MDMA pharmacokinetics: A population and physiologically based pharmacokinetics model-informed analysis.
Marilyn A. Huestis, William B Smith, Cathrine Leonowens, Rebecca Blanchard, Aurélien Viaccoz, Erin Spargo, Nicholas B Miner, Berra Yazar-Klosinski
CPT: Pharmacometrics & Systems Pharmacology February 1, 2025 DOI: 10.1002/psp4.13282 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Phase I pharmacokinetic study with population and physiologically based pharmacokinetic modeling Peer reviewed |
|---|---|
| Population | Adults (specific population not described) |
| Topics | MDMA |
| Keywords | MDMA Therapy Psychedelic medicine PTSD Treatment Drug metabolism Pharmacokinetics |
| Citations | 3 |
| Key points | A high-fat/high-calorie meal did not alter MDMA plasma concentrations, and splitting the dose delays early exposure without substantially changing overall exposure. |
Abstract
Midomafetamine (3,4-methylenedioxymethamphetamine [MDMA]) is under the U.S. Food and Drug Administration review for treatment of post-traumatic stress disorder in adults. MDMA is metabolized by CYP2D6 and is a strong inhibitor of CYP2D6, as well as a weak inhibitor of renal transporters MATE1, OCT1, and OCT2. A pharmacokinetic phase I study was conducted to evaluate the effects of food on MDMA pharmacokinetics. The results of this study, previously published pharmacokinetic data, and in vitro data were combined to develop and verify MDMA population pharmacokinetic and physiologically based pharmacokinetic models. The food effect study demonstrated that a high-fat/high-calorie meal did not alter MDMA plasma concentrations, but delayed Tmax. The population pharmacokinetic model did not identify any clinically meaningful covariates, including age, weight, sex, race, and fed status. The physiologically based pharmacokinetic model simulated pharmacokinetics for the proposed 120 and 180 mg MDMA HCl clinical doses under single- and split-dose (2 h apart) conditions, indicating minor differences in overall exposure, but lower AUC within the first 4 h and delayed Tmax when administered as a split dose compared to a single dose. The physiologically based pharmacokinetic model also investigated the drug-drug interaction magnitude by varying the fraction metabolized by a representative CYP2D6 substrate (atomoxetine) and evaluated inhibition of renal transporters. The simulations confirm MDMA is a potent CYP2D6 inhibitor, but likely has no meaningful impact on the pharmacokinetics of drugs sensitive to renal transport. This model-informed drug development approach was employed to inform drug-drug interaction potential and predict pharmacokinetics of clinically relevant dosing regimens of MDMA.
Comparable studies
Other experimental studies on MDMA, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Amphetamine-type central nervous system stimulants release norepinephrine more potently than they release dopamine and serotonin | 2000 | Experimental study | |
| Methylenedioxyamphetamine (MDA) and methylenedioxymethamphetamine (MDMA) cause selective ablation of serotonergic axon terminals in forebrain: immunocytochemical evidence for neurotoxicity Rat brain | 1988 | Experimental study | |
| The molecular mechanism of "ecstasy" [3,4-methylenedioxy-methamphetamine (MDMA)]: serotonin transporters are targets for MDMA-induced serotonin release. Human platelet plasma membrane vesicles and bovine adrenal chromaffin granule membrane... | 1992 | Laboratory study | |
| Oxytocin-dependent reopening of a social reward learning critical period with MDMA | 2019 | Experimental study | |
| Effects of certain hallucinogenic amphetamine analogs on the release of [3H]-serotonin from rat brain synaptosomes Rat whole brain synaptosomes | 1982 | Experimental study |
Citations in the library
Cites 15
- 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
- 3,4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy for post-traumatic stress disorder in military veterans, firefighters, and police officers: a randomised, double-blind, dose-response, phase 2 clinical trial. The Lancet Psychiatry May 1, 2018
- Subjective Reports of the Effects of MDMA in a Clinical Setting Journal of Psychoactive Drugs October 1, 1986
- MDMA-assisted therapy for moderate to severe PTSD: a randomized, placebo-controlled phase 3 trial. Nature Medicine October 1, 2023
and 10 more in the library