The Clinical Toxicology of Metamfetamine: ISSN: 1556-3650 Print / 1556-9519 Online DOI: 10.3109/15563650.2010.516752

Clinical Toxicology (2010) 48, 675694
Copyright Informa UK, Ltd.

ISSN: 1556-3650 print / 1556-9519 online
DOI: 10.3109/15563650.2010.516752
REVIEW
LCLT
The clinical toxicology of metamfetamine

LEO J. SCHEP, ROBIN J. SLAUGHTER, and D. MICHAEL G. BEASLEY
Metamfetamine clinical toxicology
National Poisons Centre, Department of Preventive and Social Medicine, University of Otago, Dunedin, New Zealand
Introduction. Metamfetamine is a highly addictive amfetamine analog that acts primarily as a central nervous system (CNS) stimulant. The
escalating abuse of this drug in recent years has lead to an increasing burden upon health care providers. An understanding of the drugs
toxic effects and their medical treatment is therefore essential for the successful management of patients suffering this form of intoxication.
Aim. The aim of this review is to summarize all main aspects of metamfetamine poisoning including epidemiology, mechanisms of toxicity,
toxicokinetics, clinical features, diagnosis, and management. Methods. A summary of the literature on metamfetamine was compiled by
systematically searching OVID MEDLINE and ISI Web of Science. Further information was obtained from book chapters, relevant news
reports, and web material. Epidemiology. Following its use in the Second World War, metamfetamine gained popularity as an illicit drug in
Japan and later the United States. Its manufacture and use has now spread to include East and South-East Asia, North America, Mexico, and
Australasia, and its world-wide usage, when combined with amfetamine, exceeds that of all other drugs of abuse except cannabis.
Mechanisms of toxicity. Metamfetamine acts principally by stimulating the enhanced release of catecholamines from sympathetic nerve
terminals, particularly of dopamine in the mesolimbic, mesocortical, and nigrostriatal pathways. The consequent elevation of intra-synaptic
monoamines results in an increased activation of central and peripheral a- and b-adrenergic postsynaptic receptors. This can cause
detrimental neuropsychological, cardiovascular, and other systemic effects, and, following long-term abuse, neuronal apoptosis and nerve
terminal degeneration. Toxicokinetics. Metamfetamine is rapidly absorbed and well distributed throughout the body, with extensive
distribution across high lipid content tissues such as the blood-brain barrier. In humans the major metabolic pathways are aromatic
hydroxylation producing 4-hydroxymetamfetamine and N-demethylation to form amfetamine. Metamfetamine is excreted predominantly in
the urine and to a lesser extent by sweating and fecal excretion, with reported terminal half-lives ranging from 5 to 30 h. Clinical features.
The clinical effects of metamfetamine poisoning can vary widely, depending on dose, route, duration, and frequency of use. They are
predominantly characteristic of an acute sympathomimetic toxidrome. Common features reported include tachycardia, hypertension, chest
pain, various cardiac dysrhythmias, vasculitis, headache, cerebral hemorrhage, hyperthermia, tachypnea, and violent and aggressive
behaviour. Management. Emergency stabilization of vital functions and supportive care is essential. Benzodiazepines alone may adequately
relieve agitation, hypertension, tachycardia, psychosis, and seizure, though other specific therapies can also be required for
sympathomimetic effects and their associated complications. Conclusion. Metamfetamine may cause severe sympathomimetic effects in
the intoxicated patient. However, with appropriate, symptom-directed supportive care, patients can be expected to make a full recovery.
Keywords Metamfetamine; Methamphetamine; Drug abuse; Sympathomimetic toxidrome; 4-Hydroxymetamfetamine; Amfetamine;
Amphetamine; Hypertension; Tachycardia; Necrotizing vasculitis; Psychosis
Introduction
Metamfetamine, known also as methamphetamine, methylamfetamine, N-methylamfetamine, desoxyephedrine, phenylisopropylmethylamine, and N,a-dimethylphenethylamine,
is a methylated analogue of amfetamine. It has similar pharmacological properties to amfetamine, acting primarily as a
central nervous system stimulant, but differs in having more
pronounced effects due to its greater lipophilicity.
Although metamfetamine has been used therapeutically to
treat exogenous obesity and attention deficit disorder,1 it is
Received 23 April 2010; accepted 16 August 2010.

Address correspondence to Leo J. Schep, National Poisons Centre,
Department of Preventive and Social Medicine, University of Otago,
PO Box 913, Dunedin, New Zealand. E-mail: leo.schep@otago.ac.nz
more often associated with clandestine manufacture and distribution, arising from its increasing illicit abuse as a central
nervous system (CNS) stimulant. High purity metamfetamine, commonly known as Speed (although this may also
describe amfetamine and other common stimulant drugs of
abuse), is easily manufactured in clandestine laboratories by
amateur chemists without any formal training in synthetic
chemistry. The ease and low cost of this illicit manufacturing
has resulted in metamfetamine becoming widely available
and commonly abused. In many countries around the world it
has become a significant drug of abuse and public health
problem.
Isolated or repetitive use of metamfetamine can be hazardous, and because of its popularity, intoxication has become a
relatively common clinical scenario, producing a variety of
potentially lethal effects. An understanding of these toxic
effects and medical treatment is therefore essential for the
Clinical Toxicology vol. 48 no. 7 2010
676
L.J. Schep et al.
successful management of patients suffering this form of

intoxication.
Methods
An extensive literature review was performed by systematically searching OVID MEDLINE (January 1950March
2010) and ISI Web of Science (1900March 2010). Bibliographies of identified articles were screened for additional
relevant studies including non-indexed reports. Non-peerreviewed sources were also included: books, relevant
newspaper reports, and applicable Web material. This review
identified 1,459 papers, excluding duplicates. This list was
screened for those associated with metamfetamine toxicity in
humans and those that succinctly described the mechanism of
action, clinical features, and treatment protocols. Articles
employed in this review included case reports, case series,
animal studies and review articles that were considered
relevant.
Physico-chemical properties
Metamfetamine (CAS 537-46-2) belongs to a class of sympathomimetic drugs called phenylethylamines.2 Essentially,
they consist of a phenylethylamine structure (an aromatic
ring with a two-carbon side chain leading to a terminal amine
group) with attached groups to the amine, the alpha or beta
carbons or on the aromatic ring (Fig. 1). Both amfetamine
and metamfetamine possess a methyl derivative on the alpha
carbon of the ethylamine side chain; metamfetamine has an
additional methyl derivative on the amine (Fig. 1). Its chemical formula is C10H15N and the molecular mass is 149.24.
The hydrochloride salt of metamfetamine forms as white to
translucent crystals,3 whereas the free base forms a dark liquid. The hydrochloride salt is relatively pure and, in contrast
to amfetamine sulfate, is sufficiently volatile to allow vaporization and inhalation.3 A more detailed summary of its properties is presented in Table 1.
There are therefore two isomeric forms of metamfetamine:
(+)-metamfetamine and ()-metamfetamine (Fig. 1) and their
pharmacological profiles are distinct. The former enantiomer
is the dominant CNS stimulant and is five times more biologically active than the () enantiomer,3 which has greater
peripheral sympathomimetic activity. The () enantiomer is
also formed as a metabolite of selegiline,8 an antiParkinsonian drug.
Epidemiology
Amfetamine-like drugs have been part of human history for
many centuries. Traditional Chinese medicine includes ephedrine and pseudoephedrine extracts from the stems of Ephedra sinica Stapf (ma huang) and other species of this genera,
Fig. 1. Structures of phenylethylamine and the stereoisomers of

amfetamine and metamfetamine.
Table 1. Physicochemical properties of metamfetamine47

