making the first antidepressant amphetamines

7/28/2019 MAKING THE FIRST ANTIDEPRESSANT AMPHETAMINES

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Rasmussen : Amphetamine in American Medicine 289

Miltown and the other minor tranquilizers that ushered in widespreadpharmaceutical influence over psychiatric thinking and practice, during

the second half of the 1950s.1

In either account, society today is por-trayed as overmedicated for depression and other functional psychiatricdisorders because the boundaries of illness have been overstretched bydrug company marketing, and sound professional judgment no longergoverns prescribing.

This article will argue that such accounts abbreviate and oversim-plify the longstanding and complex interplay between psychiatry andthe drug industry. In particular, they ignore an earlier period, begin-ning in the late 1930s, when amphetamine was widely used as a spe-cific therapy for neurotic depression. Here I attempt to recover thisforgotten early chapter, in order to show that amphetamine representsthe first of the anti-depressant drugs, even though it was inventedfor another purpose and is no longer regarded as an anti-depressant.Indeed, the introduction of amphetamine to psychiatry in the 1930sand 1940s played a key role in reshaping medical understanding andpractice, along with popular expectations, to create a society of psy-chiatric outpatients routinely consuming mood-altering drugs en masse.

That is, amphetamine established the needthe marketfor anti-depressants that a succession of later drugs, including the currentlydominant selective serotonin reuptake inhibitors (SSRIs, e.g., Prozac),have filled since. Furthermore, medical thinking about depressionand its treatment appears to have been influenced by the drug indus-try, in this earlier period, in much the same manner that it is said tohave been influenced in later years.2 Thus, the story of amphetamines

1. Peter Kramer, Listening to Prozac(New York: Viking, 1993), 112, 249 et passim. Forthe drug industrys role, see R. Moynihan, I. Heath, and D. Henry, Selling Sickness: ThePharmaceutical Industry and Disease Mongering, Brit. Med. J., 2002, 324, 88690;B. Mintzes, Direct to Consumer Advertising is Medicalising Normal Human Experi-ence, Brit. Med. J., 2002, 324, 9089; V. Starcevic, Opportunistic Rediscovery ofMental Disorders by the Pharmaceutical Industry, Psychother. Psychosomatics, 2002, 71,30510. For the notion that undue pharmaceutical marketing influence on psychiatric diag-nosis began with the monoamine oxidase inhibitors and other anti-depressants of the late1950s, see David Healy, The Antidepressant Era (Cambridge, Mass.: Harvard UniversityPress, 1996), 59 et passim; see also idem., The Creation of Psychopharmacology (Cambridge,Mass.: Harvard University Press, 2002). On the competing notion that it was the minortranquilizers that created a psychotropic culture from the mid-1950s, see Jonathan Metzl,

Prozac on the Couch: Prescribing Gender in the Era of Wonder Drugs (Durham, N.C.: DukeUniversity Press, 2003).

2. For an exploration of relations between drug firms and academic medicine in the1930s, see Nicolas Rasmussen, The Drug Industry and Clinical Research in InterwarAmerica: Three Types of Physician Collaborator, Bull. Hist. Med., 2005, 79, 5080.

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290 Journal of the History of Medicine : Vol. 61, July 2006

development as an anti-depressant opens large questions about theways we think about both the history of pharmaceuticals and the

history of depression.THEHISTORIOGRAPHYOFPSYCHIATRYANDTHEPSYCHIATRIC

MEDICINEOFINTERWARAMERICA

Unfortunately, the standard historiography of psychiatry presentsmajor obstacles to interpreting the story at hand and therefore mustbe addressed at the outset. According to the current standard narra-tive, biological psychiatry in the 1960s was a new and revolutionaryforce that by the end of the next decade had overthrown a thor-oughly psychoanalytic establishment, in place since before WorldWar II. Before this biological revolution, psychoanalysis and otherdynamic, talking approaches had little to do with psychiatry aspracticed in mental institutions. Freudian therapists believed thatmost if not all mental illness could be healed through insight into thedistressing early experiences that had caused it. Thus they eschewedthe use of drugs for all but the most hopeless psychoses, just as theyscorned lobotomy and electroshock and other biological therapies;

outpatients being treated for neurotic conditions largely shared thesame aversion to drugs. For their part, the institutional psychiatristswere more biologically inclined in their approaches to their seriouslyill inpatients, but they saw drugs as nothing more than sedatives andinstruments of restraint (at least until the mid-1950s introduction ofantipsychotic agents like chlorpromazine). Only after a more biolog-ical perspective spread from institution-based psychiatry in the later1960s, reinforced with newly effective drugs like the tricyclic anti-

depressants, was Freudian talking therapy put into retreat and theway paved for the biological understandingand drug treatmentofcommon, relatively minor psychiatric conditions.3 There is no place insuch a narrative for an anti-depressant drug to have been developed

3. See for example Edward Shorter,A History of Psychiatry from the Era of the Asylum to theAge of Prozac(New York: Wiley, 1997), ch. 67. See also Judith Swazey, Chlorpromazine inPsychiatry: A Study of Therapeutic Innovation (Cambridge, Mass.: MIT Press, 1974). Even JoelBraslow, to whom a great historiographic debt is owed for enriching the picture of early

twentieth-century biological psychiatry, depicts drugs before chlorpromazine as merechemical restraints; see Mental Ills and Bodily Cures: Psychiatric Treatment in the First Half of theTwentieth Century (Berkeley: University of California Press, 1997), ch. 2. On how thecurrent standard narrative relates to previous standard narratives, see John Burnham, JackPressman and the Future of the History of Psychiatry, Bull. Hist. Med., 2000, 74, 77885.

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in the late 1930s and to have achieved wide success as a specific therapyfor depressed outpatients in the 1940s and 1950s. Nonetheless, as I shall

argue here, there was such a drug, and it was amphetamine.Though this article is by no means an adequate vehicle to developa new historiography of psychiatry from whole cloth, it does pointtoward an alternative perspective already suggested by recent histor-ical work. According to this alternative view, we must regard psy-chiatric medicine in the United States as more diverse and eclectic,and less polarized, than any scenario placing a long struggle betweenpsychoanalysts and biological psychiatrists on center stage. For instance,

Jonathan Metzl has shown that minor tranquilizers, represented as aidsto talking therapy, were marketed with apparent success to Freudianpsychiatrists in the 1950s and 1960s. The same was done with amphet-amine, as we shall see. Thus a psychoanalytic approach was notinconsistent with psychiatric drug prescriptionalthough in suchsituations the drugs were thought of as acting on anxiety symptomswithout affecting the neurotic illness itself. Similarly, JonathanSadowsky has found that many Freudian psychiatrists were acceptingof electroconvulsive therapies in the early postwar period and were

easily able to accommodate their effectiveness within psychoanalytictheory. Another very important insight has come from recent workby German Berrios and collaborators, who have looked at the disjunctbetween specialist psychiatry and primary care with respect to psychi-atric diagnosis and treatment. From the early twentieth century to the1980s, Berrios observes, expert opinion in psychiatry was highly dis-cordant as to the nature of depression and its proper treatment, leavingthe general practitionerswho actually prescribed (and still prescribe)

over85% of all psychiatric drugsfree to treat their emotionally dis-tressed patients with barbiturates, minor tranquilizers, tricyclic anti-depressants at placebo doses, or whatever other therapy they thoughtmight bring symptomatic relief. It is easy to see how amphetamine,which was widely marketed to general practitioners for treatment ofmild depression from the 1940s to the mid-1960s, fits with thispicture.4

4. Metzl, Prozac on the Couch; Jonathan Sadowsky, Beyond the Metaphor of the Pendulum:Electroconvulsive Therapy, Psychoanalysis, and the Styles of American Psychiatry,J. Hist.Med. Allied Sci., 2006, 61, 125; Christopher Callahan and German Berrios, ReinventingDepression: A History of the Treatment of Depression in Primary Care19402004 (Oxford: OxfordUniversity Press, 2005).

