Stimulant Drugs of Abuse and Cardiac Arrhythmias

Abstract

Non-medical use of prescription and non-prescription drugs is a worldwide epidemic, rapidly growing in magnitude with deaths due to overdose and chronic use. A vast majority of these drugs are stimulants that have various effects on the cardiovascular system including the cardiac rhythm. Drugs, like cocaine and methamphetamine, have measured effects on the conduction system and through several direct and indirect pathways, utilizing multiple second messenger systems, change the structural and electrical substrate of the heart, thereby promoting cardiac dysrhythmias. Substituted amphetamines and cocaine affect the expression and activation kinetics of multiple ion channels and calcium signaling proteins resulting in EKG changes, and atrial and ventricular brady and tachyarrhythmias. Pre-existing conditions cause substrate changes in the heart which decrease the threshold for such drug-induced cardiac arrhythmias. The treatment of cardiac arrhythmias in patients who take drugs of abuse may be specialized and will require an understanding of the unique underlying mechanisms and necessitates a multi-disciplinary approach. The use of primary or secondary prevention defibrillators in drug abusers with chronic systolic heart failure is both sensitive and controversial. This review provides a broad overview of cardiac arrhythmias associated with stimulant substance abuse and their management.

Introduction

Non-medical use of prescription and non-prescription drugs is a worldwide epidemic, growing rapidly, leading to overdose deaths and consequences of chronic misuse. Methamphetamine, a stimulant with high potential for abuse, has quickly become the second most commonly abused illicit drug in the United States, second only to marijuana. Stimulants including cocaine and methamphetamine can produce damaging cardiovascular effects and initiate and perpetuate various arrhythmias.

Expert consensus statements and guidelines do not specifically address this issue. This review explores the current state of stimulant drug use, discusses mechanisms of and critically evaluates evidence behind stimulant drug-induced cardiac arrhythmias, and offers management strategies.

Growing Global Drug Problem:

Approximately 269 million people misused drugs for non-medical purposes in 2018, representing 5.3% of the world’s population aged 15–64 (Figure 1). Amphetamines and cocaine are the most widely used stimulants with 48 million and 19 million people, respectively, using these drugs for non-medical purposes in 2018¹ (Figures 2 and 3). Cocaine (from plants within the Erythroxylaceae family), administered by inhalation, injection, and smoking has a high potential for abuse.

Figure 1:

Global prevalence of drug use and drug use disorders, 2006–2018, Source: World Drug Report 2020 (United Nations publication, Sales No. E.20.XI.6).

Figure 2:

Trends in the misuse of pharmaceutical stimulants and methamphetamines in United States, 2015–2018. Y-axis shows the percentage US population aged 12 and older who misused pharmaceutical stimulants and methamphetamines. While the misuse of pharmaceutical stimulants declined, there was an increase in methamphetamine misuse. Source: World Drug Report 2020 (United Nations publication, Sales No. E.20.XI.6

Figure 3:

Trends in the use of cocaine and “crack” cocaine, United States, 2002–2018, Y- axis shows the percentage of US population 12 years and older who used cocaine. Source: World Drug Report 2020 (United Nations publication, Sales No. E.20.XI.6).

Medical uses of cocaine include local anesthesia and topical vasoconstriction. Cocaine is classified as a Schedule II drug by the DEA, and its non-medical use is illegal in the United States. Amphetamines represent a class of widely abused central nervous system stimulants. The prototypic drug, amphetamine is medically approved to treat attention deficit hyperactivity disorder (ADHD), narcolepsy, and obesity.

Methamphetamine, an amphetamine derivative, and strong psychostimulant with high potential for misuse, is a schedule II drug, available in powder and pill forms and is administered by injection, smoking, swallowing, and inhalation. “Ecstasy-like” substances, including 3,4-methylenedioxy-methamphetamine (MDMA), are synthesized from the prototypical amphetamine backbone. These drugs produce stimulant (e.g., euphoria), psychedelic (e.g., perceptual changes), and prosocial effects. Ecstasy has no medically accepted use and is classified as a Schedule I drug in the United States. However, the FDA recently gave “breakthrough status” to MDMA for post-traumatic stress disorder, which could speed advancement through clinical trials. (Table 1)

Table 1:

Characteristics of stimulant drugs of abuse

Drug Name	Street Names	Physical Form	Routes of administration	Estimated prevalence of non-medical use in 2018
Cocaine	Blow, Coca, Coke, Crack, Flake, Snow, Soda Cot	White, crystalline powder	Nasal insufflation, injected, smoked	19 million
Amphetamines (Including amphetamine, methamphetamine phentermine)	Batu, Bikers Coffee, Black Beauties, Chalk, ChickenFeed, Crank, Crystal, Glass, Go-Fast, Hiropon, Ice, Meth, Methlies Quick, Poor Man’s Cocaine, Shabu, Shards, Speed, Stove Top, Tina, Trash, Tweak, Uppers, Ventana, Vidrio, Yaba, Yellow Bam, Bennies, and Uppers	Pills or powder	Swallowed, nasal insufflation, injected, smoked	27 million
Ecstasy/MDMA	Adam, Beans, Clarity, Disco Biscuit, Ecstasy, Eve, Go, Hug Drug, Lover’s Speed, MDMA, Peace, STP, X, and XTC	Pills, capsules, powder, liquid	Mostly swallowed, sometimes crushed and used for nasal insufflation, occasionally smoked	21 million

