Monday, 24.02.2020

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
Neuropsychopharmacology (Volume Five): 1. Model Psychosis
Bulletin 48


            Neuropsychopharmacology studies the relationship between neuronal and mental events with the use of psychotropic drugs (Ban and Ucha Udabe 2006).

            Instrumental to the development of Neuropsychopharmacology was the introduction of effective pharmacological treatments for mental illness, the demonstration of monoamine neurotransmitters in the brain, the recognition of chemical mediation at the site of the synapse and the construction of the spectrophotofluorimeter(Ban 2001). With the employment of the new instrument in the mid-1950s Alfred Pletscher, in collaboration with Parkhurst Shore and Brodie, found a decrease in serotonin (5HT) levels after the administration of reserpine, a substance that was seen to induce depression in some hypertensive patientsand an increase in brain 5HT levels after the administration of iproniazid, a monoamine oxidase inhibitor (MAOI) that was seen to induce euphoria in some tubercular patients (Freis 1954; Pletscher 1956; Pletscher, Cole and Brodie 1955, 1956; Selikoff and Robitzek 1952).

            Neuropsychopharmacology isbased on the assumption that one might “deduce the biochemical and physiological basis of the disorders treated” from the mode of action of drugs with “known therapeutic effects.” The idea was that the information on the biology of disease would guide the development of rational pharmacological treatments (Hollister 1996; Wikler 1957).

            During the past 50 years Neuropsychopharmacology has been driven by advances in the methodology for tracking the action of psychotropic drugs in the brain. The rate-limiting step has been difficulty in identifying homogeneous clinical populations whose responsiveness to psychotropic drugs would have predictive validity.

            In the first four volumes in this series interviewees reflected on their contributions to studying drug-induced changes on behavioural measures and conditioned reflex parameters (Volume One: Starting Up); on electrical activity of the brain and cerebral metabolism (Volume Two: Neurophysiology); on molecular and sub-molecular brain structures (Volume Three: Neuropharmacology); and on mental faculties and psychopathology (Volume Four:  Psychopharmacology). In this volume (Volume Five: Neuropsychopharmacology) interviewees reflect on their contributions towards understanding the pathophysiology of mental disorders and development of rational pharmacological treatments (Ban 2011; Fink 2011; Gershon 2011; Levine 2011; Shorter 2011; Sulser 2011).  


Model Psychosis


            The roots of Neuropsychopharmacology are in the discovery by Joseph Moreau de Tours that the effect of dawamseck, an electuary of hashish, is different in depressed (melancholic) than in regressed (aliéné stupide) patients and in the recognition by Claude Bernard that drugs provide a means for the study of brain physiology (Bernard 1865; Moreau 1845). By exploring the effect of dawamseck on himself, in escalating and diminishing doses, and on his students and his patients with different diagnoses in the mid-19th century, Moreau de Tours was first to use what was to be referred to as “model psychosis” in the study of mental disorders (Caldwell 1970).

            Research with “model psychosis” took wing in the mid-1890s with the isolation of mescaline from peyote, a cactus used for centuries in religious ceremonies by American Indians to induce ecstatic and hallucinatory experiences (Heffter 1886; Lewin 1924; Shonle 1925). In the early years of the 20th century mescaline was studied by many, including Alwyn Knauer, a disciple of Kraepelin, who administered it to himself and to some of his colleagues (Knauer and Maloney1913). In the mid-1920s the phenomenology of mescaline-induced psychosis was elaborated by Kurt Beringer and Heinrich Klűver; in the early 1930s, Quastel and Wheatley showed that the substance inhibited in vitro oxidation in the brain (Beringer 1927; Kluver 1928; Quastel and Wheatley1923).

