With the incidence of colitis on the rise, is cannabis the cure we’ve been waiting for?

What is Colitis?

Colitis refers to the inflammation of the colon, a condition that triggers a myriad of distressing gastrointestinal symptoms and health complications, such as persistent diarrhea, severe abdominal pain, rectal bleeding, chronic fatigue, significant weight loss, and susceptibility to infections. This serious health issue impacts millions globally, making it a pressing concern in the medical community.

A 2023 study from the Crohn's & Colitis Foundation indicates that the rate of inflammatory bowel disease (IBD) in the United States is on the rise, with 721 cases per 100,000 individuals, affecting over 0.7% of the population.

In this two-part blog series, we delve into the world of colitis. Part 1 will cover the fundamental aspects of colitis, including its various classifications, and underlying causes. We will also explore the role of the endocannabinoid system in gastrointestinal physiology and disease. Additionally, we will delve into the promising preclinical data that explores the potential of cannabis as a novel treatment for colitis.

In Part 2, we'll turn our focus to the clinical data and patient surveys that shed light on the real-world outcomes of using cannabis to manage colitis, particularly inflammatory bowel disease. I will also offer practical recommendations for those considering cannabis as a treatment option, aiming to provide a comprehensive understanding of its potential benefits and applications.

Join us as we navigate the complexities of colitis and uncover the evolving role of cannabis in its treatment.

Types of Colitis

Colitis comes in various forms, each with distinct causes and characteristics.

Infectious colitis

Infectious colitis is triggered by bacterial, viral, or parasitic infections that inflame the colon, often resulting in severe diarrhea and abdominal discomfort.

Ischemic colitis

Ischemic colitis occurs when blood flow to the colon is reduced, typically due to a blockage or narrowed arteries, leading to pain and potential tissue damage.

Microscopic colitis

Microscopic colitis involves inflammation that can only be seen under a microscope, further divided into collagenous colitis and lymphocytic colitis.

Inflammatory colitis

Inflammatory colitis, which includes conditions like Crohn's disease and ulcerative colitis, is part of a broader category known as inflammatory bowel disease (IBD).

All types are marked by chronic inflammation and immune system dysfunction that cause persistent symptoms such as abdominal pain, bleeding, and fatigue. Understanding these different types is crucial for diagnosing and tailoring effective treatment strategies for individuals suffering from colitis.

The Role of the Endocannabinoid System in Gastrointestinal Physiology and Disease

The endocannabinoid system (ECS) is a crucial physiological system involved in maintaining homeostasis across various bodily functions, including the gastrointestinal (GI) tract. Understanding how the ECS operates within the GI system can shed light on its potential for treating a range of GI disorders.

The endocannabinoid system is found ubiquitously within all the anatomical locations of the gastrointestinal tract including the nerves (myenteric plexus and submucosal plexus), blood vessels, mucosal epithelial cells, immune cells, muscle cells, and cells which provide endocrine and exocrine function. The ECS plays a pivotal role in modulating all physiological processes of the GI tract including gut motility, immune responses, fluid secretion, pH, and mucosal integrity¹.

The Nervous System

The nervous system governing the gastrointestinal tract is a sophisticated network that integrates the enteric nervous system which resides within the GI tract, with the extrinsic nervous system controlled by the sympathetic and parasympathetic nerves. Additionally, sensory afferent neurons play a crucial role by providing essential feedback to both the intrinsic and extrinsic components, ensuring seamless communication and coordination within the gastrointestinal system².

Cannabinoid Receptors

Plant derived cannabinoids (THC, CBD, minor cannabinoids), endogenous cannabinoids, and synthetic cannabinoids can all interact with the classical cannabinoid receptors CB1 and CB2 found within the gastrointestinal tract.

CB1 receptors are found within all nervous tissue of the GI tract and broadly speaking, activation of the CB1 receptors in the myenteric plexus will decrease GI contractility/motility while activation of the CB1 receptors of the submucosal plexus will decrease intestinal fluid secretion and gastric acid production³. Additionally, CB1 receptors are found on sensory afferent neurons of the intestinal tract and respond to stretch, inflammation, and nutrient environment.

The CB2 receptors are located mainly on immune and epithelial cells of the GI tract and play an integral role in GI immunity and inflammation. To a lesser extent, CB2 receptors can also but be found on nerve cells particularly in the face of inflammation⁴. Activation of CB2 receptors can suppresses cell mediated immunity⁵, inhibit cytokine production, and decrease macrophage and mast cell activation⁶. Cannabinoids are also potent analgesics, and visceral sensation of the gut is inhibited by CB1 and CB2 agonists ^7-8.

