The Body's Own Cannabis-Like Chemical Causes Fewer Cognitive Problems Than THC in Monkeys
In squirrel monkeys, THC impaired learning, memory, attention, and cognitive flexibility in a dose-dependent manner, while stabilized forms of the body's own cannabinoid anandamide had minimal cognitive effects.
Quick Facts
What This Study Found
Using touchscreen cognitive tests in squirrel monkeys, researchers compared THC with anandamide (the brain's own cannabinoid) and drugs that boost anandamide levels.
THC produced clear, dose-related impairments across multiple cognitive domains. The order of vulnerability was: discriminative capability was most sensitive, followed by learning, cognitive flexibility, and then short-term memory.
Anandamide alone and the FAAH inhibitor URB597 (which raises natural anandamide levels) had no effect on any cognitive test. Even when anandamide was stabilized by FAAH inhibition to prevent its rapid breakdown, cognitive effects were minimal, limited to some short-term memory disruption in some subjects at high doses.
All drugs left motivation unaffected, suggesting the cognitive impairments from THC are not simply due to reduced willingness to perform.
Key Numbers
THC impaired all four cognitive domains dose-dependently. Anandamide alone: no effects. URB597 alone: no effects. Anandamide + URB597: minimal effects, limited to short-term memory in some subjects. Motivation was unaffected by all drugs.
How They Did This
Battery of five touchscreen cognitive tests in squirrel monkeys: learning (repeated acquisition), cognitive flexibility (discrimination reversal), short-term memory (delayed matching-to-sample), attention (psychomotor vigilance), and motivation (progressive ratio). Multiple cannabinoid drugs tested with rimonabant antagonism to confirm CB1 mediation.
Why This Research Matters
This study suggests that therapeutics based on boosting the body's own endocannabinoid system (via FAAH inhibition) might provide medicinal benefits without the cognitive side effects of THC. This is a critical distinction for developing cannabinoid-based medicines.
The Bigger Picture
The endocannabinoid system is an attractive therapeutic target, but THC's cognitive side effects limit its clinical utility. The finding that boosting endocannabinoid tone through enzyme inhibition preserves cognition while still activating cannabinoid pathways is a key insight for drug development.
What This Study Doesn't Tell Us
Small number of subjects typical for primate studies. Squirrel monkey cognition may not directly translate to humans. Anandamide was given exogenously rather than generated endogenously. The specific FAAH inhibitor URB597 has since been shown to have limitations in clinical translation.
Questions This Raises
- ?Would FAAH inhibitors preserve cognition while still providing pain relief or anti-anxiety effects?
- ?Does the lack of cognitive effects from endocannabinoid enhancement translate to humans?
Trust & Context
- Key Stat:
- Boosting natural anandamide caused no cognitive impairment, unlike THC
- Evidence Grade:
- Primate cognitive battery with multiple drug comparisons and antagonist confirmation. Strong preclinical evidence but limited sample size.
- Study Age:
- Published in 2016. FAAH inhibitor drug development has continued but with setbacks, including a serious adverse event in a French clinical trial.
- Original Title:
- Comparisons of Δ9-Tetrahydrocannabinol and Anandamide on a Battery of Cognition-Related Behavior in Nonhuman Primates.
- Published In:
- The Journal of pharmacology and experimental therapeutics, 357(1), 125-33 (2016)
- Authors:
- Kangas, Brian D(4), Leonard, Michael Z, Shukla, Vidyanand G(2), Alapafuja, Shakiru O, Nikas, Spyros P, Makriyannis, Alexandros, Bergman, Jack
- Database ID:
- RTHC-01190
Evidence Hierarchy
Tests effects in animals (usually mice or rats), not humans.
What do these levels mean? →Frequently Asked Questions
Does THC affect all types of thinking equally?
No. In monkeys, THC was most disruptive to discriminative ability, moderately affected learning and flexibility, and had the least impact on short-term memory. Motivation was unaffected.
Could cannabis medicines be made without cognitive side effects?
This study suggests yes. Drugs that boost the body's natural endocannabinoids (rather than adding THC) preserved cognitive function in monkeys while still activating cannabinoid pathways.
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Cite This Study
https://rethinkthc.com/research/RTHC-01190APA
Kangas, Brian D; Leonard, Michael Z; Shukla, Vidyanand G; Alapafuja, Shakiru O; Nikas, Spyros P; Makriyannis, Alexandros; Bergman, Jack. (2016). Comparisons of Δ9-Tetrahydrocannabinol and Anandamide on a Battery of Cognition-Related Behavior in Nonhuman Primates.. The Journal of pharmacology and experimental therapeutics, 357(1), 125-33. https://doi.org/10.1124/jpet.115.228189
MLA
Kangas, Brian D, et al. "Comparisons of Δ9-Tetrahydrocannabinol and Anandamide on a Battery of Cognition-Related Behavior in Nonhuman Primates.." The Journal of pharmacology and experimental therapeutics, 2016. https://doi.org/10.1124/jpet.115.228189
RethinkTHC
RethinkTHC Research Database. "Comparisons of Δ9-Tetrahydrocannabinol and Anandamide on a B..." RTHC-01190. Retrieved from https://rethinkthc.com/research/kangas-2016-comparisons-of-9tetrahydrocannabinol-and
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.