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Cocaine dependence: a disease of the brain’s reward centers
Journal of Substance Abuse Treatment 21 (2001) 111 – 117
Review
Cocaine dependence: a disease of the brain’s reward centers Charles A. Dackis, M.D.a,*, Charles P. O’Brien, M.D., Ph.D.a a
Treatment Research Center, University of Pennsylvania, 3900 Chestnut Street, Philadelphia, PA 19104, USA Received 7 February 2001; received in revised form 15 May 2001; accepted 30 May 2001
Abstract Cocaine addiction affects brain reward centers that have evolved to ensure survival. Cocaine euphoria is intensely pleasurable and results from mesolimbic dopamine (DA) neurotransmission. DA signal-receiving neurons in the nucleus accumbens synthesize endogenous opioids and project to numerous reward regions. Cocaine-induced neuroadaptations, including DA depletion, may underlie craving and hedonic dysregulation. Cue-induced craving is vigorously triggered by conditioned elements of the drug environment and associated with measurable limbic activation. Reduced frontal lobe metabolism in cocaine-addicted individuals could explain important clinical phenomena such as denial and the loss of control over limbic impulses. Cocaine addiction is rapidly progressive and associated with severe medical, psychiatric, and psychosocial consequences. Denial shields addicted individuals from their predicament and must be addressed in treatment. Lacking pharmacological options, clinicians must rely entirely on psychosocial approaches. Treatment principles, including engagement, motivational enhancement, abstinence strategies, and craving reduction are discussed in terms of biological rationales. D 2001 Elsevier Science Inc. All rights reserved. Keywords: Cocaine; Addiction; Treatment; Reward; Dopamine
1. Introduction Cocaine, an alkaloid derived from the leaf of Erythroxylon coca, can be linked to human addiction through the insect kingdom. As a naturally occurring insecticide, cocaine’s neurotoxic action in insects results from the enhancement of octopamine (Nathanson, Hunnicutt, Kantham, & Scavone, 1993). Octopamine shares structural similarity with dopamine, the key neurotransmitter implicated in the rewarding activity of cocaine and the neurobiology of cocaine addiction (Dackis & Gold, 1985; Wise, 1996). Cocaine comprises nearly 1% of the coca leaf when grown in high altitudes, and people living in the Andes Mountains have chewed these leaves for at least 1,200 years. Deleterious effects of cocaine were first recorded by Spanish conquistadors, who found that habitual users became lethargic when deprived of the drug, and the Church later distributed coca leaves to improve the productivity of enslaved Indians (Earley, 1991). After cocaine was chemically isolated in 1860, several cocaine-containing wines
* Corresponding author. Tel.: 215-662-8752; fax: 215-243-4665. E-mail address: [email protected] (C.A. Dackis).
and tonics gained popularity in Europe. In the United States, Coca-Cola contained cocaine until 1903 and is still flavored with extracts from Erythroxylon coca. The drug was initially perceived to be safe and chic. During the early years of the last century it became evident that cocaine was addicting and could produce serious medical complications, especially with the availability of cocaine powder for intranasal or intravenous use. In 1914, cocaine became illegal in the United States and its use waned. However, amphetamine emerged several years later as a popular central stimulant. The use of amphetamine declined in the 1960s when the public began to appreciate its risks, but cocaine resurfaced with a mythology of safety and glamour. This perception encouraged millions of firsttime users, forming the pool from which cocaine-addicted individuals emerged. Epidemic levels of cocaine addiction subsequently developed in the United States, especially with the advent of ‘‘crack’’ as an affordable free-base form of cocaine. A vial of crack (sufficient to produce intense euphoria) averages only US$5 in most American cities, providing increased access to all segments of our population, including our youth. Crack is a serious problem in our inner cities, where geographical pockets of heavy consumption and drug trafficking are associated with high
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rates of crime, prostitution, and infectious diseases such as AIDS and viral hepatitis. Crack has also become available in smaller urban, suburban, and rural areas, and problems associated with its use are not restricted to our inner cities. Cocaine is now widely perceived to be dangerous, and there is evidence that first-time use is on the decline. Unfortunately, history demonstrates that perceptions of danger can change for cocaine. Furthermore, new addictive drugs with similar brain actions are likely to be discovered. Therefore, effective means of treating stimulant dependence, the topic of this paper, must be further developed and refined. Scientists currently view cocaine addiction as a brain disease (Leshner & Koob, 1999), a notion that challenges prejudicial beliefs that addicted individuals merely have character deficiencies or a lack of willpower. The neurobiology of cocaine clarifies some of the dynamics of this addiction and justifies many of the treatment principles that will be reviewed in this paper. 1.1. The nature of cocaine addiction With some individuals, the recreational use of cocaine evolves into entrenched patterns of addiction that progressively dominate all aspects of their lives. Why some but not all cocaine users cross the line into addiction is not known. Surveys in the United States indicate that only 16% of those who have used cocaine eventually become addicted (Anthony & Warner, 1994), about half the addiction rate for nicotine. However, those who do become addicted to cocaine lose control over their intake and over destructive behaviors directed toward cocaine procurement. Patients addicted to cocaine readily risk death, medical complications, incarceration, job loss, financial ruin, and family turmoil in the course of using cocaine. Their profound loss of control is the hallmark of cocaine addiction and a quintessential issue in its treatment. Denial, another essential element of cocaine addiction, prevents cocaine-addicted individuals from realizing their loss of control and shields them from their progressive impairment even when it is obvious to everyone else in their life. As a result of denial, these patients overestimate their ability to quit cocaine and erroneously believe they can reduce or otherwise control the amount consumed. Because repeated cocaine use becomes a pleasure-reinforced compulsion, addicted individuals often do not want to quit even after medical complications and psychosocial problems emerge. In fact, these patients frequently seek treatment only after reality has crashed through their denial, usually in the form of one of the negative consequences listed above. Specific research-based means of assessing readiness for change and enhancing motivation have been reviewed elsewhere (Miller, 1999). Although patients cite many reasons why they use cocaine, the feeling states of craving and euphoria are the primary reinforcers of the addiction. Cocaine euphoria might be viewed as a positive reinforcer, resulting ultimately
