Boosting the Body's Own Cannabinoids Reduced THC Withdrawal Symptoms in Mice
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.
Quick Facts
What This Study 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.
Key Numbers
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 They Did This
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.
Why This Research 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 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.
What This Study Doesn't 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.
Questions This Raises
- ?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?
Trust & Context
- Key Stat:
- Both endocannabinoid enzyme inhibitors reduced withdrawal without causing dependence
- Evidence Grade:
- Well-controlled preclinical study with multiple approaches (pharmacological and genetic). Findings limited to animal models with precipitated withdrawal.
- Study Age:
- Published in 2009. FAAH inhibitors have since entered human clinical trials for various indications, though not yet specifically for cannabis withdrawal.
- Original Title:
- Inhibitors of endocannabinoid-metabolizing enzymes reduce precipitated withdrawal responses in THC-dependent mice.
- Published In:
- The AAPS journal, 11(2), 342-52 (2009)
- Authors:
- Schlosburg, Joel E(7), Carlson, Brittany L A, Ramesh, Divya(6), Abdullah, Rehab A, Long, Jonathan Z, Cravatt, Benjamin F, Lichtman, Aron H
- Database ID:
- RTHC-00391
Evidence Hierarchy
Tests effects in animals (usually mice or rats), not humans.
What do these levels mean? →Frequently Asked 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.
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Cite This Study
https://rethinkthc.com/research/RTHC-00391APA
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
MLA
Schlosburg, Joel E, et al. "Inhibitors of endocannabinoid-metabolizing enzymes reduce precipitated withdrawal responses in THC-dependent mice.." The AAPS journal, 2009. https://doi.org/10.1208/s12248-009-9110-7
RethinkTHC
RethinkTHC Research Database. "Inhibitors of endocannabinoid-metabolizing enzymes reduce pr..." RTHC-00391. Retrieved from https://rethinkthc.com/research/schlosburg-2009-inhibitors-of-endocannabinoidmetabolizing-enzymes
Access the Original Study
Study data sourced from PubMed, a service of the U.S. National Library of Medicine, National Institutes of Health.
This study breakdown was produced by the RethinkTHC research team. We analyze and report published research findings without making health recommendations. All interpretations are based solely on the published abstract and study data.