Chapter 24: Drug Addiction

Modern neuroscience has greatly increased our understanding of the phenomenology of addiction. Using animal models as well as human brain imaging studies and clinical observations, addiction can be defined fundamentally as a form of maladaptive memory. It begins with the administration of substances (e.g., cocaine) or behaviors (e.g., the thrill of gambling) that directly and intensely activate brain reward circuits. Activation of these circuits motivates normal behavior and most humans simply enjoy the experience without being compelled to repeat it. For some (~16% of those who try cocaine) the experience produces strong conditioned associations to environmental cues that signal the availability of the drug or the behavior. Thus, reflexive activation of reward circuits becomes involuntary and with a very rapid onset. The cues acquire strong salience that overwhelms other behaviors. The individual becomes drawn into compulsive repetition of the experience focusing on the immediate pleasure despite negative long-term consequences and neglect of important social responsibilities. Of course, underlying this behavior are poorly understood changes in neural circuits (Kalivas and O'Brien, 2008).

The framers of DSM-V are strongly motivated to devise a classification well-grounded in neuroscientific evidence. Unfortunately, complex psychiatric disorders still have no proven genetic basis nor are there reliable biomarkers of these disorders. Thus, the plan is to make DSM-V a flexible document that can be further revised as reliable, replicated data are developed.

Reinforcing properties of drugs are associated with their capacity to increase neuronal activity in critical brain areas (Chapter 14). Cocaine, amphetamine, ethanol, opiates, cannabinoids, and nicotine all reliably increase extracellular fluid dopamine (DA) levels in the ventral striatum, specifically the nucleus accumbens region. In experimental animals, usually rats, brain microdialysis permits sampling of extracellular fluid while the animals are freely moving or receiving drugs. Smaller increases in DA in the nucleus accumbens also are observed when the rat is presented with sweet foods or a sexual partner. In contrast, drugs that block DA receptors generally produce bad feelings, i.e., dysphoric effects. Neither animals nor humans will take such drugs spontaneously. Despite strong correlative findings, a causal relationship between DA and euphoria/dysphoria has not been established, and other findings emphasize additional roles of serotonin (5-HT), glutamate, norepinephrine (NE), endogenous opioids, and γ-aminobutyric acid (GABA) in mediating the reinforcing effects of drugs.

When coca leaves are chewed, cocaine is absorbed slowly through the buccal mucosa. This method produces low cocaine blood levels and correspondingly low levels in the brain. The mild stimulant effects produced by the chewing of coca leaves have a gradual onset, and this practice has produced few, if any, behavior problems despite use over thousands of years by natives of the Andes mountains. Beginning in the late 19th century, scientists isolated cocaine hydrochloride from coca leaves and refined the technology for extraction of pure cocaine. Cocaine could be taken in higher doses by oral ingestion (GI absorption) or by absorption through the nasal mucosa, producing higher cocaine levels in the blood and a more rapid onset of stimulation. Subsequently, it was found that a solution of cocaine hydrochloride could be administered intravenously, giving a more rapid onset of stimulatory effects. Each newly available cocaine preparation that provided greater speed of onset and an increment in blood level was paralleled by a greater likelihood of addiction. In the 1980s, the availability of cocaine to the American public was increased further with the invention of crack cocaine. Crack, sold illegally and at a low price ($1-3 per dose), is alkaloidal cocaine (free base), which can be readily vaporized by heating. Simply inhaling the vapors produces blood levels comparable to those resulting from intravenous cocaine owing to the large surface area for absorption into the pulmonary circulation following inhalation. The cocaine-containing blood then enters the left side of the heart and reaches the cerebral circulation without dilution by the systemic circulation. Thus, inhalation of crack cocaine is much more addictive than chewing, drinking, or sniffing cocaine. Inhalation, with rapid attainment of effective drug levels in the brain, also is the preferred route for users of nicotine and cannabis.

Children of alcoholics show an increased likelihood of developing alcoholism, even when adopted at birth and raised by nonalcoholic parents. The studies of genetic influences in this disorder show only an increased risk for developing alcoholism, not a 100% determinism, consistent with a polygenic disorder that has multiple determinants. Even identical twins, who share the same genetic endowment, do not have 100% concordance when one twin is alcoholic. However, the concordance rate for identical twins is much higher than that for fraternal twins. The abuse of alcohol and other drugs tends to have some familial characteristics, suggesting that common mechanisms may be involved.

Innate tolerance to alcohol as measured by level of response to alcohol administered under experimental conditions may represent a biological trait that contributes to the development of alcoholism (Chapter 23). While innate tolerance increases vulnerability to alcoholism, impaired metabolism may protect against it. See Chapter 23 for a discussion of the genetic variation common in Asian populations that results in facial flushing and reduced alcohol intake or no alcohol intake in those homozygous for the gene variant. Similarly, individuals who inherit a gene associated with slow nicotine metabolism may experience unpleasant effects when beginning to smoke and reportedly have a lower probability of becoming nicotine dependent.

Psychiatric disorders constitute another category of host variables. Drugs may produce immediate, subjective effects that relieve preexisting symptoms. People with anxiety, depression, insomnia, or even subtle symptoms such as shyness may find, on experimentation or by accident, that certain drugs give them relief. However, the apparent beneficial effects are transient, and repeated use of the drug may lead to tolerance and eventually compulsive, uncontrolled drug use. While psychiatric symptoms are seen commonly in drug abusers presenting for treatment, most of these symptoms begin after the person starts abusing drugs. Thus, drugs of abuse appear to produce more psychiatric symptoms than they relieve.

Tolerance to some drug effects develops much more rapidly than to other effects of the same drug. For example, tolerance develops rapidly to the euphoria produced by opioids such as heroin, and addicts tend to increase their dose in order to re-experience that elusive "high." In contrast, tolerance to the gastrointestinal effects of opioids develops more slowly. The discrepancy between tolerance to euphorigenic effects (rapid) and tolerance to effects on vital functions (slow), such as respiration and blood pressure, can lead to potentially fatal overdoses in sedative abusers trying to re-experience the euphoria they recall from earlier use.

Innate tolerance refers to genetically determined lack of sensitivity to a drug that is observed the first time that the drug is administered. Innate tolerance was discussed earlier as a host variable that influences the development of addiction. See Chapter 23 for discussion of the inheritance of level of response to ethanol.

Acquired tolerance can be divided into three major types: pharmacokinetic, pharmacodynamic, and learned tolerance, and includes acute, reverse, and cross-tolerance (Table 24–3).

Pharmacokinetic or dispositional tolerance refers to changes in the distribution or metabolism of a drug after repeated administrations such that a given dose produces a lower blood concentration than the same dose did on initial exposure. The most common mechanism is an increase in the rate of metabolism of the drug. For example, barbiturates stimulate the production of higher levels of hepatic CYPs, causing more rapid removal and breakdown of barbiturates from the circulation. Since the same enzymes metabolize many other drugs, they too are metabolized more quickly. This results in a decrease in their plasma levels as well and a reduction in their therapeutic effects.

Pharmacodynamic tolerance refers to adaptive changes that have taken place within systems affected by the drug so that response to a given concentration of the drug is reduced. Examples include drug-induced changes in receptor density or efficiency of receptor coupling to signal-transduction pathways (Chapters 3 and 14).

