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I I I I I I I I I I I I I I I I G O T H' S MEDICAL PHARMACOLOGY Wesley G. Clark, Ph.D. Associate Professor Department of Pharmacology Southwestern Medical School The University of Texas Southwestern Medical Center at DaIIas Dallas, Texas D. Craig Brater, M.D. Professor of yledicine and Pharntacology Chairman Department of Medicine Director of Clinical Pharmacology Indiana University School of Medicine I ndianapolis. I ndiana Alice R. Johnson, Ph.D. Professor Department of Biochemistry The University of Texas Health Center at Tyler Tyler. Texas Thirtwrtft Edftion wtth 421 iUustrations ~ ZND ~ ~ Mosby c~ I~ /1 Year Book ~ co St Lou s Balnnwre Boston Chtcago Lonoon PhHadeipn a Sydrw,w Toronm ~ ~ - - ZN7 ~ w r _ tp

I I I I I I I I I I I I I I I I I I Chapter 34 Drug abuse and dependence The opioids. central ner.ous s.stem depressants and ~ttniulant, hslluciun_~n~. camiahtnoids ~manjuana,. and some inhalants hu%e in comnwn the abiht% tu prucl1ic•L• euphoria. and thus the% provide positive retnforcement. Their reinforo.in_ proPcrtie, ma~ lead to repeated intermittent usage or. eventuall%. to chronic uwaLe. Cocnpulsnt• drug taking (a form of dependencei may develop with continued use. Emphasis in this chapter is placed on the characteristics of these drugs that lead to abuse and depen- dence. The general pharmacology of man. of the drugs is discussed elsewhere. Drugs within each class have qualitativel~ similar effects. TERMINOLOGY In contemporarv society , the term drug abuse has become svnom•mous with the nonmedical use of drugs to alter one's mental state. Individuals self-administer both prescription and illicit drugs in attempts to alter mood. to alter perception of realit~. to experience unique sensations, and/or to improve physical or mental capabilities. In general, society establishes what constitutes drug abuse by its laws and social taboos. Consequently, a particular drug-taking behavior in one societ\ or in a particular situation may be considered drug abuse, whereas in another it mav be considered appropriate. A term that is often used in place of drug abuse is drug dependence. Dependence is defined by the World Health Organization as drug self-administration that is detrimental to the individual or society. The term encompasses the biologic interaction between drugs and an individual, independently of social norms. Use of this term may be confusing because dependence also refers to alterations in physiologic or psycho- logic states that occur with chronic drug use. Accordingly, in this chapter drug abuse will refer to detrimental drug use, and dependence will denote alterations in physio- logic or psychologic conditions secondary to chronic drug administration. Perhaps the term used most often when dealing with drug abuse is addiction. Addiction, as defined b% Seevers,=6 is a state of chronic compulsive dru¢ use charac- terized by an overwhelming desire to continue obtaining and taking drugs, physical dependence. a tendencv to increase dose, and a detrimental effect on the individual taking the drug. Because this term is often used inappropriately and does not encorn- pass many aspects of drug abuse, its usefulness is limited. Indeed, it is more appro- priate to characterize drug use in terms of degree and type of dependence. Chronic administration of the drugs discussed below can lead to two types of dependence: psychologic and physical. Psychologic dependence is an emotional and 336 mental preoccupation with drug acquisition and use to receive some positive reinforce-

:-AP-_= }n Dn,g abuse ara aeaeroe~,ce I I I I I I I I I I I I I I I elru_• ment DruR u~ave becomes a habit nece»an for the subject s~%ell-hetnL .