Category Archives: Inflammatory Bowel Disease

The Endocannabinoid System: Implications in Gastrointestinal Physiology and Pathology

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“The endocannabinoid system (ECS), composed of receptors, endocannabinoids, and enzymes that regulate biosynthesis and degradation, plays a fundamental role in the physiology and pathology of the gastrointestinal tract, particularly in the small and large intestine and liver.

Specifically, cannabinoid receptor type 1 (CB1R) and cannabinoid receptor type 2 (CB2R), located principally in the nervous system and immune cells, orchestrate processes such as intestinal motility, intestinal and hepatic inflammation, and energy metabolism, respectively.

The main endocannabinoids, anandamide (AEA) and 2-arachidonoylglycerol (2-AG), influence appetite, body weight regulation, and inflammatory states and thus have implications in obesity, non-alcoholic fatty liver disease (NAFLD) and irritable bowel syndrome (IBS).

Recent studies have highlighted the therapeutic potential of targeting the ECS to modulate gastrointestinal and metabolic diseases. In particular, peripheral CB1R antagonists and CB2R agonists have shown efficacy in treating intestinal inflammation, reducing hepatic steatosis, and controlling IBS symptoms. Moreover, the ECS is emerging as a potential target for the treatment of colorectal cancer, acting on cell proliferation and apoptosis.

This review highlights the opportunity to exploit the endocannabinoid system in the search for innovative therapeutic strategies, emphasizing the importance of a targeted approach to optimize treatment efficacy and minimize side effects.”

https://pubmed.ncbi.nlm.nih.gov/39941074/

“In conclusion, these findings suggest that the ECS offers a versatile approach for modulating gastrointestinal physiological aspects and treating conditions such as obesity and its complications, IBS, and CRC. Future research should refine ECS-targeted therapies to maximize their efficacy and minimize adverse effects, unlocking new opportunities for innovative treatments of disordered metabolism, inflammation, and cancer.

Clinical studies show that medical cannabis could be a valuable adjunct to cancer and treatments for inflammation, providing symptom relief and improving patients’ overall quality of life. However, further research is needed to refine treatment protocols and explore their full therapeutic potential.”

https://www.mdpi.com/1422-0067/26/3/1306

Entourage effects of nonpsychotropic cannabinoids on visceral sensitivity in experimental colitis

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“Abdominal pain is the most disabling symptom of inflammatory bowel diseases, but current treatments are limited, leading patients to seek alternatives such as cannabis.

Cannabis contains over 100 cannabinoids which, unlike tetrahydrocannabinol, are biologically active compounds often without psychotropic effects (ie, nonpsychotropic cannabinoids [npCBs]). These npCBs have analgesic and anti-inflammatory properties and may show potentiating effects when administered in combination, referred to as the entourage effect.

Here, we investigated the analgesic effects of cannabichromene, cannabidiol (CBD), cannabidivarin, and cannabigerol (CBG), individually and in combination, using the mouse model of dextran sulfate sodium colitis-induced visceral hypersensitivity (VHS).

We then explored antinociceptive targets through patch-clamp electrophysiology on dorsal root ganglia neurons and recombinant channels. We found that a single injection of 10 mg/kg of either CBD or CBG reduced both VHS and c-Fos activation in the spinal dorsal horn. Moreover, a combination of npCBs consisting of 5 mg/kg CBD with 1 mg/kg of cannabichromene, cannabidivarin, and CBG-all at subtherapeutic dosages-reduced VHS, without altering colitis. Electrophysiological recordings revealed that the antinociceptive mixture of npCBs acts through voltage-gated sodium and calcium channels, particularly Cav2.2, but not Cav3.2 and Kv channels.

These results suggest that CBD, CBG, and a mixture of npCBs given at subtherapeutic doses may be beneficial in managing VHS associated with inflammatory bowel disease.

