Testing the impact of cannabinoid stimulation on fatty acid amide hydrolase binding in the human brain: pilot [11C]CURB PET study

Abstract Background Chronic cannabis exposure is associated with neuroadaptations within the endocannabinoid system, including reduced levels of fatty acid amide hydrolase (FAAH), the primary enzyme responsible for the degradation of anandamide. Whether repeated exposure to cannabinoid receptor agonists is associated with changes in FAAH levels in the human brain remains unknown. The present study examined the effects of repeated administration of nabilone, a synthetic cannabinoid receptor agonist, on brain FAAH levels in healthy volunteers. Methods In this exploratory Phase IV pilot study, ten healthy adults completed two positron emission tomography scans with the FAAH radiotracer [ 11 C]CURB: a baseline scan and a second scan following a 7-day oral nabilone regimen. Nabilone was titrated from 0.25 mg/day to a target dose of 2 mg/day. Brain FAAH levels ([ 11 C]CURB λk3) were quantified using a two-tissue compartment model with irreversible trapping, and regional changes were assessed using repeated-measures analysis of covariance with FAAH genotype (rs324420 C > A; Pro129Thr) included as a covariate. Subjective drug effects and mood measures were assessed before and after nabilone administration. Results Nabilone produced subjective effects, including increased marijuana-like drug effects ( p = 0.004), reductions in self-reported energy ( p = 0.02) and clear-headedness ( p = 0.01). No detectable mean change in FAAH was observed across brain regions following seven days of nabilone administration ( p = 0.357). Conclusions In this small, uncontrolled pilot study, no detectable mean change in brain FAAH was observed following seven days of nabilone administration. These findings provide preliminary evidence regarding FAAH following repeated cannabinoid receptor agonist exposure and require confirmation in larger, controlled studies. Trial registration ClinicalTrials.gov Identifier: NCT05885685.