Gut Check: Jami Kinnucan, MD, on Cannabis Use Among GI Patients

Dr Brian Lacy hosts Dr Jami Kinnucan to discuss the pros and cons of using cannabis to treat some symptoms of gastrointestinal diseases and how clinicians can talk about the subject with their patients.

Brian Lacy, MD, is a Professor of Medicine at at the Mayo Clinic in Jacksonville, Florida. Jami Kinnucan, MD, is an Associate Professor of Medicine in the Division of Gastroenterology and Hepatology at the Mayo Clinic in Jacksonville, Florida.

CLINICAL PRACTICE SUMMARY:

Cannabinoids (THC/CBD) and Gastrointestinal Effects: Clinical Takeaways for Practice

• Cannabinoids (THC, CBD) act on CB1/CB2 receptors highly expressed in the GI tract and can variably affect symptoms. THC (delta-9-tetrahydrocannabinol) preferentially binds CB1 receptors in the brain, CNS, and enteric nervous system and is associated with centrally mediated antiemetic effects, reduced motility, reduced intestinal secretions, pain modulation, and psychoactive effects. CBD (cannabidiol) preferentially binds CB2 receptors on peripheral immune cells and shows anti-inflammatory effects primarily in animal models. Patients may report improvements in nausea, vomiting, diarrhea, abdominal pain, and quality of life, but effects are inconsistent and can worsen symptoms such as heartburn, constipation, or delayed gastric emptying.

• In inflammatory bowel disease (Crohn’s disease, ulcerative colitis), clinical trials show symptom relief without improvement in inflammatory outcomes. Across small randomized controlled trials (total n <150) using THC, CBD, or combinations, patients reported reduced abdominal pain, diarrhea, nausea/vomiting, and improved quality of life. However, studies consistently failed to demonstrate clinical remission, improvement in CRP or fecal calprotectin, correction of anemia, or endoscopic remission, indicating no reduction in inflammatory burden. Cannabis is not FDA-approvable as primary IBD therapy and may lead some patients to discontinue effective conventional treatments.

• Adverse effects, drug interactions, and cannabinoid hyperemesis syndrome (CHS) require routine screening and counseling. Cannabis can cause delayed GI motility, constipation, nausea/vomiting, anxiety, psychosis, sedation, dizziness, cardiopulmonary risks with inhalation, fertility effects, and CYP-mediated drug interactions. CHS presents with severe episodic vomiting in daily, prolonged users and resolves only after sustained abstinence (≥30 days), often with symptomatic relief from hot showers. Clinicians should routinely and nonjudgmentally assess cannabis use, formulation, dose, frequency, and treatment goals in all GI care settings.

TRANSCRIPT:

Welcome to Gut Check, a podcast from the Gastroenterology Learning Network. My name is Brian Lacy. I'm a professor of medicine at the Mayo Clinic in Jacksonville, Florida, and I am absolutely delighted to be speaking today with Dr. Jamie Kinnucan, Associate Professor of Medicine at the Mayo Clinic in Jacksonville, Florida. Many of our listeners will recognize Dr. Kinnucan's name. She's a nationally recognized expert in inflammatory bowel disease. However, one of her other areas of expertise is that of cannabinoids and their effects on the gastrointestinal tract. At present 40 states, the District of Columbia, and three territories have legalized medical marijuana. So this is an important topic for patients and providers. Dr. Kinnucan, welcome. What a delight to have you here. Let's set this stage for what is a fascinating and sometimes controversial topic. First, what are cannabinoids and what is the relationship of cannabinoids with cannabis or marijuana?

Dr Kinnucan:

Thank you, Dr. Lacy, for having me today. And I agree that this is a very important topic that our patients are thinking about or even using, whether they use it medically or recreationally. But what we know is that these cannabinoids can have an impact on the gastrointestinal tract, so feels perfect for gut check. Cannabinoids refers to a class of chemical compounds that interact with the cannabinoid, or in some spaces we may say endocannabinoid receptors that are found throughout the body. There are three main types of cannabinoids when we're talking about cannabinoids. There's endocannabinoids. These are naturally produced within the body and act at these same receptors. And there are things that we can do to actually increase our endocannabinoid production. Phytocannabinoids, which is I think what you're mainly wanting to talk about today, is really what's derived from the cannabis plant. And then synthetic cannabinoids, which are chemically made in a lab. And there are some FDA-approved synthetic cannabinoids that are available in the US.

