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Exogenous Delta9-Tetrahydrocannabinol Influences Circulating Endogenous Cannabinoids in Humans

Walter, Carmen PhD; Ferreirós, Nerea PhD; Bishay, Philipp PhD; Geisslinger, Gerd MD, PhD; Tegeder, Irmgard MD; Lötsch, Jörn MD

Journal of Clinical Psychopharmacology: October 2013 - Volume 33 - Issue 5 - p 699–705
doi: 10.1097/JCP.0b013e3182984015
Brief Reports

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.

From the Institute of Clinical Pharmacology, Goethe-University, Frankfurt am Main, Germany.

Received April 25, 2012; accepted after revision December 13, 2012.

Reprints: Jörn Lötsch, MD, Institute of Clinical Pharmacology, Goethe University, Theodor Stern Kai 7, 60590 Frankfurt am Main, Germany (e-mail:

© 2013 by Lippincott Williams & Wilkins.