N e u ro l o g i c Ma n i f e s t a t i o n s o f

C h ro n i c M e t h a m p h e t a m i n e A b u s e
Daniel E. Rusyniak, MD

KEYWORDS
 Methamphetamine abuse  Psychosis  Parkinson’s  Choreoathetoid  Punding
 Formication

COMMENTARY ON METHAMPHETAMINE ABUSE FOR PSYCHIATRIC PRACTICE

Every decade seems to have its own unique drug problem. The 1970s had
hallucinogens, the 1980s had crack cocaine, the 1990s had designer drugs, the
2000s had methamphetamine (Meth), and in the 2010s we are dealing with the
scourge of prescription drug abuse. While each of these drug epidemics has
distinctive problems and history, the one with perhaps the greatest impact on
the practice of Psychiatry is Meth. By increasing the extracellular concentrations
of dopamine while slowly damaging the dopaminergic neurotransmission, Meth
is a powerfully addictive drug whose chronic use preferentially causes psychiatric
complications. Chronic Meth users have deficits in memory and executive func-
tioning as well as higher rates of anxiety, depression, and most notably psychosis.
It is because of addiction and chronic psychosis from Meth abuse that the
Meth user is most likely to come to the attention of the practicing Psychiatrist/
Psychologist.
Understanding the chronic neurologic manifestations of Meth abuse will better
arm practitioners with the diagnostic and therapeutic tools needed to make the
Meth epidemic one of historical interest only.

This article originally appeared in the August 2011 issue of Neurologic Clinics (Volume 29,
Number 3).
This work was supported by USPHS grants DA020484 and DA026867.
The author has nothing to disclose.
Department of Emergency Medicine, Indiana University School of Medicine, 1050 Wishard
Boulevard, Room 2200, Indianapolis, IN 46202, USA
E-mail address: [email protected]

Psychiatr Clin N Am - (2013) -–-

http://dx.doi.org/10.1016/j.psc.2013.02.005 psych.theclinics.com
0193-953X/13/$ – see front matter Ó 2013 Elsevier Inc. All rights reserved.
2 Rusyniak

KEY POINTS
 Methamphetamine abuse can cause a chronic psychosis similar to schizophrenia.
 A common manifestation of Meth psychosis is delusional parasitosis.
 Repetitive non-goal directed behaviors (punding) can result from chronic Meth abuse.
 As with other stimulants, Meth abuse can cause choreoathetoid movements.
 Dopamine receptor antagonists are the most effective treatments for Meth’s chronic psy-
chiatric manifestations.