Learned tolerance refers to a reduction in the effects of a drug owing to compensatory mechanisms that are acquired by past experiences. One type of learned tolerance is called behavioral tolerance. This simply describes the skills that can be developed through repeated experiences with attempting to function despite a state of mild to moderate intoxication. A common example is learning to walk a straight line despite the motor impairment produced by alcohol intoxication. This probably involves both acquisition of motor skills and the learned awareness of one's deficit, causing the person to walk more carefully. At higher levels of intoxication, behavioral tolerance is overcome, and the deficits are obvious.

Conditioned tolerance (situation-specific tolerance) develops when environmental cues such as sights, smells, or situations consistently are paired with the administration of a drug. When a drug affects homeostatic balance by producing sedation and changes in blood pressure, pulse rate, gut activity, and so on, there is usually a reflexive counteraction or adaptation in the direction of maintaining the status quo. If a drug always is taken in the presence of specific environmental cues (e.g., smell of drug preparation and sight of syringe), these cues begin to predict the effects of the drug, and the adaptations begin to occur even before the drug reaches its sites of action. If the drug always is preceded by the same cues, the adaptive response to the drug will be learned, and this will prevent the full manifestation of the drug's effects (tolerance). This mechanism of conditioned tolerance production follows classical (pavlovian) principles of learning and results in drug tolerance under circumstances where the drug is "expected." When the drug is received under novel or "unexpected" circumstances, conditioned tolerance does not occur, and drug effects are enhanced.

The term acute tolerance refers to rapid tolerance developing with repeated use on a single occasion, such as in a "binge." For example, cocaine often is used in a binge, with repeated doses over one to several hours, sometimes longer, producing a decrease in response to subsequent doses of cocaine during the binge. This is the opposite of sensitization, observed with an intermittent dosing schedule, described in the next section.

Sensitization. With stimulants such as cocaine or amphetamine, reverse tolerance, or sensitization, can occur. This refers to an increase in response with repetition of the same dose of the drug. Sensitization results in a shift to the left of the dose-response curve (Figure 24–1). For example, with repeated daily administration to rats of a dose of cocaine that produces increased motor activity, the effect increases over several days, even though the dose remains constant. A conditioned response also can be a part of sensitization to cocaine. Simply putting a rat into a cage where cocaine is expected or giving a placebo injection after several days of receiving cocaine under the same circumstances produces an increase in motor activity as though cocaine actually were given, i.e., a conditioned response. Sensitization, in contrast to acute tolerance during a binge, requires a longer interval between doses, usually ~1 day.

Sensitization has been studied in rats equipped with microdialysis cannulas for monitoring extracellular DA (Kalivas and Duffy, 1990) (Figure 24–2). The initial response to 10 mg/kg of cocaine administered intraperitoneally is an increase in measured DA levels. After seven daily injections, the DA increase is significantly greater than on the first day, and the behavioral response also is greater. Figure 24–2 also provides an example of a conditioned response (learned drug effect): injection of saline produced both an increase in DA levels and an increase in behavioral activity when administered 3 days after cocaine injections had stopped. Little research on sensitization has been conducted in human subjects, but the results suggest that the phenomenon can occur. It has been postulated that stimulant psychosis results from a sensitized response after long intermittent periods of use.

Cross-tolerance occurs when repeated use of a drug in a given category confers tolerance not only to that drug but also to other drugs in the same structural and mechanistic category. Understanding cross-tolerance is important in the medical management of persons dependent on any drug. Detoxification is a form of treatment for drug dependence that involves giving gradually decreasing doses of the drug to prevent withdrawal symptoms, thereby weaning the patient from the drug of dependence (see "Detoxification" later in the chapter). Detoxification can be accomplished with any medication in the same category as the initial drug of dependence. For example, users of heroin also are tolerant to other opioids. Thus, the detoxification of heroin-dependent patients can be accomplished with any medication that activates opioid receptors.

Medical addict is a term used to describe a patient in treatment for a medical disorder who has become "addicted" to the available prescribed drugs; the patient begins taking them in excessive doses, out of control. An example would be a patient with chronic pain, anxiety, or insomnia who begins using the prescribed medication more often than directed by the physician. If the physician restricts the prescriptions, the patient may begin seeing several doctors without the knowledge of the primary physician. Such patients also may visit emergency rooms for the purpose of obtaining additional medication. This scenario is very uncommon, considering the large number of patients who receive medications capable of producing tolerance and physical dependence. Fear of producing such medical addicts results in needless suffering among patients with pain, because physicians needlessly limit appropriate medications. Tolerance and physical dependence are inevitable consequences of chronic treatment with opioids and certain other drugs, but tolerance and physical dependence by themselves do not imply "addiction."

Alcohol impairs recent memory and, in high doses, produces the phenomenon of "blackouts": the drinker has no memory of his or her behavior while intoxicated. The effects of alcohol on memory are unclear, but evidence suggests that reports from patients about their reasons for drinking and their behavior during a binge are not reliable. Alcohol-dependent persons often say that they drink to relieve anxiety or depression. When allowed to drink under observation, however, alcoholics typically become more dysphoric as drinking continues (Mendelson and Mello, 1979), thus not supporting the idea that alcoholics drink to relieve tension.

Tolerance, Physical Dependence, and Withdrawal. Mild intoxication by alcohol is familiar to almost everyone, but the symptoms vary among individuals. Some simply experience motor incoordination and sleepiness. Others initially become stimulated and garrulous. As the blood level increases, the sedating effects increase, with eventual coma and death occurring at high alcohol levels. The initial sensitivity (innate tolerance) to alcohol varies greatly among individuals and is related to family history of alcoholism (Wilhelmsen et al., 2003). Experience with alcohol can produce greater tolerance (acquired tolerance) such that extremely high blood levels (300-400 mg/dL) can be found in alcoholics who do not appear grossly sedated. In these cases, the lethal dose does not increase proportionately to the sedating dose, and thus the margin of safety (therapeutic index) is decreased.

Heavy consumers of alcohol not only acquire tolerance but also inevitably develop a state of physical dependence. This often leads to drinking in the morning to restore blood alcohol levels diminished during the night. Eventually, they may awaken during the night and take a drink to avoid the restlessness produced by falling alcohol levels. The alcohol-withdrawal syndrome (Table 24–4) generally depends on the size of the average daily dose and usually is "treated" by resumption of alcohol ingestion. Withdrawal symptoms are experienced frequently but usually are not severe or life-threatening until they occur in conjunction with other problems, such as infection, trauma, malnutrition, or electrolyte imbalance. In the setting of such complications, the syndrome of delirium tremens becomes likely.

Alcohol addiction produces cross-tolerance to other sedatives such as benzodiazepines. This tolerance is operative in abstinent alcoholics, but while the alcoholic is drinking, the sedating effects of alcohol add to those of other sedatives, making the combination more dangerous. This is particularly true for benzodiazepines, which are relatively safe in overdose when given alone but potentially are lethal in combination with alcohol.

The chronic use of alcohol and other sedatives is associated with the development of depression (McLellan et al., 1979), and the risk of suicide among alcoholics is one of the highest of any diagnostic category. Cognitive deficits have been reported in alcoholics tested while sober. These deficits usually improve after weeks to months of abstinence. More severe recent memory impairment is associated with specific brain damage caused by nutritional deficiencies common in alcoholics (e.g., thiamine deficiency).

