The problem of barbiturates in the United States of America

Sections

I. Introduction
II. Pharmacology: physiology and therapeutic uses
III. Use, production, sale, and prescribing of barbiturates and related drugs
IV. Abuse and addiction
V. Causes
VI. Treatment, prevention and research
VII. Present and proposed legislation and enforcement
VIII. Conclusions and recommendations

Details

Author: Joel FORT
Pages: 17 to 35
Creation Date: 1964/01/01

The problem of barbiturates in the United States of America

Joel FORT MD.
Lecturer, School of Criminology, University of California: Director, Centre for Treatment and Education on Alcoholism, Oakland, California

I. Introduction

As long as man has existed, drugs such as alcohol, marijuana and opium have been used for relief of anxiety tension, or fatigue; for treatment of illness; and for religious reasons. The abuse of these drugs and of more modern compounds which also affect the brain has been a major social and health problem in many widely separate countries and epochs. In this historical context, therefore, it is not difficult to understand the contemporary widespread use and abuse of the derivatives of barbituric acid (malonylurea) accidentally discovered by von Baeyer in 1863 [ 112] . The hypnotic significance of substituting various radicals in position five was discovered in 1903 (barbital or veronal) and given impetus in 1912 with the introduction of phenobarbital (luminal). Since that time it is variously estimated that up to 2,500 barbiturates and thiobarbiturates have been synthesized with perhaps 50 being marketed for clinical use, the most used ones in the United States being nembutal (pentobarbital), seconal (secobarbital), amytal (amobarbital), and tuinal (amobarbital and secobarbital). All of these synthetic derivatives have similar chemical structures and similar pharmacological properties, with the main clinical variations being the onset and duration of their action. Levi [ 77] has summarized the trade names, chemical names, structural formulae, and molecular composition of the barbiturates and their clinical use. Other dates of specific historical significance in the evolution of sedatives and hypnotics include the 1840s, when the action of bromide was recognized, 1869 when chloral hydrate was introduced, 1882 when paraldehyde was introduced, and 1954 when the phenothiazine tranquillizers came into general use. As Glatt [ 45] has pointed out, each of these drugs or drug families including the barbiturates has aroused similar controversies and debates about their merits and dangers. Since the time of the first world war there appears both to have been a rapid increase in the use of the various barbiturates and a gradual institution of government attempts at control. In the following sections of this monograph an attempt will be made to collectively review and synthesize what is "known" about the extent of barbiturate use and abuse in the United States. As will be seen, there exist major lacunae in knowledge about this problem.

II. Pharmacology: physiology and therapeutic uses

Among the physiological effects of the barbiturates are respiratory depression proportional to the dose administered; a decrease in tonus of the gastro-intestinal musculature and a decrease in gastric secretion; and a complex of effects on the autonomic nervous system [ 47] . There appears to be no impairment of liver, renal, or cardiovascular functioning. The long-acting barbiturates are metabolized by the kidney and the short-acting ones by the liver. The central nervous system effects of the barbiturates are sometimes briefly summarized by saying they have a depressant action on all segmental levels and all levels of functional organization. Either increased fast activity or slow activity can occur in the electroencephalogram, seemingly based on individual differences and not correlated with intensity of intoxication or behavioural effects. With more than normal clinical doses a form of "intoxication" occurs which includes ataxia, nystagmus, and slurring of speech. Wikler [ 122] has summarized the neurophysiological action as a selectivity for the medial ascending reticular activating system, with specific depressant actions on the hypothalamus, spinal cord, and sympathetic ganglia. He goes on to say that it is likely that these drugs exert quite specific patterns of effects both on behaviour and on neuro-organization, but better correlation of these will depend on more detailed and more comprehensive descriptions of the behavioural effects as well as investigation of the effects of graded doses on the temporal and spatial diffusion of neuro-impulses. A number of investigators have now reported that both large doses and small "therapeutic" doses impair reaction time, visual perception, and attention even up to fourteen hours after injection [ 53] . The barbiturates have little effect on the pain threshold unless an amount sufficient to impair consciousness is administered [ 55] . Reported effects of the barbiturates on cognitive functions, learning, perception, hypnosis, etc. are unclear as to their significance or implications [ 29] .

III. Use, production, sale, and prescribing of barbiturates and related drugs

The most common therapeutic use of the barbiturates is for the production of sleep, which is brought on within 20 to 60 minutes and resembles natural sleep. Thus it would appear that the most common complaint for which barbiturates are prescribed would be insomnia. However, large amounts are also prescribed for anxiety, nervousness, tension, and other poorly defined or physically unexplainable complaints. The therapeutic dose prescribed for sedation is generally smaller than for hypnotic effects. Other normal medical uses of these drugs are as anti-convulsants (phenobarbital for epilepsy), anaesthesia (thiopental) and pre-anaesthesia, diagnostic agents to differentiate organic from functional psychiatric disorders or functional disorders from malingering, narcoanalysis, sleep therapy for psychosis (rarely used in the United States), and for research investigation, particularly in neurophysiology. Some authorities feel that the barbiturates offer unique advantages in that they can produce any degree of depression from sedation to anaesthesia, thus lending themselves to a wide variety of uses. However the ease with which they can be prescribed also results in their being employed when other sedatives or other forms of treatment might be preferable.

The reports of the U.S. Tariff Commission [ 111] on production and sale of barbituric acid (table 1) show that since 1954 at least 700,000 pounds of these substances have been produced each year. More than half of the amount produced each year is sold in undiluted or bulk form, and the rest presumably in various specific commercial preparations. Figures on amounts produced refer to known manufacturers, and probably additional quantities are produced by unknown, unregistered or illicit manufacturers. The framework of present state and federal legislation makes it impossible to ascertain the full details of manufacture and distribution. It seems safe to assume, however, that the amount of barbituric acid derivatives produced would be roughly equivalent to the amount used. The 1960 figure of 852,000 lb., although .not representing total production, would still be enough raw material to make approximately 6 billion one-grain barbiturate capsules or tablets, or about 33 for every man, woman and child in the United States. Over 1 billion tablets of another sedative drug, barbitu-rate-like in chemical structure and pharmacological effect, Doriden, have been distributed in the U.S. in the past seven years, according to its manufacturers.

TABLE 1

TABLE 1

Barbituric acid and derivatives

 

Sales

 

Production (pounds)

Quantity (pounds)

Value

Unit value (pounds)

1961 700 000 407 000
$1 903 000
$4.68
1960 852 000 456 000 2 429 000 5.33
1959 819 000 583 000 2 853 000 4.89
1958 790 000 513 000 2 433 000 4.74
1957 755 000 457 000 2 369 000 5.18
1956 756 000 467 000 2 483 000 5.32
1955 864 000 486 000 2 807 000 5.78
1954 798 000 524 000 3 204 000 6.11
1953 634 000 427 000 2 757 000 6.45
1952 537 000 418 000 3 034 000 7.26
1951 789 000 481 000 2 934 000 6.09
1950 688 500 499 100 2 739 500 5.49
1949 679 800 388 900 2 337 200 6.01
1948 679 800 455 800 2 116 400 4.64
1947 900 100 768 600 3 843 500 5.00
1946 806 500 650 900 3 093 500 4.75
1945 582 100 556 500 3 025 000 5.44
1944 559 200 558 400 3 119 800 5.59
1943 583 000 664 000 3 400 000 5.12
1942 607 000 487 000 2 430 000 4.99
1941 531 000 512 000 2 263 000 4.42
1936 231 167 174 188
-
-

Sales include only that portion of the original product which is sold in undiluted or uncompounded form including that sold in bulk, and that sold in packages.

Production data are for medicinal chemicals in bulk. They do not include finished preparations (tablets, capsules) manufactured from bulk medicinal chemicals.

Systematic, nationwide records are not available on the number of prescriptions written for barbiturates or other sedatives alone, or the amount of drugs ordered on each prescription. However, a nationwide sampling by the retail drug industry indicates that 14-18% of all prescriptions fall into the category of " sedatives and tranquillizers " ranking first or second in " popularity ", and also constituting 18 % of all refill prescriptions [ 24] .

Barbiturates rank between first and third at different times, in frequency of prescription within the sedative and tranquillizer category (11-12 % ). (One writer states that 3 to 4 billion doses of barbiturates are legally prescribed each year.) This compares with the 7 % for barbiturate prescriptions alone reported in England [ 45] . An estimate in 1957 was that 36,000,000 prescriptions were written for 1.2 billion tranquillizers, and it now constitutes a $250,000,000 per year retail business. Reports of local, state and federal law-enforcement officers and the U.S. Food and Drug Administration indicate that hundreds of thousands of barbiturate tablets or capsules are being sold illegally each year in the United States by professional criminals as well as by some manufacturers, pharmacists, and physicians [ 1] [ 17] [ 97] [ 110] .

TABLE 2

U.S. Department of Commerce census of manufacturers

 

Value of shipments including interplant transfers (Dollars)

 

1958

1954

Tranquillizers, sedatives and hypnotics
236 802 000 a
Not available
Barbiturates in preparation without other active agents
   
Parenteral
7 501 000 2 343 000
Oral solids (and liquids)
14 767 000 17 333 000
Other forms
4 214 000 4 009 000
Barbiturates in preparations containing other active agents
   
Oral solids and liquids
10 956 000 10 650 000
Other forms
2 639 000 3 543 000
All other hypnotics and seda-tives (except barbiturates and narcotics)
6 699 000 4 770 000
Tranquillizers, excluding Rau-wolfia preparations
   
Oral forms
126 615 000
-
All other forms
10 954 000
-
Tranquillizers, sedatives, hypnotics not specified by kind
209 000
-
Cough syrups, elixirs, expectorants (including narcotic preparations)
21 322 000 22 226 000
Containing anti-histaminics Not containing anti-histaminics
28 536 000  
Internal analgesics, narcotic (excluding cough and cold items, G.-I.) preparations
   
Parental
10 109 000 8 194 000
Oral
15 595 000 19 788 000
Other
2 517 000 57 000

a Not including undetermined amount reported as " not specified by kind ".

