Boosting the Body's Own Cannabinoids Reduced THC Withdrawal Symptoms in Mice | Research

The takeaway

FAAH and MAGL inhibitors each significantly reduced THC withdrawal signs in mice without causing dependence or motor impairment, supporting endocannabinoid enzyme inhibition as a potential cannabis withdrawal treatment.

Read this if you are interested in potential medication treatments for cannabis withdrawal.

Both endocannabinoid enzyme inhibitors reduced withdrawal without causing dependence

What the researchers found

Researchers tested whether increasing endocannabinoid levels could ease THC withdrawal in dependent mice.

Both the FAAH inhibitor URB597 (which raises anandamide) and the MAGL inhibitor JZL184 (which raises 2-AG) significantly attenuated withdrawal signs precipitated by the CB1 antagonist rimonabant in THC-dependent mice.

Importantly, subchronic URB597 administration did not itself produce cannabinoid dependence, and neither inhibitor impaired motor coordination on the rotarod test.

Interestingly, FAAH knockout mice (born without the enzyme) showed identical withdrawal responses as normal mice, suggesting that constitutive absence of FAAH throughout the development of dependence does not affect withdrawal, while acute FAAH inhibition during withdrawal does.

Why it matters

No FDA-approved medication exists for cannabis withdrawal. This study showed that boosting endocannabinoid levels could reduce withdrawal severity without creating new dependence, supporting a novel treatment strategy.

The numbers in context

Both URB597 (FAAH inhibitor) and JZL184 (MAGL inhibitor) significantly reduced withdrawal. Subchronic URB597 did not produce dependence. Neither drug impaired motor coordination. FAAH knockout mice showed normal withdrawal.

How the study worked

THC-dependent mice received FAAH inhibitor URB597, MAGL inhibitor JZL184, or vehicle before rimonabant-precipitated withdrawal. FAAH knockout mice were also tested. Subchronic URB597 was tested for dependence induction. Motor coordination was assessed on the rotarod.

What this study cannot tell us

Precipitated withdrawal differs from spontaneous withdrawal. Mouse models may not predict human withdrawal experiences. The finding that FAAH knockout mice showed normal withdrawal complicates the interpretation of acute FAAH inhibitor effects.

How to read the evidence

Well-controlled preclinical study with multiple approaches (pharmacological and genetic). Findings limited to animal models with precipitated withdrawal.

When this study was published

Published in 2009. FAAH inhibitors have since entered human clinical trials for various indications, though not yet specifically for cannabis withdrawal.

The bigger picture

Cannabis withdrawal contributes to relapse and continued use. Finding medications that ease withdrawal without producing their own dependence or intoxication would be a significant advance in cannabis use disorder treatment.

Questions still open

Why does acute FAAH inhibition reduce withdrawal but constitutive FAAH absence does not? Could FAAH or MAGL inhibitors be used during cannabis cessation in humans? Would combining both inhibitors be more effective?

Common questions

How is this different from just using more cannabis?

Cannabis substitution works but keeps the person dependent on cannabinoids. Endocannabinoid enzyme inhibitors boost the body's own cannabinoids to ease withdrawal without producing the full intoxicating effects of cannabis, potentially allowing a smoother transition to abstinence.

Why did FAAH knockout mice not benefit?

Mice born without FAAH developed normally and became THC-dependent just like normal mice. Their brains likely adapted to always-elevated anandamide levels. The therapeutic benefit of FAAH inhibition appears to come from acutely raising anandamide during withdrawal, not from lifetime elevation.

Read the original research

Inhibitors of endocannabinoid-metabolizing enzymes reduce precipitated withdrawal responses in THC-dependent mice.

The AAPS journal, 11(2), 342-52

View on PubMed ↗Publisher’s paper ↗

Citation

Schlosburg, Joel E; Carlson, Brittany L A; Ramesh, Divya; Abdullah, Rehab A; Long, Jonathan Z; Cravatt, Benjamin F; Lichtman, Aron H. (2009). Inhibitors of endocannabinoid-metabolizing enzymes reduce precipitated withdrawal responses in THC-dependent mice.. The AAPS journal, 11(2), 342-52. https://doi.org/10.1208/s12248-009-9110-7