The clinical diagnoses (prior to obtaining a history of barbiturate addiction from the patient's wife) were essential hypertension, toxic psychosis of undetermined etiology, and fever of undetermined origin. The immediate cause of death, clinically, was attributed to "acute heart failure," probably resulting from abstinence from barbiturates.

Autopsy-Necropsy was performed 6 hours after death on the body which had been satisfactorily embalmed.

Gross examination was largely negative and supplied no completely adequate explanation of the cause of death. The right lung weighed 460 grams; the left lung, 410 grams. Both lungs were fully crepitant throughout, except for a very small edematous area at each base. The heart weighed 500 grams and was quite firm. The pulmonary artery was explored but no evidence of a pulmonary embolus was found. All the heart valve cusps were freely movable, of normal size and texture, and presented no evidence of sclerosis or incompetency. No coronary thrombi or areas of infarction were found. The left ventricular wall was greatly thickened, measuring 26 millimeters, but there was no dilatation of any heart chamber. The liver weighed 2,235 grams and appeared enlarged with indistinct markings on section. Genitourinary tract, including kidneys, ureters and bladder, appeared grossly normal. Spleen was normal. Adrenals: The left adrenal, plus a small amount of fat, weighed 20 grams. Externally, both adrenal glands appeared normal, but on section the center of the medulla presented a cavity, probably resulting from postmortem autolysis. The medulla did not appear to be quite so distinctly brown as usual. The gastrointestinal tract was normal except for absence of the appendix and a few pericecal adhesions. The brain weighed 1,550 grams. The hemispheres were symmetrical and the brain was firm throughout. The gyri appeared to be somewhat flattened and the sulci moderately narrowed. The vessels at the base of the brain were normal in distribution and translucent, but there were a few atheromatous areas. An opening was made into the third ventricle, and only a small amount of clear fluid exuded. Following fixation in formalin, sections at 1 centimeter intervals revealed the brain tissue to be generally well preserved. The midline structures were not displaced; the ventricular system appeared approximately normal in size, with normal ependymal lining; there appeared to be some grayish mottling in some areas of the thalamus, substantia nigra, and possibly the lentiform nuclei. The substantia nigra was very prominent, both in the cerebral peduncles and in the upper midbrain, particularly on the right side. Serial sections made through the cerebellum, pons and medulla failed to reveal any significant gross abnormalities.

Microscopic examination.-The myocardium showed mild interstitial fibrosis. The pericardium and the endocardium appeared normal. An occasional small scar was seen in the myocardium. Sections from the coronary arteries showed atherosis with considerable calcareous deposit. Sections of the lungs removed from the dependent portions showed edema but practically no inflammation. The bronchioles were not unusual. The liver showed marked fatty metamorphosis, but the remaining liver cells appeared quite normal. In the pancreas, the islands and acinar tissues presented no lesions. The adrenal cortical cells were pale. The spleen showed considerable sclerosis of the artericles. The kidneys showed mild sclerosis of the medium sized arteries.

Brain.—Microscopic sections were prepared from blocks removed from Rolandic cortices bilaterally, from the basal ganglia bilaterally, including the substantia nigra, and from the midbrain, pons, dentate nucleus and cerebellum. These were stained with hematoxylin (both alum and iron) and eosin, toluidin blue, phosphotungstic acid and hematoxylin, alizarin red and thionin, alizarin red alone and with Schiff's stain, the latter being a stain for mucin.

A

Frontal cortex.-Two blocks were stained as described. These revealed no marked changes in the leptomeninges. Throughout the cortex, patchy areas of nerve cell loss were observed. Many of the neurons appeared fairly normal, but Nissl substance was poorly preserved in most of these, although it could be seen distinctly in a few of the cells. The nuclei were eccentric in many of the nerve cells; others appeared swollen and distorted, and some showed disintegration. few ghost forms were present. No intracellular vacuoles or abnormal globules were observed. Occasionally neuronophagia and, rarely, satellitosis were seen, but there was no significant increase in glial or endothelial cells generally throughout the cortex. The smaller blood vessels showed a marked thickening of their walls with fibroblasts and endothelial cells.

Basal ganglia. Foci of nerve cell degeneration and loss similar to those described in the frontal cortex were observed. The white matter in the internal capsule and elsewhere had a vacuolated appearance similar to that seen in cerebral edema. The ependyma of the third and lateral ventricles appeared normal.

