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Alcohol & Other CNS Depressants
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Alcohol and other CNS depressant intoxication proceeds in stages that depend on dosage and time following administration. Apparent CNS stimulation, which occurs early in alcohol or CNS depressant intoxication or at low dosages, results from depression of inhibitory control mechanisms. The most sensitive parts of the brain are the polysynaptic structures of the reticular activating system and the cortex, depression of which causes euphoria and dulling of performance that depends on training and previous experience. Excitation resulting from intoxication is characterized by increased activity, verbal communication, and often aggression (Table 15–6). Euphoric feelings or calming effects are typically the expressed reason for drug self-administration. Higher blood concentrations of alcohol or other CNS depressants cause mild impairment of motor skills and slowing of reaction time, followed by sedation, decreased motor coordination, impaired judgment, diminished memory and other cognitive deficits, and eventually diminished psychomotor activity and sleep. At still higher concentrations, alcohol and most CNS depressants can induce stupor, and ultimately coma and death, by progressive depression of midbrain functions and interference with spinal reflexes, temperature regulation, and the medullary centers controlling cardiorespiratory functions. Death due to benzodiazepine overdose is very unlikely unless combined with alcohol or other CNS depressants.
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The dose–response curve of ethanol has been studied in greater depth than has any other CNS depressant. Sensitivity to alcohol intoxication varies widely within the population as a whole. For example, at blood ethanol concentrations of 50, 100–150, and 200 mg/100 mL, it is estimated that approximately 10%, 64%, and almost all of the general population, respectively, would be overtly intoxicated. In contrast, at a blood ethanol concentration of 300 mg/100 mL, some alcoholic individuals may appear only mildly intoxicated even though their psychomotor performance and judgment are impaired significantly. According to the Council of Scientific Affairs of the American Medical Association, blood alcohol concentrations of 60, 100, and 150 mg/100 mL increase an individual's relative probability of causing an automobile accident 2-, 6-, and 25-fold, respectively. Legal limits of blood ethanol concentration for automobile drivers are 100 mg/100 mL (the term in common use is 0.10) for most states in the United States, 80 mg/100 mL for most countries in Western Europe, and between 0 and 50 mg/100 mL for Scandinavian and Eastern European countries.
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Drug-Seeking Behavior
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The classic sedative–hypnotic actions of ethanol, barbiturates, and benzodiazepines correlate well with their shared ability to modulate GABA-induced chloride anion fluxes in vitro. These drugs can also act as anxiolytics; however, benzodiazepines are unique among CNS depressants because of their ability to reduce anxiety while causing relatively little sedation. It is believed that the reinforcing actions and abuse potential of CNS depressants reside primarily in their anxiolytic and tension-reducing properties mediated by activation of GABAA receptors. Furthermore, in animal models, established GABA efferents from the nucleus accumbens to the substantia innominata-ventral pallidum can influence the expression of cocaine- or opioid-induced behavioral stimulation. This may explain why alcohol and other CNS depressants are often used by addicted individuals along with cocaine or opioids.
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Adaptive neuronal changes resulting from the continued presence of alcohol or other CNS depressants involve a decrease in inhibitory functions of the nervous system. Although the molecular basis of such neuronal adaptation has not been elucidated fully, the clinical consequences are well characterized and include the development of tolerance and dependence, which usually proceed in parallel. Although pharmacokinetic differences among CNS depressants may alter the duration of time the agent is present at its site of pharmacologic action, and subtle molecular differences may influence the precise interactions of the different agents with their binding site(s) and the neuronal receptors occupied, the neuroadaptive changes that eventually result from chronic ingestion of alcohol, benzodiazepines, barbiturates, or nonbarbiturate hypnosedatives are for practical purposes much the same.
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The development of tolerance to, and dependence on, CNS depressants can occur after only a few days of repeated ingestion. As with all drugs, tolerance and dependence are determined by dosage and frequency of use. For example, a drug dosage that initially caused sedation and anxiolysis may in time be insufficient to induce sleep or reduce anxiety; thus, higher dosages are needed to attain these therapeutic goals. Tolerance may not develop at the same rate to all actions of a CNS depressant. For example, whereas sedation usually diminishes after the first few days of treatment with most benzodiazepines, anxiolytic effects may persist for months without a need to increase the dosage. Euphoric effects may not be as predictable, which can cause rapid increases in dosage if the drug is being self-administered for this purpose. In general, for alcohol and other CNS depressants there is no marked elevation of the lethal dosage with repeated use, and respiratory depression may be superimposed on chronic consumption after a severe, acute overdose.