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Most important may be the work of Jack Pressman on the com-plex and eclectic state of American psychiatry in the 1930s and 1940s,

the context in which amphetamine emerged as the first anti-depressant.As Pressman has argued, in the United States, the period betweenWorld War I and World War II was one in which the previouslydistinct worlds of the isolated asylum psychiatrists and the elite neuro-logists, who advised affluent outpatients in comfortable urban con-sulting rooms, were united in a new field of neuropsychiatry. Thisinclusive American vision of mental medicine, largely conceived andconstructed by Adolph Meyer and his followers, saw the medicalapproach to psychoses in asylums, the dynamic theories and talkingtherapies of the Freudians with neuroses, laboratory experiments innerve physiology, and even empirical sociology all as valuable per-spectives that could be brought to bear on the problem of humanpsychobiology in a coordinated fashion. Distinctions betweenphysical and mental, between physiological and social, and betweeninsanity and problems of living were deliberately broken down in aneffort to create a medical discipline taking disorders of individualadjustment as its domain. Pragmatic and eclectic, and enjoying the

support of powerful philanthropies that saw a discipline of the mindbased firmly in scientific medicine as the solution to Americas socialproblems, this new neuropsychiatry was firmly established in the1920s and 1930s at influential medical schools such as Harvard andthe University of Pennsylvania. Nor was the ecumenical attituderestricted to specialists trained at these elite psychiatric centers; instandard general-medicine textbooks one finds Freud treated as justone contributor among many to the medical understanding of men-

tal illness. Meyer remained influential with his own views about theinstinctive drives and their channeling in the course of life history,emphasizing conscious adaptive mechanisms rather than the uncon-scious ones stressed by strict Freudians, and with his own approach totalking therapy as well. Because it treated mind as embodied, American(neuro)psychiatry was open to a wide range of somatic approachesin the interwar period, embracing such innovations as malarial ther-apies, insulin coma, electrical and chemical convulsion, and psycho-surgery or lobotomy, especially for treating more severe, psychoticillnesses (which were, however, typically regarded as differing fromrelated neurotic disorders only in severity but not in kind). Mindful ofthis context, one will find it less surprising that a specific drug treatment

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for milder (neurotic) depressions should find a receptive audience inthe 1930s.5

THEINVENTION OFAMPHETAMINE

Although amphetamine would find its first important medical usesin psychiatry, the path by which it was discovered shows no earlysign of leading in that direction. This synthetic drug emerged fromthe drive to make pharmaceutical products based on hormones, andin particular on adrenaline. The adrenal gland was one of the firstorgans identified as a source of internal secretion or hormones, alongwith the thyroid and testes, in the earliest days of endocrinology. Bythe 1890s the action of the adrenal hormone on various tissues andprocesses had become a major focus of experimentation amongphysiologists, while the identification of this blood pressureraisingsubstance had become a competitive field among biochemists. Soon,a number of relatively pure adrenal extracts had been prepared, eachhighly active in raising blood pressure, and a number were marketedby drug firms. But the product trademarked as Adrenalin, pre-pared by chemist Jokichi Takamine and marketed by Parke, Davis and

Company beginning in 1901, quickly came to dominate the market.6

5.Jack D. Pressman, Last Resort: Psychosurgery and the Limits of Medicine (Cambridge:Cambridge University Press, 1998). See also Gerald Grob, Mental Illness and American Society,18751940 (Princeton, N.J.: Princeton University Press, 1983), although this author does notacknowledge the union of neurology and psychiatry in the interwar period. For a relatedview of early twentieth-century neuropsychiatry, centered on Boston, see Elizabeth Lunbeck,The Psychiatric Persuasion: Knowledge, Gender, and Power in Modern America (Princeton, N.J.:Princeton University Press, 1994), and on Meyer, see Ruth Leys, Types of One: AdolfMeyers Life Chart and the Representation of Individuality, Representations, 1991, 34, 128.

For a nice example of the ecumenical attitude toward Freud in general medicine, seeHenry Christian, The Principles and Practice of Medicine, Originally Written by the late SirWilliam Osler and Revised by the late Thomas McCrae, 13th ed. (Boston: Appleton, 1938),1380. On the impact of physical therapies in early twentieth-century psychiatry, see JoelBraslow, The Influence of a Biological Therapy on Physicians Narratives and Interroga-tions: The Case of General Paralysis of the Insane and Malaria Fever Therapy, 19101950,Bull. Hist. Med.,1996, 70, 577608, and idem., Mental Ills and Bodily Cures. On the stillactive controversy concerning qualitative distinctions between depressive neuroses andpsychoses, see P. Boyce and D. Hadzi-Pavlovic, Issues in Classification: I. Some HistoricalAspects, in Melancholia: A Disorder of Movement and Mood, ed. G. Parker and D. Hadzi-Pavlovic (Cambridge: Cambridge University Press, 1996), 919.

6. Throughout, I shall use the term Adrenalin to refer to the Parke-Davis hormone

product, and adrenaline to refer to the mixture of the chemicals now known (in theUnited States) as epinephrine and norepinephrine that was the chief active product recoveredfrom the adrenal glandor, when a single chemical entity must be assumed, epinephrinealone. I also use adrenaline to refer to the substance that mediates adrenergic nerve function.This usage confirms to popular usage almost everywhere up to the present day, as well as

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Because it caused capillaries to constrict and thus restricted localblood flow, surgeons embraced the hormone drug enthusiastically as

a hemorrhage-reducing additive with local anesthetics. The bloodpressureraising (pressor) power of an adrenaline injection made ita useful treatment for shock, and the hormones relaxing effects onthe bronchial passages quickly made it essential for the treatment ofasthma. In the wake of its commercial and clinical success, somechemists sought other drugs with sympathomimetic action (socalled because adrenalines wide range of actions in general mimicthe effects of stimulation of the sympathetic nerves to each particularorgan and tissue, causing the smooth muscle of the intestine to relax,tear gland secretion to be boosted, pupils to dilate, etc.). Most nota-bly, physiologist Henry Dale and chemist George Barger at theBurroughs-Wellcome firm in Britain systematically generated dozensof synthetic compounds structurally related to adrenaline, finding onewith a longer duration of action in its pressor effect; it was eventu-ally marketed by the firm for shock under the brand name Tyramine,albeit without huge commercial success.7

widespread medical usage in the early twentieth century. On the discovery and physiologicalsignificance of the hormone, see Merriley Borell, Organotherapy, British Physiology, andthe Discovery of Internal Secretions, J. Hist. Biol.,1976, 9, 23568; Horace Davenport,Epinephrin(e), Physiologist, 1982, 25, 7682; Leonard Wilson, Internal Secretions inDisease: The Historical Relations of Clinical Medicine and Scientific Physiology,J. Hist.Med. Allied Sci., 1984, 39, 263302; V. C. Medvei, A History of Endocrinology (London:MTP, 1981), 32533. On the purification and commercial development of adrenaline, seeTom Mahoney, Merchants of Life(New York: Harper, 1959), 7374; J. J. Abel, On Epi-nephrine and Its Compounds, Am. J. Pharmacy, 1903, 75, 30125; John Parascandola,