Property
Form
Boiling point
Melting point
Density
pKa
Log p
Solubility
Description
Colorless liquid; hydrochloride salt is a
white powder or translucent crystal
212C
Crystals: 170175C
Not available
9.9
2.07
500 mg/mL water, soluble in diethyl ether
and ethanol; hydrochloride salt is readily
soluble in water
to treat asthma and other bronchial disorders.9 Amfetamine

was first synthesized in Germany in 1887, and metamfetamine in 1893 in Japan.10 The first reported misuse of amfetamine was in 1937 when it was used by students in
Minnesota to avoid sleep during examination periods.11
Thereafter both amfetamine and metamfetamine were widely
used both clinically and illicitly during the Second World
War by the Americans, Germans, and Japanese and became a
serious problem in post-war Japan.10,12 Increasing popularity
of metamfetamine as a drug of abuse within the United States
led to its illicit production in San Francisco by 1962.13 In
later years this was expanded by Mexican traffickers with

increased distribution to the West, Southwest, and Midwest
States.13,14
The total number of present metamfetamine users worldwide is uncertain. In 2007, the United Nations Office on
Drugs and Crime (UNODC) estimated that between 16 and
51 million people aged 1564 consumed amfetamines, of
whom 5459% were metamfetamine users.15 Although this
estimate is imprecise, metamfetamine consumption is clearly
at epidemic proportions. Indeed, an earlier report from the
UNODC suggests the combined consumption of metamfetamine and amfetamine exceeds all other drugs of abuse
except cannabis.16
Production and consumption of metamfetamine is currently most concentrated in East and Southeast Asia and
North America, but there are increasing reports of similar
activity in Latin America and Australasia.17 Statistical data
on drug seizures for 2007 indicated that most occurred in
East and Southeast Asia (56%), followed by North America,17 whereas Europes contribution was only 2%. Operations in China, Myanmar, and the Philippines account for
most of the recent productions in East and Southeast Asia.15
Within Europe, ecstasy is the main amfetamine of abuse,
although there is growing evidence of increased manufacturing of metamfetamine in Lithuania, increased use in Slovakia, and an outward movement of its use beyond the Czech
Republic, where it has long been established.17,18
Mechanisms of toxicity
Metamfetamine acts in a manner similar to amfetamine, but
with the addition of the methyl group to the chemical structure. It is more lipophilic (Log p value 2.07, compared with
1.76 for amfetamine),4 thereby enabling rapid and extensive
transport across the bloodbrain barrier.19
Metamfetamine causes an increased release of key endogenous monoamines,20 principally dopamine, from the sympathetic nerve terminals. Dopaminergic neurons are involved in
three major systems in the brain: the mesolimbic, mesocortical, and nigrostriatal pathways, influencing emotional and
motivation responses, reward systems, and motor control.21
Under normal physiological conditions, catecholamines,
including dopamine, are synthesized in the presynaptic terminal and are found in both the cytoplasm and the presynaptic
vesicles. They are released by exocytosis into the neuronal
synapse in response to presynaptic action potentials, and act
at postsynaptic receptors to promulgate the action potential.22
Released monoamines will be taken back into the presynaptic
terminals by the respective uptake transporters, and metabolized.23
Metamfetamine facilitates the increased release of the key
monoamine neurotransmitters by several molecular processes
(see Fig. 2). Metamfetamine enters the presynaptic terminals
by passive diffusion across the lipid membrane and through
the membrane-bound catecholamine-uptake transporters
(dopamine, norepinephrine, and serotonin transporters).24
677
Within the cytosol, metamfetamine enters the presynaptic
vesicle through membrane-bound vesicular monoamine
transporter-2 (VMAT-2) and facilitates the redistribution of
the monoamines into the cytosol by disrupting the pH gradient whose presence is essential for driving the accumulation
of the monoamines into the vesicles.24,25
Increased monoamine concentrations within the cytosol
leads to their increased movement into the synapse through
the respective catecholamine transporters; this occurs in the
opposite direction to the usual reuptake mechanism.26 Catecholamines at elevated concentrations within the synapse
compete with, and are partially blocked by, metamfetamine
for reuptake through the catecholamine transporters, thereby
promoting prolonged neuronal activity.27 Metamfetamine
also decreases the expression of catecholamine transporters
on the neuronal cell surface,28 inhibits intracellular monoamine oxidase activity,29 and promotes the intracellular expression of tyrosine hydroxylase, which leads to increased
dopamine synthesis.30
Enhanced cytosol concentrations of dopamine can also
lead to its increased oxidation in the neuronal cytoplasm to
form dopamine quinine.25 This compound, in association
with transition metals, superoxide radicals, and hydrogen peroxide, undergoes redox recycling, leading to oxidative stress,
mitochondrial injury, neuronal apoptosis, and nerve terminal
degeneration.31 The accumulated neuronal injury from
chronic metamfetamine abuse is evidenced by losses of striatal dopamine32,33 and serotonin transporters,34 and subsequent decreases in dopamine and serotonin concentrations.35
Animal studies of chronic metamfetamine exposure have also
shown evidence of long-term injuries to presynaptic dopaminergic and serotonergic terminals.36,37
Toxicokinetics
Absorption
Following ingestion, metamfetamine is readily absorbed
across the gastrointestinal tract. Controlled studies with therapeutic formulations have indicated tmax values ranging from
3.13 to 6.3 h post-ingestion.3840 Following intranasal administration of the powder, peak plasma concentrations similarly
do not occur until approximately 34 h post-exposure.41,42
With inhalation of the vapor, metamfetamine rapidly appears
in the plasma but plasma concentrations increase slowly,
peak concentrations being reached at 2.5 (0.5) h,43 possibly
because of the ongoing availability of the drug, initially
trapped in the mucosa of the upper respiratory tract. In contrast to these delays in maximum concentrations, subjects
experienced peak subjective effects as early as a few minutes
after inhalation.43
The estimated bioavailability from smoke inhalation has
ranged from 67% to 90.3 + 10.4%,41,44 with the differences in
part depending on smoking technique and the temperature of
the flame.41 Following ingestion, one estimate was 67.2
678
L.J. Schep et al.
Fig. 2. Schematic diagram summarizing the mechanisms whereby metamfetamine facilitates the release of dopamine and other
catecholamines from neuronal terminals into the synapse. Metamfetamine () enters the cell by passive diffusion (i) or via membranebound dopamine reuptake transporters (ii). Metamfetamine causes the redistribution of dopamine () from presynaptic vesicles into the
neuronal cytosol (iii) and promotes the activity and expression of tyrosine hydroxylase (iv) thereby contributing to elevated dopamine
concentrations within the cytosol, leading to increased movement into the synapse via the dopamine transporter (ii). Metamfetamine also
prolongs monoamine neuronal activities by blocking their presynaptic re-uptake (v), decreasing the expression of transporters at the cell
surface and inhibiting monoamine oxidase activity (vi).
3.1%38 whereas the percentage of unmetabolized drug

absorbed systematically following intranasal insufflations
was greater at 79%.41
venous use.48 Because of metamfetamines low molecular

weight and high lipid solubility, there is also considerable
transfer from maternal to fetal blood.4951
Distribution
Metabolism
Metamfetamine is distributed to most parts of the body.

