REVIEW doi:10.1111/j.1360-0443.2009.02564.

A review of the clinical pharmacology of

methamphetamine

Christopher C. Cruickshank1 & Kyle R. Dyer1,2

Pharmacology and Anaesthesiology Unit, School of Medicine and Pharmacology,The University of Western Australia, Crawley,WA,Australia1 and Division of Mental
Health, St George’s University of London, London, UK2

ABSTRACT

Aims To examine the literature regarding clinical pharmacokinetics, direct effects and adverse clinical outcomes
associated with methamphetamine use. Methods Relevant literature was identified through a PubMed search. Addi-
tional literature was obtained from relevant books and monographs. Findings and conclusions The mean elimination
half-life for methamphetamine is approximately 10 hours, with considerable inter-individual variability in pharmaco-
kinetics. Direct effects at low-to-moderate methamphetamine doses (5–30 mg) include arousal, positive mood, cardiac
stimulation and acute improvement in cognitive domains such as attention and psychomotor coordination. At higher
doses used typically by illicit users (ⱖ50 mg), methamphetamine can produce psychosis. Its hypertensive effect can
produce a number of acute and chronic cardiovascular complications. Repeated use may induce neurotoxicity, asso-
ciated with prolonged psychiatric symptoms, cognitive impairment and an increased risk of developing Parkinson’s
disease. Abrupt cessation of repeated methamphetamine use leads to a withdrawal syndrome consisting of depressed
mood, anxiety and sleep disturbance. Acute withdrawal lasts typically for 7–10 days, and residual symptoms associated
with neurotoxicity may persist for several months.

Keywords Amphetamine, amphetamines, methamphetamine, methylamphetamine, pharmacology, toxicology.

Correspondence to: Christopher C. Cruickshank, Pharmacology and Anaesthesiology Unit (MBDP 510), School of Medicine and Pharmacology, The
University of Western Australia, Crawley WA 6009, Australia. E-mail: ccruicks@ccwa.wa.gov.au
Submitted 14 February 2008; initial review completed 12 May 2008; final version accepted 6 February 2009

INTRODUCTION complete. Amphetamine includes S-amphetamine (i.e.

d-amphetamine; also referred to as dexamphetamine)
The United Nations Office on Drugs and Crime estimated
which is used therapeutically, and racemic amphet-
that 290 tonnes of methamphetamine was synthesized
amine sulphate powder, which is the common form of
in 2005 [1], which is equivalent to 2.9 billion 100-mg
amphetamine used illicitly in the United Kingdom. The
doses of the drug. Methamphetamine is the second most
plural ‘amphetamines’ will be used to refer to amphet-
popular illicit drug world-wide, with an annual global
amine and methamphetamine collectively, but will not
prevalence estimated at 0.4%. Use of the drug is par-
extend to derivatives such as methylphenidate and 3,4-
ticularly common in Asia, Oceania and North America
methylenedioxymethamphetamine.
[1]. Annual prevalence among adults is 14% in the Phil-
ippines [2], 3.2% in Australia [3] and 0.8% in the United
States [4]. Amphetamine tends to be more common
METHODS
than methamphetamine in Europe, except in the Czech
Republic, Slovakia, Estonia and Latvia [5]. In this paper A PubMed search of ‘methamphetamine or methylam-
we review the mechanism of action, pharmacokinetic phetamine or metamfetamine’ identified 447 articles
profile, direct drug effects and the significant adverse (limits: English language, published 1966–2007, human
clinical effects of methamphetamine. The review does studies). Abstracts were screened by hand to exclude pre-
not extend to the treatment of methamphetamine disor- clinical studies, review articles which had been super-
ders. We will refer to amphetamine studies where evi- seded by recent reviews and other papers judged by the
dence relating specifically to methamphetamine is less authors to be of lesser relevance to the present discussion.