Pons.-These sections generally showed less severe degeneration of the nerve cells, while rare vacuoles were scattered through the section. Extracellular amorphous bodies, resembling corpora amylacea, were observed frequently toward the periphery of the section. No intracellular vacuoles or globules were observed. The neurons generally were slightly swollen, with some loss of Nissl substance, while a few possessed eccentric nuclei and were more distorted in outline. Satellitosis occurred rarely, and there was no generalized increase in glial or endothelial cells. The ependyma appeared normal.

Medulla, adjacent cerebellum and dentate nucleus.-Numerous amyloid bodies were seen scattered at the periphery of the cerebellar folia; the cerebellar tissue generally had a vacuolated appearance. The Purkinje cells generally appeared swollen and showed diminution or loss of Nissl substance. A few cells were lost. Similar changes were observed in the cells of the dentate nucleus, although some of these appeared more distorted with eccentric nuclei. In some, no nuclei were demonstrable, but bluish granules were present in the cytoplasm in sections stained with thionin blue. There was some generalized increase in the number of endothelial cells in the cerebellar tissue, but no increase in glial cells was observed. Changes in the nerve cells and interstitial tissue of the medulla resembled those found in the pons. No intracellular globules or vacuoles were seen. The ependyma of the fourth ventricle appeared normal.

Comment. A special study was made in this case, in a search for mucoid bodies or globules scattered throughout the white matter or in the nerve cells themselves, as evidenced by the variety of stains used. No such collections were seen, and there was no evidence of degeneration of the basal ganglia grossly, as is sometimes described in barbiturate intoxication.

The histopathologic diagnoses were (a) myocardial fibrosis, mild; (b) pulmonary edema, mild; (c) lobular pneumonia, mild; (d) fatty metamorphosis in liver, marked; (e) arteriosclerosis in spleen; (f) nephrosclerosis, mild; (g) atrophic changes in cortical cells of adrenals; (h) cerebral encephalopathy with diffuse neural degeneration, and (i) cerebral edema.

DISCUSSION

That abstinence from barbiturates was responsible in large part for death in this case can scarcely be doubted. This opinion is supported by the confirmed history of ingestion of enormous amounts of secobarbital and by the clinical course, which was atypical only in that no convulsions were observed. What part the hypertension and the accompanying cardiovascular-renal pathology played in the fatal termination is difficult to assess. The nature and extent of the cardiovascular-renal damage were, however, hardly sufficient to account for the death alone. The same is true of the changes in the liver. The case of Meyer also developed an aggravated phase in the psychosis, a high fever and circulatory collapse after being placed in a moist pack. His patient was a 30-year-old female in good general health who had taken cyclobarbital (Phanodorn) in excess for 2 years. At the time of admission she was taking 4 to 5 grams daily. Barbiturates were abruptly withdrawn; 2 days later she was extremely weak and tremulous and had not slept for two nights. She was confused and hallucinating. She was given glucose and 4 grams of Phanodorn by proctoclysis. On the third, fourth, and fifth days hallucinations persisted, particularly at night, with intervals of relatively normal behavior. At 7 p. m. on the fifth day the temperature was 99.3° F. At 8:30 p. m. she was found in a severe delirium; she burrowed her head in the pillow and would not answer questions; she tossed about in bed and groped about with her hands. She was placed in a light moist pack in an effort to quiet her. After one-half hour she suddenly became pale and cyanotic and was gasping for breath, so she was immediately removed from the pack. The body temperature was now over 107.6° F. and the pulse was small and rapid, yet "well filled." The patient remained quiet until 12 p. m., when she suddenly died. The autopsy "revealed findings of a circulatory death with dilatation of the right heart, and congestion of the lungs." (No other autopsy observations were reported.) Impairment of cardiovascular function (usually manifested by excessive tachycardia, sharp decline in both systolic and diastolic blood pressures, dizziness and faintness on standing, or even on sitting) is a characteristic feature of severe abstinence from barbiturates. It is quite probable that impairment in circulatory function played a significant role in the death of our patient and also that of Meyer. Probably warm baths and cold packs are contraindicated in abstinence from barbiturates, since the marked circulatory changes produced by these physiotherapeutic procedures might overwhelm an already functionally impaired cardiovascular system.

Meyer, H. J.: Uber chronischen Schalfmittelmissbrauch und Phanodorn Psychosen, Psychiat.-neurol. Wehnschr, 41: 275, 1939.

