Thomas A. Ban
Neuropsychopharmacology in Historical Perspective.
Thomas A. Ban: The Birth of Drug Industry and Drugs with An Effect On Behavior
John Dalton’s atomic theory and drugs in psychiatry in the 19th century February 8, 2018
Sedatives in the 2nd part of the 19th century February 15, 2018
Substances with an effect on consciousness March 8, 2018
Morphine: From isolation to introduction of morphine March 15, 2018
John Dalton’s atomic theory and drugs in psychiatry in the 19th century
The story that led to the birth of neuropsychopharmacology in the mid-20th century begins in 1808 with John Dalton’s (1766–1844) postulation that the elementary units of all matter in the universe are indivisible and indestructible atoms (Dalton 1808; Encyclopedia Britannica 1969). Dalton’s “atomic theory” was published in Part 1 of his treatise entitled “New System of Chemical Philosophy” and its impact profoundly affected scientific development in general (Smith 1856). Within the context of our story, it opened the path for synthesizing drugs with different effects, including substances with an effect on behavior and/or mental activity
Instrumental to further development was the research of an 18-year-old English chemist named William Henry Perkins (1838-1907). He was trying to synthesize quinine and ended up with a bluish substance that he extracted from a “black mess” in his test tube, with excellent dying properties. Perkins’ discovery of the first artificial dye in history, variably referred to as aniline purple, tyrian blue or mauve, triggered a chain of events (Golin 1955). Modifications of his process led to the development of many dyes and the emergence of the dye industry in the middle of the 19th century, e.g., Bayer and Ciba in 1859 and Geigy and Sandoz in 1862 (Menzie 1983).
Recognition that a more complete exploitation of Perkins’ findings would require a new breed of organic chemists gave a strong impetus for the development of organic chemistry (Russell 1871). This, in turn, lead to the synthesis of a rapidly growing number of organic compounds and during the second half of the 19th century many of the dye companies, e.g., Ciba in 1890, Bayer in 1896,extended their activities to the development of drugs. With this development, a new industry, the pharmaceutical industry, was born (Healy 1997).
The rapidly growing pharmaceutical industry during the second half of the 19th century was instrumental to the introduction of several centrally acting drugs. By the end of the 1890s subcutaneously administered morphine (Wood 1855), along with apomorphine and hyoscine (scopolamine) were extensively used in the control of excitement, agitation and aggression; potassium bromide (Lockock 1857), for relieving restlessness, anxiety and tension; and chloral hydrate (Liebreich 1869) and paraldehyde (Cervello 1882) served for calming and inducing sleep. The judicious use of this first set of drugs in psychiatry provided day- and night-time sedation and allowed the replacement of physical restraint by pharmacological means (Ban 2001; Lehmann and Ban 1970). 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).
It was also during this period that lithium was introduced into psychiatry (Ban 2006).
During the second part of the 19th century many physicians believed in a uric acid “diathesis,” a predisposition for the accumulation of urea in the body (Garrod 1859; Johnson 1984) that could cause a variety of disorders from gout and rheumatism to cardiac disease and mental illness (Healy 2002). Since acute symptoms of gout develop suddenly and persist untreated for days or weeks before they remit, William Hammond, at the Bellevue Hospital in New York, had assumed that episodic mood disorders might be a form of cerebral gout and employed lithium successfully in their treatment (Hammond 1871; Yeragani and Gershon 1986). On the basis of the same assumption Carl Lange, a Danish neurologist, treated hundreds of patients with lithium and, in 1886, reported on its prophylactic effect in periodic mood disorders (Lange 1886). Yet, without the availability of the necessary technology for monitoring blood levels, lithium was too toxic a substance to be clinically employed (Ban 2006).
Ban TA. Pharmacotherapy of mental illness: A historical analysis. Prog Neuro-Psychopharmacol & Biol Psychiat. 2001; 28:709-27.