John J. Abel and the Early Development of Pharmacology at the Johns Hopkins University,Bull. Hist. Med., 1982, 56, 51227; Walter Sneader, Drug Discovery: The Evolution of ModernMedicines (London: Wiley, 1986), 9699; Miles Weatherall, In Search of a Cure (Oxford:Oxford University Press, 1990), 8587; Tetsumori Yamashima, Jokichi Takamine (18541922), The Samurai Chemist, and his Work on Adenalin,J. Med. Biog.,2003, 11, 95102;Horace Davenport, Epinephrin(e), Physiologist, 1982, 25, 7682; Jonathan Simon, Adrenalin,Epinephrin, or Suprarenin? Identifying the True Hypertensive Principle, unpublishedpaper presented at conference on Drug Trajectories: Historical Studies of Biology, Medi-cine, and Industry, Max Planck Institute for History of Science, Berlin, 78 June 2002.

7. See George Barger and Henry Dale, Chemical Structure and SympathomimeticAction of Amines, J. Physiol., 1910, 41, 1959, and sources cited therein. On Dale andchemical nerve transmission, see E. M. Tansey, Whats in a Name? Henry Dale and

Adrenaline, 1906, Med. Hist.,1995, 39, 45976; idem., Sir Henry Dale and Autopharma-cology: The Role of Acetylcholine in Neurotransmission, Clio Medica, 1995, 33, 18193;Zenon Bacq, Chemical Transmission of Nerve Impulses: A Historical Sketch (Oxford: PergamonPress, 1975); J. D. Robinson, Mechanisms of Synaptic Transmission: Bridging the Gaps (18901990) (Oxford: Oxford University Press, 2001), ch. 3; On sympathomimetic drugs, see also

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The next important sympathomimetic to reach the medical marketwas ephedrine, discovered in the traditional Chinese herb Ma Huang,

orEphedra vulgaris. Japanese scientists were the first to purify, charac-terize, and commercialize the drug, but its discovery for Westernmedicine came from US-trained scientists Ku Kuei Chen and CarlSchmidt at Peking Union Medical College in 1923. Like the struc-turally similar adrenaline, ephedrine was found to raise blood pressure,though not powerfully enough to replace Adrenalin and Tyramineas medicines for the treatment for shock. Its capillary-constrictingeffect, though much longer lasting than that of adrenaline, also provedinsufficient for the drug to replace Adrenalin as a surgical hemorrhagepreventive. However, this capillary-constricting effect is strong enoughto shrink swollen nasal tissue, providing hours of congestion reliefwhen applied by spray or taken as a pill, and the drug became enor-mously popular with cold and allergy sufferers soon after it wasintroduced to the market by the Lilly firm in 1926. Furthermore,ephedrine is also somewhat effective in relaxing bronchial passages,though less so than adrenaline. But since it is active when taken orally,it quickly became popular among asthmatics, who would take it to

forestall attacks (though an adrenaline injection was still needed if anattack did occur). Ephedrine and the related compound pseudoephe-drine could be synthesized, but the most economical source of supplyremained Ephedra plants grown in China, and Lilly controlled mostof the Chinese production.8 Supply of ephedrine was short, and priceshigh, in the late 1920s, so for the enterprising there was a greatincentive to find a substitute decongestant and asthma reliever.

This demand for an ephedrine substitute was the impetus behind

the development of amphetamine, together with an exuberant overallatmosphere in the business of drug development during the 1920s.

Sneader, Drug Discovery, 99100. Other chemists responded to adrenalines commercialdevelopment by pursuing natural substitutes; see Albert Crawford, The Use of SuprarenalGlands in the Physiological Testing of Drug Plants, U. S. Department of Agriculture Bureauof Plant Industry Bulletin, 1907, 112, 729.

8. See K. K. Chen and C. F. Schmidt, The Action of Ephedrine, an Alkaloid from MaHuang, Proc. Soc. Exp. Biol. Med., 1923, 21, 35154; idem., The Action and Clinical Useof Ephedrine,J. Am. Med. Assoc., 1926, 87, 83642; K. K. Chen, Chang-Ken Wu, and

Erle Henriksen, Relationship between the Pharmacological Action and the ChemicalConstitution and Configuration of the Optical Isomers of Ephedrine and Related Com-pounds, J. Pharmacol. Exp. Therapeutics, 1929, 36, 363400; Louis Goodman and AlfredGilman, The Pharmacological Basis of Therapeutics (New York: Macmillan, 1941), 42335. Seealso Sneader, Drug Discovery, 100.

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The pharmaceutical industry had recently begun looking hard for newscientifically legitimate products, having been disciplined by medical

reformers to justify advertising claims with scientific evidence. Closecollaborations were formed between drug firms and some of theleaders in biomedical research, especially in the fast-moving and com-petitive fields of endocrinology and vitamin research. Vitamin D,insulin, and a host of other new laboratory discoveries quickly foundtheir way to medical practice in the 1920s, thanks to a veritable frenzyof industrial-academic collaborations that one contemporary endo-crinologist described as a gold rush.9 Southern Californian GordonAlles received his formation as a biochemist amid this entrepreneur-ial atmosphere. Alless 1924 masters thesis at the California Instituteof Technology dealt with the chemical properties of insulin, particu-larly with ways to quantify it in vitro and thus to standardize doses,and also its possible mode of action. He began working in the largepractice of Los Angeles allergist George Piness, making proteinpreparations for allergy desensitization treatments, while continuingin a doctoral program at Cal Tech. His 1926 Ph.D. thesis dealt withphysiological effects of some novel chemicals he had derived from

guanidine, particularly their effects on blood pressure, respiration,and blood sugar in rabbits; in this, Alles appears to have been seekinga synthetic substitute for insulin.10 In 1927 to 1928, Alles spent an

9. On the American drug industry between the wars, see Jonathan Liebenau, EthicalBusiness: The Formation of the Pharmaceutical Industry in Britain, Germany, and the UnitedStates before 1914, Business Hist., 1988, 30, 11629; idem., Medical Science and Medical Indus-try: The Formation of the American Pharmaceutical Industry (Baltimore, Md.: Johns Hopkins Uni-versity Press, 1987). On academic-industry collaborations generally, see John P. Swann,

Academic Scientists and the Pharmaceutical Industry (Baltimore, Md.: Johns Hopkins UniversityPress, 1988); and Nicolas Rasmussen, The Moral Economy of the Drug Company-MedicalScientist Collaboration in Interwar America, Soc. Stud. Sci., 2004, 34, 16185. On insulin,see Michael Bliss, The Discovery of Insulin (Chicago: University of Chicago Press, 1982); andSwann,Academic Scientists, ch. 5 et passim. On Steenbock, see Rima Apple, Patenting Uni-versity Research: Harry Steenbock and the Wisconsin Alumni Research Foundation, Isis,1989, 80, 37594; and Mahoney, Merchants, 224. On endocrinology and especially sex hor-mones as a gold rush, see Nelly Oudshoorn, Beyond the Natural Body: An Archeology of the SexHormones (London: Routledge, 1994), 88 (quoted is biologist Robert Frank, 1929).