The current epidemic of methamphetamine abuse in the United States is not surpris-
ing. Methamphetamine can be produced from a wide variety of starting materials and
methods. This fact is in contrast to cocaine, which is only commercially grown in South
America, must be extracted from the plant, converted to its free-base form, shipped
overseas (escaping detection by the Drug Enforcement Administration [DEA]), and
then distributed, typically through gangs, to clients on the street.1 Based on the attrac-
tiveness of methamphetamine to both users and its manufacturers, it is only surprising
that the current outbreak of methamphetamine abuse in the United States took so long
to reach epidemic proportions.
In 1893, methamphetamine was synthesized from ephedrine (derived from the plant
Ephedra sinica) by Nagai Nagayoshi.2,3 Eventually, a synthetic version would find its
way to the consumer market as an over-the-counter (OTC) nasal decongestant and
a brochodilator.4–6 Far from an OTC drug today, the Food and Drug Administration
(FDA) has characterized methamphetamine as a schedule II drug, which can only
be prescribed for attention-deficit/hyperactivity disorder, extreme obesity, or to treat
narcolepsy.
With the world on the brink of war, and its toxic effects not yet well described, the
clinical effects of methamphetamine were thought to be ideal for the soldier in combat:
increased alertness and aggression, plus decreased hunger and need to sleep. In
World War II, the United States, Germany, and Japan all readily employed it with their
troops5,7; it has been estimated that the United States alone distributed 200 million
tablets to troops.4 After the war, Japan experienced widespread abuse as army sur-
pluses flooded the market. Although methamphetamine usage in Japan declined in
the 1960s, it resurged in the 1970s and continues to be a problem today.7,8 In 1954,
at the height of its first epidemic, there were an estimated 2 million methamphetamine
users in Japan. Although still highest in Asia, methamphetamine abuse has become a
worldwide epidemic. A 2008 United Nations Office on Drugs and Crime Reports esti-
mated 25 million abusers of amphetamines worldwide, exceeding the number of users
for both cocaine (14 million) and heroin (11 million).9
After World War II, many US soldiers and civilians continued to use methamphet-
amine, which at that time was available by prescription in an injectable form. When
Abbott and Burroughs-Wellcome withdrew their injectable formulations in the early
1960s, an opportunity arose for the illegal manufacturing and distribution of metham-
phetamine.4 West Coast motorcycle gangs, such as the infamous Hells Angels,
quickly seized on this opportunity, and by the 1970s gangs were largely responsible
for the manufacturing, distribution, and use of methamphetamine in the United States.
It was from the transportation of methamphetamine in the crankshafts of motorcycles
that it got its street name of crank.10 At that time, methamphetamine was produced
primarily from the precursors phenyl-2-propanone and methylamine (the P-2-P
 Neurologic Manifestations of Chronic Methamphetamine Abuse 3

method).5,8 The combination of a crack down by the Department of Justice on West

Coast gangs and the Controlled Substances Act of 1970, which made the ingredients
of the P-2-P method controlled substances, resulted in a shift in the manufacturing
and distribution of methamphetamine to small makeshift laboratories.
In the 1980s, a crystalline form of methamphetamine that could be smoked, called
ice, began to be imported from Asia to Hawaii.10 This highly addictive form of meth-
amphetamine quickly found its way to the US West Coast and slowly began working
it way east11; by 1990, methamphetamine had replaced cocaine as the stimulant of
choice among drug users in many areas of California.12 What would ultimately propel
methamphetamine abuse to the forefront of the DEA war on drugs, and to the front
pages of mainstream magazines and newspapers, was the rural meth lab. Unlike
the cultivation of the coca leaf or opium poppy, the manufacture of methamphetamine
is not limited by geographic location. By using OTC ephedrine and pseudoephedrine
as the main precursors, making methamphetamine became simpler and more effi-
cient. Methamphetamine laboratories manufacturing relatively pure crystal metham-
phetamine began to pop up across the Midwest; with the small investment of
approximately $200, a methamphetamine cook could easily earn between $2000
and $5000.13 Despite the relative simplicity of its synthesis (by traditional chemistry
standards), cooking methamphetamine requires heating volatile hydrocarbons.
When done by those without chemistry backgrounds and, as it often is, in poorly venti-
lated areas, fires and explosions can ensue. In fact, many methamphetamine labora-
tories have been discovered only after they have caught fire or exploded.14,15 In an
attempt to decrease the growing methamphetamine crisis, Congress passed the
2005 Combat Methamphetamine Epidemic Act, which limited access to pseudoephe-
drine. This limitation shut down vast numbers of small and medium-sized laboratories,
resulting in a decline in the number of admissions for methamphetamine abuse in
2006—the first time in 10 years.10
With increasing numbers of large-scale manufacturers in Mexico, and other parts of
the world, methamphetamine continues to be a significant problem in the United
States. Because it has its most devastating effects on the central nervous system
(CNS), it is important for neurologists to recognize signs of abuse and the many neuro-
logic problems caused by methamphetamine. This article should help the practicing
neurologist recognize and treat these patients, improving their chance to function
drug free in society.

