Cocaine was first isolated and synthesized in 1859 in Germany, and its medicinal effects were first documented in the 1880s[13,14]. Among the proponents of cocaine during this period was Sigmund Freud, who initially lauded the use of cocaine to treat a variety of conditions (most of which he retracted in 1887), including depression, alcoholism, and morphine addiction, in an 1884 paper titled On Cocaine. The surgeon William Halstead also utilized the drug for its local anesthetic effects [13,14]. Both men developed documented cocaine addictions. In 1886, the soft drink Coca-Cola, which contained cocaine and caffeine, was introduced. The ability of cocaine to reduce hunger, fatigue, and the need for sleep was highly valued during the industrial revolution in the late 19th century, and its use was encouraged to promote worker productivity[13,15]. The demand for cocaine skyrocketed during this period; the pharmaceutical company Merck produced 0.75 pounds of cocaine in 1883 and 158,352 pounds in 1884[9,12]. Cocaine was widely available during this period in cigarettes, inhalers, candy, elixirs, solutions, and over-the-counter products, as well as in wine and soft drinks[13,15]. Use of cocaine eventually reached epidemic proportions. In 1910, President Taft declared cocaine to be a public enemy, and strict controls were enacted at the state level[9,15]. Cocaine was removed from the Coca-Cola formulation in 1903, and the passage of the Harrison Narcotic Act in 1914 severely restricted the manufacture, distribution, and sale of cocaine in the United States. Cocaine use plummeted and remained very low for the next six decades[9,15].

Cocaine was first isolated and synthesized in 1859 in Germany, and its medicinal effects were first documented in the 1880s[13,14]. Among the proponents of cocaine during this period was Sigmund Freud, who initially lauded the use of cocaine to treat a variety of conditions (most of which he retracted in 1887), including depression, alcoholism, and morphine addiction, in an 1884 paper titled On Cocaine. The surgeon William Halstead also utilized the drug for its local anesthetic effects [13,14]. Both men developed documented cocaine addictions. In 1886, the soft drink Coca-Cola, which contained cocaine and caffeine, was introduced. The ability of cocaine to reduce hunger, fatigue, and the need for sleep was highly valued during the industrial revolution in the late 19th century, and its use was encouraged to promote worker productivity[13,15]. The demand for cocaine skyrocketed during this period; the pharmaceutical company Merck produced 0.75 pounds of cocaine in 1883 and 158,352 pounds in 1884[9,12]. Cocaine was widely available during this period in cigarettes, inhalers, candy, elixirs, solutions, and over-the-counter products, as well as in wine and soft drinks[13,15]. Use of cocaine eventually reached epidemic proportions. In 1910, President Taft declared cocaine to be a public enemy, and strict controls were enacted at the state level[9,15]. Cocaine was removed from the Coca-Cola formulation in 1903, and the passage of the Harrison Narcotic Act in 1914 severely restricted the manufacture, distribution, and sale of cocaine in the United States. Cocaine use plummeted and remained very low for the next six decades[9,15].

Cocaine use did not experience a resurgence until the late 1960s, coinciding with the tighter regulatory control and decreased use of amphetamines [12,16]. The seriousness of cocaine abuse and dependence was discounted in the 1960s and 1970s, and little effort was made to understand the mechanism of cocaine addiction and its treatment, partially because heroin addiction was seen as the most significant drug-related public health concern[17]. The introduction, widespread use, and substantial morbidity and mortality of freebase and crack cocaine in the early 1980s alerted scientists and clinicians of the urgency in understanding the nature of cocaine addiction and in developing effective treatments.

The increase in cocaine use in the 1980s correlated with the introduction of new forms of the drug. When cocaine is treated with hydrochloric acid (HCl), it becomes cocaine HCl, which is highly soluble in water and highly lipophilic. Until the late 1970s, this was the predominant illicit form[9]. Cocaine HCl may be administered intranasally, mixed with water and used intravenously, or combined with heroin and injected, which is referred to as a "speedball"[5,9]. Freebase cocaine is a highly pure form created by removing the hydrochloride base and is not water soluble. Unlike cocaine in the powdered hydrochloride form, which is destroyed by heat, freebase is smokable. Crack cocaine is made by dissolving cocaine HCl in water, mixing in baking soda, and heating the mixture to create a hard substance that is cut into "rocks"[12]. In the early 1980s, cheap and readily available crack cocaine was introduced, resulting in a rapidly escalating number of regular users and addicts[9].

