The endocannabinoid system is involved in multiple liver diseases including fatty liver, alcoholic liver disease, and hepatic encephalopathy, making it a potential therapeutic target despite early drug safety setbacks.
Read this if you want to understand how the endocannabinoid system relates to liver health and disease.
Endocannabinoid system involved in fatty liver, alcoholic liver disease, hepatic encephalopathy, and more
What the researchers found
This review documented the endocannabinoid system's extensive involvement in liver disease. CB1 and CB2 receptors, endocannabinoids, and their metabolic enzymes are all present in the liver and play roles in multiple conditions including non-alcoholic fatty liver disease, alcoholic liver disease, hepatic encephalopathy, and autoimmune hepatitis.
The system also influences related conditions such as altered liver blood flow, cirrhotic cardiomyopathy, metabolic syndrome, and ischemia/reperfusion injury. One drug targeting the endocannabinoid system (rimonabant, a CB1 blocker) had shown therapeutic success for liver disease but was withdrawn from the market due to serious neurological and psychiatric side effects.
The authors noted optimism about newer therapeutics that target peripheral endocannabinoid receptors without crossing the blood-brain barrier, potentially avoiding the central nervous system side effects that derailed earlier approaches.
Why it matters
Liver disease is a major global health burden, and current treatments are limited for many conditions. The endocannabinoid system offers multiple potential drug targets, but the challenge of avoiding central nervous system side effects has been a significant barrier to drug development.
The numbers in context
The review covered multiple liver conditions. Rimonabant, the first marketed CB1 blocker, was withdrawn due to adverse psychiatric events. Novel peripherally restricted compounds were in preclinical development.
How the study worked
Review of original articles and reviews summarizing preclinical and clinical research on the endocannabinoid system in liver disease pathophysiology and therapeutic targeting.
What this study cannot tell us
Much of the evidence was preclinical. The peripheral-only drug strategy was still in early development at the time of publication. The complexity of the endocannabinoid system in liver pathophysiology makes predicting drug effects challenging.
How to read the evidence
Comprehensive review of mixed preclinical and clinical evidence, with therapeutic applications still largely in development.
When this study was published
Published in 2014. Peripherally restricted endocannabinoid-targeting drugs have continued to be developed.
The bigger picture
The rimonabant story is instructive: a drug that worked well for metabolic conditions was pulled because it caused depression and suicidality by blocking CB1 receptors in the brain. The next generation of endocannabinoid-targeting drugs for liver disease aims to affect only peripheral receptors, preserving the brain's endocannabinoid signaling.
Questions still open
- Have peripherally restricted CB1 blockers reached clinical trials for liver disease? Does cannabis use itself affect liver disease progression? Can CB2 receptor activation protect the liver without the risks associated with CB1 blockade?
Common questions
Does the endocannabinoid system affect liver disease?
Why was the CB1 blocker rimonabant withdrawn?
Read the original research
Review article: the endocannabinoid system in liver disease, a potential therapeutic target.
Alimentary pharmacology & therapeutics, 39(8), 790-801
Citation
Basu, P P; Aloysius, M M; Shah, N J; Brown, R S. (2014). Review article: the endocannabinoid system in liver disease, a potential therapeutic target.. Alimentary pharmacology & therapeutics, 39(8), 790-801. https://doi.org/10.1111/apt.12673
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