relative deficiency state. The resulting symptoms of withdrawal—craving, lethargy, irritability, anger, restlessness, inability to concentrate, anxiety, depressed mood, and other symptoms that characterize a nicotine withdrawal syndrome—develop rapidly (DiFranza et al., 2002). Regular adolescent smokers report withdrawal symptoms similar to those reported by adults. Whether the withdrawal symptoms experienced by an adolescent nicotine addict are more or less intense after comparable levels of nicotine exposure is not established.

Young smokers who are still experimenting are likely to become regular smokers surprisingly rapidly. The precise numbers that go on to regular smoking and factors that influence progression from experimentation to regular smoking for any single individual remain uncertain. Measurable symptoms of nicotine dependence occur within weeks of the beginning of occasional nicotine use, probably well before daily smoking has been established. One third to one half of adolescents who experiment with more than a few cigarettes become regular smokers (Colby, Tiffany, Shiffman, & Niaura, 2000).

Nicotine dependence is associated with tolerance, cravings for tobacco, desire to use tobacco, withdrawal symptoms when nicotine dose is decreased or unavailable, and loss of control over frequency and duration of use. The criteria common to all drugs are used to diagnose dependence as defined in the DSM-IV (American Psychiatric Association, 1994).

Although traditionally it has been assumed that a period of sustained, daily use is required to produce dependence, in recent years clinical observations of adolescent smokers and data from animal laboratory experiments suggest that dependence develops rapidly in adolescent smokers and in adolescent laboratory animals (Abreu-Villaca et al., 2003; DiFranza et al., 2000; Slotkin, 2002). Some adolescent smokers demonstrate evidence of nicotine dependence well before becoming daily smokers and possibly after only a few days of intermittent tobacco smoking (DiFranza et al., 2000; O'Loughlin, Tarasuk, DiFranza, & Paradis, 2002).

This pattern is consistent with a variety of evidence from animal research showing that an adolescent brain is more susceptible to rapid development of nicotine dependence (Abreu-Villaca et al., 2003). Animal researchers have focused on possible brain mechanisms that account for the special susceptibility of adolescent brains (Slotkin, 2002). For example, nicotine exposure in adolescent rats results in greater and more persistent nicotine receptor up-regulation and cholinergic activity than in adult animals. The rapidity of change in the animal models is consistent with adolescent smokers who develop evidence of nicotine dependence after only a few days' experience with just a few cigarettes (DiFranza et al., 2000, 2002). Brief nicotine exposure results in alterations in cholinergic receptor activity lasting at least 1 month after exposure in rats, which suggests that brief exposure to nicotine changes cholinergic tone in a persistent manner. The level of exposure in the animal models was thought to be in the range experienced by adolescents occasionally smoking three to five cigarettes a day. The data suggest the possibility that brain mechanisms that account for nicotine dependence can be activated by nicotine exposure from only occasional smoking. Although nicotine has a variety of systemic effects in a smoker, particularly cardiovascular and neuroendocrine changes, some animal researchers believe they have found evidence of a primary neurotoxicity as well (Slotkin, 2002) with lasting cell injury, particularly cholinergic system cells. There is no evidence of cholinergic toxicity in human studies. In summary, animal experiments with nicotine suggest rapid and persistent changes in nicotinic receptor and cholinergic function in adolescent rat brains with doses perhaps as little as one tenth of those ingested by regular tobacco smokers.

Nicotine is essential to maintain tobacco smoking, but the beginning of tobacco addiction, as with other addictions, is influenced mostly by nonpharmacologic, learned, or conditioned factors. Peer influence, social setting, personality, and genetics determine who begins and who continues to smoke. In order to develop and implement more effective prevention and treatment programs for adolescent tobacco use, a greater understanding of the determinants of

these behaviors is needed. The following summarizes a few of these determinants.

MDMA (3,4-methylenedioxymethamphetamine), also called ecstasy and other names, has similarities to other amphetamines with stimulant and hallucinogen-like properties (Green, Mechan, Elliott, O'Shea, & Colado, 2003). Usually taken orally, it can also be injected. MDMA produces feelings of energy along with a pleasurable, altered sense of time and enhanced perception and sensory experiences. MDMA effects last 3 to 6 hr. A typical oral dose is one or two tablets, each containing 60 to 120 mg of MDMA, although recently the average dose may be increasing. As is characteristic of all illicit drugs, the chemical content and potency of the MDMA tablets vary, thus dose estimates or even unverified assumptions about the actual drug ingested are only estimates (Cole, Bailey, Sumnall, Wagstaff, & King, 2002).