Pharmacology of Stimulants

Second messenger systems involved in stimulant drug pathophysiology

In the central nervous system (CNS), stimulants interact with monoamine neurons, including dopamine, serotonin, and norepinephrine. At presynaptic terminals, these neurons express specialized plasma membrane proteins transporting neurotransmitters from the extracellular space into the cytoplasm, inactivating neurotransmitter signaling.² Drugs interacting with transporters are categorized as reuptake inhibitors or substrate-type releasers, based on their mechanism of action. Such compounds stimulate downstream monoamine receptors and signaling systems by increasing extracellular levels of endogenous monoamine neurotransmitters.

Cocaine is a nonselective inhibitor of all three monoamine transporters.³ However, behavioral effects of cocaine associated with abuse liability have been attributed primarily to actions at the dopamine transporter (DAT).⁴ Neuroimaging studies in human cocaine users correlate levels of DAT occupancy with the magnitude of the “high” following administration of cocaine⁵ or the DAT inhibitor, methylphenidate.⁶ Amphetamines, in contrast to cocaine, act as substrate-type releasers allowing intracellular transport through monoamine transporters.

COCAINE

Cocaine and Electrical Remodeling:

The propensity of stimulant drugs to initiate cardiac arrhythmias stems partly from their ability to affect expression or function of cardiac ion channels directly, based on evidence predominantly emanating from their actions on neurons. Direct effects of stimulant drugs on ion channels in isolated cells are independent of catecholaminergic changes that occur in-vivo. (Table 2)

Table 2:

Summary of available evidence of EKG changes in stimulant drugs use

	Study (n = number of patients)	Baseline QTc (means [SD])	Effect of cocaine and methamphetamine use on QT interval (means [SD])	Statistically significant (P < 0.05)
Cocaine	Gamouras et al. (n = 45) *	Not reported	QTc in Group I (with chest pain) = 510.0 [84.3] ms QTc Group II (no chest pain) = 459.0 (73.7) ms	P <0.03
	Haigney et al. (n = 29)	Not reported	QTVI† increased within first 5 minutes of cocaine infusion and peaked at 10 minutes. Dose effect seen (higher QTVI for 40mg vs 20mg of cocaine)	P <0.0001 compared with preinfusion
	Magnano et al. (n = 14)	401 [21] ms	QTc = 423 [25] ms	P <0.001
	Chakko et al. (n = 238)	Not reported	QTc prolonged (>440 ms) in 26% of patients admitted for acute cocaine toxicity vs 4% in chronic cocaine users (means 427 [38] vs 404 [19], respectively)	P = 0.00003
Methamphetamine	Bazmi et al. (n = 230)	Not reported	Sinus tachycardia plus prolonged QT interval in 34.4% of patients	-
	Haning et al. (n = 158)	Not reported	QTc prolonged (>440ms) in 27.2% of patients	-
	Paratz et al. (n = 212)	Not reported	21.7% of 106 meth users had prolonged QTc‡ with mean of 436.41 [31.61] vs 407.28 [24.38] in control group	P <0.0001

ms = milliseconds

^*Group I consisted of 23 patients with anginal chest pain in addition to cocaine abuse. Group II was composed of 22 patients with cocaine use without a history of chest pain. None of these patients had a prior history of heart disease, nor were any taking antiarrhythmic agents.

^†QTVI, therefore, is the log ratio between the QT interval and heart rate variability.

^‡As defined by >450 ms for males, >460 ms for females.

The QTc was determined using Bazett’s formula = QT/RR^1/2

Cocaine can produce electrical remodeling by altering gating properties of ion channels. Cocaine inhibits several potassium channels. Cocaine blunted action potential duration (APD) shortening effect of ATP-sensitive potassium channel (K_ATP) openers in murine ventricular myocytes.⁷ Disruption of the KCNJ11 gene encoding for Kir6, the core forming subunit of K_ATP channels, augments effects of cocaine on K_ATP channels.⁸ A substantial number of cocaine abusers simultaneously, or concurrently, use cocaine and alcohol combinations. Alcohol potentiates actions of cocaine by forming cocaethylene, a metabolite of alcohol and cocaine that inhibits IKr channels.⁹

Cocaine can inhibit sodium channels in a voltage-dependent fashion, albeit, less than lidocaine.¹⁰ Cocaine affects use-dependent inhibition of cardiac sodium channels in two phases (rapid and slower phase).¹¹ Mutations of the interdomain III-IV linker that removed the rapid inactivation selectively abolished these effects of cocaine on sodium channels,¹² by binding to a location in the internal vestibule of the sodium channel, blocking the channel pore. Cocaethylene potentiates sodium channel inhibition, mediated by its actions on the extracellular end of the S6 segment of the D4 domain of the sodium channel.¹³

