Effects of Cannabinoids on Intestinal Motility, Barrier Permeability, and Therapeutic Potential in Gastrointestinal Diseases

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“Cannabinoids and their receptors play a significant role in the regulation of gastrointestinal (GIT) peristalsis and intestinal barrier permeability. This review critically evaluates current knowledge about the mechanisms of action and biological effects of endocannabinoids and phytocannabinoids on GIT functions and the potential therapeutic applications of these compounds.

The results of ex vivo and in vivo preclinical data indicate that cannabinoids can both inhibit and stimulate gut peristalsis, depending on various factors. Endocannabinoids affect peristalsis in a cannabinoid (CB) receptor-specific manner; however, there is also an important interaction between them and the transient receptor potential cation channel subfamily V member 1 (TRPV1) system.

Phytocannabinoids such as Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD) impact gut motility mainly through the CB1 receptor. They were also found to improve intestinal barrier integrity, mainly through CB1 receptor stimulation but also via protein kinase A (PKA), mitogen-associated protein kinase (MAPK), and adenylyl cyclase signaling pathways, as well as by influencing the expression of tight junction (TJ) proteins.

The anti-inflammatory effects of cannabinoids in GIT disorders are postulated to occur by the lowering of inflammatory factors such as myeloperoxidase (MPO) activity and regulation of cytokine levels. In conclusion, there is a prospect of utilizing cannabinoids as components of therapy for GIT disorders.”

https://pubmed.ncbi.nlm.nih.gov/38928387/

“In summary, our narrative review highlights the complex interaction between cannabinoids and gastrointestinal physiology, shedding light on their potential therapeutic applications in the treatment of GIT diseases.

The findings highlight the diverse effects of cannabinoids on motility, intestinal permeability, and inflammation, which are mediated by interactions with endocannabinoids and cannabinoid receptors. It is noteworthy that cannabinoids such as THC and CBD exhibit receptor-specific effects on GIT motility via CB1 receptors, causing inhibition of muscle contractility, which may suggest targets for therapeutic interventions. Moreover, the involvement of CB1 and CB2 receptors in regulating intestinal permeability underscores the complexity of mechanisms mediated by cannabinoids in gastrointestinal health.

In addition, cannabinoids show promise as anti-inflammatory agents, offering potential benefits in the treatment of Crohn’s disease, ulcerative colitis, and IBD. Moreover, their role in modulating intestinal motility and relieving pain implicates cannabinoids as potential agents for improving quality of life in gastrointestinal disorders, especially chronic such as IBS. The results of clinical trials and data on the adverse effects of phytocannabinoids indicate that further research is needed to elucidate the exact mechanisms and optimize therapeutic strategies to realize the full potential of cannabinoids in clinical practice.”

https://www.mdpi.com/1422-0067/25/12/6682

[Phytotherapeutic recommendations in medical guidelines for the treatment of gastroenterological diseases – a systematic review]

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“Phytotherapeutics are gaining influence in the treatment of gastroenterological diseases. Their popularity and growing evidence of efficacy contribute to their integration into medical guidelines. A systematic screening identified recommended phytotherapeutic approaches. Based on current scientific data, some recommendations for the use of phytotherapeutic agents are given. For irritable bowel syndrome the use of peppermint oil is “strongly recommended”, especially for pain and flatulence. Other phytotherapeutics such as STW-5, Tibetan Padma Lax or warm caraway oil pads have proven effective in alleviating symptoms. It is “recommended” to integrate them into the treatment concept. For chronic constipation, 30g of fiber per day is recommended. Best data exists for plantago psyllium with moderate evidence and chicory inulin. In case of ulcerative colitis, plantago psyllium as well as the combination of myrrhchamomile flower extract, and coffee charcoal can be used as a complementary treatment in maintaining remission. There is also an “open recommendation” for curcumin for both, remission induction and maintenance. Some phytotherapeutic treatments (e.g., Artemisia absintiumBoswellia serata) show evidence of effectiveness for the treatment of Crohn’s disease, but data are not yet sufficient for recommendations. Cannabis-based medicines can be considered for abdominal pain and clinically relevant appetite loss if standard therapy is ineffective or contraindicated, but they should not be used for acute inflammation in active Crohn’s disease. Further recommendations for other gastroenterological diseases are discussed. The safety and tolerability of the phytotherapeutics were rated as predominantly “very good” to “acceptable”. Some clear recommendations for the use of phytotherapeutics to treat gastroenterological diseases show their great potential. Due to their wide range of effects, phytotherapeutics can be used very well as a complement to conventional medicines in case of complex regulatory disorders. However, further methodologically well-conducted impact studies would be helpful in order to be able to make further recommendations.”

