Nicholas E Goeders. Encyclopedia of Drugs, Alcohol, and Addictive Behavior. Editor: Pamela Korsmeyer & Henry R Kranzler. 3rd Edition. Volume 2. Macmillan Reference USA, 2009.
The various types of drugs that are used and abused by humans for nonmedical purposes can be divided into several major categories, based upon their general pharmacological and subjective effects. These categories include: ethanol, nicotine and tobacco, central nervous system depressants, central nervous system stimulants, cannabinoids, opioids, psychedelics, inhalants, and arylcyclohexylamines. Although the mechanisms of action may vary among the drugs within a single category, the general effects of the drugs in each category are similar. The drugs in each category are described below in terms of their pharmacology, abuse, dependence, and withdrawal, as well as their toxicity. The legal and readily available drugs (i.e., alcohol and tobacco) are described first, because the use and abuse of these drugs is more widespread than that of all of the other categories of abused drugs combined. The health problems associated with the chronic use of alcohol and tobacco are, therefore, a far-reaching problem in modern society, not only because of the vast numbers of people who suffer and die each year due to the toxic effects of these substances, but also because of the financial drain they impose due to absenteeism from work and increased health-care costs.
Prescription drugs are covered next, and then the illegal drugs are discussed. Although the illicit use of heroin, cocaine and other drugs remains a major social, legal, financial, and health problem in the United States, the percentage of the population physically dependent on these drugs is relatively low when compared to legal drugs that are abused. Finally, it is important to take into consideration the fact that individuals often do not restrict their drug use to drugs within a single category. Alcoholics typically smoke cigarettes, and they often use benzodiazepines as well. Many heroin users also smoke, and they may consume alcohol and other sedatives, cannabis, or stimulants. Multiple drug use is, therefore, a relatively common occurrence among individuals who use drugs for their subjective, nonmedical effects.
Alcohol
Although alcohol has been used throughout recorded history, it is generally accepted that the therapeutic value of ethanol is extremely limited and that chronic alcoholism is a major social and medical problem. Approximately two-thirds of all adults in the United States use alcohol occasionally. Hundreds of thousands of individuals suffer and die each year from complications associated with chronic alcoholism, and tens of thousands of innocent individuals are injured or killed each year in alcohol-related traffic accidents. Thus, alcoholism is a far-reaching problem, affecting the lives of individuals who consume ethanol as well as those who do not.
Although alcohol is considered by many people to be a stimulant drug because it typically releases an individual’s latent behavioral inhibitions, alcohol actually produces a powerful primary and continuous depression of the central nervous system, similar to that seen with general anesthetics. In general, the effects of alcohol on the central nervous system are proportional to the blood (and brain) concentrations of the drug. Initially, memory and the ability to concentrate decrease and mood swings become more evident. As the level of intoxication increases, so does the impairment of nervous function, until a condition of general anesthesia is reached. However, there is little margin of safety between an anesthetic dose of ethanol and severe respiratory depression.
In chronic alcoholism, brain damage, memory loss, sleep disturbances, psychoses, and increased seizure susceptibility often occur. Chronic alcoholism is also one of the major causes of cardiomyopathy (impaired function of the heart muscle) in the United States due to irreversible ethanol-induced damage to that tissue. Ethanol also stimulates the secretion of gastric acid in the stomach, and it can produce ulcers of the stomach and intestine. One of the primary metabolic products of ethanol is acetaldehyde, which is toxic. In chronic alcoholism, acetaldehyde can accumulate in the liver, resulting in hepatitis and cirrhosis of the liver. Finally, the long-term use of alcohol can result in a state of physical dependence.
With relatively low levels of dependence, withdrawal from alcohol may be associated with problems such as sleep disturbances, anxiety, weakness, and mild tremors. In more severe dependence, the alcohol withdrawal syndrome can include more pronounced tremors, seizures, and delirium, as well as a number of other physiological and psychological effects. In some cases, this withdrawal can be life threatening. Because alcohol has cross-tolerance with other central nervous system depressants, benzodiazepines or barbiturates can be successfully used to decrease the severity of the alcohol withdrawal syndrome. Longer-acting benzodiazepines and related drugs can be used as an ethanol substitute, and the dose of the benzodiazepine can then be gradually reduced over time to attenuate or prevent the occurrence of convulsions and other potentially life-threatening toxic reactions generally associated with alcohol withdrawal.
