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Major Physical and Psychological Harms of Methamphetamine Use

Major Physical and Psychological Harms of Methamphetamine Use

SCII.001.001.0060

Drug and Review (May 2008), 27, 253 – 262

Major physical and psychological harms of use

1 1 1 1,2 SHANE DARKE , SHARLENE KAYE , REBECCA MCKETIN , & JOHAN DUFLOU

1National and Alcohol Research Centre, University of New South Wales, Sydney, New South Wales, Australia, and 2Department of Forensic Medicine, Sydney South West Area Health Service, Sydney, New South Wales, Australia

Abstract Issues. The major physical and psychological health effects of methamphetamine use, and the factors associated with such harms. Approach. Comprehensive review. Key Findings. Physical harms reviewed included toxicity and mortality, cardiovascular/cerebrovascular pathology, dependence and blood-borne virus transmission. Psychological harms include methamphetamine , depression, suicide, and violent behaviours. Implications. While high-profile health consequences, such as psychosis, are given prominence in the public debate, the negative sequelae extend far beyond this. This is a drug class that causes serious heart disease, has serious dependence liability and high rates of suicidal behaviours. Conclusion. The current public image of methamphetamine does not portray adequately the extensive, and in many cases insidious, harms caused. [Darke S, Kaye S, McKetin R, Duflou J. Major physical and psychological harms of methamphetamine use. Drug Alcohol Rev 2008;27:253–262]

Key words: cardiovascular, methamphetamine, psychostimulants, .

methamphetamine to include both methamphetamine Introduction and its less potent analogue , which are In recent years, there has been mounting concern about sold under the street names of ‘speed’, ‘base’, ‘ice’, the increasing prevalence of methamphetamine use. ‘crystal meth’ and ‘’. Where appropriate, The extent of the problem suggests the need for a a distinction between methamphetamine and amphe- comprehensive review of the major harms that are tamine will be made. associated with such use. The current review aimed to examine the nature of the harms associated with the methamphetamine use. In particular, the current Physical harms associated with review aimed to examine: psychostimulant use (i) the major physical health effects of metham- Polydrug use, methamphetamine use and harm phetamine use; (ii) the major psychological effects of methamphe- As is the case with all illicit , methamphetamine tamine use; and users consume a variety of drugs other than their (iii) the risk factors associated with such harm. primary drug of choice. Heavy use is common, the majority drink alcohol, a substantial The area of psychostimulant use is plagued by proportion have a history of heroin use, and the use terminological ambiguities. This review will refer to of other psychostimulants is common [1,2].

Shane Darke, National Drug and Alcohol Research Centre, University of New South Wales, Sydney, New South Wales, Australia, Sharlene Kaye, National Drug and Alcohol Research Centre, University of New South Wales, Sydney, New South Wales, Australia, Rebecca McKetin, National Drug and Alcohol Research Centre, University of New South Wales, Sydney, New South Wales, Australia, Johan Duflou, National Drug and Alcohol Research Centre, University of New South Wales, Sydney, New South Wales and Department of Forensic Medicine, Sydney South West Area Health Service, Sydney, New South Wales, Australia. Correspondence to Professor Shane Darke, National Drug and Alcohol Research Centre, University of New South Wales, Sydney, NSW, 2052, Australia. Tel: 029 385 0331. Fax: 029 385 0222. E-mail: [email protected] Received 1 August 2007; accepted for publication 10 December 2007.

ISSN 0959-5236 print/ISSN 1465-3362 online/08/030253–10 ª Australasian Professional Society on Alcohol and other Drugs DOI: 10.1080/09595230801923702 SCII.001.001.0061

