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Abstract
Background Methamphetamine use and stroke are significant public health problems. Strokes among people aged below 45 years are much less common than in older age groups but have significant mortality and morbidity. Methamphetamine is a putative cause of strokes among younger people.
Methods A review of methamphetamine-related strokes was conducted. Bibliographic databases were searched until February 2017 for articles related to methamphetamine and stroke. Both haemorrhagic and ischaemic strokes were considered.
Results Of 370 articles screened, 77 were selected for inclusion. There were 81 haemorrhagic and 17 ischaemic strokes reported in case reports and series. Both types were approximately twice as common in males. Route of administration associated with haemorrhagic stroke was typically oral or injecting, but for ischaemic stroke inhalation was most common. Haemorrhagic stroke was associated with vascular abnormalities in a third of cases. One quarter of individuals completely recovered, and a third died following haemorrhagic stroke. One-fifth completely recovered, and one-fifth died following ischaemic stroke.
Conclusions There is a preponderance of haemorrhagic strokes associated with methamphetamine use in young people, and methamphetamine-related stroke is associated with poor clinical outcomes. Mechanisms of methamphetamine-associated stroke include hypertension, vasculitis, direct vascular toxicity and vasospasm. In a period of rising worldwide methamphetamine use, the incidence of methamphetamine-related stroke will increase, with a consequent increase in the burden of disease contributed by such events.
- stroke
- cerebrovascular disease
- epidemiology
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Introduction
Methamphetamine use is a significant public health problem, particularly in countries around the Pacific rim (North America, East/Southeast Asia and Oceania), with an estimated 35 million stimulant users worldwide, predominantly of methamphetamine.1–3 Harmful physical and mental health consequences are common, including cardiovascular and cerebrovascular pathology, psychosis, suicide and premature mortality.4–8 The stimulants methamphetamine and amphetamine have been available in various forms since the middle of last century.7 Methamphetamine use has changed over years: in 1950s and 1960s, it was popular as benzedrine, later amphetamine became the preferred form, while most recently there has been a substantial global increase in the availability and use of high potency, crystalline methamphetamine.1 3 9 Routes of methamphetamine administration include oral, inhalation (smoking), intranasal and intravenous use.7
Stroke too is a major public health problem, with high mortality rates and high levels of subsequent disability.10 11 Between 1990 and 2010, stroke has risen from the fifth to the third leading cause of disability-adjusted life years, with increase of 19%.10 Moreover, the incidence of stroke has been rising among younger persons.12 While stroke incidence rises with age and is less common in people aged below 45 years, stroke among young people has significant health sequelae and societal costs.12
Stroke in young people
In all-age stroke populations, ischaemic strokes (cerebral infarction) are more common.13 In younger people (<45 years), this remains the case, but a greater proportion are haemorrhagic (eg, 33.5% in those 20–44 years vs 23.1% in those 45–54 years).13 Haemorrhagic strokes in those aged 20–44 years are subarachnoid or intracerebral in approximately equal proportion.13 In young people, subarachnoid haemorrhages are most frequently due to an underlying cerebral aneurysm or arteriovenous malformation (AVM).14 Non-traumatic intracerebral haemorrhage (ICH) is associated with hypertension in 70% of all-age stroke, but in young people it may account for as little as 20%, with a high preponderance of other causes such as AVM, ruptured saccular aneurysm and sympathomimetic drug use.15
Risk factors for ischaemic stroke include dyslipidaemia, smoking and hypertension.16 17 As is the case for haemorrhagic stroke causation differs in young people (<45 years), with a higher preponderance of females, recent illicit substance use and use of the contraceptive pill/oral contraceptives than in those even slightly older (45–49 years).17
Substance use and stroke in young people
