From: bagg@ellis.uchicago.edu (matthew john baggott)
Subject: Re: MDA and MDMA neurotoxicity
Keywords: MDA, MDMA, NEUROTOXICITY, DRUGS
Reply-To: bagg@midway.uchicago.edu
Organization: University of Chicago
Date: Fri, 29 Jan 1993 01:28:46 GMT



In his article on MDA and MDMA, droberts@alfred.carleton.ca (David Roberts)
writes:

>Those who are think that MDA and MDMA are not neurotoxic may find the
>following references helpful:

Thank you for the references.  Unfortunately, these studies seem to
be mostly concerned with the mechanism of axonal damage and not the relevance
of high dose regimens to human use.  Thus, while they are informative
articles they don't address the issue being disputed: whether MDMA is safe 
in humans.

Why not cite the few human studies which exist?  Like the L-Tryptophan
challenges and the spinal taps.  And why not cite the literature
which discusses the relevance of these studies to humans?  Like
Ricaurte's writings on fenfluramine or Charles Grob's writings on
MDMA.

>Axt KJ, Mullen CA, Molliver ME (1992) Cytopathologic features indicative
>of 5-hydroxytryptamine axon degeneration are observed in rat brain after
>administration of d- and l-methylenedioxyamphetamine. Ann. NY Acad.
>Sci. 648: 244-247

Note the phrase "axon degeneration."  The lack of consistent use of a
term in these references should indicate a lack of consensus about the
best term for the phenomenon.  

>Battaglia G, Yeh SY, O'Hearn E, Molliver ME, Kuhar MJ, DeSouza EB (1987)
>3,4-Methylenedioxymethamphetamine and 3,4-methyleneamphetamine destroy
>terminals in rat brain: quantification of neurodegeneration by measurement
>of [3H]-paroxetine labelled seroto nin uptake sites. J. Pharm. exp.
>Ther. 242: 911-916
>
>Battaglia G, Sharkey J, Kuhar MJ, De Souza EB (1991) Neuroanatomic
>specificity and time course of alterations in rat brain serotonergic
>pathways induced by MDMA (3,4-methylenedioxymethamphetamine):  Assessment
>using quantitative autoradiography. Synapse 8 : 249-260

20 mg/kg 2/day for 4 days for both studies, I think.  Not comparable to 
human recreational or therapeutic doses.  The conclusions of this
study were that "the predominant effects of MDMA on serotonergic
systeems throughout the brain are mediated on 5-HT axons and terminals...
(and that) ...not all regions may be equally vulnerable to the
neurodegenerative effects of MDMA."  Most interestingly, they found
difference in rate of recovery.

>Johnson M, Stone DM, Bush LG, Hanson GR, Gibb JW (1989) Glucocorticoids
>and 3,4-methylenedioxyamphetamine (MDMA)-induced neurotoxicity. Eur. J.
>Pharmacol. 161: 181-188

Here Gibb's lab used a single high dose (20 mg/kg).  They were looking
at the mechanism of neurodegneration by giving adrenalectomies.

>Johnson MP, Huang X, Nichols DE (1991) Serotonin neurotoxicity in rats
>after combined treatment with a dopaminergic agent followed by a
>nonneurotoxic 3, 4-methylenedioxymethamphetamine (MDMA) analogue.
>Pharmacol. Biochem. Behav. 40: 915-922

Here, Dave Nichols lab demonstrates that DA plays a role in MDMA-induced
neurotoxicity.  It is important work, but how does it bear on the issues
of whether MDMA neurotoxicity exists in humans, whether the axonal damage
has any functional/behavioral correlates, and to what extent recovery
occurs?

>Johnson MP, Nichols DE (1991) Combined administration of a non-neurotoxic
>3,4-methylenedioxymethamphetamine analogue with amphetamine produces
>serotonin neurotoxicity in rats. Neuropharmacology 30: 819-822

See above.  By the way, Nichols believes that MDMA has therapeutic
uses.

>Markert LE, Roberts DCS (1991) 3,4-Methylenedioxyamphetamine (MDA)
>self-administration and neurotoxicity. Pharmacol. Biochem. Behav. 39:
>569-574

Ah, now this might have some bearing on the issue.  I haven't seen the study
yet (blush), so I can't comment much.  Certainly repeated injections
of MDA across several days, as happened here, isn't the kind of behavior 
one finds much in humans, but it IS interesting to see the relationship 
between reinforcing doses and neurotoxic doses.  

I once tried to give cocaine-drinking rats MDMA solutions to see if they'd 
like it.  Initially, they did, but then they all went cold turkey.  
The data suggests that they increased their dosage until they reached 
a dose which produced dysphoria (whether it was due to the amount taken 
or the fact that they had been taking repeated doses I cannot say).  They
all stopped by the third day.   However, the doses at which they 
stopped self-administering seemed far too low to produce neurotoxicity.  
I suspect that the fact that the rats had been trained on cocaine also 
played a role in their failure to continue self-administration.  
I regret not being able to do more experiments along those lines, 
but California was calling out to me...  :-)

If the experimenters limited the rats' ability to self administer the MDA,
so that their intake paralleled human patterns, then this would be
particularly interesting.  Although, frankly, I guess I don't know much
about patterns of MDA use in humans.  It is such a rare drug.

Could you perhaps tell us more about this study?

