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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.

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.

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.

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.
Original languageEnglish
JournalCannabis and cannabinoid research
Publication statusAccepted/In press - 10 Oct 2022


  • THC
  • CBD
  • Endocannabinoids
  • anandamide
  • 2-Arachidonoylglycerol
  • cannabis


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