Re: MAPS: Anybody up for some MDMA neurotoxicity tests on humans?

["Little John" <saintjude2k@xxxxxxxxxxx>]

> I notice that "recreational" is a very interesting anthropological and
> ethnological term. :-)

    Indeed.   It's been my observation that most illegal drug use is
actually functional/medical.   The pot smoker coping with stress, the
methamphetamine user looking for help to get through the day on hard manual
labor jobs, the emotionally disturbed self-medicating or escaping from inner
demons or even as a tool for seeking spiritual insight.    The person that
uses just because they were bored or had nothing better to do is quite
possibly the minority.

> Concerning neurotoxicity,what happened to those non-neurotoxic derivatives
> invented by Nichols et al.? Why not replace MDMA by the non-neurotoxic
> derivatives? Are they psychotropically inactive?

      I'm not familiar with those drugs, but I believe any drug that leads
to the massive release of serotonin has the potential for neurotoxicity.
  The problem, as I understand it:

      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.    According to the
article, the serotonin re-uptake transporters are powered by a Ca++ gradient
between the inside and outside of the cell membrane, with that gradient
being actively maintained by the consumption of (typically) glucose.   As a
result, flooding the synapse with serotonin can place a high demand on the
sugar supply, a problem greatly worsened by the systemic depletions of
energy resulting from hyperthermia.
     As most of us are probably aware, using a chemical or drug that
competes for access to the SERTs can reduce or stop neurotoxicity even at
quite high doses (presumeably by blocking dopamine's access to the neuron.)
 If Huether, et al. are correct (and they really do make a good argument)
getting plenty of calories before/during/after MDMA use may also be quite
valuable.     Grab a pop, Gatoraide, juice.....



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