© 2009 The Authors. Journal compilation © 2009 Society for the Study of Addiction Addiction, 104, 1085–1099
1086 Christopher C. Cruickshank & Kyle R. Dyer
Reference lists were used to identify further relevant
literature. Book chapters and relevant monographs
obtained from peak bodies were also considered. Inclu-
sion was determined by consensus between the authors.
Mechanisms of action, chemistry and molecular phar-
macology discussed in the present paper were not subject
to a structured literature search.
MOLECULAR MECHANISMS
Chemistry
‘Amphetamine’ is a contraction of ‘a-methylphenethy-
lamine’, an older description of the prototypical com-
pound of which methamphetamine (methylamphet-
amine, metamfetamine, N-methyl-1-phenylpropan-2-
amine) is the N-methyl derivative. S-methamphetamine
(d-methamphetamine) is the more biologically active
optical isomer [6]. S-methamphetamine hydrochloride
presents as white or translucent crystals and is referred to
commonly as ‘ice’ or ‘crystal meth’ [7]. Samples of crys-
talline methamphetamine seized in Australia have had,
typically, a purity of 80%, although purity may be signifi-
cantly less where the cutting agent dimethyl sulphone is
present [8]. The more common powder form of metham-
phetamine is typically 10% pure, and the purity of ‘base’,
a damp oily form, is generally 20% [9,10]. The crystalline
form is suitable for vapour inhalation because high purity
S-methamphetamine hydrochloride vaporizes without
pyrolysis [11,12]. Relative to lower purity forms, crystal-
line methamphetamine is associated with an increased
incidence of dependence [13].
Molecular pharmacology
Methamphetamine is an indirect agonist at dopamine,
noradrenaline and serotonin receptors. Due to struc-
tural similarity, methamphetamine substitutes for
monoamines at membrane-bound transporters, namely
the dopamine transporter (DAT), noradrenaline trans-
porter (NET), serotonin transporter (SERT) and vesicular
monoamine transporter-2 (VMAT-2). VMAT-2 is embed-
ded in vesicular membranes, while active DAT, NET
and SERT are cell surface integral membrane proteins
[6]. Methamphetamine redistributes monoamines from
storage vesicles into the cytosol by reversing the func-
tion of VMAT-2 and disrupting the pH gradient that
otherwise drives accumulation of monoamine in the
vesicles. The endogenous function of DAT, NET and
SERT is reversed, resulting in release of dopamine, nora-
drenaline and serotonin from the cytosol into synapses.
Synaptic monoamines are then available to stimulate
postsynaptic monoamine receptors. Methamphetamine
attenuates monoamine metabolism by inhibiting
monoamine oxidase [6].
© 2009 The Authors. Journal compilation © 2009 Society for the Study of Addiction
In vitro studies indicate that methamphetamine is
twice as potent at releasing noradrenaline as dopamine,
and its effect is 60-fold greater on noradrenaline than
serotonin release [14]. Major central nervous system
(CNS) dopaminergic circuits include the mesolimbic,
mesocortical circuit and the nigrostriatal pathways [15].
Noradrenergic regions of particular interest include: the
medial basal forebrain, which mediates arousal; the hip-
pocampus, involved in memory consolidation; and the
prefrontal cortex (PFC), which processes cognitive func-
tions [16]. Serotonin neurones are distributed widely
throughout the brain and regulate diverse functions
including reward, hyperthermia, respiration, pain per-
ception, sexual behaviour, satiety, impulsiveness, anxiety
and higher cognitive functions [17].
Several factors add substantial complexity to under-
standing psychostimulant effects upon monoamines: (i)
multiple receptor subtypes exist for noradrenaline,
dopamine and serotonin, with distinct binding affinities,
second-messenger effects, and central nervous system
(CNS) distribution; (ii) neuronal pathways interact with
each other [e.g. monoamine neurones modulate excita-
tory glutamate neurones and inhibitory g-aminobutyric
acid (GABA) neurones] [18]; and (iii) some effects of
amphetamines are mediated peripherally (e.g. [19]).
Baseline dopamine function also appears to influence the
response to amphetamines. Low baseline D2 density is
associated with a pleasant response to exogenous stimu-
lants while high baseline D2 density may produce
unpleasant responses [20].
CLINICAL PHARMACOLOGY
Clinical pharmacokinetics
A summary of the pharamacokinetic profile of metham-
phetamine is presented in Table 1. Methamphetamine is
metabolized largely in the liver via: (i) N-demethylation to
produce amphetamine, catalysed by cytochrome P450
2D6; (ii) aromatic hydroxylation via cytochrome P450
2D6, producing primarily 4-hydroxymethamphetamine;
and (iii) b-hydroxylation to produce norephedrine [21–
23]. Numerous metabolites are produced from these over-
lapping pathways [21]. Metabolites of methamphet-
amine are unlikely to contribute significantly to clinical
effects. Amphetamine arising from the metabolism of
30 mg methamphetamine reaches plasma levels sub-
stantially lower than that of the ingested drug, with peak
levels occurring after 12 hours, at which time acute
effects are minimal [11]. Involvement of the poly-
morphic cytochrome P450 2D6 may contribute to inter-
individual variability in metabolism (23). Metabolism
does not appear to be altered by chronic exposure, thus
dose escalation appears to arise from pharmacodynamic
rather than pharmacokinetic tolerance [24].
Addiction, 104, 1085–1099
 Clinical pharmacology of methamphetamine 1087

Cmax: peak plasma methamphetamine concentration; Tmax: time to reach peak plasma methamphetamine concentration; T1/2: methamphetamine plasma half-life. Data are presented as mean ⫾ standard error and/or (range) where
available. aPeak effect estimated from published plots of subjective effect versus time. bGeometric mean, determined by non-compartmental analysis; may be overestimated due to sampling interval. cBased on the inhaled dose, does
Approximately 70% of a methamphetamine dose is

[33,152,153]
excreted in the urine within 24 hours: 30–50% as meth-

[11,30]
amphetamine, up to 15% as 4-hydroxymethamphe-

[154]
[32]
tamine and 10% as amphetamine [11,25]. Urinary
excretion of methamphetamine may be enhanced by
acidifying the urine with oral ammonium chloride
[11,25,26]. With a long terminal urinary half-life of 25
Time to peak effect

18 ⫾ 2 minutes
hours, methamphetamine accumulates in the urine with

ⱕ15 minutesa
180 minutesa
<15 minutesa
repeated dosing [25,27]. Thus, methamphetamine has
been detected in urine 7 days after completing a regimen
of four daily 10-mg doses [27], and in one case following
a single 250-mg oral dose [28] (Table 2). Amphetamines
might be expected to be present in the urine for extended
periods in the context of abuse, but appropriate studies
9.1 ⫾ 0.8 (8–16)

have not been reported [29].

