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

Abstract

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.

Keywords: 2-arachidonoylglycerol; anandamide; cannabis use disorder; endocannabinoid; plasma concentration; subjective effects.

FIG. 1.

Acute subjective and physiological effects of smoked (5.6% THC) cannabis administration. Effect of smoked cannabis on (A, B) subjective drug effects and (C) heart rate, as a function of time, beginning at baseline (30 min before cannabis administration) and ending 3 h after cannabis administration. Time “0” refers to the time (in min) in which cannabis (70% of a NIDA cannabis cigarette) was smoked. Error bars represent ±SEM. (D) Mean (± SEM) plasma THC levels after smoked cannabis (from Time=0 min) through 3 h post-dose. bpm, beats per min; NIDA, National Institute of Drug Abuse; SEM, standard error of the mean; THC, Δ-9-tetrahydrocannabinol.

FIG. 2.

Acute effects of smoked (5.6% THC) cannabis administration on circulating endocannabinoid levels. Effect of smoked cannabis on plasma levels of (A) AEA and (B) 2-AG as a function of time, beginning at baseline (30 min before cannabis administration) and ending 3 h after cannabis administration. Time “0” refers to the time (in min) in which cannabis (70% of an NIDA cannabis cigarette) was smoked. Error bars represent ±SEM. 2-AG, 2-arachidonoylglycerol; AEA, anandamide.

FIG. 3.

Correlating circulating endocannabinoid levels with cannabis use measures and plasma THC/THC metabolites. (A) Baseline AEA levels (measured at 30 min before smoked cannabis administration) positively correlated with peak positive subjective drug effects (after smoked cannabis). (B) Baseline 2-AG levels (measured at 30 min before smoked cannabis administration) negatively correlated with frequency of cannabis use (mean use in days/week) as self-reported in drug use history. (C) Baseline 2-AG levels (measured at 30 min before smoked cannabis administration) negatively correlated with baseline plasma levels of the THC metabolite, THC-COOH. THC-COOH, 11-nor-9-carboxy-Δ-tetrahydrocannabinol.