biochemical pharmacology 75 (2008) 17–33 available at www.sciencedirect.com journal homepage: www.elsevier.com/locate/biochempharm Review The behavioral pharmacology of hallucinogens William E. Fantegrossi a,*, Kevin S. Murnane a, Chad J. Reissig b a Division of Neuroscience, Yerkes National Primate Research Center, Emory University, 954 Gatewood Road NE, Atlanta, GA 30322, USA b Department of Psychiatry and Behavioral Sciences, Behavioral Biology Research Center, Johns Hopkins University School of Medicine, Baltimore, MD 21224, USA article info abstract Article history: Until very recently, comparatively few scientists were studying hallucinogenic drugs. Received 15 May 2007 Nevertheless, selective antagonists are available for relevant serotonergic receptors, the Accepted 13 July 2007 majority of which have now been cloned, allowing for reasonably thorough pharmacological investigation. Animal models sensitive to the behavioral effects of the hallucinogens have been established and exploited. Sophisticated genetic techniques have enabled the devel- Keywords: opment of mutant mice, which have proven useful in the study of hallucinogens. The Hallucinogens capacity to study post-receptor signaling events has lead to the proposal of a plausible Serotonin receptors mechanism of action for these compounds. The tools currently available to study the Drug discrimination hallucinogens are thus more plentiful and scientifically advanced than were those acces- Head twitch behavior sible to earlier researchers studying the opioids, benzodiazepines, cholinergics, or other Phenethylamines centrally active compounds. The behavioral pharmacology of phenethylamine, tryptamine, Tryptamines and ergoline hallucinogens are described in this review, paying particular attention to important structure activity relationships which have emerged, receptors involved in their various actions, effects on conditioned and unconditioned behaviors, and in some cases, human psychopharmacology. As clinical interest in the therapeutic potential of these compounds is once again beginning to emerge, it is important to recognize the wealth of data derived from controlled preclinical studies on these compounds. # 2007 Elsevier Inc. All rights reserved. Contents 1. Introduction. .............................................................................. 18 2. Animal models of hallucinogen-like action . ..................................................... 19 2.1. Drug discrimination. ....................................................................... 19 2.2. Drug-elicited head twitch behavior............................................................ 19 2.3. Self-administration . ....................................................................... 20 3. Serotonin receptors and hallucinogen neuropharmacology .............................................. 22 4. Glutamatergic and dopaminergic involvement in hallucinogen neuropharmacology . ..................... 22 5. Chemical classes of hallucinogens . ................................................................ 23 5.1. Phenethylamines . ....................................................................... 23 * Corresponding author. Tel.: + 1 404 727 8512; fax: +1 404 727 1266. E-mail address: [email protected] (W.E. Fantegrossi). 0006-2952/$ – see front matter # 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.bcp.2007.07.018 18 biochemical pharmacology 75 (2008) 17–33 5.2. Tryptamines ............................................................................. 24 5.3. LSD. .................................................................................... 27 6. Summary and conclusions . .................................................................. 28 Acknowledgements ............................................................................. 28 References .................................................................................... 28 1. Introduction compounds with pharmacological effects similar to three prototypical drugs: 3,4,5-trimethoxy-phenethylamine (mesca- Although drugs producing sensory distortions have been used line, Fig. 1A), N,N-dimethyl-4-phosphoryloxytryptamine (psi- by man for several millennia, many consider the modern era locybin, Fig. 1B) and LSD (Fig. 1C). All of these drugs function as of psychedelics to have begun when the psychotropic effects agonists at 5-HT2A receptors, and much work has culminated of lysergic acid diethylamide (LSD, Fig. 1C) were discovered by in the widespread acceptance that this particular receptor Albert Hofmann in 1943 [1]. This discovery ushered in an era of initiates the molecular mechanisms responsible for the intense LSD research, with nearly 1000 articles appearing in unique effects of these compounds. Much of that