12 ⫾ 1 (8–17)

11 ⫾ 1 hoursa

The terminal plasma half-life of methamphetamine of

9.1 (3–17)

approximately 10 hours is similar across administration

T1/2 (hour)

routes, but with substantial inter-individual variability.

Acute effects persist for up to 8 hours following a single
moderate dose of 30 mg [30]. Methamphetamine arising
from an intravenous dose of 10 mg is typically detectable
in plasma for 36–48 hours [31,32]. An intravenous
216 (180–300)

dose of 30 mg methamphetamine administered over 2

Tmax (minutes)

minutes delivers a mean peak plasma concentration of

6 ⫾ 11b
150 ⫾ 30

not include drug residue remaining on the pipe [11]. dData from Harris et al. 2003 [32]. eAdministered dose was 30 mg/70 kg.
169 ⫾ 8

110 mg/l methamphetamine [33]. Cardiovascular effects

may be detected within 2 minutes and subjective effects
within 10 minutes of infusion [34].
Via vapour inhalation (smoking), methamphetamine
bioavailability ranges from 67% to 90% dependent partly
upon smoking technique [11,32]. Smoking results in the
108 ⫾ 22 (64–164)

rapid appearance of methamphetamine in the plasma,

94.1 (62–291)

indicating efficient transfer of the drug from the alveoli

into blood. However, peak plasma levels are reached typi-
47 ⫾ 6

113 ⫾ 8
Cmax (mg/l)

cally 2.5 hours after smoking, which may be due to the

slower absorption of the drug retained in the upper res-
piratory tract [30].
Methamphetamine is 79% bioavailable via the intra-
nasal route [32] and peak plasma methamphetamine con-
Table 1 Clinical pharmacokinetics of methamphetamine.

centration occurs after 4 hours [35]. Nevertheless, peak

67%d; 90 ⫾ 10%c

cardiovascular and subjective effects occur rapidly (within

Bioavailability

5–15 minutes). The dissociation between peak plasma

67 ⫾ 3%

concentration and clinical effects indicates acute toler-

100%

79%

ance, which may reflect rapid molecular processes such as

redistribution of vesicular monoamines and internaliza-
tion of monoamine receptors and transporters [6,36].
Acute subjective effects diminish over 4 hours, while
30 mge
30 mg
30 mg

50 mg

cardiovascular effects tend to remain elevated. This is

Dose

important, as the marked acute tachyphylaxis to subjec-

tive effects may drive repeated use within intervals of 4
hours, while cardiovascular risks may increase [11,35].
Although dosing patterns vary substantially between
Intravenous

