Volume Five Templet

AN ORAL HISTORY OF NEUROPSYCHOPHARMACOLOGY

THE FIRST FIFTY YEARS

Peer Interviews

Volume Six: Addiction

Thomas A. Ban (series editor)

AN ORAL HISTORY OF NEUROPSYCHOPHARMACOLOGY

Herbert D. Kleber (volume editor)

VOLUME 6 ADDICTION

Library of Congress Cataloging-in-Publication Data

Thomas A. Ban, Herbert D. Kleber (eds):

An Oral History of Neuropsychopharmacology: The First Fifty Years, Peer Interviews

Includes bibliographical references and index

ISBN-

1. Addiction Psychiatry 2. Substances of abuse

3. Treatment of addiction

4. Conditioning research in addiction 5. Genetic research in addiction

Publisher: ACNP

ACNP Executive Office

5034A Thoroughbred Lane

Brentwood, Tennessee 37027

U.S.A.

Email:

Website:

Cover design by Jessie Blackwell; JBlackwell Design

AMERICANCOLLEGE OF NEUROPSYCHOPHARMACOLOGY

AN ORAL HISTORY OF NEUROPSYCHOPHARMACOLOGY

THE FIRST FIFTY YEARS

Peer Interviews

Edited by

Thomas A. Ban

Co-editors

Volume 1: Starting Up - Edward Shorter

Volume 2: Neurophysiology - Max Fink

Volume 3: Neuropharmacology - Fridolin Sulser

Volume 4: Psychopharmacology - Jerome Levine

Volume 5: Neuropsychopharmacology - Samuel Gershon

Volume 6: Addiction - Herbert D. Kleber

Volume 7: Special Areas - Barry Blackwell

Volume 8: Diverse Topics - Carl Salzman

Volume 9: Update - Barry Blackwell

Volume 10: History of the ACNP - Martin M. Katz

VOLUME 6

ADDICTION

ACNP

2011

VOLUME 6

Herbert D. Kleber

ADDICTION

Preface

Thomas A. Ban

Dedicated to the Memory of Daniel X. Freedman, President ACNP, 1970.

PREFACE

Thomas A. Ban

Volume Six of this series is dedicated to addiction.The word itself refers to a group of disorders - alcohol, amphetamine, barbiturate, cannabis, cocaine and opioid abuse and dependence; phencyclidine and hallucinogen abuse; and tobacco dependence - that are classified in the DSM-III, and subsequent classifications, as Substance Use Disorders.[1]

In the first five volumes of this series the focus is on different methodologies used in the study of psychotropic drugs; in Volume Six the focus shifts to the employment of these methodologies in the study of “addiction”, a class of disease. Thus, while previous volumes deal with interviewees’ contributions to the development of behavioral pharmacology, neurophysiology, neuropharmacology, psychopharmacology and neuropsychopharmacology, Volume Six deals with interviewees’ contributions to the elucidation of the biological underpinning of addiction, and to the development of rational pharmacological treatments for addiction.[2],[3]

Addiction Psychiatry

Addiction psychiatry is a relatively new field. It was separated in the 1950s from “pharmacological psychiatry”, which dealt with all “chemical intoxications” (accidental, industrial and medicinal). Such, intoxications included those caused by substances that may lead to addiction assumedly through their “pleasing psychological effects”.[4] The mental manifestations of chemical intoxications share the basic syndromes of “symptomatic psychoses”, described in 1909 and 1910 by Karl Bonhoeffer[5],[6].. The difference between the two is in the superimposed mental (psychological) effects of the different “addictive drugs”. .

By standardizing the language of “addiction” between 1950 and ’57 in a series of Technical Reports, the World Health Organization (WHO)[7] had a major impact on the development of “addiction psychiatry”. Alcoholism was defined by WHO first, as any form of drinking which goes beyond the customary dietary use, or social drinking customs of the community.[8],[9],[10]And, drug addiction was defined as a state of periodic or chronic intoxication produced by the repeated consumption of a natural or synthetic drug, that is detrimental to society and the individual. It was characterized by an overpowering desire or need (compulsion) to continue taking the drug and obtain it by any means, a tendency to increase the dose (tolerance) and a psychic (psychological) and sometimes physical dependence on its effects.[11],[12]

Drug habituation was separated from drug addiction and characterized by a desire but not a compulsion to continue taking the drug. In drug habituation there is no tendency to increase the dose (tolerance) and even if there is some degree of psychic dependence on the effects of the substance, physical dependence with an abstinence syndrome is absent and the continuous taking of the drug has no detrimental effect on the individual.[13]

Tolerance was defined as an “adaptive state,” and characterized by diminishing response to the same quantity of a given drug. It is demonstrable by increasing dose requirements to produce the same degree of pharmacological effects.[14]

