals Ltd. The authors are indebted to all colleagues who contributed in this experimental work and to Yolanda Garc�a-Movell�n for administrative support.


Competing Interests


JFR, OS and CG are supported by GW Pharma for research on phytocannabinoids and motor disorders. JMO and MRP have received funds for research from GW Pharma, Ltd. RP’s research is supported in part by funding from GW Pharmaceuticals. RM is a consultant of GW Pharma.


Cannabis, the Endocannabinoid System and Good Health


As healthcare professionals continue to sort through the emerging research studies of cannabis and cannabinoids, one thing remains clear: a more functional endocannabinoid system is fundamental for overall health and wellness. From embryonic implantation on the walls of our mother’s uterus, to nursing and growth, to reacting to injuries, endocannabinoids help us survive in a quickly changing and increasingly hostile atmosphere. As a result, many researchers began to wonder, can an individual enrich their endocannabinoid system by taking supplemental cannabis? Beyond treating symptoms, beyond even curing disease, can cannabis help us prevent disease and promote health by sparking a system that is hard-wired into most people?


Research studies have demonstrated that small doses of cannabinoids from cannabis can indicate the body to create more endocannabinoids and construct more cannabinoid receptors. That is why many first-time cannabis users do not feel a consequence, but by their second or third time working with the herb they have assembled more cannabinoid receptors and are ready to respond. More receptors raise a person’s sensitivity to cannabinoids; smaller doses have bigger impacts, and the patient has an enhanced baseline of endocannabinoid activity. Healthcare professionals believe that small, regular doses of cannabis may function as a tonic to our most central physiologic therapeutic system.


Unlike artificial derivatives, herbal cannabis may contain over one hundred distinct cannabinoids, including THC, which all work synergistically to produce better medical effects and less side effects than THC alone. While cannabis is safe and works well when smoked, most patients prefer to avoid respiratory irritation and instead use a vaporizer, cannabis tincture, or topical salve. Scientific inquiry and patient testimonials indicate that herbal cannabis has superior medical qualities to synthetic cannabinoids. Of course, we want more human-based research analyzing the effectiveness of cannabis, but the evidence base is currently large and growing continuously, despite the DEA’s best efforts to dissuade cannabis-related research.


People today need safe, natural and inexpensive remedies that stimulate our bodies’ ability to self-heal and assist our population to enhance the quality of life. Medical cannabis is just one such option. The purpose of this article has been to spread the knowledge and assist to educate patients and healthcare professionals around the evidence behind the medical use of cannabis and cannabinoids and its health benefits, including its effects on neurodegenerative disorders.�Information referenced from the National Center for Biotechnology Information (NCBI).�The scope of our information is limited to chiropractic as well as to spinal injuries and conditions. To discuss the subject matter, please feel free to ask Dr. Jimenez or contact us at�915-850-0900�.


Curated by Dr. Alex Jimenez


Additional Topics: Back Pain

Back pain is one of the most prevalent causes for disability and missed days at work worldwide. As a matter of fact, back pain has been attributed as the second most common reason for doctor office visits, outnumbered only by upper-respiratory infections. Approximately 80 percent of the population will experience some type of back pain at least once throughout their life. The spine is a complex structure made up of bones, joints, ligaments and muscles, among other soft tissues. Because of this, injuries and/or aggravated conditions, such as herniated discs, can eventually lead to symptoms of back pain. Sports injuries or automobile accident injuries are often the most frequent cause of back pain, however, sometimes the simplest of movements can have painful results. Fortunately, alternative treatment options, such as chiropractic care, can help ease back pain through the use of spinal adjustments and manual manipulations, ultimately improving pain relief.


blog picture of cartoon paperboy big news



EXTRA IMPORTANT TOPIC: Low Back Pain Management


MORE TOPICS: EXTRA EXTRA:�Chronic Pain & Treatments


1.�Grlic L. A comparative study on some chemical and biological characteristics of various samples of cannabis resin.�Bull Narc.�1976;14:37�46.
2.�Mechoulam R, Parker LA, Gallily R. Cannabidiol: an overview of some pharmacological aspects.�J Clin Pharmacol.�2002;42:11S�9S.�[PubMed]
3.�Mechoulam R, Peters M, Murillo-Rodriguez E, Hanus LO. Cannabidiol-recent advances.�Chem Biodivers.�2007;4:1678�92.�[PubMed]
4.�Russo E, Guy GW. A tale of two cannabinoids: the therapeutic rationale for combining tetrahydrocannabinol and cannabidiol.�Med Hypotheses.�2006;66:234�46.�[PubMed]
5.�Costa B, Colleoni M, Conti S, Parolaro D, Franke C, Trovato AE, Giagnoni G. Oral anti-inflammatory activity of cannabidiol, a non-psychoactive constituent of cannabis, in acute carrageenan-induced inflammation in the rat paw.�Naunyn Schmiedebergs Arch Pharmacol.�2004;369:294�9.�[PubMed]
6.�Sastre-Garriga J, Vila C, Clissold S, Montalban X. THC and CBD oromucosal spray (Sativex�) in the management of spasticity associated with multiple sclerosis.�Expert Rev Neurother.�2011;11:627�37.[PubMed]
7.�Cunha JM, Carlini EA, Pereira AE, Ramos OL, Pimentel C, Gagliardi R, Sanvito WL, Lander N, Mechoulam R. Chronic administration of cannabidiol to healthy volunteers and epileptic patients.�Pharmacology.�1980;21:175�85.�[PubMed]
8.�Cortesi M, Fusar-Poli P. Potential therapeutical effects of cannabidiol in children with pharmacoresistant epilepsy.�Med Hypotheses.�2007;68:920�1.�[PubMed]
9.�Hill AJ, Williams CM, Whalley BJ, Stephens GJ. Phytocannabinoids as novel therapeutic agents in CNS disorders.�Pharmacol Ther.�2012;133:79�97.�[PubMed]
10.�Murillo-Rodr�guez E, Mill�n-Aldaco D, Palomero-Rivero M, Mechoulam R, Drucker-Col�n R. Cannabidiol, a constituent of�Cannabis sativa, modulates sleep in rats.�FEBS Lett.�2006;580:4337�45.[PubMed]
11.�Parker LA, Rock EM, Limebeer CL. Regulation of nausea and vomiting by cannabinoids.�Br J Pharmacol.�2011;163:1411�22.�[PMC free article][PubMed]
12.�Ligresti A, Moriello AS, Starowicz K, Matias I, Pisanti S, De Petrocellis L, Laezza C, Portella G, Bifulco M, Di Marzo V. Antitumor activity of plant cannabinoids with emphasis on the effect of cannabidiol on human breast carcinoma.�J Pharmacol Exp Ther.�2006;318:1375�87.�[PubMed]
13.�Massi P, Vaccani A, Bianchessi S, Costa B, Macchi P, Parolaro D. The non-psychoactive cannabidiol triggers caspase activation and oxidative stress in human glioma cells.�Cell Mol Life Sci.�2006;63:2057�66.�[PubMed]
14.�Leweke FM, Schneider U, Radwan M, Schmidt E, Emrich HM. Different effects of nabilone and cannabidiol on binocular depth inversion in man.�Pharmacol Biochem Behav.�2000;66:175�81.�[PubMed]
15.�Zuardi AW, Crippa JA, Hallak JE, Moreira FA, Guimar�es FS. Cannabidiol, a�Cannabis sativaconstituent, as an antipsychotic drug.�Braz J Med Biol Res.�2006;39:421�9.�[PubMed]
16.�Leweke FM, Piomelli D, Pahlisch F, Muhi D, Gerth CW, Hoyer C, Klosterk�tter J, Hellmich M, Koethe D. Cannabidiol enhances anandamide signaling and alleviates psychotic symptoms of schizophrenia.�Transl Psychiatry.�2012;2:e94.�[PMC free article][PubMed]
17.�Schubart CD, Sommer IE, van Gastel WA, Goetgebuer RL, Kahn RS, Boks MP. Cannabis with high cannabidiol content is associated with fewer psychotic experiences.�Schizophr Res.�2011;130:216�21.[PubMed]
18.�Gomes FV, Resstel LBM, Guimar�es FS. The anxiolytic-like effects of cannabidiol injected into the bed nucleus of the stria terminalis are mediated by 5-HT1A receptors.�Psychopharmacology.�2011;213:465�73.�[PubMed]
19.�Zanelati TV, Biojone C, Moreira FA, Guimar�es FS, Joca SRL. Antidepressant-like effects of cannabidiol in mice: possible involvement of 5-HT1A�receptors.�Br J Pharmacol.�2010;159:122�8.[PMC free article][PubMed]
20.�Castillo A, Tol�n MR, Fern�ndez-Ruiz J, Romero J, Martinez-Orgado J. The neuroprotective effect of cannabidiol in an�in vitro�model of newborn hypoxic-ischemic brain damage in mice is mediated by CB2 and adenosine receptors.�Neurobiol Dis.�2010;37:434�40.�[PubMed]
21.�Sagredo O, Ramos JA, Decio A, Mechoulam R, Fern�ndez-Ruiz J. Cannabidiol reduced the striatal atrophy caused 3-nitropropionic acid�in vivo�by mechanisms independent of the activation of cannabinoid, vanilloid TRPV1 and adenosine A2A receptors.�Eur J Neurosci.�2007;26:843�51.�[PubMed]
22.�Sagredo O, Pazos MR, Satta V, Ramos JA, Pertwee RG, Fern�ndez-Ruiz J. Neuroprotective effects of phytocannabinoid-based medicines in experimental models of Huntington’s disease.�J Neurosci Res.�2011;89:1509�18.�[PubMed]
23.�Valdeolivas S, Satta V, Pertwee RG, Fern�ndez-Ruiz J, Sagredo O. Sativex-like combination of phytocannabinoids is neuroprotective in malonate-lesioned rats, an inflammatory model of Huntington’s disease: role of CB1 and CB2 receptors.�ACS Chem Neurosci.�2012;3:400�6.�[PMC free article][PubMed]
24.�Lastres-Becker I, Molina-Holgado F, Ramos JA, Mechoulam R, Fern�ndez-Ruiz J. Cannabinoids provide neuroprotection against 6-hydroxydopamine toxicity�in vivo�and�in vitro: relevance to Parkinson’s disease.�Neurobiol Dis.�2005;19:96�107.�[PubMed]
25.�Garc�a C, Palomo-Garo C, Garc�a-Arencibia M, Ramos J, Pertwee RG, Fern�ndez-Ruiz J. Symptom-relieving and neuroprotective effects of the phytocannabinoid ?9-THCV in animal models of Parkinson’s disease.�Br J Pharmacol.�2011;163:1495�506.�[PMC free article][PubMed]
26.�Garc�a de Y�benes J. Phase II-clinical trial on neuroprotection with cannabinoids in Huntington’s disease (SAT-HD) EudraCT 2010-024227-24.
27.�Hayakawa K, Mishima K, Nozako M, Ogata A, Hazekawa M, Liu A-X, Fujioka M, Abe K, Hasebe N, Egashira N, Iwasaki K, Fujiwara M. Repeated treatment with cannabidiol but not ?9-tetrahydrocannabinol has a neuroprotective effect without the development of tolerance.�Neuropharmacology.�2007;52:1079�87.[PubMed]
28.�Mishima K, Hayakawa K, Abe K, Ikeda T, Egashira N, Iwasaki K, Fujiwara M. Cannabidiol prevents cerebral infarction via a serotonergic 5-hydroxytryptamine1A�receptor-dependent mechanism.�Stroke.�2005;36:1071�6.�[PubMed]
29.�Braida D, Pegorini S, Arcidiacono MV, Consalez GG, Croci L, Sala M. Post-ischemic treatment with cannabidiol prevents electroencephalographic flattening, hyperlocomotion and neuronal injury in gerbils.�Neurosci Lett.�2003;346:61�4.�[PubMed]
30.�Hayakawa K, Mishima K, Fujiwara M. Therapeutic potential of non-psychotropic cannabidiol in ischemic stroke.�Pharmaceuticals.�2010;3:2197�212.
31.�Esposito G, De Filippis D, Maiuri MC, De Stefano D, Carnuccio R, Iuvone T. Cannabidiol inhibits inducible nitric oxide synthase protein expression and nitric oxide production in beta-amyloid stimulated PC12 neurons through p38 MAP kinase and NF-kappaB involvement.�Neurosci Lett.�2006;99:91�5.[PubMed]
32.�Iuvone T, Esposito G, Esposito R, Santamaria R, Di Rosa M, Izzo AA. Neuroprotective effect of cannabidiol, a non-psychoactive component from Cannabis sativa, on beta-amyloid-induced toxicity in PC12 cells.�J Neurochem.�2004;89:134�41.�[PubMed]
33.�Kozela E, Lev N, Kaushansky N, Eilam R, Rimmerman N, Levy R, Ben-Nun A, Juknat A, Vogel Z. Cannabidiol inhibits pathogenic T cells, decreases spinal microglial activation and ameliorates multiple sclerosis-like disease in C57BL/6 mice.�Br J Pharmacol.�2011;163:1507�19.�[PMC free article][PubMed]
34.�de Filippis D, Iuvone T, d’amico A, Esposito G, Steardo L, Herman AG, Pelckmans PA, de Winter BY, de Man JG. Effect of cannabidiol on sepsis-induced motility disturbances in mice: involvement of CB receptors and fatty acid amide hydrolase.�Neurogastroenterol Motil.�2008;20:919�27.�[PubMed]
35.�Bisogno T, Hanus L, De Petrocellis L, Tchilibon S, Ponde DE, Brandi I, Moriello AS, Davis JB, Mechoulam R, Di Marzo V. Molecular targets for cannabidiol and its synthetic analogues: effect on vanilloid VR1 receptors and on the cellular uptake and enzymatic hydrolysis of anandamide.�Br J Pharmacol.�2001;134:845�52.�[PMC free article][PubMed]
36.�De Petrocellis L, Ligresti A, Moriello AS, Allar� M, Bisogno T, Petrosino S, Stott CG, Di Marzo V. Effects of cannabinoids and cannabinoid-enriched cannabis extracts on TRP channels and endocannabinoid metabolic enzymes.�Br J Pharmacol.�2011;163:1479�94.�[PMC free article][PubMed]
37.�Carrier EJ, Auchampach JA, Hillard CJ. Inhibition of an equilibrative nucleoside transporter by cannabidiol: a mechanism of cannabinoid immunosuppression.�Proc Natl Acad Sci USA.�2006;103:7895�900.�[PMC free article][PubMed]
38.�O’Sullivan SE, Kendall DA. Cannabinoid activation of peroxisome proliferator-activated receptors: potential for modulation of inflammatory disease.�Immunobiology.�2010;215:611�6.�[PubMed]
39.�Esposito G, Scuderi C, Valenza M, Togna GI, Latina V, De Filippis D, Cipriano M, Carrat� MR, Iuvone T, Steardo L. Cannabidiol reduces A?-induced neuroinflammation and promotes hippocampal neurogenesis through PPAR? involvement.�PLoS ONE.�2011;6:e28668.�[PMC free article][PubMed]
40.�Thomas A, Baillie GL, Phillips AM, Razdan RK, Ross RA, Pertwee RG. Cannabidiol displays unexpectedly high potency as an antagonist of CB1�and CB2�receptor agonists�in vitro.�Br J Pharmacol.�2007;150:613�23.�[PMC free article][PubMed]
41.�Pertwee RG, Howlett AC, Abood ME, Alexander SPH, Di Marzo V, Elphick MR, Greasley PJ, Hansen HS, Kunos G, Mackie K, Mechoulam R, Ross RA. International Union of Basic and Clinical Pharmacology. LXXIX. Cannabinoid receptors and their ligands: beyond CB1�and CB2.�Pharmacol Rev.�2010;62:588�631.�[PMC free article][PubMed]
42.�Yang K-H, Galadari S, Isaev D, Petroianu G, Shippenberg TS, Oz M. The nonpsychoactive cannabinoid cannabidiol inhibits 5-hydroxytryptamine3A�receptor-mediated currents in�Xenopus laevisoocytes.�J Pharmacol Exp Ther.�2010;333:547�54.�[PMC free article][PubMed]
43.�Ross HR, Napier I, Connor M. Inhibition of recombinant human T-type calcium channels by ?9-tetrahydrocannabinol and cannabidiol.�J Biol Chem.�2008;283:16124�34.�[PMC free article][PubMed]
44.�Pertwee RG. The diverse CB1�and CB2�receptor pharmacology of three plant cannabinoids: ?9-tetrahydrocannabinol, cannabidiol and ?9-tetrahydrocannabivarin.�Br J Pharmacol.�2008;153:199�215.[PMC free article][PubMed]
45.�Ahrens J, Demir R, Leuwer M, de la Roche J, Krampfl K, Foadi N, Karst M, Haeseler G. The nonpsychotropic cannabinoid cannabidiol modulates and directly activates alpha-1 and alpha-1-beta glycine receptor function.�Pharmacology.�2009;83:217�22.�[PubMed]
46.�Yamaori S, Kushihara M, Yamamoto I, Watanabe K. Characterization of major phytocannabinoids, cannabidiol and cannabinol, as isoform-selective and potent inhibitors of human CYP1 enzymes.�Biochem Pharmacol.�2010;79:1691�8.�[PubMed]
47.�Yamaori S, Maeda C, Yamamoto I, Watanabe K. Differential inhibition of human cytochrome P450 2A6 and 2B6 by major phytocannabinoids.�Forensic Toxicol.�2011;29:117�24.
48.�Yamaori S, Okamoto Y, Yamamoto I, Watanabe K. Cannabidiol, a major phytocannabinoid, as a potent atypical inhibitor for CYP2D6.�Drug Metab Dispos.�2011;39:2049�56.�[PubMed]
49.�Yamaori S, Ebisawa J, Okushima Y, Yamamoto I, Watanabe K. Potent inhibition of human cytochrome P450 3A isoforms by cannabidiol: role of phenolic hydroxyl groups in the resorcinol moiety.�Life Sci.�2011;88:730�6.�[PubMed]
50.�Koch M, Dehghani F, Habazettl I, Schomerus C, Korf H-W. Cannabinoids attenuate norepinephrine-induced melatonin biosynthesis in the rat pineal gland by reducing arylalkylamine�N-acetyltransferase activity without involvement of cannabinoid receptors.�J Neurochem.�2006;98:267�78.�[PubMed]
51.�Jenny M, Santer E, Pirich E, Schennach H, Fuchs D. ?9-tetrahydrocannabinol and cannabidiol modulate mitogen-induced tryptophan degradation and neopterin formation in peripheral blood mononuclear cells�in vitro.�J Neuroimmunol.�2009;207:75�82.�[PubMed]
52.�Takeda S, Usami N, Yamamoto I, Watanabe K. Cannabidiol-2?,6?-dimethyl ether, a cannabidiol derivative, is a highly potent and selective 15-lipoxygenase inhibitor.�Drug Metab Dispos.�2009;37:1733�7.[PubMed]
53.�Usami N, Yamamoto I, Watanabe K. Generation of reactive oxygen species during mouse hepatic microsomal metabolism of cannabidiol and cannabidiol hydroxy-quinone.�Life Sci.�2008;83:717�24.[PubMed]
54.�Watanabe K, Motoya E, Matsuzawa N, Funahashi T, Kimura T, Matsunaga T, Arizono K, Yamamoto I. Marijuana extracts possess the effects like the endocrine disrupting chemicals.�Toxicology.�2005;206:471�8.�[PubMed]
55.�Funahashi T, Ikeuchi H, Yamaori S, Kimura T, Yamamoto I, Watanabe K.�In vitro�inhibitory effects of cannabinoids on progesterone 17?-hydroxylase activity in rat testis microsomes.�J Health Sci.�2005;51:369�75.
56.�Zhu HJ, Wang J-S, Markowitz JS, Donovan JL, Gibson BB, Gefroh HA, DeVane CL. Characterization of P-glycoprotein inhibition by major cannabinoids from marijuana.�J Pharmacol Exp Ther.�2006;317:850�7.�[PubMed]
57.�Sreevalsan S, Joseph S, Jutooru I, Chadalapaka G, Safe SH. Induction of apoptosis by cannabinoids in prostate and colon cancer cells is phosphatase dependent.�Anticancer Res.�2011;31:3799�807.[PMC free article][PubMed]
58.�Rock EM, Bolognini D, Limebeer CL, Cascio MG, Anavi-Goffer S, Fletcher PJ, Mechoulam R, Pertwee RG, Parker LA. Cannabidiol, a non-psychotropic component of cannabis, attenuates vomiting and nausea-like behaviour via indirect agonism of 5-HT1A�somatodendritic autoreceptors in the dorsal raphe nucleus.�Br J Pharmacol.�2012;165:2620�34.�[PMC free article][PubMed]
59.�Dupre KB, Eskow KL, Barnum CJ, Bishop C. Striatal 5-HT1A�receptor stimulation reduces D1 receptor-induced dyskinesia and improves movement in the hemiparkinsonian rat.�Neuropharmacology.�2008;55:1321�8.�[PMC free article][PubMed]
60.�Ohno Y. Therapeutic role of 5-HT1A�receptors in the treatment of schizophrenia and Parkinson’s disease.�CNS Neurosci Ther.�2011;17:58�65.�[PubMed]
61.�Magen I, Avraham Y, Ackerman Z, Vorobiev L, Mechoulam R, Berry EM. Cannabidiol ameliorates cognitive and motor impairments in bile-duct ligated mice via 5-HT1A�receptor activation.�Br J Pharmacol.�2010;159:950�7.�[PMC free article][PubMed]
62.�Campos AC, Guimar�es FS. Involvement of 5HT1A receptors in the anxiolytic-like effects of cannabidiol injected into the dorsolateral periaqueductal gray of rats.�Psychopharmacology.�2008;199:223�30.�[PubMed]
63.�Resstel LBM, Tavares RF, Lisboa SFS, Joca SRL, Corr�a FMA, Guimar�es FS. 5-HT1A�receptors are involved in the cannabidiol-induced attenuation of behavioural and cardiovascular responses to acute restraint stress in rats.�Br J Pharmacol.�2009;156:181�8.�[PMC free article][PubMed]
64.�Soares VdeP, Campos AC, de Bortoli VC, Zangrossi H, Guimar�es FS, Zuardi AW. Intra-dorsal periaqueductal gray administration of cannabidiol blocks panic-like response by activating 5-HT1A receptors.�Behav Brain Res.�2010;213:225�9.�[PubMed]
65.�Maione S, Piscitelli F, Gatta L, Vita D, De Petrocellis L, Palazzo E, de Novellis V, Di Marzo V. Non-psychoactive cannabinoids modulate the descending pathway of antinociception in anaesthetized rats through several mechanisms of action.�Br J Pharmacol.�2011;162:584�96.�[PMC free article][PubMed]
66.�Rock EM, Goodwin JM, Limebeer CL, Breuer A, Pertwee RG, Mechoulam R, Parker LA. Interaction between non-psychotropic cannabinoids in marihuana: effect of cannabigerol (CBG) on the anti-nausea or anti-emetic effects of cannabidiol (CBD) in rats and shrews.�Psychopharmacology.�2011;215:505�12.[PubMed]
67.�Kwiatkowska M, Parker LA, Burton P, Mechoulam R. A comparative analysis of the potential of cannabinoids and ondansetron to suppress cisplatin-induced emesis in the�Suncus murinus�(house musk shrew)�Psychopharmacology.�2004;174:254�9.�[PubMed]
68.�Parker LA, Kwiatkowska M, Burton P, Mechoulam R. Effect of cannabinoids on lithium-induced vomiting in the�Suncus murinus�(house musk shrew)�Psychopharmacology.�2004;171:156�61.�[PubMed]
69.�Fern�ndez-Ruiz J, Garc�a C, Sagredo O, G�mez-Ruiz M, de Lago E. The endocannabinoid system as a target for the treatment of neuronal damage.�Expert Opin Ther Targets.�2010;14:387�404.�[PubMed]
70.�Fern�ndez-Ruiz J, Romero J, Velasco G, Tol�n RM, Ramos JA, Guzm�n M. Cannabinoid CB2 receptor: a new target for controlling neural cell survival?�Trends Pharmacol Sci.�2007;28:39�45.[PubMed]
71.�Hampson AJ, Grimaldi M, Lolic M, Wink D, Rosenthal R, Axelrod J. Neuroprotective antioxidants from marijuana.�Ann N Y Acad Sci.�2000;899:274�82.�[PubMed]
72.�El-Remessy AB, Khalil IE, Matragoon S, Abou-Mohamed G, Tsai NJ, Roon P, Caldwell RB, Caldwell RW, Green K, Liou GI. Neuroprotective effect of (-)?9-tetrahydrocannabinol and cannabidiol in N-methyl-D-aspartate-induced retinal neurotoxicity: involvement of peroxynitrite.�Am J Pathol.�2003;163:1997�2008.�[PMC free article][PubMed]
73.�Hampson AJ, Grimaldi M, Axelrod J, Wink D. Cannabidiol and (-)?9-tetrahydrocannabinol are neuroprotective antioxidants.�Proc Natl Acad Sci USA.�1998;95:8268�73.�[PMC free article][PubMed]
74.�Ruiz-Valdepe�as L, Mart�nez-Orgado JA, Benito C, Mill�n A, Tol�n RM, Romero J. Cannabidiol reduces lipopolysaccharide-induced vascular changes and inflammation in the mouse brain: an intravital microscopy study.�J Neuroinflammation.�2011;8:5.�[PMC free article][PubMed]
75.�Kwiatkoski M, Guimar�es FS, Del-Bel E. Cannabidiol-treated rats exhibited higher motor score after cryogenic spinal cord injury.�Neurotox Res.�2012;21:271�80.�[PubMed]
76.�Iuvone T, Esposito G, De Filippis D, Scuderi C, Steardo L. Cannabidiol: a promising drug for neurodegenerative disorders?�CNS Neurosci Ther.�2009;15:65�75.�[PubMed]
77.�Marsicano G, Moosmann B, Hermann H, Lutz B, Behl C. Neuroprotective properties of cannabinoids against oxidative stress: role of the cannabinoid receptor CB1.�J Neurochem.�2002;80:448�56.�[PubMed]
78.�Mart�n-Moreno AM, Reigada D, Ram�rez BG, Mechoulam R, Innamorato N, Cuadrado A, de Ceballos ML. Cannabidiol and other cannabinoids reduce microglial activation�in vitro�and�in vivo: relevance to Alzheimer’s disease.�Mol Pharmacol.�2011;79:964�73.�[PMC free article][PubMed]
79.�Juknat A, Pietr M, Kozela E, Rimmerman N, Levy R, Coppola G, Geschwind D, Vogel Z. Differential transcriptional profiles mediated by exposure to the cannabinoids cannabidiol and ?(9)-tetrahydrocannabinol in BV-2 microglial cells.�Br J Pharmacol.�2012�in press.�[PMC free article][PubMed]
80.�Walter L, Franklin A, Witting A, Wade C, Xie Y, Kunos G, Mackie K, Stella N. Nonpsychotropic cannabinoid receptors regulate microglial cell migration.�J Neurosci.�2003;23:1398�405.�[PubMed]
81.�Esposito G, Scuderi C, Savani C, Steardo L, Jr, De Filippis D, Cottone P, Iuvone T, Cuomo V, Steardo L. Cannabidiol�in vivo�blunts beta-amyloid induced neuroinflammation by suppressing IL-1beta and iNOS expression.�Br J Pharmacol.�2007;151:1272�9.�[PMC free article][PubMed]
82.�Esposito G, De Filippis D, Carnuccio R, Izzo AA, Iuvone T. The marijuana component cannabidiol inhibits beta-amyloid-induced tau protein hyperphosphorylation through Wnt/beta-catenin pathway rescue in PC12 cells.�J Mol Med (Berl)�2006;84:253�8.�[PubMed]
83.�Martinez-Orgado J, Fernandez-Lopez D, Lizasoain I, Romero J. The seek of neuroprotection: introducing cannabinoids. Recent Patents.�CNS Drug Discov.�2007;2:131�9.�[PubMed]
84.�Alvarez FJ, Lafuente H, Rey-Santano MC, Mielgo VE, Gastiasoro E, Rueda M, Pertwee RG, Castillo AI, Romero J, Mart�nez-Orgado J. Neuroprotective effects of the non-psychoactive cannabinoid cannabidiol in hypoxic-ischemic newborn piglets.�Pediatr Res.�2008;64:653�8.�[PubMed]
85.�Lafuente H, Alvarez FJ, Pazos MR, Alvarez A, Rey-Santano MC, Mielgo V, Murgia-Esteve X, Hilario E, Martinez-Orgado J. Cannabidiol reduces brain damage and improves functional recovery after acute hypoxia-ischemia in newborn pigs.�Pediatr Res.�2011;70:272�7.�[PubMed]
86.�Zuccato C, Valenza M, Cattaneo E. Molecular mechanisms and potential therapeutical targets in Huntington’s disease.�Physiol Rev.�2010;90:905�81.�[PubMed]
87.�Roze E, Bonnet C, Betuing S, Caboche J. Huntington’s disease.�Adv Exp Med Biol.�2010;685:45�63.[PubMed]
88.�Johnson CD, Davidson BL. Huntington’s disease: progress toward effective disease-modifying treatments and a cure.�Hum Mol Genet.�2010;19:R98�R102.�[PMC free article][PubMed]
89.�Sagredo O, Gonz�lez S, Aroyo I, Pazos MR, Benito C, Lastres-Becker I, Romero JP, Tol�n RM, Mechoulam R, Brouillet E, Romero J, Fern�ndez-Ruiz J. Cannabinoid CB2 receptor agonists protect the striatum against malonate toxicity: relevance for Huntington’s disease.�Glia.�2009;57:1154�67.[PMC free article][PubMed]
90.�Lastres-Becker I, Bizat N, Boyer F, Hantraye P, Brouillet E, Fern�ndez-Ruiz J. Effects of cannabinoids in the rat model of Huntington’s disease generated by an intrastriatal injection of malonate.�Neuroreport.�2003;14:813�6.�[PubMed]
91.�Palazuelos J, Aguado T, Pazos MR, Julien B, Carrasco C, Resel E, Sagredo O, Benito C, Romero J, Azcoitia I, Fern�ndez-Ruiz J, Guzm�n M, Galve-Roperh I. Microglial CB2 cannabinoid receptors are neuroprotective in Huntington’s disease excitotoxicity.�Brain.�2009;132:3152�64.�[PubMed]
92.�Bl�zquez C, Chiarlone A, Sagredo O, Aguado T, Pazos MR, Resel E, Palazuelos J, Julien B, Salazar M, B�rner C, Benito C, Carrasco C, Diez-Zaera M, Paoletti P, D�az-Hern�ndez M, Ruiz C, Sendtner M, Lucas JJ, de Y�benes JG, Marsicano G, Monory K, Lutz B, Romero J, Alberch J, Gin�s S, Kraus J, Fern�ndez-Ruiz J, Galve-Roperh I, Guzm�n M. Loss of striatal type 1 cannabinoid receptors is a key pathogenic factor in Huntington’s disease.�Brain.�2011;134:119�36.�[PubMed]
93.�Sandyk R, Snider SR, Consroe P, Elias SM. Cannabidiol in dystonic movement disorders.�Psychiatry Res.�1986;18:291.�[PubMed]
94.�Consroe P, Laguna J, Allender J, Snider S, Stern L, Sandyk R, Kennedy K, Schram K. Controlled clinical trial of cannabidiol in Huntington’s disease.�Pharmacol Biochem Behav.�1991;40:701�8.�[PubMed]
95.�Thomas B, Beal MF. Parkinson’s disease.�Hum Mol Genet.�2007;16:R183�R194.�[PubMed]
96.�Nagatsu T, Sawada M. Biochemistry of postmortem brains in Parkinson’s disease: historical overview and future prospects.�J Neural Transm Suppl.�2007;72:113�20.�[PubMed]
97.�Garc�a-Arencibia M, Gonz�lez S, de Lago E, Ramos JA, Mechoulam R, Fern�ndez-Ruiz J. Evaluation of the neuroprotective effect of cannabinoids in a rat model of Parkinson’s disease: importance of antioxidant and cannabinoid receptor-independent properties.�Brain Res.�2007;1134:162�70.�[PubMed]
98.�Fern�ndez-Ruiz J. The endocannabinoid system as a target for the treatment of motor dysfunction.�Br J Pharmacol.�2009;156:1029�40.�[PMC free article][PubMed]
99.�Fern�ndez-Ruiz J, Moreno-Martet M, Rodr�guez-Cueto C, Palomo-Garo C, G�mez-Ca�as M, Valdeolivas S, Guaza C, Romero J, Guzm�n M, Mechoulam R, Ramos JA. Prospects for cannabinoid therapies in basal ganglia disorders.�Br J Pharmacol.�2011;163:1365�78.�[PMC free article][PubMed]
100.�Consroe P, Sandyk R, Snider SR. Open label evaluation of cannabidiol in dystonic movement disorders.�Int J Neurosci.�1986;30:277�82.�[PubMed]
101.�Carroll CB, Bain PG, Teare L, Liu X, Joint C, Wroath C, Parkin SG, Fox P, Wright D, Hobart J, Zajicek JP. Cannabis for dyskinesia in Parkinson disease: a randomized double-blind crossover study.�Neurology.�2004;63:1245�50.�[PubMed]
102.�Weiss L, Zeira M, Reich S, Slavin S, Raz I, Mechoulam R, Gallily R. Cannabidiol arrests onset of autoimmune diabetes in NOD mice.�Neuropharmacology.�2008;54:244�9.�[PMC free article][PubMed]
103.�Malfait AM, Gallily R, Sumariwalla PF, Malik AS, Andreakos E, Mechoulam R, Feldmann M. The nonpsychoactive cannabis constituent cannabidiol is an oral anti-arthritic therapeutic in murine collagen-induced arthritis.�Proc Natl Acad Sci USA.�2000;97:9561�6.�[PMC free article][PubMed]
104.�Durst R, Danenberg H, Gallily R, Mechoulam R, Meir K, Grad E, Beeri R, Pugatsch T, Tarsish E, Lotan C. Cannabidiol, a nonpsychoactive cannabis constituent, protects against myocardial ischemic reperfusion injury.�Am J Physiol Heart Circ Physiol.�2007;293:H3602�H3607.�[PubMed]
105.�Mukhopadhyay P, Rajesh M, Horv�th B, B�tkai S, Park O, Tanchian G, Gao RY, Patel V, Wink DA, Liaudet L, Hask� G, Mechoulam R, Pacher P. Cannabidiol protects against hepatic ischemia/reperfusion injury by attenuating inflammatory signaling and response, oxidative/nitrative stress, and cell death.�Free Radic Biol Med.�2011;50:1368�81.�[PMC free article][PubMed]
106.�Avraham Y, Grigoriadis N, Poutahidis T, Vorobiev L, Magen I, Ilan Y, Mechoulam R, Berry E. Cannabidiol improves brain and liver function in a fulminant hepatic failure-induced model of hepatic encephalopathy in mice.�Br J Pharmacol.�2011;162:1650�8.�[PMC free article][PubMed]
107.�Bergamaschi MM, Queiroz RH, Chagas MH, de Oliveira DC, De Martinis BS, Kapczinski F, Quevedo J, Roesler R, Schr�der N, Nardi AE, Mart�n-Santos R, Hallak JE, Zuardi AW, Crippa JA. Cannabidiol reduces the anxiety induced by simulated public speaking in treatment-na�ve social phobia patients.�Neuropsychopharmacology.�2011;36:1219�26.�[PMC free article][PubMed]
108.�Morgan CJ, Schafer G, Freeman TP, Curran HV. Impact of cannabidiol on the acute memory and psychotomimetic effects of smoked cannabis: naturalistic study.�Br J Psychiatry.�2010;197:285�90.[PubMed]
109.�Sumariwalla PF, Gallily R, Tchilibon S, Fride E, Mechoulam R, Feldmann M. A novel synthetic, nonpsychoactive cannabinoid acid (HU-320) with antiinflammatory properties in murine collagen-induced arthritis.�Arthritis Rheum.�2004;50:985�98.�[PubMed]
Close Accordion
Cannabidiol for Treatment and Prevention of Movement Disorders

Cannabidiol for Treatment and Prevention of Movement Disorders

An astonishing one million Americans have Parkinson’s disease, making it the second most common neurodegenerative disorder after Alzheimer’s. This impacts more people than those influenced with other movement disorders like ALS, muscular dystrophy or multiple sclerosis, combined. Characterized by involuntary tremors and debilitating chronic pain, movement disorders are incredibly painful. They impact an individual’s well-being, which makes it hard to interact socially, and the expensive drugs and/or medications can often plummet the patient’s circumstance.


The problem is, there’s no known cure for movement disorders. Worse, no one yet knows how to prevent them. Not only do people suffer from them, they also have to rely on treatment approaches with harsh side effects for the remainder of their lives. However, there’s a new treatment in the forefront of movement disorder research, CBD oil. The results are nothing short of miraculous, reducing tremors and lessening pain. CBD is a abbreviation for cannabidiol oil. Created with an extraction process utilizing either the marijuana or hemp plant. Extracting the CBD provides the consumer the amazing medical benefits without the effects of THC. Because there are no psychedelic properties in CBD, studies have demonstrated it is completely safe for consumption. The purpose of the article below is to demonstrate as well as discuss cannabidiol as a promising strategy to treat and prevent movement disorders.


Cannabidiol as a Promising Strategy to Treat and Prevent Movement Disorders?




Movement disorders such as Parkinson’s disease and dyskinesia are highly debilitating conditions linked to oxidative stress and neurodegeneration. When available, the pharmacological therapies for these disorders are still mainly symptomatic, do not benefit all patients and induce severe side effects. Cannabidiol is a non-psychotomimetic compound from Cannabis sativa that presents antipsychotic, anxiolytic, anti-inflammatory, and neuroprotective effects. Although the studies that investigate the effects of this compound on movement disorders are surprisingly few, cannabidiol emerges as a promising compound to treat and/or prevent them. Here, we review these clinical and pre-clinical studies and draw attention to the potential of cannabidiol in this field.


Keywords: cannabidiol, movement disorders, Parkinson’s disease, Huntington’s disease, dystonic disorders, cannabinoids


Cannabidiol (CBD)


Cannabidiol (CBD) is one of the over 100 phytocannabinoids identified in Cannabis sativa (ElSohly and Gul, 2014), and constitutes up to 40% of the plant’s extract, being the second most abundant component (Grlic, 1976). CBD was first isolated from marijuana in 1940 by Adams et al. (1940) and its structure was elucidated in 1963 by Mechoulam and Shvo (1963). Ten years later, Perez-Reyes et al. (1973) reported that, unlike the main constituent of cannabis ?9-tetrahydrocannabinol (?9-THC), CBD does not induce psychological effects, leading to the suggestion that CBD was an inactive drug. Nonetheless, subsequent studies demonstrated that CBD modulates the effects of ?9-THC and displays multiple actions in the central nervous system, including antiepileptic, anxiolytic and antipsychotic effects (Zuardi, 2008).


Interestingly, CBD does not induce the cannabinoid tetrad, namely hypomotility, catalepsy, hypothermia, and antinociception. In fact, CBD mitigates the cataleptic effect of ?9-THC (El-Alfy et al., 2010). Clinical and pre-clinical studies have pointed to beneficial effects of CBD on the treatment of movement disorders. The first studies investigated CBD’s actions on dystonia, with encouraging results. More recently, the studies have been focusing on Parkinson’s (PD) and Huntington’s (HD) diseases. The mechanisms whereby CBD exerts its effects are still not completely understood, mainly because several targets have been identified. Of note, CBD displays anti-inflammatory and antioxidant actions (Campos et al., 2016), and both inflammation and oxidative stress are linked to the pathogenesis of various movement disorders, such as PD (Farooqui and Farooqui, 2011; Niranjan, 2014), HD (S�nchez-L�pez et al., 2012), and tardive dyskinesia (Zhang et al., 2007).


It is noteworthy that, when available, the pharmacological treatments for these movement disorders are mainly symptomatic and induce significant side effects (Connolly and Lang, 2014; Lerner et al., 2015; Dickey and La Spada, 2017). Nonetheless, despite its great clinical relevance, the studies evaluating CBD’s role on the pharmacotherapy of movement disorders are surprisingly few. Here, we will review the clinical and pre-clinical evidence and draw attention to the potential of CBD in this field.


CBD’s Mechanisms of Action


CBD has several molecular targets, and new ones are currently being uncovered. CBD antagonizes the action of CB1 and CB2 receptors agonists, and is suggested to act as an inverse agonist of these receptors (Pertwee, 2008). Moreover, recent evidence point to CBD as a non-competitive negative allosteric modulator of CB1 and CB2 (Laprairie et al., 2015; Mart�nez-Pinilla et al., 2017). CBD is also an agonist of the vanilloid receptor TRPV1 (Bisogno et al., 2001), and the previous administration of a TRPV1 antagonist blocks some of CBD effects (Long et al., 2006; Hassan et al., 2014). In parallel, CBD inhibits the enzymatic hydrolysis and the uptake of the main endocannabinoid anandamide (Bisogno et al., 2001), an agonist of CB1, CB2 and TRPV1 receptors (Pertwee and Ross, 2002; Ross, 2003). The increase in anandamide levels induced by CBD seems to mediate some of its effects (Leweke et al., 2012). Moreover, in some behavioral paradigms the administration of an inhibitor of anandamide metabolism promotes effects similar to CBD (Pedrazzi et al., 2015; Stern et al., 2017).


CBD has also been shown to facilitate the neurotransmission mediated by the serotonin receptor 5-HT1A. It was initially suggested that CBD would act as an agonist of 5-HT1A (Russo et al., 2005), but the latest reports propose that this interaction might be allosteric or through an indirect mechanism (Rock et al., 2012). Although this interaction is not fully elucidated, multiple CBD’s effects were reported to depend on 5-HT1A activation (Espejo-Porras et al., 2013; Gomes et al., 2013; Pazos et al., 2013; Hind et al., 2016; Sartim et al., 2016; Lee et al., 2017).


The peroxisome proliferator-activated receptor ? (PPAR?) is a nuclear receptor involved in glucose metabolism and lipid storage, and PPAR? ligands have been reported to display anti-inflammatory actions (O’Sullivan et al., 2009). Data show that CBD can activate this receptor (O’Sullivan et al., 2009), and some of CBD effects are blocked by PPAR? antagonists (Esposito et al., 2011; Dos-Santos-Pereira et al., 2016; Hind et al., 2016). CBD also up-regulates PPAR? in a mice model of multiple sclerosis, an effect suggested to mediate the CBD’s anti-inflammatory actions (Giacoppo et al., 2017b). In a rat model of Alzheimer’s disease, CBD, through interaction with PPAR?, stimulates hippocampal neurogenesis, inhibits reactive gliosis, induces a decline in pro-inflammatory molecules, and consequently inhibits neurodegeneration (Esposito et al., 2011). Moreover, in an in vitro model of the blood-brain barrier, CBD reduces the ischemia-induced increased permeability and VCAM-1 levels�both effects are attenuated by PPAR? antagonism (Hind et al., 2016).


CBD also antagonizes the G-protein-coupled receptor GPR55 (Ryberg et al., 2007). GPR55 has been suggested as a novel cannabinoid receptor (Ryberg et al., 2007), but this classification is controversial (Ross, 2009). Currently, the phospholipid lysophosphatidylinositol (LPI) is considered the GPR55 endogenous ligand (Morales and Reggio, 2017). Although only few studies link the CBD effect to its action on GPR55 (Kaplan et al., 2017), it is noteworthy that GPR55 has been associated with PD in an animal model (Celorrio et al., 2017) and with axon growth in vitro (Cherif et al., 2015).


More recently, CBD was reported to act as inverse agonist of the G-protein-coupled orphan receptors GPR3, GPR6, and GPR12 (Brown et al., 2017; Laun and Song, 2017). GPR6 has been implicated in both HD and PD. Concerning animal models of PD, GPR6 deficiency was related to both diminished dyskinesia after 6-OHDA lesion (Oeckl et al., 2014), and increased sensitivity to MPTP neurotoxicity (Oeckl and Ferger, 2016). Moreover, Hodges et al. (2006) described decreased expression of GPR6 in brain of HD patients, compared to control. GPR3 is suggested as a biomarker for the prognosis of multiple sclerosis (Hecker et al., 2011). In addition, GPR3, GPR6, and GPR12 have been implicated in cell survival and neurite outgrow (Morales et al., 2018).


CBD has also been reported to act on mitochondria. Chronic and acute CBD administration increases the activity of mitochondrial complexes (I, II, II-III, and IV), and of creatine kinase in the brain of rats (Valvassori et al., 2013). In a rodent model of iron overload�that induces pathological changes that resemble neurodegenerative disorders�CBD reverses the iron-induced epigenetic modification of mitochondrial DNA and the reduction of succinate dehydrogenase’s activity (da Silva et al., 2018). Of note, multiple studies associate mitochondrial dysfunctions with the pathophysiology of PD (Ammal Kaidery and Thomas, 2018).


