By Gabriella Wan

CBD, or cannabidiol, is a non-psychoactive component of the cannabis plant with anti-inflammatory properties.[1]  To ensure avoidance of psychoactive effects, CBD must be extracted from hemp, not traditional marijuana.[2] In recent years, CBD has become a popular supplement. CBD works in the body through the endocannabinoid system, which is highly upregulated during chronic liver disease, affecting multiple steps along the disease’s progression.[3]

Some research has been done concerning the interactions between CBD and liver disease, with mixed but promising results. The first thing to understand about CBD is that there are two important related receptors in our bodies, called CB1 and CB2. As noted in a 2008 study, cannabinoid receptors (CB1 and CB2) and their binding molecules (endocannabinoids) have emerged as novel mediators of liver diseases. While activation of CB1 receptors can contribute to NAFLD and fibrosis, activation of CB2 receptors have been characterized as antifibrogenic and regulators of inflammation.[4] With this understanding, it makes sense that inhibiting CB1 receptors has been shown to inhibit the progression of fibrosis, while activating CB2 receptors has been shown to inhibit growth and cause cell death for cultured liver fibrogenic cells. Because CB1 and CB2 receptors exert opposite effects on liver fibrosis, evaluating the net impact of using endocannabinoid signaling on liver fibrosis in a clinical setting is complicated and far from clear cut.[5]

“EC receptors expression and functions in the liver. Cannabinoid receptors CB1 and CB2 are expressed in all liver cell types at different basal levels. Both receptors are upregulated during chronic liver damage and mediate opposite functions: CB1 promotes and CB2 protects from liver damage. The experimental and clinical evidences indicate CB1 as a stronger player, contributor and an attractive target in the development of CLD. Abbreviations: ALD, alcoholic liver disease; HCC, hepatocellular carcinoma; NASH, nonalcoholic steatohepatitis; PBC, primary biliary cirrhosis; PSC, primary sclerosing cholangitis; TG, triglyceride; VLDL, very low density lipoprotein.”[6]

In animal tests, the relationship between CB1 receptors and fatty liver (both diet-induced and obesity-associated) has been made clear. Research has shown that high-fat diets induce fatty liver via activation of CB1 receptors, which are necessary for the development of diet-induced steatosis, dyslipidemia, and insulin resistance.[7] Studies with obese rats have shown that the administration of CB1 inhibitors reduced obesity-associated hepatic steatosis and certain features of metabolic syndrome.[8] The drug Rimonabant was the first selective CB1 inhibitor used in clinical practice after clinical trials showed its benefit on weight reduction, abdominal obesity, liver steatosis, and other cardiometabolic syndromes.[9] Though this may seem like good news, it is important to note the increased appearance of psychiatric disorders including depression, anxiety, irritability, and aggression.[10] Consequently, the FDA never approved Rimonabant for the treatment of obesity.

While we have lots of research on CB1 receptors and fatty liver, investigations regarding the role of CB2 receptors in this disease area are minimal. In human studies, liver samples from patients with steatosis and steatohepatitis have expressed CB2 receptors, while liver samples from normal livers showed no CB2 receptor expression.[11] In fibrogenesis, CB2 activation has exhibited some evidence of an anti-fibrogenic role.[12] In rats, studies have shown that activating CB2 receptors in the liver significantly reduced collagen content in rats with pre-existing cirrhosis and improved regenerative response to acute liver injury.[13] It is important to note that other studies have shown conflicting results regarding CB2 and NAFLD.[14]

While you should always consult with your doctor before starting to use any supplement, CBD has some special considerations. If you decide to take it even though the jury is still out on the effects of CB1 and CBD on NAFLD, please be cautious of the following things:

• Dosage
  • The amount of CBD recommended for therapeutic use in humans ranges from 0.5mg/kg/day to 20mg/kg/day.[15]
  • FDA hasn’t created any measures to regulate CBD products, so potency labels can be inaccurate.
• Quality
  • FDA hasn’t created any measures to regulate CBD products, so they may be contaminated or misrepresented.
  • To find safe and reputable products, make sure the company has third-party lab testing, good reviews, and transparency for its products (including sourcing, extraction methods, packaging, and return policies).
• Interactions with other medications being processed by CYP450 family of liver enzymes
  • Many conventional doctors do not know much about CBD since it’s not taught in medical school, so it may be best to ask them if any of the drugs you’re taking are affected by eating grapefruits, since grapefruit also affects the same liver functionality.[16]

Gabriella Wan is a Program Coordinator at the Fatty Liver Foundation with a background in public health. She is passionate about improving quality of life through lifestyle change, awareness raising, and education.

Sources

[1] Avraham, Y, et al, Cannabidiol improves brain and liver function in a fulminant hepatic failure-induced model of hepatic encephalopathy in mice, British Journal of Pharmacology, April 2011, doi: 10.1111/j.1476-5381.2010.01179.x

[2] Tesséra Naturals, Does CBD cause liver damage?, CBD Education, August 2020, https://tesseranaturals.com/does-cbd-cause-liver-damage/

[3] Mallat, A and Lotersztajn, S, Endocannabinoids and liver disease. I. Endocannabinoids and their receptors in the liver, American Journal of Gastrointestinal Liver Physiology, January 2008, doi: 10.1152/ajpgi.00467.2007

[4] Mallat, A and Lotersztajn, S.

[5] Mallat, A and Lotersztajn, S.

[6] Patsenker, E and Stickel, F, Cannabinoids in liver diseases, Clinical Liver Disease, February 2016, doi: 10.1002/cld.527

[7] Osei-Hyiaman, D, et al, Hepatic CB1 receptor is required for development of diet-induced steatosis, dyslipidemia, and insulin and leptin resistance in mice, Journal of Clinical Investigation, September 2008, doi: 10.1172/JCI34827

[8] Gary-Bobo, M, et al, Rimonabant reduces obesity-associated hepatic steatosis and features of metabolic syndrome in obese Zucker fa/fa rats, Hepatology, July 2007, doi: 10.1002/hep.21641

[9] Christopoulou, FD and Kiortsis DN, An overview of the metabolic effects of rimonabant in randomized controlled trials: Potential for other cannabinoid 1 receptor blockers in obesity, Journal of Clinical Pharmacy and Therapeutics, February 2011, doi: 10.1111/j.1365-2710.2010.01164.x

[10] Christopoulou, FD and Kiortsis DN

[11] Mendez-Sanchez, N, et al, Endocannabinoid receptor CB2 in nonalcoholic fatty liver disease, Liver International, March 2007, doi: 10.1111/j.1478-3231.2006.01401.x

[12] Julien, B, et al, Antifibrogenic role of the cannabinoid receptor CB2 in the liver, Gastroenterology, March 2005, doi: 10.1053/j.gastro.2004.12.050

[13] Muñoz-Luque, J, et al, Regression of fibrosis after chronic stimulation of cannabinoid CB2 receptor in cirrhotic rats, Journal of Pharmacology and Experimental Therapeutics, November 2007, doi: 10.1124/jpet.107.131896

[14] Dibba, P, et al, Mechanistic Potential and Therapeutic Implications of Cannabinoids in Non Alchoholic Fatty Liver Disease, Medicines, May 2018, doi: 10.3390/medicines5020047

[15] Curley, Christopher, Worried About CBD Hurting Your Liver? Here’s What the Experts Have to Say, healthline.com Health News, August 2019, https://www.healthline.com/health-news/can-cbd-hurt-your-liver-what-to-know-about-a-new-study?c=672391731507

[16] Tesséra Naturals.