#96944: Cocaine Use Disorder

Cocaine, a tropane alkaloid, is extracted from the leaves of the Erythroxylumcoca bush, which contain 0.6% to 1.8% of the alkaloid [3,5,10]. Archeologic evidence indicates that use of these leaves for their stimulant and anesthetic properties by South American natives dates back to 2000 B.C.E.[11]. Although Spanish explorers discovered the mild stimulant effects of the leaves and returned to Europe with them in the 16th century, their use did not become widespread for more than 300 years, partially because the leaves lost much of their potency on the journey back to Europe[12].

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].

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].

Dopamine receptors are grouped into two families: dopamine D1-like (D1 and D5) and dopamine D2-like (D2, D3, and D4). Both D1-like and D2-like receptors are believed to mediate the acute and chronic effects of cocaine[24,25]. A study employing multiple regression analysis to identify the biochemical receptor mechanism most associated with the reinforcing properties of cocaine examined dopamine, serotonin, choline, and norepinephrine receptors and their transporters[26]. Researchers found that cocaine binding to the dopamine transporter or cocaine inhibition of dopamine uptake accounted for most of the variability[27].

The basal ganglia, the brain region with the highest density of dopamine receptors, is the site with the highest concentration of cocaine binding[28]. In addition to affinity for mesocorticolimbic dopamine receptors, cocaine also inhibits activity in the locus coeruleus and the pons, providing an anxiolytic effect[12].

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].

Cocaine has long been used medicinally as a local anesthetic agent and is believed to be the only naturally occurring agent with this specific property[30]. Cocaine interferes with sodium channel activity, leading to diminished or blocked nerve conductivity. By entering the sodium channel and binding to the membrane interior, the drug further inhibits membrane sodium activity in electrically active cells, such as myocardium and nerve cells[29,30].

The majority of cocaine (i.e., 75% to 90%) is hydrolyzed by plasma and hepatic esterases to ecgonine methyl ester and benzoylecgonine, while a smaller proportion undergoes hepatic demethylation to produce the CNS-active norcocaine[29,30,31]. Hepatic metabolism occurs with cytochrome P450-2C9, 2C19, 3A4, and 2D6[21]. Decreased hepatic perfusion results in prolonged elevation of cocaine levels[29]. Concurrent alcohol use produces the metabolite cocaethylene, which has a longer plasma half-life than cocaine[21,29]. The rapid metabolism of cocaine in the liver accounts for its short half-life, which also influences the duration of the subjective "high" from a single dose. It is believed that both the intensity of the high and its brief duration contribute to the addictive properties of the drug[23,29].

Cocaine users often begin in the evening and use the drug continuously over several hours [32]. Over a longer period of time, cocaine use appears to follow what has been described as an "up-top-down" trajectory[33,34]. This means that use generally increases to a peak, then decreases. However, this may be more true of certain delivery routes than of others.

The intensity and quality of CNS effects of cocaine are influenced by the quantity and route of ingestion, as well as past drug use. One hundred milligrams is considered a fairly modest dose, with a high dose being several hundred milligrams [12]. Tolerance to the desired effects of cocaine can result from as little as one week of regular use, although the rapidity of the onset of tolerance varies by the route of administration, dose, and frequency of ingestion[12]. Subjective and behavioral effects from single- and multiple-dose acute ingestion of cocaine include euphoria, increased heart rate, restlessness, anxiety and panic, delusions, heightened alertness, and insomnia (Table 1).

The effects of chronic cocaine use on brain neuronal pathways are influenced by the duration and intensity of cocaine use, length of abstinence, and vulnerability to the effects of cocaine [35]. Long-term use of the drug induces a partial depletion of presynaptic dopamine reserves in the targeted brain regions, which is compensated by an increase in the number of dopamine receptors in the striatal region of the brain[12]. This results in the symptoms of dysphoria, anxiety, restlessness, and paranoia.

