Cocaine is a tropane ester alkaloid found in leaves of the Erythroxylum coca plant, a bush that grows in the Andes Mountain region of South America. Its stimulant properties have been known to the indigenous population for at least 2000 years. Oral use of the coca leaf continues to this day and is not associated with significant abuse.

Little attention was paid to coca outside South America until its active ingredient, cocaine, was isolated from the leaf in 1860 by a German graduate student, Albert Niemann. This spawned the widespread popularity of cocaine-containing consumer products, including patent medicines, wine, and other beverages. One of the most popular was a non-alcoholic drink containing about 0.75 mg of cocaine per ounce: Coca-Cola®. Increasing reports of adverse effects, such as stroke and cardiac arrest, led to strict government controls. Cocaine was removed from Coca-Cola in 1903. It received little public or medical attention for the next 70 years, until the “crack” cocaine epidemic of the 1980s.

The 1914 Harrison Narcotic Act limited cocaine to prescription drug status in the United States (US). Cocaine hydrochloride is still legally available in the US as a 4 or 10 percent solution for use as a local or topical anesthetic, although it has largely been replaced in clinical practice by synthetic local anesthetics. Cocaine is classified as a Schedule II medication under the Controlled Substances Act.

This topic addresses the pharmacology and effects of cocaine use and treatment for addiction in adults. Cocaine use by minors is discussed separately. Specific cardiovascular and pulmonary complications related to cocaine are also discussed separately.

EPIDEMIOLOGY

— Cocaine is used by more than 13 million people worldwide, about 0.3 percent of the global population age 15 to 64 years. Use and abuse are most prevalent in North America (6.3 million people, 2 percent of population older than 14 years) and South America (2.7 million people, 0.94 percent) and in Western Europe (3.4 million people, 1 percent). Current use in the United Kingdom and Spain has reached the levels of the US.

There is relatively little cocaine use in Africa, Asia, Eastern Europe, and Oceania. This pattern may be due to supply rather than demand factors, because of the difficulty in obtaining cocaine from its only source in South America and the ready availability of alternative synthetic stimulants such as amphetamines.

Most cocaine use is by urban men age 15 to 35 years. About 126,000 (6.2 percent) current users in the US are adolescents 12 to 17 years old. Cocaine use has declined somewhat among this age group in the last few years, but has remained steady in older groups.

More than one-quarter of past year cocaine users (more than 1.5 million) meet psychiatric diagnostic criteria for cocaine abuse or dependence. Yet in 2004, only 884,000 cocaine users received substance use treatment.

Cocaine is the illegal drug most often associated with visits to US hospital emergency departments. In 2005, it was involved in an estimated 31 percent of drug-related emergency department visits (about 450,000 visits), versus about 17 percent (240,000 visits) for marijuana and about 11 percent (165,000 visits) for heroin. Almost one-fifth of cocaine-related visits were by patients seeking detoxification; 3.2 percent were for suicide attempts.

Patterns of use — Cocaine is used in a variety of patterns. The typical “binge” involves short periods of heavy use (eg, payday or weekends) separated by longer periods of little or no use. Others may use for an extended period until their finances are exhausted or access to cocaine is interrupted. A small number of users who are self-medicating an underlying neuropsychiatric disorder, such as attention deficit hyperactivity disorder (ADHD) or narcolepsy, may use low doses daily without dose escalation over time.

Most cocaine users living in the community do not use very frequently. Half (49.1 percent) of past year users used less than 12 times in the year; only 2.5 percent used at least 300 times.

Risk factors for use and abuse — While cocaine use occurs in all sociodemographic groups, it is not equally distributed among the US population. The highest prevalence of use is among unemployed men in their 20s with no more than a high school education who live in urban areas.

Cocaine use is highly associated with use of other legal and illegal substances and with psychiatric disorders. Cigarette smokers and heavy alcohol drinkers are 10 times more likely than others to be cocaine users. Among current (past month) cocaine users, 92 percent use alcohol and 79 percent smoke cigarettes (73 percent use both). Almost half are heavy drinkers (five or more drinks on the same occasion on at least five days in the past 30 days). Concurrent use of cocaine and alcohol produces a new compound, cocaethylene, which is pharmacologically active.

Many cocaine users use other substances either to enhance the “high” (eg, simultaneous use of opiates [“speedballing”]) or to ameliorate adverse effects of intoxication or withdrawal (eg, use of alcohol, cannabis, or benzodiazepines). Current cocaine users are twice as likely as non-users to have symptoms of depressive or anxiety disorders. Among past year cocaine users, almost one-quarter reported serious psychological distress during that year.

Cocaine users are at high risk for abuse or dependence. Community-based interview surveys suggest that up to one in six persons who use cocaine will become dependent. Heavier users and users who take the drug intravenously or by smoking are more likely to become dependent than lighter users or intranasal and oral users. The greater abuse potential of intravenous or smoked cocaine is attributed to the faster rate of drug delivery to the brain (within 10 seconds), and faster onset of psychological effects. This faster onset is associated with a more intense pleasurable response (the so-called “rate hypothesis” of psychoactive drug action).