The prevalence of illicit drug use is highest among younger people.9 18 19 There is increased relative risk for both ischaemic and haemorrhagic stroke associated with all drug use20 and drug use as a cause of stroke is significantly more common among young people.17 Intravenous use of any illicit drug increases the risk of ischaemic stroke through thromboembolic mechanisms.21 Stroke risk factors are different among users of illicit substances, with higher rates of smoking and lower rates of hypertension and diabetes compared with those with ischaemic stroke in the absence of substance use.21 Alcohol has also been demonstrated to increase risk of stroke.17
One class of drugs that has been associated with stroke incidence is the psychostimulants.11 Cocaine, in particular, has been associated with a substantially increased risk of haemorrhagic stroke.11 Methamphetamine shares pharmacological characteristics and physiological effects in common with cocaine, and both are associated with hypertension and coronary disease.5 7 22 23 Methamphetamine, however, has a longer half-life than cocaine,7 and there is subsequently a longer exposure to systemic hypertension. Moreover, methamphetamine also substantially increases the risk of stroke.24–26 It is important to note that methamphetamine is also strongly associated with the development of ischaemic heart disease and accelerated atherosclerotic coronary artery disease.7
Despite its widespread use and potential clinical significance, however, the features and pathogenesis of methamphetamine-related stroke are poorly understood. This is of particular relevance in a period of large increases in worldwide methamphetamine use, when the incidence of methamphetamine-related stroke, particularly among young people, would be expected to increase in conjunction with use. In the context of increased use of methamphetamine, and thus of increased stroke risk, the current study aimed to review the literature on methamphetamine-related stroke among young people (defined as <45 years). Specifically, the study aimed to:
summarise the features of stroke in young amphetamine users; and
determine the evidence for the pathogenesis of methamphetamine-related stroke.
Methods
The EMBASE (Embase Classic+Embase), MedLine (Ovid MEDLINE Epub Ahead of Print, In-Process & Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid MEDLINE and Versions) and PsycINFO (PsycINFO) bibliographic databases were searched until 10 February 2017 for articles on the association between meth/amphetamine use and strokes in young people (figure 1). Search terms included: methamphetamine, amphetamine and common variants, stroke, cerebrovascular disorders and cerebral haemorrhage. Hand-searching of reference lists of included studies was also conducted. The search was restricted to English-language publications or to those with a comprehensive abstract in English that was sufficiently detailed. There was no restriction on year of publication. The search strategy is provided in detail in the online supplementary figure s1.
Supplementary file 1
Methodology of the review and flow diagram.
Inclusion criteria
Studies were eligible for inclusion if they were published in a peer-reviewed journal or referenced in a relevant journal article. Studies that focused on the relationship between methamphetamine use and incident stroke were included. Where putative additional or alternative risk factors for stroke were reported, these were detailed (table 1). Consistent with literature on strokes in young people,13 17 studies were included if they reported cases of methamphetamine/amphetamine-associated stroke in people aged 44 years or below. Both ischaemic and haemorrhagic strokes were considered. Studies were included only where the drug was used for abuse purposes, excluding studies reporting effects of prescribed amphetamines and related compounds. Where polydrug use was recorded, this was documented where relevant. Dextroamphetamine was included only where it was used for abuse purposes.
Methamphetamine-related stroke reported in case studies and case series. Haemorrhagic strokes are detailed first, followed by ischaemic*
Supplementary file 2
Results
A total of 77 papers met search criteria (figure 1). These comprised three postmortem studies, 11 case control and epidemiological studies and 63 case series/case reports.
Methamphetamine-related stroke in young people: postmortem studies
Several large postmortem series report that between 1% and 5% of all-age methamphetamine-related deaths are caused by intracranial haemorrhage, with cases of both subarachnoid and ICH reported27–29 (table 2).
