From: Octavio Rojas Diaz (orojas@data.net.mx)
Date: Fri Dec 17 1999 - 20:24:34 MST
Well I've been searching the web for more information regarding MDMA
neurotoxicity, and I've found some interesting results, the best is that
they cite some actual references and aren't based just on anecdotal
information
enjoy:
Neurotoxicity
MDMA is unambiguously neurotoxic in lab animals in high doses. Typical
dose regimens which elicit neurotoxicity are 20mg/kg (rats) or 5mg/kg
(primates) given
twice daily for four days either i.m. (intramuscularly) or s.c.
(subcutaneously). Humans typically use MDMA p.o (per oral) and at levels
of about 2.5 mg/kg or less.
Subcutaneous administration of MDMA tends to increase toxicity 2-3 times
over p.o.[1] Extrapolation of animal studies to human use is difficult,
since humans
typically use a less toxic route of administration, take somewhat less
per dose and take a smaller cumulative dose.
One study of MDMA administered to primates most closely modelled human
use and used doses of 2.5mg/kg given every 2 weeks for 4 months (2.5
mg/kg x 8)
which found no evidence of neurotoxicity[2]. A single- dose study found
a decrease in serotonin (5-HT) and it's major metabolite
5-hydroxyindoleacetic acid
(5-HIAA) in rhesus monkeys at 5mg/kg but not 2.5mg/kg. Another study
gave rhesus monkeys 2.5mg/kg twice daily for four days and found
depletions of 5-HT and
5-HIAA, but without any evidence of neurotoxicity from [3H]paroxetine
binding to the 5-HT reuptake transporter[3]. The finding that depletions
of 5-HIAA could
occur in the absense of 5-HT neurotoxicity creates problems in
interpreting the results of CSF 5-HIAA reductions in human users, which
remains the strongest
evidence of putative MDMA neurotoxicity in humans[4].
Other results of human studies in MDMA users are at odds with the
conclusion that MDMA is a human neurotoxin. McCann, et al. in the same
study which analyzed
CSF 5-HIAA, found that MDMA users tended to have better impulse control
and lower hostility while lower serotonin levels are thought to be
correlated with
increased hostility. A study of sleep patterns of MDMA users found that
MDMA users had normal sleep patterns, but with a statistically
significant decrease in stage
2 sleep, leading to an overall improvement in sleep quality -- more
importantly these results are not at all in accordance with studies on
sleep patterns of humans given
the 5-HT supressor para-chlorophenylalanine (PCPA) or with animals
having lesioned 5-HT systems[5].
Prospective studies (giving users MDMA in a controlled environment with
baseline testing and then checking for indications of neurotoxicity)
rather than retrospective
studies (after the fact with no baseline) are only just getting underway
at the Harbor-UCLA medical center (other studies are starting in
England, Switzerland and
Germany[6]). Initial retrospective results of the UCLA study indicate
that MDMA may increase cerebral blood flow [7]. This may be indicative
of benficial rather
than neurotoxic changes in the brain:
We are aware of a variety of neuro-psychiatric disorders associated
with measurements of low blood flow, including Alzheimer's Disease, HIV
Dementia, Major Depressive Disorders and Chronic Cocaine Abuse.
However, there are no known clinical disorders or drugs which induce
long-term
elevations of rates of cerebral blood flow. -- Charles S. Grob.
There have been reports of adverse psychiatric effects in the literature
particularly anxiety attacks, paranoia and depression. However, some
cases present the onset
of psychiatric symptoms after a single typical dose[8] which suggests a
psychological rather than biological/neurotoxic mechanism. Also, some
cases of paranoia
reported appear to have occured after repeated daily abuse and probably
represent a manifestation of amphetamine psychosis, possibly in part due
to adulteration or
substitution by amphetamines[9].
The diet drug d-fenfluramine (Redux) causes similar effects on the 5-HT
system, and it has been suggested that the lack of adverse psychiatric
effects to chronic
ingestion of d-fenfluramine implies that MDMA is probably without
adverse effects. However, it appears that the mechanism behind MDMA and
d-fenfluramine
neurotoxicity are not the same, and this may make extrapolation from one
drug to the other problematic[10].
To summarize the clinical data, the available evidence tends to suggest
that in human users a (probably reversable) decrease in 5-HT may occur
(possibly via
suppression of the enzyme tryptophan hydroxylase) but that 5-HT neurons
remain functionally intact. However, neurotoxic levels in humans are
probably "attainable"
and the exact amount of MDMA required to elicit a neurotoxic response in
humans is unknown.
