[Date Prev][Date Next][Thread Prev][Thread Next][Date Index][Thread Index]
Re: MAPS: Anybody up for some MDMA neurotoxicity tests on humans?
Litte John wrote:
Neither MDMA nor it's metabolites seem to be significantly
neurotoxic. The high levels of serotonin metabolites that result from
use don't seem to be nuerotoxic. Rather, what seems to happen is that
when serotonin levels become critically low (MDMA results in serotonin
depletion), the serotonin neurons start to take up dopamine (which
apparently has a lower affinity for the serotonin reuptake transporters,
but none-the-less can 'fit' into them.) This dopamine is then broken
down by MAO-B, and it's these dopamine metabolites that are toxic,
causing oxidative stress and potentially damaging or destroying the axon
terminal. The interesting wrinkle on this is offered by Huether, et
al.,
(http://www.erowid.org/chemicals/mdma/articles/references.cgi?ID=200) who
make a fascinating and rather compelling case for acute depletion of
energy reserves (glucose, but other sugers should be effective
replacements) as a necissary co-factor for toxicity. They argue
that, without this depletion of energy reserves, the serotonin neurons
should be able to handle the oxidative stress caused by this uptake of
dopamine.
It is my understanding, that on the contrary, metabolites of MDMA are the
very culprits that underly any mechanism of MDMA-associated neurotoxicity.
The most striking evidence for this comes from numerous studies showing no
long-term effects of central adminstration of MDMA upon markers of
serotonergic function (Matt Baggott & Ilsa Jerome cover this whole topic in
much more detail in their MAPS/MDMA review). Whilst 'in press' work
(Pharmacology, Biochemistry & Behaviour) from Sprague, Nichols and
colleagues demonstrates that prolonged infusion of a MAO B antisense
oligonucleotide (effectively atenuating MAO B activity. DA deamination via
MAO B in the neuron underlies Sprague & Nichols well-read hypothesis)
protects against striatal DA depletion in the rat, there does not seem to
be any association between DA and neurotoxicity in the hippocampus. This
suggests to me that there are multiple mechanisms underlying neurotoxicity.
Firstly, I am uneasy accepting Huether's hypothesis. Central admin of a
dose of MDMA that causes similar brain concentrations of MDMA as a
peripherally administered ntoxic dose of MDMA produces no long-lasting
serotonergic effects. As central admin is not neurotoxic, but releases the
same amount of hippocampal 5HT as a neurotoxic peripheral dose, one has to
question whether 5HT release and energy depletion are that essential in the
process (at least in the hippocampus, which is a good marker of overall 5HT
change after MDMA). Indeed, concentrations of neuronal ATP (cellular energy
source) are not affected by MDMA at time points when the neurotoxic cascade
is well underway. Nicotinamide, which one would expect to maintain cellular
energy supplies, actually potentiates damage. On the other hand, the
hippocampus is relatively sparse in DAergic fibres, so local admin of MDMA
would perhaps not cause an appreciable increase in DA, hence no damage
occurs (although it must be noted that some workers have proposed that DA
might be released from noradrenergic fibres in the hippocampus, see
Shankharan & Gudelsky, 1998). However, i.c.v MDMA is also without effect.
The question then arises, does central admin of MDMA also produce a similar
rise in DA?
Bai, Monks, Miller and colleagues have suggested that the ordinary
metabolic processes that deal with the excretion of MDMA inadvertently
generates neurotoxic metabolites. For example, metabolic
'enhancers'/'inhibitors' effectively modulate MDMA-induced damge. This
group have hypothesised that the metabolites in question are glutathione
and N-acetylcysteine metabolic conjugates of MDMA (e.g. adducts of
3,4-dihydroxymethamphetamine, DHMA) which readily cross the
blood-brain-barrier. As well as producing similar behavioural effects to
MDA (an active metabolite of MDMA), these are also selective 5-HT
neurotoxins [I have often wondered to what degree neurotoxic metabolites of
MDMA are responsible for the entactogenic effects of MDMA, and the
implications of this for clinical studies, but that is another issue...].
Colado and colleagues have very recently proposed (Br J
Pharm,134:1711-1723, 2002) that in mice, MDMA metabolites produce very
specific radicals which in turn react with nitrite ions to produce highly
toxic peroxynitrite ions. If damage is metabolite specific then this may
explain the diferring sensitivities between species to MDMA - for example
Lim et al (1992) showed that different types of metabolite were formed
between rats and mice.
I wouldn't like to speculate openly what this all means for harm reduction,
a quick scan of ecstasy users' newsgroups/forums shows that in many cases
preclinical messages are interpreted as "protection from MDMA-associated
ntox in animals = protection from all the harmful effects of ecstasy in
wo/man"
Referring back to the original discussion point about brain scans in
ecstasy users, it was mentioned that the use of ecstasy testing kits might
help verify drug intake. Unfortunately, i don't think that this idea would
be very effective. The axiomatic question is "has a neurotoxic dose of MDMA
been ingested", not "has MDMA been ingested". Rather conveniently ;-),
researchers from this department discuss this topic in an upcoming issue of
the Journal of Psychopharmacology [What is a dose of ecstasy ? J.C. Cole,
H.R.Sumnall, and G.F. Wagstaff Journal of Psychopharmacology
16:187-189:2002]. I think that as Dr Cozzi suggested at the beginning of
this thread you need some kind of quantification of drug intake, whether by
collecting a sample of drug ingested or sampling hair/sweat/urine. You then
run into some ethical difficulties, do you continue your study week after
week knowing that your subjects are breaking the law? In fact you have
evidence that they are, which could technically be seized by law
enforcemnet officials. If they were part of a treatment programme e..g.
methadone maintanence, then perhaps you could get away with it, or if it
were just one sample, then perhaps this might also be OK, but with an
ongoing study such as this then i'm not too sure...
Harry
__________________________________
Dr Harry Sumnall
Psychopharmacology Research Group
Department of Psychology
Eleanor Rathbone Buildin:g-
University of Liverpool
Liverpool
L69 7ZA
UK
+44 0151 794 2177
spun@xxxxxxxxx
www.liv.ac.uk/Psychology
-----------------
MAPS-Forum@xxxxxxxx, a member service of the Multidisciplinary Association
for Psychedelic Studies (see www.maps.org/memsub.html).
To [un]subscribe, email the message text,
[un]subscribe maps-forum youraddress to majordomo@xxxxxxxx
List archives: www.cerebral.org/Maps
Guidelines for authors: www.maps.org/guidelines.txt
MAPS Forum is supported by a generous grant from the Promind Foundation.