A review on the mitochondrial toxicity of “ecstasy” (3,4-methylenedioxymethamphetamine, MDMA)
João Paulo Capela, Félix Dias Carvalho
Current Research in Toxicology May 27, 2022 DOI: 10.1016/j.crtox.2022.100075 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Review Peer reviewed |
|---|---|
| Topics | MDMA |
| Keywords | 3,4-methylenedioxymethamphetamine Mitochondrial toxicity Mitochondrial membrane potential Mitochondrial trafficking Drug of abuse Neurotoxicity |
| Citations | 17 |
| Key findings | MDMA causes mitochondrial dysfunction including ATP depletion, inhibition of complexes I and III, loss of membrane potential, and impaired mitochondrial trafficking, contributing to its neurotoxicity and hepatotoxicity. |
Abstract
3,4-Methylenedioxymethamphetamine (MDMA or “ecstasy”) is a drug of abuse used by millions worldwide. MDMA human abuse and dependence is well described, but addictive properties are not always consistent among studies. This amphetamine is a substrate type releaser, binding to monoamine transporters, leading to a pronounced release of serotonin and noradrenaline and to a minor extent dopamine. The toxicity of MDMA is well studied at the pre-clinical level, with neurotoxicity and hepatotoxicity being particularly described.In this review, we describe the most relevant MDMA effects at the mitochondrial level found in in vitro and in vivo models, these later conducted in mice and rats. Most of these reports focus on the mitochondria of brain or liver. In in vitro models, MDMA causes depletion of ATP levels and inhibition of mitochondrial complex I and III, loss in mitochondrial membrane potential (ΔΨm) and induction of mitochondrial permeability transition. The involvement of mitochondria in the apoptotic cell death evoked by MDMA has also been shown, such as the release of cytochrome c. Additionally, MDMA or its metabolites impaired mitochondrial trafficking and increased the fragmentation of axonal mitochondria. In animal studies, MDMA decreased mitochondrial complex I activity and decreased ATP levels. Moreover, MDMA-evoked oxidative stress has been shown to cause deletion on mitochondrial DNA and impairment in mitochondrial protein synthesis.Although the concentrations and doses used in some studies do not always correlate to the human scenario, the mitochondrial abnormalities evoked by MDMA are well described and are in part responsible for its mechanism of toxicity.
Comparable studies
Other narrative reviews on MDMA, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Human Pharmacology of MDMA | 2004 | Review | |
| Human psychopharmacology of Ecstasy (MDMA): a review of 15 years of empirical research | 2001 | Review | |
| 3,4‐Methylenedioxymethamphetamine (MDMA, “Ecstasy”): pharmacology and toxicology in animals and humans | 1994 | Review | |
| (±)3,4-Methylenedioxymethamphetamine (‘Ecstasy’)-Induced Serotonin Neurotoxicity: Studies in Animals | 2000 | Review | |
| Amphetamine toxicities | 2010 | Review |
Citations in the library
Cited by 8
- The efficacy and safety of MDMA-assisted psychotherapy for treatment of posttraumatic stress disorder: A systematic review and meta-analysis from randomized controlled trials. Psychiatry Research September 1, 2024
- Mitochondrial Calcium Uniporter (MCU)-Mediated Calcium Overload in Psychoactive Drug Neurotoxicity: From Pathogenesis to Therapeutic Targets. International Journal of Molecular Sciences May 15, 2025
- Recreational MDMA doses do not elicit hepatotoxicity in HepG2 spheroids under normo- and hyperthermia. Toxicology March 1, 2024
- Glutathione as a Potential Neuroprotectant Against MDMA-Induced Oxidative Stress, Neuroinflammation, and Apoptosis in the Rat Brain. Neurochemical Research May 6, 2026
- Protective effects of vitamin E and quercetin against MDMA-induced cardiac and hematological dysfunction in male wistar rats. Pflügers Archiv: European Journal of Physiology April 23, 2026
and 3 more in the library
Cites 39
- MDMA-assisted therapy for severe PTSD: a randomized, double-blind, placebo-controlled phase 3 study. Nature Medicine June 1, 2021
- Human Pharmacology of MDMA Therapeutic Drug Monitoring March 19, 2004
- MDMA-assisted psychotherapy for treatment of PTSD: study design and rationale for phase 3 trials based on pooled analysis of six phase 2 randomized controlled trials. Psychopharmacology September 1, 2019
- The origin of MDMA (ecstasy) revisited: the true story reconstructed from the original documents* Addiction July 8, 2006
- Neurotoxicity of Methamphetamine and 3,4-methylenedioxymethamphetamine Life Science July 24, 2013
and 34 more in the library