375 lines
17 KiB
Plaintext
375 lines
17 KiB
Plaintext
droberts@alfred.carleton.ca (David Roberts) writes:
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Those who are think that MDA and MDMA are not neurotoxic may find the
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following references helpful:
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Axt KJ, Mullen CA, Molliver ME (1992) Cytopathologic features indicative
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of 5-hydroxytryptamine axon degeneration are observed in rat brain after
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administration of d- and l-methylenedioxyamphetamine. Ann. NY Acad.
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Sci. 648: 244-247
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Battaglia G, Yeh SY, O'Hearn E, Molliver ME, Kuhar MJ, DeSouza EB (1987)
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3,4-Methylenedioxymethamphetamine and 3,4-methyleneamphetamine destroy
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terminals in rat brain: quantification of neurodegeneration by measurement
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of [3H]-paroxetine labelled seroto nin uptake sites. J. Pharm. exp.
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Ther. 242: 911-916
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Battaglia G, Sharkey J, Kuhar MJ, De Souza EB (1991) Neuroanatomic
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specificity and time course of alterations in rat brain serotonergic
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pathways induced by MDMA (3,4-methylenedioxymethamphetamine): Assessment
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using quantitative autoradiography. Synapse 8 : 249-260
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Johnson M, Stone DM, Bush LG, Hanson GR, Gibb JW (1989) Glucocorticoids
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and 3,4-methylenedioxyamphetamine (MDMA)-induced neurotoxicity. Eur. J.
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Pharmacol. 161: 181-188
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Johnson MP, Huang X, Nichols DE (1991) Serotonin neurotoxicity in rats
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after combined treatment with a dopaminergic agent followed by a
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nonneurotoxic 3, 4-methylenedioxymethamphetamine (MDMA) analogue.
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Pharmacol. Biochem. Behav. 40: 915-922
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Johnson MP, Nichols DE (1991) Combined administration of a non-neurotoxic
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3,4-methylenedioxymethamphetamine analogue with amphetamine produces
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serotonin neurotoxicity in rats. Neuropharmacology 30: 819-822
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Markert LE, Roberts DCS (1991) 3,4-Methylenedioxyamphetamine (MDA)
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self-administration and neurotoxicity. Pharmacol. Biochem. Behav. 39:
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569-574
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McBean DE, Sharkey J, Ritchie IM, Kelly PAT (1990) Chronic effects of the
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selective serotoninergic neurotoxin, methylenedioxyamphetamine, upon
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cerebral function. Neuroscience 38: 271-275
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Nash JF, Yamamoto BK (1992) Methamphetamine neurotoxicity and striatal
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glutamate release: Comparison to 3,4-methylenedioxymethamphetamine. Brain
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Res. 581: 237-243
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O'Hearn E, Battaglia G, DeSouza EB, Kuhar MJ, Molliver ME (1988)
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Methylenedioxyamphetamine (MDA) and methylenedioxymethamphetamine (MDMA)
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cause selective ablation of serotonergic axon terminals in forebrain:
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Immunocytochemical evidence for neurotoxicity. J. Neurosci. 8: 2788-2803
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Ricaurte GA, Bryan G, Strauss L, Seiden LS, Schuster CR (1985)
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Hallucenogenic amphetamine selectively destroys brain nerve terminals.
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Science 229: 986-988
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Ricaurte GA, Martello AL, Katz JL, Martello MB (1992) Lasting effects of
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3,4-methylenedioxymethamphetamine (MDMA) on central serotonergic neurons
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in nonhuman primates: Neurochemical observations. J. Pharmacol. Exp.
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Ther. 261: 616-622
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Schechter MD (1991) Effect of MDMA neurotoxicity upon its conditioned
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place preference and discrimination. Pharmacol. Biochem. Behav. 38:
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539-544
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Schmidt CJ (1987) Neurotoxicity of the psychedelic amphetamine
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methylenedioxymethamphetamine. J. Pharm. exp. Ther. 240: 1-7
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Schmidt CJ, Abbate GM, Black CK, Taylor VL (1990a) Selective
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5-hydroxytryptamine2 receptor antagonists protect against the
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neurotoxicity of methylenedioxymethamphetamine in rats. J. Pharm. exp.