from the acute pharmacological action of cocaine on dopamine-containing neurons (Volkow, Fowler, & Wang, 1999). Cocaine produces a ‘‘rush’’ of intense euphoria that is well outside the normal range of human experience. The power of cocaine reward is demonstrated by the fact that the drug is readily self-administered to the point of death by laboratory animals and preferred over feeding and mating opportunity (Dackis & Gold, 1985). Accordingly, the ability of the cocaine ‘‘high’’ to dominate the thoughts, behaviors, and priorities of cocaine-addicted individuals should never be underestimated when treating these patients. Cocaine craving, an unpleasant state that can be immediately (although briefly) ameliorated with cocaine, serves as a negative reinforcer of the addiction cycle. Cocaine-addicted individuals describe an obsessive yearning for cocaine that diminishes gradually and irregularly over weeks of abstinence. Cocaine craving can be conceptualized as analogous to hunger and sexual arousal, and actually affects brain regions that generate these drives (Childress et al., 1999; Pothos, Creese, & Hoebel, 1995; Schultz, Dayan, & Montague, 1997; Wise, 1996). Interestingly, cocaine use engenders increased cocaine craving. Controlled studies demonstrate that shortly after the administration of cocaine there is a rebound of cocaine craving that exceeds baseline levels (Jaffe, Cascella, Kumor, & Sherer, 1989; O’Brien, Childress, McLellan, & Ehrman, 1992). Cocaine-induced craving undoubtedly influences the binge pattern of use that is typical with this drug. Cocaine craving is also vigorously precipitated by elements of the drug environment. Through conditioning, stimuli associated with the use of cocaine can produce intense craving in addicted individuals. Positron emission tomography (PET) studies of humans addicted to cocaine show pronounced limbic activation (involving the amygdala and cingulate cortex) during cue-conditioned craving, demonstrating the biological basis of this phenomenon (Childress et al., 1999). This pattern of limbic activation is similar to that measured during sexual arousal, graphically illustrating the association between cocaine craving and natural reward states. Cocaine euphoria and craving alternate over time to form a cycle of addiction that becomes increasingly entrenched and uncontrollable. The severity of cocaine addiction also progresses very rapidly in vulnerable individuals. While it may take years or decades for alcoholics to develop endstage alcoholism, progression to severe cocaine dependence typically occurs more rapidly. Rapid progression is particularly common with crack, probably because the intrapulmonary route is the quickest means of delivering a bolus of cocaine to the brain. Because cocaine addiction involves brain reward centers, it takes on the strength and characteristics of a primary survival drive. The inability of patients to control cocaine use illustrates the power of reward centers over behavior, and partially explains the relapsing nature of cocaine dependence. Relapse is often ascribed to inadequate motivation, denial, intense craving, and failure to follow specific treatment guidelines. However, the high rates of
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recidivism also reflect the basic difficulty of treating a brain disorder with psychosocial treatments alone. While nonpharmacological therapies could arguably be developed to affect brain function, the ultimate solution to recidivism may be the discovery of medications that can normalize the brains of cocaine-addicted individuals. 1.2. Cocaine and the reward centers Brain reward function provides insight into the dynamics of cocaine addiction. Mesolimbic dopamine pathways originating in the ventral tegmentum are involved in the reinforcing actions of cocaine, and in natural reward states that reinforce feeding, procreating, and taking fluid (Wise, 1996). During food consumption and mating, mesolimbic dopamine neurons show characteristic burst firing activity. Interestingly, burst firing also occurs during the procurement of food, sex, and water, well before consumption begins. This provides compelling evidence that mesolimbic dopamine neurons play a key role in reinforcing the procurement of survival needs by firing when the organism is exposed to conditioned cues of a consummatory opportunity (Schultz et al., 1997). Through this dopaminemediated phenomenon, specific stimuli associated with consumption (smells, visual stimuli, noises) can grip the organism’s attention and greatly increase the likelihood of successful feeding, mating, or drinking.
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Cocaine mimics dopamine burst firing by blocking the dopamine transporter (DAT), a membrane-bound protein found on the terminals of mesolimbic neurons. This transporter removes dopamine from the synaptic cleft; thus blockade produces an accumulation of synaptic dopamine and increases neurotransmission. Increased dopamine neurotransmission has been directly linked to cocaine euphoria (Volkow et al., 1999) indicating that cocaine activates pleasure circuitry in much the same way as survival-related activities. Two recent imaging studies found reduced dopamine function in cocaine-addicted individuals (Volkow et al., 1999; Wang et al., 1999; Wu et al., 1997) which is consistent with neuroendocrine abnormalities and animal studies showing dopamine depletion by repeated cocaine administration (Dackis & Gold, 1985; Dackis & O’Brien, 2001). Depletion of dopamine could lead to a disruption of hedonic function in people addicted to cocaine. Repeated cocaine use also renders target cells less responsive to dopamine by enhancing second messenger systems, activating nuclear transcription factors, and changing long-term gene expression (Leshner & Koob, 1999). It has been theorized that genetic changes might facilitate the transformation from casual use of cocaine to chronic addiction (Self & Nestler, 1998). Reduced dopamine-mediated reward could explain the high rates of depression, irritability, anxiety, and suicide that have been reported in cocaineaddicted individuals.
Fig. 1. Brain pathways involved in cocaine addiction. Cocaine blocks dopamine reuptake sites (DAT), causing euphoria by increasing DA neurotransmission in pleasure circuits. Repeated cocaine administration depletes DA, producing hedonic dysfunction. NAc neurons (containing GABA and endogenous opioids) in the universal addiction site become less responsive to DA suppression after chronic cocaine exposure. The glutamate-rich prefrontal cortex shows hypoactivity after repeated cocaine exposure, and this finding may contribute to the impaired judgment and denial that is prominent in cocaine addicts.