10. Gordon Alles, Experiments on the Chemical Behavior of Insulin (masters thesis,Chemistry Dept., California Institute of Technology, 1924); idem., The ComparativePhysiological Action of Some Derivatives of Guanidine (Ph.D. diss., California Institute

of Technology, 1926). Alles, draft description of Piness-Alles patent situation, 20 January1948, folder Originals January 1948, box 15, Gordon Alles Papers, California Institute ofTechnology archives (hereafter, GAP). Alles appears to have collaborated with Abel ofJohns Hopkins in this insulin research around 1924; see anonymous, undated [1963] obituarydraft, folder SKF v. Alles Documents, box 5, GAP.

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academic year getting a taste of drug companyacademic collaborationsas a postdoctoral fellow in the Harvard laboratory of Edwin Cohn,

then deeply involved with Lilly in a project to develop a perniciousanemia drug from liver extract.11

Unable to land an academic job, Alles returned to his job makingdesensitization preparations in Los Angeles and also researchingnew allergy drugs. One new sympathomimetic that he workedwith was phenylethanolamine, useful in nose drops, but lackingephedrines prized oral activity. Seeking whatever it was that madeephedrine able to withstand the stomach long enough to enter theblood, Alles prepared some more molecules related to ephedrine andsoon took a special interest in one of these, phenylisopropylaminephenylethanolamine with ephedrines extra carbon added to theside chain (and with the side chain hydroxyl group removed).Prepared as the sulfate salt, in animal tests it was active by mouthlike ephedrine, had a pressor effect much longer lasting thanadrenaline, and was not terribly toxic.12 So, in early June 1929,Alles tested this chemical, which I will from now on call amphet-amine for simplicity (though it would not receive this name offi-

cially for almost ten years), on himself. He noted a feeling of wellbeing, palpitation, and eventually a sleepless night in whichhis mind seemed to race from one subject to another. Two dayslater the chemical was given to the first of several of Dr. Pinessspatients undergoing an asthma attack. It proved a mediocre asthmaremedy, but these patients also experienced exhilaration andpalpitationthat is, central nervous system and cardiac effects.In July 1929, Piness presented the groups results of trials with their

phenylethanolamine decongestant at an American Medical Associationmeeting in Oregon and also their first findings on the treatment ofasthma and hay fever with amphetamine.13

11. Alles to Piness, 22 October1927, folder Originals1927, box 14, GAP. Alles toPiness, 24 February 1928, Hyman Miller to Alles, 29 February 1928, and Alles to Piness, 6 March1928, folder Originals1928, box 14, GAP. On the Harvard-Lilly collaborations, seeSwann, Medical Scientists, ch. 5; Alles to Piness, 24 February 1928, folder Originals1928,box 14, GAP.

12. Alles [and Leake?], undated [mid-1950s] MS, Amphetamine and Related Sub-stances, folder SKF v. Alles Documents, box 5, GAP, 1112.

13. Ibid., 1214. For animal experiments, see also e.g. Alles, 27 November1928, Exp.#2; Alles, 1 December1928, Experiment 6; Alles, 10 April 1932, untitled experimenton Dog, 9 kg; for human tests, see e.g. Alles, 3 June 1929, B-Phenyl-isopropyl amine

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Though Alles filed a patent on amphetamine in the form of sulfatesand other salts, there was no celebration over the drug, and for the

next four years his research efforts were mainly devoted to finding asynthetic, orally available asthma and allergy remedy superior toephedrinepreferably without the stimulatory side effects. Startingin 1931, he began conducting some of the animal work associatedwith his research at the pharmacology department of the Universityof California medical school in San Francisco (UCSF), an associationthat continued for many years.14 Meanwhile, Alles looked for waysto make something of his failed asthma drug. In 1933 he suppliedsome amphetamine to Myron Prinzmetal, who as a medical studenthad worked with him at UCSF, to try out in narcoleptic patients inSt. Louis; if the self-experiments had not made this idea obvious,some recent reports that ephedrine was beneficial for the disorderwould have. That year Alles also supplied Morris Nathanson, aCalifornian physician then working in Minneapolis, with amphetamineto test as a heart stimulant, along with ephedrine and adrenaline.Nathanson too tried the drug on narcoleptics, with some success,and then carried out a trial on forty patients complaining of fatigue

and asthenia. Alles also supplied some to another UCSF alumnus,S. Anderson Peoples, who wanted to try it on psychiatric patients dur-ing his fellowship at Londons Maudsley Hospital, and to Michael

Action on circulationManSubcutaneous administration; Alles, 5 June 1929, B-Phenyl-isopropyl amine Action on circulationMan Action on respirationMan; 14 November1929, B-Phenyl-isopropyl amine Action on circulationManLocal application; all in

folder SKF v. Alles Alles Lab Records, box 5, GAP. George Piness, Hyman Miller, andGordon Alles, Clinical Observations on Phenylethanolamine Sulfate,J. Am. Med. Assoc.,1930, 94, 79091.

14. U.S. Patent 1,879,003, to Gordon A. Alles, Salts of1-Phenyl-2-Aminopropane,granted 27 September1932. Chauncey Leake to Langley Porter, 14 October1931, folderSKF v. Alles documents received from Alles Office, box 2, GAP. This San Franciscoarrangement seems informally to have begun in the winter of 19311932; see Alles [andLeake?], undated [mid-1950s] MS, Amphetamine and Related Substances, folder SKFv. Alles Documents, box 5, GAP, 1416. On Alless place in the UCSF lab, see alsoLeake, Contributions from the Pharmacological Laboratory of the University of CaliforniaMedical School 19321934, annual reports, Special Collections of the University ofCalifornia Library, San Francisco. See also G. A. Alles, dl-beta- Phenylisopropylamines,

J. Am. Chem. Soc., 1932, 54, 27174; idem., The Comparative Physiological Actions of dl-beta-phenylisopropylamines. I. Pressor Effect and Toxicity,J. Pharmacol. Exp. Therapeutics,1933, 47, 33954; G. A. Alles and Myron Prinzmetal, The Comparative PhysiologicalActions of dl-beta- Phenylisopropylamines. II. Bronchial Effect,J. Pharmacol. Exp. Thera-peutics,1933, 48, 16174.

