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Sunanda Kane, MD, MSPH: Hello. I'm Dr Sunanda Kane. Welcome to Medscape's InDiscussion series on ulcerative colitis (UC). Today we'll be discussing alternative therapies in UC with our guest, Dr David Hass. Dr Hass is the medical director for the PACT Gastroenterology Center and Director of Endoscopy at the Yale New Haven Hospital, Saint Raphael Campus. Welcome to InDiscussion. David, thanks for joining me this afternoon. My question is, first, how did you get interested in this topic in the first place?
David J. Hass, MD: Thanks so much for having me. It is always a privilege to see you. Thanks for inviting me. I would say my interest in this topic about 18 years ago, when I was at the University of Pennsylvania. When I was there, I saw many veterans in my clinic who used all kinds of supplements, and I could not in any way, shape, or form counsel them on the safety of those supplements. A gentleman who was there and is still there, James Lewis, who you might know, and I started working on a project. Through the institutional review board (IRB), we wrote to every supplement company that promoted digestive health and asked for literature supporting efficacy and supporting the data for the health claim that they made. We asked them to provide safety data and we asked them to provide us medication interaction data. We learned over the course of that year that there really isn't a whole lot of data. That spawned my interest in supplement therapy and regulation. Fast-forward a few years later, I was now practicing in Connecticut and had a very, very interesting population of young college students and graduate students, many of whom had been treated for a variety of different conditions and had been to several gastroenterologists. These students had had every scope, scan, and medication trial and were coming to me for functional abdominal pain or something of that nature. I started looking into and reading to find out what was evidence-based from a complementary and alternative perspective so that I could be helpful. I was lucky enough to find someone locally who was a certified hypnotherapist. At that time, hypnotherapy wasn't really so mainstream; we're talking about maybe almost 15 years ago. I did the coursework, which was over 100 hours of coursework, to become a certified hypnotherapist so that I could implement that in my arsenal of treating functional bowel patients. From that, I was afforded wonderful opportunities to learn more and self-educate about a variety of different technologies and strategies for complementary and alternative medicine (CAM). The most important thing I learned through this journey was that it enabled me to form the best relationships with patients. Historically, we as physicians don't know a lot about CAM, so we tend to dismiss it, which interferes with the rapport between patients and physicians. When they knew I was open to the concepts of this, they were much more willing to tell me stuff that they may not have told me before.
Kane: You bring up some really great points, which is that you started in the veteran population, and then suddenly it's a different cohort, which are these younger folks who have inflammatory or noninflammatory functional chronic conditions. Let's focus on UC for just a little bit here. What therapies do you think are legit, ie, have the most robust evidence base? That might be a loaded question, but where are we at? Because as you point out, a lot of us in the allopathic medical field say there are not any data, but there are data. Is it robust? Is it solid?
Hass: Let me make the caveat that the raw data are there, but it's not nearly as robust as the data we have for traditionally prescribed therapies and for all the copious trials that we run for biologic therapies and things of that nature. However, there are data, and there are randomized data. I think if you were to look at UC, the first thing that comes to mind that has been studied, that we've known for years is somewhat helpful, is certain probiotics and specifically in the pouchitis world the data regarding VSL#3. It decreases the incidence of pouchitis in some patients who have had pouch formation. In those with chronic pouchitis, it decreased the risk for flares. We know it's effective when looking at those data. We know that there's good physiology there in the sense that that specific probiotic has been touted to decrease, with an immunomodulatory effect, certain cytokines and help increase the level of butyric acid, which is healthy for colonocytes.