SIGNIFICANCE STATEMENT: Cannabis is increasingly used as an alternative treatment for managing pain associated with chronic conditions. Nonpsychotropic cannabinoids, such as cannabidiol, interact with ionotropic and voltage-gated ion channels. In our study, we demonstrated that cannabidiol, cannabigerol, and a combination of nonpsychotropic cannabinoids, administered at subtherapeutic doses, effectively alleviated visceral hypersensitivity associated with inflammatory bowel disease.”

https://pubmed.ncbi.nlm.nih.gov/39921943/

https://jpet.aspetjournals.org/article/S0022-3565(25)09725-3/abstract

Cannabis use in Crohn’s disease: a systematic review and meta-analysis of randomized controlled trials (RCTs)

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“Objective: This meta-analysis aims to systematically evaluate the efficacy and safety of cannabis in the management of Crohn’s disease (CD) by synthesizing evidence from randomized controlled trials (RCTs). By adhering to the 2020 PRISMA guidelines and registering the study protocol with PROSPERO, this research intends to offer robust, evidence-based recommendations for healthcare practitioners on the therapeutic potential and clinical implications of cannabis use in CD management.

Methods: A literature search encompassing PubMed, Google Scholar, and the Cochrane Library was conducted to identify relevant RCTs comparing cannabis to placebo or standard therapy in CD patients. Inclusion criteria focused on outcomes such as remission rates, C-reactive protein (CRP) levels, quality of life (QoL), and adverse events (AEs). Statistical analysis using RevMan 5.3 involved weighted mean differences (MD) and 95% confidence intervals to compare outcomes between the cannabis and control groups.

Results: The meta-analysis revealed significant findings regarding the impact of cannabis on CD management. The cannabis group exhibited significantly higher clinical remission rates at 8 weeks compared to the control group, with low heterogeneity [MD = – 67.98; 95% CI: (- 100.68, – 35.29)]. However, a statistically significant improvement in QoL was observed in the placebo group compared to the cannabis-treated group [MD = 19.62; 95% CI (14.24 to 25.00)]. There was a non-significant lowering in serum CRP levels compared to the placebo group [MD: – 0.51; 95% CI: (- 1.05, 0.02)].

Conclusion: The study concludes that cannabis shows promise as a therapeutic option for CD, demonstrating higher remission rates and potential benefits for disease management. However, it also highlights the need for larger, standardized research studies to solidify conclusions regarding efficacy, safety, and biomarker responses in CD patients.”

https://pubmed.ncbi.nlm.nih.gov/39821383/

https://link.springer.com/article/10.1007/s11845-024-03844-w

Cannabidiol Alleviates Intestinal Fibrosis in Mice with Ulcerative Colitis by Regulating Transforming Growth Factor Signaling Pathway

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“Objective: The aim of this study is to investigate the protective effect of Cannabidiol (CBD) on DSS-induced colitis in C57BL/6 mice and its related pathways.

Methods: A mouse model of ulcerative colitis (US) was induced by DSS. Enzyme-linked immunosorbent assay (ELISA), quantitative reverse transcription polymerase-chain reaction (qRT-PCR), Western blot (WB) and immunofluorescence (IF) were used to identify the key factors involved in inflammatory response, oxidative stress and intestinal fibrosis. In addition, we transfected si-RNA into CCD-18Co cells.

Results: The research suggests that CBD significantly improves intestinal inflammation by up-regulating the nuclear factor erythroid 2-related factor 2 (Nrf2) expression, inhibiting the classical Nuclear Factor kappa-light-chain-enhancer of activated B cells (NF-κb) pathway, and inhibiting the release of IL-6 (Interleukin), IL-1β, Tumor Necrosis Factor-α (TNF-α) and other factors. At the same time, CBD plays an antioxidant role by regulating Nrf2/ HO-1 (Heme Oxygenase-1) pathway and activating HO-1 activity. On the other hand, CBD may regulate Transforming growth factor beta (TGF-β)/SMADs signaling pathway by inhibiting the expression of TGF-β1, thereby inhibiting the expression of α-SMA, Collagen1, TIMP1 and other factors, thus playing an anti-fibrotic role. Notably, when Nrf2 is inhibited or lacking, CBD loses the above protective effect against DSS-induced colon injury.