Intra- nasal

regular methamphetamine users, a typical pattern of

Smoking

use appears to consist of four doses daily, in binges last-

Route

Oral

ing 4 days. Self-reported data indicate illicit doses of

© 2009 The Authors. Journal compilation © 2009 Society for the Study of Addiction Addiction, 104, 1085–1099
1088 Christopher C. Cruickshank & Kyle R. Dyer
Table 2 Detection times for methamphetamine in plasma, saliva and urine.
Matrix Dose LLOQ/cut-off
Plasma 10 mg intravenous 1 mg/l
Plasma 35 mga intravenous 1 mg/l
Plasma 10 mg oral, slow-release 2.5 mg/l
Oral fluid 10 mg oral, slow-release 2.5 mg/l
Urine 10 mg oral, slow-release 2.5 mg/l
Urine 22 mg smoking 300 mg/l
Adapted from Verstraete et al. 2004 [156]. LLOQ: lower limit of quantification. aThe administered dose was 0.5 mg/kg, equivalent to 35 mg/70 kg.
50–500 mg totalling up to 4 g/day, which is substantially
greater than the doses used normally in controlled clini-
cal experiments [13]. However, these reports have not
been substantiated objectively, and the clinical pharma-
cokinetics of illicit methamphetamine remains to be
described adequately. Nevertheless, plasma levels from
forensic cases are consistent with self-reported high
doses. Among driving offenders and detainees testing
positive for methamphetamine, plasma methamphet-
amine levels were typically 300–550 mg/l, and plasma
levels up to 1665 mg/l were reported among non-fatal
cases [37,38].
Direct effects
At the low-to-moderate doses used in clinical experiments
(5–30 mg), prominent methamphetamine responses
include arousal, reduced fatigue, euphoria, positive mood,
accelerated heart rate, elevated blood pressure, pupil dila-
tion, increased temperature, reduced appetite, behav-
ioural disinhibition and short-term improvement in
cognitive domains, including sustained attention. Reports
of negative responses, particularly anxiety, are also
common [30–32,39] (see Table 3). Cardiovascular and
subjective effects appear to increase dose-dependently
[35].
There have been limited studies at higher doses
but available evidence suggests qualitatively distinct
responses. A unique study of high-dose intravenous
methamphetamine administration (55–640 mg) evoked
marked positive subjective responses, followed by psy-
chotic symptoms. At least five of 12 individuals developed
hypertension, four of 12 developed aggressive thoughts or
behaviours, eight of 12 talked almost continuously during
the experiment, and all reported throbbing headaches
[40]. Previous histories of psychosis among these subjects
should be considered when extending these findings more
generally. However, similar high-dose experiments using
amphetamine indicate that psychosis may be induced in
subjects without previous psychosis [41,42].
Based on arrest reports among automobile drivers in
the United States (amount and time of dose unknown),
© 2009 The Authors. Journal compilation © 2009 Society for the Study of Addiction
Typical detection Maximum detection
time (single dose) time (repeated dosing)
36–48 hours Not reported [32]
36–48 hours Not reported [31]
24 hours Not reported [155]
24 hours 3 days [155]
87 hours 7 days [27]
60 hours Not reported [11,156]
elevated blood methamphetamine plasma levels above
300 mg/l were associated with violent behaviours. Rapid
or confused speech, dilated pupils, agitation, paranoia,
rapid pulse, sweating, nervousness and motor restless-
ness were also noted commonly at plasma levels exceed-
ing 100 mg/l [37].
ADVERSE EFFECTS
Methamphetamine overdose
An estimated 94 000 emergency department admissions
associated with recent methamphetamine use were
reported in the United States in 2005 (not including
cases of detoxification) [43]. Based on case reports, the
common features of methamphetamine overdose include
agitation, dilated pupils, tachycardia, hypertension and
rapid respiration. Other features include shivering, dysp-
noea, chest pain, hyperpyrexia and cardiac, hepatic
and/or renal failure. Coma or seizures occur less fre-
quently [29,44–51].
Non-fatal cases of methamphetamine toxicity present
typically with tachycardia, hypertension and altered
mental status [52–54]. Altered mental state may take the
form of agitation (approximately 20% of cases), suicidal
ideation (6–12%) and/or acute psychosis (7–12%)
[52,54,55]. Rhabdomyolysis may be a factor in up to 14%
of presentations [54]. Seizures appear to be less common,
occurring in 3–4% of cases [52–54].
Case reports indicate that methamphetamine-as-
sociated fatalities arise most commonly from multiple
congestion, pulmonary oedema, pulmonary congestion,
cerebrovascular haemorrhage (attributed to hyperten-
sion), ventricular fibrillation, acute cardiac failure or
hyperpyrexia [56,57]. Other fatalities have arisen from
septic injection or asphyxia by aspiration of vomitus [57].
A number of studies suggest that a significant and
possibly greater proportion of methamphetamine-related
fatalities arise from accidents, suicide and homicides, sug-
gesting severe psychological and behavioural distur-
bances at toxic doses [58–60].
Addiction, 104, 1085–1099
 Table 3 Acute clinical effects of methamphetamine identified in prospective studies.

Effect Dose Evidence References Possible mechanisms

Subjective effects
Arousal: stimulating, ⱖ5 mg Quantitative [30–32,39,152,154] Arousal is facilitated by a1- and b-adrenoceptor stimulation in the medial basal forebrain [18].
energetic, drive, vigour, self-report Dopamine D1- and D2-receptor stimulation may be also be implicated in methamphetamine-
reduced fatigue, induced arousal [18]. Methamphetamine-induced mind-racing was correlated with activation in
mind-racing the anterior cingulated cortex and ventral striatum [157]
Euphoria: high, elation, good ⱖ5 mg Quantitative [30–32,39,152,154] Amphetamines-induced dopamine release in the nucleus accumbens was correlated with euphoria
drug effect, intoxication self-report [157–159]
Relaxation: relaxed, loss of ⱖ10 mg Quantitative [31,32,39,40] Stimulation of serotonin 5-HT1- and 5-HT2B-receptors has an anxiolytic effect [160]
tension, self-confidence, self-report
sociable
Anxiety: dysphoria, bad drug ⱖ30 mg Quantitative [31–33,39] May arise from excessive adrenergic stimulation, possibly via stimulation of a1-adrenoceptors in the
effects, nervousness self-report prefrontal cortex [18], serotonergic 5-HT3-receptor stimulation, [160] and/or excessive dopamine
stimulation in the striatum [159]
Talkativeness ⱖ50 mg Qualitative [35,40] ‘Mind racing’ correlated with activation in the anterior cingulated cortex and ventral striatum in
observation response to methamphetamine [157]. Facial motor neurones are innervated by serotonergic
trigeminal a-motor neurones [161]

© 2009 The Authors. Journal compilation © 2009 Society for the Study of Addiction
Paranoia ⱖ55 mg Qualitative [40] Amphetamine-induced psychotic symptoms correlated with excessive dopamine activation in the
observation striatum [159,162,163]
Hallucinations: auditory, ⱖ55 mg Qualitative [40] Amphetamine-induced psychotic symptoms correlated with striatal dopamine release
visual observation [159,162,163]. Auditory hallucinations were associated with increased activation of thalamus,
hippocampus and ventral striatum. Visual hallucinations associated with increased activation of
paralimbic and primary motor cortices [164]
Physiological effects
Increased heart rate ⱖ10 mg Qualitative [30–33,39,165] Amphetamine increased and heart rate in pithed rats via b-adrenoceptors [19] in cardiac tissue or
self-report, nerves arising from paravertebral ganglia. Cardiac stimulation was also centrally innervated via
qualitative noradrenergic pathways involving the forebrain and brainstem [166]
objective
Increased blood pressure ⱖ10 mg Quantitative [31,32,39,152,154] Increased heart rate in pithed rats via a-adrenoceptors [19] in cardiac tissue or nerves of the
objective paravertebral ganglia. Cardiac tissue is centrally innervated via noradrenergic pathways of the
forebrain and brainstem [166]. Elevated blood pressure may lead to headaches
Clinical pharmacology of methamphetamine

