In the Protestent tradition of nailing manifestos onto church
doors....

To the Editors of "Science" Magazine:

     Regarding the research report entitled "Severe Dopaminergic
Neurotoxicity in Primates After a Common Recreational Dose Regimen of
MDMA ("Ecstasy")", published in Science in September of 2002:

     The authors (Ricaurte et al.) casually refer to a case report as
an example of "MDMA-induced Parkinsonism." The patient in question was
a young man who had reported infrequent use of the drug (a total of
ten exposures) over the course of the past year.[1] He had not used
"ecstasy" for approximately three months when he presented for the
symptom of "slight clumsiness in upper and lower extremities." Over
several months following initial presentation for treatment, his
condition rapidly worsened, developing more features characteristic of
Parkinson's. The patient did not respond to "the maximal tolerated
doses of levodopa and pramipexole", leaving the fundamental assumption
of damage to the dopaminergic system as the source of the patient's
problems very much in doubt.

     The doctors who reported this case state that "we have no firm
evidence of a causal relation between this patient's drug use and his
parkinsonism"; their belief that it may have been caused by infrequent
MDMA use seems to be born almost entirely of their inability to make
an alternative diagnosis coupled with MDMA's known dopaminergic
neurotoxic potential in mice.

     The pathology of this case (delayed onset relative to drug use
followed by rapid progression) is inconsistent with all known research
on the progression of MDMA neurotoxicity, which produces a
maximization of damage shortly after exposure followed by slow partial
recovery.[2]

     If Ricaurte et al. have additional information about this case
that was unavailable to the doctors treating the patient, they have
made no mention of it. At the least, it was dishonest to characterize
this case simply as an example of "MDMA-induced Parkinsonism" with no
mention of the extraordinarily tenuous and speculative nature of the
proposed causal link between the patient's drug use and his
neurological symptoms.

     Equally intriguing is the author's claim that "oral
administration offers little or no significant neuroprotection"
relative to the injected route used in the experiment. Indeed,
Ricaurte's own research has demonstrated that injecting MDMA can
double and even triple it's neurotoxicity (depending on brain region)
vs. oral dosing.[3] While I will concede that "little or no" is not a
clearly defined expression, increases of whole multiples seems to
strain any common definition.

     Indeed, the very title of the report is rather difficult to
defend, as it describes the dose used as "a common recreational dose"
of MDMA. If the dose was pharmacologically equivalent to doses
routinely taken by humans, why do the authors report that 20% of their
animals died on the spot, while an additional 20% may have died had
they not been exempted from the full regimen after showing serious
distress from only part of the total 6 mg/kg dose? While dosages of
such scale do (infrequently) occur in human users, it is likely that
these users have reached such dosages in response to growing drug
tolerance; with such progressive elevations of dosage over time,
neurotoxic potential is reduced.[4] It seems unlikely to me that a man
of Ricaurte's standing within the field of MDMA neurotoxicity was
unaware of this, yet no mention of this confound is made in the
author's rush to claim equivalency between their experiment and human
patterns of use.

     The authors report that 6 mg/kg of MDMA total (2 mg/kg every two
hours for 3x) produced profound (approx. 50%) damage to the
dopaminergic system in monkeys, but fail to explain why Ricaurte's own
past work has found that a cumulative dose of 40 mg/kg (5 mg/kg at a
time 2x for four days) failed to produce any dopaminergic toxicity in
monkeys.[5] At the very least, producing a vast increase in toxicity
by giving 2 mg/kg 3x instead of a single 5 mg/kg dose seems to demand
some discussion; it suggests that at the least the authors have
managed to come upon an atypically toxic dosing regimen. If only on
the grounds of the sheer novelty of the results from this particular
dosage regimen it seems presumptuous to declare equivalency to human
users until some explanation can be offered for the sharp divergence
of results between these two experiments.

     Also of no small concern in the author's suggestions of severe
dopaminergic toxicity commonly occurring in humans is their apparent
refusal to mention retrospective studies of the brains of "ecstasy"
users that found no differences in their dopamine system relative to
non-users.[6][7] While the latter study may not have yet been
available to the authors at the time of publication, surely they
should have mentioned that there was existing evidence of the absence
of harm to user's dopamine systems before publishing a paper that so
shamelessly encourages public panic.

     The principle author (Ricaurte) has long championed a
minimalistic method of interspecies dosage scaling between non-human
primates and humans. His understanding of MDMA neurotoxicity has led
him to believe that less than 1.3 mg/kg of MDMA in a human user would
produce neurotoxic damage (a dose he arrived at by scaling from 5
mg/kg in non-human primates, which he reports as producing
neurotoxicity.)[8] If we believe Ricaurte's claims of dosage scaling
between humans and non-human primates, then the 6 mg/kg dose used in
his recent experiment (which killed a significant number of his
animals and severely damaged the serotonergic and dopaminergic
pathways in the survivors) would be equivalent to just over 1.5 mg/kg
in humans. However, prospective human brain-scan experiments have
failed to find even the slightest indication of neurotoxicity (or even
subject distress) at 1.5 mg/kg.[9] Human users routinely exceed this
dosage, mix drugs, and use under uncontrolled and adverse conditions,
yet fatalities are rare. Indeed, examinations of the brains of current
human "ecstasy" users with an average lifetime exposure of ~800
tablets found only minor reductions in SERT (serotonin transporter)
density, and when abstinent users were examined, their regional and
total SERT densities were indistinguishable from non-drug users.[10]
While regrowth of serotonin axons could explain a recovery of total
SERT density, the recovery seen in these heavy human users was
uniform, precisely restoring normal SERT density in all regions of the
brain studied, as contrasted with the patterns of serotonin axon
regrowth seen in non-human primates given neurotoxic doses of MDMA
(which produced hyperenervation of regions near the raphe nuclei but
failed to restore enervation to less proximal regions.) Given this
pattern of recovery, there is every reason to believe that the minor
temporary loss of available SERT proteins observed was not due to
neurotoxic damage (destruction of axons.)