Drugs with a potential to produce addiction were divided into three groups by the WHO.. Substances of the first group produce compulsive craving, dependence and addiction in any individual if administered in a sufficiently high dose for a sufficiently long time. In the pathogenesis of addiction with these drugs, pharmacological action is paramount and psychological makeup is adjuvant. Substances of the second group differ from the first by not producing compulsive craving; they merely increase desire and encourage habituation. In the pathogenesis of habituation with these drugs psychological make-up is paramount and pharmacological action is adjuvant. Substances in the third group differ from both, the first and the second group; they produce compulsive craving, dependence and addiction, but in those individuals only who seek to find an escape in drugs. In the pathogenesis of addiction with these drugs pharmacological action plays a prominent role but psychological make-up is the determining factor.[15],[16]

In 1964 the World Health Organization replaced the term drug addiction with the term drug dependence[17] and defined drug dependence as a state of psychic or physical dependence on a chemical which develops after periodic or continuous administration. Reviewing drug dependence, its significance and characteristics in the Bulletin of WHO in 1965, Eddy, Halbach, Isbell and Sievers emphasized that drug dependence and drug abuse might occur without the development of demonstrable tolerance.[18] They also pointed out that the characteristics of drug dependence vary with the agent involved.[19]

Substances of Abuse

Among the different substances of abuse, the story of alcohol dates back to Paleolithic times. Its use in medicine and for religious purposes has been recorded over millennia. Subsequent to the discovery of distillation of alcohol in about 800 AD, its recreational use steadily grew; by the seventeenth century alcohol became a drug of abuse on a large scale.[20] The term “alcoholism” was coined by Magnus Huss[21] in the mid-19th century and the disease concept of alcoholism -introduced by Benjamin Rush[22] and Thomas Trotter[23] - got increasing acceptance in Europe and North America. In the United States the first special institution for inebriates (alcoholics) was opened in 1841 in Boston.[24] During the years of prohibition of alcohol - Russia 1914-25; Iceland: 1915-22; Norway: 1916-27; Finland 1919-32; US: 1920-33 - the disease concept of alcoholism lost its vogue. It was revitalized in the United States by the pioneering research carried out at the Yale center for Alcohol Studies during the 1940s and ‘50s.[25]

Substances derived from the poppy plant (papaver somniferum), like opium, which produce euphoria and analgesia, have also been used since ancient times. Morphine, the active ingredient of opium was isolated in 1805 by Sertűrner.[26] After Alexander Wood’s introduction of the hypodermic needle in 1853,[27] the non-medicinal use of morphine spread so fast that by the turn of the 20th century a large number of people had become dependent on the drug. Heroin, diacetylmorphine, was synthesized by Alder Wright in 1874 and introduced for clinical use in 1898 by Bayer pharmaceuticals with the name of heroin initially as an oral cough medicine and later as a fast acting oral non-addictive substitute for morphine and opiates in general. It took about a decade to recognize that the substitute metabolizes into morphine.[28] Heroin addiction became a serious mental health problem in the 1960s in the United States. It involved mainly black ghetto populations. Meperidine (Demerol), another synthetic opioid, was synthesized in 1932 by Otto Eislib in the laboratories of IG Farben in Germany. Similar to heroin, the substance was introduced in the 1940s as a non-addictive substitute for morphine and other opioids.[29] It caused a mild epidemic of meperidine abuse among physicians.[30] A third synthetic opioid, methadone, was developed in 1937 in Germany and introduced ten years later in 1947 in the United States by Eli Lilly and company as a narcotic analgesic for the alleviation of pain. Isbell and Vogel were first, in 1949 to report on its addiction liability and its use for withdrawal from morphine.[31]

In the mid 19th century the use of hashish (marihuana), the most potent form of cannabis - endogenous in Central and South Asia - became widely used for recreational purposes in Europe, especially in France.[32],[33],[34]Hashish was also tried in the treatment of psychiatric disorders.[35],[36]It took well over 100 years before the active ingredient of marihuana, Δ-tetrahydrocannabinol, was isolated by Mechoulam and Gaoni in the mid-1960s.[37] The first documented widespread marihuana abuse (”reefer madness”) in the United States occurred in the 1930s. The second in the 1960s and ’70s.[38],[39]

Coca chewing has been endemic in the eastern Andes for thousands of years. Coca, the psychoactive ingredient of the coca plant was isolated by Frederick Gedecke in 1855, and its chemical structure was identified by Richard Willstatter in 1898.[40] The stimulating effect of coca on cognition was first reported by Paolo Montegazza in the late 1850s. He advocated the use of coca for “nervous nourishment”.[41] Sigmund Freud in the 1880s self-experimented with coca and found that it has local anesthetic effect. In his paper Über Coca (On Coca), he recommended its use for the treatment of depression and of addiction to alcohol and morphine.[42] The first cocaine abuse epidemic in the United States occurred in the early 1900s, the 2nd about 80 years later, in the 1980s.

