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 DOI: 10.1007/s00213-025-06888-7 via PubMed
Summary
AI-generated from the abstractA single oral dose of methamphetamine (20 mg) reduced blood levels of the endocannabinoid 2-AG in healthy adults, while MDMA (100 mg) did not. Neither drug affected anandamide (AEA) levels. Under placebo, higher AEA concentrations were linked to disliking the drug effects, suggesting a connection between AEA and negative expectations. These findings show how stimulants act on the endocannabinoid system and may inform treatments for substance use disorders.
Study at a glance
| Characteristics | Within-subject, double-blind, placebo-controlled trial Peer reviewed |
|---|---|
| Sample size | 22 |
| Population | Healthy adults |
| Interventions | Methamphetamine MDMA |
| Dose | 20 mg MA, 100 mg MDMA |
| Topics | MDMA |
| Keywords | Endocannabinoids Methamphetamine Stimulants Substance use disorders |
| Citations | 1 |
| 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.