All about cannabis pharmacology

Pain expert Samer Narouze, MD, PhD, talks about the pharmacology of cannabis, including the chemical structures, mechanism of action in the body and pharmacodynamics of cannabinoids. This episode also addresses clinical information related to potential drug-drug interactions and adverse events from use of these products.

Speakers

• Samer Narouze, MD, PhD, chairman, Center for Pain Medicine at Western Reserve Hospital
• Michael Suk, MD, JD, MPH, MBA, professor and chair, Musculoskeletal Institute and the Department of Orthopedic Surgery, Geisinger Health System; chair, AMA Board of Trustees
• Jesse Ehrenfeld, MD, immediate past president, American Medical Association

Listen to the episode on the go on Apple Podcasts, Spotify or anywhere podcasts are available.

Dr. Ehrenfeld: Welcome to Moving Medicine, a podcast by the American Medical Association. Today’s episode is part of the Cannabis Education series, brought to you by the AMA Cannabis Task Force. 

I'm Dr. Jesse Ehrenfeld, senior associate dean, tenured professor of anesthesiology and director of the Advancing a Healthier Wisconsin Endowment at the Medical College of Wisconsin. I'm also the immediate past president of the AMA and co-chair of the AMA Cannabis Task Force. Michael, take it away!

Dr. Suk: Thanks, Jesse. I'm Dr. Michael Suk, professor and chair of the Musculoskeletal Institute and the Department of Orthopedic Surgery at Geisinger Health System. I'm chair of the AMA Board of Trustees and your co-chair of the AMA Cannabis Task Force.

Through expert discussions and insights, this podcast series features information that can help physicians of all specialties understand cannabis and the health effects of cannabis use.

Dr. Ehrenfeld: The AMA forms mission-specific task forces like this one to tackle current medical issues in our nation. Make your voice heard by becoming a member today. Visit ama-assn.org/more. And now, on to the show. Michael.

Dr. Suk: Joining me today to talk about cannabis pharmacology is Samer Naruse, an anesthesiologist and pain medicine specialist who is a professor at the Northeast Ohio University College of Medicine. Samer, welcome to the show.

Dr. Narouze: Thank you, Dr. Suk, for having me.

Dr. Suk: Well, I'd like to start by discussing the chemicals within cannabis that have activity within the body. Could you talk to us a little bit about the chemical agents within cannabis that we should know about?

Dr. Narouze: Sure, the cannabis plant contains lots of cannabinoids, maybe more than 100 cannabinoids. The most studied of them, the most important to us clinically, are two main ones. The first one is the THC or the Delta-9 Tetrahydrocannabinol. This is the most recognized and the most studied chemical in the plant.

This is the one that has the main psychoactive effects from the plant. The other one, which is the CBD or the cannabidiol, this is less psychoactive and actually lacks the side effects or the psychoactive effects from THC. It's more prevalent in the hemp plant.

There are other chemicals in the plant, but relatively they are not well studied. We don't know much about them. And this is the issue when studying or reading clinical papers on the plant, that we really don't know much about the other 100 plus molecules in the plant. But as we said, the two most common ones that are relevant to us are the THC and the CBD.

Dr. Suk: Thanks, Dr. Narouze. Would you say that THC, CBD are clearly the most studied among the cannabinoids that are out there? Can you tell us a little bit about how those chemicals act in the body?

Dr. Narouze: Yeah. So those are the, what we talked about, the THC and the CBD, those are the phytocannabinoids. Phyto means from the plant. There are other cannabinoids, we call them endocannabinoids. They are naturally occurring in the body. And this leads us to talk about the endocannabinoid system. The endocannabinoid system is one of the most important and relevant neuromodulatory systems in the body that controls lots of CNS function cell signaling. It comprises of four things. First the endogenous cannabinoids, there are quite a few of them. Again, the two major ones are the 2-AG and the anandamide. They are the two main endocannabinoids. They are working on two enzymes, cannabinoid receptor type 1, cannabinoid receptor type 2, and then there are few enzymes that manufacture them and metabolize them.

And then there are proteins responsible for transferring those molecules through the cell membrane in and out of the cell. So, in general, the endocannabinoid system consists of the endogenous cannabinoids or endocannabinoids, the two cannabinoid receptors, the enzymes that manufacture and metabolize in and out of the cell. 

