Brain Advance Access originally published online on November 25, 2003
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Brain, Vol. 127, No. 2, 363-370, 2004
© 2004 Guarantors of Brain
doi: 10.1093/brain/awh046
Why is parkinsonism not a feature of human methamphetamine users?
1 Human Neurochemical Pathology Laboratory, Centre for Addiction and Mental Health, Toronto, 2 Division of Neuropathology, London Health Science Centre, University of Western Ontario, London, Ontario, Canada, 3 Division of Forensic Toxicology, Office of the Armed Forces Medical Examiner, Division of Forensic Toxicology, Armed Forces Institute of Pathology, Rockville, MD, 4 Santa Clara County Medical Examiner-Coroner, San Jose, CA, 5 Arkansas State Crime Laboratory, 3 Natural Resources Drive, Little Rock, AR, 6 Spokane County Medical Examiner’s Office, Spokane and 7 Clark County Office of the Medical Examiner, Vancouver, WA, USA
Correspondence to: Stephen J. Kish, PhD, Human Neurochemical Pathology Laboratory, Centre for Addiction and Mental Health, 250 College Street, Toronto, Ontario M5T 1R8, Canada E-mail: stephen_kish{at}camh.net
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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.
Key Words: Parkinson’s disease; caudate; putamen; methamphetamine; cognition
Abbreviations: MA = methamphetamine
Received July 8, 2003. Revised September 23, 2003. Accepted September 26, 2003.
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Introduction |
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Methamphetamine (MA) is a widely used psychostimulant which stimulates neuronal release of the neurotransmitter dopamine in the human brain (Laruelle et al., 1995
), an action related to the euphoric effects of the drug (Wise, 1996).
In experimental animals, MA can deplete brain stores of dopamine and, if the dose is sufficient, lead to long-term reductions in biochemical markers of dopamine neuronal integrity in the striatal nerve terminal (Fibiger and McGerr, 1971; Seiden et al., 1976; Frey et al., 1997; Harvey et al., 2000a, b) as well as those in the long axons which extend from the cell body to the nerve terminal (Harvey et al., 2000b). However, unlike the pathology of idiopathic Parkinson’s disease, the brain morphological changes following MA exposure do not include obvious loss of dopamine cell bodies in the substantia nigra of either experimental animals (Woolverton et al., 1989; Linder et al., 1995; but see Sonsalla et al., 1996) or humans (Wilson et al., 1996a).
The animal findings of long-term reduction of brain dopaminergic markers, together with histological signs suggestive of nerve terminal injury following acute MA exposure (Linder et al., 1995), have led to the prevailing assumption that MA is toxic to brain dopamine neurons (Ricaurte and McCann, 1992). However, the actual structural extent of long-term MA toxicity to brain dopamine neurons in primates remains uncertain and even controversial because of the impossibility of establishing whether the persistent [but substantially reversible in the non-human primate (Harvey et al., 2000b)] reduction of dopamine nerve terminal/axonal markers is associated with actual physical loss of part of the dopamine neuron or only with loss of expression of dopaminergic markers therein (for discussion see below and Harvey et al., 2000b).
Since the discovery that MA is harmful to brain dopamine nerve terminals in animals, by causing either short-term or persistent loss of dopamine, there has been a public health concern that illicit recreational use of the drug by humans will lead to the emergence of the symptoms of Parkinson’s disease, a brain dopamine deficiency disorder caused by degeneration of entire brain dopamine neurons (Hornykiewicz and Kish, 1986). Because parkinsonism develops only after substantial brain dopamine depletion (Hornykiewicz and Kish, 1986), we established whether dopamine levels in autopsied brain of a group of recreational MA users can be as low as those in patients with neuropathologically confirmed idiopathic Parkinson’s disease. Previously, we reported that mean striatal (caudate, putamen) dopamine levels were reduced, on average, by 
50% in the brain of 12 chronic MA users (Wilson et al., 1996a). In the present investigation we replicate this finding in a group of eight additional subjects but now show, unexpectedly, that dopamine loss in a major striatal subdivision of some of the MA users can actually be as severe as that observed in elderly patients with Parkinson’s disease.