Ban TA. Neuropsychopharmacology and the history of pharmacotherapy in psychiatry. A review of developments in the 20th century. In: Ban TA, Healy D, Shorter E, editors. Reflections on Twentieth-Century Psychopharmacology. Budapest, Hungary: Animula; 2004.
Ban TA. Academic psychiatry and the pharmaceutical industry. Progress in Neuro-Psychopharmacology & Biological Psychiatry. 1960;30:429-41.
Dalton J. New System of Chemical Philosophy. Part II. London: R. Bickerstaff, Strand; 1808.
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Garrod AB. Gout and Rheumatic Gout. London: Walton and Maberly; 1859.
Golin M. Serendipity – big word in medical progress. Does “pure lack” deserve all the credit? JAMA. 1957;165:2084-7.
Hammond WA. A Treatise on Diseases of the Nervous System. New York: Appleton; 1871.
Healy D. The Antidepressant Era. Cambridge; Oxford University Press: 1997.
Healy D. The Creation of Psychopharmacology. Cambridge: Harvard University Press; 2002.
Johnson FN. The History of Lithium. Basingstoke: MacMillan Press; 1984.
Lange C. Om periodiske Depressionstilstande og deres Patagonese. Copenhagen; Jacob Lunds Forlag; 1886.
Lehmann HE, Ban TA. Pharmacotherapy of Tension and Anxiety. Springfield; Charles C. Thomas Publisher; 1970.
Liebreich MEP. Das Chloral hydrate, ein neues Hypnoticum und Anaestheticum, und dessen Anwendung in die Medizin. Eine Arzneimeittel –Untersuchung. Berlin: Müller; 1869.
Lockock C. Comment in discussion of Edward H. Sieveking. Analysis of fifty-two cases of epilepsy. Lancet. 1857;2:136-8.
Menzie E. Geschichte der Chemische Industrie in Basel. Zeitschrift für die Chemische Industrie. 1983;5:15-30.
Russell CA. The History of Valency. Oxford: University Press: 1871.
Shorter E. A History of Psychiatry. New York: John Wiley & Sons, Inc.; 1997.
Smith RA. Memoir of John Dalton and the history of atomic theory. London: Bailliere; 1856.
Wood A. A new method of treating neuralgia by the direct application of opiates to the painful points. Edinb Med and Surg J. 1855;82: 265-81.
Yeragani VK, Gershon S. Hammond and lithium: historical update. Biological Psychiatry1986; 21:1101-2.
February 8, 2018
Sedatives in the second part of the 19th century
Sedatives are substances which produce a generalized (global) inhibition of behavioral and/or central nervous system activity. They reduce “psychic arousal” without autonomic effects. All sedatives induce sleep when given in sufficiently high doses. Those “sedatives” which are particularly useful for facilitating sleep are referred to as “hypnotics.”
There were three widely used classes of sedatives introduced into medicine and psychiatry during the second part of the 19th century: inorganic salts, chloral derivatives and cyclic ethers. Potassium bromide, chloral hydrate and paraldehyde, respectively, were extensively used drugs.
Potassium Bromide is the oldest widely used sedative in medicine. It is the potassium salt of bromine, a chemical element, first isolated in 1826 from the ashes of seaweed by A.J. Balard, an apothecary in Montpelier, France. In its natural form bromine is too corrosive to be ingested. As a potassium salt, it is well tolerated (Balard 1826; Löwig 1829).
French clinicians believed that bromine was a substitute for iodine and began using potassium bromide in a variety of disorders without tangible therapeutic effect. In 1857, 31 years after bromine was isolated, Charles Lockock, a London internist, discovered the anticonvulsant and sedative action of the drug. His discovery was one of the many quaint examples in which an utterly false theory led to correct empirical results. Lockock, like most physicians of his time, believed that there was a cause-effect relationship between masturbation, convulsions and epilepsy. Bromides were known to curb sex drive. Lockock’s rationale was to control epilepsy, i.e., convulsions, by reducing the frequency of masturbation (Garrison 1960). The treatment was a success insofar as control of convulsions was concerned. It also brought to attention the sedating properties of the drug (Balme 1975).
