Cocaine, cocaine dependence: symptoms and treatment

Cocaine and other psychostimulants

The prevalence of stimulant abuse fluctuates cyclically, in contrast to the relatively constant prevalence of opioid abuse. Cocaine has experienced two periods of high popularity in the United States in the past century. Its most recent peak was in 1985, when the number of occasional cocaine users reached 8.6 million and the number of regular users was 5.8 million. More than 23 million Americans have used cocaine at some point in their lives, but the number of continuing users has declined steadily to 2.9 million in 1988 and 1.3 million in 1992. The mid-1990s can be considered the late phase of the epidemic. Since 1991, the number of frequent (at least weekly) cocaine users has remained stable at 640,000. About 16% of cocaine users at some point lose control and become dependent. Some of the factors that influence the progression from cocaine use to abuse and then to dependence were discussed at the beginning of this chapter. Among these, availability and cost are critical. Until the 1980s, cocaine hydrochloride, suitable for intranasal or intravenous administration, was the only form of cocaine available, and it was quite expensive. The advent of cheaper cocaine alkaloids (freebase, crack), which could be inhaled and were also readily available in most major cities for $2 to $5 per dose, made cocaine accessible to children and adolescents. In general, substance abuse is more common among men than women, and for cocaine the ratio is about 2:1. However, crack use is quite common among young women, approaching levels seen in men. Consequently, cocaine use is quite common among pregnant women.

The reinforcing effect of cocaine and its analogues is best correlated with the ability of the drug to block the dopamine transporter, which ensures its presynaptic reuptake. The transporter is a specialized membrane protein that recaptures dopamine released by the presynaptic neuron, thus replenishing intracellular stores of the neurotransmitter. It is believed that blockade of the transporter enhances dopaminergic activity in critical areas of the brain, prolonging the presence of the mediator in the synaptic cleft. Cocaine also blocks the transporters that ensure the reuptake of norepinephrine (NA) and serotonin (5-HT), so long-term use of cocaine causes changes in these systems as well. Thus, the physiological and mental changes caused by cocaine intake may depend not only on the dopaminergic, but also on other neurotransmitter systems.

The pharmacological effects of cocaine in humans have been well studied in the laboratory. Cocaine causes a dose-dependent increase in heart rate and blood pressure, which is accompanied by increased activity, improved performance on attention tests, and a sense of self-satisfaction and well-being. Higher doses cause euphoria, which is short-lived and creates a desire to take the drug again. Involuntary motor activity, stereotypies, and paranoid manifestations may be observed. People who have taken large doses of cocaine for a long time experience irritability and possible outbursts of aggression. A study of the state of dopamine D2 receptors in hospitalized individuals who had used cocaine for a long time revealed a decrease in the sensitivity of these receptors, which persisted for many months after the last use of cocaine. The mechanism and consequences of the decrease in receptor sensitivity remain unclear, but it is believed that it may be associated with the symptoms of depression that are observed in individuals who have previously used cocaine and are often the cause of relapse.

The half-life of cocaine is approximately 50 min, but the desire for additional cocaine in crack users typically occurs within 10-30 min. Intranasal and intravenous administration also produce a short-lived euphoria that correlates with blood levels of cocaine, suggesting that as concentrations decline, the euphoria wanes and the desire for more cocaine appears. This theory is supported by positron emission tomography (PET) data using a radioactive preparation of cocaine containing the isotope "C", which show that during the euphoric experience, the drug is taken up and moved into the striatum (Volkow et al., 1994).

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Cocaine toxicity

Cocaine has a direct toxic effect on organ systems. It causes cardiac arrhythmia, myocardial ischemia, myocarditis, aortic dissection, cerebral vasospasm, and epileptic seizures. Cocaine use by pregnant women may cause premature labor and placental abruption. There have been reports of developmental abnormalities in children born to cocaine-using mothers, but these may be related to other factors, such as prematurity, exposure to other substances, and poor prenatal and postnatal care. Intravenous cocaine increases the risk of various hematogenous infections, but the risk of sexually transmitted infections (including HIV) is increased even with smoking crack or using cocaine intranasally.

Cocaine has been reported to produce prolonged and intense orgasms when taken before sexual intercourse. Its use is therefore associated with sexual activity that is often compulsive and disordered. However, with long-term use, decreased libido is common, and sexual dysfunction is common among cocaine users who seek treatment. In addition, psychiatric disorders, including anxiety, depression, and psychosis, are common among cocaine abusers who seek treatment. Although some of these disorders undoubtedly exist before the onset of stimulant use, many develop as a result of cocaine abuse.

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Pharmacological aspects of cocaine use

Repeated use of a drug usually causes adaptation processes in the nervous system, and subsequent administration of the same dose causes a less significant effect. This phenomenon is called tolerance. Acute tolerance, or tachyphylaxis, is the weakening of the effect with rapid repeated administration of the drug. Acute tolerance develops experimentally in both humans and animals. With intermittent use of the drug, for example, with the administration of a single dose once every few days, the opposite changes can be observed. In studies of psychostimulants (such as cocaine or amphetamine) in experimental animals (for example, rats in which behavioral activation was assessed), with repeated administration of the drug, its effect was strengthened, not weakened. This is called sensitization - a term meaning an increase in effect with repeated administration of the same dose of a psychostimulant. Cocaine users and those seeking treatment did not report the possibility of sensitization in relation to the euphorogenic effect of the drug. Sensitization has not been observed in humans in laboratory studies, although no specific experiments have been conducted to detect this effect. On the contrary, some experienced cocaine users have reported that they require increasingly higher doses of the drug over time to achieve euphoria. This indicates the development of tolerance. In the laboratory, tachyphylaxis (rapidly developing tolerance) with a weakening effect has been observed when the same dose was administered in a single experiment. Sensitization may be conditioned reflexive in nature. In this regard, it is interesting that cocaine users often report a strong effect associated with the visual perception of the dose and occurring before the drug enters the body. This reaction has been studied in the laboratory: cocaine users in a state of withdrawal were shown video clips with scenes associated with cocaine use. The conditioned reflex reaction consists of physiological activation and an increase in craving for the drug.