Dr Lacy:

Wow. What a great way to really set the stage. And I'm sure that many listeners and many healthcare providers don't even realize we make endocannabinoids, these naturally occurring substances in the body. So all cannabis is not created equal. The two main phytocannabinoids, the plant-derived cannabinoids, are THC and cannabidiol. Can you help us better understand the differences in these two chemicals and why that is so important to understand?

Dr Kinnucan:

Absolutely. You took the shortcut, sir, and said THC and cannabidiol. So cannabis is made up of actually hundreds of phytocannabinoids, but the ones that we recognize in the lay public or even what's been most studied in the medical world are two of these main phytocannabinoids, which are delta-9, tetrahydrocannabidiol, which I understand why you didn't try to say that fast, or what we refer to as THC, and then cannabidiol, which is referred to as CBD. Now, these two compounds can have very distinct, different effects in the body when we use them separately, and often that's been studied more on the medical side, but when used together can actually have a synergistic effect in terms of how they interact with the endocannabinoid system. THC itself has a higher binding affinity for the cannabinoid receptor, CB1, which is mainly located in the brain, the central nervous system, and the enteric nervous system, which is obviously important as we talk about some of the impacts that it can have in terms of patient symptoms.

But this is where we might see more benefit in terms of pain reduction or pain control, centrally mediated antiemetic or antinausea effects, maybe even reduce motility in the bowel, reduce secretions of the intestine, and where we can see some of these psychoactive effects that patients maybe use for recreational reasons. CBD, on the other hand, has a higher binding affinity for cannabinoid receptor 2 or CB2, and we see predominance of CB2 receptors in peripheral immune cells. And this is maybe why we might see benefit from an anti-inflammatory standpoint, especially in the animal models.

Dr Lacy:

All right, this is great. So that's really important to understand this distinction that really all these things are not equal, and this will be important when we talk about treatments later and how people use this. So as you've already mentioned, THC is the primary psychoactive component of cannabis. It is euphorogenic. The THC is really what gets people high, if you want to still use that term. And when someone uses medical cannabis or if they use an edible form or if they vape it or if they smoke it, how can they tell how much THC is in the product that they're using? Are there labels now to let consumers know the ratio of THC to cannabidiol or CBD?

Dr Kinnucan:

Yeah. As you mentioned, there are many formulations that individuals can get from a dispensary, whether that's a medical or recreational dispensary, depending on which state you live in. And there's various routes of administrations, and that can change the user's experience depending on how much THC or CBD is present within that product. If a patient is going to a dispensary, whether medical or recreational, they should be told, because many of the states have regulations at a state level. Now, certainly we know that federally this is not a legal substance, but they should know the strain they're using, whether it's cannabis sativa or cannabis indica as two of the common strains, as well as they should be given information about the concentration, either in a percent form or in a milligram form and the ratio of THC to CBD. But the challenge is that cannabis is not all created equal.

So there's lots of formulations, lots of dosings, and there's various state-to-state regulations in what's reported and how much maximum percent can be given. So there's a lot of variation. So if patients are living in a state where it's recreationally legal and they have curiosity, they could go visit a dispensary and see what is available and what sort of product labeling is in that state.

Dr Lacy:

Wonderful. So cannabidiol is one of the ingredients, because you've already nicely mentioned that there's a lot of ingredients in all these cannabis products, and this is maybe one that might improve GI symptoms. You've already let us know the background there about binding, but can you hone in a little bit? How does this really work in the body? And are there cannabidiol receptors everywhere in the GI tract?