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Mesolimbic dopamine neurons project to the nucleus accumbens and terminate on medium-sized spiny cells that contain GABA and endogenous opioid peptides (see Fig. 1). These opioid-containing neurons in turn project to several reward regions, including the lateral hypothalamus (feeding and sex center), medial prefrontal cortex, and other limbic structures. Medium-size spiny cells have been reported to fire in anticipation of food and water (Miyazaki, Mogi, Araki, & Matsumoto, 1998) and in anticipation of cocaine (Carelli, 2000), providing additional evidence that cocaine recruits brain mechanisms that are normally activated by survival-related opportunities. The nucleus accumbens has also been termed the universal addiction site because it is a region where drugs as diverse as cocaine, amphetamine, alcohol, opioids, marijuana, and nicotine all increase dopamine levels (Leshner & Koob, 1999). Speedballing, the simultaneous injection of cocaine and heroin, actually increases the concentration of dopamine in the nucleus accumbens by 1000% (Gerasimov et al., 1999). The fact addictive agents have a common action of releasing dopamine in the nucleus accumbens supports the long-held clinical rule that patients attempting recovery from cocaine addiction should avoid all addictive substances. A final aspect of cocaine’s neurobiology involves its effects on the frontal cortex. The glutamate-rich frontal cortex represents another important target of mesolimbic dopamine neurons and has been implicated in cocaine addiction. Recovering cocaine patients have persistent reductions in metabolic activity in the prefrontal cortex, orbitofrontal cortex, and anterior cingulate gyrus (Volkow & Fowler, 2000) and reductions in neuronal density of frontal lobe regions on MRI examination (Franklin, Childress, O’Brien, McElgin, & Ragland, 2001). Since the frontal lobe is involved in executive function and motivation, alterations in this part of the thinking brain could have a role in the psychological process of denial that is so characteristic of cocaine dependence. The frontal cortex is also involved in the suppression of limbic impulses, and reduced activity in this region might underlie the difficulty that cocaine-addicted individuals have in resisting impulses to use cocaine. 1.3. Principles of treatment It should be evident from the previous section that cocaine dependence is a biological disorder affecting brain regions involved in reward and motivation. Because researchers have yet to identify effective pharmacological treatments, clinicians must rely entirely on psychosocial approaches to this disorder. Since the cycle of cocaine addiction is pleasure-reinforced, these patients often have mixed feelings about recovery. This places clinicians in the position of having to focus largely on motivation when treating cocaine-addicted individuals. In the United States, cocaine addiction treatment ranges from hospitalization and residential care to intensive outpatient programs, individual
psychotherapy, family therapy, and self-help groups. Hospitalization, reserved for the most serious cases, is never sufficient and must always be followed by an outpatient phase of treatment. At all levels of care, treatment is based on principles of recovery that are outlined in this section. Treatment should begin with a comprehensive evaluation focusing on drug use patterns, functional impairment, and co-occurring medical and psychiatric disorders. A thorough evaluation guides the treatment plan and strengthens the therapeutic alliance, thereby improving treatment retention. Structured interviews such as the Addiction Severity Index (ASI) (McLellan, Luborsky, Woody, & O’Brien, 1980) are available to standardize the collection of clinical information, gauge progression, and determine the appropriate level of care. Whenever possible, collateral information should be obtained from family and friend informants, laboratory tests, and medical records. It is naı¨ve to assume that the patient will always provide an accurate account because these patients are often in denial or unwilling to disclose sensitive clinical information. Our center utilizes a multidisciplinary treatment team to perform the initial evaluation, including independent assessments by a physician, nurse, social worker, and/or certified substance abuse counselor. The medical and psychiatric evaluation of cocaine patients has been previously reviewed (Dackis & Gold, 1992). Of note, cocaine is a powerful vasoconstrictor that can produce tissue necrosis, including myocardial infarction, stroke, renal failure, and abortion. PET studies show significant cocaine accumulation in the human heart (Volkow, Fowler, & Ding, 1996), perhaps explaining its propensity to cause cardiotoxicity. Also, patchy perfusion defects have been reported in the brains of cocaine abusers and indicate small strokes and hemorrhages secondary to cocaine’s vasoactive properties (Volkow & Fowler, 2000). Cocaine can cause seizures and sensitization to its convulsant effect (kindling) has been reported in animal models. Numerous psychiatric syndromes may result from cocaine addiction, including psychosis (paranoia and hallucinations), suicidal impulses, mood instability, and panic anxiety. Major depression is often associated with cocaine use and requires specific antidepressant treatment. Medical and psychiatric complications of cocaine should be identified and treated in concert with drug rehabilitation. During the assessment, it is important to evaluate the patient’s motivation and readiness for change. Recovery often requires that the patient overcome denial and commit to significant changes in lifestyle. For instance, patients should avoid situations that stimulate craving, attend treatment sessions regularly, and learn drug-free coping mechanisms. Cocaine-addicted individuals are often ambivalent about recovery and sometimes enter treatment programs solely in response to external pressure. These patients present special challenges to the treatment team. Most clinicians would agree that argumentative patients who dictate their own treatment plans have a poor prognosis, while those who ‘‘give up control’’ and follow recommen-
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dations achieve higher recovery rates. Even motivated individuals will at times waiver, often in response to craving that places them at odds with the treatment plan and the treatment team. Recovery is greatly enhanced when the patient is retained in treatment and follows general treatment directives (see Table 1). When the patient is in denial, these recommendations are often perceived to be unnecessary or overly stringent. Consequently, it is very important for therapists to engage the patient, build a strong therapeutic alliance, and be willing to emphasize directives in an unambiguous manner. Establishing rapport requires a balanced approach. Overly confrontative approaches may lead to dropouts while mere placation of the patient can undermine the therapeutic alliance and the integrity of treatment. Additionally, cocaine-addicted individuals can be manipulative and may test the practitioner’s level of sophistication and gullibility. A caring, nonjudgmental approach that provides support and confronts resistance is the most effective means of engaging the patient and attaining high recovery rates. A crucial step in the recovery process is to admit one’s lack of control over the cycle of addiction. Patients should be encouraged to attain a complete awareness of being out of control rather than intellectualizing this essential issue. This process should involve mobilizing emotions (sadness, fear, guilt, and anger) that go to the heart of denial. Patients should link their suffering to the addictive process, and thereby gain internal motivation for recovery. Specific consequences of their addiction should be processed in individual, group, and family therapy. Individual therapy is ideal when discussing sensitive or embarrassing topics. Family therapy is highly effective when family members are willing to present detailed accounts directly to the patient of how they were affected by active addiction. Group therapy with recovering peers is a powerful modality that is used extensively in our inpatient and outpatient programs. Patients are encouraged to see that their destructive behaviors are part of an illness that affects people in remarkably similar ways, reinforcing the notion that they are suffering from a disease rather than exhibiting a weakness. The goal of treatment should be to improve self-esteem and empower patients with the tools of recovery. Because addiction treatment is directive by nature, it differs from standard insight-oriented psychotherapy in Table 1 General treatment directives Maintain total abstinence from cocaine, alcohol, opiods, marijuana, and addictive pills. Avoid people, places and things associated with cocaine use. Overcome denial and admit to the consequences of the addiction. Attend treatment sessions on a regular basis. Maintain openness and honesty in treatment. Discuss emotionally important issues. Learn drug-free coping skills. Utilize craving reduction techniques.
