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droberts@alfred.carleton.ca (David Roberts) writes:
Those who are think that MDA and MDMA are not neurotoxic may find the
following references helpful:
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
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
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
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
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
Markert LE, Roberts DCS (1991) 3,4-Methylenedioxyamphetamine (MDA)
self-administration and neurotoxicity. Pharmacol. Biochem. Behav. 39:
569-574
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
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
Ricaurte GA, Bryan G, Strauss L, Seiden LS, Schuster CR (1985)
Hallucenogenic amphetamine selectively destroys brain nerve terminals.
Science 229: 986-988
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
Schechter MD (1991) Effect of MDMA neurotoxicity upon its conditioned
place preference and discrimination. Pharmacol. Biochem. Behav. 38:
539-544
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
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
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
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
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
============================================================================
Matt (bagg@midway.uchicago.edu) writes:
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
===========================================================================
lamontg@u.washington.edu writes:
Azmitia-EC, Whitaker-Azmitia-PM, "Awakening the Sleeping Giant: Anatomy
and Plasticity of the Brain Serotonergic System", J-Clin-Psychiatry 52:12
(suppl), Dec 1991.
"The treatement of these [5-HTergic] disorders in the adult is achived by
using specific drugs that act on the serotonergic neuronal receptors to
produce a pharmacologic change in the functioning of the 5-HT system. These
drugs have proven extremely useful in correcting the chemical imbalance.
Unfortunately, the morphlogical deficits that underlie the chemical imbalance
often remain unchecked. In many instances, pharmacologic treatment must
be sustained indefinitely with the added burden, in many cases, of
increasing dosage due to decreasing efficiency of the drug/receptor
interaction. Can the serotonergic system be morphologically reorganized
in the adult brain using the same growth factors active during development?
In this article we will present evidence that serotonergic neurons are
plastic in the adult brain, that is, that they can sprout and innervate new
target areas. Furthermore, the signals and molecules for sprouting
in the adult brain are to a large extent similar to those functioning
during early development. However, to activate these mechanisms, the
adult serotonergic neurons must first be damaged or blocked. The adult
brain detects the lack of serotonin and "reactivates" certain development
programs to encourage their growth into the "chemically" deafferented area.
Our work suggests that this reawakening of develpomental processes
involves the 5-HT1A recetors located on astrocytes..."
[ the above was highlighted by Matt Baggott with the editorial comment
"Holy Shit!" attacted to it...:) further along... ]
"Pharmacologic intervention can alter the growth of serotongeric neurons.
Compounds such as MDMA (Ecstasy) have a bell-shaped curve (Azmitia, 1990).
At a low concentration the drug can stimulate growth of cultured
serotonergic neurons. However, at a higher dose, the drug is a powerful
serotonergic toxin. 5-Methoxy-Tryptamine, a commonly used 5-HT receptor
agonist, has a profile opposite that of MDMA. In culture, low doses of
this drug can inhibit fetal development, while high doses stimulate
growth (Whitaker-Azmitia, 1986). When this drug i sinjected into
pregnant animals, the development of the 5-HT system is similarly affected and
the behavior of the animals is abnormal (Shemer, 1988).
Azmitia-EC, Murphy-RB, Whitaker-Azmitia-PM, "MDMA (Ecstasy) effects on
cultured serotonergic neurons: evidence fo ca++ dependent toxicity linked
to release" Brain-Res 1990; 510:97-103
Whitaker-Azmitia-PM, Amitia-EC. "Autoregulation of fetal serotonergic
neuronal development: role of high-affinity serotonin receptor" Neurosci-
Lett 1986; 67:307-312.
Shemer-A, Whitaker-Azmitia-PM, Azmitia-EC, "Effects of prenatal 5-Methoxy-
Trytamine on serotonergic uptake and behavior in the neontal rat."
Pharmacol-Biochem-Behav 1988; 30:847-852."