Abstract
Methamphetamine abuse is a global epidemic associated with a wide-ranging array of adverse effects on the cardiovascular system including dilated cardiomyopathy, malignant and benign arrhythmias, coronary vasospasm, and atherosclerotic coronary artery disease. While the acute behavioral manifestations of amphetamine abuse are the most easily clinically identified, cardiovascular toxicity is common in this patient population and should be considered in this setting due to its high morbidity and mortality. The specific mechanisms for amphetamine cardiotoxicity have not been fully established, but new research implicates activation of several cellular targets including Sigma-1 receptors and trace amine-associated receptor 1 (TAAR1) leading to a myriad of negative downstream effects including increased reactive oxygenating species (ROS), mitochondrial dysfunction, and modulations of intracellular calcium. Additional pathologic effects are mediated by increased circulating catecholamines, which when chronically activated have well-established adverse effects on the cardiovascular system. In this article, we present a case report followed by a current review of the epidemiology, pathophysiology, diagnosis, and treatment modalities of amphetamine-induced cardiovascular disease.
Similar content being viewed by others
Avoid common mistakes on your manuscript.
Case report
A 28-year-old man with prior substance abuse history on methadone, without prior personal or family cardiac history, presented with nausea, vomiting, diarrhea, and diaphoresis. His hospital course was complicated by cardiac arrest requiring cardiopulmonary resuscitation with return of spontaneous circulation in 2 min. He was intubated for respiratory support. Lactate peaked at 8.6 mmol/L (normal range 0.5-2.0 mmol/L) and urine toxicology was positive for opiates, methadone, tetrahydrocannabinol, and amphetamine. Serum NT-pro BNP [37,250 (normal range: 0-450 pg/nL)] and troponin T [(1.04, normal range < 0.04 ng/mL)] were elevated. Initial echocardiogram revealed left ventricular ejection fraction (LVEF) of 10-15% with severe global hypokinesis. He was hemodynamically supported with dobutamine 5 mcg/kg/min and norepinephrine 0.8 mcg/kg/min. Endomyocardial biopsy revealed findings of cardiomyopathy and ischemic changes without evidence of myocarditis (Fig. 1). Cardiac MRI revealed severe biventricular dysfunction without late gadolinium enhancement. Patient endorsed methamphetamine use prior to presentation which raised our suspicion for methamphetamine-induced cardiomyopathy, but was unwilling to clarify his burden of use or route of administration. He was discharged on a guideline-directed heart failure regimen of sacubitril-valsartan 24-26 mg daily, carvedilol 3.125 mg twice daily, empagliflozin 10 mg once daily, and spironolactone 25 mg once daily along with 40 mg of daily furosemide as a maintenance diuretic. He was instructed to follow up with addiction medicine and psychiatry as an outpatient. A 1-month follow-up echocardiogram showed improved LVEF of 55%.
Introduction
While much mainstream medical literature and media attention is given to the worldwide opiate epidemic, methamphetamine poses an equally morbid and widely used drug of abuse. Synthesized originally in Japan in the late nineteenth century, methamphetamine was used as a stimulant for German soldiers during World War II to promote extended periods of wakefulness, and emerged as a drug of abuse due to its euphoric effects and role in appetite suppression [1,2,3]. Methamphetamine is abused on a mass scale, noted to be second only to marijuana across the globe among recreational drugs [3]. In some countries, methamphetamine surpasses opiates and serves as the number one drug of abuse [4].
After acute intoxication, cardiovascular disease is noted to be the leading cause of death in methamphetamine users [5,6,7]. The cardiac effects of methamphetamine range from benign tachycardia to malignant arrhythmias and cardiovascular collapse. For the purpose of this review, we will summarize current knowledge pertaining to the epidemiology, clinical manifestations, postulated mechanisms, and treatment of methamphetamine-associated cardiovascular pathology.
Epidemiology
Methamphetamine abuse constitutes a global epidemic with recent studies estimating approximately 51 million users worldwide between the ages of 15 and 64 [3]. In the USA alone, the National Surveys on Drug Use and Health reports between 2015 and 2018 an estimated prevalence of methamphetamine use of 6.6 per 1000 people, with frequent use encompassing 200 days or more in 27.3% of reported cases [8]. Between 2008 and 2018, age-adjusted methamphetamine-associated heart failure (MethHF) hospitalizations increased by 585% in California in the USA. A total of 42,565 patients were hospitalized with MethHF in California and the annual inflation-adjusted cost of care increased from $41.5 million to $390.2 million within the specified time period [9]. Socioeconomic disparities, such as lower attainment of formal education and low annual household income (< $50,000 annually), have been associated with abuse potential [8]. Healthcare disparities such as insurance status (Medicaid and no insurance), co-occurring substance use, and mental illness have also been associated with increased risk for methamphetamine abuse.
