psychosis develops, the cocainist is dangerous and may assault and seriously harm anyone, in the mistaken belief that he is a detective who is persecuting the addict.

Since most addicts in the United States generally push the dose of cocaine to the point described above, intoxication with cocaine in this country is usually acute and not chronic. The experienced addict generally will, on obtaining a supply of cocaine, use it all in a debauch of a few hours. Ordinarily, when toxic symptoms become marked, he will suppress them by taking very large amounts of heroin or morphine intravenously. The more cocaine the addict takes, the more morphine and heroin he needs. Such a process, obviously, cannot be carried out for any extended period of time.

Tolerance to cocaine does not develop, rather, increased sensitivity to the effects of the drug occurs. There are no true withdrawal symptoms."

Sympathomimetic Amines.-Certain sympathomimetic amines with powerful central nervous system effects, such as amphetamine (bensedrine®), d-amphetamine (dexedrine®) and methamphetamine, are abused by addicts. Usually these drugs are taken orally; only occasionally are they injected. The amounts of drugs used to reach enormous levels and addicts are known to take habitually as much as 2,000 mg. of amphetamine daily. Symptoms of intoxication with the sympathomimetic amines resemble those of intoxication with cocaine. The symptoms develop more slowly but persist longer. Sympathomimetic signs, and signs of cortical stimulation are present, and toxic psychoses may occur. Tolerance to these drugs is not usual but may occur 12 and there is no evidence that abstinence syndromes follow withdrawal. The sympathomimetic amines are very seldom used alone. A combination of barbiturates with amphetamine is extremely popular, as is the combination of amphetamine with alcohol.

Mescaline. The use of mescaline is almost entirely culturally determined. The buttons of a small cactus called peyote, which contain mescaline, are used by certain religious cults of Indian tribes in the western and southwestern United States and in Mexico. Ordinarily, the peyote is taken only during religious festivals at certain seasons of the year. The buttons of the cactus are chewed up and swallowed. The effects of peyote are not evident for an hour to an hour and a half after ingestion of the drug; they may last for 12 to 18 hours. Signs of peyote action include evidence of autonomic stimulation (increased pulse rate, blood pressure, sweating, mydriasis), evidence of marked cortical stimulation (increased tendon reflexes, twitching of muscles) and a toxic psychosis which may resemble various psychiatric entities.13 Visual hallucinations which include beautiful colors, colored patterns, geometric figures and forms are very common. Feelings of depersonalization and derealization have also been described. As far as is known, no tolerance develops to mescaline and there are no withdrawal signs. Marihuana.-Marihuana consists of the dried leaves of the female hemp plant. In other parts of the world, the resins, which contain the active principles, are concentrated in various ways to form solid cakes of hashish. Hashish may be taken orally in a wide variety of ways or smoked. In the Western Hemisphere, however, the drug is always smoked. Cigarettes are prepared from the dried leaves which are crushed and screened. Smokers inhale a small amount of smoke and then a large amount of air to dilute the smoke, which is quite irritating. Smoke is held in the lungs as long as possible. The subjective effects include elation, great amusement at simple jokes and distortions in time and space perception. Occasionally, feelings of depersonalization and derealization occur. Overt behavior usually consists of giggling, singing, and dancing. Ataxia and dysarthria do not occur. The conjunctivae are reddened and pseudoptosis creates a sleeping appearance. The breath has a characteristic odor, resembling that after smoking cubeb cigarettes; appetite is enhanced and smokers usually sleep more than they normally do. Toxic psychoses may occur in susceptible individuals. No great degree of tolerance is developed and there is no abstinence syndrome.14

12 Knapp, P. H. Amphetamine and addiction. J. Nerv. and Ment. Dis., 115: 406, 1952.

13 Hoch, P. H. Experimental Production of Psychoses. Biology of Mental Health and Disease, pp. 539547, New York, 1952, Paul B. Hoeber, Inc., medical book department of Harper & Bros.

14 Williams, E. G., Himmelsbach, C. K., Wikler, A., Ruble, D. C. and Lloyd, B. J., Studies on marlhuana and pyrahexyl compound. Public Health Report, 61: 1059, 1946.

