Introduction
Cannabis and its derivatives have been found to affect many gastrointestinal processes by affecting the endocannabinoid system (ECS) with anti-inflammatory, antinociceptive, and antisecretory effects. It is believed that some gastrointestinal disorders can be treated with cannabinoids: relieving chronic pain, nausea, and vomiting caused by chemotherapy, and improving the course of nonalcoholic fatty liver disease and inflammatory bowel disease. Studies have also shown an important role for ECS in metabolism. Despite the potential benefits of cannabis, undesirable effects have so far limited its medical use.
Cannabis contains many chemically active compounds, including cannabinoids, terpenoids, flavonoids and alkaloids. The most important of these are Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD). Besides these, more than 100 other active cannabinoids are known, each capable of modulating the ECS. The latter is a network of cannabinoid receptors, their ligands, and regulatory synthesizing and degrading enzymes that function on demand. The ligands include anandamide and 2-arachidonoylglycerol, lipids produced by arachidonic acid metabolism. The most important are cannabinoid receptors 1 and 2 (CB1 and CB2), as well as the transient cation channel potential receptor (subfamily V, member 1), peroxisome proliferator-activated receptor alpha, and the orphan G protein associated with GPR55 and GPR119 receptors. Enzymes that synthesize endocannabinoids include diacylglycerollipase, which synthesizes anandamide, and N-acylphosphatidylethanolamine-specific phospholipase D, which synthesizes 2-arachidonoylglycerol. Enzymes such as fatty acid amide hydrolase and monoacylglycerollipase degrade endocannabinoids. ECS can be activated by exogenous cannabis, other phytocannabinoids, and synthetic compounds.
Cannabis and its derivatives have been found to affect many gastrointestinal processes by affecting the endocannabinoid system (ECS) with anti-inflammatory, antinociceptive, and antisecretory effects. It is believed that some gastrointestinal disorders can be treated with cannabinoids: relieving chronic pain, nausea, and vomiting caused by chemotherapy, and improving the course of nonalcoholic fatty liver disease and inflammatory bowel disease. Studies have also shown an important role for ECS in metabolism. Despite the potential benefits of cannabis, undesirable effects have so far limited its medical use.
Cannabis contains many chemically active compounds, including cannabinoids, terpenoids, flavonoids and alkaloids. The most important of these are Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD). Besides these, more than 100 other active cannabinoids are known, each capable of modulating the ECS. The latter is a network of cannabinoid receptors, their ligands, and regulatory synthesizing and degrading enzymes that function on demand. The ligands include anandamide and 2-arachidonoylglycerol, lipids produced by arachidonic acid metabolism. The most important are cannabinoid receptors 1 and 2 (CB1 and CB2), as well as the transient cation channel potential receptor (subfamily V, member 1), peroxisome proliferator-activated receptor alpha, and the orphan G protein associated with GPR55 and GPR119 receptors. Enzymes that synthesize endocannabinoids include diacylglycerollipase, which synthesizes anandamide, and N-acylphosphatidylethanolamine-specific phospholipase D, which synthesizes 2-arachidonoylglycerol. Enzymes such as fatty acid amide hydrolase and monoacylglycerollipase degrade endocannabinoids. ECS can be activated by exogenous cannabis, other phytocannabinoids, and synthetic compounds.
Cannabis affects many gastrointestinal processes through its effects on ECS. Cannabinoid receptors and their ligands are distributed throughout the human GI tract with regional variations in their expression. Thus, CB1 receptors are expressed in the enteric nervous system on epithelial cells, in the myenteric and submucosal nerve plexuses, and are also found near motoneurons, interneurons, and primary afferent neurons. CB2 receptors are frequently expressed on immune cells and in the peripheral nervous system. ECS maintains intestinal homeostasis by modulating immune tolerance, gastrointestinal motility, visceral pain, and inflammation. Receptor activation leads to increased food intake and increased metabolic processes that affect energy balance, including lipolysis and glucose metabolism.