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Leventhal, a Chicago gynecologist who wished to try the drug fordysmenorrhea (premenstrual cramps and/or painful menstruation).15

Thus did the process of clinical development haphazardly begin,in which (to use Rein Voss memorable phrase) a drug looking for adisease may find its place, and at length become an important medi-cine.16 There was no plan to make amphetamine an anti-depressant,nor to find any use for it among neuropsychiatristsnor even todefine amphetamines stimulating central nervous system side effectsas the drugs chief action. As we shall see, in the case of amphet-amine, the process of finding this groundbreaking use seems to havehad two distinct phases. First, the major drug firm with which Allessoon allied himself cast its net more broadly and systematically, usingan extensive network of clinical collaborators to test the waters foramphetamine in a wide range of medical specialties. Then, after rulingout several unrelated, potentially lucrative possibilities and identify-ing a significant interest among neuropsychiatrists, the firm focusedboth its sponsorship of research with the drug and its marketing efforts(which were not always clearly distinguishable) on defining and pro-moting uses of the drug for that specialty. The use that caught on

among neuropsychiatrists was for therapy of common, milderdepressions, and it spread to general practice. Although medicine mighton its own have arrived at the same outcome, one can never knowwhat would have become of amphetamine if the pharmaceuticalindustry had not played such an active role in its clinical development.

THEDRUGFIRMANDTHESEARCHFORCLINICALDEMAND

While Alles was beginning to test his invention through his own,

informal network of clinical researchers, a new drug dubbedBenzedrine was released on the market by the Philadelphia firmSmith, Kline and French (SKF). Benzedrine was the same compoundas Allessphenylisopropylamine, that is, amphetamine. SKF chemist

15. Alles [and Leake?], undated [mid-1950s] MS, Amphetamine and Related Sub-stances, folder SKF v. Alles Documents, box 5, GAP, 1617; Alles to Boyer,26 December1934, folder Sale of Invention and Patent 1,879,009 on Benzedrine Salts asMedicinal Agents, box 1, GAP. J. B. Doyle and L. E. Daniels, Symptomatic Treatmentof Narcolepsy, J. Am. Med. Assoc., 1931, 96, 137072; Myron Prinzmetal and Wilfred

Bloomberg, The Use of Benzedrine for the Treatment of Narcolepsy,J. Am. Med. Assoc.,1935, 105, 205154; M. Nathanson, The Central Action of Beta-Aminopropylbenzene(Benzedrine),J. Am. Med. Assoc., 1937, 108, 52831.

16. Rein Vos, Drugs Looking for Diseases: Innovative Drug Research and the Development ofthe Beta Blockers and the Calcium Antagonists (Dordrecht: Kluwer, 1991).

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Fred Nabenhauer had developed the drug in the form of a volatilefree base rather than the orally active salts that Alles had patented;

although he might have discovered it independently (as the firmwould claim), this is doubtful, given that Alless first presentation onamphetamine at the 1929 AMA meeting in Oregon seems to havebeen reported promptly to SKF management. However the firm hap-pened to discover the drug, SKF first packaged it as an inhaler so as toexploit the bases volatility and, after sponsoring some trials by EastCoast otolaryngological specialists, began to advertise the BenzedrineInhaler as a decongestant in late 1933.17 By April 1934, Alles hadapproached both Merck and SKF, and in December he reachedagreement with SKF, assigning the firm the patent in exchange for5% royalties on sales of Benzedrine salts.18

Alles had found a strong ally for the commercial development ofamphetamine in Smith, Kline and French. The firm had just comeunder dynamic new leadership in the form of Frank Boyer andW. Furness Thompson, who aimed to move SKF away from nervetonics and dandruff remedies into the arena of science-based pharma-ceuticals. Though not the scientific powerhouse that some leading

American firms like Merck and Lilly had become by the mid-1930s,

17. U.S. Patent 1,921,424, to F. P. Nabenhauer, Therapeutic substituted benzyl carbi-namines, granted 3 August 1933. Anon., 1937, Nabenauer and Alles Amine Work,folder SKF v. Alles Documents Requested by SKF on Discovery, box 2, GAP. Council onPharmacy and Chemistry, Benzedrine,J. Am. Med. Assoc., 1933, 101, 1315; J. A. Bertolet,Benzyl Methyl Carbinamine Carbonate: A Report Based on Its Clinical effect in OneHundred and Twenty-two Rhinological Cases, Med. J. Rec., 1932, 136, 7576; HarryByrne, The Use of Benzyl Methyl Carbinamine Carbonate in the Treatment of Rhinitis,N. Engl. J. Med.,1933, 209, 104851; Joseph Scarano, Rapidity of Shrinkage and Immedi-

ate and Secondary Reactions following Local Applications of Ephedrine and Benzedrine,Med. Rec., 1934, 140, 6024. On the presence of SKF observers at the Oregon meeting,such as Albert G. Young, see Alles to Thompson, 12 December1942, folder SKF v. Allesdocuments received from Alles Office, box 2, GAP. On the subsequent, checkeredhistory of the amphetamine inhaler, see Charles Jackson, The Amphetamine Inhaler: ACase Study of Medicinal Abuse, J. Hist. Med. Allied Sci., 1971, 26, 18796; and NicolasRasmussen, On Speed: Amphetamine in American Medicine, Science, and Culture(forthcoming),ch. 45.

18. Alles to Leake, 27 April 1934, folder Correspondence Not Listed in Card File, box16, GAP. Francis Boyer to Alles, 5 June 1934; Alles to Boyer, 26 June 1934; Boyer to Alles,6 July 1934; Alles to Boyer, 1 August 1934; all in folder Sale of Invention and Patent1,879,009 on Benzedrine Salts as Medicinal Agents, box 1, GAP. Alles to Boyer,

8 September1934; Boyer to Alles, 17 September1934; Alles to Boyer, 25 September1934;Boyer to Alles, 22 October1934; Alles to Boyer, 12 November1934; Boyer to Alles,6 December1934; Alles to Boyer, 17 December1934 and attached contract; all in folderSale of Invention and Patent 1,879,009 on Benzedrine Salts as Medicinal Agents, box 1,GAP. See also Ted Wallace memo, 8 November1935, unlabeled folder, box 15, GAP.

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the firm stood among drug industry leaders in marketing sophistica-tion and innovation, including the use of science in marketing.19

This was a time of profound change in the American pharmaceuticalindustry. A reforming medical elite had managed to impose somemeasure of voluntary discipline on manufacturers during the firsttwo decades of the century, for instance barring companies fromadvertising prescription drugs directly to the public, and requiring adrugs approval by the AMAs Council on Pharmacy before it couldbe advertised to the medical profession in the Journal of the AMA(JAMA) and other cooperating journals. Thus, by the mid-1930s,ethical drug firms (those that followed the reformist rules) werelargely limited to advertising in medical and scientific journals, plusdirect marketing to physicians using their growing sales forces ofdetail men. Now that science was required to win approval toadvertise drugs, the scientific literature itself became a key arena fordrug marketing. Of course, the citation of medical articles in adver-tising copy and the distribution of journal offprints by salesmen werenot new practices, and neither was sponsorship of some research bydrug firms.20 But by the 1930s, leading firms like Smith, Kline and

French had learned to involve themselves in the medical research lit-erature to a remarkable extent, from conceiving and designing clinicalstudies that targeted particular medical audiences, to overseeing theirexecution by competent or even eminent researchers, to managingtheir writing, illustration, and publication in top journals.21

When Alles began mingling with the SKF management teamshandling new drug development in early 1935, the firms top prior-ity was improving its recently launched Benzedrine Inhalers share

of the decongestant market. Alles observed as SKF organized studiesby clinical researchers aimed at producing scientific literature that wouldshow the Inhaler to be beneficial in new ways and thus justify medicaladvertising claims. For instance, respected occupational hygiene res-earcher Howard Diehl of the University of Minnesota was attempting

19. Mahoney, Merchants, 3335.20. Peter Temin, Taking Your Medicine: Drug Regulation in the United States (Cambridge,

Mass.: Harvard University Press, 1980); Harry Marks, The Progress of Experiment(Cambridge:

Cambridge University Press, 1997). On detail men, see Jeremy Greene, Attention to Details:Etiquette and the Pharmaceutical Salesman in Post-War America, Soc. Stud. Sci., 2004, 34,27192.

