Pharmacology & Therapeutics 101 (2004) 131 – 181
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`www.elsevier.com/locate/pharmthera
`
`Associate editor: B.L. Roth
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`Hallucinogens
`
`David E. Nichols*
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`Department of Medicinal Chemistry and Molecular Pharmacology, School of Pharmacy and Pharmacal Sciences,
`Purdue University, West Lafayette, IN 47907-2091, USA
`
`Abstract
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`Hallucinogens (psychedelics) are psychoactive substances that powerfully alter perception, mood, and a host of cognitive processes. They
`are considered physiologically safe and do not produce dependence or addiction. Their origin predates written history, and they were employed
`by early cultures in a variety of sociocultural and ritual contexts. In the 1950s, after the virtually contemporaneous discovery of both serotonin
`(5-HT) and lysergic acid diethylamide (LSD-25), early brain research focused intensely on the possibility that LSD or other hallucinogens had
`a serotonergic basis of action and reinforced the idea that 5-HT was an important neurotransmitter in brain. These ideas were eventually proven,
`and today it is believed that hallucinogens stimulate 5-HT2A receptors, especially those expressed on neocortical pyramidal cells. Activation of
`5-HT2A receptors also leads to increased cortical glutamate levels presumably by a presynaptic receptor-mediated release from thalamic
`afferents. These findings have led to comparisons of the effects of classical hallucinogens with certain aspects of acute psychosis and to a focus
`on thalamocortical interactions as key to understanding both the action of these substances and the neuroanatomical sites involved in altered
`states of consciousness (ASC). In vivo brain imaging in humans using [18F]fluorodeoxyglucose has shown that hallucinogens increase
`prefrontal cortical metabolism, and correlations have been developed between activity in specific brain areas and psychological elements of the
`ASC produced by hallucinogens. The 5-HT2A receptor clearly plays an essential role in cognitive processing, including working memory, and
`ligands for this receptor may be extremely useful tools for future cognitive neuroscience research. In addition, it appears entirely possible that
`utility may still emerge for the use of hallucinogens in treating alcoholism, substance abuse, and certain psychiatric disorders.
`D 2003 Elsevier Inc. All rights reserved.
`
`Keywords: Hallucinogen; 5-HT2A receptors; Prefrontal cortex
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`Contents
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`1.
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`Introduction .
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`1.1. Historical perspective .
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`1.2.
`Toxicity and addiction .
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`The chemical classes of hallucinogens .
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`Psychopharmacological effects of hallucinogens .
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`4. How do hallucinogens work? .
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`4.1. Historical relationship between serotonin and hallucinogen action .
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`4.2.
`Early hypothesis for a presynaptic agonist mechanism of action .
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`4.3.
`Evidence for agonist activity at the serotonin2A receptor subtype .
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`4.3.1. Relevance of animal models to man: species differences in receptors .
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`Signaling through the serotonin2A receptor: agonist trafficking.
`4.3.2.
`4.3.3. Neuroanatomical localization of serotonin2A receptors .
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`Functional consequences of serotonin2A receptor activation in prefrontal cortex .
`4.3.4.
`4.3.4.1.
`Effects on cortical glutamate .
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`4.3.4.2. Hallucinogens increase cortical metabolism .
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`4.3.4.3. Dopaminergic effects of hallucinogens .
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`4.3.4.4.
`Serotonin2A receptor activation alters gene expression .
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`* Fax.: +1-765-49-414-61.
`E-mail address: david.e.nichols.1@purdue.edu (D.E. Nichols).
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`0163-7258/$ – see front matter D 2003 Elsevier Inc. All rights reserved.
`doi:10.1016/j.pharmthera.2003.11.002
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`EXHIBIT I
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`

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`132
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`D.E. Nichols / Pharmacology & Therapeutics 101 (2004) 131–181
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`5.
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`4.4. Are other receptors important to the actions of hallucinogens? .
`4.4.1. A role for the serotonin2C receptor subtype .
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`4.4.2.
`Is the serotonin1A receptor important? .
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`4.4.3.
`Possible potentiating effects of interactions at other receptor subtypes .
`Clinical relevance of serotonin2A receptors .
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`5.1.
`Lysergic acid diethylamide treatment in terminal illness.
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`5.2.
`Treatment of alcoholism and substance abuse .
