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."