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Subjects and brain material
Post-mortem brain material from MA users (n = 20) and control subjects (n = 14) was obtained from medical examiner offices in the USA and Canada. (Consent was obtained from next of kin to examine the brains and to obtain additional information on the subjects for research purposes.) Subject characteristics, including brain (occipital cortex) drug levels of 16 of the 20 MA users, have been reported previously (Wilson et al., 1996
a; Kalasinsky et al., 2001; Tong et al., 2003). The control and MA groups were matched with respect to age (controls, 34.2 ± 3.5 years; MA users, 31.4 ± 1.9 years), post-mortem interval between death and autopsy (controls, 13.9 ± 1.6 h; MA users, 14.6 ± 1.5 h; P > 0.1, Student’s two-tailed t-test) and sex (controls, 11 males, three females; MA users, 15 males, five females; P > 0.1, Yates’ corrected 
2 test).
All MA users had evidence, from the medical examiner investigation and/or structured interview with the next of kin, of the use of MA as the primary drug of abuse for at least 1 year; the presence of MA [assessed by GC-MS (gas chromatography–mass spectrometry, Kalasinsky et al., 2001)] in the blood, brain (occipital cortex) and, in the 14/20 MA users in which hair was available, in sequential scalp hair samples; and the absence, at autopsy, of brain pathology unrelated to MA use (Table 1). Sixteen MA users tested negative for other drugs of abuse, including alcohol, whereas heroin or cocaine and/or their metabolites were also detected in the blood and brain of three subjects (cases 559, 726 and 478) and in hair from four subjects (cases 559, 726, 478 and 678) (Table 1). Detailed information on the neurological status of the MA users was not available; however, anecdotal information from the next of kin and informants suggested that neurological status was not obviously abnormal. As shown in Table 2, the suspected or known causes of death of MA users were acute aortic dissection (n = 1), gunshot wounds to the chest (n = 2), severe coronary artery atherosclerosis with MA toxicity as a possible contributing factor (n = 2), multiple drug toxicity (n = 3) and MA intoxication (n = 12). Although it is likely that some of the MA users who had high blood MA levels had developed increased body temperature, examination of the body at autopsy (mean 15 h post-mortem) revealed no evidence of hyperthermia, with the exception of one subject who had an elevated temperature at autopsy (case 447). The results of biochemical analyses [dopamine and other dopamine nerve terminal markers (Wilson et al., 1996a); blood and brain MA levels (Wilson et al., 1996a; Kalasinsky et al., 2001)] on 12 of the 20 MA users have been reported previously. All control subjects were neurologically normal, had no history of drug use and tested negative for any drug of abuse in blood, autopsied brain and, in the 10 subjects for whom scalp hair was available, sequential scalp hair samples. The control subjects were selected so that most had died, like the MA users, a sudden death. The causes of death of control subjects were gunshot wound to the chest (n = 2), chest trauma (n = 2), drowning (n = 1), leukaemia (n = 1), myocardial infarction (n = 1) and cardiovascular disease (n = 7).
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At autopsy, one-half of the brain was fixed in formalin fixative and the other half was immediately frozen until dissection. Brain neuropathological analysis of the MA users (Table 1) and of the control subjects showed no significant abnormalities in any brain area, including the substantia nigra, with the exception of prominent gliosis in the putamen in case 879 and mild gliosis in the substantia nigra in case 478. For the dopamine and homovanillic acid assays, samples (20–50 mg wet weight) were examined by HPLC (high-pressure liquid chromatography) with electrochemical detection (Wilson et al., 1994
).
Statistical analyses
Differences between the control and the total MA groups were analysed by the Student’s two-tailed unpaired or, where appropriate, paired t-test.