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While extensive polydrug use is associated with myocardial oxygen from the effects of methampheta- poorer clinical profiles and increased levels of harm mine in the presence of respiratory depression from the across a range of drugs [3,4], there are specific harms effects of heroin (see below). that arise from the concomitant use of methampheta- Multiple psychostimulant use is also cause for mine with other drugs. The importance of concomitant concern. The combination of methamphetamine and use of other substances with methamphetamine is that, has been demonstrated to increase substantially when combined with alcohol, cocaine or opiates, the vasoconstrictive and cardiotoxic effects of both methamphetamine toxicity is increased [5,6]. The drugs [11,12]. Given the cardiotoxic effects of metham- pharmacology of concomitant alcohol consumption is phetamine, it is reasonable to speculate that the distinct from the other major psychostimulant, cocaine. concomitant use of alcohol or cocaine with metham- The concomitant ingestion of cocaine and alcohol phetamine may increase the risk of a toxic reaction. produces cocaethylene, an active metabolite of cocaine Compared with cocaine [13,14], few data are which is not only more toxic than cocaine itself, but available examining the role of polydrug use in fatal which has a synergistic effect in increasing the toxicity methamphetamine toxicity. Consistent with what is of cocaine [7 – 9]. The combination of alcohol and known and speculated about drug interactions, multi- methamphetamine does not produce a new psychoac- ple substances are detected in approximately half of tive substance, but does increase heart rate and blood fatal methamphetamine toxicity cases, most commonly pressure beyond that seen for methamphetamine use alcohol (10 – 25%), cocaine (12 – 25%) and morphine alone [6,10]. (20 – 30%) [15,16] (Table 1). The combination of heroin and methamphetamine may produce a situation where there is increased Toxicity and mortality myocardial oxygen demand due to methamphetamine with a contiguous depression of respiration due to Whereas heroin overdose is indicated by a specific heroin. It may be speculated that respiratory depression diagnostic triad of signs (reduced level of consciousness, may induce cardiac failure, particularly among people miosis, respiratory depression) [17], psychostimulant where cardiac disease is present, due to increased overdose is defined less clearly. Methamphetamine

Table 1. Major physical harms associated with methamphetamine use

Variable Comment

Polydrug use Alcohol Increases heart rate and blood pressure beyond methamphetamine use alone Increased myocardial oxygen demand from psychostimulants with respiratory depression from opioids Cocaine Increases vasoconstrictive and cardiotoxic effects of these drugs Mortality Demographics Mostly male, aged, on average, in their mid-30s Cause of death Typically caused by seizures, cardiac arrhythmias, or respiratory failure Dose Toxic reactions can occur irrespective of dose, frequency of use, or route of administration Cardiotoxicity Cardiovascular system Places heavy demands upon the cardiovascular system. Can cause myocardial ischaemia and infarction Coronary artery disease Premature and accelerated development of coronary artery atherosclerosis Non-fatal presentations Chest , palpitations, tachycardia and hypertension most common complaints among methamphetamine users presenting to hospital Cerebrovascular accidents Increases risk of ischaemic and haemorrhagic stroke. Higher associated risk of death after stroke Dependence Chronicity May be chronic, or involve bingeing with brief drug-free periods Route of administration Strongly associated with injecting and smoking of the drug Potency Methamphetamine potency appears to increase dependence liability Blood-borne viruses Risks Increased risk of blood borne virus transmission through sexual risk behaviour and needle sharing Sex Increases sexual arousal. Some users take methamphetamine specifically to enhance sex Sexual Use consistently higher among HIV positive gay men with HIV. Elevated incidence of HIV seroconversion SCII.001.001.0062