Alcohol is toxic to many organ systems. As a result, the medical complications of alcohol abuse and dependence include liver disease, cardiovascular disease, endocrine and GI effects, and malnutrition, in addition to the CNS dysfunctions outlined earlier. Ethanol readily crosses the placental barrier, producing the fetal alcohol syndrome, a major cause of mental retardation (Chapter 23).

Pharmacological Interventions.

Detoxification. A patient who presents in a medical setting with an alcohol-withdrawal syndrome should be considered to have a potentially lethal condition. Although most mild cases of alcohol withdrawal never come to medical attention, severe cases require general evaluation; attention to hydration and electrolytes; vitamins, especially high-dose thiamine; and a sedating medication that has cross-tolerance with alcohol. To block or diminish the symptoms described in Table 24–4, a short-acting benzodiazepine such as oxazepam can be used at a dose of 15-30 mg every 6-8 hours according to the stage and severity of withdrawal; some authorities recommend a long-acting benzodiazepine unless there is demonstrated liver impairment. Anticonvulsants such as carbamazepine have been shown to be effective in alcohol withdrawal, although they appear not to relieve subjective symptoms as well as benzodiazepines. After medical evaluation, uncomplicated alcohol withdrawal can be treated effectively on an outpatient basis. When there are medical problems, a history of seizures, or simultaneous dependence on other drugs, hospitalization is required.

Pharmacotherapy. Detoxification is only the first step of treatment. Complete abstinence is the objective of long-term treatment, and this is accomplished mainly by behavioral approaches. Medications that aid in the prevention of relapse are under development. Disulfiram (antabuse; Chapter 23) has been useful in some programs that focus behavioral efforts on ingestion of the medication. Disulfiram blocks aldehyde dehydrogenase, the second step in ethanol metabolism, resulting in the accumulation of acetaldehyde, which produces an unpleasant flushing reaction when alcohol is ingested. Knowledge of this unpleasant reaction helps the patient to resist taking a drink. Although quite effective pharmacologically, disulfiram has not been found to be effective in controlled clinical trials because so many patients failed to ingest the medication.

Naltrexone (revia; Chapter 23), an opioid receptor antagonist that blocks the reinforcing properties of alcohol, is FDA- approved as an adjunct in the treatment of alcoholism. Chronic administration of naltrexone resulted in a decreased rate of relapse to alcohol drinking in the majority of published double-blind clinical trials (Pettinati et al., 2006). It works best in combination with behavioral treatment programs that encourage adherence to medication and abstinence from alcohol. A depot preparation with a duration of 30 days (vivitrol) was approved by the FDA in 2006; it greatly improves medication adherence, the major problem with the use of medications in alcoholism.

A significant development in identifying a potential endophenotype of alcoholism has grown out of the clinical experience with naltrexone. Animal studies have demonstrated that alcohol causes the release of endogenous opioids in brain reward systems and the disinhibition or activation of DA neurons, a condition common to all drugs of abuse. Blocking opioid receptors prevents this dopaminergic effect and results in less stimulation or reward from alcohol (Ray and Hutchison, 2007). A functional allele of the gene for the μ opioid receptor that naltrexone blocks has been associated with alcohol stimulation and with good response to naltrexone treatment among alcoholics (Anton et al., 2006).

Acamprosate (campral), another FDA-approved medication for alcoholism (Mason, 2003), is a competitive inhibitor of the N-methyl-D-aspartate (NMDA)–type glutamate receptor. The drug appears to normalize the dysregulated neurotransmission associated with chronic ethanol intake and thereby to attenuate one of the mechanisms that lead to relapse (Chapter 23).

It can be difficult to distinguish withdrawal symptoms from the reappearance of the anxiety symptoms for which the benzodiazepine was prescribed initially. Some patients may increase their dose over time because tolerance definitely develops to the sedative effects. Many patients and their physicians, however, contend that anti-anxiety benefits continue to occur long after tolerance to the sedating effects. Moreover, these patients continue to take the medication for years according to medical directions without increasing their dose and are able to function very effectively as long as they take the benzodiazepine. The degree to which tolerance develops to the anxiolytic effects of benzodiazepines is a subject of controversy. There is, however, good evidence that significant tolerance does not develop to all benzodiazepine actions because some effects of acute doses on memory persist in patients who have taken benzodiazepines for years. According to a task force that reviewed the issues and published guidelines on the proper medical use of benzodiazepines (American Psychiatric Association, 1990), intermittent use only when symptoms occur retards the development of tolerance and therefore is preferable to daily use. Patients with a history of alcohol- or other drug-abuse problems have an increased risk for the development of benzodiazepine abuse and should rarely, if ever, be treated with benzodiazepines on a chronic basis.

While relatively few patients who receive benzodiazepines for medical indications abuse their medication, there are individuals who specifically seek benzodiazepines for their ability to produce a "high." Among these abusers, there are differences in drug popularity; benzodiazepines that have a rapid onset, such as diazepam and alprazolam, tend to be the most desirable. The drugs may be obtained by simulating a medical condition and deceiving physicians or simply through illicit channels. Unsupervised use can lead to self-administration of large doses and therefore tolerance to the benzodiazepine's sedating effects. For example, while 5-20 mg/day of diazepam is a typical dose for a patient receiving prescribed medication, abusers may take over 1000 mg/day and not appear grossly sedated.

Abusers may combine benzodiazepines with other drugs to increase the effect. For example, it is part of the "street lore" that taking diazepam 30 minutes after an oral dose of methadone will produce an augmented high not obtainable with either drug alone.

While there is some illicit use of benzodiazepines as a primary drug of abuse, most of the unsupervised use seems to be by abusers of other drugs who are attempting to self-medicate the side effects or withdrawal effects of their primary drug of abuse. Thus, cocaine addicts often take diazepam to relieve the irritability and agitation produced by cocaine binges, and opioid addicts find that diazepam and other benzodiazepines relieve some of the anxiety symptoms of opioid withdrawal when they are unable to obtain their preferred drug.

Pharmacological Interventions. If patients receiving long-term benzodiazepine treatment by prescription wish to stop their medication, the process may take months of gradual dose reduction. Withdrawal symptoms (Table 24–5) may occur during this outpatient detoxification, but in most cases the symptoms are mild. If anxiety symptoms return, a non-benzodiazepine such as buspirone may be prescribed, but this agent usually is less effective than benzodiazepines for treatment of anxiety in these patients. Some authorities recommend transferring the patient to a long t_1/2 benzodiazepine during detoxification; others recommend the anticonvulsants carbamazepine and phenobarbital. Controlled studies comparing different treatment regimens are lacking. Since patients who have been on low doses of benzodiazepines for years usually have no adverse effects, the physician and patient should decide jointly whether detoxification and possible transfer to a new anxiolytic are worth the effort.

The specific benzodiazepine receptor antagonist flumazenil has been found useful in the treatment of overdose and in reversing the effects of long-acting benzodiazepines used in anesthesia. It has been used experimentally in the treatment of persistent withdrawal symptoms after cessation of long-term benzodiazepine treatment.

