Download Why is parkinsonism not a feature of human methamphetamine users?

DOI: 10.1093/brain/awh046
Brain (2004), 127, 363±370
Why is parkinsonism not a feature of human
methamphetamine users?
Anna Moszczynska,1 Paul Fitzmaurice,1 Lee Ang,2 Kathryn S. Kalasinsky,3 Gregory A. Schmunk,4
Frank J. Peretti,5 Sally S. Aiken,6 Dennis J. Wickham7 and Stephen J. Kish1
1Human
Neurochemical Pathology Laboratory, Centre for
Addiction and Mental Health, Toronto, 2Division of
Neuropathology, London Health Science Centre, University
of Western Ontario, London, Ontario, Canada, 3Division of
Forensic Toxicology, Of®ce of the Armed Forces Medical
Examiner, Division of Forensic Toxicology, Armed Forces
Institute of Pathology, Rockville, MD, 4Santa Clara County
Medical Examiner-Coroner, San Jose, CA, 5Arkansas State
Crime Laboratory, 3 Natural Resources Drive, Little Rock,
AR, 6Spokane County Medical Examiner's Of®ce, Spokane
and 7Clark County Of®ce of the Medical Examiner,
Vancouver, WA, USA
Summary
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 de®ciency 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
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: [email protected]
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 suf®ciently 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.
Keywords: Parkinson's disease; caudate; putamen; methamphetamine; cognition
Abbreviations: MA = methamphetamine
Received July 8, 2003. Revised September 23, 2003. Accepted September 26, 2003. Advanced Access publication November 25, 2003
Introduction
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 suf®cient, 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
Brain Vol. 127 No. 2 ã Guarantors of Brain 2003; all rights reserved
364
A. Moszczynska et al.
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 ®ndings 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
de®ciency 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 con®rmed 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 ®nding 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.
Patients and methods
Subjects and brain material
Post-mortem brain material from MA users (n = 20) and
control subjects (n = 14) was obtained from medical examiner
of®ces 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., 1996a; Kalasinsky et al., 2001; Tong et al.,
2003). The control and MA groups were matched with respect
to age (controls, 34.2 6 3.5 years; MA users, 31.4 6 1.9
years), post-mortem interval between death and autopsy
(controls, 13.9 6 1.6 h; MA users, 14.6 6 1.5 h; P > 0.1,
Student's two-tailed t-test) and sex (controls, 11 males, three
females; MA users, 15 males, ®ve females; P > 0.1, Yates'
corrected c2 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).
At autopsy, one-half of the brain was ®xed in formalin
®xative 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 signi®cant
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
Parkinsonism in methamphetamine users
365
Table 1 Toxicology and brain pathology summaries for human methamphetamine users
Casea
Toxicology
Drug/metabolite
Blood
(mg/l)
Brain
nmol/g tissue
Molar sum
nmol/g tissue
Hair
Brain neuropathology
12.50
0.320
0.270
0.090
0.262
0.059
0.325
189
3.48
7.97
0.44
10.8
2.14
11.9
192
NA
No abnormalities
NA
No abnormalities
12.9
NA
No abnormalities
422