PHARMACOLOGY AND TOXICOLOGY

Both the acute and chronic neurologic effects of methamphetamine are the result of its
pharmacology and toxicology. The acute effects of methamphetamine are those of the
flight-or-fight response: increased heart rate and blood pressure, vasoconstriction,
bronchodilation, and hyperglycemia.16 In addition, methamphetamine causes CNS
stimulation, which may result in euphoria, increased energy and alertness, intense
curiosity and emotions, decreased anxiety, and enhanced self-esteem.16
Whether snorted, smoked, or injected, methamphetamine rapidly crosses the blood
brain barrier where it can exert powerful effects on several neurochemical systems.
Because of its lipophilic nature, methamphetamine has increased CNS penetration
and is more potent than its parent compound, amphetamine.17 Once in the CNS, it
binds to dopamine, norepinephrine, and, to a lesser extent, serotonin transporters
located on neuronal cell membranes; at higher concentrations, methamphetamine
may also cross the cell membranes independent of transporter binding. Once bound,
transporters pump methamphetamine into the neuron where it is taken up by vesicular
4 Rusyniak

monoamine transporters. The high pKa (pKa 510.1) of methamphetamine18 disrupts

the proton gradient, which normally keeps monoamines within the vesicle. This causes
monamines to leave the vesicle and accumulate in the cytoplasm where they are
reverse transported out of the cell through the same transporters that pumped meth-
amphetamine into the cell.19,20
In addition to increasing their release, methamphetamine also decreases mono-
amine reuptake and enzyme degradation.21 The net result is that methamphetamine
causes a rapid and sustained increase in the extracellular concentrations of mono-
amines. One of the reasons methamphetamine has exceeded cocaine in worldwide
usage is that it has a longer half-life (12 hours compared with 90 minutes) and, there-
fore, a much longer duration of action,22 allowing the drug addict to have a longer and
more sustained high. Although many receptors have been implicated in mediating the
complex physiologic responses to amphetamines, the underlying clinical effects asso-
ciated with methamphetamine use involve excessive stimulation of the sympathetic
nervous system. It is the rapid and sustained activation of this system that is respon-
sible for methamphetamine’s recognizable adrenergic toxidrome: tachycardia, hyper-
tension, mydriasis, diaphoresis, and psychomotor agitation. In addition, it is the
prolonged release of central monoamines and activation of the sympathetic nervous
system that is responsible for most of the acute neurologic complications associated
with methamphetamine use (eg, strokes, seizures, agitation, and hyperthermia).20,23,24
The sustained and repeated release of central monoamines is also largely to blame for
the chronic neurologic effects of methamphetamine abuse.20
With repeated use in both humans and experimental animal models, methamphet-
amine depletes the brain’s stores of dopamine and damages dopamine and seroto-
nin nerve terminals. This may be a contributing factor to methamphetamine’s high
abuse potential; without the drug, users may have an impaired ability to experience
pleasure (anhedonia), slipping into a deep depression. Based on current evidence,
the complex mechanisms by which methamphetamine damages neurons involves in-
creases in intracellular and extracellular concentrations of dopamine, which sets off a
cascade of events, including oxidative stress, neuroinflammation, and excitatory
neurotoxicity.25
It has also been shown that hyperthermia, a known complication of methamphet-
amine use, exacerbates this neurotoxicity.25 Although this article focuses predomi-
nantly on methamphetamine, the similarities in the pharmacology, toxicology, and
clinical effects between methamphetamine, amphetamine, and other stimulants (eg,
cocaine and 3,4-methylenedioxmethamphemine [ecstasy]) makes the following dis-
cussions on neurologic complications largely translatable to other CNS stimulants.