Death has also been observed following withdrawal of barbiturates from experimentally addicted dogs. Seevers and Tatum chronically intoxicated dogs with sodium barbital for 41⁄2 to 30 months. Some of their dogs died following convulsions after withdrawal of barbital. Fraser and Isbell observed 1 death following withdrawal of barbiturates from 17 chronically intoxicated dogs. The dog that died, a female that had been chronically intoxicated for 195 days with 47 milligrams per kilogram of pentobarbital daily, showed no signs when 24 hours abstinent. When 35 and again when 36 hours abstinent, this dog had a grand mal convulsion. Following the seizures she showed weakness, extreme hyperactivity, and abnormal behavior, and had a rectal temperature of 109.4° F. No pathologic changes of any significance (except for congestion of the thoracic and abdominal viscera) were found on gross and microscopic examination of the tissues, including the brain, of this animal.

Some of the histologic changes seen in the brain of our patient resemble some of those reported in experimental animals that were chronically intoxicated with barbiturates. The amyloid bodies are suggestive of those reported by McCrum et al., or of the "mucinoid" bodies of Mott, Woodhouse, and Pickworth. Loss of Nissl substance in Purkinje cells was also a feature in this case, as it was in the animals of Mott et al. None of the histopathologic changes reported in either animals or man can be regarded as being specific for chronic barbiturate intoxication, since they occur in other conditions. Furthermore, the relation of pathologic changes in animals to withdrawal of barbiturates is obscure, since none of the reported studies was designed to observe the clinical picture and pathology of withdrawal per se. It is noteworthy that most patients chronically intoxicated with barbiturates recover completely within 2 weeks (as far as can be judged by clinical means) following withdrawal of the drugs. This fact suggests that, if chronic barbiturate intoxication does produce histopathologic changes, the changes are usually either reversible or not sufficiently extensive to produce gross impairment of function.

The occurrence of this death points up the opinion previously ventured, 10 that abrupt withdrawal of barbiturates from chronically intoxicated persons is very dangerous and generally contraindicated. Withdrawal in this case was accidental and due to the patient's concealment of his enormous barbiturate intake from the physicians who were attempting to treat him. Had the diagnosis been made in time, proper treatment would have consisted of parenteral administration of barbiturates in sufficient quantity to induce 8 to 12 hours of unbroken sleep, followed by regular oral doses of amounts of barbiturates sufficient to maintain a definite, continuous, moderate degree of intoxication. After several days on this regime, dosage of barbiturates should have been reduced cautiously (no more than 0.1 gm. daily) until withdrawal was completed.

SUMMARY

The clinical course and gross and microscopic pathology of a patient who died during the course of the barbiturate abstinence syndrome is presented.

Dr. FRASER. I have one paper entitled "Clinical Characteristics of Addictions," by Dr. Isbell and Dr. White.

Senator DANIEL. That will be made a part of the appendix to the record. (See p. 2308.)

Dr. FRASER. That covers a description of these two conditions very well.

Dr. FRASER. And I have another paper entitled "Treatment of Drug Addiction."

Senator DANIEL. Who is the author of that?

Dr. FRASER. That is by Fraser and Grider.

Senator DANIEL. That will be made a part of the appendix to the record. (See p. 2315.)

• Seevers, M. H., and Tatum, A. L.: Chronic experimental barbital poisoning, J. Pharmacol. and Exper. Therap. 42: 217, 1931.

7 Fraser, H. F., and Isbell, H.: Unpublished data.

McCrum, W. R., Ingram, W. R., and Boylan, R. G.: Histology of the brain and blood in chronic experimental sedation with barbiturates and Presidon, Proc. Soc. Exper. Biol, and Med. 78: 193, 1951.

Mott, F. W., Woodhouse, D. L., and Pickworth, M. B.: The pathological effects of hypnotic drugs upon the central nervous system of animals, Brit. J. Exper. Path. 7: 325, 1926.

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

Senator DANIEL. I have a paper here by Dr. Harris Isbell, on Meeting a Growing Menace-Drug Addiction. Have you offered that paper yet?

Dr. FRASER. No, I haven't. I will have it available, though. Senator DANIEL. We have that, and that will be made a part of the record, the body of the record, at this point. (The document referred to is as follows:)

[From the Merck Report, July 1951]

MEETING A GROWING MENACE-DRUG ADDICTION

By Harris Isbell, M. D. From the National Institute of Mental Health, National Institutes of Health, Research Branch, Public Health Service Hospital, Lexington, Ky.