Deliberate abusers of high doses of benzodiazepines usually require inpatient detoxification. Frequently, benzodiazepine abuse is part of a combined dependence involving alcohol, opioids, and cocaine. Detoxification can be a complex clinical pharmacological problem requiring knowledge of the pharmacokinetics of each drug. The patient's history may be unreliable not simply because of lying but also because the patient frequently does not know the true identity or dose of drugs purchased on the street. Medication for detoxification should not be prescribed by the "cookbook" approach but by careful titration and patient observation. The withdrawal syndrome from diazepam, e.g., may not become evident until the patient develops a seizure in the second week of hospitalization. One approach to complex detoxification is to focus on the CNS-depressant drug and temporarily hold the opioid component constant with a low dose of methadone. Opioid detoxification can begin later. A long-acting benzodiazepine such as diazepam or clorazepate (tranxene, others) or a long-acting barbiturate such as phenobarbital can be used to block the sedative withdrawal symptoms. The phenobarbital dose should be determined by a series of test doses and subsequent observations to determine the level of tolerance. Most complex detoxifications can be accomplished using this phenobarbital loading-dose strategy (Robinson et al., 1981).

After detoxification, the prevention of relapse requires a long-term outpatient rehabilitation program similar to the treatment of alcoholism. No specific medications have been found to be useful in the rehabilitation of sedative abusers; but, of course, specific psychiatric disorders such as depression or schizophrenia, if present, require appropriate medications.

Nicotine has both stimulant and depressant actions. The smoker feels alert, yet there is some muscle relaxation. Nicotine activates the nucleus accumbens reward system in the brain; increased extracellular DA has been found in this region after nicotine injections in rats. Nicotine affects other systems as well, including the release of endogenous opioids and glucocorticoids.

There is evidence for tolerance to the subjective effects of nicotine. Smokers typically report that the first cigarette of the day after a night of abstinence gives the "best" feeling. Smokers who return to cigarettes after a period of abstinence may experience nausea if they return immediately to their previous dose. Persons naive to the effects of nicotine will experience nausea at low nicotine blood levels, and smokers will experience nausea if nicotine levels are raised above their accustomed levels.

Negative reinforcement refers to the benefits obtained from the termination of an unpleasant state. In dependent smokers, the urge to smoke correlates with a low blood nicotine level, as though smoking were a means to achieve a certain nicotine level and thus avoid withdrawal symptoms. Some smokers even awaken during the night to have a cigarette, which ameliorates the effect of low nicotine blood levels that could disrupt sleep. If the nicotine level is maintained artificially by a slow intravenous infusion, the number of cigarettes smoked and in the number of puffs decrease. Thus, smokers may be smoking to achieve the reward of nicotine effects, to avoid the pain of nicotine withdrawal, or most likely a combination of the two. Nicotine withdrawal symptoms are listed in Table 24–6.

Depressed mood (dysthymic disorder, affective disorder) is associated with nicotine dependence, but it is not known whether depression predisposes one to begin smoking or depression develops during the course of nicotine dependence. Depression increases significantly during smoking withdrawal, and this is cited as one reason for relapse.

Pharmacological Interventions. The nicotine withdrawal syndrome can be alleviated by nicotine-replacement therapy, available with a prescription (e.g., NICOTROL inhaler and nasal spray) or without (e.g., NICORETTE gum and others; COMMIT lozenges and others; and NICODERM CQ transdermal patch and others). Figure 24–3 shows the blood nicotine concentrations achieved by different methods of nicotine delivery. Because nicotine gum and a nicotine patch do not achieve the peak levels seen with cigarettes, they do not produce the same magnitude of subjective effects as smoking. These methods do, however, suppress the symptoms of nicotine withdrawal. Thus, smokers should be able to transfer their dependence to the alternative delivery system and gradually reduce the daily nicotine dose with minimal symptoms. Although this results in more smokers achieving abstinence, most resume smoking over the ensuing weeks or months. Comparisons with placebo treatment show large benefits of nicotine replacement at 6 weeks, but the effect diminishes with time. The nicotine patch produces a steady blood level (Figure 24–3) and seems to have better patient compliance than that observed with nicotine gum. Verified abstinence rates at 12 months are reported to be in the range of 20%. The necessary goal of complete abstinence contributes to the poor success rate; when ex-smokers "slip" and begin smoking a little, they usually relapse quickly to their prior level of dependence.

The search for better medications to treat nicotine addiction has become an important goal of the pharmaceutical industry, and other types of medication have been tested in clinical trials. A sustained-release preparation of the antidepressant bupropion (zyban; Chapter 15), improves abstinence rates among smokers and remains a useful option. The cannabinoid CB₁ receptor inverse agonist rimonabant improves abstinence rates and reduces the weight gain seen frequently in ex-smokers. Unfortunately, the CB₁ inverse agonist mechanism led to a high frequency of depressive and neurologic symptoms, ending its development in the U.S. Varenicline, a partial agonist at the α₄β₂ subtype of the nicotinic acetylcholine receptor, improves abstinence rates but has also been linked to risk of developing suicidal ideation. Varenicline partially stimulates nicotinic receptors, thereby reducing craving and preventing most withdrawal symptoms. It has high receptor affinity, thus blocking access to nicotine, so if the treated smoker relapses, there is little reward and abstinence is more likely to be maintained. In one recent clinical trial, the abstinence rate for varenicline at 1 year was 36.7% versus 7.9% for placebo (Williams et al., 2007).

The subjective effects of opioid drugs are useful in the management of acute pain. This is particularly true in high-anxiety situations, such as the crushing chest pain of myocardial infarction, when the relaxing, anxiolytic effects complement the analgesia. Normal volunteers with no pain given opioids in the laboratory may report the effects as unpleasant because of side effects such as nausea, vomiting, and sedation. Patients with pain usually do not develop abuse or addiction problems. Of course, patients receiving opioids over time develop tolerance routinely, and if the medication is stopped abruptly, they will show the signs of an opioid-withdrawal syndrome, the evidence for physical dependence.

Opioids should never be withheld from patients with cancer out of fear of producing addiction. If chronic opioid medication is indicated, it is preferable to prescribe an orally active, slow-onset opioid with a long duration of action. These qualities reduce the likelihood of producing euphoria at onset and withdrawal symptoms as the medication wears off. In selected patients, methadone is an excellent choice for the management of chronic severe pain. Controlled-release oral morphine (ms contin, others) and controlled-release oxycodone (oxycontin, others) are other possibilities. Rapid-onset, short-duration opioids are excellent for acute short-term use, such as during the postoperative period. As tolerance and physical dependence develop, however, the patient may experience the early symptoms of withdrawal between doses, and during withdrawal, the threshold for pain decreases. Thus, for chronic administration, long-acting opioids are preferred. While methadone is long acting because of its metabolism to active metabolites, the long-acting version of oxycodone has been formulated to release slowly, thereby changing a short-acting opioid into a long-acting one. Unfortunately, this mechanism can be subverted by breaking the tablet and making the full dose of oxycodone immediately available. This has led to diversion of oxycodone to illicit traffic because high-dose oxycodone produces euphoria that is sought by opiate abusers. The diversion of prescription opioids such as oxycodone and hydrocodone to illegal markets has become an important source of opiate abuse in the U.S.

The risk for addiction is highest in patients complaining of pain with no clear physical explanation or in patients with evidence of a chronic, non-life-threatening disorder. Examples are chronic headaches, backaches, abdominal pain, or peripheral neuropathy. Even in these cases, an opioid may be considered as a brief emergency treatment, but long-term treatment with opioids should be used only after other alternatives have been exhausted. In the relatively rare patient who develops abuse, the transition from legitimate use to abuse often begins when the patient returns to his physician earlier than scheduled, asking for a new prescription, or visits emergency rooms of multiple hospitals, complaining of acute pain and asking for an opioid injection.

