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A review of the clinical pharmacology of methamphetamine Article in Addiction · April 2009 DOI: 10.1111/j.1360-0443.2009.02564.x · Source: PubMed

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doi:10.1111/j.1360-0443.2009.02564.x

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. Additional 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 pharmacokinetics. 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, associated 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: [email protected] Submitted 14 February 2008; initial review completed 12 May 2008; final version accepted 6 February 2009

INTRODUCTION The United Nations Office on Drugs and Crime estimated that 290 tonnes of methamphetamine was synthesized in 2005 [1], which is equivalent to 2.9 billion 100-mg doses of the drug. Methamphetamine is the second most popular illicit drug world-wide, with an annual global prevalence estimated at 0.4%. Use of the drug is particularly common in Asia, Oceania and North America [1]. Annual prevalence among adults is 14% in the Philippines [2], 3.2% in Australia [3] and 0.8% in the United States [4]. Amphetamine tends to be more common than methamphetamine in Europe, except in the Czech Republic, Slovakia, Estonia and Latvia [5]. In this paper we review the mechanism of action, pharmacokinetic profile, direct drug effects and the significant adverse clinical effects of methamphetamine. The review does not extend to the treatment of methamphetamine disorders. We will refer to amphetamine studies where evidence relating specifically to methamphetamine is less

complete. Amphetamine includes S-amphetamine (i.e. d-amphetamine; also referred to as dexamphetamine) which is used therapeutically, and racemic amphetamine sulphate powder, which is the common form of amphetamine used illicitly in the United Kingdom. The plural ‘amphetamines’ will be used to refer to amphetamine and methamphetamine collectively, but will not extend to derivatives such as methylphenidate and 3,4methylenedioxymethamphetamine.

METHODS A PubMed search of ‘methamphetamine or methylamphetamine or metamfetamine’ identified 447 articles (limits: English language, published 1966–2007, human studies). Abstracts were screened by hand to exclude preclinical studies, review articles which had been superseded by recent reviews and other papers judged by the authors to be of lesser relevance to the present discussion.

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Reference lists were used to identify further relevant literature. Book chapters and relevant monographs obtained from peak bodies were also considered. Inclusion was determined by consensus between the authors. Mechanisms of action, chemistry and molecular pharmacology discussed in the present paper were not subject to a structured literature search.

MOLECULAR MECHANISMS Chemistry ‘Amphetamine’ is a contraction of ‘a-methylphenethylamine’, an older description of the prototypical compound of which methamphetamine (methylamphetamine, metamfetamine, N-methyl-1-phenylpropan-2amine) 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 crystalline methamphetamine seized in Australia have had, typically, a purity of 80%, although purity may be significantly less where the cutting agent dimethyl sulphone is present [8]. The more common powder form of methamphetamine 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, crystalline methamphetamine is associated with an increased incidence of dependence [13].

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 hippocampus, involved in memory consolidation; and the prefrontal cortex (PFC), which processes cognitive functions [16]. Serotonin neurones are distributed widely throughout the brain and regulate diverse functions including reward, hyperthermia, respiration, pain perception, sexual behaviour, satiety, impulsiveness, anxiety and higher cognitive functions [17]. Several factors add substantial complexity to understanding 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 excitatory 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 stimulants while high baseline D2 density may produce unpleasant responses [20]. CLINICAL PHARMACOLOGY

Molecular pharmacology

Clinical pharmacokinetics

Methamphetamine is an indirect agonist at dopamine, noradrenaline and serotonin receptors. Due to structural similarity, methamphetamine substitutes for monoamines at membrane-bound transporters, namely the dopamine transporter (DAT), noradrenaline transporter (NET), serotonin transporter (SERT) and vesicular monoamine transporter-2 (VMAT-2). VMAT-2 is embedded 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 function 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, noradrenaline 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].

A summary of the pharamacokinetic profile of methamphetamine 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 overlapping pathways [21]. Metabolites of methamphetamine are unlikely to contribute significantly to clinical effects. Amphetamine arising from the metabolism of 30 mg methamphetamine reaches plasma levels substantially 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 polymorphic cytochrome P450 2D6 may contribute to interindividual 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].