Dr Kinnucan:

Yeah. Outside of the pineal gland in the brain, the GI tract is actually the highest concentration of endocannabinoid receptors in the body. So you can imagine that there'll be some impacts of using cannabinoids in gut and gut symptoms. We see both CB1, remembering that partner for THC, as well as CB2, that partner for CBD in the GI tract. And so that's why we see potentially improvement and sometimes worsening of GI symptoms. So thinking through that a little bit more detail, a variety of use can impact symptoms in terms of reducing heartburn. Maybe it's because cannabinoids actually reduce transient lower esophageal sphincter relaxation, but we can also see some patients have the opposite effect and they actually have an increase in heartburn symptoms, and maybe that's because of delayed gastric transit. We do know that patients report having improvement in nausea and vomiting symptoms. Well, we know it delays gastric transit, so is it that the reason?

Because that would seem opposite. Or is this centrally mediated? So are we getting more binding of that CB1, which is in sort of the enteric and the central nervous system, and that's improving patient's nausea and vomiting symptoms. And maybe we'll talk a little bit later, but then there's the worsening of nausea and vomiting in the form of cannabis hyperemesis syndrome, and that's probably not helped by the fact that we do see delayed gastric emptying with cannabis use. Patients report improvement in diarrhea. I told you previously that we can see reduced motility, and that might be contributing to improvement in that symptom. We also see improvement in abdominal pain. Maybe is this due to increased compliance to distension of the lumen? And so they have less activation of that enteric nervous system. This is obviously up your alley with DGBI. We do see an increased risk for pancreatitis, and it is actually listed as a causative agent for pancreatitis, but then some studies have suggested that it might improve pain in patients with chronic pancreatitis.

In my field, in particular in inflammatory bowel disease, we have seen patients report improvement in abdominal pain, diarrhea, improved quality of life, and then thinking about the impact of cannabinoids on the liver is an entire podcast in and of itself.

Dr Lacy:

Wow. What I would say is there's a lot going on, and it can be there some positive effects, some negative effects, and let's talk about that a little bit more. And I'm going to suspect, and we'll talk about this a little bit more later, that maybe it's not even predictable in terms of how people respond. And before we get into some more of those potential benefits of cannabis, what are potential side effects? What should patients and providers be looking for if they're asked to use a cannabis product or they're experimenting on their own?

Dr Kinnucan:

Yeah, and I think you're going to be a little bit surprised by my answer upfront because some of it is just around the concept of use of a substance that doesn't have a federally legal status. So I think one of the biggest concerns that I have as a healthcare provider is that patients are not likely to disclose that they're using cannabinoids, at least on their own. And sometimes even when they're asked, and I ask every patient that comes to my practice, both new and return patients about use of complementary and alternative medicine—the newer term that I like to use is integrative medicine—just so that I understand, because many of these things can interact with different drugs and they can interact and cause different symptoms. So I think that's one of the things that I'm concerned is that their patients are potentially using cannabinoids to mask different symptoms that they're having.

What we found in an IBD study looking kind of retrospectively is that patients who have IBD and are on conventional medical therapy, but also use cannabis were over time more likely to discontinue their conventional medical therapy, which of course can have very serious implications in an IBD population where we don't have any evidence that cannabis can treat inflammatory bowel disease, and I hope we can chat a little bit more on that later. Cannabis is metabolized through an important sip system within our liver, and that's also metabolizing other medications that we're putting in our bodies. And so there are possibilities for drug interactions, either making certain drugs toxic or reducing the efficacy of other drugs that we would really not want to reduce efficacy like antiepileptics. But when I think about side effects, the way that we think about side effects of medications, obviously cannabis has implications for delayed motility.

And so we talked a little bit about maybe this is what's causing a patient's nausea and vomiting as opposed to helping it. Patients may come in and be more constipated because of delayed colonic transit. Patients see improvement in abdominal pain, and so they might be using cannabis on a daily basis because they actually wake up with abdominal pain, but it's masking some underlying pathology. For example, maybe there's a stricture with Crohn's disease, and we're not exploring that because a patient isn't feeling poorly because they've found a way to manage every day, but we haven't actually explored what's happening with their IBD. And of course, there's clinical adverse effects. Patients can experience worsening anxiety or even psychosis. There've been some studies in the cardiology literature showing a possible increased risk for arrhythmia, likely in a more at-risk population. There can be fertility impacts in both men and women.