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which specific behavioral recommendations are usually withheld. The cardinal directive in the treatment of cocaine dependence is that of total abstinence. This strategy, supported by extensive clinical experience, emphatically rejects the notion that cocaine-addicted individuals have the ability to reduce cocaine intake or engage in controlled use of cocaine. Neurochemical findings also provide support for the total abstinence strategy. Cocaine increases dopamine neurotransmission at the expense of dopamine reserves, creating a vicious cycle in which the pleasure neurotransmitter is depleted. In addition, cocaine produces rebound cocaine craving and uncontrollable binges. Complete abstinence prevents the occurrence of these phenomena and helps these patients avoid the risks of recidivism. Cocaine-addicted patients should also be advised to avoid other addictive agents such as alcohol, opioids, marijuana, and sedatives. Most clinicians would agree that the use of these drugs increases the likelihood of cocaine relapse, perhaps because addictive agents release dopamine into the nucleus accumbens and activate pleasure circuitry. People addicted to cocaine are often cross-addicted to these substances and at risk for active polysubstance abuse. A possible role for nicotine in undermining recovery warrants research (Dackis & O’Brien, 2001). Abstaining from alcohol is often disputed by these patients and may be effectively addressed in peer groups where other patients can share their experiences with alcohol and cocaine. Another important principle of recovery is to avoid stimuli that induce cocaine craving. Cocaine patients are exquisitely vulnerable to cue-conditioned craving, as evidenced by PET studies previously reviewed in this paper. Recovering individuals are asked to avoid associating with active users. This issue is very important when it involves an addicted spouse or family member because living with an active user is especially likely to precipitate relapse. Visiting places where cocaine is available can also produce intense craving and relocation may be prudent when patients live in the drug environment. The principle of avoiding conditioned stimuli is based on a healthy respect for the motivational power of cocaine craving, and an understanding of one’s vulnerability during early recovery. Treatment should specifically convey craving reduction strategies. Cognitive behavioral therapy may be very effective in this regard. Craving is approached as an unpleasant state that dissipates with time. It is lessened when openly discussed in treatment, and should not be concealed or nurtured by glamorizing the drug. During active craving, patients are taught to recall specific examples of addictionrelated suffering. This technique counters the natural inclination to focus only on the pleasurable aspect of cocaine euphoria. It is also useful for patients to view recovery as a series of small steps. Most cocaine-addicted individuals are able to remain abstinent for one day. However, worrying about staying abstinent for years or decades can be demoralizing, often leading the person to rationalize the immediate use of cocaine.
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Psychotherapy research has demonstrated efficacy for several specialized treatments in cocaine-addicted patients. Although a review of this extensive literature is beyond the scope of our discussion, research-based treatments have great potential to improve the quality of addiction care delivery. Contingency management approaches that provide payment vouchers to abstinent cocaine patients have been reported to improve both retention rates and outcome (Higgins et al., 1994). Cognitive behavioral therapy has also been shown to improve outcome in cocaine-addicted individuals and provide benefit for comorbid psychosocial problems (Carroll, 2000). Individual drug counseling utilizing a disease model is particularly effective in cocaine addiction (Crits-Christoph et al., 1999), underscoring the value of 12-step principles reviewed in this chapter and widely employed throughout the United States. These specialized therapies have been standardized with treatment manuals that provide an effective means of training clinical personnel and conducting much needed research (Budney & Higgins, 1998; Carroll, 1999; Mercer & Woody, 1999). Research into care delivery has also concluded that severely addicted individuals benefit from long-term residential programs (Simpson, Joe, Fletcher, Hubbard, & Anglin, 1999), supporting the notion that structured settings may be required to stabilize severe stimulant dependence. Patients enrolled in treatment programs should be regularly monitored for relapse. Urine benzoylecgonine levels (a cocaine metabolite with urinary persistence for several days) are randomly monitored to identify relapse and provide deterrence. Erratic behavior, absence from treatment, and changes in attitude should increase the index of suspicion for relapse and may warrant additional benzoylecgonine tests. Deterioration in attitude, such as the emergence of negativity, resistance, or cynicism, usually precedes relapse and should be openly discussed with the patient. A slip to cocaine use does not necessarily denote treatment failure and should actually be anticipated with this chronic, relapsing disorder. In fact, slips often occur when these patients deviate from treatment recommendations, and improved adherence may be attained in their aftermath.
2. Conclusion Cocaine dependence is a chronic, rapidly progressive illness that is unfortunately characterized by recidivism. Although its use dates back to antiquity, the intrapulmonary administration of crack cocaine is a recent development and produces a particularly virulent form of stimulant addiction. This paper has focused on the dynamics of cocaine addiction, its neurobiology, and the principles of psychosocial treatment. Cocaine acts directly on reward centers in the brain that have evolved to reward survivalrelated behaviors. These centers are capable, by necessity, of dominating the organism’s attention, motivation, and
behavior. By artificially stimulating this brain system, cocaine essentially tricks the brain into thinking a survival need is being met, thereby harnessing the motivational power of the reward centers to perpetuate the addiction. Since the use of cocaine is intensely pleasurable, cocaineaddicted individuals are often ambivalent about the recovery process. Their ambivalence is fostered by denial, which must be specifically reversed in the course of effective treatment. It is unclear to what extent frontal lobe dysfunction contributes to denial and the addictive process. Although we know that cocaine addiction is a brain disease, we have no pharmacological treatments at our disposal to reduce cocaine craving or reverse the numerous neuroadaptations associated with chronic use. Further research is therefore urgently needed to address this medical and societal problem. In the meantime, successful treatment often depends on the patient’s motivation, the skill of the treatment providers, and the strength of the therapeutic alliance.
