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Gut Feeling

Gut microorganism

Pain, anxiety, and sleep are major drivers of medical cannabis use. But gastrointestinal symptoms, such as nausea and upset stomach, aren’t far behind.1 Even small doses of cannabis can soothe the stomach and stimulate the appetite. In fact, of the four cannabis-derived drugs approved so far by the U.S. Food and Drug Administration, three are prescribed for the treatment of chemotherapy-induced nausea and vomiting.

One gastrointestinal condition long associated with self-medication through cannabis is inflammatory bowel disease (IBD). A flurry of recent research bears this out. In a newly published survey of 162 IBD patients in Puerto Rico, where medical cannabis is legal but recreational use is punishable with prison time, about 25% anonymously reported using cannabis to treat their symptoms. Among these, nearly all said it offered relief.

Findings from another recent survey of New York and Minnesota medical cannabis dispensary patients were similar. And two new reviews aimed at physicians and researchers concur that while further study is needed, the evidence to date leaves little doubt that IBD patients are helped by cannabis.

ECS & the Gut

On a molecular level, this all makes sense. The endocannabinoid system is widely distributed throughout the gastrointestinal system, including not only CB1 and CB2 cannabinoid receptors but also other cannabinoid targets like PPARs, GPR55, and TRPV1. The job of the endocannabinoid system here, as everywhere, is to maintain order and balance, and the endogenous compounds (ligands) that interact with these receptors can be supported in this task by cannabis-derived and synthetic cannabinoids.

(The concentration of cannabinoid receptors in the gut also helps to explain cannabis hyperemesis syndrome, in which an overabundance of exogenous cannabinoids, particularly THC, triggers debilitating nausea, vomiting, and pain that typically resolves when cannabis use stops.)

Even small doses of cannabis can soothe the stomach and stimulate the appetite.

Inflammatory bowel disease is an umbrella term for two chronic disorders of the gut: Crohn’s disease, characterized by inflammation of the lining of the digestive tract; and ulcerative colitis, which involves inflammation and sores along the lining of the large intestine (colon) and rectum. Symptoms of both include diarrhea, fatigue, abdominal pain, reduced appetite, and weight loss.

IBD in Puerto Rico

In 2016, the government of Puerto Rico legalized medicinal cannabis for a relatively short list of specific conditions, including Crohn’s disease. Only non-smokable preparations are permitted, and all unauthorized cannabis use and possession remains illegal. As of March 2022, approximately 120,000 patients were registered in the program.

The recent survey was conducted through a clinic at the University of Puerto Rico Center for Inflammatory Bowel Diseases with around 900 patients. Ultimately 162 adults (85 males) completed the 27-item questionnaire. Among these, 60 (37%) reported current or past cannabis use, of which 39 used it to treat abdominal pain, 25 to treat weight loss, and 10 to treat diarrhea, among other symptoms.

But the most telling findings involve these patients’ perceptions of cannabis use as a treatment for IBD. The vast majority of current and past users noted that cannabis was beneficial for their health (94%), that it offered an improvement in their quality of life (84%), and that they would recommend it to other patients (86%). The study was published in March 2023 in the International Journal of Environmental Research and Public Health.2

Fewer ER Visits in New York & Minnesota

When researchers with Stony Brook University Hospital, Northwestern University, and Albert Einstein College of Medicine surveyed IBD patients in New York and Minnesota about their cannabis use, both states only allowed medical use. This study was conducted at medical cannabis dispensaries and relied on self-reported IBD diagnoses. Generally speaking, the 236 eligible respondents reported mild-to-moderate IBD disease activity. Most used cannabis at least once a week, primarily through high-THC vape pens and cartridges.

Euphoria was by far the most common side effect reported.

Again, the most notable findings reveal just how helpful these patients found cannabis in managing inflammatory bowel disease. Respondents reported fewer IBD-related emergency-room visits (a common concern across the patient population) in the year after they began using cannabis. They also saw a reduced impact of symptoms on their daily life. Euphoria was by far the most common side effect (75.4%), with drowsiness, memory lapses, dry mouth, anxiety, and paranoia all reported in low-single-digit percentages. The results appeared in the Journal of Clinical Gastroenterology in October 2022.3

Rave Reviews

Scientific review papers are typically circumspect in tone, more inclined to highlight evidence gaps than to draw grand conclusions. But two recently published reviews are clear when it comes to the benefits of cannabis for inflammatory bowel disease patients.

“Cannabinoid usage in IBD treatment comes with promising results as reported in the majority of the selected studies,” reads a systemic review of the literature from 2012 to 2022 published in the journal Cureus. “The selected studies’ point of convergence is that they confirmed the promising role of cannabinoids in steering improvements in IBD treatment through some objective clinical rating scales such as weight gain, Harvey-Bradshaw Index, Mayo score, CDAI score, and general well-being.” The main caveats? Heterogeneous study designs and a dearth of high-quality evidence for ideal dosage and mode of administration.