In parallel, several studies show anti-inflammatory and antioxidant actions of CBD (Campos et al., 2016). CBD treatment decreases the levels of the pro-inflammatory cytokines IL-1?, TNF-?, IFN-?, IFN-?, IL-17, and IL-6 (Watzl et al., 1991; Weiss et al., 2006; Esposito et al., 2007, 2011; Kozela et al., 2010; Chen et al., 2016; Rajan et al., 2016; Giacoppo et al., 2017b), and increases the levels of the anti-inflammatory cytokines IL-4 and IL-10 (Weiss et al., 2006; Rajan et al., 2016). In addition, it inhibits the expression of iNOS (Esposito et al., 2007; Pan et al., 2009; Chen et al., 2016; Rajan et al., 2016) and COX-2 (Chen et al., 2016) induced by distinct mechanisms. CBD also displays antioxidant properties, being able to donate electrons under a variable voltage potential and to prevent the hydroperoxide-induced oxidative damage (Hampson et al., 1998). In rodent models of PD and HD, CBD up-regulates the mRNA levels of the antioxidant enzyme superoxide dismutase (Garcia-Arencibia et al., 2007; Sagredo et al., 2007). In accordance, CBD decreases oxidative parameters in in vitro models of neurotoxicity (Hampson et al., 1998; Iuvone et al., 2004; Mecha et al., 2012). Of note, the anti-inflammatory and antioxidant effects of CBD on lipopolysaccharide-stimulated murine macrophages are suppressed by a TRPV1 antagonist (Rajan et al., 2016). It has also been shown that CBD can affect the expression of several genes involved in zinc homeostasis, which is suggested to be linked to its anti-inflammatory and antioxidant actions (Juknat et al., 2012).


CBD’s mechanisms of action are summarized in Figure ?1.


Figure 1 CBD's Mechanism of Action


Parkinson’s Disease (PD)


PD is among the most common neurodegenerative disorders, with a prevalence that increases with age, affecting 1% of the population over 60 years old (Tysnes and Storstein, 2017). The disease is characterized by motor impairment (hypokinesia, tremors, muscle rigidity) and non-motor symptoms (e.g., sleep disturbances, cognitive deficits, anxiety, depression, psychotic symptoms) (Klockgether, 2004).


The pathophysiology of PD is mainly associated with the loss of midbrain dopaminergic neurons in the substantia nigra pars compacta (SNpc), with consequent reduced levels of dopamine in the striatum (Dauer and Przedborski, 2003). When the motor symptoms appear, about 60% of dopaminergic neurons is already lost (Dauer and Przedborski, 2003), hindering a possible early diagnosis. The most effective and used treatment for PD is L-DOPA, a precursor of dopamine that promotes an increase in the level of dopamine in the striatum, improving the motor symptoms (Connolly and Lang, 2014). However, after a long-term treatment the effect of L-DOPA can be unstable, presenting fluctuations in symptoms improvement (on / off effect) (Jankovic, 2005; Connolly and Lang, 2014). In addition, involuntary movements (namely L-DOPA-induced dyskinesia) appear in approximately 50% of the patients (Jankovic, 2005).


The first study with CBD on PD patients aimed to verify CBD’s effects on the psychotic symptoms. Treatment with CBD for 4 weeks decreased the psychotic symptoms, evaluated by the Brief Psychiatric Rating Scale and the Parkinson Psychosis Questionnaire, without worsening the motor function or inducing adverse effects (Zuardi et al., 2009). Later, in a case series with four PD patients, it was verified that CBD is able to reduce the frequency of the events related to REM sleep behavior disorder (Chagas et al., 2014a). In addition, although not ameliorating PD patients’ motor function or their general symptoms score, treatment with CBD for 6 weeks improves PD’s patients quality of life (Chagas et al., 2014b). The authors suggest that this effect might be related to CBD’s anxiolytic, antidepressant and antipsychotic properties (Chagas et al., 2014b).


Although the studies with patients with PD report beneficial effects of CBD only on the non-motor symptoms, CBD has been shown to prevent and/or reverse increased catalepsy behavior in rodents. When administered before the cataleptic agents haloperidol (antipsychotic drug), L-nitro-N-arginine (non-selective inhibitor of nitric oxide synthase) or WIN 55-212,2 (agonist of cannabinoid receptors), CBD hinders the cataleptic behavior in a dose-dependent manner (Gomes et al., 2013). A possible role of the activation of serotonin receptors 5-HT1A in this action has been proposed, because this effect of CBD is blocked by the pre-treatment with the 5-HT1A antagonist WAY100635 (Gomes et al., 2013). In accordance, Sonego et al. (2016) showed that CBD diminishes the haloperidol-induced catalepsy and c-Fos protein expression in the dorsal striatum, also by a mechanism dependent on 5-HT1A activation. Moreover, CBD prevents the increased catalepsy behavior induced by repeated administration of reserpine (Peres et al., 2016).


In addition, pre-clinical studies in animal models of PD have shown neuroprotective effects of CBD. The unilateral injection of the toxin 6-hydroxydopamine (6-OHDA) into the medial forebrain bundle promotes neurodegeneration of nigrostriatal dopaminergic neurons, being used to model PD (Bov� et al., 2005). When inside the cell, the neurotoxin 6-OHDA oxidizes in hydrogen peroxide and paraquinone, causing death mainly of catecolaminergic neurons (Breese and Traylor, 1971; Bov� et al., 2005). This neurodegeneration leads to depletion of dopamine and decrease in tyrosine hydroxylase activity in caudate-putamen (Bov� et al., 2005; Lastres-Becker et al., 2005). Treatment with CBD during the 2 weeks following 6-OHDA administration prevents these effects (Lastres-Becker et al., 2005). In another study, it was observed that CBD’s protective effects after 6-OHDA injury are accompanied by elevation of mRNA levels of the antioxidant enzyme Cu,Zn-superoxide dismutase in substantia nigra (Garcia-Arencibia et al., 2007). The protective effects of CBD in this model do not seem to depend on the activation of CB1 receptors (Garcia-Arencibia et al., 2007). In addition to preventing the loss of dopaminergic neurons�assessed by tyrosine hydroxylase immunostaining �, the administration of CBD after 6-OHDA injury attenuates the activation of microglia in substantia nigra (Garcia et al., 2011).


In an in vitro study, CBD increased the viability of cells treated with the neurotoxin N-methyl-4-phenylpyrimidine (MPP+), and prevented the MPP+-induced increase in caspase-3 activation and decrease in levels of nerve growth factor (NGF) (Santos et al., 2015). CBD treatment was also able to induce cell differentiation even in the presence of MPP+, an effect that depends on trkA receptors (Santos et al., 2015). MPP+ is a product of oxidation of MPTP that inhibits complex I of the respiratory chain in dopaminergic neurons, causing a rapid neuronal death (Schapira et al., 1990; Meredith et al., 2008).


Data from clinical and pre-clinical studies are summarized in Tables ?1, ?2, respectively.


Table 1 Effects of CBD on Movement Disorders


Table 2 Pre-Clinical Studies of CBD


Huntington’s Disease (HD)


HD is a fatal progressive neurodegenerative disease characterized by motor dysfunctions, cognitive loss and psychiatric manifestations (McColgan and Tabrizi, 2018). HD is caused by the inclusion of trinucleotides (CAG) in the exons of the huntingtin gene, on chromosome 4 (MacDonald et al., 1993; McColgan and Tabrizi, 2018), and its prevalence is 1�10,000 (McColgan and Tabrizi, 2018). Neurodegeneration in HD affects mainly the striatal region (caudate and putamen) and this neuronal loss is responsible for the motor symptoms (McColgan and Tabrizi, 2018). Cortical degeneration is seen in later stages, and huntingtin inclusions are seen in few cells, but in all patients with HD (Crook and Housman, 2011). The diagnosis of HD is based on motor signs accompanied by genetic evidence, which is positive genetic test for the expansion of the huntingtin gene or family history (Mason and Barker, 2016; McColgan and Tabrizi, 2018).


The pharmacotherapy of HD is still directed toward the symptomatic relief of the disease, i.e., the motor disorders believed to be due to dopaminergic hyperactivity. This treatment is often conducted with typical and atypical antipsychotics, but in some cases the use of dopaminergic agonists is needed (Mason and Barker, 2016; McColgan and Tabrizi, 2018). Indeed, the role of dopamine in HD is not fully elucidated yet. Regarding the cognitive deficits, none of the investigated drugs was able to promote improvements (Mason and Barker, 2016; McColgan and Tabrizi, 2018).


Recently, there has been a growing number of studies aiming to verify the therapeutic potential of cannabinoid compounds in the treatment of HD, mainly because some cannabinoids present hypokinetic characteristics (Lastres-Becker et al., 2002). In a controlled clinical trial, patients with HD were treated with CBD for 6 weeks. There was no significant reduction in the chorea indicators, but no toxicity was observed (Consroe et al., 1991).


The protective effects of CBD and other cannabinoids were also evaluated in a cell culture model of HD, with cells expressing mutated huntingtin. In this model, the induction of huntingtin promotes rapid and extensive cell death (Aiken et al., 2004). CBD and the other three cannabinoid compounds tested�?8-THC, ?9-THC, and cannabinol�show 51�84% protection against the huntingtin-induced cell death (Aiken et al., 2004). These effects seem to be independent of CB1 activation, since absence of CB1 receptors has been reported in PC12, the cell line used (Molderings et al., 2002). The authors suggest that the cannabinoids exert this protective effect by antioxidant mechanisms (Aiken et al., 2004).


Regarding studies with animal models, treatment with 3-nitropropionic acid (3-NP), an inhibitor of complex II of the respiratory chain, induces striatal damage�mainly by calpain activation and oxidative injury �, being suggested as relevant to study HD (Brouillet et al., 2005). Sub-chronic administration of 3-NP in rats reduces GABA contents and the levels of mRNA for several markers of striatal GABAergic neurons projections (Sagredo et al., 2007). In addition, 3-NP diminishes the levels of mRNA for the antioxidant enzymes superoxide dismutase-1 (SOD-1) and -2 (SOD-2) (Sagredo et al., 2007). The administration of CBD reverses or attenuates these 3-NP-induced alterations (Sagredo et al., 2007). CBD’s neuroprotective effects are not blocked by the administration of antagonists of the CB1, TRPV1 or A2A receptors (Sagredo et al., 2007).


More recently, clinical and pre-clinical HD studies started to investigate the effects of Sativex� (CBD in combination with ?9-THC in an approximately 1:1 ratio). In accordance with what previously seen with CBD alone, Sativex administration attenuates all the 3-NP induced neurochemical, histological and molecular alterations (Sagredo et al., 2011). These effects do not seem to be linked to activation of CB1 or CB2 receptors (Sagredo et al., 2011). Authors also observed a protective effect of Sativex in reducing the increased expression of iNOS gene induced by malonate (Sagredo et al., 2011). Malonate administration leads to striatal damage by apoptosis and inflammatory events related to glial activation, being used as an acute model for HD (Sagredo et al., 2011; Valdeolivas et al., 2012).


In a subsequent study, it was observed that the administration of a Sativex-like combination attenuates all the malonate-induced alterations, namely: increased edema, decreased number of surviving cells, enhanced number of degenerating cells, strong glial activation, and increased expression of inflammatory markers (iNOS and IGF-1) (Valdeolivas et al., 2012). Although the beneficial effects of Sativex on cell survival are blocked by both CB1 or CB2 antagonists, CB2 receptors seem to have a greater role in the protective effect observed (Valdeolivas et al., 2012).


The beneficial effects of Sativex have also been described in the R6/2 mice, a transgenic model of HD. Treatment with a Sativex-like combination, although not reversing animal’s deterioration in rotarod performance, attenuates the elevated clasping behavior, that reflects dystonia (Valdeolivas et al., 2017). Moreover, treatment mitigates R6/2 mice reduced metabolic activity in basal ganglia and some of the alterations in markers of brain integrity (Valdeolivas et al., 2017).


In spite of the pre-clinical encouraging results with Sativex, a pilot trial with 25 HD patients treated with Sativex for 12 weeks failed to detect improvement in symptoms or molecular changes on biomarkers (L�pez-Send�n Moreno et al., 2016). Nonetheless, Sativex did not induce severe adverse effects or clinical worsening (L�pez-Send�n Moreno et al., 2016). The authors suggest that future studies, with higher doses and/or longer treatment periods, are in need. More recently, one study described the results of administering cannabinoid drugs to 7 patients (2 of them were treated with Sativex; the others received dronabinol or nabilone, agonists of the cannabinoid receptors): patients displayed improvement on UHDRS motor score and dystonia subscore (Saft et al., 2018).


Tables ?1, ?2 summarize data from clinical and pre-clinical studies, respectively.



Dr. Alex Jimenez’s Insight

Involuntary muscle spasms, tremors and jerking are all uncontrollable movements known as dyskinesia, which are the most common symptoms of a variety of movement disorders. Movement disorders often have no known cause and these are considered to have no cure. As a result, individuals with these debilitating conditions have to turn to drugs and/or medications to keep their symptoms under control for the rest of their lives. However, several research studies have been conducted to determine the effectiveness of CBD, or cannabidiol, for the treatment and prevention of movement disorders. In one study, CBD was found to decrease pain and reduce inflammation in patients with Parkinson’s disease without the psychoactive effects of THC. Moreover, healthcare professionals and researchers alike are trying to demonstrate further health benefits of CBD on movement disorders.


Other Movement Disorders


Dystonias are the result of abnormal muscles tone, causing involuntary muscle contraction, and resulting in repetitive movements or abnormal posture (Breakefield et al., 2008). Dystonias can be primary, for instance paroxysmal dyskinesia, or secondary to other conditions or drug use, such as tardive dyskinesia after prolonged treatment with antipsychotic drugs (Breakefield et al., 2008).


Consroe et al. (1986) were the first to evaluate the effects of CBD alone in movement disorders. In this open label study, the five patients with dystonic movement disorders displayed 20�50% improvement of dystonic symptoms when treated with CBD for 6 weeks. Of note, two patients with simultaneous PD’s signs showed worsening of their hypokinesia and/or resting tremor when receiving the higher doses of CBD. However, it should be noted that in two more recent studies with PD patients no worsening of motor function was seen (Zuardi et al., 2009; Chagas et al., 2014b). In accordance, Sandyk et al. (1986) reported improvement of dystonic symptoms in two patients�one with idiopathic spasmodic torticollis and one with generalized torsion dystonia�after acute treatment with CBD.


The effects of CBD on dystonic movements were also evaluated in pre-clinical studies. In a hamster model of idiopathic paroxysmal dystonia, the higher dose of CBD showed a trend to delay the progression of dystonia (Richter and Loscher, 2002). In addition, CBD prevents the increase in vacuous chewing movements, i.e., dyskinesia, promoted by repeated administration of reserpine (Peres et al., 2016). CBD’s beneficial effects are also seen in L-DOPA-induced dyskinesia in rodents, but only when CBD is administered with capsazepine, an antagonist of TRPV1 receptors (Dos-Santos-Pereira et al., 2016). These effects seem to depend on CB1 and PPAR? receptors (Dos-Santos-Pereira et al., 2016). In addition, treatment with capsazepine and CBD decreases the expression of inflammatory markers, reinforcing the suggestion that the anti-inflammatory actions of CBD may be beneficial to the treatment of dyskinesia (Dos-Santos-Pereira et al., 2016).


Moreover, Sativex has been used in the treatment of spasticity in multiple sclerosis. Spasticity is a symptom that affects up to 80% of patients with multiple sclerosis and is associated with poorer quality of life (Flachenecker et al., 2014). A significant portion of patients does not respond to the conventional anti-spasmodic therapies, and some strategies are invasive, posing risks of complications (Flachenecker et al., 2014; Crabtree-Hartman, 2018). Recent data point to Sativex as a valid and well-tolerated therapeutic option. Sativex is able to treat the spasms, improving the quality of life, and displays a low incidence of adverse effects (Giacoppo et al., 2017a).


Data from clinical and pre-clinical studies are summarized in Tables ?1, 2, respectively.


Safety and Side Effects


One important concern is whether CBD is a safe therapeutic strategy. Several preclinical and clinical reports show that CBD does not alter metabolic and physiological parameters, such as glycemia, prolactin levels, blood pressure, and heart rate. In addition, CBD does not modify hematocrit, leukocyte and erythrocyte counts, and blood levels of bilirubin and creatinine in humans. CBD also does not affect urine osmolarity, pH, albumin levels, and leukocyte and erythrocyte counts. Moreover, in vitro studies demonstrate that CBD does not alter embryonic development nor the vitality of non-tumor cell lines. The most reported side effects of CBD are tiredness, diarrhea, and changes on appetite. CBD does not seem to induce tolerance. For a broad review of CBD’s side effects, see Bergamaschi et al. (2011) and Iffland and Grotenhermen (2017).


In the context of movement disorders with concomitant cognitive symptoms, as the ones discussed here, it is crucial to evaluate the potential motor and cognitive side effects of CBD. CBD does not induce catalepsy behavior in rodents�being even able to attenuate the effects of several cataleptic agents, as discussed above (El-Alfy et al., 2010; Gomes et al., 2013; Peres et al., 2016; Sonego et al., 2016). In accordance, CBD does not induce extrapyramidal effects in humans (Leweke et al., 2012).


With respect to cognitive effects, studies report that CBD does not impair cognition, being even able to improve it in some conditions. Pre-clinical data show that CBD restores the deficit in the novel object recognition task in mice treated with MK-801 (a protocol used to model schizophrenia) (Gomes et al., 2015), in rats submitted to neonatal iron overload (Fagherazzi et al., 2012), in a transgenic mice model for Alzheimer’s disease (Cheng et al., 2014), and in a mice model for cerebral malaria (Campos et al., 2015). CBD also reverses impaired social recognition in a murine model for Alzheimer’s disease (Cheng et al., 2014) and restores the deficits in the Morris water maze�a task that evaluates spatial learning�in rodent models for Alzheimer’s disease (Mart�n-Moreno et al., 2011), brain ischemia (Schiavon et al., 2014) and cerebral malaria (Campos et al., 2015). In addition, studies demonstrate that CBD per se does not modify animals’ performance in cognitive tasks (Osborne et al., 2017; Myers et al., 2018) and does not induce withdrawal after prolonged treatment (Myers et al., 2018). In accordance, in one recent clinical trial using CBD as an adjunctive therapy for schizophrenia, CBD group displayed greater cognitive improvement (assessed by BACS�Brief Assessment of Cognition in Schizophrenia), although it fell short of significance (McGuire et al., 2018). CBD also improves facial emotion recognition in cannabis users (Hindocha et al., 2015).


It is noteworthy that in some cases, particularly concerning multiple sclerosis and HD clinical studies, CBD per se does not seem to be beneficial. However, when CBD is administered with ?9-THC in a 1:1 ratio, therapeutic effects are observed. Therefore, it is also important to evaluate the interactions between CBD and ?9-THC as well as the adverse effects of this mixture. Multiple reports point to deleterious effects of ?9-THC on human cognition, mainly on memory and emotional processing (Colizzi and Bhattacharyya, 2017). On the other hand, studies reveal that CBD can counteract ?9-THC detrimental cognitive effects in rodents and monkeys (Wright et al., 2013; Jacobs et al., 2016; Murphy et al., 2017). Nonetheless, this protective effect depends on the doses, on the interval between CBD and ?9-THC administration, as well as on the behavioral paradigm used. In fact, some pre-clinical studies do not observe the protective effect of CBD against the ?9-THC cognitive effects (Wright et al., 2013; Jacobs et al., 2016) or even show that CBD may potentiate them (Hayakawa et al., 2008). Limited clinical evidence indicate that CBD does not worse ?9-THC cognitive effects and, depending on the dose, may protect against them (Colizzi and Bhattacharyya, 2017; Englund et al., 2017; Osborne et al., 2017). Multiple clinical studies with Sativex have not observed motor or cognitive adverse effects (Aragona et al., 2009; Rekand, 2014; L�pez-Send�n Moreno et al., 2016; Russo et al., 2016). Nevertheless, one recent open-label study compared multiple sclerosis patients who continued the treatment with Sativex to those who quitted and reported worse balance and decrease in cognitive performance in the continuers (Castelli et al., 2018). In line with these findings, in an observational study with a large population of Italian patients with multiple sclerosis, cognitive/psychiatric disturbances were seen in 3.9% of the cases (Patti et al., 2016).




The data reviewed here point to a protective role of CBD in the treatment and/or prevention of some movement disorders. Although the studies are scarce, CBD seems to be effective on treating dystonic movements, both primary and secondary. It is noteworthy that in some cases, particularly concerning multiple sclerosis and HD, the clinical beneficial effects are observed only when CBD is combined with ?9-THC in a 1:1 ratio (Sativex). In fact, these therapeutic effects are probably due to ?9-THC, since they are also seen with other cannabinoid agonists (Curtis et al., 2009; Nielsen et al., 2018; Saft et al., 2018). Nonetheless, CBD is shown to diminish the ?9-THC unwanted effects, such as sedation, memory impairments, and psychosis (Russo and Guy, 2006). Data regarding HD are scarce, but the results of using Sativex in multiple sclerosis are encouraging. Reviews of the clinical use of this compound in the last decade point to effectiveness in the treatment of spasticity as well as improvement in quality of life, with low incidence of adverse effects (Giacoppo et al., 2017a).


In respect to PD, although the pre-clinical studies are promising, the few studies with patients failed to detect improvement of the motor symptoms after treatment with CBD. There is a significant difference between the clinical and pre-clinical PD studies. In animals, the beneficial effects are seen when CBD is administered prior to or immediately after the manipulation that induces the PD-like symptoms. Of note, when treatment with CBD commences 1 week after the lesion with 6-OHDA, the protective effects are not seen (Garcia-Arencibia et al., 2007). These data suggest that CBD’s might have a preventive role rather than a therapeutic one in PD. In clinical practice, PD is diagnosed subsequently to the emergence of motor symptoms�that appear up to 10 years after the beginning of neurodegeneration and the onset of non-motor symptoms (Schrag et al., 2015). When the diagnosis occur, approximately 60% of the dopaminergic neurons has already been lost (Dauer and Przedborski, 2003). The fact that in clinical trials CBD is administered only after this substantial progression of the disease might explain the conflicting results. Unfortunately, the early diagnosis of PD remains a challenge, posing difficulty to the implementation of preventive strategies. The development of diagnosis criteria able to detect PD in early stages would probably expand the CBD’s applications in this disease.


The molecular mechanisms associated with CBD’s improvement of motor disorders are likely multifaceted. Data show that it might depend on CBD’s actions on 5-HT1A, CB1, CB2, and/or PPAR? receptors. Moreover, all movement disorders are in some extent linked to oxidative stress and inflammation, and CBD has been reported to display an antioxidant and anti-inflammatory profile, in vitro and in animal models for movement abnormalities.


The studies investigating the role of CBD on the treatment of movement disorders are few. Furthermore, differences in the dose and duration of treatment as well as in the stage of the disease (for instance, PD patients are treated only in an advanced stage of the disease) among these studies (shown in detail in Table ?Table1)1) limit the generalization of the positive effect of CBD and might explain the conflicting results. Notwithstanding, the beneficial neuroprotective profile of CBD added to the preliminary results described here are encouraging. Undoubtedly, future investigations are needed to endorse these initial data and to elucidate the mechanisms involved in the preventive and/or therapeutic potential of CBD on movement disorders.


Introduction to the Endocannabinoid System


Since you read the article concerning the effects of cannabidiol on movement disorders, one thing will become quickly evident: cannabis has a profound influence on the human body. This one herb and its own variety of therapeutic chemicals seem to impact every aspect of the brain and body. However, how is this possible? There’s a system in the human body which many individuals are not aware of nor do they known how important it’s functions are: the endocannabinoid system.


What Is The Endocannabinoid System?


The endogenous cannabinoid system, or the cannabinoid system, named after the plant that resulted in its discovery, is possibly the most important physiologic system involved in establishing and maintaining human health. Endocannabinoids and their receptors are found throughout the body: in the brain, organs, connective tissues, glands, and immune cells. In each tissue, the endocannabinoid system performs various tasks, but the goal is always the same: homeostasis, the maintenance of a stable internal environment despite changes in the external environment.


Cannabinoids promote homeostasis at every level of biological lifetime, from the sub-cellular, into the organism, and possibly into the community and more. Here is one instance: autophagy, a process where a cell sequesters part of its contents to be self-digested and recycled, is mediated by the endocannabinoid system. While this procedure keeps normal cells alive, permitting them to maintain a balance between the synthesis, degradation, and subsequent recycling of cellular products, it has a fatal effect on cancerous tumor cells, causing them to consume themselves at a programmed cellular suicide. The death of cancer cells, of course, promotes homeostasis and survival in the level of the whole organism.


Endocannabinoids and cannabinoids are also found at the intersection of the body’s various systems, enabling communication and coordination between distinct cell types. In the case of an injury, for instance, cannabinoids are available diminishing the discharge of activators and sensitizers in the injured tissue, stabilizing the nerve cell to stop excessive firing, and calming nearby immune cells to prevent discharge of pro-inflammatory substances. Three different mechanisms of action on three distinct cell types for one purpose: minimize the pain and damage caused by the injury.


The endocannabinoid system, using its complicated activities in our immune system, nervous system, and all of the body’s organs, is literally a bridge between the brain and the body. By understanding this system we begin to observe a mechanism that explains the way the states of awareness can promote disease or health.


Along with regulating the human body’s internal and cellular homeostasis, cannabinoids affect an individual’s connection with the external environment. Socially, the management of cannabinoids clearly changes human behavior, frequently promoting sharing, comedy, and imagination. By mediating neurogenesis, neuronal plasticity, and learning, cannabinoids may directly affect a person’s open-mindedness and capability to move beyond limiting patterns of thought and behaviour from past scenarios. Reformatting these older patterns is an essential part of health in our quickly changing environment. Furthermore, the article above found that CBD appears to be an effective treatment option for dystonic movements, both primary and secondary, although further reasearch studies are required. The research of CBD has been controversial, however, more and more studies are starting to demonstrate the health benefits of cannabidiol. Information referenced from the National Center for Biotechnology Information (NCBI).�The scope of our information is limited to chiropractic as well as to spinal injuries and conditions. To discuss the subject matter, please feel free to ask Dr. Jimenez or contact us at�915-850-0900�.


Curated by Dr. Alex Jimenez


Additional Topics: Back Pain

Back pain is one of the most prevalent causes for disability and missed days at work worldwide. As a matter of fact, back pain has been attributed as the second most common reason for doctor office visits, outnumbered only by upper-respiratory infections. Approximately 80 percent of the population will experience some type of back pain at least once throughout their life. The spine is a complex structure made up of bones, joints, ligaments and muscles, among other soft tissues. Because of this, injuries and/or aggravated conditions, such as herniated discs, can eventually lead to symptoms of back pain. Sports injuries or automobile accident injuries are often the most frequent cause of back pain, however, sometimes the simplest of movements can have painful results. Fortunately, alternative treatment options, such as chiropractic care, can help ease back pain through the use of spinal adjustments and manual manipulations, ultimately improving pain relief.




