Tuesday, 18.05.2021

Peter R. Martin: Historical Vocabulary of Addiction




       The title of this entry was selected because the noun stimulant has a rather explicit meaning in addiction, despite the fact that it is a nonspecific term with a range of uses.  The word is employed in the context of stimulant use disorder, the out-of-control and self-destructive use of drugs with related pharmacological actions.  According to the current electronic version of the Oxford English Dictionary (OED), stimulant is only one of a number words in the English language that convey a similar meaning.  Many of these related nouns and/or adjectives appeared in English before stimulant (1728): restorative (a1398), refreshing (1534), uplifting (1548), brisk (a1593), invigorating (1694), tonic (1756), bracing  (1761), revitalizing (1849), intoxicant (1863) pick-me-up (1867) and upper (1968). 

       The noun and adjective stimulant is derived from the Latin stimulantem, present participle of stimulāre, which means to stimulate (“To rouse to action or exertion as by pricking or goading; to spur on; to incite [a person] to do something; to impart additional energy to”; “To act as a stimulus to”; or “To administer stimulants to.”).  Accordingly, the noun stimulation, derived from the Latin stimulātiōnem, a noun of action was the first of various forms related to the verb stimulāre to be used in the English language.  The meaning of the noun stimulation is defined as: “A pricking, goading, or spurring on to action; incitement; pricking or compunction of conscience.”  The OED definition of stimulation in physiology and medicine is: “The action of a stimulus:  (a) excitation to increased activity, quickening of some vital function or process;  (b) excitation of an organ or tissue to its specific activity.”  The verb stimulāre is derived from the Latin stimulus (“Something that acts as a ‘goad’ or ‘spur’ to a languid bodily organ; an agency or influence that stimulates, increases, or quickens organic activity.”).  The origin of stimulus is “perhaps [from the] root sti- [as] in stilus”, which, in turn, had been transformed from the noun stylus (“A tracing-point used to produce the written record in a chart recorder, telegraph receiver, or the like.”).  Of particular relevance to addiction, the noun psychostimulant (“A drug that stimulates the activity of the mind or nervous system”) was formed within English relatively recently by compounding the noun stimulant with the combination form  psycho-, which is a borrowing from Greek used for “Forming words with the senses ‘of or relating to the soul or spirit’, ‘of or relating to the mind or psyche’, ‘of or relating to psychology’.”

       The first use of any word related to stimulāre in the English language is the noun stimulation which appeared in a quotation by William Bonde (d. 1530), a Bridgettine monk and author (1526): “The stimulacions of the flesshe.”  An example of the noun stimulation as it might pertain to addiction is from Robert James Graves (1796–1853), an eminent Irish surgeon after whom Graves’ disease was named (1843): “We should resort to stimulation by wine.”  An example of the first use of the noun stimulant as relevant to addiction is by Ephraim Chambers (?1680–1740) an English encyclopaedist (1728): “Stimulants produce Pain, Heat, Redness, &c.”  A later use is by Henri Milne-Edwards (1800–1885), a French zoologist (1829): “Such… stimulating remedies as do not appear to act… on a particular organ, but the exciting action of which is equally felt throughout the whole economy.”  This observation presages subsequent understanding that stimulants affect all parts of the body innervated by the autonomic nervous system and the brain.  Finally, the first use of the noun psychostimulant is found in a text Modern Pharmacology & Therapeutics (Musser and Bird 1961): “Prior to the development of these newer drugs, called psycho-stimulants or psychic energizers, apathetic and depressed patients were treated with caffeine and the amphetamines.”  This underlines that initial use of stimulants in psychiatry was for treatment of depression.