Previously, street heroin in the U.S. was highly diluted: Each 100-mg bag of powder had only ~4 mg heroin (range: 0-8 mg), and the rest was filler such as quinine. In the mid-1990s, street heroin reached 45-75% purity in many large cities, with some samples testing as high as 90%. This increase in purity has led to increased levels of physical dependence among heroin addicts. Users who interrupt regular dosing develop more severe withdrawal symptoms. Whereas heroin previously required intravenous injection, the more potent supplies can be smoked or administered nasally (snorted), making the initiation of heroin use accessible to people who would not insert a needle into their veins. There is no accurate way to count the number of heroin addicts, but based on extrapolation from overdose deaths, number of applicants for treatment, and number of heroin addicts arrested, the estimates range from 800,000 to 1 million in the U.S.; based on a stratified national sample of adults, ~1 in 4 individuals who report any use of heroin become addicted (Anthony et al., 1994). Recent law enforcement actions may presage the emergence of a domestic supply of heroin precursor (raw opium) harvested from Papaver somniferum grown in the Pacific Northwest of the U.S. (Baer, 2009).

Thus, the popularity of heroin may be due to its availability on the illicit market and its rapid onset. After intravenous injection, the effects begin in less than a minute. Heroin has high lipid solubility, crosses the blood-brain barrier quickly, and is deacetylated to the active metabolites 6-monoacetyl morphine and morphine. After the intense euphoria, which lasts from 45 seconds to several minutes, there is a period of sedation and tranquility ("on the nod") lasting up to an hour. The effects of heroin wear off in 3-5 hours, depending on the dose. Experienced users may inject two to four times per day. Thus, the heroin addict is constantly oscillating between being "high" and feeling the sickness of early withdrawal (Figure 24–4). This produces many problems in the homeostatic systems regulated at least in part by endogenous opioids. For example, the hypothalamic-pituitary-gonadal axis and the hypothalamic-pituitary-adrenal axis are abnormal in heroin addicts. Women on heroin have irregular menses, and men have a variety of sexual performance problems. Mood also is affected. Heroin addicts are relatively docile and compliant after taking heroin, but during withdrawal, they become irritable and aggressive.

Based on patient reports, tolerance develops early to the euphoria-producing effects of opioids. There also is tolerance to the respiratory depressant, analgesic, sedative, and emetic properties. Heroin users tend to increase their daily dose, depending on their financial resources and the availability of the drug. If a supply is available, the dose can be increased progressively 100 times. Even in highly tolerant individuals, the possibility of overdose remains if tolerance is exceeded. Overdose is likely to occur when potency of the street sample is unexpectedly high or when the heroin is mixed with a far more potent opioid, such as fentanyl (sublimaze, others).

Addiction to heroin or other short-acting opioids produces behavioral disruptions and usually becomes incompatible with a productive life. There is a significant risk for opioid abuse and dependence among physicians and other health care workers who have access to potent opioids, tempting them toward unsupervised experimentation. Physicians often begin by assuming that they can manage their own dose, and they may rationalize their behavior based on the beneficial effects of the drug. Over time, however, the typical unsupervised opioid user loses control, and behavioral changes are observed by family and co-workers. Apart from the behavioral changes and the risk of overdose, especially with very potent opioids, chronic use of opioids is relatively nontoxic.

Opioids frequently are used in combinations with other drugs. A common combination is heroin and cocaine ("speedball"). Users report an improved euphoria because of the combination, and there is evidence of an interaction, because cocaine reduces the signs of opiate withdrawal, and heroin may reduce the irritability seen in chronic cocaine users.

The mortality rate for street heroin users is very high. Early death comes from involvement in crime to support the habit; from the uncertain dose, purity, and even identity of what is purchased on the street; and from serious infections associated with nonsterile drugs and sharing of injection paraphernalia. Heroin users commonly acquire bacterial infections producing skin abscesses; endocarditis; pulmonary infections, especially tuberculosis; and viral infections producing hepatitis C and acquired immune deficiency syndrome (AIDS).

As with other addictions, the first stage of treatment addresses physical dependence and consists of detoxification (Kosten and O'Conner, 2003). The opioid-withdrawal syndrome (Table 24–7) is very unpleasant but not life-threatening. It begins within 6-12 hours after the last dose of a short-acting opioid and as long as 72-84 hours after a very long-acting opioid medication. Heroin addicts go through early stages of this syndrome frequently when heroin is scarce or expensive. Some therapeutic communities as a matter of policy elect not to treat withdrawal so that the addict can experience the suffering while being given group support. The duration and intensity of the syndrome are related to the clearance of the individual drug. Heroin withdrawal is brief (5-10 days) and intense. Methadone withdrawal is slower in onset and lasts longer. Protracted withdrawal also is likely to be longer with methadone. (See more detailed discussions of protracted withdrawal under "Long-Term Management" later in the chapter.)

Pharmacological Interventions. Opioid withdrawal signs and symptoms can be treated by three different approaches. The first and most commonly used approach depends on cross-tolerance and consists of transfer to a prescription opioid medication and then gradual dose reduction. The same principles of detoxification apply as for other types of physical dependence. It is convenient to change the patient from a short-acting opioid such as heroin to a long-acting one such as methadone. Detoxification and subsequent maintenance of opiate dependence with methadone is specifically limited to accredited opioid treatment programs (OTPs) and is regulated by Federal Opioid Treatment Standards. The initial dose of methadone is typically 20-30 mg. This is a test dose to determine the level needed to reduce observed withdrawal symptoms. The first day's total dose then can be calculated depending on the response and then reduced by 20% per day during the course of detoxification.

A second approach to detoxification involves the use of oral clonidine (catapres, others), a medication approved only for the treatment of hypertension. Clonidine is an α₂ adrenergic agonist that decreases adrenergic neurotransmission from the locus ceruleus. Many of the autonomic symptoms of opioid withdrawal such as nausea, vomiting, cramps, sweating, tachycardia, and hypertension result from the loss of opioid suppression of the locus ceruleus system during the abstinence syndrome. Clonidine, acting upon distinct receptors but by cellular mechanisms that mimic opioid effects, can alleviate many of the symptoms of opioid withdrawal, but not the generalized aches and opioid craving. When using clonidine to treat withdrawal, the dose must be titrated according to the stage and severity of withdrawal, beginning with 0.2 mg orally; postural hypotension is commonly a side effect. A similar drug, lofexidine (currently in clinical trials in the U.S.), has greater selectivity for α_2A adrenergic receptors and is associated with less of the hypotension that limits the usefulness of clonidine in this setting.

A third method of treating opioid withdrawal involves activation of the endogenous opioid system without medication. The techniques proposed include acupuncture and several methods of CNS activation using transcutaneous electrical stimulation. While attractive theoretically, this has not yet been found to be practical. Rapid antagonist-precipitated opioid detoxification under general anesthesia has received considerable publicity because it promises detoxification in several hours while the patient is unconscious and not experiencing withdrawal discomfort. A mixture of medications has been used, but morbidity and mortality as reported in the lay press are unacceptable, with no demonstrated advantage in long-term outcome (Collins et al., 2005).