blog picture of cartoon paperboy big news


EXTRA IMPORTANT TOPIC: Low Back Pain Management


MORE TOPICS: EXTRA EXTRA:�Chronic Pain & Treatments


  1. Adams R., Hunt M., Clark J. (1940).�Structure of cannabidiol, a product isolated from the marihuana extract of Minnesota wild hemp. I.�J. Am. Chem. Soc.62, 196�200. 10.1021/ja01858a058�[Cross Ref]
  2. Aiken C. T., Tobin A. J., Schweitzer E. S. (2004).�A cell-based screen for drugs to treat Huntington’s disease.�Neurobiol. Dis.16, 546�555. 10.1016/j.nbd.2004.04.001�[PubMed][Cross Ref]
  3. Ammal Kaidery N., Thomas B. (2018).�Current perspective of mitochondrial biology in Parkinson’s disease.�Neurochem. Int. [Epub ahead of print]. 10.1016/j.neuint.2018.03.001�[PMC free article][PubMed][Cross Ref]
  4. Aragona M., Onesti E., Tomassini V., Conte A., Gupta S., Gilio F., et al. . (2009).�Psychopathological and cognitive effects of therapeutic cannabinoids in multiple sclerosis: a double-blind, placebo controlled, crossover study.�Clin. Neuropharmacol.32, 41�47. 10.1097/WNF.0B013E3181633497[PubMed][Cross Ref]
  5. Bergamaschi M. M., Queiroz R. H., Zuardi A. W., Crippa J. A. (2011).�Safety and side effects of cannabidiol, a�Cannabis sativa�constituent.�Curr. Drug Saf.6, 237�249. 10.2174/157488611798280924�[PubMed][Cross Ref]
  6. Bisogno T., Hanus L., De Petrocellis L., Tchilibon S., Ponde D. E., Brandi I., et al. . (2001).�Molecular targets for cannabidiol and its synthetic analogues: effect on vanilloid VR1 receptors and on the cellular uptake and enzymatic hydrolysis of anandamide.�Br. J. Pharmacol.134, 845�852. 10.1038/sj.bjp.0704327�[PMC free article][PubMed][Cross Ref]
  7. Bov� J., Prou D., Perier C., Przedborski S. (2005).�Toxin-induced models of Parkinson’s disease.�NeuroRx2, 484�494. 10.1602/neurorx.2.3.484�[PMC free article][PubMed][Cross Ref]
  8. Breakefield X. O., Blood A. J., Li Y., Hallett M., Hanson P. I., Standaert D. G. (2008).�The pathophysiological basis of dystonias.�Nat. Rev. Neurosci.9, 222�234. 10.1038/nrn2337�[PubMed][Cross Ref]
  9. Breese G. R., Traylor T. D. (1971).�Depletion of brain noradrenaline and dopamine by 6-hydroxydopamine.�Br. J. Pharmacol.42, 88�99. 10.1111/j.1476-5381.1971.tb07089.x�[PMC free article][PubMed][Cross Ref]
  10. Brouillet E., Jacquard C., Bizat N., Blum D. (2005).�3-Nitropropionic acid: a mitochondrial toxin to uncover physiopathological mechanisms underlying striatal degeneration in Huntington’s disease.�J. Neurochem.95, 1521�1540. 10.1111/j.1471-4159.2005.03515.x�[PubMed][Cross Ref]
  11. Brown K. J., Laun A. S., Song Z. H. (2017).�Cannabidiol, a novel inverse agonist for GPR12.�Biochem. Biophys. Res. Commun.493, 451�454. 10.1016/j.bbrc.2017.09.001�[PMC free article][PubMed][Cross Ref]
  12. Campos A. C., Brant F., Miranda A. S., Machado F. S., Teixeira A. L. (2015).�Cannabidiol increases survival and promotes rescue of cognitive function in a murine model of cerebral malaria.�Neuroscience289, 166�180. 10.1016/j.neuroscience.2014.12.051�[PubMed][Cross Ref]
  13. Campos A. C., Fogaca M. V., Sonego A. B., Guimaraes F. S. (2016).�Cannabidiol, neuroprotection and neuropsychiatric disorders.�Pharmacol. Res.112, 119�127. 10.1016/j.phrs.2016.01.033[PubMed][Cross Ref]
  14. Castelli L., Prosperini L., Pozzilli C. (2018).�Balance worsening associated with nabiximols in multiple sclerosis.�Mult. Scler. J.�[Epub ahead of print]. 10.1177/1352458518765649�[PubMed][Cross Ref]
  15. Celorrio M., Rojo-Bustamante E., Fernandez-Suarez D., Saez E., Estella-Hermoso de Mendoza A., Muller C. E., et al. . (2017).�GPR55: a therapeutic target for Parkinson’s disease?Neuropharmacology125, 319�332. 10.1016/j.neuropharm.2017.08.017�[PubMed][Cross Ref]
  16. Chagas M. H., Eckeli A. L., Zuardi A. W., Pena-Pereira M. A., Sobreira-Neto M. A., Sobreira E. T., et al. . (2014a).�Cannabidiol can improve complex sleep-related behaviours associated with rapid eye movement sleep behaviour disorder in Parkinson’s disease patients: a case series.�J. Clin. Pharm. Ther.39, 564�566. 10.1111/jcpt.12179�[PubMed][Cross Ref]
  17. Chagas M. H., Zuardi A. W., Tumas V., Pena-Pereira M. A., Sobreira E. T., Bergamaschi M. M., et al. . (2014b).�Effects of cannabidiol in the treatment of patients with Parkinson’s disease: an exploratory double-blind trial.�J. Psychopharmacol.28, 1088�1098. 10.1177/0269881114550355[PubMed][Cross Ref]
  18. Chen J., Hou C., Chen X., Wang D., Yang P., He X., et al. (2016).�Protective effect of cannabidiol on hydrogen peroxide induced apoptosis, inflammation and oxidative stress in nucleus pulposus cells.�Mol. Med. Rep.14, 2321�2327. 10.3892/mmr.2016.5513�[PubMed][Cross Ref]
  19. Cheng D., Low J. K., Logge W., Garner B., Karl T. (2014).�Chronic cannabidiol treatment improves social and object recognition in double transgenic APPswe/PS1E9 mice.�Psychopharmacology231, 3009�3017. 10.1007/s00213-014-3478-5�[PubMed][Cross Ref]
  20. Cherif H., Argaw A., Cecyre B., Bouchard A., Gagnon J., Javadi P., et al. . (2015).�Role of GPR55 during axon growth and target innervation.�eNeuro�2:ENEURO.0011-15.2015. 10.1523/ENEURO.0011-15.2015�[PMC free article][PubMed][Cross Ref]
  21. Colizzi M., Bhattacharyya S. (2017).�Does cannabis composition matter? differential effects of delta-9-tetrahydrocannabinol and cannabidiol on human cognition.�Curr. Addict. Rep.4, 62�74. 10.1007/s40429-017-0142-2�[PMC free article][PubMed][Cross Ref]
  22. Connolly B. S., Lang A. E. (2014).�Pharmacological treatment of Parkinson disease: a review.�JAMA311, 1670�1683. 10.1001/jama.2014.3654�[PubMed][Cross Ref]
  23. Consroe P., Laguna J., Allender J., Snider S., Stern L., Sandyk R., et al. . (1991).�Controlled clinical trial of cannabidiol in Huntington’s disease.�Pharmacol. Biochem. Behav.40, 701�708. 10.1016/0091-3057(91)90386-G�[PubMed][Cross Ref]
  24. Consroe P., Sandyk R., Snider S. R. (1986).�Open label evaluation of cannabidiol in dystonic movement disorders.�Int. J. Neurosci.30, 277�282. 10.3109/00207458608985678�[PubMed][Cross Ref]
  25. Crabtree-Hartman E. (2018).�Advanced symptom management in multiple sclerosis.�Neurol. Clin.36, 197�218. 10.1016/j.ncl.2017.08.015�[PubMed][Cross Ref]
  26. Crook Z. R., Housman D. (2011).�Huntington’s disease: can mice lead the way to treatment?Neuron69, 423�435. 10.1016/j.neuron.2010.12.035�[PMC free article][PubMed][Cross Ref]
  27. Curtis A., Mitchell I., Patel S., Ives N., Rickards H. (2009).�A pilot study using nabilone for symptomatic treatment in Huntington’s disease.�Mov. Disord.24, 2254�2259. 10.1002/mds.22809[PubMed][Cross Ref]
  28. da Silva V. K., de Freitas B. S., Dornelles V. C., Kist L. W., Bogo M. R., Silva M. C., et al. . (2018).�Novel insights into mitochondrial molecular targets of iron-induced neurodegeneration: reversal by cannabidiol.�Brain Res. Bull.139, 1�8. 10.1016/j.brainresbull.2018.01.014�[PubMed][Cross Ref]
  29. Dauer W., Przedborski S. (2003).�Parkinson’s disease: mechanisms and models.�Neuron39, 889�909. 10.1016/S0896-6273(03)00568-3�[PubMed][Cross Ref]
  30. Dickey A. S., La Spada A. R. (2017).�Therapy development in Huntington disease: from current strategies to emerging opportunities.�Am. J. Med. Genet. A176, 842�861. 10.1002/ajmg.a.38494�[PMC free article][PubMed][Cross Ref]
  31. Dos-Santos-Pereira M., da-Silva C. A., Guimaraes F. S., Del-Bel E. (2016).�Co-administration of cannabidiol and capsazepine reduces L-DOPA-induced dyskinesia in mice: possible mechanism of action.�Neurobiol. Dis.94, 179�195. 10.1016/j.nbd.2016.06.013�[PubMed][Cross Ref]
  32. El-Alfy A. T., Ivey K., Robinson K., Ahmed S., Radwan M., Slade D., et al. . (2010).�Antidepressant-like effect of delta9-tetrahydrocannabinol and other cannabinoids isolated from�Cannabis sativa�L.�Pharmacol. Biochem. Behav.95, 434�442. 10.1016/j.pbb.2010.03.004�[PMC free article][PubMed][Cross Ref]
  33. ElSohly M., Gul W. (2014).�Constituents of�Cannabis sativa, in�Handbook of Cannabis, ed Pertwee R. G., editor. (New York, NY: Oxford University Press; ), 1093.
  34. Englund A., Freeman T. P., Murray R. M., McGuire P. (2017).�Can we make cannabis safer?Lancet Psychiatry4, 643�648. 10.1016/S2215-0366(17)30075-5�[PubMed][Cross Ref]
  35. Espejo-Porras F., Fernandez-Ruiz J., Pertwee R. G., Mechoulam R., Garcia C. (2013).�Motor effects of the non-psychotropic phytocannabinoid cannabidiol that are mediated by 5-HT1A receptors.�Neuropharmacology75, 155�163. 10.1016/j.neuropharm.2013.07.024�[PubMed][Cross Ref]
  36. Esposito G., Scuderi C., Savani C., Steardo L., Jr., De Filippis D., Cottone P., et al. . (2007).�Cannabidiol�in vivo�blunts beta-amyloid induced neuroinflammation by suppressing IL-1beta and iNOS expression.�Br. J. Pharmacol.151, 1272�1279. 10.1038/sj.bjp.0707337�[PMC free article][PubMed][Cross Ref]
  37. Esposito G., Scuderi C., Valenza M., Togna G. I., Latina V., De Filippis D., et al. . (2011).�Cannabidiol reduces Abeta-induced neuroinflammation and promotes hippocampal neurogenesis through PPARgamma involvement.�PLoS ONE6:e28668. 10.1371/journal.pone.0028668�[PMC free article][PubMed][Cross Ref]
  38. Fagherazzi E. V., Garcia V. A., Maurmann N., Bervanger T., Halmenschlager L. H., Busato S. B., et al. . (2012).�Memory-rescuing effects of cannabidiol in an animal model of cognitive impairment relevant to neurodegenerative disorders.�Psychopharmacology219, 1133�1140. 10.1007/s00213-011-2449-3�[PubMed][Cross Ref]
  39. Farooqui T., Farooqui A. A. (2011).�Lipid-mediated oxidative stress and inflammation in the pathogenesis of Parkinson’s disease.�Parkinsons. Dis.2011:247467. 10.4061/2011/247467�[PMC free article][PubMed][Cross Ref]
  40. Flachenecker P., Henze T., Zettl U. K. (2014).�Spasticity in patients with multiple sclerosis�clinical characteristics, treatment and quality of life.�Acta Neurol. Scand.129, 154�162. 10.1111/ane.12202[PubMed][Cross Ref]
  41. Garcia C., Palomo-Garo C., Garcia-Arencibia M., Ramos J., Pertwee R., Fernandez-Ruiz J. (2011).�Symptom-relieving and neuroprotective effects of the phytocannabinoid Delta(9)-THCV in animal models of Parkinson’s disease.�Br. J. Pharmacol.163, 1495�1506. 10.1111/j.1476-5381.2011.01278.x�[PMC free article][PubMed][Cross Ref]
  42. Garc�a-Arencibia M., Gonzalez S., de Lago E., Ramos J. A., Mechoulam R., Fernandez-Ruiz J. (2007).�Evaluation of the neuroprotective effect of cannabinoids in a rat model of Parkinson’s disease: importance of antioxidant and cannabinoid receptor-independent properties.�Brain Res.1134, 162�170. 10.1016/j.brainres.2006.11.063�[PubMed][Cross Ref]
  43. Giacoppo S., Bramanti P., Mazzon E. (2017a).�Sativex in the management of multiple sclerosis-related spasticity: an overview of the last decade of clinical evaluation.�Mult. Scler. Relat. Disord.17, 22�31. 10.1016/j.msard.2017.06.015�[PubMed][Cross Ref]
  44. Giacoppo S., Pollastro F., Grassi G., Bramanti P., Mazzon E. (2017b).�Target regulation of PI3K/Akt/mTOR pathway by cannabidiol in treatment of experimental multiple sclerosis.�Fitoterapia116, 77�84. 10.1016/j.fitote.2016.11.010�[PubMed][Cross Ref]
  45. Gomes F. V., Del Bel E. A., Guimaraes F. S. (2013).�Cannabidiol attenuates catalepsy induced by distinct pharmacological mechanisms via 5-HT1A receptor activation in mice.�Prog. Neuropsychopharmacol. Biol. Psychiatry46, 43�47. 10.1016/j.pnpbp.2013.06.005�[PubMed][Cross Ref]
  46. Gomes F. V., Llorente R., Del Bel E. A., Viveros M. P., Lopez-Gallardo M., Guimaraes F. S. (2015).�Decreased glial reactivity could be involved in the antipsychotic-like effect of cannabidiol.�Schizophr. Res.164, 155�163. 10.1016/j.schres.2015.01.015�[PubMed][Cross Ref]
  47. Grlic L. (1976).�A comparative study on some chemical and biological characteristics of various samples of cannabis resin.�Bull. Narc.14, 37�46.
  48. Hampson A. J., Grimaldi M., Axelrod J., Wink D. (1998).�Cannabidiol and (-)Delta9-tetrahydrocannabinol are neuroprotective antioxidants.�Proc. Natl. Acad. Sci. U.S.A.95, 8268�8273. 10.1073/pnas.95.14.8268�[PMC free article][PubMed][Cross Ref]
  49. Hassan S., Eldeeb K., Millns P. J., Bennett A. J., Alexander S. P., Kendall D. A. (2014).�Cannabidiol enhances microglial phagocytosis via transient receptor potential (TRP) channel activation.�Br. J. Pharmacol.171, 2426�2439. 10.1111/bph.12615�[PMC free article][PubMed][Cross Ref]
  50. Hayakawa K., Mishima K., Hazekawa M., Sano K., Irie K., Orito K., et al. . (2008).�Cannabidiol potentiates pharmacological effects of Delta(9)-tetrahydrocannabinol via CB(1) receptor-dependent mechanism.�Brain Res.1188, 157�164. 10.1016/j.brainres.2007.09.090�[PubMed][Cross Ref]
  51. Hecker M., Paap B. K., Goertsches R. H., Kandulski O., Fatum C., Koczan D., et al. . (2011).�Reassessment of blood gene expression markers for the prognosis of relapsing-remitting multiple sclerosis.�PLoS ONE6:e29648. 10.1371/journal.pone.0029648�[PMC free article][PubMed][Cross Ref]
  52. Hind W. H., England T. J., O’Sullivan S. E. (2016).�Cannabidiol protects an in vitro model of the blood-brain barrier from oxygen-glucose deprivation via PPARgamma and 5-HT1A receptors.�Br. J. Pharmacol.173, 815�825. 10.1111/bph.13368�[PMC free article][PubMed][Cross Ref]
  53. Hindocha C., Freeman T. P., Schafer G., Gardener C., Das R. K., Morgan C. J., et al. . (2015).�Acute effects of delta-9-tetrahydrocannabinol, cannabidiol and their combination on facial emotion recognition: a randomised, double-blind, placebo-controlled study in cannabis users.�Eur. Neuropsychopharmacol.25, 325�334. 10.1016/j.euroneuro.2014.11.014�[PMC free article][PubMed][Cross Ref]
  54. Hodges A., Strand A. D., Aragaki A. K., Kuhn A., Sengstag T., Hughes G., et al. . (2006).�Regional and cellular gene expression changes in human Huntington’s disease brain.�Hum. Mol. Genet.15, 965�977. 10.1093/hmg/ddl013�[PubMed][Cross Ref]
  55. Iffland K., Grotenhermen F. (2017).�An update on safety and side effects of cannabidiol: a review of clinical data and relevant animal studies.�Cannabis Cannabinoid Res.�2, 139�154. 10.1089/can.2016.0034�[PMC free article][PubMed][Cross Ref]
  56. Iuvone T., Esposito G., Esposito R., Santamaria R., Di Rosa M., Izzo A. A. (2004).�Neuroprotective effect of cannabidiol, a non-psychoactive component from�Cannabis sativa, on beta-amyloid-induced toxicity in PC12 cells.�J. Neurochem.89, 134�141. 10.1111/j.1471-4159.2003.02327.x[PubMed][Cross Ref]
  57. Jacobs D. S., Kohut S. J., Jiang S., Nikas S. P., Makriyannis A., Bergman J. (2016).�Acute and chronic effects of cannabidiol on Delta(9)-tetrahydrocannabinol (Delta(9)-THC)-induced disruption in stop signal task performance.�Exp. Clin. Psychopharmacol.24, 320�330. 10.1037/pha0000081�[PMC free article][PubMed][Cross Ref]
  58. Jankovic J. (2005).�Motor fluctuations and dyskinesias in Parkinson’s disease: clinical manifestations.�Mov Disord�20 (Suppl. 11), S11�S16. 10.1002/mds.20458�[PubMed][Cross Ref]
  59. Juknat A., Rimmerman N., Levy R., Vogel Z., Kozela E. (2012).�Cannabidiol affects the expression of genes involved in zinc homeostasis in BV-2 microglial cells.�Neurochem. Int.61, 923�930. 10.1016/j.neuint.2011.12.002�[PubMed][Cross Ref]
  60. Kaplan J. S., Stella N., Catterall W. A., Westenbroek R. E. (2017).�Cannabidiol attenuates seizures and social deficits in a mouse model of Dravet syndrome.�Proc. Natl. Acad. Sci. U.S.A.114, 11229�11234. 10.1073/pnas.1711351114�[PMC free article][PubMed][Cross Ref]
  61. Klockgether T. (2004).�Parkinson’s disease: clinical aspects.�Cell Tissue Res.318, 115�120. 10.1007/s00441-004-0975-6�[PubMed][Cross Ref]
  62. Kozela E., Pietr M., Juknat A., Rimmerman N., Levy R., Vogel Z. (2010).�Cannabinoids Delta(9)-tetrahydrocannabinol and cannabidiol differentially inhibit the lipopolysaccharide-activated NF-kappaB and interferon-beta/STAT proinflammatory pathways in BV-2 microglial cells.�J. Biol. Chem.285, 1616�1626. 10.1074/jbc.M109.069294�[PMC free article][PubMed][Cross Ref]
  63. Laprairie R., Bagher A., Kelly M., Denovan-Wright E. (2015).�Cannabidiol is a negative allosteric modulator of the cannabinoid CB1 receptor.�Br. J. Pharmacol.172, 4790�4805. 10.1111/bph.13250�[PMC free article][PubMed][Cross Ref]
  64. Lastres-Becker I., Hansen H. H., Berrendero F., De Miguel R., Perez-Rosado A., Manzanares J., et al. . (2002).�Alleviation of motor hyperactivity and neurochemical deficits by endocannabinoid uptake inhibition in a rat model of Huntington’s disease.�Synapse44, 23�35. 10.1002/syn.10054[PubMed][Cross Ref]
  65. Lastres-Becker I., Molina-Holgado F., Ramos J. A., Mechoulam R., Fernandez-Ruiz J. (2005).�Cannabinoids provide neuroprotection against 6-hydroxydopamine toxicity�in vivo�and�in vitro: relevance to Parkinson’s disease.�Neurobiol. Dis.19, 96�107. 10.1016/j.nbd.2004.11.009�[PubMed][Cross Ref]
  66. Laun A. S., Song Z. H. (2017).�GPR3 and GPR6, novel molecular targets for cannabidiol.�Biochem. Biophys. Res. Commun.490, 17�21. 10.1016/j.bbrc.2017.05.165�[PubMed][Cross Ref]
  67. Lee J. L. C., Bertoglio L. J., Guimaraes F. S., Stevenson C. W. (2017).�Cannabidiol regulation of emotion and emotional memory processing: relevance for treating anxiety-related and substance abuse disorders.�Br. J. Pharmacol.174, 3242�3256. 10.1111/bph.13724�[PMC free article][PubMed][Cross Ref]
  68. Lerner P. P., Miodownik C., Lerner V. (2015).�Tardive dyskinesia (syndrome): current concept and modern approaches to its management.�Psychiatry Clin. Neurosci.69, 321�334. 10.1111/pcn.12270[PubMed][Cross Ref]
  69. Leweke F. M., Piomelli D., Pahlisch F., Muhl D., Gerth C. W., Hoyer C., et al. . (2012).�Cannabidiol enhances anandamide signaling and alleviates psychotic symptoms of schizophrenia.�Transl. Psychiatry2:e94. 10.1038/tp.2012.15�[PMC free article][PubMed][Cross Ref]
  70. Long L. E., Malone D. T., Taylor D. A. (2006).�Cannabidiol reverses MK-801-induced disruption of prepulse inhibition in mice.�Neuropsychopharmacology31, 795�803. 10.1038/sj.npp.1300838[PubMed][Cross Ref]
  71. L�pez-Send�n Moreno J. L., Garcia Caldentey J., Trigo Cubillo P., Ruiz Romero C., Garcia Ribas G., Alonso Arias M. A., et al. . (2016).�A double-blind, randomized, cross-over, placebo-controlled, pilot trial with Sativex in Huntington’s disease.�J. Neurol.263, 1390�1400. 10.1007/s00415-016-8145-9�[PubMed][Cross Ref]
  72. MacDonald M. E., Barnes G., Srinidhi J., Duyao M. P., Ambrose C. M., Myers R. H., et al. (1993).�Gametic but not somatic instability of CAG repeat length in Huntington’s disease.�J. Med. Genet.30, 982�986. 10.1136/jmg.30.12.982�[PMC free article][PubMed][Cross Ref]
  73. Mart�nez-Pinilla E., Varani K., Reyes-Resina I., Angelats E., Vincenzi F., Ferreiro-Vera C., et al. . (2017).�Binding and signaling studies disclose a potential allosteric site for cannabidiol in cannabinoid CB2 receptors.�Front. Pharmacol.8:744. 10.3389/fphar.2017.00744�[Cross Ref]
  74. Mart�n-Moreno A. M., Reigada D., Ramirez B. G., Mechoulam R., Innamorato N., Cuadrado A., et al. . (2011).�Cannabidiol and other cannabinoids reduce microglial activation�in vitro�and�in vivo: relevance to Alzheimer’s disease.�Mol. Pharmacol.79, 964�973. 10.1124/mol.111.071290�[PMC free article][PubMed][Cross Ref]
  75. Mason S. L., Barker R. A. (2016).�Advancing pharmacotherapy for treating Huntington’s disease: a review of the existing literature.�Expert Opin. Pharmacother.17, 41�52. 10.1517/14656566.2016.1109630�[PubMed][Cross Ref]
  76. McColgan P., Tabrizi S. J. (2018).�Huntington’s disease: a clinical review.�Eur. J. Neurol.25, 24�34. 10.1111/ene.13413�[PubMed][Cross Ref]
  77. McGuire P., Robson P., Cubala W. J., Vasile D., Morrison P. D., Barron R., et al. . (2018).�Cannabidiol (CBD) as an adjunctive therapy in schizophrenia: a multicenter randomized controlled trial.�Am. J. Psychiatry175, 225�231. 10.1176/appi.ajp.2017.17030325�[PubMed][Cross Ref]
  78. Mecha M., Torrao A. S., Mestre L., Carrillo-Salinas F. J., Mechoulam R., Guaza C. (2012).�Cannabidiol protects oligodendrocyte progenitor cells from inflammation-induced apoptosis by attenuating endoplasmic reticulum stress.�Cell Death Dis.3:e331. 10.1038/cddis.2012.71�[PMC free article][PubMed][Cross Ref]
  79. Mechoulam R., Shvo Y. (1963).�Hashish�I: the structure of cannabidiol.�Tetrahedron19, 2073�2078. 10.1016/0040-4020(63)85022-X�[PubMed][Cross Ref]
  80. Meredith G. E., Totterdell S., Potashkin J. A., Surmeier D. J. (2008).�Modeling PD pathogenesis in mice: advantages of a chronic MPTP protocol.�Parkinsonism Relat. Disord.14(Suppl. 2), S112�115. 10.1016/j.parkreldis.2008.04.012�[PMC free article][PubMed][Cross Ref]
  81. Molderings G. J., Bonisch H., Hammermann R., Gothert M., Bruss M. (2002).�Noradrenaline release-inhibiting receptors on PC12 cells devoid of alpha(2(-)) and CB(1) receptors: similarities to presynaptic imidazoline and edg receptors.�Neurochem. Int.40, 157�167. 10.1016/S0197-0186(01)00076-6�[PubMed][Cross Ref]
  82. Morales P., Isawi I., Reggio P. H. (2018).�Towards a better understanding of the cannabinoid-related orphan receptors GPR3, GPR6, and GPR12.�Drug Metab. Rev.50, 74�93. 10.1080/03602532.2018.1428616�[PubMed][Cross Ref]
  83. Morales P., Reggio P. H. (2017).�An update on non-CB1, non-CB2 cannabinoid related g-protein-coupled receptors.�Cannabis Cannabinoid Res.2, 265�273. 10.1089/can.2017.0036�[PMC free article][PubMed][Cross Ref]
  84. Murphy M., Mills S., Winstone J., Leishman E., Wager-Miller J., Bradshaw H., et al. (2017).�Chronic adolescent delta(9)-tetrahydrocannabinol treatment of male mice leads to long-term cognitive and behavioral dysfunction, which are prevented by concurrent cannabidiol treatment.�Cannabis Cannabinoid Res.2, 235�246. 10.1089/can.2017.0034�[PMC free article][PubMed][Cross Ref]
  85. Myers A. M., Siegele P. B., Foss J. D., Tuma R. F., Ward S. J. (2018).�Single and combined effects of plant-derived and synthetic cannabinoids on cognition and cannabinoid-associated withdrawal signs in mice.�Br. J. Pharmacol.�[Epub ahead of print]. 10.1111/bph.14147�[PubMed][Cross Ref]
  86. Nielsen S., Germanos R., Weier M., Pollard J., Degenhardt L., Hall W., et al. . (2018).�The Use of Cannabis and Cannabinoids in Treating Symptoms of Multiple Sclerosis: a Systematic Review of Reviews.�Curr. Neurol. Neurosci. Rep.18:8. 10.1007/s11910-018-0814-x�[PubMed][Cross Ref]
  87. Niranjan R. (2014).�The role of inflammatory and oxidative stress mechanisms in the pathogenesis of Parkinson’s disease: focus on astrocytes.�Mol. Neurobiol.49, 28�38. 10.1007/s12035-013-8483-x[PubMed][Cross Ref]
  88. Oeckl P., Ferger B. (2016).�Increased susceptibility of G-protein coupled receptor 6 deficient mice to MPTP neurotoxicity.�Neuroscience337, 218�223. 10.1016/j.neuroscience.2016.09.021�[PubMed][Cross Ref]
  89. Oeckl P., Hengerer B., Ferger B. (2014).�G-protein coupled receptor 6 deficiency alters striatal dopamine and cAMP concentrations and reduces dyskinesia in a mouse model of Parkinson’s disease.�Exp. Neurol.257, 1�9. 10.1016/j.expneurol.2014.04.010�[PubMed][Cross Ref]
  90. Osborne A. L., Solowij N., Weston-Green K. (2017).�A systematic review of the effect of cannabidiol on cognitive function: relevance to schizophrenia.�Neurosci. Biobehav. Rev.72, 310�324. 10.1016/j.neubiorev.2016.11.012�[PubMed][Cross Ref]
  91. O’Sullivan S. E., Sun Y., Bennett A. J., Randall M. D., Kendall D. A. (2009).�Time-dependent vascular actions of cannabidiol in the rat aorta.�Eur. J. Pharmacol.612, 61�68. 10.1016/j.ejphar.2009.03.010�[PubMed][Cross Ref]
  92. Pan H., Mukhopadhyay P., Rajesh M., Patel V., Mukhopadhyay B., Gao B., et al. . (2009).�Cannabidiol attenuates cisplatin-induced nephrotoxicity by decreasing oxidative/nitrosative stress, inflammation, and cell death.�J. Pharmacol. Exp. Ther.328, 708�714. 10.1124/jpet.108.147181�[PMC free article][PubMed][Cross Ref]
  93. Patti F., Messina S., Solaro C., Amato M. P., Bergamaschi R., Bonavita S., et al. . (2016).�Efficacy and safety of cannabinoid oromucosal spray for multiple sclerosis spasticity.�J. Neurol. Neurosurg. Psychiatry87, 944�951. 10.1136/jnnp-2015-312591�[PMC free article][PubMed][Cross Ref]
  94. Pazos M. R., Mohammed N., Lafuente H., Santos M., Martinez-Pinilla E., Moreno E., et al. . (2013).�Mechanisms of cannabidiol neuroprotection in hypoxic-ischemic newborn pigs: role of 5HT(1A) and CB2 receptors.�Neuropharmacology71, 282�291. 10.1016/j.neuropharm.2013.03.027�[PubMed][Cross Ref]
  95. Pedrazzi J. F., Issy A. C., Gomes F. V., Guimaraes F. S., Del-Bel E. A. (2015).�Cannabidiol effects in the prepulse inhibition disruption induced by amphetamine.�Psychopharmacology232, 3057�3065. 10.1007/s00213-015-3945-7�[PubMed][Cross Ref]
  96. Peres F. F., Levin R., Suiama M. A., Diana M. C., Gouvea D. A., Almeida V., et al. . (2016).�Cannabidiol prevents motor and cognitive impairments induced by reserpine in rats.�Front. Pharmacol.7:343. 10.3389/fphar.2016.00343�[PMC free article][PubMed][Cross Ref]
  97. Perez-Reyes M., Timmons M. C., Davis K. H., Wall E. M. (1973).�A comparison of the pharmacological activity in man of intravenously administered delta9-tetrahydrocannabinol, cannabinol, and cannabidiol.�Experientia29, 1368�1369. 10.1007/BF01922823�[PubMed][Cross Ref]
  98. Pertwee R. G. (2008).�The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: delta9-tetrahydrocannabinol, cannabidiol and delta9-tetrahydrocannabivarin.�Br. J. Pharmacol.153, 199�215. 10.1038/sj.bjp.0707442�[PMC free article][PubMed][Cross Ref]
  99. Pertwee R. G., Ross R. A. (2002).�Cannabinoid receptors and their ligands.�Prostaglandins Leukot. Essent. Fatty Acids66, 101�121. 10.1054/plef.2001.0341�[PubMed][Cross Ref]
  100. Rajan T. S., Giacoppo S., Iori R., De Nicola G. R., Grassi G., Pollastro F., et al. . (2016).�Anti-inflammatory and antioxidant effects of a combination of cannabidiol and moringin in LPS-stimulated macrophages.�Fitoterapia112, 104�115. 10.1016/j.fitote.2016.05.008�[PubMed][Cross Ref]
  101. Rekand T. (2014).�THC:CBD spray and MS spasticity symptoms: data from latest studies.�Eur. Neurol.71(Suppl. 1), 4�9. 10.1159/000357742�[PubMed][Cross Ref]
  102. Richter A., Loscher W. (2002).�Effects of pharmacological manipulations of cannabinoid receptors on severity of dystonia in a genetic model of paroxysmal dyskinesia.�Eur. J. Pharmacol.454, 145�151. 10.1016/S0014-2999(02)02477-9�[PubMed][Cross Ref]
  103. Rock E. M., Bolognini D., Limebeer C. L., Cascio M. G., Anavi-Goffer S., Fletcher P. J., et al. . (2012).�Cannabidiol, a non-psychotropic component of cannabis, attenuates vomiting and nausea-like behaviour via indirect agonism of 5-HT(1A) somatodendritic autoreceptors in the dorsal raphe nucleus.�Br. J. Pharmacol.165, 2620�2634. 10.1111/j.1476-5381.2011.01621.x�[PMC free article][PubMed][Cross Ref]
  104. Ross R. A. (2003).�Anandamide and vanilloid TRPV1 receptors.�Br. J. Pharmacol.140, 790�801. 10.1038/sj.bjp.0705467�[PMC free article][PubMed][Cross Ref]
  105. Ross R. A. (2009).�The enigmatic pharmacology of GPR55.�Trends Pharmacol. Sci.30, 156�163. 10.1016/�[PubMed][Cross Ref]
  106. Russo E. B., Burnett A., Hall B., Parker K. K. (2005).�Agonistic properties of cannabidiol at 5-HT1a receptors.�Neurochem. Res.30, 1037�1043. 10.1007/s11064-005-6978-1�[PubMed][Cross Ref]
  107. Russo E., Guy G. W. (2006).�A tale of two cannabinoids: the therapeutic rationale for combining tetrahydrocannabinol and cannabidiol.�Med. Hypotheses66, 234�246. 10.1016/j.mehy.2005.08.026[PubMed][Cross Ref]
  108. Russo M., De Luca R., Torrisi M., Rifici C., Sessa E., Bramanti P., et al. . (2016).�Should we care about sativex-induced neurobehavioral effects? A 6-month follow-up study.�Eur. Rev. Med. Pharmacol. Sci.20, 3127�3133.�[PubMed]
  109. Ryberg E., Larsson N., Sjogren S., Hjorth S., Hermansson N. O., Leonova J., et al. . (2007).�The orphan receptor GPR55 is a novel cannabinoid receptor.�Br. J. Pharmacol.152, 1092�1101. 10.1038/sj.bjp.0707460�[PMC free article][PubMed][Cross Ref]
  110. Saft C., von Hein S. M., L�cke T., Thiels C., Peball M., Djamshidian A., et al. . (2018).�Cannabinoids for treatment of dystonia in Huntington’s disease.�J. Huntingtons Dis.�[Epub ahead of print]. 10.3233/JHD-170283�[PubMed][Cross Ref]
  111. Sagredo O., Pazos M. R., Satta V., Ramos J. A., Pertwee R. G., Fernandez-Ruiz J. (2011).�Neuroprotective effects of phytocannabinoid-based medicines in experimental models of Huntington’s disease.�J. Neurosci. Res.89, 1509�1518. 10.1002/jnr.22682�[PubMed][Cross Ref]
  112. Sagredo O., Ramos J. A., Decio A., Mechoulam R., Fernandez-Ruiz J. (2007).�Cannabidiol reduced the striatal atrophy caused 3-nitropropionic acid�in vivo�by mechanisms independent of the activation of cannabinoid, vanilloid TRPV1 and adenosine A2A receptors.�Eur. J. Neurosci.26, 843�851. 10.1111/j.1460-9568.2007.05717.x�[PubMed][Cross Ref]
  113. S�nchez-L�pez F., Tasset I., Aguera E., Feijoo M., Fernandez-Bolanos R., Sanchez F. M., et al. . (2012).�Oxidative stress and inflammation biomarkers in the blood of patients with Huntington’s disease.�Neurol. Res.34, 721�724. 10.1179/1743132812Y.0000000073�[PubMed][Cross Ref]
  114. Sandyk R., Snider S. R., Consroe P., Elias S. M. (1986).�Cannabidiol in dystonic movement disorders.�Psychiatry Res.18:291. 10.1016/0165-1781(86)90117-4�[PubMed][Cross Ref]
  115. Santos N. A., Martins N. M., Sisti F. M., Fernandes L. S., Ferreira R. S., Queiroz R. H., et al. . (2015).�The neuroprotection of cannabidiol against MPP(+)-induced toxicity in PC12 cells involves trkA receptors, upregulation of axonal and synaptic proteins, neuritogenesis, and might be relevant to Parkinson’s disease.�Toxicol. In Vitro30(1 Pt B), 231�240. 10.1016/j.tiv.2015.11.004�[PubMed][Cross Ref]
  116. Sartim A. G., Guimaraes F. S., Joca S. R. (2016).�Antidepressant-like effect of cannabidiol injection into the ventral medial prefrontal cortex-Possible involvement of 5-HT1A and CB1 receptors.�Behav. Brain Res.303, 218�227. 10.1016/j.bbr.2016.01.033�[PubMed][Cross Ref]
  117. Schapira A. H., Cooper J. M., Dexter D., Clark J. B., Jenner P., Marsden C. D. (1990).�Mitochondrial complex I deficiency in Parkinson’s disease.�J. Neurochem.54, 823�827. 10.1111/j.1471-4159.1990.tb02325.x�[PubMed][Cross Ref]
  118. Schiavon A. P., Soares L. M., Bonato J. M., Milani H., Guimaraes F. S., Weffort de Oliveira R. M. (2014).�Protective effects of cannabidiol against hippocampal cell death and cognitive impairment induced by bilateral common carotid artery occlusion in mice.�Neurotox. Res.26, 307�316. 10.1007/s12640-014-9457-0�[PubMed][Cross Ref]
  119. Schrag A., Horsfall L., Walters K., Noyce A., Petersen I. (2015).�Prediagnostic presentations of Parkinson’s disease in primary care: a case-control study.�Lancet Neurol.14, 57�64. 10.1016/S1474-4422(14)70287-X�[PubMed][Cross Ref]
  120. Sonego A. B., Gomes F. V., Del Bel E. A., Guimaraes F. S. (2016).�Cannabidiol attenuates haloperidol-induced catalepsy and c-Fos protein expression in the dorsolateral striatum via 5-HT1A receptors in mice.�Behav. Brain Res.309, 22�28. 10.1016/j.bbr.2016.04.042�[PubMed][Cross Ref]
  121. Stern C. A. J., da Silva T. R., Raymundi A. M., de Souza C. P., Hiroaki-Sato V. A., Kato L., et al. . (2017).�Cannabidiol disrupts the consolidation of specific and generalized fear memories via dorsal hippocampus CB1 and CB2 receptors.�Neuropharmacology125, 220�230. 10.1016/j.neuropharm.2017.07.024�[Cross Ref]
  122. Tysnes O. B., Storstein A. (2017).�Epidemiology of Parkinson’s disease.�J. Neural Transm.124, 901�905. 10.1007/s00702-017-1686-y�[PubMed][Cross Ref]
  123. Valdeolivas S., Sagredo O., Delgado M., Pozo M. A., Fernandez-Ruiz J. (2017).�Effects of a sativex-like combination of phytocannabinoids on disease progression in R6/2 mice, an experimental model of Huntington’s disease.�Int. J. Mol. Sci.18:E684. 10.3390/ijms18040684�[PMC free article][PubMed][Cross Ref]
  124. Valdeolivas S., Satta V., Pertwee R. G., Fernandez-Ruiz J., Sagredo O. (2012).�Sativex-like combination of phytocannabinoids is neuroprotective in malonate-lesioned rats, an inflammatory model of Huntington’s disease: role of CB1 and CB2 receptors.�ACS Chem. Neurosci.3, 400�406. 10.1021/cn200114w�[PMC free article][PubMed][Cross Ref]
  125. Valvassori S. S., Bavaresco D. V., Scaini G., Varela R. B., Streck E. L., Chagas M. H., et al. . (2013).�Acute and chronic administration of cannabidiol increases mitochondrial complex and creatine kinase activity in the rat brain.�Rev. Bras. Psiquiatr.35, 380�386. 10.1590/1516-4446-2012-0886[PubMed][Cross Ref]
  126. Watzl B., Scuderi P., Watson R. R. (1991).�Influence of marijuana components (THC and CBD) on human mononuclear cell cytokine secretion�in vitro, in�Drugs of Abuse, Immunity, and Immunodeficiency, eds Friedman H., Klein T. W., Specter S., editors. (Boston, MA: Springer; ), 63�70.�[PubMed]
  127. Weiss L., Zeira M., Reich S., Har-Noy M., Mechoulam R., Slavin S., et al. . (2006).�Cannabidiol lowers incidence of diabetes in non-obese diabetic mice.�Autoimmunity39, 143�151. 10.1080/08916930500356674�[PubMed][Cross Ref]
  128. Wright M. J., Jr., Vandewater S. A., Taffe M. A. (2013).�Cannabidiol attenuates deficits of visuospatial associative memory induced by Delta(9) tetrahydrocannabinol.�Br. J. Pharmacol.170, 1365�1373. 10.1111/bph.12199�[PMC free article][PubMed][Cross Ref]
  129. Zhang X. Y., Tan Y. L., Zhou D. F., Cao L. Y., Wu G. Y., Haile C. N., et al. . (2007).�Disrupted antioxidant enzyme activity and elevated lipid peroxidation products in schizophrenic patients with tardive dyskinesia.�J. Clin. Psychiatry68, 754�760. 10.4088/JCP.v68n0513�[PubMed][Cross Ref]
  130. Zuardi A. W. (2008).�Cannabidiol: from an inactive cannabinoid to a drug with wide spectrum of action.�Rev. Bras. Psiquiatr.30, 271�280. 10.1590/S1516-44462008000300015�[PubMed][Cross Ref]
  131. Zuardi A. W., Crippa J. A., Hallak J. E., Pinto J. P., Chagas M. H., Rodrigues G. G., et al. . (2009).�Cannabidiol for the treatment of psychosis in Parkinson’s disease.�J. Psychopharmacol.23, 979�983. 10.1177/0269881108096519�[PubMed][Cross Ref]
Close Accordion
Safety and Side Effects of Cannabidiol

Safety and Side Effects of Cannabidiol

Cannabidiol is a compound in the Cannabis sativa plant, also known as marijuana. More than 80 chemicals, called cannabinoids, have been identified in the Cannabis sativa plant. Even though delta-9-tetrahydrocannabinol, or THC, is the major active ingredient, cannabidiol constitutes about 40 percent of cannabis extracts and has been analyzed for many distinct uses. According to the U.S. Food and Drug Administration, or the FDA, because cannabidiol was analyzed as a new drug, products containing cannabidiol are not defined as dietary supplements. But there are still products labeled as dietary supplements available on the marketplace which contain cannabidiol.


Cannabidiol has antipsychotic results. The exact cause for these effects isn’t clear. However, cannabidiol appears to protect against the breakdown of a chemical in the brain that affects pain, mood, and mental function. Preventing the breakdown of this compound and raising its levels in the blood seems to decrease psychotic symptoms related to conditions such as schizophrenia. Cannabidiol may also block some of the untoward effects of delta-9-tetrahydrocannabinol, or THC. Additionally, cannabidiol appears to decrease pain and anxiety. The purpose of the following article is to demonstrate an update on the safety and side effects of cannabidiol involving clinical data and relevant animal studies.


An Update on Safety and Side Effects of Cannabidiol: A Review of Clinical Data and Relevant Animal Studies




  • Introduction: This literature survey aims to extend the comprehensive survey performed by Bergamaschi et al. in 2011 on cannabidiol (CBD) safety and side effects. Apart from updating the literature, this article focuses on clinical studies and CBD potential interactions with other drugs.
  • Results: In general, the often described favorable safety profile of CBD in humans was confirmed and extended by the reviewed research. The majority of studies were performed for treatment of epilepsy and psychotic disorders. Here, the most commonly reported side effects were tiredness, diarrhea, and changes of appetite/weight. In comparison with other drugs, used for the treatment of these medical conditions, CBD has a better side effect profile. This could improve patients’ compliance and adherence to treatment. CBD is often used as adjunct therapy. Therefore, more clinical research is warranted on CBD action on hepatic enzymes, drug transporters, and interactions with other drugs and to see if this mainly leads to positive or negative effects, for example, reducing the needed clobazam doses in epilepsy and therefore clobazam’s side effects.
  • Conclusion: This review also illustrates that some important toxicological parameters are yet to be studied, for example, if CBD has an effect on hormones. Additionally, more clinical trials with a greater number of participants and longer chronic CBD administration are still lacking.
  • Keywords: cannabidiol, cannabinoids, medical uses, safety, side effects, toxicity




Since several years, other pharmacologically relevant constituents of the Cannabis plant, apart from ?9-THC, have come into the focus of research and legislation. The most prominent of those is cannabidiol (CBD). In contrast to ?9-THC, it is nonintoxicating, but exerts a number of beneficial pharmacological effects. For instance, it is anxiolytic, anti-inflammatory, antiemetic, and antipsychotic. Moreover, neuroprotective properties have been shown.1,2 Consequently, it could be used at high doses for the treatment of a variety of conditions ranging in psychiatric disorders such as schizophrenia and dementia, as well as diabetes and nausea.1,2


At lower doses, it has physiological effects that promote and maintain health, including antioxidative, anti-inflammatory, and neuroprotection effects. For instance, CBD is more effective than vitamin C and E as a neuroprotective antioxidant and can ameliorate skin conditions such as acne.3,4


The comprehensive review of 132 original studies by Bergamaschi et al. describes the safety profile of CBD, mentioning several properties: catalepsy is not induced and physiological parameters are not altered (heart rate, blood pressure, and body temperature). Moreover, psychological and psychomotor functions are not adversely affected. The same holds true for gastrointestinal transit, food intake, and absence of toxicity for nontransformed cells. Chronic use and high doses of up to 1500?mg per day have been repeatedly shown to be well tolerated by humans.1


Nonetheless, some side effects have been reported for CBD, but mainly in vitro or in animal studies. They include alterations of cell viability, reduced fertilization capacity, and inhibition of hepatic drug metabolism and drug transporters (e.g., p-glycoprotein).1 Consequently, more human studies have to be conducted to see if these effects also occur in humans. In these studies, a large enough number of subjects have to be enrolled to analyze long-term safety aspects and CBD possible interactions with other substances.


This review will build on the clinical studies mentioned by Bergamaschi et al. and will update their survey with new studies published until September 2016.



Dr. Alex Jimenez’s Insight

Cannabidiol, or CBD, is a cannabis compound which is believed to have significant health benefits and can counteract the psychoactivity of THC. Because CBD is non-psychoactive or less psychoactive than THC-dominant strains, it has become an appealing treatment option for patients experiencing chronic pain, inflammation, anxiety, seizures, psychosis and other conditions without the common side effects. associated with THC. Numerous research studies have been conducted to demonstrate evidence on the health benefits of cannabidiol, or CBD, on the human body.


Relevant Preclinical Studies


Before we discuss relevant animal research on CBD possible effects on various parameters, several important differences between route of administration and pharmacokinetics between human and animal studies have to be mentioned. First, CBD has been studied in humans using oral administration or inhalation. Administration in rodents often occures either via intraperitoneal injection or via the oral route. Second, the plasma levels reached via oral administration in rodents and humans can differ. Both these observations can lead to differing active blood concentrations of CBD.1,5,6


In addition, it is possible that CBD targets differ between humans and animals. Therefore, the same blood concentration might still lead to different effects. Even if the targets, to which CBD binds, are the same in both studied animals and humans, for example, the affinity or duration of CBD binding to its targets might differ and consequently alter its effects.


The following study, which showed a positive effect of CBD on obsessive compulsive behavior in mice and reported no side effects, exemplifies the existing pharmacokinetic differences.5 When mice and humans are given the same CBD dose, more of the compound becomes available in the mouse organism. This higher bioavailability, in turn, can cause larger CBD effects.


Deiana et al. administered 120?mg/kg CBD either orally or intraperitoneally and measured peak plasma levels.5 The group of mice, which received oral CBD, had plasma levels of 2.2??g/ml CBD. In contrast, i.p. injections resulted in peak plasma levels of 14.3??g/ml. Administering 10?mg/kg oral CBD to humans leads to blood levels of 0.01??g/ml.6 This corresponds to human blood levels of 0.12??g/ml, when 120?mg/kg CBD was given to humans. This calculation was performed assuming the pharmacokinetics of a hydrophilic compound, for simplicity’s sake. We are aware that the actual levels of the lipophilic CBD will vary.


A second caveat of preclinical studies is that supraphysiological concentrations of compounds are often used. This means that the observed effects, for instance, are not caused by a specific binding of CBD to one of its receptors but are due to unspecific binding following the high compound concentration, which can inactivate the receptor or transporter.


The following example and calculations will demonstrate this. In vitro studies have shown that CBD inhibits the ABC transporters P-gp (P glycoprotein also referred to as ATP-binding cassette subfamily B member 1=ABCB1; 3�100??M CBD) and Bcrp (Breast Cancer Resistance Protein; also referred to as ABCG2=ATP-binding cassette subfamily G member 2).7 After 3 days, the P-gp protein expression was altered in leukemia cells. This can have several implications because various anticancer drugs also bind to these membrane-bound, energy-dependent efflux transporters.1 The used CBD concentrations are supraphysiological, however, 3??M CBD approximately corresponds to plasma concentrations of 1??g/ml. On the contrary, a 700?mg CBD oral dose reached a plasma level of 10?ng/ml.6 This means that to reach a 1??g/ml plasma concentration, one would need to administer considerably higher doses of oral CBD. The highest ever applied CBD dose was 1500?mg.1 Consequently, more research is warranted, where the CBD effect on ABC transporters is analyzed using CBD concentrations of, for example, 0.03�0.06??M. The rationale behind suggesting these concentrations is that studies summarized by Bih et al. on CBD effect on ABCC1 and ABCG2 in SF9 human cells showed that a CBD concentration of 0.08??M elicited the first effect.7


Using the pharmacokinetic relationships mentioned above, one would need to administer an oral CBD dose of 2100?mg CBD to affect ABCC1 and ABCG2. We used 10?ng/ml for these calculations and the ones in Table 1,6,8 based on a 6-week trial using a daily oral administration of 700?mg CBD, leading to mean plasma levels of 6�11?ng/ml, which reflects the most realistic scenario of CBD administration in patients.6 That these levels seem to be reproducible, and that chronic CBD administration does not lead to elevated mean blood concentrations, was shown by another study. A single dose of 600?mg led to reduced anxiety and mean CBD blood concentrations of 4.7�17?ng/ml.9


Table 1 Inhibition of Human Metabolic Enzymes


It also seems warranted to assume that the mean plasma concentration exerts the total of observed CBD effects, compared to using peak plasma levels, which only prevail for a short amount of time. This is not withstanding, that a recent study measured Cmax values for CBD of 221?ng/ml, 3?h after administration of 1?mg/kg fentanyl concomitantly with a single oral dose of 800?mg CBD.10


CBD-Drug Interactions


Cytochrome P450-complex enzymes. This paragraph describes CBD interaction with general (drug)-metabolizing enzymes, such as those belonging to the cytochrome P450 family. This might have an effect for coadministration of CBD with other drugs.7 For instance, CBD is metabolized, among others, via the CYP3A4 enzyme. Various drugs such as ketoconazol, itraconazol, ritonavir, and clarithromycin inhibit this enzyme.11 This leads to slower CBD degradation and can consequently lead to higher CBD doses that are longer pharmaceutically active. In contrast, phenobarbital, rifampicin, carbamazepine, and phenytoin induce CYP3A4, causing reduced CBD bioavailability.11 Approximately 60% of clinically prescribed drugs are metabolized via CYP3A4.1 Table 1 shows an overview of the cytochrome inhibiting potential of CBD. It has to be pointed out though, that the in vitro studies used supraphysiological CBD concentrations.


Studies in mice have shown that CBD inactivates cytochrome P450 isozymes in the short term, but can induce them after repeated administration. This is similar to their induction by phenobarbital, thereby implying the 2b subfamily of isozymes.1 Another study showed this effect to be mediated by upregulation of mRNA for CYP3A, 2C, and 2B10, after repeated CBD administration.1


Hexobarbital is a CYP2C19 substrate, which is an enzyme that can be inhibited by CBD and can consequently increase hexobarbital availability in the organism.12,13 Studies also propose that this effect might be caused in vivo by one of CBD metabolites.14,15 Generally, the metabolite 6a-OH-CBD was already demonstrated to be an inducer of CYP2B10. Recorcinol was also found to be involved in CYP450 induction. The enzymes CYP3A and CYP2B10 were induced after prolonged CBD administration in mice livers, as well as for human CYP1A1 in vitro.14,15 On the contrary, CBD induces CYP1A1, which is responsible for degradation of cancerogenic substances such as benzopyrene. CYP1A1 can be found in the intestine and CBD-induced higher activity could therefore prevent absorption of cancerogenic substances into the bloodstream and thereby help to protect DNA.2


Effects on P-glycoprotein activity and other drug transporters. A recent study with P-gp, Bcrp, and P-gp/Bcrp knockout mice, where 10?mg/kg was injected subcutaneously, showed that CBD is not a substrate of these transporters itself. This means that they do not reduce CBD transport to the brain.16 This phenomenon also occurs with paracetamol and haloperidol, which both inhibit P-gp, but are not actively transported substrates. The same goes for gefitinib inhibition of Bcrp.


These proteins are also expressed at the blood�brain barrier, where they can pump out drugs such as risperidone. This is hypothesized to be a cause of treatment resistance.16 In addition, polymorphisms in these genes, making transport more efficient, have been implied in interindividual differences in pharmacoresistance.10 Moreover, the CBD metabolite 7-COOH CBD might be a potent anticonvulsant itself.14 It will be interesting to see whether it is a P-gp substrate and alters pharmacokinetics of coadministered P-gp-substrate drugs.


An in vitro study using three types of trophoblast cell lines and ex vivo placenta, perfused with 15??M CBD, found BCRP inhibition leading to accumulation of xenobiotics in the fetal compartment.17 BCRP is expressed at the apical side of the syncytiotrophoblast and removes a wide variety of compounds forming a part of the placental barrier. Seventy-two hours of chronic incubation with 25??M CBD also led to morphological changes in the cell lines, but not to a direct cytotoxic effect. In contrast, 1??M CBD did not affect cell and placenta viability.17 The authors consider this effect cytostatic. Nicardipine was used as the BCRP substrate in the in vitro studies, where the Jar cell line showed the largest increase in BCRP expression correlating with the highest level of transport.17,and references therein


The ex vivo study used the antidiabetic drug and BCRP substrate glyburide.17 After 2?h of CBD perfusion, the largest difference between the CBD and the placebo placentas (n=8 each) was observed. CBD inhibition of the BCRP efflux function in the placental cotyledon warrants further research of coadministration of CBD with known BCRP substrates such as nitrofurantoin, cimetidine, and sulfasalazine. In this study, a dose�response curve should be established in male and female subjects (CBD absorption was shown to be higher in women) because the concentrations used here are usually not reached by oral or inhaled CBD administration. Nonetheless, CBD could accumulate in organs physiologically restricted via a blood barrier.17


Physiological Effects


CBD treatment of up to 14 days (3�30?mg/kg b.w. i.p.) did not affect blood pressure, heart rate, body temperature, glucose levels, pH, pCO2, pO2, hematocrit, K+ or Na+ levels, gastrointestinal transit, emesis, or rectal temperature in a study with rodents.1


Mice treated with 60?mg/kg b.w. CBD i.p. for 12 weeks (three times per week) did not show ataxia, kyphosis, generalized tremor, swaying gait, tail stiffness, changes in vocalization behavior or open-field physiological activity (urination, defecation).1


Neurological and Neurospychiatric Effects


Anxiety and depression. Some studies indicate that under certain circumstances, CBD acute anxiolytic effects in rats were reversed after repeated 14-day administration of CBD.2 However, this finding might depend on the used animal model of anxiety or depression. This is supported by a study, where CBD was administered in an acute and �chronic� (2 weeks) regimen, which measured anxiolytic/antidepressant effects, using behavioral and operative models (OBX=olfactory bulbectomy as model for depression).18 The only observed side effects were reduced sucrose preference, reduced food consumption and body weight in the nonoperated animals treated with CBD (50?mg/kg). Nonetheless, the behavioral tests (for OBX-induced hyperactivity and anhedonia related to depression and open field test for anxiety) in the CBD-treated OBX animals showed an improved emotional response. Using microdialysis, the researchers could also show elevated 5-HT and glutamate levels in the prefrontal cortex of OBX animals only. This area was previously described to be involved in maladaptive behavioral regulation in depressed patients and is a feature of the OBX animal model of depression. The fact that serotonin levels were only elevated in the OBX mice is similar to CBD differential action under physiological and pathological conditions.


A similar effect was previously described in anxiety experiments, where CBD proved to be only anxiolytic in subjects where stress had been induced before CBD administration. Elevated glutamate levels have been proposed to be responsible for ketamine’s fast antidepressant function and its dysregulation has been described in OBX mice and depressed patients. Chronic CBD treatment did not elicit behavioral changes in the nonoperated mice. In contrast, CBD was able to alleviate the affected functionality of 5HT1A receptors in limbic brain areas of OBX mice.18 and references therein.


Schiavon et al. cite three studies that used chronic CBD administration to demonstrate its anxiolytic effects in chronically stressed rats, which were mostly mediated via hippocampal neurogenesis.19 and references therein For instance, animals received daily i.p. injections of 5?mg/kg CBD. Applying a 5HT1A receptor antagonist in the DPAG (dorsal periaqueductal gray area), it was implied that CBD exerts its antipanic effects via these serotonin receptors. No adverse effects were reported in this study.


Psychosis and bipolar disorder. Various studies on CBD and psychosis have been conducted.20 For instance, an animal model of psychosis can be created in mice by using the NMDAR antagonist MK-801. The behavioral changes (tested with the prepulse inhibition [PPI] test) were concomitant with decreased mRNA expression of the NMDAR GluN1 subunit gene (GRN1) in the hippocampus, decreased parvalbumin expression (=a calcium-binding protein expressed in a subclass of GABAergic interneurons), and higher FosB/?FosB expression (=markers for neuronal activity). After 6 days of MK-801 treatment, various CBD doses were injected intraperitoneally (15, 30, 60?mg/kg) for 22 days. The two higher CBD doses had beneficial effects comparable to the atypical antipsychotic drug clozapine and also attenuated the MK-801 effects on the three markers mentioned above. The publication did not record any side effects.21


One of the theories trying to explain the etiology of bipolar disorder (BD) is that oxidative stress is crucial in its development. Valvassori et al. therefore used an animal model of amphetamine-induced hyperactivity to model one of the symptoms of mania. Rats were treated for 14 days with various CBD concentrations (15, 30, 60?mg/kg daily i.p.). Whereas CBD did not have an effect on locomotion, it did increase brain-derived neurotrophic factor (BDNF) levels and could protect against amphetamine-induced oxidative damage in proteins of the hippocampus and striatum. No adverse effects were recorded in this study.22


Another model for BD and schizophrenia is PPI of the startle reflex both in humans and animals, which is disrupted in these diseases. Peres et al., list five animal studies, where mostly 30?mg/kg CBD was administered and had a positive effect on PPI.20 Nonetheless, some inconsistencies in explaining CBD effects on PPI as model for BD exist. For example, CBD sometimes did not alter MK-801-induced PPI disruption, but disrupted PPI on its own.20 If this effect can be observed in future experiments, it could be considered to be a possible side effect.


Addiction. CBD, which is nonhedonic, can reduce heroin-seeking behavior after, for example, cue-induced reinstatement. This was shown in an animal heroin self-administration study, where mice received 5?mg/kg CBD i.p. injections. The observed effect lasted for 2 weeks after CBD administration and could normalize the changes seen after stimulus cue-induced heroin seeking (expression of AMPA, GluR1, and CB1R). In addition, the described study was able to replicate previous findings showing no CBD side effects on locomotor behavior.23


Neuroprotection and neurogenesis. There are various mechanisms underlying neuroprotection, for example, energy metabolism (whose alteration has been implied in several psychiatric disorders) and proper mitochondrial functioning.24 An early study from 1976 found no side effects and no effect of 0.3�300??g/mg protein CBD after 1?h of incubation on mitochondrial monoamine oxidase activity in porcine brains.25 In hypoischemic newborn pigs, CBD elicited a neuroprotective effect, caused no side effects, and even led to beneficial effects on ventilatory, cardiac, and hemodynamic functions.26


A study comparing acute and chronic CBD administration in rats suggests an additional mechanism of CBD neuroprotection: Animals received i.p. CBD (15, 30, 60?mg/kg b.w.) or vehicle daily, for 14 days. Mitochondrial activity was measured in the striatum, hippocampus, and the prefrontal cortex.27 Acute and chronic CBD injections led to increased mitochondrial activity (complexes I-V) and creatine kinase, whereas no side effects were documented. Chronic CBD treatment and the higher CBD doses tended to affect more brain regions. The authors hypothesized that CBD changed the intracellular Ca2+ flux to cause these effects. Since the mitochondrial complexes I and II have been implied in various neurodegenerative diseases and also altered ROS (reactive oxygen species) levels, which have also been shown to be altered by CBD, this might be an additional mechanism of CBD-mediated neuroprotection.1,27


Interestingly, it has recently been shown that the higher ROS levels observed after CBD treatment were concomitant with higher mRNA and protein levels of heat shock proteins (HSPs). In healthy cells, this can be interpreted as a way to protect against the higher ROS levels resulting from more mitochondrial activity. In addition, it was shown that HSP inhibitors increase the CBD anticancer effect in vitro.28 This is in line with the studies described by Bergamaschi et al., which also imply ROS in CBD effect on (cancer) cell viability in addition to, for example, proapoptotic pathways such as via caspase-8/9 and inhibition of the procarcinogenic lipoxygenase pathway.1


Another publication studied the difference of acute and chronic administration of two doses of CBD in nonstressed mice on anxiety. Already an acute i.p. administration of 3?mg/kg was anxiolytic to a degree comparable to 20?mg/kg imipramine (an selective serotonin reuptake inhibitor [SSRI] commonly prescribed for anxiety and depression). Fifteen days of repeated i.p. administration of 3?mg/kg CBD also increased cell proliferation and neurogenesis (using three different markers) in the subventricular zone and the hippocampal dentate gyrus. Interestingly, the repeated administration of 30?mg/kg also led to anxiolytic effects. However, the higher dose caused a decrease in neurogenesis and cell proliferation, indicating dissociation of behavioral and proliferative effects of chronic CBD treatment. The study does not mention adverse effects.19


Immune System


Numerous studies show the CBD immunomodulatory role in various diseases such as multiple sclerosis, arthritis, and diabetes. These animal and human ex vivo studies have been reviewed extensively elsewhere, but studies with pure CBD are still lacking. Often combinations of THC and CBD were used. It would be especially interesting to study when CBD is proinflammatory and under which circumstances it is anti-inflammatory and whether this leads to side effects (Burstein, 2015: Table 1 shows a summary of its anti-inflammatory actions; McAllister et al. give an extensive overview in Table 1 of the interplay between CBD anticancer effects and inflammation signaling).29,30


In case of Alzheimer’s disease (AD), studies in mice and rats showed reduced amyloid beta neuroinflammation (linked to reduced interleukin [IL]-6 and microglial activation) after CBD treatment. This led to amelioration of learning effects in a pharmacological model of AD. The chronic study we want to describe in more detail here used a transgenic mouse model of AD, where 2.5-month-old mice were treated with either placebo or daily oral CBD doses of 20?mg/kg for 8 months (mice are relatively old at this point). CBD was able to prevent the development of a social recognition deficit in the AD transgenic mice.


