Evidence continues to grow for the potential power of cannabinoids to improve the relationship between gut bacteria and digestive health
Written by- Dr. Adam Abodeely MD, MBA, FACS, FASCRS

Ten years ago, few patients were asking their doctors about what bacteria could improve their gastrointestinal health. These are eventful times for anyone who is interested in how microorganisms in our gut can affect our resistance to disease, and as a double board certified surgeon, specializing in gastrointestinal ailments, I’ve paid attention to the wealth of new research into the relationship between the human microbiome and the digestive system. Since entering private practice in 2010, I’ve treated tens of thousands of patients for conditions affecting the gastrointestinal system, and I’ve embraced every opportunity to learn what I can about how gut microbiota can help people overcome the dysfunctions that bring them to my office.

This research also matters to me as someone involved in medical cannabis. Since 2015, I’ve been a member of the Society of Cannabis Clinicians and the American Academy of Cannabinoid Medicine, and I currently serve as chairman of the Dispensary Review Committee for the Association of Cannabis Specialists, applying efforts to ensure that dispensaries operate safely and responsibly, and uphold best practices when educating their customers. I’ve tried my best to stay informed—not only because cannabis therapy can be a powerful tool in the treatment of irritable bowel syndrome, nausea, colorectal cancer, ulcerative colitis, or Crohn’s disease, but also because patient outcomes and feedback have been essential to creating the line of cannabis products that I’ve developed on my own.

An exciting new frontier in the field of gastroenterology lies in finding out how cannabinoids interact with natural bacteria in the gut, building on some already-substantial knowledge of the role that the human endocannabinoid system plays in digestion.

As many people know, this role is significant. CB1 receptors, for example, are prolifically expressed by enteric nerves in the intestines, which are responsible for motility and enzyme production. Immune cells in the digestive tract, which form our first defenses against unwanted microbes entering the body, express an abundance of CB2 receptors. Cells in the stomach and intestinal tissue also express GPR 55 receptors, transient receptor potential cation channel subfamily V (TRPV), and peroxisome proliferator-activated receptors (PPARs). Together, these help the colon to maintain a healthy barrier against pathogens, altering gastric acid and intestinal secretions, regulating appetite, and surveilling the growth of potential cancers.

There is a wealth of evidence that plant-based cannabinoids can restore the epithelial membrane, and help it recover from stress or inflammation. Mice with colitis, for example, showed improved signs of colon injury—including reduced edema in mucosal tissue, and regeneration of digestive glands—after being treated with CBD [1]. CBD has also been shown to increase zona occludens-1 mRNA expression in leaky intestinal tissue, down-regulating enzymes like nitric oxide synthase (iNOS), and inhibiting the release of cytokines and reactive oxygen species associated with inflammation [2].

Given the richness of these interactions, cannabis holds tremendous potential for treating irritable bowel syndrome (IBS), a disorder that affects approximately 9-23% of adults worldwide [3]. Symptoms such as abdominal pain, diarrhea, bloating, and altered bathroom habits can be brought on by stress or a meal, but even if they appear without a visible trigger, the endocannabinoid system can have a role in managing them: CB1 receptors, for example, have been shown to inhibit muscle contractions in the intestine, while CB2 receptors expressed by immune cells can help to reduce the amount of inflammation within the intestinal lining. In addition to numerous patient surveys, preclinical data, and anecdotal data, one randomized study looked at 52 patients with IBS, and found that subjects who received cannabinoid therapy had substantially fewer colonic contractions during fasting states—and reported a significant reduction in bowel contractions and motility—compared to those who received a placebo [4].

Cannabis can also offer a great deal of hope for people with inflammatory bowel disease (IBD), a condition brought on by an abnormal immune response within our gastrointestinal tract. In advanced stages, it can develop into Crohn’s disease, which is characterized by high levels of inflammation in the intestinal lining. By activating CB2 receptors, which can slow the release of inflammatory cytokines, cannabinoids can help to bring inflammation down to a more appropriate (“homeostatic”) level, and in my clinical practice, the majority of my IBD patients who enter cannabis into their treatment plans report significant relief from abdominal pain and diarrhea, and show improvements in overall quality of life. This is in correlation with the other published surveys, anecdotal data, and some smaller preclinical studies: animal models, for example, have shown decreased IBD symptoms with the introduction of plant-based cannabinoids like THC, CBD, and CBG, or with synthetic cannabinoid analogs such as O-1602 and WIN-55,212-2 [5].

Most dramatic of all has been the impact of cannabis on the lives of patients with colorectal cancer (CRC), which is the cause of 50,000 deaths every year [6]. Part of this is in the treatment of cancer- or chemotherapy-induced pain: by binding to receptors on a nerve cell transmitting a pain signal, endocannabinoid neuromodulators, such as anandamide (AEA) or 2-arachidonoyl-glycerol (2-AG) have the power to muffle that signal by inhibiting the release of neurotransmitters such as histamine, bradykinin, GABA, or serotonin. In support of this pathway, the phytocannabinoid CBD has been shown to reduce the expression of fatty acid amide hydrolase (FAAH), an enzyme that typically breaks down the endocannabinoid AEA, thus activating a negative feedback mechanism to slow a pain signal down [7].

Cannabis also has a well-established role in reducing the nausea and vomiting induced by chemotherapy, which is cited by 40%-90% of patients undergoing this type of treatment, including those who already use anti-nausea or antiemetic drugs. Numerous clinical studies have highlighted the efficacy of cannabis treatments in this area, particularly among patients who cannot tolerate oral medications due to nausea, and who seek out cannabis in its inhalational form. This offers a potential solution to a major problem: one study from 2015 found that a third of cancer patients—who received a combination of 5-hydroxytryptamine 3 (5-HT3) antagonist and corticosteroid medications—were not able to overcome nausea and vomiting, despite the use of a prophylaxis [8]. In 2017, in recognition of the help cannabis could bring, the National Academy of Medicine, Science and Engineering made the conclusion that, “there is conclusive evidence that oral cannabinoids are effective antiemetics in the treatment against chemotherapy-induced nausea and vomiting [9]”.

