Can targeting the CB1 receptor treat obesity? A review of past failures and new approaches | Research

The takeaway

A review of CB1 receptor drugs for obesity found that while rimonabant was effective but unsafe, newer approaches including peripheral-only blockers and neutral antagonists may retain weight-loss benefits without psychiatric side effects.

Obesity researchers, endocrinologists, pharmaceutical developers, and metabolic disease specialists.

Cannabis use inversely associated with BMI; new CB1 approaches aim to avoid psychiatric risks

What the researchers found

Rimonabant (CB1 inverse agonist) effectively produced weight loss but was withdrawn due to depression and suicidal ideation. An inverse relationship between cannabis use and BMI has been confirmed by multiple groups. Newer preclinical approaches, including peripheral-only CB1 blockers and neutral antagonists, may retain therapeutic potential for obesity without brain-related side effects.

Why it matters

Obesity rates are rising globally and treatment options are limited. The CB1 receptor remains one of the most promising therapeutic targets, but the rimonabant experience showed that brain-penetrant CB1 blockers are too risky.

The numbers in context

Rimonabant was effective for weight loss but withdrawn for psychiatric side effects; inverse cannabis use-BMI relationship confirmed by multiple studies; peripheral-only CB1 approaches in development.

How the study worked

Narrative review of preclinical and clinical studies on CB1 receptor ligands (inverse agonists, agonists, partial agonists, neutral antagonists) and their effects on body weight.

What this study cannot tell us

Narrative review; most novel approaches are preclinical only; the cannabis use-BMI paradox has multiple possible explanations beyond CB1 effects; translating peripheral-only CB1 blockers to humans remains unproven.

How to read the evidence

Moderate: synthesizes extensive preclinical and clinical literature but newer approaches remain unproven in humans.

When this study was published

Published 2020.

The bigger picture

The paradox that chronic cannabis use is associated with lower BMI, despite THC acutely stimulating appetite, points to complex regulatory mechanisms in the endocannabinoid system that could be harnessed therapeutically.

Questions still open

Will peripheral-only CB1 blockers work in human obesity trials? Does the cannabis-BMI association hold across all populations and use patterns?

Common questions

Can the endocannabinoid system be targeted for weight loss?

Yes. The CB1 receptor was proven effective for weight loss (rimonabant), but brain-penetrant blockers caused psychiatric side effects. Peripheral-only approaches may retain benefits without risks.

Why are cannabis users often thinner despite getting "the munchies"?

The acute appetite stimulation from THC is well-known, but chronic cannabis use is paradoxically associated with lower BMI. This may involve complex receptor adaptations that could inform obesity treatment.

Read the original research

Targeting the Endocannabinoid CB1 Receptor to Treat Body Weight Disorders: A Preclinical and Clinical Review of the Therapeutic Potential of Past and Present CB1 Drugs.

Biomolecules, 10(6)

View on PubMed ↗Publisher’s paper ↗

Citation

Murphy, Thomas; Le Foll, Bernard. (2020). Targeting the Endocannabinoid CB1 Receptor to Treat Body Weight Disorders: A Preclinical and Clinical Review of the Therapeutic Potential of Past and Present CB1 Drugs.. Biomolecules, 10(6). https://doi.org/10.3390/biom10060855