As outlined above, the chronic use of ethanol can result in a wide range of toxic effects on a variety of organ systems. However, the mechanisms through which ethanol produces its varied effects are not clearly understood. The anesthetic or central nervous system depressant effects may result, in part, from general changes in the function of ion channels that occur when ethanol dissolves in lipid membranes. Other research suggests that alcohol may interact with specific binding sites associated with the inhibitory neurotransmitter gamma-aminobutyric acid (GABA), in a manner somewhat analogous to other central nervous system depressants (e.g., benzodia-zepines or barbiturates). However, because an ethanol receptor site has not yet been conclusively identified, specific receptor agonists and antagonists are not yet available for the treatment of ethanol intoxication or withdrawal, or for the maintenance of abstinence.
Disulfiram is sometimes used in the treatment of chronic alcoholism, although the drug does not cure alcoholism. Rather, disulfiram interacts with ethanol to alter the intermediate metabolism of ethanol, resulting in a five- to tenfold increase in plasma acetaldehyde concentrations. This acetaldehyde syndrome results in vasodilatation, headache, breathing difficulties, nausea, vomiting, sweating, faintness, weakness, and vertigo. Thus, it helps persuade alcoholics to remain abstinent, because they realize that they cannot drink ethanol for up to two weeks after taking disulfiram. More recently, naltrexone was approved as the first agent for the pathological reward and reinforcement effects of alcohol. Naltrexone is an opioid receptor antagonist that appears to reduce these responses in alcoholics via the endogenous opioid system. Oral naltrexone has demonstrated efficacy and safety in the treatment of alcohol dependence in controlled clinical trials. A long-acting injectable formulation of naltrexone has also been approved for use in the United States. Finally, acamprosate, a medication first evaluated in Europe, has also been approved for use in the United States. This medication acts on both GABA and glutamate (an excitatory neurotransmitter) to maintain abstinence in alcohol-dependent individuals.
Tobacco
Tobacco was first introduced to Europe by the crews that accompanied Christopher Columbus to the “New World.” By the middle of the nineteenth century, tobacco use had become widespread. Although tobacco use has declined dramatically in recent years, 18 to 24 percent of the adults in the United States are still regular tobacco smokers. This relatively high use of tobacco exists despite the large body of scientific evidence linking cigarette smoking to numerous life-threatening health disorders, including lung cancer and heart disease. The constituents of tobacco smoke that are most likely to contribute to these health problems include carbon monoxide, nicotine, and “tar.”
Nicotine is the primary component of tobacco smoke that promotes smoking. Nicotine facilitates memory, reduces aggression, and decreases weight gain. Each of these effects could, by itself, provide a rationale for continued tobacco use, as most individuals find increased alertness and memory, decreased irritability, and decreased weight gain to be positive effects. However, these effects may actually be secondary to the primary reinforcing effects of nicotine itself. In laboratory settings, smokers report that the intravenous injection of nicotine produces a pleasant feeling on its own. However, nicotine causes unpleasant effects in nonsmokers, often resulting in dizziness, nausea, and vomiting. Tolerance to these unpleasant effects develops rapidly, however. Although nicotine obviously binds to nicotinic receptors associated with the neurotransmitter acetylcholine, there is evidence that the reinforcing or rewarding properties of nicotine may result from an activation of ascending limbic neurons that release the neurotransmitter dopamine (i.e., in the mesocorticolimbic dopaminergic system, which has been implicated in the reinforcing properties of a variety of drugs, including stimulants and opiates).
