Head Magazine gets an education on Endocannabinoids from the smartest guy we know on the subject, Dr. Nicholas DiPatrizio, associate professor of Biomedical Sciences at the University of California, Riverside School of Medicine.
Charlotte Parker: Hi, Professor. Thank you for joining us at Head Magazine.
Professor DiPatrizio: Thank you. My pleasure.
Charlotte: Can you tell us : What is the endocannabinoid system?
Professor DiPatrizio: The endocannabinoid system, it has this funny word in it. Looks like cannabis. A lot of folks are, “Well, what is this? Is this cannabis or what is happening here?” The endocannabinoid system is a system that I’ll go through in a minute, but it’s basically hijacked by some chemicals in the cannabis plant in particular Delta-9- Tetrahydrocannabinol one of the main psychotropic ingredients in the cannabis plant.
Charlotte: Is that what is commonly known as THC?
Professor DiPatrizio: Yes. THC. That sort of hijacks this system. What is this system? The system obviously is in the body and wouldn’t have been selected by evolution to be there to respond to a drug that doesn’t make much sense. The system is there to regulate pretty much every physiological function in the body. A nice way to think about this is that we produce our body’s own natural cannabis, and these molecules are called the endocannabinoids.
You can think of endocannabinoids again, as our body’s own natural cannabis, THC from the plant hijacks this system and mimics these natural chemicals, but where THC and the endocannabinoid share commonalities is that they both activate the same receptors in cells throughout the body. When I say that THC, for example, hijacks the cannabinoid system, what I mean is it’s hyper activating the cannabinoid receptors throughout the body.
These are the same receptors that the endocannabinoids — again, our body’s natural cannabis– produce and activate these receptors. The key difference here is that endocannabinoids, the body’s natural cannabis, are really produced on demand in specific areas of the body whenever they’re needed to control some physiological process or to slow down certain physiological processes. This is in contrast to ingesting cannabis and ingesting THC. You can imagine that goes through your circulation and activates cannabinoid receptors really throughout the entire body.
Again, the endocannabinoid system is comprised of the natural molecules that our body produces called the endocannabinoids, as well as, the receptors that they bind and activate which are located on cells –and then activating them leads to a whole bunch of different intracellular responses. One good and easy way I think to conceptualize this is the lock and key hypothesis. You can think of the endocannabinoids as well as THC as a key.
The receptors are located on cells and they are the locks and only certain keys can access those locks. Therefore, another molecule that floats around the body, let’s say, an endorphin. Or we can even now contrast that to an exogenous chemical that’s similar, an opioid, a morphine, they have their keys that do not fit the cannabinoid locks. They have their own locks, the opioid receptors, for example.
Charlotte: When our body produces the endocannabinoids by itself, what does that look like? Does everybody produce them or are they produced at different times for different reasons?
Professor DiPatrizio: Good question. The evidence suggests that these chemicals are produced on demand. I like to think of them as nature’s safety net. This is just one example, and I can go through a couple others as well. If you’re, for example, leading to a hyperexcitable state, let’s say leading up to a seizure, your body would have lots of glutamate and an excitatory neurotransmitter being released in certain areas of the brain.
What’s been found is that thought that when you have tons of glutamate, this produces the endocannabinoids. What they do is they travel retrograde, bind presynaptic cannabinoid receptors, and in essence, slow down and reduce and block glutamate release. You can see it’s a safety net. If you have too much of something being produced, the endocannabinoids come along and go, “Whoa, whoa, whoa let’s slow things down here.”
Ball-and-stick model of the THC molecule
In fact, these systems may be faulty in folks that are prone to seizures, as well as, a host of other diseases. For example, again the system is activated during challenge. I’m just using different terminology here, but it’s the same thing. When the system is challenged. For example, we have discovered that our body produces these natural cannabinoids in the small intestinal lining in our body.
They’re everywhere in the body, but under this certain instance when you’re fasting and when you’re very hungry, they’re being produced in the small intestinal lining. We believe this provides this urge and pressure to go consume food because we’re hungry. Now, you can see another example of that we’ve discovered recently that in diet-induced obesity. Again, another challenge. The first challenge was a hyperexcitable state.