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Ther. 255: 478-483
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Schmidt CJ, Black CK, Abbate GM, Taylor VL (1990)
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Methylenedioxymethamphetamine-induced hyperthermia and neurotoxicity are
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independently mediated by 5-HT2 receptors. Brain Res. 529: 85-90
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Schmidt CJ, Black CK, Abbate GM, Taylor VL (1990) Chloral hydrate
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anesthesia antagonizes the neurotoxicity of
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3,4-methylenedioxymethamphetamine. Eur. J. Pharmacol. 191: 213-216
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Schmidt CJ, Black CK, Taylor VL (1990) Antagonism of the neurotoxicity
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due to a single administration of methylenedioxymethamphetamine. Eur. J.
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Pharmacol. 181: 59-70
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Schmidt CJ, Taylor VL, Abbate GM, Nieduzak TR (1991) 5-HT2 antagonists
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stereoselectively prevent the neurotoxicity of
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3,4-methylenedioxymethamphetamine by blocking the acute stimulation of
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dopamine synthesis: Reversal by L-dopa. J. Pharm. exp. Ther. 25 6:
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230-235
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Wilson MA, Ricaurte GA, Molliver ME (1989) Distinct morphologic classes of
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serotonergic axons in primates exhibit differential vulnerability to the
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psychotropic drug 3,4-methylenedioxymethamphetamine. Neuroscience 28:
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121-138
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============================================================================
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Matt (bagg@midway.uchicago.edu) writes:
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In his article on MDA and MDMA, droberts@alfred.carleton.ca (David Roberts)
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writes:
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>Those who are think that MDA and MDMA are not neurotoxic may find the
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>following references helpful:
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Thank you for the references. Unfortunately, these studies seem to
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be mostly concerned with the mechanism of axonal damage and not the relevance
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of high dose regimens to human use. Thus, while they are informative
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articles they don't address the issue being disputed: whether MDMA is safe
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in humans.
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Why not cite the few human studies which exist? Like the L-Tryptophan
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challenges and the spinal taps. And why not cite the literature
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which discusses the relevance of these studies to humans? Like
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Ricaurte's writings on fenfluramine or Charles Grob's writings on
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MDMA.
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>Axt KJ, Mullen CA, Molliver ME (1992) Cytopathologic features indicative
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>of 5-hydroxytryptamine axon degeneration are observed in rat brain after
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>administration of d- and l-methylenedioxyamphetamine. Ann. NY Acad.
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>Sci. 648: 244-247
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Note the phrase "axon degeneration." The lack of consistent use of a
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term in these references should indicate a lack of consensus about the
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best term for the phenomenon.
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>Battaglia G, Yeh SY, O'Hearn E, Molliver ME, Kuhar MJ, DeSouza EB (1987)
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>3,4-Methylenedioxymethamphetamine and 3,4-methyleneamphetamine destroy
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>terminals in rat brain: quantification of neurodegeneration by measurement
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>of [3H]-paroxetine labelled seroto nin uptake sites. J. Pharm. exp.
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>Ther. 242: 911-916
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>
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>Battaglia G, Sharkey J, Kuhar MJ, De Souza EB (1991) Neuroanatomic
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>specificity and time course of alterations in rat brain serotonergic
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>pathways induced by MDMA (3,4-methylenedioxymethamphetamine): Assessment
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>using quantitative autoradiography. Synapse 8 : 249-260
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20 mg/kg 2/day for 4 days for both studies, I think. Not comparable to
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human recreational or therapeutic doses. The conclusions of this
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study were that "the predominant effects of MDMA on serotonergic
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systeems throughout the brain are mediated on 5-HT axons and terminals...
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(and that) ...not all regions may be equally vulnerable to the
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neurodegenerative effects of MDMA." Most interestingly, they found
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difference in rate of recovery.