-0 discussed in thi-, chapter can pruduc•e p,%choloQtc dependence. ln contrast. not all r,t them produce ph' %stcal dependence Physical dependence is an altered ph%.siuluLtc condition caused b~ chronic exposure to a drul: It results in repruducihle ph\. sioloQtc stzns and symptoms when thC druc is «tthdrawn abruptl• These btr_ns and t,.mptunt~ constitute the abstinence or u,•ithdrau•al syndrome and uccur after chronic use uf opiates. barbiturates. antianxtety aeents, ethanol. and nonbarbiturate sedati~eb Tzble 3-1-1.. Chronic use of marn dru¢s leads to development of tolerance 'Tahle 3-1-1 Toler- ance is a phenomenon in which prior exposure to a drug decreases the respottse to a 2i\en dose: thus more dru; is necessarn to produce the desired effect. Tolerance that develops as a consequence of enhanced elimination of a drug (for example. induction of hepatic enzymes) is called dispositional or metabolic tolerance. Tolerance that develops as a result of adaptive processes within cells is termed functional or cellular tolerance. in addition. persons who chronically self-administer drugs often learn to modif} their behavior (usuall\, toward normal) while under the influence of the drug. This adaptation is called behacioral tolerance. When a person becomes tolerant to one drug, he often becomes tolerant to other drugs as well. This phenomenon is termed cross-tolerance. There are two types of cross-tolerance. Specific cross-tolerance occurs among srugs within a given pharmaco- logic class, presumably because they have similar mechanisms of action at the cellular level (that is. via the same recepton, second messengers, and so forth). Nonspecific cross-tolerance occurs when drugs share a common and inducible metabolic pathway. Thus enhanced metabolism produced by one drug increases metabolism of another. %Note that specific cross-tolerance is related to cellular tolerance, whereas nonspecific cross-tolerance is a dispositional tolerance. TABLE 34-1 Compartson of commonty abused drugs Drug category Todsrance Psycnow9Ic Pnys,w asAenoe" osps"oence' Psyd+otopernc . 0pioitls X X X Barbiturates Xt X X AnUanxiety agents XT X X Ethyl alcohol Xt X X Amphetamines X X Xi Coca ne X X Xt N cotine X X LSD X X X PhersCyClWtne X X X2 Cannabmads X X Xx inhalants ~ X X! •A prhnp iDSiMtt:! lynOrOrtM OCCWS atter i0n,Ot OSC=nWtiOn •L.urtk tollfiflc! wRm olRtN lyectt Lin r~titwl~y Rq1 OOAK © PI~ W lV w .r- 1L

I I I I I I I I I I I I I I I I I I I 338 :._ ._-- _-. Finall.. an +ndi% +dual ~~ho +~, ph>>+call\ dependent on , >nr dru_ ,i a _nc+, L ',.I•. ,•u; substitute another ui that clas, to pre%rnt al>,t+nence This cr< y,-~Ie ~ t+c+ +• +• .! t<< therapeut+c ad~anta<_e in (,ontroll+nZ 5%rnptum~ of %iithdra%ka! ~iirrle clrtowt% i;,_ p, tients «hc are phkstcalk dependent OPIOIDS Dru¢s are clas~-tfied as up+utds see C:hapter if the~ htnd ~tereusprr+hc.rll~ to opioid receptors and pussess some nrurphrne-like ach\rth . In addition to nath+ralk oc•c•urrmn: opium. murphrne. and eodetne. this class include!, sc'utis\nthrthc cun+l)uund, such as heroin (alsu known as hurse. smack. junk. H:. usymurphune. and h\ clr+nnur- phone as well as synthetic compounds such as meperidine. nrethadune. pentau,c+++t• (Ts). and propox%phene Such opioids are used therapeuticalk to relie~e pain. tu treat diarrhea and d} senter, . and to suppress cough. Characteristics of Opioids are abused primaril~, for their euphoric and sedatv. e effects. The euphoria abuse is characterized by feelings of peace and contentment. Normal concerns and an.iet, are diminished or absent. Initial use of opioids, however, ma% produce d> sphuna rather than euphoria. Furthermore. opioids can produce some central nervous s\ stem stimulation. including activation of the chemoreceptor trigger zone and consedurntl~~ nausea or vomiting. Heroin is the most widely abused opioid. Users believe heroin is more euphoric than other opioids, but its abuse potential is equivalent to that of morphine. Indeed, after administration, heroin is rapidly hydrolyzed to morphine. It acts more rapidly than morphine, however, because it enters the brain more readily. This mav largel}• account for the preference of users for heroin. When heroin is administered intravenously, the user may experience a thrilling sensation, in the lower abdominal area, that has been compared to a sexual orgasm. This is accompanied by feelings of warmth and tingling. Because opioids depress the central nervous system, users may become sedated. The degree of sedation depends on the dose taken and on the user's level of tolerance to the opioid. In nontolerant individuals. opioids can induce sleep and vivid dreams. Opioids also depress respira- tion, and many produce marked miosis (pin-point pupils). The patterns of opioid abuse vary widely. Some individuals use the drugs sporad- ically for recreation and do not become dependent. Others