work will the medical literature by 1961 [2]. Most of this early research be reviewed herein. was based upon the drug’s capacity to produce a ‘‘model The aim of this review is to mark the sea change which psychosis’’ [3] although there are significant differences seems to be occurring within the field of hallucinogen between LSD-induced and endogenously occurring psychotic research. Until very recently, comparatively few scientists behaviors [4]. By the mid-1960s, LSD and other related drugs were studying these particular compounds, perhaps due to had become associated with various counterculture move- their unfortunate association with somewhat less than ments, depicted as dangerous, and widely popularized as rigorous research techniques. In Nichols’ recent review [14], drugs of abuse. Accordingly, scientific interest in these drugs for example, prominent clinicians are quoted as stating that faded by the late 1960s, but human research with related the effects of hallucinogens transcend pharmacology, are psychedelics has recently experienced a slight renaissance [5– unpredictable, and border on the mystical. Nevertheless, the 13]. state of hallucinogen research is now approaching something The term ‘‘hallucinogen’’ has come to describe LSD and of a high water mark. Selective antagonists are available for related compounds based on the supposition that these drugs relevant serotonergic receptors, the majority of which have elicit hallucinations, but it has been argued that, at the doses now been cloned, allowing for reasonably thorough pharma- commonly taken recreationally, frank hallucinations are cological investigation. Animal models sensitive to hallucino- produced only rarely [14]. Nevertheless, other designations gen-like effects have been established and exploited to yield a for this class of drugs (for example, psychedelics, psychotomi- wealth of largely concordant data. Along similar lines, metics, entheogens, etc.) have not necessarily caught on, and so sophisticated genetic techniques have enabled the develop- we will use the term hallucinogen to refer to these com- ment of mutant mice, which have proven useful in the study of pounds, despite the controversy surrounding the appropriate- hallucinogens. Finally, the capacity to study post-receptor ness of this appellation. As a drug category, hallucinogens are signaling events has lead to the proposal of a plausible typically accepted to encompass an enormous range of mechanism of action for these compounds. The tools pharmacological substances, with mechanisms of action currently available to study the hallucinogens are thus more ranging from cannabinoid agonism (i.e., D9-tetrahydrocanna- plentiful and scientifically advanced than were those acces- binol), N-methyl-D-aspartate (NMDA) antagonism (i.e., phen- sible to earlier researchers studying the opioids, benzodiaze- cyclidine), muscarinic receptor antagonism (i.e., scopo- pines, cholinergics, or other centrally active compounds. lamine), k opioid agonism (i.e., salvinorin A), mixed action Those interested in hallucinogen research should thus be monoamine release (i.e., 3,4-methylenedioxymethampheta- encouraged by all of these recent developments, and it is mine [MDMA]), and more. Thus, within the confines of this hoped that the perceived ‘‘scientific respectability’’ of the field review, we will use the term hallucinogen to denote will continue to increase. Fig. 1 – Chemical structures of the prototypical phenethylamine hallucinongen 3,4,5-trimethoxy-phenethylamine (mescaline, A), the representative tryptamine hallucinogen N,N-dimethyl-4-phosphoryloxytryptamine (psilocybin, B), and the archetypal ergoline hallucinogen lysergic acid diethylamide (LSD, C). biochemical pharmacology 75 (2008) 17–33 19 2. Animal models of hallucinogen-like action when injected with a novel drug that has actions in common with the training drug, in which case the test compound is said 2.1. Drug discrimination to ‘‘substitute’’ for the training drug. Importantly, novel compounds that are active, but pharmacologically dissimilar Given the profound effects of hallucinogens on perception and to the training drug, typically occasion responding on the lever other subjective variables, an animal model capable of reinforced following administration of the drug vehicle during assessing mechanisms of action of these drugs that informs training sessions. The discriminative stimulus effects of their subjective effects in man would be especially useful. The various hallucinogens will be described below. main methodology presently employed in this regard is drug discrimination. In a typical discrimination task, an animal is 2.2. Drug-elicited head twitch behavior trained to emit one response during experimental sessions initiated by the