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Review
Cocaine dependence: a disease of the brain’s reward centers Charles A. Dackis, M.D.a,*, Charles P. O’Brien, M.D., Ph.D.a a
Treatment Research Center, University of Pennsylvania, 3900 Chestnut Street, Philadelphia, PA 19104, USA Received 7 February 2001; received in revised form 15 May 2001; accepted 30 May 2001
Abstract Cocaine addiction affects brain reward centers that have evolved to ensure survival. Cocaine euphoria is intensely pleasurable and results from mesolimbic dopamine (DA) neurotransmission. DA signal-receiving neurons in the nucleus accumbens synthesize endogenous opioids and project to numerous reward regions. Cocaine-induced neuroadaptations, including DA depletion, may underlie craving and hedonic dysregulation. Cue-induced craving is vigorously triggered by conditioned elements of the drug environment and associated with measurable limbic activation. Reduced frontal lobe metabolism in cocaine-addicted individuals could explain important clinical phenomena such as denial and the loss of control over limbic impulses. Cocaine addiction is rapidly progressive and associated with severe medical, psychiatric, and psychosocial consequences. Denial shields addicted individuals from their predicament and must be addressed in treatment. Lacking pharmacological options, clinicians must rely entirely on psychosocial approaches. Treatment principles, including engagement, motivational enhancement, abstinence strategies, and craving reduction are discussed in terms of biological rationales. D 2001 Elsevier Science Inc. All rights reserved. Keywords: Cocaine; Addiction; Treatment; Reward; Dopamine
1. Introduction Cocaine, an alkaloid derived from the leaf of Erythroxylon coca, can be linked to human addiction through the insect kingdom. As a naturally occurring insecticide, cocaine’s neurotoxic action in insects results from the enhancement of octopamine (Nathanson, Hunnicutt, Kantham, & Scavone, 1993). Octopamine shares structural similarity with dopamine, the key neurotransmitter implicated in the rewarding activity of cocaine and the neurobiology of cocaine addiction (Dackis & Gold, 1985; Wise, 1996). Cocaine comprises nearly 1% of the coca leaf when grown in high altitudes, and people living in the Andes Mountains have chewed these leaves for at least 1,200 years. Deleterious effects of cocaine were first recorded by Spanish conquistadors, who found that habitual users became lethargic when deprived of the drug, and the Church later distributed coca leaves to improve the productivity of enslaved Indians (Earley, 1991). After cocaine was chemically isolated in 1860, several cocaine-containing wines
* Corresponding author. Tel.: 215-662-8752; fax: 215-243-4665. E-mail address: [email protected] (C.A. Dackis).
and tonics gained popularity in Europe. In the United States, Coca-Cola contained cocaine until 1903 and is still flavored with extracts from Erythroxylon coca. The drug was initially perceived to be safe and chic. During the early years of the last century it became evident that cocaine was addicting and could produce serious medical complications, especially with the availability of cocaine powder for intranasal or intravenous use. In 1914, cocaine became illegal in the United States and its use waned. However, amphetamine emerged several years later as a popular central stimulant. The use of amphetamine declined in the 1960s when the public began to appreciate its risks, but cocaine resurfaced with a mythology of safety and glamour. This perception encouraged millions of firsttime users, forming the pool from which cocaine-addicted individuals emerged. Epidemic levels of cocaine addiction subsequently developed in the United States, especially with the advent of ‘‘crack’’ as an affordable free-base form of cocaine. A vial of crack (sufficient to produce intense euphoria) averages only US$5 in most American cities, providing increased access to all segments of our population, including our youth. Crack is a serious problem in our inner cities, where geographical pockets of heavy consumption and drug trafficking are associated with high
0740-5472/01/$ – see front matter D 2001 Elsevier Science Inc. All rights reserved. PII: S 0 7 4 0 - 5 4 7 2 ( 0 1 ) 0 0 1 9 2 - 1
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rates of crime, prostitution, and infectious diseases such as AIDS and viral hepatitis. Crack has also become available in smaller urban, suburban, and rural areas, and problems associated with its use are not restricted to our inner cities. Cocaine is now widely perceived to be dangerous, and there is evidence that first-time use is on the decline. Unfortunately, history demonstrates that perceptions of danger can change for cocaine. Furthermore, new addictive drugs with similar brain actions are likely to be discovered. Therefore, effective means of treating stimulant dependence, the topic of this paper, must be further developed and refined. Scientists currently view cocaine addiction as a brain disease (Leshner & Koob, 1999), a notion that challenges prejudicial beliefs that addicted individuals merely have character deficiencies or a lack of willpower. The neurobiology of cocaine clarifies some of the dynamics of this addiction and justifies many of the treatment principles that will be reviewed in this paper. 1.1. The nature of cocaine addiction With some individuals, the recreational use of cocaine evolves into entrenched patterns of addiction that progressively dominate all aspects of their lives. Why some but not all cocaine users cross the line into addiction is not known. Surveys in the United States indicate that only 16% of those who have used cocaine eventually become addicted (Anthony & Warner, 1994), about half the addiction rate for nicotine. However, those who do become addicted to cocaine lose control over their intake and over destructive behaviors directed toward cocaine procurement. Patients addicted to cocaine readily risk death, medical complications, incarceration, job loss, financial ruin, and family turmoil in the course of using cocaine. Their profound loss of control is the hallmark of cocaine addiction and a quintessential issue in its treatment. Denial, another essential element of cocaine addiction, prevents cocaine-addicted individuals from realizing their loss of control and shields them from their progressive impairment even when it is obvious to everyone else in their life. As a result of denial, these patients overestimate their ability to quit cocaine and erroneously believe they can reduce or otherwise control the amount consumed. Because repeated cocaine use becomes a pleasure-reinforced compulsion, addicted individuals often do not want to quit even after medical complications and psychosocial problems emerge. In fact, these patients frequently seek treatment only after reality has crashed through their denial, usually in the form of one of the negative consequences listed above. Specific research-based means of assessing readiness for change and enhancing motivation have been reviewed elsewhere (Miller, 1999). Although patients cite many reasons why they use cocaine, the feeling states of craving and euphoria are the primary reinforcers of the addiction. Cocaine euphoria might be viewed as a positive reinforcer, resulting ultimately