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`5.3. Obsessive-compulsive disorder
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`5.4.
`Clinical studies of N,N-dimethyltryptamine .
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`5.5.
`Studies of mescaline .
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`5.6.
`Studies of psilocybin .
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`5.7.
`Effects on cognition and perception: future tools for cognitive neuroscience .
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`Conclusions .
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`6.
`Acknowledgments .
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`References .
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`1. Introduction
`
`What are hallucinogens? This term was originally coined
`because of the notion that these substances produce halluci-
`nations, an effect, however, that they do not ordinarily elicit,
`at least at typical dosages. Thus, that name is a misnomer.
`Today, unfortunately, hallucinogen appears almost to have
`become a catchall category, often representing pharmaco-
`logical substances ranging from cannabinoids and N-meth-
`yl-D-aspartate (NMDA) antagonists to anticholinergic
`agents, ecstasy (MDMA; 3,4-methylenedioxymethamphet-
`amine), and many others. The common theme of all these
`classes of pharmacologically active substances is that they
`alter consciousness, often in dramatic and unpredictable
`ways, and in high doses may produce delirium, true hallu-
`cinations, loss of contact with reality, and in some cases
`death. To describe at least some of those substances, the
`term ‘‘psychotomimetic’’ (psychosis mimicking; Hoffer,
`1967), widely used for many years, seems more appropriate.
`Ecstasy, presently a popular recreational drug, has in
`some cases also been called a hallucinogen because it has
`subjective effects that are to a certain degree similar,
`including altered time perception and changes in visual
`perception. MDMA has unique psychopharmacology, how-
`ever, appearing to have major components of action that
`involve interaction with monoamine uptake transporters,
`and does not properly fit within the hallucinogen classifi-
`cation (Nichols & Oberlender, 1990; Nichols, 1994; Bank-
`son & Cunningham, 2001; O’Leary et al., 2001). Thus, one
`needs to be very specific about definitions when ‘‘halluci-
`nogens’’ are being discussed.
`Hallucinogens, for the purposes of this review, will mean
`only substances with psychopharmacology resembling that
`of the natural products mescaline and psilocybin and the
`semisynthetic substance known as lysergic acid diethyla-
`mide (LSD-25). More specifically, now that there is appre-
`ciation of their probable molecular mechanism of action, we
`shall review those substances that principally exert their
`central nervous system (CNS) effects by an agonist (or
`partial agonist) action at serotonin (5-HT)2A receptors.
`
`Many different names have been proposed over the years
`for this drug class. The famous German toxicologist Louis
`Lewin used the name phantastica earlier in this century
`(Lewin, 1964), and as we shall see later, such a descriptor is
`not so farfetched. The most popular names, hallucinogen,
`psychotomimetic, and psychedelic (‘‘mind manifesting’’;
`Osmond, 1957), have often been used interchangeably.
`Hallucinogen is now, however, the most common designa-
`tion in the scientific literature, although it is an inaccurate
`descriptor of the actual effects of these drugs. In the lay
`press, the term psychedelic is still the most popular and has
`held sway for nearly four decades. Most recently, there has
`been a movement in nonscientific circles to recognize the
`ability of these substances to provoke mystical experiences
`and evoke feelings of spiritual significance. Thus, the term
`entheogen, derived from the Greek word entheos, which
`means ‘‘god within,’’ was introduced by Ruck et al. (1979)
`and has seen increasing use. This term suggests that these
`substances reveal or allow a connection to the ‘‘divine
`within.’’ Although it seems unlikely that this name will
`ever be accepted in formal scientific circles, its use has
`dramatically increased in the popular media and on internet
`sites. Indeed, in much of the counterculture that uses these
`substances, entheogen has replaced psychedelic as the name
`of choice and we may expect to see this trend continue.
`There is only a meager amount of factual information
`about hallucinogenic drugs among the general public today.
`Furthermore, in the scientific and medical communities,
`where one expects to find expertise on drugs, there is now
`a whole generation who knows almost nothing about
`hallucinogens other than the fact that they are subject to
`the strictest legal controls applied to any class of pharma-
`cological agents. These drugs presently lack demonstrated
`therapeutic utility and still remain, as they have for more
`than 50 years, pharmacological curiosities. Research efforts
`directed toward examining their potential medical utility are
`extremely limited not only in the United States but also
`internationally. Studies of the mechanism of action of
`hallucinogens are still incomplete and have not attracted a
`high level of scientific interest for more than four decades.