Cocaine alters function of calcium-related channels and calcium handling proteins. Cocaine blocks the sarcoplasmic reticulum from the cytoplasmic side resulting in reduced current amplitude¹⁴ and calcium transients in cocaine-treated rat ventricular myocytes,¹⁵ an effect that is accentuated by simultaneous exposure to ethanol and cocaine.¹⁶ Cocaine disrupts calcium-dependent oligomerization of calsequestrin ¹⁷ by its high affinity binding, thereby affecting sarcoplasmic reticulum calcium storage and release. Finally, cocaine increases calcium calmodulin kinase II activity, which may affect multiple mechanisms of atrial and ventricular arrhythmias.¹⁸ Cocaine’s effects on calcium channels and calcium handling proteins is manifested as a dose dependent increase in APD, frequent early afterdepolarizations,¹⁹ and field potential duration.²⁰

Cocaine and Structural Remodeling:

Stimulant drugs can cause myocyte cell death and fibrosis resulting in reduced systolic function, increasing the risk of arrhythmias. Cocaine increases the risk of myocardial infarction (MI), heart failure, cardiomyopathy, arrhythmias, aortic dissection, endocarditis, and other cardiovascular diseases.^21–24 Cocaine users have a higher overall incidence of MI (odds ratio up to 6.9) versus nonusers,²⁵ with the risk of MI increasing by 24-fold in the first hour after cocaine use.²² Cocaine-induced cardiomyopathy is associated with myocardial inflammation, necrosis, fibrosis,^24,26 left ventricular hypertrophy,²¹ and alterations in gene expression.²⁷ Pre-clinical studies in rabbit models demonstrate regional wall motion abnormalities (mostly anteroseptal) associated with decreased left ventricular fractional shortening and increased systolic dimension with acute cocaine intoxication.²⁸ In mouse models, acute and chronic cocaine-ingestion causes myocardial hypertrophy, contractile dysfunction, and remodeling.²⁹

Cocaine and EKG changes (Table 3):

Table 3:

Effect of Cocaine and Methamphetamines on Ions Channels and EKG

	Cocaine	Methamphetamine
Effect of agent on cardiac ion channels
Na+ (INa)	⬇	−
K+	⬇ (KATP, IKr)	⬇ (Kto and Kir)
Ca2+	⬇ & ⬆ (ICa,L =increases with low cocaine concentration, ICa,L = decreases with high cocaine concentrations)	⬇/⬆ (ICa,L)
Effect of agent on EKG
PR interval	−	−
QRS duration	⬆
QTc interval	⬆	+
ST-T wave changes	+	+
Atrial dysrhythmias
Sinus tachycardia	+	+
Atrial fibrillation	+	+/−
Atrial tachycardias (including SVT)	+	+
Ventricular arrhythmias
Ventricular tachycardia	+	+
Ventricular fibrillation	+	?
Torsade de pointes	+	+
Bradyarrhythmias
Bradycardia	+	−
Heart block	+	−

I_Ca,L = L-type calcium channels

K_ATP= ATP sensitive potassium channels

IKr= Rapidly activating delayed rectifier potassium channels

K_ir= Inwardly rectifying potassium channels

K_to= Transient outward potassium channel

⬆ indicates increase in current or ECG parameter

⬇ indicates decrease in current or ECG parameter

⁺indicates a known effect of the drug on the EKG parameters or cardiac arrhythmias

⁻indicates no effect or unknown effect

^?indicates unknown or controversial data on effect

Cocaine blocks voltage-dependent potassium channels to prolong QT intervals.³⁰ In addition, cocaine blocks fast inward sodium channels similar to class IC antiarrhythmic drugs³¹ prolonging QRS duration. Retrospective review of EKGs from 97 cocaine-dependent patients and 8,513 non-using subjects from the Atherosclerosis Risk in Communities study found a notable effect of cocaine on early repolarization (odds ratio=4.92, 95% confidence interval (CI): 2.73–8.87).³² Cocaine’s sympathomimetic effects increased ventricular ectopy.³³ Cocaine-induced myocardial ischemia may further promote reentrant tachycardias.³⁴ In patients presenting to the Emergency Department with chest pain, the incidence of cocaine-associated MI was 0.7–6%. EKG abnormalities included ST-elevation, ST-depression, voltage criteria for left ventricular hypertrophy, and non-specific ST and T wave abnormalities.³⁵ Moreover, cocaine-induced Brugada pattern has been described.^36,37

Cocaine and Bradyarrhythmias:

While stimulant drugs tend to cause tachyarrhythmias, they can also cause bradyarrhythmias. (Table 2) Various degrees of AV block have been reported with cocaine use.^38,39 In animal studies, cocaine can cause rate-dependent conduction delays and prolonged refractoriness in the atria, AV node, His-Purkinje system and ventricular myocardium.⁴⁰ However, data supporting similar effects in humans is scarce. Sinus bradycardia has been observed with chronic cocaine use ^{32, 41} the severity of which was related to length of cocaine use. Desensitization of β-adrenergic receptors secondary to repeated cocaine exposure has been postulated.⁴¹

Cocaine and Atrial Arrhythmias:

