Mice Without the Anandamide Breakdown Enzyme Were More Sensitive to THC-Like Effects of Other Cannabinoids
Mice genetically lacking the enzyme FAAH, which breaks down the endocannabinoid anandamide, showed enhanced sensitivity to the subjective-like effects of anandamide and a MAGL inhibitor in a THC discrimination task.
Quick Facts
What This Study Found
Researchers compared mice lacking fatty acid amide hydrolase (FAAH), the enzyme primarily responsible for breaking down anandamide, with normal mice in a drug discrimination test using THC.
Both groups learned to discriminate THC at similar rates and showed similar THC dose-response curves. However, anandamide fully substituted for THC only in FAAH knockout mice, not in normal mice. A metabolically stable anandamide analog worked in both groups but was more potent in knockouts.
The MAGL inhibitor JZL184, which boosts 2-AG levels, produced near-full THC-like effects in normal mice and full substitution in FAAH knockouts. Combined FAAH and MAGL inhibition produced similar effects in both groups.
Key Numbers
THC training dose: 5.6 mg/kg. Anandamide fully substituted for THC in FAAH knockouts but not wildtypes. JZL184 produced near-full substitution in wildtypes and full substitution in knockouts. Brain anandamide was elevated in FAAH knockouts. JZL184 increased 2-AG levels equally in both genotypes.
How They Did This
FAAH knockout and wildtype mice were trained to discriminate THC (5.6 mg/kg) from vehicle in a two-lever operant task. Various cannabinoid compounds were tested for substitution. Brain endocannabinoid levels were quantified. The CB1 antagonist rimonabant was used to confirm receptor involvement.
Why This Research Matters
Understanding how the endocannabinoid system's own signaling molecules produce THC-like effects informs research on both cannabis pharmacology and potential therapeutic approaches that target endocannabinoid metabolism rather than directly activating cannabinoid receptors.
The Bigger Picture
This study illustrates that THC's subjective effects can be mimicked by boosting the brain's own cannabinoids. The finding that FAAH knockout mice respond normally to THC despite having chronically elevated anandamide suggests that baseline endocannabinoid tone does not alter THC sensitivity, a nuance relevant to developing FAAH inhibitor therapeutics.
What This Study Doesn't Tell Us
Drug discrimination in mice does not directly translate to human subjective experiences. Genetically engineered mice may have developmental compensations that differ from pharmacological enzyme inhibition. The study examined acute effects and may not reflect chronic exposure patterns.
Questions This Raises
- ?Would FAAH inhibitors produce THC-like subjective effects in humans?
- ?How does chronic elevation of one endocannabinoid affect sensitivity to changes in the other?
Trust & Context
- Key Stat:
- Anandamide fully mimicked THC only when its breakdown enzyme was absent
- Evidence Grade:
- This is an animal study using genetically modified mice. It provides mechanistic insights about endocannabinoid pharmacology that require validation in other contexts.
- Study Age:
- Published in 2015. Research on FAAH inhibitors as potential therapeutics has continued with some clinical trials in humans.
- Original Title:
- Phenotypic assessment of THC discriminative stimulus properties in fatty acid amide hydrolase knockout and wildtype mice.
- Published In:
- Neuropharmacology, 93, 237-42 (2015)
- Authors:
- Walentiny, D Matthew(3), Vann, Robert E(4), Wiley, Jenny L(13)
- Database ID:
- RTHC-01073
Evidence Hierarchy
Tests effects in animals (usually mice or rats), not humans.
What do these levels mean? →Frequently Asked Questions
Does this mean anandamide normally produces a high like THC?
Under normal conditions, anandamide is broken down too quickly by FAAH to accumulate to levels that mimic THC. Only when FAAH is absent or inhibited does anandamide build up enough to produce THC-like effects in this test.
Why would researchers want to boost endocannabinoids instead of just using THC?
Boosting the brain's own cannabinoids at sites where they are naturally released could potentially provide therapeutic benefits with greater specificity and fewer side effects than flooding all cannabinoid receptors with THC.
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Cite This Study
https://rethinkthc.com/research/RTHC-01073APA
Walentiny, D Matthew; Vann, Robert E; Wiley, Jenny L. (2015). Phenotypic assessment of THC discriminative stimulus properties in fatty acid amide hydrolase knockout and wildtype mice.. Neuropharmacology, 93, 237-42. https://doi.org/10.1016/j.neuropharm.2015.02.004
MLA
Walentiny, D Matthew, et al. "Phenotypic assessment of THC discriminative stimulus properties in fatty acid amide hydrolase knockout and wildtype mice.." Neuropharmacology, 2015. https://doi.org/10.1016/j.neuropharm.2015.02.004
RethinkTHC
RethinkTHC Research Database. "Phenotypic assessment of THC discriminative stimulus propert..." RTHC-01073. Retrieved from https://rethinkthc.com/research/walentiny-2015-phenotypic-assessment-of-thc
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.