TY - JOUR
T1 - Pharmacokinetic profile of single and repeated oral doses of MDMA in squirrel monkeys
T2 - Relationship to lasting effects on brain serotonin neurons
AU - Mechan, Annis
AU - Yuan, Jie
AU - Hatzidimitriou, George
AU - Irvine, Rodney J.
AU - McCann, Una D.
AU - Ricaurte, George A.
N1 - Funding Information:
We thank Christopher Mehl for his guidance in using the pharmacokinetic program (Pharsight Corp., Mountain View, CA). Portions of this work were presented in abstract form (G Ricaurte, International Congress of Therapeutic Drug Monitoring and Clinical Toxicology, Basel, Switzerland, September 2003). This work was supported by USPHS Grants DA5707 and DA00206 (GAR) and the National Health and Medical Research Council of Australia (RJI).
PY - 2006/2
Y1 - 2006/2
N2 - 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.
AB - 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.
KW - Amphetamines
KW - MDMA
KW - Pharmacokinetics
KW - Plasma
KW - Serotonin
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U2 - 10.1038/sj.npp.1300808
DO - 10.1038/sj.npp.1300808
M3 - Article
C2 - 15999148
AN - SCOPUS:30944431901
SN - 0893-133X
VL - 31
SP - 339
EP - 350
JO - Neuropsychopharmacology
JF - Neuropsychopharmacology
IS - 2
ER -