So, the two major receptors site of actions of cannabinoids in general are cannabinoid receptor 1 and cannabinoid receptor 2. Generally speaking, cannabinoid receptor 1 are centrally located which means they are abundant in the CNS spinal cord dorsal root ganglia.

That's why they are responsible for the behavior components of the pain modulation. On the other hand, the type 2 receptor, cannabinoid type 2 receptor, they are peripherally located, which means that they are more in the immune system. However, with stress, with injury, with acute inflammation, the body got the signal to manufacture more of them. So, they are upregulated, and they can be expressed in the CNS mainly in the microglia and astrocyte. That's why they might have a potential important role in the modulation of neuroinflammation.

The two known endocannabinoids are the 2AG and anandamide. The 2AG works more on the cannabinoid receptor, CB1 and CB2. However, the anandamide acts mainly on the CB1, so it has more central mechanism of action. What's unique about the anandamide that it also modulates an important receptor. We call it the TRPV1, which is well known as the capsaicin receptors, which are responsible for temperature. That's why those molecules also have an important role in temperature regulations.

Dr. Suk: That is useful information to understand when it comes to cannabis and its actions within the body. Could you tell us about the pharmacokinetics? This may help physicians understand the clinical implications these agents may have on their practices.

Dr. Narouze: The pharmacokinetics of cannabis or cannabinoid in general is very diverse because it depends mainly on the route of administration, how you take it. So, the most common routes of administration are inhalation or vaping, and there are oral, which we call them the edibles, and then there are the topical or transdermal ones.

So, inhalation is like the smoking or vaping. This leads to rapid increase in the plasma level of the cannabis or cannabinoids, THC. Actually, within few seconds of smoking, they will be detected in the plasma. And the THC are very lipophilic, which means very lipid solid. So, it crosses the blood-brain barrier quickly. So, within a minute or two, the patient will feel the effect of the inhaled cannabis. However, the duration of action is shorter. So, it reaches peak plasma concentration in a few minutes, but shorter duration of action. Bioavailability is very variable. It could be as low as 10% or as high as 30% or 40%. Why? Because it depends on how you smoke or how you vape. What's the pattern?

The number of inhalation, the depth of inhalation, the duration of inhalation, are you doing breath holding or not, all those will affect the bioavailability of the inhaled cannabis. On the other hand, the oral one is different. The oral one, it has slow onset of action. It takes time till the patient feels the effect or the user feels the effect. It might take up to two or three or four hours to reach the maximum plasma effect because of the slow absorption and the first pass metabolism. The duration of action can last longer but the onset of action can be two to three hours different than the few minutes from inhalation. 

Why we talk about this because this has very clinical relevance to us as practitioners. The patient, they start to ingest a little bit of the edible ones. They don't feel the effect that they used to get with inhalation because in two minutes they will feel it. So, they tend to take more, ingest more and more because they are waiting for the response. They feel that they are taking small dose. They are not aware that it's low action. It takes time to have a peak plasma. That's why they got in trouble.

The transdermal one, it's more common with CBD because CBD is less lipophilic, so it's not as lip soluble as THC. So, it can be used as a transdermal, still THC, but the bioavailability is very low because it cannot cross through the aqueous media of the skin. But it's another route of administration. Bioavailability is very, very variable and slow.

Dr. Suk: Dr. Narouze, wonder if you could talk a little bit more about distribution of cannabis once in the body, its metabolism, and ultimately, its elimination.

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Dr. Narouze: Sure. This is a very tough topic. But there are lots of basic signs, let's just show that describe the distribution. It varies if the patient is infrequent users versus frequent users, the volume of distribution is variable, the rate of administration different. But in general, those molecules, THC and CBD are very lipophilic, so they cross the blood-brain barrier quickly. They have very high peak plasma quickly after inhalation. And then they get distributed to the highly vascular organs vessel, then to the less vascularized organs. And then they get stored in the adipose tissue.

Later on, they could be released. They equilibrate again with the blood from the adipose tissue. That's why we call it three-phase distribution model. This is important that THC gets stored in the adipose tissue and then can be re-released later, especially in frequent users or heavy users. Why? Because it affects the detection of the metabolites in the urine sample or even the plasma. So, you can inhale or smoke the THC and you still show metabolites in your urine actually for up to weeks. So, this is important when we determine when the patient last used the substance.

