The Relationship Between Circulating Endogenous Cannabinoids and the Effects of Smoked Cannabis.

Background: The endogenous cannabinoid system (ECS), including the endocannabinoids (eCBs), anandamide (AEA), and 2-arachidonoylglycerol (2-AG), plays an integral role in psychophysiological functions. Although frequent cannabis use is associated with adaptations in the ECS, the impact of acute smoked cannabis administration on circulating eCBs, and the relationship between cannabis effects and circulating eCBs are poorly understood. Methods: This study measured the plasma levels of AEA, 2-AG, and Δ-9-tetrahydrocannabinol (THC), subjective drug-effects ratings, and cardiovascular measures at baseline and 15-180 min after cannabis users (n=26) smoked 70% of a cannabis cigarette (5.6% THC). Results: Cannabis administration increased the ratings of intoxication, heart rate, and plasma THC levels relative to baseline. Although cannabis administration did not affect eCB levels relative to baseline, there was a significant positive correlation between baseline AEA levels and peak ratings of "High" and "Good Drug Effect." Further, baseline 2-AG levels negatively correlated with frequency of cannabis use (mean days/week) and with baseline THC metabolite levels. Conclusions: In a subset of heavy cannabis smokers: (1) more frequent cannabis use was associated with lower baseline 2-AG, and (2) those with lower AEA got less intoxicated after smoking cannabis. These findings contribute to a sparse literature on the interaction between endo- and phyto-cannabinoids. Future studies in participants with varied cannabis use patterns are needed to clarify the association between circulating eCBs and the abuse-related effects of cannabis, and to test whether baseline eCBs predict the intoxicating effects of cannabis and are a potential biomarker of cannabis tolerance.

Repetitive transcranial magnetic stimulation as a potential treatment approach for cannabis use disorder.

The expanding legalization of cannabis across the United States is associated with increases in cannabis use, and accordingly, an increase in the number and severity of individuals with cannabis use disorder (CUD). The lack of FDA-approved pharmacotherapies and modest efficacy of psychotherapeutic interventions means that many of those who seek treatment for CUD relapse within the first few months. Consequently, there is a pressing need for innovative, evidence-based treatment development for CUD. Preliminary evidence suggests that repetitive transcranial magnetic stimulation (rTMS) may be a novel, non-invasive therapeutic neuromodulation tool for the treatment of a variety of substance use disorders (SUDs), including recently receiving FDA clearance (August 2020) for use as a smoking cessation aid in tobacco cigarette smokers. However, the potential of rTMS for CUD has not yet been reviewed. This paper provides a primer on therapeutic neuromodulation techniques for SUDs, with a particular focus on reviewing the current status of rTMS research in people who use cannabis. Lastly, future directions are proposed for rTMS treatment development in CUD, with suggestions for study design parameters and clinical endpoints based on current gold-standard practices for therapeutic neuromodulation research.