EXHIBIT No. 2

[From the May 1953 issue of The American Journal of Medicine]

TREATMENT OF DRUG ADDICTION 1

H. F. Fraser, M. D., and James A. Grider, Jr., M. D., Lexington, Ky. This discussion will be limited to the treatment of patients addicted to natural and synthetic narcotics, cocaine, marihuana, and barbiturates. Although addiction to alcohol constitutes the greatest single addiction problem in most of the world, it will not be discussed since a separate treatise would be required for alcohol alone. For convenience of presentation treatment of addiction will be discussed under three phases, (1) outpatient or office management, (2) withdrawal of drugs and (3) rehabilitative and psychiatric treatment.

OUTPATIENT MANAGEMENT

Office handling of narcotic addicts. A comprehensive procedure for the physician to follow when an addict appears in his office has been described recently in the Journal of the American Medical Association. First, the physician must be familiar with the Federal narcotic laws and regulations. The addicting drugs which are controlled by the Harrison Narcotic Act include opium, morphine, heroin, dihydromorphinone (dilaudid), methyl-dihydromorphinone (metopon), 3-hydroxy-N-methylmorphinan (dromoran), codeine, dihydrocodeinone (hycodan), meperidine (demerol), methadone (dolophine), and cocaine. Marihuana is controlled separately by the Marihuana Tax Act. The United States Bureau of Narcotics has interpreted the Harrison Narcotic Act, insofar as it affects physicians and pharmacists, in pamphlet No. 56, Prescribing and Dispensing of Narcotics Under the Harrison Narcotic Law. The most pertinent provision of the narcotic regulations respecting addiction reads in part as follows: "An order purporting to be a prescription issued to an addict or habitual user of narcotics, not in the course of professional treatment, but for the purpose of providing the user with sufficient narcotics to keep him comfortable is not a prescription within the meaning and intent of the act; and the person filling such an order, as well as the person issuing it, may be charged with violation of the law." In addition to Federal laws there are State laws with which the physician must familiarize himself, but, in general, the physician will be acting in accordance with the consensus of medical opinion with regard to addiction and will be complying with the letter and spirit of both Federal and State laws if he follows two principles set forth by the house of delegates of the American Medical Association: (1) Ambulatory treatment of narcotic addicts should not be attempted as institutional treatment is always required; (2) narcotic drugs should never be given to an addict for selfadministration.

The physician should realize that treatment of drug addiction of any type is primarily a psychiatric problem and favorable results cannot be anticipated unless treatment has been continued for several months. Attempts to carry out such therapy in the home or office fail almost invariably.

When the patient has agreed to go to an institution for treatment and has presented satisfactory evidence that he has taken steps to obtain admission, the physician may then administer narcotics in minimal doses but only for the minimal period of time necessary for the patient to complete arrangements for institutional treatment. Drugs must be administered by the physician or, if the patient is in a hospital, by nurses on proper written orders. Drugs, or prescriptions for drugs, must never be given to the patient for self-administration. It is advisable to limit the initial dose to 16 milligrams (4 gram) of morphine or 10 milligrams (% gram) of methadone. It practically never should be necessary to exceed as a single dose 60 milligrams (1 gram) of morphine or 30 milligrams (1⁄2 gram) of methadone. The type of drug administered and the dose should be unknown to the addict and every precaution should be taken to prevent the addict from obtaining narcotics from other sources.

The narcotic laws do not, of course, prohibit the use of opiates in patients suffering from advanced carcinoma, tuberculosis, or other chronic painful diseases. In such cases the physician is concerned primarily with relieving suffering and only secondarily with addiction. Nevertheless, ethical medical practice demands

1 From the National Institute of Mental Health, Addiction Research Center and the Clinical Division, Public Health Service Hospital, Lexington, Ky.

2 What to do with a drug addict. Report of the Council on Pharmacy and Chemistry, American Medical Association. J. A. M. A., 149: 1220-1223, 1952.

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that certain principles be followed: (1) The physician prescribing narcotics for such patients should be personally attending them; (2) the diagnosis of a painful, incurable disease should be confirmed by consultation; (3) all means for relieving pain other than narcotics should be exhausted and (4) narcotics should not be given to the patient for self-medication.

While it is known that it is practically impossible for addicts in advanced states of tolerance to take a lethal dose of narcotics, addicts who have lost their tolerance may take a fatal dose. N-allylnormorphine (nalline), a chemical analogue of morphine, is a specific antidote and in these cases it should be administered intravenously in a dose of 5 to 20 milligrams.3 4

Office treatment of barbiturate addicts.-The Harrison Narcotic Act does not apply to barbiturates, which are controlled by State laws and by the Federal Food and Drug Law.

