MDMA Neurotoxicity Research in Primates:
Dr. Ricaurte's July 15, 2003 Progress Report to the
National Institute on Drug Abuse
Released in response to a Freedom of Information Act (FOIA) request by the
Multidisciplinary Association for Psychedelic Studies (MAPS)
Rick Doblin, Ph.D., MAPS President
On October 10, 2003, MAPS submitted a Freedom on Information Act (FOIA)
request to the National Institute on Drug Abuse (NIDA) seeking additional
information about Dr. Ricaurte's research studies exploring the possible effect
of MDMA on dopamine neurons. This FOIA request was submitted several weeks
after Dr. Ricaurte formally retracted his September 2002 paper in Science,
which had reported that MDMA damaged dopaminergic neurons in non-human
primates. The paper was retracted because the researchers had unknowingly
administered methamphetamine instead of MDMA to the primates.
On January 26, 2004, NIDA's FOIA office sent its reply to MAPS' FOIA request
consisting of a cover letter, Dr. Ricaurte's July 15, 2003 Progress Report to
NIDA, and Dr. Ricaurte's October 10, 2003 letter to NIDA.
While many of MAPS' questions were not addressed completely,
much could be learned from the material released.
It was satisfying to learn that MAPS' first-ever and well-quoted press release questioning the initial paper in Science contributed somewhat to the eventual retraction of the paper. According to Dr. Ricaurte, "Upon publication of our findings in Science (9/27/02), our report received considerable attention, both from the media and from the scientific community. There was quite a bit of discussion regarding the two animals (one squirrel monkey and one baboon) that died during the course of the study, and whether doses given subcutaneously were
fundamentally different (i.e., more potent) than oral doses typically used by
humans (even though previous studies cited in the paper suggested that this
was not so). To directly address the question regarding potential differences
between oral versus subcutaneous dosing regimens, oral dosing studies were
initiated in squirrel monkeys in October, 2002."
Dr. Ricaurte's comment that previous studies cited in the paper suggested no
difference between oral versus subcutaneous dosing regimens is not reflective
of what his paper actually showed. In squirrel monkeys, subcutaneous
administration of MDMA is up to twice as neurotoxic as oral administration,
depending on brain region. Perhaps Dr. Ricaurte felt his results were vulnerable
to challenge on this point precisely because his own prior research showed that
there was indeed a significant and substantial difference between oral versus
subcutaneous dosing regimens.
Also important to note is that Dr. Ricaurte began the first attempt to replicate
his results with oral dosing in October 2002. By the end of 2002 or by early
2003 at the latest, he knew that oral administration of MDMA wasn't causing
dopaminergic neurotoxicity. Nevertheless, he continued to defend his study
results in public until he retracted his study in September 2003.
The report also contains important dosing information from the studies with
genuine MDMA that showed no dopaminergic neurotoxicity. According to Dr.
Ricaurte, "Animals were treated with various sequential dose-regimens of oral
MDMA, with doses ranging from 2 to 8.6 mg/kg MDMA. Each dose was given
three times, at three hour intervals..." I'm surprised and pleased that Dr.
Ricaurte tried oral doses as high at 8.6 mg/kg. In a person who weighs 125
pounds, for example, 8.6 mg/kg equals 488 mgs in each dose or a total of
1.46 grams over six hours. In a person who weighs 165 pounds, this would
equal 645 milligrams in each dose or a total of 1.9 grams within six hours.
These are excessive amounts of MDMA which vanishingly few actual MDMA
users consume, yet Dr. Ricaurte has shown that even these cause no
dopaminergic neurotoxicity. [This comparison doesn't take into account any
interspecies scaling model, with the one used by Dr. Ricaurte being highly
After oral administration failed to produce dopaminergic neurotoxicity,
subcutaneous administration of genuine MDMA was tried with doses of 2 mg/kg
administered three times at three hour intervals, again with no DA
In March and April 2003, the same subcutaneous regimen was tried again but at
two different temperatures, 26 C and 29 C , but still no DA neurotoxicity was
found. Then, studies were conducted "in animal rooms at high humidity" with no
DA neurotoxicity. Then, studies were conducted with subcutaneous
administration of genuine MDMA with doses of 4 mg/kg administered three
times at three hour intervals, still causing no DA neurotoxicity.