            Another major impetus for research with “model psychosis” was the synthesis of lysergic acid diethylamide (LSD-25), isolated from ergot in the mid-1930s by Jacobs and Craig, and the discovery of its psychomimetic effects by Albert Hofmann in 1943 (Hoffmann 1970; Jacobs and Craig 1934). Albert Stoll’s report in 1947 on the mental pathology induced by LSD-25 was followed by a series of publications on the behavioural and mental effects of the substance (Arnold and Hoffmann 1955; Elkes, Elkes and Bradley 1954; Stoll 1947).  In the mid-1950s John Gaddum, and independently Wooley and Shaw, proposed that the pharmacological antagonism between LSD-25 and 5HT caused the psychosis induced by the drug (Abramson, Jarvik, Kaufman et al.1955; Amin, Crawford and Gaddum 1954; Gaddum 1953, 1957; Gaddum and Hamead 1954; Graham-Smith 2006; Woolley and Shaw 1957).  It proved not to be the case: in 1965 Cerletti and Rothlin showed that 2-bromo-LSD (BOL), a substance which has no effect on mental faculties, is just as potent an inhibitor of 5HT’s action as LSD-25 (Cerletti and Rothlin 1955; Rothlin 1957). 

              While mescaline and LSD-25 remained for years in the center of human research interest, in the mid-1950s the hallucinogenic effect of N, N-dimethyltryptamine (DMT), one of the ingredients of the South American snuff “cohoba,” entered the scene (Hoch 1951; Hollister and Hartman 1962; Mayer-Gross 1951). The substance was extracted along with bufotenin (dimethyl-N-oxide, 5-hydroxydimethyltryptamine) from the seeds of Piptadenia peregrina and macrocarpa by Fish, Johnson and Horning; in 1956 Stephen Szara, demonstrated its psychomimetic properties (Arnold and Hoffmann 1957; Fish and Horning 1956; Szara 1956).   His initial findings were further substantiated in the late 1950s by several investigators, including Turner and Merlis (Boszormenyi, Deri and Nagy, 1959; Sai-Halasz, Brunecker and Szara 1958; Turner and Merlis 1959). Szara also compared, in self-experiments, the psychopathology induced by DMT, mescaline and LSD-25 (Szara 1957).

            In 1959 the armamentarium of psychomimetic drugs was further extended with the inclusion of phencyclidine (Sernyl), a fast-acting anaesthetic that was found to induce “symptoms of sensory isolation” by Meyer and his associates and was characterized as a “schizophrenomimetic” by Luby and his associates (Brown 1972; Catenacci 1958; Chen 1968; Luby, Cohen, Rosenbaum et al. 1959; Meyers, Griefenstein and Devault 1959).  The psychopathology induced by Sernyl was further refined by Ban, Lohrenz and Lehmann who found that in low doses Sernyl had a disinhibiting effect that gave way in increasing doses to a feeling of weightlessness and body image disturbances in normals, and in psychiatric patients it accentuated pre-existing features of psychopathology (Ban 1965; Ban, Lohrenz and Lehmann 1961).

                By the end of the 1950s there were numerous psychomimetic indoles, phenylethylamines and piperidines available for inducing “model psychosis,” including psilocybin, reserpine, yohimbine, amphetamine, atropine, Ditran (1-ethyl-3-piperidyl-cyclopentylglycolate) and many others (Connell 1958; Forrer 1951; Hoffman, Heim and Kobel 1958; Hoffman and Troxler 1959; Holmberg and Gershon 1961; Jensen 1959; Krogsgaard 1958; Meduna and Abood 1959).    The “psychosis” induced by atropine, a substance isolated in the early 19th century from the Belladonna plant, was in the center of a debate concerning “association” or “dissociation,” between electroencephalographic changes and behaviour (Innes and Nickerson 1965).

In the 1950s atropine was used, in the “pharmacotoxic therapy” of schizophrenia and in studying the neurophysiology of hallucinations (Alexander 1951; Gaszner 1974; Giljarovski 1954). The psychopathology it induced was an “acute organic syndrome,” Bonhoeffer’s exogenous reaction type,dominated by delirium, whereas the psychopathology seen with reserpine was dominated by depression, with iproniazid by euphoria, with yohimbine by anxiety and with amphetamine by delusions, a clinical picture resembling some forms of schizophrenia (Bonhoeffer 1909; Brown1972; Mayer-Gross, Slater and Roth 1960).