Moreover, the elevated IL-1 beta and TNF alpha levels observed in the transgenic mice could be reduced to WT (wild-type) levels with CBD treatment. Using statistical analysis by analysis of variance, this was shown to be only a trend. This might have been caused by the high variation in the transgenic mouse group, though. Also, CBD increased cholesterol levels in WT mice but not in CBD-treated transgenic mice. This was probably due to already elevated cholesterol in the transgenic mice. The study observed no side effects.31 and references within


In nonobese diabetes-prone female mice (NOD), CBD was administered i.p. for 4 weeks (5 days a week) at a dose of 5?mg/kg per day. After CBD treatment was stopped, observation continued until the mice were 24 weeks old. CBD treatment lead to considerable reduction of diabetes development (32% developed glucosuria in the CBD group compared to 100% in untreated controls) and to more intact islet of Langerhans cells. CBD increased IL-10 levels, which is thought to act as an anti-inflammatory cytokine in this context. The IL-12 production of splenocytes was reduced in the CBD group and no side effects were recorded.32


After inducing arthritis in rats using Freund’s adjuvant, various CBD doses (0.6, 3.1, 6.2, or 62.3?mg/day) were applied daily in a gel for transdermal administration for 4 days. CBD reduced joint swelling, immune cell infiltration. thickening of the synovial membrane, and nociceptive sensitization/spontaneous pain in a dose-dependent manner, after four consecutive days of CBD treatment. Proinflammatory biomarkers were also reduced in a dose-dependent manner in the dorsal root ganglia (TNF alpha) and spinal cord (CGRP, OX42). No side effects were evident and exploratory behavior was not altered (in contrast to ?9-THC, which caused hypolocomotion).33


Cell Migration


Embryogenesis. CBD was shown to be able to influence migratory behavior in cancer, which is also an important aspect of embryogenesis.1 For instance, it was recently shown that CBD inhibits Id-1. Helix-loop-helix Id proteins play a role in embryogenesis and normal development via regulation of cell differentiation. High Id1-levels were also found in breast, prostate, brain, and head and neck tumor cells, which were highly aggressive. In contrast, Id1 expression was low in noninvasive tumor cells. Id1 seems to influence the tumor cell phenotype by regulation of invasion, epithelial to mesenchymal transition, angiogenesis, and cell proliferation.34


There only seems to exist one study that could not show an adverse CBD effect on embryogenesis. An in vitro study could show that the development of two-cell embryos was not arrested at CBD concentrations of 6.4, 32, and 160?nM.35


Cancer. Various studies have been performed to study CBD anticancer effects. CBD anti-invasive actions seem to be mediated by its TRPV1 stimulation and its action on the CB receptors. Intraperitoneal application of 5?mg/kg b.w. CBD every 3 days for a total of 28 weeks, almost completely reduced the development of metastatic nodules caused by injection of human lung carcinoma cells (A549) in nude mice.36 This effect was mediated by upregulation of ICAM1 and TIMP1. This, in turn, was caused by upstream regulation of p38 and p42/44 MAPK pathways. The typical side effects of traditional anticancer medication, emesis, and collateral toxicity were not described in these studies. Consequently, CBD could be an alternative to other MMP1 inhibitors such as marimastat and prinomastat, which have shown disappointing clinical results due to these drugs’ adverse muscoskeletal effects.37,38


Two studies showed in various cell lines and in tumor-bearing mice that CBD was able to reduce tumor metastasis.34,39 Unfortunately, the in vivo study was only described in a conference abstract and no route of administration or CBD doses were mentioned.36 However, an earlier study used 0.1, 1.0, or 1.5??mol/L CBD for 3 days in the aggressive breast cancer cells MDA-MB231. CBD downregulated Id1 at promoter level and reduced tumor aggressiveness.40


Another study used xenografts to study the proapoptotic effect of CBD, this time in LNCaP prostate carcinoma cells.36 In this 5-week study, 100?mg/kg CBD was administered daily i.p. Tumor volume was reduced by 60% and no adverse effects of treatment were described in the study. The authors assumed that the observed antitumor effects were mediated via TRPM8 together with ROS release and p53 activation.41 It has to be pointed out though, that xenograft studies only have limited predictive validity to results with humans. Moreover, to carry out these experiments, animals are often immunologically compromised, to avoid immunogenic reactions as a result to implantation of human cells into the animals, which in turn can also affect the results.42


Another approach was chosen by Aviello et al.43 They used the carcinogen azoxymethane to induce colon cancer in mice. Treatment occurred using IP injections of 1 or 5?mg/kg CBD, three times a week for 3 weeks (including 1 week before carcinogen administration). After 3 months, the number of aberrant crypt foci, polyps, and tumors was analyzed. The high CBD concentration led to a significant decrease in polyps and a return to near-normal levels of phosphorylated Akt (elevation caused by the carcinogen).42 No adverse effects were mentioned in the described study.43


Food Intake and Glycemic Effects


Animal studies summarized by Bergamaschi et al. showed inconclusive effects of CBD on food intake1: i.p. administration of 3�100?mg/kg b.w. had no effect on food intake in mice and rats. On the contrary, the induction of hyperphagia by CB1 and 5HT1A agonists in rats could be decreased with CBD (20?mg/kg b.w. i.p.). Chronic administration (14 days, 2.5 or 5?mg/kg i.p.) reduced the weight gain in rats. This effect could be inhibited by coadministration of a CB2R antagonist.1


The positive effects of CBD on hyperglycemia seem to be mainly mediated via CBD anti-inflammatory and antioxidant effects. For instance, in ob/ob mice (an animal model of obesity), 4-week treatment with 3?mg/kg (route of administration was not mentioned) increased the HDL-C concentration by 55% and reduced total cholesterol levels by more than 25%. In addition, treatment increased adiponectin and liver glycogen concentrations.44 and references therein.


Endocrine Effects


High CBD concentrations (1?mM) inhibited progesterone 17-hydroxylase, which creates precursors for sex steroid and glucocorticoid synthesis, whereas 100??M CBD did not in an in vitro experiment with primary testis microsomes.45 Rats treated with 10?mg/kg i.p. b.w. CBD showed inhibition of testosterone oxidation in the liver.46


Genotoxicity and Mutagenicity


Jones et al. mention that 120?mg/kg CBD delivered intraperetonially to Wistar Kyoto rats showed no mutagenicity and genotoxicity based on personal communication with GW Pharmaceuticals47,48 These data are yet to be published. The 2012 study with an epilepsy mouse model could also show that CBD did not influence grip strength, which the study describes as a �putative test for functional neurotoxicity.�48


Motor function was also tested on a rotarod, which was also not affected by CBD administration. Static beam performance, as an indicator of sensorimotor coordination, showed more footslips in the CBD group, but CBD treatment did not interfere with the animals’ speed and ability to complete the test. Compared to other anticonvulsant drugs, this effect was minimal.48 Unfortunately, we could not find more studies solely focusing on genotoxicity by other research groups neither in animals nor in humans.



Dr. Alex Jimenez’s Insight

Clinical and scientific research has attempted to show the effects of cannabidiol, or CBD, for the treatment of a wide range of conditions, including arthritis, diabetes, multiple sclerosis, chronic pain, schizophrenia, PTSD, depression, anxiety, infections, epilepsy, and many other neurological disorders. Evidence has also found that cannabidiol has neuroprotective and neurogenic effects and its anti-cancer properties are currently being investigated in many research studies. Further evidence has suggested that CBD can also be safe and effective even in higher doses, as recommended by a healthcare professional.


Acute Clinical Data


Bergamaschi et al. list an impressive number of acute and chronic studies in humans, showing CBD safety for a wide array of side effects.1 They also conclude from their survey, that none of the studies reported tolerance to CBD. Already in the 1970s, it was shown that oral CBD (15�160?mg), iv injection (5�30?mg), and inhalation of 0.15?mg/kg b.w. CBD did not lead to adverse effects. In addition, psychomotor function and psychological functions were not disturbed. Treatment with up to 600?mg CBD neither influenced physiological parameters (blood pressure, heart rate) nor performance on a verbal paired-associate learning test.1


Fasinu et al. created a table with an overview of clinical studies currently underway, registered in Clinical Trials. gov.49 In the following chapter, we highlight recent, acute clinical studies with CBD.


CBD-Drug Interactions


CBD can inhibit CYP2D6, which is also targeted by omeprazole and risperidone.2,14 There are also indications that CBD inhibits the hepatic enzyme CYP2C9, reducing the metabolization of warfarin and diclofenac.2,14 More clinical studies are needed, to check whether this interaction warrants an adaption of the used doses of the coadministered drugs.


The antibiotic rifampicin induces CYP3A4, leading to reduced CBD peak plasma concentrations.14 In contrast, the CYP3A4 inhibitor ketoconazole, an antifungal drug, almost doubles CBD peak plasma concentration. Interestingly, the CYP2C19 inhibitor omeprazole, used to treat gastroesophageal reflux, could not significantly affect the pharmacokinetics of CBD.14


A study, where a regimen of 6�100?mg CBD daily was coadministered with hexobarbital in 10 subjects, found that CBD increased the bioavailability and elimination half-time of the latter. Unfortunately, it was not mentioned whether this effect was mediated via the cytochrome P450 complex.16


Another aspect, which has not been thoroughly looked at, to our knowledge, is that several cytochrome isozymes are not only expressed in the liver but also in the brain. It might be interesting to research organ-specific differences in the level of CBD inhibition of various isozymes. Apart from altering the bioavailability in the overall plasma of the patient, this interaction might alter therapeutic outcomes on another level. Dopamine and tyramine are metabolized by CYP2D6, and neurosteroid metabolism also occurs via the isozymes of the CYP3A subgroup.50,51 Studying CBD interaction with neurovascular cytochrome P450 enzymes might also offer new mechanisms of action. It could be possible that CBD-mediated CYP2D6 inhibition increases dopamine levels in the brain, which could help to explain the positive CBD effects in addiction/withdrawal scenarios and might support its 5HT (=serotonin) elevating effect in depression.


Also, CBD can be a substrate of UDP glucuronosyltransferase.14 Whether this enzyme is indeed involved in the glucuronidation of CBD and also causes clinically relevant drug interactions in humans is yet to be determined in clinical studies. Generally, more human studies, which monitor CBD-drug interactions, are needed.


Physiological Effects


In a double-blind, placebo-controlled crossover study, CBD was coadministered with intravenous fentanyl to a total of 17 subjects.10 Blood samples were obtained before and after 400?mg CBD (previously demonstrated to decrease blood flow to (para)limbic areas related to drug craving) or 800?mg CBD pretreatment. This was followed by a single 0.5 (Session 1) or 1.0?g/kg (Session 2, after 1 week of first administration to allow for sufficient drug washout) intravenous fentanyl dose. Adverse effects and safety were evaluated with both forms of the Systematic Assessment for Treatment Emergent Events (SAFTEE). This extensive tool tests, for example, 78 adverse effects divided into 23 categories corresponding to organ systems or body parts. The SAFTEE outcomes were similar between groups. No respiratory depression or cardiovascular complications were recorded during any test session.


The results of the evaluation of pharmacokinetics, to see if interaction between the drugs occurred, were as follows. Peak CBD plasma concentrations of the 400 and 800?mg group were measured after 4?h in the first session (CBD administration 2?h after light breakfast). Peak urinary CBD and its metabolite concentrations occurred after 6?h in the low CBD group and after 4?h in the high CBD group. No effect was evident for urinary CBD and metabolite excretion except at the higher fentanyl dose, in which CBD clearance was reduced. Importantly, fentanyl coadministration did not produce respiratory depression or cardiovascular complications during the test sessions and CBD did not potentiate fentanyl’s effects. No correlation was found between CBD dose and plasma cortisol levels.


Various vital signs were also measured (blood pressure, respiratory/heart rate, oxygen saturation, EKG, respiratory function): CBD did not worsen the adverse effects (e.g., cardiovascular compromise, respiratory depression) of iv fentanyl. Coadministration was safe and well tolerated, paving the way to use CBD as a potential treatment for opioid addiction. The validated subjective measures scales Anxiety (visual analog scale [VAS]), PANAS (positive and negative subscores), and OVAS (specific opiate VAS) were administered across eight time points for each session without any significant main effects for CBD for any of the subjective effects on mood.10


A Dutch study compared subjective adverse effects of three different strains of medicinal cannabis, distributed via pharmacies, using VAS. �Visual analog scale is one of the most frequently used psychometric instruments to measure the extent and nature of subjective effects and adverse effects. The 12 adjectives used for this study were as follows: alertness, tranquility, confidence, dejection, dizziness, confusion/disorientation, fatigue, anxiety, irritability, appetite, creative stimulation, and sociability.� The high CBD strain contained the following concentrations: 6% ?9-THC/7.5% CBD (n=25). This strain showed significantly lower levels of anxiety and dejection. Moreover, appetite increased less in the high CBD strain. The biggest observed adverse effect was �fatigue� with a score of 7 (out of 10), which did not differ between the three strains.52


Neurological and Neurospychiatric Effects


Anxiety. Forty-eight participants received subanxiolytic levels (32?mg) of CBD, either before or after the extinction phase in a double-blind, placebo-controlled design of a Pavlovian fear-conditioning experiment (recall with conditioned stimulus and context after 48?h and exposure to unconditioned stimulus after reinstatement). Skin conductance (=autonomic response to conditioning) and shock expectancy measures (=explicit aspects) of conditioned responding were recorded throughout. Among other scales, the Mood Rating Scale (MRS) and the Bond and Bodily Symptoms Scale were used to assess anxiety, current mood, and physical symptoms. �CBD given postextinction (active after consolidation phase) enhanced consolidation of extinction learning as assessed by shock expectancy.� Apart from the extinction-enhancing effects of CBD in human aversive conditioned memory, CBD showed a trend toward some protection against reinstatement of contextual memory. No side/adverse effects were reported.53


Psychosis. The review by Bergamaschi et al. mentions three acute human studies that have demonstrated the CBD antipsychotic effect without any adverse effects being observed. This holds especially true for the extrapyramidal motor side effects elicited by classical antipsychotic medication.1


Fifteen male, healthy subjects with minimal prior ?9-THC exposure (<15 times) were tested for CBD affecting ?9-THC propsychotic effects using functional magnetic resonance imaging (fMRI) and various questionnaires on three occasions, at 1-month intervals, following administration of 10?mg delta-9-?9-THC, 600?mg CBD, or placebo. Order of drug administration was pseudorandomized across subjects, so that an equal number of subjects received any of the drugs during the first, second, or third session in a double-blind, repeated-measures, within-subject design.54 No CBD effect on psychotic symptoms as measured with PANSS positive symptoms subscale, anxiety as indexed by the State Trait Anxiety Inventory (STAI) state, and Visual Analogue Mood Scale (VAMS) tranquilization or calming subscale, compared to the placebo group, was observed. The same is true for a verbal learning task (=behavioral performance of the verbal memory).


Moreover, pretreatment with CBD and subsequent ?9-THC administration could reduce the latter’s psychotic and anxiety symptoms, as measured using a standardized scale. This effect was caused by opposite neural activation of relevant brain areas. In addition, no effects on peripheral cardiovascular measures such as heart rate and blood pressure were measured.54


A randomized, double-blind, crossover, placebo-controlled trial was conducted in 16 healthy nonanxious subjects using a within-subject design. Oral ?9-THC=10?mg, CBD=600?mg, or placebo was administered in three consecutive sessions at 1-month intervals. The doses were selected to only evoke neurocognitive effects without causing severe toxic, physical, or psychiatric reactions. The 600?mg CBD corresponded to mean (standard deviation) whole blood levels of 0.36 (0.64), 1.62 (2.98), and 3.4 (6.42) ng/mL, 1, 2, and 3?h after administration, respectively.


Physiological measures and symptomatic effects were assessed before, and at 1, 2, and 3?h postdrug administration using PANSS (a 30-item rating instrument used to assess psychotic symptoms, with ratings based on a semistructured clinical interview yielding subscores for positive, negative, and general psychopathology domains), the self-administered VAMS with 16 items (e.g., mental sedation or intellectual impairment, physical sedation or bodily impairments, anxiety effects and other types of feelings or attitudes), the ARCI (Addiction Research Center Inventory; containing empirically derived drug-induced euphoria; stimulant-like effects; intellectual efficiency and energy; sedation; dysphoria; and somatic effects) to assess drug effects and the STAI-T/S, where subjects were evaluated on their current mood and their feelings in general.


There were no significant differences between the effects of CBD and placebo on positive and negative psychotic symptoms, general psychopathology (PANSS), anxiety (STAI-S), dysphoria (ARCI), sedation (VAMS, ARCI), and the level of subjective intoxication (ASI, ARCI), where ?9-THC did have a pronounced effect. The physiological parameters, heart rate and blood pressure, were also monitored and no significant difference between the placebo and the CBD group was observed.55


Addiction. A case study describes a patient treated for cannabis withdrawal according to the following CBD regimen: �treated with oral 300?mg on Day 1; CBD 600?mg on Days 2�10 (divided into two doses of 300?mg), and CBD 300?mg on Day 11.� CBD treatment resulted in a fast and progressive reduction in withdrawal, dissociative and anxiety symptoms, as measured with the Withdrawal Discomfort Score, the Marijuana Withdrawal Symptom Checklist, Beck Anxiety Inventory, and Beck Depression Inventory (BDI). Hepatic enzymes were also measured daily, but no effect was reported.56


Naturalistic studies with smokers inhaling cannabis with varying amounts of CBD showed that the CBD levels were not altering psychomimetic symptoms.1 Interestingly, CBD was able to reduce the �wanting/liking�=implicit attentional bias caused by exposure to cannabis and food-related stimuli. CBD might work to alleviate disorders of addiction, by altering the attentive salience of drug cues. The study did not further measure side effects.57


CBD can also reduce heroin-seeking behaviors (e.g., induced by a conditioned cue). This was shown in the preclinical data mentioned earlier and was also replicated in a small double-blind pilot study with individuals addicted to opioids, who have been abstinent for 7 days.52,53 They either received placebo or 400 or 800?mg oral CBD on three consecutive days. Craving was induced with a cue-induced reinstatement paradigm (1?h after CBD administration). One hour after the video session, subjective craving was already reduced after a single CBD administration. The effect persisted for 7 days after the last CBD treatment. Interestingly, anxiety measures were also reduced after treatment, whereas no adverse effects were described.23,58


A pilot study with 24 subjects was conducted in a randomized, double-blind, placebo-controlled design to evaluate the impact of the ad hoc use of CBD in smokers, who wished to stop smoking. Pre- and post-testing for mood and craving of the participants was executed. These tests included the Behaviour Impulsivity Scale, BDI, STAI, and the Severity of Dependence Scale. During the week of CBD inhalator use, subjects used a diary to log their craving (on a scale from 1 to 100=VAS measuring momentary subjective craving), the cigarettes smoked, and the number of times they used the inhaler. Craving was assessed using the Tiffany Craving Questionnaire (11). On day 1 and 7, exhaled CO was measured to test smoking status. Sedation, depression, and anxiety were evaluated with the MRS.


Over the course of 1 week, participants used the inhaler when they felt the urge to smoke and received a dose of 400??g CBD via the inhaler (leading to >65% bioavailability); this significantly reduced the number of cigarettes smoked by ca. 40%, while craving was not significantly different in the groups post-test. At day 7, the anxiety levels for placebo and CBD group did not differ. CBD did not increase depression (in contract to the selective CB1 antagonist rimonabant). CBD might weaken the attentional bias to smoking cues or could have disrupted reconsolidation, thereby destabilizing drug-related memories.59


Cell Migration


According to our literature survey, there currently are no studies about CBD role in embryogenesis/cell migration in humans, even though cell migration does play a role in embryogenesis and CBD was shown to be able to at least influence migratory behavior in cancer.1


Endocrine Effects and Glycemic (Including Appetite) Effects


To the best of our knowledge, no acute studies were performed that solely concentrated on CBD glycemic effects. Moreover, the only acute study that also measured CBD effect on appetite was the study we described above, comparing different cannabis strains. In this study, the strain high in CBD elicited less appetite increase compared to the THC-only strain.52


Eleven healthy volunteers were treated with 300?mg (seven patients) and 600?mg (four patients) oral CBD in a double-blind, placebo-controlled study. Growth hormone and prolactin levels were unchanged. In contrast, the normal decrease of cortisol levels in the morning (basal measurement=11.0�3.7??g/dl; 120?min after placebo=7.1�3.9??g/dl) was inhibited by CBD treatment (basal measurement=10.5�4.9??g/dl; 120?min after 300?mg CBD=9.9�6.2??g/dl; 120?min after 600?mg CBD=11.6�11.6??g/dl).60


A more recent study also used 600?mg oral CBD for a week and compared 24 healthy subjects to people at risk for psychosis (n=32; 16 received placebo and 16 CBD). Serum cortisol levels were taken before the TSST (Trier Social Stress Test), immediately after, as well as 10 and 20?min after the test. Compared to the healthy individuals, the cortisol levels increased less after TSST in the 32 at-risk individuals. The CBD group showed less reduced cortisol levels but differences were not significant.61 It has to be mentioned that these data were presented at a conference and are not yet published (to our knowledge) in a peer-reviewed journal.


Chronic CBD Studies in Humans


Truly chronic studies with CBD are still scarce. One can often argue that what the studies call �chronic� CBD administration only differs to acute treatment, because of repeated administration of CBD. Nonetheless, we also included these studies with repeated CBD treatment, because we think that compared to a one-time dose of CBD, repeated CBD regimens add value and knowledge to the field and therefore should be mentioned here.


CBD-Drug Interactions


An 8-week-long clinical study, including 13 children who were treated for epilepsy with clobazam (initial average dose of 1?mg/kg b.w.) and CBD (oral; starting dose of 5?mg/kg b.w. raised to maximum of 25?mg/kg b.w.), showed the following. The CBD interaction with isozymes CYP3A4 and CYP2C19 caused increased clobazam bioavailability, making it possible to reduce the dose of the antiepileptic drug, which in turn reduced its side effects.62


These results are supported by another study described in the review by Grotenhermen et al.63 In this study, 33 children were treated with a daily dose of 5?mg/kg CBD, which was increased every week by 5?mg/kg increments, up to a maximum level of 25?mg/kg. CBD was administered on average with three other drugs, including clobazam (54.5%), valproic acid (36.4%), levetiracetam (30.3%), felbamate (21.2%), lamotrigine (18.2%), and zonisamide (18.2%). The coadministration led to an alteration of blood levels of several antiepileptic drugs. In the case of clobazam this led to sedation, and its levels were subsequently lowered in the course of the study.


Physiological Effects


A first pilot study in healthy volunteers in 1973 by Mincis et al. administering 10?mg oral CBD for 21 days did not find any neurological and clinical changes (EEG; EKG).64 The same holds true for psychiatry and blood and urine examinations. A similar testing battery was performed in 1980, at weekly intervals for 30 days with daily oral CBD administration of 3?mg/kg b.w., which had the same result.65


Neurological and Neuropsychiatric Effects


Anxiety. Clinical chronic (lasting longer than a couple of weeks) studies in humans are crucial here but were mostly still lacking at the time of writing this review. They hopefully will shed light on the inconsistencies observerd in animal studies. Chronic studies in humans may, for instance, help to test whether, for example, an anxiolytic effect always prevails after chronic CBD treatment or whether this was an artifact of using different animal models of anxiety or depression.2,18


Psychosis and bipolar disorder. In a 4-week open trial, CBD was tested on Parkinson’s patients with psychotic symptoms. Oral doses of 150�400?mg/day CBD (in the last week) were administered. This led to a reduction of their psychotic symptoms. Moreover, no serious side effects or cognitive and motor symptoms were reported.66


Bergamaschi et al. describe a chronic study, where a teenager with severe side effects of traditional antipsychotics was treated with up to 1500?mg/day of CBD for 4 weeks. No adverse effects were observed and her symptoms improved. The same positive outcome was registered in another study described by Bergamaschi et al., where three patients were treated with a starting dose of CBD of 40?mg, which was ramped up to 1280?mg/day for 4 weeks.1 A double-blind, randomized clinical trial of CBD versus amisulpride, a potent antipsychotic in acute schizophrenia, was performed on a total of 42 subjects, who were treated for 28 days starting with 200?mg CBD per day each.67 The dose was increased stepwise by 200?mg per day to 4�200?mg CBD daily (total 800?mg per day) within the first week. The respective treatment was maintained for three additional weeks. A reduction of each treatment to 600?mg per day was allowed for clinical reasons, such as unwanted side effects after week 2. This was the case for three patients in the CBD group and five patients in the amisulpride group. While both treatments were effective (no significant difference in PANSS total score), CBD showed the better side effect profile. Amisulpride, working as a dopamine D2/D3-receptor antagonist, is one of the most effective treatment options for schizophrenia. CBD treatment was accompanied by a substantial increase in serum anandamide levels, which was significantly associated with clinical improvement, suggesting inhibition of anandamide deactivation via reduced FAAH activity.


In addition, the FAAH substrates palmitoylethanolamide and linoleoyl-ethanolamide (both lipid mediators) were also elevated in the CBD group. CBD showed less serum prolactin increase (predictor of galactorrhoea and sexual dysfunction), fewer extrapyramidal symptoms measured with the Extrapyramidal Symptom Scale, and less weight gain. Moreover, electrocardiograms as well as routine blood parameters were other parameters whose effects were measured but not reported in the study. CBD better safety profile might improve acute compliance and long-term treatment adherence.67,68


A press release by GW Pharmaceuticals of September 15th, 2015, described 88 patients with treatment-resistant schizophrenic psychosis, treated either with CBD (in addition to their regular medication) or placebo. Important clinical parameters improved in the CBD group and the number of mild side effects was comparable to the placebo group.2 Table 2 shows an overview of studies with CBD for the treatment of psychotic symptoms and its positive effect on symptomatology and the absence of side effects.69


Table 2 Studies with CBD


Treatment of two patients for 24 days with 600�1200?mg/day CBD, who were suffering from BD, did not lead to side effects.70 Apart from the study with two patients mentioned above, CBD has not been tested systematically in acute or chronic administration scenarios in humans for BD according to our own literature search.71


Epilepsy. Epileptic patients were treated for 135 days with 200�300?mg oral CBD daily and evaluated every week for changes in urine and blood. Moreover, neurological and physiological examinations were performed, which neither showed signs of CBD toxicity nor severe side effects. The study also illustrated that CBD was well tolerated.65


A review by Grotenhermen and M�ller-Vahl describes several clinical studies with CBD2: 23 patients with therapy-resistant epilepsy (e.g., Dravet syndrome) were treated for 3 months with increasing doses of up to 25?mg/kg b.w. CBD in addition to their regular epilepsy medication. Apart from reducing the seizure frequency in 39% of the patients, the side effects were only mild to moderate and included reduced/increased appetite, weight gain/loss, and tiredness.


Another clinical study lasting at least 3 months with 137 children and young adults with various forms of epilepsy, who were treated with the CBD drug Epidiolex, was presented at the American Academy for Neurology in 2015. The patients were suffering from Dravet syndrome (16%), Lennox�Gastaut syndrome (16%), and 10 other forms of epilepsy (some among them were very rare conditions). In this study, almost 50% of the patients experienced a reduction of seizure frequency. The reported side effects were 21% experienced tiredness, 17% diarrhea, and 16% reduced appetite. In a few cases, severe side effects occurred, but it is not clear, if these were caused by Epidiolex. These were status epilepticus (n=10), diarrhea (n=3), weight loss (n=2), and liver damage in one case.


The largest CBD study conducted thus far was an open-label study with Epidiolex in 261 patients (mainly children, the average age of the participants was 11) suffering from severe epilepsy, who could not be treated sufficiently with standard medication. After 3 months of treatment, where patients received CBD together with their regular medication, a median reduction of seizure frequency of 45% was observed. Ten percent of the patients reported side effects (tiredness, diarrhea, and exhaustion).2


After extensive literature study of the available trials performed until September 2016, CBD side effects were generally mild and infrequent. The only exception seems to be a multicenter open-label study with a total of 162 patients aged 1�30 years, with treatment-resistant epilepsy. Subjects were treated for 1 year with a maximum of 25?mg/kg (in some clinics 50?mg/kg) oral CBD, in addition to their standard medication.


This led to a reduction in seizure frequency. In this study, 79% of the cohort experienced side effects. The three most common adverse effects were somnolence (n=41 [25%]), decreased appetite (n=31 [19%]), and diarrhea (n=31 [19%]).72 It has to be pointed out that no control group existed in this study (e.g., placebo or another drug). It is therefore difficult to put the side effect frequency into perspective. Attributing the side effects to CBD is also not straightforward in severely sick patients. Thus, it is not possible to draw reliable conclusions on the causation of the observed side effects in this study.


Parkinson’s disease. In a study with a total of 21 Parkinson’s patients (without comorbid psychiatric conditions or dementia) who were treated with either placebo, 75?mg/day CBD or 300?mg/day CBD in an exploratory double-blind trial for 6 weeks, the higher CBD dose showed significant improvement of quality of life, as measured with PDQ-39. This rating instrument comprised the following factors: mobility, activities of daily living, emotional well-being, stigma, social support, cognition, communication, and bodily discomfort. For the factor, �activities of daily living,� a possible dose-dependent relationship could exist between the low and high CBD group�the two CBD groups scored significantly different here. Side effects were evaluated with the UKU (Udvalg for Kliniske Unders�gelser). This assessment instrument analyzes adverse medication effects, including psychic, neurologic, autonomic, and other manifestations. Using the UKU and verbal reports, no significant side effects were recognized in any of the CBD groups.73


Huntington’s disease. Fifteen neuroleptic-free patients with Huntington’s disease were treated with either placebo or oral CBD (10?mg/kg b.w. per day) for 6 weeks in a double-blind, randomized, crossover study design. Using various safety outcome variables, clinical tests, and the cannabis side effect inventory, it was shown that there were no differences between the placebo group and the CBD group in the observed side effects.6


Immune System


Forty-eight patients were treated with 300?mg/kg oral CBD, 7 days before and until 30 days after the transplantation of allogeneic hematopoietic cells from an unrelated donor to treat acute leukemia or myelodysplastic syndrome in combination with standard measures to avoid GVHD (graft vs. host disease; cyclosporine and short course of MTX). The occurrence of various degrees of GVHD was compared with historical data from 108 patients, who had only received the standard treatment. Patients treated with CBD did not develop acute GVHD. In the 16 months after transplantation, the incidence of GHVD was significantly reduced in the CBD group. Side effects were graded using the Common Terminology Criteria for Adverse Events (CTCAE v4.0) classification, which did not detect severe adverse effects.74


Endocrine and Glycemic (Including Appetite, Weight Gain) Effects


In a placebo-controlled, randomized, double-blind study with 62 subjects with noninsulin-treated type 2 diabetes, 13 patients were treated with twice-daily oral doses of 100?mg CBD for 13 weeks. This resulted in lower resistin levels compared to baseline. The hormone resistin is associated with obesity and insulin resistance. Compared to baseline, glucose-dependent insulinotropic peptide levels were elevated after CBD treatment. This incretin hormone is produced in the proximal duodenum by K cells and has insulinotropic and pancreatic b cell preserving effects. CBD was well tolerated in the patients. However, with the comparatively low CBD concentrations used in this phase-2-trial, no overall improvement of glycemic control was observed.40


When weight and appetite were measured as part of a measurement battery for side effects, results were inconclusive. For instance, the study mentioned above, where 23 children with Dravet syndrome were treated, increases as well as decreases in appetite and weight were observed as side effects.2 An open-label trial with 214 patients suffering from treatment-resistant epilepsy showed decreased appetite in 32 cases. However, in the safety analysis group, consisting of 162 subjects, 10 showed decreased weight and 12 had gained weight.52 This could be either due to the fact that CBD only has a small effect on these factors, or appetite and weight are complex endpoints influenced by multiple factors such as diet and genetic predisposition. Both these factors were not controlled for in the reviewed studies.



Dr. Alex Jimenez’s Insight

One of the most crucially important qualities of cannabidiol, or CBD, is its lack of psychoactivity. When taken on its own, consumers can experience the many health benefits of CBD without experiencing the euphoric sensations commonly known to be caused by THC. Cannabidiol acts directly with the endocannabinoid system, an essential system in the human body which many individuals may not be particularly familiar with. When CBD binds to the endocannabinoid system’s receptors, it can stimulate all kinds of changes in the human body. Most of those changes are beneficial, and research studies keep uncovering real and potential medical uses for them.




This review could substantiate and expand the findings of Bergamaschi et al. about CBD favorable safety profile.1 Nonetheless, various areas of CBD research should be extended. First, more studies researching CBD side effects after real chronic administration need to be conducted. Many so-called chronic administration studies, cited here were only a couple of weeks long. Second, many trials were conducted with a small number of individuals only. To perform a throrough general safety evaluation, more individuals have to be recruited into future clinical trials. Third, several aspects of a toxicological evaluation of a compound such as genotoxicity studies and research evaluating CBD effect on hormones are still scarce. Especially, chronic studies on CBD effect on, for example, genotoxicity and the immune system are still missing. Last, studies that evaluate whether CBD-drug interactions occur in clinical trials have to be performed.


In conclusion, CBD safety profile is already established in a plethora of ways. However, some knowledge gaps detailed above should be closed by additional clinical trials to have a completely well-tested pharmaceutical compound.


Abbreviations Used


  • AD – Alzheimer’s disease
  • ARCI – Addiction Research Center Inventory
  • BD – bipolar disorder
  • BDI – Beck Depression Inventory
  • CBD – cannabidiol
  • HSP – heat shock protein
  • IL – interleukin
  • MRS – Mood Rating Scale
  • PPI – prepulse inhibition
  • ROS – reactive oxygen species
  • SAFTEE – Systematic Assessment for Treatment Emergent Events
  • STAI – State Trait Anxiety Inventory
  • TSST – Trier Social Stress Test
  • UKU – Udvalg for Kliniske Unders�gelser
  • VAMS – Visual Analogue Mood Scale
  • VAS – Visual Analog Scales




The study was commissioned by the European Industrial Hemp Association. The authors thank Michal Carus, Executive Director of the EIHA, for making this review possible, for his encouragement, and helpful hints.


Author Disclosure Statement


EIHA paid nova-Institute for the review. F.G. is Executive Director of IACM.


Chiropractic Care Guide to CBD


Chiropractors and health professionals everywhere have become increasingly curious about the health benefits of CBD, or cannabidiol. Below, we will summarize what CBD oil is and we will also discuss its benefits to help guide consumers regarding the use of CBD oil. Incorporating CBD oil into chiropractic care with patients who can benefit from it’s various advantages, may be an innovative approach to help effectively treat a variety of health issues.


What is CBD Oil?


Cannabidiol, or CBD, is one of the compounds available today with the most growing interest behind its use but it is also one of the most controversial, and consumers worldwide are discovering its own health benefits. CBD is a cannabinoid, a type of over 100 chemical compounds found in the cannabis plant, such as marijuana and hemp. Found in the cannabis plant’s flowers, seeds, and stalks, CBD could be extracted from the plant as part of its cannabis oil. This oil can then be processed into many CBD supplements which can be used to boost well-being and the human body’s ability to keep equilibrium. When CBD oil has been extracted from low-THC hemp, the resulting products are non-psychoactive and safe to use by anyone.


How is CBD Used on Patients?


These CBD oil products can be given to patients to assist them attain health and wellness by promoting proper sleep, appetite, metabolism, immune reaction, and much more.


When CBD petroleum goods are utilized, plant-based cannabinoids or phytocannabinoids such as CBD are consumed by the body in the place where they make their way to the bloodstream and are transported through the body to interact with specific cannabinoid receptors in both peripheral and central nervous systems.


The neural communication network that employs these cannabinoid neurotransmitters, known as the endocannabinoid system, plays a fundamental role in the nervous system’s normal functioning. Endocannabinoids, such as anandamide and 2-AG, function as neurotransmitters, delivering chemical messages between nerve cells throughout the nervous system.


Phytocannabinoids mimic the functions of the body’s endogenous, or naturally-occurring, cannabinoids like anandamide and 2-AG. CBD and THC’s chemical structures are similar to those of 2-AG and anandamide, letting us use them to control the endocannabinoid system to achieve beneficial effects in the body.


CBD oil products come in many different consumption forms, such as capsules, tinctures, topical salves, vaporizers, pure hemp oil oral applicators, and more. These daily use products supply all the benefits of CBD with none of the worry over THC from other medical marijuana solutions.


But is CBD Legal?


Hemp products, such as nutritional supplements, are lawful in the U.S. provided that they’re manufactured using imported hemp. Hemp is defined at the U.S. as any cannabis plant containing 0.3 percent THC per dry weight or less. At those levels, the THC in hemp-derived CBD petroleum merchandise is far too low to produce psychoactive effects in people. Because our products are derived from low-THC hemp, they’re legal from the U.S. and in over 40 countries globally. However, we suggest you check your regional laws to find out if CBD oil products possess some particular restrictions.



Dr. Alex Jimenez’s Insight

Cannabidiol, or CBD, is a phytocannabinoid which is devoid of psychoactive activity which is why it has been used to provide its many benefits to patients without the side effects commonly associated with THC, or marijuana. Many healthcare professionals, including chiropractors, have started utilizing CBD as a part of their treatment program. Numerous research studies have demonstrated the many health benefits of cannabidiol, or CBD. According to the article above, the favorable safety profile of CBD in humans was confirmed and extended by the reviewed research. Cannabidiol, or CBD, is most often utilized as an adjunct therapy, therefore, it’s interaction with other drugs and/or medications requires further research.


Is CBD Safe to Use on Patients?


CBD is regarded as safe and nontoxic for humans, even at large quantities. Researchers have conducted numerous studies regarding the use of cannabidiol, or CBD, for its health benefits.


In conclusion, the use of cannabidiol, or CBD, has been a controversial topic for many years. However, due to it’s reported health benefits, more and more research studies regarding its advantages in the human body have been conducted in attempts to shine light on the safety and efficiency of this compound as well as thoroughly discussing its side effects. Furthermore, the use of CBD by healthcare professionals, including chiropractors, has become a new treatment approach for a variety of underlying health issues. Further research studies are still required to conclude the health benefits of cannabidiol, or CBD.Information referenced from the National Center for Biotechnology Information (NCBI).�The scope of our information is limited to chiropractic as well as to spinal injuries and conditions. To discuss the subject matter, please feel free to ask Dr. Jimenez or contact us at�915-850-0900�.