During the second half of the 19th century potassium bromide and other inorganic bromide salts were widely used as sedatives and anticonvulsants (Shorter 1997).They were undoubtedly effective, but their relatively low therapeutic efficacy coupled with high toxicity had by the mid-20th century virtually eliminated them from clinical use (Lehmann and Ban 1970).
It was just a few years after the first clinical application of bromides, in the 1850s, that the first chloral derivative, chloral hydrate, was introduced. Similar to potassium bromide, the discovery of the sedative and hypnotic properties of chloral hydrate was also the result of an erroneous idea, but in this case of a chemical theory.
Chloral, or trichloroacetaldehyde, was first prepared in 1832 by Justus von Liebig, a professor of chemistry in Giessen (Germany). It was about 37 years later, in 1869, that its hydrate, chloral hydrate, was introduced into clinical therapeutics by Otto Liebreich, a professor of pharmacology in Berlin. Liebreich assumed that one of the components into which chloral hydrate splits in the body is chloroform and since chloroform induces sleep, so would chloral hydrate. Although no chloroform results from the degradation of chloral hydrate, chloral hydrate became the first synthetically produced reliable hypnotic. Today, after almost 150 years after its introduction, it is still used in clinical practice (Ban 2004).
Paraldehyde, a cyclic ether, is a polymer of acetaldehyde without a free aldehyde group. It was first observed in 1835 by Julius von Liebig and synthesized in 1848 by H. Weidenbusch. Subsequently, however, 35 years passed before it was introduced, in 1883, by Vincenzo Cervello (1883, 1884), into clinical use. Introduction of paraldehyde was a success. The substance was used extensively for many years, particularly in mental hospitals. However, by the mid-1950s, its use became almost entirely restricted to the control and treatment of the withdrawal symptoms of alcoholics (Lehmann and Ban 1970).
It was in 1863, between the introduction of potassium bromide and chloral hydrate into clinical use, that malonylurea, the condensation product of urea and malonic acid was first synthesized by Adolph von Baeyer. Apparently, Baeyer celebrated the synthesis of the substance with his friends on St. Barbara’s Day, the patron saint of artillery officers (Fiesler 1944). Whether the name “barbituric acid” for malonylurea was the result of adding urea to the name of this saint or the name of a popular Munich waitress will never be known. Although “barbituric acid” itself is an inactive preparation, it is carrier for synthetic preparations from which at least 50 were introduced during the first 50 years of the 20th century. During those years, sedative and hypnotic barbiturates were the most extensively prescribed drugs in medicine, not only in psychiatry.
Baeyer A. Untersuchungen ueber die Hamsauregruppe. Annalen der Chemie, 1863;127:1–27; 199–236.
Balard A. Memoir on a peculiar substance contained in sea water. Annals of Philosophy. 1826;28:381–7.
Balme RH. Early medicinal use of bromides. Journal of the Royal College of Physicians. 1976;10: 205-208.
Ban TA. Neuropsychopharmacology and the history of pharmacotherapy in psychiatry. A review of developments in the 20th century. In: Ban TA, Healy D, Shorter E, editors. Reflections on Twentieth-Century Psychopharmacology. Budapest, Hungary; Animula; 2004;697-72.
Cervello V. Sull'azione fisiologica della paraldeide e contributo allo studio del cloralio idrato. Archivio per le Scienze Mediche. 1883;6:177-14.
Cervello V. Recherches cliniques et physiologiques sur la paraldehyde Archives italiennes de biologie. 1884;6:113–34.
Fiesler LF. Organic Chemistry. Boston: Heath and Company; 1944.
Garrison FH. An Introduction to the History of Medicine. Fourth Edition. Philadelphia and London; W.B. Saunders Company; 1960.
Lehmann HE, Ban TA. Pharmacotherapy of Tension and Anxiety. Springfield; Charles C. Thomas Publisher; 1970;12-13.