https://pubmed.ncbi.nlm.nih.gov/38604221/

https://www.thieme-connect.de/products/ejournals/abstract/10.1055/a-2279-5045


Neuro-Gastro-Cannabinology: A Novel Paradigm for Regulating Mood and Digestive Health

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“The maintenance of homeostasis in the gastrointestinal (GI) tract is ensured by the presence of the endocannabinoid system (ECS), which regulates important physiological activities, such as motility, permeability, fluid secretion, immunity, and visceral pain sensation. Beside its direct effects on the GI system, the ECS in the central nervous system indirectly regulates GI functions, such as food intake and energy balance. Mounting evidence suggests that the ECS may play an important role in modulating central neurotransmission which affects GI functioning. It has also been found that the interaction between the ECS and microbiota affects brain and gut activity in a bidirectional manner, and a number of studies demonstrate that there is a strong relationship between GI dysfunctions and mood disorders. Thus, microbiota can regulate the tone of the ECS. Conversely, changes in intestinal ECS tone may influence microbiota composition. In this mini-review, we propose the concept of neuro-gastro-cannabinology as a novel and alternative paradigm for studying and treating GI disorders that affect mood, as well as mood disorders that imbalance GI physiology. This concept suggests the use of prebiotics or probiotics for improving the tone of the ECS, as well as the use of phytocannabinoids or endocannabinoid-like molecules, such as palmitoylethanolamide, to restore the normal intestinal microbiota. This approach may be effective in ameliorating the negative effects of GI dysfunctions on mood and/or the effects of mood disorders on digestive health.”

https://pubmed.ncbi.nlm.nih.gov/37920559/

“In particular, the use of cannabis-derived compounds that decrease the impact of stress, regulate circadian rhythm, and improve mood may represent a winning strategy in case of functional GI diseases.”

https://karger.com/mca/article/6/1/130/868373/Neuro-Gastro-Cannabinology-A-Novel-Paradigm-for

Pharmacohistory of Cannabis Use-A New Possibility in Future Drug Development for Gastrointestinal Diseases

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“Humans have employed cannabis for multiple uses including medicine, recreation, food, and fibre. The various components such as roots, flowers, seeds, and leaves have been utilized to alleviate pain, inflammation, anxiety, and gastrointestinal disorders like nausea, vomiting, diarrhoea, and inflammatory bowel diseases (IBDs). It has occupied a significant space in ethnomedicines across cultures and religions. Despite multi-dimensional uses, the global prohibition of cannabis by the USA through the introduction of the Marijuana Tax Act in 1937 led to prejudice about the perceived risks of cannabis, overshadowing its medicinal potential. Nevertheless, the discovery of tetrahydrocannabinol (THC), the primary psychoactive compound in cannabis, and the endocannabinoid system renewed scientific interest in understanding the role of cannabis in modulating different conditions, including gastrointestinal disorders. Preparations combining cannabidiol and THC have shown promise in mitigating gut symptoms through anti-inflammatory and motility-enhancing effects. This review revisits the ethnomedicinal use of cannabis in gastrointestinal diseases and emphasizes the need for further research to determine optimal dosages, formulations, and safety profiles of cannabis-based medicines. It also underscores the future potential of cannabinoid-based therapies by leveraging the role of the expanded endocannabinoid system, an endocannabinoidome, in the modulation of gastrointestinal ailments.”