Long-Term Management. If patients are simply discharged from the hospital after withdrawal from opioids, there is a high probability of a quick return to compulsive opioid use. Addiction is a chronic disorder that requires long-term treatment. Numerous factors influence relapse. One factor is that the withdrawal syndrome does not end in 5-7 days. There are subtle signs and symptoms often called the protracted withdrawal syndrome (Table 24–7) that persist for up to 6 months. Physiological measures tend to oscillate as though a new set point were being established; during this phase, outpatient drug-free treatment has a low probability of success, even when the patient has received intensive prior treatment while protected from relapse in a residential program.

The most successful treatment for heroin addiction consists of stabilization on methadone in accordance with state and federal regulations. Patients who relapse repeatedly during drug-free treatment can be transferred directly to methadone without requiring detoxification. The dose of methadone must be sufficient to prevent withdrawal symptoms for at least 24 hours. The introduction of buprenorphine, a partial agonist at μ opioid receptors (Chapter 18), represents a major change in the treatment of opiate addiction. This drug produces minimal withdrawal symptoms when discontinued and has a low potential for overdose, a long duration of action, and the ability to block heroin effects. Treatment can take place in a qualified physician's private office rather than in a special center, as required for methadone. When taken sublingually, buprenorphine (subutex) is active, but it also has the potential to be dissolved and injected (abused). A buprenorphine-naloxone combination (suboxone) is also available. When taken orally (sublingually), the naloxone moiety is not effective, but if the patient abuses the medication by injecting, the naloxone will block or diminish the subjective high that could be produced by buprenorphine alone.

Agonist or Partial-Agonist Maintenance. Patients receiving methadone or buprenorphine will not experience the ups and downs produced by heroin (Figure 24–4). Drug craving diminishes and may disappear. Neuroendocrine rhythms eventually are restored (Kreek et al., 2002). Because of cross-tolerance (from methadone to heroin), patients who inject street heroin report a reduced effect from usual heroin doses. This cross-tolerance effect is dose-related, so higher methadone maintenance doses result in less illicit opioid use, as determined by random urine testing. Buprenorphine, as a partial agonist, has a ceiling effect at ~16 mg of the sublingual tablet equaling no more than 60 mg methadone. If the patient has a higher level of physical dependence, a full agonist (methadone) must be used. Patients become tolerant to the sedating effects of methadone and can attend school or function in a job. Opioids also have a persistent, mild, stimulating effect noticeable after tolerance to the sedating effect, such that reaction time is quicker and vigilance is increased while on a stable dose of methadone.

Antagonist Treatment. Another pharmacological option is opioid antagonist treatment. Naltrexone (revia, others; Chapter 18) is an antagonist with a high affinity for the μ opioid receptor (MOR); it will competitively block the effects of heroin or other MOR agonists. Naltrexone has almost no agonist effects of its own and will not satisfy craving or relieve protracted withdrawal symptoms. For these reasons, naltrexone treatment does not appeal to the average heroin addict, but it can be used after detoxification for patients with high motivation to remain opioid-free. Physicians, nurses, and pharmacists who have frequent access to opioid drugs make excellent candidates for this treatment approach. A depot formulation of naltrexone that provides 30 days of medication after a single injection (vivitrol) has been approved for the treatment of alcoholism. This formulation eliminates the necessity of daily pill-taking and prevent relapse when the recently detoxified patient leaves a protected environment.

The reinforcing effects of cocaine and cocaine analogs correlate best with their effectiveness in blocking the transporter that recovers DA from the synapse. This leads to increased DA concentrations at critical brain sites (Ritz et al., 1987). However, cocaine also blocks both NE and 5-HT reuptake, and chronic use of cocaine leads to reductions in the neurotransmitter metabolites 3-methoxy-4 hydroxyphenethyleneglycol (MOPEG or MHPG) and 5-hydroxyindoleacetic acid (5-HIAA).

The general pharmacology and medicinal use of cocaine as a local anesthetic are discussed in Chapter 20. Cocaine produces a dose-dependent increase in heart rate and blood pressure accompanied by increased arousal, improved performance on tasks of vigilance and alertness, and a sense of self-confidence and well-being. Higher doses produce euphoria, which has a brief duration and often is followed by a desire for more drug. Repeated doses may lead to involuntary motor activity, stereotyped behavior, and paranoia. Irritability and increased risk of violence are found among heavy chronic users. The t_1/2 of cocaine in plasma is ~50 minutes, but inhalant (crack) users typically desire more cocaine after 10-30 minutes. Intranasal and intravenous uses also result in a high of shorter duration than would be predicted by plasma cocaine levels, suggesting that a declining plasma concentration is associated with termination of the high and resumption of cocaine seeking. This theory is supported by positron-emission tomographic imaging studies using ¹¹C-labeled cocaine, which show that the time course of subjective euphoria parallels the accumulation and decline of the drug in the corpus striatum (Volkow et al., 2003).

The major route for cocaine metabolism involves hydrolysis of each of its two ester groups. Benzoylecgonine, produced on loss of the methyl group, represents the major urinary metabolite and can be found in the urine for 2-5 days after a binge. As a result, the benzoylecgonine test is a valid method for detecting cocaine use; the metabolite remains detectable in the urine of heavy users for up to 10 days. Cocaine frequently is used in combination with other drugs, as discussed previously. Ethanol is frequently abused with cocaine, as it reduces the irritability induced by cocaine. Dual addiction to alcohol and cocaine is common. When cocaine and alcohol are taken concurrently, cocaine may be transesterified to cocaethylene, which is equipotent to cocaine in blocking DA reuptake (Hearn et al., 1991).

Addiction is the most common complication of cocaine abuse. Intranasal users can continue intermittent use for years. Others become compulsive users despite elaborate methods to maintain control. In general, stimulants tend to be abused much more irregularly than opioids, nicotine, and alcohol. Binge use is very common, and a binge may last hours to days, terminating only when supplies of the drug are exhausted.

Toxicity. Other risks of cocaine, beyond the potential for addiction, include cardiac arrhythmias, myocardial ischemia, myocarditis, aortic dissection, cerebral vasoconstriction, and seizures. Death from trauma also is associated with cocaine use. Cocaine may induce premature labor and abruptio placentae (Chasnoff et al., 1989). The developmental abnormalities reported in infants born to cocaine users may be the result of cocaine effects as well as multiple other factors (the infant's prematurity, multiple-drug and alcohol exposure, and inadequate pre- and postnatal care).

Cocaine has been reported to produce a prolonged and intense orgasm if taken prior to intercourse, and users often indulge in compulsive and promiscuous sexual activity. However, chronic cocaine use reduces sexual drive. Chronic use is also associated with psychiatric disorders, including anxiety, depression, and psychosis, and while some of these disorders undoubtedly existed prior to addiction, many are likely attributable to the drug (McLellan et al., 1979).

Tolerance, Dependence, and Withdrawal. Sensitization, a consistent finding in animal studies of cocaine and other stimulants, is produced by intermittent use and typically is manifested as behavioral hyperactivity. In human cocaine users, the euphoric effect typically is not subject to sensitization. On the contrary, most experienced users become desensitized and, over time, require more cocaine to obtain euphoria, i.e., tolerance develops. In the laboratory, tolerance is rapidly induced by repeated administration of the same dose in one session (tachyphylaxis). Sensitization may involve conditioning (Figure 24–2). Cocaine users often report a strong response on seeing cocaine before it is administered, consisting of physiological arousal and increased drug craving with concomitant activation of brain limbic structures (Childress et al., 1999). Sensitization in humans has been linked to paranoid, psychotic manifestations of cocaine use (Satel et al., 1991). Since cocaine typically is used intermittently, even heavy users go through frequent periods of withdrawal or "crash." The symptoms of withdrawal seen in users admitted to hospitals are listed in Table 24–8. Careful studies of cocaine users during withdrawal show gradual diminution of these symptoms over 1-3 weeks (Weddington et al., 1990). Residual depression, often seen after cocaine withdrawal, should be treated with antidepressant agents if it persists (Chapter 15).