Liebig J. Ueber die Verbindungen welche durch die Einwirkung des Chlors auf Alcohol, Aether, Olbildendes Gas und Effiggeist Entstehen. Liebigs Annalen der Pharmazie 1832;1:182-230.
Liebig J Ueber die Producte der Oxydation des Alkohols. Annalen der Chemie 1835;14:133-67.
Liebreich MEP. Das Chloral hydrate, ein neues Hypnoticum und Anaestheticum, und dessen Anwendung in die Medizin. Eine Arzneimeittel –Untersuchung. Nerlin: Muller; 1869.
Löwig CJ. Das Brom und seine chemischen Verhältnisse (Bromine and its chemical relationships). Heidelberg; Carl Winter; 1829.
Shorter E. A History of Psychiatry. New York/Chichester/Brisbane/Toronto/Weinheim; John Wiley & Sons, Inc. 1997;190-238.
Weidenbusch, H. Ueber einige Producte der Einwirkung von Alkalien und Säuren auf den Aldehyd. Annalen der Chemie. 1848:66: 152-165.
February 15, 2018
Substances with an effect on consciousness
Substances with an effect on consciousness were first synthesized in the mid-18th century. They were “gases,” such as “nitrous oxide” and “ether,” which could block consciousness, i.e., awareness of one’s body, self and environment, transiently, when administered in a particular concentration. Development of the necessary technology for the purification and measured administration of these gases, was instrumental to the birth of general anesthesia during the first half of the 19th century (Ban 1969).
The term anesthesia was coined and introduced by Oliver Wendell Holmes (1809-1894), in 1846 for a drug-induced state characterized by “lack of sensation” (Rice 1859). Under “general anesthesia” there is a loss of ability to perceive pain associated with loss of consciousness for a period covered by amnesia (Stedman 1990).
Nitrous Oxide is a colorless, non-toxic gas with a faint, sweet odor. It was first developed by Joseph Priestley (1733 -1804), who described the procedure he used for producing it in the second volume of his “Experiments and Observations on Different Kinds of Air,” first published in 1775.
To render “gases” accessible for study, James Watt (1736-1819) built a special machine that made the measured administration of “nitrous oxide” possible by “inhalation” (Beddoes and Watt 1794).
Humphry Davy (1778-1829) was first to explore the effects of the substance with the employment of Watt’s machine. He noted that nitrous oxide inhalation produced a “thrilling” and “pleasant” feeling of “merriment” and coined the term “laughing gas” to characterize the substance. Davy was also first to recognize the “analgesic” effect of “nitrous oxide” and its potential use in “surgical operations.”
Davy presented his observations and findings with “nitrous oxide” in his Researches, Chemical and Philosophical, published in 1800. Nevertheless, almost half a century passed after Humphrey’s report that Horace Wells (1815–1848), in 1844, first demonstrated the “anesthetic” effect of the substance, i.e., insensitivity to pain during dental extraction. Another quarter of a century went by before, in the early 1870s, the use of the substance was generally accepted in “dental anesthesia” (Jacobsohn 1995; Shaw, Kumar and Doods 2011).
In the 20th century nitrous oxide found its special place among the “anaesthetics,” e.g., for use in child birth. It was also in the 20th century that explorations of its possible use in the facilitation of “psychological” and “pharmacological” treatments” began (Lecore 1994). In the early years of the 21st century explorations of its use in the pharmacological treatment of psychiatric disorders, e.g., depressions, were intensified (Nagele, Duma, Kopec et al. 2015). It still remains to be seen whether the substance could be used in psychiatric emergencies, e.g., relieving suicidal ideation, in view of its unique prompt euphorizing properties.
Ether (diethyl ether) is a white, colourless, volatile, highly inflammable liquid with a powerful characteristic odour and a hot sweetish taste (Encyclopedia Britannica 1969). Wilhelm Godefroy Froben, a German chemist was first, in 1735, to describe the substance and name it (Gibbson 1929).