Effect of cannabis on gastrointestinal motility
In animal studies, CB1 agonists decreased motility, whereas CB1 antagonists had a prokinetic effect. CB1 receptors are found on presynaptic neurons in the myenteric plexus and submucosal neurons. CB1 agonists inhibit excitatory cholinergic neurons, which leads to a decrease in contractile activity and subsequent inhibition of peristalsis. In addition, CB1 modulate interneuron-mediated neurotransmission and peristaltic reflexes by inhibiting substance P secretion and vasointestinal peptide release. These effects are dose-dependent and independent of rhythm-guiding cells (such as Cajal interstitial cells). The role of CB2 in physiological processes is less well understood, but their role in inflammatory conditions is well understood.
THC and esophageal function
Several studies have evaluated the effects of cannabis on esophageal motility and the pathogenesis of gastroesophageal reflux disease. Two studies found cannabinoid-related relaxation of the lower esophageal sphincter; short-term use of THC reduced esophageal sphincter pressure and relaxed it, whereas the CB1 antagonist rimonabant increased NPS pressure after a meal. In contrast, a limited retrospective study showed a higher prevalence of esophageal sphincter hypertension in chronic cannabis users, and further research is needed in this area. THC administration temporarily reduced the frequency of transient esophageal sphincter relaxation and acid reflux episodes.
Data on the role of cannabinoids in the pathogenesis of functional chest pain are still limited. In a prospective study, it was found that use of the CB1 agonist dronabinol for 4 weeks resulted in an increase in pain threshold, a decrease in pain intensity, and odynophagia compared to placebo without significant side effects. Thus, cannabis may improve esophageal function and reduce symptoms of gastroesophageal reflux disease and noncardiac chest pain, although further studies are needed to confirm these effects.
Gastric emptying and gastroparesis
Gastric emptying is slowed after cannabinoid use, as shown in animal studies and limited studies involving humans, mainly by the effects of CB1 agonists on the peripheral and central nervous system pathways. In two placebo-controlled studies, THC and dronabinol slowed gastric emptying. Notably, the response to dronabinol depended on gender: women had longer gastric emptying times and men had higher fasting gastric volumes, possibly due to hormonal differences.
A survey of patients with gastroparesis showed that cannabis use was associated with an improvement in symptoms that was less pronounced with oral dronabinol compared to cannabis inhalation, possibly due to potential lower bioavailability. This suggests that the dose and route of administration of cannabis may contribute to gastroparesis by influencing pathogenetic mechanisms other than gastric emptying. More research is needed to determine the benefits of clinical use of cannabis in certain subgroups of patients with gastroparesis (idiopathic, diabetic, postoperative).
In animal studies, CB1 agonists decreased motility, whereas CB1 antagonists had a prokinetic effect. CB1 receptors are found on presynaptic neurons in the myenteric plexus and submucosal neurons. CB1 agonists inhibit excitatory cholinergic neurons, which leads to a decrease in contractile activity and subsequent inhibition of peristalsis. In addition, CB1 modulate interneuron-mediated neurotransmission and peristaltic reflexes by inhibiting substance P secretion and vasointestinal peptide release. These effects are dose-dependent and independent of rhythm-guiding cells (such as Cajal interstitial cells). The role of CB2 in physiological processes is less well understood, but their role in inflammatory conditions is well understood.
THC and esophageal function
Several studies have evaluated the effects of cannabis on esophageal motility and the pathogenesis of gastroesophageal reflux disease. Two studies found cannabinoid-related relaxation of the lower esophageal sphincter; short-term use of THC reduced esophageal sphincter pressure and relaxed it, whereas the CB1 antagonist rimonabant increased NPS pressure after a meal. In contrast, a limited retrospective study showed a higher prevalence of esophageal sphincter hypertension in chronic cannabis users, and further research is needed in this area. THC administration temporarily reduced the frequency of transient esophageal sphincter relaxation and acid reflux episodes.
