Blocking the Enzyme That Breaks Down 2-AG Produces Cannabis-Like Subjective Effects in Mice
Inhibiting MAGL (which breaks down the endocannabinoid 2-AG) produced a discriminative stimulus in mice that felt like cannabis to them, suggesting MAGL normally prevents 2-AG from reaching psychoactive levels.
Quick Facts
What This Study Found
This study demonstrated that blocking MAGL, the enzyme that breaks down the endocannabinoid 2-AG, produces subjective effects in mice that are indistinguishable from those produced by THC-like drugs.
12 of 13 mice successfully learned to discriminate the MAGL inhibitor MJN110 from vehicle, and the CB1 receptor antagonist rimonabant blocked this discriminative stimulus, confirming it works through CB1 receptors.
The synthetic cannabinoid CP55,940, another MAGL inhibitor (JZL184), and the dual FAAH/MAGL inhibitor SA-57 all fully substituted for MJN110, meaning they felt the same to the mice. However, the FAAH inhibitor PF-3845 (which boosts anandamide instead of 2-AG) did not substitute, showing that enhancing anandamide alone does not produce cannabis-like subjective effects.
Combining FAAH inhibition with MAGL inhibition made the MAGL effect stronger (1.6x leftward shift), suggesting anandamide and 2-AG interact.
The findings suggest MAGL normally acts as a "brake" on 2-AG, keeping it below levels that would produce cannabis-like intoxication.
Key Numbers
12 of 13 mice learned the discrimination. FAAH inhibitor caused 1.6x (95% CI 1.1-2.2) leftward shift of MAGL inhibitor dose-response. Rimonabant dose-dependently blocked the discriminative stimulus.
How They Did This
Drug discrimination paradigm in C57BL/6J mice trained to distinguish MAGL inhibitor MJN110 from vehicle. Substitution tests with multiple compounds (CP55,940, SA-57, JZL184, PF-3845, ABHD6 inhibitor, COX-2 inhibitor, nicotine, diazepam). Rimonabant used to confirm CB1 mediation.
Why This Research Matters
This study reveals that the brain's own endocannabinoid system is capable of producing cannabis-like intoxication if 2-AG accumulates beyond normal levels. Understanding this has implications for MAGL inhibitor drug development, which must consider abuse potential.
The Bigger Picture
The distinction between MAGL and FAAH inhibition is clinically relevant. FAAH inhibitors (boosting anandamide) do not produce cannabis-like subjective effects, making them potentially safer therapeutic agents. MAGL inhibitors (boosting 2-AG) do produce such effects, suggesting they carry abuse potential similar to cannabis.
What This Study Doesn't Tell Us
Mouse drug discrimination may not perfectly predict human subjective experiences. The study used a single MAGL inhibitor for training. The ecological relevance of pharmacologically elevated 2-AG levels to natural endocannabinoid function is uncertain.
Questions This Raises
- ?Do MAGL inhibitors have abuse potential in humans similar to cannabis?
- ?Could partial MAGL inhibitors provide therapeutic benefit without producing intoxicating levels of 2-AG?
- ?Why does anandamide enhancement not produce cannabis-like subjective effects while 2-AG enhancement does?
Trust & Context
- Key Stat:
- MAGL normally prevents 2-AG from reaching levels that produce cannabis-like intoxication
- Evidence Grade:
- Well-controlled drug discrimination study with comprehensive substitution testing. Preliminary because the subjective experience parallel between mice and humans is inferred.
- Study Age:
- Published in 2017.
- Original Title:
- Inhibition of the endocannabinoid-regulating enzyme monoacylglycerol lipase elicits a CB1 receptor-mediated discriminative stimulus in mice.
- Published In:
- Neuropharmacology, 125, 80-86 (2017)
- Authors:
- Owens, Robert A(3), Mustafa, Mohammed A(2), Ignatowska-Jankowska, Bogna M(5), Damaj, M Imad, Beardsley, Patrick M, Wiley, Jenny L, Niphakis, Micah J, Cravatt, Benjamin F, Lichtman, Aron H
- Database ID:
- RTHC-01473
Evidence Hierarchy
Tests effects in animals (usually mice or rats), not humans.
What do these levels mean? →Frequently Asked Questions
Can the brain produce its own cannabis-like high?
Yes. This study showed that blocking MAGL (which breaks down the endocannabinoid 2-AG) produces subjective effects in mice indistinguishable from THC. This suggests the brain has the machinery for self-intoxication but normally keeps 2-AG levels below the threshold.
What is the difference between anandamide and 2-AG?
Both are endocannabinoids, but they produce different subjective effects. Boosting 2-AG (via MAGL inhibition) produces cannabis-like intoxication, while boosting anandamide (via FAAH inhibition) does not. This distinction is important for drug development.
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Cite This Study
https://rethinkthc.com/research/RTHC-01473APA
Owens, Robert A; Mustafa, Mohammed A; Ignatowska-Jankowska, Bogna M; Damaj, M Imad; Beardsley, Patrick M; Wiley, Jenny L; Niphakis, Micah J; Cravatt, Benjamin F; Lichtman, Aron H. (2017). Inhibition of the endocannabinoid-regulating enzyme monoacylglycerol lipase elicits a CB1 receptor-mediated discriminative stimulus in mice.. Neuropharmacology, 125, 80-86. https://doi.org/10.1016/j.neuropharm.2017.06.032
MLA
Owens, Robert A, et al. "Inhibition of the endocannabinoid-regulating enzyme monoacylglycerol lipase elicits a CB1 receptor-mediated discriminative stimulus in mice.." Neuropharmacology, 2017. https://doi.org/10.1016/j.neuropharm.2017.06.032
RethinkTHC
RethinkTHC Research Database. "Inhibition of the endocannabinoid-regulating enzyme monoacyl..." RTHC-01473. Retrieved from https://rethinkthc.com/research/owens-2017-inhibition-of-the-endocannabinoidregulating
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.