Curated by Dr. Alex Jimenez


Additional Topics: Back Pain

Back pain is one of the most prevalent causes for disability and missed days at work worldwide. As a matter of fact, back pain has been attributed as the second most common reason for doctor office visits, outnumbered only by upper-respiratory infections. Approximately 80 percent of the population will experience some type of back pain at least once throughout their life. The spine is a complex structure made up of bones, joints, ligaments and muscles, among other soft tissues. Because of this, injuries and/or aggravated conditions, such as herniated discs, can eventually lead to symptoms of back pain. Sports injuries or automobile accident injuries are often the most frequent cause of back pain, however, sometimes the simplest of movements can have painful results. Fortunately, alternative treatment options, such as chiropractic care, can help ease back pain through the use of spinal adjustments and manual manipulations, ultimately improving pain relief.




blog picture of cartoon paperboy big news


EXTRA IMPORTANT TOPIC: Low Back Pain Management


MORE TOPICS: EXTRA EXTRA:�Chronic Pain & Treatments


1.�Bergamaschi MM, Queiroz RH, Zuardi AW, et al.�Safety and side effects of cannabidiol, a Cannabis sativa constituent.�Curr Drug Saf. 2011;6:237�249�[PubMed]
2.�Grotenhermen F, M�ller-Vahl K.�Cannabis und Cannabinoide in der Medizin: Fakten und Ausblick.�Suchttherapie. 2016;17:71�76
3.�Hampson AJ, Grimaldi M, Axelrod J, et al.�Cannabidiol and ?9-tetrahydrocannabinol are neuroprotective antioxidants.�PNAS. 1998;95:8268�8273�[PMC free article][PubMed]
4.�Ol�h A, T�th BI, Borb�r� I, et al.�Cannabidiol exerts sebostatic and antiinflammatory effects on human sebocytes.�J Clin Invest. 2014:124:3713.�[PMC free article][PubMed]
5.�Deiana S, Watanabe A, Yamasaki Y, et al.�Plasma and brain pharmacokinetic profile of Cannabidiol (CBD), cannabidivarine (CBDV), Delta (9)-tetrahydrocannabivarin (?9-THCV) and cannabigerol (CBG) in rats and mice following oral and intraperitoneal administration and CBD action on obsessive compulsive behaviour.�Psychopharmacology. 2012;219:859�873�[PubMed]
6.�Consroe P, Laguna J, Allender J, et al.�Controlled clinical trial of cannabidiol in Huntington’s disease.�Pharmacol Biochem Beh. 1991;40:701�708�[PubMed]
7.�Bih CI, Chen T, Nunn AV, et al.�Molecular targets of cannabidiol in neurological disorders.�Neurotherapeutics. 2015;12:699�730�[PMC free article][PubMed]
8.�Stout SM, Cimino NM.�Exogenous cannabinoids as substrates, inhibitors, and inducers of human drug metabolizing enzymes: a systematic review.�Drug Metab Rev. 2014;46:86�95�[PubMed]
9.�Fusar-Poli P, Crippa JA, Bhattacharyya S, et al.�Distinct effects of D9-tetrahydro-cannabinoland cannabidiol on neural activation during emotional processing.�Arch Gen Psychiat. 2009;66:9�5.�[PubMed]
10.�Manini AF, Yiannoulos G, Bergamaschi MM, et al.�Safety and pharmacokinetics of oral cannabidiol when administered concomitantly with intravenous fentanyl in humans.�J Addict Med. 2014;9:204�210�[PMC free article][PubMed]
11.�Monographie NN.�Cannabidiol. Deutscher Arzneimittel-Codex (DAC) inkl. Neues Rezeptur-Formularium (NRF). DAC/NRF October 22, 2015
12.�Pelkonen O, M�eenp�e� J, Taavitsainen P, et al.�Inhibition and induction of human cytochrome P450 (CYP) enzymes.�Xenobiotica. 1998;28:1203�1253�[PubMed]
13.�Karlgren M, Bergstr�m CA.�How physicochemical properties of drugs affect their metabolism and clearance. In:�New horizons in predictive drug metabolism and pharmacokinetics. Royal Society of Chemistry: Cambridge, UK, 2015
14.�Ujv�ry I, Hanu� L.�Human metabolites of cannabidiol: a review on their formation, biological activity, and relevance in therapy.�Cannabis Cannabinoid Res. 2016;1:90�101
15.�Bornheim LM, Everhart ET, Li J, et al.�Induction and genetic regulation of mouse hepatic cytochrome P450 by cannabidiol.�Biochem Pharmacol. 1994;48:161�171�[PubMed]
16.�Brzozowska N, Li KM, Wang XS, et al.�ABC transporters P-gp and Bcrp do not limit the brain uptake of the novel antipsychotic and anticonvulsant drug cannabidiol in mice.�Peer J. 2016;4:e208�1.�[PMC free article][PubMed]
17.�Feinshtein V, Erez O, Ben-Zvi Z, et al.�Cannabidiol enhances xenobiotic permeability through the human placental barrier by direct inhibition of breast cancer resistance protein: an ex vivo study.�Am J Obstet Gynecol. 2013;209:573-e1�[PubMed]
18.�Linge R, Jim�nez-S�nchez L, Campa L, et al.�Cannabidiol induces rapid-acting antidepressant-like effects and enhances cortical 5-HT/glutamate neurotransmission: role of 5-HT 1A receptors.�Neuropharmacology. 2016;103:16�26�[PubMed]
19.�Schiavon AP, Bonato JM, Milani H, et al.�Influence of single and repeated cannabidiol administration on emotional behavior and markers of cell proliferation and neurogenesis in non-stressed mice.�Prog Neuropsychopharmacol. 2016;64:27�34�[PubMed]
20.�Peres FF, Levin R, Almeida V, et al.�Cannabidiol, among other cannabinoid drugs, modulates prepulse inhibition of startle in the SHR animal model: implications for schizophrenia pharmacotherapy.�Front Pharmacol. 2016;7:30�3.�[PMC free article][PubMed]
21.�Gomes FV, Issy AC, Ferreira FR, et al.�Cannabidiol attenuates sensorimotor gating disruption and molecular changes induced by chronic antagonism of NMDA receptors in mice.�J Neuropsychopharmacol. 2015;18:pyu04�1.�[PMC free article][PubMed]
22.�Valvassori SS, Elias G, de Souza B, et al.�Effects of cannabidiol on amphetamine-induced oxidative stress generation in an animal model of mania.�J Psychopharmacol. 2011;25:274�280�[PubMed]
23.�Ren Y, Whittard J, Higuera-Matas A, et al.�Cannabidiol, a nonpsychotropic component of cannabis, inhibits cue-induced heroin seeking and normalizes discrete mesolimbic neuronal disturbances.�J Neurosci. 2009;29:14764�14769�[PMC free article][PubMed]
24.�Sun S, Hu F, Wu J, Zhang S.�Cannabidiol attenuates OGD/R-induced damage by enhancing mitochondrial bioenergetics and modulating glucose metabolism via pentose-phosphate pathway in hippocampal neurons.�Redox Biol. 2017;11:577�585�[PMC free article][PubMed]
25.�Schurr A, Livne A.�Differential inhibition of mitochondrial monoamine oxidase from brain by hashish components.�Biochem Pharmacol. 1976;25:1201�1203�[PubMed]
26.�Alvarez FJ, Lafuente H, Rey-Santano MC.�Neuroprotective effects of the nonpsychoactive cannabinoid cannabidiol in hypoxicischemic newborn piglets.�Pediatr Res. 2008;64:653�658�[PubMed]
27.�Valvassori SS, Bavaresco DV, Scaini G.�Acute and chronic administration of cannabidiol increases mitochondrial complex and creatine kinase activity in the rat brain.�Rev Bras Psiquiatr. 2013;35:380�386[PubMed]
28.�Scott KA, Dennis JL, Dalgleish AG, et al.�Inhibiting heat shock proteins can potentiate the cytotoxic effect of cannabidiol in human glioma cells.�Anticancer Res. 2015;35:5827�5837�[PubMed]
29.�Burstein S.�Cannabidiol (CBD) and its analogs: a review of their effects on inflammation.�Bioorg Med Chem. 2015;23:1377�1385�[PubMed]
30.�McAllister SD, Soroceanu L, Desprez PY.�The antitumor activity of plant-derived non-psychoactive cannabinoids.�J Neuroimmune Pharmacol. 2015;10:255�267�[PMC free article][PubMed]
31.�Cheng D, Spiro AS, Jenner AM, et al.�Long-term cannabidiol treatment prevents the development of social recognition memory deficits in Alzheimer’s disease transgenic mice.�J Alzheimers Dis. 2014;42:1383�1396�[PubMed]
32.�Weiss L, Zeira M, Reich S, et al.�Cannabidiol arrests onset of autoimmune diabetes in NOD mice.�Neuropharmacology. 2008;54:244�249�[PMC free article][PubMed]
33.�Hammell DC, Zhang LP, Ma F, et al.�Transdermal cannabidiol reduces inflammation and pain-related behaviours in a rat model of arthritis.�Eur J Pain. 2015;20:936�948�[PMC free article][PubMed]
34.�Murase R, Limbad C, Murase R.�Id-1 gene and protein as novel therapeutic targets for metastatic cancer.�Cancer Res. 2012;72:530�8.
35.�Paria BC, Das SK, Dey SK.�The preimplantation mouse embryo is a target for cannabinoid ligand-receptor signaling.�PNAS. 1995;92:9460�9464�[PMC free article][PubMed]
36.�Leanza L, Manag� A, Zoratti M, et al.�Pharmacological targeting of ion channels for cancer therapy: in vivo evidences.�Biochim Biophys Acta. 2016;1863:1385�1397�[PubMed]
37.�Ramer R, Merkord J, Rohde H, et al.�Cannabidiol inhibits cancer cell invasion via upregulation of tissue inhibitor of matrix metalloproteinases-1.�Biochem Pharmacol. 2010;79:955�966�[PubMed]
38.�Ramer R, Bublitz K, Freimuth N.�Cannabidiol inhibits lung cancer cell invasion and metastasis via intercellular adhesion molecule-1.�FASEB J. 2012;26:1535�1548�[PubMed]
39.�Benhamou Y.�Gene and protein as novel therapeutic targets for metastatic cancer. Available at��(accessed on October1, 2016)
40.�McAllister SD, Christian RT, Horowitz MP.�Cannabidiol as a novel inhibitor of Id-1 gene expression in aggressive breast cancer cells.�Mol Cancer Ther. 2007;6:2921�2927�[PubMed]
41.�De Petrocellis L, Ligresti A, Schiano Moriello A, et al.�Non-?9-THC cannabinoids inhibit prostate carcinoma growth in vitro and in vivo: pro-apoptotic effects and underlying mechanisms.�Br J Pharmacol. 2013;168:79�102�[PMC free article][PubMed]
42.�Fowler CJ.�Delta9-tetrahydrocannabinol and cannabidiol as potential curative agents for cancer: a critical examination of the preclinical literature.�Pharmacol Ther. 2015;97:587�596�[PubMed]
43.�Aviello G, Romano B, Borrelli F, et al.�Chemopreventive effect of the non-psychotropic phytocannabinoid cannabidiol on experimental colon cancer.�J Mol Med. 2012;90:925�934�[PubMed]
44.�Jadoon KA, Ratcliffe SH, Barrett DA.�Efficacy and safety of cannabidiol and tetrahydrocannabivarin on glycemic and lipid parameters in patients with type 2 diabetes: a randomized, double-blind, placebo-controlled, parallel group pilot study.�Diabetes Care. 2016;39:1777�1786�[PubMed]
45.�Watanabe K, Motoya E, Matsuzawa N, et al.�Marijuana extracts possess the effects like the endocrine disrupting chemicals.�Toxicology. 2005;206:471�478�[PubMed]
46.�Narimatsu S, Watanabe K, Yamamoto I.�Inhibition of hepatic microsomal cytochrome P450 by cannabidiol in adult male rats.�Chem Pharm Bull. 1990;38:1365�1368�[PubMed]
47.�Jones NA, Hill AJ, Smith I, et al.�Cannabidiol displays antiepileptiform and antiseizure properties in vitro and in vivo.�J Pharm Ex Ther. 2010;332:569�577�[PMC free article][PubMed]
48.�Jones NA, Glyn SE, Akiyama S, et al.�Cannabidiol exerts anti-convulsant effects in animal models of temporal lobe and partial seizures.�Seizure. 2012;21:344�352�[PubMed]
49.�Fasinu PS, Phillips S, ElSohly MA, et al.�Current status and prospects for cannabidiol preparations as new therapeutic agents.�Pharmacotherapy. 2016;36:781�796�[PubMed]
50.�Persson A, Ingelman-Sundberg M.�Pharmacogenomics of cytochrome P450 dependent metabolism of endogenous compounds: implications for behavior, psychopathology and treatment.�J Pharmacogenomics Pharmacoproteomics�2014;5:12�7.
51.�Ghosh C, Hossain M, Solanki J, et al.�Pathophysiological implications of neurovascular P450 in brain disorders.�Drug Discov Today. 2016;21:1609�1619�[PMC free article][PubMed]
52.�Brunt TM, van Genugten M, H�ner-Snoeken K, et al.�Therapeutic satisfaction and subjective effects of different strains of pharmaceutical-grade cannabis.�J Clin Psychopharmacol. 2014;34:344�349�[PubMed]
53.�Das RK, Kamboj SK, Ramadas M, et al.�Cannabidiol enhances consolidation of explicit fear extinction in humans.�Psychopharmacology. 2013;226:781�792�[PubMed]
54.�Bhattacharyya S, Morrison PD, Fusar-Poli P, et al.�Opposite effects of ?-9-tetrahydrocannabinol and cannabidiol on human brain function and psychopathology.�Neuropsychopharmacology. 2010;35:764�774�[PMC free article][PubMed]
55.�Martin-Santos R, Crippa J, Batalla A.�Acute effects of a single, oral dose of d9-tetrahydrocannabinol (?9-THC) and cannabidiol (CBD) administration in healthy volunteers.�Curr Pharm Des. 2012;18:4966�4979�[PubMed]
56.�Crippa JAS, Hallak JEC, Machado-de-Sousa JP, et al.�Cannabidiol for the treatment of cannabis withdrawal syndrome: a case report.�J Clin Pharm Ther. 2013;38:162�164�[PubMed]
57.�Morgan CJ, Freeman TP, Schafer GL.�Cannabidiol attenuates the appetitive effects of ?9-tetrahydrocannabinol in humans smoking their chosen cannabis.�Neuropsychopharmacology. 2010;35:1879�1885�[PMC free article][PubMed]
58.�Hurd YL, Yoon M, Manini AF.�Early phase in the development of cannabidiol as a treatment for addiction: opioid relapse takes initial center stage.�Neurotherapeutics. 2015;12:807�815�[PMC free article][PubMed]
59.�Morgan CJ, Das RK, Joye A, et al.�Cannabidiol reduces cigarette consumption in tobacco smokers: preliminary findings.�Addictive Behav. 2013;38:2433�2436�[PubMed]
60.�Zuardi AW, Guimaraes FS, Moreira AC.�Effect of cannabidiol on plasma prolactin, growth hormone and cortisol in human volunteers.�Braz J Med Biol Res. 1993;26:213�217�[PubMed]
61.�Appiah-Kusi E, Mondelli V, McGuire P, et al.�Effects of cannabidiol treatment on cortisol response to social stress in subjects at high risk of developing psychosis.�Psychoneuroendocrinology. 2016;7(Supplement):23�24
62.�Geffrey AL, Pollack SF, Bruno PL, et al.�Drug�drug interaction between clobazam and cannabidiol in children with refractory epilepsy.�Epilepsia. 2015;56:1246�1251�[PubMed]
63.�Grotenhermen F, Gebhardt K, Berger M.�Cannabidiol. Nachtschatten Verlag: Solothurn, Switzerland, 2016
64.�Mincis M, Pfeferman A, Guimar�es RX.�Chronic administration of cannabidiol in man. Pilot study.�AMB Rev Assoc Med Bras.�1973;19:185�190�[PubMed]
65.�Cunha J, Carlini EA, Pereira AE, et al.�Chronic administration of cannabidiol to healthy volunteers and epileptic patients.�Pharmacology. 1980;21:175�185�[PubMed]
66.�Zuardi AW, Crippa JAS, Hallak JEC, et al.�Cannabidiol for the treatment of psychosis in Parkinson’s disease.�J Psychopharmacol. 2009;3:979�983�[PubMed]
67.�Leweke FM, Piomelli D, Pahlisch F.�Cannabidiol enhances anandamide signaling and alleviates psychotic symptoms of schizophrenia.�Transl psychiatry. 2012;2:e9�4.�[PMC free article][PubMed]
68.�Leweke F, Koethe D, Gerth C.�Cannabidiol as an antipsychotic: a double-blind, controlled clinical trial of cannabidiol versus amisulpiride in acute schizophrenia. In: 15th annual symposium on cannabinoidsCannabinoid Research Society: Clearwater Beach, FL, 2005
69.�Iseger TA, Bossong MG.�A systematic review of the antipsychotic properties of cannabidiol in humans.�Schizophr Res. 2015;162:153�161�[PubMed]
70.�Zuardi AW, Crippa JAS, Dursun SM, et al.�Cannabidiol was ineffective for manic episode of bipolar affective disorder.�J Psychopharmacol. 2010;24:135�137�[PubMed]
71.�Braga RJ, Abdelmessih S, Tseng J, et al.�Cannabinoids and bipolar disorder. Cannabinoids in neurologic and mental disease. Elsevier, Amsterdam, 2015, p. 205
72.�Devinsky O, Marsh E, Friedman D, et al.�Cannabidiol in patients with treatment-resistant epilepsy: an open-label interventional trial.�Lancet Neurol. 2016;15:270�278�[PubMed]
73.�Chagas MHN, Zuardi AW, Tumas V, et al.�Effects of cannabidiol in the treatment of patients with Parkinson’s disease: an exploratory double-blind trial.�J Psychopharmacol. 2014;28:1088�1098�[PubMed]
74.�Yeshurun M, Shpilberg O, Herscovici C, et al.�Cannabidiol for the prevention of graft-versus- host-disease after allogeneic hematopoietic cell transplantation: results of a phase II study.�Biol Blood Marrow Transplant. 2015;21:1770�1775�[PubMed]
Close Accordion
Understanding Phytocannabinoids

Understanding Phytocannabinoids

Phytocannabinoids: With the discovery of the endocannabinoid system (ECS)�during the 1980s provided researchers a new perspective on the�compounds in hemp and marijuana identified 40 years before. And one of the new perspectives was how these compounds interacted with the human body.

Phytocannabinoids: (Phyto) – For Plant Was The Name Given To These Compounds

Over 80 phytocannabinoids have been identified in marijuana and hemp. The psychoactive phytocannabinoid in marijuana� known as tetrahydrocannabinol (THC) represents only one of the many phytocannabinoids being studied for its health benefits.1

The more science learns about the effects of the ECS in supporting brain health, enhancing immune function, maintaining a healthy inflammatory response, and promoting GI health, fertility, bone health, etc. Now there is more interest in finding phytocannabinoids in nature and learning how they affect human health.

Because of this interest, phytocannabinoids have now been identified in many plants outside of the Cannabis species. An example is in plants like clove, black pepper, echinacea, broccoli, ginseng, and carrots.2

Phytocannabinoids In Hemp

Most people have heard of cannabadiol (CBD), but this is only one of many components in hemp that interacts with the ECS.

phytocannabinoids el paso tx.

Two other phytocannabinoids include:

Cannabichromene (CBC)

  • CBC research began in the 1980’s when it was found that it would act upon a normal inflammatory response in rats.3 Recently CBC has shown to promote brain health,4 skin health,5 and keep normal movement in the digestive system.6

Cannabigerol (CBG)

  • CBG research focuses on how it supports nervous system health. CBG has multiple jobs in the ECS. These include inhibiting the re-uptake of anandamide. Although still unknown, but CBG could possibly provide support for immune function, skin health, and being in a good mood. And CBG is found in much higher levels in industrial hemp than in marijuana.7

Phytocannabinoids In Other Plants

Current research has found phytocannabionids in many other plants. Some of these include:

Beta-caryophyllene (BCP)

  • BCP is found in the flowers and leaves of hemp, and since only the hemp stalk is used in supplements, BCP content gets lost. But, BCP is contained in many other plants, i.e. cloves and black pepper. BCP joins itself to the CB2 cannabinoid receptor. This helps maintain a healthy inflammatory response while at the same time promoting health to the digestive system, skin, and liver.8,9

Diindolylmethane (DIM)

  • DIM is a compound that is produced in our bodies when consuming vegetables like broccoli, cauliflower and cabbage. DIM is a readily available dietary supplement. Just like beta-caryophyllene, DIM binds to the CB2 cannabinoid receptor.10 The immune system is abundant in CB2 receptors, this could explain�benefits of these foods especially in immune system health.


  • Alkylamides also play a role in the ECS, that is generating interest. It is found in the herb Echinacea, These compounds act on the CB2 receptor for regulation of cytokine synthes�is and immune function support.11 This helps explain the common uses of Echinacea.


  • Falcarinol is found in carrots, celery, parsley, and Panax or Asian ginseng. Falcarinol compound binds to the CB1 cannabinoid receptor but has the opposite effect of anandamide. Because of this, falcarinol can cause allergic skin reactions due to the blocking of our own ECS from regulating local inflammation.12


  • This phytocannabinoid is found in the Kava plant (Piper methysticum).�This compound binds to CB1 receptors and acts on GABA receptors in the nervous system. Yangonin�has shown to promote relaxation and regulate responses to stress, however, it could be unhealthy for the liver.13

Information and knowledge of the endocannabinoid system is growing at a rapid rate. Science and scientists continue their research in order to find more phytocannabinoids in foods/plants that will benefit human health.


  1. Borgelt L, Franson K, Nussbaum A, Wang G. The pharmacologic and clinical effects of medical cannabis. Pharmacotherapy 2013;33(2):195-209.
  2. Gertsch J, Roger G, Vincenzo D. Phytocannabinoids beyond the cannabis plant � do they exist? Br J Pharmacol 2010;160(3):523-529.
  3. Wirth P, Watson E, ElSohly M, et al. Anti-inflammatory properties of cannabichromene. Life Sci 1980;26(23):1991-1995.
  4. Shinjyo N, Di Marzo V. The effect of cannabichromene on adult neural stem/progenitor cells. Neurochem Int 2013;63(5):432-437.
  5. Izzo A, Capasso R, Aviello G, et al. Inhibitory effect of cannabichromene, a major non?psychotropic cannabinoid extracted from Cannabis sativa, on inflammation?induced hypermotility in mice. Br J Pharmacol 2012;166(4):1444-1460.
  6. Ol�h A, Markovics A, Szab�?Papp J, et al. Differential effectiveness of selected non?psychotropic phytocannabinoids on human sebocyte functions implicates their introduction in dry/seborrheic skin and acne treatment. Exp Dermatol 2016;25(9):701-707.
  7. De Meijer E, Hammond K. The inheritance of chemical phenotype in Cannabis sativa L.(II): cannabigerol predominant plants. Euphytica 2005;145(1-2):189-198.
  8. Gertsch J, Leonti M, Raduner S, et al. Beta-caryophyllene is a dietary cannabinoid. Proc Natl Acad Sci 2008;105(26):9099-9104.
  9. Klauke A, Racz I, Pradier B, et al. The cannabinoid CB2 receptor-selective phytocannabinoid beta-caryophyllene exerts analgesic effects in mouse models of inflammatory and neuropathic pain. Eur Neuropsychopharmacol 2014;24(4):608-620.
  10. Yin H, Chu A, Li W, et al. Lipid G protein-coupled receptor ligand identification using ?-arrestin PathHunter� assay. J Biol Chem 2009;284(18):12328-12338.
  11. Raduner S, Majewska A, Chen J, et al. Alkylamides from Echinacea are a new class of cannabinomimetics Cannabinoid type 2 receptor-dependent and-independent immunomodulatory effects. J Biol Chem 2006;281(20):14192-14206.
  12. Leonti M, Casu L, Raduner S, et al. Falcarinol is a covalent cannabinoid CB1 receptor antagonist and induces pro-allergic effects in skin. Biochem Pharmacol 2010;79(12):1815-1826.
  13. Tang J, Dunlop R, Rowe A, et al. Kavalactones Yangonin and Methysticin induce apoptosis in human hepatocytes (HepG2) in vitro. Phytother Res 2011;25(3):417-423.
Cannabidiol (CBD) For Migraines And Headaches?

Cannabidiol (CBD) For Migraines And Headaches?

The therapeutic effects of Cannabidiol or CBD, is often the cannabinoid�s pain soothing effect that gets talked about. Headaches are the most common source of pain for the general population. Therefore, it makes sense that CBD use for migraines and headaches is an obvious.

Migraines and headaches can be a medical mystery, but usually their causes are brought on by problems with brain stem centers. The only treatments thus far, has been painkillers i.e. paracetamol or ibuprofen. Triptan medications, which constricts the blood vessels in order to block pain pathways in the brain are used as well. But is there a better more natural way to treat headaches and migraines?

cannabidiol el paso, tx.

Cannabis Has Been Treating Headaches For Quite Awhile

CBD oil for headaches is not a new therapy. Cannabis is mentioned as treatment for headaches in ancient texts that go back thousands of years. However, its use didn’t become familiar in the west until the 19th century when it would be prescribed by doctors as a tincture.

Today conclusive clinical evidence is incomplete, as far as, medical cannabis and hemp oil use for headaches. But scientists do know when it comes to CBD oil use for headaches and migraines, that the endocannabinoid system is working in conjunction with the compounds.

cannabidiol el paso, tx.

The Endocannabinoid System &�Migraines

A theory brought about a possible contributing cause of migraines is dysfunction�in the endocannabinoid system or (ECS). This is the body’s network of receptors and cannabis-like chemicals that respond and regulate:

  • Pain
  • Immune system
  • Mood
  • Sleep
  • Appetite
  • Memory

Researchers have noted ECS mechanisms that could have a connection to migraine attacks.

Anandamide (AEA)�is one of the prime endocannabinoids in the body. It is both a painkiller and has been found to power the serotonin 5-HT1A receptors.

The clearest record of endocannabinoid dysfunction that contributes to migraines is from a study in 2007 at the University of Perugia and published in the Journal of Neuropsychopharmacology. Researchers measured endocannabinoid levels in the cerebrospinal fluid of patients with chronic migraines and found significantly lower amounts of Anandamide. These findings, could “reflect an impairment of the endocannabinoid system in these patients, which may contribute to chronic head pain.�

cannabidiol el paso, tx.

Clinical Endocannabinoid Deficiency? Migraines Could Be A Sign

The link between lower levels of endocannabinoids in migraine patients has contributed to the formulation of what has been termed Clinical Endocannabinoid Deficiency. This theory was developed by Neurologist and Cannabinoid Researcher Dr. Ethan Russo.

cannabidiol el paso, tx.

The theory comes from how many brain disorders are inadequate or missing neurotransmitters like acetylcholine. Russo has suggested �a comparable de?ciency in endocannabinoid levels might manifest similarly in certain disorders that display predictable clinical features as sequelae of this de?ciency.�

In an interview he describes how, �If you don�t have enough endocannabinoids you have pain where there shouldn�t be pain. You would be sick, meaning nauseated. You would have a lowered seizure threshold. And just a whole litany of other problems.�

Russo relates these deficiencies can be addressed through introduction to plant cannabinoids, which act almost like those found in the body, by stimulating the endocannabinoid receptors. There is CB1 agonists such as Marinol and Nabilone have been tested for migraines, Russo suggests that the ECS needs a �gentle nudge� rather than a �forceful shove� given by these synthetic alternatives. He suggests small doses of whole plant cannabis, which contain �additional synergistic and buffering components, such as CBD and cannabis terpenoids.��

Cannabidiol CBD Oil: Migraines

Russo in particular singles out CBD (Cannabidiol) in that it�brings balance to the endocannabinoid system. In his interview with Martin Lee from Project CBD he says, �cannabidiol is an endocannabinoid modulator, in other words, when given chronically it actually increases the gain of the system�. So, if there�s too much activity in a system, homeostasis requires that it be brought back down. If there�s too little, it�s got to come up. And that�s what cannabidiol can do as a promoter of endocannabinoid tone.�

Scientists still are not exactly sure of how CBD interacts with the endocannabinoid system. Unlike psychoactive THC, CBD does not bind with any of the endocannabinoid receptors. Instead it activates a host of other non-endocannabinoid receptors, which work in the development and treatment of migraines, i.e. the 5-HT1A serotonin and TRPV-1 receptors.

cannabidiol el paso, tx.

Another possible explanation is CBD�s role as a fatty acid amide hydrolase (FAAH) inhibitor, which breaks down anandamide in the body. By inhibiting its production the theory is that it might lead to higher levels of pain relieving endocannabinoid. This is something that would benefit migraine sufferers.

Lack Of Clinical Evidence

Currently there are no gold standard, double blind, placebo clinical studies published to back up any accounts that suggest CBD or cannabis is an effective treatment for headaches and migraines.

One placebo controlled study has been conducted, documenting the safety and efficacy of synthetic THC medication Dronabinol for migraines. However, the results are still pending.

The largest study to take place was done from a retrospective basis. It was published in 2016 and found that out of 121 participants that suffer from migraines and were prescribed medical cannabis by a doctor; 103 participants found their migraine frequency reduced by half.

Can Cannabidiol Cause A Headache?

There are those who tried CBD and noted persistent headaches and even migraines. Does CBD cause headaches, even though the research suggests the contrary.

Those who reported getting headaches after taking CBD oil noted that the oil they bought was low quality, and the ingredients used included ethanol, various alcohols, preservatives and harsh chemicals.

When purchasing CBD oil for migraines or other conditions, get the best quality, not the cheapest!

How To Use CBD For Head Pain

There are different ways to apply CBD oil for headaches. If taking CBD for tension headaches, migraines or general headaches, there are many way to administer. Probably the simplest and most effective ways of using CBD is the sublingual method.

With this method one places a few drops of oil underneath the tongue. There it permeates through the membrane and makes its way to where it needs to go.

This isn�t the only method and many others can be just as effective. Make sure to do research when looking for CBD products online and the methods of administering these products.

Just like the nature of migraines, CBD for headaches and migraines is still not completely and scientifically understood. But with continued research of CBD and Cannabinoid based medicine, the future of sufferers of headaches and migraines will get better.

Injury Medical Clinic: Migraine Treatment & Recovery

Mechanisms of Acute Pain vs Chronic Pain

Mechanisms of Acute Pain vs Chronic Pain

Pain is a very important function of the human body, including the involvement of nociceptors and the central nervous system, or CNS, to transmit messages from noxious stimulation to the brain. Nociceptors are adrenal glands which are responsible for detecting hazardous or harmful stimuli and transmitting electrical signals into the nervous system. The receptors are present in skin, viscera, muscles, joints and meninges to discover a range of stimulation, which might be mechanical, thermal or chemical.


There are two types of nociceptors:


  • C-fibres would be the most common type and are slow to conduct and respond to stimuli. As the proteins in the membrane of the receptor convert the stimulation into electrical impulses that can be taken through the nervous system.
  • A-delta fibers are known to conduct more rapidly and convey messages of sharp, momentary pain.


Additionally, there are silent nociceptors which are usually restricted to stimuli but can be “awoken” with high-intensity mechanical stimulation in response to chemical mediators from the body. Nociceptors may have many different voltage-gated stations for transduction that cause a set of action potentials to commence the electric signaling to the nervous system. The excitability and behavior of the cell are based on the types of channels within the nociceptor.


It is important to differentiate between nociception and pain when considering the mechanism of the pain. Nociception is the normal response of the body to noxious stimuli, including reflexes below the suprathreshold that protect the human body from injury. Pain is just perceived when superthreshold for those nociceptors to reach an action possible and initiate the pain pathway is attained, which is comparatively high. The purpose of the article below is to demonstrate the cellular and molecular mechanisms of pain, including acute pain and chronic pain, or persistent pain, as referred to below.


Cellular and Molecular Mechanisms of Pain




The nervous system detects and interprets a wide range of thermal and mechanical stimuli as well as environmental and endogenous chemical irritants. When intense, these stimuli generate acute pain, and in the setting of persistent injury, both peripheral and central nervous system components of the pain transmission pathway exhibit tremendous plasticity, enhancing pain signals and producing hypersensitivity. When plasticity facilitates protective reflexes, it can be beneficial, but when the changes persist, a chronic pain condition may result. Genetic, electrophysiological, and pharmacological studies are elucidating the molecular mechanisms that underlie detection, coding, and modulation of noxious stimuli that generate pain.


Introduction: Acute Versus Persistent Pain


The ability to detect noxious stimuli is essential to an organism’s survival and wellbeing. This is dramatically illustrated by examination of individuals who suffer from congenital abnormalities that render them incapable of detecting painful stimuli. These people cannot feel piercing pain from a sharp object, heat of an open flame, or even discomfort associated with internal injuries, such as a broken bone. As a result, they do not engage appropriate protective behaviors against these conditions, many of which can be life threatening.


More commonly, alterations of the pain pathway lead to hypersensitivity, such that pain outlives its usefulness as an acute warning system and instead becomes chronic and debilitating. This may be seen, at some level, as an extension of the normal healing process, whereby tissue or nerve damage elicits hyperactivity to promote guarding of the injured area. For example, sunburn produces temporary sensitization of the affected area. As a result normally innocuous stimuli, such as light touch or warmth, are perceived as painful (a phenomenon referred to as allodynia), or normally painful stimuli elicit pain of greater intensity (referred to as hyperalgesia). At its extreme, the sensitization does not resolve. Indeed, individuals who suffer from arthritis, post-herpetic neuralgia (following a bout of shingles), or bone cancer, experience intense and often unremitting pain that is not only physiologically and psychologically debilitating, but may also hamper recovery. Chronic pain may even persist long after an acute injury, perhaps most commonly experienced as lower back pain or sciatica.


Persistent or chronic pain syndromes can be initiated or maintained at peripheral and/or central loci. In either case, the elucidation of molecules and cell types that underlie normal (acute) pain sensation is key to understanding the mechanisms underlying pain hypersensitivity. In the present review we highlight the molecular complexity of the primary afferent nerve fibers that detect noxious stimuli. We not only summarize the processing of acute pain, but also describe how changes in pain processing occur in the setting of tissue or nerve injury.


The profound differences between acute and chronic pain emphasize the fact that pain is not generated by an immutable, hard-wired system, but rather results from the engagement of highly plastic molecules and circuits, the molecular biochemical and neuroanatomical basis of which are the focus of current studies. Importantly, this new information has identified a host of potential therapeutic targets for the treatment of pain. We focus here on the peripheral and second order neurons in the spinal cord; the reader is referred to some excellent reviews of supraspinal pain processing mechanisms, which include remarkable insights that imaging studies have brought to the field (Apkarian et al., 2005).


Anatomical Overview


Nociception is the process by which intense thermal, mechanical or chemical stimuli are detected by a subpopulation of peripheral nerve fibers, called nociceptors (Basbaum and Jessell, 2000). The cell bodies of nociceptors are located in the dorsal root ganglia (DRG) for the body and the trigeminal ganglion for the face, and have both a peripheral and central axonal branch that innervates their target organ and the spinal cord, respectively. Nociceptors are excited only when stimulus intensities reach the noxious range, suggesting that they possess biophysical and molecular properties that enable them to selectively detect and respond to potentially injurious stimuli. There are two major classes of nociceptors. The first includes medium diameter myelinated (A?) afferents that mediate acute, well-localized �first� or fast pain. These myelinated afferents differ considerably from the larger diameter and rapidly conducting A? fibers that respond to innocuous mechanical stimulation (i.e. light touch). The second class of nociceptor includes small diameter unmyelinated �C� fibers that convey poorly localized, �second� or slow pain.


Electrophysiological studies have further subdivided A? nociceptors into two main classes. Type I (HTM: high threshold mechanical nociceptors) respond to both mechanical and chemical stimuli, but have relatively high heat thresholds (>50C). If, however, the heat stimulus is maintained, these afferents will respond at lower temperatures. And most importantly, they will sensitize (i.e. the heat or mechanical threshold will drop) in the setting of tissue injury. Type II A? nociceptors have a much lower heat threshold, but a very high mechanical threshold. Activity of this afferent almost certainly mediates the �first� acute pain response to noxious heat. Indeed, compression block of myelinated peripheral nerve fibers eliminates first, but not second, pain. By contrast, the Type I fiber likely mediates the first pain provoked by pinprick and other intense mechanical stimuli.


The unmyelinated C fibers are also heterogeneous. Like the myelinated afferents, most C fibers are polymodal, that is, they include a population that is both heat and mechanically sensitive (CMHs) (Perl, 2007). Of particular interest are the heat responsive, but mechanically insensitive unmyelinated afferents (so-called silent nociceptors) that develop mechanical sensitivity only in the setting of injury (Schmidt et al., 1995). These afferents are more responsive to chemical stimuli (capsaicin or histamine) compared to the CMHs, and likely come into play when the chemical milieu of inflammation alters their properties. Subsets of these afferents are also responsive to a variety of itch-producing pruritogens. It is worth noting that not all C fibers are nociceptors. Some respond to cooling, and a particularly interesting population of unmyelinated afferents responds to innocuous stroking of the hairy skin, but not to heat or chemical stimulation. These latter fibers appear to mediate pleasant touch (Olausson et al., 2008).


Neuroanatomical and molecular characterization of nociceptors has further demonstrated their heterogeneity, particularly for the C fibers (Snider and McMahon, 1998). For example, the so-called �peptidergic� population of C nociceptors releases the neuropeptides, substance P, and calcitonin-gene related peptide (CGRP); they also express the TrkA neurotrophin receptor, which responds to nerve growth factor (NGF). The non-peptidergic population of C nociceptors expresses the c-Ret neurotrophin receptor that is targeted by glial-derived neurotrophic factor (GDNF), as well as neurturin and artemin. A large percentage of the c-Ret-positive population also binds the IB4 isolectin, and expresses G protein-coupled receptors of the Mrg family (Dong et al., 2001), as well as specific purinergic receptor subtypes, notably P2X3. Nociceptors can also be distinguished according to their differential expression of channels that confer sensitivity to heat (TRPV1), cold (TRPM8), acidic milieu (ASICs), and a host of chemical irritants (TRPA1) (Julius and Basbaum, 2001). As noted below, these functionally and molecularly heterogeneous classes of nociceptors associate with specific function in the detection of distinct pain modalities.


The Nociceptor: a Bidirectional Signaling Machine


One generally thinks of the nociceptor as carrying information in one direction, transmitting noxious stimuli from the periphery to the spinal cord. However, primary afferent fibers have a unique morphology, called pseudo-unipolar, wherein both central and peripheral terminals emanate from a common axonal stalk. The majority of proteins synthesized by the DRG or trigeminal ganglion cell are distributed to both central and peripheral terminals. This distinguishes the primary afferent neuron from the prototypical neuron, where the recipient branch of the neuron (the dendrite) is biochemically distinct from the transmission branch (the axon). The biochemical equivalency of central and peripheral terminals means that the nociceptor can send and receive messages from either end. For example, just as the central terminal is the locus of Ca2+-dependent neurotransmitter release, so the peripheral terminal releases a variety of molecules that influence the local tissue environment. Neurogenic inflammation, in fact, refers to the process whereby peripheral release of the neuropeptides, CGRP and substance P, induces vasodilation and extravasation of plasma proteins, respectively (Basbaum and Jessell, 2000). Furthermore, whereas only the peripheral terminal of the nociceptor will respond to environmental stimuli (painful heat, cold and mechanical stimulation), both the peripheral and central terminals can be targeted by a host of endogenous molecules (such as pH, lipids, and neurotransmitters) that regulate its sensitivity. It follows that therapeutics directed at both terminals can be developed to influence the transmission of pain messages. For example, spinal (intrathecal) delivery of morphine targets opioid receptors expressed by the central terminal of nociceptors, whereas topically applied drugs (such as local anesthetics or capsaicin) regulate pain via an action at the peripheral terminal.


Central Projections of the Nociceptor


Primary afferent nerve fibers project to the dorsal horn of the spinal cord, which is organized into anatomically and electrophysiological distinct laminae (Basbaum and Jessell, 2000) (Figure 1). For example, A? nociceptors project to lamina I as well as to deeper dorsal horn (lamina V). The low threshold, rapidly conducting A? afferents, which respond to light touch, project to deep laminae (III, IV, and V). By contrast, C nociceptors project more superficially to laminae I and II.


Figure 1 Anatomy of the Pain Pathway


This remarkable stratification of afferent subtypes within the superficial dorsal horn is further highlighted by the distinct projection patterns of C nociceptors (Snider and McMahon, 1998). For example, most peptidergic C fibers terminate within lamina I and the most dorsal part of lamina II. By contrast, the nonpeptidergic afferents, including the Mrg-expressing subset, terminate in the mid-region of lamina II. The most ventral part of lamina II is characterized by the presence of excitatory interneurons that express the gamma isoform of protein kinase C (PKC), which has been implicated in injury-induced persistent pain (Malmberg et al., 1997). Recent studies indicate that this PKC? layer is targeted predominantly by myelinated non-nociceptive afferents (Neumann et al., 2008). Consistent with these anatomical studies, electrophysiological analyses demonstrate that spinal cord neurons within lamina I are generally responsive to noxious stimulation (via A? and C fibers), neurons in laminae III and IV are primarily responsive to innocuous stimulation (via A?), and neurons in lamina V receive a convergent non-noxious and noxious input via direct (monosynaptic) A? and A? inputs and indirect (polysynaptic) C fiber inputs. The latter are called wide dynamic range (WDR) neurons, in that they respond to a broad range of stimulus intensities. There is also commonly a visceral input to these WDR neurons, such that the resultant convergence of somatic and visceral likely contributes to the phenomenon of referred pain, whereby pain secondary to an injury affecting a visceral tissue (for example, the heart in angina) is referred to a somatic structure (for example, the shoulder).


Ascending Pathways and the Supraspinal Processing of Pain


Projection neurons within laminae I and V constitute the major output from the dorsal horn to the brain (Basbaum and Jessell, 2000). These neurons are at the origin of multiple ascending pathways, including the spinothalamic and spinoreticulothalamic tracts, which carry pain messages to the thalamus and brainstem, respectively (Figure 2). The former is particularly relevant to the sensory-discriminative aspects of the pain experience (that is, where is the stimulus and how intense is it?), whereas the latter may be more relevant to poorly localized pains. More recently, attention has focused on spinal cord projections to the parabrachial region of the dorsolateral pons, because the output of this region provides for a very rapid connection with the amygdala, a region generally considered to process information relevant to the aversive properties of the pain experience.


Figure 2 Primary Afferent Fibers and Spinal Cord


From these brainstem and thalamic loci, information reaches cortical structures. There is no single brain area essential for pain (Apkarian et al., 2005). Rather, pain results from activation of a distributed group of structures, some of which are more associated with the sensory-discriminative properties (such as the somatosensory cortex) and others with the emotional aspects (such as the anterior cingulate gyrus and insular cortex). More recently, imaging studies demonstrate activation of prefrontal cortical areas, as well as regions not generally associated with pain processing (such as the basal ganglia and cerebellum). Whether and to what extent activation of these regions is more related to the response of the individual to the stimulus, or to the perception of the pain is not clear. Finally, Figure 2 illustrates the powerful descending controls that influence (both positive and negatively) the transmission of pain messages at the level of the spinal cord.


Acute Pain


The primary afferent nerve fiber detects environmental stimuli (of a thermal, mechanical, or chemical nature) and transduces this information into the language of the nervous system, namely electrical current. First, we review progress in understanding the molecular basis of signal detection, and follow this with a brief overview of recent genetic studies that highlight the contribution of voltage-gated channels to pain transmission (Figure 3).


Figure 3 Nociceptor Diversity


Activating the Nociceptor: Heat


Human psychophysical studies have shown that there is a clear and reproducible demarcation between the perception of innocuous warmth and noxious heat, which enables us to recognize and avoid temperatures capable of causing tissue damage. This pain threshold, which typically rests around 43�C, parallels the heat sensitivity of C and Type II A? nociceptors described earlier. Indeed, cultured neurons from dissociated dorsal root ganglia show similar heat sensitivity. The majority display a threshold of 43�C, with a smaller cohort activated by more intense heat (threshold >50�C) (Cesare and McNaughton, 1996; Kirschstein et al., 1997; Leffler et al., 2007; Nagy and Rang, 1999). Molecular insights into the process of heat sensation came from the cloning and functional characterization of the receptor for capsaicin, the main pungent ingredient in �hot� chili peppers. Capsaicin and related vanilloid compounds produce burning pain by depolarizing specific subsets of C and A? nociceptors through activation of the capsaicin (or vanilloid) receptor, TRPV1, one of approximately 30 members of the greater transient receptor potential (TRP) ion channel family (Caterina et al., 1997). The cloned TRPV1 channel is also gated by increases in ambient temperature, with a thermal activation threshold (?43�C).


Several lines of evidence support the hypothesis that TRPV1 an endogenous transducer of noxious heat. First, TRPV1 is expressed in the majority of heat-sensitive nociceptors (Caterina et al., 1997). Second, capsaicin- and heat-evoked currents are similar, if not identical, in regard to their pharmacological and biophysical properties, as are those of heterologously expressed TRPV1 channels. Third, and as described in greater detail below, TRPV1-evoked responses are markedly enhanced by pro-algesic or pro-inflammatory agents (such as extracellular protons, neurotrophins, or bradykinin), all of which produce hypersensitivity to heat in vivo (Tominaga et al., 1998)). Fourth, analysis of mice lacking this ion channel not only revealed a complete loss of capsaicin sensitivity, but these animals also exhibit significant impairment in their ability to detect and respond to noxious heat (Caterina et al., 2000; Davis et al., 2000). These studies also demonstrated an essential role for this channel in the process whereby tissue injury and inflammation leads to heat hypersensitivity, reflecting the ability of TRPV1 to serve as a molecular integrator of thermal and chemical stimuli (Caterina et al., 2000; Davis et al., 2000).


The contribution of TRPV1 to acute heat sensation, however, has been challenged by data collected from an ex vivo preparation in which recordings are obtained from the soma of DRG neurons with intact central and peripheral fibers. In one study, no differences were observed in heat-evoked responses from wild type and TRPV1-deficient animals (Woodbury et al., 2004), but a more recent analysis from this group found that TRPV1-deficient mice do, indeed, lack a cohort of neurons robustly activated by noxious heat (Lawson et al., 2008). Taken together with the results described above we conclude that TRPV1 unquestionably contributes to acute heat sensation, but agree that TRPV1 is not solely responsible for heat transduction.


In this regard, whereas TRPV1-deficient mice lack a component of behavioral heat sensitivity, the use of high dose capsaicin to ablate the central terminals of TRPV1-expressing primary afferent fibers results in a more profound, if not complete loss of acute heat pain sensitivity (Cavanaugh et al., 2009). As for the TRPV1 mutant, there is also a loss of tissue injury-evoked heat hyperalgesia. Taken together these results indicate that both the TRPV1-dependent and TRPV1-independent component of noxious heat sensitivity is mediated via TRPV1-expressing nociceptors.


What accounts for the TRPV1-independent component of heat sensation? A number of other TRPV channel subtypes, including TRPV2, 3 and 4, have emerged as candidate heat transducers that could potentially cover detection of stimulus intensities flanking that of TRPV1, including both very hot (>50�C) and warm (mid-30�Cs) temperatures (Lumpkin and Caterina, 2007). Heterologously expressed TRPV2 channels display a temperature activation threshold of ?52�C, whereas TRPV3 and TRPV4 are activated between 25 – 35�C. TRPV2 is expressed in a subpopulation of A? neurons that respond to high threshold noxious heat and its biophysical properties resemble those of native high threshold heat-evoked currents (Leffler et al., 2007; Rau et al., 2007). As yet, there are no published reports describing either physiological or behavioral tests of TRPV2 knockout mice. On the other hand, TRPV3- and TRPV4-deficient mice do display altered thermal preference when placed on a surface of graded temperatures, suggesting that these channels contribute in some way to temperature detection in vivo (Guler et al., 2002). Interestingly, both TRPV3 and TRPV4 show substantially greater expression in keratinocytes and epithelial cells compared to sensory neurons, raising the possibility that detection of innocuous heat stimuli involves a functional interplay between skin and the underlying primary afferent fibers (Chung et al., 2003; Peier et al., 2002b).