Sensitization in humans may also underlie the paranoid psychotic manifestations that occur with cocaine use. This suggestion is supported by the fact that paranoid manifestations associated with binge drinking occur only after prolonged cocaine use (an average of 35 months) and only in susceptible individuals. Thus, repeated administration of cocaine may be required for sensitization to develop and paranoid symptoms to appear. The phenomenon of kindling has also been invoked to explain cocaine sensitization. Repeated administration of subconvulsive doses of cocaine eventually leads to the appearance of epileptic seizures in rats. This observation can be compared with the kindling process that leads to the development of epileptic seizures with subthreshold electrical stimulation of the brain. It is possible that a similar process explains the gradual development of paranoid symptoms.

Because cocaine is usually used episodically, even frequent cocaine users experience frequent episodes of withdrawal, or "crashes." Withdrawal symptoms seen in cocaine addicts. Careful study of cocaine withdrawal symptoms has shown a gradual attenuation of symptoms over 1-3 weeks. After the withdrawal period is over, residual depression may occur, requiring treatment with antidepressants if persistent.

Cocaine abuse and addiction

Addiction is the most common complication of cocaine use. However, some individuals, especially those who snort cocaine, may use the drug sporadically for many years. For others, use becomes compulsive despite careful measures to limit use. For example, a medical student may vow to use cocaine only on weekends, or a lawyer may resolve not to spend more on cocaine than an ATM can provide. Eventually, these restrictions no longer work, and the person begins to use cocaine more frequently or spend more money on it than he or she had previously intended. Psychostimulants are usually taken less regularly than opioids, nicotine, or alcohol. A cocaine binge is common, lasting from a few hours to several days and ending only when the drug supply runs out.

The primary route of cocaine metabolism is hydrolysis of each of its two ester groups, resulting in the loss of its pharmacological activity. Benzoylecgonine-demethylated form is the major metabolite of cocaine found in urine. Standard laboratory tests for the diagnosis of cocaine use rely on the detection of benzoylecgonine, which can be detected in urine 2-5 days after a binge. In high-dose users, this metabolite can be detected in urine for up to 10 days. Thus, urine testing may show that a person has used cocaine in the past few days, but not necessarily currently.

Cocaine is often used in combination with other substances. Alcohol is another drug that cocaine users use to reduce the irritability experienced when taking high doses of cocaine. Some people develop alcohol dependence in addition to cocaine dependence. When taken together, cocaine and alcohol can interact. Some cocaine is transesterified to cocaethylene, a metabolite that is as effective as cocaine in blocking dopamine reuptake. Like cocaine, cocaethylene increases locomotor activity in rats and is highly addictive (spontaneous) in primates.

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Symptoms of cocaine withdrawal syndrome

• Dysphoria, depression
• Drowsiness
• Fatigue
• Increased craving for cocaine
• Bradycardia.

The anticonvulsant carbamazepine has been proposed for treatment based on its ability to block the kindling process, a hypothetical mechanism for the development of cocaine dependence. However, several controlled trials have failed to demonstrate an effect of carbamazepine. Recent studies have shown that disulfiram (probably due to its ability to inhibit dopamine beta-hydroxylase) may be useful in the treatment of cocaine dependence in patients with comorbid alcoholism and opioid abuse. Fluoxetine, a selective serotonin reuptake inhibitor, has been reported to cause a statistically significant reduction in cocaine use, as assessed by measuring urinary levels of the cocaine metabolite benzoylecgonine, compared with placebo. Buprenorphine, a partial opioid agonist, has been shown to inhibit spontaneous cocaine use in primates, but in a controlled study of patients co-dependent on opioids and cocaine, no reduction in cocaine use was observed. Thus, all drugs studied to help prevent relapse to cocaine addiction have at best had a moderate effect. Even small improvements are difficult to replicate, and it is now generally accepted that there is no drug that is effective in treating cocaine addiction.

Drug treatment for cocaine addiction

Because cocaine withdrawal is usually mild, it often does not require specific treatment. The primary goal in treating cocaine addiction is not so much to stop using the drug as to help the patient resist the urge to return to compulsive cocaine use. Some evidence suggests that rehabilitation programs that include individual and group psychotherapy and are based on the principles of Alcoholics Anonymous and behavioral therapy methods (using urine cocaine metabolite testing as a reinforcer) may significantly increase the effectiveness of treatment. However, there is great interest in finding a drug that could help rehabilitate cocaine addicts.

Desipramine is a tricyclic antidepressant that has been tested in several double-blind studies in cocaine dependence. Like cocaine, desipramine inhibits monoamine reuptake but acts primarily on noradrenergic transmission. Some suggest that desipramine may alleviate some of the symptoms of cocaine withdrawal and craving during the first month after cessation of cocaine use, a period when relapse is most common. Desipramine had a clinically significant effect early in the epidemic in a population that was predominantly white-collar and used cocaine intranasally. Subsequent studies of desipramine in intravenous cocaine injectors and crack smokers have had mixed results. Some evidence suggests that the beta-blocker propranolol may alleviate withdrawal symptoms in cocaine dependence.

Other drugs that have been shown to be effective include amantadine, a dopaminergic agent that may have a short-term effect in detoxification.

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