When barbiturates are administered in the usual therapeutic doses under supervision of a physician, addiction does not occur even though the drugs may be taken for many months. However, chronic consumption of large amounts of barbiturates results in true addiction." Abrupt withdrawal of barbiturates from persons who have been consuming 0.8 gram or more of these drugs daily may provoke a serious abstinence syndrome characterized by convulsions and delirium. Institutional treatment of barbiturate addiction is just as necessary as it is in narcotic addiction. The physician should refuse to prescribe barbiturates for a person he believes is addicted to them until the patient agrees to institutional treatment and he should not continue to prescribe these drugs if the patient procrastinates and does not promptly complete arrangements for institutional treatment.

Selection of an institution for treatment.-When the diagnosis of addiction has been made and the patient has agreed to go to an institution for treatment, the next step is the choice of the institution. The selection will depend upon the type of case, the financial situation of the patient and other factors. Many private sanitoriums make a specialty of treating various kinds of addiction. Advice regarding these private institutions may be obtained from local medical societies or from the American Medical Association. If the addict is unable to pay for treatment, local or state facilities may be available. Advice concerning these can be obtained from city and State health departments. If no such facilities are available, the patient may be referred to one of the two Federal hospitals that treat narcotic addiction, the United States Public Health Service hospitals located in Lexington, Ky. and Forth Worth, Tex. Communications respecting admission may be directed to the medical officer in charge of either hospital. Patients addicted to opiates, synthetic analgesics, marihuana and cocaine are eligible for admission to these institutions. Patients addicted to alcohol and barbiturates are not eligible for admission to these Federal hospitals unless they are concurrently addicted to narcotic drugs. If the patient is indigent, there is no charge for treatment; but if the patient has funds, there is a charge of $5 per day. The hospital in Lexington accepts both men and women but in the Fort Worth hospital only males are admitted.

The physician should explain to the patient that withdrawal from drugs is an unpleasant but not a dangerous procedure, and that the patient should cooperate with the institution until the full program of treatment is completed. Although physical dependence on drugs may be relieved in two weeks, psychic dependence and a poor physical condition persist, so patients are requested to remain a minimum of 135 days in these hospitals.

WITHDRAWAL OF DRUGS

Opiates. Although a great many withdrawal procedures have been published,-8 the best method of withdrawing heroin, morphine or similar drugs from addicted patients involves substitution of methadone for whatever opiate or synthetic analgesic the patient has been using, followed by reduction of the dosage of methadone over a period of about 10 days. This method of treatment is based

Eckenhoff, J. E., Elder, J. D., Jr., and King, B. D. N-allyl-normorphine in the treatment of morphine or demerol narcosis. Am. J. M. Sc., 223: 191-197, 1952.

Fraser, H. F., Wikler, A., Eisenman, A. J. and Isbell, H. Use of N-allylnormorphine in treatment of methadone poisoning in man. J. A. M. A., 148: 1205-1207, 1952.

Isbell, H., Altschul, S., Kornetsky, C. H., Eisenman, A. J., Flanary, H. G. and Fraser, H. F. Chronic barbiturate intoxication. Arch. Neurol. and Psychiat., 64: 1-28, 1950.

Wolff, P. O. The treatment of drug addicts. A critical survey. Bull. Health Organ., League of Nations, 12: 455-688, 1945-46.

Isbell, H. and Fraser, H. F. Addiction to analgesics and barbiturates. J. Pharmacol. & Exper. Therap., 99: part 2, no. 4, 1950.

Kolb, L. and Himmelsbach, C. K. Clinical studies of drug addiction. II. A critical review of the withdrawal treatments with method for evaluating abstinence symptoms. Am. J. Psychiat., 94: 759–799, 1938.

on the facts that methadone will prevent the appearance of signs of abstinence from any known analgesic drug and that abstinence from methadone is milder than abstinence from any of the other commonly used analgesics. One milligram of methadone can be substituted for 4 mg, of morphine, 2 mg. of heroin, 1 mg. of dilaudid, or 20 to 30 mg. of either meperidine (demerol) or codeine.