There are more than 7,000 drug and chemical wholesalers in the United States and more than 56,000 retail drug stores with total sales in 1960 of $7,530,000,000. Table 2 [ 103] shows a break-down of 1954-1958 shipments of tranquillizers, barbiturates, etc. Table 3 shows a break-down of the various barbituric acid derivatives, tranquillizers, etc. produced in 1960.

The most recent listing for physicians of approved drugs available for prescription [ 87] include 49 listed as hypnotics, and 136 as sedatives plus more than 100 different barbiturate preparations. A number of drugs are listed in more than one of these three categories, but the total number of preparations available is even greater if one includes the various forms of each drug, such as tablets, capsules, syrup, spansules, gradumets (two different long-release dose forms designed to dissolve at different time intervals to provide a sustained blood level usually for a twelve-hour period), suppositories, elixirs, etc. Many different manufacturers produce these drugs, and they are also often produced in combination with various other substances such as analgesics or antispasmodics. There are also available to the public more than 130 other preparations called " sleeping aids " with such names as At-Eaze, Dormeez, Doze-Off, Lullaby, Quietabs, Relax, Serene, Sominex, Super-Sleep and Tranquil (usually containing some combination of an anti-histaminic, aspirin, and belladonna or scopolamine). All of these are available without prescription since they do not contain barbiturates or other " habit-forming " drugs. An example of the range or recommended uses for the barbiturate drugs is the following quotation about nembutal gradumets (pentobarbital sodium 100 mg in a long-release dose form): " Especially useful for continuous daytime sedation, obviates the need for multiple small doses or other shortacting barbiturates for daytime sedation, obviates the use of longer-acting barbiturates which may produce cumulative effects; specific indications include anxiety, restlessness, irritability, and adjunctive use in dermatosis, allergies, hyperthyroidism, psychoneuroses, cardiovascular disorders, toxemia of pregnancy, menopausal syndrome, pre-menstrual tension, nausea and vomiting, motion sickness, gastro-intestinal disturbances." The only sedative or tranquillizer being produced in greater official or legal quantities than barbiturates is meprobamate, which although advertised as a tranquillizer has been shown to be pharmacologically more related to sedatives, including being addicting. One of the most heavily prescribed compounds is Dexamyl, or like combinations of amphetamines and barbiturates, seemingly considered a cure-all by many physicians.

TABLE 3

TABLE 3

Production and sales of barbiturates and tranquilizers (1960)

 

Sales

Medicinal chemicals

Production (pounds)

Quantity (1000 pounds)

Value ($1000)

Unit value ($ per lb.)

Barbituric acid derivatives, total
852 000 456 12 429 5.33
5-Allyl-5 (1-methylbutyl) barbituric acid (secobar bital) and salt
-
16 111 6.94
5-Ethyl-5 (l-methyl-n-butyl) barbituric acid (pen- tobarbital)
-
7 41 5.86
5-Ethyl-5 (l-methyl-n-butyl) barbituric acid, sodium salt
80 000 34 208 6.12
5-Ethyl-5-phenylbarbituric acid (phenobarbital, lumi nal)
270 000 237 703 2.97
5-Ethyl-5-phenylbarbituric acid sodium salt
17 000 11 42 3.82
All other
485 000 151 1 324 8.77
Tranquillizers (cyclic)
175 000 18 555 30.83
Tranquillizers: 2 methyl-2-n-propyl-l,3-propanediol dicarbamate (acyclic)
989 000 970 3 480 3.59

IV. Abuse and addiction

Figures and information cited above would tend to indicate that amounts of barbiturates far in excess of therapeutic needs are being produced and distributed. In doing the research for this monograph, it can be said that I learned much more about what is not known concerning the abuse of barbiturates than about what is known. As is brought out in a recent book on narcotics [ 25] , there is an astonishing lack of accurate and complete data, a predominance of opinion rather than fact, emotion rather than reason, lack of planning, omissions, duplications, and misuse of statistics. If this can be rightly said about the use and abuse of narcotics in America, it is all the more true about the problem of barbiturates. A special ad hoc panel on drug abuse appointed in 1963 by President Kennedy stated in its report that the present records of various agencies connected with drug abuse are frequently inaccurate, incomplete and unreliable, generally limited to individuals apprehended by enforcement agencies, and unco-ordinated with other agencies, thus demonstrating a marked need for a standard core of information common to all record systems [ 1] . They go on to state that there are large numbers of drug abusers who never come to the attention of the community; that there is increasing abuse of non-narcotic drugs concomitant with a decrease in the abuse of narcotics; that there is an entirely new and increasing abuse of drugs periodically on a spree basis; and that the possible abuse of barbiturates (and amphetamines) among juveniles may be increasing because they are cheaper, easier to handle, and more readily obtainable. One physician's estimate is that there are at least one million people taking sleeping pills in this country, with 10-25% of the habitual users being unsuspecting addicts. Another has said that there are 50,000 "true addicts" and many more habitues. I would hypothesize that the total number of people using barbiturates, other sedatives, stimulants and tranquillizers would approach five million, not to mention our several hundred thousand marihuana and narcotic users and 75,000,000 users of alcohol, including 6,000,000 alcoholics. There are also problems involving sniffing of glue or gasolene fumes, drinking cough syrups containing codeine and alcohol, and abuse of a whole range of other substances affecting the mind, including lysergic acid and mescaline (peyote).

The World Health Organization has given the following definition of drug addiction:

"Drug addiction is a state of periodic or chronic intoxication 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 generally a physical dependence on the effects of the drug;

" (4) Detrimental effect on the individual and on society." [ 1]

Wikler has suggested that the term "drug addiction" be restricted to the compulsive use of such agents as are harmful to the user or society, or both, and which for various reasons are condemned by the culture in which the individual lives. Isbell prefers restricting the term "addiction" to physical dependence, as distinct from habituation, which he defines as a state in which a person compulsively uses the drug as one of his major means of adaptation to stress. In common usage in the United States the term is used synonymously with illegal use or abuse of drugs which affect the brain. Without exception, all the individuals who have studied this problem agree that there is extensive abuse of the barbiturates, that it constitutes a serious social and health problem, and that it is increasing.

TABLE 4

Habit-forming drugs specified in section 502 (d) of the Federal Food, Drug andComestic Act

PARENT SUBSTANCE, BARBITURATE ACID

Chemical description of derivative

Common or official name of chemical derivative or its salts

Some trade or other names of chemical derivative or its salts

5-Allyl-5-cyclopentenylbarbituric acid
 
Cyclopal
   
Cyclopen
5-Allyl-5-isobutylbarbituric acid
Allylbarbituric acid
Sandoptal
 
Allylisobutylbarbituric acid
 
5-Allyl-5-isopropylbarbituric acid
Aprobarbital
Alurate
 
Allylisopropylbarbituric acid
Numal
 
Allylisopropylmalonylurea
 
5-Allyl-5-isopropyl-l-methyl-barbituric acid
 
Narconumal
5-(2-Bromoallyl)-5-isopropyl- l-methylbarbituric acid
 
Eunarcon
5-(2-Bromoallyl)-5-(1-methylbutyl)-barbituric acid
β-Bromoallyl sec-amylbarbituric acid
Sigmodal
   
Rectidon
   
R239
5-sec- Butyl-5-(2-bromoallyl)-barbituric acid
Butallylonal
Pernoston
   
Pernocton
5,5-Diallylbarbituric acid
Diallyl barbituric acid
Dial
   
Allobarbital
   
Allobarbitone
   
Curral
   
Diadol
5,5-Diethylbarbituric acid
Barbital
Deba
 
Barbitone
Dormonal
 
Diethylbarbituric acid
Hypnogene
 
Diethylmalonylurea
Malonal
   
Medinal
   
Sedeval
   
Veronal
   
Uronal
   
Vesperal
1,5-Dimethyl-5-(1-cyclohexenyl)-barbituric acid
Hexobarbital sodium
Cyclonal sodium
   
Dorico soluble
   
Evipal sodium
   
Evipan sodium
   
Hexanastab
   
Hexobarbitone sodium
   
Methenexyl sodium
5,5-Dipropylbarbituric acid
Dipropylbarbituric acid
Proponal
5-Ethyl-5-butylbarbituric acid
Butethal
Etoval
 
Butobarbital
Neonal Butobarbital
   
Soneryl
5-Ethyl-5-sec-butylbarbituric acid
Butabarbital sodium
Butisol sodium

TABLE 4 ( continued )

Chemical description of derivative

Common or official name of chemical derivative or its salts

Some trade or other names of chemical derivative or its salts

5- Ethyl-5-(1-cyclohexenyl )-barbituric acid
Cyclobarbital
Cyclobarbitonc
   
Namuron
   
Palinum
   
Phanodorm
   
Phanodorn
   
Tetrahydrophenobarbital
5-Ethyl-5-cyclopentenyl-barbituric acid
 
Pentenal
5- Ethyl-5-hexylbarbituric acid
Hexethal sodium
Hebaral
   
Ortal sodium
5-Ethyl-5-isoamylbarbituric acid
Amobarbital
Amytal
5-Ethyl-5-isoprophlbarbituric acid
Probarbital
Ipral
5-Ethyl-5-(l-methylbutyl)-barbituric acid
Pentobarbital sodium
844
 
