Historical Aspects

Cocaine is a naturally occurring substance derived from the leaves of the Erythroxylum coca plant. Its use is thought to have originated more than 5000 years ago in religious ceremonies among the ancient civilizations of South America, but was greatly increased following the conquest of South America by the Spanish, who valued its effects in decreasing appetite and increasing stamina in the slaves who worked in the silver mines. The first chemical purification of cocaine was achieved by Albert Niemann in 1860 and shortly thereafter it was incorporated into a variety of patent medicines and “tonics,” including the original recipe for Coca-Cola, which was marketed as a temperance drink, “offering the virtues of coca, without the vices of alcohol.” Its use was promoted by several prominent figures of the time, perhaps most notably by Sigmund Freud. Growing concern about the potential toxicity of cocaine helped lead to the passage of the Harrison Narcotics Tax Act in 1914. However, cocaine continued to be sold over the counter in the United States in a variety of forms until 1916.

Sex and Gender Differences

A variety of studies over the past decade have shown that the responses of men and women to cocaine differ markedly in several important aspects. These differences extend to all phases of the addictive process including induction, maintenance, relapse, and response to treatment. Compared to men, women have been reported to initiate cocaine use at later ages, but progress more rapidly from first use to dependence, a phenomenon termed “telescoping.” Women have also been reported to experience decreased subjective effects of cocaine, including both positive (“feel high”) and negative (“paranoid/suspicious,” “heart racing/pounding”) effects, a phenomenon that may be partly explained by the lower peak blood levels of cocaine observed in women after administration of a the same dose of cocaine, although other studies have reported an increase in negative nervousness effects among women. Cocaine-dependent women have also been reported to differ from their male counterparts in their subjective and physiological response to stress, factors that may place them at increased risk for stress-induced relapse after an initial period of sobriety. This is consistent with recent findings that severity of childhood trauma is predictive of cocaine-relapse outcomes in women but not men. Cocaine-dependent women have also been reported to have a higher incidence of psychiatric, medical, social/family, and employment problems than men. Moreover, cocaine-dependent men and women may have differential responses to treatment for cocaine dependence. A recent meta-analysis found that compared with men, women had poorer treatment outcomes on multiple measures of cocaine use during treatment and at posttreatment follow-up. These differences may relate to the finding that disulfiram appears to be less effective in women than in men (see section below on treatment).

Animal studies have shown that estrogen and progesterone have opposing effects on cocaine-enhanced behavioral responses, with estrogen generally increasing sensitivity to the behavioral effects of cocaine while progesterone blunts those effects. Recently, progesterone was found to reduce reinstatement of cocaine-seeking behavior in female rats, but not in male rats, while the combination of progesterone and the norepinephrine reuptake inhibitor, atomoxetine, was effective in both male and female rats.

Progesterone has been found to decrease the effects of smoked cocaine in women, but not in men. Pregnancy is a condition during which levels of progesterone naturally rise by several-fold. Pregnancy is also a time when cocaine-dependent women often reduce their use of cocaine, with a resumption of cocaine use after delivery when progesterone levels fall. A recent pilot study found evidence that exogenous progesterone, given after delivery, could reduce the self-reported days of cocaine use during a 12-week trial compared to placebo, although there was no significant difference in the proportion of women with urine tests that are positive for cocaine.

In addition, progesterone has differential effects on response to stress, with women but not men reporting lower rates of stress-induced negative emotion if they were treated with progesterone. These effects may be mediated by the conversion of progesterone to the neuroactive steroid allopregnanolone (ALLO). A recent study in our lab found that exogenous progesterone increased levels of ALLO. This was associated with normalized basal and stress response levels of cortisol, decreased cocaine craving, and improvements in positive emotion and Stroop performance in response to stress and drug-cue exposures. These findings highlight the need to consider individual factors including gender when discussing both the pathophysiology and approaches to treatment for cocaine dependence.