The metabolism is very fascinating. Why? Because most of the cannabinoids, and we're going to talk mainly about the THC and the CBD, they are metabolized by the cytochrome P450, variable isoenzymes different from THC and CBD.

This is relevant clinically because it has potential drug-drug interactions. Medications are metabolized by different substrates or are different substrates to the Cytochrome B450.

So, any other substance or medicine that either inhibits or stimulates those cytochrome P450 enzymes, accordingly, they will affect the concentration of THC or CBD.

They metabolize too, some of them are active metabolites. So mainly they are metabolized in the liver. THC metabolized mainly to 11-hydroxy-THC, which has still psychoactive effects. It's an active metabolite and actually long-acting. And this is why, again, the metabolites will be detected in the urine for maybe even few weeks after its use. Same with CBD, it metabolizes mainly to other, less active substances with longer duration of action.

Dr. Suk: Thanks Dr. Narouze. You know, now that we understand the pharmacokinetics and dynamics of the chemical structures, can you bring this home clinically for us and share with us some clinical considerations of all the information you've given us so far?

Dr. Narouze: Interactions with the cannabinoid to the receptor, it dictates the signaling, intracellular signaling, which eventually will lead to decrease in the release of the excitatory neurotransmitters.

The type 2 receptors are mainly peripherally and they're responsible for the anti-inflammatory effect of the THC and mainly CBD. It affects the body in variable mechanisms. So mainly on the cardiovascular system.

Usually in small infrequent doses, you are stimulating the sympathetic. So, it increases the sympathetic drive. And this will lead to tachycardia, some tachyarrhythmias, and actually maybe vasospasm or vasoconstriction of the blood vessels and even the coronaries, even without high risk factors for coronary disease.

On the GI system it can lead to anhedonia and vomiting effect in small doses. This leads us to know that the effect, physiological effect varies depending on the organ, the expression of the receptors are more type 1 or type 2 receptors and the dose of the THC, and actually we have a synthetic THC that's FDA approved for the treatment of severe nausea and vomiting associated with chemotherapy. However, on high doses, it leads to actual nausea and vomiting.

Respiratory effects, it's no-brainer that if you are using the molecule by smoking or vaping, you will cause irritation, bronchus, PAS, chronic users, they are a risk for COPD.

There is also cannabis withdrawal symptoms, and we see this mainly in the heavy users, long-term users, more than 20 days a month. They can get into cannabis withdrawal symptoms, which mainly present as lack of sleep, and anxiety, pain, which is the paradoxical effect, pain, tachycardia, tremors, but usually it’s not really serious than the other with the symptoms that we see with other substances.

There is an important point that we need to make also because THC is highly lipophilic, it readily cross the placenta and also it's excreted in the breast milk.

So, it's our obligation to counsel the pregnant patients on the use of cannabis or cannabis product because of the potential effect on the embryo and the newborn.

Dr. Suk: That's great, Dr. Narouze. In closing, I think I wanted to summarize just a couple of points. One is that cannabis, as you've described, is two main active agents, THC and CBD, that both work through the endocannabinoid system. The pharmacokinetics and the pharmacodynamics of cannabis is not well understood and has the potential for many variations based on patient-specific factors. And finally, there may be clinical scenarios where patients may be more at risk for adverse events based on the pharmacodynamics of cannabis. I think with those summary points I wanted to thank you for joining us on this educational series and for sharing your knowledge of the cannabis pharmacokinetics.

Dr. Narouze: Thank you, Dr. Suk and the AMA for having me. Thanks for the opportunity.

Dr. Ehrenfeld: Don’t miss the next episode in this series—be sure to subscribe to Moving Medicine on your favorite podcast platform. This content is for educational and informational purposes only and does not constitute medical or legal advice. The viewpoints expressed in this podcast are those of the participants and do not reflect the views and policies of the AMA, unless otherwise indicated. 

Dr. Suk: And this has been Moving Medicine. Thanks for listening.

Disclaimer: The viewpoints expressed in this podcast are those of the participants and/or do not necessarily reflect the views and policies of the AMA.