Reported volumes of distribution in one study of habitual
abusers were 3.73 0.94 and 3.80 1.05 L/kg following
doses of 0.25 mg/kg and 0.5 mg/kg, respectively.45 One study
has suggested that in the presence of ethanol, the volume of
distribution of metamfetamine decreases, which may be due
to ethanol displacing metamfetamine from peripheral binding
sites.45 There is limited information on whether metamfetamine significantly binds to plasma proteins; some binding
has been demonstrated for amfetamine (20%).46
As metamfetamine has a relatively high lipophilicity
(Table 1), it would be expected to distribute extensively
across high lipid-content tissues such as the bloodbrain barrier.47 Unsurprisingly, metamfetamine is also distributed into
breast milk,48 appearing in the milk within minutes of intra-
The predominant site of metamfetamine metabolism is the

liver, mainly involving the cytochrome isoenzyme, CYP2D6.
In humans, the major metabolic pathways are aromatic
hydroxylation producing 4-hydroxymetamfetamine and
N-demethylation to form amfetamine.52,53 Other minor
metabolites include norephedrine, 4-hydroxyamfetamine,
4-hydroxynorephedrine, and possibly benzyl methyl
ketoxime and benzoic acid.52,54 A summary of these pathways is presented in Fig. 3. Glucuronide and sulfate conjugates of 4-hydroxymetamfetamine are also formed.55
Interindividual differences in metabolism may be largely due
to CYP2D6 variability.53 Metabolism appears to be suppressed by ethanol consumption,56,57 although, paradoxically,
chronic ingestion of ethanol may increase the rate of metamfetamine hydroxylation.56
679
Fig. 3. A summary of the metabolic pathways of metamfetamine52,54: (i) Aromatic hydroxylation, (ii) N-demethylation, (iii) -hydroxylation,
(iv) oxidative deamination, and (v) side chain oxidation. In humans, the major metabolites are 4-OH metamfetamine and amfetamine.
Although metamfetamine is metabolized to amfetamine

(Fig. 3), investigations with therapeutic doses of
metamfetamine suggest that the contribution of amfetamine
to observed subjective effects is negligible.43,44 Peak concentrations of amfetamine in volunteers were substantially lower
than those of the parent drug throughout the investigated time
interval. In addition, the time to achieve peak plasma concentrations of amfetamine was delayed. Studies found that the
amfetamine peak can be delayed from 10 to 24 h following
inhalation43,44 and 17 + 3.3 h following intravenous injection.44 Although it is expected there would be at least some
delay before the concentrations of the metabolite peaked, the
authors of these studies did not hypothesize why it was so
long. However, the clinical pharmacokinetics of high doses
of illicit metamfetamine remain to be described adequately
and theoretically higher doses may produce greater clinical
effects attributable to the amfetamine metabolite.
Elimination
Metamfetamine is excreted predominantly in the urine, and to
a lesser extent by sweating and fecal excretion.52,58 One study
found that about 90% of a 14C-labelled dose was excreted in
urine over the first 4 days following ingestion, with the
majority of the drug appearing in the first 48 h.54 Studies
investigating the percentage of renal elimination of the parent
drug compared with metabolites have produced varied
results, with values for the former ranging from 18% to 55%,
versus up to 15% as the 4-hydroxymetamfetamine metabolite, and 2% to 10% as amfetamine.38,44,54,59,60 However, such
differences are not surprising, given the likely considerable
interindividual variability in metabolism, and possible
changes in individual metabolic efficiency with more regular
use. Other factors affecting urinary elimination include dose,
urine flow, and urinary pH.38
As metamfetamine is a weak base (pKa 9.9),61 acidification
of the urine can markedly enhance its excretion.59 Under these
conditions it remains predominantly in the ionized state, resulting in significantly decreased renal tubular reabsorption, leading
to 5570% excretion of the unchanged drug. In contrast, as little
as 12% is eliminated unchanged in highly alkaline urine.59
The renal clearance of metamfetamine averaged 214
120 mL/min following a 10-mg dose and 120 33 mL/min
following a 20-mg dose.60 In a second study, following the
ingestion of 10 or 20 mg doses, clearance averaged 159 18
mL/min.38 As renal clearance values have been reported in
excess of glomerular filtration rates, it is postulated that elimination could occur partly by active transport, which may
become saturated.60
Reported terminal half-lives for metamfetamine have varied considerably from 9.1 4.0 h to 25.2 6.0 h,38,39,44,60,62
64
although most of the reports cited mean values between 9
and 12 h.38,39,44,62,64 The route of drug administration does
not appear to significantly alter the half-life.41,44
680
Clinical features
Exposure to metamfetamine can occur through a variety of
routes, including ingestion,131,179 injection,147 nasal insufflation,113 and inhalation (smoking)70; less common routes are
urethral,180 rectal,67,82 and vaginal.72
Effects following metamfetamine exposure can vary
widely, depending on dose, route, duration (acute and/or
chronic), and pattern (e.g., frequency) of use. A comprehensive summary of signs and symptoms reported in published
case reports and case series is presented in Table 2. The
reviewed literature indicates a predominance of adrenergic
effects, characteristic of a sympathomimetic toxidrome,
although with significant variations between patients. At relatively low doses of between 5 and 50 mg, the major effects
include euphoria, positive mood, heightened general arousal,
and decreased fatigue, with acute improvement in sustained
attention and a reduced appetite, as well as evidence of moderate tachycardia and hypertension.4144,62,64,181191
A summary of doseresponses with key cardiovascular parameters are presented in Table 3. Subjective effects and measures of
cardiovascular function seem to increase with dose,42 although
there is limited information pertaining to specific effects at higher
doses. One clinical study involved 16 inpatients in a psychiatric
unit, all of whom had previously been admitted for amfetaminerelated psychosis, were administered escalating intravenous
doses of metamfetamine to replicate their previous condition.192
The drug precipitated clinical psychosis in 11 patients with doses
ranging from 55 to 240 mg; another patient required 640 mg to
induce this clinical condition. Reported effects included thirst,
diaphoresis, paresthesia, hypertension, throbbing headaches,
paranoia, hallucinations, and aggressive thoughts or behaviors.192
It is predicted that doses greater than 150 mg would cause toxic
effects in an infrequent user.3
Overall, reported clinical effects following higher doses of
metamfetamine in adults may include tachycardia, hypertension, palpitations, tachypnea, chest pain, gastrointestinal
upset, mydriasis, diaphoresis, hyperthermia, and hyperreflexia, along with CNS effects of anxiety, agitation, delirium,
and psychosis.72,73,81,83,89,94,114
A variety of cardiovascular and cerebrovascular injuries
may develop following exposure to metamfetamine. Effects
include ventricular dysrhythmias,77 myocardial dysfunction
and ischemia with or without infarction,78,83,106,113 cardiomyopathy,70,123 and aortic and other vascular dissections.105,145,148 A major factor is vasoconstriction and/or
vasospasm, which can occur because of excess catecholamine activity upon a1-adrenoreceptors. This may result in
myocardial and other tissue ischemia and, along with the
hyperdynamic circulation, is a major cause of hypertension.
Inadvertent arterial injections of sympathomimetic drugs may
additionally cause localized vasospasm,193 although this does
not appear to have been reported for metamfetamine.
Traditional or magnetic resonance angiography of cerebral
vessels may demonstrate narrowing or frank occlusion of
small- and medium-sized arteries, or beading (regions of
L.J. Schep et al.

