The effect of methamphetamine and 3,4-methylenedioxymethamphetamine on peripheral endocannabinoid concentrations: a study in healthy adults
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'.
Authors
- Harriet de Wit
- Anya Bershad
Published
Abstract
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.
Research Summary of 'The effect of methamphetamine and 3,4-methylenedioxymethamphetamine on peripheral endocannabinoid concentrations: a study in healthy adults'
Introduction
Mayo and colleagues situate this study within a broader effort to understand how stimulant drugs affect neurobiological systems involved in stress, reward and substance use disorders. The endocannabinoid (eCB) system — comprising CB1/CB2 receptors and the endogenous ligands anandamide (AEA) and 2-arachidonoylglycerol (2-AG) — is implicated in emotion regulation, reward processing and HPA-axis stress responsivity, and preclinical data suggest interactions between stimulants and eCB signalling. Human data are limited and mixed: chronic stimulant users show altered peripheral eCB profiles, but acute effects of prototypical stimulants on circulating AEA and 2-AG have not been well characterised in healthy participants. The present study aimed to test whether acute administration of methamphetamine (MA) and 3,4-methylenedioxymethamphetamine (MDMA) differentially alter peripheral eCB concentrations in healthy adults. Based on prior findings and mechanistic differences between the drugs, the investigators hypothesised that MA would increase 2-AG concentrations, whereas MDMA would not affect eCB levels. The study also measured cortisol, brain-derived neurotrophic factor (BDNF), physiological responses and subjective drug effects to relate any eCB changes to stress and subjective experience.
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Study Details
- Study Typeindividual
- Journal
- Compounds
- Topics
- Authors
- APA Citation
Deutsch, A., Haggarty, C. J., Petrie, G. N., Hill, M. N., Bershad, A. K., de Wit, H., & Mayo, L. M. (2026). The effect of methamphetamine and 3,4-methylenedioxymethamphetamine on peripheral endocannabinoid concentrations: a study in healthy adults. Psychopharmacology, 243(2), 413-426. https://doi.org/10.1007/s00213-025-06888-7
References (8)
Papers cited by this study that are also in Blossom
Haggarty, C. J., Bershad, A. K., Kumar, M. K. et al. · European Journal of Neurology (2024)
Holze, F., Vizeli, P., Müller, F. et al. · Neuropsychopharmacology (2019)
Aarde, S. M., Taffe, M. A. · Neuropharmacology (2016)
Bedi, G., Hyman, D., De Wit, H. · Biological Psychiatry (2010)
Dolder, P. C., Müller, F., Schmid, Y. et al. · Psychopharmacology (2017)
Straumann, I., Avedisian, I., Klaiber, A. et al. · Neuropsychopharmacology (2024)
Mitchell, J., Bogenschutz, M. P., Lilienstein, A. et al. · Nature Medicine (2021)
Mitchell, J., Ot’alora G, M., van der Kolk, B. et al. · Nature Medicine (2023)
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