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

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 following an intravenous dose of 20 mg [29] and elsewhere an experimental subject was observed to survive an intravenous 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, delusions and odd speech [28,62,63]. Methamphetamineinduced hallucinations are predominantly auditory (experienced in 85% of cases of methamphetamine psychosis), visual (46%) and tactile (21%). Delusions of persecution (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 symptoms (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 indefinitely 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 symptoms 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 antipsychotic medication. Psychotic symptoms deteriorate with increased duration and frequency of methamphetamine use [66,67]. Sensitization to methamphetamine psychosis may be related to neurotoxicity because positive symptoms correlate inversely with DAT density in the striatum and PFC [67]. Non-specific environmental stressors such as incarceration, severe insomnia and heavy alcohol consumption 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

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methamphetamine psychosis. Individuals with psychotic symptoms persisting for more than 1 month after withdrawal are three times more likely to have a family history of schizophrenia than those exhibiting shorter psychoses [69]. Methamphetamine-related psychosis is also associated with gene variations affecting a range of protein complexes [70]. Cardiovascular complications Few systematic studies have been conducted to examine cardiovascular complications arising from methamphetamine, 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 methamphetamine 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 cardiomyopathy [76]. Impaired myocardial contractility and left ventricular 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 anticoagulant 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]. Headaches have been reported to precede methamphetamineassociated 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 ‘amphetamine-type stimulant withdrawal syndrome’ by the American Psychiatric Association [81]. Methamphetamine 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

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unpleasant dreams, reduced energy and methamphetamine craving [87,90]. The severity and profile of withdrawal 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 following 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 methamphetamine withdrawal [85]. Depressed mood and anxiety associated with methamphetamine withdrawal can reach the level of suicidal ideation [28,66,88] and panic [91]. Depression associated with methamphetamine withdrawal typically features 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 methamphetamine users may exacerbate anxiety and depression [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-

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 terminals [99]. In vivo human positron emission tomography and magnetic resonance imaging data also indicate brain abnormalities that persist beyond the period of methamphetamine consumption (reviewed in [100,101]). Abnormalities include inflammation [102], reduced neuronal 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 coordination [105]. Psychotic symptoms correlate with diminished 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 concluded that methamphetamine use is associated with moderate impairment in neuropsychological performance corresponding with frontostriatal and limbic abnormalities[113]. Principle neurocognitive impairments appear to occur in the domains of executive function, 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], perseveration [124,126] and fluency [84,124]. These findings correspond with clinical observations that methamphetamine-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].

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Parkinson’s disease Because Parkinson’s disease (PD) is a neurodegenerative disorder affecting dopamine neurones in the nigrostriatal pathway [128], several investigators have examined links with methamphetamine neurotoxicity (reviewed in [129,130]). While some studies have identified psychomotor dysfunction consistent with PD [105], others have failed to observe such deficits, despite neuronal pathology qualitatively consistent with the disorder [107,123]. Signs of PD are associated with striatal DAT deficits of ⱖ47% [131], but DAT deficits among recently abstinent methamphetamine users are typically 20–30% of normal levels [104,105,112,131]. Therefore, marked psychomotor dysfunction is not always observed [129]. Nevertheless, PD-like psychomotor disturbances have been reported among cases of methamphetamineassociated dopaminergic damage that was within the range consistent with PD [105]. Given that DAT density normally declines with age by approximately 4.5% per decade [132], regular methamphetamine use may be expected to have an increased risk of developing PD in later life. In support of this hypothesis, a retrospective case–control study revealed that prolonged use of amphetamines is associated with an eight-fold increased risk of PD, with an average of 27 years between amphetamine exposure and the onset of PD signs [133]. Sexual behaviour The effects of methamphetamine on sexual behaviour have not been examined systematically in clinical studies. The available evidence for sexual effects stems largely from self-reported survey data, often conducted among regular methamphetamine users with problematic sexual behaviours. It is therefore unclear how broadly these effects apply. Methamphetamine use has been reported to enhance sexual pleasure among a sample of dependent heterosexual females users engaged in highrisk sexual behaviours [134]. Some users reported that methamphetamine delays orgasm, facilitating prolonged sexual activity and a particularly intense orgasm [135]. Others have reported an association with erectile dysfunction and that methamphetamine is used commonly in combination with drugs such as sildenafil (Viagra®) to enhance sexual performance [135,136]. Compulsive sexual activity and highrisk activities such as unprotected, anonymous and/or receptive anal sex, are reportedly common among homosexual methamphetamine users, particularly dependent users [137–139]. There are some indications that the prevalence of methamphetamine use is particularly high among urban homosexual men, raising concern about sexual disease transmission [140,141]. That methamphetamine use has been associated with high-risk sexual