https://pubmed.ncbi.nlm.nih.gov/37834122/

“Taken together, the future of cannabis and cannabinoids research for gastrointestinal disorders involves a comprehensive understanding of their mechanisms of action, multi-centred rigorous clinical trials, personalized medicine approaches, and continued exploration of formulation development and safety considerations. These efforts have the potential to yield novel therapeutic options and improve the quality of life for patients with gastrointestinal disorders.”

https://www.mdpi.com/1422-0067/24/19/14677

Cannabinoids and the GI Tract

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“The synthesis and degradation of endocannabinoids, location of cannabinoid (CB) receptors, and cannabinoid mechanisms of action on immune/inflammatory, neuromuscular, and sensory functions in digestive organs are well documented. CB2 mechanisms are particularly relevant in immune and sensory functions. Increasing use of cannabinoids in the USA is impacted by social determinants of health including racial discrimination which is associated with tobacco and cannabis co-use, and combined use disorders. Several conditions associated with emesis are related to cannabinoid use, including cannabinoid hyperemesis or withdrawal, cyclic vomiting syndrome, nausea and vomiting of pregnancy. Cannabinoids generally inhibit gastrointestinal motor function; yet they relieve symptoms in patients with gastroparesis and diverse nausea syndromes. Cannabinoid effects on inflammatory mechanisms have shown promise in relatively small placebo-controlled studies in reducing disease activity and abdominal pain in patients with inflammatory bowel disease (IBD). Cannabinoids have been studied in disorders of motility, pain, and disorders of gut brain interaction. The CB2 receptor agonist, cannabidiol, reduced total Gastroparesis Cardinal Symptom Index and increased ability to tolerate a meal in patients with gastroparesis appraised over 4 weeks of treatment. In contrast, predominant-pain endpoints in functional dyspepsia with normal gastric emptying were not significantly improved with cannabidiol. The CB2 agonist, olorinab, reduced abdominal pain in IBD in an open-label trial and in constipation-predominant irritable bowel syndrome in a placebo-controlled trial. Cannabinoid mechanisms alter inflammation in pancreatic and liver diseases. In conclusion, cannabinoids, particularly agents affecting CB2 mechanisms, have potential for inflammatory, gastroparesis, and pain disorders; however, the trials require replication and further understanding of risk-benefit to enhance use of cannabinoids in gastrointestinal diseases.”

https://pubmed.ncbi.nlm.nih.gov/37678488/

Cannabidiol Reduced the Severity of Gastrointestinal Symptoms of Opioid Withdrawal in Male and Female Mice

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“Introduction: Opioid withdrawal is a powerful driver of drug-seeking behavior as relief from this aversive state through drug-taking is a strong negative reinforcer. There are currently limited treatment options available for opioid withdrawal and cannabidiol (CBD) has been identified as a potential novel therapeutic. This study explored the efficacy and dose dependency of CBD for reducing the severity of naloxone-precipitated and spontaneous oxycodone withdrawal (PW and SW, respectively) in male and female mice. 

Methods: Mice were administered saline or escalating doses of oxycodone, whereby 9, 17.8, 23.7, and 33 mg/kg oxycodone IP was administered twice daily on days 1-2, 3-4, 5-6, and 7-8, respectively. On the 9th day, a single 33 mg/kg dose of oxycodone (or saline) was administered. To precipitate withdrawal, on day 9, mice in the withdrawal conditions were administered an IP injection of 10 mg/kg naloxone 2 h after the final oxycodone injection and immediately before withdrawal testing. To elicit SW, a separate group of mice underwent withdrawal testing 24 h after their final oxycodone injection. Mice were treated with an IP injection of 0, 10, 30 or 100 mg/kg of CBD 60 min before testing. Withdrawal symptoms examined included gastrointestinal symptoms (fecal boli, diarrhea, and body weight loss), somatic symptoms (paw tremors), and negative affect (jumping). 