Soluble pentobarbital
Embutal
   
Nembutal
   
Napethal
   
Pentyl
5-Ethyl-5-(1-methylbutyl)-2-thiobarbituric acid
Thiopental sodium
lntraval sodium
 
Thiopentone sodium
Nesdonal sodium
   
Pentothal sodium
   
Thiothal sodium
5-Ethyl-5-(1-methyl-l-butenyl)-barbituric acid
Vinbarbital
Delvinal sodium
5-Ethyl-5-phenylbarbituric acid
Phenobarbital
Barbenyl
 
Phenobarbitone
Barbiphenyl
 
Phenylethylmalonylurea
Dormiral
   
Euneryl
   
Gardenal
   
Luminal
   
Nunol
   
Neurobarb
   
Phenonyl
   
Somonal
5-Ethyl-5-phenyl-1-methylbarbituric acid
Mephobarbital
Mebaral
   
Phemitone
   
Prominal
5-Ethyl-5-(l-piperidyl)-barbituric acid
 
Eldoral
5-Isoprophyl-5-(2-bromoallyl)-barbituric acid
Propallylonal
Noctal
   
Nostal
5-Methyl-5-phenylbarbituric acid
Phenylmethytbarbituric acid
Rutonal
All lithium, sodium, potassium, magnesium, calcium, strontium, and ammonium salts of the foregoing chemical derivatives of barbituric acid
   
Sodium-5-allyl-5-(l-methylbutyl)-barbiturate
Secobarbital sodium
Seconal sodium
 
Soluble secobarbital
Evronal sodium
All salts of the foregoing chemical derivatives formed by replacing the sodiumwith lithium, potassium, magnesium, calcium, strontium, or ammonium radical
   

Senator Thomas Dodd, Chairman of the U.S. Senate Subcommittee on Juvenile Delinquency, stated this year that five billion dangerous-drug (barbiturates and amphetamines) pills find their way into the illegal market each year, that these are produced almost entirely by American firms, and that the use of these drugs by juveniles and young adults is mushrooming all over the country. He went on to add that these drugs cause people to commit various serious crimes; that they are increasingly used by children who formerly were not delinquent; that in some places the drugs have become substitutes for heroin; and that in Los Angeles since 1954 arrests involving dangerous drugs have increased 468 %. Some say that the group using barbiturates most frequently consists of 30-50-year-old urban women.

In a similar vein the California Attorney-General has claimed that there is a new and growing problem with the dangerous drugs, and a whole new class of addicts is being created. He cites the California figures which show that the number of arrests for dangerous-drug offences (no distinction being made between amphetamines and barbiturates) climbed 31% from a figure of 3,807 in 1960 to 5,016 in 1961. Similar situations are said to exist in San Diego and San Francisco with half the juvenile drug arrests involving misuse of the dangerous drugs. However, the San Diego figures include those individuals turned over for prosecution by the U.S. Bureau of Customs for illegally bringing dangerous drugs across the Mexican border into California. Newspapers in San Francisco, Washington, D.C., and Texas have reported serious and growing problems with the promiscuous sale and use of barbiturates. The Executive Director of the New York City Youth Board has reported that 25 % of the children studied by his agency are involved in the use of drugs ranging from narcotics to barbiturates. The Director of the Student Health Service at the University of California has publicly expressed concern about the peddling of barbiturates and tranquillizers to students. The Police Director of Newark, New Jersey, has described an alarming increase in use of, and addiction to, barbiturates by teenagers since 1959 along with a doubling of the death rate from barbiturate poisoning. Until August 1962 there was no law in New Jersey making sale or possession of barbiturates illegal.

They now have penalties of up to one year in prison. Newark has also conducted an extensive educational campaign with schools and businesses, and has enlarged its narcotics bureau.

Multiple or combined use of various drugs must also be occurring to an unknown extent, particularly joint use of barbiturates and alcohol. This would be of special significance in terms of the nearly 40,000 highway deaths and much greater number of injuries occurring yearly in America, with one-third to one-half associated with drinking. California has made it unlawful for a person to drive while under the influence of any dangerous drug (including barbiturates)" to a degree which renders him incapable of safely driving ". Fines and jail sentences are stipulated with the penalty increasing if bodily harm results. Nearly 20,000 deaths by suicide and 1,700 accidental deaths from poison occur yearly, with 3,000 per year or more being attributed to barbiturates. New and tighter laws on the use and sale of barbiturates are now being called for in California, Texas, Indiana, Hawaii and other states. A growing body of similar anecdotal and statistical material now exists to sketch the framework of the problem with the precise details not yet available.

Despite conclusive evidence to the contrary, many physicians in the United States appear to think and act as though barbiturates are completely harmless drugs that can be prescribed in unlimited quantities. While doctors deny the dangers, police officers continue to collect data showing a relationship between these drugs and delinquency. The addicting properties also seem unknown or are denied by many physicians with both ignorance and callousness seeming to be involved. As the President's panel pointed out, the medical community has yet to define the range of legitimate medical use of these drugs. Individual doctors and medical-association representatives repeatedly minimize or deny the existence of any barbiturate problem, with such statements as " I have prescribed barbiturates for thousands of patients in thirty years of practice, and have never seen a single case of addiction." The pharmaceutical manufacturers and the American Medical Association have both opposed increased governmental control of the barbiturates [ 105] , and in 1962 they were successful in having Congress eliminate a key section dealing with barbiturates from the new drug control legislation passed following the world-wide thalidomide debacle. Illustrative of at least three major medical errors in the clinical use of barbiturates was another event heard around the world, the tragic death of the motion-picture actress Marilyn Monroe. Despite long evidence of emotional instability and severe depression, Miss Monroe's physicians, including a psychoanalyst, according to newspaper reports, had been prescribing barbiturates for many months; prescribing them in large quantities far in excess of ordinary use, and also prescribing concurrently other sedatives and tranquillizers; and permitting her to refill large prescriptions within a short period of time - e.g., 50 pentobarbital capsules obtained just prior to her suicide only a few days after a previous 50 had been prescribed. The United States Public Health Service has stated that, although useful depressants of the central nervous system when taken in small amounts under medical supervision, the barbiturates can be dangerous, intoxicating drugs, habit-forming and addictive when taken in large and uncontrolled amounts [ 109] . That some, probably large, segment of the barbiturate problem is iatrogenic seems indisputable with drugs being loosely and hurriedly prescribed for patients whom the doctor is too busy to talk with or examine thoroughly. A letter sent to me last year by a Los Angeles woman illustrated this point. She had written as follows to a doctor who opposed more stringent controls of the barbiturates: " The experience of living with a barbiturate addict is a hell in which you wander helplessly, receiving little or no help from the medical profession. Why don't you doctors think when you prescribe pills? Probably a pill is the easy way out for you - but how about the families who bear the later burden? "

Full size image: 22 kB

Acute intoxication or poisoning from barbiturates accounts for about 25 % of all patients admitted to general hospitals with some form of poisoning. In addition to the number of deaths mentioned above, there are indications that acute barbiturate intoxication is increasing at an alarming rate. In 1958 alone, 1,111 cases of barbiturate poisoning were reported to the New York City Poison Control Centre. As with the other facets of this problem, comprehensive nationwide statistics are not available. Mild, moderate, and severe forms of acute barbiturate intoxication have been described. These are differentiated primarily by the degree of unconsciousness with the severe form involving a comatose patient who cannot be aroused by stimulation, slow and shallow respiration, markedly depressed reflexes, rapid pulse, and a fallen blood pressure. The details of diagnosis and treatment of this condition have been described in many clinical reports [ 60] . The literature indicates that a wide variety of treatments are utilized, and that no single treatment has gained universal acceptance. The main difference of opinion centres around whether or not to utilize central nervous system stimulants or analeptics in addition to supportive measures. Dobos et al. [ 21] , in a study of 141 patients, found that those treated with amphetamine, caffeine, or picrotoxin did no better than those treated supportively with regard to the duration of coma, number of complications, or mortality rate. Other writers have advocated use of Metrazol, bemegride, ACTH, electro-stimulation, hemodialysis, and more recently Tham (trishydroxymethylaminomethane), a buffer and diuretic. Whatever regimen is used, there seems to be an overall mortality rate of about 4 %.

With a now classical series of papers published in the early 1950s [ 35] [ 37] [ 63] [ 64] [ 65] Isbell and his co-workers at the Addiction Research Centre in Lexington, Kentucky, conclusively demonstrated that barbiturates taken regularly in large quantities produce all three of the characteristic symptoms of addiction: tolerance, physical dependence, and psychic dependence or habituation. Ingestion of less than 0.4 g daily for six weeks or more will be followed by minor withdrawal symptoms if the drug is abruptly discontinued; up to 0.6 g daily for a comparable period of time will produce moderate symptoms including anxiety, tremor and weakness, if abruptly withdrawn; and 0.8 g or more daily for six weeks or longer will produce severe addiction and withdrawal, with an average of 75 % of such patients having convulsions and 60 % a toxic psychosis or delirium. The symptoms of chronic intoxication are similar to those of chronic alcoholism, inducing similar changes in the functioning of the central nervous system. It has been found that adequate doses of either alcohol or barbiturates will suppress the withdrawal symptoms arising from addiction to the other. Barbiturate addicts generally prefer the short-acting compounds, pentobarbital or secobarbital.