Perhaps MDMA has a special appeal to adolescents because its usual effects include, along with mental stimulation, feelings of relatedness and empathy toward other people and feelings of well-being (Cole & Sumnall, 2003). These mood effects along with the experience of enhanced sensory perception make MDMA an appealing drug, particularly as typically used in social gatherings, dances, and concerts. At higher doses or in susceptible individuals, undesirable effects include rapid onset of anxiety, agitation, and feelings of restlessness (Gowing, Henry-Edwards, Irvine, & Ali, 2002). During the period of marked intoxication, memory is impaired, sometimes for days or longer in regular users. Information processing and task performance are disrupted. Regular users and sometimes even occasional users report withdrawal phenomena when MDMA effects are wearing off. Withdrawal effects include feelings of depression, difficulty concentrating, unusual calmness, fluctuating mood, and feelings of pervasive sadness sometimes lasting a week or more after an evening of moderate MDMA use (Parrott et al., 2002).

MDMA can be associated with addictive drug-using patterns. Some users report continued use to relieve the feelings that follow MDMA use. Compared to nonusers, regular MDMA users report increased anxiety, greater impulsiveness, and feelings of aggression, sleep disturbance, loss of appetite, and reduced sexual interest (Parrott, 2001). Whether reports from users result from their MDMA use or are symptoms and behaviors that predate MDMA use is not established.

As with other amphetamine-like stimulant drugs, high doses of MDMA, particularly if used with other stimulants, can be associated with nausea, chills, sweating, muscle cramps, and blurred vision. Anxiety, paranoid thinking, and, later, depression are common. After higher doses, markedly increased blood pressure, loss of consciousness, and seizures may occur, and under certain conditions of dose, or drug combinations and heat, the body's thermoregulation mechanisms fail. The resultant marked increase in body temperature (hyperthermia) under some circumstances is rapidly followed by multiple organ failure and death (Schifano, 2003). MDMA is commonly used with alcohol, increasing MDMA toxicity.

The nature of MDMA metabolism in the body contributes to toxicity. After a dose of MDMA is rapidly absorbed, it slows its own breakdown, resulting in unexpectedly high MDMA concentrations with repeated doses (Farre et al., 2004; Green, Mechan, et al., 2003). After regular use, tolerance to the desired MDMA effects develops (Verheyden, Henry, & Curran, 2003). This tolerance leads regular MDMA users to take larger or more frequent doses, resulting in the accumulation of toxic blood levels because of the drug-induced slowdown in its own metabolism.

MDMA increases the activity of brain serotonin, dopamine, and norepinephrine (Gerra et al., 2002; Vollenweider, Liechti, Gamma, Greer, & Geyer, 2002). When compared with methamphetamine, MDMA produces greater serotonin and less dopamine release. In animals, moderate to high doses of MDMA are toxic to serotonergic nerve cells and are associated with persistent cellular changes. As MDMA behavioral

effects wear off, serotonin levels decrease for days, perhaps longer. One controversy about the toxicity of MDMA involves the correct extrapolation of human doses to doses used in animal models in which signs of toxic effects can be directly observed (Green, Mechan, et al., 2003).

A relative serotonin deficit experienced by frequent MDMA users may account for the mood, sleep, and other behaviors and symptoms associated with frequent MDMA use (Parrott, 2002). As with all psychoactive drugs, the general considerations of gender, dose, frequency of exposure, and concurrent use of other drugs, along with genetic and environmental factors, are probably important determinants of the consequences of MDMA exposure for any specific individual (Daumann et al., 2003; De Win et al., 2004; Obrocki et al., 2002; Roiser & Sahakian, 2003). Certainly many people have used MDMA and appear to have avoided measurable harm, but some have died after taking MDMA. As with nicotine, animal experiments suggest that younger brains may be more susceptible to the neurotoxic effects of MDMA (Williams et al., 2003), although important experiments with adolescent animals have not yet been reported.

Thousands of chemicals produce vapors or can be delivered as aerosols and inhaled to produce psychoactive effects (Anderson & Loomis, 2003). Inhalants can be organized by their chemical classification (toluene or nitrous oxide, for example), by their legitimate use (as an anesthetic, solvent, adhesive, fuel, etc.), or by their means of delivery (as a gas, a vapor, or an aerosol) (Balster, 1987). What inhalants have in common is that they are rarely taken by other routes when abused, although some can be swallowed or injected.

Volatile solvents include common household and workplace products—cleaning fluids, felt-tip markers, glues, paint thinners, and gasoline (Anderson & Loomis, 2003). Volatile medical anesthetics, halothane or isofluane, and other ethers occasionally turn up among adolescent inhalant users. Another category of inhalants, aerosols, is available as the solvents in spray cans that de liver paint, deodorants, hairspray, insecticides, and other products. Inhalant gases include household and commercial gases—butane in cigarette lighters, and nitrous oxide in whipped cream delivery cans or from medical sources. Nitrites are a special class of inhalants occasionally encountered by adolescents. When inhaled, nitrites dilate blood vessels, relax smooth muscles, and, unlike other inhalants, are more stimulating than depressant and are used primarily to enhance sexual activities.