become both psvchoiugi- cally and physically dependent. Chronic use of opioids does not necessarily result in mental or physical deterioration. Many persons dependent on opioids function well in society. maintaining careers and family life provided they take the drug on a regular basis. Others tend to sacrifice "normal" lives for the sake of increased drug experi- ences. These individuals are consumed with drug-seeking and drug-taking behaviors and often use many different drugs. There are no known predictors of the pattern of dependence that will develop. Tolerance and When opioids are used regularly, pronounced tolerance lessens most of their dependence ef£ects, including sedation, euphoria, and respiratory depression. In contrast, their miotic and constipating actions persist. The degree and rapidity of tolerance develup-

I I I I I 1 I I I I I I „r+AP-=9 34 Drug aDuse arc eeeenoence ment are dependent on the opioid taken. the dose, and the frequenc% of admini~ tion. Because tolerance develops to the reinforcing actions of opiotds. most u increase dusage over time. Upon withdra~val tolerance rapidl%. diminishes. Coi quentl}, tolerant individuals often withdrau intentionall% for short penods to red the amount of drug the% need. Although a high degree of cross-tolerance de%e: among opioids that act at the same receptor subtype, that is µ. &. o;- K, less cr tolerance develops between agonists that act predominantl} at different recepwr subtypes. Pronounced psychologic and physical dependence develop rapidh during contin- uous use of opioids. As in the case of tolerance, the degree of dependence vanes with the individual, the drug administered, and the dosage. It is often the psychologic dependence, rather than the physical dependence, that dictates continued use of the drug and/or recidivism after withdrawal. t pon cessation of drug usage, however. persons who are physically dependent exhibit a characteristic abstinence syndrome. For the shorter acting opioids, such as heroin or morphine, symptoms appear about 5 hours after the last dose and reach peak intensity between 36 and 72 hours. Lacnma- tion. rhinorrhea, yawning, and diaphoresis develop between 8 and 12 hours. At about 13 hours, restless sleep may occur. At about 20 hours, gooseflesh, dilated pupils, agitation, and tremors usually appear. During the second and third day, the abstinence syndrome is at its peak, with symptoms and signs of weakness, insomnia, chills, intestinal cramps, nausea, vomiting, diarrhea, violent yawning, muscle aches in the legs. severe low back pain, elevation of blood pressure and pulse rate, diaphoresis, and gooseflesh. Although withdrawal is generally not life-tlareatening (that is, convulsions do not occur), fluid depletion during the witbdrawal period hm reanited in cardiovas- cular collapse and death. At any point during the course of withdrawal, administration of an opioid agonist in adequate dosage will dramatically eliminate the symptoms and restore a state of apparent normalcy (cross-dependence). Although the duration of the syndrome is roughly ' to 10 days, mild symptoms may persist for months, and the "craving" for opioids may continue for years. Other opioid abstinence syndromes are qualitatively similar to that of morphine or heroin. Opioids with a longer duration of action, such as methadone, usually produce a milder and more prolonged syndrome. Opioid abstinence syndromes also develop in babies born to opioid-dependent mothers, because these newborns are physically dependent. Withdrawal is character- ized by high-pitched crying, tremors, hyperreflexia, sucking of the fist, sneezing, yawning, vomiting, and hyperthermia. With heroin dependence the abstinence syn- drome usually appears in the first day of life. Withdrawal symptoms may not occur for days in babies born to methadone-dependent mothers. These babies need to be detoxified slowly by first administering sufficient opioid (usually paregoric) to control signs and symptoms; opioid dosage is then tapered. There are two components to treatment of opioid dependence: withdrawal (detox- Treatment of opioid ification) and rehabilitation. Withdrawal can be accomplished over several days by dependence gradually reducing the dosage of the opioid on which the user is dependent. More