Conclusion: CBD affects the classical NF-κb pathway, Nrf2/ Heme Oxygenase-1 (HO-1) pathway, and Transforming growth factor beta (TGF-β)/SMAD pathway by regulating Nrf2, thereby reducing colonic inflammation and oxidative stress and improving the progression of colonic fibrosis.”

https://pubmed.ncbi.nlm.nih.gov/39802511/

“Taken together, our study demonstrated that CBD affected the classical NF-κb pathway, Nrf2/HO-1 pathway, and TGF-β1/SMAD pathway by regulating Nrf2, thereby reducing intestinal inflammation, oxidative stress and intestinal fibrosis, improving intestinal function and pathological symptoms, and thereby protecting against DSS-induced colon injury. These findings provide new ideas and directions for the treatment of UC.”

https://www.dovepress.com/cannabidiol-alleviates-intestinal-fibrosis-in-mice-with-ulcerative-col-peer-reviewed-fulltext-article-JIR

Cannabis sativa alleviates experimentally acetic acid- induced ulcerative colitis in rats: targeting CB1/SIRT/MAPK signaling pathways

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“Background: Ulcerative colitis (UC) is a frequent inflammatory bowel disease (IBD) that causes long-lasting inflammation in the innermost lining of the rectum and colon.

Objective: The aim of this study was to evaluate the therapeutic effect of Cannabis sativa (C. sativa) on the amelioration of acetic acid-induced colitis in rats.

Materials and methods: Group 1: normal control group was intrarectally administered saline solution (0.9%); group 2: acetic acid (AA) group was given AA intra-rectally (2 mL of 4% (v/v) in 0.9% NaCl) once.; group 3&4: This group represented the ulcerative colitis-induced rats that were injected with acetic acid intra-rectally, then s.c. injection with C. sativa (20 and 40 mg/kg daily for 8 days).

Results: Colonic architectural abnormality significantly improved after pretreatment with C. sativa. Additionally, it significantly reduced the MDA level and prevented the depletion of GSH content. Moreover, C. sativa administration showed suppressive activities on pro-inflammatory cytokines, including NF-κB, MAPK, ERK, PI3K, AKT, HIF-1α, and TLR4. Moreover, it significantly upregulated the level of SIRT and CB1 in the colon tissue.

Conclusion: This study provided a novel impact for CB1 receptor activation produced by C. sativa against AA-induced UC in rats through inhibiting the TLR-4 MAPK/ERK, PI3K, and NFκB signaling pathways.”

https://pubmed.ncbi.nlm.nih.gov/39721800/

https://www.tandfonline.com/doi/full/10.1080/08923973.2024.2445733

Cannabidiol Enhances Mitochondrial Metabolism and Antioxidant Defenses in Human Intestinal Epithelial Caco-2 Cells

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“Background: The reintroduction of hemp production has resulted in increased consumption of cannabidiol (CBD) products, particularly CBD oil, yet their effects on intestinal health are not fully understood. Proper mitochondrial function and antioxidant defenses are vital for maintaining the intestinal epithelial barrier. AMP-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor gamma coactivator (PGC)1α are key mediators of mitochondrial metabolism.

Methods & results: Using Caco-2 cells, we found that CBD oil promoted AMPK phosphorylation, upregulated differentiation markers, and enhanced PGC1α/SIRT3 mitochondrial signaling. CBD oil reduced reactive oxygen species production and increased antioxidant enzymes. Moreover, CBD oil also increased levels of citrate, malate, and succinate-key metabolites of the tricarboxylic acid cycle-alongside upregulation of pyruvate dehydrogenase and isocitrate dehydrogenase 1. Similarly, pure CBD induced metabolic and antioxidant signaling.