Inhalants have been used as intoxicants for hundreds of years. Inhalants, particularly solvents, are often one of the first psychoactive drugs used by children. An estimated 6% of children had tried inhalants on at least one occasion by the fourth grade. Inhalants stand out among abused drugs by being used more by younger than older children, though on occasion, inhalant abuse persists into adulthood (Balster, 1987). Although inhalant abusers generally use whatever is available, preferred agents exist, varying from region to region in an almost fad-like way.

National and state surveys indicate inhalant use peaks around the seventh to ninth grades, with 6% of eighth graders reporting use of inhalants within the previous 30 days. The prevalence of inhalant use in young adolescents exceeds marijuana use and is more frequent in boys and in adverse socioeconomic conditions. Poverty, childhood abuse, poor grades, and early school dropout are associated with greater inhalant abuse (Beauvais, Wayman, Jumper-Thurman, Plested, & Helm, 2002; Kurtzman, Otsuka, & Wahl, 2001).

Inhalants are easy to self-administer and readily available, which explains their appeal to children. The solvents can be inhaled from a bag, from a cloth held over the face, or by sniffing from the container. Aerosol propellants can be sprayed directly into the mouth, inhaled from a balloon, or sprayed into a bag and then inhaled.

As with smoked drugs, inhalant effects depend on the substance used, efficiency of the inhalant delivery system, and the amount inhaled. Length and frequency of use are important because tolerance to many effects develops.

When inhaled, the drugs move from the lungs to brain and an onset of effects occurs within seconds. Psychoactive effects dissipate within minutes when inhalation is stopped. The chemicals are distributed to other organs, potentially damaging the liver, kidneys, and peripheral nerves. The experience produced by most inhalants is similar to that of drinking alcohol: an initial feeling of relaxation, anxiety relief, and feelings of disinhibition. As the intoxication increases with repeated doses, speech becomes slurred, fine motor movements and ability to walk are impaired, and, with increasing and repeated doses, loss of consciousness and an anesthetic state or coma occur. The neural mechanisms by which inhalant intoxication occurs are not well understood (Balster, 1998). During the period of intoxication many neural systems become dysfunctional.

As intoxication wears off, a hangover state commonly ensues. The severity of the postintoxication effect depends on dose, duration of exposure, and the amount used, but typically includes headache or nausea. Inadvertent overdose is possible, particularly when the bag or other inhalant delivery system becomes positioned so that when consciousness or coordination is lost, delivery of the inhalant continues.

Long-term effects vary with inhalant and frequency of use, but can include central nervous symptoms such as fatigue, difficulty concentrating, and impaired memory (Lorenc, 2003). Some solvents or aerosols produce nosebleed, bloodshot eyes, cough, and sores on the lips, nose, or mouth. If used over long periods of time, permanent brain damage or other organ damage (kidney, liver, and peripheral nerves) can develop (Aydin et al., 2002). Tolerance to the depressant effects develops with repeated use. In frequent users, withdrawal phenomena have been described on cessation of inhalant use.

A common cause of death during inhalant use is rapid inhalation of large amounts of solvents, followed by strenuous activity. This results in impaired cardiac function and arrhythmias. Injury and death may result from accidents associated with impaired judgment, motor impairment, or falls. Suffocation from inadequate air during the inhalation of concentrated gases or solvents is possible, and because many inhalants are flammable, fires or explosions may lead to injury or death.

When asked, children typically report that they sniff inhalants because it's fun and they like the feeling of intoxication. Initial use is often in a group with considerable peer pressure. Some users report that the intoxicated state is a way to avoid experiencing or dealing with worries and problems. Although most child inhalant use is transient and initially stems from curiosity, with the wrong kind of group pressure, it becomes a repeated behavior.

A potent CNS depressant, GHB is typically taken to produce euphoria and a relaxed and uninhibited state, similar to that produced by alcohol (Nicholson & Balster, 2001; Teter & Guthrie, 2001). GHB is a clear, odorless, slightly salty-tasting liquid. Because of its steep dose–effect curve inadvertent overdose is frequent. Nausea, vomiting, slowed heart rate, loss of consciousness, coma, respiratory depression, and seizures can require emergency treatment. Coma, along with vomiting and an obstructed airway, can lead to death. The purity and the strength of individual doses of GHB vary greatly and can contribute to overdoses, particularly by inexperienced users. When GHB is taken with other CNS depressants, lethality increases. Deaths from GHB typically occur after combined use with alcohol. GHB is so rapidly metabolized that postmortem toxicology statistics may underestimate its frequency.

Regular users of GHB report that they must increase the dose to attain euphoric and relaxing effects; thus tolerance seems likely. A withdrawal state with increased heart rate, restlessness, anxiety, agitation, delirium, and disrupted sleep follows sudden cessation of regular GHB use (Miotto et al., 2001). GHB has been perceived as a safe drug because it was available in health food stores as a dietary supplement. Its potential toxicity may be underestimated by adolescents (Mason & Kerns, 2002). Although now a con