Abramson AJ, Jarvik ME, Kaufman MR, Kornetsky C, Levine A, Wagner M. Lysergic acid diethylamide (LSD-25):Physiological and perceptual responses. J Psychol 1955; 39: 3-6.

Alexander L. Treatment of Mental Disorders. Philadelphia: Saunders; 1953.

Amin AH, Crawford TBB, Gaddum JH. The distribution of Substance P and 5–hydroxytryptamine in the central nervous system of the dog. J Physiol 1954; 125: 596-618.

Arnold OH, Hofmann G. UntersuchungenûberBernsteinsäuereeffektebei LSD-25-Vergiftungen und Schizophrenia. Wien Z Nervenheilk 1955; 11: 92-3.

Arnold OH, Hofmann G. ZurPsychopathologie des Dimethyltryptamin. Wien Z Nervenhelk 1957; 13: 438-45.

Ban TA. Action of psychotogenic drugs in animal and man. Discussion. In: Bente D, Bradley PB, editors. Neuropsychopharmacology. Amsterdam: Elsevier; 1965. p. 127-8.

Ban TA. Pharmacotherapy of mental illness. A historical analysis. Prog Neuropsychopharmacol& Biol Psychiatry 2001; 25: 709-27.

Ban TA, Preface. In Gershon S, editor. Neuropsychopharmacology. In Ban TA,editor. An Oral History of Neuropsychopharmacology The First FiftyYears Peer Interviews. Volume 5. Budapest: Animula; 2011, pp. 9-29.

Ban TA, Lohrenz J, Lehmann HE. Observations on the action of Sernyl, a new psychotropic drug. Can Psychiat Assoc J 1961; 6: 10-7. 

Ban TA, Ucha Udabe R. The neurotransmitter era in neuropsychopharmacology. In: Ban TA, Ucha Udabe R, editors. The Neurotransmitter Era in Neuropsychopharmacology. Buenos Aires: Editorial Polemos; 2006. p. 265-74.

Beringer G. Mescalinrausch. Berlin: Julius Springer; 1927.

Bernard C. Introduction a l’étude de la médicineexpérimentale. Paris: Baillière; 1865.

Bonhoeffer K. Zur Frage der exogenenPsychosen. NeurZlb 1909; 32: 499-505.

Böszörményi Z, Déri P, Nagy T. Observations on the psychotogenic effect of N, +N-dimethyltryptamine, a new tryptamine derivative. J Ment Sci 1959; 105: 171-81.

Brown FC. Hallucinogenic Drugs. Springfield: Charles C. Thomas; 1972. p. 131-4.

Caldwell AE. Origins of Psychopharmacology. From CPZ` to LSD. Springfield: Charles C. Thomas; 1970. p. 185-187.

Catenacci AJ. Evaluation of 1-(1-phenylcyclohexyl )-piperidine (Sernyl) as an anesthetic and pre-anesthetic . Fed Proc 1958; 17: 357-8.  

Cerletti A, Rothlin E. Role of 5-hydroxytryptamine in mental diseases and its antagonism to lysergic acid derivatives.  Nature 1955; 176: 785-6

Chen G. Pharmacology of 1-(1-phenylcyclohexyl)-piperidine  HCl. Fed Proc 1968; 17: 358-9.

Connell PH. Amphetamine Psychoses. London: Chapman and Hall; 1958.

Elkes J, Elkes C, Bradley PB. The effects of some drugs on the electrical activity of the brain and behavior. J Ment Sci. 1954; 100: 125-8.

Fink M, editor. Neuropharmacology. In Ban TA, editor. An Oral History of Neuropsychopharmacology The First Fifty Years Peer Interviews. Volume 2. Budapest: Animula; 2011.

