Study shows dopaminergic toxicity from amphetamine in non-human primates, using doses consistent with its medical use

Note: I'm being a bad Netizen. I've already posted this citation to another group because of its relevance to that audience, but I'd be interested to hear commentary from this group. I probably should've just cross-posted it in the first place.

Link to citation:
<http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=abstract&list_uids=16014752>

========================================================
J Pharmacol Exp Ther. 2005 Jul 13; [Epub ahead of print]

Amphetamine treatment similar to that used in the treatment of adult ADHD damages dopaminergic nerve endings in the striatum of adult non-human primates.

Mechan-Mayne A, Yuan J, Hatzidimitriou G, Xie T, Mayne A, McCann UD, Ricaurte GA.

Johns Hopkins University.

Pharmacotherapy with amphetamine is effective in the management of attention-deficit/ hyperactivity disorder (ADHD), now recognized in adults, as well as in children and adolescents. Here we demonstrate that amphetamine treatment, similar to that used clinically for adult ADHD, damages dopaminergic nerve endings in the striatum of adult non-human primates. Furthermore, plasma concentrations of amphetamine associated with dopaminergic neurotoxicity in non-human primates are on the order of those reported in young patients receiving amphetamine for the management of ADHD. These findings may have implications for the pathophysiology and treatment of ADHD. Further preclinical and clinical studies are needed to evaluate the dopaminergic neurotoxic potential of therapeutic doses of amphetamine, in children as well as adults.

PMID: 16014752
========================================================

A cursory scan of the 43 paper (PDF, to be sure) says that a reduction of some 30-50% of dopamine neuronal markers were observed after four weeks. The subjects received oral preparations (self-administered) of a 3:1 ratio of the d- and l- amphetamine isomers (sounds familiar). The doses were similar to the upper end of the range used in medicine, as were plasma drug concentrations. Because "amphetamine" is sometimes misappropriated to derivatives and structurally similar chemicals, I should point out that the study did in fact involve amphetamine.

Have any of you seen a decent article (preferably peer-reviewed) that gives an estimation of a human NOAEL of amphetamine (d- or racemic), in addition to, of course, its basis? None of the animal studies that I've read thus far provide justification for the current prescribing guidelines or the FDA's MRTD (whether such evidence should be necessary to justify its medical use is another subject entirely). Postmortem histopathological observations of former methamphetamine addicts are wholly unimpressive.

Methylphenidate doesn't appear nearly as neurotoxic as amphetamine in animal studies (indeed, it has even prevented amphetamine-induced neurotoxicity in some studies), so I'm interested to know why the latter is often used in place of the former, when the difference is usually only marginal.

BTW, is Johns Hopkins known for a tendency toward bias concerning the controversial use of these medicines?

Dave
.