Thomas A. Ban
Neuropsychopharmacology in Historical Perspective
Education in the Field in the Post-Neuropsychopharmacology Era
Background to An Oral History of the First Fifty Years
Addiction (Volume Six): 2. Substances of abuse
(Bulletin 55)

            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 17^th century alcohol became a drug of abuse on a large scale (Rouche 1960). The term “alcoholism” was coined by Magnus Huss in the mid-19^th century and the disease concept of alcoholism -introduced by Benjamin Rush and Thomas Trotter - received increasing acceptance in Europe and North America (Huss 1849-51; Rush 1784; Trotter 1804). In the United States the first special institution for inebriates (alcoholics) was opened in 1841 in Boston (Jellinek 1960). 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 (Jellinek 1952).

            Substances derived from the poppy plant (papaversomniferum), 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 (Sertűrner 1806). After Alexander Wood’s introduction of the hypodermic needle in 1853, the non-medicinal use of morphine spread so fast that by the turn of the 20^th century a large number of people had become dependent on the drug (Lawrence 2002). 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 (Hosztafi 2001). 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 (Martins, Schoulkens and Rudolf 2007). It caused a mild epidemic of meperidine abuse among physicians (Goodwin and Guze 1989). 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 with drawal from morphine (Isbell and Vogel 1949).

            In the mid-19^th century the use of hashish (an extract of the cannabis plant), the most potent form of cannabis - endogenous in Central and South Asia - became widely used for recreational purposes in Europe, especially in France (Baudelaire 1851, 1860; Ludlow 1857).Hashish was also tried in the treatment of psychiatric disorders (Ban 2006a; Moreau de Tours1845).It took well over 100 years before the active ingredient of marihuana, Δ-tetrahydrocannabinol, was isolated by Mechoulam and Gaoni in the mid-1960s (Mechoulam and Gaoni 1765). The first documented widespread cannabis abuse (“reefer madness”) in the United States occurred in the 1930s. The second in the 1960s and ’70s (Bloomquist 1969; Opra 1969).

            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 (Humphrey and O’Hagan 1953). 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” (Montegazza 1975). Sigmund Freud, in the 1880s, self-experimented with coca and found that it had 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 (Freud 1984). The first cocaine abuse epidemic in the United States occurred in the early 1900s, the second 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 (Carter 2003). They were replaced by the bromides, first introduced into medicine by Magendie in 1821 (Lehmann and Ban 1970). In the second half of the 19^th century bromides were extensively used for sedation and controlling seizures (Joynt 1974). They were also occasionally employed in the treatment of addiction (McLeod 1897). Then, in the mid-20th century, it was conclusively demonstrated that bromides are toxic and addictive drugs (Ewing and Gantt 1965). In 1869, chloral hydrate, the first synthetic sedative-hypnotic, was introduced for psychiatric indications (Liebreich 1869). In the late 19^th century it led to addiction, especially in woman, on a large scale (Shorter 1997).

            The first 50 years of the 20^th century was dominated by barbiturates. The first, barbital (Veronal), was synthesized by Emil Fisher in 1902 and a year later Joseph von Mering demonstrated its hypnotic effect (Fischer and Mering 1903). In the years that followed more than 2,500 different barbiturate preparations were synthesized, of which at least 50 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 (Isbell 1950).

            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. Meprobamate was synthesized by B. J. Ludwig in 1950 and introduced for clinical use in the United States in 1956 (Berger 1970, 1998). 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 introduced in 1860 and the second, diazepam in 1962 (Ban 2006). The addiction-producing properties of meprobamate and chlordiazepoxide were first shown by Leo Hollister in 1960 and 1961, respectively (Geenblatt and Shader 1974; Hollister and Glazener 1960; Hollster, Motzenbecker and Dean 1961).

            Many of the psychostimulants have abuse potential. The abuse of khat - a substance derived from the shrub, Catha Adulis, native to East Africa and southern Arabia - had been a major concern in colonial Kenya (Anderson and Camer 2009). 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; its methylated analogue, methamphetamine (street name “speed”) by Akira Ogata in 1919; and racemic amphetamine (Benzedrine) by Gordon Alles in 1927 (Alles 1927; Edeleano 1887; Iversen 2006). In the mid-1940s, it was Nathensonwho was first to report that Benzedrine, in normal subjects, produced a sense of wellbeing, exhilaration and lessened fatigue (Nathenson 1935; Rasmussen 2008). The first recorded major amphetamine abuse epidemic occurred in postwar Japan. It was sosevere that it required the opening of special psychiatric facilities and stringent legal measures to control its use. In the United States amphetamines became a major abuse problem by the late 1950s (Griffith 1966; Lemere1966; Suwaki 1991; Woodruff, Goodwin and Guze 1971).

            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 in the laboratories of Sandoz (Hoffmann 1970). In the late 1940s LSD was introduced for the facilitation of psychotherapy and by the 1960s its efficacy was tested in the treatment of alcoholism and a variety of psychiatric disorders (Brown 1972; Condreau1949). In the 1950s several other synthetic hallucinogens, e.g., psilocybin, dimethyltryptamine, were introduced and more and more people, especially late adolescents and students on college campuses, were experimenting with them (Hoffmann, Frey, Ott, Petrzilka and Troxler 1958).

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Ban TA. Academic psychiatry and the pharmaceutical industry. Progress in Neuro-Psychopharmacology  & Biological Psychiatry 2006a; 30: 429-41.

Ban T. The role of serendipity in drug discovery. Discoveries in Clinical Neuroscience 2006b; 8: 335-44.

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January 31, 2019