Tuesday, 18.05.2021

Peter R. Martin: Historical Vocabulary of Addiction




        According to the current electronic version of Oxford English Dictionary (OED), the noun sleep, corresponding to the verb sleep, comes from the Old English slǽp (sláp), slép, Old Frisian slêp, Middle Dutch slaep, Old Saxon slâp, Old High German slâfsclâfsclâph, Gothic slēps.  The relevant definition in OED with respect to addiction is: “The unconscious state or condition regularly and naturally assumed by man and animals, during which the activity of the nervous system is almost or entirely suspended, and recuperation of its powers takes place; slumber, repose.”  In addition to the main definition, OED adds the following: “Also, a similar state artificially induced, as hypnotic (or magnetic) sleep.”    

        The word sleep was first used in the English language circa 825 in The Vespasian Psalter (Kuhn 1965), an Anglo-Saxon illuminated psalter produced in the second or third quarter of the 8th century, containing the oldest extant English translation of any portion of the Bible: “Ðonne seleð scyldum his slep.”  The meaning of the word is easily recognizable to modern readers from the circa 1369 quotation of the great English literary figure, Geoffrey Chaucer (c. 1340s –1400), in The booke of the Duchesse (1954): “Goo..to Morpheus, Thou knowist hym well, the god of slepe.”  This was an invocation to the Greek God of Sleep and Dreams, whose name was to become synonymous with the highly addictive substance, morphine.   John Lydgate (c.1370–1449), the English monk and poet, referred (1923) to the ability of milk to enhance the quality of sleep in circa 1430–40: “She gaue him milke, ye slepe fell in his hede.”  This description, so reminiscent of the soothing nature of the primal nutrient, mother’s milk, was considered scientifically grounded even to the modern era (Brezinová and Oswald 1972), presumably due to absorption of the amino acid precursor of the sleep hormone melatonin

        Throughout history, mankind has sought sleep as a pleasant and restful state after an active day (Goldsmith 1774): “Sleep is,..to some, a very agreeable period of their existence.”  In addition, sleep has been considered a period for healing and recovery of health (Allestree 1658): “Sleep comes as a Medicine to..weariness, as a repairer of..decay.” The German physician Franz Anton Mesmer (1734−1815), who was interested in astronomy and the transfer of natural energy between animate and inanimate objects (“animal magnetism”), viewed the associated phenomena, resembling sleep, as a means of healing.  He induced such states, known as mesmerism or hypnosis, by having patients ingest “healing metals” and placing magnets on different parts of the subject’s body; later on, he used movements with his bare hands to transfer “fluidum” from one person to another (Mesmer 1785).

        Physicians have always been fascinated by sleep and how this state differs from time awake (Stancliffe 1810): “That state in which our perceptions are distinct, and in which we direct the muscles of voluntary action according to the will, is that in which we are awake; that in which we are neither sensible (of external objects) nor capable of producing motion by the will is called sleep.”  Recent research in sleep physiology and chronobiology has established that sleep plays a vitally important integrating role in the circadian cycle of animals and humans and hence, influences all aspects of health (Karatsoreos, Bhagat, Bloss et al. 2011; Poggiogalle, Jamshed and Peterson 2018).  Such research findings are inconsistent with the OED definition of sleep that indicates (see above), “the activity of the nervous system is almost or entirely suspended.” 

        Formal scientific examination of sleep seems to have begun with identification by Loomis, Harvey and Hobart (1935) of changes in the electroencephalogram between when a person was awake and sleeping: “During sleep trains of waves appear which cannot be correlated with any detectable external stimulus, but which may be connected with internal disturbances of unknown origin. The cause of these very regular bursts is now under investigation.”  It was still uncertain whether hypnosis was another state of consciousness underneath a person’s awake self or a variant of sleep until it was formally demonstrated by electroencephalography that any resemblance to sleep was only superficial (Dynes 1947).  Sleep research quickened with the discovery of rapid eye movement (REM) sleep by Aserinsky and Kleitman (1953).  Rechtschaffen and Kales (1968) operationalized sleep parameters based on conventional visual sleep scoring, leading to normative data that could be used to distinguish normal from pathologic sleep; thus, it could be demonstrated that many neuropsychiatric disorders were characterized sleep abnormalities.   