Cocaine obtained illicitly is always adulterated, or "cut," resulting in wide variations in concentration and purity. Consequently, users may underestimate the purity of the drug and overdose, which can result in toxicity or even death. Certain adulterants can produce harmful effects, as evidenced by the exaggerated sympathetic stimulation caused by ephedrine, Parkinson-type symptoms caused by manganese salts, and the increased likelihood of seizures with the addition of lidocaine[13]. Cocaine use is responsible for more hospital admissions than any other recreational or illicit drug, and the actual incidence of cocaine-induced toxicity is likely to be under-reported[29,30].

Because a number of people in the United States are believed to use cocaine during pregnancy (estimated at up to 10,000 each year), serious concern has been raised regarding the effects of cocaine on fetal development [19]. There were approximately 800 admissions with positive pregnancy status to treatment centers for primary cocaine use in 2020, compared with 1,300 in 2013[20,42].

The adverse effects of cocaine on fetal development stem from its diffusion across the placental barrier, where its vasoconstrictive effect diminishes the flow of blood and oxygen. The resultant hypoxia can retard fetal somatic and CNS development. Damage to the developing fetus can occur in both early and later pregnancy. Although ascertaining the impact of prenatal cocaine exposure is complicated by the influence of other factors (e.g., maternal nutrition, exposure to STIs/STI treatments, amount and route of ingestion of cocaine, use of alcohol, use of tobacco/nicotine, other illicit drug use, the postnatal environment), it is believed that the cocaine-induced effects originate in systems mediated by dopamine function, encompassing the cognitive, motor, emotional, and reward development of the infant[2,12,43,44]. However, some of these effects may be minor in severity and transient in nature, and there is no specific syndrome or condition associated with prenatal cocaine exposure[44,45]. Other adverse effects from maternal cocaine ingestion include spontaneous abortion, stillbirth, prematurity, and low birth weight[2,12,46].

A 2013 systematic review found that the effects of prenatal cocaine exposure may not be as clearly clinically significant as once thought[44]. Although there are obvious early effects (e.g., prematurity, low birth weight) and possible effects on childhood development (e.g., reduced cognition/school performance), test scores and developmental measures were within normal limits in nearly all studies. It is difficult to accurately assess the role of prenatal cocaine exposure on adolescent outcomes due to a host of environmental factors in the prenatal period and during childhood (e.g., violence exposure, second-hand smoke, malnutrition, toxic exposures). One study demonstrated that prenatal cocaine exposure had direct effects on young adult emotion regulation problems, arrest history, and conduct disorder not explained by earlier adolescent behavior[47]. It is safe to say that cocaine exposure can cause premature birth or low birth weight, which are known risk factors for hyperactivity disorders[48].

Repeated heavy cocaine use can lead to the development of symptoms that resemble distinct psychiatric and neurologic conditions; therefore, a thorough differential diagnosis is vital. Careful history, observation, and monitoring are useful in performing an accurate differential diagnosis [48]. Some conditions to consider in the differential diagnosis process include mood and psychotic disorders.

The affect and behavior of patients intoxicated with cocaine can mimic a broad spectrum of mood disorders, including the elevated and expansive mood, hypertalkativeness, euphoria, irritability, and sleep and appetite reduction of mania; the volatile cycling of euphoria and dysphoria of bipolar disorder; and the dysphoria, anergia, anhedonia, and suicidal ideation that characterizes acute withdrawal resembling major depression[48]. Cocaine use can also induce the paranoia and delusional thinking that resemble a psychotic disorder[49]. The most frequent delusion types observed in cocaine abusers are the persecutory, jealous, and somatic types[48].

Cocaine has a profound liability of abuse and dependency associated with its use [50]. Perhaps the most serious condition associated with repeated use of cocaine is the development of addiction, which may extend to other substances.

Alcohol is a frequently abused substance among patients who use stimulants. Many patients are dependent on both cocaine and alcohol, presenting a challenge for researchers and clinicians in optimizing treatment outcomes[28,29,42].