Pregnancy and Effects of Prenatal Exposure

The increasing prevalence in recent years of cocaine use among women of childbearing age has significance not only for the women themselves, but for the potential consequences to children exposed in utero. The pathophysiology of cocaine’s effects on the developing nervous system has been conceptualized as occurring along three interrelated pathways. The first of these is the direct neurochemical effects of cocaine on the developing nervous system, the second are sequelae related to the vasoconstrictive effects of cocaine on both the fetal and placental vessels. Finally, and perhaps most insidious are the epigenetic changes that may be induced by cocaine’s effects on the developing brain, leading to long-term changes in both reward and stress-related circuits in the brain. Studies using animal models of in utero cocaine exposure, suggest that there may be latent differences in neurocircuitry that are not revealed until the offspring are exposed to various stressors in adulthood. Moreover, neuroimaging studies of adolescents who were exposed prenatally to cocaine confirm the presence of subtle differences in brain activation. These differences in brain function may interact with various environmental factors to increase the risk for a variety of adverse outcomes including the development of cocaine dependence. An ongoing longitudinal study of a cohort of children who were exposed to cocaine in utero and followed from the fourth gestational month found that exposure to cocaine during the first trimester was associated with self-reported delinquent behavior; poorer problem solving and abstract reasoning; and reduced weight, height, and head circumference at 15 years of age. Additional effects of cocaine during pregnancy and development are discussed in Chapter 71 .

Youth

Data from the National Institute on Drug Abuse (NIDA) Monitoring the Future Study show that cocaine use among youth has declined somewhat over the past four years. Lifetime use of cocaine among 8th graders decreased from 1.9% in 2012 to 1.6% in 2015. Among 10th graders it decreased from 3.3% to 2.7%, and among 12th graders from 4.9% to 4.0%. Furthermore, all of these numbers represent a substantial decrease from the peak levels seen in the late 1970s and early 1980s, suggesting that efforts aimed at primary prevention are having some effect. However, given the devastating consequences associated with cocaine abuse and dependence, these numbers are certainly not cause for complacency.

Criminality

Studies conducted in the 1990s have suggested that the arrival of crack cocaine in urban centers in the United States and elsewhere was associated with a significant increase in the rates of a variety of types of crime. Concerns about the relationship between cocaine use and criminality have resurfaced at the end of the first decade of the 21st century in connection with the drug wars taking place in Columbia and along Mexico’s northern border.

Broadly speaking, the relationship between cocaine use and criminality can be considered in (at least) two complementary ways. The first is the relationship between cocaine use and criminality on the local level by users and small-scale dealers of cocaine (frequently these groups overlap). The second is the relationship between the illegal sale of cocaine and criminality on the national or international scale. On the individual level, cocaine use and dependence clearly increase the likelihood of engaging in other criminal activity including prostitution, theft, and violent crime. Conversely, successful treatment of substance dependence is associated with decreased likelihood of re-offending among substance abusers in the criminal justice system. On the national and international scale, the funds provided to international criminal organizations through the sale of illegal drugs and the violence perpetrated by these organizations can undermine the stability of entire nations and regions. These findings highlight the need for new approaches to treatment for cocaine-abusing individuals in the criminal justice system, as well as improved national and international efforts to direct treatment to persons in need.

Definition/Diagnostic Criteria

Cocaine addiction or dependence can be conceptualized in a number of different ways. As defined by the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), the previous categories of “cocaine dependence” and “cocaine abuse” have been combined into a single category termed “cocaine use disorder,” with modifiers for “mild,” “moderate,” or “severe,” depending on the number of diagnostic criteria met by the individual. Diagnosis of stimulant use disorder is based on the same criteria used to diagnose substance use disorders involving other drugs of abuse. These include the presence of at least two of the following within the past year :

• 1.
  

  Taking cocaine in larger amounts or over a longer period than was intended.

  
  
• 2.
  

  Persistent desire or unsuccessful efforts to cut down or control cocaine use.

  
  
• 3.
  

  Spending a great deal of time in activities necessary to obtain cocaine, use cocaine, or recover from its effects.

  
  
• 4.
  

  Craving, or a strong desire or urge to use cocaine.

  
  
• 5.
  

  Failure to fulfill major role obligations at work, school, or home as a result of recurrent cocaine use.

  
  
• 6.
  

  Continued cocaine use despite persistent or recurrent social or interpersonal problems caused or exacerbated by the effects of cocaine.

