Associate editor: B.L. Roth
Hallucinogens

https://doi.org/10.1016/j.pharmthera.2003.11.002Get rights and content

Abstract

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.

Introduction

What are hallucinogens? This term was originally coined because of the notion that these substances produce hallucinations, 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 pharmacological substances ranging from cannabinoids and N-methyl-d-aspartate (NMDA) antagonists to anticholinergic agents, ecstasy (MDMA; 3,4-methylenedioxymethamphetamine), 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 hallucinations, 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, however, appearing to have major components of action that involve interaction with monoamine uptake transporters, and does not properly fit within the hallucinogen classification Nichols & Oberlender, 1990, Nichols, 1994, Bankson & Cunningham, 2001, O'Leary et al., 2001. Thus, one needs to be very specific about definitions when “hallucinogens” 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 diethylamide (LSD-25). More specifically, now that there is appreciation 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 designation 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 pharmacological 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. 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 Controlled 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.

Naturally occurring hallucinogenic drugs played a significant 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 theologies. 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 hallucinogen 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 convicted of murder to participate in the secret all-night ceremony each September that involved the drinking of a special potion known as κψκεον. Today, we know very little about this ceremony, but reasonable arguments have been made that κψκεον 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 ayahuasca as a sacrament, a psychoactive plant decoction containing the hallucinogen N,N-dimethyltryptamine (DMT) combined with β-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, Riba et al., 2003, Yritia et al., 2002. Ayahuasca, also known as yagé 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 psychotomimetic, 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…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.” (Freedman, 1968). It might be noted in this context that one doctoral dissertation has even provided evidence that psilocybin-induced mystical-religious experiences could not be distinguished, by objective criteria, from spontaneously occurring ones (Pahnke, 1963).

Although these descriptions focus on the more spectacular effects that these substances are capable of producing, low doses generally elicit less dramatic results. Typical 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, difficulty 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, Freedman, 1969, Nieforth, 1971, Brawley & Duffield, 1972, Brimblecombe, 1973, Brimblecombe & Pinder, 1975, Siva Sankar, 1975, Boarder, 1977, Hollister, 1978, Hollister, 1984, Shulgin, 1978, Shulgin, 1981, Nichols, 1981, Nichols, 1986, Nichols, 1997, Jacobs, 1984, Nichols et al., 1991a, Strassman, 1995, Abraham et al., 1996, Marek & Aghajanian, 1998b, Aghajanian & Marek, 1999a.

Hallucinogens are generally considered to be physiologically safe molecules whose principal effects are on consciousness. 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 vegetative 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 mesolimbic 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 pharmacology 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 fenfluramine also produces CPP in these rats (Meehan & Schechter, 1994), whereas it produces aversion in Sprague-Dawley rats Meehan & Schechter, 1994, Marona-Lewicka et al., 1996. Among all of the known hallucinogens, only LSD has high affinity for DA receptors (see, e.g., Watts et al., 1995, Giacomelli et al., 1998). Furthermore, 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 Strassman'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 discussed 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 recreational use. A flashback essentially consists of the reexperiencing 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 relationship between frequency of hallucinogen use and rate of occurrence. Recently, Halpern and Pope (2003) have reviewed the evidence on hallucinogen persisting perception 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 impossible to discern the true incidence of the disorder. They do conclude that at least for some individuals, particularly users of LSD, a long-lasting HPPD syndrome can occur with symptoms of “persistent perceptual abnormalities 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 intoxication have occurred (Jaffe, 1985). This danger is significant, 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 & Mendelblatt, 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 administration 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 “flashbacks, 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 symptomatic use of LSD as an attempt at self-treatment, or finally the onset of psychosis triggered by the use of the hallucinogen. 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 psychotics 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 Medline 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 specifically on the dangers of LSD, all of the hallucinogens can cause similar psychological reactions, and one might anticipate comparable results if the numbers of users of other hallucinogens had been correspondingly large.

Section snippets

The chemical classes of hallucinogens

The chemical structures of hallucinogens can be classified into two broad categories: (1) the tryptamines and (2) the phenethylamines. Within the tryptamines, however, one should probably include two subsets, the simple tryptamines 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

Psychopharmacological effects of hallucinogens

In contrast to virtually every other class of CNS drug, where the action is usually predictable, the effects of hallucinogens are heavily dependent on the expectations of the user (“set”) and the environment (“setting”) in which the use takes place. Indeed, no clinician experienced with these substances would fail to consider set and setting as primary determinants of the experience. Thus, expectations and environments that would foster religious or spiritual experiences increase the

How do hallucinogens work?