The recent outbreak of addiction to heroin, which has reached very serious proportions among young people in certain areas of large cities in the Eastern and Middle Western United States, has emphasized the tragic consequences of addiction and pointed up the need for dissemination of available information on this subject. There also has been a marked increase in the consumption of barbiturates in the United States within the past 10 years and, since it now is known that chronic intoxication with these drugs is more damaging physically than is addiction to opiates, all practitioners should be informed concerning the manifestations and treatment of addiction to barbiturates.

DEFINITION OF ADDICTION

The Expert Committee on Drugs Liable to Produce Addiction, of the World Health Organization of the United Nations, has recently established the following definition of addiction:

"Drug addiction is a state of periodic or chronic intoxication detrimental to the individual and to society, produced by the repeated consumption of a drug (natural or synthetic). Its characteristics include: (1) an overpowering desire or need (compulsion) to continue taking the drug and to obtain it by any means; (2) a tendency to increase the dose; (3) a psychic (psychological) and, sometimes, a physical dependence on the effects of the drug."

Under the terms of this definition, a large number of drugs are addicting. For the purpose of description, they may be divided into two great classes: (1) stimulants-drugs which induce sleeplessness or hyperirritability, and (2) depressants— drugs which tend to induce sleep and lessen nervousness. The stimulants regarded as addicting include cocaine, amphetamine (Benzedrine), and mescaline. The depressants include morphine and all its derivatives (heroin, Dilaudid, codeine, dihydrocodeinone, and metopon); the synthetic analgesics-methadone and meperidine (Demerol); all the hypnotics and sedatives (chloral, paraldehyde, bromides, barbiturates, marihuana, and alcohol). Statistically, alcohol is the most important of all addicting depressant drugs. In this article, we will be concerned only with addiction to analgesic drugs, both natural and synthetic, and with addiction to barbiturates.

ETIOLOGY OF ADDICTION

Addiction is caused by human weakness-not by drugs-and is a symptom of a personality maladjustment rather than a disease in its own right. Usually, people who become addicted are either hedonistic, pleasure-seeking individuals (psychopaths) or ere psychoneurotics. Emotionally normal, mature individuals practically never become addicted. In addition to a personality so constituted as to make the individual susceptible to addiction, contact with an addicting drug is necessary and the method of contact is extremely important. If a person learns about drugs and begins their use as a result of association with addicts, addiction is much more likely to occur than if the drug is administered for medical reasons. This is another way of saying that addiction, like a contagious disease, spreads from person to person. The current outbreak of addiction among minors in our large cities appears to be spread chiefly through association with other young addicts. Abuse of one drug predisposes to abuse of another drug. Individuals who smoke marihuana are likely to "graduate" to heroin or morphine. Alcoholics frequently discontinue alcohol in favor of barbiturates or morphine.

Harris Isbell, M. D., head of the only laboratory in the world exclusively devoted to the study of drug addiction-The Research Branch, United States Public Health Service Hospital, Lexington, Ky. Graduated from Tulane University in 1934. Interned at Charity Hospital, New Orleans and then entered the United States Public Health Service where he engaged in research in nutritional diseases at the National Institutes of Health, Bethesda, Md. Since 1944, he has devoted his time to investigation of drug addiction. He is a member of the American College of Physicians, the Society for Pharmacology and Experimental Therapeutics, and the World Health Organization of the United Nations.

WHY DO ADDICTS TAKE MORPHINE OR BARBITURATES?

Initially, these drugs are used to induce a state which we all desire-case, contentment, and comfort. This state is due to the decrease in psychic tension which both morphine and barbiturates produce. Either drug produces a sensation of pleasant relaxation and psychic ease, nervousness is lessened, worries vanish, and the individual can dream or sleep, deferring all decisions until tomorrow. The drugs enable a predisposed individual to feel at ease in social situations, to meet people easily, to laugh readily, and to talk freely. Persons who take these drugs may feel that their efficiency is increased. Actually, both morphine and barbiturates decrease mental efficiency, do not increase courage, and do not permit the individual who uses them to engage in greater physical and mental effort. Impairment of efficiency is much greater during addiction to barbiturates than during addiction to morphine. Morphine does not produce clouding of the sensorium, or ataxia, whereas barbiturates, like alcohol, induce marked mental confusion and great ataxia. If morphine is taken intravenously, a pleasant tingling spreads through the entire body. This sensation is most marked in the abdominal region and has been compared by some addicts to the sensation of a sexual orgasm. For this reason, intravenous injection of morphine appears to be especially attractive to individuals with psychopathic personalities.