In 2021, 4.8 million Americans (1.7%) had used cocaine within the past year, with 1.4 million individuals 12 years of age or older classified as dependent on or abusing cocaine [18]. Every day, 1,310 people use a cocaine product for the first time, with 60% of initiates 18 to 25 years of age and 39% of initiates 26 years of age or older[18]. Between 2002 and 2021, the number of annual initiates of cocaine declined from 1,032,000 to 478,000[18]. Older estimates in the United States have shown that cocaine is used primarily by young men, who outnumber female users by approximately 2 to 1[19]. Past-year cocaine use rates do not differ significantly by race/ethnicity, except among multiracial (defined as more than one race, but not Hispanic or Latino) individuals, of whom 3.2% reportedly used cocaine in the past year [18]. Overall, environmental and social factors (e.g., approached by someone selling cocaine, parental involvement, religious beliefs, scholastic environment) account for risk of cocaine use considerably more than race or ethnicity[19].

Certain populations are more vulnerable to cocaine-induced toxicity, primarily due to their inefficient capacity for metabolism and clearance of the drug and its breakdown products. These include the elderly, infants, fetuses, pregnant women, and patients with liver disease[13]. Other factors that influence individual variation in susceptibility to cocaine-induced toxicity include age, sex, body mass, hepatic and renal function, drug-drug interactions, and genetic variability[21]. Black American users are more likely than non-black users to experience rhabdomyolysis, excited delirium, and changes in cardiac rhythm[13].

Gender differences in the effects of cocaine have also been observed. Men who use cocaine experience higher blood concentration levels and greater drug effect than women, and women are more sensitive to the cardiovascular effects than men[12,22]. Women presenting for treatment of cocaine dependence are more likely than males to be severely dependent, to abuse other drugs, to have a briefer period of abstinence, and to have childhood histories of physical or sexual abuse[17]. Gender differences in comorbidity have also been found, with female cocaine abusers more likely to have major depression and male cocaine abusers more likely to have antisocial personality disorder[17].

Cocaine's specific mechanism of action involves increasing the synaptic transmission of dopamine, serotonin, and norepinephrine by interaction with plasma membrane transporters to block presynaptic reuptake. Action involving the dopamine transporter is the most important in producing the reinforcing effects, which lead to dependence [23]. The increased postsynaptic dopamine activity following its blocked presynaptic reuptake forms the basis of cocaine action[17].

Cocaine's specific mechanism of action involves increasing the synaptic transmission of dopamine, serotonin, and norepinephrine by interaction with plasma membrane transporters to block presynaptic reuptake. Action involving the dopamine transporter is the most important in producing the reinforcing effects, which lead to dependence [23]. The increased postsynaptic dopamine activity following its blocked presynaptic reuptake forms the basis of cocaine action[17].

Cocaine can be absorbed through any mucous membrane. Different routes of cocaine delivery into the body produce different patterns and levels of blood cocaine concentration. Intranasally administered cocaine is absorbed and distributed into the body gradually, while the onset of effect is rapid when smoked or injected. The effect of cocaine is experienced most rapidly and intensely when smoked, with an onset of effects typically occurring within 8 to 10 seconds; thus, cocaine is most addictive when smoked [23]. Injected cocaine takes twice as long to enter the brain (i.e., 16 to 20 seconds), and snorted cocaine begins to act in three to five minutes[12]. The lungs are the most rapid and efficient cocaine delivery modality because of the large surface area of absorption and rapidity of arterial circulation to the brain[9,29].

Peak plasma levels of cocaine occur 20 to 40 minutes following intranasal ingestion, with a typical concentration of 100–500 mcg/L. Toxicity is rarely seen at this dose level. Plasma half-life ranges from 31 to 82 minutes, with a mean of 38 minutes[13].

Drugs that increase brain monoamine concentration also have the potential to elevate peripheral monoamine activity [28]. Cocaine stimulates dopamine and alpha- and beta-adrenergic receptors in the CNS and in the peripheral nervous system, which is the underlying basis of the adverse systemic effects of this drug[12,29]. The cerebrovascular complications caused by cocaine are the result of its effect on noradrenergic neurotransmission and include vasoconstriction and resultant decrease in blood flow, inflammation of blood vessel walls, and hyperpyrexia[23,29].

Cocaine produces cardiovascular pathology in susceptible users by altering the myocardium and vasculature in a manner that may eventually manifest as cardiac disease, hypertension, or atherosclerosis[30]. The cocaine molecule has a high affinity for cardiac tissue, and both acute and chronic cocaine use can induce a variety of cardiac complications in persons with a negative history of such conditions, primarily from the powerful sympathomimetic properties of the drug[28,39]. Specific cocaine-induced cardiac conditions include myocardial infarction, ischemia, arterial thrombosis, ventricular tachycardia, ventricular fibrillation, and sudden death. Other cardiac conditions attributable to cocaine use include dilated cardiomyopathy, hypertension, myocarditis, and coronary artery occlusion[12,29].