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activity among heterosexual females broadens this concern [134]. Intravenous administration of the substituted amphetamine, methylphenidate, leads to increased in sexual desire [142] and pathological hypersexuality has been associated with dopamine agonist therapy [143]. Therefore, sexual effects may be mediated by excessive dopaminergic activation. Impulsiveness and impaired decision-making associated with chronic methamphetamine use may also play a role (see Neuropsychological impairment). Teratogenic effects In 2005, an expert panel concluded that there was insufficient evidence regarding the consequences of prenatal exposure to amphetamines, because poor prenatal care and high rates of nicotine use largely confounded the available research [144]. Nevertheless, various studies have reported that use of amphetamines during pregnancy is associated with low rates of prenatal care [145– 147], low birth weight [146–148], increased frequency of hospitalization for pregnancy complications [146], perinatal mortality [146,149], preterm deliveries [146], maternal anaemia [147], premature membrane rupture [147], pre-eclampsia [146,147], meconium-stained amniotic fluid [146,147], post-partum haemorrhage [145,146], unplanned caesarean delivery [146], vacuum extraction with forceps [146], and neonatal infection [146]. Neonatal amphetamine withdrawal is uncommon, occurring in approximately 2% of affected neonates, and generally resolves spontaneously within a week. The syndrome consists of poor feeding, drowsiness and tremor, and is considered less severe than both neonatal alcohol and opiate withdrawal syndromes [145]. Cases of neonatal birth defects associated with prenatal methamphetamine exposure include atresia, hydrocephalus, cardiac defects, epidermolysis bullosa and Down’s syndrome [146,147]. However, congential anomolies occur at low frequency (~2–4% of cases) and there are insufficient data to determine whether these defects occur at higher than normal rates [144]. Animal experiments suggest that maternal methamphetamine exposure increases the risk of perinatal mortality, low birth weight, congenital anomalies and neurobehavioural impairments that persist into adulthood [144]. Possible mechanisms may include increased uterine and umbilical vascular resistance, fetal hypoxia and accumulation of methamphetamine in the fetus [144]. Other adverse effects Methamphetamine intoxication is associated with dry mouth, which may lead to dental caries, and activation of mandibular muscles, which may lead to bruxism and, in

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some cases, tooth fracture [150]. Recent methamphetamine use appears to be a risk factor for methicillinresistant Staphylococcus aureus skin infections. Skin infections may be associated with formication (a sensation of something crawling on the skin) and skin-picking [151]. Tactile hallucinations are common features of methamphetamine psychosis and may contribute to skinpicking 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 hypertension, 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 withdrawal symptoms when use of the drug is ceased. Neurotoxicity 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 developing 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 impairment, psychosis and Parkinson’s disease. Determination of factors affecting individual variation in acute methamphetamine 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, prospective observational studies of illicit methamphetamine use would be useful to clarify outstanding issues regarding the course and prognoses of methamphetamine psychosis, cardiovascular toxicity, neurotoxicity and dependence. Such studies may improve the management of methamphetamine-related disorders. Declarations of interest None.

Acknowledgements The authors wish to thank Professor Kenneth Ilett, Professor James Bell and Associate Professor David Joyce for kindly providing their expert opinions on a draft manuscript. Christopher Cruickshank was supported by a Dora Lush Scholarship from the National Health and Medical Research Council of Australia.

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Addiction, 104, 1085–1099