Peter R. Martin: Historical Vocabulary of Addiction II
According to the current electronic version of the Oxford English Dictionary (OED), the noun hallucinogen was formed within English by combination of three elements: hallucin- (as in the noun hallucination), the suffix -o (forms nouns, adjectives and interjections) and the combinatorial form -gen (used for forming nouns in modern scientific use). The noun hallucination is from the late Latin ālūcinātiōn-em (all-, hall-), which is the noun of action of the past participial stem of Latin (h)allūcinārī (more correctly ālūcinārī), meaning “to wander in mind, talk idly, prate.”
The definition in OED of hallucination as used in psychopathology is: “The apparent perception (usually by sight or hearing) of an external object when no such object is actually present. (Distinguished from illusion in the strict sense, as not necessarily involving a false belief.)” An early example of the use of hallucination is by the English physician, author and polymath Sir Thomas Browne (1605–1682) in Pseudodoxia epidemica (Browne 1646): “If vision be abolished it is called cæcitas, or blindnesse, if depraved and receive its objects erroneously, Hallucination.” A later view of hallucination was held by Edmund Gurney (1847–1888), an English psychologist and parapsychologist, in Phantasms of the living (Gurney, Myers and Podmore 1886): “The definition of a sensory hallucination would thus be a percept which lacks, but which can only by distinct reflection be recognised as lacking, the objective basis which it suggests.”
With the maturing of psychopharmacology in mid-20th century (Shorter 2021), the word psychotomimetic became quite fashionable; it was used much as the term hallucinogen until it was demonstrated that these drugs do not actually provide a useful model of psychosis or mental illnesses as initially proposed (Osmond and Smythies 1952; Nichols 2016). The adjective and noun psychotomimetic is a variant or alteration of another lexical term, the adjective psychosomimetic which was formed within English by compounding of psychosis (“Originally: any kind of disordered mental state or mental illness. Later: specifically severe mental illness, characterized by loss of contact with reality [in the form of delusions and hallucinations] and deterioration of intellectual and social functioning, occurring as a primary disorder or secondary to other diseases, drug ingestion, etc.; an instance of this.”), the connective -o- and the adjective mimetic (“Relating to, characterized by, or of the nature of imitation; specifically representing, picturing, or presenting the real world [especially in literature, art, etc.]...”).
Psychotomimetic is defined in OED as: “Having an effect on the mind originally likened to that of a psychotic state, with abnormal changes in thought, perception, and mood and a subjective feeling of an expansion of consciousness; of or relating to a substance with this effect.” On the other hand, hallucinogen is simply, and perhaps more appropriatedly, defined as: “A drug which causes hallucinations.” An example of the early use of the term psychomimetic occurred in a conference, The Pharmacology of Psychotomimetic and Psychotherapeutic Drugs, organized by the American neuroscientist Seymour S. Kety (1915–2000) under the auspices of the New York Academy of Sciences (Kety 1957; Osmond 1957): “We are using Gerard's term ‘psychotomimetics’ generally for compounds that have been called schizogens, psychotica, psychotogens, phantastica, hallucinogens and elixirs.”
Contrary to the term psychomimetic, hallucinogen was not only used in psychiatry but also in literary circles and in cultural domains. There was considerable initial psychiatric interest in hallucinogens because of their characteristic effects on the sensorium (Klüver 1926), which seemed to resemble certain of the experiences in psychotic disorders — the reasoning was that if hallucinations resulted from administration of this class of drugs, they might be used to delve into the phenomenology and pathophysiology of the important psychiatric disorders, including schizophrenia.
Osmond and Smythies (1952) began to explore psychopharmacologically modelling psychosis in their article The Schizophrenia: A New Approach in which the following quote appeared: “There are many other hallucinogenic drugs, but none has either such striking properties or such a simple chemical constitution as mescaline.” Aldous Leonard Huxley (1894–1963), the English writer and philosopher used the term in the autobiographical book The Doors of Perception, in which he elaborated his experience under the influence of mescaline and also discussed some general psychopharmacologic principles he had learned in his journey of self-discovery (Huxley 1954): “Lysergic acid, an extremely potent hallucinogen derived from ergot.”