There can be pulmonary impacts, especially if patients are using an inhalation form of the substance. Patients can actually use it for sleep-related disturbances, but over time become dependent or actually get a rebound effect. And so they can have worsening sleep quality, which we know can have significant impacts downstream and just in terms of our quality of life as well as our overall general health. There are sedation effects, dizziness, headache, interaction with other substances like alcohol. And then there's some studies that have shown that it might be, quote, that gateway drug. People are using cannabinoids, and then that's opening the doors for potentially use of other controlled substances.

Dr Lacy:

So many wonderful teaching points buried in there. I'd like to just highlight 2, although we could spend 30 minutes just highlighting what you said. One is that I too, you and I have not discussed this, but I too now routinely ask every patient about cannabis use. And I make it very nonjudgmental. I just say, look, I want to let you know I ask everyone the exact same questions. Tell me about alcohol use, tell me about tobacco use, tell me about cannabis use, very nonjudgmental because you're right, people won't offer that. And to me, what you just told me is a little bit worrisome that in some of your IBD patients, they're stopping maybe medicines that are very effective like biologics, and that makes me very nervous. So we all as providers need be aware of that.

So, Dr. Kinnucan, as I mentioned, one of your specialty areas, as many people know, is that of inflammatory bowel disease and Crohn's disease and ulcerative colitis. And you've already mentioned a little bit some of the impacts in IBD patients. What about data to support the use of these products? So you've mentioned maybe some worrisome things. What about data to support its use?

Dr Kinnucan:

Yeah, it's a great question. And after diet in my practice usually the second question that patients are inquiring about maybe because if you Google my name and now you'll Google GutCheck podcast and you'll see cannabis. And so they believe that I'm procannabis and I'm not necessarily anticannabis, but I am proscience and I want to understand the science that would lead to either recommendations for use or without use. Again, we have legalization status issues in the US because it's federally illegal, although states have their own legalization. High quality data in this space still remains very limited. Now with a federal scheduled class change that we anticipate coming up, we might be able to have more robust prospective studies, but as you know, that takes years to be able to get high quality data. So in the few randomized controlled studies that have been done in patients with ulcerative colitis or Crohn's disease, which when we look at it as less than 150 patients.

So we're basing data and recommendations on a very, very small sample size. But in these studies that had varying types of cannabinoids, some used THC only, some used CBD, some used a combination of both. Patients did report overall improvement in symptoms. They had reduced abdominal pain, reduced diarrhea, reduced nausea and vomiting, some reported improvement in joint symptoms, improved appetite, improved quality of life scores. And we talked a little bit about why that happens because of the endocannabinoid receptor locations and how these different cannabinoids act there. But the thing that continues to come up in all of these studies is they fail to show that we achieve clinical remission in these patients. So despite feeling better, these patients do not meet a primary endpoint in many clinical trials for FDA-approved therapies of clinical remission, absence of symptoms. In addition, so in not meeting that endpoint, they don't have an improvement in their C-reactive protein, a very important marker for inflammation in addition to fecal calprotectin, and their anemia doesn't get better.

So that all points towards inflammation is not improving, but symptoms are improving. And that's good. We want patients to feel better, but the inflammatory burden is not improving. And some studies that have done endoscopic evaluation did not show that there was endoscopic remission. So the substance would not pass the FDA for approval to use as a primary therapy in patients with inflammatory bowel disease because of that lack of improvement of inflammatory burden. But I will say that cannabis in the current studied form might not be the compound that we should be after to look at those positive anti-inflammatory benefits. We see benefits in animal models. Well, why? Because we're targeting those receptors. CB2 in particular, when we target CB2 as a binding, so pretty high offending to bind this receptor, we do see reduction in inflammatory burden in these animal models. So I do think that there's more dialogue and there's more research and data to come in this space, but in its current form, I don't think cannabis is going to be our Hail Mary in patients with inflammatory bowel disease.