     Ricaurte also fails to explain why his "common [human]
recreational dose" of MDMA produced a significant and prolonged (even
lethal) hyperthermic response (as much as 41.6C) when human
experiments have consistently produced little or no hyperthermic
response at any dose attempted.[11][12] As hyperthermic response is
well-established as a critical factor in MDMA neurotoxicity[13], I
must again question why Ricaurte believes the dosages he uses are
pharmacologically equivalent to those used by humans when the
physiological responses produced are not equivalent. It's certainly
true that malignant hyperthermia appears with some frequency among
human users, but such cases are usually associated with prolonged
dancing at clubs. Are we to believe that Ricaurte et al. threw a 'rave
party' for their animals?

     In the final analysis, I must regard this recent product of
Ricaurte et al. as more of an act of propaganda than a sincere attempt
to advance public understanding. There is no reason to believe that
there is a coming wave of 'Ecstasy Parkinsonism' among human "ecstasy"
users, or even that common patterns of use pose a risk of injury to
the dopaminergic system. Shame on the authors for the incomplete,
misleading and sensationalistic nature of this research report, and
shame on the editors of Science for publishing it.

Nathan Luno

References:

1. Mintzer S, Hickenbottom S, Gilman S "Parkinsonism after taking
ecstasy" N Engl J Med, 1999; 340(18):1443.

2. Scanzello CR, Hatzidimitriou G, Martello AL, Katz JL, Ricaurte GA
"Serotonergic recovery after (+/-)3,4-(methylenedioxy) methamphetamine
injury: observations in rats" J Pharmacol Exp Ther, 1993;
264(3):1484-91.

3. Finnegan KT, Ricaurte GA, Ritchie LD, Irwin I, Peroutka SJ,
Langston JW "Orally administered MDMA causes a long-term depletion of
serotonin in rat brain" Brain Res, 1988; 447(1):141-4.

4. Frederick DL, Ali SF, Slikker W Jr, Gillam MP, Allen RR, Paule MG
"Behavioral and neurochemical effects of chronic
methylenedioxymethamphetamine (MDMA) treatment in rhesus monkeys"
Neurotoxicol Teratol, 1995; 17(5):531-43.

5. Ricaurte GA, Forno LS, Wilson MA, DeLanney LE, Irwin I, Molliver
ME, Langston JW "(+/-)3,4-Methylenedioxymethamphetamine selectively
damages central serotonergic neurons in nonhuman primates" JAMA, 1988;
260(1):51-5.

6. Semple DM, Ebmeier KP, Glabus MF, O'Carroll RE, Johnstone EC
"Reduced in vivo binding to the serotonin transporter in the cerebral
cortex of MDMA ("ecstasy") users", British Journal of Psychiatry, Vol
175, 63-69 (1999).

7. Reneman L, Booij J, Lavalaye J, de Bruin K, Reitsma JB, Gunning B,
den Heeten GJ, van Den Brink W "Use of amphetamine by recreational
users of ecstasy (MDMA) is associated with reduced striatal dopamine
transporter densities: a [123I]beta-CIT SPECT study-- preliminary
report" Psychopharmacology (Berl), 2002; 159(3):335-340.

8. Ricaurte GA, Yuan J, McCann UD
"(+/-)3,4-Methylenedioxymethamphetamine (`Ecstasy')-Induced Serotonin
Neurotoxicity: Studies in Animals" Neuropsychobiology, 2000;
42(1):5-10.

9. Vollenweider FX, Gucker P, Schönbächler R, Kamber E,
Vollenweider-Scherpenhuyzen MFI, Schubiger G, Hell D "Effects of MDMA
on 5-HT uptake sites using PET and [11C]-McN5652 in humans" Conference
of the German Society for Psychiatry, Psychotherapy and Neuromedicine,
2000.

10. Buchert R, Thomasius R, Nebeling B, Petersen K, Obrocki J, Jenicke
L, Wilke F, Wartberg L, Zapletalova P, Clausen M "Long-term effects of
"Ecstasy" use on serotonin transporters of the brain investigated by
PET." J Nucl Med 44: 375-84 (2003).

11. Mas M, Farre M, de la Torre R, Roset PN, Ortuno J, Segura J, Cami
J "Cardiovascular and neuroendocrine effects and pharmacokinetics of
3, 4-methylenedioxymethamphetamine in humans" J Pharmacol Exp Ther,
1999; 290(1):136-45.

12. de la Torre R, Farre M, Roset PN, Hernandez Lopez C, Mas M, Ortuno
J, Menoyo E, Pizarro N, Segura J, Cami J "Pharmacology of MDMA in
humans" Ann N Y Acad Sci, 2000; 914:225-37.

13. Yuan J, Cord BJ, McCann UD, Callahan BT, Ricaurte GA "Effect of
depleting vesicular and cytoplasmic dopamine on MDMA neurotoxicity",
Journal of Neurochemistry, Vol 80, 960-969 (2002).

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