Methamphetamine-related stroke reported in postmortem series
Methamphetamine-related stroke in young people: epidemiological studies
Case series conducted over the past four decades identify amphetamines as a cause of stroke in 6%–13% of haemorrhagic15 20 30–32 and 2%–6% of ischaemic stroke16 21 (table 3). These differences reflect rates of use in the area the study was undertaken, and change in use patterns over time. It is noteworthy that higher rates of stroke associated with methamphetamine were recorded in the past decade, with three studies of haemorrhagic stroke32–34 reporting rates of methamphetamine use between 7% and 13%, despite these series being in all-age populations. Because methamphetamine use is predominantly associated with younger age, the proportion of methamphetamine-associated strokes in these series among those <45 years (though unreported) is likely to be even higher. Similarly, Phillips and coworkers’16 case series of ischaemic stroke among individuals aged 15–50 years reports a higher rate due to amphetamine (6%) than the 2% identified in a study conducted a decade earlier.21 In addition, it is likely that drug use as a contributory cause may often be underestimated, as suitable investigations or testing for drug use may not be conducted or recorded.
Methamphetamine-related stroke reported in case control and epidemiological studies
Several epidemiological studies have demonstrated a significantly increased risk of stroke among young meth/amphetamine users.24 25 Westover and coworkers25 conducted separate analyses for haemorrhagic and ischaemic stroke. Amphetamine use was significantly associated with a 4.95 increased risk of haemorrhagic stroke, a risk more than twice that conferred by either cocaine or tobacco use. The authors also noted a dramatic increase in the rate of amphetamine-associated stroke over the 3-year timeframe of their study, which was greater than the rate of increase in strokes associated with any other illicit drug. Consistent with these findings, Huang and coworkers26 compared stroke events in a large cohort of methamphetamine users of all ages and found significantly increased risk of haemorrhagic stroke among methamphetamine users, but not of ischaemic stroke.
Methamphetamine-related stroke in young people: case reports and case series
Table 1 summarises a total of 63 case studies and series of 98 strokes associated with methamphetamine use in young people aged <45 years.
Haemorrhagic stroke
Of the 81 reported strokes that were haemorrhagic, the male to female ratio was 2:1. There was variation in the route of administration, with an oral to injection to inhalation ratio of 3:3:1. Methamphetamine-related stroke was thus not solely associated with a particular route of administration. Headache was a prominent early clinical feature, with vomiting, one-sided weakness and seizures often developing over time. ICHs were present in 60 cases, predominantly in the temporal, parietal and occipital cortices. Less common sites were the cerebellum (two) and brainstem (three). There were 32 cases of subarachnoid haemorrhage (SAH), among whom 13 had both ICH and SAH. Intraventricular haemorrhage was present in five cases, but only in one case in the absence of ICH. Aneurysms and AVMs were present in 17% and 8%, respectively. Other vasculature abnormalities were reported in a third of cases, most commonly beading of vessel wall or cerebral arteritis with or without occlusive changes in the small arteries. Irregularities of the vessel lumen were present in a minority of cases. No abnormality of vasculature was found in less than half of cases (47%).
Haemorrhagic stroke resulted in death in a third of cases. Complete recovery was reported in one quarter and the remainder (approximately 40%) had residual symptoms ranging from mild weakness and memory difficulties, to permanent hemiparesis, speech and language difficulties and visual defects.
Ischaemic stroke
Of the 17 ischaemic strokes, the male to female ratio was 12:5. The route of administration differed notably from haemorrhagic stroke with a higher preponderance of inhalational use (the oral:injection:inhalation ratio was 1:1:4). Again, these strokes occurred across all routes of administration. Headache was again the predominant early presenting feature, with hypertension frequently reported. Ischaemic strokes were predominantly located in regions whose blood supply derives from the anterior circulation: the frontal and parietal lobes and/or the basal ganglia. A minority were located in the occipital lobe or caudal thalamus indicating a posterior circulation infarction. One case extended from frontal to occipital lobes, suggestive of involvement of both anterior and posterior circulations. Of note, Philips and coworkers16 found that methamphetamine use was significantly more common among individuals aged 15–50 years with stroke involving both vascular territories compared with their whole study population. Angiography was less commonly conducted in ischaemic stroke cases. Where performed, beading suggestive of arteritis was present in three cases and intimal wall thickening in one. No abnormality was detected in four cases, which was interpreted by some authors as suggestive that vasospasm may have been the cause, due to absence of any permanent vessel occlusion.33 Other causes of infarction included bacterial embolus (one case) and thrombus from carotid artery dissection (two cases).