Instrumental to the introduction of the substance into medicinal use was William Cullen’s recognition, in 1773, that “ether” was effective only when vaporized. Observations, in the late 1790s, with the employment of James Watt’s “machine,” indicated that the effects of the substance were similar to the effects of “nitrous oxide” (Beddoes and Watt 1794; Donovan 1975). Both induced “inhibition” of “nervous activity” when inhaled in high concentration and “disinhibition” of “verbal activity” when inhaled in low.
It was Crawford Williamson Long who first, in 1842, used “ether” successfully as an “anesthetic,” but he did not report on his successful induction of “anesthesia” with “ether” for some time (Boland 1950). Nevertheless, the name of William Green Morton (1819-1868) became associated with “ether anesthesia.” Morton used “ether” for “anesthesia” first in 1844 and on September 30, 1846, successfully demonstrated the use of diethyl ether in “general anesthesia” at the Massachusetts General Hospital (Committee of Citizens in Boston 1871). In the years that followed, until well into the first half of the he 20th century, “ethyl ether” remained the he most extensively used substance in “general anesthesia.”
The possible use of the “disinhibiting” properties of “ether” (in low concentrations) for the facilitation of psychotherapy was first raised in the 1920s by Schielder and Weissmann (1927). They were also first to employ the substance in “chemically-induced excitatory abreactions.” Yet, almost 20 years passed before, in the mid-1940s, “excitatory abreactions with ether” found their place in psychiatry, in the treatment of “war neurosis.” Under the influence of “ether forgotten memories are experienced visibly by excitement that raises to a crescendo, followed by silence” (Ban 1969; Palmer 1945; Sargant and Shorvon 1945; Sim 1963).
Nitrous oxide and ether were among the first substances which could predictably affect mental functioning. By their potential of producing loss of consciousness, a state in which with the blockade of sensorial experiencing one’s reflection of one’s body, self and environment is discontinued, research with these drugs opened the path for studying the relationship between the brain and mental activity.
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Nagele P, Duma A, Kopec M, Gebara MA, Parsoei A, Walker M, Janski A, Panagopoulos VN, Cristancho P, Miller JP, Zorumski CF, Conway CR. Nitrous Oxide for Treatment-Resistant Major Depression: A Proof-of-Concept Trial. Biol Psychiatry. 2015;78(1):10-18.
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March 8, 2018
Morphine: From isolation to introduction
Administration of “general anesthetics” induces a state characterized by “loss of consciousness” with loss of “sensation” (“anesthesia”), whereas the administration of “narcotic analgesics” induces a state characterized by “impaired consciousness” and diminution of responsiveness to environmental stimuli with “analgesia.” Analgesia is defined as insensibility to pain without loss of consciousness (Stedman 1990).
The story of “narcotic analgesics” begins in the early years of the 19th century with the isolation of “morphium” from opium and its timeline parallels the story of “general anesthetics.” The story of remedies which were to be referred to as “narcotic analgesia” parallels the story of “opium” and it is difficult to determine when and where it begins. The “psychological effects” of opium had been known to ancient Sumerians and its dependency-producing effect to the Greeks. The first undisputed reference to it can be traced to Theophrastus, who lived in the third century BC (Ban 1969).
In the early 16th century Paracelsus (Theophrastus Hohenheim 1493-1541) referred to an opium-based elixir, Laudanum, that was a potent “painkiller” (Hartmann 1918; Pichot 1983). During the 17th and 18th centuries opium was extensively used in Britain and in the West “to quiet the mind” of the “insane” and to help those suffering from “insomnia” to sleep. Although opium usually induces a feeling of well-being, it was noted that in the treatment of “madness,” opium could cause “anger” and “sadness”; in the treatment of “sadness,” opium could have, in the long run, a negative effect (Kramer 1979).
The active ingredient of opium, responsible for its somnolence producing and analgesic effects, was first isolated (extracted) from the opium poppy (Papaver Somniferum) between 1803 and 1805 by Friedrich Wilhelm Adam Sertürner (1783-1841), a German pharmacist. It was the first substance ever isolated from a plant that was responsible for its particular effects, such as, in case of opium, “sleep-inducing analgesic.”