Data on the role of cannabinoids in the pathogenesis of functional chest pain are still limited. In a prospective study, it was found that use of the CB1 agonist dronabinol for 4 weeks resulted in an increase in pain threshold, a decrease in pain intensity, and odynophagia compared to placebo without significant side effects. Thus, cannabis may improve esophageal function and reduce symptoms of gastroesophageal reflux disease and noncardiac chest pain, although further studies are needed to confirm these effects.
Gastric emptying and gastroparesis
Gastric emptying is slowed after cannabinoid use, as shown in animal studies and limited studies involving humans, mainly by the effects of CB1 agonists on the peripheral and central nervous system pathways. In two placebo-controlled studies, THC and dronabinol slowed gastric emptying. Notably, the response to dronabinol depended on gender: women had longer gastric emptying times and men had higher fasting gastric volumes, possibly due to hormonal differences.
A survey of patients with gastroparesis showed that cannabis use was associated with an improvement in symptoms that was less pronounced with oral dronabinol compared to cannabis inhalation, possibly due to potential lower bioavailability. This suggests that the dose and route of administration of cannabis may contribute to gastroparesis by influencing pathogenetic mechanisms other than gastric emptying. More research is needed to determine the benefits of clinical use of cannabis in certain subgroups of patients with gastroparesis (idiopathic, diabetic, postoperative).
Intestinal transit
Cannabinoid use delays colonic transit. In animal and human studies, it has been found that increased ECS tone suppresses cholinergic contractility, which contributes to delayed transit through the colon. In a randomized, placebo-controlled study, dronabinol reduced the contractile activity of the colon of patients during meals and in the postprandial period. In addition, in a retrospective case series evaluation, 6 patients with refractory diarrhea treated with the CB1 agonist nabilone showed decreased defecation frequency and increased defecation weight. At the same time, only 1 patient had significant side effects, which resolved on their own after discontinuation of the drug. In addition, CB1 antagonists increase colonic motility, which was shown in a meta-analysis: the incidence of diarrhea increased with rimonabant or taranabant.
Dysregulation of the enzymes that synthesize and degrade endocannabinoids (fatty acid amide hydrolase (FAAH), monoacylglycerollipase and diacylglycerollipase) may contribute to impaired colon motility. Inhibition of these enzymes increases endocannabinoid potential, thereby reducing transit through the colon. In a series of cases, the activity of fatty acid amide hydrolase was evaluated in patients with constipation against the background of delayed intestinal transit. Compared with control samples, higher levels of anandamide, 2-arachidonoylglycerol, and palmitoyl ethanolamide (inversely related to FAAH) were found in the serum of patients with delayed intestinal transit, confirming - low FAAH levels contribute to delayed intestinal transit. In addition, patients with delayed intestinal transit have increased CB1 expression in myenteric nerve fibers, indicating increased sensitivity to the action of endocannabinoids.
Despite these findings, a nationwide review of the available database showed that cannabis use was associated with decreased constipation. This discrepancy may be due to differences in assessing the mode of delivery of cannabis (inhaled or ingested) or with the dose. In addition, CBD can inhibit CB1, with the result that different formulations with altered CBD/THC ratios may attenuate CB1-mediated activity. Overall, the data suggest that ECS affects colonic motility and may be an effective target in the treatment of colonic motility disorders.
Cannabis and irritable bowel syndrome
The pathogenesis of irritable bowel syndrome (IBS) includes disruption of the brain-gut axis, changes in GI motility, visceral hypersensitivity, low-intensity inflammation, immune dysregulation and intestinal dysbiosis. Considering the interactions of the ECS with many of these processes, we can conclude that changes in the tone of the ECS may influence the pathogenesis of IBS. For example, studies in mice have helped to detect direct or indirect activation of CB1 and probably CB2 receptors, which can inhibit visceral sensitivity and pain. Accordingly, CB1 expression is decreased under stress conditions, and visceral hyperalgesia is noted after CB1 antagonist application (WIN 55,212-2). CB1 activation also affects other pain pathways outside the ECS. Low CB1 expression in the dorsal radicular ganglion leads to increased expression of the transient cation channel potential receptor (subfamily V, member 1). These data indicate that there is a link between the ECS and the vanilloid system responsible for sensation and pain, which in turn indicates a role for CB1 in pain perception.