The mechanism of action of hallucinogens has been sought ever since their modern rediscovery initially because it was felt that understanding how they affect the brain would lead to insights into the nature of schizophrenia. Later, it became of interest to understand the neuronal targets that were involved because those brain substrates clearly had to be involved in processing sensory information and making executive decisions. More recently, the focus has again shifted to understanding certain

Clinical relevance of serotonin2A receptors

There were numerous clinical studies of hallucinogens in the 1950s and 1960s, mostly with LSD, with literally thousands of subjects, but those efforts ceased by about 1970, with the last reports of U.S. work published in 1973 (Grob et al., 1998). In general, hallucinogens are now viewed as a closed chapter in psychiatry research. The early clinical studies were generally focused on studying the effects of LSD either as a “psychotomimetic” (i.e., producing a model psychosis) or as an adjunct to

Conclusions

The tools of today's neuroscience, including in vivo brain imaging technologies, have put a modern face on the hallucinogens. Scientists can no longer see them as “magic” drugs but rather as 5-HT2A receptor-specific molecules that affect membrane potentials, neuronal firing frequencies, and neurotransmitter release in particular areas of the brain. One can now begin to speculate in reasonable ways about how these cellular changes transform our perceptions of reality and produce ASC. It is

Acknowledgements

The author gratefully acknowledges more than two decades of continuous support for studies of hallucinogens provided by grant DA02189 from the National Institute on Drug Abuse. The author also thanks Dr. George Aghajanian for helpful discussions concerning electrophysiology studies. Finally, I offer apologies to many outstanding scientists whose complete work I was not able to incorporate into this review; there is such a vast literature on this topic, beginning in the early 1950s, that it

References (520)

  • N. Almaula et al.

    Mapping the binding site pocket of the serotonin 5-hydroxytryptamine2A receptor. Ser3.36(159) provides a second interaction site for the protonated amine of serotonin but not of lysergic acid diethylamide or bufotenin

    J Biol Chem

    (1996)
  • N.E. Anden et al.

    Hallucinogenic phenylethylamines: interactions with serotonin turnover and receptors

    Eur J Pharmacol

    (1974)
  • L. Antkiewicz-Michaluk et al.

    Ca2+ channel blockade prevents lysergic acid diethylamide-induced changes in dopamine and serotonin metabolism

    Eur J Pharmacol

    (1997)
  • R. Araneda et al.

    5-hydroxytryptamine 2 and 5-hydroxytryptamine 1A receptors mediate opposing responses on membrane excitability in rat association cortex

    Neuroscience

    (1991)
  • J. Arnt et al.

    Facilitation of 8-OHDPAT-induced forepaw treading of rats by the 5-HT2 agonist DOI

    Eur J Pharmacol

    (1989)
  • S.A. Barker et al.

    N,N-dimethyltryptamine: an endogenous hallucinogen

    Int Rev Neurobiol

    (1981)
  • R.P. Behrendt

    Hallucinations: synchronisation of thalamocortical gamma oscillations underconstrained by sensory input

    Conscious Cogn

    (2003)
  • M.E. Blue et al.

    Correspondence between 5-HT2 receptors and serotonergic axons in rat neocortex

    Brain Res

    (1988)
  • R.G. Browne et al.

    Role of serotonin in the discriminative stimulus properties of mescaline

    Pharmacol Biochem Behav

    (1975)
  • N.S. Buckholtz et al.

    Daily LSD administration selectively decreases serotonin2 receptor binding in rat brain

    Eur J Pharmacol

    (1985)
  • N.S. Buckholtz et al.

    Serotonin2 agonist administration down-regulates rat brain serotonin2 receptors

    Life Sci

    (1988)
  • P.W. Burnet et al.

    The distribution of 5-HT1A and 5-HT2A receptor mRNA in human brain

    Brain Res

    (1995)
  • P.W. Burnet et al.

    The effects of clozapine and haloperidol on serotonin-1A, -2A and -2C receptor gene expression and serotonin metabolism in the rat forebrain

    Neuroscience

    (1996)
  • D. Carter et al.

    Characterization of a postjunctional 5-HT receptor mediating relaxation of guinea-pig isolated ileum

    Eur J Pharmacol

    (1995)
  • J.M. Cedarbaum et al.

    Activation of locus coeruleus neurons by peripheral stimuli: modulation by a collateral inhibitory mechanism

    Life Sci

    (1978)
  • C. Chiang et al.

    A 5-hydroxytryptamine2 agonist augments gamma-aminobutyric acid and excitatory amino acid inputs to noradrenergic locus coeruleus neurons

    Neuroscience

    (1993)
  • H.D. Chilcoat et al.