  
  
• 7.
  

  Giving up or reducing important social, occupational, or recreational activities because of cocaine use.

  
  
• 8.
  

  Repeatedly using cocaine in situations in which it is physically hazardous.

  
  
• 9.
  

  Continued cocaine use despite persistent or recurrent physical or psychological problems caused or exacerbated by cocaine.

  
  
• 10.
  

  Tolerance, as defined by either of the following:

  
  
  
  
  • •
    

    Needing increased amounts of cocaine to achieve intoxication or desired effects.

    
    
  • •
    

    Diminished effects with continued use of the same amount of cocaine.

  
  
  
  
• 11.
  

  Withdrawal, as manifested by either of the following:

  
  
  
  
  • •
    

    The characteristic withdrawal syndrome for cocaine (see section on cocaine withdrawal, below).

    
    
  • •
    

    Cocaine (or a closely related substance) is taken to relieve or avoid withdrawal symptoms.

  
  

Patients who meet two to three of these criteria are classified as a having a mild substance use disorder, those meeting four or five criteria would be classified as moderate, and those meeting six or more criteria would be classified as severe.

Note that this definition does not require the presence of physiological dependence, although the presence of physiological dependence may contribute to making the diagnosis (i.e., criteria 10 or 11 in the preceding text). Rather, as conceptualized in DSM-5, the diagnosis of Cocaine use disorder is made primarily based on the pattern of maladaptive behavior associated with its use. Moreover, when symptoms of tolerance and withdrawal are associated with appropriate medical treatment with prescribed medications (e.g., use of stimulants to treat attention-deficit/hyperactivity disorder [ADHD]), those symptoms are specifically NOT counted toward a diagnosis of a substance use disorder. However, since there are no US Food and Drug Administration (FDA)–approved indications for cocaine, symptoms of tolerance and withdrawal should be counted toward a diagnosis of cocaine use disorder.

Physiological dependence on cocaine is characterized by tolerance (criteria 10, above) and the occurrence of specific withdrawal symptoms when use is stopped. Symptoms of cocaine withdrawal include cocaine craving, depressed mood, sleep disturbance, appetite disturbance, and increased anxiety. These symptoms have been incorporated into the current diagnostic criteria for cocaine withdrawal (discussed in subsequent text) and standardized instruments have been developed for rating the severity of these symptoms.

Molecular/Biological Basis

Development of cocaine dependence is thought to be due to long-term consequences of repeated cocaine use in several areas of the brain, particularly those related to processing of reward-related information and executive control of behavior. Molecular changes that occur following chronic administration of cocaine include changes in both dopaminergic and glutamatergic signaling pathways. Chronic administration of cocaine increases the expression of a number of important genes including tyrosine hydroxylase (TH), the rate-limiting enzymes in dopamine synthesis, glutamate receptor GluR1, and the transcription factor Δ FosB. These effects are mediated, at least in part, by the transcription factor cyclic AMP (cAMP) response element binding protein (CREB). More recent work has focused on the role of epigenetic mechanisms in maintaining the altered state of brain circuitry through long-lasting changes in gene expression. These mechanisms include changes in DNA methylation and the expression and phosphorylation state of methyl CpG binding protein 2 (MeCP2) ; changes in histone acetylation and methylation ; changes in RNA-binding proteins ; and changes in the expression of noncoding RNAs (microRNAs) that regulate the half-life and expression of coding RNAs.

Studies in animals show that the effects of cocaine use on the brain can be extremely long lasting, and in some cases can continue to increase during a period of abstinence such that the abstinent user, far from being back to normal after a brief or even a prolonged period of abstinence, may be even more sensitive to drug-related cues than someone who is actively using. In addition to the changes in brain chemistry described earlier, long-term exposure to cocaine can also cause structural changes in the brain. In particular, long-term exposure to cocaine can increase the number of dendritic branches and the density of spines in a part of the brain called the nucleus accumbens, part of the limbic system that regulates our response to natural rewards such as food or sex. Dendrites, and more specifically dendritic spines, are the specialized parts of brain cells that receive input from other cells and other brain regions. Changes in the number and structure of dendritic branches in the nucleus accumbens may account for some of the extremely long-lasting changes in brain function seen in cocaine addiction. With this in mind, treatment strategies for cocaine dependence must focus on long-term treatment outcomes and developing strategies for preventing or minimizing the impact of relapses over the lifetime of the cocaine-dependent patient.