Methamphetamine
Amphetamine
Methamphetamine
Amphetamine
Methamphetamine
Amphetamine
Methamphetamine
12.9
NA
424
Amphetamine
Methamphetamine
0.044
7.000
1.04
129
Slightly pale substantia nigra
but no evidence of cell loss
Positive
Slightly pale substantia nigra
but no evidence of cell loss
374
375
407
442
448
510
523
590
524
447
677
767
867
879
559
678
726
478
Amphetamine
Methamphetamine
Amphetamine
Methamphetamine
Amphetamine
Methamphetamine
Amphetamine
Methamphetamine
Amphetamine
Methamphetamine
Amphetamine
Methamphetamine
Amphetamine
Methamphetamine
Amphetamine
Methamphetamine
Amphetamine
Methamphetamine
Amphetamine
Methamphetamine
Amphetamine
Methamphetamine
Amphetamine
Methamphetamine
Amphetamine
Morphine
Methamphetamine
Amphetamine
Cocaine/BZE
Methamphetamine
Amphetamine
Morphine
Methamphetamine
Amphetamine
Cocaine/BZE
0.034
0.217
0.034
0.835
0.080
1.743
0.078
0.664
0.072
0.220
0.043
0.714
0.067
0.176
0.029
0.180
ND
3.000
ND
0.200
0.060
0.370
ND
0.260
ND
0.090
1.400
ND
ND/ND
ND
0.680
Positive
0.140
ND
4.28/5.83
1.26
2.41
0.37
13.3
0.52
47.5
1.85
8.71
0.52
5.90
0.22
19.0
0.81
31.3
2.22
10.9
4.73
296
23.5
4.77
2.37
9.12
1.70
13.4
1.41
0.36
67.3
4.13
ND/ND
9.80
53.5
0.31
7.63
ND
14.9/13.0
8.41
130
2.78
13.8
49.3
9.23
6.12
19.8
33.5
15.6
319
7.14
10.8
14.8
71.4
63.3
7.63
Positive
Positive
Positive
Positive
Positive
Positive
Positive
Positive
Positive
Positive
Positive
Positive
Positive
Positive
Positive
NA
Positive
Positive
Positive
Positive
Positive
Positive
Positive
Positive
Positive
Positive
Positive
Positive/positive
NA
Positive
Positive
Positive/ND
No abnormalities
No abnormalities
No abnormalities
No abnormalities
No abnormalities
No abnormalities
No abnormalities
No abnormalities
No abnormalities
No abnormalities
Prominent gliosis in putamen
No abnormalities
No abnormalities
No abnormalities
Mild gliosis in substantia nigra
BZE = benzoylecgonine; NA = not available for analysis; ND = not detected. aAmong the 20 MA users, the ®rst 12 cases were originally
described in Wilson et al. (1996a).
478. For the dopamine and homovanillic acid assays, samples
(20±50 mg wet weight) were examined by HPLC (highpressure 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.
F
M
M
M
M
M
M
M
F
M
M
F
M
M
F
M
M
M
F
M
374
375
407
422
424
442
448
510
523
590
524
447
677
767
867
879
559b
678b
726b
478b
White
White
White
White
White
White
White
White
White
White
White
White
White
Black
White
White
White
White
White
White
Race
30
15
37
20
44
29
35
39
26
26
33
34
36
22
42
20
28
39
28
44
Age
(years)
6
21
4.5
21
24
11
22
23
12
15
7
14
5
16
10
21
14
19
4
23
PI
(h)
>1
>1
8
3±4
15
>8
>1
15
>1
10
18
10
>10
8
>20
1
16
23
10
10
Duration of MA
use (years)
Chronic user, probably daily
Line every 2 weeks
Daily, 1/4 g per day
Unknown
Every few days
Unknown
Binges for 3±4 days,
a few weeks apart;
2±3 days MA, 1 day heroin
MA unknown, cocaine unknown
MA unknown, heroin unknown
MA unknown, cocaine 2±3 times
per week
Daily, limited only by funds
$10 per day, daily
~ once per month
75 cc/hit daily, if money available
3±4 times per week
Unknown
Binges for 2±3 days, 7±10 days apart
Daily, 4±5 hits per day
Every 2 weeks
1±2 lines per day
Amount/pattern of recent
MA use
I.v.
I.v.
Oral, nasal
Smoking, oral,
nasal
Oral, nasal
Nasal
Nasal
Unknown
Oral, i.v.
Unknown
I.v.
Nasal
Nasal, i.v.
i.v.
Oral, nasal
Oral
I.v., smoking
I.v.
I.v.