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>Johnson M, Stone DM, Bush LG, Hanson GR, Gibb JW (1989) Glucocorticoids
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>and 3,4-methylenedioxyamphetamine (MDMA)-induced neurotoxicity. Eur. J.
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>Pharmacol. 161: 181-188
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Here Gibb's lab used a single high dose (20 mg/kg). They were looking
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at the mechanism of neurodegneration by giving adrenalectomies.
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>Johnson MP, Huang X, Nichols DE (1991) Serotonin neurotoxicity in rats
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>after combined treatment with a dopaminergic agent followed by a
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>nonneurotoxic 3, 4-methylenedioxymethamphetamine (MDMA) analogue.
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>Pharmacol. Biochem. Behav. 40: 915-922
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Here, Dave Nichols lab demonstrates that DA plays a role in MDMA-induced
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neurotoxicity. It is important work, but how does it bear on the issues
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of whether MDMA neurotoxicity exists in humans, whether the axonal damage
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has any functional/behavioral correlates, and to what extent recovery
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occurs?
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>Johnson MP, Nichols DE (1991) Combined administration of a non-neurotoxic
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>3,4-methylenedioxymethamphetamine analogue with amphetamine produces
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>serotonin neurotoxicity in rats. Neuropharmacology 30: 819-822
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See above. By the way, Nichols believes that MDMA has therapeutic
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uses.
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>Markert LE, Roberts DCS (1991) 3,4-Methylenedioxyamphetamine (MDA)
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>self-administration and neurotoxicity. Pharmacol. Biochem. Behav. 39:
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>569-574
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Ah, now this might have some bearing on the issue. I haven't seen the study
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yet (blush), so I can't comment much. Certainly repeated injections
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of MDA across several days, as happened here, isn't the kind of behavior
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one finds much in humans, but it IS interesting to see the relationship
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between reinforcing doses and neurotoxic doses.
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I once tried to give cocaine-drinking rats MDMA solutions to see if they'd
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like it. Initially, they did, but then they all went cold turkey.
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The data suggests that they increased their dosage until they reached
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a dose which produced dysphoria (whether it was due to the amount taken
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or the fact that they had been taking repeated doses I cannot say). They
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all stopped by the third day. However, the doses at which they
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stopped self-administering seemed far too low to produce neurotoxicity.
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I suspect that the fact that the rats had been trained on cocaine also
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played a role in their failure to continue self-administration.
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I regret not being able to do more experiments along those lines,
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but California was calling out to me... :-)
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If the experimenters limited the rats' ability to self administer the MDA,
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so that their intake paralleled human patterns, then this would be
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particularly interesting. Although, frankly, I guess I don't know much
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about patterns of MDA use in humans. It is such a rare drug.
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Could you perhaps tell us more about this study?
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>McBean DE, Sharkey J, Ritchie IM, Kelly PAT (1990) Chronic effects of the
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>selective serotoninergic neurotoxin, methylenedioxyamphetamine, upon
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>cerebral function. Neuroscience 38: 271-275
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>Nash JF, Yamamoto BK (1992) Methamphetamine neurotoxicity and striatal
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>glutamate release: Comparison to 3,4-methylenedioxymethamphetamine. Brain
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>Res. 581: 237-243
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This is an exploration of the gluatamate hypothesis of neurotoxicity.
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13.8 mg/kg given 3 times (every 2 hours). Ouch!
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>O'Hearn E, Battaglia G, DeSouza EB, Kuhar MJ, Molliver ME (1988)
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>Methylenedioxyamphetamine (MDA) and methylenedioxymethamphetamine (MDMA)
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>cause selective ablation of serotonergic axon terminals in forebrain:
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>Immunocytochemical evidence for neurotoxicity. J. Neurosci. 8: 2788-2803
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Same Battaglia regimen as above. They found that it was the fine axons
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which were selectively damaged.
