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
Starting Up (Volume One): 2. Psychiatry
(Bulletin 34)


             Naturally occurring substances have been used to heal the mind and induce ecstasy throughout history. Yet the story that leads to the development of neuropsychopharmacology begins only in the early 19th century with the emergence of organic chemistry, pharmacology. and the pharmaceutical industry (Ban 2006; Healy 1997).The rapid growth of drug companies during the second half of the 19th century was instrumental to the introduction of several centrally acting drugs. By the end of the 1890s morphine,a substance isolated from opiumalong with apomorphine and hyoscine (scopolamine), was extensively used in the control of excitement and agitation; chloral hydrate and paraldehyde for calming and inducing sleep; and potassium bromidefor relieving restlessness, anxiety and tension (Cervello 1882; Joynt 1974; Liebig 1832; Liebreich 1869; Serturner 1806; Shorter 2005; Wood 1855). The use of these drugs provided day-and night time sedation in the asylums and reduced the need for physical restraint (Ban 2006). It was during this period – between 1850 and 1900 – that academic psychiatry was born with more than 20 academic departments established in German-speaking universities alone (Shorter 1997, 2005).

By the end of the 19th century, pharmacological control of behavior made it possible to study the symptoms and signs of psychiatric patients during the entire course of their illness (Ban 2006).The information collected opened the path for the further development of psychopathology, the discipline that deals with the symptoms and signs of psychiatric disease,and psychiatric nosology, the discipline that deals with the methodology of synthesizing and classifying diseases (Boissier de Sauvages 1768; Jaspers 1910, 1913; Kahlbaum 1863).During the first half of the 20th, century psychopathology provided a common language for the description of the mental state of patients, and nosology the necessary orientation points to classify them into groups with some predictability of behavior and response to treatment. In the new classification, the psychoses – which originally included all mental pathologies – were split into “organic”and “endogenous”; the “endogenous psychoses” were divided into manic-depressive insanity (illness) and dementia praecox (schizophrenia); the “exogenous (toxic) psychoses” were distinguished from the “reactive (psychogenic) psychoses”; and the “psychoses” (manifestations of disease) were separated from the “personality disorders” (manifestations of anomalous development) (Bayle 1826; Bonhoeffer 1909; Feuchtersleben 1845; Jaspers 1910; Kraepelin 1896, 1899; Mobius 1893; Schneider 1950; Wimmer 1916). 

Simultaneously with the development of modern psychiatry, the armamentarium of drugs used in psychiatric disorders had grown. In 1903 the barbiturates, a group of sedative drugs appeared; they found their place in clinical practice in a variety of disorders, including insomnia, epilepsy and inhibited catatonia (Fischer and Mering 1903; Lehmann and Ban 1970; Thorner 1935). They were also used in general anesthesia and in the facilitation of psychotherapy (Lehmann and Ban1970). In 1936, after the recognition of their central nervous system stimulating effect (initially described in 1927), the amphetamines entered the psychiatric scene; Benzedrine (amphetamine sulfate) was shown to have therapeutic effect in narcolepsyand in calming hyper-excitable and hyperactive children (Alles 1927; Bradley 1937; Prinzmetal and Blumberg 1935).In the 1940s, with the introduction of nicotinic acidand penicillin, cerebral pellagraand cerebral syphilis were wiped out in psychiatry; and with the introduction of thiamine and diphenylhydantoin the psychiatric population with amnestic syndrome and epilepsy was drastically decreased in psychiatric hospitals (De Wardener and Lennox 1947; Elvehjem et al.  1937; Fleming 1929; Fouts et al. 1937; Jansen and Donath 1926; Putnam 1970; Stokes et al. 1944; Wernicke 1881).      

The use of drugs in the study of mental pathology – advocated in the mid-19th century by Moreau de Tours – was re-vitalized with the introduction of phenomenological psychopathology, the branch of psychopathology that deals with the subjective experiences of psychic life (Jaspers 1913; Moreau de Tours 1845).Initially, phenomenological studies with mescaline, the active ingredient of peyote (a cactus plant),were in vogue (Beringer 1927; Knauer and Maloney 1913; Lehmann 1993; Lewin 1931.) Interest shifted to lysergic acid diethylamide (LSD), an ergot alkaloid, after its accidental discovery in 1943 by Hofmannwhile working with synthetic ergot alkaloids in order to develop a nikethamide-like analeptic in the laboratories of Sandoz, a Swiss pharmaceutical company at the time (Hofmann 1970; Stoll and Hofmann 1943). LSD was more than 1,000 times more potent than mescaline; it was active in 0.5 to 1.0 microgram per kilogram (Brown 1972).The possibility that a chemical in such minute amounts could induce hallucinations had fueled the contemporary hypothesis that undetectable traces of psychoactive substances produced by the body might be responsible for the pathogenesis of some mental illness.

            The idea that autointoxication plays a role in the pathogenesis of some psychoses entered psychiatry in the 1930s with Rolv Gjessing’s finding of nitrogen retention in certain phases of periodic catatonia (Gjessing 1938). His postulation that the alteration of metabolism by the production of mescaline-like substances in the body is responsible for periodic catatonia profoundly affected psychiatric thinking in the 1940s and ’50s. John Cade,stimulated by the work of Gjessing and Hofmann,hypothesized that mania, as thyrotoxicosis, was a state of intoxication by a product of the body in excess, and melancholia, as myxedema, was a state of deficiency of the same substance (Cade 1948, 1970; Gjessing 1938; Stoll and Hofmann 1943). The hypothesis was wrong, but it led to the serendipitous discovery of the therapeutic effect of lithium in mania in the late 1940s (Cade 1948).

            Autointoxication, combined with Walter Cannon’s findings about the role of the adrenals in the adaptation to stress, is at the core of Osmond and Smythies (1952) postulation that schizophrenia is the result of stress-induced anxiety and a failure in the metabolism of norepinephrine. Harley-Mason (1952) suggested that a trans-methylation product of norepinephrine, DMPEA (3, 4- dimethoxyphenylalanine) – a toxic substance that could induce experimental catatonia– was responsible for the pathogenesis of schizophrenia; Hoffer, Osmond and Smythiesproposed that adrenochrome, an oxidation product of epinephrine,was the culprit (Ban and Lehmann 1970; Green and Richter1937; Harley-Mason 1952; Hoffer, Osmond and Smythies 1954; Noteboom 1934; Osmond and Smythies 1952). Both hypotheses were wrong. Yet they stimulated research in the biochemistry of mental illness in a period (1950s) when psychodynamic schools dominated psychiatry in North America and schizophrenia (“schizophrenic reactions”) was perceived as the outcome of poor mothering manifesting as narcissistic withdrawal with regression to early autoerotic stages of ego development (Noyes and Kolb 1958).

It was against this background that within a period of five years five effective pharmacological treatments appeared on the psychiatric scene.



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September 6, 2018