As stated above, tobacco smoking has been associated with a wide variety of serious health effects, including cancer and heart disease. However, the chances of developing these health problems decrease once smoking is terminated. Although some of the smoking-induced damage is irreversible, the incidence rates for cancer and heart disease gradually become more similar to that of nonsmokers the longer that the smoker refrains from smoking. However, those who quit smoking experience a withdrawal syndrome that varies in intensity from individual to individual and often leads to a relapse. This syndrome consists of a craving for tobacco, irritability, weight gain, difficulty concentrating, drowsiness, and sleep disturbances. The introduction of nicotine replacement therapy (in the form of chewing gum, transdermal patches, nasal spray, inhalers, tablets, or lozenges) has significantly helped to sustain abstinence from smoking in a number of individuals by delivering nicotine in a less toxic way. The orally administered medications varenicline and bupropion, which are not nicotine replacement therapies, are also regarded as first-line treatments, either used alone or as an adjunct to nicotine replacement therapy. Second-line treatments include clonidine and nortriptyline. Other treatment strategies that have been examined include monoamine oxidase inhibitors (MAOIs) and selective serotonin-reuptake inhibitors (SSRIs), but efficacy has yet to be proven definitively for these medications. A novel approach to treatment using the cannabi-noid-1 receptor antagonist rimonabant is also under investigation.
Central Nervous System Depressants
Central nervous system depressants include barbiturates, benzodiazepines, and related drugs. Receptor binding sites for benzodiazepines and barbiturates are part of a macromolecular complex associated with chloride ion channels and the inhibitory neurotransmitter GABA. The interaction of these drugs with their distinct binding sites results in a facilitation of GABAergic neurotrans-mission, producing an inhibitory effect on neuronal impulse flow in the central nervous system. The shorter-acting barbiturates such as pentobarbital (“yellow jackets”) or secobarbital (“red devils”) are usually preferred to the longer-acting drugs such as phenobarbital. Nonbarbiturates such as meprobamate, glutethimide, methyprylon, and methaqualone (Quaalude) are also abused, though these medications are not as widely available as they were before the introduction of the benzodiaze-pines. Some of the shorter-acting benzodiazepines are also abused, providing evidence that the quicker the onset of action for a particular central nervous system depressant, the better the “high.” There is no general rule that can be used to predict the pattern of use of a central nervous system depressant for a given individual. There is often a fine line between the appropriate therapy for insomnia or anxiety and drug dependence. Some individuals exhibit cyclic patterns of abuse, with gross intoxication for a few days interspersed with periods of abstinence. Other barbiturate or benzodiazepine users maintain a chronic low level of intoxication without any observable signs of impairment. Such individuals have developed a tolerance to many of the side effects of these drugs. When higher doses are used, however, the intoxication may resemble alcohol intoxication, with slurred speech, difficulty thinking, memory impairment, sluggish behavior, and emotional instability. Withdrawal from chronic barbiturate or benzodiazepine use can also be manifested to varying degrees. In the mildest form, the individual may only experience mild anxiety or insomnia. With greater degrees of physical dependence, tremors and weakness may also occur. In severe withdrawal, delirium and tonic-clonic seizures may also be present. This severe withdrawal syndrome can be life threatening. The degree of severity of the withdrawal syndrome appears to be related to the pharmacokinetics of the drug used. For example, shorter-acting benzodiaze-pines and barbiturates produce much more severe cases of withdrawal than the longer-acting drugs. Therefore, in the case of severe withdrawal symptoms associated with the chronic use of a short-acting drug, a longer-acting drug should be substituted. The dose of this longer-acting drug can thus be gradually decreased so that the individual experiences a much milder and less threatening withdrawal.
Central Nervous System Stimulants
Central nervous system stimulants include caffeine, cocaine, and amphetamine. Perhaps 80 percent of the world’s population ingests caffeine in the form of tea, coffee, cola-flavored drinks, or chocolate. In the central nervous system, caffeine decreases drowsiness and fatigue and produces a more rapid and clearer flow of thought. With higher doses, however, nervousness, restlessness, insomnia, and tremors may result. Cardiac and gastrointestinal disturbances may also be seen. Tolerance typically develops to the anxiety and dysphoria (negative mood) experienced by some individuals. However, some degree of physical dependence has been associated with the chronic consumption of caffeine. The most characteristic symptom of caffeine withdrawal is a headache, although fatigue, lethargy, and some degree of anxiety are also common. In general, the long-term consequences of chronic caffeine consumption are relatively minor. On the other hand, the problems associated with chronic cocaine and amphetamine use and withdrawal are much more serious.
