Cannabis abstinence may trigger a rebound in the body’s endocannabinoid system

Preclinical evidence indicates a link between the endocannabinoid system (ECS) and addiction by modulating reward and stress processes. Rodent and recent human studies reported ECS alterations in cannabis use disorder. However, little is known about cannabis abstinence effects on the ECS in humans. We performed a secondary data analysis from a prospective study comparing changes in plasma endocannabinoids anandamide (AEA) and 1-arachidonoylglycerol (1-AG) from baseline (L1) to 2-3 weeks later (L2) between four groups: individuals with ad libitum cannabis and nicotine use at L1 who 1) abstained from cannabis for three days and nicotine for at least 15h prior to L2 (n = 30; Abstain), or 2) sustained ad libitum cannabis-only use but abstained from nicotine for at least 15h prior to L2 (n = 18; Can-only); 3) individuals with ad libitum nicotine-only use at L1, who abstained from nicotine for at least 15h prior to L2 (n = 17; Nic-only); and 4) healthy controls (n = 13) who were drug-naïve at L1 and L2. We found a significant increase of AEA from L1 to L2 but no differences of 1-AG, within the Abstain group (p = .004). In contrast, AEA levels decreased significantly within the Can-only group at L2 (p = .011). Controls and the Nic-only group showed stable AEA and 1-AG levels over time. Our findings indicate alterations of the ECS related to cannabis abstinence. While AEA decreased in the Can-only group, AEA increased in the Abstain group, which might indicate a compensatory response of the ECS during cannabis abstinence after chronic excitatory activation of the ECS.