The second challenge that I’m talking about would be under fasting conditions, or when you’re starving, the system’s there to again be a safety net and help you consume food. It does this and drives you to eat through a bunch of mechanisms we’ve discovered. The other example is, for example, in diet-induced obesity. The same chemicals are produced again in high amounts in the small intestinal lining and we’ve been using rodent studies to really figure out these mechanisms.
Charlotte: Diet-induced obesity?
Professor DiPatrizio: Yes. For example, using a mouse model feeding the mice for up to 60 days a high fat, high sugar diet, we call it the western diet, the animals plump up very, very fast. Their endocannabinoid levels spike in the small intestinal lining. We found that if you block that spike in cannabinoids, basically, we clogged the cannabinoid receptors, so those endocannabinoids can’t work anymore, we basically take other keys and break them off in the locks, and then all of a sudden the natural key can’t put that lock anymore. We clog it and what we do is we block overeating that’s associated with diet-induced obesity.
Charlotte: Well, how would that work in a person?
Professor DiPatrizio: Yes. Very similarly there was a drug out on the market. In Europe, it was called Acomplia. This would be a CB1, cannabinoid receptor antagonist. Think of it as opposite of THC. If you give THC under certain conditions you drive feeding, but if you give that’s the key that goes into that lock and activates it. However, if you clog those locks with these keys, you basically break them off in it, but they don’t activate it, but they block they’re called antagonists.
The pharmacological term will be antagonist, they block and antagonize the receptor. They’re blocking the natural activity, the animals lose body weight. In humans, a very similar thing happens, of course. There was a drug that was– In 2007, it was very, very close to be gaining full FDA approval in the United States. It had completed nearly all of the stages to bring this drug to market. In Europe, they were about a year or two ahead in that the restrictions were a little bit less, they put this drug out on the market and it worked wonders. While THC may increase feeding this drug reduced feeding at least initially, but more importantly reduced weight circumference.
It was a treatment for obesity and it worked really, really well. Unfortunately, in Europe once thousands of people started taking this drug, there were increased psychiatric side effects, including increased depression in folks that may be vulnerable. There were several extra suicides associated with taking this drug. This leads back to the work that we do in our lab. What was going on with that drug? Anyhow, the United States caught wind of it and rightfully so shut it down, and right before it was about to gain approval the FDA said, “No, No this is not going on the market.” For probably pretty good reason.
Well, this illustrates a very important point about the cannabinoid system that it’s located throughout the body. That drug that clogged the receptors and blocked the overactive system in obese patients, it also accessed the brain where cannabinoid receptors and the locks are located on cells in areas of the brain that control mood and emotion. What was happening was that drug was not only blocking cannabinoid receptors in the periphery and improving things.
It disrupted psychiatric– Led to increased psychiatric side effects and changed and altered how our brain was processing very likely mood and emotion. You could see the clogging and blocking it in one hand may have some benefits, but on the other hand it can have some detriments. That leads to the work we do in our lab. We’ve discovered that we can remotely control the brain from the periphery. We along with colleagues of ours had generated a very similar molecule like that one called Rimonabant that I talked about. They generated this new molecule– There’s several of them out there now– that cross the blood-brain barrier that access the brain. Over the past several years, work from my laboratory, as well as others, have shown that you can get all the same pro-metabolic anti-obesity effects that Rimonabant had, but without having to access the brain directly. Drugs have been developed that basically have taken that Rimonabant molecule and tweak it so it doesn’t cross into the brain. It only stays in the body, outside of the head, outside of the brain.
What you see with these molecules is you get the same pro-metabolic anti-obesity effects. What we believe is that we can remotely control the brain to consume food and control energy homeostasis, without directly manipulating the cannabinoid system in the brain. We believe we can manipulate it in the periphery including in the intestinal lining, and that indirectly controls brain activity, and hopefully, these drugs would be devoid of the psychiatric side effects that are seen with that grain penetrant Rimonabant.
Charlotte: I know you were a contributor to the documentary, CBD Nation, and I’d like to know why you think that that’s an important documentary at this time if you do think that.