Methamphetamine and harm 255 toxicity may manifest as a variety of acute physical and similar rates might be expected for methamphetamine. psychological symptoms. The presentation of a Indeed, given the wider availability of methampheta- methamphetamine overdose can vary among indivi- mine, rates may well be higher. duals and does not necessarily entail a loss of Deaths due to methamphetamine toxicity occur consciousness. Indeed, overdose signs such as excited typically among male, experienced drug users, aged in , which may result in cardiac arrest and death, their mid-30s [10,12,15,23,28,29]. The older age by definition preclude loss of consciousness. Physical profile of fatalities may simply reflect the cumulative symptoms of psychostimulant overdose include nausea risk exposure of repeated use. The effects of repeated and vomiting, chest , tremors, increased body psychostimulant administration are, however, quite temperature, increased heart rate, breathing irregula- distinct from those seen in the use of opioids. Repeated rities and seizures. Psychological symptoms such as administration of either cocaine or methamphetamine extreme anxiety, panic, extreme agitation, extreme results in a cumulative risk of cardiac and coronary , and are also artery disease, most commonly ventricular hypertrophy indicative of methamphetamine overdose [9,18]. and coronary artery atherosclerosis [9,10,12,15] (see Psychostimulant-related deaths are caused typically below). The accumulated damage from long-term by seizures, cardiac arrhythmias or respiratory failure, methamphetamine use may increase risk of myocardial with cardiovascular complications accounting for the infarction substantially as the user ages, and increase majority of deaths [9,15]. Fatal overdose has also substantially the risk for each individual use episode occurred due to brain haemorrhage, ischaemic stroke over time. and kidney failure [9,19,20]. While dose and frequency of use may influence the Cardiovascular and cerebrovascular pathology likelihood of coronary and cerebrovascular complica- tions, the threshold over which potentially fatal reac- Methamphetamine is distinguishable from the opioids tions occur varies widely. Toxic reactions can occur in that, like cocaine, it is known to be cardiotoxic, and irrespective of dose, frequency of use or route of places heavy demands upon the cardiovascular system administration, and have been reported with small by increasing heart rate and blood pressure [9,12,30]. amounts and on the first occasion of use [9,12]. As such, two of the most serious sequelae of metham- Overall there appears to be no well-delineated dose phetamine use are cardiovascular and cerebrovascular response for either methamphetamine or cocaine complications, both of which occur regardless of route [9,12,15,21 – 23]. of administration [9,12,30 – 32]. While much has been Methamphetamine-related fatalities are less common written about the cardiotoxicity of cocaine [14,22], the than toxicity deaths. This is demonstrated by pathological effects of methamphetamine on the cardi- worldwide data, which demonstrate repeatedly that the ovascular system are similar to, or indistinguishable highest rates of mortality are associated with the opioids from, those attributable to cocaine [9,33,34]. [10]. By way of example, there were 68 fatal metham- Both methamphetamine and cocaine can cause phetamine toxicity cases in Australia during 2005 (i.e. myocardial ischaemia and infarction via several me- cases where methamphetamine was mentioned by the chanisms: an increase in myocardial oxygen demand, forensic pathologist as either the primary cause of death vasoconstriction of the coronary arteries and coronary or noted in ‘toxic quantities’ where another drug was thrombosis [9,12,15,22,23,30,32,35]. Importantly, listed the primary cause of death) [24]. By comparison, sudden acute aortic dissection and coronary vasospasm 374 deaths were attributed to opioid toxicity [25]. It may occur where there is no underlying coronary artery should be borne in mind that toxicity deaths do not disease [9,12,22,35]. include other drug-related deaths, such as accidents Although methamphetamine can induce cardiovas- and suicides. cular complications in users with normal coronary In discussing toxicity it is essential to bear in mind arteries [9,12,22,31], underlying atherosclerosis has that fatalities form only a proportion of overdose cases, been demonstrated consistently [9,12,15,16,32]. The and that the harms associated with overdose extend far premature and accelerated development of coronary beyond death per se. In the case of heroin, it is estimated artery atherosclerosis, which increases the risk of that the proportion of overdoses that results in death is myocardial infarction, has been associated with the 2 – 4% [26]. To date, there are no comparable data on chronic use of methamphetamine [9,12,15,16,32]. methamphetamine toxicity, but one Australian study Chronic use is also associated with ventricular hyper- has been conducted on non-fatal cocaine overdose trophy, a condition that can predispose to methamphe- [27]. This found that 13% of regular cocaine users had tamine-induced myocardial ischaemia and/or overdosed on cocaine, and 7% had done so in the arrhythmia [9,12,15]. Consistent with the pathological preceding 12 months. Given the psychopharmacologi- effects of amphetamine, chest pains, palpitation, cal similarities between these two psychostimulants, tachycardia and hypertension are the most common SCII.001.001.0063