NEUROPSYCHIATRIC COMPLICATIONS

Dopamine and serotonin neurons project widely throughout the CNS and are known to
influence a variety of behaviors and functions. It should not be surprising that chronic
methamphetamine abuse, which can damage dopamine and serotonin nerve termi-
nals, is associated with deficits in neuropsychological testing. It has been estimated
that 40% of methamphetamine users have abnormalities on neuropsychiatric tests.26
In a well-done meta-analysis of studies examining the effects of chronic methamphet-
amine abuse on neuropsychiatric function, the most frequently reported deficits
involve episodic memory, executive function, and motor function.27 Of these, the
greatest impairments are in episodic memory; this form of memory is thought to be
the most susceptible to neuronal dysfunction.28 As episodic memory allows one to
consciously re-experience past events,28 methamphetamine users who, by virtue of
 Neurologic Manifestations of Chronic Methamphetamine Abuse 5

damaged episodic memory, forget past mistakes associated with their drug usage
may be doomed to repeat them.
Another effect of chronic methamphetamine abuse is damage to executive function.
With impaired executive function, methamphetamine abusers are likely to be distract-
ible, impulsive, act inappropriately despite social cues to the contrary, and lack goals.
In studies, patients addicted to methamphetamine prefer smaller, immediate rewards
over larger, delayed rewards.29 To overcome that wish for immediate rewards, addicts
must activate the higher cognitive control systems, which, by virtue of their damaged
executive system, is not an easy task for methamphetamine-dependent individuals.29
Another consequence of impaired executive function, demonstrated in patients with
damaged frontal lobes, is perseveration: the inability to change behavior even when
the current behavior becomes destructive.30 It is easy to imagine how damage to
episodic memory and executive function might result in continued methamphetamine
abuse despite the physical and emotional toil it reaps on users and their families. By
chemically converting users into a modern Phineas Gage, methamphetamine exerts a
powerful influence on behavior and decision making. Although not specifically tested,
it is also possible that persons with damaged episodic memory and executive func-
tion, before using drugs, may be more susceptible to drug abuse and addiction and
may have a greater risk for relapse.
Although studies show motor deficits in chronic methamphetamine abusers, these
deficits do not typically involve gross movements, as with Parkinson’s disease, but
rather affect fine-motor dexterity (eg, placing pegs in a pegboard). These deficits
would seem to be in line with studies showing that damage to dopamine terminals
is more prevalent in the caudate (more involved in cognitive motor activities) then
the putamen (more involved in pure motor activities) regions of the basal ganglia.31,32
Along with neuropsychiatric deficits, methamphetamine abusers suffer from mental
illnesses, with anxiety,33–35 depression,27,35–37 and psychosis22,27,37,38 being the most
commonly reported. Of these, the neurologist is perhaps most likely to be confronted
with patients suffering from psychosis.
After World War II, Japan suffered not only from a methamphetamine epidemic
but also from an epidemic of drug-induced psychosis.39–42 It has been estimated
that at its height (between 1945–1955), there were as many as 200,000 persons
in Japan with drug-induced psychosis.42 Although much of the research on
methamphetamine-induced psychosis has been conducted in Japan, similar reports
have been reported in the United States and other countries.43,44
The symptoms of methamphetamine-induced psychosis are similar to those seen
with schizophrenia; the most frequently reported symptoms are delusions of persecu-
tion and auditory hallucinations.39–42,44–46 Although not as commonly reported, nega-
tive symptoms (eg, poverty of speech and psychomotor retardation) have also been
seen with methamphetamine-induced psychosis.44 In addition to a similar symptom-
atology, both schizophrenia and amphetamine-evoked psychosis can be effectively
treated with dopamine antagonists.47 The similarities between these disorders have
lead many researchers to use amphetamines to model schizophrenia in laboratory
animals.42,48
The development of psychosis is more readily seen in people using higher metham-
phetamine concentrations for prolonged periods of time.39,45,46,49,50 The reported
doses required, duration of abuse, and onset of symptoms are highly variable, as is
the duration of psychotic symptoms (from 1 week to an indefinite duration).16,51
Even if symptoms abate with abstinence, they can reemerge with repeat usage or un-
der stressful situations.40 One of the debates associated with psychosis and metham-
phetamine is whether it is the result of methamphetamine-induced neurotoxicity
6 Rusyniak