`
`

`

`D.E. Nichols / Pharmacology & Therapeutics 101 (2004) 131–181
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`133
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`We know relatively little about how they affect the brain in
`spite of their continued popularity as recreational drugs
`among a significant proportion of the population.
`Despite their high degree of physiological safety and lack
`of dependence liability, hallucinogens have been branded by
`law enforcement officials as among the most dangerous
`drugs that exist, being placed into Schedule I of the Con-
`trolled Substances Act. Depending on the locale, especially
`in the United States, punishments for using or distributing
`drugs like LSD are often more draconian than if the user had
`committed a violent crime. Although there is a common
`perception that Schedule I drugs are particularly dangerous,
`the 3-pronged test for placement of a drug into schedule I
`requires only that (1) the drug has no currently accepted
`medical use in the United States, (2) there is a lack of safety
`for use of the drug under medical supervision, and (3) the
`substance has a high ‘‘potential for abuse.’’ The practical
`consequence of this scheduling means that applications and
`procedures to gain approval to carry out research with them,
`especially in humans, are very burdensome. This situation is
`true virtually everywhere in the world, although in a few
`European countries, most notably in Switzerland, a more
`progressive attitude has recently prevailed. Within the past
`decade, there appears to have been a resurgence of research
`interest in these substances as well as the initiation of several
`new clinical studies, even in the United States.
`What is it, exactly, that makes these pharmacological
`curiosities so fearsome? The answer lies, in large measure,
`beyond hard science and within a complex sociological and
`political agenda that surround psychedelics, which is well
`outside the scope of this review. Nevertheless, a very brief
`discussion of the history and background of these unique
`substances is warranted to provide a little insight into how
`this situation arose.
`
`1.1. Historical perspective
`
`Naturally occurring hallucinogenic drugs played a sig-
`nificant role in the development of philosophy and religious
`thought in many earlier cultures. One can argue persuasively
`that hallucinogenic drugs might have been catalysts for the
`development of humankind’s earliest philosophies and the-
`ologies. How many Neolithic hunters, one might wonder,
`eking out an existence in the wild, were likely to sit before
`the fire at night contemplating the nature of man and the
`meaning of life? By contrast,
`if the same group had
`discovered and ingested some hallucinogenic mushrooms,
`they would be compelled to confront and would surely have
`discussed and attempted to understand the nature of their
`otherworldly mushroom-induced encounters. Assuming that
`their neurochemistry was not so different from ours today,
`those occurrences would have been well beyond the bounds
`of their everyday experiences and vocabulary. They could
`easily have concluded that these plants were ‘‘the residences
`of divinities or other spiritual forces’’ (Schultes & Hofmann,
`1979).
`
`Well-documented and important examples of hallucino-
`gen use in other cultures include the soma of ancient India
`(Wasson & Ingalls, 1971) to which numerous Vedic hymns
`were written, teonanacatl, ‘‘god’s flesh’’ used by the Aztec
`shaman (Ott & Bigwood, 1978; Schultes & Hofmann,
`1979), and peyote taken as a sacrament during services of
`the Native American Church (Stewart, 1987). In Mexico,
`there were about 40 plants, some of which still remain
`unidentified, that were used ritually or were regarded as
`sacred (Diaz, 1977). In the village of Eleusis in ancient
`Greece, for more than 2000 years,
`it was a treasured
`opportunity for any Greek citizen who had not been con-
`victed of murder to participate in the secret all-night cere-
`mony each September that involved the drinking of a special
`potion known as ncnqvr. Today, we know very little about
`this ceremony, but reasonable arguments have been made
`that ncnqvr was some sort of hallucinogenic brew. The
`ritual was partially described in the 2nd century A.D.: ‘‘. . .of
`all the divine things that exist among men, it is both the most
`awesome and the most luminous’’ (Wasson et al., 1978).
`Today, in modern Brazil, a respected religion uses ayahua-
`sca as a sacrament, a psychoactive plant decoction contain-
`ing the hallucinogen N,N-dimethyltryptamine (DMT)
`combined with h-carboline monoamine oxidase inhibitors
`that confer it with oral activity (McKenna & Towers, 1984;
`McKenna et al., 1984; Callaway et al., 1996; Grob et al.,
`1996; Riba et al., 2002, 2003; Yritia et al., 2002). Ayahua-
`sca, also known as yage´ or hoasca, has a long history of
`ceremonial use by natives in the Amazon valley of South
`America (Dobkin, 1971; Schultes & Hofmann, 1979).