The outcome was death in approximately 20% of cases. Complete recovery was achieved in a further 20%. The majority of cases (approximately 60%), however, experienced residual impairments such as hemiparesis, speech and visual deficits.
Discussion
This review highlights the preponderance of haemorrhagic rather than ischaemic strokes associated with methamphetamine use in young people. In case reports and series, 80% of methamphetamine-related strokes reported were haemorrhagic. This is strikingly high compared with reported rates of haemorrhagic stroke in stroke populations below 45 years (40%–55%) and higher again than in the general stroke population (15%–20%).12 Thus it is possible that this may to some extent reflect reporting bias. Thus, it is possible that instances of young individuals experiencing haemorrhagic stroke associated with methamphetamine use may be more likely to be reported, and the resultant case study published, than is the case for ischaemic stroke. Both ischaemic and haemorrhagic strokes occur in young people. While haemorrhagic strokes are relatively more common than in older stroke populations, ischaemic strokes remain more common than haemorrhagic even in young people.13 Alternatively, it may be that the cases reported reflect the number of cases occurring. Moreover, the finding is in keeping with population-based evidence that methamphetamine use is associated with a highly increased risk of haemorrhagic stroke among individuals aged 18–44 years.25 A significantly increased preponderance of haemorrhagic compared with ischaemic strokes was found in several stroke case series.26 35 While the ratios were less stark than the 4:1 reported here, both studies considered all-age populations (in which ischaemia would be expected to be more prominent), rather than young adults. Furthermore, the cerebrovascular pathology reported here must be viewed within the context of a range of known methamphetamine-related cardiovascular pathologies, including accelerated atherosclerosis, ischaemic heart disease, hypertensive heart disease, various cardiomyopathies, arrhythmias, cardiomegaly and aortic dissection.7 8 22 23 26
Individual and use-related characteristics
In keeping with previous reports,34 this review highlights that strokes can occur following any route of methamphetamine administration. Haemorrhagic strokes occurred following oral or intravenous use in similar numbers. Stroke may result following injection of any drug due to increased risk of bacterial endocarditis and embolism, or due to the use of fillers such as talc, which may contribute to both ischaemic and haemorrhagic stroke.36 Injecting alone, however, does not explain all strokes. In these cases, it is use of methamphetamine that confers the risk. The proportions of strokes due to oral, injecting or inhalational routes may reflect general use prevalence of the drug, but it is noteworthy that starkly different use patterns exist between ischaemic and haemorrhagic strokes, with a relatively higher proportion of ischaemic strokes associated with inhalation. Methamphetamine-associated stroke was less common in women than men, which may reflect the 3:1 ratio of use patterns in the general population, and/or other risk factors for stroke in this age population.15 17 Many studies did not report additional risk factors for stroke in the affected individuals, suggesting that in this young population haemorrhagic strokes in particular were related primarily to methamphetamine use. However, the presence of other undetected or unreported risk factors cannot be excluded. In the ischaemic stroke literature, other risk factors for stroke were detailed in some cases (table 1). It is notable that several young people were reported to have resting hypertension, which may or may not been a consequence of chronic methamphetamine use.