More than 20 million people have used cocaine in the United States alone. Following the introduction of cocaine in the free alkaloid base (“freebase” or “crack”) form, there was a significant increase in cocaine-related medical, economic, social, and legal problems. In the freebase form, cocaine can be smoked, resulting in blood levels and brain concentrations of the drug that compare to those observed when the drug is injected intravenously. In normal subjects in a laboratory setting, the administration of cocaine or amphetamine produces an elevation of mood, an increase in energy and alertness, and a decrease in fatigue and boredom. In some individuals, however, anxiety, irritability, and insomnia may be observed. In non-laboratory settings, heavy users of cocaine often take the drug in bouts or binges, only stopping when their supply runs out or they collapse from exhaustion. Immediately following the intravenous administration or inhalation of cocaine, the individual experiences an intense pleasurable sensation known as a “rush” or “flash,” that is followed by a sense of euphoria. Cocaine rapidly penetrates into the brain to produce these effects, but it is then rapidly redistributed to other tissues. In many cases, the intense pleasure followed by the rapid decline in the cocaine-induced elevation of mood is sufficient for the individual to begin immediately to seek out, procure, and use more of the drug to prolong these pleasurable effects. With the intranasal administration of cocaine, the pleasure is less intense and the decline in brain concentrations is much slower, so that the craving for more of the drug is less pronounced.
Cocaine and amphetamine appear to produce their reinforcing or pleasurable effects through interactions with the neurotransmitter dopamine, especially in the limbic and cortical regions of the brain (i.e., within the mesocorticolimbic dopaminergic system). Both cocaine and amphetamine block the reabsorption of dopamine into the neurons where it was released, thereby prolonging the action of dopamine in the synapse (the space between nerve cells). Amphetamine can also cause the direct release of dopamine from nerve cells, and it can inhibit the metabolism of the neurotransmitter. It is important to note, however, that every drug that augments the action of dopamine does not produce pleasurable or rewarding subjective effects. Toxicity associated with cocaine or amphetamine use can be quite severe and is often unrelated to the duration of use or to any preexisting medical conditions in the individual. This potential for serious toxic side effects is amplified by the fact that tolerance usually develops to the subjective feelings of the cocaine-induced rush and euphoria, but not to some of the other central nervous system effects of the drug, especially seizure susceptibility.
Some of the more minor toxic reactions include dizziness, confusion, nausea, headache, sweating, and mild tremors. These symptoms are experienced by virtually all cocaine and amphetamine users to some degree as a result of the stimulation of the sympathetic nervous system. However, more serious reactions are also frequently observed, including irregular heartbeats, convulsions and seizures, heart attack, liver failure, kidney failure, heart failure, respiratory depression, stroke, coma, and death. The effects on the heart and vascular system can sometimes be treated with alpha- and beta-nor-adrenergic receptor antagonists or calcium channel blockers, although even prompt medical attention is not always successful. The convulsions can sometimes be controlled with diazepam, and ventilation may be required for the respiratory depression.
In addition to the effects described above for cocaine, amphetamine has been reported to produce direct and irreversible neuronal damage to dopaminergic and nondopaminergic neurons. A similar effect for cocaine has not yet been identified. Psychiatric abnormalities resulting from chronic central nervous system stimulant abuse can include anxiety, depression, hallucinations, and, in some cases, a paranoid psychosis that is virtually indistinguishable from a paranoid schizophrenic psychosis.
A withdrawal syndrome is also observed following the abrupt cessation of chronic cocaine or amphetamine use. This syndrome begins with exhaustion during the “crash” phase and is followed by prolonged periods of anxiety, depression, anhedonia (reduced capacity to experience pleasure), hyperphagia (voracious eating), and an intense craving for the drug that may persist for several weeks, depending on the individual. The administration of dopaminergic agonists or tricyclic antidepressants may have some utility in decreasing the severity of withdrawal symptoms, which could reduce the risk of relapse. More recently, however, a number of novel targets for cocaine pharmacotherapy have emerged. Disulfiram, a medication with dopaminergic effects, has been reported to reduce cocaine use in a number of clinical trials, as have GABA medications, such as tiagabine and topiramate. A beta-adrenergic blocker, propranolol, may also be effective, especially among cocaine-addicted individuals with high withdrawal severity. Treatment with mod-afinil, a stimulant medication, has also been reported to reduce cocaine use. Finally, a cocaine vaccine that slows entry of cocaine into the brain by binding cocaine in the bloodstream may eventually hold promise. However, there is no FDA-approved medication for the treatment of dependence on cocaine, amphetamine or related drugs.