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>Ricaurte GA, Bryan G, Strauss L, Seiden LS, Schuster CR (1985)
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>Hallucenogenic amphetamine selectively destroys brain nerve terminals.
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>Science 229: 986-988
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Ah, the classic paper!
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>Ricaurte GA, Martello AL, Katz JL, Martello MB (1992) Lasting effects of
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>3,4-methylenedioxymethamphetamine (MDMA) on central serotonergic neurons
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>in nonhuman primates: Neurochemical observations. J. Pharmacol. Exp.
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>Ther. 261: 616-622
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An important piece of work. Finally, we're getting down to the monkey
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business. George Ricaurte et al found that squirrel monkeys given
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5 mg/kg twice a day for 4 days hadn't completely recovered at 18
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months and had in fact seemingly returned to an earlier state of
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damage. Papers like this really make you realize how difficult it is
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to say when "neurotoxicity" has taken place and when it has been
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repaired.
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He got increases in 5-HT in one area ("hyperenervation" of the hypothalamus).
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Others have gotten similar effects with phenethylamine "neurotoxins" and it
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seems to happen in the areas from which the neurons originate, as if new
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growth sprouts out from there. And he also got partial recovery
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(63% of controls) of 5-HT levels in the thalamus. But all the other
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sites looked as if they were down at what you'd expect 2 weeks after
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the high dose regimen.
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At one point he basically says that we have no idea what is happening
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here. I'll second that. Importantly, he has still-unpublished (I think)
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data that fails to find any neurotoxic effects from a less punishing,
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human-like regimen.
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>Schechter MD (1991) Effect of MDMA neurotoxicity upon its conditioned
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>place preference and discrimination. Pharmacol. Biochem. Behav. 38:
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>539-544
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This is interesting. They trained rats to discriminate 1.5 mg/kg MDMA
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from vehicle and then established that the same dose produced
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conditioned place preference, meaning the rats liked it. Then, they
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gave the Battaglia regimen of 20 mg/kg 2/day for 4 days. They
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found that the high dose regimen didn't change the place preference,
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but did make the rats more sensitive to 1.0 mg/kg on the discrimination
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task.
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Note the difference between giving single injections of 1.5 mg/kg and
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giving 8 injections of 20 mg/kg. One is pleasurable and probably not
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damaging, the other is damaging and unpleasurable. The question then
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is whether there are pleasurable and damaging doses. There are
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probably pleasurable and damaging regimens, since repeated low doses
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seem to be damaging. But what about isolated or infrequently given
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doses?
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>Schmidt CJ (1987) Neurotoxicity of the psychedelic amphetamine
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>methylenedioxymethamphetamine. J. Pharm. exp. Ther. 240: 1-7
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>Schmidt CJ, Abbate GM, Black CK, Taylor VL (1990a) Selective
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>5-hydroxytryptamine2 receptor antagonists protect against the
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>neurotoxicity of methylenedioxymethamphetamine in rats. J. Pharm. exp.
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>Ther. 255: 478-483
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An interesting paper. It made me think, "would 5-HT2 AGONISTS also
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protect against the neurotoxicity?" That would be of interest to
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the people who take LSD and MDMA at the same time.
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>Schmidt CJ, Black CK, Abbate GM, Taylor VL (1990)
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>Methylenedioxymethamphetamine-induced hyperthermia and neurotoxicity are
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>independently mediated by 5-HT2 receptors. Brain Res. 529: 85-90
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Suggests hyperthermia contributes to neurotoxicity.
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>Schmidt CJ, Black CK, Abbate GM, Taylor VL (1990) Chloral hydrate
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>anesthesia antagonizes the neurotoxicity of
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>3,4-methylenedioxymethamphetamine. Eur. J. Pharmacol. 191: 213-216
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>Schmidt CJ, Black CK, Taylor VL (1990) Antagonism of the neurotoxicity
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>due to a single administration of methylenedioxymethamphetamine. Eur. J.
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>Pharmacol. 181: 59-70
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Further evidence that dopamine plays a role in MDMA-induced 5-HT
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neurotoxicity.