Little evidence implicates a relationship between stimulant drugs and atrial arrhythmias. Sinus tachycardia is the most common arrhythmia that results from cocaine toxicity but supraventricular tachycardia and atrial fibrillation can also occur.³¹ These tachycardias are primarily due to cocaine’s effect on increasing circulating catecholamines. There is a report of atrial flutter in newborns associated with perinatal maternal cocaine use.⁴²

Cocaine and Ventricular Arrhythmias:

Documentation of ventricular arrhythmias in stimulant drug users is sparse. Patients with cocaine-induced arrhythmias often have additional risk factors for arrhythmias, such as, pre-existing coronary artery disease, myocarditis, or cardiomyopathy (please refer to section on Stimulant Misuse and Co-occurring Risk Factors for Arrhythmias in supplementary material). In cases where these drugs do cause arrhythmias, the patients are usually young, and the heart rhythm usually produces rapid, and erratic death outside the medical system.

Ventricular tachycardia has been reported with cocaine use in patients with myocarditis supported by MRI-proven sub-epicardial scar.⁴³ Reports of frequent premature ventricular contractions (PVCs), non-sustained VT, idioventricular rhythm, sustained VT, VF, torsade de pointes and SCD, have been reported in patients aged 20–44 without underlying ischemia.⁴⁴ Animal studies indicate post MI episodes of VF after cocaine exposure are reduced by verapamil.⁴⁵

A prospective study of 10 patients with hypertension and active cocaine use indicated that 1 of 10 patients had non-sustained VT.⁴⁶ In a study of 45 hospitalized patients for cocaine abuse, those with CP had a longer QTc intervals (510 ms) vs those with no CP (459 ms). Among patients with CP, 13% had sustained ventricular arrhythmias; all had repolarization abnormalities.³⁰ In 7 studies evaluating outcomes of 70,302 patients admitted with cocaine-related CP, 0.8–13%% of those with CP admitted with an MI had sustained ventricular arrhythmias^23,47. Brugada syndrome-like EKG changes, ventricular arrhythmias, and sudden cardiac arrest have been reported with cocaine exposure.³⁷

Cocaine and Sudden Arrhythmic Deaths:

Evidence regarding cocaine abuse and SCD stems primarily from autopsy studies. An Australian study⁴⁸ examined autopsy cases of sudden and unexpected death where cocaine or its metabolites were detected for case circumstances, pathology, toxicology, and coronial findings. The concentration of cocaine was low in 44% deemed to have died from cocaine cardiotoxicity (median age 30, mostly men). Multiple drug use was found with opioids (47%), amphetamines (31%), and ethanol (35%). Coexistent heart disease was present in 31%, with coronary artery disease being most common (73%). Cardiomegaly was present in 33% of cases.⁴⁸

Another study of 668 SCD patients found 3.1% to be cocaine-related, most with concomitant ethanol use⁴⁹. Recent cocaine use was significantly associated with an increased risk of SCD due to cardiovascular causes in individuals aged 15–49 years.⁵⁰ In a pooled autopsy report summarizing 4 studies, only 23 (22%) had coronary artery disease out of 107 deaths related to cocaine. No definitive findings could explain the cause of death in most patients, suggesting an arrhythmia-related SCD.⁴⁴ In a single-center retrospective study (n=2,578) comparing heart failure patients with and without HIV, cocaine use predicted a 3-fold increase in SCD in patients with HIV, compared to those without HIV.⁵¹

Treatment of Arrhythmias in Patients with Cocaine use:

Treatment of cocaine-induced cardiac arrhythmias is multifaceted. General medical conditions, ischemia and hemodynamics of the patient need to be addressed. Treatment of cocaine-induced excitability to stop the catecholaminergic surge and sympathetic tone, could have positive benefit.³¹ Aside from a baseline EKG and cardiac monitoring,⁵² electrolyte abnormalities, especially hypokalemia and hypomagnesemia, must be corrected to prevent QT-prolonging and arrhythmogenic effects.

Beta-blocker use in patients with cocaine-induced chest pain and arrhythmias is controversial. Experimental studies and some case reports indicate that beta-blocker use can lead to unopposed alpha-adrenergic actions of cocaine producing severe hypertension, coronary vasospasm, and death. However, a recent meta-analysis reported no difference in outcomes in active cocaine users started on a beta-blocker to treat hypertension, chest pain or tachycardia vs those who were not.⁵³ The authors concluded unopposed alpha-agonistic actions are probably very rare and likely due to myriad effects of cocaine itself rather than concomitant beta-blocker use.⁵⁴ Use of non- labetalol and carvedilol may be preferred as they can act as alpha blockers as well.⁵⁴

Prazosin, an alpha-adrenergic receptor antagonist can reduce VF in a cocaine and MI dog model⁵⁵ but no clinical evidence supports benefit in humans. Calcium-channel blockers can be used safely in cocaine toxicity, although studies show that these drugs do not reduce tachycardia in cocaine users.⁵⁶ Amiodarone has not been tested for cocaine-induced arrhythmias in humans. Procainamide can inhibit human plasma butyrylcholinesterase, an enzyme essential in the metabolic degradation of cocaine. Although interactions between cocaine and procainamide in the clinical setting has not been well studied, in-vitro studies of these two compounds in pooled human serum samples demonstrated that procainamide profoundly inhibited cocaine and cocaethylene degradation.⁵⁷