256 S. Darke et al. presenting symptoms in emergency departments relat- illustrated by a recent study of Australian methamphe- ing to acute amphetamine intoxication [20,36,37]. tamine users, in which approximately half were Psychostimulant-induced cerebrovascular accidents methamphetamine-dependent [43]. Dependence was are also well recognised [14,19,38]. In a recent US related strongly to route of administration. Thus, two- study there was a 14-fold increase in the risk of thirds of injectors were dependent, as were 58% of ischaemic or haemorrhagic stroke among cocaine users smokers of the drug. Substantially lower levels of compared with matched controls, and a fourfold dependence were seen among intranasal (33%) and increased risk for methamphetamine [19]. Similarly, oral (22%) users. The higher rates of dependence Westover et al. [38] reported a fivefold increase in risk among injectors and smokers, in all probability, relates of ischaemic stroke associated with methamphetamine to the rapid bioavailability associated with these routes use, and a substantially higher associated risk of death of administration. Those who were dependent also after such events. used the drug more frequently. Importantly, the use of While both cocaine and methamphetamine are ‘ice’ was associated independently with dependence. It cardiotoxic, the incidence of serious pathological effects is not only frequency of use, but the potency of the drug of methamphetamine appears less common than with that appears to increase dependence liability. cocaine [9,19,32,39]. This may explain why cocaine constitutes a larger proportion of overdose fatalities Blood-borne virus transmission than does methamphetamine [10,13], despite the widespread use of methamphetamine. This observation Methamphetamine use can increase the risk of blood- must, however, be tempered by the fact that sub- borne virus transmission through sexual risk behaviour stantially less research has been conducted into and sharing used needles. While needle sharing is an methamphetamine-related death than is the case with important vector for the transmission of viruses such as cocaine. human immunodeficiency virus (HIV) and hepatitis C, needle sharing rates among methamphetamine injectors appear to be similar to those seen among opioid Dependence injectors [1,44]. Dependence on psychostimulants, like all psychoactive Unlike the opioids, however, methamphetamine use drugs, is defined by tolerance, withdrawal, preoccupa- increases sexual arousal, and some users take the drug tion with the drug, an inability to reduce use and using specifically to enhance sex [45,46]. Indeed, it has been the drug despite significant social, health or psycholo- reported that approximately half of users are more likely gical impairment [40]. Tolerance and withdrawal are to engage in high-risk sexual activities while intoxicated clearly marked in the case of substances such as alcohol with methamphetamine [45]. Consistent with this, and the opioids, with clearly defined withdrawal elevated levels of sexual activity and unprotected sex syndromes. Despite being a less marked syndrome, have been noted among heterosexual methampheta- tolerance and withdrawal are a key feature of the mine users [47 – 52]. methamphetamine dependence syndrome [40,41]. Methamphetamine-using homosexual men are a Withdrawal symptoms consist of fatigue, lethargy, sleep high-risk group for HIV seroconversion. Methamphe- disturbances, appetite disturbances, depressed mood, tamine use is consistently higher among homosexual irritability, or agitation and men who engage in risky sexual practices and those strong cravings for the drug [40 – 42]. Tolerance may with HIV [53,54]. More importantly, homosexual men be demonstrated by a transition from non-injecting who use the drug show an elevated incidence of HIV routes of administration to injecting methamphetamine seroconversion [55,56]. or cocaine use, using higher doses of the drug per use episode, more frequent use and a preference for more Psychopathological harms associated with potent forms of these drugs; thus, in the case of methamphetamine use methamphetamine, for high purity crystalline metham- phetamine rather than powder [43]. Methamphetamine use is associated with a substantial The patterns and course of methamphetamine burden of psychopathology, which includes elevated dependence are similar to that seen with cocaine [40]. rates of psychosis, mood and anxiety disorders, violent This is not surprising, as both drugs are psychostimu- behaviours and cognitive deficits. The extent of this lants with similar psychoactive and sympathomimetic burden is illustrated in Zweben et al. [57], where a effects. Methamphetamine dependence may be quarter of methamphetamine users had psychiatric chronic, or involve bingeing with brief drug-free symptoms severe enough to warrant hospitalisation, periods. Methamphetamine dependence is associated and a third had a history of prescribed psychiatric strongly with injecting and smoking of the drug [43]. medications. Similarly, McKetin et al. [1] reported that, The extent of methamphetamine dependence is among current methamphetamine users, a quarter were SCII.001.001.0064