Pharmacological Interventions. Since cocaine withdrawal is generally mild, treatment of withdrawal symptoms usually is not required. The major problem in treatment is not detoxification but helping the patient to resist the urge to resume compulsive cocaine use. Rehabilitation programs involving individual and group psychotherapy based on the principles of Alcoholics Anonymous, and behavioral treatments based on reinforcing cocaine-free urine tests, result in significant improvement in the majority of cocaine users (Alterman et al., 1994; Higgins et al., 1994). Nonetheless, there is great interest in finding a medication that can aid in the rehabilitation of cocaine addicts.

Numerous medications have been tried in placebo-controlled clinical trials with cocaine addicts, but no medication has yet consistently improved upon the results of behavior therapy alone. Animal models suggest that enhancing GABAergic inhibition can reduce reinstatement of cocaine self-administration, and a controlled clinical trial of topiramate (topamax) showed a significant reduction in cocaine use. Topiramate also reduced the relapse rate in alcoholics, prompting current studies in patients dually dependent on cocaine and alcohol. Baclofen (lioresal, others), a GABA_B agonist, was found in a single-site trial to reduce relapse in cocaine addicts, but was not effective in a multisite trial. A different approach was taken using modafinil (provigil), a medication that increases alertness and is approved for the treatment of narcolepsy. This medication was found to reduce the euphoria produced by cocaine and to relieve cocaine withdrawal symptoms. Modafinil is currently being tested in clinical trials of cocaine, methamphetamine, alcohol, and other substance abuse disorders. A novel approach to cocaine addiction employs a vaccine that produces cocaine-binding antibodies. Preliminary studies showed some success in reducing cocaine use. Larger trials are in progress. For now, behavioral therapy remains the treatment of choice, with medication indicated for specific co-existing disorders such as depression.

Methamphetamine can be synthesized from ephedrine in small, clandestine laboratories. Methamphetamine addiction has become a major public health problem, particularly in the western half of the U.S. Behavioral and medical treatments for methamphetamine addiction are similar to those used for cocaine. Until recently, ephedrine was a widely available nonprescription stimulant (a "wake-up" pill). Oral stimulants, such as those prescribed in a weight-reduction program, have short-term efficacy because of tolerance development. Only a small proportion of patients introduced to these appetite suppressants subsequently exhibits dose escalation or drug-seeking from various physicians; such patients may meet diagnostic criteria for abuse or addiction.

Cannabinoid receptors CB₁ (mainly CNS) and CB₂ (peripheral) have been identified and cloned. An arachidonic acid derivative, anandamide, has been proposed as an endogenous ligand for CB receptors. While the physiological function of these receptors and their endogenous ligands are incompletely understood, they are likely to have important functions because they are dispersed widely with high densities in the cerebral cortex, hippocampus, striatum, and cerebellum (Iversen, 2003). Specific CB₁ antagonists have been developed and tested in controlled clinical trials. One of these, rimonabant, was found to reduce relapse in cigarette smokers and to produce weight loss in obese patients; however, its development has been abandoned because of depressive and neurologic side effects.

The pharmacological effects of Δ-9-THC vary with the dose, route of administration, experience of the user, vulnerability to psychoactive effects, and setting of use. Intoxication with marijuana produces changes in mood, perception, and motivation, but the effect most frequently sought is the "high" and "mellowing out." This effect is described as different from the high produced by a stimulant or opiate. Effects vary with dose, but typically last ~2 hours. During the high, cognitive functions, perception, reaction time, learning, and memory are impaired. Coordination and tracking behavior may be impaired for several hours beyond the perception of the high, with obvious implications for the operation of a motor vehicle and performance in the workplace or at school.

Marijuana also produces complex behavioral changes such as giddiness and increased hunger. There are unsubstantiated claims of increased pleasure from sex and increased insight during a marijuana high. Unpleasant reactions such as panic or hallucinations and even acute psychosis may occur; several surveys indicate that 50-60% of marijuana users have reported at least one anxiety experience. These reactions are seen commonly with higher doses and with oral ingestion rather than smoked marijuana, because smoking permits the titration of dose according to the effects. While there is no convincing evidence that marijuana can produce a lasting schizophrenia-like syndrome, association studies suggest a correlation of early marijuana use with an increased risk of later developing schizophrenia. Numerous clinical reports suggest that marijuana use may precipitate a recurrence of psychosis in people with a history of schizophrenia.

One of the most controversial of the reputed effects of marijuana is the production of an "amotivational syndrome." This syndrome is not an official diagnosis, but it has been used to describe young people who drop out of social activities and show little interest in school, work, or other goal-directed activity. When heavy marijuana use accompanies these symptoms, the drug often is cited as the cause, even though there are no data that demonstrate a causal relationship between marijuana smoking and these behavioral characteristics. There is no evidence that marijuana damages brain cells or produces any permanent functional changes, although there are animal data indicating impairment of maze learning that persists for weeks after the last dose. These findings are consistent with clinical reports of gradual improvement in mental state after cessation of chronic high-dose marijuana use.

Tolerance, Dependence, and Withdrawal. Tolerance to most of the effects of marijuana can develop rapidly after only a few doses, but also disappears rapidly (Martin et al., 2004). Tolerance to large doses persists in experimental animals for long periods after cessation of drug use. Withdrawal symptoms and signs typically are not seen in clinical populations. In fact, few patients ever seek treatment for marijuana addiction. Human subjects develop a withdrawal syndrome when they receive regular oral doses of the agent (Table 24–9). This syndrome, however, is only seen clinically in persons who use marijuana on a daily basis and then suddenly stop.

Pharmacological Interventions. Marijuana abuse and addiction have no specific treatments. Heavy users may suffer from accompanying depression and thus may respond to antidepressant medication, but this should be decided on an individual basis considering the severity of the affective symptoms after the marijuana effects have dissipated. The residual drug effects may continue for several weeks. The CB₁ receptor antagonist rimonabant has been reported to block the acute effects of smoked marijuana, but development of this drug has been halted due to safety concerns (discussed under "Pharmacological Interventions" in the nicotine section earlier in the chapter).

LSD. LSD is the most potent hallucinogenic drug and produces significant psychedelic effects with a total dose of as little as 25-50 μg. This drug is > 3000 times more potent than mescaline. LSD is sold on the illicit market in a variety of forms. A popular contemporary system involves postage stamp-sized papers impregnated with varying doses of LSD (50-300 μg or more). While most street samples sold as LSD actually contain LSD, samples of mushrooms and other botanicals sold as sources of psilocybin and other psychedelics have a low probability of containing the advertised hallucinogen.