Many cocaine-induced arrhythmias, especially those occurring immediately after cocaine use, are thought to be due to sodium blockade. Translational studies suggest sodium bicarbonate is an antidote for cocaine’s sodium blockade effects based on its ability to reverse QRS prolongation in dog models.⁵⁸ Case reports show that cocaine toxicity-induced wide-complex tachycardia mimicking flecainide toxicity can be reversed by sodium bicarbonate.³² Sodium bicarbonate has also been cited as the preferred drug of choice for cocaine induced VT by the AHA scientific statement from the Acute Care Committee of the Council of Cardiology.⁵⁹

However, use of lidocaine to treat cocaine-induced arrhythmias is controversial. Lidocaine can directly inhibit binding of cocaine to sodium channels and shift the concentration-effect curve rightward in animal studies,^60,61. The dose of lidocaine required for such effects may be well above that used clinically.⁶² Lidocaine can reduce seizure threshold and produce increased seizure risk in cocaine-treated animals⁶³. Despite these findings, a study of 29 patients reported that patients hospitalized with cocaine-related MI treated with lidocaine had no seizures⁶⁴. Another study compared the effects of lidocaine versus sodium bicarbonate in ex-vivo guinea pig hearts exposed to cocaine and found that both were equally effective in reducing cocaine-induced QRS prolongation⁶⁵.

Finally, monoamine neurotransmitter receptor antagonists, specifically dopamine type 1 receptor antagonists⁶⁶ and serotonin type 4 receptor antagonists⁶⁷ have been shown in animal models to reverse cocaine-associated cardiac arrhythmias; however, these drugs have not yet advanced to studies in humans. In contrast to cardiac arrhythmias occurring immediately after cocaine use, thought to be due to direct cardiotoxicity and ion channel actions, ventricular arrhythmias appearing several hours later are predominantly secondary to ischemia.⁵⁹

SUBSTITUTED AMPHETAMINES:

Substituted amphetamines and Electrical Remodeling:

Methamphetamine can remodel ion channels directly. In-vitro treatment of rat ventricular myocytes with methamphetamine resulted in inhibition of transient outward potassium current (K_to), and inward rectifying potassium current (K_ir).⁶⁸ While actions of methamphetamine on potassium channels are clear, effects on calcium channels are more controversial. Methamphetamine exposure to neonatal rat ventricular myocytes increased intracellular calcium oscillations, cardiomyocyte beating rates, and calcium entry through L-type calcium channels.⁶⁹ However, methamphetamine can inhibit L-type calcium currents,⁶⁸ by shifting the recovery curve downwards, making it longer for the channel to recover from inactivation for similar calcium concentrations without altering steady-state activation or inactivation curves of the channel.

Besides altering functions of ion channels, methamphetamine reduced transcription of ion channels. Expression of mRNA and protein levels of CACNA1C, CACNB2, KCNA4, KCNA7, KCNC4, KCND2, KCNJ2, KCNJ12, KCNJ4, and KCNJ14 were reduced in vitro and in vivo following methamphetamine exposure. Changes in ion channel expression reversed with methamphetamine withdrawal⁷⁰. Methamphetamine can also produce epigenetic DNA methylation, thereby, increasing transcription and translation of L-type calcium channels in animal models of HIV infection, a finding of potential significance in the HIV population that is known to have an increased prevalence of stimulant drug use⁷¹.

Amphetamine-derived stimulants, including MDMA, can increase field potential duration of human inducible stem cell-derived cardiomyocytes in a concentration-dependent manner²⁰. In addition, a single dose of MDMA can decrease connexin 43 expression in animal models, leading to a reduction in N-cadherin, and altered calcium oscillation patterns⁷².

Substituted amphetamines and Structural Remodeling:

Toxicities associated with methamphetamine use include: hypertension, arrhythmias, coronary vasospasm, myocardial infarction, and cardiomyopathy⁷³. Evidence from clinical case studies of methamphetamine users demonstrated reduced left ventricular ejection fraction, left ventricular chamber dilatation, myocardial lesions, cardiac hypertrophy, fibrosis, and inflammation in younger patients (age ≤50) even without cardiac risk factors^74,75. Severe left ventricular ejection fraction attenuation with chamber dilatation can occur in methamphetamine users^75,76. A routine screening of >4000 patients positive for methamphetamine showed heart failure in 18% patients; >10% patients had abnormal brain natriuretic peptide (BNP) levels⁷⁷. Autopsies of patients using methamphetamine showed increased collagen deposition and fibrotic remodeling in the perivascular and interstitial spaces of the heart⁷⁸.