Dr Lacy:

Jamie, great explanation. And I think this is really how science evolves. So when we start with a big topic and maybe substances that aren't very pure, as we learn more and more about it, now we're starting to refine things, although that makes it complicated for both providers and patients when they look at the literature because we're talking about different substances being used in different doses and different frequency. And so your point is such a good one that is maybe as we hone in and refine the science here, we'll get better data. Now, I want to come back to something we discussed a little bit earlier about the potential for treating liver disease. And I know you already mentioned we could probably spend at least half an hour talking about that, but I can't let you off the hook that easily because I know there's a little bit of animal data showing that cannabidiol might slow some inflammation in the liver.

And if you could just give us your view on, are you aware of any human data and might this be useful in liver disease, knowing you're not a hepatologist?

Dr Kinnucan:

Yeah, so I'm glad you disclosed that because I am definitely not a hepatologist. But the challenge is that cannabis has a very complex dose-dependent interaction with the liver that can vary based on cannabinoid type, which we talked about, the dose, the pattern of use, and whether or not that particular individual already has underlying liver disease. So you can imagine it's a very hard thing to study. So for example, in patients with hepatitis C, we did see that daily use was associated with accelerated liver fibrosis. Well, that's not something that we want for our hepatitis C patients if they aren't having fibrosis right now to even have progressive liver disease. So certainly there's some caution in use in that population. On the other hand, there was some data that showed reduced presence of NAFLD in cannabis users in a larger population-based study. So take that with a grain of salt, and I can't even explain the mechanism as to why that would happen. Could be a little bit of bias again in population-based studies. CBD has been shown to actually be associated with elevated liver enzymes.

Now, most people that are using this medicinally or recreationally are not routinely getting follow-up labs. So this was obviously looking at a particular compound and following up patients' lab patterns, but chronic liver disease is associated with an upregulation of endocannabinoid receptors. And so the AASLD has advised that those patients with chronic liver disease like cirrhosis to use cannabinoids with caution and for avoidance in those with severe liver disease, mainly around the THC containing products because of the studies that have shown a risk for fibrosis progression. So again, I think that it's very complicated this interaction with the liver, and it really is dependent on what type of patient that is to start, but I think it's more to come in terms of if there is any benefit in a particular liver population.

Dr Lacy:

No, that's really, really important information because unfortunately so many people in the United States have liver disease and maybe stopping alcohol and switching to cannabis is not a great idea. So more to come in that field.

Let's go back to some of our patients who use cannabis to treat symptoms of nausea and vomiting. And I'm thinking about a patient I saw in follow-up just this morning referred for cyclic vomiting syndrome, but we teased it out and she was using a lot of cannabis, and now 6 months later after stopping it, her symptoms have essentially resolved. So in your opinion, thinking about patients with nausea and vomiting for any reason, is cannabis a good strategy? Could this backfire? Educate us a little bit about CHS or cannabinoid hyperemesis.

Dr Kinnucan:

Yeah, I think it's important for our patient-based listeners today to just ensure that they've had a workup done for symptoms, especially newer symptoms of nausea or vomiting that have persisted. I think that the fact that there has been improvement shown in nausea and vomiting, mainly the data that I've seen clinically has been in patients with known underlying gastroparesis and likely related to central mediated improvement in that antinausea effect, because we do also see that same population with delayed gastric emptying. So you'd assume that their symptoms may actually get worse. But I think that what you're bringing up is cannabis hyperemesis syndrome. So we know that younger patients with daily use, and this is kind of the population we're seeing now as this younger population gets away from using alcohol and using other substances, those are the type of patients that present with cannabis hyperemesis syndrome.

And you're right, it takes that really careful history to be able to tease out that that patient is using cannabis on a regular basis, maybe because they've been reluctant to share based on concerns of bias or potentially judgment. But cannabis hyperemesis syndrome is characterized by severe episodic vomiting, I know you know this, that resembles cyclical vomiting syndrome. In a patient with prolonged, and I don't love, and I know you're part of the Rome group, excessive use, because that passes judgment, the word excessive, but somebody who's using daily prolonged cannabis, but then they have sustained relief of their symptoms when they've been without cannabis for at least 30 days, because now you have patients who come in and say, "It's not the cannabis. I stopped it for a couple days and I didn't feel better." They really need sustained. And some of the studies suggest even longer than 30 days.

