We review major postmortem and in vitro studies documenting cocaine-induced vascular toxicity. Cocaine is a tropane alkaloid compound that can be extracted from the leaves of an Andean shrub, Erythroxylon coca, in South America. Cocaine was originally used for local surgeries as an anesthetic agent in the 1880s, but it became a recreational drug in the 1970s. In the 1980s, there was an epidemic of cocaine use, with the number of cocaine users in the US estimated at 5.8 million in 1985 1. Approximately 34% of these cocaine users resided in North America, and 20% resided in Western and Central Europe.
Cardiac complications resulting from cocaine use have been extensively studied because of the complicated pathophysiological mechanisms. This study aims to review the underlying cellular and molecular mechanisms of acute and chronic effects of cocaine on the cardiovascular system with a specific focus on human studies. Studies have consistently reported the acute effects of cocaine on the heart (e.g., electrocardiographic abnormalities, acute hypertension, arrhythmia, and acute myocardial infarction) through multifactorial mechanisms. Some studies found no association of cocaine use with coronary artery disease (CAD), while others reported its association with subclinical coronary atherosclerosis. These inconsistent findings might be due to the heterogeneity of study subjects with regard to cardiac risk.
- Cocaine use, and especially crack cocaine abuse, creates a rare but extremely fatal aortic dissection condition, probably due to decreased aortic elasticity and sudden and profound hypertension and tachycardia 102.
- Cocaine-induced chronic neurotoxicity consists of monoamine re-uptake inhibition, anti-cholinergic activity, and alpha-adrenergic stimulation 19.
- The issue is complicated further by the fact that contaminants such as procainamide, quinidine and antihistamines, which are often mixed with the cocaine, may contribute to the effects seen and influence the underlying pathophysiology 30.
- It is also known that high levels of oxidative stress can cause mitochondrial transition pore opening, leading to the generation of abnormal ROS levels and so-called ROS-induced ROS release.
- Treatment may be similar to indications in patients with traditional risk-factors, with few exceptions such as enhanced supportive care and use of benzodiazepines and phentolamine for sedation, and avoiding β-blockers.
Cocaine stimulates the adrenergic system by binding to norepinephrine transporters, resulting in increased norepinephrine effects at postsynaptic receptor sites. Blocking norepinephrine reuptake induces tachycardia and hypertension, which increases myocardial oxygen demand and reduces myocardial oxygen supply by vasoconstriction 11,14,15. As such, cocaine induces sympathetic effects on the cardiovascular system by enhanced inotropic and chronotropic effects through increased vasoconstriction.
Metabolites of Cocaine with Expressed Cardiotoxicity
In addition, cocaine blocks the reuptake of serotonin by interacting with the serotonin transporter, inducing leptin-dependent anorexic effect 107,108. Prior studies demonstrated that cocaine also upregulated neuromodulators such as cocaine- and amphetamine-regulated transcript (CART), which plays an important role in regulating food intake, maintaining body weight, and in endocrine and cardiovascular functions 109,110. Overexpression of CART has been reported to decrease food intake and change lipid metabolism related to fat storage 111,112. A number of studies have reported a possible link between cocaine use and acute cardiovascular conditions such as acute hypertension, arrhythmia, coronary artery aneurysms (CAAs), and acute MI. Because the study populations and data sources varied across the studies, the findings of these studies should be interpreted carefully in the context of each individual study. Additionally, inflammation and atherosclerosis are substantial potentially lethal vascular effects of cocaine use that have acute and chronic systemic impact 2,4,10,13,16,23,35,37,38,42,50.
