Retraction of Research Findings
Severe Dopaminergic Neurotoxicity in Primates After a Common Recreational Dose Regimen of MDMA ("Ecstasy")
Sep 5, 2003
Review of Article
Article Index Page
We write to retract our report "Severe dopaminergic neurotoxicity in primates after a common recreational dose regimen of methylenedioxymethamphetamine (MDMA)" (1) following our recent discovery that the drug used to treat all but one animal in that report came from a bottle that contained d-methamphetamine instead of the intended drug, racemic MDMA. Notably, d-methamphetamine would be expected to produce the same pattern of combined dopaminergic/serotonergic neurotoxicity (2) as that seen in the animals reported in our paper (1).
The originally published report (1) presented results from multiple studies performed in our laboratory over a span of approximately two years demonstrating that a novel systemic dose regimen of what we believed was MDMA produced severe dopamine neurotoxicity in two species of nonhuman primates, in addition to the previously reported serotonin neurotoxicity (3-6). Subsequent to the publication of those findings, we were unable to extend the dopamine neurotoxicity to orally administered doses. Multiple subsequent attempts to reproduce the original findings with systemically administered doses of MDMA identical to those used in the original study were also unsuccessful, under a variety of laboratory conditions.
We then noted that our studies aimed at extending and replicating the finding of MDMA-induced dopamine neurotoxicity were performed using a new batch of MDMA. This new batch of MDMA was determined to be authentic by several methods, including gas chromatography/mass spectrometry (GC/MS). Upon investigation of our laboratory records, we determined that the studies detailed in our paper (1) utilized a batch of MDMA that had been requested on the same date as a batch of d-methamphetamine, and that both drug requests were for the same amount (10 g), and were processed by the supplier on the same day. Both drugs were delivered to our laboratory on the same day, in the same package. At delivery, the two bottles had different affixed labels, the same delivery reference number, but different batch numbers, as specified in their respective chemical data sheets. Following receipt, both drugs were stored in our laboratory in their original containers, in a locked safe.
When we began to suspect that the two bottles of drug might have borne incorrect labels (i.e., that the putative MDMA was actually d-methamphetamine, and vice versa), we requested that a sample of the drug in the bottle bearing the original and intact label of "d-methamphetamine" be analyzed by various analytical techniques, including GC/MS. Three independent laboratories found the sample to consist of MDMA, with no evidence of even trace amounts of methamphetamine.
Although the drug sample used in our original studies (1) was depleted and the empty bottle labeled MDMA had been discarded, we did have frozen brains from two animals that died shortly after drug treatment during the course ofthe original experiments (1). When these brains were analyzed by GC/MS by three independent laboratories, they were found to contain methamphetamine and its metabolite, amphetamine, neither of which is a metabolite of MDMA(7). Not even trace amounts of MDMA nor its metabolite, MDA, were found inthese brains. Detailed review of our laboratory records revealed that allbut one animal in our study (1) had been treated with the drug in the bottle labeled "(±)methylenedioxymethamphetamine" (MDMA) processed at the same time as the bottle labeled "d-methamphetamine".
This labeling error does not call into question the results of multiple previous studies demonstrating the serotonin neurotoxic potential of MDMA invarious animal species, including several nonhuman primate species (3-6,8). Regarding the dopamine neurotoxic potential of MDMA in nonhumanprimates, it remains possible that dose regimens in the range of those used by some humans, but different from those thus far tested, produce dopamine neurotoxicity in primates, as they do in rodents (9, 10). Moreover, lasting effects of MDMA on dopaminergic function in humans have recently been reported (11), and some humans with a history of MDMA abuse have developed Parkinsonism (12-14). However, until the dopamine neurotoxic potential ofMDMA in primates can be examined more fully, this possibility remains uncertain.
George A. Ricaurte1, Jie Yuan1, George Hatzidimitriou1, Branden J. Cord2, Una D. McCann3
Department of Neurology, 2 - Department of Neurosciences, 3 - Department of Psychiatry
Johns Hopkins Bayview Medical Center
Johns Hopkins University
School of Medicine, Baltimore, MD 21224, USA.
References
Article Index Page
We write to retract our report "Severe dopaminergic neurotoxicity in primates after a common recreational dose regimen of methylenedioxymethamphetamine (MDMA)" (1) following our recent discovery that the drug used to treat all but one animal in that report came from a bottle that contained d-methamphetamine instead of the intended drug, racemic MDMA. Notably, d-methamphetamine would be expected to produce the same pattern of combined dopaminergic/serotonergic neurotoxicity (2) as that seen in the animals reported in our paper (1).