Some of the criteria that may be supportive is that these patients are taking a hot bath or a shower to relieve their symptoms. And so I'm often asked by patients that why do I feel better when I get into a hot bath or shower? I know it when I'm not feeling good, I actually too also like a hot bath or shower, but the hypothesis is that you have these TRPV1 receptors that are located in the medulla and in the skin, and that chronic use of cannabis desensitizes these receptors and then leads to overall reduced antiemetic effects that we see that are again, centrally mediated of cannabis. Hot water in turn increases these receptors function within your skin and then improves the antiemetic effect. So you get improvement in those active symptoms during a hot bath or shower.

Dr Lacy:

Yeah, it's really interesting how science has evolved. Now we understand why what was first reported is just, oh, my boyfriend, girlfriend, spouse, wife, spends 30 minutes a day in a hot shower and my hot water bill is crazy. Now we understand there's actually real science to support that reported symptom. So thinking about patients who do use cannabis to treat GI symptoms in one form of therapy or another, do we have data showing that maybe one form is better than another? Is it better to use oil or edible or, I hate to even mention it, but smoking or inhaling?

Dr Kinnucan:

So there, again, a lot of limited stuff. Most of the studies or many things that are reported are more retrospective and observational, but inhalation form of cannabis has a faster onset of action, but it has a reduced duration of effect. So think about the IV medication that we're taking that we want the effect immediately, but then it's not going to last very long. As opposed to the edible form has a slower onset of action, but a more prolonged effect. So it's not going to give you that immediate relief of whatever symptom you might be using it to treat. So I think it really depends on the symptoms that the patient is having and why they're wanting to introduce cannabinoids into their medical practice or medical treatment strategy. Of course, I think that the edible form is quote safer because there's obviously concerns about risks of inhalation and the pulmonary effects there, but really there's no high quality data to suggest which one is better.

And there's even topical forms. People can use lotions. I have some patients who use enema—they do not recommend putting cannabis in an enema—but there are different formulations that have been experimented with either in medicinal or recreational forms.

Dr Lacy:

Jamie, this has been a wonderful conversation. I know I've learned a lot. I know our listeners have learned an awful lot. Any last thoughts for our listeners?

Dr Kinnucan:

Sure. I could talk about this all day. So I think really separating it out for the patient listeners, I want to emphasize how important it is to start this conversation with your healthcare team if you're using cannabis for medicinal reasons, or even if you're using cannabis for recreational reasons, because some of these cannabinoids can have impacts in terms of your health and symptoms that you might be experiencing. We want to make sure that we're taking this adequate history. If you're having issues with constipation and you've recently introduced cannabinoids into your daily practice, that might be a contributing symptom, and I wouldn't know unless I asked about it. I certainly don't want you to have drug-to-drug interactions. There are several common interactions of cannabinoids with things that you might be using on a regular basis. And so we also want to make sure that cannabis is not making your symptoms or inflammation worse. So I think that's for our patient listeners.

I know that you have a really robust provider listening group too, and I think you said it even yourself. The most important thing that we can do is to start the conversation, inquire about routine use of integrative therapies, including cannabis, make a safe, nonjudgmental space. I think the questions that you use are exactly in line with how I ask. And then when they say yes, be inquisitive about what type they're using, what formulation, how often are they using it? What symptoms are they trying to treat with using whatever that integrative medicine approach is, including cannabis, and ask about side effects, just the same way you would ask about side effects of any new medication in their medical history. So I think those are the two kind of takeaways, is talk about it and start the conversation and create that safe space.

Dr Lacy:

I like that. And like you said earlier, being just nonjudgmental, just this is the way it is. And let's just gather information so we can approach things scientifically to improve your health. So Dr. Kinnucan, and once again, thank you so much for this amazing discussion today to our listeners on Apple, Spotify, and other streaming networks. I'm Brian Lacy, a professor of medicine at the Mayo Clinic in Jacksonville, Florida. You have been listening to GutCheck, a podcast from the Gastroenterology Learning Network. Our guest today was Dr. Jamie Kinnucan, Associate Professor of Medicine at the Mayo Clinic in Jacksonville, Florida. I hope you found this just as enjoyable as I did, and I look forward to having you join us for Future Gut Check podcasts. Stay well.