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Cessation of alcohol or CNS depressant intake after prolonged use is associated with a syndrome of neuronal hyperexcitability with increased noradrenergic and adrenocortical activity. This syndrome is initially characterized by anxiety, apprehension, restlessness, irritability, and insomnia with clinically apparent tremor and hyperreflexia (see Table 15–6). Moderately severe cases progress to signs of autonomic hyperactivity with tachycardia, hypertension, diaphoresis, hyperthermia, and muscle fasciculations. Often patients experience anorexia, nausea, or vomiting with subsequent dehydration and electrolyte disturbances. Paroxysmal EEG discharges may precede generalized tonic–clonic seizure activity. The most severe cases develop delirium (agitation, disorientation, fluctuating level of consciousness, visual and auditory hallucinations, and intense autonomic arousal).
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Among the CNS depressants, the most severe and potentially dangerous withdrawal syndrome results from barbiturates and nonbarbiturate hypnosedatives; alcohol withdrawal is of intermediate severity; and withdrawal from benzodiazepines poses the least risk. The onset, severity, and duration of the withdrawal syndrome in a given class of CNS depressants are determined by the rate of elimination of the drug and its metabolites from the body. In the alcohol withdrawal syndrome, generalized tonic–clonic seizures typically occur 12–48 hours after the last drink, and delirium tremens begins at 48–72 hours. The signs of acute alcohol withdrawal typically abate by 3–5 days after the last drink, but subtle brain abnormalities may persist for an undetermined period. Among the barbiturates, nonbarbiturate hypnosedatives, and benzodiazepines, withdrawal usually begins within 12 hours and is most severe for rapidly eliminated compounds (e.g., amobarbital, methyprylon, triazolam). For slowly metabolized compounds (e.g., phenobarbital, diazepam, clonazepam), the syndrome may be delayed for several days after drug discontinuation. More protracted effects of withdrawal from CNS depressants have not been well studied, but residual problems related to cognitive impairment, anxiety and depressive symptoms, and insomnia may result.
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Psychostimulants: Cocaine & Amphetamines
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The main clinically relevant pharmacologic action of cocaine and amphetamine-related stimulants is the blockade of reuptake of the catecholamine neurotransmitters norepinephrine and dopamine. The consequences of noradrenergic reuptake blockade include tachycardia, hypertension, vasoconstriction, mydriasis, diaphoresis, and tremor. The effects of dopamine reuptake blockade include self-stimulation, anorexia, stereotyped movements, hyperactivity, and sexual excitement. As a result, many of the signs and symptoms of cocaine and amphetamine intoxication are similar (Table 15–7). CNS stimulation and a subjective “high” are accompanied by an increased sense of energy, psychomotor agitation, and autonomic arousal.
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The psychoactive effects of most amphetamine-like substances last longer than those of cocaine. Furthermore, because cocaine has local anesthetic actions, the risk of its causing severe medical complications such as cardiac arrhythmia and seizures is greater than for amphetamine-like stimulants. Amphetamine-related compounds therefore remain popular in the stimulant-abusing population.
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Drug-Seeking Behavior
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The most striking pharmacologic characteristic of cocaine is its tremendous reinforcing effect. Women who are cocaine dependent have higher rates of primary major depression than do cocaine-dependent men, consistent with drug use as a form of self-medication. Men with cocaine dependence have higher rates of co-occurring antisocial personality disorder than do cocaine-dependent women. Studies in animal models have shown that animals will self-administer cocaine in preference to food, leading to emaciation and death (in contrast to other highly reinforcing agents such as opioids). Dopamine seems to be the main neurotransmitter involved in the positive reinforcement of cocaine.
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Although not well-understood, neuroadaptation appears to occur in response to chronic psychostimulant use. Users develop acute tolerance to the subjective effects of cocaine, which can play a major role in dose escalation and subsequent toxicity. Sensitization appears to play a role in cocaine-induced panic attacks, paranoia, and lethality.
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In humans, discontinuation of cocaine leads to dysphoria (a so-called “crash”). Hypersomnolence and anergia are also common (see Table 15–7). In rats, termination of repeated cocaine administration produces interoceptive stimuli that are similar to the discriminative stimulus effects of pentetrazole, a drug that is anxiogenic in humans. As a result, the typical cycle of use consists of binges, each followed by a “crash” (lasting 9 hours to 4 days), followed by withdrawal (lasting 1–10 weeks), during which craving and relapse is common.
