Got the Munchies for an Egg Sandwich? The Effects of Cannabis on Bowel Motility and Beyond

LET’S GET INTO THE WEEDS: DEFINING CANNABIS, CANNABINOIDS, AND NOMENCLATURE

Because of the variety of cannabis plants and cannabinoid compounds, we will first review some definitions and nomenclature. Cannabis sativa, Cannabis indica, and Cannabis ruderalis are the primary plant species from which commercial cannabis is derived. These plants are known by many other street names, such as marijuana, Mary Jane, weed, pot, grass, ganja, hash, and purple haze, to name a few. Inhalation of smoked cannabis is the most common form of intake.

The principal psychoactive component of cannabis is δ-9-tetrahydrocannabinol, which activates CB1 receptors and decreases bowel motility. The other primary cannabinoid of interest is cannabidiol, which may have desirable antiinflammatory effects and play a role in motility. There are approximately 80 other naturally occurring, plant-based phytocannabinoids within cannabis whose actions continue to be studied.

Pharmaceutical (synthetic) tetrahydrocannabinol includes drugs such as dronabinol (Marinol; Unimed Pharmaceuticals), which shares the same chemical structure as organic tetrahydrocannabinol found in cannabis. It has been approved by the U.S. Food and Drug Administration for appetite stimulation in HIV/AIDS anorexic patients and treatment of chemotherapy-induced nausea and vomiting. It is also used off-label for innumerable other illnesses. A pharmaceutical synthetic form of cannabidiol also exists (Epidiolex; Jazz Pharmaceuticals), which has been approved for rare intractable seizure disorders. Hemp is legally defined in the United States as all other parts of the cannabis plant, such as the fibrous stem, which contain less than 0.3% tetrahydrocannabinol and are used in various industrial products.

Synthetic (neo)cannabinoids have an altered chemical structure but mimic the effect of tetrahydrocannabinol on cannabinoid receptors. These drugs were marketed as “legal highs” or “fake weed” and became popular in the early 2000s because of their commercial availability and undetectability on drug tests. Common product names include K2 and Spice. Early synthetics are now illegal because of their unregulated status and dangerous potency, but newer agents continue to enter the market. Drug companies are attempting to synthesize new, safer formulations (8).

Endocannabinoids are lipid substrates made endogenously by the human body. Anandamide was first discovered in 1992 and was characterized as a neurotransmitter. The more recently discovered endocannabinoid is 2-archidonoyl glycerol. It is now known that the action of these endocannabinoid bioactive lipids extends far beyond the central nervous system. Beyond their function at the CB1 and CB2 receptors, anandamide and 2-archidonoyl glycerol also interact with a multitude of other receptors such as transient receptor potential vanilloid type 1, peroxisome proliferator-activated receptor-α and -γ, and G-protein–coupled receptor. A complex interplay with other pathways exists, which can lead to the synthesis and degradation of prostaglandins and other bioactive lipids such as palmitoyl ethanolamide and anorexigenic oleoyl ethanolamide. Each has actions linked to motility and the inflammatory cascade. A recent article by Srivastava et al. provides a thorough review on this topic (9).

EFFECT OF CANNABINOIDS ON GUT MOTILITY

Although decreased gastrointestinal motility due to cannabinoids has been established in both human and experimental animal models, it has not been definitively established in cannabis users with gastroparesis. To clarify these potentially discordant findings, we will examine the literature.

THERAPEUTIC POTENTIAL OF ENDOCANNABINOID SYSTEM

The endocannabinoid system plays a crucial role in maintaining gastrointestinal balance and has therapeutic potential. Cannabinoids have demonstrated antiinflammatory and pain-relieving properties and may benefit patients with gastrointestinal conditions, as suggested by small studies on patients with inflammatory bowel disease. However, findings from epidemiologic studies contradict some animal and human research, particularly regarding potential benefits in obesity, fatty liver, gastroparesis, and irritable bowel syndrome. These inconsistencies highlight the complex interactions between the endocannabinoid system and other systems such as the gut microbiome. Current studies focusing mainly on CB1 and CB2 receptors and exploring substrates responsible for the synthesis and degradation of endocannabinoids could open new therapeutic possibilities (17,23).

DRUGS AND BUGS: CANNABINOIDS AND GUT MICROBIOME

Further complicating our understanding of the endocannabinoid system is its relationship to the gut microbiome (Fig. 1). The gut microbiome has emerged as a key component of human health in recent years, with far-reaching effects on nutrition, cancer susceptibility, and gastrointestinal disorders, among others. Consumers are inundated by marketing which claims that pre- or probiotic products will enhance our health through recolonization of healthy gut flora. Although the efficacy of these products is debated, there is a plethora of evidence demonstrating that the microbiome in our gut does impact our health. The homeostatic imbalance between the microbiome and the human host is termed dysbiosis as opposed to the ideal state of symbiosis (9). A recent large systematic review found that nearly half of patients with gastroparesis are also affected by small-intestinal bacterial overgrowth, further strengthening the connection between motility and the gut microbiome (30).