Treatment Approaches

Nonpharmacologic Treatments for Cocaine Dependence

Nonpharmacologic treatments for cocaine dependence include a variety of individual psychotherapies, group therapies, and 12-step programs such as Narcotics Anonymous. Not surprisingly perhaps, the primary determinant of outcome for most such psychosocial treatments appears to be length of retention in treatment, with better outcomes generally reported by those treated 90 days or longer in both residential and outpatient settings. These findings reinforce the need to focus on long-term outcomes and relapse prevention as the primary goal of treatments (both pharmacological and psychosocial) for cocaine dependence. Specific psychotherapeutic approaches to the treatment of cocaine dependence are discussed in more detail in the section on craving and relapse.

Definition/Diagnostic Criteria

Acute cocaine intoxication is typically characterized by a high feeling and stimulant effects including euphoria, increased pulse and blood pressure, and psychomotor activation. It can also include any of the following: alertness, anger, anxiety, belligerence, cognitive impairment, gregariousness, grandiosity, hyperactivity, hypervigilance, impaired judgment, impaired social and occupational functioning, interpersonal sensitivity, mood lability, restlessness, stereotyped and repetitive behavior, increased talkativeness, and tension. With chronic intoxication there can also be depressant effects such as social withdrawal, sadness, bradycardia, decreased blood pressure, and decreased psychomotor activity. Both acute and chronic intoxication are associated with impaired social and occupational function. Severe intoxication is associated with a number of medical complications including seizures, cardiac arrhythmias, hyperpyrexia, and vasoconstriction, leading to increased risk for myocardial infarction, stroke, and even death. Diagnostic criteria for cocaine intoxication include

• A.
  

  Recent use of cocaine.

  
  
• B.
  

  A clinically significant maladaptive behavioral or psychological changes (described above) that develops during or shortly after use of cocaine.

  
  
• C.
  

  Two (or more) of the following physical symptoms:

  
  
  
  
  • 1.
    

    tachycardia or bradycardia

    
    
  • 2.
    

    papillary dilation

    
    
  • 3.
    

    altered blood pressure (elevated or lowered)

    
    
  • 4.
    

    chills or perspiration

    
    
  • 5.
    

    nausea or vomiting

    
    
  • 6.
    

    evidence of weight loss

    
    
  • 7.
    

    psychomotor agitation or retardation

    
    
  • 8.
    

    muscular weakness, respiratory depression, chest pain, or cardiac arrhythmias

    
    
  • 9.
    

    confusion, seizures, dyskinesias, dystonias, or coma

  
  
  
  
• D.
  

  The symptoms observed are not due to a general medical condition or better accounted for by another mental disorder.

Molecular/Biological Basis

Cocaine, administered by any of the commonly used routes including snorting, smoking, and intravenous injection, enters the bloodstream and rapidly crosses the blood-brain barrier. Although cocaine inhibits reuptake of all three monoamine neurotransmitters (dopamine, norepinephrine, and serotonin), both the acute effect of cocaine and the long-term changes responsible for the development of cocaine dependence are thought to be related primarily to its effects on dopamine signaling. The neurotransmitter dopamine is synthesized in a small number of specialized dopamine-producing (dopaminergic) cells in the brain, and serves to regulate a number of important physiological processes. In particular, dopaminergic signaling in the so-called limbic system, including the ventral tegmental area (which produces dopamine) and the nucleus accumbens (one of the main sites of dopamine’s actions), functions to signal the presence of naturally occurring rewards. Cocaine inhibits the reuptake of the neurotransmitter dopamine from the synaptic cleft and thus prolongs its actions in the brain. Increased dopamine activity in the nucleus accumbens is thought to produce the high felt after cocaine use. In addition to its effects on the brain, cocaine can have direct effects on the circulatory system, leading to increased blood pressure and risk for myocardial infarction and stroke.