Withdrawal or abstinence symptoms develop within eight to sixteen hours after the drug is discontinued, progressing in the untreated case to convulsions on the second day, and delirium on the third day. Abrupt withdrawal of barbiturates from addicted persons is absolutely contraindicated. The treatment of choice is to stabilize the person for several days on an amount of one of the rapid-acting barbiturates sufficient to maintain a continuous state of mild barbiturate intoxication (usually a dose of 0.2 to 0.3 g every six hours). Gradual withdrawal of 0.1 g daily is then begun until the patient is completely withdrawn. Present evidence would be against placing reliance on anticonvulsant drugs or tranquillizers during the withdrawal period. Following successful completion of the withdrawal treatment, there should begin the much more difficult long-term treatment to prevent a relapse to the use of the drug.

V. Causes

A complex combination of pharmacological, sociological and psychological forces undoubtedly interacts in a particular individual to produce abuse of or addiction to the barbiturates or other drugs affecting the central nervous system.

Among the sociological factors would be accessibility and availability of the drug either through illegal channels or by too-ready and excessive prescription on the part of physicians; attitudinal tolerance towards the use of the drug by one's family, peer group, or society; advertising pressures; disturbed family or social relationships; general national and international tensions; availability of other possible outlets for anxiety or tension; and chance exposure to the drug with experience of " euphoria ". A group much broader than those who ordinarily use narcotics appears to be involved in barbiturate abuse in terms of socio-economic class, prior delinquency, or psychological makeup.

Numerous psychiatric explanations have been proposed for drug addiction ( [ 2] - [ 125] ). These are invariably speculative, descriptive, and non-specific. Most are untestable or based only on a single class of variables. Furthermore few barbiturate "addicts " have been intensively studied as such, so that theoretical formulations come primarily from study of narcotic addicts. Addicts have been described as immature, suspicious, intolerant of stress or frustration, passive and over-dependent. Most drug addicts are diagnosed as having some form of character disorder (inadequate personality, etc.) or to a lesser extent, neurosis.

As far back as 1919 [ 99] it was suggested that neurotic individuals use chemical agents to seek relief from anxiety (" negative euphoria "); psychopaths for elation (" positive euphoria "); psychotics to relieve depression; and normals to relieve pain. Where physical dependence occurs it would be an undesired side effect which would make euphoria more difficult to attain.

Psychoanalytic formulations speak of the addict as a person whose psycho-sexual development has been arrested at, or has regressed to, the oral level with resulting frustration, hostility, self-destructiveness, and depression. The drug then serves to relieve these symptoms, in part by inducing euphoria. A predisposition to use drugs is considered to exist prior to the actual experience.

Wikler [ 125] has proposed a " pharmaco-dynamic formulation " which says that different classes of drugs alter patterns of behaviour in different ways, through different effects on motivations of a primary or secondary nature. The drug use is an attempt at self-therapy and the choice of a particular drug depends upon whether it facilitates or hinders specific patterns of behaviour acceptable to the user. He suggests also that the self-perpetuating nature of barbiturate use is related directly to its pharmacologic properties, as is the case with opiates. Also as tolerance develops, a new motivation, the relief of withdrawal symptoms, becomes a major source of gratification, replacing other drives - e.g., in narcotic addicts: pain, sexuality, and expression of aggression. Ultimately complications of a legal, economic, family, vocational or health nature ensue and "treatment" becomes necessary and may be imposed upon the person. Relapse is affected by the pleasure in the instantaneous relief of abstinence provided by the drug, by the occurrence of conditioned symptoms long after " cure "; and by rejection on the part of society.

Another possible conceptualization is the Pavlovian concept that in relatively low dose ranges barbiturates augment "internal inhibition" with large doses possibly exerting an opposite effect. Masserman and Siever [ 79] concluded that amobarbital disorganizes recently formed, intricate, and complexly motivated adaptive patterns into earlier and more direct perception-responses, thereby temporarily mitigating experimentally induced neurotic behaviour. Bailey & Miller [ 4] found that amobarbital produces a greater decrement in the avoidance motivated by fear than in the approach motivated by hunger. Hill et al. [ 55] found in man that pentobarbital did not reduce anxiety associated with anticipation of pain.

Addiction may exist m individuals with all types of personality organization (and addicts may recover without any apparent change in personality). Chein's work [ 15] on the premorbid personality of addicts showed specific psychiatric disturbances predisposing to addiction. Gerard [ 42] held that all juvenile (narcotic) addicts were very disturbed individuals who would probably have required help in meeting their problems whether or not they took drugs.

From all this we can go on to agree with Wikler [ 122] that behavioural effects are not isolated, elementary changes in consciousness, perception, emotion, ideation or learning which are simply increased or decreased by depressants or stimulants, but are complex patterns of change proceeding in time, involving all of these aspects of behaviour to varying degrees, and dependent not only on the drug, but also on biographical and environmental factors.

Thus to understand the causes of barbiturate abuse requires a multi-factorial, multi-dimensional approach with much fuller use of experimental methodology including controls, objective measurements, statistical techniques, and operational definitions.

VI. Treatment, prevention and research

The treatment of Overdosage and of physical addiction has been described above. The difficult problem is to treat the chronic underlying illness which we might call " barbiturism " (if we can redefine that term to parallel alcoholism). For best results the heavy user or addict to barbiturates should be hospitalized both for management of withdrawal and for institution of long-term treatment. Thorough psychiatric evaluation and physical rehabilitation should come first, followed whenever possible by vocational training, social-work services, and psychiatric treatment, including group and individual psychotherapy. Adequate facilities for such hospital treatment are rarely available, and even less available are out-patient facilities where the services and treatments begun in the hospital could be continued. The failure of physicians to recognize this illness also presents a barrier.

It is unlikely that treatment, even if extensively available and maximally effective, will ever solve what is apparently a large and growing problem. Preventive measures based upon extensive education of physicians and the public about the proper uses of barbiturates and upon widespread research beginning with the compilation of accurate statistics are the only things likely to be successful. A punitive approach of increasing penalties for excessive or illegal use of barbiturates will not stem the tide of social and psychological forces leading to addiction. Preventive approaches that might be used in addition to education include decreasing the availability of barbiturates; removing existing sources of " infection " (addicts via treatment and pedlars via prison) from the community; reducing the number of potentially susceptible individuals by mental health programmes, by correction of deleterious social and economic conditions, and by allowing alternative, constructive outlets for anxiety and frustrations.

Innumerable research projects are necessary before we " solve " the problem of barbiturates. This should include comparative studies of regular, irregular, and non-users of barbiturates to be correlated with personality and with cultural background; study and comparison of various treatment methods and programmes; longitudinal studies of the natural history of " barbiturism ", with and without treatment, epidemiological investigations; further study on the mechanisms of action of barbiturates and the physical basis of addiction; systematic evaluation of current legislation and law enforcement methods; and development of accurate and detailed national statistics so that programmes can be based on a solid foundation of fact rather than opinion, and reason rather than emotion.

VII. Present and proposed legislation and enforcement

A 1952 report of the Expert Committee on Addiction-producing Drugs of the World Health Organization recommended increased national controls over barbiturates, including dispensing only on prescription, specifying thenumber of times a prescription may be refilled, and keeping a careful record of all prescriptions. At subsequent sessions, the Committee stated that barbiturate consumption continued to increase and constituted a danger to public health, and expressed the view that while, at the time, control measures at the national level were sufficient, they needed close attention and in some instances definite strengthening. The Expert Committee also expressed the opinion that barbiturates are habit-forming and, in some cases, can produce true addiction (characterized by physical dependence).

Meanwhile, the United Nations Commission on Narcotic Drugs, a functional organ of the United Nations Economic and Social Council, had placed the question of barbiturates on its agenda in 1956, and in 1957 passed a resolution recommending governments to take the appropriate legislative and administrative measures of control to prevent their abuse. In its 1960 session the Commission, like the WHO Expert Committee, expressed the view that barbiturates should not be sold without medical prescription except where a very weak preparation was involved. Subsequently two attempts, one at the Plenipotentiary Conference for the Adoption of a Single Convention on Narcotic Drugs, held in New York in 1961, and the other at the 1962 session of the Commission on Narcotic Drugs, both narrowly failed to command enough support for a move towards the international control of barbiturates. However, the 1962 session of the Commission on Narcotic Drugs confirmed that the abuse of barbiturates still represented a social danger and a danger to public health, and recommended governments to take the appropriate measures to place the production, distribution and use of these drugs under strict control.

The so-called Durham-Humphrey Amendment enacted in 1951 was the first federal legislation in the United States to specifically restrict barbiturates (and amphetamines) to prescription and refill only upon the authorization of a physician. The Congress also said that the barbiturates posed a special problem not common to all drugs, because they are desired by addicts for non-medical use and predicted this would call for further legislative controls in the future.

A Presidential Interdepartmental Committee surveyed the problem in 1954, pointed out similarities between the individual and social problems raised by narcotic abuse and those raised by barbiturate abuse, going on to recommend study of the extent and effects of the improper use of the barbiturates in order to determine what federal, state and local regulatory controls would be necessary. Committees of both the House of Representatives and Senate of the 84th Congress received testimony on the barbiturate problem in this country. The House Committee concluded that the barbiturates, unlike narcotics, should be regulated under the commerce power of Congress rather than the taxing power, and that more stringent federal control over the manufacture and distribution of these drugs was necessary [ 106] . They also made a series of detailed recommendations which tragically have yet to be adopted. A bill introduced at that time to amend the federal Food, Drug and Cosmetic Act would have prohibited the manufacture, sale or possession of barbiturates except by persons specifically authorized by the bill, and would have required that records be kept of all transactions involving barbiturates. This bill and other subsequent Congressional bills to increase controls on barbiturates, failed to pass. As Stephens [ 98] has said: "The public health problem commented upon by Congress has not improved and in fact has worsened since 1956 with large amounts of barbiturates escaping from legitimate channels of commerce at every level of the chain of distribution."