Hallucinogens can be classified based on the psychopharmacological changes they produce in the sensorium, namely they could act as psychedelics, dissociatives, or deliriants. The noun or adjective psychedelic is defined in OED as: “A drug (especially an illicit one) which produces an alteration in the mind, especially an apparent expansion of consciousness […through greater awareness of the sensations, emotions, and unconscious motivations…] often accompanied by hallucinations.” The word psychedelic is a borrowing from the ancient Greek noun ψυχή, meaning psyche and δηλοῦν (“to make manifest, reveal” [ δῆλος “manifest, visible”]) and the suffix -ic, combined with an English element.
An example of the early use of psychedelic in Letters of Aldous Huxley is from Humphry Fortescue Osmond (1917–2004), an English psychiatrist (first mentioned above), expatriated to Canada and then the U.S., known for inventing the word psychedelic and for his research on applications for psychedelic drugs (Huxley 1969): “To fathom Hell or soar angelic, Just take a pinch of psychedelic (Delos to manifest).”
The adjective dissociative is defined in OED as: “Characterized by or relating to disconnection between usually integrated psychological processes.” This indicates that the pharmacological action of these hallucinogens produces a psychological state of dissociation (“The process or result of breaking up associations of ideas.” Or “The disintegration of personality or consciousness; the state in which a person suffers from dissociated personality.”) in an individual who self-administers these agents. The American philosopher, historian and psychologist William James (1842–1910) considered by many as the “Father of American Psychology” used the term dissociation in his textbook The principles of psychology (James 1890): “What is associated now with one thing and now with another tends to become dissociated from either... One might call this the law of dissociation by varying concomitants.”
The noun and adjective deliriant is defined in OED as: “Causing delirium” or “A drug or other agent that causes delirium.” This word was “Either (i) formed within English, by derivation. Or (ii) a borrowing from Latin, combined with an English element.” It is derived from the classical Latin dēlīrium combined with the suffix -ant. The noun delirium is defined as: “A disordered state of mind or consciousness; (in later use) specifically an acute, transient condition associated with fever, intoxication with alcohol or drugs, and various other physical disorders, typically characterized by symptoms such as confusion, disorientation, agitation, hallucinations, and disturbances of thought, memory, and mood. Also: an instance or episode of this.”
An example of the early use of deliriant by the English physician Frederick William Headland (1830–1875) can be found in The action of medicines in the system (Headland 1853): “The Deliriant Narcotics, i.e. Hyoscyamus, Belladonna, and Stramonium, dilate the pupil, and in large doses cause delirium.” This quotation indicates that pharmacological action of a deliriant is not restricted to agents classified as hallucinogens but may be seen with other classes of psychopharmacologic agents such as opioids (see Opium). Furthermore, characteristics of an individual may determine whether a drug can cause delirium when the agent is administered, as suggested by John Harley (1833–1921) in his Goulstonian lecture The old vegetable neurotics… (Harley 1869): “There are some persons who experience only the excitant and deliriant effects [of morphia and opium].”
The classical hallucinogens have a very long history of use by mankind for religious rituals and healing. In ancient India, as mentioned in the Rigveda, the early Vedic Indo-Aryans used a ritual drink soma in their religious tradition. The actual constituents of this potion are still controversial but have been postulated to be Psilocybe cubensis, a hallucinogenic mushroom that grows in cow dung in certain climates (McKenna 1992). It is, therefore, no coincidence that Aldous Huxley selected “Soma” as the name for the seamingly all-purpose drug (“All the advantages of Christianity and alcohol; none of their defects.”) in his classic book Brave New World (Huxley 1932). Psilocybin mushrooms, known as teonanacatl, meaning “God’s flesh” were also used by the Aztecs for their medicinal effects and in religious rituals (Schultes and Hofmann 1979).
There are anthropological traces of the use of various psychoactive plant materials and substances in pre-Columbian Mesoamerican societies as well as in Australasia and Africa (Pettigrew 2011; Carod-Artal 2015). Samples of peyote (Lophophora williamsii), a small cactus native to the American Southwest and Northern Mexico containing mescaline, from a cave on the Rio Grande River in Texas were determined by radiocarbon dating to be from 3780–3660 BCE (El-Seedi, Smet, Beck et al. 2005). This finding supports the use of peyote by Native North Americans as long ago as 5,700 years (Bruhn, Smet, El-Seedi et al. 2002). Historical evidence of ritual and medicinal use has been established for many of the classic hallucinogens or psychedelics derived from plant materials, including LSD, mescaline, psilocybin, and N,N-dimethyltryptamine.