from the acute pharmacological action of cocaine on dopamine-containing neurons (Volkow, Fowler, & Wang, 1999). Cocaine produces a ‘‘rush’’ of intense euphoria that is well outside the normal range of human experience. The power of cocaine reward is demonstrated by the fact that the drug is readily self-administered to the point of death by laboratory animals and preferred over feeding and mating opportunity (Dackis & Gold, 1985). Accordingly, the ability of the cocaine ‘‘high’’ to dominate the thoughts, behaviors, and priorities of cocaine-addicted individuals should never be underestimated when treating these patients. Cocaine craving, an unpleasant state that can be immediately (although briefly) ameliorated with cocaine, serves as a negative reinforcer of the addiction cycle. Cocaine-addicted individuals describe an obsessive yearning for cocaine that diminishes gradually and irregularly over weeks of abstinence. Cocaine craving can be conceptualized as analogous to hunger and sexual arousal, and actually affects brain regions that generate these drives (Childress et al., 1999; Pothos, Creese, & Hoebel, 1995; Schultz, Dayan, & Montague, 1997; Wise, 1996). Interestingly, cocaine use engenders increased cocaine craving. Controlled studies demonstrate that shortly after the administration of cocaine there is a rebound of cocaine craving that exceeds baseline levels (Jaffe, Cascella, Kumor, & Sherer, 1989; O’Brien, Childress, McLellan, & Ehrman, 1992). Cocaine-induced craving undoubtedly influences the binge pattern of use that is typical with this drug. Cocaine craving is also vigorously precipitated by elements of the drug environment. Through conditioning, stimuli associated with the use of cocaine can produce intense craving in addicted individuals. Positron emission tomography (PET) studies of humans addicted to cocaine show pronounced limbic activation (involving the amygdala and cingulate cortex) during cue-conditioned craving, demonstrating the biological basis of this phenomenon (Childress et al., 1999). This pattern of limbic activation is similar to that measured during sexual arousal, graphically illustrating the association between cocaine craving and natural reward states. Cocaine euphoria and craving alternate over time to form a cycle of addiction that becomes increasingly entrenched and uncontrollable. The severity of cocaine addiction also progresses very rapidly in vulnerable individuals. While it may take years or decades for alcoholics to develop endstage alcoholism, progression to severe cocaine dependence typically occurs more rapidly. Rapid progression is particularly common with crack, probably because the intrapulmonary route is the quickest means of delivering a bolus of cocaine to the brain. Because cocaine addiction involves brain reward centers, it takes on the strength and characteristics of a primary survival drive. The inability of patients to control cocaine use illustrates the power of reward centers over behavior, and partially explains the relapsing nature of cocaine dependence. Relapse is often ascribed to inadequate motivation, denial, intense craving, and failure to follow specific treatment guidelines. However, the high rates of
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recidivism also reflect the basic difficulty of treating a brain disorder with psychosocial treatments alone. While nonpharmacological therapies could arguably be developed to affect brain function, the ultimate solution to recidivism may be the discovery of medications that can normalize the brains of cocaine-addicted individuals. 1.2. Cocaine and the reward centers Brain reward function provides insight into the dynamics of cocaine addiction. Mesolimbic dopamine pathways originating in the ventral tegmentum are involved in the reinforcing actions of cocaine, and in natural reward states that reinforce feeding, procreating, and taking fluid (Wise, 1996). During food consumption and mating, mesolimbic dopamine neurons show characteristic burst firing activity. Interestingly, burst firing also occurs during the procurement of food, sex, and water, well before consumption begins. This provides compelling evidence that mesolimbic dopamine neurons play a key role in reinforcing the procurement of survival needs by firing when the organism is exposed to conditioned cues of a consummatory opportunity (Schultz et al., 1997). Through this dopaminemediated phenomenon, specific stimuli associated with consumption (smells, visual stimuli, noises) can grip the organism’s attention and greatly increase the likelihood of successful feeding, mating, or drinking.
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Cocaine mimics dopamine burst firing by blocking the dopamine transporter (DAT), a membrane-bound protein found on the terminals of mesolimbic neurons. This transporter removes dopamine from the synaptic cleft; thus blockade produces an accumulation of synaptic dopamine and increases neurotransmission. Increased dopamine neurotransmission has been directly linked to cocaine euphoria (Volkow et al., 1999) indicating that cocaine activates pleasure circuitry in much the same way as survival-related activities. Two recent imaging studies found reduced dopamine function in cocaine-addicted individuals (Volkow et al., 1999; Wang et al., 1999; Wu et al., 1997) which is consistent with neuroendocrine abnormalities and animal studies showing dopamine depletion by repeated cocaine administration (Dackis & Gold, 1985; Dackis & O’Brien, 2001). Depletion of dopamine could lead to a disruption of hedonic function in people addicted to cocaine. Repeated cocaine use also renders target cells less responsive to dopamine by enhancing second messenger systems, activating nuclear transcription factors, and changing long-term gene expression (Leshner & Koob, 1999). It has been theorized that genetic changes might facilitate the transformation from casual use of cocaine to chronic addiction (Self & Nestler, 1998). Reduced dopamine-mediated reward could explain the high rates of depression, irritability, anxiety, and suicide that have been reported in cocaineaddicted individuals.
Fig. 1. Brain pathways involved in cocaine addiction. Cocaine blocks dopamine reuptake sites (DAT), causing euphoria by increasing DA neurotransmission in pleasure circuits. Repeated cocaine administration depletes DA, producing hedonic dysfunction. NAc neurons (containing GABA and endogenous opioids) in the universal addiction site become less responsive to DA suppression after chronic cocaine exposure. The glutamate-rich prefrontal cortex shows hypoactivity after repeated cocaine exposure, and this finding may contribute to the impaired judgment and denial that is prominent in cocaine addicts.