Where methamphetamine use has directly led to a stroke, headache, nausea, vomiting and confusion (and sometimes motor and sensory neurological signs) are early symptoms of stroke that will typically onset within minutes to hours of taking the drug.37 Hypertension is more often detected when medical support is sought quickly, presumably due to the effects of the drug still being present. The time from most recent use to onset of symptoms (or help-seeking for these) varied widely between studies from hours to weeks. It is likely that this range of use histories and use-to-stroke intervals is explained by different mechanisms of action of methamphetamine-associated stroke that include hypertension, vasculitis, direct vascular toxicity and vasospasm.38
Pathogenesis of haemorrhagic stroke
Intracranial haemorrhage may occur secondary to methamphetamine-induced hypertension and tachycardia, even in the absence of pre-existing cerebrovascular disease.39 Transient increases in blood pressure caused by methamphetamine through its direct action as a sympathomimetic agent may lead to ICH. Repeated use can raise blood pressure, increasing the risk for stroke, even in those without baseline hypertension.40 As is the case in essential hypertension, intracranial haemorrhage risk is increased by vessel wall damage that increases the likelihood of subsequent rupture and haemorrhage, particularly during an acute stress such as methamphetamine use.35
Chronic use can cause long-term systemic hypertension,5 7 a major risk factor for stroke. Both methamphetamine and cocaine contribute to physiological vascular fatigue by their pharmacological actions of hypertension and tachycardia.41 The more prolonged cardiovascular effect of methamphetamine compared with cocaine41 is a possible explanation for increased rates of ICH in methamphetamine abuse compared with cocaine.25 Vascular fatigue in a berry aneurysm leads to rupture and, often, to death. Furthermore, because vascular fatigue is cumulative, chronic previous methamphetamine use may be a significant factor in the development of berry aneurysms.41 McEvoy and coworkers42 suggest that cerebral aneurysms may form acutely in response to hypertensive crisis and or vasculitis induced by methamphetamine use.
Methamphetamine-induced subarachnoid haemorrhage in the absence of berry aneurysm or AVM can occur associated with necrotising angiitis.43–47 Methamphetamine is believed to directly affect the integrity of vasculature, giving rise to fibrinoid necrosis of the intima and media of blood vessel walls and destruction of their vascular smooth muscle predisposing to vessel rupture.46 47 Affected vessels are described to have a ‘beaded’ appearance with segmental narrowing and aneurysm formation46 also referred to as cerebral arteritis. Angiography and tissue microscopic examination have identified these abnormalities following intravenous,43 44 48 oral45 49 and inhalational use.50 In some cases, where angiography was repeated several weeks later, these appearances were no longer present51 52 suggesting that these may be transient abnormalities that remit on drug discontinuation or following corticosteroid treatment.53 Cerebral vasculitis is not specific to meth/amphetamine and is associated with the abuse of other illicit drugs, including cocaine and heroin.54 The possibility that methamphetamine may induce these changes is supported by animal models that show microaneurysm formation, spasm and perivascular cuffing in brains of adult Rhesus monkeys following intravenous injection of methamphetamine over 2 weeks.55
Pathogenesis of ischaemic stroke
Methamphetamine-associated ischaemic strokes may occur by various mechanisms. Vasculitis has been demonstrated in several young people with cerebral infarction secondary to methamphetamine use.50 56 57 Methamphetamine-associated cerebral vasculitis and its characteristic arterial narrowing, cerebral artery beading and pronounced irregularity of flow50 51 may increase the potential for a vessel to become occluded, such as in acute vascular spasm, with consequent ischaemia and infarction in the brain region supplied by the affected vessel.50 58 59 Vasospasm or cerebral vasoconstriction may follow a rapid rise in blood pressure60 and/or direct stimulation by methamphetamine of sympathomimetic α-adrenergic and β-adrenergic receptors, with resultant ischaemia.61
In a large case series of 30 all-age methamphetamine related stroke, however, Ho and coworkers35 found no evidence of an inflammatory vasculitic process underlying ischaemic stroke. Rather, they concluded that methamphetamine-associated vessel damage may occur as a result of accelerated atherosclerosis. Methamphetamine increases both systolic and diastolic blood pressures. Repeated exposure to transient use-related hypertension or the development of chronic hypertension in habitual methamphetamine users exposes individuals to heightened risk of arteriosclerosis pathogenesis, and associated arterial weakness, many years prematurely compared with the general population. Methamphetamine may also increase the risk of stroke through the highly increased risk of cardiomyopathy, and with that an increased risk of arrhythmias and thrombosis, leading to thromboembolic strokes.