Results: A robust PW syndrome was observed in both male and female mice, whereas only male mice displayed an SW syndrome. CBD dose dependently reduced gastrointestinal symptoms during both PW and SW in male mice and during PW in female mice. CBD had no effect on PW- or SW-induced jumping in male mice. However, in female mice, the PW-induced increase in jumps was less pronounced in CBD-treated mice. The highest dose of CBD inhibited paw tremors during PW, but not SW, in male mice. Neither PW- nor SW-induced paw tremors were observed in female mice. 

Conclusions: The magnitude of effects on the gastrointestinal symptoms, their consistency across PW and SW, and both sexes, alongside the availability of CBD for clinical use, suggest further exploration of the potential for CBD to treat these symptoms could be justified.”

https://pubmed.ncbi.nlm.nih.gov/36577048/

https://www.liebertpub.com/doi/10.1089/can.2022.0036

The Enteric Glia and Its Modulation by the Endocannabinoid System, a New Target for Cannabinoid-Based Nutraceuticals?

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“The enteric nervous system (ENS) is a part of the autonomic nervous system that intrinsically innervates the gastrointestinal (GI) tract. Whereas enteric neurons have been deeply studied, the enteric glial cells (EGCs) have received less attention. However, these are immune-competent cells that contribute to the maintenance of the GI tract homeostasis through supporting epithelial integrity, providing neuroprotection, and influencing the GI motor function and sensation. The endogenous cannabinoid system (ECS) includes endogenous classical cannabinoids (anandamide, 2-arachidonoylglycerol), cannabinoid-like ligands (oleoylethanolamide (OEA) and palmitoylethanolamide (PEA)), enzymes involved in their metabolism (FAAH, MAGL, COX-2) and classical (CB1 and CB2) and non-classical (TRPV1, GPR55, PPAR) receptors. The ECS participates in many processes crucial for the proper functioning of the GI tract, in which the EGCs are involved. Thus, the modulation of the EGCs through the ECS might be beneficial to treat some dysfunctions of the GI tract. This review explores the role of EGCs and ECS on the GI tract functions and dysfunctions, and the current knowledge about how EGCs may be modulated by the ECS components, as possible new targets for cannabinoids and cannabinoid-like molecules, particularly those with potential nutraceutical use.”

https://pubmed.ncbi.nlm.nih.gov/36235308/

“Although further studies are needed to define the connections between the ECS and EGCs as a possible target to treat or reduce alterations associated with GI disorders, the use of cannabinoids may be beneficial in prevalent pathologies such as inflammatory bowel disease (IBD) and, maybe, other types of GI pathologies displaying ENS inflammation.”

https://www.mdpi.com/1420-3049/27/19/6773/htm

Therapeutic Effects of Medicinal Cannabinoids on the Gastrointestinal System in Pediatric Patients: A Systematic Review

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“Changes in cannabis legalization have generated interest in medicinal cannabinoids for therapeutic uses, including those that target the gastrointestinal (GI) tract. These effects are mediated through interactions with the endocannabinoid system. Given the increasing societal awareness of the therapeutic potential of cannabinoids, it is important to ensure pediatric representation in clinical studies investigating cannabinoid use.

This systematic review aims to assess the efficacy of medicinal cannabinoids in treating GI symptoms in pediatric patients. A literature search of Medline, Embase, CINAHL, Web of Science, and the Cochrane Library was performed from inception until June 23, 2020. Study design, patient characteristics, type, dose and duration of medicinal cannabinoid therapy, and GI outcomes were extracted. From 7303 records identified, 5 studies met all inclusion criteria. Included studies focused on chemotherapy-induced nausea, inflammatory bowel disease, and GI symptoms associated with severe complex motor disorders.

