Nonlinear Pharmacokinetics of (±)3,4-Methylenedioxymethamphetamine (MDMA) and Its Pharmacodynamic Consequences in the Rat
Marta Concheiro, Michael H. Baumann, Karl B. Scheidweiler, Richard B Rothman, Gina F. Marrone, Marilyn A. Huestis
Drug Metabolism and Disposition October 19, 2013 DOI: 10.1124/dmd.113.053678 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical pharmacokinetic and pharmacodynamic study Peer reviewed |
|---|---|
| Population | Male rats |
| Intervention | MDMA |
| Dose | 2.5, 5, and 10 mg/kg s.c. |
| Duration | 24 hours |
| Topics | MDMA Serotonin |
| Keywords | Pharmacology Pharmacokinetics Pharmacodynamics Cmax Toxicokinetics |
| Citations | 32 |
| Key points | MDMA and MDA display nonlinear accumulation via metabolic autoinhibition in rats, with serotonin syndrome severity correlated to MDMA concentrations and hyperthermia correlated to MDA concentrations. |
Abstract
3,4-Methylenedioxymethamphetamine (MDMA) is a widely abused illicit drug that can cause severe and even fatal adverse effects. However, interest remains for its possible clinical applications in posttraumatic stress disorder and anxiety treatment. Preclinical studies to determine MDMA's safety are needed. We evaluated MDMA's pharmacokinetics and metabolism in male rats receiving 2.5, 5, and 10 mg/kg s.c. MDMA, and the associated pharmacodynamic consequences. Blood was collected via jugular catheter at 0, 0.5, 1, 2, 4, 6, 8, 16, and 24 hours, with simultaneous serotonin (5-HT) behavioral syndrome and core temperature monitoring. Plasma specimens were analyzed for MDMA and the metabolites (±)-3,4-dihydroxymethamphetamine (HHMA), (±)-4-hydroxy-3-methoxymethamphetamine (HMMA), and (±)-3,4-methylenedioxyamphetamine (MDA) by liquid chromatography-tandem mass spectrometry. After 2.5 mg/kg MDMA, mean MDMA Cmax was 164 ± 47.1 ng/ml, HHMA and HMMA were major metabolites, and <20% of MDMA was metabolized to MDA. After 5- and 10-mg/kg doses, MDMA areas under the curve (AUCs) were 3- and 10-fold greater than those after 2.5 mg/kg; HHMA and HMMA AUC values were relatively constant across doses; and MDA AUC values were greater than dose-proportional. Our data provide decisive in vivo evidence that MDMA and MDA display nonlinear accumulation via metabolic autoinhibition in the rat. Importantly, 5-HT syndrome severity correlated with MDMA concentrations (r = 0.8083; P < 0.0001) and core temperature correlated with MDA concentrations (r = 0.7595; P < 0.0001), suggesting that MDMA's behavioral and hyperthermic effects may involve distinct mechanisms. Given key similarities between MDMA pharmacokinetics in rats and humans, data from rats can be useful when provided at clinically relevant doses.
Comparable studies
Other preclinical and animal studies on MDMA, most cited first.
Citations in the library
Cited by 17
- Baths Salts, Spice, and Related Designer Drugs: The Science Behind the Headlines Journal of Neuroscience November 12, 2014
- Pharmacokinetic, Ambulatory, and Hyperthermic Effects of 3,4-Methylenedioxy-N-Methylcathinone (Methylone) in Rats Frontiers in Psychiatry November 17, 2017
- Critical Role of Peripheral Vasoconstriction in Fatal Brain Hyperthermia Induced by MDMA (Ecstasy) under Conditions That Mimic Human Drug Use Journal of Neuroscience June 4, 2014
- Metabolites of the ring-substituted stimulants MDMA, methylone and MDPV differentially affect human monoaminergic systems Journal of Psychopharmacology April 30, 2019
- Key interindividual determinants in MDMA pharmacodynamics Expert Opinion on Drug Metabolism & Toxicology January 5, 2018
and 12 more in the library
Cites 25
- The safety and efficacy of {+/-}3,4-methylenedioxymethamphetamine-assisted psychotherapy in subjects with chronic, treatment-resistant posttraumatic stress disorder: the first randomized controlled pilot study. Journal of Psychopharmacology July 19, 2010
- Human Pharmacology of MDMA Therapeutic Drug Monitoring March 19, 2004
- Cardiovascular and neuroendocrine effects and pharmacokinetics of 3, 4-methylenedioxymethamphetamine in humans. Journal of Pharmacology and Experimental Therapeutics July 1, 1999
- (±)3,4-Methylenedioxymethamphetamine (‘Ecstasy’)-Induced Serotonin Neurotoxicity: Studies in Animals Neuropsychobiology 2000
- 3,4-Methylenedioxymethamphetamine (MDMA) neurotoxicity in rats: a reappraisal of past and present findings Psychopharmacology March 15, 2006
and 20 more in the library