`What exactly are these substances feared by modern man
`yet held sacred and even worshipped by ancient cultures?
`Jaffe (1990) provided a definition that is most consistent
`with their ritual use in other cultures. Arguing that the name
`psychedelic is better than either hallucinogen or psychoto-
`mimetic, he stated ‘‘. . .the feature that distinguishes the
`psychedelic agents from other classes of drugs is their
`capacity reliably to induce states of altered perception,
`thought, and feeling that are not experienced otherwise
`except in dreams or at times of religious exaltation.’’ The
`late Daniel X. Freedman, one of the great pioneers of LSD
`research, made comments consistent with that assessment,
`stating, ‘‘. . .one basic dimension of behavior. . .compel-
`compellingly revealed in LSD states is ‘‘portentous-
`ness’’—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.’’ (Freedman, 1968). It might be
`noted in this context that one doctoral dissertation has even
`provided evidence that psilocybin-induced mystical-reli-
`gious experiences could not be distinguished, by objective
`criteria, from spontaneously occurring ones (Pahnke, 1963).
`Although these descriptions focus on the more spectac-
`ular effects that these substances are capable of producing,
`low doses generally elicit
`less dramatic results. Typical
`
`

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`134
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`D.E. Nichols / Pharmacology & Therapeutics 101 (2004) 131–181
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`clinical effects of hallucinogens would include the following
`(Hollister, 1984):
`
`1. Somatic symptoms: dizziness, weakness, tremors, nausea,
`drowsiness, paresthesias, and blurred vision.
`2. Perceptual symptoms: altered shapes and colors, diffi-
`culty in focusing on objects, sharpened sense of hearing,
`and rarely synesthesias.
`3. Psychic symptoms: alterations in mood (happy, sad, or
`irritable at varying times), tension, distorted time sense,
`difficulty in expressing thoughts, depersonalization,
`dreamlike feelings, and visual hallucinations.
`
`It should be apparent from the foregoing discussion that
`hallucinogens have a unique and powerful ability to affect
`the human psyche. They may alter one’s concepts of reality,
`may change one’s views on life and death, and can provoke
`and challenge one’s most cherished beliefs. Therein, this
`writer believes,
`lay the roots of much of the fear and
`hysteria that these substances have fostered in our society.
`Numerous books and treatises have been written on all
`aspects of the subject of hallucinogens, and previous
`scientific reviews on the subject can be consulted to
`supplement the present discussion (Cohen, 1967; Freed-
`man, 1969; Nieforth, 1971; Brawley & Duffield, 1972;
`Brimblecombe, 1973; Brimblecombe & Pinder, 1975; Siva
`Sankar, 1975; Boarder, 1977; Hollister, 1978, 1984; Shul-
`gin, 1978, 1981; Nichols, 1981, 1986, 1997; Jacobs, 1984;
`Nichols et al., 1991a; Strassman, 1995; Abraham et al.,
`1996; Marek & Aghajanian, 1998b; Aghajanian & Marek,
`1999a).
`
`1.2. Toxicity and addiction
`
`Hallucinogens are generally considered to be physiolog-
`ically safe molecules whose principal effects are on con-
`sciousness. That is, hallucinogens are powerful in producing
`altered states of consciousness (ASC), but they do so at
`doses that are not toxic to mammalian organ systems. There
`is no evidence that any of the hallucinogens, even the very
`powerful semisynthetic LSD, causes damage to any human
`body organ. Cohen (1967) has stated, ‘‘Death directly
`caused by the toxicity of LSD is unknown.’’ This statement
`was reiterated 20 years later by Jaffe (1985), ‘‘In man,
`deaths attributable to direct effects of LSD are unknown.’’
`This observation still remains true today. Hallucinogens do
`not cause life-threatening changes in cardiovascular, renal,
`or hepatic function because they have little or no affinity for
`the biological receptors and targets that mediate vital veg-
`etative functions.