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Mesolimbic dopamine neurons project to the nucleus accumbens and terminate on medium-sized spiny cells that contain GABA and endogenous opioid peptides (see Fig. 1). These opioid-containing neurons in turn project to several reward regions, including the lateral hypothalamus (feeding and sex center), medial prefrontal cortex, and other limbic structures. Medium-size spiny cells have been reported to fire in anticipation of food and water (Miyazaki, Mogi, Araki, & Matsumoto, 1998) and in anticipation of cocaine (Carelli, 2000), providing additional evidence that cocaine recruits brain mechanisms that are normally activated by survival-related opportunities. The nucleus accumbens has also been termed the universal addiction site because it is a region where drugs as diverse as cocaine, amphetamine, alcohol, opioids, marijuana, and nicotine all increase dopamine levels (Leshner & Koob, 1999). Speedballing, the simultaneous injection of cocaine and heroin, actually increases the concentration of dopamine in the nucleus accumbens by 1000% (Gerasimov et al., 1999). The fact addictive agents have a common action of releasing dopamine in the nucleus accumbens supports the long-held clinical rule that patients attempting recovery from cocaine addiction should avoid all addictive substances. A final aspect of cocaine’s neurobiology involves its effects on the frontal cortex. The glutamate-rich frontal cortex represents another important target of mesolimbic dopamine neurons and has been implicated in cocaine addiction. Recovering cocaine patients have persistent reductions in metabolic activity in the prefrontal cortex, orbitofrontal cortex, and anterior cingulate gyrus (Volkow & Fowler, 2000) and reductions in neuronal density of frontal lobe regions on MRI examination (Franklin, Childress, O’Brien, McElgin, & Ragland, 2001). Since the frontal lobe is involved in executive function and motivation, alterations in this part of the thinking brain could have a role in the psychological process of denial that is so characteristic of cocaine dependence. The frontal cortex is also involved in the suppression of limbic impulses, and reduced activity in this region might underlie the difficulty that cocaine-addicted individuals have in resisting impulses to use cocaine. 1.3. Principles of treatment It should be evident from the previous section that cocaine dependence is a biological disorder affecting brain regions involved in reward and motivation. Because researchers have yet to identify effective pharmacological treatments, clinicians must rely entirely on psychosocial approaches to this disorder. Since the cycle of cocaine addiction is pleasure-reinforced, these patients often have mixed feelings about recovery. This places clinicians in the position of having to focus largely on motivation when treating cocaine-addicted individuals. In the United States, cocaine addiction treatment ranges from hospitalization and residential care to intensive outpatient programs, individual
psychotherapy, family therapy, and self-help groups. Hospitalization, reserved for the most serious cases, is never sufficient and must always be followed by an outpatient phase of treatment. At all levels of care, treatment is based on principles of recovery that are outlined in this section. Treatment should begin with a comprehensive evaluation focusing on drug use patterns, functional impairment, and co-occurring medical and psychiatric disorders. A thorough evaluation guides the treatment plan and strengthens the therapeutic alliance, thereby improving treatment retention. Structured interviews such as the Addiction Severity Index (ASI) (McLellan, Luborsky, Woody, & O’Brien, 1980) are available to standardize the collection of clinical information, gauge progression, and determine the appropriate level of care. Whenever possible, collateral information should be obtained from family and friend informants, laboratory tests, and medical records. It is naı¨ve to assume that the patient will always provide an accurate account because these patients are often in denial or unwilling to disclose sensitive clinical information. Our center utilizes a multidisciplinary treatment team to perform the initial evaluation, including independent assessments by a physician, nurse, social worker, and/or certified substance abuse counselor. The medical and psychiatric evaluation of cocaine patients has been previously reviewed (Dackis & Gold, 1992). Of note, cocaine is a powerful vasoconstrictor that can produce tissue necrosis, including myocardial infarction, stroke, renal failure, and abortion. PET studies show significant cocaine accumulation in the human heart (Volkow, Fowler, & Ding, 1996), perhaps explaining its propensity to cause cardiotoxicity. Also, patchy perfusion defects have been reported in the brains of cocaine abusers and indicate small strokes and hemorrhages secondary to cocaine’s vasoactive properties (Volkow & Fowler, 2000). Cocaine can cause seizures and sensitization to its convulsant effect (kindling) has been reported in animal models. Numerous psychiatric syndromes may result from cocaine addiction, including psychosis (paranoia and hallucinations), suicidal impulses, mood instability, and panic anxiety. Major depression is often associated with cocaine use and requires specific antidepressant treatment. Medical and psychiatric complications of cocaine should be identified and treated in concert with drug rehabilitation. During the assessment, it is important to evaluate the patient’s motivation and readiness for change. Recovery often requires that the patient overcome denial and commit to significant changes in lifestyle. For instance, patients should avoid situations that stimulate craving, attend treatment sessions regularly, and learn drug-free coping mechanisms. Cocaine-addicted individuals are often ambivalent about recovery and sometimes enter treatment programs solely in response to external pressure. These patients present special challenges to the treatment team. Most clinicians would agree that argumentative patients who dictate their own treatment plans have a poor prognosis, while those who ‘‘give up control’’ and follow recommen-
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dations achieve higher recovery rates. Even motivated individuals will at times waiver, often in response to craving that places them at odds with the treatment plan and the treatment team. Recovery is greatly enhanced when the patient is retained in treatment and follows general treatment directives (see Table 1). When the patient is in denial, these recommendations are often perceived to be unnecessary or overly stringent. Consequently, it is very important for therapists to engage the patient, build a strong therapeutic alliance, and be willing to emphasize directives in an unambiguous manner. Establishing rapport requires a balanced approach. Overly confrontative approaches may lead to dropouts while mere placation of the patient can undermine the therapeutic alliance and the integrity of treatment. Additionally, cocaine-addicted individuals can be manipulative and may test the practitioner’s level of sophistication and gullibility. A caring, nonjudgmental approach that provides support and confronts resistance is the most effective means of engaging the patient and attaining high recovery rates. A crucial step in the recovery process is to admit one’s lack of control over the cycle of addiction. Patients should be encouraged to attain a complete awareness of being out of control rather than intellectualizing this essential issue. This process should involve mobilizing emotions (sadness, fear, guilt, and anger) that go to the heart of denial. Patients should link their suffering to the addictive process, and thereby gain internal motivation for recovery. Specific consequences of their addiction should be processed in individual, group, and family therapy. Individual therapy is ideal when discussing sensitive or embarrassing topics. Family therapy is highly effective when family members are willing to present detailed accounts directly to the patient of how they were affected by active addiction. Group therapy with recovering peers is a powerful modality that is used extensively in our inpatient and outpatient programs. Patients are encouraged to see that their destructive behaviors are part of an illness that affects people in remarkably similar ways, reinforcing the notion that they are suffering from a disease rather than exhibiting a weakness. The goal of treatment should be to improve self-esteem and empower patients with the tools of recovery. Because addiction treatment is directive by nature, it differs from standard insight-oriented psychotherapy in Table 1 General treatment directives Maintain total abstinence from cocaine, alcohol, opiods, marijuana, and addictive pills. Avoid people, places and things associated with cocaine use. Overcome denial and admit to the consequences of the addiction. Attend treatment sessions on a regular basis. Maintain openness and honesty in treatment. Discuss emotionally important issues. Learn drug-free coping skills. Utilize craving reduction techniques.