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The characteristic pharmacologic action of opioids is analgesia. Centrally, opioids are activating at low dosages and sedating at higher dosages. Other major features of intoxication are feelings of euphoria or dysphoria, feelings of warmth, facial flushing, itchy face, dry mouth, and pupil constriction (Table 15–8). Intravenous use can cause lower abdominal sensations described as an orgasm-like “rush.” This is followed by a feeling of sedation (called the “nod”) and dreaming. Severe intoxication may cause respiratory suppression, areflexia, hypotension, tachycardia, apnea, cyanosis, and death.
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Drug-Seeking Behavior
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Addiction to opioids (particularly heroin) can be severe and often leads individuals to dysfunctional behavior to support their habit. Animals tend to repeat opioid self-administration and prolong its effects.
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Self-administered opioid compounds affect the endogenous opioid systems of the body. Endogenous opioid peptides are distributed throughout the brain and form three major functional systems defined by their precursor molecules: β-endorphin from pro-opiomelanocortin, enkephalins from proenkephalin, and dynorphin from prodynorphin. Endogenous opioids modulate nociceptive responses to painful stimuli, stressors, reward, and homeostatic adaptive functions (hunger, thirst, and temperature regulation). Rats will self-administer opioid peptides into the ventral tegmental area and nucleus accumbens, suggesting that these regions may be responsible, at least in part, for the reinforcing properties of opioids (and cocaine). Other regions supporting rewarding effects for opioids are the hippocampus and hypothalamus. Endogenous opioid tone contributes to the maintenance of normal mood and a nondopaminergic system of opioid reward.
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There are three main types of opioid receptor: μ, δ, and κ. These G protein-coupled proteins inhibit adenylcyclases in various tissues and cause their pharmacologic actions by reducing cyclic adenosine monophosphate levels. The μ-opioid receptor appears to be important for the reinforcing actions of opioids, whereas the δ-opioid receptor may play a role in the opioid motor stimulation that is dopamine (D1 receptor) dependent. Like other substances of abuse, opioids can increase dopamine release in the nucleus accumbens as measured by in vivo microdialysis in awake, freely moving animals; but the reinforcing effect of opioids in the nucleus accumbens can be independent of dopamine release. The reinforcing actions of opioids may involve both a dopamine-dependent (i.e., ventral tegmental area) and a dopamine-independent (nucleus accumbens) mechanism.
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Neuroadaptation occurs in response to regular opioid use. For example, when chronically abused by humans, heroin rapidly loses its aversive properties and increases its reinforcing ones. The tolerance that develops when opioids are administered repeatedly appears to be receptor selective. It has been theorized that μ receptors couple less well to G proteins in rat locus coeruleus neurons that have been chronically treated with morphine. Tolerance occurs both to specific opioid effects such as analgesia and motor inhibition and to the generally depressant properties of opioids, whereas the psychomotor effects are potentiated.
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Withdrawal of opioids is characterized by hyperalgesia, photophobia, goose flesh, diarrhea, tachycardia, increased blood pressure, gastrointestinal cramps, joint and muscle aches, and anxiety and depressed mood (see Table 15–8). Spontaneous withdrawal results in intense craving because of the reduction of dopamine release in the nucleus accumbens, but the degree of physical dependence does not predict the severity of craving. The motivational (affective) properties of withdrawal are independent of the intensity and pattern of the physical symptoms. Because opioids can counteract withdrawal dysphoria and the reduction of dopaminergic transmission, these changes may contribute to maintenance of opioid addiction.
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The subjective effect of marijuana intoxication varies from individual to individual. It is determined in part by highly variable pharmacokinetics, dosage, route of administration, setting, experience and expectation, and individual vulnerability to certain psychotoxic effects. Typically, intoxication is characterized by an initial period of “high” that has been described as a sense of well-being and happiness (Table 15–9). This euphoria is followed frequently by a period of drowsiness or sedation. The perception of time is altered and hearing and vision distorted. The subjective effects of intoxication often include dissociative reactions. Impaired functioning occurs in a variety of cognitive and performance tasks, including memory, reaction time, concept formation, learning, perception, motor coordination, attention, and signal detection. At dosages equivalent to one or two “joints” (marijuana cigarettes), processes involved in the operation of motor vehicles or airplanes are impaired. The impairment persists for 4–8 hours, long after the user perceives the subjective effects of the drug. The impairment produced by alcohol is additive to that produced by marijuana. Tolerant individuals may exhibit somewhat less performance decrement.