The exact mechanism of MDMA neurotoxicity in animals is not presently
known [11], but it seems to require dopamine activity, oxidation, and
access to the 5-HT
transporter. Increasing dopamine activity via ingestion of
methamphetamine, l-tyrosine, phenylalanine or l-dopa would tend to
increase MDMA neurotoxicity. This is
a concern since phenylalanine is in diet soft drinks and products
sweeted with aspartame(tm) and is also in many "smart drinks" sold at
raves and of course
methamphetamine is a concern since MDMA is often cut with crystal. On
the other hand ascorbate (vitamin C) and l-cystine which are
anti-oxidants have been
shown to prevent MDMA induced neurotoxicity in animals, as has the
administration of a SSRI antidepressant (Prozac, Zoloft, Paxil, Luvox,
etc.). Studies indicate
that taking either an anti-oxidant or a SSRI up to 5 hours after taking
MDMA will prevent neurotoxicity in animals[12].
It may be sensible irregardless of if MDMA is neurotoxic in humans for
users to take an antioxidant (e.g. 2-4 g vitamin C, orange juice) along
with some 5-HT
precursors (l-trytophan or 5-hydroxytryptophan (5-HTP), bananas, milk).
1. Ricaurte, GA, DeLanney, LE, Irwin, I, Langston, JW. "Toxic Effects of
MDMA on Central Serotonergic Neurons in the Primate: Importance of Route
and
Frequency of Drug Administration," Brain Research, Vol 446, P165-168,
1988.
2. Ricarute, GA, personal communication on the findings of an
unpublished study.
3. Insel, TR, Battaglia, G, Johannessen, JN, Marra, S, DeSouza, EB,
"3,4-Methylenedioxymethamphetamine (Ecstasy) Selectively Destroys Brain
Serotonin
Terminals in Rhesus Monkeys," Journal of Pharmacology and Experimental
Therapeutics, Vol 249(1), P 713-720, 1989.
4. McCann, UD, Ridenour, A, Shaham, Y, Ricaurte, GA. "Serotonin
neurotoxicity after (+/-) 3,4-methylenedioxy-methamphetamine (MDMA,
Ecstasy): a
controlled study in humans," Neuropsychopharmacology, Vol 10(2), P
129-138, 1994.
5. Allen, RP, McCann, UD, Ricaurte, GA, "Persistent effects of (+-)
3,4-methylenedioxymethamphetamine (MDMA, Ecstasy) on human sleep,"
Sleep, Vol 16(6), P
560-564.
6. MAPS Newslatter Vol 6, No 3, Summer 1996.
http://www.maps.org/news-letters/v06n3/
7. MAPS Newsletter Vol 5, No 4, Summer 1995.
http://www.maps.org/news-letters/v05n4/05402mdm.html. Grob-C-S,
Poland-R-E Chang-L, Ernst-T,
"Psychobiologic effects of 3,4-methylenedioxymethamphetamine in humans:
methodological considerations and preliminary observations," Behav.
Brain Res., 1996
73(1-2), P 103-7.
8. McCann-U-D, Ricaurte-G-A, "MDMA ('ecstasy') and panic disorder:
induction by a single dose," Biol. Psychiatry 1992 Nov 15 32(10):950-3.
9. McGuire-P-K, Cope-H, Fahy-T-A, "Diversity of psychopathology
associated with use of 3,4-methylenedioxymethamphetamine ('Ecstasy'),"
Br. J. Psychiatry,
1994 Sep 165(3):391-5.
10. Colado-M-I, O'Shea-E, Granados-R, Murray-T-K, Green-A-R, "In vivo
evidence for free radical involvement in the degeneration of rat brain
5-HT following
administration of MDMA ('ecstasy') and p-chloroamphetamine but not the
degeneration following fenfluramine," Br. J. Pharmacol., 1997 Jul
121(5):889-900.
11. Seiden-L-S, Sabol-K-E, "Methamphetamine and
methylenedioxymethamphetamine neurotoxicity: possible mechanisms of cell
destruction," NIDA Res. Monogr.
1996 163:251-76.
12. Gudelsky-G-A, "Effect of ascorbate and cysteine on the
3,4-methylenedioxymethamphetamine-induced depletion of brain serotonin,"
J. Neural Transm., 1996
103(12), P 1397-404. McCann-U-D, Ricaurte-G-A, "Reinforcing subjective
effects of (+/-) 3,4-methylenedioxymethamphetamine ('ecstasy') may be
separable
from its neurotoxic actions: clinical evidence." J. Clin.
Psychopharmacol. 1993 Jun 13(3):214-7. Schmidt-C-J, Kehne-J-H,
"Neurotoxicity of MDMA:
neurochemical effects.", Ann. N.Y. Acad. Sci. 1990 600:665-80.
Steranka-L-R, Rhind-A-W, "Effect of cysteine on the persistent depletion
of brain monoamines by
amphetamine, p-chloroamphetamine and MPTP," Eur. J. Pharmacol. 1987 Jan
13 133(2):191-7. Battaglia-G, Yeh-S-Y, De-Souza-E-B, "MDMA-induced
neurotoxicity: parameters of degeneration and recovery of brain
serotonin neurons," Pharmacol. Biochem. Behav. 1988 Feb 29(2):269-74.
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