Activating the Nociceptor: Cold


As for capsaicin and TRPV1, natural cooling agents, such as menthol and eucalyptol, have been exploited as pharmacological probes to identify and characterize cold-sensitive fibers and cells (Hensel and Zotterman, 1951; Reid and Flonta, 2001) and the molecules that underlie their behavior. Indeed, most cold-sensitive neurons respond to menthol and display a thermal activation threshold of ?25�C. TRPM8 is a cold and menthol-sen sitive channel whose physiological characteristics match those of native cold currents and TRPM8-deficient mice show a very substantial loss of menthol and cold-evoked responses at the cellular or nerve fiber level. Likewise, these animals display severe deficits in cold-evoked behavioral responses (Bautista et al., 2007; Colburn et al., 2007; Dhaka et al., 2007) over a wide range of temperatures spanning 30 to 10�C. As in the case of TRPV1 and he at, TRPM8-deficient mice are not completely insensitive to cold. For example, there remains a small (?4%) cohort of cold-sensitive, menthol-insensitive neurons that have a low threshold of activation, of approximately 12�C. These may account for the residual cold sensitivity seen in behavioral tests, wherein TRPM8-deficient animals can still avoid extremely cold surfaces below 10�C. Importantly, TRPM8-deficient mice show normal sensitivity to noxious heat. Indeed, TRPV1 and TRPM8 are expressed in largely non-overlapping neuronal populations, consistent with the notion that hot and cold detection mechanisms are organized into anatomically and functionally distinct �labeled lines.�


Based on heterologous expression systems, TRPA1 has also been suggested to detect cold, specifically within the noxious (<15�C) range. Moreover TRPA1 is activated by the cooling compounds icilin and menthol (Bandell et al., 2004; Karashima et al., 2007; Story et al., 2003), albeit at relatively high concentrations compared to their actions at TRPM8. However, there continues to be disagreement as to whether native or recombinant TRPA1 are intrinsically cold sensitive (Bandell et al., 2004; Jordt et al., 2004; Karashima et al., 2009; Nagata et al., 2005; Zurborg et al., 2007). This controversy has not been resolved by the analysis of two independent TRPA1-deficient mouse lines. At the cellular level, one study showed normal cold-evoked responses in TRPA1-deficient neurons following a 30 second drop in temperature from 22�C to 4 �C (Bautista et al., 2006); a more recent study has shown a decrease in cold sensitive neurons from 26% (WT) to 10% (TRPA1-/-), when tested after a 200 sec drop in temperature, from 30�C to 10�C (Karashima et al., 2009). In behavioral studies, TRPA1-deficient mice display responses similar to wild-type littermates in the cold-plate and acetone-evoked evaporative cooling assays (Bautista et al., 2006). A second study using the same assays showed that female, but not male, TRPA1 knockout animals displayed attenuated cold sensitivity compared to wild type littermates (Kwan et al., 2006). Karashima et al found no difference in shivering or paw withdrawal latencies in male or female TRPA1-deficient mice on the cold plate test, but observed that prolonged exposure to the cold surface elicited jumping in wild type, but not TRPA1-deficient animals (Karashima et al., 2009). Conceivably, the latter phenotype reflects a contribution of TRPA1 to cold sensitivity in the setting of tissue injury, but not to acute cold pain. Consistent with the latter hypothesis, single nerve fiber recordings show no decrement in acute cold sensitivity in TRPA1-deficient mice (Cavanaugh et al., 2009; Kwan et al., 2009). Finally, it is noteworthy that capsaicin-treated mice lacking the central terminals of TRPV1-expressing fibers show intact behavioral responses to cool and noxious cold stimuli (Cavanaugh et al., 2009). Because TRPA1 is expressed in a subset of TRPV1-positive neurons, it follows that TRPA1 is not required for normal acute cold sensitivity. Future studies using mice deficient for both TRPM8 and TRPA1 will help to resolve these issues and to identify the molecules and cell types that underlie the residual TRPM8-independent component of cold sensitivity.


Additional molecules, including voltage-gated sodium channels (discussed below), voltage-gated potassium channels, and two-pore background KCNK potassium channels, coordinate with TRPM8 to fine tune cold thresholds or to propagate cold-evoked action potentials (Viana et al., 2002; Zimmermann et al., 2007; Noel et al., 2009). For example, specific Kv1 inhibitors increase the temperature threshold of cold-sensitive neurons and injection of these inhibitors into the rodent hindpaw reduces behavioral responses to cold, but not to heat or mechanical stimuli (Madrid et al., 2009). Two members of the KCNK channel family, KCNK2 (TREK-1) and KCNK4 (TRAAK) are expressed in a subset of C-fiber nociceptors (Noel et al., 2009) and can be modulated by numerous physiological and pharmacological stimuli, including pressure and temperature. Furthermore, mice lacking these channels display abnormalities in sensitivity to pressure, heat, and cold (Noel et al., 2009). Although these findings suggest that TREK-1 and TRAAK channels modulate nociceptor excitability, it remains unclear how their intrinsic sensitivity to physical stimuli relates to their in vivo contribution to thermal or mechanical transduction.


Activating the Nociceptor: Mechanical


The somatosensory system detects quantitatively and qualitatively diverse mechanical stimuli, ranging from light brush of the skin to distension of the bladder wall. A variety of mechanosensitive neuronal subtypes are specialized to detect this diverse array of mechanical stimuli and can be categorized according to threshold sensitivity. High threshold mechanoreceptors include C fibers and slowly adapting A? mechanoreceptor (AM) fibers, both of which terminate as free nerve endings in the skin. Low threshold mechanoreceptors include A? D-hair fibers that terminate on down hairs in the skin and detect light touch. Finally, A? fibers that innervate Merkel cells, Pacinian corpuscles and hair follicles detect texture, vibration, and light pressure.


As in the case of thermal stimuli, mechanical sensitivity has been probed at a number of levels, including dissociated sensory neurons in culture, ex-vivo fiber recordings, as well as recordings from central (i.e. dorsal horn neurons) and measurements of behavioral output. Ex-vivo skin-nerve recordings have been most informative in matching stimulus properties (such as intensity, frequency, speed, and adaptation) to specific fiber subtypes. For example, A? fibers are primarily associated with sensitivity to light touch, whereas C and A? fibers are primarily responsive to noxious mechanical insults. At the behavioral level, mechanical sensitivity is typically assessed using two techniques. The most common involves measuring reflex responses to constant force applied to the rodent hind paw by calibrated filaments (Von Frey hairs). The second applies increasing pressure to the paw or tail via a clamp system. In either case, information about mechanical thresholds is obtained under normal (acute) or injury (hypersensitivity) situations. One of the challenges in this area has been to develop additional behavioral assays that measure different aspects of mechanosensation, such as texture discrimination and vibration, which will facilitate the study of both noxious and non-noxious touch (Wetzel et al., 2007).


At the cellular level, pressure can be applied to the cell bodies of cultured somatosensory neurons (or to their neurites) using a glass probe, changes in osmotic strength, or stretch via distension of an elastic culture surface, though it is unclear which stimulus best mimics physiological pressure (Bhattacharya et al., 2008; Cho et al., 2006; Cho et al., 2002; Drew et al., 2002; Hu and Lewin, 2006; Lin et al., 2009; Takahashi and Gotoh, 2000). Responses can be assessed using electrophysiological or live cell imaging methods. The consensus from such studies is that that pressure opens a mechanosensitive cation channel to elicit rapid depolarization. However, a dearth of specific pharmacological probes and molecular markers with which to characterize these responses or to label relevant neuronal subtypes has hampered attempts to match cellular activities with anatomically or functionally defined nerve fiber subclasses. These limitations have also impeded the molecular analysis of mechansosensation and the identification of molecules that constitute the mechanotransduction machinery. Nonetheless, a number of candidates have emerged, based largely on studies of mechanosensation in model genetic organisms. Mammalian orthologues of these proteins have been examined using gene targeting approaches in mice, in which the techniques mentioned above can be used to assess deficits in mechanosensation at all levels. Below we briefly summarize some of the candidates revealed in these studies.


Candidate Mechanotransducers: DEG/ENaC Channels


Studies in the nematode Caenorhabditis elegans (C. elegans) have identified mec-4 and mec-10, members of the degenerin/epithelial Na+ channel (DEG/ENaC) families, as mechanotransducers in body touch neurons (Chalfie, 2009). Based on these studies, the mammalian orthologues ASIC 1, 2 and 3 have been proposed as mechanotransduction channels. ASICs are acid-sensitive ion channels that serve as receptors for extracellular protons (tissue acidosis) produced during ischemia (see below). Although these channels are expressed by both low and high threshold mechanosensitive neurons, genetic studies do not uniformly support an essential role in mechanotransduction. Mice lacking functional ASIC1 channels display normal behavioral responses to cutaneous touch, and little or no change in mechanical sensitivity when assessed by single fiber recording (Page et al., 2004; Price et al., 2000). Likewise, peripheral nerve fibers from ASIC2-deficient mice display only a slight decrease in action potential firing to mechanical stimuli, whereas ASIC3-deficient fibers display a slight increase (no change in mechanical thresholds or baseline behavioral mechanical sensitivity was observed in these animals) (Price et al., 2001; Roza et al., 2004). Analysis of mice deficient for both ASIC2 and ASIC3 also fails to support a role for these channels in cutaneous mechanotransduction (Drew et al., 2004). Thus, although these channels appear to play a role in musculoskeletal and ischemic pain (see below), their contribution to mechanosensation remains unresolved.


Genetic studies suggest that C. elegans mec-4/mec-10 channels exist in a complex with the stomatin-like protein MEC-2 (Chalfie, 2009). Mice lacking the MEC-2 orthologue, SLP3, display a loss of mechanosensitivity in low-threshold A? and A? fibers, but not in C fibers (Wetzel et al., 2007). These mice exhibit altered tactile acuity, but display normal responses to noxious pressure, suggesting that SLP3 contributes to the detection of innocuous, but not noxious mechanical stimuli. Whether SLP3 functions in a mechanotransduction complex or interacts with ASICs in mammalian sensory neurons is unknown.


Candidate Mechanotransducers: TRP Channels


As noted above, when expressed heterologously, TRPV2 not only responds to noxious heat, but also to osmotic stretch. Additionally, native TRPV2 channels in vascular smooth muscle cells are activated by direct suction and osmotic stimuli (Muraki et al., 2003). A role for TRPV2 for somatosensory mechanotransduction in vivo has not yet been tested.


TRPV2 is robustly expressed in medium and large diameter, A? fibers that respond to both mechanical and thermal stimuli (Caterina et al., 1999; Muraki et al., 2003). TRPV4 shows modest expression in sensory ganglia, but is more abundantly expressed in the kidney and stretch-sensitive urothelial cells of the bladder (Gevaert et al., 2007; Mochizuki et al., 2009). When heterologously expressed, both TRPV2 and TRPV4 have been shown to respond to changes in osmotic pressure (Guler et al., 2002; Liedtke et al., 2000; Mochizuki et al., 2009; Strotmann et al., 2000). Analysis of TRPV4-deficient animals suggests a role in osmosensation as knockout animals display defects in blood pressure, water balance, and bladder voiding (Gevaert et al., 2007; Liedtke and Friedman, 2003). These animals exhibit normal acute cutaneous mechanosensation, but show deficits in models of mechanical and thermal hyperalgesia (Alessandri-Haber et al., 2006; Chen et al., 2007; Grant et al., 2007; Suzuki et al., 2003). Thus, TRPV4 is unlikely to serve as a primary mechanotransducer in sensory neurons, but may contribute to injury-evoked pain hypersensitivity.


TRPA1 has also been proposed to serve as a detector of mechanical stimuli. Heterologously expressed mammalian TRPA1 is activated by membrane crenators (Hill and Schaefer, 2007) and the worm orthologue is sensitive to mechanical pressure applied via a suction pipette (Kindt et al., 2007). However, TRPA1-deficient mice display only weak defects in mechanosensory behavior and the results are inconsistent. Two studies reported no change in mechanical thresholds in TRPA1-deficient animals (Bautista et al., 2006; Petrus et al., 2007), whereas a third study reported deficits (Kwan et al., 2006). A more recent study shows that C and A? mechanosensitive fibers in TRPA1 knockout animals have altered responses to mechanical stimulation (some increased and others decreased) (Kwan et al., 2009). Whether and how these differential physiological effects are manifest at the level of behavior is unclear. Taken together, TRPA1 does not appear to function as a primary detector of acute mechanical stimuli, but perhaps modulates excitability of mechanosensitive afferents.


Candidate Mechanotransducers: KCNK Channels


In addition to the potential mechanotransducer role of KCNK2 and 4 (see above), KCNK18 has been discussed for its possible contribution to mechanosensation. Thus, KCNK18 is targeted by hydroxy-a-sanshool, the pungent ingredient in Szechuan peppercorns that produces tingling and numbing sensations, suggestive of an interaction with touch-sensitive neurons (Bautista et al., 2008; Bryant and Mezine, 1999; Sugai et al., 2005). KCNK18 is expressed in a subset of presumptive peptidergic C fibers and low threshold (A?) mechanoreceptors, where it serves as a major regulator of action potential duration and excitability (Bautista et al., 2008; Dobler et al., 2007). Moreover, sanshool depolarizes osmo- and mechanosensitive large diameter sensory neurons, as well as a subset of nociceptors (Bautista et al., 2008; Bhattacharya et al., 2008). Although it is not known if KCNK18 is directly sensitive to mechanical stimulation, it may be a critical regulator of the excitability of neurons involved in innocuous or noxious touch sensation.


In summary, the molecular basis of mammalian mechanotransduction is far from clarified. Mechanical hypersensitivity in response to tissue or nerve injury represents a major clinical problem and thus elucidating the biological basis of touch under normal and pathophysiological conditions remains one of the main challenges in somatosensory and pain research.


Activating the Nociceptor: Chemical


Chemo-nociception is the process by which primary afferent neurons detect environmental irritants and endogenous factors produced by physiological stress. In the context of acute pain, chemo-nociceptive mechanisms trigger aversive responses to a variety of environmental irritants. Here, again, TRP channels have prominent roles, which is perhaps not surprising given that they function as receptors for plant-derived irritants, including capsaicin (TRPV1), menthol (TRPM8), as well as the pungent ingredients in mustard and garlic plants, isothiocyanates and thiosulfinates (TRPA1) (Bandell et al., 2004; Caterina et al., 1997; Jordt et al., 2004; McKemy et al., 2002; Peier et al., 2002a).


With respect to environmental irritants, TRPA1 has emerged as a particularly interesting member of this group. This is because TRPA1 responds to compounds that are structurally diverse but unified in their ability to form covalent adducts with thiol groups. For example, allyl isothiocyanate (from wasabi) or allicin (from garlic) are membrane permeable electrophiles that activate TRPA1 by covalently modifying cysteine residues within the amino-terminal cytoplasmic domain of the channel (Hinman et al., 2006; Macpherson et al., 2007). How this promotes channel gating is currently unknown. Nevertheless, simply establishing the importance of thiol reactivity in this process has implicated TRPA1 as a key physiological target for a wide and chemically diverse group of environmental toxicants. One notable example is acrolein (2-propenal), a highly reactive ?,?-unsaturated aldehyde present in tear gas, vehicle exhaust, or smoke from burning vegetation (i.e. forest fires and cigarettes). Acrolein and other volatile irritants (such as hypochlorite, hydrogen peroxide, formalin, and isocyanates) activate sensory neurons that innervate the eyes and airways, producing pain and inflammation (Bautista et al., 2006; Bessac and Jordt, 2008; Caceres et al., 2009). This action can have especially dire consequences for those suffering from asthma, chronic cough, or other pulmonary disorders. Mice lacking TRPA1 show greatly reduced sensitivity to such agents, underscoring the critical nature of this channel as a sensory detector of reactive environmental irritants (Caceres et al., 2009). In addition to these environmental toxins, TRPA1 is targeted by some general anesthetics (such as isofluorane) or metabolic byproducts of chemotherapeutic agents (such as cyclophosphamide), which likely underlies some of the adverse side effects of these drugs, including acute pain and robust neuroinflammation (Bautista et al., 2006; Matta et al., 2008).


Finally, chemical irritants and other pro-algesic agents are also produced endogenously in response to tissue damage or physiological stress, including oxidative stress. Such factors can act alone, or in combination, to sensitize nociceptors to thermal and/or mechanical stimuli, thereby lowering pain thresholds. The result of this action is to enhance guarding and protective reflexes in the aftermath of injury. Thus, chemo-nociception represents an important interface between acute and persistent pain, especially in the context of peripheral tissue injury and inflammation, as discussed in greater detail below.


Acute Pain: Conducting the Pain Signal


Once thermal and mechanical signals are transduced by the primary afferent terminal, the receptor potential activates a variety of voltage-gated ion channels. Voltage-gated sodium and potassium channels are critical to the generation of action potentials that convey nociceptor signals to synapses in the dorsal horn. Voltage-gated calcium channels play a key role in neurotransmitter release from central or peripheral nociceptor terminals to generate pain or neurogenic inflammation, respectively. We restrict our discussion to members of the sodium and calcium channel families that serve as targets of currently used analgesic drugs, or for which human genetics support a role in pain transmission. A recent review has discussed the important contribution of KCNQ potassium channels, including the therapeutic benefit of increasing K+ channel activity for the treatment of persistent pain (Brown and Passmore, 2009).


Voltage-Gated Sodium Channels


A variety of sodium channels are expressed in somatosensory neurons, including the tetrodotoxin (TTX)-sensitive channels Nav1.1, 1.6 and 1.7, and the TTX-insensitive channels, Nav1.8 and 1.9. In recent years, the contribution of Nav1.7 has received much attention, as altered activity of this channel leads to a variety of human pain disorders (Cox et al., 2006; Dib-Hajj et al., 2008). Patients with loss-of-function mutations within this gene are unable to detect noxious stimuli, and as a result suffer injuries due to lack of protective reflexes. In contrast, a number of gain-of-function mutations in Nav1.7 leads to hyperexcitability of the channel and are associated with two distinct pain disorders in humans, erythromelalgia, and paroxysmal extreme pain disorder, both of which cause intense burning sensations (Estacion et al., 2008; Fertleman et al., 2006; Yang et al., 2004). Animal studies have demonstrated that Nav1.7 is highly upregulated in a variety of inflammatory pain models. Indeed, analysis of mice lacking Nav1.7 in C nociceptors supports a key role for this channel in mechanical and thermal hypersensitivity following inflammation, and in acute responses to noxious mechanical stimuli (Nassar et al., 2004). Somewhat surprisingly, pain induced by nerve injury is unaltered, suggesting that distinct sodium channel subtypes, or another population of Nav1.7-expressing afferents, contribute to neuropathic pain (Nassar et al., 2005).


The Nav1.8 sodium channel is also highly expressed by most C nociceptors. As with Nav1.7 knockout animals, those lacking Nav1.8 display modest deficits in sensitivity to innocuous or noxious heat, or innocuous pressure; however, they display attenuated responses to noxious mechanical stimuli (Akopian et al., 1999). Nav1.8 is also required for the transmission of cold stimuli, as mice lacking this channel are insensitive to cold over a wide range of temperatures (Zimmermann et al., 2007). This is because Nav1.8 is unique among voltage-sensitive sodium channels in that it does not inactivate at low temperature, making it the predominant action potential generator under cold conditions.


Interestingly, transgenic mice lacking the Nav1.8 expressing subset of sensory neurons, which were deleted by targeted expression of diphtheria toxin A (Abrahamsen et al., 2008), display attenuated responses to both low and high threshold mechanical stimuli and cold. In addition, mechanical and thermal hypersensitivity in inflammatory pain models is severely attenuated. The differential phenotypes of mice lacking Nav1.8 channels versus deletion of the Nav1.8-expressing neurons presumably reflects the contribution of multiple voltage-gated sodium channel subtypes to transmission of pain messages.


Voltage-gated sodium channels are targets of local anesthetic drugs, highlighting the potential for the development of subtype-specific analgesics. Nav1.7 is a particularly interesting target for treating inflammatory pain syndromes, in part, because the human genetic studies suggest that Nav1.7 inhibitors should reduce pain without altering other essential physiological processes (see above). Another potential application of sodium channel blockers may be to treat extreme hypersensitivity to cold, a particularly troublesome adverse side effect of platinum-based chemotherapeutics, such as oxaliplatin (Attal et al., 2009). Nav1.8 (or TRPM8) antagonists may alleviate this, or other forms of cold allodynia. Finally, the great utility of the antidepressant serotonin and norepinephrine reuptake inhibitors for the treatment of neuropathic pain may, in fact, result from their ability to block voltage gated sodium channels (Dick et al., 2007).


Voltage-Gated Calcium Channels


A variety of voltage-gated calcium channels are expressed in nociceptors. N-, P/Q- and T-type calcium channels have received the most attention. P/Q-type channels are expressed at synaptic terminals in laminae II-IV of the dorsal horn. Their exact role in nociception is not completely resolved. However, mutations in these channels have been linked to familial hemiplegic migraine (de Vries et al., 2009). N- and T-type calcium channels are also expressed by C-fibers and are upregulated under pathophysiological states, as in models of diabetic neuropathy or after other forms of nerve injury. Animals lacking Cav2.2 or 3.2 show reduced sensitization to mechanical or thermal stimuli following inflammation or nerve injury, respectively (Cao, 2006; Swayne and Bourinet, 2008; Zamponi et al., 2009; Messinger et al., 2009). Moreover, ?-conotoxin GVIA, which blocks N-type channels, is administered intrathecally (as ziconotide) to provide relief for intractable cancer pain (Rauck et al., 2009).


All calcium channels are heteromeric proteins composed of ?1 pore forming subunits and the modulatory subunits ?2?, ?2? or ?2?. The ?2? subunit regulates current density and kinetics of activation and inactivation. In C nociceptors, the ?2? subunit is dramatically upregulated following nerve injury and plays a key role in injury-evoked hypersensitivity and allodynia (Luo et al., 2001). Indeed, this subunit is the target of gabapentinoid class of anticonvulsants, which are now widely used to treat neuropathic pain (Davies et al., 2007).


Persistent Pain: Peripheral Mechanisms


Persistent pain associated with injury or diseases (such as diabetes, arthritis, or tumor growth) can result from alterations in the properties of peripheral nerves. This can occur as a consequence of damage to nerve fibers, leading to increased spontaneous firing or alterations in their conduction or neurotransmitter properties. In fact, the utility of topical and even systemic local anesthetics for the treatment of different neuropathic pain conditions (such as postherpetic neuralgia) likely reflects their action on sodium channels that accumulate in injured nerve fibers.


The Chemical Milieu of Inflammation


Peripheral sensitization more commonly results from inflammation-associated changes in the chemical environment of the nerve fiber (McMahon et al., 2008). Thus, tissue damage is often accompanied by the accumulation of endogenous factors released from activated nociceptors or non-neural cells that reside within or infiltrate into the injured area (including mast cells, basophils, platelets, macrophages, neutrophils, endothelial cells, keratinocytes, and fibroblasts). Collectively. these factors, referred to as the �inflammatory soup�, represent a wide array of signaling molecules, including neurotransmitters, peptides (substance P, CGRP, bradykinin), eicosinoids and related lipids (prostaglandins, thromboxanes, leukotrienes, endocannabinoids), neurotrophins, cytokines, and chemokines, as well as extracellular proteases and protons. Remarkably, nociceptors express one or more cell surface receptors capable of recognizing and responding to each of these pro-inflammatory or pro-algesic agents (Figure 4). Such interactions enhance excitability of the nerve fiber, thereby heightening its sensitivity to temperature or touch.


Figure 4 Peripheral Mediators of Inflammation


Unquestionably the most common approach to reducing inflammatory pain involves inhibiting the synthesis or accumulation of components of the inflammatory soup. This is best exemplified by non-steroidal anti-inflammatory drugs, such as aspirin or ibuprofen, which reduce inflammatory pain and hyperalgesia by inhibiting cyclooxygenases (Cox-1 and Cox-2) involved in prostaglandin synthesis. A second approach is to block the actions of inflammatory agents at the nociceptor. Here, we highlight examples that provide new insight into cellular mechanisms of peripheral sensitization, or which form the basis of new therapeutic strategies for treating inflammatory pain.


NGF is perhaps best known for its role as a neurotrophic factor required for survival and development of sensory neurons during embryogenesis, but in the adult, NGF is also produced in the setting of tissue injury and constitutes an important component of the inflammatory soup (Ritner et al., 2009). Among its many cellular targets, NGF acts directly on peptidergic C fiber nociceptors, which express the high affinity NGF receptor tyrosine kinase, TrkA, as well as the low affinity neurotrophin receptor, p75 (Chao, 2003; Snider and McMahon, 1998). NGF produces profound hypersensitivity to heat and mechanical stimuli through two temporally distinct mechanisms. At first, a NGF-TrkA interaction activates downstream signaling pathways, including phospholipase C (PLC), mitogen-activated protein kinase (MAPK), and phosphoinositide 3-kinase (PI3K). This results in functional potentiation of target proteins at the peripheral nociceptor terminal, most notably TRPV1, leading to a rapid change in cellular and behavioral heat sensitivity (Chuang et al., 2001). In addition to these rapid actions, NGF is also retrogradely transported to the nucleus of the nociceptor, where it promotes increased expression of pro-nociceptive proteins, including substance P, TRPV1, and the Nav1.8 voltage-gated sodium channel subunit (Chao, 2003; Ji et al., 2002). Together, these changes in gene expression enhance excitability of the nociceptor and amplify the neurogenic inflammatory response.


In addition to neurotrophins, injury promotes the release of numerous cytokines, chief among them interleukin 1? (IL-1?) and IL-6, and tumor necrosis factor ? (TNF-?) (Ritner et al., 2009). Although there is evidence to support a direct action of these cytokines on nociceptors, their primary contribution to pain hypersensitivity results from potentiation of the inflammatory response and increased production of pro-algesic agents (such as prostaglandins, NGF, bradykinin, and extracellular protons).


Irrespective of their pro-nociceptive mechanisms, interfering with neurotrophin or cytokine signaling has become a major strategy for controlling inflammatory disease or resulting pain. The main approach involves blocking NGF or TNF-? action with a neutralizing antibody. In the case of TNF-?, this has been remarkably effective in the treatment of numerous autoimmune diseases, including rheumatoid arthritis, leading to dramatic reduction in both tissue destruction and accompanying hyperalgesia (Atzeni et al., 2005). Because the main actions of NGF on the adult nociceptor occur in the setting of inflammation, the advantage of this approach is that hyperalgesia will decrease without affecting normal pain perception. Indeed, anti-NGF antibodies are currently in clinical trials for treatment of inflammatory pain syndromes (Hefti et al., 2006).


Targets of the Inflammatory Soup


TRPV1. Robust hypersensitivity to heat can develop with inflammation or after injection of specific components of the inflammatory soup (such as bradykinin or NGF). Lack of such sensitization in TRPV1-deficient mice provides genetic support for the idea that TRPV1 is a key component of the mechanism through which inflammation produces thermal hyperalgesia (Caterina et al., 2000; Davis et al., 2000). Indeed, in vitro studies have shown that TRPV1 functions as a polymodal signal integrator whose thermal sensitivity can be profoundly modulated by components of the inflammatory soup (Tominaga et al., 1998). Some of these inflammatory agents (for example, extracellular protons and lipids) function as direct positive allosteric modulators of the channel, whereas others (bradykinin, ATP, and NGF) bind to their own receptors on primary afferents and modulate TRPV1 through activation of downstream intracellular signaling pathways. In either case, these interactions result in a profound decrease in the channel’s thermal activation threshold, as well as an increase in the magnitude of responses at supra-threshold temperatures�the biophysical equivalents of allodynia and hyperalgesia, respectively.


However, there remains controversy concerning the intracellular signaling mechanisms most responsible for TRPV1 modulation (Lumpkin and Caterina, 2007). Reminiscent of ancestral TRP channels in the fly eye, many mammalian TRP channels are activated or positively modulated by phospholipase C-mediated cleavage of plasma membrane phosphatidyl inositol 4,5 bisphosphate (PIP2). Of course, there are many downstream consequences of this action, including a decrease in membrane PIP2, increase levels of diacylglycerol and its metabolites, increased cytoplasmic calcium, as well as consequent activation of protein kinases. In the case of TRPV1, most, if not all, of these pathways have been implicated in the sensitization process and it remains to be seen which are most relevant to behavioral thermal hypersensitivity. Nevertheless, there is broad agreement that TRPV1 modulation is relevant to tissue injury-evoked pain hypersensitivity, particularly in the setting of inflammation. This would include conditions such as sunburn, infection, rheumatoid or osteoarthritis, and inflammatory bowl disease. Another interesting example includes pain from bone cancer (Honore et al., 2009), where tumor growth and bone destruction are accompanied by extremely robust tissue acidosis, as well as production of cytokines, neurotrophins, and prostaglandins.


TRPA1. As described above, TRPA1 is activated by compounds that form covalent adducts with cysteine residues. In addition to environmental toxins, this includes endogenous thiol reactive electrophiles that are produced during tissue injury and inflammation, or as a consequence of oxidative or nitrative stress. Chief among such agents are 4-hydroxy-2-nonenal and 15-deoxy-?12,14-prostaglandin J2, which are both ?,? unsaturated aldehydes generated through peroxidation or spontaneous dehydration of lipid second messengers (Andersson et al., 2008; Cruz-Orengo et al., 2008; Materazzi et al., 2008; Trevisani et al., 2007). Other endogenous TRPA1 agonists include nitrooleic acid, hydrogen peroxide, and hydrogen sulfide. In addition to these directly acting agents, TRPA1 is also modulated indirectly by pro-algesic agents, such as bradykinin, which act via PLC-coupled receptors. Indeed, TRPA1-deficient mice show dramatically reduced cellular and behavioral responses to all of these agents, as well as a reduction in tissue injury-evoked thermal and mechanical hypersensitivity (Bautista et al., 2006; Kwan et al., 2006). Finally, because TRPA1 plays a key role in neurogenic and other inflammatory responses to both endogenous agents and volatile environmental toxins, its contribution to airway inflammation, such as occurs in asthma, is of particular interest. Indeed, genetic or pharmacological blockade of TRPA1 reduces airway inflammation in a rodent model of allergen-evoked asthma (Caceres et al., 2009).


ASICs. As noted above, ASIC channels are members of the DEG/ENaC family that are activated by acidification, and thus represent another important site for the action of extracellular protons produced as a consequence of tissue injury or metabolic stress. ASIC subtypes can form a variety of homomeric or heteromeric channels, each having distinct pH sensitivity and expression profile. Channels containing the ASIC3 subtype are specifically expressed by nociceptors and especially well represented in fibers that innervate skeletal and cardiac muscle. In these tissues, anaerobic metabolism leads to buildup of lactic acid and protons, which activate nociceptors to generate musculoskeletal or cardiac pain (Immke and McCleskey, 2001). Interestingly, ASIC3-containing channels open in response to the modest decrease in pH (e.g. 7.4 to 7.0) that occurs with cardiac ischemia (Yagi et al., 2006). Lactic acid also significantly potentiates proton-evoked gating through a mechanism involving calcium chelation (Immke and McCleskey, 2003). Thus, ASIC3-containing channels detect and integrate signals specifically associated with muscle ischemia and, in this way, are functionally distinct from other acid sensors on the primary afferent, such as TRPV1 or other ASIC channel subtypes.


Persistent Pain: Central Mechanisms


Central sensitization refers to the process through which a state of hyperexcitability is established in the central nervous system, leading to enhanced processing of nociceptive (pain) messages (Woolf, 1983). Although numerous mechanisms have been implicated in central sensitization here we focus on three: alteration in glutamatergic neurotransmission/NMDA receptor-mediated hypersensitivity, loss of tonic inhibitory controls (disinhibition) and glial-neuronal interactions (Figure 5).


Figure 5 Spinal Cord Central Sensitization


Glutamate/NMDA Receptor-Mediated Sensitization


Acute pain is signaled by the release of glutamate from the central terminals of nociceptors, generating excitatory post-synaptic currents (EPSCs) in second order dorsal horn neurons. This occurs primarily through activation of postsynaptic AMPA and kainate subtypes of ionotropic glutamate receptors. Summation of sub-threshold EPSCs in the postsynaptic neuron will eventually result in action potential firing and transmission of the pain message to higher order neurons. Under these conditions, the NMDA subtype of glutamate channel is silent, but in the setting of injury, increased release of neurotransmitters from nociceptors will sufficiently depolarize postsynaptic neurons to activate quiescent NMDA receptors. The consequent increase in calcium influx can strengthen synaptic connections between nociceptors and dorsal horn pain transmission neurons, which in turn will exacerbate responses to noxious stimuli (that is, generate hyperalgesia).


In many ways, this processes is comparable to that implicated in the plastic changes associated with hippocampal long-term potentiation (LTP) (for a review on LTP in the pain pathway, see Drdla and Sandkuhler, 2008). Indeed, drugs that block spinal LTP reduce tissue injury-induced hyperalgesia. As in the case of hippocampal LTP, spinal cord central sensitization is dependent on NMDA-mediated elevations of cytosolic Ca2+ in the postsynaptic neuron. Concurrent activation of metabotropic glutamate and substance P receptors on the postsynaptic neuron may also contribute to sensitization by augmenting cytosolic calcium. Downstream activation of a host of signaling pathways and second messenger systems, notably kinases (such as MAPK, PKA, PKC, PI3K, Src), further increases excitability of these neurons, in part by modulating NMDA receptor function (Latremoliere and Woolf, 2009). Illustrative of this model is the demonstration that spinal injections of a nine amino acid peptide fragment of Src not only disrupts an NMDA receptor�Src interaction but also markedly decreases the hypersensitivity produced by peripheral injury, without changing acute pain. Src null mutant mice also display reduced mechanical allodynia after nerve injury (Liu et al., 2008).


In addition to enhancing inputs from the site of injury (primary hyperalgesia), central sensitization contributes to the condition in which innocuous stimulation of areas surrounding the injury site can produce pain. This secondary hyperalgesia involves heterosynaptic facilitation, wherein inputs from A? afferents, which normally respond to light touch, now engage pain transmission circuits, resulting in profound mechanical allodynia. The fact that compression block of peripheral nerve fibers concurrently interrupts conduction in A? afferents and eliminates secondary hyperalgesia indicates that these abnormal circuits are established in clinical settings as well as in animal models (Campbell et al., 1988).


Loss of GABAergic and Glycinergic Controls: Disinhibition


GABAergic or glycinergic inhibitory interneurons are densely distributed in the superficial dorsal horn and are at the basis of the longstanding gate control theory of pain, which postulates that loss of function of these inhibitory interneurons (disinhibition) would result in increased pain (Melzack and Wall, 1965). Indeed, in rodents, spinal administration of GABA (bicuculline) or glycine (strychnine) receptor antagonists (Malan et al., 2002; Sivilotti and Woolf, 1994; Yaksh, 1989) produces behavioral hypersensitivity resembling that observed after peripheral injury. Consistent with these observations, peripheral injury leads to a decrease in inhibitory postsynaptic currents in superficial dorsal horn neurons. Although Moore et al. (2002) suggested that the disinhibition results from peripheral nerve injury-induced death of GABAergic interneurons, this claim has been contested (Polgar et al., 2005). Regardless of the etiology, the resulting decreased tonic inhibition enhances depolarization and excitation of projection neurons. As for NMDA-mediated central sensitization, disinhibition enhances spinal cord output in response to painful and non-painful stimulation, contributing to mechanical allodynia (Keller et al., 2007; Torsney and MacDermott, 2006).


Following upon an earlier report that deletion of the gene encoding PKC? in the mouse leads to a marked decrease in nerve injury-evoked mechanical hypersensitivity (Malmberg et al., 1997), recent studies address the involvement of these neurons in the disinhibitory process. Thus, after blockade of glycinergic inhibition with strychnine, innocuous brushing of the hindpaw activates PKC?-positive interneurons in lamina II (Miraucourt et al., 2007), as well as projection neurons in lamina I. Because PKC?-positive neurons in the spinal cord are located only in the innermost part of lamina II (Figure 1), it follows that these neurons are essential for the expression of nerve injury-evoked persistent pain, and that disinhibitory mechanisms lead to their hyperactivation.


Other studies indicate that changes in the projection neuron, itself, contribute to the dis-inhibitory process. For example, peripheral nerve injury profoundly down-regulates the K+-Cl- co-transporter KCC2, which is essential for maintaining normal K+ and Cl- gradients across the plasma membrane (Coull et al., 2003). Downregulating KCC2, which is expressed in lamina I projection neurons, results in a shift in the Cl- gradient, such that activation of GABA-A receptors depolarize, rather than hyperpolarize the lamina I projection neurons. This would, in turn, enhance excitability and increase pain transmission. Indeed, pharmacological blockade or siRNA-mediated downregulation of KCC2 in the rat induces mechanical allodynia. Nonetheless, Zeilhofer and colleagues suggest that, even after injury, sufficient inhibitory tone remains such that enhancement of spinal GABAergic neurotransmission might be a valuable approach to reduce pain hypersensitivity induced by peripheral nerve injury (Knabl et al., 2008). In fact, studies in mice suggest that drugs specifically targeting GABAA complexes containing ?2 and/or ?3 subunits reduce inflammatory and neuropathic pain without producing sedative-hypnotic side effects typically associated with benzodiazepines, which enhance activity of ?1-containing channels.


Disinhibition can also occur through modulation of glycinergic signaling. In this case the mechanism involves a spinal cord action of prostaglandins (Harvey et al., 2004). Specifically, tissue injury induces spinal release of the prostaglandin, PGE2, which acts on EP2 receptors expressed by excitatory interneurons and projection neurons in the superficial dorsal horn. Resultant stimulation of the cAMP-PKA pathway phosphorylates GlyRa3 glycine receptor subunits, rendering the neurons unresponsive to the inhibitory effects of glycine. Accordingly, mice lacking the GlyRa3 gene have decreased heat and mechanical hypersensitivity in models of tissue injury.


Glial-Neuronal Interactions


Finally, glial cells, notably microglia and astrocytes, also contribute to the central sensitization process that occurs in the setting of injury. Under normal conditions, microglia function as resident macrophages of the central nervous system. They are homogeneously distributed within the grey matter of the spinal cord and are presumed to function as sentinels of injury or infection. Within hours of peripheral nerve injury, however, microglia accumulate in the superficial dorsal horn within the termination zone of injured peripheral nerve fibers. Microglia also surround the cell bodies of ventral horn motoneurons, whose peripheral axons are concurrently damaged. The activated microglia release a panoply of signaling molecules, including cytokines (such as TNF-?, interleukin-1? and 6), which enhance neuronal central sensitization and nerve injury-induced persistent pain (DeLeo et al., 2007). Indeed, injection of activated brain microglia into the cerebral spinal fluid at the level of the spinal cord can reproduce the behavioral changes observed after nerve injury (Coull et al., 2005). Thus, it appears that microglial activation is sufficient to trigger the persistent pain condition (Tsuda et al., 2003).


As microglia are activated following nerve, but not inflammatory tissue injury, it follows that activation of the afferent fiber, which occurs under both injury conditions, is not the critical trigger for microglial activation. Rather, physical damage of the peripheral afferent must induce the release of specific signals that are detected by microglia. Chief among these is ATP, which targets microglial P2-type purinergic receptors. Of particular interest are P2X4 (Tsuda et al., 2003), P2X7 (Chessell et al., 2005) and P2Y12 (Haynes et al., 2006; Kobayashi et al., 2008) receptor subtypes. Indeed, ATP was used to activate brain microglia in the spinal cord transplant studies referred to above (Tsuda et al., 2003). Furthermore, genetic or pharmacological blockade of purinergic receptor function (Chessell et al., 2005; Tozaki-Saitoh et al., 2008; Ulmann et al., 2008) prevents or reverses nerve injury-induced mechanical allodynia (Honore et al., 2006; Kobayashi et al., 2008; Tozaki-Saitoh et al., 2008; Tsuda et al., 2003).


Coull and colleagues proposed a model in which ATP/P2X4-mediated activation of microglia triggers a mechanism of disinhibition (Coull et al., 2005). Specifically, they demonstrated that ATP-evoked activation of P2X4 receptors induces release of the brain-derived neurotrophic factor (BDNF) from microglia. The BDNF, in turn, acts upon TrkB receptors on lamina I projection neurons, to generate a change in the Cl- gradient, which as described above, would shift the action of GABA from hyperpolarization to depolarization. Whether the BDNF-induced effect involves KCC2 expression, as occurs after nerve injury, is not known. Regardless of the mechanism, the net result is that activation of microglia will sensitize lamina I neurons such that their response to monosynaptic inputs from nociceptors, or indirect inputs from A? afferents, is enhanced.


In addition to BDNF, activated microglia, like peripheral macrophages, release and respond to numerous chemokines and cytokines, and these also contribute to central sensitization. For example, in the uninjured (normal) animal, the chemokine fractalkine (CXCL1) is expressed by both primary afferents and spinal cord neurons (Lindia et al., 2005; Verge et al., 2004; Zhuang et al., 2007). In contrast, the fractalkine receptor (CX3CR1) is expressed on microglial cells and importantly, is upregulated after peripheral nerve injury (Lindia et al., 2005; Zhuang et al., 2007). Because spinal delivery of fractalkine can activate microglia, it appears that nerve injury-induced release of fractalkine provides yet another route through which microglia can be engaged in the process of central sensitization. Indeed blockade of CX3CR1 with a neutralizing antibody prevents both the development and maintenance of injury-induced persistent pain (Milligan et al., 2004; Zhuang et al., 2007). This pathway may also be part of a positive feedback loop through which injured nerve fibers and microglial cells interact in a reciprocal and recurrent fashion to amplify pain signals. This point is underscored by the fact that fractalkine must be cleaved from the neuronal surface prior to signaling, an action that is carried out by the microglial-derived protease, cathepsin S, inhibitors of which reduce nerve injury-induced allodynia and hyperalgesia (Clark et al., 2007). Importantly, spinal administration of cathepsin S generates behavioral hypersensitivity in wild type, but not in CX3CX1 knockout mice, linking cathepsin S to fractalkine signaling (Clark et al., 2007; Zhuang et al., 2007). Although the factor(s) that initiates release of cathepsin S from microglia remains to be determined,. ATP seems a reasonable possibility.


Very recently, several members of the Toll-like receptors (TLRs) family have also been implicated in the activation of microglia following nerve injury. TLRs are transmembrane signaling proteins expressed in peripheral immune cells and glia. As part of the innate immune system, they recognize molecules that are broadly shared by pathogens. Genetic or pharmacological inhibition of TLR2, TLR3 or TLR4 function in mice results not only in decreased microglial activation, but also reduces the hypersensitivity triggered by peripheral nerve injury (Kim et al., 2007; Obata et al., 2008; Tanga et al., 2005). Unknown are the endogenous ligands that activate TLR2-4 after nerve-injury. Among the candidates are mRNAs or heat shock proteins that could leak from the damaged primary afferent neurons and diffuse into the extracellular milieu of the spinal cord.


The contribution of astrocytes to central sensitization is less clear. Astrocytes are unquestionably induced in the spinal cord after injury to either tissue or nerve (for a review, see Ren and Dubner, 2008). But, in contrast to microglia, astrocyte activation is generally delayed and persists much longer, up to several months. One interesting possibility is that astrocytes are more critical to the maintenance, rather than to the induction of central sensitization and persistent pain.


Finally, it is worth noting that peripheral injury not only activates glia in the spinal cord, but also in the brainstem, where glia contribute to supraspinal facilitatory influences on the processing of pain messages in the spinal cord (see Figure 2), a phenomenon named descending facilitation (for a review, see Ren and Dubner, 2008). Such facilitation is especially prominent in the setting of injury, and appears to counteract the feedback inhibitory controls that concurrently arise from various brainstem loci (Porreca et al., 2002).



Dr. Alex Jimenez’s Insight

As established by the International Association for the Study of Pain, or the IASP, pain is “an unpleasant sensory and emotional experience associated with acutal or potential tissue damage, or described in terms of tissue damage or both. Numerous research studies have been proposed to demonstrate the physiological basis of pain, however, none has been able to include the entire aspects associated with pain perception. Understanding the pain mechanisms of acute pain versus chronic pain is fundamental during clinical evaluations as this can help determine the best treatment approach for patients with underlying health issues.


Specificity in the Transmission and Control of Pain Messages


Understanding how stimuli are encoded by the nervous system to elicit appropriate behaviors is of fundamental importance to the study of all sensory systems. In the simplest form, a sensory system uses labeled lines to transduce stimuli and elicit behaviors through strictly segregated circuits. This is perhaps best exemplified by the taste system, where exchanging a sweet receptor for a bitter one in a population of �sweet taste afferents� does not alter the behavior provoked by activity in that labeled line; under these conditions, a bitter tastant stimulates these afferents to elicit a perception of sweetness (Mueller et al., 2005).


In the pain pathway, there is also evidence to support the existence of labeled lines. As mentioned above, heat and cold are detected by largely distinct subsets of primary afferent fibers. Moreover, elimination of subsets of nociceptors can produce selective deficits in the behavioral response to a particular noxious modality. For example, destruction of TRPV1-expressing nociceptors produces a profound loss of heat pain (including heat hyperalgesia), with no change in sensitivity to painful mechanical or cold stimuli. Conversely, deletion of the MrgprD subset of nociceptors results in a highly selective deficit in mechanical responsiveness, with no change in heat sensitivity (Cavanaugh et al., 2009). Further evidence for functional segregation at the level of the nociceptor comes from the analysis of two different opioid receptor subtypes (Scherrer et al., 2009). Specifically, the mu opioid receptor (MOR) predominates in the peptidergic population, whereas the delta opioid receptor (DOR) is expressed in non-peptidergic nociceptors. MOR-selective agonists block heat pain, whereas DOR selective agonists block mechanical pain, again illustrating functional separation of molecularly distinct nociceptor populations.