Conclusions: CBD enhances mitochondrial metabolic activity and antioxidant defense in Caco-2 cells, making it a promising candidate for treating intestinal dysfunction.”

https://pubmed.ncbi.nlm.nih.gov/39599629/

https://www.mdpi.com/2072-6643/16/22/3843

The Modulatory Effects and Therapeutic Potential of Cannabidiol in the Gut

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“Cannabidiol (CBD) is a major non-psychotropic phytocannabinoid that exists in the Cannabis sativa plant.

CBD has been found to act on various receptors, including both cannabinoid and non-cannabinoid receptors. In addition, CBD has antioxidant effects that are independent of receptors. CBD has demonstrated modulatory effects at different organ systems, such as the central nervous system, immune system, and the gastrointestinal system. Due to its broad effects within the body and its safety profile, CBD has become a topic of therapeutic interest.

This literature review summarizes previous research findings with regard to the effect of CBD on the gastrointestinal (GI) system, including its effects at the molecular, cellular, organ, and whole-body levels. Both pre-clinical animal studies and human clinical trials are reviewed.

The results of the studies included in this literature review suggest that CBD has significant impact on intestinal permeability, the microbiome, immune cells and cytokines. As a result, CBD has been shown to have therapeutic potential for GI disorders such as inflammatory bowel disease (IBD).

Furthermore, through interactions with the gut, CBD may also be helpful in the treatment of disorders outside the GI system, such as non-alcoholic liver disease, postmenopausal disorders, epilepsy, and multiple sclerosis. In the future, more mechanistic studies are warranted to elucidate the detailed mechanisms of action of CBD in the gut. In addition, more well-designed clinical trials are needed to explore the full therapeutic potential of CBD on and through the gut.”

https://pubmed.ncbi.nlm.nih.gov/39404382/

“CBD has exhibited modulatory effects on both the intestinal barrier permeability and the gut microbiome. In addition, CBD has displayed therapeutic potential for the treatment of GI disorders such as IBD. Furthermore, CBD may produce therapeutic effects on diseases outside the GI system by regulating gut–liver, gut–bone, and gut–brain axes.”

https://www.mdpi.com/2073-4409/13/19/1618

Meta-analysis of the Therapeutic Impact of Cannabinoids in Inflammatory Bowel Disease

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“Background: With the increasing legalization of medical and recreational cannabis, patients and providers have growing interest in the role of cannabinoids in treating inflammatory bowel disease. Prior meta-analysis has shown inconclusive evidence for efficacy of cannabinoids. We sought to produce an up-to-date meta-analysis that pools new data to evaluate the therapeutic effects of cannabinoids in both Crohn’s disease (CD) and ulcerative colitis (UC).

Methods: PubMed, Embase, CENTRAL and CINAHL were queried for randomized-controlled trials evaluating the impact cannabinoids in CD or UC. Random effects modeling was used to compute pooled estimates of risk difference. Heterogeneity was assessed using I2.

Results: Eight studies, including 4 studies of CD, 3 studies of UC, and 1 study of both diseases met inclusion criteria. Among 5 studies of CD, a statistically significant decrease in clinical disease activity following intervention was observed (risk ratios [RR], -0.91; 95% CI, CI:1.54 to CI:0.28, I2 = 71.9%). Clinical disease activity in UC was not significantly lower in the pooled analysis (RR, -2.13; 95% CI, -4.80 to 0.55; I2 = 90.3%). Improvement in quality of life (QoL) was observed in both CD and UC combined (RR, 1.79; 95% CI, 0.92-0.2.66; I2 = 82.8%), as well as individually. No differences were observed in the analysis on endoscopic disease activity and inflammatory markers.