`In contrast to many other abused drugs, hallucinogens
`do not engender drug dependence or addiction and are
`not considered to be reinforcing substances (O’Brien,
`2001). It is generally believed that most if not all drugs
`that possess dependence liability have the ability to affect
`dopaminergic (DA) transmission, particularly in mesolim-
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`bic areas of the brain. The behavioral correlate of this
`effect is increased mood and often euphoria. By contrast,
`nearly all hallucinogens lack affinity either
`for DA
`receptors or for the DA uptake transporter and therefore
`do not directly affect DA neurotransmission. In an article
`reviewing drugs of abuse that activate brain reward
`pathways, drugs identified with this action included
`opiates, nicotine, cannabis, phencyclidine (PCP), cocaine,
`amphetamine, alcohol, benzodiazepines, barbiturates, and
`even caffeine, but there was no mention of hallucinogens
`(Wise, 1998).
`There are no literature reports of successful attempts to
`train animals to self-administer classical hallucinogens, an
`animal model predictive of abuse liability, indicating that
`these substances do not possess the necessary pharmacol-
`ogy to either initiate or maintain dependence. Hoffmeister
`(1975) has reported that LSD actually had negative
`reinforcing properties in rhesus monkeys trained in an
`avoidance task. LSD may have weak reinforcing effects
`in rats, however, because Parker (1996) reported that a
`relatively high dose of LSD (0.2 mg/kg i.p.) produced
`conditioned place preference (CPP) in rats, another animal
`model that is often predictive of the reinforcing quality of
`a drug. It
`is important
`to point out
`that
`this dose is
`sufficient
`to enable LSD to activate postsynaptic DA
`receptors, a pharmacological property that
`is unique to
`this hallucinogen. Using the same 0.2 mg/kg dose of
`LSD, Meehan and Schechter (1998) also reported that
`LSD produced CPP in male but not
`in female Fawn
`Hooded rats. The Fawn Hooded strain of rats, however, is
`differentially sensitive to serotonergic agents, and fenflur-
`amine also produces CPP in these rats (Meehan &
`Schechter, 1994), whereas it produces aversion in Spra-
`gue-Dawley rats (Meehan & Schechter, 1994; Marona-
`Lewicka et al., 1996). Among all of the known halluci-
`nogens, only LSD has high affinity for DA receptors (see,
`e.g., Watts et al., 1995; Giacomelli et al., 1998). Further-
`more, although the acute behavioral effects of LSD are
`generally attributed to activation of 5-HT2A receptors,
`behavioral effects in rats occurring more than 1 hr after
`LSD administration recently have been reported to be
`primarily mediated by DA pathways (Marona-Lewicka &
`Nichols, 2002).
`Strassman (1984) and Halpern and Pope (1999) have
`analyzed the published reports on adverse reactions and
`negative long-term sequelae following hallucinogen use.
`Halpern and Pope reached a conclusion similar to Strass-
`man’s earlier analysis that concerning repeated use of
`psychedelic drugs the results were controversial, but
`if
`any long-term adverse effect did occur it was ‘‘subtle or
`nonsignificant.’’ It should be noted, however, that in both
`studies their conclusions were specifically developed
`based on reviews of supervised clinical research with
`hallucinogens.
`One adverse consequence of hallucinogen use is
`known as ‘‘flashbacks.’’ Flashbacks were widely dis-
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`135
`
`cussed in the press, particularly in earlier decades, as one
`of the most common adverse effects of hallucinogens;
`their occurrence was emphasized as a deterrent to recre-
`ational use. A flashback essentially consists of the reex-
`periencing of one or more of the perceptual effects that
`were induced by hallucinogens but occurring after the
`effect of the drug has worn off or at some later time in
`the complete absence of the drug. Flashbacks most often
`appear as visual symptoms and can persist for months or
`in some cases years, and there appears to be no relation-
`ship between frequency of hallucinogen use and rate of
`occurrence. Recently, Halpern and Pope (2003) have
`reviewed the evidence on hallucinogen persisting percep-
`tion disorder
`(HPPD),
`the Diagnostic and Statistical
`Manual of Mental Disorders, Fourth Edition category
`for flashbacks. First,
`they note that
`the term flashback
`itself has been defined in so many different ways that
`they believe it
`is now virtually useless. Second,
`they
`point out that when LSD was used in a therapeutic or
`research setting, HPPD appeared less frequently than
`when it was used recreationally. Finally, because of the
`different ways that flashbacks were defined, it is impos-
`sible to discern the true incidence of the disorder. They
`do conclude that at
`least for some individuals, particu-
`larly users of LSD, a long-lasting HPPD syndrome can
`occur with symptoms of ‘‘persistent perceptual abnormal-
`ities reminiscent of acute intoxication.’’ Based on the
`millions of people who have taken hallucinogens,
`the
`incidence of HPPD appears to be very small, and there is
`presently no effective treatment.