Not only are the harmful effects of cocaine well-known, but also those of its metabolites 13, which can cause serious and irreversible damage to the entire cardiovascular system 14,15. Cocaine exerts its toxicity on the human body by generating reactive oxygen species (ROS) such as hydrogen peroxide, hydroperoxides, alkyl peroxides, superoxide, hydroxyl, and others 16,17. According to the data, ROS production and oxidative damage are considered significant factors in cocaine-induced cardiotoxicity 18,19 and the pathogenesis of cardiovascular disease 20. Cocaine, compared to other illicit drugs, poses a particular risk for vascular disease and is most involved in emergency room visits (40.3%), with highest rates for men aged 35–44 years, amounting to a vast social and economic burden 1. Cocaine-induced damage to the cardiovascular and cerebrovascular systems is widely reported, and is linked with hypertension, tachycardia, ventricular arrhythmias 2,myocardial infarction 3,4, stroke 4,5, resulting in severe functional impairments or sudden mortality 6–10.
Although cocaine-induced toxicity is considered a brain disease and is one of the most studied neuropsychiatric disorders 104, OS-induced cocaine toxicity affects not only the brain but also the body as a whole. As a result, one of the most affected systems of oxidative damage is the cardiovascular system 20. Acute use of low-dose cocaine increases heart rate, blood pressure, and myocardial contractility, which increases myocardial oxygen demand while reducing its supply. The mechanisms show typical autopsy findings such as acute myocardial infarction, fibrosis replacement, and coronary thrombosis 83.
Acute Cardiovascular Toxicity of Cocaine
Based on the finding that cocaine users had a significantly higher CAA compared with cocaine non-users (30.4% vs. 7.6%, respectively), the authors concluded that cocaine users were likely to be at increased risk of acute MI. Cocaine belongs to the group of psychomotor stimulants and is considered one of the most addictive drugs. Its narcotic effect consists of increasing extracellular dopamine (DA), and dopamine dysregulation underlies the addictive behavior 22,23. The mechanism involves inhibition of dopamine reuptake in the central neural system (CNS) 11,24. The cocaine molecule acts on the presynaptic transporters of monoamines and facilitates the activity of the monoamine neurotransmitters dopamine, norepinephrine (NE), and serotonin (SE) in the CNS and peripheral nervous system 1,25,26. Depending on the stimulant, the pathophysiological mechanisms of drug action include direct toxicity, neurohormonal activation, altered calcium homeostasis, and oxidative stress.
Concomitant Drug Use and Lifestyle
With decades of research and an increase in the amount of marijuana usage among adults, as well as teenagers, the adverse effects of THC on the CVS still remains unclear. In this review, the current state of the literature on marijuana usage and adverse CVD events will be examined along with clarification on possible connection between marijuana and CV pathology. Cocaine use promotes vascular disease, while also influencing the course of disease management, and therapy. Here too, it is helpful to briefly review prevention and treatment recommendations separately for acute vascular events. Cocaine works mainly by blocking the dopamine transporter, while amphetamine competitively prevents the reuptake of dopamine by the DAT.
Oxidative Stress and Cocaine Intoxication as Start Points in the Pathology of Cocaine-Induced Cardiotoxicity
Cocaine’s acute hematological effects on the vessel (Fig. 1, upper box) 10,23,24 center on the loss of the endothelium’s protective functions, a common denominator in the pathogenesis of ischemic vascular disease 35,36. Cocaine releases endothelin-145, which is found to be elevated in CUD and declines with detoxification 36,46,47. When vessels are stressed, endothelin-1 (a vasoconstrictor protein produced by vascular endothelial cells) is elevated and nitric oxide (a blood vessel dilator) decreases, leading to vasoconstriction 35,36. It was recently demonstrated that cocaine elicits autophagy involving nitric oxide and glyceraldehyde-3-phosphate dehydrogenase signaling cascade 48. Additional mechanisms implicated in cocaine induced vasoconstriction include increases in calcium 49.
2.2. Atherosclerosis
Second, because of the above-mentioned reason and multicollinearity of several factors (age, cocaine years use, HIV infection), it was difficult to identify the synergistic effects of HIV infection and cocaine use on coronary plaque volume. Third, our participants were limited to asymptomatic men and women without overt cardiovascular disease or acute coronary syndrome. Information about coronary plaque volume and cocaine use in symptomatic individuals requires further investigation. Fourth, we could not use DSM-IVR or DSM-5 criteria represented by the American Psychiatric Association’s (APA) Diagnostic and Statistical Manual of Mental Disorders (DSM) for diagnosis of cocaine dependence since those criteria have to be used by physicians. Finally, causal relations cannot be assessed in this cross-sectional study, and generalizability of the results from this study should be evaluated in a large cohort.