Methamphetamine and harm 257 experiencing severe disability in their had experienced a clinically significant psychotic functioning. symptom in the past year and 13% screened positive for a psychotic disorder (compared with 1.2% of the general population). Earlier Australian research re- Psychosis ported that half of methamphetamine users had One of the key clinical differences between psychosti- experienced clinically significant feelings of persecution mulants and other illicit drugs, such as the opioids, is or hallucinations since using methamphetamine [70]. that psychostimulant use can induce psychosis. Case – Moreover, the prevalence of symptoms had increased control studies have demonstrated that psychostimu- significantly since the onset of methamphetamine use. lant users have higher levels of psychosis compared with Similarly high proportions of psychosis and psychotic users of opioids, and symptoms have been reported internationally [58 – 61]. Psychosis induced by methamphetamine is [57,66,71 – 73]. a typically transient phenomenon that involves symp- A number of factors have been associated with an toms of and hallucinations. Less common increased risk of developing psychotic symptoms. symptoms include disorganised speech and grossly Symptoms of psychosis are most likely to occur among disorganised behaviour [40]. Delusions usually involve chronic, dependent users of the drug [57,69,73]. In the themes of persecution. Hallucinations manifest most McKetin et al. [69] study, 31% of dependent metham- commonly in the auditory and visual senses, but can phetamine users had psychotic symptoms, compared occur in any of the senses. Psychostimulant psychosis with 13% of non-dependent users. Longer periods of can also be accompanied by an emotionally labile state, psychostimulant use, and heavier use, also increase risk agitation and seemingly irrational hostile behaviour [57,58,74]. The injection of psychostimulants has also [40]. These symptoms can be accompanied by repeti- been associated with increased risk of psychotic tive stereotyped behaviour and social withdrawal symptoms [57,70,71,75]. These findings, however, [62,63]. may reflect the higher levels of dependence seen among Symptoms of psychosis usually last hours to days injectors than the effects of route of administration per and, in severe cases, can require hospitalisation, se. Finally, as would be expected, a pre-existing history sedation and/or medication. Psychosis of psychotic symptoms increases the risk of psychosis, induced by methamphetamine is a typically transient or psychotic symptoms, induced by psychostimulants phenomenon remitting rapidly following detoxification [66,69,70] (Table 2). [58]. There have been, however, reports of more chronic symptom profiles, which suggests the precipita- Depression, suicide and anxiety tion of a more chronic psychotic condition [9,64,65]. Chronic symptom profiles are more likely to occur Psychostimulant psychosis is certainly the most con- among users with a premorbid schizoid/ spicuous form of psychopathology associated with the schizotypal personality or a family history of schizo- use of such drugs. The fact that psychosis is so phrenia [66,67], although there has been little empirical conspicuous, however, should not distract attention research on the risk for transgression to more chronic from other forms of psychopathology that are more psychotic disorders among people who experience common, more chronic and potentially more debilitat- methamphetamine psychosis. ing. Depressive symptoms are particularly common, As noted above, methamphetamine users are at high and may have fatal consequences [1,57,72,76,77,78]. risk of experiencing psychotic symptoms if they suffer Among methamphetamine users the majority report a from pre-existing , or other psy- lifetime prevalence of depression [57,70], and a recent chotic disorders. Among such individuals, these drugs study reported that a third of methamphetamine users can precipitate or exacerbate psychotic episodes [58]. had been diagnosed with depression at some point in What needs to be borne in mind is that psychostimulant their lives [1]. As would be expected, given these high users, like all illicit drug-using populations, have rates of depression, rates of suicidal ideation and elevated rates of pre-existing schizophrenia and other attempted suicide are also high. Approximately a psychotic disorders [68]. Despite this, the majority of quarter of psychostimulant users have a lifetime history methamphetamine users who experience psychotic of attempted suicide [57,70]. By comparison, less than symptoms after taking these drugs have no known 5% of the general population have a lifetime history of history of schizophrenia, mania or other chronic attempted suicide [79]. psychotic disorders [69]. Consistent with the high levels of depression and Although vulnerability to psychotic symptoms varies global pathology, high levels of anxiety disorders are among methamphetamine users, these symptoms ap- also reported [1,57,70,72]. Half of methamphetamine pear to be remarkably common among regular users users in Hall et al.’s study [70] reported symptoms of [57,66,69 – 73]. McKetin et al. [69] reported that 23% anxiety prior to initiation into methamphetamine use, SCII.001.001.0065

