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.
Read this if you are interested in how THC affects cognition differently than the body's natural cannabis-like chemicals.
Boosting natural anandamide caused no cognitive impairment, unlike THC
What the researchers 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.
Why it 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 numbers in context
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 the study worked
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.
What this study cannot 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.
How to read the evidence
Primate cognitive battery with multiple drug comparisons and antagonist confirmation. Strong preclinical evidence but limited sample size.
When this study was published
Published in 2016. FAAH inhibitor drug development has continued but with setbacks, including a serious adverse event in a French clinical trial.
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.
Questions still open
- 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?
Common questions
Does THC affect all types of thinking equally?
Could cannabis medicines be made without cognitive side effects?
Read the original research
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
Citation
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
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