Increased respiration rate 30 mg Quantitative [31,39] a-Adrenoreceptors in pontomedullary respiratory centres of the lower brain stem [167]. Serotonin
objective modulation of respiration via phrenic motor neuronal 5-HT2 receptors [161]
1089

Addiction, 104, 1085–1099

 1090

Table 3 Cont.
Effect Dose Evidence References Possible mechanisms

Elevated body temperature 30 mg Quantitative [39] Excessive dopamine, noradrenaline and serotonin release in the hypothalamus. Noradrenaline-
objective mediated uncoupling of mitochondrial energy transfer. Heat retention is facilitated by
vasoconstriction [168]
Pupil dilation ⱖ30 mg Quantitative [39] a1-Adrenoceptor stimulation causes contraction of the dilator muscle of the iris [169]
objective
Psychomotor activation ⱖ55 mg Qualitative [40] Nigrostriatal dopamine release, indirect prefrontal a1-receptor stimulation, dopamine release in the
observation nucleus accumbens [170–172] and activation of central serotonin 5-HT1A receptors can mediate
motor activity [173]. Amphetamines may act peripherally on skeletal muscle [174]
Reduced appetite ⱖ5 mg Quantitative [35,39,175] Activation of a1 receptors activation in paraventricular nucleus, b2 receptors of lateral
objective
Christopher C. Cruickshank & Kyle R. Dyer

hypothalamic area, mesolimbic dopamine D1 and D2 receptors, serotonin 5-HT1 and 5-HT2
receptors [176]
Acute cognitive effects
Impaired response sensitivity 10 mg Quantitative [177] D2 dopamine receptor binding in the striatum may facilitate impaired response sensitivity [178]
objective
Improved attentiona 30 mg Quantitative [154,165,179,180] D2 dopamine receptor binding in the ventral striatum and basal forebrain correlated with attention

© 2009 The Authors. Journal compilation © 2009 Society for the Study of Addiction
sustained, divided objective [178]. Arousal component of attention may be facilitated by a1- and b-adrenoceptor stimulation
attention in the medial basal forebrain [18]. See also arousal
Improved reasoning abilitya 30 mg Quantitative [165] D1 dopamine receptor and a2-adrenoceptor stimulation in the frontal cortex facilitated working
objective memory [181,182]
Improved pattern 30 mg Quantitative [154] D1 dopamine receptor and a2-adrenoceptor stimulation in the frontal cortex facilitated working
recognitiona objective memory [181,182]
Improved motor 30 mg Quantitative [35,154] Dopaminergic activation in the striatum, particular the putamen, modulated motor activity [183]
coordinationa objective

a
These effects diminish with chronic use.