Malnutrition is the most common gastrointestinal (GI) complication from cocaine use. This is influenced by the adverse effect of cocaine on food and beverage consumption, taste, and nutrient absorption. Other GI complications from cocaine use are less common and include gastroduodenal ulceration, acute bowel perforation, liver toxicity, and pancreatic and endocrine disease [12].

Community reinforcement approaches (CRAs) are biopsychosocial interventions designed to engage and change the lifestyle of the drug abuser by addressing the role of environmental cues and alternative reinforcers in influencing behavior. The theoretical basis of the CRA is that substance abuse is maintained by substance-related reinforcers as well as by the absence of competing alternative reinforcers. The primary goal of the CRA is to build and strengthen relationships, recognize appropriate leisure activities, and identify vocational interests of the patient to provide competing reinforcement with cocaine use and the drug-using lifestyle [64]. CRA aims to increase abstinence by increasing or highlighting the opportunity cost of relationships and social support the patient stands to lose through drug use[58]. In addition to integrating cognitive-behavioral and, in some cases, pharmacologic approaches, CRA may also include the use of vouchers, whereby tokens are given to the patient for producing substance-free urine samples, which are then used to purchase goods and services desired by the patient.

A review of four studies utilizing CRA with patients with cocaine use disorder found evidence that CRA employing abstinence-contingent incentives in the form of vouchers was more effective in promoting abstinence than CRA using noncontingent incentives and usual care. Patients assigned to CRA incorporating abstinence-contingent incentives experienced a greater reduction in disease severity as measured by the Addiction Severity Index than comparison groups[64]. Despite early, promising reports of CRA with patients with alcohol use disorder and evidence that patients receiving CRA have demonstrated more favorable drug use outcomes than patients receiving standard outpatient counseling, CRA is seldom used because of the relatively high cost and labor intensity[53,65].

Motivational interventions for substance abuse stem from the theory that targeting and enhancing motivation to quit drugs will increase positive outcome; positive outcome is increased when motivation comes internally rather than when it is externally imposed. Specifically, motivational-enhancement therapies (MET) are based on the Transtheoretical Stages of Change Theory, which postulates that patients pass through a series of stages of thought, planning, and action in the process of behavior change [66]. MET is intended to enhance motivation and commitment to change, activate patient resources, and facilitate movement along the readiness-to-change spectrum[67]. MET helps patients build internal motivation through the resolution of issues related to ambivalence. The therapeutic approach is characterized by nonconfrontive, nonjudgmental interviewing that helps the patient consider the pros and cons of change. MET also strives to enhance patient self-efficacy[66]. MET seems to be more effective in patients with low initial levels of motivation when used for patients with cocaine use disorder. It tends to result in less relapse to cocaine use and fewer total days of cocaine use[68].

Disulfiram is an oral medication used for decades as aversive therapy for alcohol dependence. It acts by inhibiting aldehyde dehydrogenase, thereby increasing the amount of the toxic alcohol metabolite acetaldehyde. Disulfiram also inhibits the enzyme that converts dopamine to norepinephrine. This increase in dopamine has been hypothesized to make disulfiram a helpful drug for cocaine use disorder. Several studies have been performed with patients with cocaine use disorder, and researchers have found that, relative to placebo, use of disulfiram results in decreased craving for cocaine, increased dysphoria in patients who have ingested cocaine concurrently, decreased quantity and frequency of cocaine use, and reduced number of cocaine-positive urine samples. These results are encouraging. However, additional trials are needed to determine the optimal dose and duration of treatment [24,80,90]. A small 2016 trial sought to determine if supplementing CBT with disulfiram would enhance abstinence outcomes but found no benefit with addition of the drug[91].

Pharmacotherapy for cocaine use disorder targets brain neuronal pathways, whereas immunotherapy for cocaine use disorder acts peripherally to inhibit the effects of cocaine by blocking or delaying entry of the cocaine molecule into the brain [24]. The impetus for the development and evaluation of biologic therapies for cocaine use disorder stems, in part, from the potential side effects and disappointing results of pharmacotherapy trials targeting reward pathways that mediate the addictive effects of cocaine[23].

Phase two can last one to ten weeks, during which time patients are likely to experience prolonged anhedonia, impaired motivation, dysphoria, and craving. It is during this period that patients are at highest risk of relapse. Outpatients are especially vulnerable to environmental cue-induced triggers for cocaine use. Persons, places, and things associated with cocaine use stimulate vivid recollection and cocaine-induced euphoria that, when contrasted with the ongoing dysphoria, can make resumption of use irresistible. If relapse occurs during this phase, it can activate the vicious cycle of heavy use, attempts to quit, and relapse[17].