Pharmacokinetic Profile of Single and Repeated Oral Doses of MDMA in Squirrel Monkeys: Relationship to Lasting Effects on Brain Serotonin Neurons
Abstract
A large body of data indicates that (+/-)3,4-methylenedioxymethamphetamine (MDMA, 'ecstasy') can damage brain serotonin neurons in animals. However, the relevance of these preclinical data to humans is uncertain, because doses and routes of administration used in animals have generally differed from those used by humans. Here, we examined the pharmacokinetic profile of MDMA in squirrel monkeys after different routes of administration, and explored the relationship between acute plasma MDMA concentrations after repeated oral dosing and subsequent brain serotonin deficits. Oral MDMA administration engendered a plasma profile of MDMA in squirrel monkeys resembling that seen in humans, although the half-life of MDMA in monkeys is shorter (3 vs 6-9 h). MDMA was biotransformed into MDA, and the plasma ratio of MDA to MDMA was 3-5 / 100, similar to that in humans. MDMA accumulation in squirrel monkeys was nonlinear, and plasma levels were highly correlated with regional brain serotonin deficits observed 2 weeks later. The present results indicate that plasma concentrations of MDMA shown here to produce lasting serotonergic deficits in squirrel monkeys overlap those reported by other laboratories in some recreational 'ecstasy' consumers, and are two to three times higher than those found in humans administered a single 100-150 mg dose of MDMA in a controlled setting. Additional studies are needed on the relative sensitivity of brain serotonin neurons to MDMA toxicity in humans and non-human primates, the pharmacokinetic parameter(s) of MDMA most closely linked to the neurotoxic process, and metabolites other than MDA that may play a role.
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A longer interval between sessions may have been needed to ensure no carry-over effects.
“Thus, it is possible that a longer period between sessions was required to ensure the absence of carry-over effects.”
From Effects of MDMA on sociability and neural response to social threat and social reward (2009) · cites this paper as Mechan et al. 2005
Preclinical findings suggest serotonin depletion may persist up to two weeks after single or repeated oral doses.
“preclinical findings suggest that in non-human primates serotonin depletion may persist for up to two weeks after single doses (Ricaurte et al. 1988) or repeated oral doses (Mechan et al. 2005).”
From Effects of MDMA on sociability and neural response to social threat and social reward (2009) · cites this paper as Mechan et al. 2005
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References 67 · Cited by 67
- Authors
- Mechan, A., Yuan, J., Hatzidimitriou, G., Irvine, R. J., McCann, U. D., & Ricaurte, G. A.
- Affiliations
- Johns Hopkins University (US)
- The University of Adelaide (AU)
- Corresponding author
- Ricaurte, George A
- ORCID
- Yuan, Jie
- Venue
- Neuropsychopharmacology
- Published
- 2005-07-06
- Volume
- 31
- Issue
- 2
- Pages
- 339-350
- ISSN
- 0893-133X (ISSN-L)
- 1740-634X
- OpenAlex
- W2165440826
- Cited by
- 67
- References
- 67
- Citations by year
- 2024: 1 · 2023: 1 · 2022: 1 · 2018: 1 · 2017: 1 · 2016: 1 · 2015: 1 · 2014: 1 · 2013: 3 · 2012: 6
- FWCI
- 10.40
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Neuropsychopharmacology (publishedVersion)
- PubMed (publishedVersion)
- Adelaide Research & Scholarship (AR&S) (University of Adelaide) (submittedVersion)
- Funders
- U.S. Public Health Service
- Medical Research Council
- National Health and Medical Research Council
- National Medical Research Council
- National Institute on Drug Abuse (DA 00206, DA5707)
- Topics
- Social Sciences › Psychology › Clinical Psychology › Psychedelics and Drug Studies
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Toxicology › Forensic Toxicology and Drug Analysis
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Keywords
- MDMA, ecstasy, pharmacokinetics, serotonergic neurons, neurotoxicity, repeated oral dosing, squirrel monkey, methamphetamine metabolites, dose-response relationship, route of administration, non-human primates
- MeSH terms
- Administration, Oral, Analysis of Variance, Animals, Brain, Brain Chemistry, Chromatography, High Pressure Liquid, Cocaine, Dose-Response Relationship, Drug, Drug Administration Routes, Drug Administration Schedule, Drug Interactions, Electrochemistry, Female, Hallucinogens, Male, Neurons, Protein Binding, Saimiri, Serotonin, Time Factors, 3,4-Methylenedioxyamphetamine, N-Methyl-3,4-methylenedioxyamphetamine, Radiopharmaceuticals, Serotonin Plasma Membrane Transport Proteins
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