The first recorded note by Sertürner about his isolation of a “sleep-inducing” molecule from opium was in a letter to the editor of the Trommsdorff Journal de Pharmacie in 1805. A year later, in 1806, he followed up his letter in the same journal with a report in which he determined that the substance was a weak base, soluble in acidic solution and described its chemical characteristics. He named the substance “morphium” after the Greek god of sleep and dreams (Sertürner 1806).
Sertürner continued his research with the substance and, in 1817, published a comprehensive paper on its isolation, crystallization, crystal structure and chemical characterization. He also described some of its pharmacological properties and the effects of orally administered morphium to rats, dogs, himself and others. In these experiments he noted that in different doses the substance had different effects. In a relatively low dose morphium induced happy, light-headed sensations; in a higher dose it caused drowsiness and excessive fatigue; and subjects receiving an even higher dose became somnolent and confused. On the basis of his “findings” in these “experiments,” Sertürner determined the optimal dose (15 mg.) of orally administered morphium for “analgesia” (Sertürner 1817).
In 1818, one year after Sertürner published his comprehensive report, the term “alkaloid” was introduced by Wilhelm Meissner (1792-1853) for nitrogen-containing organic compounds of plant origin with pharmacological action. Since his substance qualified for an “alkaloid,” Sertürner changed its name to “morphine,” to render it comparable to the names of other “alkaloids” by replacing the last three letters in morphium with the suffix “ine.” By emphasising that morphine was an alkaloid, Sertürner challenged the prevailing notion of the time that all medicinal substances isolated from plants were acidic in nature. His success of developing morphine for clinical use stimulated interest in medicinal substances extracted from plants. By the end of the 19th century, the “alkaloids” were an important class of drugs used in treatment (Halmai 1966; Huxtable and Schwarz 2001; Jacobsen 1882; Schmitz 1985).
Morphine became available for clinical use in 1817 when offered by Sertürner and Company as a pain medication (analgesic); in 1827, production of morphine began in Darmstadt, Germany, by the pharmacy that was to become the pharmaceutical company Merck. In 1833 another natural psychologically active opium alkaloid, “codeine,” was isolated by Pierre Jean Robiquet (1780-1844), and, in 1848, again another, “papaverine” by George Merck (1825-1873), but this one lacked psychological effects. With the growing number of opium alkaloids isolated and studied, it was recognized that they belong to one of two classes: the phenanthrenes, like morphine with, and the benzyl isoquinolines, like papaverine, without psychological effects (Merck 1848; Robiquet 1833).
With the introduction of the “hypodermic needle” in the 1850s, the story of morphine entered a new phase. The possibility of parenteral administration of morphine broadened the scope of its use for analgesia. It also extended its indications from pain control to the control of hyperactivity, excitement and agitation of patients in mental hospitals (Shorter 1997). The first recorded use of morphine for analgesia by hypodermic needle took place in 1853, but it was reported only two years later (Wood 1855). Subcutaneous morphine for behavioral control was first introduced in 1863 in German mental hospitals (Grunau 1905).
In 1880, Albert Ladenburg, a German chemist, extracted “hyoscine” (scopolamine) from hyosciamine, a tropane alkaloid, isolated in 1833 from the henbane species of the Solanacea plant (Issekutz 1971). By the end of the 19th century, the potent synergistic effect of morphine-hyoscine combinations were recognized and until the introduction of chlorpromazine in the 1950s, parenterally administered morphine-hyoscine combinations remained the primary choice of treatment of patients in need for rapid behavioral control.
Since the isolation of morphine more than 200 years have passed. During these years numerous other “narcotic analgesics” were introduced. In spite of the availability of many drugs from this class, morphium is still extensively used for the relief of pain, and especially of pain after surgery (Hamilton and Baskett 2000). Irrespective of its clinical use, morphine provided the first means to show that one can affect selectively by drugs the sensory input to the brain that is experienced as pain.
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March 15, 2018
September 19, 2019