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Physically, dilation of conjunctival blood vessels and tachycardia may be noted. Blood pressure remains relatively unchanged unless high dosages are used, in which case orthostatic hypotension ensues. Increased appetite is often attributed to marijuana but has not been observed consistently in controlled studies. At higher dosages, acute panic reactions, paranoia, hallucinations, illusions, thought disorganization, and agitation have been observed. With extremely high dosages, an acute toxic psychosis is accompanied by depersonalization and loss of insight.
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Drug-Seeking Behavior
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In chronic cannabinoid users, dependence and degree of drug-seeking behaviors are controversial. In some patients, drug-seeking behavior appears to be manifested primarily as drug craving. The psychological and physiologic mechanisms underpinning this craving are not understood. Laboratory animals do not self-administer the drug. The recognition and characterization of the endogenous cannabinoid system has led to important advances in our understanding of cannabinoid abuse and dependence. Moreover, there is a growing body of evidence that the endogenous cannabinoid system might participate in the motivational and dopamine-releasing effects of several drugs of abuse other than cannabinoids.
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Neuroadaptation in response to cannabinoid use has been more difficult to document than in some of the other drugs of abuse. Tolerance to cannabinoids appears to develop in animals and in humans, although it does not seem to be as profound as with some other drugs. It occurs mostly with heavy use. Chronic abuse of exogenous cannabinoids activates the same receptors as do endogenous cannabinoids, the CB1 and CB2 cannabinoid receptors. These G protein-coupled receptors play an important role in many processes, including metabolic regulation, craving, pain, anxiety, bone growth, and immune function. The functioning of cannabinoid receptors can now be studied directly by the use of agonists or antagonists, or indirectly by manipulating endocannabinoid metabolism and this will likely help elucidate processes of neuroadaptation.
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Cannabinoid withdrawal does not produce well-characterized withdrawal symptoms, perhaps because cannabinoids are so lipophilic that they are very slowly eliminated from the body. The DSM-IV does not include cannabis withdrawal, but there is an impetus to include the condition in future versions of DSM. Converging evidence from basic laboratory and clinical studies indicates that a withdrawal syndrome consistently follows discontinuation of chronic heavy use of cannabis, or treatment with cannabinoid receptor antagonists. Some patients report insomnia, irritability, dysphoria, anorexia, weight loss, hand tremor, mild fever, or slight nausea with discontinuation of use. These symptoms occur primarily in patients who smoke very potent preparations.
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Nicotine intoxication is not a DSM-IV diagnosis. However, nicotine intake has multiple effects. For example, many users report improved mood, skeletal muscle relaxation, and diminished anxiety and appetite. In addition, cognitive effects including enhanced attention, problem solving, learning, and memory have been reported.
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Drug-Seeking Behavior
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Users of tobacco products frequently exhibit substance-seeking behavior. Smokers often describe strong cravings for tobacco, especially in particular situations such as after eating or while experiencing stress. The degree of craving differs among individuals, and the ability to discontinue tobacco products varies greatly.
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Nicotine is thought to be the chief substance in tobacco that causes neuroadaptation. Tolerance to nicotine has been shown in both laboratory animals and humans. Dependence is indicated by the difficulty of discontinuing use of nicotine products despite a desire to quit.
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The primary pharmacologic actions of nicotine appear to occur via nicotine binding to acetylcholine receptors in the brain and autonomic ganglia. Several subtypes of nicotinic cholinergic receptors are found in the CNS. Activation of these receptors appears to cause the reinforcing effects and diminished appetite associated with nicotine. Some of the reinforcing actions of nicotine may be due to the effects of nicotine on dopamine pathways projecting from the ventral tegmental area to the limbic system and the cerebral cortex. Stimulation of peripheral nicotine receptors causes many of the autonomic effects associated with nicotine use. Short-term use of tobacco appears to increase cerebral blood flow, whereas long-term use has the opposite effect. Aspects of neuroadaptation to nicotine may also be secondary to release of hormones such as β-endorphin, adrenocorticotropic hormone, cortisol, epinephrine, norepinephrine, endocannabinoids, and vasopressin.
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Withdrawal symptoms often occur with abrupt discontinuation of nicotine intake: craving, anxiety, depression, irritability, headaches, poor concentration, sleep disturbances, enhanced blood pressure, and increased heart rate. In some cases, craving lasts for years under appropriate circumstances. Management of withdrawal symptoms has been one strategy to prevent relapse in those trying to quit smoking.