Cannabinoids
Marijuana, or cannabis (commonly referred to as “grass,” “weed,” or “pot”), is still the most commonly used illicit drug in the United States, with about 55 percent of young adults reporting some experience with the drug during their lifetimes. The active ingredient in marijuana is δ9-tetrahydro-cannabinol (δ9-THC), which exerts its most prominent effects on the central nervous system and the cardiovascular system. A marijuana cigarette containing approximately 2 percent δ9-THC produces an increase in feelings of well-being or euphoria and relaxation. Short-term memory is impaired, however, as is the ability to carry out goal-directed behavior, such as driving or operating machinery, effects that often persist for much longer than the subjective effects. With higher doses, paranoia, hallucinations, and anxiety or panic may be manifested. Chronic marijuana users sometimes exhibit what is called the “amotivational syndrome,” which consists of apathy, impairment of judgment, and a loss of interest in personal appearance and the pursuit of conventional goals. However, it is not clear whether this syndrome results from the use of marijuana alone or from other factors. δ9-THC also produces a dose-related increase in heart rate, although this is seldom severe. Tolerance develops to the effects of marijuana, and in some countries, regular users of hashish (a concentrated resin containing high levels of δ9-THC) consume quantities of the drug that would be toxic to most marijuana users in the United States. The withdrawal associated with the cessation of marijuana smoking is relatively mild and consists of irritability, restlessness, nervousness, insomnia, weight loss, chills, and increased body temperature.
The endogenous cannabinoid system—called the endocannabinoid system—was discovered in the 1980s, and the compounds that modify this system are currently being reconsidered for their therapeutic potential. Thus, the term cannabinoid includes the numerous synthetic cannabinoids obtained by modifications of plant-derived cannabinoids or from the compounds that behave as endogenous ligands for the different cannabinoid receptor types. The term also refers to some prototypes of selective antagonists for these receptors. The explanation for this exponential growth in cannabinoid pharmacology is the discovery and characterization of the endocannabinoid signaling system (receptors, ligands, and inactivation system), which plays a modulatory role mainly in the brain, but also in the periphery. The endocannabinoid system is currently under investigation, not only for its role in marijuana dependence, but also for its ability to mediate dependence on other drugs, such as cocaine.
Opioids
According to the 2005 Monitoring the Future Survey, the use of opioids in the United States is much less prevalent than the other drugs discussed above. Data suggest that less than 1.5 percent of young adults have reported trying heroin at some time during their lives, although the incidence of prescription opioid abuse is on the increase. There are three basic patterns of opioid use and dependence in the United States. The smallest percentage of opioid users includes those individuals who initially began using morphine-like drugs medically for the relief of pain. A second group began using these drugs through experimentation and then progressed to chronic use and dependence. A third group comprises physically addicted individuals who eventually switched to oral methadone obtained through organized treatment centers. Interestingly, the incidence of opioid addiction is greater among physicians, nurses, and related health-care professionals than among any other group with a comparable educational background. In many instances, individuals addicted either to heroin purchased illegally on the street or to methadone are able to hold jobs and raise a family. Opioids reduce pain, aggression, and sexual drives, so that the use of these drugs is unlikely to induce crime. Obviously, however, other individuals (e.g., “junkies”) are unable or unwilling to hold a job and resort to crime to support their drug habit.
Opioid drugs produce their pharmacological effects by binding to opiate receptors. The euphoria associated with the use of opioids results from the interaction of these drugs with the µ -opiate (or mu-opiate) receptor, possibly resulting in the stimulation of mesocorticolimbic dopaminergic neuronal activity. The rapid intravenous injection of morphine (or heroin, which is converted to morphine once it enters the brain) results in a warm flushing of the skin and sensations in the lower abdomen that are often described as being similar in intensity and quality to sexual orgasm. This initial “rush” (or “kick” or “thrill”) lasts for about 45 seconds and is followed by a “high” that has been described as a state of dreamy indifference. Depending on the individual, good health and productive work are not incompatible with the regular use of opioids. Tolerance can develop to the analgesic, respiratory depressant, sedative, and reinforcing properties of opioids, but the degree and extent of tolerance depends largely on the pattern of use. The desired analgesia can often be maintained through the intermittent use of morphine. Tolerance develops more rapidly with more continuous opioid administration.
