Why is parkinsonism not a feature of human methamphetamine users?

Abstract

For more than 50 years, methamphetamine has been a widely used stimulant drug taken to maintain wakefulness and performance and, in high doses, to cause intense euphoria. Animal studies show that methamphetamine can cause short-term and even persistent depletion of brain levels of the neurotransmitter dopamine. However, the clinical features of Parkinson's disease, a dopamine deficiency disorder of the brain, do not appear to be characteristic of human methamphetamine users. We compared dopamine levels in autopsied brain tissue of chronic methamphetamine users with those in patients with Parkinson's disease and in a control group. Mean dopamine levels in the methamphetamine users were reduced more in the caudate (-61%) than in the putamen (-50%), a pattern opposite to that of Parkinson's disease. Some methamphetamine users had severely decreased dopamine levels, within the parkinsonian range, in the caudate (up to 97% dopamine loss) but not in the putamen. As the putamen and caudate subserve aspects of motor and cognitive function, respectively, our data suggest that methamphetamine users are not parkinsonian because dopamine levels are not sufficiently decreased in the motor component of the striatum. However, the near-total reduction in the caudate could explain reports of cognitive disturbances, sometimes disabling, in some drug users, and suggests that treatment with dopamine substitution medication (e.g. levodopa) during drug rehabilitation might be helpful.

Rapid Recovery of Vesicular Dopamine Levels in Methamphetamine Users in Early Abstinence

“…However, we cannot exclude the possibility that VMAT2 (protein) level itself might also be influenced as part of a compensatory process to changes in dopamine levels or that binding of the tracer to VMAT2 might possibly have been reduced to some extent by competition with residual MA (at scan 1) (Partilla et al, 2006). Our PET imaging findings are consistent with and support our previous post-mortem brain findings of a dopamine loss (putamen − 61%; caudate − 50%; expressed per control mean) in MA users who had taken the drug within 3 days of death, although the intrastriatal difference in the imaging investigation was only slight (and not statistically significant) in the living brain (AST, +31%; SMST, +26%) (Moszczynska et al, 2004;Wilson et al, 1996a). The lack of change in cocaine users is consistent with a less prominent action of cocaine (vs MA) as a dopamine releaser (see Kish, 2014) and the short half-life of cocaine vs MA.…”

“…Results of our autopsied brain and brain PET investigations of 'dopamine' measures are generally similar to the currently reported finding and point to differences in the actions of MA vs cocaine in human brain: MA users having marked differences relative to HC (Moszczynska et al, 2004;Wilson et al, 1996a), whereas cocaine users have, at most, only modest differences (Narendran et al, 2012;Wilson et al, 1996b, see Kish, 2014.…”

“…MA stimulates release of the brain neurotransmitter dopamine, considered to be involved in the rewarding property of MA (see Kish, 2008). In two post-mortem brain investigations, we reported very low (up to 90% depletion) levels of dopamine in the striatum (caudate, putamen) of the brain of some recreational MA users who all tested positive for the drug at autopsy (Moszczynska et al, 2004;Wilson et al, 1996a). This suggested that recreational doses of MA might cause a massive release of dopamine in humans sufficient to deplete, at least transiently, tissue stores of dopamine, and, speculatively, that treatment of MA users during drug rehabilitation with dopamine substitution medication (levodopa) might normalize the deficit and perhaps diminish risk for relapse and or behavioral (eg, cognitive and affective) disturbances.…”

Cholinesterase inhibitors might alleviate methamphetamine-induced delusions, hallucinations and cognitive impairment, while reducing craving and addiction

“…Methamphetamine psychosis has been successfully treated with atypical anti-psychotic agents such as olanzapine (Misra et al 2000), but it would be helpful to have other therapeutic options for patients with intolerance or non-response. A new approach is suggested by an intriguing autopsy study of 20 chronic methamphetamine users with 14 normal controls which found that the chronic methamphetamine users had markedly depleted dopamine in the non-motor portion of the basal ganglia system, confirming previous animal data ( Moszczynska et al 2004). Thus, from a neurochemical standpoint, chronic methamphetamine users may resemble Parkinsonian patients.…”

Mitochondrial proteomics as a selective tool for unraveling Parkinson’s disease pathogenesis

“…It's been suggested that these metabolites may neutralize the neuroprotection offered by the drug [134]. For instance, in rats, exposure to amphetamine and METH may cause destruction of striatal dopaminergic nerve fibers [135] and of depleted striatal DA content in human METH users [136]. However, large-scale trials of selegiline-use by PD patients failed to confirm these adverse effects [137].…”