Nonclassical Cannabinoid Receptors

In addition to the CB1 and CB2 receptors, there are a host of other nonclassical cannabinoid receptors of the ECS distributed within the anatomical locations of the GI tract including serotonin receptors, transient receptor potential channels (TRP receptors), peroxisome proliferator activated receptors (PPARs), and other G-protein coupled receptors including GPR55. The action of these receptors within the GI tract are not fully understood but appear to play a role in several GI functions.

The Endocannabinoid System and Gastrointestinal Disorders

Research has highlighted significant alterations in the endocannabinoid system (ECS) within the gastrointestinal tracts of both experimental animal models and patients suffering from inflammatory bowel diseases (IBD)^9-10. These changes encompass a wide range of ECS components, including fluctuations in the levels of endocannabinoids (AEA, 2-AG), variations in the expression of cannabinoid receptors (CB1, CB2), and alterations in the activity of enzymes responsible for the synthesis and degradation of endocannabinoids (FAAH, MAGL)^11-13.

Understanding these ECS modifications offers promising insights into the potential therapeutic applications of cannabinoids for managing IBD symptoms and improving patient outcomes. As we delve deeper, the intricate interplay between the ECS and IBD underscores the necessity for ongoing research to harness the full potential of cannabinoid-based treatments in gastrointestinal health.

Preclinical Data on Cannabinoids for Colitis

The following data outlines some of the preclinical data surrounding the use of cannabinoids for inflammation of the intestinal tract.

Acute Colitis:

Research on mice with a CB1 receptor deletion revealed a severe colonic inflammatory response following DNBS administration, a method used to induce colitis. These knockout mice showed significant epithelial disruption, hemorrhagic necrosis, and neutrophil infiltration¹⁴. Pharmacologically blocking the CB1 receptor in wild-type mice produced similar inflammation, including bowel wall thickening and lymphoid follicle enlargement. Wild-type mice maintained better body weight post-DNBS treatment compared to knockout mice.

Treatment with the synthetic CB1 and CB2 agonist HU-210 significantly reduced colonic inflammation. Mice lacking the FAAH enzyme also exhibited a milder inflammatory response than their wild-type counterparts. Similarly, a similar study also demonstrated how CB1 and CB2 knockout mice experienced significant increases in inflammation compared to wild type mice in models of colonic inflammation¹⁵.

In experimental mouse models, intraperitoneal inflammation leads to increased expression of the CB2 receptor emphasizing its role in inflammatory states. In the same study, administration of CB2 agonists resulted in a decrease in both macroscopic and microscopic inflammation while antagonism of the CB2 receptor led to an increased inflammatory reaction ¹⁶. Furthermore, another mouse model supported these findings showing how the introduction of CB1 and CB2 receptor agonists also resulted in decreased markers of inflammation ¹⁷.

In a separate mouse study, inhibiting the enzyme MAGL prior to inducing acute colitis resulted in reduced colon inflammation and lower levels of pro-inflammatory cytokines. This inhibition also decreased colitis-related inflammation in the liver and central nervous system. However, the protective effects were negated when CB1 or CB2 receptor antagonists were co-administered ¹⁸.

Tetrahydrocannabinol (THC) and Cannabidiol (CBD) for Intestinal Inflammation

In animal models of colitis, the intraperitoneal injection of CBD was associated with reduced weight loss, tissue damage, and inflammation while the addition of CBD was also found to attenuate the increased biological markers of inflammation and oxidative stress ¹⁹.

Additionally, a second study confirmed these findings however, when CBD was administered orally, no significant reduction in inflammation was noted ²⁰ while a separate study showed decreased hypermotility and inflammation during administration of a high CBD whole plant extract while the administration of pure CBD did not show any significant reduction in inflammation or the hypermotility associated with inflammation ²¹.

In yet another mouse model, the intraperitoneal injection of a CB2 receptor agonist (JWH-133) resulted in significantly decreased amounts of inflammation, leukocyte inflammation, tissue damage, and reduced T-cell proliferation, while increasing the numbers of mucosal and systemic mast cells ²². 

Summary and Future Directions

Preclinical studies provide a promising foundation for the use of cannabis in managing colitis. These studies highlight the anti-inflammatory and potential therapeutic properties of cannabinoids, offering a potential alternative to traditional therapies. However, it is essential to recognize that most of this evidence comes from animal models and in vitro studies which do not always translate into human clinical outcomes.

In Part 2 of this blog, we will explore the current clinical data on the use of cannabis for inflammatory bowel disease and colitis. We will also discuss patient surveys the gaps in current research, and the need for clinical trials to validate the efficacy and safety of cannabis for colitis in humans. Stay tuned as we delve deeper into the clinical landscape and prospects of cannabinoid-based therapies for colitis.

References:

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