(ie, altered dopaminergic neurotransmission) or whether the 2 disorders coexist so

that persons with mental illness are more likely to abuse methamphetamine (so-called
dual diagnosis). The later seems to be supported by data showing that persons with
predispositions to mental illness, such as strong family histories, are significantly
more likely to develop methamphetamine-associated psychosis.49,50 Furthermore,
schizophrenics given low doses of methamphetamine will have exacerbations of their
symptoms.52 Therefore, it has been suggested that in susceptible individuals metham-
phetamine abuse may be a trigger that unmasks schizophrenia/psychosis.53 Others
have suggested that persons with schizophrenia/psychosis seek out illicit drugs as
a form of self-treatment,54 or, as recent data suggests, that neuronal deficits underly-
ing the development of schizophrenia make individuals more prone to develop drug
addiction.55 Either way, it is clear that methamphetamine abuse can result in the
development of acute and, in some cases, chronic psychosis and that practicing neu-
rologists should be aware of this association. With the significant increase in the num-
ber of persons abusing methamphetamine, it remains to be seen if there will be a
concomitant rise in patients requiring treatment for psychosis.

FORMICATION

One interesting aspect of chronic methamphetamine psychosis is the delusion of

parasitosis or formication (the thought that one is infested with and being bitten by
bugs).43,46,56–59 Commonly known as meth mites, this is a frequent complaint in heavy
daily users of methamphetamine. In studies of patients admitted to drug treatment
facilities for methamphetamine abuse, approximately 40% of the patients report
having had formication43,46; if the patients had ever suffered from psychosis, then
the percentage of persons experiencing formication rose to 70%.46 It is interesting
that similar symptoms have been reported in animals chronically administered
d-amphetamine.57,58,60 These delusions may cause patients to repetitively pick at
their skin resulting in scarring of their face and extremities.59,61 Constant picking com-
bined with neglect of hygiene also increase the risk for developing skin infections,
including abscesses and cellulitis from methicillin-resistant Staphylococcus aureus.62
Along with abstinence from drug usage, dopamine antagonists have been shown to
help patients with drug-induced formication.57 Although formication is not unique to
methamphetamine (it has also been reported with cocaine63 and schizophrenia57),
the finding of multiple pockmarks on a patient’s face and extremities, or recurrent
skin abscesses in these areas, should increase a clinician’s suspicion of chronic meth-
amphetamine abuse.

STEREOTYPY OR PUNDING

One of the unique manifestations of methamphetamine abuse is the development of

punding. The word punding is Swedish for “blockhead.”64,65 It was first coined by
Rylander, who learned of the slang term from chronic amphetamine and phenmetra-
zine (another stimulant abused in Sweden in the 1960s) users as they described the
abnormal persistent behaviors displayed by themselves and other addicts.64 Punding
has since become a term for non–goal-directed repetitive activity. Patient-reported
examples include assembling and disassembling clocks and watches or incessantly
sorting through purses. What makes these behaviors troublesome is the duration of
time users would dedicate to such tasks without any apparent gain. There seems to
be a predilection for punding to entail activities that users had previously been
involved with. For example, a carpenter abusing amphetamines may repetitively build
wooden objects; artists may doodle, paint, or draw excessively; a businessman may
 Neurologic Manifestations of Chronic Methamphetamine Abuse 7