In pre-clinical rodent models, acute and chronic methamphetamine-mediated cardiomyopathy has been reported.^79,80 A common methamphetamine use pattern is ‘binge and crash’; such patients tend to take approximately 1.5 times more drugs/month than chronic users.⁸¹ A recent study showed that ‘binge and crash’ methamphetamine administration in mice resulted in cardiac hypertrophy, fibrotic remodeling, and mitochondrial dysfunction leading to contractile dysfunction.⁷⁸ Pre-clinical studies to determine molecular signaling mediating methamphetamine toxicity point to Sigmar1 as a target. Cardiomyopathy associated with methamphetamine in mice resulted from Sigmar1 inhibition by methamphetamine, resulting in alteration of mitochondrial dynamics and function⁷⁸. In addition, methamphetamine causes increased oxidative stress, altered intracellular calcium dynamics, enhanced inflammatory markers, and reduced cardiac contractility^10,82.

Substituted amphetamines and EKG changes:

In a retrospective cohort study, only 28.3% of methamphetamine users had a normal EKG. Tachyarrhythmias, right axis deviation, left ventricular hypertrophy, P-pulmonale pattern, inferior Q waves, lateral T-wave inversion, and prolonged QTc interval were common findings in the methamphetamine group. QTc >440 ms (Table 3) was observed in 27.2% of patients, ^83,84. Emergency department data showed sinus tachycardia to be the predominant tachyarrhythmia in methamphetamine admissions.⁸⁵ Methamphetamine-induced myocardial ischemia evident by EKG changes have been reported; in a retrospective analysis of 627 EKGs of patients using methamphetamine, 6.5% showed evidence of MI.⁸⁶ MDMA caused sinus tachycardia, hypertension, hyperthermia, and vasospasm.⁸⁷ Further, MDMA can cause MI and associated EKG changes. MDMA use has been associated with ST-elevation and non-ST elevation MI in case reports.⁸⁸

Substituted Amphetamines and Bradyarrhythmias:

Bradyarrhythmias have not been associated with methamphetamine.^83,84 Decreased heart-rate variability (HRV) in chronic methamphetamine users suggests autonomic nervous system dysfunction.⁸⁹ HRV and parasympathetic cardiovascular tone were decreased in repeat MDMA users versus non-users.⁹⁰

Substituted Amphetamines and Atrial Arrhythmias:

Active methamphetamine users have increased left atrial size vs non-users or those who have discontinued methamphetamine^74,91 increasing the risk of atrial arrhythmias, specifically, atrial fibrillation.⁹² Similarly, a small, prospective, study using ambulatory monitors found atrial ectopy and atrial tachycardia during cocaine use in 6/7 hypertensive cocaine users.⁴⁶ A retrospective study with >11,000 heart failure patients (5% methamphetamine users, 0.6% cocaine users) found an increased incidence of atrial fibrillation and flutter in substance users vs non-users.⁹³

Methamphetamine-associated cardiomyopathy may increase the risk of atrial arrhythmias in methamphetamine users. In a retrospective study of 296 patients with methamphetamine-induced cardiomyopathy and 356 with methamphetamine use but no cardiomyopathy, atrial fibrillation was much more prevalent in cardiomyopathy patients with methamphetamine use.⁷⁵ Another study with >20,000 patients confirmed these findings, showing that the odds of atrial fibrillation associated with heart failure in methamphetamine users was significantly higher (OR: 27.4, 95% CI: 15.8–47.5).

However, patients with methamphetamine-associated cardiomyopathy were less likely to have atrial fibrillation vs those with cardiomyopathy due to other causes (adjusting for comorbidities)⁹⁴. This inverse association between atrial fibrillation and methamphetamine use in cardiomyopathy patients was corroborated by a large Veterans Administration study. Patients with methamphetamine-associated cardiomyopathy, however, were approximately 10-years younger.⁹⁵ Although MDMA has been reported to cause atrial fibrillation in isolated case reports, systematic reporting of any association is lacking.⁹⁶

Substituted Amphetamines and Ventricular Arrhythmias

Although studies have documented a higher incidence of SCD in people using methamphetamine, evidence for ventricular arrhythmias in the clinical setting is lacking. Case reports have documented monomorphic VT,⁹⁷ polymorphic VT,⁹⁸ and VF⁹⁹ with methamphetamine use. A study of 230 patients presenting to the emergency department with methamphetamine use showed that ~6% had cardiac arrhythmias, including ventricular tachycardia and frequent PVCs.¹⁰⁰

A longitudinal study of 1,315 inpatient methamphetamine users and >5,000 control patients, followed for 10 years, found twice the incidence of “cardiac arrhythmias” in methamphetamine users vs controls. However, any arrhythmia diagnosis was not made clear.¹⁰¹ Recently an analysis of the United States National Inpatient Sample database showed that patients admitted with acute heart failure and stimulant use (cocaine and/or amphetamines) had a significantly higher risk of ventricular tachycardia vs. acute heart failure patients without co-existent stimulant use.¹⁰²

Although methamphetamine use patients admitted with heart failure had almost twice the rate of in-hospital mortality as cocaine use (1.4% vs 0.7%), ventricular arrhythmias were just slightly higher in the cocaine use patients compared to methamphetamine use patients (7.8% versus 7.2%). A comparison of methamphetamine and cocaine related arrhythmias based on real life reporting to Federal Adverse Event Reporting System (FAERS) database was performed and reported under the section on stimulant use with cocaine and methamphetamine: a pharmacovigilance analysis in the supplementary material.