Nasal
Route of
administration
Acute MA toxicity
Acute multiple drug toxicity
Acute multiple drug toxicity
Acute MA toxicity
Acute MA toxicity
Acute MA toxicity
Acute MA toxicity
Acute MA toxicity
Gunshot wound to chest
Gunshot wound to chest
Acute MA toxicity
Coronary artery
atherosclerosis
Coronary artery
atherosclerosis
Acute MA toxicity
Acute MA toxicity
Acute aortic dissection
Acute MA toxicity
Acute MA toxicity
Acute MA toxicity
Acute multiple drug toxicity
Suspected/known cause of death
<72
<72
~1
<72
<72
<72
<72
<12
<72
<72
~6
~16
12
3
~6
~1
~3
<72
<12
8
Estimated interval since
last administration (h)
M = male; F = female; PI = post-mortem interval; MA = methamphetamine. For cases 523, 590 and 677, MA toxicity was considered to be a possible contributing factor to the cause
of death. aAmong the 20 MA users, the ®rst 12 cases were originally described in Wilson et al. (1996a); bMA users who tested positive for other drugs in addition to MA in blood,
brain and/or hair.
Sex
Casea
Table 2 Subject information and drug histories of 20 chronic methamphetamine users
366
A. Moszczynska et al.
Parkinsonism in methamphetamine users
367
Fig. 2 Individual caudate and putamen levels in control subjects,
methamphetamine (MA) users and patients with Parkinson's
disease (PD). Parkinson's disease values are from Wilson et al.
(1996b). Note that some MA users have dopamine levels which
fall within the range of levels in patients with Parkinson's disease
in the caudate nucleus, but not in the putamen.
Fig. 1 Individual caudate and putamen dopamine and
homovanillic acid levels in 14 control subjects and in 20
methamphetamine (MA) users. Dopamine levels are reported
separately for the 12 MA users from our earlier study (Wilson
et al., 1996a) and for the eight new MA users of the present
investigation. Note that the caudate dopamine but not
homovanillic acid values for most of the MA users fall below the
lower limit of the control range. The letters `a' and `b' denote two
MA users with nearly total loss of striatal dopamine levels but
who have above-normal (b) or normal (a) striatal levels of
homovanillic acid, the major dopamine metabolite in human brain.
Dopamine, but not homovanillic acid, levels in the 20 MA users
were signi®cantly different from values in control subjects (P <
0.0001; Student's two-tailed t-test).
Results
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.,
1996a) 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
signi®cantly 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).
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 signi®cantly 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.
368
A. Moszczynska et al.
Table 3 Levels of dopamine and its metabolites in the striatum of control subjects (n = 14), methamphetamine (MA) users
(n = 20) and patients with Parkinson's disease (n = 12)
Caudate
Controls
MA users
Parkinson's disease group
Putamen
Controls
MA users
Parkinson's disease group
Dopamine
DOPAC
HVA
3-MT
7.03 6 0.50
2.76 6 0.31* (±61%)
1.24 6 0.27* (±82%)
0.41 6 0.05
0.36 6 0.04 (±12%)
0.16 6 0.03 (±61%)
6.78 6 0.66
7.33 6 0.65 (+8%)
3.19 6 0.53 (±53%)
1.99 6 0.16
1.96 6 0.16 (±2%)
1.06 6 0.22 (±47%)
7.61 6 0.61
3.78 6 0.47* (±50%)
0.21 6 0.05* (±97%)
0.52 6 0.07
0.44 6 0.05 (±15%)
0.07 6 0.01* (±87%)
10.3 6 0.9
10.5 6 0.9 (+2%)
3.09 6 0.43* (±70%)
2.51 6 0.19
2.40 6 0.15 (+4%)
0.35 6 0.08* (±86%)
Data (ng/mg tissue) are mean 6 SEM. Dopamine and metabolite levels in 12 of the MA users (Wilson et al., 1996a) and in the patients
with Parkinson's disease (Wilson et al., 1996b) have been published previously. (Reproduced with permission from Lippincott, Williams
& Wilkins and Nature Publishing Group, respectively). *Signi®cantly different from the controls (P < 0.05; Student's two-tailed t-test).
DOPAC = 3,4-dihydroxyphenylacetic acid; HVA = homovanillic acid; 3-MT = 3-methoxytyramine.
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 signi®cant 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 signi®cant 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 ®ndings (Adolfsson et al., 1979; Spokes, 1979).