Conclusions: This meta-analysis of clinical trials suggests that cannabinoids are associated with improved quality of life in both CD and UC, as well as improved disease activity but not inflammation.”

https://pubmed.ncbi.nlm.nih.gov/39197096/

https://academic.oup.com/ibdjournal/advance-article-abstract/doi/10.1093/ibd/izae158/7743320?redirectedFrom=fulltext&login=false

Cannabinoids for Inflammatory Bowel Disease: A Scoping Review

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“Purpose: Inflammatory bowel disease (IBD) has two main variants, ulcerative colitis (UC) and Crohn’s disease (CD), which are characterized by a cycle of remission and relapse. The aim of this scoping review is to understand the landscape of unprescribed and prescribed cannabis use among patients with IBD and investigate objective clinical benefits. 

Methodology: A literature search was performed across Medline, Embase via Ovid, Scopus, and Cochrane Library databases. We included 40 studies (14 abstracts/letters, 7 randomized controlled trials [RCTs], 6 cohort studies [2 case-matched], 10 cross-sectional surveys, and 3 meta-analyses) in the review. 

Results: Between 11% and 17.6% of surveyed patients used cannabis for symptom control with a lifetime prevalence of 39.8-78.2%. Patients reported reduced abdominal pain, emotional distress, stool frequency, and anorexia. There was a higher rate of depression, tobacco, and alcohol use among patients with IBD who used cannabis. Individual studies showed patients who were prescribed cannabis were more likely to have had surgery for IBD (14.5% vs. 4.7%, p = 0.0008), require future abdominal surgery (odds ratio = 5.03), report a lower quality of life (p = 0.0001), currently be on corticosteroids (18.1% vs. 10.4%, p = 0.04) and opioids (27.7% vs. 6.4%, p = 0.0001). RCTs of cannabinoids reported mild reductions in disease activity and variable endoscopic inflammation improvement. 

Conclusions: Patients who use cannabis for IBD are a cohort with refractory disease and lower quality of life who report improvements in symptom management. However, the ability to reduce underlying disease activity appears very modest. Further trials using refined cannabinoid formulations may define a use in IBD.”

https://pubmed.ncbi.nlm.nih.gov/39029906/

https://www.liebertpub.com/doi/10.1089/can.2024.0061

High cannabigerol hemp extract moderates colitis and modulates the microbiome in an inflammatory bowel disease model

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“Cannabis sativa L. has a long history of medicinal use, particularly for gastrointestinal diseases. Patients with inflammatory bowel disease (IBD) report using cannabis to manage their symptoms, despite little data to support the use of cannabis or cannabis products to treat the disease.

In this study, we utilize the well-described dextran sodium sulfate (DSS) model of colitis in mice to assess the impact of commercially available, non-euphorigenic, high cannabigerol (CBG) hemp extract (20 mg/mL cannabigerol, 20.7 mg/mL cannabidiol, 1 mg/mL cannabichromene) on IBD activity and the colonic microbiome. Mice were given 2% DSS in drinking water for 5 days, followed by 2 days of regular drinking water. Over the 7 days, mice were dosed daily with either high CBG hemp extract or matched vehicle control.

Daily treatment with high CBG hemp extract dramatically reduces the severity of disease at the histological and organismal levels as measured by decreased disease activity index, increased colon length, and decreases in percent colon tissue damage. 16S rRNA gene sequencing of the fecal microbiota reveals high CBG hemp extract treatment results in alterations in the microbiota, that may be beneficial for colitis. Finally, using metabolomic analysis of fecal pellets, we find that mice treated with high CBG hemp extract have a normalization of several metabolic pathways, including those involved in inflammation.

Taken together these data suggest that high CBG hemp extracts may offer a novel treatment option for patients. 

Significance Statement Using the DSS model of colitis, we show that treatment with high CBG hemp extract reduces the severity of symptoms associated with colitis. Additionally, we show that treatment modulates both the fecal microbiota and metabolome with potential functional significance.”

https://pubmed.ncbi.nlm.nih.gov/39009468/

https://jpet.aspetjournals.org/content/early/2024/07/15/jpet.124.002204