The speed with which withdrawal is completed is dependent on the physical condition of the patient and the extent to which he is dependent on narcotics. Addicted patients with serious organic disease should not be subjected to the strain of relatively rapid withdrawal. In such cases it is best to treat the organic disease before attempting to treat the addiction. When, in the judgment of the physician, the organic disease has improved to the point where mild abstinence carries no danger, withdrawal is cautiously begun and, depending on the patient's response, withdrawal is completed in 14 to 30 days. In the experience at the Lexington Hospital less than one-half of 1 percent of narcotic addicts require such special treatment.

The first decision which must be reached before withdrawal begins is the degree of dependence on narcotics. The patient's history is of little use in this connection since addicts frequently exaggerate the quantities of drugs taken in the hope of receiving large amounts of narcotics in the first part of withdrawal. Furthermore, illegal drugs, especially heroin, are adulterated and the narcotic concentration may vary enormously. Hence the patient, unless he has had considerable experience with various narcotics, is unable to estimate the quantity of narcotics used.

The degree of dependence is best estimated by the physical examination, which will disclose whether the patient is intoxicated with narcotics or is exhibiting symptoms of abstinence.89 If a patient shows morphine-like intoxication, or if he displays no signs of abstinence, narcotics should not be administered until definite symptoms of abstinence appear. When symptoms of abstinence are present on admission or develop shortly afterward, it is usually possible to estimate the addiction dosage, especially if the physical findings are considered in conjunction with the addiction history. Information regarding the specific drug and the number of hours which have elapsed since the last does of self-administered narcotics is very helpful in this connection

During the first 2 days of hospitalization the dose of methadone should be sufficient to control nearly all symptoms of abstinence. By this method the patient will be able to eat, become oriented to the hospital regimen and psychiatric rapport may be established with the physician. During this interval routine laboratory work, roentgenograms and physical examination should be completed. Depending on the severity of abstinence, a dose range of 5 to 40 mg. of methadone three times daily is usually sufficient to prevent the appearance of abstinence signs, regardless of the amount or the drugs the patient has been using. Reduction is started after 2 days by cutting the dosage of methadone by 50 percent. This level should be maintained for about 2 days, after which the dose is reduced at approximately 2-day intervals to 30, 10 and 5 percent of the amount of mathadone which just prevented the appearance of abstinence in the initial phase of treatment. As the end of withdrawal approaches both the amount and frequency of medication should be reduced. If the degree of physical dependence is not great, withdrawal may be completed in 5 to 7 days and, in some cases, even less time may be required.

While narcotics are being withdrawn all addicts require reassurance; they should be examined daily for withdrawal signs so that appropriate changes in the treatment schedule may be made.

No special dietary measures are necessary during withdrawal unless the presence of an organic disease requires a special diet. Fruit juices and other attractive drinks should be available during the first 4 or 5 days. Anorexia is very common during withdrawal but a return of appetite is spontaneous and rapid.

Insomnia is conspicuous during withdrawal.

After 3 to 5 days it is advisable to give 0.1 to 0.2 gm. of pentobarbital or a similar hypnotic at bedtime, but the use of sedatives should not be continued for more than a few nights.

It is not advisable to permit visitors during this phase of treatment since the addict may be depressed, his craving for narcotics has not diminished and he may attempt to have relatives or friends smuggle drugs to him. Furthermore, addicts receiving narcotic drugs should be segregated from other addicts who are

Kolb, L. and Himmelsbach, C. K. Clinical studies of drug addiction. III. A critical review of the withdrawal treatments with method for evaluating abstinence symptoms. Am. J. Psychiat., 94: 759-799, 1938.

Himmelsbach, C. K. Studies of certain addiction characteristics of (a) dihydromorphine, (b) didihydrodexosymorphine-D, (c) dihydrodesoxycodeine-D, (d) methyl dihydromorphinone. J. Pharmacol. & Exper. Therap., 67: 239-249, 1939.

in the rehabilitative phase of treatment. Observing other patients receiving narcotics creates a situation which is favorable for developing an intensified craving for morphine.