blood vessels where segments of stenosis alternate with normal or dilated intervening sections).75,76,135137,143,194 Pathological assessment has shown evidence of necrotizing
vasculitis (an inflammatory reaction of blood vessels, resulting in fibrinoid necrosis of tissue and associated leukocytic
infiltration of the blood vessel walls) that is similar to periarteritis nodosa.195 Ensuing disorders may include cerebral
ischemia152 with ischemic stroke143 and/or hemorrhagic
stroke, which may arise from intracerebral104,194 or subarachnoid hemorrhage.152,194 Cerebral edema,153 acute lung
injury,171 and ischemic colitis have also been reported.131,133
Vasculitis can also result in impaired limb perfusion,140
visual compromise,174 and/or renal and hepatic failure.93,108
Hepatic damage may also arise from any of a variety of
causes, including direct toxicity, the secondary effects of
hypotension, hypoxia, hyperthermia or lipid peroxidation, or
as a complication of viral hepatitis or other infection caused
by the use of contaminated needles.71,95,111
Repetitive movement disorders such as choreoathetosis,
although uncommon, can develop in both adults and children.85,96,118 Serotonin toxicity, although not reported specifically for metamfetamine, has been reported with dexamfetamine
in combination with venlafaxine and citalopram.196 As metamfetamine both increases presynaptic release and prevents reuptake
of serotonin,197 there is a theoretical risk of serotonin toxicity
following its use in association with other serotonergic agents.
Patients with agitation, excessive muscular activity, and hyperthermia are at risk of developing rhabdomyolysis65,81,96,118,178
and subsequent renal failure.89,101,111,178 Hyperkalemia can
occur secondary to renal impairment93,94 or as a result of
rhabdomyolysis. Profuse sweating and tachypnea may lead to
significant fluid and electrolyte depletion.94 Metabolic acidosis and coagulopathy can develop secondary to dehydration,
inadequate peripheral perfusion, seizures, or hyperthermia.66,68,79,81 However, hyponatremia secondary to increased
secretion of antidiuretic hormone and/or increased fluid
intake, as described with 3,4-methylenedioxymetamfetamine
(ecstasy) intoxication,198 has not been reported following
exposure to metamfetamine.
Ocular effects can include not only mydriasis,79,94 but also
keratitis,175 corneal ulceration,175,176 decreased visual acuity
or transient loss of vision,173,174 and retinal hemorrhage.173
Most of these ocular effects are thought to be due to the sympathomimetic effects of vasoconstriction, vasospasm, or
complicating necrotizing vasculitis.173,174
Fatal outcomes are well recognized, typically arising from
cardiac dysrhythmias, myocardial infarction, cardiorespiratory arrest, intractable seizures, hypoxic brain damage,
hyperthermia, or intracerebral bleed.68,70,73,79,89,92,109,150,153,199
Chronic misuse
In addition to these effects, the long-term use of metamfetamine
in high doses may lead to non-ischemic cardiomyopathy,112
congestive heart failure,70,112,117 pulmonary hypertension,122
681
Table 2. Anticipated signs and symptoms following acute and chronic exposure to metamfetamine
Class
Cardiac
Vasculature
Neurological
Signs and symptom
Case reports (references)
Tachycardia
Hypertension
Bradycardia
Hypotension
Cardiomegaly
Congestive heart failure
Chest Pain
Coronary vasospasm
Myocardial infarction/Ischemia
Elevated troponin
ECG abnormalities
Abnormal Q
Abnormal QRS
Poor R wave progression
Abnormal QT
T changes
ST changes
Unspecified dysrhythmia
Sinus tachycardia
Sinus bradycardia
Ventricular tachycardia
Ventricular fibrillation
Left or right bundle branch block
Heart block
Myocardial hypertrophy
Ventricular dysfunction
Cardiomyopathy
Myocarditis
Myocardial necrosis
Contraction band necrosis
Ischemic colitis
Vasculitis (angiitis)
Carotid artery aneurysm
Vascular dissection
Vascular beading
Paresthesia
Numbness
Hyperreflexia
Tremor
Rapid and rolling eye
movements
Drowsiness
Headache (including occipital)
6593
65, 67, 69, 72, 75, 77, 84, 9093, 101103
106
66, 70, 74, 79, 106108
91
111
66, 77, 83, 106, 113
106
70, 78, 83, 101, 106, 113
65, 77, 82, 106, 111
Cerebral ischemia
Cerebral infarcts/stroke
Cerebral hemorrhage
Intracerebral/intracranial/
intraventricular
Subarachnoid
Hemiparesis or hemiplegia
116
107
77, 103, 118
77, 78, 101
77, 83, 101, 106, 107, 113
75
70, 72, 89, 101, 116
78, 121
106
122124
70, 77, 122, 123
70, 77, 107, 123
111
101
101, 129, 130
131134
75, 76, 93, 103, 108, 135144
145
105, 109, 116, 145148
75, 76, 135138, 143
67, 81
136, 143
72, 137, 138, 147
65, 73, 74, 92
85, 88
66, 73, 75, 76, 80, 102, 107, 135, 147
66, 75, 80, 81, 87, 101103, 135, 136, 138,
142144, 146, 147, 149151
101, 143
102, 136, 143, 146
75, 76, 80, 87, 135, 137139, 141, 142,
144, 147, 149151, 153156
80, 138, 139, 147, 149
87, 91, 102, 135, 137, 142144, 146, 147,
151, 154
Case series (references)

94100
97, 99, 100, 104, 105
94
109, 110
112
105, 112, 114
99, 110, 115
100
115, 117
117
117
115, 117
99, 115, 117
117
117
117, 119
119, 120
110, 117, 125, 126

110, 112, 117
112, 127, 128
109, 110, 112, 126

104
105
98
104, 114
152
104, 152
104, 109, 127, 152
104, 109, 110, 125, 152
104
(Continued)
682
L.J. Schep et al.
Table 2. (Continued)
Class
Signs and symptom