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>Schmidt CJ, Taylor VL, Abbate GM, Nieduzak TR (1991) 5-HT2 antagonists
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>stereoselectively prevent the neurotoxicity of
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>3,4-methylenedioxymethamphetamine by blocking the acute stimulation of
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>dopamine synthesis: Reversal by L-dopa. J. Pharm. exp. Ther. 25 6:
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>230-235
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As above.
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>Wilson MA, Ricaurte GA, Molliver ME (1989) Distinct morphologic classes of
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>serotonergic axons in primates exhibit differential vulnerability to the
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>psychotropic drug 3,4-methylenedioxymethamphetamine. Neuroscience 28:
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>121-138
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------
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Well, if you have any other references feel free to post them, particularly
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if they use non-adversive doses of the drugs.
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--Matt
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===========================================================================
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lamontg@u.washington.edu writes:
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Azmitia-EC, Whitaker-Azmitia-PM, "Awakening the Sleeping Giant: Anatomy
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and Plasticity of the Brain Serotonergic System", J-Clin-Psychiatry 52:12
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(suppl), Dec 1991.
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"The treatement of these [5-HTergic] disorders in the adult is achived by
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using specific drugs that act on the serotonergic neuronal receptors to
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produce a pharmacologic change in the functioning of the 5-HT system. These
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drugs have proven extremely useful in correcting the chemical imbalance.
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Unfortunately, the morphlogical deficits that underlie the chemical imbalance
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often remain unchecked. In many instances, pharmacologic treatment must
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be sustained indefinitely with the added burden, in many cases, of
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increasing dosage due to decreasing efficiency of the drug/receptor
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interaction. Can the serotonergic system be morphologically reorganized
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in the adult brain using the same growth factors active during development?
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In this article we will present evidence that serotonergic neurons are
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plastic in the adult brain, that is, that they can sprout and innervate new
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target areas. Furthermore, the signals and molecules for sprouting
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in the adult brain are to a large extent similar to those functioning
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during early development. However, to activate these mechanisms, the
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adult serotonergic neurons must first be damaged or blocked. The adult
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brain detects the lack of serotonin and "reactivates" certain development
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programs to encourage their growth into the "chemically" deafferented area.
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Our work suggests that this reawakening of develpomental processes
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involves the 5-HT1A recetors located on astrocytes..."
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[ the above was highlighted by Matt Baggott with the editorial comment
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"Holy Shit!" attacted to it...:) further along... ]
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"Pharmacologic intervention can alter the growth of serotongeric neurons.
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Compounds such as MDMA (Ecstasy) have a bell-shaped curve (Azmitia, 1990).
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At a low concentration the drug can stimulate growth of cultured
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serotonergic neurons. However, at a higher dose, the drug is a powerful
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serotonergic toxin. 5-Methoxy-Tryptamine, a commonly used 5-HT receptor
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agonist, has a profile opposite that of MDMA. In culture, low doses of
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this drug can inhibit fetal development, while high doses stimulate
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growth (Whitaker-Azmitia, 1986). When this drug i sinjected into
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pregnant animals, the development of the 5-HT system is similarly affected and
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the behavior of the animals is abnormal (Shemer, 1988).
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Azmitia-EC, Murphy-RB, Whitaker-Azmitia-PM, "MDMA (Ecstasy) effects on
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cultured serotonergic neurons: evidence fo ca++ dependent toxicity linked
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to release" Brain-Res 1990; 510:97-103
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Whitaker-Azmitia-PM, Amitia-EC. "Autoregulation of fetal serotonergic
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neuronal development: role of high-affinity serotonin receptor" Neurosci-
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Lett 1986; 67:307-312.
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Shemer-A, Whitaker-Azmitia-PM, Azmitia-EC, "Effects of prenatal 5-Methoxy-
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Trytamine on serotonergic uptake and behavior in the neontal rat."
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Pharmacol-Biochem-Behav 1988; 30:847-852."
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