title: Exogenous delta⁹-tetrahydrocannabinol influences circulating endogenous cannabinoids in humans.
abstract: Delta⁹-tetrahydrocannabinol (THC) competes with the endogenous cannabinoids arachidonoyl ethanolamide (anandamide) and 2-arachidonoyl glycerol (2-AG) at cannabinoid receptors. This may cause adaptive changes in the endocannabinoid signaling cascade with possible consequences for the biological functions of the endocannabinoid system. We show that administration of a single oral dose of 20 mg THC to 30 healthy volunteers resulted in higher circulating concentrations of anandamide, 2-AG, palmitoyl ethanolamide, and oleoylethanolamide at 2 and 3 hours after administration as compared with placebo. At 2 hours after THC administration, changes in oleoylethanolamide plasma concentrations from baseline were linearly related to the THC plasma concentrations. In rats, treatment with the CB₁/CB₂ agonist WIN 55,212 also increased plasma endocannabinoid concentrations. However, this was associated with a decrease of ethanolamide endocannabinoids in specific brain regions including spinal cord, cortex, and hypothalamus; whereas 2-arachidonoyl glycerol increased in the cortex. Thus, administration of THC to human volunteers influenced the concentrations of circulating endocannabinoids, which was mimicked by WIN-55,212 in rats, suggesting that exogenous cannabinoids may lead to changes in the endocannabinoid system that can be detected in plasma.
authors.affiliation: Institute of Clinical Pharmacology, Goethe-University, Frankfurt am Main, Germany.
authors.forename: Carmen
authors.initials: C
authors.lastname: Walter
authors.forename: Nerea
authors.initials: N
authors.lastname: Ferreirós
authors.forename: Philipp
authors.initials: P
authors.lastname: Bishay
authors.forename: Gerd
authors.initials: G
authors.lastname: Geisslinger
authors.forename: Irmgard
authors.initials: I
authors.lastname: Tegeder
authors.forename: Jörn
authors.initials: J
authors.lastname: Lötsch
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000818:Animals; D048588:Benzoxazines / Q000494:pharmacology; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D018592:Cross-Over Studies; D004311:Double-Blind Method; D013759:Dronabinol / Q000008:administration & dosage*; D063388:Endocannabinoids / Q000097:blood*; D005260:Female; D005858:Germany; D064368:Healthy Volunteers; D006801:Humans; D008297:Male; D009025:Morpholines / Q000494:pharmacology; D009281:Naphthalenes / Q000494:pharmacology; D011619:Psychotropic Drugs / Q000008:administration & dosage*; D051381:Rats; D011917:Rats, Inbred Lew; D043884:Receptor, Cannabinoid, CB1 / Q000187:drug effects / Q000378:metabolism; D043885:Receptor, Cannabinoid, CB2 / Q000187:drug effects / Q000378:metabolism; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism; D013997:Time Factors; D015854:Up-Regulation
chemical_list: D048588:Benzoxazines; C543264:Cnr1 protein, rat; C469526:Cnr2 protein, rat; D063388:Endocannabinoids; D009025:Morpholines; D009281:Naphthalenes; D011619:Psychotropic Drugs; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; D013759:Dronabinol