A retrospective review of 9491 veterans with heart failure found that 4.5% had associated methamphetamine use history [10]. The incidence of MethHF doubled from 3.4 to 6.7% from 2005 to 2015 in veterans. Veterans with MethHF were younger (61 versus 72 years), more likely to be depressed, homeless or unemployed, and with comorbid post-traumatic stress disorder [10]. These trends are disturbing and highlight the need for more attention to prevention and treatment of methamphetamine use disorder.
Clinical presentation and clinical course
The clinical presentation of acute methamphetamine abuse depends on chronicity of use and level of intoxication, but generally presents with a myriad of neurologic manifestations including agitation and insomnia, as well as psychomotor symptoms including excessive speech and motor hyperactivity [11]. On physical examination, other non-cardiac signs include track marks from injection site, diaphoresis, and xerostomia with tooth decay.
Cardiovascular manifestations of methamphetamine toxicity include dilated cardiomyopathy, atherosclerotic coronary artery disease, malignant hypertension, ventricular and supraventricular arrhythmias, coronary vasospasm, heart failure, cardiogenic shock, and sudden cardiac death.
Methamphetamine-induced heart failure frequently presents with dilated cardiomyopathy and global left ventricular dysfunction [12], which can progress to fatal cardiogenic shock [13]. One proposed mechanism for cardiac dysfunction is similar to stress cardiomyopathy in the setting of catecholaminergic overload [14], although there are direct myocardial effects of methamphetamines that have also been described. Coronary angiography performed in patients presenting with acute methamphetamine intoxication and acute ST-segment myocardial infarction have demonstrated thrombolysis in myocardial infarction (TIMI) I flow without obstructive epicardial coronary artery disease, suggesting coronary vasospasm and microvascular dysfunction [15]. Methamphetamine has been shown to prolong QTc intervals, theoretically raising the risk of early-after depolarizations and torsade de pointes [16]. Table 1 highlights the acute and chronic cardiac manifestations of methamphetamine compared with other drugs of abuse.
Pathophysiology and molecular mechanism
While the physiology behind the euphoric effects of methamphetamine is relatively well understood, the toxic effects are less delineated. The euphoria is thought to be secondary to increased dopamine availability in the synaptic clefts of the mesolimbic nervous system, which is facilitated by methamphetamine’s methyl group enhancing lipophilicity, resulting in increased blood–brain barrier penetration [17]. Methamphetamine dysregulates monoamine regulation through the disruption of intracellular storage vesicles containing monoamines, inducing dopamine efflux into the synaptic cleft, and downregulation of dopamine active transporters (DAT) [18, 19].
The mechanisms of the cardiovascular effects of methamphetamine are multifactorial and include intra and extracellular signaling, upregulation of reactive oxygenating species, and mitochondrial dysregulation via catecholamine-dependent and independent mechanisms [2, 3, 20, 21]. Methamphetamine effects on catecholamine release and metabolism increase catecholamine levels, which can cause direct myocardial injury, stimulate hypertrophy via myocyte adrenergic receptor activation, increase oxygen free radical generation, cause mitochondrial dysfunction, and impair intracellular calcium hemostasis [7, 21, 22]. Furthermore, catecholamine increases blood pressure, heart rate, and vasospasm, all of which promote cardiac ischemia which can exacerbate contractile dysfunction [20].
The proposed mechanisms of action for methamphetamine to trigger arrhythmias include the inhibition of potassium current and L-type calcium, which has been demonstrated in a murine model [23], and through the stimulation of cardiac structural changes causing electrical remodeling, which can manifest by QTc prolongation. In a postmortem analysis of methamphetamine-related deaths in Australia, coronary artery atherosclerosis was detected in 54% of decedents [24] while severe coronary artery disease was present in 19% [25]. The production of reactive oxygen species and reactive nitrogen species, from a direct effect of methamphetamine on mitochondria, has been implicated as the potential mechanism of atherogenesis [26].