make and add to spreadsheets for hours.66 There is also a gender-related component:
men typically tinkering with electronics and women more commonly involved in
grooming behaviors, such as hair brushing and nail polishing.64,65,67–69 It is interesting
that stereotyped repetitive movements, such as head bobbing, licking, gnawing, and
sniffing, are also seen in a variety of animals given amphetamines.70
Although first reported in amphetamine abusers, punding has also been reported in
cocaine users71 and, more recently, in patients with Parkinson’s disease receiving
dopamine replacement therapy.66,67 Similar to chronic stimulant abusers, patients
with Parkinson’s disease have dysfunctional dopaminergic neurotransmission and
can develop psychosis.67 This finding suggests a similar pathophysiologic mecha-
nism. Although few controlled studies have been done on punding with substance
abuse, there is some data available on its incidence. In a study of 50 patients
addicted to cocaine, Fasano reported that 38% had some form of punding.66 These
patients spent, on average, 3 hours a day engaged in their repetitive activities.66 One
patient reported spending up to 14 hours a day playing computer games and collect-
ing things.67 It is interesting that the majority of interviewed patients in this study re-
ported that their behavior began shortly after their first drug usage. In addition, the
duration and amount of drug use did not seem to predict which users would develop
punding and which would not.67 This finding suggests that, like the development of
stimulant-induced psychosis, there may be a predisposition for the development of
punding that is merely brought out by the drug. As previously discussed, the same
abnormal brain circuitry that increases one’s risk for becoming addicted may also
be involved in the development of such stereotyped behaviors. In his first report on
the topic, Rylander described punding in 26% (40 of 150) of the amphetamine addicts
he interviewed.64 These patients shared identical symptomatology as the cocaine ad-
dicts and patients with Parkinson’s disease who engaged in punding. The majority of
the drug addicts did not describe associated anxiety or distress over their activities,
but thought of them with amusement. Some even found them pleasurable. When
abstaining from drug usage, punding typically abates. Although the neurologic mech-
anisms behind punding are not yet well delineated, it appears to involve dopamine.
Repeated dosing of amphetamines in animals results in behavioral sensitization.
This sensitization is manifested as increased locomotion and stereotypic behavior
with each subsequent dose of amphetamine. This sensitization appears to involve
both glutamate and dopamine, and, more recently, dopamine-mediated decreases
in acetylcholine have been implicated.67,72,73 As concentrations of extracellular dopa-
mine increase with each subsequent dose of amphetamine, one could envision over
time this excess dopamine causing neurotoxicity or change the normal balance be-
tween dopamine 1 (D1) and dopamine 2 (D2) receptor activity52; In a review on the
topic, Fasano makes a strong argument for the involvement of both D1 and D2 recep-
tors in the development of punding, and suggests that, if needed, treatments might
include atypical antipsychotics.66

CHRONIC METHAMPHETAMINE ABUSE AND THE DEVELOPMENT OF PARKINSON’S

DISEASE

People with Parkinson’s disease66,67 also exhibit unusual impulse-control disorders

and punding. Similar to methamphetamine abusers, patients with Parkinson’s dis-
ease, whether they are newly diagnosed74 or have had dopamine-replacement
therapies,75 have gender-specific compulsivity problems. Men more frequently suffer
from pathologic gambling and compulsive sexual behavior, whereas women tend to-
ward compulsive buying and binge eating. The collective animal and human data
8 Rusyniak