Cocaine abusers consume alcohol for several reasons, including the enhancement and prolongation of euphoria and minimization of the undesired effects. The rewarding effects of both substances are mediated through the mesocorticolimbic dopamine pathway. As noted, the combined effects of cocaine and alcohol can also be explained by the formation of cocaethylene, a metabolic byproduct of ingestion of both substances. Cocaethylene is speculated to be less anxiogenic than cocaine and thus may counteract or mask the dysphoria that can accompany cocaine use. Cocaethylene shares many neurochemical and pharmacologic properties with cocaine and is also an indirect dopamine agonist. Alcohol enhancement of cocaine toxicity is partially explained by the presence of cocaethylene, which increases heart rate and systolic blood pressure. As the result of the substance's cardiotoxic effects, it contributes to the increase in ischemia, infarction, and arrhythmia seen in patients abusing both cocaine and alcohol. Additionally, cocaethylene may elevate the potential of violent ideation, threatening behavior, and violent behavior[51,52].

Differences in the patterns of combined cocaine and alcohol use have been observed between persons who smoke cocaine compared with those who use intranasally. Users of intranasally administered cocaine typically use alcohol both concurrently and in alternating doses. They also tend to use alcohol excessively. These users usually increase the quantity of both substances when using them together. Crack cocaine users, however, are more likely to ingest alcohol at the end of an episode of use and to drink less alcohol when using cocaine[52]. Co-abusers are also more likely to use alcohol to alleviate the unpleasant after-effects of cocaine use.

Treatment of substance use and dependence with psychosocial or behavioral therapy is based on the assumption that addictive behavior is developed and maintained by specific mechanisms [55]:

The goal of these types of treatments is to modify drug-seeking and other behavioral aspects of drug dependency [53]. Psychosocial therapy and pharmacotherapy are not mutually exclusive; in fact, some drug therapies for substance abuse are considered useless without a psychosocial/behavioral component[53,55].

Psychosocial therapies for stimulant abuse disorders can be divided into two broad categories. The first category consists of therapies that were originally developed for patients with anxiety and depression and modified for use with patients with addictive disorders. This group of therapeutic approaches includes cognitive-behavioral therapy (CBT), the behavioral therapies, and interpersonal therapy. The second group of psychosocial therapies was developed explicitly for substance-abusing patients and includes motivational interviewing and motivation enhancement therapy[53,57]. All psychotherapies are intended to be delivered in a supportive, empathic manner that minimizes confrontation.

Drug counseling is a widely used therapy approach with cocaine and other substance abusers. It consists of a focus on abstinence, problem solving, and 12-step orientation and involvement. Drug counseling is usually provided by counselors who have a certificate in addiction counseling. A fair number of addiction counselors are themselves recovering from alcohol and/or substance abuse disorders[57].

Because dropout and relapse rates are high among patients in treatment for stimulant abuse, pharmacologic therapy has been used to augment standard psychosocial therapy, with the goal of increasing retention in treatment, reducing relapse rate, and treating coexisting psychiatric disorders that may contribute to poorer prognoses. Pharmacotherapy is based on the classic medical model that addresses any given disorder as the manifestation of neurochemical or biologic imbalance and dysregulation. This imbalance is viewed either as a precursor for addictive behavior or the consequence of repeated exposure to alcohol or drugs [53].

Pharmacotherapy for cocaine use disorder follows the model used in the treatment of alcoholism and heroin addiction, which targets the neurobiologic and behavioral components of addiction[23]. Agonist therapy is a component of several different pharmacotherapy strategies for stimulant abuse and dependence; it partially replaces the effects of the abused drug to stabilize the patient. Antagonist therapy, which blocks the abused drug effect, may be utilized to preclude use, alleviate symptoms of use or withdrawal, or treat comorbid conditions. A combination of these approaches may also be utilized[73].