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Hallucinogens & Volatile Inhalants
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Intoxication with hallucinogens causes effects that vary greatly and may last 8–12 hours. Flashbacks are possible after termination of use (Table 15–10). The cardinal features of hallucinogen intoxication include visual hallucinations and disturbance of thoughts and perception in multiple sensory modalities. These features can lead to devastating consequences if they occur in dangerous situations (e.g., when driving or standing in precarious areas such as on a balcony). Other features include sensory changes (e.g., colors, shapes), synesthesia (the perception in one modality when a different modality has been stimulated), delusions, paranoia, derealization, depersonalization, cognitive impairment, coordination problems, behavioral changes, euphoria (or dysphoria), nausea, tremors, time distortion, dizziness, weakness, and giddiness. A “bad trip” involves striking dysphoria. Visual hallucinations with perception of various light patterns, and incorrect movement perception or object recognition have been reported. Augmented sensory perception (particularly tactile), which can be pleasurable (thus the term “ecstasy” for MDMA), often occurs with methamphetamine use. Other symptoms such as ataxia, dizziness, nausea, perspiration, and bruxism can occur with use. Many complications are related to hallucinogen use (e.g., panic reactions, seizures, exacerbation of psychiatric illnesses). Suicidal or homicidal tendencies may be enhanced.
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Anticholinergic drugs of abuse include antihistamines and the belladonna alkaloids such as scopolamine and atropine. Anticholinergic drugs are characterized by “dream-like” states, feelings of euphoria, heightened social interaction, and sedation. At high dosages, disorientation or paranoia may occur. These substances are sometimes used with mild opioids (called “Juice and Beans” or “T's and Blues” on the streets) to enhance the euphoric effect.
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Arylcyclohexylamines, such as PCP (phencyclidine), act as dissociative anesthetics. Behavioral alterations include paranoia, mood shift, agitation, catalepsy, and violence. PCP may be smoked, snorted, or injected. It causes reddening of the skin, pupillary changes, dissociation, delusions, amnesia, dry skin, dizziness, poor coordination, excitement, and nystagmus. Increased blood pressure and tachycardia may also occur.
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Intoxication by volatile inhalants generally lasts only several minutes. Confusion, sedation, and euphoria may often result from use. Physical effects include analgesia, respiratory depression, hypotension, and ataxia. Nitrous oxide is associated with euphoria and laughter (“laughing gas”).
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Drug-Seeking Behavior
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Psychedelic substances produce little or no dependence, and regular use is not common. Animals generally do not self-administer these drugs (except for MDMA-like compounds), and frequent users generally do not report craving. Tolerance to LSD occurs after only days of use; however, the intoxicating effects return after a few days without use. Other indolamines are cross-tolerant with LSD, but the phenylethylamine hallucinogens are not. Tolerance to anticholinergic drugs can also occur but usually requires prolonged use.
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Little is known about neuroadaptation to the actions of hallucinogens. Phenylalkylamines and indolamines are serotonin receptor agonists, which probably relates to their clinical effects. Phosphatidylinositol hydrolysis is stimulated after receptor binding and leads to enhanced excitability of certain neurons in the limbic system, cerebral cortex, and brainstem.
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The phenylisopropylamines inhibit reuptake of catecholamine and indolamine neurotransmitters and may be transported into serotonin neurons. It is hypothesized that the serotonergic action of these drugs accounts for their hallucinogenic effects (as with other hallucinogens), while the effect on catecholamines causes arousal.
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Anticholinergic drugs such as scopolamine and atropine act as antagonists of muscarinic receptors. These receptors are found in the cerebral cortex, and several subtypes have been reported. Stimulation may excite or inhibit neuronal activity including effects on serotonin receptors.
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Arylcyclohexylamines, such as PCP, act as antagonists to the N-methyl-d-aspartate class of glutamate receptors, which are themselves ion channels. PCP also binds to σ-type opioid receptors and inhibits catecholamine reuptake.
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Withdrawal symptoms are not common with these drugs; however, the anticholinergic substances may cause tachycardia, sweating, depression, anxiety, or psychomotor agitation after use has been discontinued.
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Psychological Testing
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Alcohol and other substances of abuse can cause both transient and enduring damage to the brain. Neuropsychological testing is important in the overall assessment of some patients with substance-related disorders. Most of these tests are readily available, noninvasive, and inexpensive. They require the full participation of the patient; therefore, they may not be as objective as blood chemistries or radiologic procedures. Neuropsychological tests are preferably conducted at least 3 weeks after the most recent substance use so that lasting brain dysfunction can be detected. Although these tests are useful, many factors influence them, including medication, co-occurring medical conditions or psychiatric disorder, and compliance with testing.