It is perhaps not surprising that some of the same psychedelic hallucinogens used historically for rituals and healing, namely mescaline, LSD, psilocybin and DMT have had the largest scientific and cultural influence during the last century (Leary 1964; Freedman 1968; Grof 1975; McKenna 1992).
The first serotonergic hallucinogen was synthesised in 1938 by the Swiss chemist Albert Hofmann (1906–2008) while working for Sandoz in Switzerland (Hofmann 1980). He synthesised lysergic acid diethylamide (LSD) while studying the chemistry of alkaloid compounds contained in ergot, a fungus which forms on rye (Secale cereale). Hofmann is also recognized as being the first person to ingest and experience the psychedelic effects of LSD and to isolate, synthesize and name the principal psychedelic mushroom compounds psilocybin and psilocin.
LSD was introduced as a commercial medication under the trade-name “Delysid” for various psychiatric uses in 1947. Hence, syntheses of hallucingenic agents by the pharmaceutical industry was intended to continue the evolution of the medicinal uses for these agents, augmenting the sparse therapeutic armamentarium of the psychiatrist at mid-20th century (Salomon, Gabrio and Thale 1949; Hoch, Cattel and Pennes 1952; Barr, Langs, Holt et al. 1972).
Hallucinogens soon acquired a reputation consistent with their use as drugs for recreational purposes and enlightment by the counterculture (Leary 1964; Grinspoon and Bakalar 1979). Major clinical concerns emerged concerning the increased popularity of using LSD and related hallucinogens, moreso than their abuse liability (Anonymous 1966). The toxidromes associated with LSD use were described as having three somewhat overlapping clinical features: panic reaction; reappearance of "drug" symptoms without reingestion of the drug; and overt psychosis (Frosch, Robbins and Stern 1965).
Despite promising psychopharmacological research in treatment of alcoholism (Krebs and Johansen 2012) and of other psychiatric conditions in combination with psychotherapy (Grof 1975), legal prohibition of psychedelics was soon mandated. As Bill W., the co-founder of AA, undertook self-experimentation with psychedelics (Hartigan 2000) to help him maintain sobriety, the following editorial appeared in the Journal of the American Medical Association (Anonymous 1966):
“Recent reports from European and American urban centers suggest that increased use of LSD has been associated with severe adverse reactions. The manufacturer has suspended production; a United Nations committee has called for immediate worldwide regulatory action; and the drug has been interdicted in the United States. Anxiety has been expressed that the drug may exaggerate psychoses and increase depressions, homicide, and addiction.”
The subsequent designation of hallucinogens under the Controlled Substances Act of 1970 essentially quashed any potential therapeutic uses of hallucinogens for decades to come (Anthony 1979).
The American clinical psychopharmacologist Leo E. Hollister (1920–2000) proposed the following criteria to define the hallucinogens in his monograph Chemical psychoses: LSD and related drugs (Hollister 1968):
(a) in proportion to other effects, changes in thought, perception, and mood should predominate;
(b) intellectual or memory impairment should be minimal;
(c) stupor, narcosis, or excessive stimulation should not be an integral part of the action;
(d) autonomic nervous system side-effects should be neither disabling nor severely disconcerting;
(e) addictive craving should be minimal.
Even with criteria such as these, drugs admissible to the list may vary, depending on the investigator.
The following agents can be designated as satisfying the Hollister criteria of hallucinogens:
Lysergic acid derivatives (e.g., Lysergic acid diethylamide [LSD]);
Phenylethylamines (e.g., Mescaline);
Indolealkylamines (e.g. N,N-Dimethyltryptamine [DMT]);
Other indolic derivatives (e.g., Harmala alkaloids, Ibogaine);
Piperidyl benzilate esters (JB-329);
Phenylcyclohexyl compounds (Phencyclidine [PCP]); and
Miscellaneous agents (Kawain, Dimethylacetamide, Cannabinoids).
The list above includes highly diverse and heterogeneous agents that produce quite dissimilar effects acting through distinct mechanisms. Accordingly, the so-called “classical hallucinogens” were later redefined, narrowing the Hollister criteria, so that they also needed to meet two additional conditions (Glennon 1999):
(a) bind at 5-HT2 serotonin receptors, and
(b) are recognized by animals trained to discriminate 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane (DOM) from vehicle.