I 1 I I I I I I I I I I I I I I I 340 Sc'--7Ch =~',ua Otner _ a• e .:e- _ - : - oRen. howe,er, methadone is used for detoxification Methadont. ~uh•tlt~Al ,(Ir ,,;L,.: other opioids. is well absorbed ,;,hen administered orall,, and h.,~ action than other opioids. Thus. graduall~ decreastngdoses need be ci1 Vn on;x ~ mLC;r, a 24-hour penod. and parenteral administration is avoided. Furthermore. thr mrth.,- done abstinence syndrome is less severe than that produced bN heroin ur murphtnt- In methadone maintenance programs, as in detoxification. methadone is ,uii,t;- tuted for the opioid that the patient has been abusine The patient is not detoufied, however. but is given a high dail.% dose of methadone to maintain tolerance Lnd dependencei. The rationales are 1, that exposure to additional opioid superimposed on the methadone) outside the clinic environment should lack reinforcing qualities and (2i that patients who no longer need to engage in illegal and time-consuming druQ- seeking behavior will pursue more useful activities, 4lthough programs invol%ine methadone maintenance and psychologic counseling appear some-hat successful in decreasing recidivism rates, many patients eventually return to illicit opioid use.°y=' Clonidine (see Chapter 21) reduces the severity of opioid withdrawal, probably b\ depressing preganglionic sympathetic nerve activity.11 It appears to be a safe nonopi- oid therapy that diminishes withdrawal symptoms.i'•32 Because a major side effect of clonidine is hypotension, the drug should be used with caution. After detoxification, rehabilitation, a far more difficult task, confronts the clinician. The craving for opioids persists for months to years after detoxification and results in exceedingly high rates of recidivism. One adjunctive approach to rehabilitation after detoxification utilizes a narcotic antagonist. Administration of a pure opioid antagonist should prevent the reinforcing effects of opioid agonists and thus diminish opioid abuse. Naltrexone, a long-acting antagonist, has been used for this purpose with some success.ls Of course, such treatment must not be started before detoxification is complete, because the antagonist will precipitate abstinence in an opioid-dependent individual. Medical problems of Other medical problems also occur secondary to opioid use. A major problem with opioid abuse most illicit drugs is not knowing the amount of drug an individual is taking. Street heroin is usually 2% to 5% opioid. The remaining powder comprises adulterants that increase the volume. A user who obtains an unusually pure sample of drug ma-, overdose unintentionally. As mentioned above, tolerance to the actions of opioids reverses quickly upon withdrawal. Consequently, overdose is likely after withdrawal if a user takes a dose that was effective previously when he was still tolerant. Overdose is characterized by respiratory and central nervous system depression and miosis (although not all overdose patients have pin-point pupils). Death occurs as a result of respiratory arrest and/or noncardiogenic pulmonary edema. The opioid antagonist naloxone (Narcan) reverses the apnea and coma caused by opioid overdose. In an opioid-dependent individual, naloxone can precipitate a full abstinence syndrome. Although the drug may be needed to treat an overdose, such patients may rapidly go from coma into withdrawaL extreme caution is essential. Naloxone neither depresses respiration nor enhances toxic effects of barbiturates or other central nervous svstem depressants, and it is often used in the emergency room to differentiate opioid from

I I I I I I I I I I I I I I I 1 I ; xaP-c= 34 Drug aouse ano oeoenoence central depre,,ant merd »e Because its acUcrn t, shurt•lt%ed. repc•.ited adnttnt,tratt,n tu likel% to he necess:n Patwnts ~kho e~hthtt a ~.ilutan response to a ,tn_lc cio~,(- ot naloxone should be obsen ed for a proloneed period hefure ducharee. Additional medical problems are ,econdsn to tntra%enous optotd .tdmtnt,trathon with unsterile needles. These c•omplications include AIDS. ~tral hepatttts, l actenul and fun¢al infections, chronic lr.er disease. thrombuphlehitis. celluittiu. 