duce cocaine-like subjective effects that result from their similar neurotransmitter actions in reward-related brain circuits (Dackis & O'Brien, 2001). Methamphetamine is used predominantly in the western regions of the United States, and is particularly addicting when injected or smoked. Although many adolescents are able to experiment with stimulants without suffering long-term consequences, others are pulled into a tenacious cycle of addiction that all too often persists into adulthood. About 6% of the adolescents who try cocaine become addicted within 1 year, and most of the additional 10% who ultimately become addicted do so within 3 years (Wagner & Anthony, 2002a). The constitutional and environmental vulnerabilities that predispose individuals to cocaine addiction are not entirely understood, and it is very difficult to predict which adolescents will ultimately become afflicted. Considerable resources have been allocated to prevention, on the basis of the undeniable fact that cocaine addiction cannot occur if cocaine is never tried. Prevention initiatives include educational and advertising campaigns that convey the dangers of cocaine, school and community programs, and law enforcement efforts that target the key variable of cocaine supply. However, preventive measures (discussed in Chapter 19) are most likely to benefit cocaine-naive individuals and are of limited value to adolescents who are already in the grips of full-fledged cocaine addiction.

The historic use of cocaine has varied extensively, reaching epidemic levels when its addictiveness was unappreciated and receding when perceived risk was great. The chemical isolation of cocaine in 1860 produced a white powder that could be efficiently consumed by oral, intranasal, and intravenous routes. Cocaine became immensely popular in Europe and the United States in the 19th century, and was sold in wine or soda (a bottle of Coca-Cola originally contained 10 mg of cocaine) for its medicinal, antidepressant, and energy-enhancing qualities. Its availability and perceived harmlessness proved to be essential ingredients that quickly unleashed a cocaine epidemic in the late 19th century. Cocaine use declined precipitously after the risk of medical, psychiatric, and behavioral consequences became widely appreciated. Amphet amine was developed in the mid-20th century and widely abused until perceived risk became appreciated, partly in response to the “speed kills” prevention initiative. Its appearance illustrates both the latent human demand for stimulants and the potential danger posed by new compounds, including designer drugs that have similar actions on reward-related brain circuits. The reversibility of perceived risk was demonstrated by the reemergence of cocaine in the 1980s as a popular drug with a mythology of harmlessness.

In recent years, it is likely that the availability of inexpensive crack has actually increased cocaine access to adolescents. Crack can now be purchased for as little as $2 in many regions of the United States. Although there was a reduction in cocaine use among adolescents between 1985 and 1995, findings of the U.S. Substance Abuse and Mental Health Service Administration (SAMHSA) and the United Nations Office for Drug Control and Crime Prevention provide evidence that cocaine use in the United States and throughout the world actually increased during the late 1990s (Chen & Anthony, 2004). Data on American adolescents (ages 12–17) from the National Household Surveys on Drug Use and Health (SAMHSA, 2000) reported 397,000 active cocaine (including crack) users (1.7% prevalence) and 275,000 (1.2% incidence) recent-onset users. Stimulants other than cocaine were actively used by 561,000 (2.4% prevalence) adolescents, of which 322,000 (1.4% incidence) were recent-onset users. These data indicate that many adolescents continue to experiment with cocaine and other stimulants even though their risks are widely known.

Crack provides adolescents with a convenient and highly efficient means of administering cocaine that is particularly acceptable to adolescents who are already smoking tobacco or marijuana. Marketing inexpensive crack, whether by design or chance, has apparently provided the illegal drug industry with adolescent cocaine customers that number in the hundreds of thousands. In addition, smoking crack (a free-base form of cocaine that can be vaporized without loss of potency) has long been recognized to be more hazardous than snorting cocaine HCl (Hatsukami & Fischman, 1996). Crack is taken

by the intrapulmonary route that delivers cocaine to the brain much more rapidly than snorting (6 to 8 sec vs. 3 to 5 min), resulting in more intense euphoria and a greater likelihood of addiction (Volkow, Fowler, & Wang, 1999). A recent epidemiological study concluded that smoking crack might double the likelihood of developing cocaine dependence (Chen & Anthony, 2004). To make matters worse, crack is often sold in dangerous urban areas where drug trafficking, crime, prostitution, and infectious diseases present convergent hazards for adolescents. The risk of suffering procurement-related medical hazards, including trauma, is especially high because adolescents who use drugs are more likely to engage in unprotected sex and illegal behavior (Jessor, 1991).

Although there are large numbers of adolescents who need effective treatment for cocaine dependence, specialized adolescent addiction treatment programs are scarce and difficult to access throughout the United States. This situation is incongruous with the clinical importance of arresting a progressive and reversible disorder at an early stage, thereby averting functional impairment, morbidity, and mortality. In fact, adolescence is the ideal age for recovery. Unfortunately, cocaine addiction often persists into adulthood with predictable medical, psychiatric, behavioral, and societal ramifications that probably exhaust more resources than would be expended by a serious attempt to establish an appropriate treatment infrastructure for our children.

The transition from cocaine use to addiction is influenced by the route of administration (Chen & Anthony, 2004), the environment (Dackis & O'Brien, 2001), and constitutional factors that affect the attractiveness and rewarding qualities of cocaine (Tsuang et al., 1999). Environmental and psychosocial factors strongly influence the likelihood of first-time use. In some communities, drug dealers are viewed as successful role models and are actually emulated by adolescents who have few educational or vocational alternatives. Disenfranchised adolescents might be particularly vulnerable to cocaine use as a means of gaining peer acceptance, and parents are well advised to be cognizant of peer group changes (DuRant, 1995). Family members, particularly older siblings, are often instrumental in providing adolescents with their first dose of cocaine or normalizing its use through example. Studies indicate that the vulnerability for cocaine dependence is enhanced when there is a family history of alcoholism or drug dependency. Epidemiological studies conclude that the vulnerability to develop cocaine dependence is partially inherited. Twin studies report significantly higher concordance rates for identical twins than for nonidentical twins (Cadoret, Troughton, O'Gorman, & Heywood, 1986; Tsuang et al., 1996; van den Bree, Johnson, Neale, & Pickens, 1998), although research into candidate genes that encode enzymes involved in cocaine metabolism and receptors that mediate cocaine effects has not identified reliable genetic vulnerability markers.