The reactive oxygen species generation, toxic metabolites formation, and oxidative stress play a significant role in cocaine-induced cardiotoxicity. The aim of the present review is to assess acute and chronic cocaine toxicity by focusing on the published literature regarding oxidative stress levels. Hypothetically, this study can serve as a basis for developing a rapid and effective method for determining oxidative stress levels by monitoring changes in the redox status of patients with cocaine intoxication. The primary goal of the current study was to investigate the effects of cocaine use on the amount of coronary artery plaque volume among a cohort with or without HIV infection. The study groups between chronic cocaine users and non-cocaine users were well-characterized with similar demographics including sex, age, BMI, diabetes, and HIV status with or without ART treatment. Our findings suggest that cocaine use may increase the total plaque burden and prolonged cocaine use accelerates the development of sub-clinical atherosclerosis.
- According to the National Institute of Drug Abuse, marijuana is the most commonly used illicit drug in the US and the third most common cause of drug-related emergency department visits between 2004–2011.
- One study showed that cocaine users had more plaques than non-cocaine users and concluded that cocaine users have greater development of coronary atherosclerosis (10).
- Overexpression of CART has been reported to decrease food intake and change lipid metabolism related to fat storage 111,112.
1.1. Acute Hypertension and Coronary Spasm
In response, it leads to addiction and dependence, leading to chronic use, and increases the risk of damage to the whole organism 6. In addition to its effects on the CNS, its use can lead to significant cardiovascular complications and sudden cardiac death (SCD). SCD is characterized as a dynamic event and represents the sudden and unexpected death of cardiac etiology. It is defined as a sudden, unexpected pulseless condition, which usually occurs within ≤1 h of the onset of symptoms and is often due to cardiac arrhythmia 7,8,9,10. Satran et al. 83 investigated the prevalence of CAAs among cocaine users undergoing coronary angiography using a database from a medical center in the US. The study population included 112 patients with a history of cocaine use aged 44 ± 8 years (79% male) and 79 patients with no history of cocaine use aged 46 ± 5 years (61% male).
The toxic effects of cocaine and its metabolites on other organs and systems, such as respiratory, immune, and digestive, were not considered as they are not the subject of this topic. “Crack-Cocaine” was introduced in the mid-1980s involving a new route of administration, smoking (as opposed to sniffing), which enhances vascular toxicity. Furthermore, the phenomenology of CUD consists of repeated drug use leading to tolerance, withdrawal, and compulsive drug-seeking behavior with inability to abstain, despite adverse effects to medical, social and occupational functioning. Underlying this addiction is CUD’s association with abnormal brain morphology 11 and function involving inefficiencies in circuits that coordinate reward and self-control processes 12.
The National Survey on Drug Use and Health found that 5.5 million people used cocaine in 2018 (4). Kozor et al. 81 in Australia compared blood pressure, aortic stiffness, and LV mass in cocaine users with those in cocaine non-users. The authors recruited 20 regular cocaine users aged 37 ± 7 years (85% male) and 20 control subjects aged 33 ± 7 years (95% male).
And G.N.; acute and chronic effects of cocaine on cardiovascular health pmc formal analysis, E.G.; writing—original draft preparation, E.G. and G.N.; writing—review and editing, E.G., H.A. And R.M.; supervision, E.G. and G.N.; project administration, E.G. and G.N.; funding acquisition, E.G. and G.N. It is known that Tempol has therapeutic potential and finds application in medical conditions with a high level of oxidative stress. It is characterized by dose-dependent effects and acts as an antioxidant by inhibiting the Fenton reaction 108. Dr. Subramaniam is currently affiliated with the Banner University Medical Center, Phoenix, Arizona. These publications illustrate that when a user smokes marijuana, numerous other chemicals, poisons, and toxin producing fungi and bacteria enter the bloodstream along with THC.