Cannabinoid use delays colonic transit. In animal and human studies, it has been found that increased ECS tone suppresses cholinergic contractility, which contributes to delayed transit through the colon. In a randomized, placebo-controlled study, dronabinol reduced the contractile activity of the colon of patients during meals and in the postprandial period. In addition, in a retrospective case series evaluation, 6 patients with refractory diarrhea treated with the CB1 agonist nabilone showed decreased defecation frequency and increased defecation weight. At the same time, only 1 patient had significant side effects, which resolved on their own after discontinuation of the drug. In addition, CB1 antagonists increase colonic motility, which was shown in a meta-analysis: the incidence of diarrhea increased with rimonabant or taranabant.
Dysregulation of the enzymes that synthesize and degrade endocannabinoids (fatty acid amide hydrolase (FAAH), monoacylglycerollipase and diacylglycerollipase) may contribute to impaired colon motility. Inhibition of these enzymes increases endocannabinoid potential, thereby reducing transit through the colon. In a series of cases, the activity of fatty acid amide hydrolase was evaluated in patients with constipation against the background of delayed intestinal transit. Compared with control samples, higher levels of anandamide, 2-arachidonoylglycerol, and palmitoyl ethanolamide (inversely related to FAAH) were found in the serum of patients with delayed intestinal transit, confirming - low FAAH levels contribute to delayed intestinal transit. In addition, patients with delayed intestinal transit have increased CB1 expression in myenteric nerve fibers, indicating increased sensitivity to the action of endocannabinoids.
Despite these findings, a nationwide review of the available database showed that cannabis use was associated with decreased constipation. This discrepancy may be due to differences in assessing the mode of delivery of cannabis (inhaled or ingested) or with the dose. In addition, CBD can inhibit CB1, with the result that different formulations with altered CBD/THC ratios may attenuate CB1-mediated activity. Overall, the data suggest that ECS affects colonic motility and may be an effective target in the treatment of colonic motility disorders.
Cannabis and irritable bowel syndrome
The pathogenesis of irritable bowel syndrome (IBS) includes disruption of the brain-gut axis, changes in GI motility, visceral hypersensitivity, low-intensity inflammation, immune dysregulation and intestinal dysbiosis. Considering the interactions of the ECS with many of these processes, we can conclude that changes in the tone of the ECS may influence the pathogenesis of IBS. For example, studies in mice have helped to detect direct or indirect activation of CB1 and probably CB2 receptors, which can inhibit visceral sensitivity and pain. Accordingly, CB1 expression is decreased under stress conditions, and visceral hyperalgesia is noted after CB1 antagonist application (WIN 55,212-2). CB1 activation also affects other pain pathways outside the ECS. Low CB1 expression in the dorsal radicular ganglion leads to increased expression of the transient cation channel potential receptor (subfamily V, member 1). These data indicate that there is a link between the ECS and the vanilloid system responsible for sensation and pain, which in turn indicates a role for CB1 in pain perception.
It has been suggested that ECS is sensitized in an inflammatory or hyperalgesic state by modulation of CB2 expression. This is very important because patients with IBS usually have concomitant low-grade intestinal inflammation. Studies in rats with colitis support this observation. For example, administration of the CB2 agonist (PF-03550096) increased the pain threshold in response to intestinal distension, which was dose- and route-dependent. CB2 activation can also inhibit other inflammatory mediators, including bradykinin, which is responsible for inflammation-induced pain. In addition to its direct effect on cannabinoid receptors, modification of degrading enzymes may also affect IBS symptoms. In mice with visceral inflammation (induced by acetic acid) and distension-induced pain, FAAH inhibitors and monoacylglycerollipase had an analgesic effect, reducing inflammation-induced pain and increasing the threshold of pain perception due to gut distension. Thus, ECS controls pain sensation under physiological conditions and in inflammatory conditions.