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Intelligence tests such as the Wechsler Adult Intelligence Scale (WAIS) are useful in determining the patient's global behavioral and adaptive potential. The WAIS is predictive of the patient's likely success in activities such as work and school. Other intelligence tests may be more appropriate for specific patient populations. Different aspects of cognition may be evaluated by specific tests. For example, the Wechsler Memory Scale is useful for patients who have possible substance-induced memory impairment.
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Neuropsychological batteries such as the Halstead-Reitan Neuropsychological Test Battery and the Luria-Nebraska Neuropsychological Battery can provide comprehensive information about many aspects of brain functioning. In alcoholic patients, the Halstead-Reitan Battery frequently reveals impairment on many of the individual tests such as Tactual Performance, Categories (visual–spatial abstracting), Trails B (perceptual motor speed), and Tactual Performance Test-Location (incidental memory for spatial relationships).
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Some assessment tools have been developed for evaluation of substance abuse itself (as opposed to possible causes or consequences thereof). One of the major difficulties in using such measures is in distinguishing use from abuse. The four-question CAGE assessment is used to screen patients for alcoholism. CAGE stands for an acronym reflecting (1) the subjective need to cut down, (2) being annoyed at other people when they comment on one's drinking, (3) feelings of guilt over use, and (4) the need for an “eye opener.” Generally, two out of four yes answers are considered positive. Sensitivity and specificity are high for most populations. The more complex Michigan Alcoholism Screening Test (MAST) is often used in the assessment of alcohol intake and the consequences of consumption. It has 25 differentially weighted items in a true–false format. Sensitivity, specificity, and validity testing have all been favorable. Shorter 10- and 13-item forms are available with reasonably good validity. A reliable test of the consumption and consequences of drug abuse is the Drug Abuse Screening Test. It has 28 items (unlike the MAST, not differentially weighted), in a true–false format. Another useful instrument is the Alcohol Dependence Scale. This scale has 25 multiple-choice items and is concerned primarily with the loss of ability to control drinking.
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Because co-occurring psychiatric illnesses and social difficulties are common in substance abusers, other psychological tests may be of value in certain patients. For example, the Addiction Severity Index (ASI), a semistructured interview designed to address seven problem areas in substance-abusing patients: medical status, employment and support, drug use, alcohol use, legal status, family/social status, and psychiatric status. The ASI provides an overview of recent (past 30 days) and lifetime problems related to substance use. The Minnesota Multiphasic Personality Inventory, a commonly used assessment tool with over 500 items (with results formatted into 10 clinical scales and 3 validity scales), provides typical personality profiles for substance-dependent patients. (See also Chapter 6, Psychological and Neuropsychological Assessment.)
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Alcohol & Other CNS Depressants
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The CNS depressants include brewed or distilled alcoholic beverages and various pharmaceutical agents prescribed for the treatment of insomnia, anxiety, depression, and, less frequently, for seizure control or as muscle relaxants (see Table 15–2). No CNS depressant (e.g., alprazolam, zolpidem, eszopiclone, zaleplon) has been developed that is totally free of abuse liability and the potential for a withdrawal syndrome, problems shared with alcoholic beverages.
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Alcoholic beverages are readily available at affordable cost with minimal legal restrictions. Accordingly, there is widespread use of alcohol in diverse recreational and work-related circumstances, and traumatic injuries sustained while under the influence of elevated blood alcohol are among the most common public health problems today. Youngsters with little experience with drinking are particularly vulnerable as they first begin to participate in high-risk activities such as sports, sexuality, and driving. Heavy drinkers, who often have blood alcohol concentrations that impair judgment and motor skills or who use other drugs in combination with alcohol, are particularly at risk for alcohol-related violence, traumatic injury, and death.