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Striatal dopamine levels can be profoundly decreased in some MA users
Figure 1 shows the individual striatal dopamine levels of the 12 MA users reported in our earlier study (Wilson et al., 1996
a) and of the eight new subjects of the present investigation. As shown in Fig. 1, mean striatal dopamine levels, compared with control values, were markedly and significantly reduced in both groups of MA users (Wilson et al., 1996a: caudate –55%, putamen –51%; new MA users: caudate –61%, putamen –50%); the extent of the reduction in the caudate nucleus (–61%) exceeded that in the putamen (–50%) in the overall group of 20 MA users (Table 3; P < 0.05, Student’s paired two-tailed t-test).
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Analysis of the individual subject data (Fig. 1) revealed that the majority of the striatal dopamine values of the MA users fell below the lower limit of the control range. Striatal dopamine loss in some MA users was quite severe, six subjects having caudate dopamine reduction of >70% and two subjects having nearly total loss of dopamine in the caudate (case 448, –95%; case 678, –97%) and, to a lesser extent, in the putamen (case 448, –89%; case 678, –90%).
In the total group of MA users, mean striatal levels of the dopamine metabolites homovanillic acid, dihydroxyphenylacetic acid and 3-methoxytyramine, unlike those of dopamine, did not differ significantly from the control values (Table 3 and Fig. 1). Thus, as shown in Fig. 1, the two MA users with severely depleted striatal dopamine had above-normal (448) or normal (678) striatal levels of homovanillic acid, the major dopamine metabolite in the human brain.
Dopamine levels in some MA users can be parkinsonian in the caudate but not in the putamen
To establish whether dopamine levels in any of the MA users might be as low as those in patients with Parkinson’s disease, we compared the levels of dopamine in the striatum of each of the MA users with the levels we reported previously for the striatum of 12 patients (mean age, 77 years) with Parkinson’s disease, who ranged in clinical severity from the early to the late stage (Wilson et al., 1996b). As shown in Fig. 2, the extent of dopamine loss was, as expected (Bernheimer et al., 1973; Kish et al., 1988), much more marked in the putamen than in the caudate of the patients with Parkinson’s disease. None of the MA users had putamen dopamine values falling within the range of the Parkinson’s disease patients, whereas a substantial overlap occurred between the ranges of the dopamine values in the caudate for the MA and Parkinson’s disease groups.
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We previously reported that levels of the sum of MA and its metabolite amphetamine are homogeneously distributed in the post-mortem brain of human MA users (Kalasinsky et al., 2001
). No statistically significant correlation was observed between the molar sum of MA and amphetamine (measured in the occipital cortex) and dopamine levels in the putamen (R = –0.25, Spearman rank correlation test), whereas a trend for a negative correlation was found between brain MA and dopamine levels in the caudate nucleus (R = –0.43, P = 0.059). No statistically significant correlation was observed between brain dopamine or homovanillic acid levels and post-mortem time (range 4–24 h) in the caudate or putamen of either the control subjects or the MA users, consistent with previous findings (Adolfsson et al., 1979; Spokes, 1979). |
Discussion |
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Our major finding is that striatal dopamine levels in some MA users can be reduced to those observed in patients with Parkinson’s disease in the caudate but not in the putamen subdivision of the striatum.
Striatal dopamine is decreased in MA users
Previously, we reported that mean striatal dopamine levels were reduced by 50% in the brain of 12 chronic MA users (Wilson et al., 1996a). We now replicate this finding in a group of eight additional subjects and provide the individual values for all 20 subjects. As shown in Fig. 1, although the extent of striatal dopamine reduction in MA users is variable, dopamine levels in most of the MA users fall below the lower limit of the control range, and the decrease is near-total in some cases. The suspected cause of death in five of the six MA users with marked (>70%) dopamine loss was drug intoxication, indicating that severe dopamine depletion might be a normal consequence of taking a dose of MA sufficient to cause death by cardiovascular toxicity. However, the cause of death in one of the MA users having very low dopamine levels (–95% in the caudate) was trauma, suggesting that severe dopamine reduction probably occurs in users who take lower doses of the drug which are not life-threatening.