There have been only a few studies investigating the role of ECS in patients with IBS. For example, patients with IBS with 2 variants of the CNR1 gene and patients without IBS studied small- and largeintestinal transit using scintigraphy in response to isobaric distension of the colon. Researchers found a significant association between the CNR1 gene polymorphism (rs806378 allele) and accelerated colonic transit in patients with IBS with diarrhea (IBS-d). There was also an association between this gene variant and flatulence but not pain, confirming the role of cannabinoid receptors in the regulation of motility and sensitivity. The modulation of ECS by dronabinol was also evaluated in 75 patients with different subtypes of IBS and ECS gene polymorphisms. Regardless of IBS subtype, dronabinol reduced the proximal colonic motility index on an empty stomach compared with placebo, although the greatest effect was seen in patients with IBS-D. Another randomized study evaluated single nucleotide polymorphisms of the CNR1 rs806378 and FAAH rs324420 genes in patients with IBS-D. However, in this study, dronabinol showed no statistically significant effect on transit. In subjects without IBS, dronabinol inhibited colon motility after a meal, which was previously observed in patients with IBS, but these subjects had an increased pain threshold for bowel distension. The findings suggest that the response to cannabinoids appears to be different in IBS patients and healthy subjects.
CB2 can also modulate inflammation and pain in patients with IBS. Dietary supplementation with polydatin and palmitoylethanolamide (structurally related to anandamide) for 12 weeks in patients with IBS was accompanied by a decrease in the severity of abdominal pain compared to placebo. These patients also had a higher number of mast cells in the intestinal mucosa and higher levels of CB2 expression.
A recent study by Dothel et al. showed increased levels of μ-opioid receptor, CB2 messenger RNA and protein, and β-endorphin in colonic mucosal biopsies in patients with IBS compared with asymptomatic subjects, with higher levels of CB2 messenger RNA in mucosa biopsies from women than from men. In contrast, in the asymptomatic control group, men had higher expression of it than women. These results suggest that cannabinoids via CB2 are able to influence immune-mediated visceral pain. Although cannabinoids may be essential in the treatment of dysmotor disorders, they are not yet used in practice because further research is needed.
Effect of cannabis on the intestinal microbiome
Cannabis is thought to have the ability to modify the intestinal microbiome (IM) and as such is used in the treatment of various conditions associated with intestinal dysbiosis. For example, in a nationwide inpatient database analysis, cannabis use (including dependent and independent use) was associated with a significant 28% reduced risk (by 28%) of Clostridioides difficile infection in hospitalized patients compared to those who did not use it. However, there is little data on the overall effect of cannabis on IM, especially because preclinical studies of cannabinoid receptor agonists and antagonists have produced inconsistent results. In addition, because of limited medical oversight and lack of standardization, there have been reports of contamination of medicinal cannabis with bacterial and fungal pathogens, leading to legitimate concerns about its negative effects on IM composition.
There have been only a few studies investigating the role of ECS in patients with IBS. For example, patients with IBS with 2 variants of the CNR1 gene and patients without IBS studied small- and largeintestinal transit using scintigraphy in response to isobaric distension of the colon. Researchers found a significant association between the CNR1 gene polymorphism (rs806378 allele) and accelerated colonic transit in patients with IBS with diarrhea (IBS-d). There was also an association between this gene variant and flatulence but not pain, confirming the role of cannabinoid receptors in the regulation of motility and sensitivity. The modulation of ECS by dronabinol was also evaluated in 75 patients with different subtypes of IBS and ECS gene polymorphisms. Regardless of IBS subtype, dronabinol reduced the proximal colonic motility index on an empty stomach compared with placebo, although the greatest effect was seen in patients with IBS-D. Another randomized study evaluated single nucleotide polymorphisms of the CNR1 rs806378 and FAAH rs324420 genes in patients with IBS-D. However, in this study, dronabinol showed no statistically significant effect on transit. In subjects without IBS, dronabinol inhibited colon motility after a meal, which was previously observed in patients with IBS, but these subjects had an increased pain threshold for bowel distension. The findings suggest that the response to cannabinoids appears to be different in IBS patients and healthy subjects.