Substituted Amphetamines and Sudden Arrhythmic Deaths:

Methamphetamine and MDMA use increase risk of SCD in patients with pre-excitation syndromes¹⁰³ and in patients with various cardiovascular diseases based on case reports.¹⁰⁴ MDMA has been reported to provoke SCD in patients with channelopathies⁹⁸ and electrical storm as a result of serotonin syndrome.¹⁰⁵ Prescription amphetamine use has not been associated with SCD in children,¹⁰⁶ and adults.¹⁰⁷

In a study involving 100 autopsies¹⁰⁸ of individuals testing positive for methamphetamine, moderate-to-severe atherosclerosis was found in only 17%. Direct methamphetamine toxicity, with no other identifiable cause of death, was the attributed cause of death in 68%, suggesting arrhythmias as a factor. Myocardial fiber hypertrophy and focal myocardial necrosis were observed in many of these individuals.¹⁰⁸ A retrospective study of 1,649 Australian patients who died with known toxicology positive for methamphetamine showed that 3.7% of patients died most likely from arrhythmic causes.¹⁰⁹ Like cocaine, a large majority of methamphetamine users in autopsy series of SCD had well below toxic levels of the drug.¹¹⁰

Treatment of Arrhythmias in Patients with Substituted amphetamines use:

Treatment options for methamphetamine-induced cardiac arrhythmias have to be weighed against negative inotropic effects of the drug as many patients with methamphetamine use have co-existent methamphetamine-induced cardiomyopathy. Unlike cocaine, there is no specific contraindication, or controversy, surrounding use of beta-blockers in methamphetamine patients with cardiac arrhythmias. Selective and non-selective beta-blockers can be used with slow titration, especially in patients with methamphetamine-induced cardiomyopathy, to treat methamphetamine-related cardiac arrhythmias.¹¹¹ One of the few randomized studies testing beta-blockers in MDMA users found no adverse effects and effective antihypertensive and anti-tachycardic effect when using the combined alpha and beta antagonist carvedilol in patients taking MDMA.¹¹²

Benzodiazepines may be useful to treat methamphetamine-induced cardiac arrhythmias by mitigating agitation and sympathetic tone.¹¹³ If supplementary antipsychotic agents are needed in the care of patients with methamphetamine-induced arrhythmias, shorter acting drugs like droperidol may be preferred over haloperidol and should always be coupled with close monitoring of QT_C interval. Electrical storms due to MDMA-induced serotonin syndrome can be treated by treating hyperthermia, managing autonomic instability, and serotonin antagonism.¹⁰⁵ Extra-corporeal life support has been previously used for recurrent and refractory electrical storms caused by substituted amphetamines.¹⁰⁵

The Ethics of Defibrillator Use in Patients with Stimulant Use Disorder and Risk of Sudden Cardiac Death:

Patients with stimulant substance use and non-ischemic cardiomyopathy have high likelihood of having substance-induced cardiomyopathy. As abstinence could lead to recovery of cardiac function, efforts and resources should be dedicated to promoting abstinence and recovery (please refer to section on multidisciplinary team approach to stimulant use in the supplementary material). This is particularly true in patients with stimulant substance use as they may be using multiple substances, that each individually increase the risk of cardiomyopathy.

Cardiac MRI can be used as an adjunctive tool to predict recovery from stimulant drug-induced cardiomyopathy and therefore in the decision of implantable cardioverter defibrillator (ICD) implant for primary prevention.¹¹⁴ While a majority of patients with stimulant-related cardiomyopathy are prescribed goal-directed medical therapy, only 14%−33% underwent an ICD implant.^74,75

Reasons for this are multifold: 1) Patients with methamphetamine-related cardiomyopathy often abuse other substances and lack insight into their illness and treatment options, 2) Patients with methamphetamine use often have co-occurring psychiatric illnesses¹¹⁵ making them unreliable for follow-up after ICD implantation, 3) Methamphetamine users may be homeless and lack social support, making it difficult to attend device clinics.

A large proportion of heart failure patients with comorbid stimulant use leave care against medical advice (7.8% vs. 1.1% in acute heart failure admissions without stimulant use),¹⁰² raising questions about their ability to follow through with the plan of care and follow-up appointments. Unfortunately, issues with compliance can set them up for increased complications or risk that the complications will go undetected, such as pocket infection, lead malfunction, or battery depletion.