The abrupt discontinuation of opioid use can lead to a withdrawal syndrome that varies in degree and severity, depending on both the individual and the particular opioid used. Watery eyes (lacrimation), a runny nose (rhinorrhea), yawning, and sweating occur within 12 hours of the last dose of the opioid. As the syndrome progresses, dilated pupils, anorexia, gooseflesh (“cold turkey”), restlessness, irritability, and tremors can develop. As the syndrome intensifies, weakness and depression are pronounced, and nausea, vomiting, diarrhea, and intestinal spasms are common. Muscle cramps and spasms, including involuntary kicking movements (“kicking the habit”), are also characteristic of opioid withdrawal. However, seizures do not occur and the withdrawal syndrome is rarely life threatening. Without treatment, the morphine-induced withdrawal syndrome usually runs its course within 7 to 10 days.
Opiate receptor antagonists (e.g., naloxone) are contraindicated in opioid withdrawal as these drugs can precipitate a more severe withdrawal on their own. Rather, longer-acting and less potent opiate receptor agonists such as methadone are more commonly prescribed. The symptoms associated with methadone withdrawal are milder, although more protracted, than those observed with morphine or heroin. Therefore, methadone therapy can be gradually discontinued in some heroin-dependent individuals. If the patient refuses to withdraw from methadone, the individual can be maintained on methadone more or less indefinitely. In addition, a high-affinity partial m agonist, buprenorphine, has been demonstrated to be as effective as methadone in the treatment of heroin dependence, with significantly better opiate abuse control. This treatment may therefore allow for longer and more effective treatment programs with reduced relapse rates.
Psychedelics
The psychedelics include drugs related to the indolealkylamines, such as lysergic acid diethyla-mide (LSD), psilocybin, psilocin, dimethyltrypt-amine (DMT), and diethyltryptamine (DET); to the phenylethylamines (e.g., mescaline); or to the phenylisopropylamines, such as 2,5-dimethoxy-4-methylamphetamine (DOM, or “STP”), as well as 3,4-methylenedioxyamphetamine (MDA) and 3,4-methylenedioxymethamphetamine (MDMA, or “Ecstasy”). According to the National Institute on Drug Abuse, in 2004, 9.7 percent of Americans aged 12 and older reported using LSD at least once in their lifetimes, while 0.2 percent had used it in the past year, and 0.1 percent had used it in the past month. Lifetime use declined significantly from 2003 to 2004 among persons aged 12 to 17 and 18 to 25. Also according to the National Institute on Drug Abuse, an estimated 450,000 people in the United States aged 12 and older reported having used MDMA in the previous 30 days. MDMA use dropped significantly among persons 18 to 25—from 14.8 percent in 2003 to 13.8 percent in 2004 for lifetime use, and from 3.7 percent to 3.1 percent for past-year use. The feature that distinguishes these psychedelic agents from other classes of drugs is their capacity to reliably induce states of altered perception, thought, and feeling. There is a heightened awareness of sensory input accompanied by an enhanced sense of clarity, but there is also a diminished control over what is experienced. The effects of LSD and related psychedelic drugs appear to be mediated through a subclass of receptors associated with the inhibitory neurotransmitter serotonin (i.e., serotonin 5HT2 receptors). Immediately after the administration of LSD, somatic symptoms such as dizziness, weakness, and nausea are present, although euphoric effects usually predominate. Within two to three hours, visual perceptions become distorted; for example, colors are heard and sounds may be seen. Vivid visual hallucinations are also often present. Many times this loss of control is disconcerting to the individual, resulting in the need for structure in the form of experienced companions during the “trip.” The entire syndrome begins to clear after about 12 hours. However, there is little evidence of long-term changes in personality, beliefs, values, or behavior produced by the drug. Tolerance rapidly develops to the behavioral effects of LSD after three or four daily doses of the drug. In general, however, the psychedelic drugs do not give rise to patterns of continued use over extended periods. The use of these drugs is generally restricted to the occasional “trip.”