The originally published report (1) presented results from multiple studies performed in our laboratory over a span of approximately two years demonstrating that a novel systemic dose regimen of what we believed was MDMA produced severe dopamine neurotoxicity in two species of nonhuman primates, in addition to the previously reported serotonin neurotoxicity (3-6). Subsequent to the publication of those findings, we were unable to extend the dopamine neurotoxicity to orally administered doses. Multiple subsequent attempts to reproduce the original findings with systemically administered doses of MDMA identical to those used in the original study were also unsuccessful, under a variety of laboratory conditions.
We then noted that our studies aimed at extending and replicating the finding of MDMA-induced dopamine neurotoxicity were performed using a new batch of MDMA. This new batch of MDMA was determined to be authentic by several methods, including gas chromatography/mass spectrometry (GC/MS). Upon investigation of our laboratory records, we determined that the studies detailed in our paper (1) utilized a batch of MDMA that had been requested on the same date as a batch of d-methamphetamine, and that both drug requests were for the same amount (10 g), and were processed by the supplier on the same day. Both drugs were delivered to our laboratory on the same day, in the same package. At delivery, the two bottles had different affixed labels, the same delivery reference number, but different batch numbers, as specified in their respective chemical data sheets. Following receipt, both drugs were stored in our laboratory in their original containers, in a locked safe.
When we began to suspect that the two bottles of drug might have borne incorrect labels (i.e., that the putative MDMA was actually d-methamphetamine, and vice versa), we requested that a sample of the drug in the bottle bearing the original and intact label of "d-methamphetamine" be analyzed by various analytical techniques, including GC/MS. Three independent laboratories found the sample to consist of MDMA, with no evidence of even trace amounts of methamphetamine.
Although the drug sample used in our original studies (1) was depleted and the empty bottle labeled MDMA had been discarded, we did have frozen brains from two animals that died shortly after drug treatment during the course ofthe original experiments (1). When these brains were analyzed by GC/MS by three independent laboratories, they were found to contain methamphetamine and its metabolite, amphetamine, neither of which is a metabolite of MDMA(7). Not even trace amounts of MDMA nor its metabolite, MDA, were found inthese brains. Detailed review of our laboratory records revealed that allbut one animal in our study (1) had been treated with the drug in the bottle labeled "(±)methylenedioxymethamphetamine" (MDMA) processed at the same time as the bottle labeled "d-methamphetamine".
This labeling error does not call into question the results of multiple previous studies demonstrating the serotonin neurotoxic potential of MDMA invarious animal species, including several nonhuman primate species (3-6,8). Regarding the dopamine neurotoxic potential of MDMA in nonhumanprimates, it remains possible that dose regimens in the range of those used by some humans, but different from those thus far tested, produce dopamine neurotoxicity in primates, as they do in rodents (9, 10). Moreover, lasting effects of MDMA on dopaminergic function in humans have recently been reported (11), and some humans with a history of MDMA abuse have developed Parkinsonism (12-14). However, until the dopamine neurotoxic potential ofMDMA in primates can be examined more fully, this possibility remains uncertain.
George A. Ricaurte1, Jie Yuan1, George Hatzidimitriou1, Branden J. Cord2, Una D. McCann3
Department of Neurology, 2 - Department of Neurosciences, 3 - Department of Psychiatry
Johns Hopkins Bayview Medical Center
Johns Hopkins University
School of Medicine, Baltimore, MD 21224, USA.
References
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- A. Cho, Y. Kumagai, in Amphetamine and its Analogs: Neuropsychopharmacology, Toxicology and Abuse, A. Cho, D. Segal, Eds. (Academic Press, New York, 1994), pp. 43-77.
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- G. Ricaurte, unpublished data.
- We gratefully acknowledge helpful discussions with Dr. Jonathan Katz of the NIDA Intramural Research Program, Baltimore, MD, Dr. W. Lee Hearn, Laboratory Director of the Miami-Dade County Medical Examiner Department, Miami, FL and Dr. Nancy Ator, Johns Hopkins University School of Medicine, Baltimore, MD. We are also grateful for the expert chemical analytical assistance of Ms. Rebecca Fernandez, Toxicologist I, Miami-Dade County Medical Examiner Department, Miami, FL, Terry L. DalCason of the DEA North Central Laboratory, Chicago, IL., Dr. Max Courtney, Forensic Consultant Services, Fort Worth, TX., Dr. Michael Daggett, Quest Diagnostics-Nichols Institute, Chantilly, VA, Dr. Ivy Carroll and associates at RTI International, Research Triangle Park, NC, and Dr. Roger Foltz at the University of Utah, Salt Lake City, UT.