The endocannabinoid system, which links the gut to the brain, is affected by the gut microbiome. It is postulated that their interaction occurs via 3 pathways: the hypothalamic–pituitary–adrenal axis, the vagus nerve, and systemic neurotransmitter–hormonal regulation. Researchers have validated these relationships by measuring changes in endocannabinoid tone after introducing specific bacteria to germ-free mice. Manipulation of gut microbiota through antibiotics, probiotics, a high-fat diet, and gene-knockout expression results in alterations of endocannabinoid levels (anandamide and 2-archidonoyl glycerol) and cannabinoid receptor expression. Conversely, the opposite is true when endocannabinoid tone is manipulated, thereby altering microbiota composition. Even more astounding, researchers have discovered receptor sites on bacteria (e.g., Helicobacter pylori, Escherichia coli, and Pseudomonas aeruginosa) that respond to human neurotransmitters (epinephrine, norepinephrine serotonin), hormones (gastrin, somatostatin, insulin, steroids), and immune factors resulting in measurable changes in microbiota composition and virulence, reinforcing the bidirectional aspect of the gut–brain–microbiome axis (31,32). Mouse models can mimic a variety of pathophysiologic disease states, thereby enabling researchers to study the effect of microbiota in inflammatory conditions, metabolic disorders, and stress (9). Although this research is limited to endocannabinoid signaling, phytocannabinoids likely have a similar effect given their shared receptors. Animal models and human cross-sectional studies have successfully demonstrated alterations in gut microbiota caused by phytocannabinoid exposure. More importantly, inflammatory markers and clinical symptoms were improved after correction of the pathologic dysbiosis in animal models (33–35).

The highly personalized microbiota among individuals, cultures, and geographic regions could significantly impact the effect of cannabinoids. In the age of precision medicine, emerging technologies that rely on big data attempt to uniquely characterize an individual’s microbiome (36). Researchers have identified unique subpopulations of microbiota along different segments of the gastrointestinal tract within single individuals and have expanded their work to characterize the gut virome (37,38). Continued advances within molecular imaging such as attempts to radiolabel microorganisms may allow us in the future to visually assess the collective function of our gut flora (39). One could postulate that careful selection of one’s diet could cultivate gut microbiota optimized for desirable therapeutic effects.

THE MUNCHIES

This article would not be complete without a discussion of the well-known phenomenon of a surge in appetite and food consumption after cannabis use, colloquially known as the munchies. Tetrahydrocannabinol activates CB1 receptors in the brain, thereby increasing appetite and the desirability of food. This homeostatic balance is regulated by the endocannabinoid system’s action on the hypothalamus, which modulates the hunger hormones ghrelin and leptin. Ghrelin stimulates appetite and increases motility, whereas leptin curbs hunger and decreases motility. Because endocannabinoids exert their action on the upstream hypothalamic homeostatic regulator, it is possible that the interaction between exogenous cannabis exposure and the native endocannabinoid system could produce both promotile and antimotile effects depending on the incompletely understood physiologic feedback loop (40,41). Cannabinoids also act on pleasure pathways in the brain that increase dopamine and result in the characteristic insatiable hunger. An animal study looked at the relationship between different macronutrient stimuli and endocannabinoid signaling in mice. They found that endocannabinoid levels highly regulate dietary fat intake, whereas no measurable response was identified in carbohydrate- or protein-based meals. These effects have led to medications that either stimulate or block cannabinoid signaling. At present, they can be prescribed as an appetite stimulant in anorexic patients. CB1 receptor antagonists have been tried for weight loss in obesity but were stopped because of severe neuropsychiatric side effects (15,42).

HIGH-YIELD CLINICAL CONSIDERATIONS IN NUCLEAR MEDICINE

There is limited evidence that cannabinoids result in significant delays in gastric emptying. Any significant delays would likely be limited to instances of very recent intake (<12 h). The social history should be reviewed for all forms of cannabinoids (medical or recreational marijuana, dronabinol–tetrahydrocannabinol, synthetic cannabinoids such as K2 or Spice). To avoid false-positive results, it is recommended to avoid cannabinoid intake for at least 72 h before GES, although no cannabis after midnight would likely suffice (43). This measure is conservative and extends several half-lives beyond the 4-h serum half-life of tetrahydrocannabinol. Cannabinoids should be added to the list of medications that may affect gastric emptying per the Society of Nuclear Medicine and Molecular Imaging procedure standards for GES.

If GES is requested for a chronic cannabis user, it is important to recognize that a negative result is more helpful. In patients with gastroparetic symptoms and a normal GES result, other functional gastrointestinal disorders should be considered such as functional dyspepsia. If the result is positive, cannabis may or may not contribute to the result and should be correlated with the timing of intake. The collective research does not suggest a significant difference in gastric emptying times in chronic users. A trial of prolonged cessation to assess improvement in symptoms and repeat GES could be considered. If gastroparetic symptoms improve with cannabis, abnormal GES times should yield to symptom index scoring systems as the primary measure of treatment effect.

GES has limited utility in differentiating cannabinoid hyperemesis syndrome from cyclic vomiting syndrome. Rapid gastric emptying is more characteristic of cyclic vomiting syndrome but should serve only as a supporting criterion given the significant overlap of GES times between the two conditions. A history of cannabis use and resolution of symptoms after cessation are the primary differentiating diagnostic features of cannabinoid hyperemesis syndrome.

Cannabinoids should be suspended before small- or large-bowel transit studies to avoid false-positive (slow transit) results, unless measuring the cannabinoid effect is the purpose of the examination. Although this issue is incompletely studied, our current understanding is that cannabinoids could decrease bowel motility and thereby increase transit times. The effect on transit times in chronic users is currently unknown.

DISCLOSURE

Mary Beth Farrell is an employee of the IAC. The views expressed are those of the authors and do not reflect the official policy or position of Brooke Army Medical Center, the U.S. Army Medical Department, the U.S. Army Office of the Surgeon General, the Department of the Army, the Department of Defense, or the U.S. government. No other potential conflict of interest relevant to this article was reported.