       In the early 19th century, the word stimulant did not convey a specific pharmacologic action as it does today but was used along the lines of restorative, invigorating or tonic – hot and cold water were recommended stimulants for the treatment of burns (Philanthropus 1809).  This is not surprising, as it was not until 1849 that the German pharmacologist Rudolf Buchheim (1820–1879), now considered the “Father of Pharmacology,” started the first department of pharmacology at the University of Dorpat (now Tartu) in Estonia.  In the early days, the role of pharmacology was to elucidate how medications then employed in medical practice interacted with as yet incompletely understood physiological functions.  Pharmacologists strove to recognize classes of medicines that putatively shared mechanisms of action and therapeutic indications (Snow 1875):

       “It appears to me that the science of therapeutics is at present much impeded by the want of a rational system of classification; and also by the vagueness of the general terms in ordinary use: that when men speak, for example, of a stimulant or narcotic, their ideas of what constitutes a stimulant or narcotic, of the essential feature in the stimulating or narcotising process, are more or less hazy and empirical. Since Dr. George Johnson's discoveries [contributions of the eminent English physician Sir George Johnson (1818–1896) on the physiology and pathology of the circulation (1871)] have directed attention to the contractility of the arterioles, it has become obvious that nearly all our drugs (excluding those prescribed merely for their chemical affinities) produce their effects upon the body – of course, through the agency of the nervous system – by the alterations they induce in the calibre of these vessels.

       “Premising that the arterioles are dilated by the vaso-motor nerves, which belong to the cerebro-spinal system, and contracted by the fibres of Remak (sympathetic), I will first notice the medicines, which are commonly called stimulants, and which agree in producing exhilaration of the mind, a genial feeling of warmth throughout the body, and increased force and frequency of the heart's contractions.  The primary and essential feature of this process, I take to be dilatation of the arterioles (teste the flushed face), to which the increased energy of the heart is but secondary, following as a necessary sequence.  

       “Tea, coffee, and guarana seem to be the purest we have; most of the others, as alcohol and opium, are only purely stimulant in small doses.  After a larger dose, that is, after a greater dilatation of the arterioles, a train of other symptoms succeeds; and the former stimulant now becomes either a hypnotic or a narcotic.”

       The above observations were accurate but the proposed unifying mechanism of action based on vascular dilatation for “stimulants” would soon be supplanted by an emphasis on neural activity.

       Discoveries during the 18th century that led to understanding of the autonomic nervous system were retold by the British physiologist John Newport Langley (1852–1925), whose own contributions to elucidating the anatomy of the autonomic nervous system included his being the first to explicitly propose that specific receptors in tissues bind drugs or transmitter substances onto cells to initiate or inhibit their pharmacologic actions (Langley 1903, 1916; Maehle 2004).   As the anatomy and physiology of the autonomic nervous system (Langley 1903; Elliott 1905) and electrochemical conduction between neural cells (Dale 1935) were clarified, understanding of the physiological substrata for pharmacological actions of stimulants became possible (Vincent and Curtis 1927; Von Euler 1946; Ahlquist 1948).

       Advances in pharmacology continued along with those in the biochemistry and physiology of body functions, including investigation of the actions of compounds produced endogenously in the body (Oliver and Schäfer 1895).  Once identified, these were purified or synthesized de novo, and modified by medicinal chemistry to produce novel pharmaceuticals with shared biochemical or physiological effects.  Pharmacologists have also identified and utilized for therapeutic purposes relevant molecules naturally occurring in botanicals used for centuries by mankind to alter sensorium, mood and thinking for medicinal, recreational and ritualistic purposes (Runge 1820; Posselt and Reimann 1828; Chen and Schmidt 1924).  Many of these molecules have emerged as pharmaceutical agents employed in medicine and surgery (Phelps 1930; Brun 1947).  However, some can also be used for self-medication or for their euphoric effects with progression to addiction in those so predisposed (Martin, Weinberg and Bealer 2007).

       Stimulant drugs came to the forefront in medicine due to their sympathomimetic effects (Anonymous 1925):

       “Tasted by the Emperor Shen Nung about 5100 years ago… and described by Li Shih Cheng in 1596 A.D. as a diaphoretic, circulatory stimulant, antipyretic, cough sedative, etc., ephedrine emerged from seclusion in 1887, though really its possibilities have been fully revealed only within the last two years.  Ephedrine is the active alkaloid of Ma Huang, or Ephedra vulgaris var. helvetica, closely resembling epinephrine in its actions qualitatively, but differing quantitatively and in some other important particulars. Recent studies of the drug, which is an ingredient of many famous Chinese prescriptions, have been made by… Chen and Schmidt of the Peking Union Medical College (1924)…  The promising therapeutic usefulness of ephedrine and its advantages over epinephrine merit attention at this time.

