MAPS: The role of heat and dopamine in MDMA neurotoxicity

["Little John" <saintjude2k@xxxxxxxxxxx>]

       Mildly to my surprise, something showing a glimmer of insight has
come out of the famous Ricaurte/McCann dog-and-pony research show.     (Why
don't I like Ricaurte?   Because I believe he habitually extrapolates to and
overly-strongly clings to conclusions that are far beyond the strength of
the experimental data produced.)    In spite of what I view as his generally
untrustworthy interpretation of data, his groups have in fact produced a
number of  interesting pieces of research.

       The latest item:

      http://www.erowid.org/chemicals/mdma/articles/references.cgi?ID=1365
(abstract)

   or:
http://www.erowid.org/chemicals/mdma/articles/texts/2002_yuan_1.pdf  (full
text)

       Rats were treated with chemicals to strip their dopamine supplies
down to essentially nothing, then given what would normally be a neurotoxic
dose of MDMA.   At moderate ambient temperatures, as would be expected from
rats with no dopamine, the high dosing regimen of MDMA showed little
neurotoxicity.     Where things get interesting is when the rats were placed
in warm environments, promoting a hyperthermic response.    Under these
conditions, the dopamine-depleted rats showed essentially the same level of
neurotoxicity as the control rats given an identical dose of MDMA.    The
logical conclusion is that dopamine's principle role in MDMA neurotoxicity
is not, in fact, as the principle toxic species entering the serotonin axon
terminal.    Rather, it's importance lies in dopamine's ability to provoke
and sustain a hyperthermic response.    MDMA doesn't fry brain cells?MDMA
plus overheating does.
       Interestingly, the research also depleted serotonin supplies, but
again, when temps were increased this did not protect the rats.      The
implication is that the actual primary toxic species may be either MDMA
itself or a metabolite of it (or some other previously unconsidered
candidate.)     Frankly, the toxic metabolite theory was always one of the
weakest in my opinion, but this seem to breath new life into it...the
research continues at a very encouraging pace.   I'm convinced we're no more
than a few years from completely nailing this little puzzle down.
(Whatever the toxic species is, it's presumed to be a monoamine, since a
number of MAO-B inhibitors are protective.   Personally, I like MDMA itself
as the candidate, but that's just an intuitive impulse.    There's more
recent research to read that may shed more light on it.)
         So.   How to explain this?    Apparently something fairly drastic
is happening as a result of the overheating.   Is it reduced glucose
metabolism?   Thermal inhibition of enzymes that break down reactive oxygen
species like superoxide, hydrogen peroxide, hydroxyl?     Overheating itself
doesn't produce neurotoxicity (at that level.)   A sane dose of MDMA doesn't
produce neurotoxicity at normal body temps.    But the combined insult of
hyperthermic metabolic impairement and MDMA-related strain on the serotonin
neurons is (I presume the increased temperature promotes a more oxidative
environment as well.)

         None of this really has a lot of impact on harm reduction efforts,
since most harm prevention ideas where based more on emperical data than a
specific theory in the first place.    Antioxidants to absorb reactive
species formed, moderation of use, some fluid intake to combat
dehydration/heatstroke.    SSRIs if you feel adventurous.   MAOIs like
deprenyl if you *really* feel adventurous and are sure you know what you're
doing.    IMO getting some calories is also a very good idea.    (Fruit
juice, sports drinks, etc.)
       It does, however, make staying cool even more important.
Clubs/raves should be kept cool with plenty of airflow and dancers should be
encouraged to take short breaks to cool down and cautiously rehydrate.

       Through it all, I retain my opinion that MDMA is not, at moderate,
infrequent doses under reasonable environmental conditions, any credible
threat to your brain.     The prohibitionists keep running around screaming
'brain damage', and my challenge to them remains the same:   Show me the
victems.    No, I don't care that you found three people taking fifty pills
a month that had statistically lower than average (but within the normal
range) serotonin transporter density.     Nor am I impressed with all the
retrospective 'studies' that found that the people that stayed out all night
partying, taking MDMA, and smoking enough pot to kill a Rastafarian had
modestly lower cognitive function within selected areas than their sober
control groups.     Well, I could go on all night about the generally low
quality of some of this stuff.    Suffice to say, that something gets
published doesn't mean it deserved to be.   :-)


___________________
Reality is an aproximation of the Math.

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