Although a large number of medications have been used in patients with cocaine use disorder, all are either U.S. Food and Drug Administration (FDA)-approved drugs used off label or investigational drugs[2,5]. The following overview is comprised mainly of review papers that summarize the efficacy in individual therapeutic classes of drugs.

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].

The two biologic-based therapies for cocaine use disorder that have been subjected to empirical evaluation are immunization and vaccination. Both are variants of the concept of antagonist therapy to block drug effect[73]. In passive immunization, the catalytic antibodies that bind with and convert circulating cocaine molecules to an inactive molecule through hydrolysis are injected into the patient. The action of the antibody breaks down cocaine into ecgonine methyl ester and benzoic acid, resulting in a lack of desired effects. Active immunization employs vaccination, which triggers the production of antibodies against cocaine through the administration of a cocaine-protein conjugate. Both inactive and active immunization prevent induction of the positive effects of cocaine ingestion. Several drawbacks to vaccine therapy for cocaine use disorder have been identified. These include the lack of protection against drugs that are structurally distinct from cocaine, but that produce the same effect; lack of effect on craving; wide variation in antibody formation across individuals; and patient motivational factors[102,103].

As noted, patients with cocaine use disorder are often found to be addicted to or abuse other substances, such as alcohol, opioids, and benzodiazepines. These patients should be treated with therapies with established efficacy to manage the coexisting substance dependence, such as methadone or buprenorphine for patients with opioid use disorder, or naltrexone, acamprosate, or disulfiram for alcohol dependence [39].

As discussed, methylphenidate has not been shown to be effective in reducing cocaine use in patients with cocaine use disorder and comorbid ADHD. However, it does substantially reduce ADHD symptoms [109]. The FDA warns that priapism may occur in men taking methylphenidate products, particularly after a dosage increase or following drug abstinence or an unusually long length of time between doses[110].

Mood disorders are associated with substance abuse in general, and cocaine abuse and dependence are specifically associated with depression. Lifetime rates of major depression range from 25% to 61% among cocaine-dependent inpatients [111]. Managing both disorders is essential because the presence of one of these disorders decreases the likelihood of remission from the other[111]. With many depressive symptoms resolving in early abstinence, the traditional approach has been to monitor depressive symptoms during the first four weeks of treatment and withhold antidepressant treatment until the end of the four weeks. However, this approach often is not practical, as many cocaine-addicted patients cannot abstain during the initial four weeks. This problem is compounded by the increasing scarceness of resources for inpatient treatment, which underscores the importance of treating both conditions simultaneously[112].

Results from numerous clinical trials support the use of antidepressants in patients with comorbid depression and cocaine abuse. Research has suggested that the more activating antidepressants, such as bupropion and the tricyclics, are more effective than SSRIs, supporting the observation that substance-abusing patients respond preferentially to medications whose direct or side effect profiles resemble the effects of their drug of choice[111]. Unfortunately, tricyclics have worse side effects, tolerability, and safety profiles than SSRIs and should be used with extreme caution in depressed patients[112]. As previously noted, there is no empirical support for antidepressant treatment to reduce cocaine usage in these patients. Although limited, research on behavioral therapy treatment of comorbid depression and cocaine abuse suggests that CBT can promote greater treatment retention and longer periods of abstinence, and patients receiving motivational interviewing remain engaged in aftercare longer and have fewer depression-related hospitalizations following treatment[63,111].

Auricular (ear) acupuncture has become a widely used treatment for cocaine use disorder and is employed by hundreds of treatment centers and clinics in the United States. The procedure, which was developed at Lincoln Hospital in New York City in the 1970s, entails the placement of needles in five ear locations that represent the lung, kidney, liver, sympathetic, and shen men (a universal enhancer) points. This specific methodology has become a standardized treatment for substance abuse and is not specific to cocaine use disorder or abuse [113].

