This within-subject, double-blind study (n=22) found that acute administration of methamphetamine (14 mg/70 kg) significantly lowered plasma 2-arachidonoylglycerol concentrations compared to placebo at 150-180 minutes post-administration, whilst MDMA (100 mg) did not affect endocannabinoid levels, and higher anandamide concentrations during the placebo condition correlated with disliking the ‘drug effects’.
Abstract of The effect of methamphetamine and MDMA on peripheral endocannabinoid concentrations
“Rationale 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.
Objectives 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.
Methods 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.
Results 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.
Conclusions These findings provide novel insights into how stimulant drugs act on the eCB system and may help to develop treatments for SUDs.”
Authors: Ana Deutsch, Connor J. Haggarty, Gavin N. Petrie, Matthew N. Hill, Anya K. Bershad, Harriet de Wit & Leah M. Mayo
Summary of The effect of methamphetamine and MDMA on peripheral endocannabinoid concentrations
Deutsch and colleagues set out to test whether two psychostimulants—methamphetamine (MA) and MDMA—acutely alter circulating endocannabinoids in humans, and whether any such changes relate to subjective drug effects. The endocannabinoid (eCB) system—principally the ligands anandamide (AEA) and 2-arachidonoylglycerol (2-AG) acting at CB1 and CB2 receptors—regulates stress, reward, motivation, and mood. In preclinical work, stimulants can shift eCB tone and CB1 signalling, but human data are sparse and often confounded by chronic use. Here, the authors directly compared single oral doses of MA and MDMA with placebo in healthy adults under controlled laboratory conditions, measuring plasma AEA and 2-AG near expected peak drug effects alongside cortisol, brain-derived neurotrophic factor (BDNF), cardiovascular indices, and self-reported experiences.
The introduction situates MA as a prototypical stimulant with strong dopaminergic actions and a long elimination half-life, and MDMA as a methamphetamine derivative with relatively stronger serotonergic actions and characteristic prosocial effects. The authors highlight that stimulant misuse is rising while pharmacotherapies for stimulant use disorder remain limited. Because eCB signalling is implicated in both stress reactivity (via the hypothalamic–pituitary–adrenal, HPA, axis) and drug reward, clarifying how acute stimulant exposure impacts circulating eCBs could inform new treatment targets. Earlier research in animals shows mixed effects of acute stimulants on 2-AG and AEA, and human studies in chronic stimulant users show altered baseline eCBs, but the acute, within-person effects in healthy participants had not been defined.
Finally, the authors note that acute psychostimulants increase cortisol, yet links between eCBs and cortisol after stimulant dosing in humans are unclear. They pre-registered a straightforward hypothesis: MA would increase plasma 2-AG (by analogy to some prior findings in stimulant-using populations), whereas MDMA would leave eCBs unchanged. They also anticipated that comparing MA with MDMA would reveal mechanistic differences consistent with their distinct monoaminergic profiles.
Methods
Study design and setting
Find this paper
https://doi.org/10.1007/s00213-025-06888-7
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Cite this paper (APA)
Deutsch, A., Haggarty, C. J., Petrie, G. N., Hill, M. N., Bershad, A. K., de Wit, H., & Mayo, L. M. (2025). The effect of methamphetamine and 3, 4-methylenedioxymethamphetamine on peripheral endocannabinoid concentrations: a study in healthy adults. Psychopharmacology, 1-14.
Study details
Compounds studied
MDMA
Placebo
Topics studied
Neuroscience
Study characteristics
Original
Placebo-Controlled
Active Placebo
Double-Blind
Within-Subject
Participants
22
Humans
Compound Details
The psychedelics given at which dose and how many times
MDMA 100 μg | 1x