Committee on Problems of Alcohol: A Report of Its Activities From 1949 to 1955, the Research Work It Has Supported and the Place of This Work in the Field of Alcoholism (1956)

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-8- on the effects of vitamin deficiencies on the metabolism of alcohol, espe- cially considering the frequency with which vitamin deficiency states are found associated with chronic alcoholism, ., Aided by a grant from the CCTpdttee..on,';Problems of Alcohol, Dr. Riehter at the Johns Hopkins Hospital has shown that rats fed an alcohol solution alone did not live appreciably longer if thiamine (vitamin BI) was added to it, whereas rats fed dextrose and water.and thiamine ILived several times longer than those given dextrose'and water alone. He feels that'in some de- ficiency states alcohol may be more easily metabolized than glucose. ' •" Dr. Hulpieu, (15) in addition to his work with bone charcoal, has studied the effects of thiamine (BI) deficiency on the metabolism of alcohol in 'dogs'/ both by giving them a diet,without. .thiamin^.in it and by giving them one of two other compounds (oxythiamine andneopyrithiamine)' which act to block the action of the thiamine in the body a^nd so produce a..sudden artificial thia- mine deficiency. One of these two compounds, oxythiamine, caused a sharp drop in blood sugar to occur when alco'hol or acetaldehyde were given as well. He has postulated that thiamine /plays some role in the metabolism of alcohol beyond the acetaldehyde stage. '.'• "' • •••• >•• . ' . •-. -V .. .. ••f.-. In clinical medicine insulin and glucose have been used extensively in the treatment of acute alcoholic intoxication on the assumption that the .metabolism of alcohol was speeded by this procedure. Well-defined studies of the actual metabolic effects of this treatment.in rian have unfortunately been few. (19) In the dog this method is effective if the ^nimg.} is metabolizing alcohol at an initially subnormal rate, as described above, but is not ef- fective otherwise. In man it would seem that large doses of insulin may in- crease the rate of alcohol metabolism by 50 per cent, but many patients do not show this effect. • . III. CENTRAL NERVOUS SYSTEM ASPECTS OF ALCOHOL AND ALCOHOLISM '• * • ' •' ' ..." *•• * Despite the very obvious effects of alcohol on brain function, in pro- ducing good cheer in some people, violence in others, and ataxia or stupor in still others, it was, until recently, difficult to demonstrate any effect of alcohol on the metabolism of brain slices until massive levels, never found in the blood stream of any living alcoholic, were reached. However,' a piece of brain by itself, in a solution in a laboratory bottle, is not being constantly stimulated by nerve impulses .as it would be in the intact brain. The brain piece therefore shows only a basal - i.ei minimum - rate of oxygen consumption. It is now found that if this piece of brain is artificially stimulated, its metabolic;rate rises sharply, and it can then be observed that alcohol levels equivalent to those found in moderate intoxication will markedly reduce this rise in metabolism. (30) • •* Beside this evidence^ there is evidence that, in the sympathetic gangli- onic nerve cells which act as a relay station in the transmission of nerve impulses from the spinal cord to the intestines, the passage of nerve impulses is blocked by levels of alcohol still too low to affect .the metabolic rate of these cells, (23) So the question is open as to whether alcohol affects the