Aphasia
Ataxia
Seizure
Coma
Cerebral edema
Death
Psychiatric
Agitation
Respiratory
Anxiety
Crying
Aggressive behavior
Confusion/disorientation
Delirium/hallucinations
Paranoia
Psychosis
Choreoathetosis
Tachypnea
Dyspnea
Apnea
Aspiration pneumonia
Pulmonary edema
Hepatic
Ocular
Renal
Metabolic
Pulmonary hypertension
Abnormal liver function tests
Acute liver failure
Mydriasis
Intraretinal hemorrhage
Decreased/blurred vision
Amaurosis fugax (transient loss
of vision)
Retinal vasculitis
Keratitis/corneal ulceration
Crystalline retinopathy
Elevated serum creatinine
Elevated blood urea nitrogen
Urinary retention
Hematuria
Hyperuricemia
Oliguria
Renal insufficiency/failure
Hyperkalemia
Hypokalemia
Hypocalcemia
Hyperglycemia
Hypoglycemia
Elevated lactate dehydrogenase

102, 143, 144, 146
150
72, 73, 75, 76, 87, 89, 92, 139, 147, 153
72, 75, 79, 92, 101, 139, 151, 153, 154,
158
76, 79, 101, 141, 149, 153, 156, 159, 160
68, 70, 73, 75, 79, 89, 92, 101, 108, 120,
124, 139, 141, 145, 149, 151, 153, 156,
158163
65, 67, 69, 72, 81, 82, 85, 88, 111, 147,
163
86
66, 71, 74, 84, 89, 150
73, 76, 80, 87, 89, 111, 138, 151
68, 71, 74, 85, 89, 165168
85, 165, 167, 168
71, 85, 165167
85, 86, 88, 118
66, 67, 70, 74, 75, 79, 8486, 88, 91, 107,
111
66, 70, 77, 107
72, 92
72
68, 70, 73, 75, 79, 91, 103, 107, 111, 123,
129, 130, 141, 156, 158162, 171
122
71, 111, 153
71, 79, 89, 111
65, 69, 7275, 79, 82, 84, 90, 150, 154
173
80, 103, 136, 173
86, 174

104
98
97, 98, 157
94, 157
127
104, 105, 110, 127
94100, 114
99, 100
96, 98
99
104, 114, 164
94, 95, 99, 114, 164, 169
164
95, 164, 169, 170
96
112
110, 127
172
94
75, 174
175, 176
177
66, 74, 89, 93, 101, 103, 111
101, 103
90
90, 107, 138
81
79, 81, 90
79, 89, 91, 93, 101, 108
79, 93, 101
107
81
66, 72, 121
85
71, 84, 91, 118
157
157
157
94, 100, 105, 157
94
(Continued)
683
Table 2. (Continued)
Class
Signs and symptom

Metabolic acidosis
Hyperthermia
Hematological
Musculoskeletal
Gastrointestinal
Thrombocytopenia
Leukocytosis
Disseminated intravascular
coagulation
Muscle rigidity
Elevated creatinine kinase
Myalgia
Rhabdomyolysis
Nausea/vomiting
Diarrhea
Abdominal pain
Hematemesis
Hematochezia
Diaphoresis
Flushed face
Dermal
66, 68, 71, 72, 74, 84, 107, 121

71, 74, 75, 79, 81, 89, 91, 101, 108, 111,
163
111, 153
81, 85, 90, 108, 133
81, 94, 111
74
65, 71, 72, 74, 78, 8184, 89, 101, 111,
118, 121
81
65, 71, 72, 74, 81, 101, 111, 118
77, 80, 81, 93, 103, 107, 108, 135, 142,
144, 147, 149, 160
81, 133
65, 81, 90, 103, 106, 108, 131134, 158
89, 138
89, 132
66, 74, 81, 85, 89, 113
76
and
cognitive
impairment.200
Irreversible
neuronal
201,202
likely caused in part by long-term dopamine
changes,
depletion32 may develop, and isolated reports suggests that some
syndromes such as parkinsonism may be causally linked in some
patients with a previous history of metamfetamine abuse.203
The adverse psychiatric effects following irreversible
neuronal changes can include a lasting psychosis, similar to
66, 97, 100, 157

94, 9698, 100, 104, 125, 157
110
94
94, 96, 97, 100, 178
94, 98, 100, 157, 178

95, 98, 104
95, 105, 114
94, 99
paranoid schizophrenia.164,204 This is typically manifested by

hallucinations, delusions, and paranoia;164,167 behavior can
become bizarre, destructive, and violent.205 Self-mutilation
without suicidal ideation has been reported.206
Changes in the physical appearance of chronic abusers
often occur, as an aging effect is commonly produced.207 These
physical changes usually result from associated malnutrition,
Table 3. Mean changes in key cardiovascular parameters of heart rate, diastolic and systolic blood pressure
(relative to their respective baseline values) following exposure to metamfetamine by various routes
Dose (mg)
12*
15
15*
15.5
17.5*
25*
30
30
30
30
30
30
30*
30*
35*
40
50
50*
Route
Heart
rate (BPM)
Diastolic
BP (mmHg)
Systolic
BP (mmHg)
Reference
Intranasal
Intravenous
Oral
Intravenous
Intravenous
Intranasal
Inhalation
Inhalation
Intravenous
Intravenous
Intravenous
Intravenous
Oral
Oral
Intravenous
Inhalation
Intranasal
Intranasal
1
9
9
25
18
13
32
30
21
18
28
13
8
14
30
21
19
7
12
10
6
14
9
17
17
12
9
14
14
20
14
20
10
10
17
4.9
11
13
23
22
16
18
20
21
18
18
20
30
28
35
16
20
24
42
181
185
44
62
42
44
43
189
186
182
181
185
64
62
41
41
42
*Doses were based on the weight of a 70-kg adult.
684
weight loss, and poor hygiene.207 A further physical complication is meth mouth (significant caries of the teeth), which
is thought to be due mainly to neglect and poor oral hygiene
or poor diet. Additional contributing factors may also include
xerostoma and/or bruxism.208,209 Excessive tooth decay has
been erroneously attributed to contaminants of illicitly manufactured metamfetamine; contaminants appear not to contribute in any significant manner to meth mouth.209
Tolerance to the effects of metamfetamine has been
reported in chronic users.92,210 Reports describe long-term
addicts taking up to 15 g per day in divided doses without
evidence of serious acute morbidity.211 Dependence can also
develop with chronic use, so that a period of abstinence typically results in a withdrawal syndrome, marked more by psychological than physical complaints.212 Initial symptoms are
thought to be due to depletion of CNS neurotransmitters and
may consist of exhaustion, depression, agitation, and anxiety;
this early phase is typically labeled the crash.212214
Following this initial phase, further withdrawal effects may
occur, including symptoms of prolonged depression with
anhedonia, as well as insomnia or hypersomnia, anxiety, irritability, paranoia, aggression, and craving for the
drug.212,214,215 The severity appears related to the dosage and
duration of previous metamfetamine use.216 The majority of
withdrawal symptoms tend to regress linearly over time,213
typically persisting for 5 days to 3 weeks,215,216 although
fatigue and depression may continue for up to 12 months.212
Severe depression during withdrawal may lead to suicidal
ideation requiring inpatient psychiatric management.212
Although there are presently no pharmaceutical agents available that may assist in minimizing metamfetamine dependence, recent clinical trials suggest some medications and
two agonist replacements show some promise.217
Effects during pregnancy
Metamfetamine use during pregnancy may have adverse
effects upon the growth and development of the fetus. It is
thought complications can occur by either direct transplacental
transfer of the drug itself or secondary to its placental or maternal effects, leading to changes in the in utero environment.
Such secondary changes may result from the vasoconstrictive
effects of the drug; ovine models have demonstrated maternal
hypertension and decreased uteroplacental blood flow, accompanied by fetal hypertension, hypoxia, and acidosis.218,219
Chronic metamfetamine use may also lead to poor maternal
nutrition, thereby contributing to adverse fetal effects.220 The
most common effect noted in newborns appears to be
decreased weight, length, and head circumference.220222
Metamfetamine abuse during pregnancy may also lead to placental insufficiency and/or abruption;49,220 premature delivery,
fetal death, and maternal deaths have also been reported.153
Congenital anomalies including clefting, cardiac anomalies, cranial abnormalities, and abnormal brain development
have additionally been reported with metamfetamine and
L.J. Schep et al.