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Table 2. Major psychological harms associated with methamphetamine use

Variable Comment

Psychosis General Unlike opioids, methamphetamine can induce psychosis. Usually transient, with delusions and hallucinations Comparisons Psychostimulant users have higher levels of psychosis than users of opioids, benzodiazepines, barbiturates Dependence Most likely among chronic, dependent users. Longer periods of psychostimulant use, and heavier use, increase risk Pre-existing pathology High risk of psychotic symptoms if pre-existing schizophrenia, mania or other psychotic disorders Route of administration Injection associated with increased risk Depression rates Suicide Rates of major depression substantially higher than general population Risk factors Rates of attempted suicide substantially higher than general population Higher levels of depression and suicide associated with longer use careers, more frequent use, dependence and injecting Anxiety rates Risk factors Rates of anxiety disorders substantially higher than general population Anxiety disorders associated with longer use careers, more frequent use, dependence and injecting Violent behaviours Rates Violent behaviours appear common Reasons Experimental evidence that chronic use can increase aggressive behaviour. Acute intoxication may enhance or augment aggressive response when threatened or provoked Psychosis may be accompanied by violent behaviours Neurotoxicity Animals Neurotoxic effects in rodents, other mammalian non-primate species and non-human primates. Degeneration of dopamine and serotonin in frontostriatal region Humans Neurochemical abnormalities found in chronic methamphetamine users. Primarily involve monamine function

and three-quarters had experienced severe anxiety drug can increase aggressive behaviour [82,83]. Sec- symptoms since methamphetamine use. As with ondly, acute intoxication may enhance or augment depression, these figures are emphasised by the fact aggressive response in someone who is threatened or that 11% of methamphetamine users have received a provoked [84]. Finally, as discussed above, psychosti- diagnosis of an at some stage in their mulant use is associated with a risk of psychosis, which lives [1]. It should be borne in mind, however, that can be accompanied by violent behaviours. It should methamphetamine induce hyperarousal. This may be also be noted that part of such an association may be misattributed by some users as anxiety. due to high rates of pre-existing conduct disorder As was the case with psychosis, higher levels of amongst methamphetamine users [81]. Thus, those depression, suicide and anxiety have been associated with a propensity to violence may well be at most risk of with longer methamphetamine use careers, more responding with violence under the effects of the drug. frequent use, dependence and injecting [57,69,70,72, Violent behaviours appear common among psychos- 77,78,80]. The latter finding could be a reflection of timulant users, particularly among people who inject higher levels of psychostimulant dependence seen these drugs [57,70,72,81]. Hall et al. [70] reported that among injectors, rather than injecting per se. half of methamphetamine users exhibited violent behaviours since beginning methamphetamine use. Importantly, violence was more common after initia- Violent behaviours tion into methamphetamine use, and among injectors. There has been increasing attention in recent years to a More recent data confirm high rates of violence perceived link between psychostimulant use and violent [1,57,72]. McKetin et al. [1] reported that 12% of behaviours. According to McKetin et al. [81], such an methamphetamine users had committed a violent crime association is plausible for three main reasons. First, in the preceding year. Zweben et al. [57] reported there is experimental evidence that chronic use of the that 43% of methamphetamine users had problems SCII.001.001.0066