Why is striatal dopamine decreased?
As all of the MA users used the drug recently as well as chronically, any dopamine reduction could be explained by an actual physical loss of entire dopamine neurons or nerve endings, down-regulation of dopamine biosynthesis, and/or dopamine depletion due to excessive release and metabolism of the neurotransmitter.
We found no evidence of loss of pigmented cell bodies in the substantia nigra of the MA users in either our first (Wilson et al., 1996a) or our present investigation, indicating that there could not have been substantial loss of entire dopamine neurons in the MA users. However, our qualitative histopathological analysis, conducted by a neuropathologist experienced in examination of patients with degenerative parkinsonisms, would not have disclosed a slight loss of dopaminergic cell bodies.
It is beyond the scope of the present investigation to establish whether the low brain dopamine level in the MA users could have been caused by an actual physical loss of dopamine nerve terminals. Because brain levels of dopamine nerve markers (e.g. dopamine, dopamine transporter) can change independently of differences in the number of dopamine neurons (for extensive discussion see Harvey et al., 2000b; Wilson et al., 1996a), we believe that it might never be possible to establish unequivocally whether there is loss of dopamine nerve terminals in human MA users using the presently available biochemical probes.
However, striatal concentrations of one marker, the vesicular monoamine transporter (VMAT2), considered to be a somewhat more ‘stable’ marker of striatal dopamine nerve terminal integrity (Vander Borght et al., 1995; Wilson and Kish 1996; but see Riddle et al., 2002 and de la Fuente-Fernández et al., 2003), are normal in postmortem brain of MA users (Wilson et al., 1996a) whereas in living brain of self-reported MA users (using PET) VMAT2 levels are, at most, only slightly reduced (personal communication, C. Schuster and C.-E. Johanson, Wayne State University, Detroit MI; K. Frey, University of Michigan, Ann Arbor MI). These data suggest that striatal dopamine nerve terminal number might not be substantially decreased in human MA users.
As all of the MA users had used the drug recently (MA was present in post-mortem blood and brain) it is more likely that much, if not all, of the decreased striatal dopamine in the MA users is explained by a recent massive drug-induced release of the neurotransmitter (Laruelle et al., 1995) which could not be compensated for by maximal dopamine biosynthesis. It is also not possible to exclude the possibility that some part of the reduction had occurred post-mortem. An acute effect of MA is suggested by our observation that striatal levels of the major dopamine metabolite homovanillic acid (Fig. 1) were not decreased in the MA users as a whole or even in the subgroup of six MA users with very low dopamine levels (caudate dopamine –85% versus homovanillic acid +13%), as is the case in Parkinson’s disease (Table 3), a disorder characterized by the physical loss of entire dopamine neurons.
Striatal dopamine levels in MA users versus Parkinson’s disease
Irrespective of the cause of the dopamine reduction, we can now address the question of whether the magnitude of the striatal dopamine loss in the MA users is likely to be sufficient to cause parkinsonism. Using the same high-pressure liquid chromatography procedure for post-mortem brain measurement in a group of much older (mean age 77 years) patients with mild to severe Parkinson’s disease, we reported (Wilson et al., 1996b) levels of dopamine in the putamen, the ‘motor’ nucleus of the striatum (Alexander et al., 1986), ranging from 0.08 to 0.54 ng/mg tissue (Fig. 2). Although the extent of putamen dopamine reduction required for the occurrence of very mild parkinsonism must be somewhat less than 0.54 ng/mg tissue, none of the MA user values (range, 0.73–9.39 ng/mg tissue) fell within the parkinsonian range (Fig. 2). Assuming that our biochemical data on 20 subjects are generally representative of MA users who regularly become intoxicated with the drug, the lack of a sufficiently severe reduction in putamen dopamine to achieve the critical threshold probably explains the apparent absence of reports in the clinical literature of parkinsonism in MA users. In this regard, discussions with three centres extensively involved in the acute (acute MA intoxication) or chronic (rehabilitation during drug abstinence) treatment of MA users disclose no evidence of clinically obvious parkinsonism or even neuroleptic drug-induced parkinsonism during drug intoxication (personal communications, R. Rawson, Matrix, Los Angeles, CA, USA; R. Derlet, Emergency Department, University California at Davis, Sacramento, CA, USA; W. Haning, University of Hawaii, Honolulu, HI, USA). However, it is possible that some MA users might be found to have subtle motor problems that are uncovered on formal testing. The available published literature on the question of movement disorders in MA/amphetamine users appears to be limited to anecdotal findings of stereotyped behaviour or dyskinesias in a small minority of subjects (see Lundh and Tunving, 1981), and a report demonstrating normal motor function in MA users during abstinence on a motor task (pegboard) which patients with Parkinson’s disease perform poorly (Chang et al., 2002).