other amfetamines.223226 However, the overall validity of
these reports may be limited due to small sample sizes,
reporting bias, reliance on maternal reporting of drug use,
multiple drug exposures, or other nondrug factors.
A mild withdrawal syndrome has been noted in newborns.220,227 There is only limited data, but one series of
reports following children exposed to amfetamines in utero
reported increased behavioral problems at 4 years old (especially if the mother was still addicted),228 aggression and
hyperactivity at 8 years,229,230 and difficulties with physical
fitness activities at 14 years.231 The work was, however, limited by small sample size, prenatal polydrug use, the lack of a
control group, and the possible contribution of poor parental
skills associated with the continued abuse of metamfetamine.
Effects upon children

In children, the effects of direct exposure most commonly
consist of agitation, irritability, crying, tachycardia, and vomiting. Less common effects include hyperthermia, ataxia, roving
eye movements, rhabdomyolysis, and seizures.69,86,88,9698,232
However, severe toxicity is not often reported in children following exploratory ingestions; in one series of 22 cases, seizures only occurred in 2 (9%) of 22 patients.97
Management
Diagnosis
The diagnosis of metamfetamine intoxication is typically
made on the basis of the patients history along with clinical
features of sympathomimetic poisoning. This diagnosis
should be considered for any clinical presentation involving
hyperthermia, excess sympathetic tone, or hallucinations.233
Confusion can arise particularly with pediatric admissions,
for example, in which intoxicated patients have been misdiagnosed as with Centruroides sculpturatus envenoming.88,98
Qualitative analytical tests have been developed and a variety of immunoassays are available for the detection of
metamfetamine and other related amfetamines. Unfortunately, these urine immunoassays are not highly sensitive or
specific, and can lead to false-positive results.234236 Additionally, a true-positive result does not necessarily indicate
that the presenting illness is due to metamfetamine toxicity. If
required, confirmation of metamfetamine exposure can typically be obtained using gas chromatography-mass spectrometry,237 liquid chromatography-mass spectrometry, or thinlayered chromatography. However, the lack of correlation
between serum or urine concentrations and clinical effects
means such tests are of limited value in acute management of
the patient and should not be considered a routine component
of assessment procedures. Additionally, as the diagnosis is
usually made based on clinical effects, neither is identification of the stimulant often required.
685
Stabilization
Supportive care
Patients may present to an emergency department in a critical