Addiction, 104, 1085–1099


Inoue and colleagues proposed toxic plasma metham-
phetamine ranges of 200–5000 mg/l and fatal levels at
>10 000 mg/l [56]. These figures should be considered as
guides only, as fatalities have been reported at plasma
concentrations as low as 90 mg/l [58], whereas survival
has been reported at 9460 mg/l [37]. In terms of dose,
fatal methamphetamine overdose has been reported fol-
lowing an intravenous dose of 20 mg [29] and elsewhere
an experimental subject was observed to survive an intra-
venous dose of 640 mg methamphetamine, albeit with
transient psychosis [40].
Psychosis
Methamphetamine psychosis refers to paranoid–
hallucinatory states induced by methamphetamine
which are largely indistinguishable from acute paranoid
schizophrenia [28,40,42]. Regular methamphetamine
use is also associated with a high incidence of chronic
psychotic symptoms [61]. The most common signs of
methamphetamine psychosis are hallucinations, delu-
sions and odd speech [28,62,63]. Methamphetamine-
induced hallucinations are predominantly auditory
(experienced in 85% of cases of methamphetamine psy-
chosis), visual (46%) and tactile (21%). Delusions of per-
secution (71%), of reference (63%) and of ‘mind-reading’
(40%) are also common [62].
There is considerable variability in both the dose
required (55–640 mg) and the onset of psychotic symp-
toms (7 minutes–34 hours post-dose) [40]. The duration
of psychotic symptoms is also variable, dissipating within
a week of abstinence in some cases, and persisting indefi-
nitely in others [28,40,63,64]. Among a sample of 170
Japanese methamphetamine users affected by psychosis,
59% recovered from psychosis within 30 days, but symp-
toms persisted for more than a month among 41%,
including 28% expressing symptoms after more than 6
months’ abstinence [65]. These findings suggest that, in
more than 50% of cases, psychotic symptoms resolve
spontaneously and may not require long-term antipsy-
chotic medication.
Psychotic symptoms deteriorate with increased dura-
tion and frequency of methamphetamine use [66,67].
Sensitization to methamphetamine psychosis may be
related to neurotoxicity because positive symptoms cor-
relate inversely with DAT density in the striatum and PFC
[67]. Non-specific environmental stressors such as incar-
ceration, severe insomnia and heavy alcohol consump-
tion may induce psychotic symptoms during periods of
methamphetamine abstinence [65,68]. Stress-induced
psychosis among former methamphetamine users
appears to be associated with increased noradrenergic
and dopaminergc sensitivity [68]. A familial history of
psychotic illness may be associated with persistent
© 2009 The Authors. Journal compilation © 2009 Society for the Study of Addiction
Clinical pharmacology of methamphetamine 1091
methamphetamine psychosis. Individuals with psychotic
symptoms persisting for more than 1 month after with-
drawal are three times more likely to have a family history
of schizophrenia than those exhibiting shorter psychoses
[69]. Methamphetamine-related psychosis is also associ-
ated with gene variations affecting a range of protein
complexes [70].
Cardiovascular complications
Few systematic studies have been conducted to examine
cardiovascular complications arising from methamphet-
amine, so much of the clinical evidence derives from case
studies (reviewed in [71]). Methamphetamine-induced
hypertension and arrhythmias can lead to acute events
such as acute coronary syndrome [72,73], acute aortic
dissection [74] and sudden cardiac death [71].
Repeated methamphetamine insult can also lead to
chronic conditions, including coronary heart disease and
cardiomyopathy [71]. Coronary heart disease appears to
occur more frequently and at a younger age among meth-
amphetamine users than others [75]. Methamphetamine
users have a 3.7-fold increased risk for cardiomyopathy,
and the associated left ventricular dysfunction is more
severe compared with other patients with cardiomyopa-
thy [76]. Impaired myocardial contractility and left ven-
tricular hypertrophy result commonly, leading to chronic
fatigue and shortness of breath [47,48,75]. Based on case
reports, the prognosis for methamphetamine-associated
cardiomyopathy appears to be poor [48,56,75]. However,
improvement has been reported following cessation of
methamphetamine use with digoxin, diuretic and/or anti-
coagulant treatment [77].
Population studies indicate that methamphetamine
increases the risk of haemorrhagic and ischaemic stroke
[50,78]. Outcomes range from spontaneous recovery to
permanent neurological damage or death [50,79]. Head-
aches have been reported to precede methamphetamine-
associated stroke [50,80]. Hypertension leading to
elevated cerebral pressure appears to be the underlying
cause [79].
Methamphetamine withdrawal syndrome
Abrupt cessation of regular methamphetamine use
induces a withdrawal syndrome designated ‘amphe-
tamine-type stimulant withdrawal syndrome’ by the
American Psychiatric Association [81]. Methamphet-
amine withdrawal may arise from the depletion of
presynaptic monoamine stores, down-regulation of
receptors and neurotoxicity [70,82]. The most prominent
signs and symptoms of methamphetamine withdrawal
are disturbed sleep, depressed mood and anxiety, craving
and cognitive impairment [83–89]. Other significant
symptoms include hyperphagia, agitation, vivid or
Addiction, 104, 1085–1099
1092 Christopher C. Cruickshank & Kyle R. Dyer