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The benzodiazepines are currently (as barbiturates were previously) among the most widely prescribed medications and the most commonly misused or abused type of prescription drug. With continued use, individuals develop tolerance and need higher doses to achieve symptomatic relief. If the physician does not educate the patient and provide careful prescription monitoring, the patient may eventually receive high doses of these medications with attendant side effects such as mood disorder, cognitive dysfunction, social difficulties, impaired work performance, and traumatic injury due to falls or vehicular accidents. In order to maintain symptomatic relief in the face of tighter controls by the prescribing physician, the patient may combine alcohol, medications, or illicit drugs (e.g., marijuana, opioids) with the prescribed dose of CNS depressant, seeking other physicians to provide additional prescriptions (so-called doctor shopping), or engaging in illegal activities such as forging prescriptions. The combination of alcohol with other CNS depressants greatly increases the risk associated with its use and is the most common clinical cause of severe drug overdose. Cessation of drug use leads to undesirable, and potentially harmful, withdrawal symptoms (such as seizures). Thus, drug-seeking behavior and repeated drug use is often continued in order to prevent these effects. Fulminant withdrawal occasionally occurs in patients who discontinue CNS depressant use because of illness or other unforeseen circumstances such as hospitalization for a motor vehicle accident.
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Psychostimulants: Cocaine & Amphetamines
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The alkaloid cocaine is derived from Erythroxylon coca, a plant indigenous to South America, where since time immemorial its leaves have been chewed for their stimulating effects. Because the only contemporary medical use for cocaine is as a local anesthetic, the drug is almost always purchased illegally by users. Amphetamine and amphetamine-like stimulants may be obtained by prescription for the treatment of obesity, attention-deficit/hyperactivity disorder, and narcolepsy. As a result, prescribed stimulants are commonly diverted into the illegal market (see Table 15–2). An epidemic of cocaine use started in the late 1970s, preceded by a period in which it was thought not to be particularly dangerous. Cocaine's significant dependence liability came to be recognized later, resulting in a diminution in use of the drug in the late 1980s. Abuse of amphetamine-like compounds has continued unabated because of their widespread availability and relatively low cost. Recently, use of illegally manufactured methamphetamine derivatives has reached epidemic proportions, reminiscent of the cocaine epidemic of the 1980s. Methamphetamine, including a crystallized, smokable form called “ice,” is representative of a group of “designer drugs”. These ring-substituted derivatives of amphetamine and methamphetamine, synthesized in clandestine laboratories, derive their popularity from their mixed stimulant and hallucinogenic effects.
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Cocaine and other stimulants are almost always used with other psychoactive substances, most commonly alcohol but also other CNS depressants or opioids. Alcohol is considered a gateway drug for cocaine and other stimulant use. It can accentuate the “high” obtained from stimulants, alleviate some of the adverse effects (e.g., “wired” feelings), and is a readily available (i.e., legal) substitute. Heroin (sometimes called “speedball”) is another drug that is commonly combined with cocaine and is reported to increase cocaine euphoria.
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Methods of use include inhalation via the nostrils (“snorting”), subcutaneous or intravenous injection, and smoking (“free basing”). Nasal insufflation is the most common and least dangerous method, but it does not provide the ecstatic sensation associated with smoking or injection. These latter routes of administration give the drug rapid access to the brain, thereby increasing its reinforcing effect and toxicity.
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Opioid use and addiction has occurred for centuries, and many opioid compounds are abused throughout the world (see Table 15–2). Opioid abuse may start with initially appropriate use for medical analgesia. Some drugs such as codeine and pentazocine can be found in nonprescription medications such as cough syrup and abused when more potent illicit drugs are not readily available. The use of long acting oral forms (e.g., morphine sulfate, MS Contin and oxycodone, OxyContin) has surpassed that of illicit heroin or morphine in most Western countries. Urban dwellers in the northeast are the most frequent abusers of heroin, whereas in rural regions, oral formulations of morphine and oxycodone have become the primary opioids of abuse. Medical professionals with easy access to opioids are at increased risk. In Asia, opium use is still widespread.
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Unrefined opium is often smoked using a water pipe. Intravenous heroin (mainlining) and morphine are popular because of the sudden (less than a minute) “rush” produced. Subcutaneous injection is sometimes used, especially if veins have become unusable because of frequent injections. Refined opioids can also be nasal insufflation, a method often preferred by new users. Long-acting oral opioid preparations are typically used with medical prescription or ground up and injected. Although the euphoric state of opioid intake is short, its sedative and analgesic effects can continue for hours. Street drugs are frequently “cut” (mixed or combined) with other substances, such as caffeine, powdered milk, quinine, and strychnine, to dilute the concentration of the active ingredient. These other substances can lead to altered clinical effects and medical difficulties beyond those associated with the opioid; however, the unpredictable potency of these street preparations can often lead to accidental overdose.