    Age-specific patterns of hallucinogen use in the US population: an analysis using generalized additive models

    Drug Alcohol Depend

    (1996)
  • K.O. Cho et al.

    The rat brain postsynaptic density fraction contains a homolog of the Drosophila discs-large tumor suppressor protein

    Neuron

    (1992)
  • J.M. Chou-Green et al.

    Compulsive behavior in the 5-HT2C receptor knockout mouse

    Physiol Behav

    (2003)
  • F.C. Colpaert et al.

    A characterization of LSD-antagonist effects of pirenperone in the rat

    Neuropharmacology

    (1983)
  • P.J. Conn et al.

    Selective 5HT-2 antagonists inhibit serotonin stimulated phosphatidylinositol metabolism in cerebral cortex

    Neuropharmacology

    (1984)
  • I. Creese et al.

    The dopamine receptor: differential binding of d-LSD and related agents to agonist and antagonist states

    Life Sci

    (1975)
  • M. Cyr et al.

    Modulation by estrogen-receptor directed drugs of 5-hydroxytryptamine-2A receptors in rat brain

    Neuropsychopharmacology

    (2000)
  • C. Acuna-Castillo et al.

    Differences in potency and efficacy of a series of phenylisopropylamine/phenylethylamine pairs at 5-HT(2A) and 5-HT(2C) receptors

    Br J Pharmacol

    (2002)
  • G.K. Aghajanian et al.

    Persistence of lysergic acid diethylamide in the plasma of human subjects

    Clin Pharmacol Ther

    (1964)
  • G.K. Aghajanian et al.

    Hallucinogenic indoleamines: preferential action upon presynaptic serotonin receptors

    Psychopharmacol Commun

    (1975)
  • G.K. Aghajanian et al.

    Serotonin 5-HT2A receptors enhance asynchronous excitatory transmission in pyramidal cells (layer V) of prefrontal cortex

    Soc Neurosci Abstr

    (1998)
  • G.K. Aghajanian et al.

    Lysergic acid diethylamide: sensitive neuronal units in the midbrain raphe

    Science

    (1968)
  • G.K. Aghajanian et al.

    Action of psychotogenic drugs on single midbrain raphe neurons

    J Pharmacol Exp Ther

    (1970)
  • D. Akin et al.

    Agonist-directed trafficking explaining the difference between response pattern of naratriptan and sumatriptan in rabbit common carotid artery

    Br J Pharmacol

    (2002)
  • N. Almaula et al.

    Contribution of a helix 5 locus to selectivity of hallucinogenic and nonhallucinogenic ligands for the human 5-hydroxytryptamine2A and 5-hydroxytryptamine2C receptors: direct and indirect effects on ligand affinity mediated by the same locus

    Mol Pharmacol

    (1996)
  • N.E. Anden et al.

    Evidence for a central 5-hydroxytryptamine receptor stimulation by lysergic acid diethylamide

    Br J Pharmacol

    (1968)
  • N.E. Anden et al.

    Hallucinogenic drugs of the indolealkylamine type and central monoamine neurons

    J Pharmacol Exp Ther

    (1971)
  • G.M. Anderson et al.

    Absolute configuration and psychotomimetic activity

    NIDA Res Monogr

    (1978)
  • B. Angrist et al.

    Assessment of tolerance to the hallucinogenic effects of DOM

    Psychopharmacologia

    (1974)
  • C. Aoki et al.

    Electron microscopic immunocytochemical detection of PSD-95, PSD-93, SAP-102, and SAP-97 at postsynaptic, presynaptic, and nonsynaptic sites of adult and neonatal rat visual cortex

    Synapse

    (2001)
  • J.B. Appel et al.

    Tolerance and cross-tolerance among psychotomimetic drugs

    Psychopharmacologia

    (1968)
  • V.L. Arvanov et al.

    A pre- and postsynaptic modulatory action of 5-HT and the 5-HT2A,2C receptor agonist DOB on NMDA-evoked responses in the rat medial prefrontal cortex

    Eur J Neurosci

    (1999)
  • V.L. Arvanov et al.

    LSD and DOB: interaction with 5-HT2A receptors to inhibit NMDA receptor-mediated transmission in the rat prefrontal cortex

    Eur J Neurosci

    (1999)
  • C. Asanuma

    Noradrenergic innervation of the thalamic reticular nucleus: a light and electron microscopic immunohistochemical study in rats

    J Comp Neurol

    (1992)
  • Cited by (0)

    View full text