unpleasant dreams, reduced energy and methamphet-
amine craving [87,90]. The severity and profile of with-
drawal is related to the dosage and duration of
methamphetamine use [85].
Early case reports have indicated that, initially, acute
withdrawal features a period of increased sleep duration,
particularly rapid eye movement sleep [86,88], from 3 to
8 days in duration [83,85]. Protracted insomnia follow-
ing the period of hypersomnolence has been reported
[83], but is not a consistent finding. Some researchers
report reduced sleep quality but not quantity [85], while
others have not found insomnia to be a significant
symptom [87]. Where observed, impaired sleep quality
during later withdrawal has been associated with
reduced clear-headedness upon waking, suggesting a link
between sleep, mood and cognitive function during meth-
amphetamine withdrawal [85].
Depressed mood and anxiety associated with meth-
amphetamine withdrawal can reach the level of suicidal
ideation [28,66,88] and panic [91]. Depression associ-
ated with methamphetamine withdrawal typically fea-
tures dysphoric mood, anhedonia, irritability, inactivity
and impaired concentration [83–89]. Depression and
anxiety are most severe after 2–3 days of abstinence,
with gradual improvement over 7–10 days [85].
Although in most cases depression largely resolves after
2 weeks of abstinence, 24% report depression in the
moderate to severe range after 3 weeks’ abstinence [85],
and some may experience significant depression for
several months [88]. Neuroimaging studies suggest
that persistent depression may be associated with
methamphetamine-induced neurotoxicity [92]. The
high incidence of psychological trauma among meth-
amphetamine users may exacerbate anxiety and depres-
sion [93].
Neurotoxicity
Repeated exposure to amphetamines leads to damage at
dopaminergic and serotonergic axons.The mechanisms of
neurotoxicity are not understood completely, but the
selectivity of damage may be explained by the oxidation of
cytosolic dopamine and serotonin to 6-hydroxydopamine
and 5,6-dihydroxytryptamine, which can oxidize proteins
and lipids in dopamine and serotonin-rich neurones.
Elevated cerebral temperature is also thought to be an
important contributing factor [94]. Neuronal damage
induced by amphetamines is localized generally to axons
and termini, while cell bodies are typically spared [95,96].
Primate experiments demonstrate that episodes of
methamphetamine use, within a dose range consistent
with human illicit use, can lead to prolonged neurotoxicity
that may require more than a year for complete recovery.
Among baboons administered 8 mg/kg methamphet-
© 2009 The Authors. Journal compilation © 2009 Society for the Study of Addiction
amine over 8 hours (approximately equivalent to four
140 mg doses given to a 70-kg person), striatal DAT
density was reduced by up to 70% when the animals were
killed 2–3 weeks post-dose [97]. In vervet monkeys,
2 mg/kg methamphetamine doses delivered 6 hours apart
reduced nigrostriatal DAT density by 80% when measured
after 7 days. Recovery was substantial but incomplete
after 18 months [98]. Recovery may reflect emerging DAT
populations on dendrites branching from damaged termi-
nals [99].
In vivo human positron emission tomography and
magnetic resonance imaging data also indicate brain
abnormalities that persist beyond the period of metham-
phetamine consumption (reviewed in [100,101]).
Abnormalities include inflammation [102], reduced neu-
ronal density [103] and reduced density of dopaminergic
markers such as DAT [67,104,105], D2 receptor [106],
VMAT-2 [107] and the serotonergic marker SERT [108].
Striatal abnormalities can persist for years after cessation
of dependent methamphetamine use, but may recover
partially after 6–12 months of abstinence [104,109–
111].
Methamphetamine-associated neurotoxicity in the
striatum correlates with psychotic symptoms [102,112],
memory deficits [105] and impaired psychomotor coordi-
nation [105]. Psychotic symptoms correlate with dimin-
ished DAT density in the frontal cortex and reduced global
SERT density [112]. In the anterior cingulate, prefrontal
and temporal cortices, reduced SERT density correlates
with measures of aggression [108].
Neuropsychological impairment
A meta-analysis of neurocognitive impairments con-
cluded that methamphetamine use is associated with
moderate impairment in neuropsychological perfor-
mance corresponding with frontostriatal and limbic
abnormalities[113]. Principle neurocognitive impair-
ments appear to occur in the domains of executive func-
tion, learning, episodic memory, speed of information
processing, motor skills, working memory and perceptual
narrowing [113]. Among the studies reviewed, previous
methamphetamine use was associated with specific
impairments in impulse control [89,114–119], memory
recall [84,107,115,119–121], sustained attention
[89,122], working memory [107,123–125], persevera-
tion [124,126] and fluency [84,124]. These findings cor-
respond with clinical observations that methamphe-
tamine-dependent patients tend to present as distractible
and have difficulty sustaining attention [127]. Several
studies document cognitive deficits persisting for longer
than 6 months after withdrawal [105,114,117,126],
although some improvements have been reported with
protracted abstinence [126].
Addiction, 104, 1085–1099
 Clinical pharmacology of methamphetamine 1093