>McBean DE, Sharkey J, Ritchie IM, Kelly PAT (1990) Chronic effects of the
>selective serotoninergic neurotoxin, methylenedioxyamphetamine, upon
>cerebral function. Neuroscience 38: 271-275

>Nash JF, Yamamoto BK (1992) Methamphetamine neurotoxicity and striatal
>glutamate release:  Comparison to 3,4-methylenedioxymethamphetamine. Brain
>Res. 581: 237-243

This is an exploration of the gluatamate hypothesis of neurotoxicity.
13.8 mg/kg given 3 times (every 2 hours).  Ouch!

>O'Hearn E, Battaglia G, DeSouza EB, Kuhar MJ, Molliver ME (1988)
>Methylenedioxyamphetamine (MDA) and methylenedioxymethamphetamine (MDMA)
>cause selective ablation of serotonergic axon terminals in forebrain:
>Immunocytochemical evidence for neurotoxicity.  J. Neurosci. 8: 2788-2803

Same Battaglia regimen as above.  They found that it was the fine axons
which were selectively damaged.

>Ricaurte GA, Bryan G, Strauss L, Seiden LS, Schuster CR (1985)
>Hallucenogenic amphetamine selectively destroys brain nerve terminals.
>Science 229: 986-988

Ah, the classic paper!

>Ricaurte GA, Martello AL, Katz JL, Martello MB (1992) Lasting effects of
>3,4-methylenedioxymethamphetamine (MDMA) on central serotonergic neurons
>in nonhuman primates:  Neurochemical observations. J. Pharmacol. Exp.
>Ther. 261: 616-622

An important piece of work.  Finally, we're getting down to the monkey
business.  George Ricaurte et al found that squirrel monkeys given
5 mg/kg twice a day for 4 days hadn't completely recovered at 18
months and had in fact seemingly returned to an earlier state of
damage.  Papers like this really make you realize how difficult it is
to say when "neurotoxicity" has taken place and when it has been 
repaired.  

He got increases in 5-HT in one area ("hyperenervation" of the hypothalamus).
Others have gotten similar effects with phenethylamine "neurotoxins" and it 
seems to happen in the areas from which the neurons originate, as if new 
growth sprouts out from there.  And he also got partial recovery 
(63% of controls) of 5-HT levels in the thalamus.  But all the other
sites looked as if they were down at what you'd expect 2 weeks after
the high dose regimen.

At one point he basically says that we have no idea what is happening
here.  I'll second that.  Importantly, he has still-unpublished (I think)
data that fails to find any neurotoxic effects from a less punishing,
human-like regimen.

>Schechter MD (1991) Effect of MDMA neurotoxicity upon its conditioned
>place preference and discrimination. Pharmacol. Biochem. Behav. 38:
>539-544

This is interesting.  They trained rats to discriminate 1.5 mg/kg MDMA
from vehicle and then established that the same dose produced
conditioned place preference, meaning the rats liked it.  Then, they
 gave the Battaglia regimen of 20 mg/kg 2/day for 4 days.  They
found that the high dose regimen didn't change the place preference,
but did make the rats more sensitive to 1.0 mg/kg on the discrimination
task.

Note the difference between giving single injections of 1.5 mg/kg and
giving 8 injections of 20 mg/kg.  One is pleasurable and probably not
damaging, the other is damaging and unpleasurable.  The question then
is whether there are pleasurable and damaging doses.  There are
probably pleasurable and damaging regimens, since repeated low doses
seem to be damaging.  But what about isolated or infrequently given
doses?    

>Schmidt CJ (1987) Neurotoxicity of the psychedelic amphetamine
>methylenedioxymethamphetamine. J. Pharm. exp. Ther. 240: 1-7

>Schmidt CJ, Abbate GM, Black CK, Taylor VL (1990a) Selective
>5-hydroxytryptamine2 receptor antagonists protect against the
>neurotoxicity of methylenedioxymethamphetamine in rats. J. Pharm. exp.
>Ther. 255: 478-483

An interesting paper.  It made me think, "would 5-HT2 AGONISTS also
protect against the neurotoxicity?"  That would be of interest to
the people who take LSD and MDMA at the same time.

>Schmidt CJ, Black CK, Abbate GM, Taylor VL (1990)
>Methylenedioxymethamphetamine-induced hyperthermia and neurotoxicity are
>independently mediated by 5-HT2 receptors. Brain Res. 529: 85-90

Suggests hyperthermia contributes to neurotoxicity.

>Schmidt CJ, Black CK, Abbate GM, Taylor VL (1990) Chloral hydrate
>anesthesia antagonizes the neurotoxicity of
>3,4-methylenedioxymethamphetamine. Eur. J. Pharmacol. 191: 213-216

>Schmidt CJ, Black CK, Taylor VL (1990) Antagonism of the neurotoxicity
>due to a single administration of methylenedioxymethamphetamine. Eur. J.
>Pharmacol. 181: 59-70

Further evidence that dopamine plays a role in MDMA-induced 5-HT
neurotoxicity.  

>Schmidt CJ, Taylor VL, Abbate GM, Nieduzak TR (1991) 5-HT2 antagonists
>stereoselectively prevent the neurotoxicity of
>3,4-methylenedioxymethamphetamine by blocking the acute stimulation of
>dopamine synthesis:  Reversal by L-dopa. J. Pharm. exp. Ther. 25 6:
>230-235

As above.

>Wilson MA, Ricaurte GA, Molliver ME (1989) Distinct morphologic classes of
>serotonergic axons in primates exhibit differential vulnerability to the
>psychotropic drug 3,4-methylenedioxymethamphetamine. Neuroscience 28:
>121-138

------

Well, if you have any other references feel free to post them, particularly
if they use non-adversive doses of the drugs.  

     --Matt