Professor DiPatrizio: Yes, great question. I do agree. I think CBD Nation is very timely. I think it’s very important to get information out to the public. It’s tough sometimes translating the science effectively to the public, and I think the movie does a good job at that. We can get into the details of the biochemistry of the system, and all these fun things that I find fun as a scientist, but that doesn’t really resonate with the public. In order to understand the system, you don’t have to understand the deep, deep biochemistry of the system.
I think the movie did a good job in portraying how the system works to the general public. Now, there was a heavy emphasis in the movie on CBD. CBD, of course, does not give this high that’s associated with Delta-9 THC, so I could see some benefits with that molecule.
How the molecule interacts with the body is really not entirely known. There are a few pathways that it’s thought to interact with, and it may in fact indirectly interact with the endocannabinoid system, but there may be other systems as well. CBD is really popularized now. It’s sold in lots of different places. You see it everywhere. We have to be careful the scientists out there to support for sure possibly anti-inflammatory effects of CBD.
It’s on the market and only approved for one use, and that is in several different types of childhood seizures. It’s not approved for pain or inflammation or any of these other effects that is reported to have. What I can assure you there are lots of experiments going on out there now to see what does CBD really do.
Delta-9 THC, for example, I would say it’s a bit more well characterized. The mechanism of action for blocking pain and inflammation, and possibly even promoting food intake in, for example, cancer patients going through chemotherapy. A lot of these mechanisms are a bit more well fleshed out. How CBD works, again, it’s not entirely fleshed out yet.
Nick DiPatrizio Ph. D. (Image Credit: Stan Lim)
Charlotte: Delta-9 THC, is that just a general kind of THC that is found in the cannabis plant?
Professor DiPatrizio: Yes, it’s the one that really gives the high.
Charlotte: I want to ask you, how does cannabis work with the endocannabinoid system?
Professor DiPatrizio: Great. That will loop right back to the first little talk we had. Where that molecule for it– Again, we have to isolate, which molecule is doing what. There’s tons of different chemicals in the plant. My laboratory right now is studying and beginning to go through these different molecules. We’re testing side-by-side THC, with extracts from the plant — through mass spectrometry and liquid chromatography, we match the THC content.
We’re giving rodents that are obese, for example, THC to see how it affects the metabolism. Then side-by-side and other rodents match same amount of THC, but it has all the other chemicals that are in the plant. We’ll have to talk next year, or a year from now to give you the results. They’re just slowly starting to come in now. That’s why we have to isolate it. If we’re talking about THC, how THC is known to work on the body is that it hijacks that endocannabinoid system.
Charlotte: You consider that a good thing?
Professor DiPatrizio: It depends. It can have certainly some anti-inflammatory effects, it’s known. Can block pain to a degree, that’s good. It could be, for example, used in combination with very low doses of opioids, and in which mind you opioids are terrible medications. Unfortunately, there’s only a small arsenal that physicians have for treating pain, but opioid has a huge addiction liability. You can see unfortunately thousands of folks a year die from this drug. It’s very addictive.
However, there were some experiments showing that if you would give THC along with very small amounts of opioids, you get what would be called synergy in pharmacology, and you have great pain-blocking with greatly minimized side effects from the opioid.
Charlotte: The MORE Act is going in front of Congress shortly, and the idea is to take it off the listing as a Schedule I drug, so the doctors can prescribe it for pain or various other ailments. How do you feel about that?
Professor DiPatrizio: I am fully supportive of that. Of it being removed from a Schedule I. There is no reason this drug should be a Schedule I compound. I can tell you it makes it very difficult to study this drug. It being controlled just as much as heroin, for example, is going to be controlled, or some other drugs that are Schedule I drugs. The hoops that we have to jump through to study it because it’s a Schedule I really impedes the field.
I can tell you from first-hand knowledge of us trying to study this, it just takes forever to get the clearance and approvals. Yes, and if we could take that off from being a Schedule I, it would make it a lot easier to study and it would increase the distribution of it legally federally to folks for treatment of several different ailments. Schedule I drugs are Schedule I for several reasons. One, that there is no medicinal value to it, and that’s just inaccurate with cannabis.
