FAAH and MAGL inhibitors reduced compulsive marble-burying behavior in mice at doses that did not affect locomotion, while THC only reduced burying at sedating doses, suggesting endocannabinoid enhancement offers anxiolytic effects without sedation.
Read this if you are interested in whether targeting the endocannabinoid system could treat anxiety without the side effects of cannabis.
Endocannabinoid boosters reduced anxiety without sedation; THC could not
What the researchers found
Researchers tested whether boosting either of the two main endocannabinoids could reduce anxiety-like behavior in a marble-burying test, a model relevant to compulsive behaviors in disorders like OCD.
The FAAH inhibitor PF-3845 (which boosts anandamide) and the MAGL inhibitor JZL184 (which boosts 2-AG) both reduced marble burying at doses that did not impair locomotor activity. The benzodiazepine diazepam also reduced burying.
In contrast, THC did not consistently reduce marble burying without also causing profound decreases in locomotor activity, meaning its apparent anxiolytic effect was inseparable from sedation.
The CB1 antagonist rimonabant blocked the anti-burying effects of both FAAH and MAGL inhibitors but not diazepam, confirming a CB1 receptor mechanism.
Why it matters
The separation of anxiolytic effects from sedation was a key advantage of endocannabinoid-boosting drugs over direct cannabinoid agonists like THC, supporting their development as potential anxiety treatments.
The numbers in context
PF-3845, JZL184, and diazepam reduced marble burying without affecting locomotion. THC reduced burying only at doses that also impaired movement. Rimonabant blocked FAAH/MAGL inhibitor effects but not diazepam.
How the study worked
Controlled animal study in mice using the marble burying assay. FAAH inhibitor PF-3845, MAGL inhibitor JZL184, diazepam, and THC tested at multiple doses. Locomotor activity measured concurrently. CB1 receptor involvement confirmed with rimonabant.
What this study cannot tell us
Mouse model with a single behavioral measure. Marble burying is only one model of anxiety/compulsive behavior. Translation to human anxiety disorders is uncertain.
How to read the evidence
Well-controlled animal study with multiple comparators and receptor confirmation, but limited to one behavioral model.
When this study was published
Published in 2011. FAAH inhibitor clinical development for anxiety has progressed.
The bigger picture
This study positioned endocannabinoid-enhancing drugs as a potentially superior anxiety treatment approach compared to direct cannabinoid agonists, avoiding sedation and other THC-related side effects.
Questions still open
- Would endocannabinoid-boosting drugs be effective for human OCD or anxiety disorders? Can the separation of anxiolytic and sedative effects be maintained at clinical doses?
Common questions
Could endocannabinoid drugs treat anxiety without making you high?
What is marble burying?
Read the original research
Inhibition of endocannabinoid catabolic enzymes elicits anxiolytic-like effects in the marble burying assay.
Pharmacology, biochemistry, and behavior, 98(1), 21-7
Citation
Kinsey, Steven G; O'Neal, Scott T; Long, Jonathan Z; Cravatt, Benjamin F; Lichtman, Aron H. (2011). Inhibition of endocannabinoid catabolic enzymes elicits anxiolytic-like effects in the marble burying assay.. Pharmacology, biochemistry, and behavior, 98(1), 21-7. https://doi.org/10.1016/j.pbb.2010.12.002
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