In May 2003, another monkey was tested with a new batch of MDMA, no dose
mentioned. No DA neurotoxicity. Dr. Ricaurte mentioned that there was
evidence of an effect on serotonin neurons in this single animal.
In baboons, the first attempt to replicate took place in February 2003 with oral dosing of 2 mg/kg three times with three hour intervals at "a relatively cool temperature for a baboon ( 22 C)", finding "a possible effect on 5-HT but no
effect on DA." (At least 2 baboons in this experiment.) In March 2003, this
experiment was conducted again with one baboon at a temperature of 25 C,
still no DA toxicity. In April 2003, another baboon was given genuine MDMA, 2
mg/kg three times with a three hour interval, (temperature not stated), but this
time subcutaneously, resulting in no DA neurotoxicity.
Unanswered question: How many monkeys and baboons were tested with
genuine MDMA? It seems like a minimum of 13 squirrel monkeys and probably
more, and a minimum of 4 baboons. None died or were not administered their
third dose due to behavioral toxicity and no hyperthermia was reported, despite
some remarkably high doses. It's obvious in retrospect that the side effect
profile of MDMA is strikingly different from that of methamphetamine.
However, this was already well understood prior to this study.
According to Dr. Ricaurte, "the pattern of serotonergic and dopaminergic
neurotoxicity seen in animals that were studied in the Science paper is precisely
what would be anticipated following methamphetamine treatment." This fact,
which Dr. Ricaurte provides, coupled with the unusual deaths that resulted in
the original experiment, should have alerted Dr. Ricaurte and associates that
something was amiss in the data gathered for the Science paper. Instead, in
their zeal to discover new damage from MDMA, caution was thrown to the wind.
Unanswered question: Were there any other deaths in other studies in animals
treated with what was thought to be MDMA but was actually meth? If not,
perhaps the MDMA and meth weren't switched until later. If there were
additional deaths, why didn't these cause Dr. Ricaurte to question his results?
Unanswered question: Nothing is said about serotonin toxicity in the last two
baboons or the temperature of the last two baboon studies. Are baboons less
sensitive to serotonin neurotoxicity than squirrel monkeys? If so, which species
is more likely to reflect effects in humans?
In their progress report, Dr. Ricaurte states, "Our top priority and overarching
concern is the ensure the integrity of the science supported by NIDA, and to
inform the scientific and lay communities of a mistake (if, indeed, one occurred)
in the most expeditious manner possible." Yet months after a series of studies
in both monkeys and baboons, at very high doses, temperatures and humidities,
Dr. Ricaurte was still defending his study results in public, in his letter published in Science in June 2003 and in a talk in Spain in June 2003.
In the section of his report about future plans, Dr. Ricaurte reports that he still wants to find out whether MDMA causes DA neurotoxicity. He states, "This will be done by exploring fuller dose ranges that simulate human MDMA use
patterns." Apparently, he wants to administer oral doses higher than 8.6
mg/kg three times with three hour intervals at temperatures higher than 29 C ,
and subcutaneous doses higher than 4 mg/kg, though these doses are taken by
virtually no one. Do more animals really need to die for this research? Dr.
Ricaurte notes that "since we do not know which animal species best models the
human being, we think it is crucially important to determine if, under certain
conditions, MDMA has the potential to damage brain DA neurons in non-human
primates." Crucially important, perhaps, to Dr. Ricaurte's career, but not to
hardly any actual human users of MDMA. This progress report shows that, in part on the basis of erroneous findings that MDMA caused DA neurotoxicity, Dr. Ricaurte obtained a 5 year NIDA grant for a study of MDMA Neurotoxicity in the Primate, with the grant running from July 2002 to June 2007.
This progress report reveals that Dr. Ricaurte has already convincingly
demonstrated that genuine MDMA given in remarkably large doses both orally (up to
8.6 mg/kg given three times in three hour intervals) and subcutaneously (up to
4 mg/kg given three times in three hour intervals), at elevated temperatures
and humidities, does not cause DA neurotoxicity.