Marijuana is the most commonly used illicit drug among adolescents in the United States (see Figs. 17.1 and 17.2 for comparison). It shares some attributes and possible health consequences with tobacco in that marijuana is a plant material, is most commonly smoked, and contains hundreds of compounds including at least 60 termed cannabinoids that are unique to the cannabis plant. The pharmacology of most of the cannabinoids is relatively unknown, but the most potent psychoactive agent, δ-9-tetrahydrocannabinol (THC), has been isolated, can be synthesized, and has been well researched in adults since the early 1970s. The noncannabinoid materials in the plant and its combustion products when smoked are similar to many of those from tobacco leaf smoking with, of course, the exception of nicotine.

In recent years the technology of growing and distributing illicit marijuana has become sophisticated and much improved. The THC content of plants from different sources and strains varies a great deal. Improved growing techniques, particularly plant breeding, have changed the THC content from a typical 10 mg in a marijuana cigarette in the 1960s to a 1 g marijuana cigarette that contains 150 to 200 mg. One consequence of the increased potency is that much of the human research done in the 1970s and 1980s with relatively low-potency smoked marijuana may be less relevant to the pharmacology of and consequences from marijuana now readily available to adolescents in most parts of the world. What is clear from past research is that the biological effects of THC are dependent on dose. The availability of potent marijuana has greatly increased so that far higher doses of THC are now available to adolescent marijuana users than was possible 10 or 20 years ago.

Although marijuana is typically smoked in the

form of cigarettes or from pipes, THC can also be easily extracted with ethanol and the THC extract or raw plant material can be added to baked goods or to sugar cubes or even an oral spray. Because THC and other cannabinoids are not water soluble, intravenous use leads to major toxic effects unless very special preparations and delivery systems are used.

The pharmacokinetics—that is, the manner in which cannabinoids are distributed and metabolized in the body—are more complex than that of most psychoactive drugs. As with the use of any smoked drug, the final absorbed dose is very much under the control of the individual and subject to learning processes similar to those involved in learning to smoke tobacco. Thus, beginning adolescent marijuana smokers may well underdose or overdose themselves until they learn how to smoke. That traditionally most marijuana smoking follows some prior experience with tobacco smoking probably facilitates the learning process. About half of the THC in a marijuana cigarette enters the lungs and most is absorbed rapidly, reaching the brain within seconds of a puff. After oral ingestion, absorption is much less, slower, and more variable. The onset of effects after an oral dose of THC can be delayed as long as an hour and absorption continues slowly. Thus either through chance or for other reasons, overdose with oral ingestion is more likely than after smoking.

THC and other cannabinoids move rapidly into fat and other body tissues during smoking but are only very slowly released from those tissue stores back into blood (and brain) over days, weeks, and months; they are gradually cleared from the body in urine and feces. Thus, the half-life of elimination of even a single, modest dose of THC from tissue stores is very slow, from 7 to 18 days with complete elimination of cannabinoids from one smoked dose taking up to 30 or more days. One consequence of this pattern of slow elimination from the body is that, with repeated doses, even doses taken only a few times weekly, cannabinoids gradually accumulate throughout the body, including the brain. Concentrations in brain areas vary but are highest in cortical, limbic, sensory, and motor areas of the brain. Cannabinoids are primarily metabolized in the liver into a host of metabolites, most of which are not known to be biologically active. The metabolites are very slowly cleared from the body, thus making urine tests useful as an indicator of past marijuana use. Because of the very long presence of cannabinoids in the body, there is no relationship between plasma or urine concentrations of THC or metabolites and degree of intoxication once an hour or less has passed after smoking.

THC alters brain functions by binding to specific receptors widely distributed throughout the brain and elsewhere in the body. As the actions of naturally occurring ligands (hormones) that alter the state of these receptors have become better understood, it has become apparent that there is a complex system of multiple cannabinoid receptors interacting with a series of endogenous ligands. One of these ligands or hormones is called anandamide. The neuropharmacology of this cannabinoid receptor system is only beginning to be understood, but it appears to involve cannabinoids acting as neuromodulators of the large family of other neurotransmitters such as dopamine. Given the extensive distribution of cannabinoid receptors, it should not be sur-prising that virtually every system in the body is affected to some degree by marijuana. Marijuana appears to have sedative, analgesic, anxiolytic, hallucinogenic, appetite-suppressing, and appetite-enhancing properties and less well-characterized effects on the immune system. Firm conclusions about any medical treatment applications of marijuana are premature, but the discussions of marijuana use as a treatment makes it a more interesting drug to an adolescent.

Marijuana is used by adolescents to produce a mild, relatively short period of intoxication, often imprecisely characterized as euphoria. THC is an extremely potent psychoactive drug, so that less than a milligram smoked can produce relaxation, decreased anxiety, and feelings of less inhibition. The intoxication typically lasts a few hours. With higher doses, or with an inexperienced or sensitive individual, a single dose can produce severe anxiety, paranoid delusional thinking, and perceptual distortions that are not unlike those produced by hallucinogen drugs. Individuals with a genetic predisposition for developing schizophrenia, depression, or other