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D-amp M-amp MDMA toxicity » cumulative

Posted by Dade on August 13, 2008, at 18:56:29

In reply to re: Ricaurte therapeutic dose study., posted by cumulative on August 10, 2008, at 23:58:27

> It is my opinion that the changes in dopamine transporters in that study reflect plastic changes, not neurotoxicity. Homeostatic changes in the dopamine transporter (and many other systems -- some of which seem to sensitize) are well-known to occur with dopaminergic psychostimulants, and that study does not show anything different. Also, ever since his hysterical MDMA mess-ups (where it was later found that they accidently used methamphetamine instead of MDMA, later being long after MDMA's neurotoxicity was trumpeted all over the news media) I don't really trust anything coming out of Ricaurte's lab. Other than that study, neurotoxicity from dextroamphetamine (unlike dextromethamphetamine, which has an additional mechanism of neurotoxicity that has a good chance of being active at therapeutic dosing, due to its serotonergic affinity) neurotoxicity is not known to occur at anything near human therapeutic doses of amphetamine.


hi there....desoxyn = (S)-methamphetamine, and dexedrine = d-amphetamine. There is a body of literature that reports that methamphetamine is about twice as potent as d-amphetamine. potency is derived from dose/response evaluations of subjects, and i can point you to several citations that conclude that (S)-methamphetamine and d-amphetamine are actually equipotent. HOWEVER, it turns out that (in at least 1 study examining a D_{1} antagonist) the mechanisms of neurotoxicity at high doses of desoxyn and dexedrine are different, as the antagonist protected against death from dexedrine in a dose-dependent fashion but not for desoxyn. (Derlet et al., Life Sci. 47:821-827 (2000)). but, the equipotency has been established, too. [e.g., Woolverton et al., Pharmacol. Biochem. Behav. 13:869-876 (1980)]. but then, see Peachey et al., Psychopharmacology 51:137-140 (1977) for evidence of greater stimulation (not potency) of desoxyn than dexedrine. more recently, Melega et al. JPET 274:90-96 (1995) concluded that low doses of either drug exhibited similar pharmacokinetics and dopamine response, although this is not a measure of potency nor were the doses extreme. from an abstract by Ellison and Switzer in Neuroreport. 25:17-20 (1993), they report (i quote) ``Both [dexedrine] and [cocaine] induced pronounced degeneeration in fasciculus retroflexus, but only [dexedrine] further induced substantial degeneration in striatum...[Desoxyn] administered in the very high dose but less prolonged drug regimen often employed in studies of dopamine toxicity induce pronounced degeneration in striatum, but widespread degeneration in many other regions as well.'' and then there is one paper by the man who instigated the FDA to make MDMA illegal: Ricaurte et al., Neuropharmacology 22:1165-1169 (1983), in which ``Repeated administration of large doses of [desoxyn] produce long-lasting depletion of brain dopamine and serotonin, as well as persistent decreases in the activity of their respective biosynthetic enzymes...'' interestingly, dexedrine - in ``a comparable regimen'' to the desoxyn dosing - ``did not did not produce long-lasting depletion of 5-HT in either the neostriatum or hippocampus.'' but, it turns out (and not just in this ref) that pretreatment with fluoxetine likely inhibits metabolism of amphetamines in general. so, in summary: potency is derived from dose/response curves, and in low doses, it appears as if desoxyn and dexedrine exhibit similar pharmacokinetics and are somewhat equipotent. however, at high doses of both drugs, the potency of desoxyn is greater and the toxicity is, as well, due to the larger amount of the brain affected in re: dopamine and 5-HT response. most drugs exhibit linear pharacokinetics/dynamics in the recommended dose ranges. the LD_{50} for desoxyn and dexedrine are almost identical, but at higher doses, desoxyn is more lethal. finally, as i posted some time ago, the study by (again) Ricaurte et al. in Science 297:2260-2263 (2003) entitled ``Severe dopaminergic neurotoxicity in primates after a common recreational dose regimen of MDMA (``ecstact'')'' - which was later retracted because the drugs given to the 5 monkeys tunred out to be methamphetamine and not MDMA - is actually testament to the neurotoxicity to methamphetamine (desoxyn). the dose was 6 mg/kg over 6 hours. recalling that this was pure methamphetamine, this means that your 100 mg desoxyn would correspond to your weight at about 16 kg, or about 35 lbs. 1 monkey died, 1 was unable to continue after the second dose (dosing was 2 mg/kg tid), and the 3 surviving monkeys were examined over several weeks after the acute dosing (there's more, and i can send you the PDF of the article if you desire, or anyone else). conclusions: severe dopaminergic injury and serotonergic neuortoxicity (for subjects using methamphetamine in repeated doses over several hours). the implication is that using desoxyn for a prolonged period - which is essentially what this last study showed - is bad news compared to dexedrine. hope this helps, and all the best,


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poster:Dade thread:845093
URL: http://www.dr-bob.org/babble/20080805/msgs/846012.html