The mechanism behind vascular effects of methamphetamine is complicated due to the complex regulation of baseline vascular tone that involves a complex array of interworking mechanisms involving vaso-modulating factors such as nitric oxide, prostacyclin, angiotensin II, and adrenergic compounds [3]. In a mouse model, TAAR1 was implicated in methamphetamine-related effects that has the potential to promote methamphetamine use [27], thus making TAAR1 a potential target for therapeutic intervention. One of the mechanisms of methamphetamine-induced vasoconstriction is through the release of endothelin-1 [28] or TAAR1 signaling [29]. TAAR1-dependent vasoconstriction has been proposed to be mediated by phenylethylamine-specific receptors [30].
New research has demonstrated involvement of Sigma-1 receptor in methamphetamine toxicity, which results in dysregulated modulation of intracellular signaling affecting overall cellular homeostasis through mechanisms such as cellular calcium and gene transcription regulation [31, 32]. Sigma-1 receptor is a chaperone protein associated with the endoplasmic reticulum predominantly in the central nervous system, but is also heavily expressed elsewhere, including cardiac tissue [33]. Some studies demonstrate a relationship between Sigma-1 and DAT [34]. One proposed mechanism of calcium modulation is through the interaction of Sigma-1 receptor and inositol-1,4,5-triphosphate which regulates calcium storage in the endoplasmic reticulum [33].
Modulation of Sigma-1 receptor activity has been associated with myocardial disease. Mice lacking Sigma-1 receptor expression due to genetic disruption of expression develop progressive cardiac dysfunction associated with ventricular dilatation and myocardial fibrosis [35]. Similarly, in mice exposed to methamphetamine, cardiac hypertrophy, fibrotic remodeling, and mitochondrial dysfunction are the pathological hallmarks [32]. Inhibiting Sigma-1 receptor results in the inactivation of the cyclic adenosine monophosphate response element-binding protein (CREB), and decreased expression of mitochondrial fission 1 protein (FIS1), which ultimately alters mitochondrial dynamics and function [32]. Activation of Sigma-1 receptor has been explored as a therapeutic strategy for cardioprotection. For example, the selective serotonin reuptake inhibitor class of antidepressants are known activators of Sigma-1 receptor, and treatment of rodents with selective serotonin reuptake inhibitors is cardioprotective against pressure overload-induced heart failure [36]. Figure 2 shows various receptors implicated in the pathogenesis of MethHF.
Diagnostic workup
A high index of clinical suspicion is needed to diagnose MethHF, since there is no single diagnostic tool utilized. Clinical symptoms listed above, especially non-cardiac signs such as track marks, tooth decay, and psychomotor symptoms, should raise suspicion [20, 37]. Table 2 shows common diagnostic tools utilized in the diagnosis of MethHF.
Treatment
Since treatment options specifically tailored to methamphetamine-induced cardiomyopathy are not available, current management is limited to interventions that promote abstinence from methamphetamine and comorbid drugs of abuse, as well as use of standard heart failure therapies. Public health policies targeting those who are vulnerable to methamphetamine are imperative. This may require psychosocial strategies which target risk factors for methamphetamine use such as low income, unemployment, and other socioeconomic disadvantage. The importance of the patients discontinuing methamphetamine use cannot be overstated, as data suggests abstaining from methamphetamine is the most important predictor in reversing the cardiomyopathy [4, 38]. Current pharmacologic therapeutics designed to curb addiction include bupropion and modafinil [38]. Addiction rehabilitation should be recommended to methamphetamine users.
The mainstay of therapy in the acute setting is targeted towards the specific end-organ clinical manifestations of acute intoxication, including managing agitation, decompensated heart failure, coronary vasospasm, and hypertensive emergency. With regard to hypertensive emergency, it is generally recommended to first initiate alpha blockade prior to beta-adrenergic receptor blockade, with the concern of impeded alpha constriction due to the adrenergic properties of methamphetamine, similar to cocaine toxicity [1].
Heart failure treatment should be initiated in accordance with current guidelines. In symptomatic patients with heart failure with reduced ejection fraction as a result of methamphetamine toxicity, current guideline therapies include neurohormonal blockade with a beta-adrenergic receptor blocker (metoprolol succinate, carvedilol, or bisoprolol), an angiotensin-converting enzyme inhibitor (ACEI), angiotensin receptor blocker or an angiotensin receptor-neprolysin inhibitor (ARNi), mineralocorticoid receptor antagonist, and a sodium-glucose cotransporter 2 (SGLT-2) inhibitor [23, 39]. In the case of patients with advanced heart failure, referral for transplant or mechanical circulatory support devices is often impeded by psychosocial complications and substance abuse frequently associated with patients abusing amphetamines.