21. See Rasmussen, Moral Economy; idem., The Drug Industry and ClinicalResearch.

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to prove for the firm that the Inhaler could abort or preventincipient colds, and pediatrician Joseph Stokes of the University of

Pennsylvania was funded for a study to test the Inhaler on childrenof various age groups.22 The firms medical research staff designedprotocols and sometimes outlined in advance the research articles to bewritten, once results were obtained, for some of these researchers.For example, Philadelphia rhinologist Joe Scarano, one of the clini-cians who did an early trial comparing ephedrine and Benzedrine astopical decongestants to help win AMA approval of the drug, wasengaged to follow up with articles showing that the Inhaler causedno harmful changes in nasal tissue and no problems for use in chil-dren and even infants. This office practitioner was clearly one of thefirms regular stable of clinical investigators, but so too were distin-guished medical authorities like University of Pennsylvania pediatri-cian Joseph Sulman, similarly engaged by SKF.23 Beyond merelyestablishing the efficacy and comparative safety of their product forAMA Council review, the firm also showed considerable finesse inusing science to address a marketing problem surrounding the Inhalersnon-prescription sales to the general public. SKF had discovered

that consumers perceived the Inhaler as dangerous, largely due todruggists cautious attitudesphysicians high confidence in theproduct notwithstanding. Interviews with consumers suggested thatremoving the Do Not Overdose warning label on the Inhaler wouldhelp the products safety image. So the firm commissioned studiesby academic pharmacologists and clinicians to quantify the amphet-amine dosage absorbed from inhaling and to show that damage to nasalcilia would not occur from overuse of the Inhaler. Thus, removal of

22. On sales, see memo from Mister Valentine, 15 February 1935; on Diehl, seeWallace memo of 20 June 1935; on Stokes, Wallace memos of 5 September1935 and6 December1935; on progress of both studies, Wallace memo, 3 August 1937; all in unla-beled folder, box 15, GAP. Also on Stokes, [anon.], SKF Research Program (# 18), 8 June1938, folder SKF v. Alles documents received from Alles Office, box 2, GAP.

23. On Sulman, see Wallace memo of5 September1935; on Scarano, Wallace memos of7 February 1935, 28 February 1935, 9 May 1935, and 6 December1935, all in unlabeledfolder, box 15, GAP. See also Joseph Scarano, Rapidity of Shrinkage; idem., GrossChanges Produced in the Nose by Benzedrine Inhalation: An Analysis of100 Cases, Med.Rec., 1936, 143, 16162; J. Scarano and J. F. Cioppolino, The Use of Benzedrine Vapor in

Children,Arch. Pediat.,1937, 54, 97100; L. D. Sulman, Certain Conditions in whichVolatile Vasoconstrictor has Proved of Particular Value: A Preliminary Report, Med.Times Long Island Med. J., 1935, 63, 37475. On drug companymedical researcher collabo-rations in the period generally, see Rasmussen, Moral Economy; idem., The DrugIndustry and Clinical Research.

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the warning could be justified, and published findings on the Inhalerssafety generated for use in advertisements.24

Around the beginning of 1936, Smith, Kline and French com-missioned toxicity studies of amphetamine sulfate. University ofPennsylvania pathology professor Edward Krumbhaar found minimalharm in rats given large doses over several weeks, and an abstract ofthese results was written up in early 1937, mimeographed, and sentto all clinicians using the drug experimentally so that they would bereassured about its safety.25 The firm was already distributing 10 mgtablets of amphetamine sulfate and identical placebos for experimen-tal use to Alless physician contacts such as Nathanson, as well as toother clinical researchers engaged by the firm. For instance, Univer-sity of Pennsylvania Internal Medicine professor Wallace Dyer wasfunded to study its effects on blood pressure in wider patientpopulations, in order to see whether the drug might be usefulordangerousin people with high or low blood pressure. But apartfrom these company-commissioned and -designed trials, there werealso many by freelancers, to whom the firm only supplied drugs inexchange for regular updates on results.26 Once word of Prinzmetals

studies on narcolepsy began to spread, by mid-1935, neurologistsand psychiatrists in particular approached SKF with inquiries andrequests for the drug. After the narcolepsy paper appeared at the endof the year, the firm began marketing the drug for that condition.

24. Wallace memos of31 May 1935, 6 December1935, 19 December1935, 17 September1936, 11 January 1937, 3 August 1937, 20 September1937; all in unlabeled folder, box 15,GAP. See Scarano, Gross Changes; N. A. Simpson and E. Simon, Experimental Determi-nation of Amount of Benzedrine in Therapeutic Dose from Benzedrine Inhaler, Am. J.

Pharm., 1937, 109, 34347; A. W. Proetz, Further Experiments in the Action of Drugs onthe Nasal Mucosa,Archives Otolaryngol., 1939, 30, 50915. See advertisements quoting Pro-etz, e.g., A Less Irritating Vasoconstrictor, Calif. Western. Med., Sept. 1945, 63, 57 (adv), andNo Appreciable Ciliary Inhibition, Calif. Western. Med., Nov. 1945, 63, 39 (adv).

25. Wallace research memos of 27 February 1936, 29 May 1936, 16 July 1936, and3 August 1937, unlabeled folder, box 15, GAP. W. E. Ehrich and E. B. Krumbhaar, TheEffects of Large Doses of Benzedrine Sulfate on the Albino Rat: Functional and TissueChanges,Ann. Internal Med., 1937, 10, 187488. Thompson memos of6 February 1937and 23 February 1937, unlabeled folder, box 15, GAP.

26. Wallace memos of21 February 1935, 14 March 1935, 18 April 1935, 9 May 1935,11 February 1936, 27 February 1936, and 3 August 1937; all in unlabeled folder, box 15,GAP; Thompson research memo 25 January 1937, and Anon., SKF Research Program, 8

June 1938; in folder SKF v. Alles documents received from Alles Office, box 2, GAP.See W. W. Dyer, The Pressor Effects of Amphetamine (Benzedrine) on Normal,Hypotensive, and Hypertensive Patients,Am. J. Med. Sci., 1939, 197, 1038. On the dif-ferent collaborative arrangements with firms, see Rasmussen, The Drug Industry andClinical Research.