Many of the substances used in the control of anxiety, psychic tension, psychomotor restlessness and insomnia, traditionally referred to as sedatives and hypnotics, are potentially addictive. The oldest drugs of this category are henbane and other members of the Solanaceae family.[43] They were replaced by the bromides, first introduced into medicine by Magendie in 1821.[44] In the second half of the 19th century bromides were extensively used for sedation and controlling seizures.[45] They were also occasionally employed in the treatment of addiction.[46] Then, in the mid-20th century it was conclusively demonstrated that bromides are toxic and addictive drugs.[47]. In 1869, chloral hydrate,[48] the first synthetic sedative-hypnotic was introduced for psychiatric indications. In the late 19th century it led to addiction, especially in woman, on a large scale.[49] The first fifty years in the 20th century was dominated by barbiturates. The first, barbital (Veronal) was synthesized by Emil Fisher in 1902 and a year later, in 1903, Joseph von Mering demonstrated its hypnotic effect.[50] In the years that followed more than 2,500 different barbiturate preparations were synthesized, of which at least fifty found clinical use. There were numerous reports on physical and psychological dependence on barbiturates over decades. Yet, it was Harris Isbell first, in 1950, to conclusively demonstrate addiction to these drugs.[51] In the second half of the 1950s the barbiturates were rapidly replaced in the treatment of anxiety by meprobamate, a propanediol preparation, linked to the name of Frank Berger at Wallace Laboratories of Carter Products. (See, Berger Volumes 3 & 9.) Meprobamate, was synthesized by B. J. Ludwig in 1950 and introduced for clinical use in the United States in 1956.[52],[53]Then, in the 1960s meprobamate was replaced by the benzodiazepines, chlordiazepoxide first in 1960 and diazepam in 1963, a group of drugs synthesized by Leo Sternbach, a pharmacist and chemist working at Hoffmann-La Roche’s research facility in Nutley, New Jersey. The first benzodiazepine, chlordiazepoxide, was intrduced in 1860 and the second, diazepami in 1962.[54] The addiction-producing properties of meprobamate,[55] and chlordiazepoxide,[56]were first shown by Leo Hollister in 1960 and 1961, respectively.[57] (See, Hollister Volume 1 & 9.)

Many of the psychostimulants have abuse potential. The abuse of khat - a substance derived from the shrub, Catha Adulis, native in East Africa and southern Arabia - had been a major concern in colonial Kenya.[58] The active ingredient of khat is cathinone, an amphetamine-like substance. The amphetamines are a group of psychostimulants. The parent substance, phenethylamine, was synthesized by Edeleano in 1887[59]; its methylated analogue, methamphetamine (street name “speed”) by Akira Ogata in 1919[60]; and racemic amphetamine (Benzedrine) by Gordon Alles in 1927.[61] In the mid-1940s, it was Nathenson first to report that Benzedrine in normal subjects produced a sense of well being, exhilaration and lessened fatigue. [62],[63]The first recorded major amphetamine abuse epidemic occurred in postwar Japan. It was sosever that it required the opening of special psychiatric facilities and stringent legal measures to control.[64],[65]In the United States amphetamines became a major abuse problem by the late 1950s.[66],[67]

In the 1950s psychomimetics emerged as a group of drugs with abuse potential. The story begins in 1943 with the accidental discovery of the psychomimetic (hallucinogenic) effect of lysergic acid diethylamide (LSD-25) by Albert Hofmann while trying to develop a new ergot analeptic[68] in the laboratories of Sandoz. In the late 1940s LSD was introduced for the facilitation of psychotherapy[69] and by the 1960s its efficacy was tested in the treatment of alcoholism and a variety of psychiatric disorders.[70] (See, Levine Volumes 4 & 9.) In the 1950s several other synthetic hallucinogens, e.g., psilocybin,[71] dimethyltryptamine were introduced and more and more people, especially late adolescents and students on college campuses, were experimenting with them. (See, Szara Volume 1.)