Discussion
Our major ®nding 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 ®nding 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 ®ve 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 suf®cient 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 ®rst (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 FuenteFernaÂndez 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
Parkinsonism in methamphetamine users
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 suf®cient
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 suf®ciently 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
369
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 ®ndings 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 signi®cantly 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 ®nding of cognitive dif®culties 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 suf®ciently 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 ®nd 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
370
A. Moszczynska et al.
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.
Disclaimer
The opinions and assertions contained herein are the private
views of the authors and are not to be construed as of®cial or
as re¯ecting views of the United States Department of Army
or Department of Defense.
Acknowledgement
This study was supported by US NIH NIDA DA07182 to
S.J.K.
References
Adolfsson R, Gottfries CG, Roos BE, Winblad B. Post-mortem distribution
of dopamine and homovanillic acid in human brain, variations related to
age, and a review of the literature. J Neural Transm 1979; 45: 81±105.
Alexander GE, DeLong MR, Strick PL. Parallel organization of functionally
segregated circuits linking basal ganglia and cortex. Annu Rev Neurosci
1986; 9: 357±81.
Bernheimer H, Birkmayer W, Hornykiewicz O, Jellinger K, Seitelberger F.
Brain dopamine and the syndromes of Parkinson and Huntington. Clinical,
morphological and neurochemical correlations. J Neurol Sci 1973; 20:
415±55.
Chang L, Ernst T, Speck O, Patel H, DeSilva M, Leonido-Yee M, et al.
Perfusion MRI and computerized cognitive test abnormalities in abstinent
methamphetamine users. Psychiatry Res 2002; 114: 65±79.
De La Fuente-FernaÂndez R, Furtado S, Guttman M, Furukawa Y, Lee CS,
et al. VMAT2 binding is elevated in dopa-responsive dystonia: visualizing
empty vesicles by PET. Synapse 2003; 49: 20±28.
Fibiger HC, MoGeer EG. Effect of acute and chronic methamphetamine
treatment on tyrosine hydroxylase activity in brain and adrenal medulla.
Eur J Pharmacol 1971; 16: 176±80.
Frey K, Kilbourn M, Robinson T. Reduced striatal vesicular monoamine
transporters after neurotoxic but not after behaviorally-sensitizing doses
of methamphetamine. Eur J Pharmacol 1997; 334: 273±9.
Harvey DC, Lacan G, Melegan WP. Regional heterogeneity of dopaminergic
de®cits in vervet monkey striatum and substantia nigra after
methamphetamine exposure. Exp Brain Res 2000a; 133: 349±58.
Harvey DC, Lacan G, Tanious SP, Melega WP. Recovery from
methamphetamine induced long-term nigrostriatal dopaminergic de®cits
without substantia nigra cell loss. Brain Res 2000b; 871: 259±70.
Hornykiewicz O, Kish SJ. Biochemical pathophysiology of Parkinson's
disease. Adv Neurol 1986; 45: 19±34.
Kalasinsky KS, Bosy TZ, Schmunk GA, Reiber G, Anthony RM, Furukawa
Y, et al. Regional distribution of methamphetamine in autopsied brain of
chronic human methamphetamine users. Forensic Sci Int 2001; 116: 163±9.
Kish SJ, Shannak K, Hornykiewicz O. Uneven pattern of dopamine loss in
the striatum of patients with idiopathic Parkinson's disease.
Pathophysiologic and clinical implications. New Engl J Med 1988; 318:
876±80.
Kramer JC, Fischman VS, Little®eld DC. Amphetamine abuse. Pattern and
effects of high doses taken intravenously. JAMA 1967; 201: 305±9.
Laruelle M, Abi-Dargham A, van Dyck CH, Rosenblatt W, Zea-Ponce Y,
Zoghbi SS, et al. SPECT imaging of striatal dopamine release after
amphetamine challenge. J Nucl Med 1995; 36: 1182±90.
Linder JC, Young SJ, Groves PM. Electron microscopic evidence for
neurotoxicity in the basal ganglia. Neurochem Int 1995; 26: 195±202.
Lundh H, Tunving K. An extrapyramidal choreiform syndrome caused by
amphetamine addiction. J Neurol Neurosurg Psychiatry 1981; 44: 728±30.
