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Effects of cannabidiol and delta-9-tetrahydrocannabinol on plasma endocannabinoid levels in healthy volunteers: a randomised double-blind four-arm cross-over study

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Lucy Chester, Amir Englund, Edward Chesney, Dominic Oliver, Jack Wilson, Simina Sovi, Alex M Dickens, Matej Oresic, Tuomas Linderman, John Hodsoll, Amedeo Minichino, John Strang, Robin Murray, Tom P Freeman, Philip McGuire

Original languageEnglish
JournalCannabis and cannabinoid research
Accepted/In press10 Oct 2022

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Abstract

Background
The effects of cannabis are thought to be mediated by interactions between its constituents and the endocannabinoid system. Delta-9-tetrahydrocannabinol (THC) binds to central cannabinoid receptors, while cannabidiol (CBD) may influence endocannabinoid function without directly acting on cannabinoid receptors. We examined the effects of THC co-administered with different doses of CBD on plasma levels of endocannabinoids in healthy volunteers.

Methods
In a randomised, double-blind, four-arm cross-over study, healthy volunteers (n=46) inhaled cannabis vapour containing 10mg THC plus either 0, 10, 20 or 30mg CBD, in four experimental sessions. The median time between sessions was 14 days (IQR=20). Blood samples were taken pre-cannabis inhalation and at 0-, 5-, 15- and 90-min post-inhalation. Plasma concentrations of THC, CBD, anandamide, 2-arachidonoylglycerol (2-AG) and related non-cannabinoid lipids were measured using liquid chromatography-mass spectrometry.

Results
Administration of cannabis induced acute increases in plasma concentrations of anandamide (+18.0%, 0.042ng/ml [95%CI: 0.023–0.062]), and the non-cannabinoid ethanolamides, docosatetraenylethanolamide (DEA) (+35.8%, 0.012ng/ml [95%CI: 0.008–0.016]), oleoylethanolamide (OEA) (+16.1%, 0.184ng/ml [95%CI: 0.076–0.293]), and N-arachidonoyl-L-serine (ARA-S) (+25.1%, 0.011ng/ml [95%CI: 0.004–0.017]) (p<0.05). CBD had no significant effect on the plasma concentration of anandamide, 2-AG or related non-cannabinoid lipids at any of three doses used. Over the four sessions, there were progressive decreases in the pre-inhalation concentrations of anandamide and DEA, from 0.254ng/ml [95%CI: 0.223–0.286] to 0.194ng/ml [95%CI: 0.163–0.226], and from 0.039ng/ml [95%CI: 0.032–0.045] to 0.027ng/ml [95%CI: 0.020–0.034] (p<0.05), respectively.

Discussion
THC induced acute increases in plasma levels of anandamide and non-cannabinoid ethanolamides, but there was no evidence that these effects were influenced by the co-administration of CBD. It is possible that such effects may be evident with higher doses of CBD or following chronic administration. The progressive reduction in pre-treatment anandamide and DEA levels across sessions may be related to repeated exposure to THC or participants becoming less anxious about the testing procedure and requires further investigation.

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