clearly show that high-dose methamphetamine abuse causes alterations in striatal

dopaminergic neurotransmission. Numerous pathology and imaging studies have
shown reductions in striatal dopamine, tyrosine hydroxylase, and dopamine trans-
porters.6,32,76–80 Because these findings are also found in persons with Parkinson’s
disease, it is logical to expect that chronic methamphetamine addicts would develop
signs of Parkinson’s disease.
The current and prevailing theory is that abusing methamphetamine does not in-
crease one’s risk of developing Parkinson’s disease or Parkinsonism.31,32,76 Several
hypotheses have been put forth to explain the discrepancy between the research
and clinical data.31,32,76 The simplest hypothesis is that they are different disorders.
Parkinson’s disease involves loss of dopaminergic neurons in the substantia nigra,
whereas methamphetamine abuse causes alterations in dopaminergic nerve terminals,
but not in the cell bodies themselves.32 In studies of methamphetamine abusers, the
reductions in dopamine have a different distribution than in patients with Parkinson’s
disease. Methamphetamine users have greater dopamine reductions in the caudate
compared with the putamen, with patients with Parkinson’s disease showing the oppo-
site.32 Another hypothesis is that once users become drug abstinent, the damaged
dopaminergic nerve terminals begin to recover; decreases in dopamine transporters
of methamphetamine abusers were found to significantly recover with prolonged
(>12 months) abstinence.79
Another hypothesis is that methamphetamine abusers do not actually damage their
dopaminergic nerve terminals, and that the findings of reduce dopamine levels repre-
sent a compensatory response to repeated elevations in monoamines. The strongest
argument for this has been that the vesicular transporter-2 (VMAT2), which is known to
be reduced in Parkinson’s disease and to be resistant to drug-compensatory regula-
tion, is not significantly reduced in abstinent methamphetamine abusers.6,81 In fact, a
more recent positron emission tomography (PET) study of nonabstinent methamphet-
amine abusers found increases in VMAT2.82 This finding was thought to be caused by
reductions in vesicular dopamine, depleted from recent release, resulting in less dopa-
mine being available to compete for binding to VMAT2.82
Another intriguing hypothesis involves nicotine and nicotine receptors. Acetylcholine
nicotinic mechanisms can influence the behavioral and neurochemical effects of psy-
chomotor stimulant drugs and vice versa.83 An overwhelming number of methamphet-
amine users smoke cigarettes compared with the general population (87%–92%
vs 22%).84 Because cigarette smoking negatively correlates with development of
Parkinson’s disease,85 methamphetamine abusers may be protected or self-treated.31
Some researchers think that methamphetamine abuse does increase the risk for
developing Parkinson’s disease.76,86,87 One retrospective study, looking at hospital
admissions over a 10-year period, found an increased incidence of Parkinson’s
disease among patients who had a prior history of being admitted with a
methamphetamine-related problem.87 Because it may take many years before reduc-
tions in dopamine reach the levels mediating clinical symptoms, it is possible that the
patients enrolled in many of the prospective clinical studies are not old enough to show
symptoms; the majority of studies involve young adults. What instead may occur is that
as methamphetamine use increases in young adults, we may see a shift in the age of
onset of Parkinson’s disease. There have been 2 studies involving the same group of
patients that support this idea. In a phone survey of patients with Parkinson’s disease
receiving care at 1 of 3 clinics, patients with Parkinson’s disease were significantly
more likely (odds ratio 5 8, confidence interval 1.6–41.4) to have used amphetamines
than their unaffected spouses,88 and in the majority of these patients, their exposures
to amphetamines occurred years (w27) before symptoms onset.88 Compared with
 Neurologic Manifestations of Chronic Methamphetamine Abuse 9

patients with Parkinson’s disease without a history of exposure, those patients with a
history of amphetamine use were significantly younger at the age of symptom onset,
but not at the age of diagnosis.86 This study is small, however, and subject, by its
design, to recall bias. Further work is needed to confirm whether there is, in fact, an as-
sociation between amphetamine use and the development of Parkinson’s disease.