McKetin R, Mattick RP. Attention and memory in illicit amphetamine users.
Drug Alcohol Depend 1997; 48: 235±42.
Paulus MP, Hozack NE, Zauscher BE, Frank L, Brown GG, Braff DL, et al.
Behavioral and functional neuroimaging evidence for prefrontal
dysfunction in methamphetamine-dependent subjects. Neuropsychopharmacology 2002; 26: 53±63.
Ricaurte GA, McCann UD. Neurotoxic amphetamine analogues: effects in
monkeys and implications for humans. Ann NY Acad Sci 1992; 648: 371±
82.
Riddle EL, Topham MK, Haycock JW, Hanson GR, Fleckenstein AE.
Differential traf®cking of the vesicular monoamine transporter-2 by
methamphetamine and cocaine. Eur J Pharmacol 2002; 449: 71±4.
Rogers RD, Everitt BJ, Baldacchino A, Blackshaw AJ, Swainson R,
Wynne K, et al. Dissociable de®cits in the decision-making cognition of
chronic amphetamine abusers, opiate abusers, patients with focal damage
to prefrontal cortex, and tryptophan-depleted normal volunteers: evidence
for monaminergic mechanisms. Neuropsychopharmacology 1999; 20:
322±39.
Seiden LS, Fischman MW, Schuster CR. Long-term methamphetamine
induced changes in brain catecholamines in tolerant rhesus monkeys.
Drug Alcohol Depend 1976; 1: 215±9.
Simon SL, Domier C, Carnell J, Brethen P, Rawson R, Ling W. Cognitive
impairment in individuals currently using methamphetamine. Am J Addict
2000; 9: 222±31.
Sonsalla PK, Jochnowitz ND, Zeevalk GD, Oostveen JA, Hall ED.
Treatment of mice with methamphetamine produces cell loss in the
substantia nigra. Brain Res 1996; 738: 172±5.
Spokes EG. An analysis of factors in¯uencing measurements of dopamine,
noradrenaline, glutamate decarboxylase and choline acetylase in human
post-mortem brain tissue. Brain 1979; 102: 333±46.
Tong J, Ross BM, Schmunk GA, Peretti FJ, Kalasinsky KS, Furukawa Y,
et al. Decreased striatal dopamine D1 receptor-stimulated adenylyl cyclase
activity in human methamphetamine users. Am J Psychiatry 2003; 160:
896±903.
Vander Borght T, Kilbourn M, Desmond T, Kuhl DE, Frey KA. The
vesicular monoamine transporter is not regulated by dopaminergic drug
treatments. Eur J Pharmacol 1995; 294: 577±83.
Wilson JM, Kish SJ. The vesicular monoamine transporter, in contrast to the
dopamine transporter, is not altered by chronic cocaine self-administration
in the rat. J Neurosci 1996; 16: 3507±10.
Wilson JM, Nobrega JN, Carroll ME, Niznik HB, Shannak K, Lac ST, et al.
Heterogeneous subregional binding patterns of 3H-WIN 35,428 and 3HGBR 12,935 are differentially regulated by chronic cocaine selfadministration. J Neurosci 1994; 14: 2966±79.
Wilson JM, Kalasinsky KS, Levey AI, Bergeron C, Reiber G, Anthony RM,
et al. Striatal dopamine nerve terminal markers in human, chronic
methamphetamine users. Nat Med 1996a; 2: 699±703.
Wilson JM, Levey AI, Rajput A, Ang L, Guttman M, Shannak K, et al.
Differential changes in neurochemical markers of striatal dopamine nerve
terminals in idiopathic Parkinson's disease. Neurology 1996b; 47: 718±26.
Wise RA. Neurobiology of addiction. Curr Opin Neurobiol 1996; 6: 243±51.
Woolverton WL, Ricaurte GA, Forno LS, Seiden LS. Long-term effects of
chronic methamphetamine administration in rhesus monkeys. Brain Res
1989; 486: 73±8.
Yeterian EH, Pandya DN. Laminar origin of striatal and thalamic projections
of the prefrontal cortex in rhesus monkeys. Exp Brain Res 1994; 99: 383±
98.