That's probably the most well-known complementary therapy because it's a probiotic or a supplement per se that people know about when we talk about UC. I'm much more interested nowadays in some other supplements. If you look at the data for inflammatory bowel disease (IBD) in general, about 30%-40% of patients are self-reporting implementing some sort of CAM therapy that doesn't necessarily have to be supplements. It could be mind-body therapies like hypnotherapy, cognitive-behavioral therapy, or it could be something like acupuncture. At least 30%-40% of your patients with IBD, both Crohn's and UC, are self-reporting implementing CAM therapies. The most common CAM therapies that people are implementing are probably supplements. When we talk about a very common supplement, above and beyond the probiotic I just mentioned, the first one that comes to mind is turmeric. Turmeric has been fairly well studied. When we talk about turmeric, there's good reason for it because it has been touted to decrease tumor necrosis factor (TNF) levels. It actually inhibits nuclear factor (NF)–kappa beta activation and it inhibits the synthesis of proinflammatory prostaglandins. There's good physiologic sense that this could be helpful.
Anecdotally, many populations around the world use turmeric on a regular basis for simple things. For example, say you have a cut. There are people that I know who grew up in India who have a jar of turmeric on their counter, and instead of putting on Neosporin, they stick their hand in the jar of turmeric. That's something that's healthy. But in terms of the data, there are some strong data for UC, specifically. Several years ago in Clinical Gastroenterology and Hepatology there was a trial that studied whether or not turmeric in conjunction with the mesalamine-based agents was helpful. It was noted that turmeric actually helped by creating remission patterns in patients, coexisting with mesalamine agents to a significant degree. This was compared with placebo or just to mesalamine itself. Subsequent to that, maybe in 2019, there's been a whole host of randomized trials looking at odds ratios for UC, mostly presented in abstract form, looking at clinical relapse, endoscopic response, and clinical response with odds ratios of about three for those that use turmeric in conjunction with mesalamine-based agents.
Kane: It's certainly exciting because we all understand that turmeric is available in all sorts of forms. If a patient comes to you and says, "I want to do turmeric," how do you counsel them? The trials use a different formulation that isn't available with a GNC or your vitamin shop. Taking a handful from the jar to put it on a cut on your hand is completely different than trying to ingest it to get down to an inflamed colon. I'm going to put you on the spot and say the devil's in the details. Right? How do you take it from the bench to the bedside, if you will, for the turmeric story? It's really intriguing and very compelling.
Hass: One of the most important things to note, especially for supplement therapies, is that they're not regulated by the FDA. So the onus is on healthcare providers, physicians, nurses, dentists, or whomever to report anything that's concerning and to that effect, you really want to understand what patients are taking. So turmeric, for example, has an antiplatelet effect. In someone who is taking medications for other issues, whether it be for hypercoagulability or cardiovascular disease, you certainly want to counsel those patients appropriately that turmeric might have a slightly increased risk for bleeding diathesis if they're going to take it. That all being said, you really do need to look, as their healthcare provider, at any sort of potential adverse effect. Practically speaking, what I tell people is at least 3 g of turmeric is what's been studied. Now, the best formulation that I have found is something called Theracurmin, and it's the most potent because curcumin is the active ingredient, quite frankly, in turmeric, and it's what has been studied in many of the trials. But to your point, it's not readily available, and so what I typically tell people is at least 3 g tends to be the dosage that I typically recommend. I do tell them to get it wherever they can find it. Most of the time they're going to things like GNC or the Vitamin Shoppe — or maybe if there's an Asian health food store or sometimes there are other supermarkets. Asian supermarkets are helpful; they do have turmeric capsules. There have also been some data on turmeric enemas.
Kane: I didn't know about those. Okay.
Hass: The experience with that is not so robust. It is problematic because it stains everyone's clothing. For patients with ulcerative proctitis or with distal UC, there are some very limited studies looking at turmeric enemas and turmeric suppositories. They are not very well published and mostly not published in the English language, so it's hard to interpret. Again, very limited because it stains things and patients don't really tolerate it very well.
Kane: I think that that's an important point, too, that more is not better? Three grams is the recommended dosage, and so 6 g is probably not going to be better and is certainly going to raise your risk for bleeding. Would you agree with that?
Hass: I would agree. And I think that, again, the literature really does support that 3-g dosage, and that is typically what I recommend.