Fish MS, Horning JR. Studies of hallucinogenic snuffs. J NervMent Dis 1956; 124-37.

Forrer GR. Atropine toxicity in the treatment of mental disease. Am J Psychiatry 1951; 108: 107-12.

Freis ED. Mental depression in hypertensive patients treated for long-periods with large doses of reserpine. New Engl J Med 1954; 251: 1006-8.

Gaddum JH. Antagonism between lysergic acid diethylamide and 5-hydrxytryptophan. J Physiol (London) 1953; 121: 15-8.

Gaddum JH. Serotonin-LSD interaction. Annals of the New York Academy of Sciences 1957; 66: 643-8.

Gaddum JH, Hamead KA. Drugs which antagonize 5-hydroxytryptamine . Br J Phramacol 1954; 9: 240-8.

Gaszner P. Az atropine-coma terápiamethodikájárol, kűlönostekintettelaz atropine-é rzékenységváltozására. IdeggyogyászatiSzemle. 1974; 27: 172-7.

Gershon M, editor. Neuropharmacology. In Ban TA, editor. An Oral History of Neuropsychopharmacology The First Fifty Years Peer Interviews. Volume 5. Budapest: Animula; 2011.

Giljarovskij AW. Pszihiatrija. Moscow: Medgiz; 1954. 

Graham-Smith DG. Serotonin and the neurotransmitter era in neuropsychopharmacology. In: Ban TA, Ucha Udabe R, editors. The Neurotransmitter Era in Neuropsychopharmacology. Buenos-Aires: Editorial Polemos; 2006. p. 65-77.

HeffterA.ÜberCactenalkaloide. Berl Deutsch Chem Ges   1886; 29: 216-27.

Hoch PH. Experimentally produced psychoses. Amer J Psychiat 1951; 107: 607-11.

Hofmann A. The discovery of LSD and subsequent investigations on naturally occurring hallucinogens. In: Ayd FJ, Blackwell B, editors. Discoveries in Biological Psychiatry. Philadelphia: JB Lippincott; 1970. p. 91-106.

Hofmann A, Heim R, Brack A, Kobel H. Psilocybin, einpsychotroperWirkstuffaus dem mexikanischenRauchpilzPsilocybe Mexicana  Heim. Experimentia 1958; 14: 107-9.

Hollister LE. Review of Wikler’s The Relation of Psychiatry to Pharmacology. In: Ban TA, Ray OS, editors. A History of the CINP. Brentwood; JM Productions; 1996. p. 339-43.

Hollister LE, Hartman AM. Mescaline, lysergic acid diethylamide and psilocybin: comparison of clinical syndromes, effects on color perception and biochemical measures. Comp Psychiat 1962; 3: 235-41.

Holmberg G, Gershon S. Autonomic and psychic effects of yohimbine hydrochloride 1961; 2: 93-106.

Innes IR, Nickerson  M. Drugs inhibiting the action of acetylcholine structures innervated by postganglionic  parasympathetic nerves. In: Goodman C, Gilman A, editors. The Pharmacological Basis of Therapeutics. New York: Macmillan; 1965.

JacobsWA, Craig IC.  The ergot alkaloids III. On lysergic acid.  J Biol Chem  1934;  106: 93-6.

Jensen K. Depression in patients treated with reserpine for arterial hypertension. Acta PsychiatricaScandinavica 1959; 34: 195-204.

Klűver H. Mescal: The Divine Plant. London: Kegan; 1928.

Knauer A, Maloney WJ. A preliminary note on the psychic action of mescaline. J NervMent Dis 1913; 40: 397-398.

Krogsgaard AR. Side-effects of reserpine in the treatment of arterial hypertension. Journal of Internal  Medicine 1958; 162: 465-74.

Levine J, editor. Psychopharmacology. In Ban TA, editor. An Oral History of Neuropsychopharmacology The First Fifty Years Peer Interviews. Volume 4. Budapest: Animula; 2011.