Charlotte: Right. There doesn’t seem to be a logical or “good for you” reason for them to keep it a Schedule I.
Professor DiPatrizio: That’s right. Now, I’m not saying there aren’t side effects with cannabis. For sure there’s going to be and we need to study this more, but it should not be a Schedule I compound. That’s my opinion.
Charlotte: When someone takes cannabis is it different if you take it through smoking as opposed to ingesting through a gummy let’s say? Is there a difference in the responses to the endocannabinoid system or is it very similar depending on the strain?
Professor DiPatrizio: Well, there’s a lot of factors here. If you ingest it orally you have what’s called first pass. It’s a safety net build up. Our body has all these wonderful safety nets build up. I’ll give you the punchline and then I’ll come back to the reasoning behind it. You have this thing called first pass. Basically, your liver breaks down a lot of the molecules in cannabis. That’s for good reason because if we eat– Let’s imagine eating toxins, you don’t want that to immediately go to your bloodstream.
Let’s say you eat a food that you don’t know is toxic, so again let’s go back in the Savannah. Now we know what foods may be toxic and not, but growing up evolutionarily, we did not have the beauty of that hindsight. You have these mechanisms in our body to be able to break down certain toxins, for example, or break down certain foods, and our liver does a pretty good job of that. When you orally ingest something, it’s broken down in part by the liver and when you smoke it, for example, and ingested it goes directly into circulation and that’s very different, has a very different pharmacokinetic and pharmacodynamic profile when you would ingest through these different routes of administration.
Charlotte: Someone either ingests or smokes cannabis, what happens with the endocannabinoid system? From watching some of the information on the film, it seems like different people have different receptors or different levels of receptors and so one person might respond very differently from another. Is that your opinion or how do you feel about that particular issue?
Professor DiPatrizio: The reasoning why folks respond differently is not really well ironed out. I think that that’s probably accurate, that’s one component, not the only component, the fact that some folks have different distribution of the system throughout the body for sure. There are other components of the system that we didn’t touch on, such as the biosynthetic enzymes that produce the endocannabinoids as well as those that degrade the endocannabinoids in the body, as well as other enzymes that break down THC, for example.
We may have different distributions of a whole host of different proteins in our body basically, that could lead to that, it may not just be that. I respond differently than you do to the drug because I have more receptors in this one area of the brain than another. That for sure could be one component to it, but I think it’s a little bit more complex, a little it is more complex than that. There’s that other side to it including many different sides, that how our body processes these molecules as well. One person may have more Cytochrome P450 or some different enzymes that break down cannabis may be differently distributed throughout the body.
It’s broken down and then released in feces as well as in urine. Transit can be different in folks, how kidney function can be different in folks. I think in general, it’s tough to really summarize it in one sentence to say, “It’s because of this.” When someone tells you that it’s because of something one specific, that’s usually not accurate, it’s a whole variety of reasons why, but as scientists, we have to isolate systems and look at one at a time or we’ll never figure it out.
Charlotte: That’s complex basically?
Professor DiPatrizio: Very complex, yes. I think that’s sort of the punch line here. It’s certainly a job for the rest of my life and hopefully, all my PhD students that come through my lab and trainees, they will have a job for the rest of their lives because there’s just so much that still needs to be known about how our body interacts with these chemicals. It’s very exciting.
Charlotte: Yes, it is. Would you say in terms of the endocannabinoid system– is cannabis unique in terms of that it is able to seize upon that system and like you say ride on it or whatever it is or connect with it, is it unique in terms of that, is it more so than, let’s say, other plants or other drugs in your opinion?
Professor DiPatrizio: Well, it will be tough to compare with other drugs, I can only compare it to, for example, opioids it’s similar, it’s analogous in that endocannabinoids are produced from within. Endorphins, for example, are produced from within. Endocannabinoids activate the cannabinoid receptors, endorphins activate opioid receptors now exogenously cannabis, and THC exclusively activate CB1 and CB2 receptors and other ones — maybe whereas, heroin or opium, for example, or morphine, anything derived from that plant, or synthetic opioids activate the opioid system.