3nd lucal abscesses. Further danaer arises from foretcn substances rntentwnalk or .,,c•cidentalk added h% the supplier as adulterants to dilute -cut the drug. Recentk - ne%~ de.t_ner" dru_s ha~e appeared. The,. are so-named because the' \ are desi:ned %%tth unulut• chemical substitutions to circumvent the law, while producin¢ effects similar to their illeeal counterparts. One such meperidine analog was found to be contaminated %%ith 1-meth% 1--1-phenvl-1.2.3.6-tetrahydropyridine NPTP). which causes selecti%e deQen- eration of nigrostriatal dopamine neurons and a syndrome similar to Parkinsons dis- ease isee Chapter 30J.'y Finallv, although opioid users are not likely to be hostile or aggressise while on the drug, their need for more drug to avoid abstinence as tolerance develops ma% cause many chronic users to engage in criminal activities. 34 Included within this class of compounds are the barbiturates, nonbarbiturate CENTRAL NERVOUS sedatives. antianxiety agents, and alcohol (see Chapter 29). Such drugs are used SYSTEM medically to relieve anxiety. induce sleep, and control seizures. Abuse of central DEPRESSANTS depressants is more common than that of opioids and often originates with their medical use. In general, short-acting barbiturates are preferred by abusers. This class includes earbrturates secobarbital (reds, red devils, red birds), pentobarbital (yellow jackets), and amobar- CHaAAcrERtsncs of bital (blues, blue heavens). They are abused for feelings of tranquility. relaxation, and AeusE disinhibition. As with opioids, patterns of abuse vary greatly from occasional to com- pulsive chronic use. Unlike opioids, however, long-term administration of these drugs can cause physical or mental deterioration of the user. Effects of barbiturates include sedation iwithout analgesia), decreased mental activity, slowed speech, and emotional labilitv. Individuals taking these drugs appear as if intoxicated with ethvl alcohol. Higher doses produce atzxia, diplopia, nystagmus. vertigo, stupor, sleep, and, eventu- ally, respiratory depression. coma. and death. The risk of overdose with these agents is high because actions of central depressants are additive with one another. Further- more. because these agents decrease mental acuity and impair memory, individuals ma% ingest more drug than they intend in a short period of time. Treatment of acute barbiturate overdose involves maintaining respiration and supporting the cardiovascu- lar system. There is no specific antagonist that will reverse the apnea or coma. T &weliop 1e t6e w6tive aad iatosicating actions of TOLERANCE ANo i~ let~tRg the l~CCypi pippPStieS Of t11CSe DE'El/DENCE agenI ~-t ~~,,I~cage over time. A component of the tolerance is dispositional because chronic use of barbiturates can induce hepatic microsomal enzymes. Func- tional tolerance also develops, but the mechanism remains unknown. Littje tokrance

342 st---'orr Otne, :.r.gs wirr -~. ..o,.. _,.,..: _ . -_ I I I I I I I I I I I I I I I I develops to the lethal actions of these drugs. Thus. as dosage u mcreabed. thr ri,h „i overdose becomes ¢reater. Chronic use of barbiturates can produce both ps}choioeic and ph%si~al ~,- dence. and acute withdrawal produces a dangerous abstinence s' %ndrome. .~< «iti, optoids. the onset and sevenh of abstinence is dependent on the dru, used. ~~ „h- drawal of short-actin2 drues generall, produces more rapid and se%ere s%mptsxn„ Unlike opioids. however. withdrawal from barbiturates is often life-threatening. «'tth- drawal symptoms progress from weakness, restlessness. tremulousness, and tnsomnia to abdominal cramps, nausea, vomiting, hyperthermia, orthostatic htipotension, confu- sion, disorientation, and. eventually. eonvulsions. including status epilepticus. A¢ita- tion and hyperthermia may lead to exhaustion and cardiovascular collapse. With short-acting barbiturates. convulsions are most likely to appear during the second or third day of abstinence. With long-acting barbiturates, such as phenobarbital. convul- sions are less likelv, but if thev do occur it is usuallv between the third and eiehth da~ of abstinence. raE,,rMENr OF Treatment of barbiturate withdnwal requires hospitalization. First, patients are aAAerruacrF stabilized on a suitable barbiturate, usually pentobarbital. The dosage is titrated to the DEPENOENCE individual patient. Dosage is subsequently tapered over the next 7 to 14 days. The long withdrawal period is required to minimize the