Treatment Approaches

There are no specific treatments for cocaine intoxication, and in most cases acute cocaine intoxication can be managed with supportive care. Benzodiazepines are considered first-line treatment for agitation associated with acute cocaine intoxication. Typical antipsychotic medications (e.g., perphenazine and haloperidol) can be used for treatment of paranoia or psychosis associated with cocaine intoxication; however, these should be used with caution because of the possibility of acute hyperthermia syndromes associated with acute cocaine intoxication, which may be confused with neuroleptic malignant syndrome. Cardiac or neurological symptoms associated with severe intoxication may require referral to an intensive care unit. Patients who are pregnant will require additional monitoring, since vasoconstriction associated with cocaine intoxication may lead to premature delivery.

Given the chronic, relapsing nature of cocaine abuse and dependence it is important to focus, as soon as possible, on planning for long-term treatment and relapse prevention. In most cases referral to residential or other long-term treatment modalities can be made, even prior to the resolution of the acute symptoms associated with cocaine intoxication.

Definition/Diagnostic Criteria

Withdrawal from cocaine occurs after cessation or reduction of heavy and prolonged cocaine use and is characterized by dysphoric mood and two or more of the following:

• A.
  

  fatigue

  
  
• B.
  

  vivid, unpleasant dreams

  
  
• C.
  

  insomnia or hypersomnia

  
  
• D.
  

  increased appetite

  
  
• E.
  

  psychomotor retardation or agitation.

These symptoms must also cause clinically significant distress or impairment in social, occupational, or other important areas of functioning in order to be diagnosed as cocaine withdrawal. In some cases this is associated with a profound depression and suicidal ideation and actions can occur.

Molecular/Biological Basis

Cocaine withdrawal is thought to occur as the result of long-term adaptations in brain physiology and functioning caused by prolonged exposure to cocaine. Such adaptations are generally homeostatic in nature. That is to say, they oppose the acute effects of cocaine and enable the brain to function as well as possible despite the massive barrage of dopamine signaling induced by cocaine. The synaptic architecture and signaling properties of a number of brain regions, including the limbic system, frontal cortex, and amygdala, is reconfigured such that functioning in the presence of cocaine becomes the new normal. The abrupt withdrawal or reduction of cocaine intake is perceived as a state of dopamine deficiency, and triggers the occurrence of the symptoms described earlier, as well as an intense desire to resume cocaine use in order to restore what is now perceived as a normal level of functioning. Molecular changes associated with the development of cocaine withdrawal include the accumulation of the transcription factor ΔFosB and increased cAMP-CREB signaling in the medium spiny neurons of the nucleus accumbens, increases in tyrosine hydroxylase (the rate limiting enzyme in dopamine synthesis), and increased neurotrophin and CREB signaling in the ventral tegmental area where the dopaminergic projections to the nucleus accumbens originate. These changes have the net effect of decreasing basal dopamine signaling, but increasing cocaine-stimulated release of dopamine, and thus reduce to body’s ability to respond to rewards other than cocaine. It is notable that although the acute phase of cocaine withdrawal typically resolves within several days, some of the neuroadaptations induced by prolonged exposure to cocaine may persist for months or even longer, resulting in a heightened sensitivity to both cocaine and cocaine-associated cues. Thus resolution of acute withdrawal symptoms does not imply that the patient is no longer dependent on cocaine.

Treatment Approaches

There are no specific treatments for cocaine withdrawal, and in most cases acute cocaine withdrawal can be managed with supportive care. Mood changes including depression, irritability, anhedonia, emotional lability and disturbances in attention and concentration are common. In some instances, cocaine withdrawal can be associated with a profound depressive state, and suicidal ideation and actions are not infrequent. In these cases, hospitalization to prevent self-harm may be necessary. As noted above, resolution of acute withdrawal symptoms should not be construed as implying that the patient is no longer dependent on cocaine. Therefore, as soon as possible, the focus of treatment should shift to planning for long-term treatment. Ideally this should include referral to residential or other long-term treatment modalities with a focus on relapse prevention.