Cocaine and marihuana.—Since no physical dependence is produced by cocaine or marihuana, withdrawal should be abrupt and complete and no substitution therapy is necessary. Insomnia and irritability should be treated with sedatives Barbiturates.-Isbell 10 has emphasized that barbituarates should be withdrawn very slowly and cautiously from barbiturate addicts. As in the case of morphine addicts, statements of the barbiturate addict regarding daily intake may be very unreliable. Parients showing barbiturate intoxication 5 11 on admission should not be given additional sedatives until signs of intoxication have become mild. Patients who show signs of mild barbiturate abstinence on admission such as anxiety, weakness, nausea and tremor are in danger of developing convulsions and/or psychosis.5 11 Such cases should be given 0.2 to 0.5 gm. (3 to 6 gr.) of pentobarbital (nembutal ®) orally or parentally at once. If symptoms are not relieved after 1 hour, the dose should be repeated.

After symptoms of intoxication have become mild, or after early withdrawal symptoms have been brought under control, the patient should be given barbiturates orally four times daily. The dosage of barbiturates should be adjusted tothat which just maintains a mild degree of intoxication. Ordinarily 0.2 to 0.4 gm. of pentobarbital four times daily will suffice for this purpose.

After the patient has been observed for a day or two, reduction of barbiturates can be started. The dosage should not be reduced more than 0.1 gm. (11⁄2 gr.) daily. If the patient has been taking 1.0 or more gm, daily, the total withdrawal period should extend over a period of 3 or 4 weeks. If the patient becomes nervous, apprehensive and weak, or if paroxysmal high voltage spike and dome waves appear in the electroencephalogram, the reduction should be stopped until these signs have cleared.

Patients being withdrawn from barbiturates must be kept under close observation. Their beds should be provided with sideboards or else their bed should be a mattress on the floor so that if convulsions occur they will not fall to the floor. Patients should not attempt to walk, bathe or go to the bathroom unattended. Diet should be light during the first few days but subsequently no restrictions are necessary. The diagnosis of barbiturate addiction should always be borne in mind in patients who suddenly develop convulsions and/or a toxic psychosis. If such cases are not recognized and properly treated, a fatal result may ensue.13 14 If after complete examination of such cases the diagnosis of abstinence from barbiturates seems likely, appropriate treatment consists of rapid reintoxication with barbiturates which may be given intramuscularly or intravenously if necessary. This program will arrest further convulsions but it may not completely control the toxic psychosis.14 Prompt administration of sufficient barbiturates will control excessive hyperactivity during the delirium and prevent exhaustion.

Delirious patients must be under continuous observation, rectal temperature checked three times daily and adequate fluid and food intake maintained. Fever of more than 104° F. is a serious sign 13, 14 and should be combatted by measures which favor body heat loss, such as keeping the room cool, the patient uncovered and administration of antipyretics. "Cold packs" should be avoided since these place undue strain on an already impaired circulatory mechanism.13 14 improvement is noted withdrawal is accomplished by gradual reduction of barbiturates as described previously.

Once

It should be remembered that acute barbiturate intoxication may be superimposed on chronic barbiturate intoxication. Patients who are chronically intoxicated with barbiturates may become confused and ingest such large amounts of barbiturates that serious acute poisoning develops. Whenever a patient who has been acutely poisoned with barbiturates recovers from coma, every effort should be made to ascertain if he has been taking large doses of barbiturates daily and, if so, he should be mildly reintoxicated with barbiturates and then gradual reduction begun as described above.

Combined barbiturate and opiate addiction has become quite common. Withdrawal of both drugs can proceed concurrently with more time usually being required to withdraw barbiturates than opiates.

Isbell, H., Altschul, S., Kornetsky C. H. Eiseman, A. J., Flanary, H G., and Fraser, H. F. Chronic Barbiturate Intoxication. Arch. Neuro! and psychiat., 64: 1-28, 1950.

10 Isbell, H. Addiction to barbiturates and the barbiturate abstinence syndrome. Ann, Int. Med., 33: 108, 1950.

11 Isbell, H. and White, W. M. Clinical characteristics of drug addiction. Am. J. Med., 14: 558, 1953.

12 Isbell, H. Treatment of barbiturate addiction. Postgrad. Med., 9: 256-258, 1951.

13 Meyer, H. J. Uber chronischen Schlabmittelmissbrauch und Phanodorn Psychosen. Psychiat.. neurol. Wchnschr., 41: 275, 1939.

14 Fraser, H. F., Shaver, M. R., Maxwell, E. S. and Isbell, H. Death due to withdrawal of barbiturates. Report of a case. In press.