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therapies mingled with innovative physical interventions such asconvulsant and coma therapies.30 Drug therapies represented another

promising avenue in this context. The neuropsychiatry marketspromise was obvious in March 1936: If we havent got a bearcat bythe tail then Im a Dutchman, reported one SKF observer at a Bostonpsychiatry meeting. The meeting had featured the debut of new workby Alless friend Prinzmetal on the beneficial effects of BenzedrineSulfate on certain forms of Parkinsons disease. More importantly,Boston neurologist and psychiatrist Abraham Myerson had reportedthree studies there, two of them on Benzedrines effects on the auto-nomic nervous system, and one on the drugs effects on mood innormals and outpatients. In certain depressed neuroses wheresubjective symptoms are worst in the morning, the drug was defi-nitely ameliorative, although not curative, according to Myerson.31

Although he was well funded already, SKF quickly began fundingMyerson, who appears to have become interested in BenzedrineSulfate on his own initiative. His enthusiasm, facilities, and standingwould soon make him a champion of the product and a key asset forSKF in its efforts to create a psychiatric niche for amphetamine.32

ABRAHAMMYERSONANDTHENEUROPSYCHIATRISTS

Myerson was a very eminent man indeed. Simultaneously Professorof Neurology at Tufts and of Clinical Psychiatry at Harvard MedicalSchools, and also Research Director at Boston State mental hospital,he headed a lab impressively equipped for physiological work andgenerously backed by the Rockefeller Foundation.33 Beyond academic

30. Shorter, History, ch. 6; Grob, Mental Illness, ch. 11. See also Braslow, Mental Ills,although this work underestimates theoretical interest and innovative uses of drugs in thelate 1930s, as compared with convulsive therapies.

31. Richard Webb to Alles, 23 March 1936, folder SKF v. Alles documents receivedfrom Alles Office, box 2, GAP. See H. Houston Merritt, minutes of431st meeting of theBoston Society of Psychiatry and Neurology, 19 March 1936,J. Nerv. Ment. Dis., 1937, 85,2026 (Myerson quotations on 204).

32. Wallace memo, 6 December1935, unlabeled folder, box 15, GAP.33. Myerson to Alan Gregg, 18 June 1935, folder872, box 72, Series 200A of Record

Group 1.1 at the Rockefeller Archive Center in Tarrytown, New York (hereafter, RAC).Myerson, undated [April 1938], Boston State HospitalPsychiatry Annual Report March

1936March 1937, and Myerson, December 1939, Boston State HospitalPsychiatryAnnual Report December1, 1937November301938, folder875, box 73, RAC. See alsopersonal correspondence, Susan Irving, RAC, 23 April 2004, to the effect that Myersonenjoyed Rockefeller research grants averaging more than $13,000 per year from 1934through 1941.

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distinction, Myerson was also a public intellectual well known for hiscritiques of the science behind eugenics, and for several popular

books. In The Nervous Housewife of 1920, Myerson discussed themounting prevalence of neuroses in American women, explaining thisrise as chiefly due to the frustration by wifely social roles of instinctivedrives oriented toward worldly action, together with upbringingsinculcating vanity, emotionality, and unrealistic expectations frommarriage. In this book Myerson showed a style typical of Meyer-influenced neuropsychiatry in interwar America, with his stress onthe adaptation of the individual to social context and his insistence onthe treatment of emotions as bodily, physiological statesa discoveryfor which he credited Pavlov and Walter B. Cannon, the Harvardphysiologist famous for his studies of the psychophysical survivalfunction of adrenaline. And although he gave a central place toinstinctual drives and their repression in his psychology, Myersonwas no Freudian: whereas the Viennese had hypothesized sexualtraumas of early childhood as the root cause of neuroses, Myerson,like Meyer, saw no great need to look beyond recent adult experi-ence and conditions. He recommended treating most neuroses with

a combination of healthy physical conditions and diet, togetherwith talking therapy to instill more adaptive habits and outlooks onlife.34

Myersons popular1925 book When Life Loses Its Zesthad madehim an authority on depression. Here he elaborated ideas on depres-sion first proposed in 1922, when he described a depressive symptomcomplex he dubbed anhedonia (thus reviving and reinterpretingan obsolete nineteenth-century term, literally meaning lack of plea-

sure), which was marked by lack of interest in sleep, food, and sex,and a low level of the energy feeling that motivates projects in theworld. Though anhedonic symptoms were common to a number ofconditions, such as menopause, the early stages of schizophrenia, andrecovery from surgery and infectious disease, a chronic illness hecalled idiopathic or recurrent anhedonia represented a distinct

34. Abraham Myerson, The Nervous Housewife(Boston: Little, Brown, 1920), ch. 23, 9

et passim, especially 34, 41. On Myersons background, see Lunbeck, Psychiatric Persuasion,3233 et passim. On Cannon, see Donald Fleming, Walter B. Cannon and Homeostasis,Soc. Res., 1984, 51, 60940. Walter Cannon, Bodily Changes in Pain, Hunger, Fear and Rage(New York: Appleton, 1915); idem., The Wisdom of the Body (London: Routledge & KeganPaul, 1939).

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neurotic disorder in its own right. Indeed, Myerson argued, this par-ticular neurosis was reaching epidemic proportions, especially among

women but increasingly among middle- and upper-class male brain-workers. As with the hysterias of married women he had focusedupon in The Nervous Housewife, this disorder of reduced desire andpleasure could be explained as stemming from frustration of instinctualurges, particularly through the artificial overstimulation and rigorousdiscipline of industrial civilization. Anhedonia was best understood asa deficiency in a persons feeling of psychic energy; indeed, althoughanhedonia is not always accompanied by subjective despair, it isprobable that what we call sadness is to a large extent the disappearanceof the energy feeling, Myerson speculated.35

Myerson customarily treated his private patients for anhedonia bya combination of occupational, physical, and talking therapies, alldirected to restoring pep, zeal, courage, concentration, interest, andpleasure. First, he would establish an unstressful routine of whole-some diet and moderate exercise, coupled with an energy-restoringprogram of graduated exertion to bring the patient out of himselfand into a realm of interesting and achievable goals (whether in light

reading, sports such as hunting or golf, or crafts such as basket weav-ing). He would talk with and advise the patient, but not encourageheavy introspection; indeed, he considered Freudian psychoanalysistoo introspective generally, and especially destructive for the anhe-donic. And, to reestablish a regular pattern of activity and break thetypical anhedonics cycle of insomnia, he would also treat patientswith sedatives like bromides at night and stimulants like caffeine inthe morning. Because mind and body were ultimately one, biologi-

cal and psychodynamic approaches did not conflict for Myerson; ashe wrote in 1922, if the individual is depressed . . . you can changehis attitude . . . by physical means just as surely as you can change hisdigestion by distressing thought . . . [D]rugs and physical therapeu-tics are just as much psychical agents as good advice and analysis andmust be used together with these latter agents of cure.36

35. Abraham Myerson, Anhedonia,Am. J. Psych., 1922, 79, 87103, 91; idem., WhenLife Loses Its Zest (Boston: Little, Brown, 1925). On the prehistory of concepts cognate toanhedonia, see German Berrios and J. M. Olivares, The Anhedonias: A Conceptual His-tory, Hist. Psych.,1995, 6, 45370.