Definition/Diagnostic Criteria

Cocaine craving and relapse are not specific diagnoses but are associated with all cocaine-related disorders. As discussed above, prolonged use of cocaine results in an intense desire to consume more cocaine. This effect has been noted for over 100 years and is one reason that cocaine dependence is so difficult to treat. Relapse refers to the resumption of drug use after a period of abstinence. However, defining relapse in cocaine users is complex, since many users frequently engage in binge and other styles of periodic use, such that short intervals of abstinence are the rule even among current users. Factors associated with increased risk for relapse include current levels of cocaine craving, exposure to stress or drug-related cues, and history of childhood abuse.

Molecular/Biological Basis

As discussed in the preceding text, prolonged exposure to cocaine or other drugs of abuse produces homeostatic changes in the brain, such that it is no longer able to function normally in the absence of the abused drug. Changes in glutamatergic signaling from the anterior cingulate and orbitofrontal cortex to the nucleus accumbens may be important in the transition from abuse to dependence (end-stage addiction). Animal studies suggest roles for the basolateral amygdala in cue-primed reinstatement, the ventral tegmental area in drug-primed reinstatement, and adrenergic innervation of the extended amygdala in stress-primed reinstatement. All three forms of priming may converge on the anterior cingulate cortex and have a final common output through the core of the nucleus accumbens. Neuroimaging studies also support a role for the projections from the anterior cingulate and orbitofrontal cortex to the nucleus accumbens in drug addiction.

Parallel evidence from human laboratory and relapse outcome studies also substantiate preclinical evidence of neuroadaptations in brain stress and reward pathways that are associated with increased stress- and drug cue–induced drug craving, anxiety and dysfunctional physiological, and neuroendocrine responses in treatment-engaged cocaine-dependent individuals as compared to healthy social drinkers. Stress- and cue-induced cocaine craving and neuroendocrine responses have been shown to predict cocaine relapse outcomes. Brain imaging studies of stress- and drug cue–induced cocaine craving show specific positive association with the dorsal striatum regions, whereas inhibitory control deficits show decreased activity in the prefrontal and anterior cingulated regions in cocaine-dependent individuals.

Treatment Approaches

Treatments for cocaine craving and relapse are at the heart of all treatments for cocaine addiction. These include both pharmacologic and nonpharmacologic treatments. As discussed above, pharmacological approaches to the treatment of cocaine addiction include dopaminergic, GABAergic, and glutamatergic agents, although none are specifically approved by the FDA for this use. Psychosocial approaches to the treatment of cocaine craving and relapse include contingency management, relapse prevention, general cognitive behavior therapy, and treatments combining cognitive behavior therapy and contingency management. Contingency management interventions are based on principles of operant conditioning and offer monetary and/or nonmonetary rewards that are contingent on negative toxicology screens, indicating abstinence from drug use. This approach has been evaluated in several controlled trials, and has shown consistent, if modest, effects in reducing relapse (reviewed in Dutra et al. ). Potential barriers to more widespread use of this approach include costs associated with monetary incentives and frequent drug testing as well as social prohibitions against paying drug users for good behavior. However, some studies have found that contingency management approaches using prizes worth from $1 to $100 can achieve short-term abstinence with a lower per-patient cost.

Relapse prevention is an alternative approach that focuses on identifying high-risk situations for relapse to drug use and avoiding or managing these situations by rehearsing alternative responses. Several studies have evaluated the effectiveness of relapse prevention techniques in cocaine-dependent subjects with mixed results. A 1991 study by Carroll et al., that compared relapse prevention therapy (RPT) to interpersonal psychotherapy (IPT) found no significant main effect for treatment. However, among the subgroup of more severe users, subjects who received RPT were significantly more likely to achieve abstinence (54% versus 9%) and be classified as recovered (54% versus 0%) than those who received IPT, while among the less severely addicted group there was no difference between the two treatments. A 1994 study by the same group comparing RPT to pharmacologic treatment with the antidepressant imipramine or a combination of RPT + desipramine found no significant effects in outcome for either RPT or medication. However, a 1-year follow-up study showed evidence of significant continuing improvement among the group who had received RPT. Another study comparing RPT to 12-step programs in a group of 110 treatment-seeking subjects found no difference between the two treatments. Thus the available evidence is limited and does not strongly support RPT over other approaches to treating cocaine craving and relapse.