The second new review, set to be published in July in Current Opinion in Gastroenterology,4 similarly concludes that “there is a considerable amount of patient-reported outcome data that is significant in supporting the use of cannabis to provide symptom relief and overall increase in quality of life in patients with IBD.”

The authors do make an important distinction between symptoms and underlying conditions, however, by noting that existing evidence addresses the former, not the latter: “There are no data that cannabis has any benefit in decreasing the inflammation/fibrosis that continues to affect patients with IBD.”

This doesn’t mean that cannabinoids have been proven ineffective in addressing the root cause of IBD, just that there’s no evidence yet establishing that they do. “The most important point is that gastroenterologists need to ask their patients about their [cannabinoid] use, including discussion of the benefits and risks of using them,” the authors conclude.

Nate Seltenrich, Project CBD contributing writer, is the author of the column Bridging the Gap. An independent science journalist based in the San Francisco Bay Area, he covers a wide range of subjects, including environmental health, neuroscience, and pharmacology. © Copyright, Project CBD. May not be reprinted without permission.

Footnotes

  1. Leung, Janni et al. “Prevalence and self-reported reasons of cannabis use for medical purposes in USA and Canada.” Psychopharmacology vol. 239,5 (2022): 1509-1519. doi:10.1007/s00213-021-06047-8
  2. Velez-Santiago, Alondra et al. “A Survey of Cannabis Use among Patients with Inflammatory Bowel Disease (IBD).” International journal of environmental research and public health vol. 20,6 5129. 15 Mar. 2023, doi:10.3390/ijerph20065129
  3. Greywoode, Ruby et al. “Medical Cannabis Use Patterns and Adverse Effects in Inflammatory Bowel Disease.” Journal of clinical gastroenterology, 10.1097/MCG.0000000000001782. 14 Oct. 2022, doi:10.1097/MCG.0000000000001782
  4. Saidman, Jakob et al. “Inflammatory bowel disease and cannabis: key counseling strategies.” Current opinion in gastroenterology vol. 39,4 (2023): 301-307. doi:10.1097/MOG.0000000000000946

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Mental Health & the CB2 Receptor

In the first part of this series, we reviewed recent research into the role of the CB2 cannabinoid receptor in cancer proliferation. This week we turn our attention to another fascinating aspect of CB2 function: its impact on psychiatric and mood disorders despite not being concentrated in the central nervous system (CNS).

After all, the CNS is the domain of its sibling, the CB1 cannabinoid receptor — the primary target of THC and the mediator of cannabis’ intoxicating effects. CB2, by contrast, is more prominently expressed in the peripheral nervous system, where it regulates inflammation, pain, and neuroprotection. CB2 is found to a much lesser extent in the brain, where it modulates dopamine signaling, neuroinflammation, and neurogenesis.

The CB2 receptor was of particular interest to visionary cannabinoid scientist Raphael Mechoulam. In the year prior to his recent passing at age 92, Mechoulam was still actively involved in research investigating CB2 in a variety of disease models. Here we look at a couple of his final papers on CB2 and mental health, as well as two related reviews published in the same timeframe.

CB2 & Schizophrenia

First comes a paper on CB2’s role in schizophrenia, a condition related to psychosis whose symptoms include hallucinations, delusions, disorganized thinking, social withdrawal, decreased emotional expression, and apathy. Coauthored by Brazilian scientists affiliated with the University of São Paulo, it appeared in the journal Progress in Neuro-Psychopharmacology & Biological Psychiatry1 in July 2022.

“The CB2 receptor modulates dopaminergic neurotransmission, which is abnormally enhanced in schizophrenia patients,” the authors explain. That much is clear. Given this, they wanted to know, how might “HU-910,” a synthetic research compound that selectively activates the CB2 receptor, affect behavior in a rodent model of the disease?

Through a series of tests, they found that HU-910 administration did indeed produce an anti-psychotic-like effect through the CB2 receptor. The authors suggest that these results “support further research on the potential therapeutic properties of this compound to treat schizophrenia.”

But their conclusion that HU-910 could serve as a drug warrants some caution. Cannabinoid receptors don’t function simply as on/off switches. As Project CBD has addressed in the past relative to proposed therapies for bone disease, Alzheimer’s Disease, and autoimmune dysfunction, selective CB2 agonists thus far have been disappointing in the clinical context due to unintended consequences and other unwelcome outcomes resulting from the receptor’s wide reach in the body.

CB2 & Depression

The very last paper bearing Mechoulam’s name before his death — among a body of work encompassing 379 total articles listed at Pubmed — concerns the role of the CB2 receptor in mediating the antidepressive effect of cannabidiolic acid-methyl ester (CBDA-ME). Titled “Cannabinoid Receptor 2 Blockade Prevents Anti-Depressive-like Effect of Cannabidiol Acid Methyl Ester in Female WKY Rats,” it appeared in the February 2023 special issue of the International Journal of Molecular Sciences,2 which explored the biological mechanisms of cannabinoids in mental health.