Another factor that adds to reservations of ICD implantation in active substance abusers is risk of lead endocarditis in case of intravenous drug abuse. In the spirit of “primum non nocere,” first, do no harm, a most pressing concern is the risk of inappropriate shocks due to sinus tachycardia or supraventricular tachycardia triggered by active substance use. In a retrospective study of 326 patients with ICDs, with and without HIV, cocaine use was positively associated with risk of ICD therapies, approximately half of which were inappropriate. Not surprisingly, a retrospective study evaluating characteristic features of patients with phantom shocks found an association between phantom shocks, previous electrical storms and cocaine use.¹¹⁶

Increased defibrillation thresholds in active stimulant substance users is a concern that makes ICD therapy potentially futile or increases the risk of repeated shocks, making the decision to implant an ICD more complicated. Compared to age and sex-matched controls, methamphetamine-associated cardiomyopathy patients receiving ICDs had a defibrillation threshold almost 10 Joules higher.¹¹⁷ Similarly, studies comparing chronic cocaine users to control patients showed up to 13 joules higher defibrillation threshold in cocaine users receiving ICDs.^118,119

We observed a direct time-dependent correlation between cocaine use and failed ICD therapies. A 36-year-old patient with ischemic cardiomyopathy and ICD implantation 6 years ago was admitted with VT/VF storm and multiple ICD shocks, including multiple failed shocks 16 hours after cocaine use with no evidence of ischemia. Defibrillation threshold testing 4 days later showed successful defibrillation at approximately half the energy of the therapies that failed during active cocaine use. Importantly, no studies show that ICDs reduce risk of sudden death or total mortality in stimulant users with or without cardiomyopathy and for primary or secondary prevention with or without other established cardiovascular disease.

Unanswered questions and future research

While there is a large body of literature related to mechanisms, prevalence, and treatment of cardiac arrhythmias in stimulant drug users, there are significant deficits in the current knowledge. Table 4 summarizes the gaps in understanding and possible avenues for new research.

Table 4:

Current knowledge, gaps in understanding and avenues of new research in stimulant use related cardiac arrhythmias

Current Knowledge	Unanswered Questions	New areas of Research
Stimulant drugs alter expression and gating properties of multiple ion channels and calcium handling proteins affecting the ventricular myocyte action potential	Is there a cause-and-effect relationship between stimulant drugs and cardiac arrhythmias?  Does electrical remodeling caused by stimulant drugs translate or lead to ventricular arrhythmias at the level of the organ or the organism?	In-vivo and ex-vivo animal models of stimulant use and cardiac arrhythmias
Stimulant drugs cause multiple EKG changes including QT prolongation, QRS prolongation, early repolarization and ST changes	Are the EKG changes induced by stimulant drugs dose dependent and/or affected by presence of other stimulant and non-stimulant drugs of abuse and/or affected by other comorbidities?	Cohort or retrospective human studies and animal studies focusing on EKG changes with stimulant drug use with emphasis on dose response, co-existent drugs of abuse and comorbidities
Stimulant drugs are associated with increased atrial and ventricular arrhythmias based on retrospective studies	The exact incidence and prevalence of atrial and ventricular arrhythmias in subjects using stimulant drugs is currently unknown	Systematic prospective continuous cardiac monitoring of stimulant drug users to evaluate incidence and prevalence of atrial and ventricular arrhythmias
Current treatment of stimulant drug induced arrhythmias is based on anecdotal evidence, retrospective studies and small randomized control studies	What is the safety and efficacy of drugs including beta-blockers, calcium channel blockers and antiarrhythmic drugs in stimulant drug induced cardiac arrhythmias?	Randomized controlled trials of selective and non-selective beta-blockers, alpha-blockers, calcium channel blockers and antiarrhythmic drugs in the treatment of stimulant drug induced cardiac arrhythmias
Active stimulant drug use alters defibrillation thresholds. Stimulant drug users have poor compliance and follow up after ICD placement for primary/secondary prevention of SCD	What is the safety and efficacy of ICDs in patients with a history of stimulant drug use for primary or secondary prevention of SCD?	Randomized controlled trials or retrospective review focusing on the benefit of ICD in patients with history of stimulant drug use

Conclusions:

Cocaine and methamphetamine cause structural and electrical remodeling of the atria and ventricles with subsequent EKG changes and ensuing atrial and ventricular arrhythmias. Mechanisms behind, and the true incidence of, stimulant drug-induced cardiac arrhythmias need further investigation. Treatment of stimulant drug-induced cardiac arrhythmias based on general principles of cardiac rhythm management, experience from stimulant drug toxicities and case reports, requires further refinement by larger clinical studies and/or observations. A multidisciplinary approach to the treatment of patients with stimulant use disorder will heighten success rates. ICD use in patients with stimulant drug use remains controversial.

Abbreviations:

ADHD

Attention deficit hyperactivity disorder

MDMA

3,4-methylenedioxy-methamphetamine

CNS

Central nervous system

DAT

Dopamine transporter

K_ATP

ATP-sensitive potassium channel

IKr

inward rectifying potassium channel

APD

action potential duration

CaMKII

Calcium calmodulin kinase II

K_to

Transient outward potassium channel

HIV

Human immunodeficiency virus

MI

Myocardial Infarction

BNP

Brain natriuretic peptide

cAMP

Cyclic adenosine monophosphate

VF

Ventricular fibrillation

VT

Ventricular tachycardia

SCD

Sudden cardiac death

HRV

Heart rate variability

PVC

Premature ventricular contraction

CP

Chest pain

FAERS

FDA’s adverse event reporting system

PRR

Proportional reporting ratio

HTN

Hypertension

ICD

Implantable cardioverter-defibrillator