Lewin L. Phantastica, Narcotic and Stimulating Drugs: Their Use and Abuse. New York: Dutton; 1924.

Luby ED, Cohen BD, Rosenbaum G, Gottlieb JS, Kelley R.Study of a new schizophrenomimetic drug; sernyl. AMA Arch Neurol Psychiatry. 1959 Mar;81(3):363-9.

Mayer-Gross W. Experimental psychosis and other mental abnormalities produced by drugs. Brit Med J 1951; 57: 317-21.

Mayer-Gross W, Slater E, Roth M. Clinical Psychiatry.  Second edition. Melbourne: Cassell; 1960. p. 336-87.

Meduna LJ, Abood  LG. Studies of a new drug (Ditran) in depressive states. J Neuropsychiat 1959; 1: 20-22,

Meyers JS, Griefenstein F, Devault M. A new drug causing symptoms of sensory deprivation. J NervMent Dis  1959; 54: 54-61.

Moreau de Tours J. Du Hachisch et de l’AlienationMentale. Etudes Psychologiques. Paris: Fortin & Masson; 1845. p. 432-2

Pletscher A. Beeinflussung des 5-hydroxytryptamine–stoffwechsels in GehirndurchIsonikotinsäuerehydrazide. Experientia 1956; 1956; 12: 479- 80.

Pletscher A, Shore PA Brodie BB. Serotonin release as a possible mechanism of reserpine psychosis. Science 1955; 122: 574-5.

Pletscher A, Shore PA, Brodie BB. Serotonin as a modulator of reserpine action in brain. J PharmacolExperTher 1956; 116: 84-9.

Quastel JH, Wheatley AHM. The effect of amines on oxidation of the brain. Biochem J 1933; 27: 1609-10.

Rothlin E. Lysergic acid diethylamide and related substances. Annals of the New York Academy of Sciences 1957; 66: 668-76.

Sai-Halasz A, Brunecker G, Szara SI. Dimethyltryptamine einneuesPsychoticum. Psychiat Neurol 1958: 285-301.

Selikoff IJ, Robitzek EH, Orenstein GG. Treatment of pulmonary tuberculosis with hydrazine derivatives of isonicotinic acid. JAMA 1952; 150: 973-87.

Shonle R. Peyote, the giver of visions. American Anthropologist 1925; 27: 53-75.

Shorter E, editor. Starting Up. In Ban TA, editor. An Oral History of Neuropsychopharmacology The First Fifty Years Peer Interviews. Volume 1. Budapest: Animula; 2011.

Stoll WA. Lysergic acid diethylamide, a “phantasticum” derived from the ergot group of drugs. Schweiz Arch  Neurol Psychiat  1947; 60:279-80.

Sulser F, editor. Neuropharmacology. In Ban TA, editor. An Oral History of Neuropsychopharmacology The First Fifty Years Peer Interviews. Volume 3. Budapest: Animula; 2011.

Szara S. Dimethyltryptamine: its metabolism in man; the relation of its psychotoxic effect to serotonin metabolism. Experientia 1956; 12: 441-2.

Szara S. Comparison of the psychotic effect of tryptamine derivatives with the effects of mescaline and LSD-25 in self-experiments. In: Garattini S, Ghetti V, editors. Psychotropic Drugs. Amstrad am: Elsevier; 1957. p. 460-7.

Turner WJ, Merlis S. Effect of some indole alkylamineson man. Arch Neurol Psychiat 1959; 81: 121-9.

Wikler A. The Relation of Psychiatry to Pharmacology. Baltimore; American Society for Pharmacology andExperimental Therapeutics and the Williams & Wilkins Company; 1957.

Woolley DW, Shaw E. A biochemical and pharmacological suggestion about certain mental disorders. Proc Natl Acad Sci 1954; 40: 238 - 41.


December 13,  2018