Furthermore, the endocannabinoid system has indicated some ability to identify and destroy gastrointestinal tumor cells, reduce blood flow to tumors, and inhibit the ability of these tumors to migrate and spread. On one hand, it’s worth remembering that cannabinoid therapy for CRC is extremely complex, and that caution must be used when recommending cannabis to treat it, since certain cannabinoid receptors, when activated, may in fact promote tumor growth and progression. On the other hand, activation of the CB2 receptor has been directly connected to tumor suppression, and there is a wealth of evidence that activation of CB2 is involved in assisting our immune system to detect certain tumor cells before they develop into malignancies [10]. It’s also worth mentioning that many of the conventional pharmaceutical agents used to treat IBD are often associated with significant side effects and toxicity; they have the power to make patients more susceptible to other opportunistic infections and even cancer. Moreover, by using cannabis in the place of opioid medications for the treatment of pain, patients can avoid unpleasant side-effects, including constipation, fatigue, somnolence, and sedation, as well as serious addiction and dependency risks—all of which, in turn, can affect the loved ones who are caring for a person with CRC.

Again and again, researchers have found that there is a direct link between the endocannabinoid system and our immune system’s response to gastrointestinal disease, and the work done by bacteria is crucial to this relationship. Of course, the microbiome is also crucial to the proper function of so many other organ groups. Patients with hepatic encephalopathy, for example, showed significant improvement after being treated with oral antibiotics, in a study during the 1990s that opened up discussion about the existence of a gut-brain axis (GBA). More recent investigations have found that certain gut bacteria can help people resist symptoms of anxiety and depression; there is also some evidence connecting imbalances in gut bacteria with some of the more severe consequences of autism [11].

At the same time, the disruption of the GBA has been closely associated with changes in intestinal motility and strength. In some cases, this can begin with the use of antibiotics, leading to bacterial overgrowth, and the occurrence of post-infectious IBS. I’ve seen this many times in my practice: someone with an infection will be prescribed antibiotics, leading to a severe adjustment of their intestinal flora. Ultimately, antibiotics can make inflammation even worse, so that soon, steroids like prednisone are thrown into the mix, leading to even further immune dysfunction. Another consequence of a mistreated microbiome is “leaky gut syndrome,” a term used to describe changes in the ratio of gut bacteria that leads to inflammation, affecting the permeability of the intestinal walls. When that ratio is wrong, some otherwise helpful microorganisms can form a colony that penetrates the mucosal lining of the colon.

This process can furthermore lead to CRC. It’s worth noting that about 80% of CRC cases are sporadic—meaning the patient had no family history of the disease. Factors like diet or alcohol consumption can affect our risk, but what we’re starting to learn is that inflammation associated with the disease is often a direct response to imbalances in gut bacteria. In response to other changes in the genetic and immunological microenvironment of the gut, tumor cells in an otherwise normal epithelium can begin to spread and proliferate, forming a polyp that protrudes from the inside of the colon, and sometimes becomes malignant [12]. Microbes such as E. coli can increase the frequency of mutation, for example, while Enterococcus faecalis can stimulate the release of high levels of reactive oxygen species, a mediator of inflammation, which can also do damage to DNA [13] [14] [15]. In earlier stages, it’s not at all unusual for this process to manifest itself in IBD, which is why the American Cancer Society guidelines recommend screening colonoscopies every 1-2 years for patients with these conditions.

It is also why cannabis therapy can be appropriate. There is a wealth of evidence that the endocannabinoid system can help to manage inflammation, keep endothelial membranes healthy, improve cellular regeneration, and block reactive oxygen species, which promote the growth of certain tumors. By activating CB1 receptors in the intestine, CBD has been shown exert anti-proliferative effects on colorectal carcinoma cells, and several studies have indicated that cannabinoids can prevent the growth and migration of epithelial malignancies in both CB1 and CB2 receptors [16].

Cannabis may furthermore have a role in altering gut microbiota to stimulate weight loss, which can help obese patients reduce their risk of CRC. This was borne out in a study from 2015, in which lean and obese adult male mice were treated daily with small doses of THC for a period of four weeks. The authors found that THC reduced weight gain, fat mass gain, and energy intake in the obese mice, in addition to an increased ratio of the bacteria Firmicutes to Bacteroidetes, which has been correlated with the progression of colorectal cancer [17]. Though it is unclear whether these changes in gut microbiota caused the weight-loss associated with THC, or vice versa, these are extremely interesting findings.

Over three thousand years ago, cannabis was mentioned in the Atharva Veda, a collection of religious and ethical texts, written in Sanskrit, which remain a primary source for information about the customs, beliefs, and scientific advances of ancient India [18]. The plant was recommended as a sedative and spasmolytic, and, in moderate use, was said to support healthy digestion, and in the modern era, moderate cannabis use continues to have a place in Ayurvedic therapy, based on its ability to stimulate the nervous system, and resolve intestinal dysfunction. In a sense, Western medicine is simply catching up with these insights, as evidence continues to accumulate for the potential power of cannabinoids to improve the signaling that exists between gut bacteria and the human endocrine, lymphatic, and nervous systems. Witnessing these advancements, and seeing how they can help my patients, has made it deeply rewarding to be a gastrointestinal surgeon and specialist in cannabinoid therapy in the present day.

References

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