CHOREOATHETOID MOVEMENTS AND DYSKINESIAS

A potential complication of methamphetamine-induced damage to the dopaminergic

nervous system is the development of dyskinesias and choreoathetoid movements.89
There have been numerous reports of choreoathetoid movements (involuntary pur-
poseless and uncontrollable movements with features of both chorea and athetosis)
in patients using or abusing amphetamines.46,68,69,90–94 In one report, patients with un-
derlying chorea (Sydenham, Huntington, and Lupus) were given an intravenous dose
of amphetamine to assess its effect on their baseline movements. In each of these pa-
tients, amphetamine dramatically worsened their underlying chorea.95 The increases
in limb movements provoked by amphetamines could be prevented if patients were
pretreated with the D2 antagonist haloperidol.95 Because a group of control patients
without chorea that were given amphetamine did not develop movement disorders,
the investigators suggested that the development of chorea from amphetamines
may require a underlying damage to the striatum.95 This supposition would seem to
be supported from several lines of evidence. For one, numerous studies have shown
that methamphetamine abusers have evidence of dopaminergic neurotoxicity in the
striatum.6,25,96 Additionally, chronic methamphetamine abusers, even without frank
chorea, often have demonstrable movement disorders.97 Furthermore, in some pa-
tients, movement disorders can last for years even after they have stopped using am-
phetamines.64,68 Lastly, patients who have stopped abusing amphetamine, and
subsequently recovered from their choreoathetoid movement disorder, will often
redevelop symptoms the first time they use amphetamines again, suggesting that pa-
tients may become permanently susceptible.68
The description of choreoathetoid movements typically involves the limbs, neck,
and face and often has a rhythmic dancelike quality. Similar to other dyskinesias,
symptoms disappear while patients sleep.68 Although in some patients dopamine an-
tagonists and benzodiazepines have been found to relieve symptoms,69,91,95 in others
they have had no benefit.68 Not limited to amphetamines, choreoathetoid movements
have also been reported with other stimulants, including cocaine (known as crack
dancing).64,97–99 Although the paucity of literature on this topic suggests that the
development of these symptoms is rare, the fact that there are street names for this
in English and Spanish suggests that it may occur more commonly than reported.98
It is a sad and real possibility that, among other reasons, many of the homeless per-
sons seen dancing and writhing around on the street corners of many major cities may
be manifesting signs of stimulant-induced choreoathetoid movements.

DENTAL CARIES

Although not traditionally considered a neurologic complication, the development

of dental caries and teeth erosion in chronic methamphetamine abusers may be
the result of elevations in brain monoamines. Referred to as meth mouth, advanced
dental caries, tooth loss, and tooth fractures seen among methamphetamine users is
the result of decreased saliva production (xerostomia) combined with teeth grinding
(bruxism) and jaw clenching.100–108 Additional contributors to methamphetamine-
related tooth decay include poor oral hygiene combined with the consumption of
10 Rusyniak

sugar-containing carbonated soft drinks, which is a common habit among metham-

phetamine users, with Mountain Dew being their drink of choice.100–102,106,109 Dental
caries seen with meth mouth occur in a similar pattern to other disorders involving
xerostomia (eg, Sjögren and radiation), involving the buccal smooth surface of the
posterior teeth and the interproximal areas of the anterior teeth.100,102 Decay can
progress to complete destruction of dental enamel, with many young methamphet-
amine addicts requiring dentures.110 The mechanism of methamphetamine-
induced xerostomia appears to be mediated by central alpha-2 receptors, which,
when bound by norepinephrine, decreases salivary flow.103,109,111 Along with
increasing dopamine, methamphetamine causes sustained increases in extracellular
concentrations of norepinephrine.112 Although the cause of bruxism is not well
known, it is thought to be of central origin and, likewise, to involve central mono-
amines.107,108,113 Unlike nocturnal bruxism, methamphetamine users will often
have bruxism day and night.107,108 Although the practicing neurologist is unlikely to
be consulted to see patients because of dental caries, recognizing the dental and
dermatologic manifestations of chronic methamphetamine abuse may help to iden-
tify at-risk patients.

SUMMARY

Chronic methamphetamine abuse has devastating effects on the CNS. The degree to
which addicts will tolerate the dysfunction in the way they think, feel, move, and even
look, is a powerful testimony to the addictive properties of this drug. Although the
mechanisms behind these disorders are complex, at their heart they involve the recur-
ring increase in the concentrations of central monoamines with subsequent dysfunc-
tion in dopaminergic neurotransmission. The mainstay of treatment for the problems
associated with chronic methamphetamine abuse is abstinence. However, by recog-
nizing the manifestations of chronic abuse, clinicians will be better able to help their
patients get treatment for their addiction and to deal with the neurologic complications
related to chronic abuse.

ACKNOWLEDGMENTS

The author would like to acknowledge the valuable editorial assistance of Pamela J.
Durant.

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