The commonality is that both have– They’re separate drugs that work through different systems in the body for sure. There may be some interaction there, but they’re similar in that we produce endocannabinoids, and we produce endorphin that activates their own individual pathways and then if you flip that outside and look at the cannabis plant, some of the chemicals activate the system in the plant, in the cannabinoid system where some of the chemicals in the opium plant, poppy plant will activate the opioid system.
Yes, you are exactly correct THC is very well characterized to interact and activate the cannabinoid CB1 and CB2 receptors, as well as, a few others very likely handful of others in the body and its hijacking, it’s just hyper activating that system. It’s almost like the lock and key hypothesis I was talking about, you’re ingesting tons of little key THC keys and they just float around your body and bind and activate the locks, the cannabinoid receptors that are on cells throughout the body.
Charlotte: Well, is there in your opinion something in terms of cannabis versus these other pathways? Is there something safer about that?
Professor DiPatrizio: This is a wonderful question actually, this is a very, very good, and astute question. The why? I don’t know the complete answer, but I can give you one example here. Why is one plant killing you, opioids whereas the other plant no one’s ever died directly of an overdose?
What is that discrepancy? Why is that? The easy answer is obviously that the systems are different and distributed differently throughout the body. The one major point I would like to make is that opioid receptors are located in areas in the brainstem that control breathing. Lots of times folks that unfortunately overdose is they stopped breathing. Contrast that with cannabinoid, those locks, the cannabinoid receptors, they are not located in that breathing center in the brainstem. You could see you would not die from cannabis, you’re not going to die from cannabis or stop breathing. Did you see the difference there?
Charlotte: I see the difference in the mortality issue there, but in terms of, let’s say, addiction or– Is there any other significant differences, or safety or efficacy? Do you see any significant differences between cannabis and some of these other drugs or systems?
Professor DiPatrizio: Yes. Cannabis while we talk about it, not killing folks, it still is technically considered an addictive substance, you can build a tolerance to it. It checks off certain categories, but if you’re asking me is it safer? Yes, because it does not have these bad, these side effects such as decreased respiration that’s found with opioids. Again, I’m not saying cannabis is without side effects, there are side effects, there can be mood and emotion changes, there can be learning deficits if it’s consumed during adolescence.
The adolescent brain, that’s a very dangerous time period to be messing around with these types of compounds and that’s when a lot of folks generally are beginning to mess around with them. It looks like a lot of the evidence is suggesting that during adolescence cannabinoids can disrupt learning, memory, and different processes in the brain. Again, it’s not all well ironed out, we need more experiments, we need more funding, and we need to have this drug off of the Schedule.
Charlotte: What age would you say is safe in the sense for people to start using or experimenting with it?
Professor DiPatrizio: I wouldn’t want to say an age that’s the time to begin experimenting with it. All I can do as a scientist, I just form my opinions based off the evidence that I see in the experiments and those are showing in rodent models that mimic adolescence and there are some studies now in humans as well showing during adolescence may have changes later on, but all we can see is that during this adolescent time frame they– Again, haven’t been ironed out, whether it’s one-year-old, five-year-old, 10, 15, 20-year-old, we don’t know yet, but it looks like during that adolescent timeframe can lead to some long-lasting changes and long-lasting effects that may be detrimental.
Again it’s not across the board, I would be willing to say this isn’t every person this is going to happen to. We just don’t know enough about it yet, we need more experiments. There’s a lot of information already known about it, but there’s just much that’s unknown and these are great questions, and we need to tackle this. What timeframe during adolescence is the most detrimental? There are colleagues that are directly asking these questions.
Charlotte: Now in terms of cannabis, is there would you say, an overall positive in terms of– Is there a positive use to it in terms of harnessing the endocannabinoid system? How do you feel about that?
Professor DiPatrizio: Yes, again, we have to discriminate between when we’re talking. This is the one issue that gets confused a lot. When we talk about cannabis, there’s multiple compounds you’re ingesting. Which one does what? THC, for example, can have anti-inflammatory effects. It’s known. Can stimulate food intake in folks that may be on chemotherapy during cancer treatment, during age wasting syndrome, you may want to activate the system and promote food intake. Under other circumstances, you may want to block the system. I just look at it as modulating the system, either up or down, has its own benefit depending upon which disorder you’re looking at.