As is the case for haemorrhagic stroke, methamphetamine-induced ischaemic stroke may occur in the absence of evidence of cerebral vascular abnormalities, chronic hypertension62 or other stroke risk factors.63 Other reports, however, indicate that patients with methamphetamine-associated stroke do carry additional risk factors for stroke including smoking, alcohol, hyperlipidaemia and AVM.62 64 65 Lifestyle factors associated with methamphetamine use including smoking and alcohol are likely to increase risk of stroke development as may additional common risk factors such as stroke history in either parent,66 dyslipidaemia and diabetes mellitus.17
Prognosis and outcomes
This review demonstrated that complete recovery was achieved in less than a quarter of cases. One-third of haemorrhagic strokes and one quarter of ischaemic strokes resulted in death. The remainder of individuals suffered a range of disability. It is likely that minor transient cerebrovascular events that resolve spontaneously would not result in help-seeking in this population, so the cases reported in the literature may reflect the more severe end of the spectrum. Nonetheless, these results compare unfavourably with evidence from a recent case series of all-cause stroke patients aged 16–45 years in whom an outcome of absence of symptoms is achieved by approximately two-thirds with a much lower death rate (3%).67 It is well known that among young people strokes associated with substance use carry a higher mortality.20 There is evidence for methamphetamine-associated aneurysmal subarachnoid haemorrhage that clinical outcomes are worse than age-matched controls at discharge30 and at 1-year and 3-year follow-up.31
Clinical implications
This review highlights the heightened risk of haemorrhagic stroke associated with methamphetamine use. With the use of methamphetamine increasing, particularly more potent forms, there is a growing burden of methamphetamine-related disease and harms, particularly among young people, in whom the majority of methamphetamine use occurs. Indeed, it is likely that methamphetamine abuse is making a disproportionate contribution to the increased incidence of stroke among young people observed over recent years.12 25
Clinicians treating methamphetamine users, and users themselves, need to be aware of the elevated risk of stroke in young methamphetamine users and to be aware of early signs and symptoms. Of note, symptoms such as paraesthesiae, headache, speech and language difficulties and visual defects, may be experienced transiently as a result of vasospasm, for example, and may herald later experience of a catastrophic stroke event. Conversely, young people presenting with signs and symptoms of stoke may well be methamphetamine users, highlighting the need for illicit drug use to be investigated as a contributory cause. A thorough substance use history should be sought and toxicological screening of urine and serum performed in young people presenting with stroke. This review focused on illicit amphetamine use and the data relating to stroke associated with prescribed amphetamines is beyond its scope. The possibility of increased stroke risk related to prescribed amphetamines for conditions such as attention deficit disorder is important and has been reviewed elsewhere.68 Similarly, the therapeutic use of amphetamines in stroke recovery has been systematically reviewed and found to be associated with increased death compared with control groups.69 Due consideration should be given to these risks when contemplating treatment options in young people.
The increased risk of haemorrhagic stroke in particular should be highlighted to young people who may use methamphetamine and to their communities in order to ensure appropriate help seeking, detection and intervention. Increasing the number of methamphetamine users in treatment appears to be a priority. There are no proven pharmacotherapies for methamphetamine dependence,70 but long-term residential rehabilitation has been shown to reduce methamphetamine use and harm.71
Conclusions
There is a preponderance of haemorrhagic strokes associated with methamphetamine use in young people, and methamphetamine-related stroke is associated with poorer clinical outcomes. Mechanisms of methamphetamine-associated stroke include hypertension, vasculitis, direct vascular toxicity and vasospasm. In a period of rising worldwide methamphetamine use, the incidence of methamphetamine-related stroke will increase, with a consequent increase in the burden of disease contributed by such events.
Acknowledgments
We wish to thank Mary Kumvaj for her assistance and insights in conducting the literature review.
References
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Footnotes
Contributors Dr JML performed the literature searches and conducted the statistical analyses and write-up of the paper. Professors SD and MF contributed to writing the manuscript and to subsequent revisions. All authors have approved the final manuscript.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.