The effects of hallucinogenic drugs are variable, even in the same individual on different occasions. LSD is absorbed rapidly after oral administration, with effects beginning at 40-60 minutes, peaking at 2-4 hours, and gradually returning to baseline over 6-8 hours. At a dose of 100 μg, LSD produces perceptual distortions and sometimes hallucinations; mood changes, including elation, paranoia, or depression; intense arousal; and sometimes a feeling of panic. Signs of LSD ingestion include pupillary dilation, increased blood pressure and pulse, flushing, salivation, lacrimation, and hyperreflexia. Visual effects are prominent. Colors seem more intense, and shapes may appear altered. The subject may focus attention on unusual items such as the pattern of hairs on the back of the hand.

A "bad trip" usually consists of severe anxiety, although at times it is marked by intense depression and suicidal thoughts. Visual disturbances usually are prominent. The bad trip from LSD may be difficult to distinguish from reactions to anticholinergic drugs and phencyclidine. There are no documented toxic fatalities from LSD use, but fatal accidents and suicides have occurred during or shortly after intoxication. Prolonged psychotic reactions lasting 2 days or more may occur after the ingestion of a hallucinogen. Schizophrenic episodes may be precipitated in susceptible individuals, and there is some evidence that chronic use of these drugs is associated with the development of persistent psychotic disorders (McLellan et al., 1979).

Claims about the potential of psychedelic drugs for enhancing psychotherapy and for treating addictions and other mental disorders have not been supported by controlled treatment outcome studies. Consequently, there is no current indication for these drugs as medications.

Tolerance, Physical Dependence, and Withdrawal. Frequent, repeated use of psychedelic drugs is unusual, and thus tolerance is not commonly seen. Tolerance does develop to the behavioral effects of LSD after three or four daily doses, but no withdrawal syndrome has been observed. Cross-tolerance among LSD, mescaline, and psilocybin has been demonstrated in animal models.

Pharmacological Intervention. Because of the unpredictability of psychedelic drug effects, any use carries some risk. Dependence and addiction do not occur, but users may require medical attention because of "bad trips." Severe agitation may respond to diazepam (20 mg orally). "Talking down" by reassurance also is effective and is the management of first choice. Antipsychotic medications (Chapter 16) may intensify the experience and thus are not indicated.

A particularly troubling after-effect of the use of LSD and similar drugs is the occasional occurrence of episodic visual disturbances. These originally were called "flashbacks" and resembled the experiences of prior LSD trips. Flashbacks belong to an official diagnostic category called the hallucinogen persisting perception disorder (HPPD; American Psychiatric Association, 1994). The symptoms include false fleeting perceptions in the peripheral fields, flashes of color, geometric pseudohallucinations, and positive afterimages (Abraham and Aldridge, 1993). The visual disorder appears stable in half the cases and represents an apparently permanent alteration of the visual system. Precipitants include stress, fatigue, emergence into a dark environment, marijuana, antipsychotic agents, and anxiety states.

MDMA ("Ecstasy") and MDA. MDMA and MDA are phenylethylamines that have stimulant as well as psychedelic effects. MDMA became popular during the 1980s on college campuses because of testimonials that it enhances insight and self-knowledge. It was recommended by some psychotherapists as an aid to the process of therapy, although no controlled data exist to support this contention. Acute effects are dose-dependent and include feelings of energy, altered sense of time, and pleasant sensory experiences with enhanced perception. Negative effects include tachycardia, dry mouth, jaw clenching, and muscle aches. At higher doses, visual hallucinations, agitation, hyperthermia, and panic attacks have been reported. A typical oral dose is one or two 100-mg tablets and lasts 3-6 hours, although dosage and potency of street samples are variable (~100 mg per tablet).

MDA and MDMA produce degeneration of serotonergic nerve cells and axons in rats. While nerve degeneration has not been demonstrated in humans, the cerebrospinal fluid of chronic MDMA users has low levels of serotonin metabolites (Ricaurte et al., 2000). Thus, there is possible neurotoxicity with no evidence that the claimed benefits of MDMA actually occur.

Phencyclidine (PCP). PCP deserves special mention because of its widespread availability and because its pharmacological effects are different from those of the psychedelics such as LSD. PCP was developed originally as an anesthetic in the 1950s and later was abandoned because of a high frequency of postoperative delirium with hallucinations. It was classified as a dissociative anesthetic because, in the anesthetized state, the patient remains conscious with staring gaze, flat facies, and rigid muscles. PCP became a drug of abuse in the 1970s, first in an oral form and then in a smoked version enabling a better regulation of the dose. The effects of PCP have been observed in normal volunteers under controlled conditions. As little as 50 μg/kg produces emotional withdrawal, concrete thinking, and bizarre responses to projective testing. Catatonic posturing also is produced and resembles that of schizophrenia. Abusers taking higher doses may appear to be reacting to hallucinations and may exhibit hostile or assaultive behavior. Anesthetic effects increase with dosage; stupor or coma may occur with muscular rigidity, rhabdomyolysis, and hyperthermia. Intoxicated patients in the emergency room may progress from aggressive behavior to coma, with elevated blood pressure and enlarged nonreactive pupils.

PCP binds with high affinity to sites located in the cortex and limbic structures, resulting in blocking of N-methyl-D-aspartate (NMDA)–type glutamate receptors (Chapter 14). LSD and other psychedelics do not bind to NMDA receptors. There is evidence that NMDA receptors are involved in ischemic neuronal death caused by high levels of excitatory amino acids; as a result, there is interest in PCP analogs that block NMDA receptors but with fewer psychoactive effects. Both PCP and ketamine ("Special K"), another "club drug," produce similar effects by altering the distribution of the neurotransmitter glutamate.

Tolerance, Dependence, and Withdrawal. PCP is reinforcing in monkeys, as evidenced by self-administration patterns that produce continuous intoxication. Humans tend to use PCP intermittently, but a small fraction may use it daily. Tolerance to the behavioral effects of PCP develops in animals, but this has not been studied systematically in humans. Signs of a PCP withdrawal syndrome have been observed in monkeys after interruption of daily access to the drug, and include somnolence, tremor, seizures, diarrhea, piloerection, bruxism, and vocalizations.

Pharmacological Intervention. Overdose must be treated by life support because there is no antagonist of PCP effects and no proven way to enhance excretion, although acidification of the urine has been proposed. PCP coma may last 7-10 days. The agitated or psychotic state produced by PCP can be treated with diazepam. Prolonged psychotic behavior requires antipsychotic medication. Because of the anticholinergic activity of PCP, antipsychotic agents with significant anticholinergic effects such as chlorpromazine should be avoided.

Amyl nitrite produces dilation of smooth muscle, has been used in the past for the treatment of angina, and continues to be available by prescription as a component of cyanide antidote kits and for certain diagnostic procedures. It is a yellow, volatile, flammable liquid with a fruity odor. In recent years, amyl nitrite and butyl nitrite have been used to relax smooth muscle and enhance orgasm, particularly by male homosexuals. These agents are commercially available as room deodorizers and can produce a feeling of "rush," flushing, and dizziness. Adverse effects include palpitations, postural hypotension, and headache progressing to loss of consciousness.

Anesthetic gases such as nitrous oxide and halothane sometimes are used as intoxicants by medical personnel. Nitrous oxide also is abused by food-service employees because it is supplied for use as a propellant in disposable aluminum mini tanks for whipping cream canisters. Nitrous oxide produces euphoria and analgesia and then loss of consciousness. Compulsive use and chronic toxicity are reported rarely, but there are obvious risks of overdose (coma) and chronic use (neuropathy) associated with the abuse of this anesthetic.