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Marijuana is the common name for the plant Cannabis sativa. Other names for the plant or its products include hemp, hashish, chasra, bhang, ganja, and daga. The highest concentrations of the psychoactive cannabinoids are found in the flowering tops of both male and female plants. Most commonly the plant is cut, dried, chopped, and then incorporated into cigarettes. The primary psychoactive constituent of marijuana is delta-9-tetrahydrocannabinol, although many other active cannabinoids are known. The hemp plant synthesizes at least 400 of these chemicals.
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Since the 1960s, marijuana has been the most commonly used illicit substance. It is a leading candidate for legalization for medical purposes. Marijuana is often the first illicit drug, other than alcohol, used by youngsters. For the first time in history, the use rate in females appears to be higher than in males. The likelihood of having used cocaine and other illicit drugs increases with the extent of marijuana use in all age groups. The epidemiology of marijuana use, therefore, can be viewed as a predictor of illicit drug-related problems in a given population.
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Tobacco is a substance commonly used in many countries and across age groups, from early teens to the elderly. Cigarette smoking is the most common method of use, although cigar smoking, pipe smoking, and smokeless tobacco (snuff) use each have had varying levels of popularity at different times and among different groups. Primarily because of educational programs, the use of tobacco products has declined over the past 30 years in North America. Nevertheless, the use of tobacco products continues to be a significant public health problem and has increased recently in some subpopulations, such as teenage girls.
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According to studies that alter the nicotine and tar content of cigarettes, user satisfaction appears to be related to nicotine content, suggesting that this agent is responsible for the reinforcing effects. Heated debate, litigation, changes in laws, and greater enforcement of existing laws regulating the cigarette industry have evolved as the adverse public health effects of smoking have become more widely appreciated.
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Hallucinogens & Volatile Inhalants
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Hallucinogens are subdivided into two major categories: the indoalkylamines (such as d-lysergic acid diethylamide [LSD], dimethyltryptamine [DMT], psilocin, psilocybin, diethyltryptamine [DET]), the phenylethylamines (such as trimethoxyphenyl ethylamine [mescaline], 3,4-methylenedioxy methamphetamine [MDMA; called “ecstasy” on the streets], 2,5-dimethoxytryptamine [DOM, STP], and 3,4-methylenedioxy amphetamine [MDA]). Other hallucinogens include peyote (mescaline, from Mexican cactus), Myristica fragrans (nutmeg), and morning-glory seeds (similar in effect to LSD). Arylcyclohexylamines include phencyclidine (PCP; called “angel dust,” “crystal,” “weed,” and “hog” on the streets) and ketamine. Ketamine is most commonly used as an anesthetic in veterinary medicine; PCP has no current medical uses.
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Volatile inhalants include aromatic, aliphatic, and halogenated hydrocarbon compounds such as gasoline, industrial solvents (e.g., acetone, toluene), paints, glues, refrigerants (e.g., Freon), and paint thinners (e.g., turpentine). Nitrous oxide (an anesthetic) and amyl nitrite (a vasodilator; called “poppers” on the streets) are included.
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Native Americans used psychedelic drugs such as mushrooms (psilocybin and psilocin) and peyote before the Spanish exploration of Mexico. Hoffman described the hallucinogenic effects of LSD in 1943. Scopolamine (and other belladonna alkaloids), mescaline (a plant product), and amphetamine designer drugs have similar effects. Hallucinogens in the United States were most popular in the 1960s and early 1970s, with a dramatic decline shortly afterward. The use of these drugs has continued, however, at a fairly constant level since the late 1970s. An increase of use, particularly of the designer drugs, has been noted among teens and young adults. A recent disturbing trend involves the use of several of these drugs by large numbers of youngsters during all-night dance parties (“raves”). Some Native Americans and other groups continue to use plant hallucinogens in their mystic ceremonies. PCP is used most commonly in urban areas.
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Users of volatile inhalants are most often in their preteen and teenage years. Professionals, such as dentists, who have easy access to substances such as nitrous oxide, are also at increased risk of use. The use of volatile inhalants was perhaps greatest in the late 1970s and early 1980s.
Budney AJ, Hughes JR, Moore BA, Vandrey R:
Review of the validity and significance of cannabis withdrawal syndrome.
Am J Psychiatry 2004;161:1967–1977.
[PubMed: 15514394]
Volkow ND, Fowler JS, Wang GJ:
The addicted human brain viewed in the light of imaging studies: Brain circuits and treatment strategies.
Neuropharmacology 2004;47:3–13.
[PubMed: 15464121]