The extent of reduction of striatal dopamine in the MA users was slightly more marked in the caudate than in the putamen, with dopamine levels in the caudate decreased more than in the putamen in 15 of the 20 MA users. Interestingly, this subregional pattern of dopamine loss differs from that in Parkinson’s disease, in which the putamen is much more severely affected (Fig. 2) (Bernheimer et al., 1973; Kish et al., 1988). As post-mortem levels of MA are similar in the caudate and putamen of MA users (Kalasinsky et al., 2001), it is unlikely that the intraregional difference is due to drug pharmacokinetic characteristics between the two striatal subdivisions, but it might be explained by differences in dopamine uptake, storage or release mechanisms.
Since some of the MA subjects had caudate dopamine levels falling within the range observed in Parkinson’s disease (Fig. 2), brain function subserved by the caudate dopamine system might be significantly compromised, especially in the two MA users having very low caudate dopamine concentrations (0.22 and 0.38 ng/mg tissue). As the caudate nucleus is involved in aspects of cognitive behaviour (Alexander et al., 1986; Yeterian and Pandya, 1994), dopamine reduction in this striatal subdivision might explain the clinical finding of cognitive difficulties in chronic MA users (Kramer et al., 1967; McKetin and Mattick, 1997; Rogers et al., 1999; Simon et al., 2000; Chang et al., 2002; Paulus et al., 2002). Cognitive problems in some MA users appear to be sufficiently severe to decrease retention in a drug rehabilitation programme (personal communication, R. Rawson, Matrix, Los Angeles, CA, USA). Our post-mortem brain data further suggest the possibility that dopamine substitution medication (e.g. levodopa) might ameliorate cognitive impairment during MA abstinence and thereby increase retention in a treatment programme. However, consideration also has to be given to the possibility that exposure to dopamine-replenishing therapy following recent MA exposure might enhance the neurotoxic and rewarding effects of any residual MA.
In conclusion, we find that dopamine levels in the putamen of human MA users do not fall within the range observed in idiopathic Parkinson’s disease, an observation which explains the absence of reports of overt parkinsonism as a feature of MA exposure in humans. However, the more marked reduction of the neurotransmitter in a striatal subdivision subserving aspects of cognition could explain in part the presence of cognitive problems in MA users. To date, most work on the harmful effects of MA on the human brain has been limited to the question whether MA causes an actual lesion of dopamine nerve terminals in humans, an issue which we believe will not be resolvable because of the lack of stability of the components of the dopamine nerve terminal markers which are used to assess neuronal integrity. However, given the severity of the striatal dopamine reduction in some MA users, from a public health perspective attention must also be devoted to the clinical consequences of brain dopamine depletion, irrespective of whether this abnormality is associated with physical loss of the nerve ending.
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The opinions and assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting views of the United States Department of Army or Department of Defense.
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Acknowledgement |
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This study was supported by US NIH NIDA DA07182 to S.J.K.
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References |
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