Kane: Perfect. I love that you're branching out and talking about not just the supplements, which are probably the most talked about part of this, but the complementary type of medicine like massage therapy, exercise, reiki, tai chi, acupuncture, acupressure, and those sorts of things. I think that could be another whole discussion. I do want to stick to the supplement or alternative therapies because I think we need to have a discussion about fecal microbiota transplant (FMT) for UC.
Hass: FMT! Absolutely.
Kane: FMT! Where are we with that?
Hass: We're somewhere, actually, and more data are coming out now there's more data that's coming out now. Everyone who might be listening to this podcast is aware, especially if they're in our field, that at some point in the past couple of years, the FDA determined that stool was actually a drug. It put a little bit of a damper on our abilities to regularly and robustly perform FMT. But in terms of FMT, we're all familiar with recurrence of C diff, and that's really where it's made its name. But there's now increasing data looking at FMT for IBD. Why would that be helpful? Just this year there was an article that was published in Evidence-Based Complementary and Alternative Medicine by Jia and colleagues. It was a meta-analysis looking at about 14 trials, and they calculated risk ratios for FMT and then looked at the clinical response rates and the clinical remission rates in patients who underwent FMT for UC or Crohn's disease. The bulk of these patients in this meta-analysis… There was about 485 patients with UC; there were only 17 or so with Crohn's. So I think we can make this applicable given the podcast to UC. But what was found was that the risk ratios favored FMT of about 1.4 for clinical remission and 1.34 for clinical response. And when we look at clinical response rate and clinical remission rates, it was somewhere in the neighborhood of 30%-40% for FMT for UC. There was really no significant heterogeneity among these studies. As I mentioned, this study in particular, given that it's a meta-analysis, helped to sort of compile all of the trials that have been put forth so far with UC for FMT.
Obviously, the microbiome is what we're talking about here; populating the microbiome with healthy bacteria that can decrease inflammatory cytokines in the physiology that exists to perpetuate inflammation and UC. What was seen when they looked at the types of bacteria post-FMT was a significant increase in Bacteroides species and a significant decrease in both E coli and Aspergillus. There seems to be something going on in the microbiome. We know that for C diff, it's Firmicutes and Bacteroides that tend to be high in prevalence to be favorable for decreasing recurrence. Bacteroides, again here, seems to be the favorable type of species we want to see to decrease inflammation in UC. Subsequent to that meta-analysis, there have been several other studies looking at the differences as to whether or not FMT is helpful. All of those other studies, one published by Pai and colleagues and one published by Caldeira and colleagues, look at remission and response rates in the 40%-50% range. There doesn't seem to be a difference in the mode of administration, whether it's via enema or oral ingestion. There doesn't seem to be a significant difference if it's fresh vs frozen, and there doesn't seem to be a significant difference, at least for these studies, with FMT if the donor was anonymous vs a household contact. No significant differences there, but we are seeing significant response and significant remission rates for FMT with UC.
Kane: That's super interesting. I think, again, the caveats right now are that any provider doing this needs to have an Investigational New Drug (IND) application from the FDA and that this is not inexpensive if you are doing it via colonoscopy. It is not covered by insurance, and nobody is sure how many you have to do because the studies are very heterogeneous in that they were given enemas for 8 weeks vs a colonoscopy installation just once vs oral. Maybe that's where we're trending as well because Seres Therapeutics now has their oral bacterial stool capsules, and everything ultimately centers around the gut microbiome: migraine headaches, depression, obesity, UC, whatever. I think that the listeners should understand that these are all evolving data and that if you are doing it via colonoscopy, there is that risk for perforation or for aspiration. Ultimately, these might be safer but are not totally risk free.
Hass: Agreed, 100%. And the IND issue that you mentioned is critical because it really limits availability.
Kane: If that practitioner doesn't have the IND, which is one of those "oh yeah, by the way" type of things for some people, you can get in a lot of trouble because you're treating somebody without a proper authority or regulatory oversight. We should not be letting people do this out of back alleys and out of their vans.
Hass: Absolutely. Yeah.