36. Myerson, Anhedonia (quotes 91, 101); idem., When Life Loses Its Zest.

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In When Life Loses Its Zest, Myerson not only introduced chroniclack of pleasure as a mental disease, but also proposed a major revi-

sion of standard diagnostic categories for neurosis that he hadaccepted in The Nervous Housewife(neurasthenia, psychasthenia, andhysteria), effectively reinventing depression to make room for anhe-donia. Anhedonia should be counted the most common of the neuroticdisorders, and the most fundamental manifestation of the conditionheretofore known as neurasthenia, he argued. (The concept ofdepression as a physical weakness caused by nervous depletion, neur-asthenia, had been popular among American neurologists since thelate nineteenth century. Anhedonia would now replace neurastheniaon the grounds that, like sadness, physical weakness was only one symp-tom of depression, while for Myerson, apathy was more fundamental.)Furthermore, psychasthenia, which normally included anxiety neuroses,phobias, and obsessive-compulsive conditions, should be reduced byreclassifying the anxiety conditions as variant expressions of anhedonia.This followed from the sense of unfocused nervous energy and over-sensitivity to stimuli typically created when anhedonia broke theconnection between drives and their normal mechanisms of satisfac-

tion. Although When Life Loses Its Zestwas widely noticed, Myersonsconcept of anhedonia was not generally taken up by psychiatrists inthe decade following its publication, judging by standard texts;neurasthenia remained the usual name for mild, neurotic depression,while hysterical, obsessive, and anxiety disorders were still treated asbelonging to psychasthenia. In the mid-1930s, few beyond Myersonsimmediate circle appear to have accepted that lack of pleasure andapathy represented a basic mental disorder.37

Given his stance on depression, it comes as no surprise that Myersonshould be very interested in a drug that reliably enhanced pep or,for him, energy-feeling. With little hesitation he tried the newdrug on his depressed patients when it became available in 1935, andon himself, too. When, at an American Psychological Association

37. Myerson, Anhedonia; idem., When Life Loses Its Zest, ch. 8, 10 (see esp. 119) etpassim. On neurasthenia and the history of American psychiatry, see Shorter, History,12936; see also Simon Wessely, Neurasthenia and Fatigue Syndromes, in A History of

Clinical Psychiatry, ed. German Berrios and Roy Porter (London: Athlone, 1995), 50944. Forevidence that Myersons theories on depression and anhedonia made no great mainstreamimpression, see absence of its mention in standard 1930s textbooks such as Edward Streckerand Frank Ebaugh, Practical Clinical Psychiatry for Students and Practitioners (Philadelphia: Blakiston,1935); and also Christian, Principles, 137988.

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meeting in September 1936, Myerson already recommended pre-scribing Benzedrine to gloomy, anhedonic depressives as well as

normal people with morning hangovers and low moods, Timemag-azine reported his favorable results.38 Thus Myersons enthusiasmfor amphetamine reached the general public as well as the medicalprofession. Beyond publicity, Myerson and his Boston circle madeanother key contribution to Benzedrines success, assimilating thedrug to contemporary biological theory about the chemical mediationof neural function. At the time it was becoming widely acceptedthat signals in the sympathetic nerves were mediated by adrenaline(or a similar adrenergic hormonesympathin, for Walter Cannon)released from the nerve endings, and also that the signals of the para-sympathetic nerves, which generally exerted opposite effects on tar-get organs, were mediated by acetylcholine. Benzedrine evidentlyamplified the effects of adrenergic neurons, either by mimicking theeffects of the chief adrenergic neurohormone or by sensitizing recep-tive neurons to its effects. Myerson probably supposed that similarnerve circuits existed in the brainand, in this thinking, was unlikelyto be alone, at least wherever Cannons work was influential. Myersons

more original contribution was to suggest that mood disorders were theresult of imbalance between unidentified brain centers tending to sleep(perhaps cholinergic) and brain centers tending to activity and wake-fulness (perhaps adrenergic). Amphetamine, the adrenergic agonist,shifted the balance of brain chemistry in the active, wakeful direction.39

38. Anon., Trial and Error, Time, 14 September1936, 33.39. A. Myerson, Julius Loman, and William Damashek, Physiologic Effect of Benzedrine

and Its Relationship to Other Drugs of the Autonomic Nervous System,Am. J. Med. Sci.,1936, 192, 56074; Abraham Myerson, Human Autonomic Pharmacology XII. Theoriesand Results of Autonomic Drug Administration, J. Am. Med. Assoc., 1938, 110, 1013;Wilfred Bloomberg, Effects of Benzedrine in Altering Mental and Emotional Processes,Proc. Assoc. Res. Ment. Nerv. Dis., 1939, 19, 17279; Abraham Myerson, The Rationale forAmphetamine (Benzedrine) Sulphate Therapy,Am. J. Med. Sci.,1940, 199, 72937; J. D.Robinson, Mechanisms of Synaptic Transmission: Bridging the Gaps (18901990) (Oxford: OxfordUniversity Press, 2001), ch. 3, describes the development of ideas about chemical transmis-sion in the central nervous system in the 1930s and early 1940s, particularly based on analogyto peripheral nerve transmission. There was considerable evidence for chemical transmissionas the main mechanism of nerve signaling at the time, but prominent neurophysiologistsfiercely opposed the concept, long delaying its universal acceptance; Elliott Valenstein, The

War of the Soups and the Sparks: The Discovery of Neurotransmitters and the Dispute Over HowNerves Communicate (New York: Columbia University Press, 2005). The pharmacologybible of the day acknowledged these theories about amphetamine in a backhanded way, bypronouncing it premature to speculate on the relationship between the drugs sympathomi-metic action and its action in the central nervous system; Louis Goodman and Alfred Gilman,The Pharmacological Basis of Therapeutics (New York: Macmillan, 1941), 437.

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Myerson was by no means the only Benzedrine enthusiast amongneuropsychiatrists, many of whom were eager to try the new drug

on mental conditions. Indeed, members of this specialty accountedfor at least a third of an SKF list of over sixty physicians doing clini-cal investigations on amphetamine sulfate in mid-1936. Some hadbeen commissioned to do studies specified by the firm, but morewere freelancers receiving only drugs and placebos from SKF andregularly contacted to see what results were emerging.40 The firstbatch of experimental studies with the drug reached publication that

year. Myerson, who had begun with the abovementioned investiga-tions of Benzedrines effects on the peripheral nervous system inpsychiatric inpatients, shifted focus to its central nervous systemaction and particularly its beneficial impact on the mood and behaviorof anhedonics and similar neurotic depressives (mainly outpatients).41

Eugene Davidoff at Syracuse Psychopathic Hospital tried the drug,along with placebo and ephedrine, on thirty seriously self-absorbedpatients diagnosed as schizophrenic, finding that about a third ofthem improved. Almost all patients in this varied population grew moreactive and talkative on Benzedrine; some became surly or antag-

onistic, but the drugs stimulatory effects produced improvementfor the asthenic depressed types, who became more accessible totalking psychotherapy.42 Alless friend Nathanson reported that four-fifths of forty neurasthenic outpatients experienced improvement oftheir chronic fatigue and exhaustion and an increased sense of well-being, particularly those with low mood. Such elevation of mood,including euphoria, was also found among eighty hospital staff takingthe drug as normal controls.43 Alless contacts at Londons Maudsley

Hospital, who had begun by investigating the effects of blood pres-sure on mental conditions, similarly found that depressives benefitedfrom Benzedrine, especially the milder neurasthenic types, but also

40. Wallace memo, 13 March 1936, Possibilities on Benzedrine Sulfate;