Parkinson’s disease activity among heterosexual females broadens this

concern [134].
Because Parkinson’s disease (PD) is a neurodegenerative
Intravenous administration of the substituted amphet-
disorder affecting dopamine neurones in the nigrostriatal
amine, methylphenidate, leads to increased in sexual
pathway [128], several investigators have examined links
desire [142] and pathological hypersexuality has
with methamphetamine neurotoxicity (reviewed in
been associated with dopamine agonist therapy [143].
[129,130]). While some studies have identified psycho-
Therefore, sexual effects may be mediated by excessive
motor dysfunction consistent with PD [105], others have
dopaminergic activation. Impulsiveness and impaired
failed to observe such deficits, despite neuronal pathology
decision-making associated with chronic methamphet-
qualitatively consistent with the disorder [107,123].
amine use may also play a role (see Neuropsychological
Signs of PD are associated with striatal DAT deficits of
impairment).
ⱖ47% [131], but DAT deficits among recently abstinent
methamphetamine users are typically 20–30% of
Teratogenic effects
normal levels [104,105,112,131]. Therefore, marked
psychomotor dysfunction is not always observed [129]. In 2005, an expert panel concluded that there was insuf-
Nevertheless, PD-like psychomotor disturbances have ficient evidence regarding the consequences of prenatal
been reported among cases of methamphetamine- exposure to amphetamines, because poor prenatal care
associated dopaminergic damage that was within the and high rates of nicotine use largely confounded the
range consistent with PD [105]. Given that DAT density available research [144]. Nevertheless, various studies
normally declines with age by approximately 4.5% per have reported that use of amphetamines during preg-
decade [132], regular methamphetamine use may be nancy is associated with low rates of prenatal care [145–
expected to have an increased risk of developing PD in 147], low birth weight [146–148], increased frequency of
later life. In support of this hypothesis, a retrospective hospitalization for pregnancy complications [146], peri-
case–control study revealed that prolonged use of natal mortality [146,149], preterm deliveries [146],
amphetamines is associated with an eight-fold increased maternal anaemia [147], premature membrane rupture
risk of PD, with an average of 27 years between amphet- [147], pre-eclampsia [146,147], meconium-stained
amine exposure and the onset of PD signs [133]. amniotic fluid [146,147], post-partum haemorrhage
[145,146], unplanned caesarean delivery [146], vacuum
Sexual behaviour extraction with forceps [146], and neonatal infection
[146]. Neonatal amphetamine withdrawal is uncommon,
The effects of methamphetamine on sexual behaviour
occurring in approximately 2% of affected neonates, and
have not been examined systematically in clinical studies.
generally resolves spontaneously within a week. The syn-
The available evidence for sexual effects stems largely
drome consists of poor feeding, drowsiness and tremor,
from self-reported survey data, often conducted among
and is considered less severe than both neonatal alcohol
regular methamphetamine users with problematic
and opiate withdrawal syndromes [145].
sexual behaviours. It is therefore unclear how broadly
Cases of neonatal birth defects associated with prena-
these effects apply. Methamphetamine use has been
tal methamphetamine exposure include atresia, hydro-
reported to enhance sexual pleasure among a sample of
cephalus, cardiac defects, epidermolysis bullosa and
dependent heterosexual females users engaged in high-
Down’s syndrome [146,147]. However, congential ano-
risk sexual behaviours [134].
molies occur at low frequency (~2–4% of cases) and there
Some users reported that methamphetamine delays
are insufficient data to determine whether these defects
orgasm, facilitating prolonged sexual activity and a par-
occur at higher than normal rates [144]. Animal experi-
ticularly intense orgasm [135]. Others have reported an
ments suggest that maternal methamphetamine expo-
association with erectile dysfunction and that metham-
sure increases the risk of perinatal mortality, low birth
phetamine is used commonly in combination with drugs
weight, congenital anomalies and neurobehavioural
such as sildenafil (Viagra®) to enhance sexual perfor-
impairments that persist into adulthood [144]. Possible
mance [135,136]. Compulsive sexual activity and high-
mechanisms may include increased uterine and umbili-
risk activities such as unprotected, anonymous and/or
cal vascular resistance, fetal hypoxia and accumulation
receptive anal sex, are reportedly common among homo-
of methamphetamine in the fetus [144].
sexual methamphetamine users, particularly dependent
users [137–139]. There are some indications that the
Other adverse effects
prevalence of methamphetamine use is particularly high
among urban homosexual men, raising concern about Methamphetamine intoxication is associated with dry
sexual disease transmission [140,141]. That metham- mouth, which may lead to dental caries, and activation of
phetamine use has been associated with high-risk sexual mandibular muscles, which may lead to bruxism and, in

© 2009 The Authors. Journal compilation © 2009 Society for the Study of Addiction Addiction, 104, 1085–1099
1094 Christopher C. Cruickshank & Kyle R. Dyer
some cases, tooth fracture [150]. Recent methamphet-
amine use appears to be a risk factor for methicillin-
resistant Staphylococcus aureus skin infections. Skin
infections may be associated with formication (a sensa-
tion of something crawling on the skin) and skin-picking
[151]. Tactile hallucinations are common features of
methamphetamine psychosis and may contribute to skin-
picking and infection [62].
SUMMARY
Methamphetamine produces a range of direct effects
including subjective euphoria, arousal and psychomotor
activation. At higher doses, stimulation of striatal
dopamine D2 receptors appears to mediate psychosis.
Stimulation of the myocardium—either directly or via
CNS efferents—can lead to tachycardia and hyperten-
sion, which may result in a range of severe acute and
chronic cardiovascular pathologies.
Repeated dosing leads to neuroadaptation and
impaired baseline functioning which may result in
depressed mood, cognitive impairment and other with-
drawal symptoms when use of the drug is ceased. Neuro-
toxicity arising from chronic methamphetamine use is
associated with long-lasting impairment in mood and
cognitive functions. Damage to dopamine neurones in
the nigrostriatal pathway may increase the risk of devel-
oping Parkinson’s disease in later life.
The range of potential adverse effects suggests that
clinical management of individuals presenting with
problematic methamphetamine may require assessment
of cardiovascular, neurocognitive, dental, dermatological
and sexual health issues in addition to dependence and
mental health concerns.
This review suggests a number of potential areas for
research. For example, research is necessary to examine
the mechanisms underlying cardiovascular harms,
sexual risk-taking behaviour, neurocognitive impair-
ment, psychosis and Parkinson’s disease. Determination
of factors affecting individual variation in acute metham-
phetamine responses and chronic harms may assist in
identifying individuals at particular risk. To date, many
important features of high-dose illicit methamphetamine
use have been explored indirectly or retrospectively.
Although potentially problematic to implement, prospec-
tive observational studies of illicit methamphetamine use
would be useful to clarify outstanding issues regarding
the course and prognoses of methamphetamine psycho-
sis, cardiovascular toxicity, neurotoxicity and depen-
dence. Such studies may improve the management of
methamphetamine-related disorders.
Declarations of interest
None.
© 2009 The Authors. Journal compilation © 2009 Society for the Study of Addiction
Acknowledgements
The authors wish to thank Professor Kenneth Ilett, Pro-
fessor James Bell and Associate Professor David Joyce for
kindly providing their expert opinions on a draft manu-
script. Christopher Cruickshank was supported by a Dora
Lush Scholarship from the National Health and Medical
Research Council of Australia.
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