condition with seizures, cardiac arrest, or stroke (or other
acute consequences of arterial spasm or rupture). Those
ingesting packaged metamfetamine (body packers/stuffers)
may suffer overwhelming poisoning if packages leak their
contents.73,158,159 Agitation and combativeness can make initial treatment of these patients difficult, and emergency intervention is often the priority. Significant hypertension,
agitation, neurological, or respiratory compromise, or hyperthermia requires prompt, aggressive treatment. Appropriate
airway management including airway control, oxygenation,
and ventilation are required in obtunded patients.
Cardiovascular
Hypertension is common, often severe, and presents a risk for
intracranial hemorrhage. In mild cases, a benzodiazepine
should suffice, along with providing a calming environment.
If blood pressure does not settle, further control should be
attempted with short-acting titratable antihypertensive agents
such as nitroprusside246 0.51.5 g/kg/min initially by intravenous infusion, then increased in steps of 500 ng/kg/min
every 5 min within the range 0.58 g/kg/min247 or an
1-adrenergic receptor antagonists such as phentolamine248
25 mg intravenously, repeated if necessary.247 Beta blockers
are contraindicated as the blockade of 2-receptors could theoretically lead to increases in blood pressure because of
unopposed 1-adrenergic receptor stimulation.246 Labetalol,
50200 mg by intravenous infusion at a rate of 2 mg/min,247
has been recommended as a third-line agent in patients with
refractory hypertension given its mixed - and -receptor
antagonist properties,246 but caution is still warranted as its
-antagonist effects exceed its -antagonist effect.249 Acute
aortic dissection secondary to hypertensive crisis should be
treated with both - and -blockers in combination.105 Periodic clinical and radiographic follow-up is recommended to
help identify any secondary aneurysmal dilation that may
occur.105
Mild sinus tachycardia may also respond to a benzodiazepine and the provision of a non-stimulating environment. In
the absence of circulatory compromise, further intervention
may not be required, but hemodynamically significant sinus
tachycardia may increase the risk of myocardial ischemia and
infarction and/or ventricular dysrhythmias.246 Therefore, if
refractory to benzodiazepine treatment, very cautious use of a
nonselective -blocking agent to control heart rate may be
considered.246 Serial ECGs should be monitored for onset of
dysrhythmias. Supraventricular and ventricular dysrhythmias should be managed following standard advanced cardiac life support.233 Correction of hypoxia, acidosis, and
metabolic abnormalities will minimize the risk of dysrhythmia.250
Elevated serial cardiac enzymes in association with ECG
features of ischemia and chest pains may suggest the occurrence of an acute coronary syndrome (a collection of clinical
effects consistent with myocardial ischemia), which can
progress to acute myocardial infarction.112,113 These parameters should therefore be monitored closely. Additionally, coronary artery angiography may be required for diagnostic,
prognostic, and therapeutic reasons. Echocardiography may
be indicated and is especially recommended if there is cause
to suspect cardiomyopathy (more associated with chronic
metamfetamine use).70,123 Treatment recommendations for
stimulant-induced acute coronary syndromes are mainly
derived from those for cocaine intoxication,246 which recommend a benzodiazepine initially and a calming environment.
Pharmacological treatments for unstable angina and myocardial infarction generally follow standard protocols. Nitroglycerin in either sublingual, oral, topical, or intravenous
Decontamination
There are limited data on the benefits or otherwise of decontamination following oral ingestion; however, it is unlikely to
be of significant benefit in the majority, because of the drugs
rapid absorption, and patients often present late and are less
than cooperative.
Nevertheless, although the efficacy of activated charcoal
has not been assessed formally in human metamfetamine poisoning, its prompt use may assist in minimizing the adverse
effects from a large recent ingestion. In a mouse model, activated charcoal given contemporaneously with metamfetamine has been shown to delay the onset of toxicity and
decrease early mortality.238 However, charcoal should only
be considered in patients who are alert, stable, and cooperative, and who have ingested a potentially toxic amount up to
1 h previously.239 Charcoal 50100 g should be administered
cautiously, because of the risk of impending seizures and/or
loss of airway protective reflexes.233 In the case of significantly symptomatic patients, the risk of administration likely
outweighs any benefit74 and general supportive measures
should take precedence. Gastric lavage is unlikely to be of
benefit233 and the induction of emesis is not recommended.240
Patients suspected of body packing158,241 or stuffing242
should undergo abdominal imaging using CT, although this
may not be conclusive.100 Gastrointestinal decontamination
may be of benefit in these patients. The role of activated charcoal in this situation has not been well defined, but it can be
considered in those at risk of packet rupture.243 Whole bowel
irrigation with polyethylene glycol solution can also be considered for the removal of ingested packets of illicit drugs.244
This is best administered through a nasogastric tube with suggested dosing regimens of 500 mL/h in children 9 months to 6
years, 1000 mL/h in children 612 years, and 15002000 mL/
h in adolescents and adults.244 It should be continued until the
rectal effluent is clear or until there is no evidence of packages
in the gastrointestinal tract.244 In situations of symptomatic
body packers who are expelling degenerating or leaking packages, or if complete mechanical bowel obstruction occurs,
monitoring in an intensive care unit and surgical removal of
packages through laparotomy may be required.243,245
686
form has been used and titrated to effect in patients suffering
from cocaine intoxication.251,252 In cases of unstable angina
and myocardial infarction refractory to benzodiazepine and
nitrate therapy, a potent 1-receptor antagonist such as
phentolamine246,253 25 mg intravenously may be considered.247 Angioplasty may be indicated in cases of coronary
artery stenosis.113
Hypotension is a rare finding, usually occurring late in the
course of poisoning secondary to other factors, and appears to
be associated with a poor prognosis.73,89,94 Milder cases are
treated initially with intravenous fluids such as plasma
expanders or crystalloids; a poor response or progression to
shock requires vasopressors233 and admission to an intensive
care unit with central cardiovascular monitoring.
Neurological/psychiatric
Severe agitation, psychosis, and/or choreoathetoid movements may be prominent following metamfetamine intoxication. Patients with only minor agitation may be managed
without pharmaceutical intervention by providing a quiet,
nonstimulating environment. More severely agitated
patients may require physical restraints to prevent self
harm; pharmacological sedation should then be instituted
immediately as resistance to restraints can lead to continued
heat production and rhabdomyolysis. The intravenous route
of drug administration may be difficult or unsafe in agitated
patients, although it has the advantage of enabling titration
of the medication to effect.254 In these circumstances, initial
intramuscular administration can be used until intravenous
access is gained.255 With repeat intramuscular administration there is the risk that under- or over-sedation may
occur.254,256
There is controversy concerning the role of benzodiazepines versus antipsychotics for controlling agitation.254,257
Benzodiazepines, antipsychotics, or both appear to be commonly used in emergency departments for treating agitation
of uncertain etiology,255,258 but there are few studies systematically comparing the use of these agents,258 and this limitation also applies to agitation induced specifically by
metamfetamine. However, initial control of agitation should
be undertaken with benzodiazepines rather than antipsychotic
medications.233,257,259261 Initially, in an adult diazepam 510 mg
intravenous or lorazepam 12 mg intravenous should be
given; doses can be repeated until the patient is sedated.261
Midazolam 14 mg can be administered intramuscularly in
patients without intravenous access.233 High doses may be
required;262 one author describes total doses exceeding 100 mg
of diazepam or its equivalent being required to achieve adequate sedation.260
Antipsychotics such as droperidol, olanzapine, and haloperidol can induce cardiac dysrhythmia or hypotension,
interfere with thermoregulation, or precipitate extrapyramidal side-effects including dystonic reactions.257,259,263 Consequently, they have not generally been recommended as
first-line agents for the control of agitation.257 Nevertheless,
L.J. Schep et al.

droperidol has been used successfully to sedate patients
with metamfetamine toxicity.84,264 In an open-label
study264 involving a subset of metamfetamine-intoxicated
patients presenting to an emergency department,265 it was
shown to act more quickly and require fewer repeat doses
than lorazepam to achieve adequate sedation.264 However,
use of these compounds as second-line management should
only be considered in patients without cardiovascular
abnormalities or elevated temperature.250 They may antagonize some of the effects of amfetamines by dopamine
blockade,248 and therefore may be helpful for symptoms
arising from stimulation of dopaminergic receptors, such as
choreoathetosis.96
Intracerebral and subarachnoid hemorrhages are recognized complications of intoxication, and are thought to be
due to acute hypertension (secondary to vasoconstriction or
vasculitis, and/or increased cardiac output), leading to vessel wall stress and rupture.80,102,135,138,143,152,194,266 In addition, vasoconstriction may possibly lead to cerebral
ischemia101,152 with risk of ischemic stroke.143 Any patient
complaining of a severe headache, or displaying evidence
of hemiparesis, hemiplegia, or reduced consciousness,
requires intracranial CT imaging; this, however, may not
detect all abnormalities. Susceptibility may be increased
in patients with arteriovenous malformations.80 Significantly symptomatic or comatose patients may develop
intracranial hematomas requiring surgical evacuation.102,135,142,147,154,267 Although corticosteroids have been
used in the management of vasculitis and intracerebral hemorrhage,76,104,108,137,153 only slow improvement of neurological symptoms has been reported, generally in alert patients
with evidence of only minor injuries.76
Seizures typically appear to be short-lived and respond
to benzodiazepines.233 However, if prolonged, they may
contribute to hyperthermia, metabolic acidosis, and rhabdomyolysis. Initial pharmacological treatment should be
with a benzodiazepine: lorazepam 4 mg by slow intravenous injection (into a large vein) in an adult (in a child
under 12 years 100 g/kg; max. 4 mg), repeated once after
10 min if necessary; alternatively, diazepam 10 mg intravenously in an adult at a rate of 5 mg/min (in a child under
12 years 300400 g/kg), repeated once after 10 min if
necessary.247 If, however, seizures are refractory, phenobarbital (10 mg/kg, infused at a rate of not more than
100 mg/min)247 may be necessary as second-line therapy.
If adequate control is still not achieved, muscle paralysis
with assisted ventilation (general anesthesia) may be
required.233
Fluid and electrolytes
Significant body fluid depletion can arise from various factors, including tachypnea and profuse sweating, which may be
due in part to hyperthermia generated by the increased muscular and metabolic activity. Decreased fluid intakes may also
exacerbate dehydration. Acidbase status, serum electrolytes,