One future direction that shows promise in animal models is the use of anti-methamphetamine monoclonal antibodies which have been demonstrated to reduce acute locomotor toxicity and have a protective effect against both cardiovascular and neurologic toxicity [23, 40]. Additionally, preliminary research suggests the partial dopamine and serotonin agonist aripiprazole, commonly used now in the management of cognitive decline, may reduce acute stimulant properties of methamphetamine [23, 41].
Conclusion
Methamphetamine abuse confers significant global morbidity and mortality. Cardiovascular complications from methamphetamine have dire public health consequences including a profound economic impact. Resources should be dedicated to promoting methamphetamine cessation and rehabilitation. While modern research has given some insight into the specific mechanisms behind methamphetamine toxicity, continued research into mitigating the addictive use patterns and specific pharmacological targets are needed.
References
Schwarzbach V, Lenk K, Laufs U (2020) Methamphetamine-related cardiovascular diseases. ESC Heart Fail 7(2):407–414
Ben-Yehuda O, Siecke N (2018) Crystal methamphetamine: a drug and cardiovascular epidemic. JACC Heart Fail 6(3):219–221
Kevil CG et al (2019) Methamphetamine use and cardiovascular disease. Arterioscler Thromb Vasc Biol 39(9):1739–1746
Zhao SX et al (2018) Clinical characteristics and outcome of methamphetamine-associated pulmonary arterial hypertension and dilated cardiomyopathy. JACC Heart Fail 6(3):209–218
Freeling JL, McFadden LM (2020) The emergence of cardiac changes following the self-administration of methamphetamine. Drug Alcohol Depend 212:108029
Paratz ED et al (2017) Is an abnormal ECG just the tip of the ice-berg? examining the utility of electrocardiography in detecting methamphetamine-induced cardiac pathology. Heart Lung Circ 26(7):684–689
JafariGiv M (2017) Exposure to amphetamines leads to development of amphetamine type stimulants associated cardiomyopathy (ATSAC). Cardiovasc Toxicol 17(1):13–24
Jones CM, Compton WM, Mustaquim D (2020) Patterns and characteristics of methamphetamine use among adults - United States, 2015–2018. MMWR Morb Mortal Wkly Rep 69(12):317–323
Zhao SX et al (2021) Socioeconomic burden of rising methamphetamine-associated heart failure hospitalizations in California from 2008 to 2018. Circ Cardiovasc Qual Outcomes 14(7):e007638
Nishimura M et al (2019) Characteristics and outcomes of methamphetamine abuse among veterans with heart failure. Am J Cardiol 124(6):907–911
Paulus MP, Stewart JL (2020) Neurobiology, clinical presentation, and treatment of methamphetamine use disorder: a review. JAMA Psychiat 77(9):959–966
Wijetunga M et al (2003) Crystal methamphetamine-associated cardiomyopathy: tip of the iceberg? J Toxicol Clin Toxicol 41(7):981–986
Hong R, Matsuyama E, Nur K (1991) Cardiomyopathy associated with the smoking of crystal methamphetamine. JAMA 265(9):1152–1154
Srikanth S, Barua R, Ambrose J (2008) Methamphetamine-associated acute left ventricular dysfunction: a variant of stress-induced cardiomyopathy. Cardiology 109(3):188–192
Chen JP (2007) Methamphetamine-associated acute myocardial infarction and cardiogenic shock with normal coronary arteries: refractory global coronary microvascular spasm. J Invasive Cardiol 19(4):E89-92
Haning W, Goebert D (2007) Electrocardiographic abnormalities in methamphetamine abusers. Addiction 102(Suppl 1):70–75
Panenka WJ et al (2013) Methamphetamine use: a comprehensive review of molecular, preclinical and clinical findings. Drug Alcohol Depend 129(3):167–179
Shaerzadeh F et al (2018) Methamphetamine neurotoxicity, microglia, and neuroinflammation. J Neuroinflammation 15(1):341
Sambo DO et al (2017) The sigma-1 receptor modulates methamphetamine dysregulation of dopamine neurotransmission. Nat Commun 8(1):2228
Reddy PKV et al (2020) Clinical characteristics and management of methamphetamine-associated cardiomyopathy: state-of-the-art review. J Am Heart Assoc 9(11):e016704