        Alcoholic beverages have a very long history of use by man for the purpose inducing sleep in those who were unable to do so of their own accord.  In fact, this role has given rise to a specific noun, sleep-drink, derived from the Dutch slaapdrank and German schlaftrunk, which is defined in OED as “a portion of liquor taken just before bed-time.”  This term is found in The four Georges sketches of manners, morals, court and town life of Thackeray (1861): “Every evening they shall have their beer, and at night their sleep-drink.”  Thomas Sydenham, “The English Hippocrates” (1624 –1689), in his Medical Observations Concerning the History and Cure of Acute Disease (1722), recommended a tincture of opium in alcohol, or laudanum, for insomnia and many other ailments.  Certain electroencephalographic similarities were eventually identified between opioid-induced and natural sleep (Wikler 1952).  Other agents have been employed in medicine to help patients sleep, as suggested by MacDonald (1887): “Those [new hypnotics] I propose shortly discussing are: hyoscyamine, paraldehyde, urethane, and the hydrobromate and hydriodate of hyoscine… With the question of hypnotics is closely associated the great question of sleep, the physiology and pathology of which we yet know so little. One day the necessary and natural element of health, the next by its absence a symptom of disease.”  

        The search for sleep-inducing pharmaceutical agents, or hypnotics, has continued through the 20th century, even to the present day, starting with the barbiturates (Fischer and von Mering 1903; Willcox, Pickworth and Young 1927), non-barbiturate hypnosedatives (Berger 1954; Gruber, Kohlstaedt, Moore and Peck 1954), benzodiazepines (Sternbach Fryer, Keller et al. 1963; Greenblatt and Shader 1971) and most recently, the non-benzodiazepine hypnosedatives, or so-called “Z-drugs”  (Dundar, Boland, Strobl et al. 2004).  Additionally, agents such as the cannabinoids that can be sedating (Kubena and Barry 1970) but are not typically used clinically as a hypnotic because of legal stigma concerning their abuse liability.  The goal in pharmaceutical development of hypnotics has always been to improve natural sleep without toxicity, such as hangover, overdose or abuse liability.  Relative improvements in toxicity were achieved at each stage of medication development, but changes in addictive potential were ephemeral (Martin, Bhushan, Kapur et al. 1979).  

        Although sleep is considered pleasant and healing by many, there are those for whom this state seems but a distraction from other activities deemed of greater priority due to the press of work, seeking pleasure or thrills or various forms of psychopathology.  This conundrum of a need for alternatives to restful sleep and associated dangers have been understood for some time (Hart 1892): “That all men and women feel the weariness of life is testified” by the fact that the people of all nations and climes have the universal habit of daily seeking a restorative and stimulant in one of the vegetable products which contain a substance or alkaloid capable of exercising a definite effect on the nervous and cardiac systems. Thus, the Chinese and Japanese sip their tea, and the English, following their example, brew the five o'clock cup of the fragrant herb to sustain them in the day's work; the Arab and Turk seek, like the French and Germans, restorative powers in the aromatic coffee berry; the Cingalese chew the betel nut; and the natives of Peru on the slopes of the Andes find in coca leaves a principle which sustains the body in fatigue and comforts the mind in hopelessness. Von Bibra says of coca: “It satisfies the hungry, lends new strength to the weary and fatigued, and makes the unhappy forget his grief.” What, then, is this strange substance which seems to conceal a fairy's wand? We shall find, however, that, resembling other fairies' wands for the cure of the plagues of life, it may turn, like the magician's rod, into a viper.” 

        Historically, attempts to frustrate the natural need for sleep started with the use of plant-derived stimulants.  Subsequently, chemists purified the active substances from plants, progressed to synthesis of chemical modifications of the nature-derived substances and eventually succeeded in synthesis of novel compounds, modeled on nature, possessing even more powerful pharmacological effects.   The typical course begins as exemplified by the work of Ko Kuei Chen (1898–1988), a Chinese-American scientist known for bringing the natural sympathomimetic ephedrine to the western world (Chen 1927): “MA HUANG has been identified as Ephedra vulgaris, var. helvetica. It is a low, dioecious, practically leafless shrub, 60 to 90 cm. high. The stem, which is green, ribbed, and channeled, is the part sold in Chinese drug stores. It is usually cut into pieces, 1 to 1.5 cm. long. Ephedrine, a natural secondary amine, is the physiologically active constituent and can be easily isolated from the plant by immiscible solvents. It was first discovered by Nagai in 1889, and its structural formula has been studied by different observers.” 

        In 1887, only two years after first synthesis of ephedrine, Lazăr Edeleanu (1861–1941), a Rumanian chemist, synthesized amphetamine from ephedrine.  In 1929, Gordon A. Alles (1901–1963), an American chemist and pharmacologist first reported the physiological properties of amphetamine as a synthetic analog of ephedrine, and therefore, received credit for this discovery (Fairchild and Alles 1967).  Soon after Alles' discovery, pharmaceutical companies developed amphetamine-related medications for treating nasal congestion and asthma, and eventually, also for treatment of depression, obesity, attention deficit disorder, and narcolepsy. 