Methamphetamine and harm 259 controlling aggressive behaviour, with symptoms monoamine regulation [96 – 99]. There is also a more common among injectors and more frequent growing literature on cognitive deficits among users users. Similarly, Sommers et al. [72] reported of the drug (e.g. impairment in sustained attention recently that more than a third of methamphetamine [96,100], delayed verbal memory [101] and executive users had assaulted someone while intoxicated with functioning [102], although decrements in neuropsy- methamphetamine. chological functioning are not observed consistently [103,104], and they are often confounded by factors that co-occur with chronic stimulant use, including Neurotoxicity depression [105], attention deficit hyperactivity Methamphetamine has been shown to have neurotoxic disorder [106], HIV [107], hepatitis C [108] and effects in rodents, several other mammalian non- polydrug use [109]. Cognitive deficits among primate species and non-human primates [85 – 88]. methamphetamine-exposed individuals have been cor- These neurotoxic effects involve the degeneration of related with various indices of brain function in the dopamine and serotonin nerve terminals in the cingulate, frontal and striatal regions [102,110,111], frontostriatal region, leading to long-lasting depletion but the correlational nature of these findings prevents of these monoamines and alterations in the regulation any causal inference that cognitive decrements are due of these systems [85 – 89]. The mechanism through to methamphetamine neurotoxicity. Finally, metham- which methamphetamine induces neurotoxicity is phetamine-induced neurotoxicity has evolved as an complex and not understood completely, although the animal model of Parkinsonian symptoms and other commonly cited mechanisms involve oxidative stress movement disorders [112]. While these types of move- and apoptosis [86,90,91]. In line with this hypothesis, ment pathologies can be induced in animal models, there is emerging evidence that selective anti-oxidants they do not present as an obvious element of the may protect against methamphetamine-induced neuro- methamphetamine dependence syndrome in humans. toxicity [92]. Methamphetamine-induced neurotoxicity This suggests that neurotoxicity that in chronic may also compromise other neurochemical systems methamphetamine users, if indeed it occurs, may be [85], while gender differences in vulnerability to expressed differently than in animal models [112]. neurotoxicity have led to speculation that certain In summary, methamphetamine has neurotoxic hormones (e.g. oestrogen) may modulate the risk of potential which may occur in humans following chronic neurotoxicity [93]. Although there has been little heavy use, but this is difficult to establish with certainty. research examining the impact of polydrug use on Neurochemical abnormalities that are found in chronic methamphetamine-induced neurotoxicity, combining methamphetamine users involve primarily monamine methamphetamine with methylene-dioxymethamphe- function, and are likely to be related to many of the tamine (MDMA) appears to increase neurochemical psychiatric phenomena that are disproportionately toxicity [89]. prevalent among this population. Whether these Evidence of methamphetamine’s neurotoxic effect in neurochemical abnormalities mediate cognitive deficits humans is less complete [89]. Neurochemical changes found in users of the drug, or are the result of in the dopamine system similar to those seen in animal neurotoxicity, is less clear. models of neurotoxicity have been observed in chronic methamphetamine users, including decreased dopa- Summary mine binding in the striatal region, which shows evidence of remission in the months following cessation To summarise, methamphetamine use is associated of methamphetamine use [94,95]. Unlike animal with a number of extremely serious negative health models of methamphetamine-induced neurotoxicity, it effects. While high profile consequences, such as is not possible to determine whether the anomalies in psychosis, are given prominence in the public debate, dopamine function found in chronic users of the drug the sequelae extend far beyond this. This is a drug class precede the onset of methamphetamine use. Similarly, that causes serious heart disease, has serious depen- it is less clear that dopamine depletion in chronic dence liability and high rates of suicidal behaviours. methamphetamine users is the result of neurotoxicity The current public image of methamphetamine does per se [89] or alterations in the regulation of these not adequately portray the extensive, and in many cases systems, which could occur irrespective of nerve insidious, harm it causes. degeneration. Regardless of their cause, low levels of dopamine and other abnormalities in monoamine function may have clinical implications. Acknowledgements Many of the core behavioural and psychiatric sequelae associated with heavy methamphetamine use This research was funded by the Australian Govern- and withdrawal are likely to be related to altered ment Department of Health and Ageing. SCII.001.001.0067

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