CB2 can also modulate inflammation and pain in patients with IBS. Dietary supplementation with polydatin and palmitoylethanolamide (structurally related to anandamide) for 12 weeks in patients with IBS was accompanied by a decrease in the severity of abdominal pain compared to placebo. These patients also had a higher number of mast cells in the intestinal mucosa and higher levels of CB2 expression.
A recent study by Dothel et al. showed increased levels of μ-opioid receptor, CB2 messenger RNA and protein, and β-endorphin in colonic mucosal biopsies in patients with IBS compared with asymptomatic subjects, with higher levels of CB2 messenger RNA in mucosa biopsies from women than from men. In contrast, in the asymptomatic control group, men had higher expression of it than women. These results suggest that cannabinoids via CB2 are able to influence immune-mediated visceral pain. Although cannabinoids may be essential in the treatment of dysmotor disorders, they are not yet used in practice because further research is needed.
Effect of cannabis on the intestinal microbiome
Cannabis is thought to have the ability to modify the intestinal microbiome (IM) and as such is used in the treatment of various conditions associated with intestinal dysbiosis. For example, in a nationwide inpatient database analysis, cannabis use (including dependent and independent use) was associated with a significant 28% reduced risk (by 28%) of Clostridioides difficile infection in hospitalized patients compared to those who did not use it. However, there is little data on the overall effect of cannabis on IM, especially because preclinical studies of cannabinoid receptor agonists and antagonists have produced inconsistent results. In addition, because of limited medical oversight and lack of standardization, there have been reports of contamination of medicinal cannabis with bacterial and fungal pathogens, leading to legitimate concerns about its negative effects on IM composition.
Nevertheless, in spite of the existing barriers and limitations, several studies on IM and its connection with cannabis intake have nevertheless been conducted. It was found that ECS may play an important role in modulating the sensation of visceral pain in patients with intestinal dysbiosis, which is an important pathogenetic factor of functional gastrointestinal disorders. Thus, administration of Lactobacillus acidophilus strains resulted in increased expression of CB2 and μ-opioid receptors in intestinal epithelial cells in rats with induced intestinal hypersensitivity. Thus, IM may enhance or modify the perception of visceral pain through ECS and be involved in treatment strategies for functional gastrointestinal disorders.
Studies in mice have shown that IM affects metabolism by affecting intestinal ECS tone. Dysbiosis developing as a response to a high-fat diet can increase ECS tone, modulate intestinal permeability, and lead to subsequent increases in plasma lipopolysaccharide levels that contribute to metabolic disturbances and inflammation. The proposed endocannabinoid-LPS-regulatory loop is probably dependent on genetic and environmental factors such as diet. Thus, ECS may be a factor linking intestinal dysbiosis to obesity. This theory is supported by the increased ratio of Firmicutes to Bacteroidetes observed in THC-treated mice with diet-induced obesity. These findings suggest that THC may affect IM and obesity, but further research in this direction is needed.
Studies in mice have shown that IM affects metabolism by affecting intestinal ECS tone. Dysbiosis developing as a response to a high-fat diet can increase ECS tone, modulate intestinal permeability, and lead to subsequent increases in plasma lipopolysaccharide levels that contribute to metabolic disturbances and inflammation. The proposed endocannabinoid-LPS-regulatory loop is probably dependent on genetic and environmental factors such as diet. Thus, ECS may be a factor linking intestinal dysbiosis to obesity. This theory is supported by the increased ratio of Firmicutes to Bacteroidetes observed in THC-treated mice with diet-induced obesity. These findings suggest that THC may affect IM and obesity, but further research in this direction is needed.