The Hollister criteria clearly indicated that for hallucinogens “addictive craving should be minimal.” This criterion was supported by classical studies of abuse liability — mescaline was not self-administered by nonhuman primates whereas self-administration of stimulants and various other drugs with well-recognized abuse potential were initiated and actively maintained under the same conditions (Deneau, Yanagita and Seevers 1969).
More recently, however, it is believed that assessments of hallucinogens for abuse liability must be based on the “real world experience” of those who use them with or without clinical supervision. Such observations do not support the criterion of their having no abuse liability, especially as the universe of pharmacological agents now considered psychedelic is ever-expanding. There is a “lack of consensus on what constitutes a psychedelic drug, including other drugs from other pharmacological classes that induce hallucinations and mind-expanding experiences as having psychedelic properties” such that the following pharmacological classes of drugs, some of which clearly have “addictive craving” associated with their use, are now accepted as psychedelic hallucinogens (Heal, Gosden and Smith 2018):
5-HT2 agonists including 5-HT2A agonists and 5-HT2C agonists, e.g., lorcaserin;
Indirect 5-HT2 agonists including MDMA (5-HT and dopamine releasing agent) and fenfluramine and dexfenfluramine (5-HT releasing agents);
NMDA antagonists, i.e., phencyclidine and ketamine;
κ-opioid receptor agonists, i.e., salvinorin A and (−)-pentazocine.
Several of these newly considered hallucinogens affect brain reward pathways and have significant abuse potential. This may partially explain why psychedelic hallucinogen use among young adults has reached an all-time high as reported by the Monitoring the Future study of the National Institute of Drug Abuse (Patrick, Schulenberg, Miech et al. 2022).
Investigators who studied the effects of psychedelic hallucinogens during clinical administration and otherwise observed that their effects are greatly influenced by the individual’s personality and life experience (Barr, Langs, Holt et al. 1972; Grof 1975). Daniel X. Freedman (1921–1993) an American biological psychiatrist and pioneering LSD researcher made insightful observations about the quality of the experience associated with use of this psychedelic hallucinogen (Freedman 1968):
“…one basic dimension of behavior… compellingly revealed in LSD states is ‘portentousness’— the capacity of the mind to see more than it can tell, to experience more than it can explicate, to believe in and be impressed with more than it can rationally justify, to experience boundlessness and ‘boundaryless’ events, from the banal to the profound.”
Repeated administration of psychedelics leads to a very rapid development of diminishing response to successive doses (see Tolerance), presumably explained by downregulation of the 5-HT2A receptor, even in the hallucinogenic stimulants (Nichols 2016). Daily administration of LSD leads to almost complete loss of sensitivity to the effects of the drug by the fourth dose (Cholden, Kurland and Savage 1955; Isbell, Belleville, Fraser et al. 1956). Likewise, daily administration of the hallucinogenic amphetamine 2,5-dimethoxy-4-methylamphetamine (DOM) in humans was also found to lead to significant tolerance to the drug by the third day (Angrist, Rotrosen and Gershon 1974). In humans, cross-tolerance has been reported between mescaline and LSD (Balestrieri and Fontanari 1959) and between psilocybin and LSD (Isbell, Wolbach, Wikler et al. 1961).
With the new century, immense interest has emerged in the role of psychedelics in neuropsychopharmacology (Nutt, Erritzoe and Carhart-Harris 2020), possibly in response to lack of real progress in the field for decades (Shorter 2021). There is early evidence supporting psychedelics for pharmacotherapy of anxiety, post-traumatic stress disorder (PTSD), depression, smoking and alcoholism. High quality studies are beginning (Carhart-Harris, Giribaldi , Watts et al. 2021), but there is still considerable work to be done to reverse the attitude of the previous generations of physicians.
Beyond the most important issue of efficacy, the need to determine the abuse liability in humans of psychedelic hallucinogens has become more relevant than ever if these agents are to find clinical uses for treating psychiatric disorders, of particular relevance to addiction (Sellers, Romach and Leiderman 2018). It is somewhat ironic that Bill W. may have been more right than wrong in his explorations of psychedelic hallucinogens (Hartigan 2000), considering the recent impetus to evaluate this class of drugs in the treatment of alcoholism (Bogenschutz, Ross, Bhatt et al. 2022).
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September 22, 2022