These observations argue for behaviorally-relevant specificity at the level of the nociceptor. However, this is likely to be an oversimplification for at least two reasons. First, many nociceptors are polymodal and can therefore be activated by thermal, mechanical, or chemical stimuli, leaving one to wonder how elimination of large cohorts of nociceptors can have modality-specific effects. This argues for a substantial contribution of spinal circuits to the process whereby nociceptive signals are encoded into distinct pain modalities. Indeed, an important future goal is to better delineate neuronal subtypes within the dorsal horn and characterize their synaptic interactions with functionally or molecularly defined subpopulations of nociceptors. Second, the pain system shows a tremendous capacity for change, particularly in the setting of injury, raising questions about whether and how a labeled line system might accommodate such plasticity, and how alterations in such mechanisms underlie maladaptive changes that produce chronic pain. Indeed, we know that substance P-saporin-mediated deletion of a discrete population of lamina I dorsal horn neurons, which express the substance P receptor, can reduce both the thermal and mechanical pain hypersensitivity that occurs after tissue or nerve injury (Nichols et al., 1999). Such observations suggest that in the setting of injury specificity of the labeled line is not strictly maintained as information is transmitted to higher levels of the neuraxis.


Clearly, answers to these questions will require the combined use of anatomical, electrophysiological, and behavioral methods to map the physical and functional circuitry that underlies nociception and pain. The ongoing identification of molecules and genes that mark specific neuronal cell types (both peripheral and central) provides essential tools with which to manipulate genetically or pharmacologically these neurons and to link their activities to specific components of pain behavior under normal and pathophysiological circumstances. Doing so should bring us closer to understanding how acute pain gives way to the maladaptive changes that produce chronic pain, and how this switch can be prevented or reversed.


Hemp vs Marijuana - What's the Difference? | El Paso, TX Chiropractor


Hemp vs Marijuana: What’s the Difference?


With approximately half of U.S. states now permitting the sale of medical marijuana, and a few even allowing the sale of marijuana for recreational use, more and more people are becoming interested in the possible health benefits of this controversial plant.


Whilst science on its medical use continues to advance, many people these days are considering how they could access the plant’s health benefits without experiencing its well-known unwanted psychoactive effect. This is completely possible with marijuana’s close relative, hemp but it is essential that you be aware of the difference so that you may be a smart consumer.


One Cultivars of the Exact Same Plant


Fundamentally, both hemp and marijuana are the exact same plant: Cannabis sativa. There is evidence that Cannabis sativa L has been grown in Asia thousands of years back for its fiber as well as a food supply. Humans eventually realized that the flowering tops of the plant had psychoactive properties. With time, as humans have done so with many other plants, Cannabis farmers began cultivating specific plants to enhance specific properties.


Nowadays, though some might argue the true number of plant types, there are really two simple distinctions,


Hemp – A plant primarily cultivated outside the United States, although a few U.S. countries let it be grown for study purposes) for use in clothes, paper, biofuels, bioplastics, dietary supplements, cosmetics, and foods. Hemp is cultivated outdoors as a large crop with both male and female plants being present to boost pollination and improve seed production. Legally imported industrial hemp contains less than 0.3 percent of its carcinogenic chemical tetrahydrocannabinol, or THC, content. In reality, legally imported hemp will usually specifically eliminate any extracts in the plant’s dried flowering tops.


Marijuana (Marihuana) – Cannabis sativa especially cultivated to enhance its THC content to be used for medicinal or recreational purposes. Marijuana plants are typically grown indoors, under controlled conditions, and growers eliminate all of the male plants from the harvest to prevent fertilization because fertilization lowers the plant’s THC degree.


Legality of Medical Marijuana


The medical use of marijuana is an increased area of controversy for researchers and consumers alike. Although maybe not quite half of U.S. states have legalized the medical use of this plant, it remains illegal under federal law, and consequently its use remains controversial regardless of the fact that there does seem to be real health benefits for various serious health issues.


Those that are looking to use marijuana for medical use should talk about its benefits versus its dangers with a skilled health-care professional before using it. In addition, many consumers who have an interest in its health benefits do not need the psychoactive side effects of THC or the danger of a positive drug test.


Hemp: Health Benefits without the Risks


Imported hemp, that has a very low, almost absent, level of THC, can be a solution for consumers that are looking for the plant’s health benefits minus the effects of THC.


Though THC has some health benefits, hemp comprises more than 80 bioactive compounds that could provide excellent support for a range of health issues, such as stress response, positive mood, and physical discomfort or pain. Hemp can also benefit gastrointestinal health, help keep a healthy inflammatory response throughout the entire body, and support normal immune function.


If you are considering the use of a nutritional supplement product which includes hemp, then it’s ideal to buy a product from a trusted source.


In conclusion,�both the peripheral and central nervous system detect, interpret and regulate a wide range of thermal and mechanical stimulation as well as environmental and endogenous chemical irritants. If the stimuli is too intense, it can generate acute pain where in the instance of persistent or chronic pain, pain transmission can be tremendously affected. The article above describes the cellular and molecular mechanisms of pain for guidance in clinical assessments. Furthermore, the use of hemp can have many health benefits in comparison to the controversial effects of marijuana. Information referenced from the National Center for Biotechnology Information (NCBI).�The scope of our information is limited to chiropractic as well as to spinal injuries and conditions. To discuss the subject matter, please feel free to ask Dr. Jimenez or contact us at�915-850-0900�.


Curated by Dr. Alex Jimenez


Additional Topics: Back Pain

Back pain is one of the most prevalent causes for disability and missed days at work worldwide. As a matter of fact, back pain has been attributed as the second most common reason for doctor office visits, outnumbered only by upper-respiratory infections. Approximately 80 percent of the population will experience some type of back pain at least once throughout their life. The spine is a complex structure made up of bones, joints, ligaments and muscles, among other soft tissues. Because of this, injuries and/or aggravated conditions, such as herniated discs, can eventually lead to symptoms of back pain. Sports injuries or automobile accident injuries are often the most frequent cause of back pain, however, sometimes the simplest of movements can have painful results. Fortunately, alternative treatment options, such as chiropractic care, can help ease back pain through the use of spinal adjustments and manual manipulations, ultimately improving pain relief.




blog picture of cartoon paperboy big news


EXTRA IMPORTANT TOPIC: Low Back Pain Management


MORE TOPICS: EXTRA EXTRA:�Chronic Pain & Treatments


  1. Abrahamsen B, Zhao J, Asante CO, Cendan CM, Marsh S, Martinez-Barbera JP, Nassar MA, Dickenson AH, Wood JN. The cell and molecular basis of mechanical, cold, and inflammatory pain.�Science.�2008;321:702�705.�[PubMed]
  2. Akopian AN, Souslova V, England S, Okuse K, Ogata N, Ure J, Smith A, Kerr BJ, McMahon SB, Boyce S, et al. The tetrodotoxin-resistant sodium channel SNS has a specialized function in pain pathways.�Nat Neurosci.�1999;2:541�548.�[PubMed]
  3. Alessandri-Haber N, Dina OA, Joseph EK, Reichling D, Levine JD. A transient receptor potential vanilloid 4-dependent mechanism of hyperalgesia is engaged by concerted action of inflammatory mediators.�J Neurosci.�2006;26:3864�3874.�[PubMed]
  4. Andersson DA, Gentry C, Moss S, Bevan S. Transient receptor potential A1 is a sensory receptor for multiple products of oxidative stress.�J Neurosci.�2008;28:2485�2494.�[PMC free article][PubMed]
  5. Apkarian AV, Bushnell MC, Treede RD, Zubieta JK. Human brain mechanisms of pain perception and regulation in health and disease.�Eur J Pain.�2005;9:463�484.�[PubMed]
  6. Attal N, Bouhassira D, Gautron M, Vaillant JN, Mitry E, Lepere C, Rougier P, Guirimand F. Thermal hyperalgesia as a marker of oxaliplatin neurotoxicity: a prospective quantified sensory assessment study.�Pain.�2009;144:245�252.�[PubMed]
  7. Atzeni F, Turiel M, Capsoni F, Doria A, Meroni P, Sarzi-Puttini P. Autoimmunity and anti-TNF-alpha agents.�Ann N Y Acad Sci.�2005;1051:559�569.�[PubMed]
  8. Bandell M, Story GM, Hwang SW, Viswanath V, Eid SR, Petrus MJ, Earley TJ, Patapoutian A. Noxious cold ion channel TRPA1 is activated by pungent compounds and bradykinin.�Neuron.�2004;41:849�857.�[PubMed]
  9. Basbaum AI, Jessell T. The Perception of Pain. In: Kandel ER, Schwartz J, Jessell T, editors.�Principles of Neuroscience.�New York: Appleton and Lange; 2000. pp. 472�491.
  10. Bautista DM, Jordt SE, Nikai T, Tsuruda PR, Read AJ, Poblete J, Yamoah EN, Basbaum AI, Julius D. TRPA1 mediates the inflammatory actions of environmental irritants and proalgesic agents.�Cell.�2006;124:1269�1282.�[PubMed]
  11. Bautista DM, Siemens J, Glazer JM, Tsuruda PR, Basbaum AI, Stucky CL, Jordt SE, Julius D. The menthol receptor TRPM8 is the principal detector of environmental cold.�Nature.�2007;448:204�208.[PubMed]
  12. Bautista DM, Sigal YM, Milstein AD, Garrison JL, Zorn JA, Tsuruda PR, Nicoll RA, Julius D. Pungent agents from Szechuan peppers excite sensory neurons by inhibiting two-pore potassium channels.�Nat Neurosci.�2008;11:772�779.�[PMC free article][PubMed]
  13. Bessac BF, Jordt SE. Breathtaking TRP channels: TRPA1 and TRPV1 in airway chemosensation and reflex control.�Physiology (Bethesda)�2008;23:360�370.�[PMC free article][PubMed]
  14. Bhattacharya MR, Bautista DM, Wu K, Haeberle H, Lumpkin EA, Julius D. Radial stretch reveals distinct populations of mechanosensitive mammalian somatosensory neurons.�Proc Natl Acad Sci U S A.�2008;105:20015�20020.�[PMC free article][PubMed]
  15. Brown DA, Passmore GM. Neural KCNQ (Kv7) channels.�Br J Pharmacol.�2009;156:1185�1195.[PMC free article][PubMed]
  16. Bryant BP, Mezine I. Alkylamides that produce tingling paresthesia activate tactile and thermal trigeminal neurons.�Brain Res.�1999;842:452�460.�[PubMed]
  17. Caceres AI, Brackmann M, Elia MD, Bessac BF, del Camino D, D’Amours M, Witek JS, Fanger CM, Chong JA, Hayward NJ, et al. A sensory neuronal ion channel essential for airway inflammation and hyperreactivity in asthma.�Proc Natl Acad Sci U S A.�2009;106:9099�9104.[PMC free article][PubMed]
  18. Campbell JN, Raja SN, Meyer RA, Mackinnon SE. Myelinated afferents signal the hyperalgesia associated with nerve injury.�Pain.�1988;32:89�94.�[PubMed]
  19. Cao YQ. Voltage-gated calcium channels and pain.�Pain.�2006;126:5�9.�[PubMed]
  20. Caterina MJ, Leffler A, Malmberg AB, Martin WJ, Trafton J, Petersen-Zeitz KR, Koltzenburg M, Basbaum AI, Julius D. Impaired nociception and pain sensation in mice lacking the capsaicin receptor.�Science.�2000;288:306�313.�[PubMed]
  21. Caterina MJ, Rosen TA, Tominaga M, Brake AJ, Julius D. A capsaicin-receptor homologue with a high threshold for noxious heat.�Nature.�1999;398:436�441.�[PubMed]
  22. Caterina MJ, Schumacher MA, Tominaga M, Rosen TA, Levine JD, Julius D. The capsaicin receptor: a heat-activated ion channel in the pain pathway.�Nature.�1997;389:816�824.�[PubMed]
  23. Cavanaugh DJ, Lee H, Lo L, Shields SD, Zylka MJ, Basbaum AI, Anderson DJ. Distinct subsets of unmyelinated primary sensory fibers mediate behavioral responses to noxious thermal and mechanical stimuli.�Proc Natl Acad Sci U S A.�2009;106:9075�9080.�[PMC free article][PubMed]
  24. Cesare P, McNaughton P. A novel heat-activated current in nociceptive neurons and its sensitization by bradykinin.�Proc Natl Acad Sci U S A.�1996;93:15435�15439.�[PMC free article][PubMed]
  25. Chalfie M. Neurosensory mechanotransduction.�Nat Rev Mol Cell Biol.�2009;10:44�52.�[PubMed]
  26. Chao MV. Neurotrophins and their receptors: a convergence point for many signalling pathways.�Nat Rev Neurosci.�2003;4:299�309.�[PubMed]
  27. Chen L, Huang LY. Protein kinase C reduces Mg2+ block of NMDA-receptor channels as a mechanism of modulation.�Nature.�1992;356:521�523.�[PubMed]
  28. Chen X, Alessandri-Haber N, Levine JD. Marked attenuation of inflammatory mediator-induced C-fiber sensitization for mechanical and hypotonic stimuli in TRPV4-/- mice.�Mol Pain.�2007;3:31.[PMC free article][PubMed]
  29. Chessell IP, Hatcher JP, Bountra C, Michel AD, Hughes JP, Green P, Egerton J, Murfin M, Richardson J, Peck WL, et al. Disruption of the P2X7 purinoceptor gene abolishes chronic inflammatory and neuropathic pain.�Pain.�2005;114:386�396.�[PubMed]
  30. Cho H, Koo JY, Kim S, Park SP, Yang Y, Oh U. A novel mechanosensitive channel identified in sensory neurons.�Eur J Neurosci.�2006;23:2543�2550.�[PubMed]
  31. Cho H, Shin J, Shin CY, Lee SY, Oh U. Mechanosensitive ion channels in cultured sensory neurons of neonatal rats.�J Neurosci.�2002;22:1238�1247.�[PubMed]
  32. Chuang HH, Prescott ED, Kong H, Shields S, Jordt SE, Basbaum AI, Chao MV, Julius D. Bradykinin and nerve growth factor release the capsaicin receptor from PtdIns(4,5)P2-mediated inhibition.�Nature.�2001;411:957�962.�[PubMed]
  33. Chung MK, Lee H, Caterina MJ. Warm temperatures activate TRPV4 in mouse 308 keratinocytes.�J Biol Chem.�2003;278:32037�32046.�[PubMed]
  34. Clark AK, Yip PK, Grist J, Gentry C, Staniland AA, Marchand F, Dehvari M, Wotherspoon G, Winter J, Ullah J, et al. Inhibition of spinal microglial cathepsin S for the reversal of neuropathic pain.�Proc Natl Acad Sci U S A.�2007;104:10655�10660.�[PMC free article][PubMed]
  35. Colburn RW, Lubin ML, Stone DJ, Jr, Wang Y, Lawrence D, D’Andrea MR, Brandt MR, Liu Y, Flores CM, Qin N. Attenuated cold sensitivity in TRPM8 null mice.�Neuron.�2007;54:379�386.[PubMed]
  36. Coull JA, Beggs S, Boudreau D, Boivin D, Tsuda M, Inoue K, Gravel C, Salter MW, De Koninck Y. BDNF from microglia causes the shift in neuronal anion gradient underlying neuropathic pain.�Nature.�2005;438:1017�1021.�[PubMed]
  37. Coull JA, Boudreau D, Bachand K, Prescott SA, Nault F, Sik A, De Koninck P, De Koninck Y. Trans-synaptic shift in anion gradient in spinal lamina I neurons as a mechanism of neuropathic pain.�Nature.�2003;424:938�942.�[PubMed]
  38. Cox JJ, Reimann F, Nicholas AK, Thornton G, Roberts E, Springell K, Karbani G, Jafri H, Mannan J, Raashid Y, et al. An SCN9A channelopathy causes congenital inability to experience pain.�Nature.�2006;444:894�898.�[PubMed]
  39. Cruz-Orengo L, Dhaka A, Heuermann RJ, Young TJ, Montana MC, Cavanaugh EJ, Kim D, Story GM. Cutaneous nociception evoked by 15-delta PGJ2 via activation of ion channel TRPA1.�Mol Pain.�2008;4:30.�[PMC free article][PubMed]
  40. Davies A, Hendrich J, Van Minh AT, Wratten J, Douglas L, Dolphin AC. Functional biology of the alpha(2)delta subunits of voltage-gated calcium channels.�Trends Pharmacol Sci.�2007;28:220�228.[PubMed]
  41. Davis JB, Gray J, Gunthorpe MJ, Hatcher JP, Davey PT, Overend P, Harries MH, Latcham J, Clapham C, Atkinson K, et al. Vanilloid receptor-1 is essential for inflammatory thermal hyperalgesia.�Nature.�2000;405:183�187.�[PubMed]
  42. DeLeo JA, Sorkin LS, Watkins LR, editors.�Immune and Glial Regulation of Pain.�IASP; Seattle: 2007.
  43. de Vries B, Frants RR, Ferrari MD, van den Maagdenberg AM. Molecular genetics of migraine.�Hum Genet.�2009;126:115�132.�[PubMed]
  44. Dhaka A, Murray AN, Mathur J, Earley TJ, Petrus MJ, Patapoutian A. TRPM8 is required for cold sensation in mice.�Neuron.�2007;54:371�378.�[PubMed]
  45. Dib-Hajj SD, Yang Y, Waxman SG. Genetics and molecular pathophysiology of Na(v)1.7-related pain syndromes.�Adv Genet.�2008;63:85�110.�[PubMed]
  46. Dick IE, Brochu RM, Purohit Y, Kaczorowski GJ, Martin WJ, Priest BT. Sodium channel blockade may contribute to the analgesic efficacy of antidepressants.�J Pain.�2007;8:315�324.�[PubMed]
  47. Dobler TM, Springauf A, Tovornik S, Weber M, Schmitt A, Sedlmeier R, Wischmeyer E, Doring F. TRESK two-pore-domain K+ channels constitute a significant component of background potassium currents in murine DRG neurones.�J Physiol�2007�[PMC free article][PubMed]
  48. Dong X, Han S, Zylka MJ, Simon MI, Anderson DJ. A diverse family of GPCRs expressed in specific subsets of nociceptive sensory neurons.�Cell.�2001;106:619�632.�[PubMed]
  49. Drdla R, Sandkuhler J. Long-term potentiation at C-fibre synapses by low-level presynaptic activity in vivo.�Mol Pain.�2008;4:18.�[PMC free article][PubMed]
  50. Drew LJ, Rohrer DK, Price MP, Blaver KE, Cockayne DA, Cesare P, Wood JN. Acid-sensing ion channels ASIC2 and ASIC3 do not contribute to mechanically activated currents in mammalian sensory neurones.�J Physiol.�2004;556:691�710.�[PMC free article][PubMed]
  51. Drew LJ, Wood JN, Cesare P. Distinct mechanosensitive properties of capsaicin-sensitive and -insensitive sensory neurons.�J Neurosci.�2002;22:RC228.�[PubMed]
  52. Estacion M, Dib-Hajj SD, Benke PJ, Te Morsche RH, Eastman EM, Macala LJ, Drenth JP, Waxman SG. NaV1.7 gain-of-function mutations as a continuum: A1632E displays physiological changes associated with erythromelalgia and paroxysmal extreme pain disorder mutations and produces symptoms of both disorders.�J Neurosci.�2008;28:11079�11088.�[PubMed]
  53. Fertleman CR, Baker MD, Parker KA, Moffatt S, Elmslie FV, Abrahamsen B, Ostman J, Klugbauer N, Wood JN, Gardiner RM, et al. SCN9A mutations in paroxysmal extreme pain disorder: allelic variants underlie distinct channel defects and phenotypes.�Neuron.�2006;52:767�774.�[PubMed]
  54. Gevaert T, Vriens J, Segal A, Everaerts W, Roskams T, Talavera K, Owsianik G, Liedtke W, Daelemans D, Dewachter I, et al. Deletion of the transient receptor potential cation channel TRPV4 impairs murine bladder voiding.�J Clin Invest.�2007;117:3453�3462.�[PMC free article][PubMed]
  55. Grant AD, Cottrell GS, Amadesi S, Trevisani M, Nicoletti P, Materazzi S, Altier C, Cenac N, Zamponi GW, Bautista-Cruz F, et al. Protease-activated receptor 2 sensitizes the transient receptor potential vanilloid 4 ion channel to cause mechanical hyperalgesia in mice.�J Physiol.�2007;578:715�733.�[PMC free article][PubMed]
  56. Guler AD, Lee H, Iida T, Shimizu I, Tominaga M, Caterina M. Heat-evoked activation of the ion channel, TRPV4.�J Neurosci.�2002;22:6408�6414.�[PubMed]
  57. Harvey RJ, Depner UB, Wassle H, Ahmadi S, Heindl C, Reinold H, Smart TG, Harvey K, Schutz B, Abo-Salem OM, et al. GlyR alpha3: an essential target for spinal PGE2-mediated inflammatory pain sensitization.�Science.�2004;304:884�887.�[PubMed]
  58. Haynes SE, Hollopeter G, Yang G, Kurpius D, Dailey ME, Gan WB, Julius D. The P2Y12 receptor regulates microglial activation by extracellular nucleotides.�Nat Neurosci.�2006;9:1512�1519.[PubMed]
  59. Hensel H, Zotterman Y. The effect of menthol on the thermoreceptors.�Acta Physiol Scand.�1951;24:27�34.�[PubMed]
  60. Hefti FF, Rosenthal A, Walicke PA, Wyatt S, Vergara G, Shelton DL, Davies AM. Novel class of pain drugs based on antagonism of NGF.�Trends Pharmacol Sci.�2006;27:85�91.�[PubMed]
  61. Hensel H, Zotterman Y. The effect of menthol on the thermoreceptors.�Acta Physiol Scand.�1951;24:27�34.�[PubMed]
  62. Hill K, Schaefer M. TRPA1 is differentially modulated by the amphipathic molecules trinitrophenol and chlorpromazine.�J Biol Chem.�2007;282:7145�7153.�[PubMed]
  63. Hinman A, Chuang HH, Bautista DM, Julius D. TRP channel activation by reversible covalent modification.�Proc Natl Acad Sci U S A.�2006;103:19564�19568.�[PMC free article][PubMed]
  64. Honore P, Chandran P, Hernandez G, Gauvin DM, Mikusa JP, Zhong C, Joshi SK, Ghilardi JR, Sevcik MA, Fryer RM, et al. Repeated dosing of ABT-102, a potent and selective TRPV1 antagonist, enhances TRPV1-mediated analgesic activity in rodents, but attenuates antagonist-induced hyperthermia.�Pain.�2009;142:27�35.�[PubMed]
  65. Honore P, Donnelly-Roberts D, Namovic MT, Hsieh G, Zhu CZ, Mikusa JP, Hernandez G, Zhong C, Gauvin DM, Chandran P, et al. A-740003 [N-(1-{[(cyanoimino)(5-quinolinylamino) methyl]amino}-2,2-dimethylpropyl)-2-(3,4-dimethoxyphenyl)acetamide], a novel and selective P2X7 receptor antagonist, dose-dependently reduces neuropathic pain in the rat.�J Pharmacol Exp Ther.�2006;319:1376�1385.�[PubMed]
  66. Hu J, Lewin GR. Mechanosensitive currents in the neurites of cultured mouse sensory neurones.�J Physiol.�2006;577:815�828.�[PMC free article][PubMed]
  67. Immke DC, McCleskey EW. Lactate enhances the acid-sensing Na+ channel on ischemia-sensing neurons.�Nat Neurosci.�2001;4:869�870.�[PubMed]
  68. Immke DC, McCleskey EW. Protons open acid-sensing ion channels by catalyzing relief of Ca2+ blockade.�Neuron.�2003;37:75�84.�[PubMed]
  69. Ji RR, Samad TA, Jin SX, Schmoll R, Woolf CJ. p38 MAPK activation by NGF in primary sensory neurons after inflammation increases TRPV1 levels and maintains heat hyperalgesia.�Neuron.�2002;36:57�68.�[PubMed]
  70. Jordt SE, Bautista DM, Chuang HH, McKemy DD, Zygmunt PM, Hogestatt ED, Meng ID, Julius D. Mustard oils and cannabinoids excite sensory nerve fibres through the TRP channel ANKTM1.�Nature.�2004;427:260�265.�Epub 2004 Jan 2007.�[PubMed]
  71. Julius D, Basbaum AI. Molecular mechanisms of nociception.�Nature.�2001;413:203�210.�[PubMed]
  72. Karashima Y, Damann N, Prenen J, Talavera K, Segal A, Voets T, Nilius B. Bimodal action of menthol on the transient receptor potential channel TRPA1.�J Neurosci.�2007;27:9874�9884.[PubMed]
  73. Karashima Y, Talavera K, Everaerts W, Janssens A, Kwan KY, Vennekens R, Nilius B, Voets T. TRPA1 acts as a cold sensor in vitro and in vivo.�Proc Natl Acad Sci U S A.�2009;106:1273�1278.[PMC free article][PubMed]
  74. Kawasaki Y, Kohno T, Zhuang ZY, Brenner GJ, Wang H, Van Der Meer C, Befort K, Woolf CJ, Ji RR. Ionotropic and metabotropic receptors, protein kinase A, protein kinase C, and Src contribute to C-fiber-induced ERK activation and cAMP response element-binding protein phosphorylation in dorsal horn neurons, leading to central sensitization.�J Neurosci.�2004;24:8310�8321.�[PubMed]
  75. Keller AF, Beggs S, Salter MW, De Koninck Y. Transformation of the output of spinal lamina I neurons after nerve injury and microglia stimulation underlying neuropathic pain.�Mol Pain.�2007;3:27.�[PMC free article][PubMed]
  76. Kim D, Kim MA, Cho IH, Kim MS, Lee S, Jo EK, Choi SY, Park K, Kim JS, Akira S, et al. A critical role of toll-like receptor 2 in nerve injury-induced spinal cord glial cell activation and pain hypersensitivity.�J Biol Chem.�2007;282:14975�14983.�[PubMed]
  77. Kindt KS, Viswanath V, Macpherson L, Quast K, Hu H, Patapoutian A, Schafer WR. Caenorhabditis elegans TRPA-1 functions in mechanosensation.�Nat Neurosci.�2007;10:568�577.�[PubMed]
  78. Kirschstein T, Busselberg D, Treede RD. Coexpression of heat-evoked and capsaicin-evoked inward currents in acutely dissociated rat dorsal root ganglion neurons.�Neurosci Lett.�1997;231:33�36.[PubMed]
  79. Knabl J, Witschi R, Hosl K, Reinold H, Zeilhofer UB, Ahmadi S, Brockhaus J, Sergejeva M, Hess A, Brune K, et al. Reversal of pathological pain through specific spinal GABAA receptor subtypes.�Nature.�2008;451:330�334.�[PubMed]
  80. Kobayashi K, Yamanaka H, Fukuoka T, Dai Y, Obata K, Noguchi K. P2Y12 receptor upregulation in activated microglia is a gateway of p38 signaling and neuropathic pain.�J Neurosci.�2008;28:2892�2902.�[PubMed]
  81. Kwan KY, Allchorne AJ, Vollrath MA, Christensen AP, Zhang DS, Woolf CJ, Corey DP. TRPA1 contributes to cold, mechanical, and chemical nociception but is not essential for hair-cell transduction.�Neuron.�2006;50:277�289.�[PubMed]
  82. Kwan KY, Glazer JM, Corey DP, Rice FL, Stucky CL. TRPA1 modulates mechanotransduction in cutaneous sensory neurons.�J Neurosci.�2009;29:4808�4819.�[PMC free article][PubMed]
  83. Latremoliere A, Woolf CJ. Central sensitization: a generator of pain hypersensitivity by central neural plasticity.�J Pain.�2009;10:895�926.�[PMC free article][PubMed]
  84. Lawson JJ, McIlwrath SL, Woodbury CJ, Davis BM, Koerber HR. TRPV1 unlike TRPV2 is restricted to a subset of mechanically insensitive cutaneous nociceptors responding to heat.�J Pain.�2008;9:298�308.�[PMC free article][PubMed]
  85. Leffler A, Linte RM, Nau C, Reeh P, Babes A. A high-threshold heat-activated channel in cultured rat dorsal root ganglion neurons resembles TRPV2 and is blocked by gadolinium.�Eur J Neurosci.�2007;26:12�22.�[PubMed]
  86. Liedtke W, Choe Y, Marti-Renom MA, Bell AM, Denis CS, Sali A, Hudspeth AJ, Friedman JM, Heller S. Vanilloid receptor-related osmotically activated channel (VR-OAC), a candidate vertebrate osmoreceptor.�Cell.�2000;103:525�535.�[PMC free article][PubMed]
  87. Liedtke W, Friedman JM. Abnormal osmotic regulation in trpv4-/-mice.�Proc Natl Acad Sci U S A.�2003;100:13698�13703.�[PMC free article][PubMed]
  88. Lin YW, Cheng CM, Leduc PR, Chen CC. Understanding sensory nerve mechanotransduction through localized elastomeric matrix control.�PLoS One.�2009;4:e4293.�[PMC free article][PubMed]
  89. Lindia JA, McGowan E, Jochnowitz N, Abbadie C. Induction of CX3CL1 expression in astrocytes and CX3CR1 in microglia in the spinal cord of a rat model of neuropathic pain.�J Pain.�2005;6:434�438.�[PubMed]
  90. Liu XJ, Gingrich JR, Vargas-Caballero M, Dong YN, Sengar A, Beggs S, Wang SH, Ding HK, Frankland PW, Salter MW. Treatment of inflammatory and neuropathic pain by uncoupling Src from the NMDA receptor complex.�Nat Med.�2008;14:1325�1332.�[PMC free article][PubMed]
  91. Lumpkin EA, Caterina MJ. Mechanisms of sensory transduction in the skin.�Nature.�2007;445:858�865.�[PubMed]
  92. Luo ZD, Chaplan SR, Higuera ES, Sorkin LS, Stauderman KA, Williams ME, Yaksh TL. Upregulation of dorsal root ganglion (alpha)2(delta) calcium channel subunit and its correlation with allodynia in spinal nerve-injured rats.�J Neurosci.�2001;21:1868�1875.�[PubMed]
  93. Macpherson LJ, Dubin AE, Evans MJ, Marr F, Schultz PG, Cravatt BF, Patapoutian A. Noxious compounds activate TRPA1 ion channels through covalent modification of cysteines.�Nature.�2007;445:541�545.�[PubMed]
  94. Madrid R, de la Pena E, Donovan-Rodriguez T, Belmonte C, Viana F. Variable threshold of trigeminal cold-thermosensitive neurons is determined by a balance between TRPM8 and Kv1 potassium channels.�J Neurosci.�2009;29:3120�3131.�[PubMed]
  95. Malan TP, Mata HP, Porreca F. Spinal GABA(A) and GABA(B) receptor pharmacology in a rat model of neuropathic pain.�Anesthesiology.�2002;96:1161�1167.�[PubMed]
  96. Malmberg AB, Chen C, Tonegawa S, Basbaum AI. Preserved acute pain and reduced neuropathic pain in mice lacking PKCgamma.�Science.�1997;278:279�283.�[PubMed]
  97. Mandadi S, Sokabe T, Shibasaki K, Katanosaka K, Mizuno A, Moqrich A, Patapoutian A, Fukumi-Tominaga T, Mizumura K, Tominaga M. TRPV3 in keratinocytes transmits temperature information to sensory neurons�2009�[PMC free article][PubMed]
  98. Materazzi S, Nassini R, Andre E, Campi B, Amadesi S, Trevisani M, Bunnett NW, Patacchini R, Geppetti P. Cox-dependent fatty acid metabolites cause pain through activation of the irritant receptor TRPA1.�Proc Natl Acad Sci U S A.�2008;105:12045�12050.�[PMC free article][PubMed]
  99. Matta JA, Cornett PM, Miyares RL, Abe K, Sahibzada N, Ahern GP. General anesthetics activate a nociceptive ion channel to enhance pain and inflammation.�Proc Natl Acad Sci U S A.�2008;105:8784�8789.�[PMC free article][PubMed]
  100. McKemy DD, Neuhausser WM, Julius D. Identification of a cold receptor reveals a general role for TRP channels in thermosensation.�Nature.�2002;416:52�58.�[PubMed]
  101. McMahon SB, Bennett DLH, Bevan S. Inflammatory mediators and modulators of pain. In: McMahon SB, Koltzenburg M, editors.�Wall and Melzack’s textbook of Pain.�Elsevier; 2008. pp. 49�72.
  102. Melzack R, Wall PD. Pain mechanisms: a new theory.�Science.�1965;150:971�979.�[PubMed]
  103. Messinger RB, Naik AK, Jagodic MM, Nelson MT, Lee WY, Choe WJ, Orestes P, Latham JR, Todorovic SM, Jevtovic-Todorovic V. In vivo silencing of the Ca(V)3.2 T-type calcium channels in sensory neurons alleviates hyperalgesia in rats with streptozocin-induced diabetic neuropathy.�Pain.�2009;145:184�195.�[PMC free article][PubMed]
  104. Milligan ED, Sloane EM, Watkins LR. Glia in pathological pain: a role for fractalkine.�J Neuroimmunol.�2008;198:113�120.�[PMC free article][PubMed]
  105. Milligan ED, Zapata V, Chacur M, Schoeniger D, Biedenkapp J, O’Connor KA, Verge GM, Chapman G, Green P, Foster AC, et al. Evidence that exogenous and endogenous fractalkine can induce spinal nociceptive facilitation in rats.�Eur J Neurosci.�2004;20:2294�2302.�[PubMed]
  106. Miraucourt LS, Dallel R, Voisin DL. Glycine inhibitory dysfunction turns touch into pain through PKCgamma interneurons.�PLoS One.�2007;2:e1116.�[PMC free article][PubMed]
  107. Mochizuki T, Sokabe T, Araki I, Fujishita K, Shibasaki K, Uchida K, Naruse K, Koizumi S, Takeda M, Tominaga M. The TRPV4 cation channel mediates stretch-evoked Ca2+ influx and ATP release in primary urothelial cell cultures.�J Biol Chem.�2009;284:21257�21264.�[PMC free article][PubMed]
  108. Moore KA, Kohno T, Karchewski LA, Scholz J, Baba H, Woolf CJ. Partial peripheral nerve injury promotes a selective loss of GABAergic inhibition in the superficial dorsal horn of the spinal cord.�J Neurosci.�2002;22:6724�6731.�[PubMed]
  109. Mueller KL, Hoon MA, Erlenbach I, Chandrashekar J, Zuker CS, Ryba NJ. The receptors and coding logic for bitter taste.�Nature.�2005;434:225�229.�[PubMed]
  110. Muraki K, Iwata Y, Katanosaka Y, Ito T, Ohya S, Shigekawa M, Imaizumi Y. TRPV2 is a component of osmotically sensitive cation channels in murine aortic myocytes.�Circ Res.�2003;93:829�838.[PubMed]
  111. Nagata K, Duggan A, Kumar G, Garcia-Anoveros J. Nociceptor and hair cell transducer properties of TRPA1, a channel for pain and hearing.�J Neurosci.�2005;25:4052�4061.�[PubMed]
  112. Nagy I, Rang H. Noxious heat activates all capsaicin-sensitive and also a sub-population of capsaicin-insensitive dorsal root ganglion neurons.�Neuroscience.�1999;88:995�997.�[PubMed]
  113. Nassar MA, Levato A, Stirling LC, Wood JN. Neuropathic pain develops normally in mice lacking both Na(v)1.7 and Na(v)1.8.�Mol Pain.�2005;1:24.�[PMC free article][PubMed]
  114. Nassar MA, Stirling LC, Forlani G, Baker MD, Matthews EA, Dickenson AH, Wood JN. Nociceptor-specific gene deletion reveals a major role for Nav1.7 (PN1) in acute and inflammatory pain.�Proc Natl Acad Sci U S A.�2004;101:12706�12711.�[PMC free article][PubMed]
  115. Neumann S, Braz JM, Skinner K, Llewellyn-Smith IJ, Basbaum AI. Innocuous, not noxious, input activates PKCgamma interneurons of the spinal dorsal horn via myelinated afferent fibers.�J Neurosci.�2008;28:7936�7944.�[PMC free article][PubMed]
  116. Nichols ML, Allen BJ, Rogers SD, Ghilardi JR, Honore P, Luger NM, Finke MP, Li J, Lappi DA, Simone DA, et al. Transmission of chronic nociception by spinal neurons expressing the substance P receptor.�Science.�1999;286:1558�1561.�[PubMed]
  117. Noel J, Zimmermann K, Busserolles J, Deval E, Alloui A, Diochot S, Guy N, Borsotto M, Reeh P, Eschalier A, et al. The mechano-activated K+ channels TRAAK and TREK-1 control both warm and cold perception.�EMBO J.�2009;28:1308�1318.�[PMC free article][PubMed]
  118. Obata K, Katsura H, Miyoshi K, Kondo T, Yamanaka H, Kobayashi K, Dai Y, Fukuoka T, Akira S, Noguchi K. Toll-like receptor 3 contributes to spinal glial activation and tactile allodynia after nerve injury.�J Neurochem�2008�[PubMed]
  119. Olausson H, Cole J, Rylander K, McGlone F, Lamarre Y, Wallin BG, Kramer H, Wessberg J, Elam M, Bushnell MC, et al. Functional role of unmyelinated tactile afferents in human hairy skin: sympathetic response and perceptual localization.�Exp Brain Res.�2008;184:135�140.�[PubMed]
  120. Page AJ, Brierley SM, Martin CM, Martinez-Salgado C, Wemmie JA, Brennan TJ, Symonds E, Omari T, Lewin GR, Welsh MJ, et al. The ion channel ASIC1 contributes to visceral but not cutaneous mechanoreceptor function.�Gastroenterology.�2004;127:1739�1747.�[PubMed]
  121. Peier AM, Moqrich A, Hergarden AC, Reeve AJ, Andersson DA, Story GM, Earley TJ, Dragoni I, McIntyre P, Bevan S, et al. A TRP channel that senses cold stimuli and menthol.�Cell.�2002a;108:705�715.�[PubMed]
  122. Peier AM, Reeve AJ, Andersson DA, Moqrich A, Earley TJ, Hergarden AC, Story GM, Colley S, Hogenesch JB, McIntyre P, et al. A heat-sensitive TRP channel expressed in keratinocytes.�Science.�2002b;296:2046�2049.�[PubMed]
  123. Perl ER. Ideas about pain, a historical view.�Nat Rev Neurosci.�2007;8:71�80.�[PubMed]
  124. Petrus M, Peier AM, Bandell M, Hwang SW, Huynh T, Olney N, Jegla T, Patapoutian A. A role of TRPA1 in mechanical hyperalgesia is revealed by pharmacological inhibition.�Mol Pain.�2007;3:40.[PMC free article][PubMed]
  125. Polgar E, Hughes DI, Arham AZ, Todd AJ. Loss of neurons from laminas I-III of the spinal dorsal horn is not required for development of tactile allodynia in the spared nerve injury model of neuropathic pain.�J Neurosci.�2005;25:6658�6666.�[PubMed]
  126. Porreca F, Ossipov MH, Gebhart GF. Chronic pain and medullary descending facilitation.�Trends Neurosci.�2002;25:319�325.�[PubMed]
  127. Price MP, Lewin GR, McIlwrath SL, Cheng C, Xie J, Heppenstall PA, Stucky CL, Mannsfeldt AG, Brennan TJ, Drummond HA, et al. The mammalian sodium channel BNC1 is required for normal touch sensation.�Nature.�2000;407:1007�1011.�[PubMed]
  128. Price MP, McIlwrath SL, Xie J, Cheng C, Qiao J, Tarr DE, Sluka KA, Brennan TJ, Lewin GR, Welsh MJ. The DRASIC cation channel contributes to the detection of cutaneous touch and acid stimuli in mice.�Neuron.�2001;32:1071�1083.�[PubMed]
  129. Rau KK, Jiang N, Johnson RD, Cooper BY. Heat sensitization in skin and muscle nociceptors expressing distinct combinations of TRPV1 and TRPV2 protein.�J Neurophysiol.�2007;97:2651�2662.�[PubMed]
  130. Rauck RL, Wallace MS, Burton AW, Kapural L, North JM. Intrathecal ziconotide for neuropathic pain: a review.�Pain Pract.�2009;9:327�337.�[PubMed]
  131. Reid G, Flonta ML. Physiology. Cold current in thermoreceptive neurons.�Nature.�2001;413:480.[PubMed]
  132. Ren K, Dubner R. Neuron-glia crosstalk gets serious: role in pain hypersensitivity.�Curr Opin Anaesthesiol.�2008;21:570�579.�[PMC free article][PubMed]
  133. Ritner HL, Machelska H, Stein C. Immune System Pain and Analgesia. In: Basbaum AI, Bushnell M, editors.�Science of Pain.�2009. pp. 407�427.
  134. Roza C, Puel JL, Kress M, Baron A, Diochot S, Lazdunski M, Waldmann R. Knockout of the ASIC2 channel in mice does not impair cutaneous mechanosensation, visceral mechanonociception and hearing.�J Physiol.�2004;558:659�669.�[PMC free article][PubMed]
  135. Scherrer G, Imamachi N, Cao YQ, Contet C, Mennicken F, O’Donnell D, Kieffer BL, Basbaum AI. Dissociation of the opioid receptor mechanisms that control mechanical and heat pain.�Cell.�2009;137:1148�1159.�[PMC free article][PubMed]
  136. Schmidt R, Schmelz M, Forster C, Ringkamp M, Torebjork E, Handwerker H. Novel classes of responsive and unresponsive C nociceptors in human skin.�J Neurosci.�1995;15:333�341.�[PubMed]
  137. Sivilotti L, Woolf CJ. The contribution of GABAA and glycine receptors to central sensitization: disinhibition and touch-evoked allodynia in the spinal cord.�J Neurophysiol.�1994;72:169�179.[PubMed]
  138. Snider WD, McMahon SB. Tackling pain at the source: new ideas about nociceptors.�Neuron.�1998;20:629�632.�[PubMed]
  139. Story GM, Peier AM, Reeve AJ, Eid SR, Mosbacher J, Hricik TR, Earley TJ, Hergarden AC, Andersson DA, Hwang SW, et al. ANKTM1, a TRP-like channel expressed in nociceptive neurons, is activated by cold temperatures.�Cell.�2003;112:819�829.�[PubMed]
  140. Strotmann R, Harteneck C, Nunnenmacher K, Schultz G, Plant TD. OTRPC4, a nonselective cation channel that confers sensitivity to extracellular osmolarity.�Nat Cell Biol.�2000;2:695�702.[PubMed]
  141. Sugai E, Morimitsu Y, Iwasaki Y, Morita A, Watanabe T, Kubota K. Pungent qualities of sanshool-related compounds evaluated by a sensory test and activation of rat TRPV1.�Biosci Biotechnol Biochem.�2005;69:1951�1957.�[PubMed]
  142. Suzuki M, Watanabe Y, Oyama Y, Mizuno A, Kusano E, Hirao A, Ookawara S. Localization of mechanosensitive channel TRPV4 in mouse skin.�Neurosci Lett.�2003;353:189�192.�[PubMed]
  143. Swayne LA, Bourinet E. Voltage-gated calcium channels in chronic pain: emerging role of alternative splicing.�Pflugers Arch.�2008;456:459�466.�[PubMed]
  144. Takahashi A, Gotoh H. Mechanosensitive whole-cell currents in cultured rat somatosensory neurons.�Brain Res.�2000;869:225�230.�[PubMed]
  145. Tanga FY, Nutile-McMenemy N, DeLeo JA. The CNS role of Toll-like receptor 4 in innate neuroimmunity and painful neuropathy.�Proc Natl Acad Sci U S A.�2005;102:5856�5861.[PMC free article][PubMed]
  146. Tominaga M, Caterina MJ, Malmberg AB, Rosen TA, Gilbert H, Skinner K, Raumann BE, Basbaum AI, Julius D. The cloned capsaicin receptor integrates multiple pain-producing stimuli.�Neuron.�1998;21:531�543.�[PubMed]
  147. Torsney C, MacDermott AB. Disinhibition opens the gate to pathological pain signaling in superficial neurokinin 1 receptor-expressing neurons in rat spinal cord.�J Neurosci.�2006;26:1833�1843.�[PubMed]
  148. Tozaki-Saitoh H, Tsuda M, Miyata H, Ueda K, Kohsaka S, Inoue K. P2Y12 receptors in spinal microglia are required for neuropathic pain after peripheral nerve injury.�J Neurosci.�2008;28:4949�4956.�[PubMed]
  149. Trevisani M, Siemens J, Materazzi S, Bautista DM, Nassini R, Campi B, Imamachi N, Andre E, Patacchini R, Cottrell GS, et al. 4-Hydroxynonenal, an endogenous aldehyde, causes pain and neurogenic inflammation through activation of the irritant receptor TRPA1.�Proc Natl Acad Sci U S A.�2007;104:13519�13524.�[PMC free article][PubMed]
  150. Tsuda M, Shigemoto-Mogami Y, Koizumi S, Mizokoshi A, Kohsaka S, Salter MW, Inoue K. P2X4 receptors induced in spinal microglia gate tactile allodynia after nerve injury.�Nature.�2003;424:778�783.�[PubMed]
  151. Ulmann L, Hatcher JP, Hughes JP, Chaumont S, Green PJ, Conquet F, Buell GN, Reeve AJ, Chessell IP, Rassendren F. Up-regulation of P2X4 receptors in spinal microglia after peripheral nerve injury mediates BDNF release and neuropathic pain.�J Neurosci.�2008;28:11263�11268.�[PubMed]
  152. Verge GM, Milligan ED, Maier SF, Watkins LR, Naeve GS, Foster AC. Fractalkine (CX3CL1) and fractalkine receptor (CX3CR1) distribution in spinal cord and dorsal root ganglia under basal and neuropathic pain conditions.�Eur J Neurosci.�2004;20:1150�1160.�[PubMed]
  153. Viana F, de la Pena E, Belmonte C. Specificity of cold thermotransduction is determined by differential ionic channel expression.�Nat Neurosci.�2002;5:254�260.�[PubMed]
  154. Wetzel C, Hu J, Riethmacher D, Benckendorff A, Harder L, Eilers A, Moshourab R, Kozlenkov A, Labuz D, Caspani O, et al. A stomatin-domain protein essential for touch sensation in the mouse.�Nature.�2007;445:206�209.�[PubMed]
  155. Woodbury CJ, Zwick M, Wang S, Lawson JJ, Caterina MJ, Koltzenburg M, Albers KM, Koerber HR, Davis BM. Nociceptors lacking TRPV1 and TRPV2 have normal heat responses.�J Neurosci.�2004;24:6410�6415.�[PubMed]
  156. Woolf CJ. Evidence for a central component of post-injury pain hypersensitivity.�Nature.�1983;306:686�688.�[PubMed]
  157. Yagi J, Wenk HN, Naves LA, McCleskey EW. Sustained currents through ASIC3 ion channels at the modest pH changes that occur during myocardial ischemia.�Circ Res.�2006;99:501�509.�[PubMed]
  158. Yaksh TL. Behavioral and autonomic correlates of the tactile evoked allodynia produced by spinal glycine inhibition: effects of modulatory receptor systems and excitatory amino acid antagonists.�Pain.�1989;37:111�123.�[PubMed]
  159. Yang Y, Wang Y, Li S, Xu Z, Li H, Ma L, Fan J, Bu D, Liu B, Fan Z, et al. Mutations in SCN9A, encoding a sodium channel alpha subunit, in patients with primary erythermalgia.�J Med Genet.�2004;41:171�174.�[PMC free article][PubMed]
  160. Zamponi GW, Lewis RJ, Todorovic SM, Arneric SP, Snutch TP. Role of voltage-gated calcium channels in ascending pain pathways.�Brain Res Rev.�2009;60:84�89.�[PMC free article][PubMed]
  161. Zhuang ZY, Kawasaki Y, Tan PH, Wen YR, Huang J, Ji RR. Role of the CX3CR1/p38 MAPK pathway in spinal microglia for the development of neuropathic pain following nerve injury-induced cleavage of fractalkine.�Brain Behav Immun.�2007;21:642�651.�[PMC free article][PubMed]
  162. Zimmermann K, Leffler A, Babes A, Cendan CM, Carr RW, Kobayashi J, Nau C, Wood JN, Reeh PW. Sensory neuron sodium channel Nav1.8 is essential for pain at low temperatures.�Nature.�2007;447:855�858.�[PubMed]
  163. Zurborg S, Yurgionas B, Jira JA, Caspani O, Heppenstall PA. Direct activation of the ion channel TRPA1 by Ca2+�Nat Neurosci.�2007;10:277�279.�[PubMed]
Close Accordion
Cannabinoids And Plant Medicine

Cannabinoids And Plant Medicine

Cannabinoids:�Plants and medicine have come around like never before. With more research taking place and more information coming to the medical field, there are now more options for ailments, conditions, diseases and disorders. Chiropractor, Dr. Alex Jimenez analyzes the data and brings insight to these developing medicines and treatments. How they can help patients, what can they do and what can’t they do?