Gates et al. performed a review of seven randomized, controlled trials enrolling 1,433 subjects of auricular acupuncture with cocaine use disorder[113]. Overall, there was little evidence of significant improvement among acupuncture recipients compared to groups receiving either nonaccupoint acupuncture or no acupuncture on measures of severity of dependence, cocaine use self-report, cocaine use assessed by urine toxicology screen, and cocaine craving. As is the case with many studies of addiction, high rates of subject attrition limited the quality of evidence. With any alternative therapy, it is difficult to separate the therapeutic effect of the intervention from the nonspecific effects of interaction with the practitioner and the heightened expectancy of therapeutic benefit. These limitations result in unreliable evidence.

Twelve-step programs for stimulant and other drug abuse and dependence, such as NA and CA, are modeled after AA, an abstinence-based support and self-improvement program that is based on the 12-step model of recovery [114,115]. AA is widely considered the most successful treatment program for alcoholism and has helped hundreds of thousands of alcoholics achieve sobriety. The 12-step model emphasizes acceptance of addiction as a chronic progressive disease that can be arrested through abstinence but not cured. Additional elements of the AA model include spiritual growth, personal responsibility, and helping other addicted individuals. By inducing a shift in the consciousness of the addict, 12-step programs offer a holistic solution and a resource for emotional support[116,117].

The understanding of drug addiction as a chronic and relapsing disorder has helped professionals gain a better understanding of the vital role played by 12-step programs. All patients attempting to recover from a substance use disorder will encounter a time when they face urges to use without having access to the resources or assistance of addiction professionals. Twelve-step programs are not considered substitutes for treatment. Instead, they provide ongoing and indefinite support in the achievement and maintenance of abstinence and in personal growth and character development[117,118].

Part of the effectiveness of AA, NA, and CA is rooted in their ability to provide a competing and alternative reinforcer to drug use. Involvement in a 12-step program can enhance the quality of social support and the social network of the member, which is a potentially highly reinforcing aspect that would be forfeited if drug use was resumed[72]. Other reinforcing elements of 12-step involvement include recognition for increasingly durable periods of abstinence and frequent awareness of the consequences of drug and alcohol use through attendance at meetings[58]. Research has shown that establishing a pattern of 12-step program attendance early in treatment predicts the level of ongoing involvement. Thus, healthcare providers should emphasize and facilitate early engagement in a 12-step program[119].

Although research on efficacy and patient outcome in NA and CA is limited, many prominent addiction researchers have emphasized the important role that ongoing involvement in a 12-step program plays in recovery from substance abuse[118]. An important finding related to 12-step program efficacy was observed by Weiss et al., who found that 12-step attendance was not associated with decreased drug use, but that 12-step involvement (i.e., speaking or performing service work at a meeting, working with a sponsor outside of the meeting, reading 12-step literature, or working on a step) was[72,119]. In particular, active involvement in a given month predicted a significant reduction in cocaine use the following month. An interesting finding was that patients who involved themselves in 12-step program activities but whose attendance at meetings was inconsistent achieved rates of drug use reduction that were comparable to those who regularly attended and were involved in the 12-step meetings and program.

One study found that the majority of cocaine-dependent outpatients who attended 12-step programs actually attended AA more often than CA. The authors speculated that in addition to AA being more established and available than CA, some patients might have urges for cocaine triggered by the explicit cocaine-related discussion content found in CA[72].

For patients who are not proficient in English, it is important that information regarding the risks associated with the use of cocaine and available resources be provided in their native language, if possible. When there is an obvious disconnect in the communication process between the practitioner and patient due to the patient's lack of proficiency in the English language, an interpreter is required. Interpreters can be a valuable resource to help bridge the communication and cultural gap between patients and practitioners. Interpreters are more than passive agents who translate and transmit information back and forth from party to party. When they are enlisted and treated as part of the interdisciplinary clinical team, they serve as cultural brokers who ultimately enhance the clinical encounter. In any case in which information regarding treatment options and medication/treatment measures are being provided, the use of an interpreter should be considered. Print materials are also available in many languages, and these should be offered whenever necessary.