Current federal law in the United States applies solely to barbiturates shipped in interstate commerce; requires no inventory control; and does not require that copies of purchase orders for these drugs be made available for inspection by appropriate government agencies. Those barbiturates shipped in interstate commerce must meet certain standards of strength and quality and must bear the statement, "Caution: Federal law prohibits dispensing without prescription ". The recently adjourned 1962 session of Congress specifically rejected provisions to increase controls on barbiturates (H.R.11581 and S.1552). If passed, this would have limited the manufacture, compounding, processing, or possession of barbiturates (and amphetamines) to certain specifically enumerated classes including registered manufacturers, pharmacists, physicians, researchers, etc.; would have prohibited the manufacture or sale of such drugs by those not authorized by law; would have required detailed records to have been prepared and kept for three years of all such drugs manufactured or sold and to whom; and would have authorized inspection and inventory by designated officials. This proposed legislation, and previous attempts to improve the controls on barbiturates was opposed in whole or in part by the Pharmaceutical Manufacturers Association, the National Association of Retail Druggists, and by the American Medical Association. These special interest groups in their testimony claimed that the FDA wanted excessive authority and such legislation was unnecessary, discriminatory, and based on insufficient inquiry (despite extensive hearings going back to 1955). The Congressional testimony indicates that from 1 July 1949 to April 1962 over 1,100 cases were prosecuted (144 in the fiscal year 1961 alone) involving illegal sales of prescription drugs (a "substantial" portion of which were barbiturates) byretail druggists and 1,900 defendants were convicted. During that same period only 17 cases against physicians were prosecuted with a total of 20 convictions. A separate bill, which was introduced in Congress in 1962 without being acted upon, would have regulated importation of barbiturates, provided for seizure of drugs brought in illegally, and set minimum and maximum sentences for importing, buying, selling, receiving, or concealing such drugs.

Among the complicated and dangerous factors brought out by the lengthy Congressional hearings on the drug industry and by the experience of the experts of the Food and Drug Administration is the practice of the drug manufacturers of selecting only " co-operative " physicians for clinical testing of drugs, often writing their papers for them, seeing that they are published when favourable, and suppressing negative results or reports of adverse effects. In addition, the American Medical Society, which derives one-half of its total income from advertising revenue in its journals, seven years ago drastically reduced its standards of accuracy and truthfulness for advertising. Among the advertising statements at present being published are the following examples, some of which were cited in the above-mentioned Congressional investigation of the drug industry: "When you prescribe a single morning dose... she will stick to her diet more willingly. She will feel better all day long "; " Provides a night of undisturbed rest virtually identical to physiologic sleep "; "In obstetrics, gynaecology, well tolerated for use during complete pregnancy cycle "; "Unsurpassed safety, prompt action and a cheerful wakening without hangover ";" So gentle, yet so persuasive, sure as the sunrise ", etc. The advertisements commonly used attempt to convey images of youth, beauty, radiant health, serenity, happiness, security, pleasure, and sometimes sexuality. They frequently attempt to stress that the drug is completely safe, non-addicting, and without side effects. They are often full of non-sequiturs, incomplete information, distortions and misrepresentations. The busy practising physician would ordinarily use a sedative drug on the basis of what he has seen in the advertisements about its safety and efficacy.

Internal bureaucratic conflicts have also hampered passage of new legislation in this field, including such things as arguments over whether the Food and Drug Administration or the Federal Bureau on Narcotics should handle the enforcement, and if it were the Food and Drug Administration, should they have police power. Effective operation of the Food and Drug Administration, even within the present quite limited federal legislation, is hampered by insufficient personnel and budget. The FDA carries on its programme against illegal distribution of barbiturates mainly through 600 inspectors located in 18 district offices across the United States. Only one part of the day-to-day activities of these inspectors involves surveillance of prescription drugs to prohibit illegal sale without prescription. Investigations of illegal sales are undertaken when information is received indicating violations of the Durham-Humphrey Amendment either by pharmacists or totally illicit outlets. Fewer than ten physicians are available in the FDA to review reports on inspection findings (or on advertising practices).

The new general legislation passed by Congress in 1962 following the thalidomide controversy, in order to " insure the safety, efficacy, and reliability of drugs, authorize standardization of drug names, and clarify and strengthen existing inspection authority ", provides for factory inspection and requires that manufacturers of drugs (including barbiturates) register with the government. Thus, bootleg production of barbiturates will now be illegal, but the FDA will be unable to do anything when they discover violations upon inspection unless interstate commerce is involved. Present penalties of a $1,000 fine plus one year in jail may be adequate if they can be invoked against violators. When the FDA finds a user of dangerous drugs, they must work backwards to try to catch the supplier furnishing drugs illegally but, since interstate shipment must be proved and since no records are available for inspection, they must rely on circumstantial evidence, which is difficult and time-consuming to prepare.

Other federal laws and another federal agency, the United States Custom Service, are also involved with the illegal traffic in barbiturates, particularly at the Mexico-California border. Considerable testimony by law enforcement officials in California states that huge quantities of barbiturates manufactured by American companies are shipped to Mexican border towns where they are sold without prescription to American consumers. A single firm shipped one million tablets into one Mexican town within 23 days, and another firm shipped 600,000 tablets into the same town in a three-day period. These drugs are sold by the manufacturer for 76 cents per thousand units, and are peddled illegally for 10 cents a unit, or more than 1,000% profit. In the fiscal year 1960, the United States Custom Service seized only 33,635 units of dangerous drugs purchased in Mexico and smuggled into the United States. No specific penalties exist against such smuggling and, when detected, it is handled in the same manner as would be smuggling of clothing, etc.

One further abuse which appears to require federal regulation is the mail-order business of providing small or large quantities of barbiturates and other drugs to anyone writing in claiming to be a physician or pharmacist. Such orders are filled by out-of-state drug manufacturerswithout investigation of the legitimacy of the person ordering the drugs. Again, since present federal laws do not require that records be kept or that the government receive duplicates of purchase orders, no effective control exists for this form of illegal trafficking.

It has been pointed out by the FDA that in order to make regulation and protection of interstate commerce in barbiturates effective, regulation of intrastate commerce is necessary because such drugs, when held for illicit sale, often do not bear labelling showing their places of origin and because, in the form in which they are held or consumed, a determination of their place of origin is sometimes difficult or impossible. They also state that to subject interstate commerce to the needed controls without applying them to intrastate commerce would have the effect of discriminating against and depressing interstate commerce.

Paralleling the federal concern and development of legislation, there has been concern in various states about the abuse of barbiturates. Back in 1955 the Council on State Governments proposed a model state barbiturate act for those states which might require new legislation or might wish to broaden or strengthen their existing legislation. This act would require careful and specific record-keeping, including inventories and prescriptions; ban refills of prescriptions unless specifically authorized; require physicians to confirm telephone orders for a drug in writing within seventy-two hours; prohibit possession of the drug unless prescribed by a physician; bar the use of fraud, deceit, misrepresentation, or subterfuge in obtaining the drug; require that records be open to inspection, and provide for a fine up to $1,000 or imprisonment for not more than one year or both for a first offence and a combination of $10,000 or three years, or both, for a subsequent offence.

Most state food and drug laws are very inadequate, particularly in their enforcement provisions. The present California law is probably the most adequate in this respect [ 86] . This law states that any person who possesses a hypnotic drug without a prescription is guilty of a misdemeanour; any person furnishing a dangerous drug to an adult except upon prescription is guilty of a misdemeanour; any person furnishing a hypnotic drug to an adult without having a licence to do so is guilty of a misdemeanour (when furnished to a minor it is considered a felony). Prescriptions for dangerous drugs may be refilled at any time upon the oral authorization of the physician or by the written authority on the original prescription. Those licensed to furnish hypnotic drugs and all physicians, dentists, chiropodists and veterinarians are required to fill out a hypnotic-drugs purchase order form in triplicate for each order from a supplier. The original and duplicate orders must be forwarded to the supplier. Any person who alters or forges the quantity of dangerous drugs in any prescription or who uses a forged prescription is punishable by a fine of $100 to $500 for a first offence and imprisonment from six months up to six years for subsequent offences. No inventory control, record keeping or inspection is required. Those who ship barbiturates into California must be registered with the State Board of Pharmacy. In 1960 the legal sale in California alone of sedative and hypnotic drugs totalled $4,000,000. Not even rough estimates of the illegal sales are available.

It has been announced that during this fiscal year the Food and Drug Administration will survey state and local food and drug laws and facilities to determine what improvements are needed.

VIII. Conclusions and recommendations

  1. Adequate objective data are not at present available to draw final conclusions about the dimensions of the barbiturate problem (barbiturism) in the United States or to propose complete " solutions "

    It seems vital before more years pass that new or already existing state and federal agencies be assigned the specific responsibility of compiling and maintaining accurate statistics about the production, sale, users, prescribing, abuse, arrests, convictions, sentences, hospitalizations, suicides, driving offences and other data involving barbiturates. Similar data should also be collected on the other sedatives, hypnotics, tranquillizers and on narcotics, alcohol and stimulants, including interrelationships with barbiturates.

    To facilitate the compilation of accurate data, such things as physicians' prescriptions and distributors' shipments should be recorded in duplicate with one copy going to the above-mentioned agency. This might be accomplished easily by the use of partially prepunched IBM cards which could be tabulated by computers as they come in.

  2. The figures on production and prescribing of barbiturates, the statements of physicians minimizing or denying any problem, and the law enforcement reports all indicate serious deficiencies of knowledge and practice on the part of the American medical profession in regard to the barbiturates.