and fluid balance should be closely monitored. Intravenous
rehydration may be required, guided with invasive hemodynamic monitoring, if necessary.94 Severe hyperkalemia
should be treated with hemodialysis94 if it does not respond to
dextrose and insulin.
Metabolic
Severe hyperthermia may develop as a result of disturbance of central thermoregulatory systems or muscle
hyperactivity because of agitation or seizures.263 As outlined above, benzodiazepines should be used to control
agitation and reduce muscle activity, whereas fluid
replacement is required to correct dehydration. External
cooling measures should also be employed; these include
water mist and fans, ice packs, and baths.250,263 If unsuccessful, neuromuscular paralysis with ventilatory support
is recommended.263 Metabolic acidosis, which may arise
secondary to seizures and/or inadequate tissue perfusion,250 is associated with a poor outcome,94 and should be
managed with adequate administration of sodium bicarbonate and fluid replacement.72,74
Refractory hyperthermia could also suggest serotonin
toxicity; particularly at risk are those taking other therapeutic or recreational serotonergic drugs. As noted, benzodiazepines are useful for agitation, and experimental animal
studies suggest that they may also have a nonspecific serotonin agonist effect.268 Although there have been no
randomized controlled trials, cyproheptadine and chlorpromazine may be useful if a diagnosis of serotonin toxicity is
made.269,270 Cyproheptadine is only available in oral form
and should be given by mouth or through a nasogastric tube
in unconscious patients. The suggested initial dose is 12 mg,
followed by 2 mg 2 h later, then titrating against response
until improvement in autonomic and neurological abnormalities is achieved.269,271 A recommended maintenance
dose regimen is 8 mg every 6 h.269 Chlorpromazine can be
administered parenterally; the initial suggested dose is
12.5 mg, with a maximum of 1 mg/kg.272
Rhabdomyolysis
Those suffering severe agitation, excessive muscular
activity, or hyperthermia are at risk of developing rhabdomyolysis.94,118,263 Any patient who presents to hospital
with severe agitation should have their creatine kinase
activity measured. 273 Serum or urine myoglobin concentrations may also be of use. 274 If present, rhabdomyolysis
should be treated aggressively with intravenous fluids to
ensure good renal output, thus reducing urine myoglobin
concentrations and the attendant risk of renal damage.275
Although urinary alkalinization might also help minimize
risk of myoglobin-induced renal damage, 97,275 care
should be taken as alkalinization has the effect of
increasing retention of metamfetamine, slowing its
excretion.59
687
Renal
Metamfetamine may cause contraction of the bladder sphincter leading to urinary retention.90 If the patient has a distended bladder or is suffering suprapubic pain, they require a
physical examination and ultrasonography. If there is evidence of a contracted bladder sphincter, catheterization
should be undertaken.
Acute renal failure can develop subsequent to rhabdomyolysis, vasculitis, hyperthermia, circulatory collapse, or a combination of these factors.79,84,93,273 Careful monitoring to
detect evidence of early renal failure is required. This
includes monitoring urine output and serum creatinine concentrations. Acute renal failure should be treated urgently
with hemodialysis, hemodialfiltration, or hemofiltation.
Gastrointestinal
Any patient presenting with abdominal pain or a history of
recent bloody diarrhea and having a history of drug abuse
suggests the possibility of ischemic colitis, and therefore
requires a CT scan or sonography. Low-grade ischemia typically heals within a short period of time, whereas full thickness ischemia may require prompt resection.133
Enhanced elimination
As metamfetamine is a weak base (pKa 9.9),61 acidification
of the urine can enhance its excretion59 because in more
acidic urine it becomes mostly ionized, and thus renal tubular
reabsorption is minimized.84 An early case report advised urinary acidification;84 however, this is no longer recommended
clinically as there are limited data on its effectiveness, and
the attendant risk of causing or aggravating acidosis, seizures,
or rhabdomyolysis would outweigh any potential benefits.276
Hemodialysis, hemoperfusion, hemofiltration, and other
techniques to enhance removal of metamfetamine are
unlikely to be effective, because of its high volume of distribution, and are not recommended. Multiple doses of activated
charcoal are not thought to be of significant benefit. In a rat
model, it did not enhance the elimination of metamfetamine.277
Conclusions
Metamfetamine, an N-methylated analog of amfetamine, is a
widely abused drug that acts as a stimulant by causing
enhanced release of catecholamines from sympathetic nerve
terminals, particularly those in the mesolimbic, mesocortical,
and nigrostriatal pathways. The resulting elevated concentrations can lead to detrimental psychological, cardiovascular,
and other systemic effects, and, following long-term abuse,
neuronal apoptosis, and nerve terminal degeneration. Patients
with metamfetamine poisoning are expected to make a full
recovery, provided they receive prompt supportive care.
688
Acknowledgments
We thank AJ Barnes (New Zealand National Poison Centre)
for drawing Fig. 2.
Declaration of interest
The authors report no conflicts of interest. The authors alone
are responsible for the content and writing of this paper.
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Clinical Toxicology (2010) 48, 675694

Copyright Informa UK, Ltd.

The clinical toxicology of metamfetamine

Received 23 April 2010; accepted 16 August 2010.

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L.J. Schep et al.

successful management of patients suffering this form of

Fig. 1. Structures of phenylethylamine and the stereoisomers of

Table 1. Physicochemical properties of metamfetamine47

to treat asthma and other bronchial disorders.9 Amfetamine

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3.1%38 whereas the percentage of unmetabolized drug

venous use.48 Because of metamfetamines low molecular

Metamfetamine is distributed to most parts of the body.

The predominant site of metamfetamine metabolism is the

Clinical Toxicology vol. 48 no. 7 2010

Metamfetamine clinical toxicology

Although metamfetamine is metabolized to amfetamine

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Metamfetamine clinical toxicology

Signs and symptom

Case reports (references)

Case series (references)

110, 117, 125, 126

109, 110, 112, 126

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Signs and symptom

Case reports (references)

Case series (references)

Clinical Toxicology vol. 48 no. 7 2010

Metamfetamine clinical toxicology

Signs and symptom

Case reports (references)

Case series (references)

66, 68, 71, 72, 74, 84, 107, 121

66, 97, 100, 157

94, 96, 97, 100, 178

94, 98, 100, 157, 178

95, 105, 114

paranoid schizophrenia.164,204 This is typically manifested by

*Doses were based on the weight of a 70-kg adult.

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Effects upon children

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Metamfetamine clinical toxicology

Patients may present to an emergency department in a critical

Clinical Toxicology vol. 48 no. 7 2010

L.J. Schep et al.

Clinical Toxicology vol. 48 no. 7 2010

Metamfetamine clinical toxicology

Clinical Toxicology vol. 48 no. 7 2010

L.J. Schep et al.

Clinical Toxicology vol. 48 no. 7 2010

Metamfetamine clinical toxicology

Clinical Toxicology vol. 48 no. 7 2010