`There are, however, real and significant dangers that can
`accompany recreational use of these substances. Although
`LSD or other classical hallucinogens have not directly
`caused overdose death, fatal accidents during LSD intoxi-
`cation have occurred (Jaffe, 1985). This danger is signifi-
`cant, particularly when these drugs are used recreationally in
`unsupervised settings. Belief that one has superhuman
`powers while judgment is impaired by hallucinogens can
`lead to injury or death when an unsupervised user carries out
`dangerous activities such as walking out on a freeway or
`attempting to fly (see, e.g., Reynolds & Jindrich, 1985).
`Less serious but still very substantial injuries can occur in
`unusual ways. For example, severe and irreversible ocular
`damage has resulted from prolonged staring at the sun by
`individuals under the influence of LSD (Schatz & Mendel-
`blatt, 1973; Fuller, 1976).
`The most significant dangers of psychedelics, however,
`appear to lie principally in their psychological effects. LSD
`can induce disturbances of experience, otherwise observed
`only in psychoses, such as alteration of cognitive functions,
`and depersonalization. Hallucinogens can catalyze the onset
`of psychosis or depression, which has sometimes led to
`suicide, and Cohen (1960) has estimated the incidence of
`LSD-related psychosis to be about 8 per 10,000 subjects. In
`another study, one case of psychosis was reported in a survey
`of 247 LSD users (McGlothlin & Arnold, 1971). Fortunately,
`
`however, these drugs do not appear to produce illness de
`novo in otherwise emotionally healthy persons, but these
`problems seem to be precipitated in predisposed individuals.
`In atypical courses of intoxication, so-called bad trips,
`anxiety and excitement predominate. Bad trips can usually
`be treated successfully by ‘‘talk-down’’ therapy and admin-
`istration of benzodiazepines. In an early report, Taschner
`and Wanke (1975) saw in their clinic several LSD users with
`psychoses. At the time, they classified them into ‘‘flash-
`backs, exogenic (toxic) psychoses, and so-called endoform
`psychoses.’’ They considered three possible explanations
`for the latter category: accidental coincidence of LSD use
`and onset of psychosis, preexisting psychosis with symp-
`tomatic use of LSD as an attempt at self-treatment, or finally
`the onset of psychosis triggered by the use of the halluci-
`nogen. Based on the presenting symptoms, these patients
`could not be reliably distinguished from real schizophrenics.
`A somewhat
`later study by Vardy and Kay (1983)
`compared patients hospitalized for LSD psychosis with
`first-break schizophrenics. In most respects, the LSD psy-
`chotics were fundamentally similar to schizophrenics in
`genealogy, phenomenology, and course of illness. Their
`findings support a model of LSD psychosis as a drug-
`induced schizophreniform reaction in persons vulnerable
`to both substance abuse and psychosis.
`Although these studies demonstrate a significant danger
`of LSD use, the number of such reports is very small relative
`to the numbers of persons who are believed to have self-
`administered LSD in recreational settings. A search of Med-
`line in early 2003 for case reports of LSD-induced psychosis
`found only three reports in the previous 20 years. Although
`nearly all of the reports that do exist focus attention specif-
`ically on the dangers of LSD, all of the hallucinogens can
`cause similar psychological reactions, and one might antic-
`ipate comparable results if the numbers of users of other
`hallucinogens had been correspondingly large.
`
`2. The chemical classes of hallucinogens
`
`The chemical structures of hallucinogens can be classi-
`fied into two broad categories: (1) the tryptamines and (2)
`the phenethylamines. Within the tryptamines, however, one
`should probably include two subsets,
`the simple trypt-
`amines such as DMT, 5-methoxy-DMT (5-MeO-DMT),
`and psilocybin, which possess considerable conformational
`flexibility, and the ergolines, relatively rigid analogues
`including LSD and a few very closely related compounds.