Results varied based on the symptom being treated, the type of cannabinoid, and the patient population. Medicinal cannabinoids may have a potential role in treating specific GI symptoms in specific patient populations. The limited number and heterogenicity of included studies highlight the demand for future research to distinguish effects among different cannabinoid types and patient populations and to examine drug interactions. As interest increases, higher quality studies are needed to understand the efficacy of cannabinoids as a pediatric GI treatment and whether these benefits outweigh the associated risks (Registration Number: PROSPERO CRD42020202486).”

https://pubmed.ncbi.nlm.nih.gov/36219741/

https://www.liebertpub.com/doi/10.1089/can.2022.0192

Cannabinoids Lead to Significant Improvement in Gastroparesis—Related Abdominal Pain

“Neuropathy plays a large role in the pathogenesis of gastroparesis. Neuropathic pain in gastroparesis is an often difficult—to—treat symptom of the disease, despite 80—90% of patients with gastroparesis reporting abdominal pain as a symptom. Treatment for gastroparesis—related pain is especially limited. Neuromodulators are used for this purpose despite a lack of evidence supporting their effectiveness.

Cannabinoids, primarily delta—9—tetrahydrocannabinol (THC) and cannabidiol (CBD), are increasingly utilized for medicinal purposes. In New York medical marijuana is approved for the treatment of neuropathy with severe pain. Similarly, Dronabinol (a synthetic THC analogue) has been used for nausea vomiting and anorexia for years.

We showed that cannabinoids are effective in the treatment of gastroparesis—related abdominal pain.”

“Conclusion: Our study shows that cannabinoids may play an important role in the management of gastroparesis—related abdominal pain. There are currently no treatments shown to be effective for gastroparetic pain in clinical trials, and cannabinoids may serve a niche for this under—treated symptom.”

https://journals.lww.com/ajg/fulltext/2018/10001/cannabinoids_lead_to_significant_improvement_in.1204.aspx

Plasma endocannabinoids and cannabimimetic fatty acid derivatives are altered in gastroparesis: A sex- and subtype-dependent observation

“Background: Gastroparesis (GP) is a motility disorder of the stomach presenting with upper gastrointestinal symptoms in the setting of delayed gastric emptying. Endocannabinoids are involved in the regulation of GI function including motility. However, their role in the pathophysiology of GP has not been sufficiently investigated. Our goal was to compare the circulating levels of endocannabinoids and cannabimimetic fatty acid derivatives in GP versus control subjects.

Methods: The study compared plasma concentrations of endocannabinoids and their lipoamine and 2-acyl glycerol congeners, measured by high-pressure liquid chromatography/tandem mass spectrometry (HPLC-MS-MS), in adult patients with diabetic gastroparesis (DM-GP; n = 24; n = 16 female), idiopathic gastroparesis (ID-GP; n = 19; n = 11 female), diabetic patients without GP (DM; n = 19; n = 10 female), and healthy controls (HC; n = 18; n = 10 female). Data, presented as mean ± SEM, were analyzed with ANOVA (Sidak post hoc).

Key results: Endocannabinoids anandamide (AEA: 0.5 ± 0.1 nMol/L) and 2-arachidonoyl glycerol (2-AG: 2.6 ± 0.7 nMol/L) were significantly lower in female DM-GP patients vs. DM females (AEA: 2.5 ± 0.7 nMol/L and 2-AG: 9.4 ± 3.3 nMol/L). Other monoacylglycerols including 2-palmitoyl glycerol and 2-oleoyl glycerol were also lower in female DM-GP patients compared to DM females. No changes were observed in men.

Conclusions & inferences: Endocannabinoids and other fatty acid derivatives with cannabimimetic properties are reduced in female DM-GP patients. Since GP, particularly with diabetic etiology, is more prevalent among women and since cannabinoids are antiemetic, this decrease in levels may contribute to symptom development in these subjects. Targeting the endocannabinoid system may be a future therapeutic option in DM-GP patients.”

https://pubmed.ncbi.nlm.nih.gov/32779297/

“Targeting the endocannabinoid system may be a future therapeutic option in DM-GP patients.”

https://onlinelibrary.wiley.com/doi/full/10.1111/nmo.13961