       “The crude drug, Ephedra vulgaris, yields two alkaloids, namely, ephedrine and pseudo-ephedrine, the latter being isomeric with ephedrine and their physiological actions are identical. Ephedrine was first isolated by Nagai in 1887 [Nagai Nagayoshi (1844–1929) was a Japanese organic chemist and pharmacologist trained at the University of Berlin in Prussia]…  The outstanding effect in animals… is circulatory stimulation, characterized by marked cardiac acceleration and a sustained rise of blood pressure lasting 30 minutes and longer.  The cardiac acceleration is due to stimulation of the stellate ganglia and the accelerator endings…  With moderate doses, the heart volume is increased and the rate slowed as the maximal level of blood pressure is reached, thus resulting in an increased output of blood from the heart.  With high doses and concentrations the heart is depressed and finally stops from direct paralysis by the drug, though the stoppage is usually preceded by fibrillation...  Atropine and section of the vagi do not prevent the circulatory effects, and, hence, they are of sympathetic origin.

       “The work of Chen and Schmidt proves conclusively that ephedrine, just like epinephrine, is a sympathomimetic drug, and that it has distinct advantages over epinephrine, namely, that its actions are more prolonged, those of epinephrine being fleeting, and that it is effective by mouth, while epinephrine is not.

       “The widest range of therapeutic usefulness of ephedrine will be in the treatment of asthma, hypotension and acute circulatory depression, and in certain congestive nasal conditions.  

       “Thus, it appears that the newer methods of experimentation confirm, extend and rationalize the effects and uses of an ancient drug understood in a general way and used quite intelligently, though empirically, by the Chinese thousands of years ago.” 

       Shortly following these pioneering studies, the role of the sympathetic arm of the autonomic nervous system were described in psychophysiological responses to threat (“fight or flight”), in stress and in reward (Cannon 1920; Selye 1937; Olds and Olds 1958).  Accordingly, studies of the effects of stimulants swiftly expanded beyond the cardiovascular and respiratory systems to include mental stimulation (euphoria, hypervigilance, anxiety, tension, anger, impaired judgement); psychomotor agitation (stereotyped behaviors, dyskinesias, dystonias); energy (less need for sleep) and performance enhancement; anorexia; and delirium, psychosis and seizures.  Stimulants were, hence, developed for effects on brain functions to treat disorders such as depression, fatigue, obesity, narcolepsy and more recently attention deficit and hyperactivity disorder (ADHD).  These agents were preferentially referred to as psychostimulants.  

       A congener of ephedrine, amphetamine, was first synthesized de novo in 1887 at the University of Berlin by Romanian chemist Lazăr Edeleanu (1861–1941) who named it phenylisopropylamine.  Nagai Nagayoshi synthesized methamphetamine (N-methylamphetamine) from ephedrine (1893).  Gordon Alles (1901–1963) independently resynthesized amphetamine and identified its medically useful sympathomimetic properties (Alles 1927; Rasmussen 2008).  In 1933, Smith, Kline and French (SKF) began selling amphetamine as an inhaler under the brand name Benzedrine for asthma and as a decongestant.  In 1937, the American Medical Association (AMA) first approved advertising of SKF’s “Benzedrine Sulfate” racemic amphetamine tablets for narcolepsy, postencephalitic Parkinsonism, low energy and minor depression (AMA Council on Pharmacy and Chemistry 1937).  Reference was made to the work of Abraham Myerson (1881–1948), an American neurologist and psychiatrist, who described (1936) his experience with Benzedrine Sulfate administration to normal and “neurotic” persons: 

       “Drugs that affect mood are few.  Alcohol produces in many persons euphoria which is followed by depression, although the changes in mood brought about by alcohol are so diverse as to give rise to the famous aphorism in vino veritas, meaning that the true underlying mood of the person comes out while he is drunk. Narcotics deaden the personality and thus bring about an escape from an intolerable mood.  The anesthesia of mood which is sought and obtained by this means is purchased at an enormous price, so far as personality worth is concerned.