The environment (including family, religious, and social factors) has the strongest influence on initial cocaine use. Studies of drug use by pairs of fraternal (dizygotic) and identical (monozygotic) twins suggest a significant genetic influence on the risk of developing cocaine abuse or dependence after use has begun. Several promising candidate genes have been identified, including those for dopamine receptors and the dopamine transporter, but no specific gene has been clearly linked with cocaine addiction.

MECHANISM OF ACTION — Cocaine enhances monoamine neurotransmitter (dopamine, norepinephrine, and serotonin) activity in the central and peripheral nervous systems by blocking the presynaptic reuptake pumps (transporters) for these neurotransmitters. Cocaine’s positive psychological effects and abuse liability are considered to be due to its enhancement of brain dopamine activity, especially in the so-called corticomesolimbic dopamine reward circuit. Thus, cocaine addiction has been termed a disease of the brain’s dopamine reward system.

Cocaine is unique among stimulant drugs in having a second action of blocking voltage-gated membrane sodium ion channels. This action accounts for its local anesthetic effect, and may contribute to cardiac arrhythmias.

PHARMACOKINETICS

— Illegal cocaine comes in two forms: base (alkaloid, as in coca leaves) and salt. Both forms consist of the same cocaine molecule and exert the same pharmacological actions once they reach the brain or other target organ. They differ in physical properties, which allow different routes of administration.

Cocaine base (“crack,” “freebase”) can be smoked because it has a relatively low melting point (98C) and vaporizes before substantial pyrolytic destruction has occurred. Conversely, it is difficult to dissolve for injection because it is relatively insoluble in water.

In contrast, cocaine salt can not be efficiently smoked because it melts at 195C, with substantial breakdown of the cocaine molecule before vaporization. Cocaine salt is readily injected or insufflated (“snorted”) through the nose; it is highly water soluble, making it easy to dissolve for injection purposes and facilitating absorption across mucus membranes.

The average purity of seized cocaine samples is around 60 percent. Added diluents include both inert fillers that resemble cocaine in appearance (such as dextrose, lactose, mannitol, or starch) and active chemicals that either mimic the local anesthetic effect of cocaine (such as benzocaine, lidocaine, or procaine) or provide some psychoactive effect (such as ephedrine, amphetamine, caffeine, or PCP). Street cocaine also may contain contaminants from the preparation process (such as benzene, acetone, or sodium bicarbonate). The role of diluents and contaminants in the toxicity of illegal cocaine use is not well understood.

Absorption — Cocaine is readily absorbed through the mucous membranes of the nose and mouth, and from the genitourinary, gastrointestinal, and respiratory tracts. Passive absorption may occur through intact skin or by inhalation of second-hand cocaine smoke. Such passive exposure can cause adverse effects in infants.

Distribution — Cocaine is rapidly taken up into most body organs, including the heart, kidney, adrenal glands, and liver. Cocaine (and its hydrolytic metabolites) appears in blood, urine, hair , sweat, saliva, and breast milk . It crosses the placenta to appear in meconium. Analysis of these tissues and fluids is used for drug detection in workplace, legal, and treatment settings.

Onset of action — The onset of action for cocaine depends on the route of administration. Intravenous and inhaled (smoked) administration results in onset of action within seconds. Intranasal and gastrointestinal administration result in slower onsets of 20 to 30 minutes and up to 90 minutes, respectively.

Duration of action — The effects of intravenous or inhaled cocaine administration typically last 15 to 30 minutes; effects of intranasal and gastrointestinal administration are about one and three hours, respectively.

Metabolism — Cocaine is 95 percent metabolized by hydrolysis of its ester bonds to benzoylecgonine (by carboxyesterases in the liver) and to ecgonine methylester (by butyrylcholinesterase in the liver, plasma, brain, lung, and other tissues). The remaining 5 percent is N-demethylated to norcocaine by the liver cytochrome P450 microsomal enzyme system. The hydrolytic metabolites appear to be largely inactive. Norcocaine has some pharmacological actions similar to those of cocaine, and is hepatotoxic.

Smoked cocaine produces an additional series of pyrolysis products, the chief of which are anhydroecgonine methylester and noranydroecgonine methylester.

Cocaine use together with alcohol leads to formation of a new compound, cocaethylene, by transesterification. Cocaethylene has pharmacological actions similar to, but less potent than, those of cocaine, and has a longer half-life. Formation of cocaethylene may contribute to more severe or longer lasting toxic effects of cocaine when it is used along with alcohol.

Elimination — Cocaine is largely eliminated in the urine. Benzoylecgonine is the metabolite found in highest concentration in urine. It is this metabolite, rather than the parent drug cocaine, that is measured in urine drug tests for cocaine.

Author
David A Gorelick, MD, PhD

Deputy Editor
H Nancy Sokol, MD

REFERENCES