-9- . brain by interfering with the oxygen metabolism of brain cells or by blocking the transmission of nerve impulses ,f,roji one cell to another by some other method. One problem which may.have. influenced some.of the results reported in the literature of the past.is.the failure. of investigators'to allow for the evap- oration of alcohol from the solutions in which the brain slices were being incubated, as Dr. Grehell of the University of Maryland Medical School has pointed out. Under a grant from this Committee, he is currently working on the effects of both alcohol, and acetaldehyde on'slices of brain tissue and on small areas of the,iufc^ct brain. He will study the changes produced in metabo- lism and electrical activity as well as in the concentration of adenosine tri- phosphate, a coenzyme shown to be of great importance in providing energy to nerve cells. He plans tp compare the effects of alcohol to those of other narcotics. He has a number .of ..animals being maintained on high, steady doses of alcohol for long periods, and is planning to compare the metabolism of their brains with those of animals getting ,a single dose of alcohol as well as with those of normal animals, •"'.. ., ^ •;•.• ., • ::; r j .;:.:'• •••: i ''"• •"...• .'•'.••' • Using a technique developed for the study of anti-epilepsy drugs, Dr. Swinyard (l) of the University of Utah College of Medicine, with the aid of a grant from the Committee on Problems of Alcohol, has been studying the effect of the chrpnic administration of alcohol upon the amount of electrical stimu- lation needed to produce.a convulsion in the rat. He has found that the amount of electric current needed was at first much greater in the alcohol-fed rat than in the normal rat, but this difference dropped gradually back to the normal level after about two weeks of daily convulsions and constant alcohol intake. No lowering of the convulsion threshold occurred after the alcqhol was stopped. These .findings imply that the brairi adapts to alcohol over a period of time, and support the common observation that heavy drinkers can • often function well at,blood alcohol levels that would cause intoxication in a relative abstainer. More work on this problem of "tolerance" to higher. blood levels of alcohol is badly needed. •••. • ' it "•••'• ' , The effect of alcohol on a particular property of'the brain was studied in the cat by Drs. A.. E. Walker and W. J. Horsey (13) of The Johns Hopkins Medical School under a Committee on Problems of Alcohol grant. Most soluble substances, salts, drugs, .dyes, etc., spread out through most of the body in a uniform manner; but between the blood and. the central nervous system there is a "barrier" through which many substances move at a very slow rate and through which some substances, like dyes, cannot pass at all. Now, in autopsies done on alcoholics» what is:called a "wet brain" is generally found, i.e. a brain which is swollen with extra water. The reasPn for this is unknown. Dr. Walker hypothesized that alcohol might break down this blood-brain .barrier, allowing more water and salts to pass through, there- fore producing the observed "wet brain". In his experiments on cats, however, he could find no significant increase in brain weight or water content in "alcoholic" cats, nor could he observe any change in the permeability of the barrier to certain dyes. He felt, therefore, that the "wet brain" could not . be attributed to alcohol per se, and wondered whether lack of vitamins or other

. .. , • .. . .•• factors cbntributing to death in; chronic alcoholics might be the» cause of the observed cerebral changes at ppst-mortem .examinations. . He also' studied the brain wave changes vMch occurred : when cats were studied at various blood alcohol levels and found ithe expected gradual depression of .brain function. One possible approach to the problem; of alcoholism, as well as tb'drug ad- diction and to the observed differences in the effects of drugs with1 potent psychological effects in differing individuals, is the more detailed study of the effects of these drugs on specific centers and pathways in the central nervous system. Work of this sort is complex and difficult, but techniques of neurophysiolbgy necessary for such work are rapidly' improving. It seems at least possible that the hypothalamus, the part of the brain which most ....« directly controls endocrine gland .function and cardiovascular, gastrb-intestin- al, and other autonomie functions of the body may be involved and that alcohol, at least in some alcoholics^ serves to decrease. or 'eliminate. such painful .•'. emotions as anxiety, tension* resentment, or i depression. .... ; ' " " . *Good work along these lines will moat often be done by. .investigators who, plan to study a number of different drugs along1 With ethyl alcohol itself . ' %', . . To obtain the knowledge needed in the field of chronic alcoholism it will' be ... necessary to support work by investigators who are riot always working with •'.•.. alcohol alone i '". • .•.•i. •••" ;• . ••. . . •••/.• ;•• ... r-.•• Dr. Oskar Diethelm (A5) of Cornell University Medical College has been .V. working' with three "autonomie11 substances found in the blood, which affect the contractions of isolated" rabbit intestine and rat uterus in specific ways. The blood levels of these three substances correlate well with clinically \ . observed levels of anxiety, tension, and resentment, respectively, in psychi- atric patients. A group of fifty-seven chronic alcoholics have been studied.;.• Many of these showed consistently higher ^'resentment" substance levels in ' .. their blood than did other psychiatric patients* and appeared clinically re- sentful as well. This substance was found to be especially elevated before ".. the patients went on a drinking spree, and, in the laboratory, six. ounces of alcohol given to these patients would usually bring thO resentment substance level in the blood almost to zero. Tension substance along with observed • ; . tension was also markedly reduced in some alcoholic patients by alcohol feed- , ing. . .-.- •• '-.:• ' •." '."; ' ...; .*"*v \.: f'. ' . ••'-••.< '••• • •••-,•' " •''•.•.... ' ':•.••.. • - •• f J'"•'" In nonalcoholic psychiatric patients neither tension n'or resentment Was '; dramatically changed by drinking alcohol (whiskey). ••' '• ..".•. • • «.•••» ;;; ..'.. Other drugs such as dexedrine (a stimulant), sodium amytal (a sedative-. . barbiturate), and mephenesin (a muscle relaxant) were able to cut down both observed tension and. "tension substance" in some alcoholic and some nonalco- holic patients, but no. drug other than alcohol has been found which has af- fected resentment. substance levels appreciably. The blood substances involved in the above research are currently being isolated for further study by spe- cial biochemical procedures in the Department of Pharmacology at Cornell.