        Other uses of these agents were eventually revealed, including as an aphrodisiac, euphoriant and cognitive or physical enhancer.  Scientific enquiry has demonstrated that over the long run, these putative enhancement effects were more apparent than real.  Rather, such beneficial effects obey the Yerkes–Dodson law, an empirical relationship between arousal and performance, indicating that performance increases with physiological or mental arousal, but only up to a point; when levels of arousal become too high, performance decreases (Yerkes and Dodson 1908).   As Wood, Sage, Shuman and Anagnostaras (2014) state in their review of popular stimulants (cocaine, amphetamine, methylphenidate, modafinil, and caffeine): “...dose is the critical determining factor [although dose-response relationships may differ among individuals] in cognitive effects of stimulant drugs... One common graphic depiction of the cognitive effects of psychostimulants is an inverted U–shaped dose-effect curve.  Moderate arousal is beneficial to cognition, whereas too much activation leads to cognitive impairment.  In parallel to this schematic, we propose a continuum of psychostimulant activation that covers the transition from one drug effect to another as stimulant intake is increased. Low doses of stimulants effect increased arousal, attention, and cognitive enhancement; moderate doses can lead to feelings of euphoria and power, as well as addiction and cognitive impairment; and very high doses lead to psychosis and circulatory collapse.”

        Accumulating research has clearly demonstrated that sleep is an active neurobiological state with multiple physiologic roles, most importantly, body energy and temperature regulation which underpin many physical illnesses (Karatsoreos, Bhagat, Bloss et al. 2011; Poggiogalle, Jamshed and Peterson 2018) and consolidation of memory which allows the individual to accumulate and appreciate life-long experiences in all sensory modalities and thus, greatly affects mental health (Ngo and Born 2019).  However, by use of a variety of hypnotics and analeptics, mankind has acquired the means, almost-at-will, to enter into or postpone the need for sleep, but not with impunity.  A significant consequence of the use and eventual overuse of either hypnotics or analeptics is disturbed sleep.  In particular, drug-induced toxic effects on sleep are well-recognized for all drugs of abuse and these effects can occur during intoxication, withdrawal, chronic use and well beyond when the person has achieved abstinence (Yules, Freedman and Chandler 1966; Oswald 1968; Brower 2001; Reid-Varley, Ponce and Khurshid 2020).  It is not difficult to appreciate how useful these agents can appear to an individual for self-medication — of sleeplessness due to anxiety, stress and pain from various causes and of lagging mood or energy as a euphoriant, aphrodisiac and as a cognitive or performance enhancer (Martin 2019).  Therefore, insomnia may be both a precursor to and consequence of alcohol/drug use disorders.  In addition, disturbed sleep per se is characteristic of many medical (e.g., pain, impaired respiratory function or neurocognitive disorders) and psychiatric (e.g., anxiety, depression or psychosis) conditions which can result in self-medication to enhance sleep and can progress to addiction.  Therefore, it is important to disentangle whether a drug use disorder is primary or secondary to a medical or psychiatric cause for poor sleep and address underlying conditions.  In addition, there has been a recent emphasis on using behavioral (Okajima, Akitomi, Kajiyama et al. 2020) and other techniques (Figueiro, Plitnick, Roohan et al. 2019) to treat sleep disorders that are not strictly a result of treatable medical or psychiatric conditions so as to circumvent the slippery slope of the progression of hypnotic use to addiction.

        Sleep disturbance, whether primary or secondary, is very closely intertwined with alcohol/drug use disorders (Martin, Weinberg and Bealer 2007).  If the individual begins to use central nervous system depressants to allow sleep when she/he is suffering from sleeplessness, the drug use can progress to an out-of-control and self-destructive pattern.  Conversely, if an individual desires not to sleep and uses an analeptic to “burn the candle at both ends,” going without sleep may eventually have significant health consequences, including the inability to sleep and compounding the situation by self-administration of hypnotics, which can more greatly disrupt circadian rhythms and result in exhaustion.  Importantly, all of these medications have abuse liability and their repeated use alters the central nervous system and sleep and circadian functions in a way that perpetuates use.  The neuroadaptive changes, or allostasis, that accompany the progression of addiction have been mechanistically associated with the neurobiology of sleep disturbances in addiction (Koob and Colrain 2020).  In addition, the influence of sleep has been incorporated in conceptualization of not only of the risk for development of addiction, but also in identifying those who are most likely to relapse once they have become abstinent (Brower and Perron 2010).



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November 5, 2020