Plasma levels of parent compound and metabolites after doses of either d-fenfluramine or d-3,4-methylenedioxymethamphetamine (MDMA) that produce long-term serotonergic alterations.
John F Bowyer, John F Young, William Slikker, Yossef Itzak, A J Mayorga, Glenn D. Newport, Syed F. Ali, David L Frederick, Merle G. Paule
Neurotoxicology June 2003 DOI: 10.1016/s0161-813x(03)00030-5 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Observational cohort Peer reviewed |
|---|---|
| Population | Adult rhesus monkeys |
| Interventions | d-fenfluramine MDMA |
| Dose | 5 mg/kg d-fenfluramine, 10 mg/kg MDMA |
| Duration | 4 days of dosing, 6-month follow-up |
| Topics | MDMA Serotonin |
| Key findings | Repeated FEN or MDMA dosing led to metabolite accumulation and long-term serotonin transporter reductions of 80% at six months. FEN peak levels increased 35% and NFEN 500% by the seventh dose; MDMA peak increased 30% and MDA over 200%. High inter-subject variability in MDMA and MDA exposure may relate to behavioral variability. |
Abstract
Plasma levels of parent compounds and metabolites were determined in adult rhesus monkeys after doses of either 5mg/kg d-fenfluramine (FEN) or 10mg/kg d-3, 4-methylenedioxymethamphetamine (MDMA) i.m. twice daily for four consecutive days. These treatment regimens have been previously shown to produce long-term serotonin (5-HT) depletions. Peak plasma levels of 2.0+/-0.4 microM FEN were reached within 40min after the first dose of FEN, and then declined rapidly, while peak plasma levels (0.4+/-0.1 microM) of the metabolite norfenfluramine (NFEN) were not reached until 6h after dosing. After the seventh (next to last) dose of FEN, peak plasma levels of FEN were 35% greater than after the first dose while peak NFEN-levels were 500% greater. The t(1/2) for FEN was 2.6+/-0.3h after the first dose and 3.2+/-0.2h after the seventh. The estimated t(1/2) for NFEN was more than 37.6+/-20.5h. Peak plasma levels of 9.5+/-2.5 microM MDMA were reached within 20min after the first dose of MDMA, and then declined rapidly, while peak plasma levels (0.9+/-0.2 microM) of the metabolite 3,4-methylenedioxyamphetamine (MDA) were not reached until 3-6h after dosing. After the seventh (next to last) dose of MDMA, peak plasma levels of MDMA were 30% greater than the first dose while peak MDA levels were elevated over 200%. The t(1/2) for MDMA was 2.8+/-0.4h after the first and 3.9+/-1.1h after the seventh dose. The estimated t(1/2) for MDA was about 8.3+/-1.0h. Variability in plasma levels of MDMA and MDA between subjects was much greater than that for FEN and NFEN. This variability in MDMA and MDA exposure levels may have lead to variability in the subsequent disruption of some behaviors seen in these same subjects. There were 80% reductions in the plasma membrane-associated 5-HT transporters 6 months after either the FEN or MDMA dosing regimen indicating that both treatments produced long-term serotonergic effects.
Comparable studies
Other preclinical and animal studies on MDMA, most cited first.
Citations in the library
Cited by 11
- Recreational ecstasy use and the neurotoxic potential of MDMA: current status of the controversy and methodological issues Drug and Alcohol Review May 1, 2006
- A PET study of effects of chronic 3,4‐methylenedioxymethamphetamine (MDMA, “ecstasy”) on serotonin markers in Göttingen minipig brain Synapse April 5, 2007
- Serotonin concentration enhancers at clinically relevant doses reduce [11C]AZ10419369 binding to the 5-HT1B receptors in the nonhuman primate brain Translational Psychiatry July 16, 2018
- Extinction training following cocaine or MDMA self-administration produces discrete changes in D2-like and mGlu5 receptor density in the rat brain. Pharmacological Reports October 2019
- Toxicity of ecstasy (MDMA) towards embryonic stem cell-derived cardiac and neural cells. Toxicology in Vitro June 2010
and 6 more in the library
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- Cardiovascular and neuroendocrine effects and pharmacokinetics of 3, 4-methylenedioxymethamphetamine in humans. Journal of Pharmacology and Experimental Therapeutics July 1, 1999
- 3,4‐Methylenedioxymethamphetamine (MDMA, “Ecstasy”): pharmacology and toxicology in animals and humans Addiction May 1, 1994
- A Method of Conducting Therapeutic Sessions with MDMA Journal of Psychoactive Drugs December 1, 1998
and 12 more in the library