Jiang JP, Downing SE (1990) Catecholamine cardiomyopathy: review and analysis of pathogenetic mechanisms. Yale J Biol Med 63(6):581–591
Brown JM, Yamamoto BK (2003) Effects of amphetamines on mitochondrial function: role of free radicals and oxidative stress. Pharmacol Ther 99(1):45–53
Won S et al (2013) Methamphetamine-associated cardiomyopathy. Clin Cardiol 36(12):737–742
Kaye S et al (2008) Methamphetamine-related fatalities in Australia: demographics, circumstances, toxicology and major organ pathology. Addiction 103(8):1353–1360
Darke S, Duflou J, Kaye S (2017) Prevalence and nature of cardiovascular disease in methamphetamine-related death: a national study. Drug Alcohol Depend 179:174–179
Potula R et al (2010) Methamphetamine causes mitrochondrial oxidative damage in human T lymphocytes leading to functional impairment. J Immunol 185(5):2867–2876
Phillips TJ et al (2021) Confirmation of a causal Taar1 allelic variant in addiction-relevant methamphetamine behaviors. Front Psychiatry 12:725839
Seo JW et al (2016) Methamphetamine induces the release of endothelin. J Neurosci Res 94(2):170–178
Fehler M et al (2010) Identification of trace-amine-associated receptors (TAAR) in the rat aorta and their role in vasoconstriction by beta-phenylethylamine. Naunyn Schmiedebergs Arch Pharmacol 382(4):385–398
Herbert AA, Kidd EJ, Broadley KJ (2008) Dietary trace amine-dependent vasoconstriction in porcine coronary artery. Br J Pharmacol 155(4):525–534
Nguyen EC et al (2005) Involvement of sigma (sigma) receptors in the acute actions of methamphetamine: receptor binding and behavioral studies. Neuropharmacology 49(5):638–645
Abdullah CS et al (2020) Methamphetamine induces cardiomyopathy by Sigmar1 inhibition-dependent impairment of mitochondrial dynamics and function. Commun Biol 3(1):682
Pontisso I, Combettes L (2021) Role of Sigma-1 receptor in calcium modulation: possible involvement in cancer. Genes 12(2):139
Hong WC et al (2017) The sigma-1 receptor modulates dopamine transporter conformation and cocaine binding and may thereby potentiate cocaine self-administration in rats. J Biol Chem 292(27):11250–11261
Abdullah CS et al (2018) Cardiac dysfunction in the Sigma 1 receptor knockout mouse associated with impaired mitochondrial dynamics and bioenergetics. J Am Heart Assoc 7(20):e009775
Bhuiyan MS, Tagashira H, Fukunaga K (2013) Crucial interactions between selective serotonin uptake inhibitors and sigma-1 receptor in heart failure. J Pharmacol Sci 121(3):177–184
Hart CL et al (2008) Acute physiological and behavioral effects of intranasal methamphetamine in humans. Neuropsychopharmacology 33(8):1847–1855
Osekowski M et al (2022) A comprehensive approach to managing methamphetamine-associated cardiomyopathy. Am J Cardiovasc Drugs
Heidenreich Paul A et al (2022) 2022 AHA/ACC/HFSA guideline for the management of heart failure. J Am Coll Cardiol 79(17):e263–e421
Gentry WB et al (2006) Safety and efficiency of an anti-(+)-methamphetamine monoclonal antibody in the protection against cardiovascular and central nervous system effects of (+)-methamphetamine in rats. Int Immunopharmacol 6(6):968–977
Sevak RJ et al (2011) Discriminative-stimulus, subject-rated, and physiological effects of methamphetamine in humans pretreated with aripiprazole. J Clin Psychopharmacol 31(4):470–480
Acknowledgements
The authors thank Katherine Rose Champlin for the graphic design of Fig. 1.
Funding
Douglas B. Sawyer is supported by NIH/NIGMS P20GM139745 and NIH/NHLBI HL139887.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing interests.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Tobolski, J., Sawyer, D.B., Song, S.J. et al. Cardiovascular disease associated with methamphetamine use: a review. Heart Fail Rev 27, 2059–2065 (2022). https://doi.org/10.1007/s10741-022-10261-7
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10741-022-10261-7