`It also should be pointed out that psilocybin is actually a
`prodrug for psilocin. That is, after ingestion of psilocybin,
`alkaline phosphatases in the digestive system, kidney, and
`perhaps in the blood readily cleave the O-phosphoryl ester
`to generate the hydroxy compound psilocin, which is the
`species that actually is biologically active (Horita & Weber,
`1961; Horita, 1963; Hasler et al., 1997). Whenever a
`reference is made to the in vivo effects of psilocybin
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`
`(e.g., in the clinical studies discussed in later sections), it
`should be understood that the actual hallucinogenic species
`is psilocin.
`
`The doses, duration of action, and routes of administra-
`tion vary for the different classes of hallucinogens. The
`simple tryptamines DMT and 5-MeO-DMT are not active
`
`The prototype of the phenethylamines is the naturally
`occurring compound mescaline, the principal active compo-
`nent in the peyote cactus Lophophora williamsii. Extensive
`structure-activity relationship studies carried out over several
`decades principally in the laboratories of Nichols (1981,
`1994, 1997), Glennon et al. (1986), Glennon (1989, 1999),
`Nichols et al. (1991a), and Shulgin and Shulgin (1991b)
`have led to a good general understanding of the structural
`and stereochemical features that lead to hallucinogenic
`activity in substituted phenethylamine derivatives. In this
`process, extremely potent compounds have also been dis-
`covered, and many of the resulting molecules have proven to
`be useful tools for studies of the mechanism of action.
`For many years, medicinal chemists envisioned ‘‘ergo-
`line-like’’ binding orientations for the phenethylamines
`that might suggest some structural congruence between
`the two types of classes on receptor binding (Marini-
`Bettolo et al., 1951; Barfknecht & Nichols, 1972; Glennon
`et al., 1983b). Recently, however, it seems unlikely that
`such a structural congruence exists and that various
`ligands may bind to and activate the receptor in a variety
`of different orientations (Monte et al., 1998; Chambers
`et al., 2003).
`
`orally but are typically smoked or nasally insufflated. These
`were often the psychoactive components of native South
`American plant preparations that were used as snuffs. The
`dose of DMT is typically 60 – 100 mg of the free base and 6 –
`20 mg for 5-MeO-DMT (Ott, 2001; Beyerstein et al., 2003).
`When smoked or injected, the onset of action for DMT is
`typically 10 – 15 sec. The duration of action for these simple
`tryptamines is very short, with the effects typically dissipated
`in less than 1 hr for DMT and 20 – 30 min for 5-MeO-DMT.
`Psilocybin is orally active, with effective doses in the
`range of 6 – 20 mg. The onset of action is typically 20 – 30
`min, with the effects completely gone within about 4 – 6 hr
`(Shulgin, 1980). The most detailed clinical studies of psilo-
`cybin have been reported by Vollenweider et al. (1998). Drug
`effects began 20 – 30 min after an oral dose of 0.25 mg/kg,
`peaked after another 30 – 50 min, and lasted another 1 – 2 hr.
`The greatest psychological effects occurred at about 80 min
`after drug administration and coincided with the peak plasma
`concentration of psilocin (Hasler et al., 1997).
`Our modern awareness of hallucinogens began on Friday,
`April 16, 1943, when Albert Hofmann, a natural products
`chemist with Sandoz Pharmaceuticals in Basel, Switzerland,
`experienced unusual mental effects following work with
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`137
`
`LSD-25, the diethylamide of lysergic acid (Hofmann, 1979,
`1994). His suspicion that the effects he had experienced on
`the previous Friday were due to accidental exposure to a tiny
`unknown amount of LSD were confirmed three days later on
`April 19 by his deliberate oral ingestion of a solution
`containing 0.25 mg of LSD tartrate, a relatively large dose
`of this substance. On that occasion, the effects were very
`profound and left no doubt that the unusual intoxication of
`the previous Friday had been due to ingestion of LSD. No
`drug had been discovered up to that time that possessed such
`high potency, so the research management at Sandoz was
`initially skeptical of Dr. Hofmann’s report. Nevertheless,
`several other scientists at the company ingested this new
`substance (albeit in smaller doses) and confirmed its remark-
`able psychopharmacology. LSD (tartrate) is p.o. active and is
`the most potent of all the h