    Either organized medicine must " clean its own house " by establishing responsible standards for prescription of the barbiturates or legal controls should be instituted to insure that prescriptions for barbiturates be limited to an amount that would not be sufficient in quantity or length of time prescribed to produce habituation or addiction and would be less than lethal if consumed all at once. These prescriptions should have the amount written both in figures and words, should notbe refillable without a new prescription (or at the least should state in writing the minimum time between refills and the maximum number of refills) and should not be given for simple insomnia or daytime sedation or as treatment for emotional problems.

    In part this is an educational problem and should be combined with additional educational efforts directed at physicians, particularly psychiatrists, and beginning in medical school, about the nature and extent of habituation and addiction and about the prevention, diagnosis and treatment of barbiturate addiction.

    A genuine doctor-patient relationship should exist with thorough history-taking and physical examination before prescribing barbiturates.

  3. Manufacturers, distributors, and dealers in barbiturates should be strictly regulated and controlled through uniform federal legislation to prohibit misleading, incomplete, or false advertising claims; to require registration and licensing; to require that complete inventories and records be maintained of all transactions involving barbiturates and that these records be open to official (and regular) inspection at any time; to permit shipping or handling only by federal purchase orders (in duplicate with a copy to the federal agency) and only by and to those having legitimate need; and to make illegal intrastate, interstate, and international Shipments a federal offence.

    Prescriptions of these drugs should carry a prominent label warning both about its being habit-forming and dangerous to take before driving (or performing other highly skilled acts).

  4. International action has already been taken (see page 27 above) in the form of recommendations for countries to watch out in this field; such action should be taken again in order to bring about legislative changes in countries which do not require prescription for barbiturates so that such countries would establish penalties for illegal possession and do their best to prohibit shipment or transport into another country if and when that country has declared the entry of such drugs on its territory as illegal. Along with this the U.S. Customs Bureau needs to be made aware of that danger and given additional powers to deal with the importation of large amounts of barbiturates into this country in the same way as it is empowered to stop other dangerous imports.

  5. Professional societies and licensing boards for physicians and pharmacists in each state should maintain active educational programmes for their members and licensees, and should institute formal regulations and penalties for abuses in prescribing or selling barbiturates.

    These groups and such organizations as the American Medical Association should also take a positive active role in supporting badly needed state and federal legislative controls as outlined in the above recommendations.

  6. Extensive educational and preventive programmes for the general public should be instituted beginning at the high-school level (10th to 12th grade) and stressing objective, detailed, technical presentations by knowledgeable teachers, health educators or experts in the field. The content should include the proper uses of barbiturates and other dangerous drugs; the physiological and psychological effects; and the possible dangers of habituation, addiction, or driving under the influence of these drugs.

    There should also be a public health educational effort to counteract the apparently widespread beliefs and attitudes fostered by our mass media and advertising industry, that sedatives and tranquillizers are harmless, easy, non-addictive " answers " for worry, tension, business and family problems, etc.

  7. Illicit possession or sale of barbiturates should be made a criminal offence, but care should be exercised to establish penalties that are reasonable deterrents rather than (paradoxically) creating a greater criminal problem and increased illegal traffic through excessive penalties.

    Driving vehicles under the influence of barbiturates should be prohibited and penalized in the same manner as driving under the influence of alcohol.

    Local, state and national law-enforcement agencies should give increased attention to the barbiturate problem and to improving their co-operation and co-ordination, which are often sadly deficient.

  8. In line with the 1962 recommendations of its Citizens Advisory Committee, the Food and Drug Administration should be reorganized with scientist-administrators in top-policy positions and increased attention to education of physicians and the general public. I believe that the FDA should also be given an increase in budget, personnel and enforcement powers to carry out my recommendations made above as well as their present responsibilities.

  9. Specific, specialized treatment and rehabilitation programmes should be established for barbiturate abusers. This should include general hospital treatment for withdrawal when necessary and outpatient rehabilitation (similar to that now in existence for alcoholism) including psychotherapy, social work services and, where a law violation has occurred, intensive probation or parole supervision.

    In the meantime, existing rehabilitation programmes for alcoholics or narcotics addicts should be modified or expanded to include barbiturate (and stimulant) abusers.

    Civil commitment procedures should be established for barbiturate addicts to permit lengthy voluntary or involuntary hospitalization when necessary without criminal stigma.

    Barbiturates Anonymous (B.A.) chapters or groups should be organized in our major cities along lines parallel to Alcoholics Anonymous or Narcotics Anonymous in order to provide an additional avenue of treatment.

    Simple, practical chemical testing methods for barbiturates in urine or blood should be developed and then widely used for detection of possible illicit use in connexion with driving, criminal offences, diagnosis of unconsciousness, and as part of rehabilitation or control programmes (analogous to the use of Nalline with narcotic addicts).

    Since an increasing proportion of the American public depends upon medical insurance to help pay hospital costs, we need to include coverage for barbiturate addiction in such plans.

  10. Accelerated research programmes are necessary to ascertain the psychological and sociological reasons for drug use and the choice of a particular drug; the factors leading to abuse and addiction; and a host of other unsolved problems (see section VI). Only a small fraction of federal research funds have been given for research on addiction with almost none for barbiturates per se.

  11. Safer and less toxic, but equally effective and dependable drugs should be sought as replacements for the barbiturates. A sedative or hypnotic without concomitant euphoriant properties or one with an unpleasant taste or odour - e.g., paraldehyde - might reduce habitual use. Tranquillizers fulfil these criteria only to a limited extent, and several of the ones in common usage such as Librium (chlordiazepoxide), and Miltown or Equanil (meprobamate) actually appeared to be misrepresented as tranquillizers since they are pharmacologically closer to sedatives and have been reported by several objective observers to have the same addicting properties as the barbiturates [ 26] [ 56a] .

    The inclusion of corrective [ 73] or safeguard drugs in barbiturate preparations should be tried more widely to ascertain whether it will prevent fatal overdoses from being taken.

  12. While all of the above are attempted or accomplished, we must also seek to correct the general social and psychological problems underlying abuse of barbiturates - the disturbed family relationships; feelings of cynicism, rootlessness or rebellion; immaturity and aimless thrill-seeking. We must simultaneously reduce the number of potential addicts, reduce the availability of drugs, and decrease attitudinal tolerance towards the drugs.

    We are dealing here with a problem that affects many more people than narcotics addiction, yet has received far less attention. However, it will do us little good if the barbiturates, because of the growing reports of their dangers, fall into ill-repute as did the bromides, only to be replaced with another equally harmful and possibly less beneficial drug. We seem to be concerned about the barbiturates because their over-use is associated in our minds with irresponsibility and escapism, with lowering of productivity, impaired judgment and co-ordination, and antisocial behaviour. On the other hand to a limited extent it is possible that both the individual and society are the better if some people have shifted, as reported, from narcotics to barbiturates.

    As I have stated in the past, the problem of abuse of any drug cannot be understood apart from the total context of drug use and the society in which it occurs [ 33] . "Barbiturism" is a chronic disease with many causes and no one treatment. We would gain little by proposing oversimplified panaceas. Nevertheless we should immediately embark upon an all-out attack on the barbiturate problem, along each of the dimensions discussed above.

    As President F. John Kennedy stated at a White House Conference on Narcotic and Drug Abuse, "it should be our earnest intention to ensure that drugs should not be employed to debase mankind, but to serve it".

001p020

1 World Health Organization, Technical Report Series, No. 116, 1957.

IX. References

001

Ad hoc Panel on Drug Abuse , Progress Report, The White House, 1962.

002

Arieti, Silvano: American Handbook of Psychiatry , vol. I, Basic Books, Inc., New York, 1959.

003

Ausubel, David P.: Drug addiction: physiological, psychological and sociological aspects , Random House, New York, 1958.

004

Bailey, C. J. & Miller, N. E.: The effect of sodium amytal on an approach-avoidance conflict in cats. J. Comp. Physiol. Psychol , 45 : 205-208, 1952.

005

Bain, J. A.: Enzymatic aspects of barbiturate action. Fed. Proc ., 11 : 653-657, 1952.

006

Bales, L. N.: Goofballs, red birds, yellow jackets, red devils and other barbiturates and their effects. Peace Officers' Association of the State of California Proceedings , 29 : 59-62, 1949.

007

Beecher, H. K.: The powerful placebo. J.A.M.A., 159 : 1602-1606 1955.

008

Beecher, H. K., McDonough, F. K. & Forbes, A.: Similarity of effects of barbiturate anaesthesia and spinal transection, J. Neurophysicol ., 2 : 81-88, 1939.

009

Belleville, R. E. & Fraser, H. F.: Tolerance to some effects of barbiturates. J. Pharmacol. & Exper. Ther ., 120 : (4) 469-474, 1957.

010

Bergman, P. S., Stroo, H. H. & Feinstein, R.: Mental and etectroenchephalographic changes following intravenous barbiturates in organic disease of the brain. Amer. J. Psychiatry, 110 : 770-773, 1954.

011

Brazier, M. A. & Finesinger, J. E.: Action of barbiturates on the cerebral cortex. Arch. Neurol. Psychiatry , 53 : 51-58, 1945.

012

Britannica Book of the Year. Narcotics, 472-473, 1958.

013

Brody, T. M. & Bain, J. A.: Barbiturates and oxidative phos-phorylation. J. Pharmacol , 110 : 148-156, 1954.

014

Brody, T. M. & Bain, J. A.: Effect of barbiturates on oxidative phosphorylation. Proc., Soc. Exp. Biol ., 77 : 50-53, 1951.

015

Chein, I. & Rosenfeld, E.: Juvenile narcotic use. Law and Contemporary Problems , 22 : 52-68, 1957.

