The effect of methamphetamine and 3,4-methylenedioxymethamphetamine on peripheral endocannabinoid concentrations: a study in healthy adults.
Ana Deutsch, Connor J Haggarty, Gavin N Petrie, Matthew N Hill, Anya K Bershad, Harriet de Wit, Leah M Mayo
Psychopharmacology February 1, 2026 Peer reviewed DOI: 10.1007/s00213-025-06888-7 via PubMed
Summary
Acute methamphetamine (MA), but not MDMA, reduces circulating levels of the endocannabinoid 2-arachidonoylglycerol (2-AG) in healthy adults. Neither drug affects anandamide (AEA) concentrations. Higher AEA levels during placebo were linked to disliking drug effects, suggesting a role for AEA in negative expectations. These findings reveal how stimulants interact with the endocannabinoid system, potentially informing treatments for substance use disorders.
Study at a glance
| Design | within-subject, double-blind, placebo-controlled trial |
|---|---|
| Sample size | 22 |
| Population | healthy adults |
| Key finding | Methamphetamine, but not MDMA, significantly lowered plasma 2-AG concentrations compared to placebo, while neither drug affected AEA levels. |
Abstract
Stimulant drugs such as methamphetamine (MA) and 3,4-methylenedioxymethamphetamine (MDMA) can impact neurobiological systems implicated in stress, reward processing, and drug use. Although recent preclinical evidence implicates the endocannabinoid (eCB) system in these processes, little is known about the acute effects of stimulants on eCB levels in humans. The aim of the present study was to investigate the effects of acute administration of the prototypical psychostimulant MA and the psychostimulant-empathogen MDMA on circulating eCB levels in healthy adults. Using a within-subject, double-blind design, this study assessed the acute effects of MA (20 mg), MDMA (100 mg), and placebo on plasma eCB levels in healthy human participants (N = 22) during three separate sessions. Blood samples assessing concentrations of the eCBs anandamide (AEA) and 2-Arachidonoylglycerol (2-AG) were collected between 150- and 180-minutes post-drug administration, and subjective measures of drug effects were collected at regular intervals. MA, but not MDMA, was associated with significantly lower 2-AG plasma concentrations compared to placebo. Neither drug impacted AEA concentrations. However, during the placebo condition, higher AEA concentrations were correlated with disliking the 'drug effects', suggesting a possible relationship between AEA levels and negative expectations of subjective drug effects. These findings provide novel insights into how stimulant drugs act on the eCB system and may help to develop treatments for SUDs.