likelihood of an abstinence syn- drome and convulsions. Babies born to mothers who are physically dependent on central nervous system depressants will also be dependent. The newborn abstinence syndrome is similar to that described for opioids, but is more dangerous. As with adults, babies are first stabilized on a central nervous system depressant. usually a benzodiazepine, then detoxified by gradually reducing the dosage. Nonbarbiturate There are numerous other central nervous system depressants that have the sedatives and potential for abuse. These include meprobamate. methaqualone (quaalude. ludes}, antianxiety agents glutethimide. chloral hydrate, and the benzodiazepines. Like barbiturates, these drugs are abused for euphoria, feelings of tranquility, and the intoxication they produce. Effects of overdose with most of these agents are similar to those of the barbiturates. Benzodiazepines, however, are less powerful than barbiturates; severe respirator.• depression and coma are unlikely, but if they occur flumazenil (see p. 270) can reverse them.2 Methaqualone in large doses may produce convulsions, pulmonary edema, and respiratory arrest. As with barbiturates, tolerance and cross-tolerance develop to the sedative and reinforcing properties of the nonbarbiturate sedatives including the benzodiazepines. but little tolerance is observed to the lethal effects. Strong psychologic and physical • dependence can develop with chronic use of these drugs.' Abrupt withdrawal ma% produce a life-threatening abstinence syndrome. The severity of withdrawal depends on the drug used, the amount taken, and the duration of abuse. For example, with- drawal from therapeutic doses of diazepam generally produces anxiety and irritability. but rarely results in convulsions.

~NAA'c? 3s Drug aeuse ane eeoer,eerce I I I 1 I I I I I I 1 I I I I I I .klcohol abuse is still the most serious druo abuse problem in Western socirn . it c?r+yL ALCCr.OL not in all countnes. Alcohol is a contnbutrno factor in 33CC to S0<< of cases oti mantal Cnaracteristics oi v1olence and 10cc of occupational in)uries. Some 15.U00 or more traffic deaths about abuse -i0%, in the United States are alcohol related. A.lcohol is a central nen ous s\stem depressant. and e%en small amounts decrease mental acurt\ and impair motor coordination This compound is abused for intoxicating and euphoric feelings and for relief from anxieth. Acute ingestion of relati,.el\ small doses of alcohol produces feelines of warmth and relasation, with onl% slight impair- ment in motor skills. Higher doses mav produce paradoxic stimulation with feeltnQs of buo.anc\ and exaggerated emotions. Further escalation of dosage can cause marked impairment of motor skills, slurred speech. unsteady eait. stupor, and ultimatel\, unconsciousness. Genetic factors appear to be important in the predisposition to alcohol depen- dence. Familial occurrence of alcoholism is well documented. and the nsk of becom- ing an alcoholic increases wnth the number of close relatives who are alcoholics. A higher rate of alcohol dependence occurs in identical twins as compared with fraternal twins. Furthermore, children from families of alcoholics, when adopted by other families show a fourfold higher risk of alcoholism than contrnls, whereas children of nonalcoholics reared by alcoholics are at no greater risk than controls.u As with other central nervous system depressants, both dispositional and functional Tolerance and tolerance develop when alcohol is ingested chronically. Cross-tolerance between alco- dependence hol and other central nervous system depressants likewise has components of both dispositional and functional tolerance. Chronk use of aleobol can produce both psy- , chologic and physical dependence, and the abstrnence syndrome may be life threat- ening. Withdnwal symptoms appear within a few hours after the last dose of alcohol and are chsracterized by t:emors, weLlmests, awdety, intest3naI cramps, and hyrxrr+e- flexia. Between 12 and 24 hours after the last dose, patients may have visual halluci- nations. By 48 hours, an acute neurologic syndrome may become apparent, with confusion, disorientation, and delusional thinking. When this syndrome is accompa- nied by gross tremors it is called "delirium tremens." Convulsions are less