Now, we need to contrast THC with CBD. While they share some similar effects, they do not share all effects. It’s not like CBD has all the same anti-inflammatory and anti-pain effects that THC does, it doesn’t. It has its own unique set of properties. We don’t ever want to confuse this, but it gets confusing to put it together because when you’re ingesting it, it’s all in the plant. The difference is when you buy it from a store, CBD, for example, it’s huge amounts that aren’t in the plant. We have to be careful. A lot of the stores have been shown to have– I’m not going to call out certain states or areas, but the tinctures that they’re selling that are CBD, it’s mostly all THC that’s in there.
I could tell you as an analytical chemist, CBD and THC is a very, very similar molecule, has the same molecular mass. You have to be very sophisticated to separate these molecules and very sophisticated to be able to tell the differences. Unfortunately, the analytical chemistry side of the industry has not met the challenge yet..
Charlotte: Do you have anything further to say about the film (CBD Nation) or your experiences with David Jakubovic or your experiences on the film?
Professor DiPatrizio: Yes, I think the film was great and does a good job of trying to translate complex topics into understandable bits of information for the general public. I think David did a very good job at that. It’s difficult. It’s a difficult needle to thread. I greatly enjoyed the documentary. I enjoyed really everything about it, interacting with David, he was just a wonderful director and kept contacting, asking different questions, and really wanting to know further and deeper into the complexities of the system. It takes a long time to really start to understand how these things work.
I think that the movie did a good job at that, translating the science, to show that CBD, for example, the one molecule does have benefits for seizures. The only approved use for that product the FDA has granted is for seizures. It was a very heartfelt movie and I think he did a good job.
Charlotte: Yes, once it goes off of Schedule I there can be other good uses of what it could be beneficial for. Also, they have other things now like CBG and so forth, different compounds.
Professor DiPatrizio: Yes, we need to study those, especially the other ones. They’re not characterized very well at all. We’re beginning to do this. We’re beginning to start to look at these other molecules.
Charlotte: Can you mention those briefly before you go? The other ones that you want to study in the future? The CBG and so forth.
Professor DiPatrizio: Yes, I can’t give away too much, but that’s included, for sure. We’ll go down the line. What we do know, Charlotte is that THC is very well characterized for benefits. CBD looks to have some benefits for sure, as well, but it’s a bit less characterized.
Charlotte: What does that mean characterized?
Professor DiPatrizio: As a scientist, I need to see experiments that show, “This experiment blocks pain in this model. This experiment blocks inflammation in this model. This drug, this molecule blocks X, Y, and Z using this molecule.” It is not enough for me to just hear it anecdotally from folks that, “Oh, hey, I took this thing that said it has CBD and I have less pain.” That’s not a controlled experiment. We need to be careful with these anecdotal instances of things. It just highlights the fact that we need to study these compounds more and have a more well-controlled placebo, controlled trials for these different compounds.
Charlotte: Yes, because THC at least from my personal experience, can significantly lessen pain.
Professor DiPatrizio: Anecdotally, but there’s also more than anecdotally. There are experiments to show that it has some benefits for pain, certain types of pain. Neuropathic pain, for example, mostly. That has been shown and has been well characterized. CBD may as well. The mechanism isn’t quite fleshed out. That’s why I hesitate a bit more in promoting CBD for these sorts of ailments.
Charlotte: Any final words about the endocannabinoid system and cannabis before you go?
Professor DiPatrizio: I think the system holds great potential therapeutically. We need to have cannabis off of Schedule — We need to remove it from a Schedule I drug.
Charlotte: Thank you so much for your time. We really appreciate it.
Professor DiPatrizio: You got it, Charlotte. I really appreciate that you reached out. I really appreciate what you’re doing here, too, and talking with scientists. We need more of this and I can’t thank you enough.
Charlotte: Take care. Have a great rest of your day.
Nicholas DiPatrizio, Ph.D., is an associate professor of Biomedical Sciences at the University of California, Riverside School of Medicine.