Kane: And people are, right? I mean, you can look up the FMT videos.
Hass: I wouldn't be surprised to hear that, especially desperate patients.
Kane: Yes, exactly. And at the end of the day, we want to offer hope as we talk about these things and the evolving data. I think that that's important. We have a few minutes left. We have to talk about tetrahydrocannabinol (THC).
Hass: Oh my gosh. Music to my ears. I am very, very interested in the endocannabinoid system. For those that aren't familiar: THC is one of the phytocannabinoids that's in cannabis, otherwise known as marijuana. There are several phytocannabinoids, but the two active ones are THC and cannabidiol (CBD). You've seen CBD stores pop up all over the country, and now, marijuana is medically and recreationally legal in almost 38 states — not recreationally available in 38 states but medically in 38 states. There's good data I didn't learn in medical school. Susie, I don't know about you, but I didn't learn anything about the endocannabinoid system.
Kane: It was taboo!
Hass: Yeah. But it's something that is so ripe for helping us, especially with UC and Crohn's disease, because it's significantly by activating those CB1 and CB2 receptors, which are on gut epithelium — inflamed gut epithelium. We decrease the same cytokines that we're trying to block with all of our biologic agents: TNF, interleukin (IL)–12, IL-23. It stands to reason that we have a built-in mechanism that we're just not taking advantage of yet. There are not a robust amount of data, as you might expect. There's only been one randomized placebo-controlled trial looking at THC, quite frankly, in IBD in general, and that was in patients with Crohn's. There has been one study on UC, but it's pretty limited. The only randomized, double-blind, placebo-controlled trial was on 21 patients back in 2013, where it didn't meet its primary endpoint of remission, but it did show clinical response with a decrease in the Clinical Disease Activity Index in patients who had ingested about 115 mg of THC vs placebo. It was a blinded study, but generally speaking, I think there's so much more research that needs to be done. Just recently, federal legislation made it so that now people who are interested in doing NIH-funded research do not have to procure the cannabis solely from the University of Mississippi, which was the only location that was available to provide product to study this on a national level. There were a lot of questions about the potency and the quality of that product. Now, it's going to be much easier and it's going to be, as we see legislation coming down the pike, much more readily available to do studies to see if we can actually take advantage of the system within our body to help our patients with IBD.
Kane: I tell my patients that the number of people who have been in a controlled trial is not even as high as the number of people I've had around my Thanksgiving table. You're absolutely right. Nature gave us these pathways and systems that have just been basically taboo to investigate up until now. Tapping into some of these things makes sense because it is more natural to try to take advantage of what nature has given us as opposed to doing the opposite and actually inhibiting what nature has given us, which is what we do now.
Hass: Interestingly, when we do survey data for patients with IBD, 50% are currently using cannabis and the other 50% are considering it. It's definitely something they need to think about as a provider who takes care of these patients. They're definitely thinking about it or they're already using it, right? It's important to address or at least acknowledge that you're aware of that.
Kane: I think it's a lot easier to do these studies now because people have access to it, in one way or the other, and we don't have to spend as much time with the legal hoops and logistics. I think that that is a great place to finish up our discussion.
Hass: Best part of my day.
Kane: I want to just summarize for folks: We talked about some agents that have gotten a lot more public press because of their sexiness. Turmeric is the real deal, FMT and the evolving data, for sure we know probiotics are good for lots of things, not just the patients with pouchitis. It's important to know that probiotics are like perfume or aftershave lotion in that it's not one size fits all. Finally, THC is here and it's not going away and can actually be our friend.
Hass: Great. Thank you so much for inviting me and for helping to educate everybody so that we can take care of patients better.
Kane: Always good to chat with you.
Resources
Gut Microbiota and Autoimmune Diseases: A Charming Real World Together With Probiotics
Marijuana Use Patterns Among Patients With Inflammatory Bowel Disease
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Cite this: Alternative Therapies in Ulcerative Colitis: An Expert Perspective - Medscape - Feb 22, 2023.
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