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which specific behavioral recommendations are usually withheld. The cardinal directive in the treatment of cocaine dependence is that of total abstinence. This strategy, supported by extensive clinical experience, emphatically rejects the notion that cocaine-addicted individuals have the ability to reduce cocaine intake or engage in controlled use of cocaine. Neurochemical findings also provide support for the total abstinence strategy. Cocaine increases dopamine neurotransmission at the expense of dopamine reserves, creating a vicious cycle in which the pleasure neurotransmitter is depleted. In addition, cocaine produces rebound cocaine craving and uncontrollable binges. Complete abstinence prevents the occurrence of these phenomena and helps these patients avoid the risks of recidivism. Cocaine-addicted patients should also be advised to avoid other addictive agents such as alcohol, opioids, marijuana, and sedatives. Most clinicians would agree that the use of these drugs increases the likelihood of cocaine relapse, perhaps because addictive agents release dopamine into the nucleus accumbens and activate pleasure circuitry. People addicted to cocaine are often cross-addicted to these substances and at risk for active polysubstance abuse. A possible role for nicotine in undermining recovery warrants research (Dackis & O’Brien, 2001). Abstaining from alcohol is often disputed by these patients and may be effectively addressed in peer groups where other patients can share their experiences with alcohol and cocaine. Another important principle of recovery is to avoid stimuli that induce cocaine craving. Cocaine patients are exquisitely vulnerable to cue-conditioned craving, as evidenced by PET studies previously reviewed in this paper. Recovering individuals are asked to avoid associating with active users. This issue is very important when it involves an addicted spouse or family member because living with an active user is especially likely to precipitate relapse. Visiting places where cocaine is available can also produce intense craving and relocation may be prudent when patients live in the drug environment. The principle of avoiding conditioned stimuli is based on a healthy respect for the motivational power of cocaine craving, and an understanding of one’s vulnerability during early recovery. Treatment should specifically convey craving reduction strategies. Cognitive behavioral therapy may be very effective in this regard. Craving is approached as an unpleasant state that dissipates with time. It is lessened when openly discussed in treatment, and should not be concealed or nurtured by glamorizing the drug. During active craving, patients are taught to recall specific examples of addictionrelated suffering. This technique counters the natural inclination to focus only on the pleasurable aspect of cocaine euphoria. It is also useful for patients to view recovery as a series of small steps. Most cocaine-addicted individuals are able to remain abstinent for one day. However, worrying about staying abstinent for years or decades can be demoralizing, often leading the person to rationalize the immediate use of cocaine.
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Psychotherapy research has demonstrated efficacy for several specialized treatments in cocaine-addicted patients. Although a review of this extensive literature is beyond the scope of our discussion, research-based treatments have great potential to improve the quality of addiction care delivery. Contingency management approaches that provide payment vouchers to abstinent cocaine patients have been reported to improve both retention rates and outcome (Higgins et al., 1994). Cognitive behavioral therapy has also been shown to improve outcome in cocaine-addicted individuals and provide benefit for comorbid psychosocial problems (Carroll, 2000). Individual drug counseling utilizing a disease model is particularly effective in cocaine addiction (Crits-Christoph et al., 1999), underscoring the value of 12-step principles reviewed in this chapter and widely employed throughout the United States. These specialized therapies have been standardized with treatment manuals that provide an effective means of training clinical personnel and conducting much needed research (Budney & Higgins, 1998; Carroll, 1999; Mercer & Woody, 1999). Research into care delivery has also concluded that severely addicted individuals benefit from long-term residential programs (Simpson, Joe, Fletcher, Hubbard, & Anglin, 1999), supporting the notion that structured settings may be required to stabilize severe stimulant dependence. Patients enrolled in treatment programs should be regularly monitored for relapse. Urine benzoylecgonine levels (a cocaine metabolite with urinary persistence for several days) are randomly monitored to identify relapse and provide deterrence. Erratic behavior, absence from treatment, and changes in attitude should increase the index of suspicion for relapse and may warrant additional benzoylecgonine tests. Deterioration in attitude, such as the emergence of negativity, resistance, or cynicism, usually precedes relapse and should be openly discussed with the patient. A slip to cocaine use does not necessarily denote treatment failure and should actually be anticipated with this chronic, relapsing disorder. In fact, slips often occur when these patients deviate from treatment recommendations, and improved adherence may be attained in their aftermath.
2. Conclusion Cocaine dependence is a chronic, rapidly progressive illness that is unfortunately characterized by recidivism. Although its use dates back to antiquity, the intrapulmonary administration of crack cocaine is a recent development and produces a particularly virulent form of stimulant addiction. This paper has focused on the dynamics of cocaine addiction, its neurobiology, and the principles of psychosocial treatment. Cocaine acts directly on reward centers in the brain that have evolved to reward survivalrelated behaviors. These centers are capable, by necessity, of dominating the organism’s attention, motivation, and
behavior. By artificially stimulating this brain system, cocaine essentially tricks the brain into thinking a survival need is being met, thereby harnessing the motivational power of the reward centers to perpetuate the addiction. Since the use of cocaine is intensely pleasurable, cocaineaddicted individuals are often ambivalent about the recovery process. Their ambivalence is fostered by denial, which must be specifically reversed in the course of effective treatment. It is unclear to what extent frontal lobe dysfunction contributes to denial and the addictive process. Although we know that cocaine addiction is a brain disease, we have no pharmacological treatments at our disposal to reduce cocaine craving or reverse the numerous neuroadaptations associated with chronic use. Further research is therefore urgently needed to address this medical and societal problem. In the meantime, successful treatment often depends on the patient’s motivation, the skill of the treatment providers, and the strength of the therapeutic alliance.
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