       “Caffeine, in the form of tea and coffee, has a place in the daily habits of the human being largely because of the mild toning-up process which takes place. 

       “Certain effects of benzedrine sulfate on mood and fatigue… may be stated to exist:

       “First, normal nonpsychotic and nonneurotic persons who suffer from the fatigue and slight malaise due to insufficient rest, especially to insufficient sleep, receive immediate benefit and relief of a pleasant type when from 5 to 20 mg. of benzedrine sulfate is taken on arising. When this dose is taken toward the latter part of the day sleep is impaired in a striking manner.

       “Second, in certain cases of the neuroses associated with depression, fatigue and anhedonia and in certain cases of the minor stages of the psychoses of the same general type, benzedrine sulfate acts as an ameliorative influence. It is not in any sense curative and its effects are not permanent, but it helps to dissipate the morning apathy and depression, and its ameliorative effect is sufficiently important to recommend it during the treatment of the patient by other means and while the process of natural recovery is taking place.”

       In the late 1930s, based on these and similar observations, amphetamine began to be widely used for minor (“neurotic”) depression.  Presumably, the actions of amphetamine provided a means of amplifying adrenergic stimulation in the central nervous system, thereby enhancing the blunted natural drives (anhedonia) that characterized minor depression.  During World War II both amphetamine and methamphetamine found widespread use for their stimulant and performance-enhancing effects among all combatants but not without adverse psychiatric complications (Rasmussen 2008; Defalque and Wright 2011).  

       Controlled and limited self-administration of psychostimulants can be highly rewarding because of pleasurable and invigorating effects, which powerfully reinforce repeated use (Ritz and Kuhar 1989; Wang, Volkow, Chang et al. 2004).  However, increased frequency of self-administration can progress to out-of-control use, resulting in allostatic neuroadaptive changes via sensitization which alter the experience despite the augmented urge to continue use (Robinson and Berridge 1993).  Extended use can result in toxic effects in many organs of the body, including the nervous system, liver, heart, kidney toxicity (rhabdomyolysis) and psychotic features characterized elevated mood  and delusions of persecution (Connell 1968; Kalant 1973; Carvalho, Carmo, Costa et al. 2012). 

       As the abuse potential of stimulants was recognized, they were designated as controlled (schedule II) substances in the United States in the 1970s.  Most commonly abused stimulants are various amphetamines and cocaine.  (Naturally-occurring stimulants, cocaine, caffeine, nicotine and Catha edulis [Khat] are discussed in independent entries.)  Synthetic amphetamine-related stimulants, methamphetamine, ephedrine, 3,4-Methyl​enedioxy​methamphetamine (MDMA) or ecstacy, Methylenedioxypyrovalerone (MDPV), mephedrone, methylphenidate, phenylpropanolamine, propylhexedrine, pseudoephedrine among others are characterized by sympathomimetic effects (Axelrod 1954; Fairchild and Alles 1967) but can also affect dopaminergic and serotonergic neurotransmission.  Amphetamine-type stimulants, most commonly methamphetamine, remain widely used illicit drugs (0.5% to 1.0% of the U.S. population) in part, due to widespread diversion of stimulants (lisdexamfetamine, methylphenidate, and amphetamine) prescribed for treatment of ADHD (Arria and DuPont 2010).  Prevalence of amphetamine-type stimulant use disorders have been rising in the last decade in the U.S. population (from 0.1% to 0.2%), especially among individuals aged 18-25 years (Courtney and Ray 2014).  Methamphetamine, illegally synthesized in domestic clandestine labs from household chemicals, has wreaked havoc due to physical and emotional injuries (Centers for Disease Control and Prevention 2000).  Nevertheless, stimulants continue to be used as performance-enhancing or recreational drugs despite potential behavioral toxicities raising unresolved social and ethical problems (Farah, Illes, Cook-Deegan et al. 2004).  



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Month 11, 2021