Withdrawal phenomena are not observed after the abrupt discontinuation of LSD-like drugs, and no deaths directly related to the pharmacological effects of LSD have been reported. However, other drugs chemically similar to MDMA, such as MDA (methylenedioxyamphetamine, the parent drug of MDMA) and PMA (paramethoxyamphetamine, which has been associated with fatalities in the United States and Australia) are sometimes sold as MDMA. These drugs can be neurotoxic or create additional health risks to the user. MDMA tablets may also contain other substances in addition to MDMA, such as ephedrine (a stimulant), dextromethorphan (DXM, a cough suppressant that has PCP-like effects at high doses), ketamine (an anesthetic used by veterinarians that also has PCP-like effects), caffeine, cocaine, and methamphetamine. While the combination of MDMA with one or more of these drugs may be inherently dangerous, users also combine them with substances such as marijuana and alcohol, putting themselves at further physical risk.
Inhalants
The intoxicating and euphorigenic properties of nitrous oxide and ethyl ether were well known even before their potential as anesthetics was recognized. Physicians, nurses and other health-care professionals have been known to inhale anesthetic gases, even though they have access to a wide variety of other drugs. Adolescents with restricted access to alcohol often resort to “glue sniffing” or the inhalation of vapors from substances with marked toxicity such as gasoline, paint thinners, or other industrial solvents. The alkyl nitrites (butyl nitrite, isobutyl nitrite, and amyl nitrite) have been used as aphrodisiacs because the inhalation of these agents is thought to intensify and prolong orgasm. More than 17 percent of young adults have reported some experience with inhalants. However, fatal toxic reactions (usually due to cardiac arrhythmias) are often associated with the inhalation of many of these drugs. Inhalation from a plastic bag can result in hypoxia as well as an extremely high concentration of vapor; fluorinated hydrocarbons can produce cardiac arrhythmias and ischemia; chlorinated solvents depress myocardial contractility; and ketones can produce pulmonary hypertension. Neurological impairment can also occur with a variety of solvents.
Arylcyclohexylamines
Arylcyclohexylamines include phencyclidine (PCP, or “angel dust”) and related drugs that possess central nervous system stimulant and depressant effects and hallucinogenic and analgesic properties. These drugs (also known as dissociative anesthetics) are well absorbed using all methods of administration. Even small doses can produce an intoxication characterized by staggering gait, slurred speech, and numbness in the extremities. PCP users may also exhibit sweating, catatonia, and a blank stare, as well as hostile and bizarre behavior. Amnesia during the intoxication may also occur. In higher doses, anesthesia, stupor, convulsions, and coma may appear. The typical “high” from a single dose can last four to six hours and is followed by a prolonged period of “coming down.” PCP and related compounds bind with high affinity to a number of distinct sites in the central nervous system, although it is not certain which site (or sites) is responsible for the primary pharmacological effects of these drugs. PCP binds to the sigma site, which also has a high affinity for opioids. PCP also blocks the cation channel (e.g., Ca2+) that is regulated by N-methyl-D-aspartate (NMDA), one type of receptor for excitatory amino acid neurotransmitters such as glutamate or aspartate. PCP also blocks the reabsorption of the neurotransmitter dopamine into the neurons from which it was released, resulting in a prolonged action of the neurotransmitter, especially within the mesocorticolimbic dopaminergic neuronal system.
There appears to be some degree of tolerance to the effects of PCP, and some chronic users of PCP complain of cravings and difficulties with recent memory, thinking, and speech after discontinuing the use of the drug. Personality changes following repeated use can range from social withdrawal and isolation to severe anxiety, nervousness, and depression. Although the frequency is uncertain, deaths due to direct toxicity, violent behavior, and accidents have been reported following the use of PCP. The drug can also produce acute behavioral toxicity consisting of intoxication, aggression, and confusion, as well as coma, convulsions, and psychoses. A PCP-induced psychosis can persist for several weeks following a single dose of the drug.