Concepts and Treatments of Addiction

In the 1950s psychoanalysis was dominant in American psychiatry and addiction was conceptualized in various ways by the different psychodynamic schools. For Sandor Rado it was reactivation of the satisfaction of the “orgiastic experience” of infants after breast feeding by the dependency producing drugs.[72] For Ernest Glover it served to control sadism, a protective device against paranoid psychosis.[73] For Thomas Szasz it served to deny any possible loss of primal love, a protective mechanism against phobia.[74]

In Arthur Noyes and Lawrence Kolb’s Modern Clinical Psychiatry, the most widely used textbook of psychiatry in the United States at the time, addiction was symptomatic of sociopathic personality disorder.[75]

The US Government opened the Lexington Narcotic Farm (US Public Health Service Hospital) in 1935. It was to become one of the first Addiction Research Centers in the country.[76] Research at the center by the 1950s yielded two models of drug dependence, the “cellular model” and the “conditioning model”. The “cellular model”, pioneered by Harris Isbell, is based on the observation that to some drugs, as for example to opiates, tolerance develops, which then, is followed by physical dependence and later by psychic or emotional dependence. Isbell perceived the decreased response seen in tolerance as the result of “occupation of receptors on certain myelinated neurons”, by the dependency producing drug. For Isbell, tolerance was the consequence of either a maximal cell-receptor saturation, or a change in the excitability of the cell body, or both.[77],[78],[79]In the same frame of reference, it was suggested that physical dependence was the result of the increased excitability of the cell body in the period of abstinence by the “loss” of the protecting drug.[80],[81]

The “conditioning model”, pioneered by Abraham Wikler, is based on the observation that “cured” opiate addicts experienced craving and repetition of some of the abstinence-syndrome manifestations when exposed to stimuli which were formerly strongly associated with their previous drug experiences. Wikler perceived drug dependence as a process of conditioning in which the actual drug experience serves as the unconditional stimulus and the associated environmental factors as conditional stimuli.[82],[83],[84],[85],[86]

Conditioning was employed in the 1950s in the treatment of alcoholism.[87] In “aversion therapy,” nausea and vomiting are elicited at the sight, smell or taste of alcohol (conditioned reflex) by associating it with the nausea and vomiting produced by the pharmacological effect of apomorphine (unconditional reflex).[88] The treatment was first described in 1915[89] and introduced in 1934 simultaneously by Markovnikov in the Soviet Union and Dent in England.[90],[91]

An alternative treatment of alcoholism was disulfiram (Antabuse). It is based on the findings of Hald, Jacobsen and Larsen in 1948 that disulfiram, by interfering with the metabolism of alcohol, produces a marked increase of blood acetaldehyde levels and sensitizes the organism to alcohol.[92] The flushing of the face, sweating, dyspnea, headache and tachycardia experienced, even after a small amount of alcohol consumption, makes drinking difficult for patients on the drug.[93] In 1949 Jacobsen and Larsen were first to report on the use disulfiram in the treatment of alcoholism.[94]

Conditioning and Addiction

Recognition by the 1950s that conditioning, classical or operant, plays a role in the pathogenesis of addiction, lead the identification of brain structures and biochemical substrates involved in addiction. The signal difference between the two paradigms of conditioning is that in classical conditioning, the establishment and retention of conditioned reflex (CR) depends exclusively on the associated administration of the conditioned and unconditional stimuli, whereas in instrumental conditioning, a third factor, reward or punishment that follows the reflex also plays a role.[95] (See also in Preafce to Volume 2.)

The roots of the instrumental paradigm of conditioning are in Edward Thorndike’s recognition in 1911 that some behavior is regulated by its consequences.[96] Miller and Konorski were first, in the late 1920s, to describe what was to become the instrumental paradigm of conditioning, in which the establishment and retention of a CR depended on reward or punishment that followed the reflex.[97] From the two modern learning theories, “contiguity theory” is based on the classical paradigm and “reinforcement theory” on the instrumental. For Edward Ray Guthrie[98],[99]and Edward C. Tolman,[100],[101]the basic condition necessary for learning is that of contiguity of experience. For Clark L, Hull drive reduction is crucial. If in the course of trial and error responses the organism performs the response that is associated with the reduction of motivation, the probability increases that the response will occur again under similar conditions. In Hull’s “law of effect”, drive reduction is the “principle of reinforcement”.[102], [103], [104]

In the mid-1930, H. Schlossberg demonstrated that autonomically-mediated, involuntary visceral reactions, follow the principle of association or “sheer contiguity”, whereas voluntary “precise adaptive responses” of the skeletal muscles, follow the principle of success or reinforcement.[105],[106],[107].Schlossberg’s “two-factor theory” was further elaborated by Burrhus Frederic Skinner, who introduced the term “operant behavior” and replaced the term “instrumental conditioning” with the term “operant conditioning”. For Skinner, the difference between the two paradigms of conditioning is that in “operant conditioning” the animal only receives the reinforcing, rewarding stimulus, if it does something, e.g., operates a lever.[108] He argues that a stimulus is reinforcing if it strengthens the response that precedes it regardless whether it satisfies a drive.[109],[110],[111]