Most associate cannabinoids with the marijuana plant. This is the most recognized cannabinoid compound – tetrahydrocannabinol (THC), which is what causes feelings of euphoria.

However, scientists have identified cannabinoids in many plants, which include black pepper, broccoli, carrots, clove, echinacea, and ginseng.�None of these will get you high. But with an understanding of how the cannabinoids in these various plants affect the human body can create a path to important health discoveries.

Plants Are Medicine

Many modern drugs were developed through plant research. Researching compounds in these plants led to discovering life saving drugs and furthered the knowledge of how the human body functions. An example is the foxglove plant, which�gave us digoxin and digitoxin. Two very important heart medications.1

Humans have been especially resourceful when finding plants for pleasure or to decrease pain.

Caffeine provides energy, while nicotine from tobacco stimulates and relaxes. This explains why tobacco is still popular even though we know the health risks of smoking.2

Pain-Relieving Drugs & Their Origin


In ancient times, medical practitioners drank tea made from willow tree, in order to reduce fever and pain. It took hundreds of years for scientists to find and isolate the active compound, which is�salicylic acid. This�led to the discovery of aspirin and from there, it evolved into inflammation reduction.4


Coca plant leaves were used by the Incan’s in South America. It was used to treat headaches, wounds, and fractures. However, the coca plant also brought about cocaine. But is an effective anesthetic. To have an understanding of how cocaine blocks pain has created common anesthetics like lidocaine, which is used in dental procedures.5


Scientists studying opium from the poppy plant, have discovered opiate receptors in the human body and how they manage pain. This led to morphine, codeine, and other opiate based medications.3

Human Health & Cannabis

Cannabis has been used for centuries. Chinese text from the year A.D. 1 has recorded the use of hemp in treating over 100 ailments, which date back to 2737 B.C.6 After this, the tops of the cannabis plant were cultivated for their psychoactive attributes. While this was happening a different strain of the plant was grown for industrial hemp use, in making clothing, paper, biofuels, foods, and other products.

cannabinoids plant medicine el paso, tx.

Based on the controversy surrounding marijuana, it has not been easy for researchers to study the effects of the non-THC components in cannabis. THC was identified in the 1940’s, but it was not until 50 years later that research revealed humans (and almost all animals) have a system of cannabinoid receptors.

Humans make cannabinoids (endocannabinoids) and they act on these receptors.7

This system is called the endocannabinoid system (ECS). The ECS is involved in multiple processes, which include:

  • Pain Sensation
  • Appetite
  • Memory
  • Mood

Ever hit your toe, digest a piece of fruit or forget a password? Then the ECS was involved.

Discovery of the ECS along with the�natural compounds identified in cannabis helped science and medicine. Researchers called these compounds phytocannabinoids,�from the prefix �phyto” for plant. Over 80 phytocannabinoids have now been discovered in marijuana and hemp. THC is just one of the many compounds being studied for their health benefits.8

Cannabis & THC Moving Forward

Now that many plants are known to contain these compounds, phytocannabinoids are no longer just associated with cannabis.9 Chances are you have some source of phytocannabinoids in your diet right now.

Remember it could be just a small amount, and not all phytocannabinoids interact strongly with the ECS.

How Far Has This Research Developed?

Current research shows that some of the phytocannabinoids in hemp, clove, and black pepper can support the ECS to promote relaxation, decrease nerve discomfort, and improve digestive health. And as these compounds do not contain THC there is no mind-altering effects. Therefore, the option of using phytocannabinoids for health benefits,�without feeling the psychoactive effects is definitely something to look forward to.10


  1. Gurib-Fakim A. Medicinal plants: traditions of yesterday and drugs of tomorrow. Mol Aspects Med 2006;27(1):1-93.
  2. Singh Y, Blumenthal M. Kava: an overview. Distribution, mythology, botany, culture, chemistry and pharmacology of the South Pacific�s most revered herb. Herbalgram 1997;39(suppl):34-56.
  3. Brownstein M. A brief history of opiates, opioid peptides, and opioid receptors. Proc Natl Acad Sci U S A 1993;90(12):5391-5393.
  4. Vainio H, Gareth M. Aspirin for the second hundred years: new uses for an old drug. Pharmacol Toxicol 1997;81(4):151-152.
  5. Ruetsch Y, Thomas B, Alain B. From cocaine to ropivacaine: the history of local anesthetic drugs. Curr Top Med Chem 2001;1(3):175-182.
  6. [Accessed April 16, 2018].
  7. Pertwee R. Cannabinoid pharmacology: the first 66 years. Br J Pharmacol 2006;147(Supp 1):163-171.
  8. Borgelt L, Franson K, Nussbaum A, Wang G. The pharmacologic and clinical effects of medical cannabis. Pharmacotherapy 2013;33(2):195-209.
  9. Gertsch J, Roger G, Vincenzo D. Phytocannabinoids beyond the Cannabis plant � do they exist? Br J Pharmacol 2010;160(3):523-529.
  10. Russo E. Taming THC: potential cannabis synergy and phytocannabinoid?terpenoid entourage effects. Br J Pharmacol 2011;163(7):1344-1364.
Brain Changes Associated with Chronic Pain

Brain Changes Associated with Chronic Pain

Pain is the human body’s natural response to injury or illness, and it is often a warning that something is wrong. Once the problem is healed, we generally stop experiencing this painful symptoms, however, what happens when the pain continues long after the cause is gone? Chronic pain is medically defined as persistent pain that lasts 3 to 6 months or more. Chronic pain is certainly a challenging condition to live with, affecting everything from the individual’s activity levels and their ability to work as well as their personal relationships and psychological conditions. But, are you aware that chronic pain may also be affecting the structure and function of your brain? It turns out these brain changes may lead to both cognitive and psychological impairment.


Chronic pain doesn’t just influence a singular region of the mind, as a matter of fact, it can result in changes to numerous essential areas of the brain, most of which are involved in many fundamental processes and functions. Various research studies over the years have found alterations to the hippocampus, along with reduction in grey matter from the dorsolateral prefrontal cortex, amygdala, brainstem and right insular cortex, to name a few, associated with chronic pain. A breakdown of a few of the structure of these regions and their related functions might help to put these brain changes into context, for a lot of individuals with chronic pain. The purpose of the following article is to demonstrate as well as discuss the structural and functional brain changes associated with chronic pain, particularly in the case where those reflect probably neither damage nor atrophy.


Structural Brain Changes in Chronic Pain Reflect Probably Neither Damage Nor Atrophy




Chronic pain appears to be associated with brain gray matter reduction in areas ascribable to the transmission of pain. The morphological processes underlying these structural changes, probably following functional reorganisation and central plasticity in the brain, remain unclear. The pain in hip osteoarthritis is one of the few chronic pain syndromes which are principally curable. We investigated 20 patients with chronic pain due to unilateral coxarthrosis (mean age 63.25�9.46 (SD) years, 10 female) before hip joint endoprosthetic surgery (pain state) and monitored brain structural changes up to 1 year after surgery: 6�8 weeks, 12�18 weeks and 10�14 month when completely pain free. Patients with chronic pain due to unilateral coxarthrosis had significantly less gray matter compared to controls in the anterior cingulate cortex (ACC), insular cortex and operculum, dorsolateral prefrontal cortex (DLPFC) and orbitofrontal cortex. These regions function as multi-integrative structures during the experience and the anticipation of pain. When the patients were pain free after recovery from endoprosthetic surgery, a gray matter increase in nearly the same areas was found. We also found a progressive increase of brain gray matter in the premotor cortex and the supplementary motor area (SMA). We conclude that gray matter abnormalities in chronic pain are not the cause, but secondary to the disease and are at least in part due to changes in motor function and bodily integration.




Evidence of functional and structural reorganization in chronic pain patients support the idea that chronic pain should not only be conceptualized as an altered functional state, but also as a consequence of functional and structural brain plasticity [1], [2], [3], [4], [5], [6]. In the last six years, more than 20 studies were published demonstrating structural brain changes in 14 chronic pain syndromes. A striking feature of all of these studies is the fact that the gray matter changes were not randomly distributed, but occur in defined and functionally highly specific brain areas � namely, involvement in supraspinal nociceptive processing. The most prominent findings were different for each pain syndrome, but overlapped in the cingulate cortex, the orbitofrontal cortex, the insula and dorsal pons [4]. Further structures comprise the thalamus, dorsolateral prefrontal cortex, basal ganglia and hippocampal area. These findings are often discussed as cellular atrophy, reinforcing the idea of damage or loss of brain gray matter [7], [8], [9]. In fact, researchers found a correlation between brain gray matter decreases and duration of pain [6], [10]. But the duration of pain is also linked to the patient�s age, and the age dependent global, but also regionally specific decline of gray matter is well documented [11]. On the other hand, these structural changes could also be a decrease in cell size, extracellular fluids, synaptogenesis, angiogenesis or even due to blood volume changes [4], [12], [13]. Whatever the source is, for our interpretation of such findings it is important to see these morphometric findings in the light of a wealth of morphometric studies in exercise dependant plasticity, given that regionally specific structural brain changes have been repeatedly shown following cognitive and physical exercise [14].


It is not understood why only a relatively small proportion of humans develop a chronic pain syndrome, considering that pain is a universal experience. The question arises whether in some humans a structural difference in central pain transmitting systems may act as a diathesis for chronic pain. Gray matter changes in phantom pain due to amputation [15] and spinal cord injury [3] indicate that the morphological changes of the brain are, at least in part, a consequence of chronic pain. However, the pain in hip osteoarthritis (OA) is one of the few chronic pain syndrome which is principally curable, as 88% of these patients are regularly free of pain following total hip replacement (THR) surgery [16]. In a pilot study we have analysed ten patients with hip OA before and shortly after surgery. We found decreases of gray matter in the anterior cingulated cortex (ACC) and insula during chronic pain before THR surgery and found increases of gray matter in the corresponding brain areas in the pain free condition after surgery [17]. Focussing on this result, we now expanded our studies investigating more patients (n?=?20) after successful THR and monitored structural brain changes in four time intervals, up to one year following surgery. To control for gray matter changes due to motor improvement or depression we also administered questionnaires targeting improvement of motor function and mental health.


Materials and Methods




The patients reported here are a subgroup of 20 patients out of 32 patients published recently who were compared to an age- and gender-matched healthy control group [17] but participated in an additional one year follow-up investigation. After surgery 12 patients dropped out because of a second endoprosthetic surgery (n?=?2), severe illness (n?=?2) and withdrawal of consent (n?=?8). This left a group of twenty patients with unilateral primary hip OA (mean age 63.25�9.46 (SD) years, 10 female) who were investigated four times: before surgery (pain state) and again 6�8 and 12�18 weeks and 10�14 months after endoprosthetic surgery, when completely pain free. All patients with primary hip OA had a pain history longer than 12 months, ranging from 1 to 33 years (mean 7.35 years) and a mean pain score of 65.5 (ranging from 40 to 90) on a visual analogue scale (VAS) ranging from 0 (no pain) to 100 (worst imaginable pain). We assessed any occurrence of minor pain events, including tooth-, ear- and headache up to 4 weeks prior to the study. We also randomly selected the data from 20 sex- and age matched healthy controls (mean age 60,95�8,52 (SD) years, 10 female) of the 32 of the above mentioned pilot study [17]. None of the 20 patients or of the 20 sex- and age matched healthy volunteers had any neurological or internal medical history. The study was given ethical approval by the local Ethics committee and written informed consent was obtained from all study participants prior to examination.


Behavioural Data


We collected data on depression, somatization, anxiety, pain and physical and mental health in all patients and all four time points using the following standardized questionnaires: Beck Depression Inventory (BDI) [18], Brief Symptom Inventory (BSI) [19], Schmerzempfindungs-Skala (SES?=?pain unpleasantness scale) [20] and Health Survey 36-Item Short Form (SF-36) [21] and the Nottingham Health Profile (NHP). We conducted repeated measures ANOVA and paired two-tailed t-Tests to analyse the longitudinal behavioural data using SPSS 13.0 for Windows (SPSS Inc., Chicago, IL), and used Greenhouse Geisser correction if the assumption for sphericity was violated. The significance level was set at p<0.05.


VBM – Data Acquisition


Image acquisition. High-resolution MR scanning was performed on a 3T MRI system (Siemens Trio) with a standard 12-channel head coil. For each of the four time points, scan I (between 1 day and 3 month before endoprosthetic surgery), scan II (6 to 8 weeks after surgery), scan III (12 to 18 weeks after surgery) and scan IV (10�14 months after surgery), a T1 weighted structural MRI was acquired for each patient using a 3D-FLASH sequence (TR 15 ms, TE 4.9 ms, flip angle 25�, 1 mm slices, FOV 256�256, voxel size 1�1�1 mm).


Image Processing and Statistical Analysis


Data pre-processing and analysis were performed with SPM2 (Wellcome Department of Cognitive Neurology, London, UK) running under Matlab (Mathworks, Sherborn, MA, USA) and containing a voxel-based morphometry (VBM)-toolbox for longitudinal data, that is based on high resolution structural 3D MR images and allows for applying voxel-wise statistics to detect regional differences in gray matter density or volumes [22], [23]. In summary, pre-processing involved spatial normalization, gray matter segmentation and 10 mm spatial smoothing with a Gaussian kernel. For the pre-processing steps, we used an optimized protocol [22], [23] and a scanner- and study-specific gray matter template [17]. We used SPM2 rather than SPM5 or SPM8 to make this analysis comparable to our pilot study [17]. as it allows an excellent normalisation and segmentation of longitudinal data. However, as a more recent update of VBM (VBM8) became available recently (, we also used VBM8.


Cross-Sectional Analysis


We used a two-sample t-test in order to detect regional differences in brain gray matter between groups (patients at time point scan I (chronic pain) and healthy controls). We applied a threshold of p<0.001 (uncorrected) across the whole brain because of our strong a priory hypothesis, which is based on 9 independent studies and cohorts showing decreases in gray matter in chronic pain patients [7], [8], [9], [15], [24], [25], [26], [27], [28], that gray matter increases will appear in the same (for pain processing relevant) regions as in our pilot study (17). The groups were matched for age and sex with no significant differences between the groups. To investigate whether the differences between groups changed after one year, we also compared patients at time point scan IV (pain free, one year follow-up) to our healthy control group.


Longitudinal Analysis


To detect differences between time points (Scan I�IV) we compared the scans before surgery (pain state) and again 6�8 and 12�18 weeks and 10�14 months after endoprosthetic surgery (pain free) as repeated measure ANOVA. Because any brain changes due to chronic pain may need some time to recede following operation and cessation of pain and because of the post surgery pain the patients reported, we compared in the longitudinal analysis scan I and II with scan III and IV. For detecting changes that are not closely linked to pain, we also looked for progressive changes over all time intervals. We flipped the brains of patients with OA of the left hip (n?=?7) in order to normalize for the side of the pain for both, the group comparison and the longitudinal analysis, but primarily analysed the unflipped data. We used the BDI score as a covariate in the model.




Behavioral Data


All patients reported chronic hip pain before surgery and were pain free (regarding this chronic pain) immediately after surgery, but reported rather acute post-surgery pain on scan II which was different from the pain due to osteoarthritis. The mental health score of the SF-36 (F(1.925/17.322)?=?0.352, p?=?0.7) and the BSI global score GSI (F(1.706/27.302)?=?3.189, p?=?0.064) showed no changes over the time course and no mental co-morbidity. None of the controls reported any acute or chronic pain and none showed any symptoms of depression or physical/mental disability.


Before surgery, some patients showed mild to moderate depressive symptoms in BDI scores that significantly decreased on scan III (t(17)?=?2.317, p?=?0.033) and IV (t(16)?=?2.132, p?=?0.049). Additionally, the SES scores (pain unpleasantness) of all patients improved significantly from scan I (before the surgery) to scan II (t(16)?=?4.676, p<0.001), scan III (t(14)?=?4.760, p<0.001) and scan IV (t(14)?=?4.981, p<0.001, 1 year after surgery) as pain unpleasantness decreased with pain intensity. The pain rating on scan 1 and 2 were positive, the same rating on day 3 and 4 negative. The SES only describes the quality of perceived pain. It was therefore positive on day 1 and 2 (mean 19.6 on day 1 and 13.5 on day 2) and negative (n.a.) on day 3 & 4. However, some patients did not understand this procedure and used the SES as a global �quality of life� measure. This is why all patients were asked on the same day individually and by the same person regarding pain occurrence.


In the short form health survey (SF-36), which consists of the summary measures of a Physical Health Score and a Mental Health Score [29], the patients improved significantly in the Physical Health score from scan I to scan II (t(17)?=??4.266, p?=?0.001), scan III (t(16)?=??8.584, p<0.001) and IV (t(12)?=??7.148, p<0.001), but not in the Mental Health Score. The results of the NHP were similar, in the subscale �pain� (reversed polarity) we observed a significant change from scan I to scan II (t(14)?=??5.674, p<0.001, scan III (t(12)?=??7.040, p<0.001 and scan IV (t(10)?=??3.258, p?=?0.009). We also found a significant increase in the subscale �physical mobility� from scan I to scan III (t(12)?=??3.974, p?=?0.002) and scan IV (t(10)?=??2.511, p?=?0.031). There was no significant change between scan I and scan II (six weeks after surgery).


Structural Data


Cross-sectional analysis. We included age as a covariate in the general linear model and found no age confounds. Compared to sex and age matched controls, patients with primary hip OA (n?=?20) showed pre-operatively (Scan I) reduced gray matter in the anterior cingulate cortex (ACC), the insular cortex, operculum, dorsolateral prefrontal cortex (DLPFC), right temporal pole and cerebellum (Table 1 and Figure 1). Except for the right putamen (x?=?31, y?=??14, z?=??1; p<0.001, t?=?3.32) no significant increase in gray matter density was found in patients with OA compared to healthy controls. Comparing patients at time point scan IV with matched controls, the same results were found as in the cross-sectional analysis using scan I compared to controls.


Figure 1 Statistical Parametric Maps

Figure 1: Statistical parametric maps demonstrating the structural differences in gray matter in patients with chronic pain due to primary hip OA compared to controls and longitudinally compared to themselves over time. Significant gray matter changes are shown superimposed in color, cross-sectional data is depicted in red and longitudinal data in yellow. Axial plane: the left side of the picture is the left side of the brain. top: Areas of significant decrease of gray matter between patients with chronic pain due to primary hip OA and unaffected control subjects. p<0.001 uncorrected bottom: Gray matter increase in 20 pain free patients at the third and fourth scanning period after total hip replacement surgery, as compared to the first (preoperative) and second (6�8 weeks post surgery) scan. p<0.001 uncorrected Plots: Contrast estimates and 90% Confidence interval, effects of interest, arbitrary units. x-axis: contrasts for the 4 timepoints, y-axis: contrast estimate at ?3, 50, 2 for ACC and contrast estimate at 36, 39, 3 for insula.


Table 1 Cross-Sectional Data


Flipping the data of patients with left hip OA (n?=?7) and comparing them with healthy controls did not change the results significantly, but for a decrease in the thalamus (x?=?10, y?=??20, z?=?3, p<0.001, t?=?3.44) and an increase in the right cerebellum (x?=?25, y?=??37, z?=??50, p<0.001, t?=?5.12) that did not reach significance in the unflipped data of the patients compared to controls.


Longitudinal analysis. In the longitudinal analysis, a significant increase (p<.001 uncorrected) of gray matter was detected by comparing the first and second scan (chronic pain/post-surgery pain) with the third and fourth scan (pain free) in the ACC, insular cortex, cerebellum and pars orbitalis in the patients with OA (Table 2 and Figure 1). Gray matter decreased over time (p<.001 whole brain analysis uncorrected) in the secondary somatosensory cortex, hippocampus, midcingulate cortex, thalamus and caudate nucleus in patients with OA (Figure 2).


Figure 2 Increases in Brain Gray Matter

Figure 2: a) Significant increases in brain gray matter following successful operation. Axial view of significant decrease of gray matter in patients with chronic pain due to primary hip OA compared to control subjects. p<0.001 uncorrected (cross-sectional analysis), b) Longitudinal increase of gray matter over time in yellow comparing scan I&IIscan III>scan IV) in patients with OA. p<0.001 uncorrected (longitudinal analysis). The left side of the picture is the left side of the brain.


Table 2 Longitudinal Data


Flipping the data of patients with left hip OA (n?=?7) did not change the results significantly, but for a decrease of brain gray matter in the Heschl�s Gyrus (x?=??41, y?=??21, z?=?10, p<0.001, t?=?3.69) and Precuneus (x?=?15, y?=??36, z?=?3, p<0.001, t?=?4.60).


By contrasting the first scan (presurgery) with scans 3+4 (postsurgery), we found an increase of gray matter in the frontal cortex and motor cortex (p<0.001 uncorrected). We note that this contrast is less stringent as we have now less scans per condition (pain vs. non-pain). When we lower the threshold we repeat what we have found using contrast of 1+2 vs. 3+4.


By looking for areas that increase over all time intervals, we found changes of brain gray matter in motor areas (area 6) in patients with coxarthrosis following total hip replacement (scan I<scan II<scan III<scan IV)). Adding the BDI scores as a covariate did not change the results. Using the recently available software tool VBM8 including DARTEL normalisation ( we could replicate this finding in the anterior and mid-cingulate cortex and both anterior insulae.


We calculated the effect sizes and the cross-sectional analysis (patients vs. controls) yielded a Cohen�s d of 1.78751 in the peak voxel of the ACC (x?=??12, y?=?25, z?=??16). We also calculated Cohen�s d for the longitudinal analysis (contrasting scan 1+2 vs. scan 3+4). This resulted in a Cohen�s d of 1.1158 in the ACC (x?=??3, y?=?50, z?=?2). Regarding the insula (x?=??33, y?=?21, z?=?13) and related to the same contrast, Cohen�s d is 1.0949. Additionally, we calculated the mean of the non-zero voxel values of the Cohen�s d map within the ROI (comprised of the anterior division of the cingulate gyrus and the subcallosal cortex, derived from the Harvard-Oxford Cortical Structural Atlas): 1.251223.



Dr. Alex Jimenez’s Insight

Chronic pain patients can experience a variety of health issues over time, aside from their already debilitating symptoms. For instance, many individuals will experience sleeping problems as a result of their pain, but most importantly, chronic pain can lead to various mental health issues as well, including anxiety and depression. The effects that pain can have on the brain may seem all too overwhelming but growing evidence suggests that these brain changes are not permanent and can be reversed when chronic pain patients receive the proper treatment for their underlying health issues. According to the article, gray matter abnormalities found in chronic pain do not reflect brain damage, but rather, they are a reversible consequence which normalizes when the pain is adequately treated. Fortunately, a variety of treatment approaches are available to help ease chronic pain symptoms and restore the structure and function of the brain.




Monitoring whole brain structure over time, we confirm and expand our pilot data published recently [17]. We found changes in brain gray matter in patients with primary hip osteoarthritis in the chronic pain state, which reverse partly when these patients are pain free, following hip joint endoprosthetic surgery. The partial increase in gray matter after surgery is nearly in the same areas where a decrease of gray matter has been seen before surgery. Flipping the data of patients with left hip OA (and therefore normalizing for the side of the pain) had only little impact on the results but additionally showed a decrease of gray matter in the Heschl�s gyrus and Precuneus that we cannot easily explain and, as no a priori hypothesis exists, regard with great caution. However, the difference seen between patients and healthy controls at scan I was still observable in the cross-sectional analysis at scan IV. The relative increase of gray matter over time is therefore subtle, i.e. not sufficiently distinct to have an effect on the cross sectional analysis, a finding that has already been shown in studies investigating experience dependant plasticity [30], [31]. We note that the fact that we show some parts of brain-changes due to chronic pain to be reversible does not exclude that some other parts of these changes are irreversible.


Interestingly, we observed that the gray matter decrease in the ACC in chronic pain patients before surgery seems to continue 6 weeks after surgery (scan II) and only increases towards scan III and IV, possibly due to post-surgery pain, or decrease in motor function. This is in line with the behavioural data of the physical mobility score included in the NHP, which post-operatively did not show any significant change at time point II but significantly increased towards scan III and IV. Of note, our patients reported no pain in the hip after surgery, but experienced post-surgery pain in surrounding muscles and skin which was perceived very differently by patients. However, as patients still reported some pain at scan II, we also contrasted the first scan (pre-surgery) with scans III+IV (post-surgery), revealing an increase of gray matter in the frontal cortex and motor cortex. We note that this contrast is less stringent because of less scans per condition (pain vs. non-pain). When we lowered the threshold we repeat what we have found using contrast of I+II vs. III+IV.


Our data strongly suggest that gray matter alterations in chronic pain patients, which are usually found in areas involved in supraspinal nociceptive processing [4] are neither due to neuronal atrophy nor brain damage. The fact that these changes seen in the chronic pain state do not reverse completely could be explained with the relatively short period of observation (one year after operation versus a mean of seven years of chronic pain before the operation). Neuroplastic brain changes that may have developed over several years (as a consequence of constant nociceptive input) need probably more time to reverse completely. Another possibility why the increase of gray matter can only be detected in the longitudinal data but not in the cross-sectional data (i.e. between cohorts at time point IV) is that the number of patients (n?=?20) is too small. It needs to be pointed out that the variance between brains of several individuals is quite large and that longitudinal data have the advantage that the variance is relatively small as the same brains are scanned several times. Consequently, subtle changes will only be detectable in longitudinal data [30], [31], [32]. Of course we cannot exclude that these changes are at least partly irreversible although that is unlikely, given the findings of exercise specific structural plasticity and reorganisation [4], [12], [30], [33], [34]. To answer this question, future studies need to investigate patients repeatedly over longer time frames, possibly years.


We note that we can only make limited conclusions regarding the dynamics of morphological brain changes over time. The reason is that when we designed this study in 2007 and scanned in 2008 and 2009, it was not known whether structural changes would occur at all and for reasons of feasibility we chose the scan dates and time frames as described here. One could argue that the gray matter changes in time, which we describe for the patient group, might have happened in the control group as well (time effect). However, any changes due to aging, if at all, would be expected to be a decrease in volume. Given our a priori hypothesis, based on 9 independent studies and cohorts showing decreases in gray matter in chronic pain patients [7], [8], [9], [15], [24], [25], [26], [27], [28], we focussed on regional increases over time and therefore believe our finding not to be a simple time effect. Of note, we cannot rule out that the gray matter decrease over time that we found in our patient group could be due to a time effect, as we have not scanned our control group in the same time frame. Given the findings, future studies should aim at more and shorter time intervals, given that exercise dependant morphometric brain changes may occur as fast as after 1 week [32], [33].


In addition to the impact of the nociceptive aspect of pain on brain gray matter [17], [34] we observed that changes in motor function probably also contribute to the structural changes. We found motor and premotor areas (area 6) to increase over all time intervals (Figure 3). Intuitively this may be due to improvement of motor function over time as the patients were no more restricted in living a normal life. Notably we did not focus on motor function but an improvement in pain experience, given our original quest to investigate whether the well-known reduction in brain gray matter in chronic pain patients is in principle reversible. Consequently, we did not use specific instruments to investigate motor function. Nevertheless, (functional) motor cortex reorganization in patients with pain syndromes is well documented [35], [36], [37], [38]. Moreover, the motor cortex is one target in therapeutic approaches in medically intractable chronic pain patients using direct brain stimulation [39], [40], transcranial direct current stimulation [41], and repetitive transcranial magnetic stimulation [42], [43]. The exact mechanisms of such modulation (facilitation vs. inhibition, or simply interference in the pain-related networks) are not yet elucidated [40]. A recent study demonstrated that a specific motor experience can alter the structure of the brain [13]. Synaptogenesis, reorganisation of movement representations and angiogenesis in motor cortex may occur with special demands of a motor task. Tsao et al. showed reorganisation in the motor cortex of patients with chronic low back pain that seem to be back pain-specific [44] and Puri et al. observed a reduction in left supplemental motor area gray matter in fibromyalgia sufferers [45]. Our study was not designed to disentangle the different factors that may change the brain in chronic pain but we interpret our data concerning the gray matter changes that they do not exclusively mirror the consequences of constant nociceptive input. In fact, a recent study in neuropathic pain patients pointed out abnormalities in brain regions that encompass emotional, autonomic, and pain perception, implying that they play a critical role in the global clinical picture of chronic pain [28].


Figure 3 Statistical Parametric Maps

Figure 3: Statistical parametric maps demonstrating a significant increase of brain gray matter in motor areas (area 6) in patients with coxarthrosis before compared to after THR (longitudinal analysis, scan I<scan II<scan III<scan IV). Contrast estimates at x?=?19, y?=??12, z?=?70.


Two recent pilot studies focussed on hip replacement therapy in osteoarthritis patients, the only chronic pain syndrome which is principally curable with total hip replacement [17], [46] and these data are flanked by a very recent study in chronic low back pain patients [47]. These studies need to be seen in the light of several longitudinal studies investigating experience-dependent neuronal plasticity in humans on a structural level [30], [31] and a recent study on structural brain changes in healthy volunteers experiencing repeated painful stimulation [34]. The key message of all these studies is that the main difference in the brain structure between pain patients and controls may recede when the pain is cured. However, it must be taken into account that it is simply not clear whether the changes in chronic pain patients are solely due to nociceptive input or due to the consequences of pain or both. It is more than likely that behavioural changes, such as deprivation or enhancement of social contacts, agility, physical training and life style changes are sufficient to shape the brain [6], [12], [28], [48]. Particularly depression as a co-morbidity or consequence of pain is a key candidate to explain the differences between patients and controls. A small group of our patients with OA showed mild to moderate depressive symptoms that changed with time. We did not find the structural alterations to covary significantly with the BDI-score but the question arises how many other behavioural changes due to the absence of pain and motor improvement may contribute to the results and to what extent they do. These behavioural changes can possibly influence a gray matter decrease in chronic pain as well as a gray matter increase when pain is gone.


Another important factor which may bias our interpretation of the results is the fact that nearly all patients with chronic pain took medications against pain, which they stopped when they were pain free. One could argue that NSAIDs such as diclofenac or ibuprofen have some effects on neural systems and the same holds true for opioids, antiepileptics and antidepressants, medications which are frequently used in chronic pain therapy. The impact of pain killers and other medications on morphometric findings may well be important (48). No study so far has shown effects of pain medication on brain morphology but several papers found that changes in brain structure in chronic pain patients are neither solely explained by pain related inactivity [15], nor by pain medication [7], [9], [49]. However, specific studies are lacking. Further research should focus the experience-dependent changes in cortical plasticity, which may have vast clinical implications for the treatment of chronic pain.


We also found decreases of gray matter in the longitudinal analysis, possibly due to reorganisation processes that accompany changes in motor function and pain perception. There is little information available about longitudinal changes in brain gray matter in pain conditions, for this reason we have no hypothesis for a gray matter decrease in these areas after the operation. Teutsch et al. [25] found an increase of brain gray matter in the somatosensory and midcingulate cortex in healthy volunteers that experienced painful stimulation in a daily protocol for eight consecutive days. The finding of gray matter increase following experimental nociceptive input overlapped anatomically to some degree with the decrease of brain gray matter in this study in patients that were cured of long-lasting chronic pain. This implies that nociceptive input in healthy volunteers leads to exercise dependant structural changes, as it possibly does in patients with chronic pain, and that these changes reverse in healthy volunteers when nociceptive input stops. Consequently, the decrease of gray matter in these areas seen in patients with OA could be interpreted to follow the same fundamental process: exercise dependant changes brain changes [50]. As a non-invasive procedure, MR Morphometry is the ideal tool for the quest to find the morphological substrates of diseases, deepening our understanding of the relationship between brain structure and function, and even to monitor therapeutic interventions. One of the great challenges in the future is to adapt this powerful tool for multicentre and therapeutic trials of chronic pain.


Limitations of this Study


Although this study is an extension of our previous study expanding the follow-up data to 12 months and investigating more patients, our principle finding that morphometric brain changes in chronic pain are reversible is rather subtle. The effect sizes are small (see above) and the effects are partly driven by a further reduction of regional brain gray matter volume at the time-point of scan 2. When we exclude the data from scan 2 (directly after the operation) only significant increases in brain gray matter for motor cortex and frontal cortex survive a threshold of p<0.001 uncorrected (Table 3).


Table 3 Longitudinal Data




It is not possible to distinguish to what extent the structural alterations we observed are due to changes in nociceptive input, changes in motor function or medication consumption or changes in well-being as such. Masking the group contrasts of the first and last scan with each other revealed much less differences than expected. Presumably, brain alterations due to chronic pain with all consequences are developing over quite a long time course and may also need some time to revert. Nevertheless, these results reveal processes of reorganisation, strongly suggesting that chronic nociceptive input and motor impairment in these patients leads to altered processing in cortical regions and consequently structural brain changes which are in principle reversible.




We thank all volunteers for the participation in this study and the Physics and Methods group at NeuroImage Nord in Hamburg. The study was given ethical approval by the local Ethics committee and written informed consent was obtained from all study participants prior to examination.


Funding Statement


This work was supported by grants from the DFG (German Research Foundation) (MA 1862/2-3) and BMBF (The Federal Ministry of Education and Research) (371 57 01 and NeuroImage Nord). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.


Endocannabinoid System | El Paso, TX Chiropractor


The Endocannabinoid System: The Essential System You�ve Never Heard Of


In case you haven’t heard of the endocannabinoid system, or ECS, there’s no need to feel embarrassed. Back in the 1960’s, the investigators that became interested in the bioactivity of Cannabis eventually isolated many of its active chemicals. It took another 30 years, however, for researchers studying animal models to find a receptor for these ECS chemicals in the brains of rodents, a discovery which opened a whole world of inquiry into the ECS receptors existence and what their physiological purpose is.


We now know that most animals, from fish to birds to mammals, possess an endocannabinoid, and we know that humans not only make their own cannabinoids that interact with this particular system, but we also produce other compounds that interact with the ECS, those of which are observed in many different plants and foods, well beyond the Cannabis species.


As a system of the human body, the ECS isn’t an isolated structural platform like the nervous system or cardiovascular system. Instead, the ECS is a set of receptors widely distributed throughout the body which are activated through a set of ligands we collectively know as endocannabinoids, or endogenous cannabinoids. Both verified receptors are just called CB1 and CB2, although there are others which were proposed. PPAR and TRP channels also mediate some functions. Likewise, you will find just two well-documented endocannabinoids: anadamide and 2-arachidonoyl glycerol, or 2-AG.


Moreover, fundamental to the endocannabinoid system are the enzymes that synthesize and break down the endocannabinoids. Endocannabinoids are believed to be synthesized in an as-needed foundation. The primary enzymes involved are diacylglycerol lipase and N-acyl-phosphatidylethanolamine-phospholipase D, which respectively synthesize 2-AG and anandamide. The two main degrading enzymes are fatty acid amide hydrolase, or FAAH, which breaks down anandamide, and monoacylglycerol lipase, or MAGL, which breaks down 2-AG. The regulation of these two enzymes may increase or decrease the modulation of the ECS.


What is the Function of the ECS?


The ECS is the principal homeostatic regulatory system of the body. It may readily be viewed as the body’s internal adaptogenic system, always working to maintain the balance of a variety of function. Endocannabinoids broadly work as neuromodulators and, as such, they regulate a broad range of bodily processes, from fertility to pain. Some of those better-known functions from the ECS are as follows:


Nervous System


From the central nervous system, or the CNS, general stimulation of the CB1 receptors will inhibit the release of glutamate and GABA. In the CNS, the ECS plays a role in memory formation and learning, promotes neurogenesis in the hippocampus, also regulates neuronal excitability. The ECS also plays a part in the way the brain will react to injury and inflammation. From the spinal cord, the ECS modulates pain signaling and boosts natural analgesia. In the peripheral nervous system, in which CB2 receptors control, the ECS acts primarily in the sympathetic nervous system to regulate functions of the intestinal, urinary, and reproductive tracts.


Stress and Mood


The ECS has multiple impacts on stress reactions and emotional regulation, such as initiation of this bodily response to acute stress and adaptation over time to more long-term emotions, such as fear and anxiety. A healthy working endocannabinoid system is critical to how humans modulate between a satisfying degree of arousal compared to a level that is excessive and unpleasant. The ECS also plays a role in memory formation and possibly especially in the way in which the brain imprints memories from stress or injury. Because the ECS modulates the release of dopamine, noradrenaline, serotonin, and cortisol, it can also widely influence emotional response and behaviors.


Digestive System


The digestive tract is populated with both CB1 and CB2 receptors that regulate several important aspects of GI health. It’s thought that the ECS might be the “missing link” in describing the gut-brain-immune link that plays a significant role in the functional health of the digestive tract. The ECS is a regulator of gut immunity, perhaps by limiting the immune system from destroying healthy flora, and also through the modulation of cytokine signaling. The ECS modulates the natural inflammatory response in the digestive tract, which has important implications for a wide range of health issues. Gastric and general GI motility also appears to be partially governed by the ECS.


Appetite and Metabolism


The ECS, particularly the CB1 receptors, plays a part in appetite, metabolism, and regulation of body fat. Stimulation of the CB1 receptors raises food-seeking behaviour, enhances awareness of smell, also regulates energy balance. Both animals and humans that are overweight have ECS dysregulation that may lead this system to become hyperactive, which contributes to both overeating and reduced energy expenditure. Circulating levels of anandamide and 2-AG have been shown to be elevated in obesity, which might be in part due to decreased production of the FAAH degrading enzyme.


Immune Health and Inflammatory Response


The cells and organs of the immune system are rich with endocannabinoid receptors. Cannabinoid receptors are expressed in the thymus gland, spleen, tonsils, and bone marrow, as well as on T- and B-lymphocytes, macrophages, mast cells, neutrophils, and natural killer cells. The ECS is regarded as the primary driver of immune system balance and homeostasis. Though not all the functions of the ECS from the immune system are understood, the ECS appears to regulate cytokine production and also to have a role in preventing overactivity in the immune system. Inflammation is a natural part of the immune response, and it plays a very normal role in acute insults to the body, including injury and disease ; nonetheless, when it isn’t kept in check it can become chronic and contribute to a cascade of adverse health problems, such as chronic pain. By keeping the immune response in check, the ECS helps to maintain a more balanced inflammatory response through the body.


Other areas of health regulated by the ECS:


  • Bone health
  • Fertility
  • Skin health
  • Arterial and respiratory health
  • Sleep and circadian rhythm


How to best support a healthy ECS is a question many researchers are now trying to answer. Stay tuned for more information on this emerging topic.


In conclusion,�chronic pain has been associated with brain changes, including the reduction of gray matter. However, the article above demonstrated that chronic pain can alter the overall structure and function of the brain. Although chronic pain may lead to these, among other health issues, the proper treatment of the patient’s underlying symptoms can reverse brain changes and regulate gray matter. Furthermore, more and more research studies have emerged behind the importance of the endocannabinoid system and it’s function in controlling as well as managing chronic pain and other health issues. Information referenced from the National Center for Biotechnology Information (NCBI).�The scope of our information is limited to chiropractic as well as to spinal injuries and conditions. To discuss the subject matter, please feel free to ask Dr. Jimenez or contact us at�915-850-0900�.


Curated by Dr. Alex Jimenez


Additional Topics: Back Pain

Back pain is one of the most prevalent causes for disability and missed days at work worldwide. As a matter of fact, back pain has been attributed as the second most common reason for doctor office visits, outnumbered only by upper-respiratory infections. Approximately 80 percent of the population will experience some type of back pain at least once throughout their life. The spine is a complex structure made up of bones, joints, ligaments and muscles, among other soft tissues. Because of this, injuries and/or aggravated conditions, such as herniated discs, can eventually lead to symptoms of back pain. Sports injuries or automobile accident injuries are often the most frequent cause of back pain, however, sometimes the simplest of movements can have painful results. Fortunately, alternative treatment options, such as chiropractic care, can help ease back pain through the use of spinal adjustments and manual manipulations, ultimately improving pain relief.




blog picture of cartoon paperboy big news


EXTRA IMPORTANT TOPIC: Low Back Pain Management


MORE TOPICS: EXTRA EXTRA:�Chronic Pain & Treatments


1.�Woolf CJ, Salter MW (2000)�Neuronal plasticity: increasing the gain in pain.�Science288: 1765�1769.[PubMed]
2.�Flor H, Nikolajsen L, Staehelin Jensen T (2006)�Phantom limb pain: a case of maladaptive CNS plasticity?Nat Rev Neurosci7: 873�881.�[PubMed]
3.�Wrigley PJ, Gustin SM, Macey PM, Nash PG, Gandevia SC, et al. (2009)�Anatomical changes in human motor cortex and motor pathways following complete thoracic spinal cord injury.�Cereb Cortex19: 224�232.�[PubMed]
4.�May A (2008)�Chronic pain may change the structure of the brain.�Pain137: 7�15.�[PubMed]
5.�May A (2009) Morphing voxels: the hype around structural imaging of headache patients. Brain.[PubMed]