common than with barbiturate withdrawal. If the abstinence syndrome is not fatal, the patient will recover by the fifth to the seventh day after the drug is withdrawn. The treatment of alcohol dependence, like that of other types of drug dependence, Treatment ot alcohol requires detoxification and rehabilitation. Because the abstinence syndrome can be dependence fatal, a strategy similar to that used for other central depressants should be employed. However, alcoholic patients often require fluids, nutrients, and vitamins (especially B vitamins) prior to detoxification to counter nutritional deficiencies. Patients are stabi- lized on another central nervous system - depressant, usually a benzodiazepine, the dosage of which is gradually reduced. For rehabilitation, Alcoholics Anonymous presents a unique and often pivotal source of help for alcoholics. In addition, the drug disulfiram (Antabuse) may help

I I I I I I I I I I I I I I ~ I I 344 SECTION =OuP Otner ,: rugs N,r ' ~ .npn C~. a - . mtnimtte rectdi<<tirn hk deto,kifird alcoholics ~' When patient5 t.ikin_ ch,ulhr,ui, e%an a~n7a11 an uunt ot aicohul. the% l>ecome ph%stcall% ill duc to accuum;i„,, .. acetaldeh\de. Presumuhk thu illnes~, or the potential for it pro% ide> >ufhLirnt [,t _,:• tive retnfurc•enment to discoura2e drinlon2. The use of disulfiram oh%uni,k ropllr~•t complisnce on the part of the alcoholic•. Medical problems of Chronic use Uf alcohol can result in patholoeic conditions and diseabe] not u.+<<aIlk aicorto/ abuse associated with other ttipe5 of drug abuse. These include ecrrhoais of the li% er «tth or without complications ot portal h}•pertensioni• penpheral polkneuropathk. aicuhultc gastritis, Korsakoffs psychosis. and Wernickes encephalopathk. Some of the,e arr believed to be consequences of nutritional deficiencies. Hmvek,er. alcohol appears to contribute dtrectl\ to the pathogenesis of the liver disease. Prenatal exposure to alcohol may produce developmental defects in the brain k% ith motor dysfunction. hypotonia. cognitive deficiencies, and microcephalk. as mank as _C- of all babies born in the Western world may suffer to some extent from this fetal alcohol syndrome. Finally, there is evidence that alcoholism interferes with immune function and thereby predisposes individuals to infection.`3 CENTRAL NERVOUS Drugs in this class include amphetamines (bennies. dex), methamphetamine 1 meth. SYSTEM speed, crvstal, ice, crank), cocaine (coke. crack, rock. snow, toot). methylphenidate. and STIMULANTS the less potent stimulants caffeine and nicotine. Amphetamines and Because the characteristics of dependence on amphetamine and cocaine are quite cocaine similar, they will be discussed together. Indeed there is evidence that experienced Cw4RAcrFarsncs oF users cannot distinguish between the subjective effects of these drugs.10 The major ABUSE difference between amphetamine and cocaine is in their durations of action. with cocaine being much shorter acting than amphetamine• Amphetamines have been used medically as appetite suppressants and to treat narcolepsy and attention-deficit hyperactivity disorder. These potent stimulants are abused for their ability to cause euphoria, elevate mood, enhance a sense of well• being, and reduce fatigue. They are also taken in attempts to enhance mental or physical performance. Amphetamines are usually taken orally, sniffed, or injected intravenously. Administration by the latter route quickly produces a short-lived. ex- tremely pleasant sensation (rush). Recently, a highly purified form ("ice") of inetham- phetamine that can be smoked has appeared,3 This potent form for delivery of the dru2 is likely to increase the incidence of inethamphetamine overdose: a large dose of drug can be absorbed quickly, without the need for intravenous injection. In moderate doses. amphetamines produce a sense of well-being. They tend to lower anxiety and social inhibitions, to elevate mood, and to increase self-confidence. Users feel that their physical and mental abilities are heightened and that performance of simple tasks is enhanced. Amphetamines also promote insomnia and loss of appetite. At higher doses, they reduce mental acuity and impair performance of complex tasks. Users become anxious, restless, irritable, and irrational. Symptoms of amphetamine