CBDA-ME is a stable synthetic analogue of cannabidiolic acid (CBDA), the raw, unheated version of CBD present in cannabis flower. (The fact that CBDA becomes CBD in the presence of sunlight or heat makes it difficult to study, hence the need for a more stable CBDA-related compound.) First described in 19693 by Mechoulam and a coauthor, CBDA-ME has in recent years been shown to exert anxiolytic,4 anti-hyperalgesic,5 and anti-depressive6 effects in male rodents at low doses.

The Israel-based authors assessed the antidepressant effect of CBDA-ME in mice through a common laboratory model known as the “forced swim test.” Among the authors’ findings, one stands out (and makes its way into the paper’s title): a synthetic CB2 antagonist called “AM-630” blocked CBDA-ME’s anti-depressive effect in female rats, but not in males, indicating that the CB2 receptor is involved in mediating the compound’s effect.

Does this suggest that CB2 activation — perhaps indirectly triggered by CBD or CBDA as well as CBDA-ME — could help fight depression, at least in women? Possibly, the authors conclude, but “the cumulative data indicate that these pathways are still ambiguous and require future research in order to fully understand the mechanisms of action of acute CBDA-ME in relieving the symptoms of depression.”

Targeting CB2 in CNS Disorders

Two other reviews from 2022 provide a broader perspective on CB2’s role in several emotional, cognitive, and psychiatric disorders — from addiction and anxiety to Huntington’s and Parkinson’s diseases.

A report published in the International Journal of Molecular Sciences, coauthored by Emmanuel Onaivi at William Patterson University in New Jersey and a team of Japanese scientists, concludes that CB2 receptors “are highly expressed in neuropsychiatric and neurodegenerative disorders, and that selective CB2 ligands have promising effects on the symptomatic management of these disorders.”

However, given the potential for such drugs to have significant side effects, the authors also recommend further study of cannabis-derived compounds to target CB2 in tandem with CB1, as well as less directly through the broader endocannabinoid system.

Next, an April 2022 review in Frontiers in Psychiatry7 notes that recent findings of CB2’s presence in several brain areas and different brain cell types, including neurons and glia, indicate that “CB2 may closely relate the immune system and the brain circuits regulating inflammation, mood, and cognitive functions.” This receptor is particularly implicated in neuropsychiatric diseases associated with neuroinflammation, according to the European scientists, who conclude that future research should continue to zero in on the critical link between CB2, inflammation, and psychiatric disorders.

Read part 1 of this 2-part series: Cancer & the CB2 Receptor

Nate Seltenrich, an independent science journalist based in the San Francisco Bay Area, covers a wide range of subjects including environmental health, neuroscience, and pharmacology. Copyright, Project CBD. May not be reprinted without permission.

Footnotes

  1. Cortez, Isadora Lopes et al. “HU-910, a CB2 receptor agonist, reverses behavioral changes in pharmacological rodent models for schizophrenia.” Progress in neuro-psychopharmacology & biological psychiatry vol. 117 (2022): 110553. doi:10.1016/j.pnpbp.2022.110553
  2. Hen-Shoval, Danielle et al. “Cannabinoid Receptor 2 Blockade Prevents Anti-Depressive-like Effect of Cannabidiol Acid Methyl Ester in Female WKY Rats.” International journal of molecular sciences vol. 24,4 3828. 14 Feb. 2023, doi:10.3390/ijms24043828
  3. Mechoulam, R et al. “Carboxylation of resorcinols with methylmagnesium carbonate. Synthesis of cannabinoid acids.” Journal of the chemical society D: chemical communications vol. 1,7 (1969): 343-344. doi:10.1039/C29690000343
  4. Pertwee, Roger G et al. “Cannabidiolic acid methyl ester, a stable synthetic analogue of cannabidiolic acid, can produce 5-HT1A receptor-mediated suppression of nausea and anxiety in rats.” British journal of pharmacology vol. 175,1 (2018): 100-112. doi:10.1111/bph.14073
  5. Zhu, Yong Fang et al. “An evaluation of the anti-hyperalgesic effects of cannabidiolic acid-methyl ester in a preclinical model of peripheral neuropathic pain.” British journal of pharmacology vol. 177,12 (2020): 2712-2725. doi:10.1111/bph.14997
  6. Hen-Shoval, D et al. “Acute oral cannabidiolic acid methyl ester reduces depression-like behavior in two genetic animal models of depression.” Behavioural brain research vol. 351 (2018): 1-3. doi:10.1016/j.bbr.2018.05.027
  7. Kibret, Berhanu Geresu et al. “New Insights and Potential Therapeutic Targeting of CB2 Cannabinoid Receptors in CNS Disorders.” International journal of molecular sciences vol. 23,2 975. 17 Jan. 2022, doi:10.3390/ijms23020975
  8. Morcuende, Alvaro et al. “Immunomodulatory Role of CB2 Receptors in Emotional and Cognitive Disorders.” Frontiers in psychiatry vol. 13 866052. 15 Apr. 2022, doi:10.3389/fpsyt.2022.866052

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