016

Cohen, B. D., Senf, R. & Huston, P. E.: Effect of amobarbital (amytal) and effect on conceptual thinking in schizophrenia, depression and neurosis, Arch. Neurol. Psychiatry , 71 : 170-180, 1954.IX. References

017

Dangerous Drugs , Public Hearing, Assembly Interim Committee on Criminal Procedure, California Legislature, 1961.

018

Davis, H.: The prescribing of barbiturates, Brit. J. Addiction , 53 : 102, 1957.

019

Dews, P. B.: Comparison of effects of phenobarbital and chlorpromazine on discriminatory performance in pigeons. J. Pharmacol ., 116 : 16, 1956.

020

Dews, P. B.: Studies on behaviour. I. Differential sensitivity to pentobarbital of pecking performance in pigeons depending on the schedule of reward. J. Pharmacol ., 113 : 393-401, 1955.

021

Dobos, J. K., Phillips, J. & Covo, G. A.: Acute barbiturate intoxication. J.A.M.A.., 176 : 268-272, April 1961.

022

Domino, E. F.: A pharmacological analysis of the functional relationship between the brain stem arousal and diffuse thalamic projection systems. J. Pharmacol ., 115 : 449-463, 1955.

023

Domino, E. F., Fox, K. E. & Brody, T. M.: Pharmacological actions of a convulsant barbiturate (sodium-5-ethyl-t-(1,3-dimethylbutyl) barbiturate).-I. Stimulant and depressant effects. J. Pharmacol ., 114 : 473-483, 1955.

024

Drug Trade News , 10 E. 15th St., N.Y., N.Y., 1961-1962.

025

Eldridge, William B.: Narcotics and the law. American Bar Foundation, 1962

026

Essig, C. F. & Ainslie, J. D.: Addiction to meprobamate (Equanil, Miltown). J.A.M.A., 146 : 1382, 1957.

027

Essig, C. F. & Carter, W. W.: Failure of diphenylhydantoin in preventing barbiturate withdrawal convulsions in the dog. Neurology , 12 : 7, July 1962.

028

Essig, C. F. & Flannary, H. G.: Convulsive aspects of barbital sodium withdrawal in the cat. Experimental Neurology , 3 : 2, February 1961.

029

Eysenck, H. J.: Handbook of Abnormal Psychology. Basic Books, Inc., New York, 1961.

030

Felsinger, J. M. von, et al. : Personality and reaction to drugs. J.A.M.A., 157 : 1113, 1955.

031

Fischelis, Robert P.: A review of the present status of barbiturate regulation; before the conference on regulation and use and distribution of barbiturates, Washington, D.C., October 12, 1945, J. Pharmaceutical Assoc ., 35 : 193-204, July 1946.

032

Fort, J.: Narcotics: The international picture, Calif. Youth Authority Quarterly , 14 : summer 1961.

033

Fort, J.: The use and abuse of alcohol and narcotics around the world. Proceedings, III World Congress of Psychiatry, McGill Univ. Press, 1962.

034

Fraser, H. F.: Tolerance to and physical dependence on opiates, barbiturates, and alcohol. Annual Review of Medicine , 8 , 1957.

035

Fraser, H. G. et al.: Chronic barbiturate intoxication: further studies. Archives of Internal Medicine, 94 : 34-41, July 1954.

036

Fraser, H. J. & Isbell, H.: Abstinence syndrome in dogs after chronic barbiturate medication. J. Pharmacol. and Exper. Therap ., 112 : 261-267, November 1954.

037

Fraser, H. F., Isbell, H., Eisenman, A. J., Wikler, A. & Pescor, F. T.: Chronic barbiturate intoxication. Further studies. Arch. Neurol and Psychiatry , 94 : 34-41, July 1954.

038

Fraser, H. G., Shaver, M. R., Maxwell, E. S. & Isbell, H.: Death due to withdrawal of barbiturates. Ann. Int. Med ., 38: 1319-1325, June 1953.

039

Fraser, H. G., Wikler, A., Belleville, Essig & Hill, H. E.: Minimum dose of barbiturates required to produce physical dependence. Federation Proceed ., 15 : 1, March 1956.

040

Frenkel-Brunswik, E.: Meaning of psychoanalytic concepts and confirmation of psychoanalytic theories. Scientific Monthly , 79 : 292-300, 1954.

041

Gellhorn, E.: Physiological processes related to consciousness and perception. Brain, 77 : 401-415, 1954.

042

Gerard, D. & Kornetsky, C.: Adolescent opiate addiction: a study of control and addict subjects, Psychiatric Quart ., 29 : 457, 1955.

043

Gerard, R. W.: The biological roots of psychiatry. Amer. J. Psychiatry , 112 : 81-90, 1955.

044

Gibbs, F. A. & Maltby, G. L.: Effect on the electrical activity of the cortex of certain depressant and stimulant drugs-barbiturates, morphine, caffeine, benzedrine and adrenalin. J. Pharmacol ., 78 : 1-10, 1943.

045

Glatt, M. M.: The abuse of barbiturates in the U.K., Bull. on Narcotics , XIV : 2, Apr.-June 1962.

046

Goldstein, S. W.: Barbiturates- are they narcotics? Jour. Amer. Pharmaceutical Assoc ., 36 : 97-100, April 1947.

047

Goodman, L. S. & Gilman, A.: The pharmacological basis of therapeutics. The MacMillan Co., N.Y., 1956.

048

Goodnow, R. E., Beecher, H. K., Brazier, M. A. B., Mosteller, F. & Taguiri, R.: Physiological performance following a hypnotic dose of a barbiturate. J. Pharmacol, 102 : 55-61, 1951.

049

Hambourger, W. E.: Promiscuous use of the barbiturates, J.A.M.A., 2015, 1940.

050

Hambourger, W. E.: A study of the promiscuous use of the barbiturates. J.A.M.A., 1340, 1939.

051

Heath, R. G.: The problem of the clinical evaluation of sedative and hypnotic drugs, Symposium on Sedatives and Hypnotics. 57-80, Williams and Wilkins, Baltimore, 1954.

052

Hebb, D. O.: The organization of behaviour. A neurophysio-logical theory. Wiley, N.Y., 1949.

053

Hill, H. E. & Belleville, R. E.: Effects of chronic barbiturate intoxication on motivation and muscular coordination. Arch. Neurol. Psychiatry , 70 : 180-188, 1953.

054

Hill, H. E., Belleville, R. E. & Wikler, A.: Motivational determinants in the modification of behaviour by morphine and pentobarbital. Arch. Neurol. and Psychiatry , 77 : 28-35, 1957.

055

Hill, H. E., Belleville, R. E. & Wikler, A.: Studies on anxiety associated with anticipation of pain. II. Comparative effects of pentobarbital and morphine. Arch. Neurol. Psychiatry , 73 : 602-608, 1955.

056

Hoch, Paul H. & Zubin, J., edit.: Problems of addiction and habituation. Grune and Stratton, Inc., N.Y., 1958.

056a

Hollister, L. E. et al.: Withdrawal reactions of sodium amytal and amphetamine sulfate on mental chlordiazepoxide (Librum). Psychopharmacologia, 2: 63-68, 1961.

057

Huston, P. E. & Singer, M. M.: Effect of sodium amytal and amphetamine sulfate on mental set in schizophrenia. Arch. Neurol. Psychiatry , 53 : 365-369, 1945.

058

Inventory (North Carolina Alcoholic Rehabilitation Programme). Barbiturates as addicting drugs, 9: 10-12, Sept.-Oct. 1959.

059

Isbell, H.: Abuse of barbiturates. J.A.M.A., 162 : 660, 1956.

060

Isbell, H.: Acute and chronic barbiturate intoxication. Veterans Adm. Tech. Bulletin, August 15, 1951.

061

Isbell, H.: Addiction to barbiturates. Annals of Internal Medicine , 33 : 108-121, July 1950.

062

Isbell, H.: Addiction to hypnotic and sedative drugs. Assn. of Food and Drug Officials of the U.S., XXIII, 1 , January 1959.

063

Isbell, H.: Manifestations and treatment of addiction to narcotic drugs and barbiturates. Medical Clinics of North America , 34 : 425-438, March 1950.

064

Isbell, H. & Fraser, H. F.: Addiction to analgesics and barbiturates. J. of Pharmacol. and Exper. Therap ., 99 : 355-397. Aug. 1950.

065

Isbell, H., Altschul, S., Kornetsky, C. H., Eisenman, A. J., Flanary, H. G. & Fraser, H. F.: Chronic barbiturate intoxication: an experimental study. Arch. Neurol. and Psychiatry , 64 : 1-28, July 1950.

066

Isbell, H., Fraser, H. F., Wikler, A., Belleville, R. E. & Eisenman, A. J.: An experimental study of the etiology of "rum fits" and delerium tremens. Quart. J. Stud. on Alcohol , 16 : 1-33, March 1955.

067

Kahn, R. L., Fink, M. & Weinstein, E. A.: Relation of amobarbital test to clinical improvement in electroshock. Arch. Neur. Psychiat ., 76 : 23-29, 1956.

068

Kalinowsky, L. B.: Convulsions in non-epileptic patients on withdrawal of barbiturates, alcohol, and other drugs. Arch. Neur. and Psychiatry , 48 : 946-956, December 1942.

069

Kass, E., Retterstöl, N. & Sirnes, T.: Barbiturate intoxication and addiction as a public health problem in Oslo. Bull. on Narcotics , XI : 3, 15-29, 1959.

070

Kety, S. S.: Consideration of pharmacological agents on the over-all circulation and metabolism of the brain. Neuro-pharmacology, Josiah Macy Jr. Foundation, New York, 13-89, 1954.

071

King, E. E., Naquet, R. & Magoun, H. W.: Action of pento-barbital on somatic afferent conduction in the cat with special reference to the thalamic relay. J. Pharmacol ., 113 : 31, 1955.

072

Kline, N. S.: Psychopharmacology. Progress in Neurol. and Psychiat ., 13: 441-464, 1958.

073

Koppanyi, Theo. & Fazekas, J. F.: The use of correctives in the prevention of barbiturate intoxication. Amer. J. of the Med. Sciences , 226 : 597-606, Dec. 1953.

074

Kornetsky, C. H.: Psychological effects of chronic barbiturate intoxication. A.M.A. Arch. of Neur. and Psychiatry , 65 : 557-567, May 1951.

075

Kornetsky, C. H.: Relationship between Rorschach determinants and psychosis in barbiturate withdrawal syndrome. A.M.A. Arch. of Neur. and Psychiatry , 72 : 452-454, Oct. 1954.

076

Levi, Leo, Ph.D,: The barbituric acids, their chemical structure, synthesis and nomenclature. Bull. on Narcotics , IX : 1, 30-41, 1957.

077

Levi, L. & Hubley, C. E.: Detection and identification of clinically important barbiturates. Analytical Chem ., 28 : 1591, 1956.

078

Lindemann, E. & Felsinger, J. M.: Drug effects and personality theory. Psychopharmacologia, 2 : fasc. 1, 1962.

079

Masserman, J. H. & Siever, P. W.: Dominance, neurosis and aggression. Psychosom. Med ., 6 : 7-16, 1944.

080

Maynert, E. W. & Van Dyke, H. B.: The metabolism of barbiturates. Jour. Pharm. and Exper. Therap ., 96 : 217, 1949.

081

McNally, W. D.: The use and abuse of barbiturates. Michigan Med. Soc. Jour ., 41 : 635-642, August 1942.

082

Narcotics, a symposium. Law and Contemporary Problems , 22 : 1-154, winter 1957.

083

New and nonofficial remedies , J. B. Lippincott Co., Philadelphia, 1962.

084

Nyswander, M.: The drug addict as a patient , Grune and Stratton, New York, 1956.

085

Parker, K. D. & Kirk, P. L.: Separation and identification of barbiturates by gas chromatograph. Analytical Chem ., 33 : Sept. 1961.

086

Pharmacy laws of California and administrative rules of board of pharmacy, 1962.

087

Physician's Desk Reference , 16th ed. Med. Econ. New Jersey, 1961.

088

Pohlisch, K.: Ober psychiasche reactionsformen bei arznei-mittelvergiftungen. Monatsschr. f. Psychiat. u Neurol ., 69 : 351-367, 1928.

089

Problem of barbiturates in the United States of America. Bull. on Narcotics , IX : 15-19, Apr.-June 1957.

090

Pruitt, R. S.: Medicolegal aspects of the sale and use of barbiturates. Missouri Med. Assoc. Jour ., 44 : 419-423, June 1947.

091

Behavioural research in preclinical psycho-pharmacology. Psychopharmacology Ser. Center Bull. , U.S. Dept. Health, Education, Welfare, 1962.

092

Psychopharmacology Ser. Center Bull ., U.S. Dept. H.E.W. 2: 1, March 1962.

093

Quarton, G. C. & Talland, G. A.: The effects of methamphetamine and pentobarbital on two measures of attention. Psychopharmacologia, 3: fasc. 1, 1961.

094

Rosner, H., Levine, S., Hess, H. & Kaye, H.: A comparative study of the effect on anxiety of chlorpromazine, reserpine, phenobarbital and a placebo. J. Nerv. Ment. Dis ., 122: 505-512, 1955.

095

Sargant, W., Slater, P., Halstead, H. & Glen, M.: Effects of alcohol and sodium amytal on intelligence test score. Lancet, 1: 617-618, 1945.

096

Shideman, F. E., Ph.D.: Clinical pharmacology of hypnotics and sedatives. Clin. Pharmacol. and Therap ., 313 : 1961.

097

Special Study Commission on Narcotics , Interim and final report. State of California, June 1961.

098

Stephens, M. R.: The food and drug administration's responsibilities and obligations in drug distribution. Address. Annual Convention of the American College of Apothecaries. Feb. 1960.

099

Straus, E.: Zur pathogenese des chronischen Morphinismus. Monatsschr. f. Psychiat. u. Neurol ., 46 : 1-20, 1919.

100

Taylor, N.: Flight from reality , Duell, Sloan and Pearce, New York, 1949.

101

Tompkins, D. C.: Drug addiction : A bibliography. Bureau of Public Administration, Univ. of California, Berkeley, 1960.

102

Trichter, J.: The barbiturate problem of the city of New York, Food and Drug Cosmetic Law Jour ., 7: 222-224, March 1952.

103

U.S. Commerce, Dept. of: Report on tranquillizers and stimulants , Office of Technical Service, Govt. Research, 1961.

104

U.S. Congress: House of Rep. report pursuant to H.R. 357. The relationship between highway accidents and use of drugs by drivers. Spec. Subcom. on Traffic Safety. H. Rep., 2971, 84: 2, Wash., D.C., 3 Jan. 1957.

105

U.S. Congress: House of Rep. Drug Industry act of 1962. Hearings, Comm. on Interstate and Foreign Comm. 7th Cong., 1962.

106

U.S. Congress: House of Rep. Traffic in, and control of narcotics, barbiturates, and amphetamines. Hearings, Subcommittee of the Committee on Ways and Means, 84th Cong., 1955-56.

107

U.S. Congress: Drug industry anti-trust act. Hearings, Sub-Committee on Anti-trust and Monopoly of the U.S. Senate Committee on the Judiciary 87th Congress, 1962. See particularly part 6: Advertising Provisions.

108

U.S. Congress: Administered prices in the drug industry. Hearings, Sub-Committee on Anti-trust and Monopoly of the U.S. Senate Committee on the Judiciary, 86th Congress, 1960. See particularly part 16: Tranquillizers.

109

U.S. Public Health Service: Barbiturates as addicting drugs. National Institute of Mental Health. Publication 545, Wash. D.C., 1957.

110

U.S. Congress: Senate: Treatment and rehabilitation of juvenile drug addicts. Subcommittee to Investigate Juvenile Delinquency, Committee on the Judiciary. Hearings, pursuant to S.R. 173 and S.R. 303, Dec. 1956, 984: 2, Wash., D.C., 1957.

111

U.S. Tariff Commission: Report: synthetic organic chemicals, U.S. production and sales. U.S. Gov. Print. Office., Wash. D.C., 1936-1961.

112

Von Baeyer, A.: Untersuchungen uber die harnsauregruppe, Annalen der Chemie , 127 : 1, 199 (1863); 130:129 (1864).

113

Von Felsinger, J. M., Lasagna, L. & Beecher, H. K.: The persistence of mental impairment following a hypnotic dose of a barbiturate. J. Pharmacol. , 109 : 284-291, 1953.

114

Weinstein, E. A., Kahn, R. L., Sugarman, L. A. & Malitz, S.: Serial administration of the "Amytal test" for brain disease. Its diagnostic and prognostic value. Arch. Neurol. Psychiat ., 71 : 217-226, 1954.

115

Wikler, A.: Drug Addiction. Tice's Practice of Med ., vol. VIII, 1957, p. 17-49.

116

Wikler, A.: Fundamentals of scientific research in psychiatry. Neuropsychiatry, 2 : 87-98, 1952.

117

Wikler, A.: Neurophysiological aspects of the opiate and barbiturate abstinence syndromes. Proceedings of the Assn. for Research in Nervous and Mental Disease. Williams and Wilkins Co., Baltimore, 1953.

118

Wikler, A.: On the nature of addiction and habituation. British J. of Addiction , 57 : 2, July 1961.

119

Wikler, A.: Opiate addiction. Psychological and neurophysiological aspects in relation to clinical problems. Thomas, Springfield, 1952.

120

Wikler, A.: A psychodynamic study of a patient during experimental self-regulated readdiction to morphine. Psychiatric Quart ., 26 : 270-293, 1952.

121

Wikler, A.: Relationships between clinical effects of barbiturates and their neurophysiological mechanisms of action. Fed. Proc ., II : 647-652, 1952.

122

Wikler, A.: The relation of psychiatry to pharmacology. Williams and Wilkins, Baltimore, M.D., 1957.

123

Wilker, A.: The uses of drugs in psychiatric research. Amer. J. Psychiat ., 112 : 961-969, 1956.

124

Wikler, A., Fraser, H. F., Isbell, H. & Pescor, F. T.: Electroencephalograms during cycles of addiction to barbiturates in man. Electroenceph. Clin. Neurophysiol , 7 : 1-13, 1955.

125

Wikler, A. & Rasor, R. W.: Psychiatric aspects of drug addiction, in symposium on drug addiction, ed. by Eddy, N. B. Amer. J. of Med ., 14 : 566-570, May 1953.

126

Winick, C.: The use of drugs by jazz musicians. Soc. Problems , 7 : 240-253, winter 1959-60.

127

Wold, S. & Ripley, H. S.: Studies on the action of intravenously administered sodium amytal. Amer. J. Med. Sci ., 215 : 56-62, 1948.

128

Wortis, J.: Soviet psychiatry , Williams and Wilkins, Baltimore, 1950.

129

Yost, O. B.: The bane of drug addiction. Macmillan, N.Y., 1954.

130

Young, J. Z.: Doubt and certainty in science. Oxford, Clarendon Press, London, 1951.

131

Zimmering, P., Toolon, J., Safrin, R. & Wortis, S. B.: Drug addiction in relation to problems of adolescence. Amer. J. Psychiat ., 109 : 272-278, 1952.