The behavioral pharmacology of hallucinogens

Abstract

Until very recently, comparatively few scientists were studying hallucinogenic drugs. Nevertheless, selective antagonists are available for relevant serotonergic receptors, the 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 development of mutant mice, which have proven useful in the study of hallucinogens. The capacity to study post-receptor signaling events has lead to the proposal of a plausible mechanism of action for these compounds. The tools currently available to study the hallucinogens are thus more plentiful and scientifically advanced than were those accessible to earlier researchers studying the opioids, benzodiazepines, cholinergics, or other centrally active compounds. The behavioral pharmacology of phenethylamine, tryptamine, 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.

Introduction

Although drugs producing sensory distortions have been used by man for several millennia, many consider the modern era of psychedelics to have begun when the psychotropic effects of lysergic acid diethylamide (LSD, Fig. 1C) were discovered by Albert Hofmann in 1943 [1]. This discovery ushered in an era of intense LSD research, with nearly 1000 articles appearing in the medical literature by 1961 [2]. Most of this early research was based upon the drug's capacity to produce a “model psychosis”[3] although there are significant differences between LSD-induced and endogenously occurring psychotic behaviors [4]. By the mid-1960s, LSD and other related drugs had become associated with various counterculture movements, depicted as dangerous, and widely popularized as drugs of abuse. Accordingly, scientific interest in these drugs faded by the late 1960s, but human research with related psychedelics has recently experienced a slight renaissance [5], [6], [7], [8], [9], [10], [11], [12], [13].

The term “hallucinogen” has come to describe LSD and related compounds based on the supposition that these drugs elicit hallucinations, but it has been argued that, at the doses commonly taken recreationally, frank hallucinations are produced only rarely [14]. Nevertheless, other designations for this class of drugs (for example, psychedelics, psychotomimetics, entheogens, etc.) have not necessarily caught on, and so we will use the term hallucinogen to refer to these compounds, despite the controversy surrounding the appropriateness of this appellation. As a drug category, hallucinogens are typically accepted to encompass an enormous range of pharmacological substances, with mechanisms of action ranging from cannabinoid agonism (i.e., Δ9-tetrahydrocannabinol), N-methyl-d-aspartate (NMDA) antagonism (i.e., phencyclidine), muscarinic receptor antagonism (i.e., scopolamine), κ opioid agonism (i.e., salvinorin A), mixed action monoamine release (i.e., 3,4-methylenedioxymethamphetamine [MDMA]), and more. Thus, within the confines of this review, we will use the term hallucinogen to denote compounds with pharmacological effects similar to three prototypical drugs: 3,4,5-trimethoxy-phenethylamine (mescaline, Fig. 1A), N,N-dimethyl-4-phosphoryloxytryptamine (psilocybin, Fig. 1B) and LSD (Fig. 1C). All of these drugs function as agonists at 5-HT_2A receptors, and much work has culminated in the widespread acceptance that this particular receptor initiates the molecular mechanisms responsible for the unique effects of these compounds. Much of that work will be reviewed herein.

The aim of this review is to mark the sea change which seems to be occurring within the field of hallucinogen research. Until very recently, comparatively few scientists were studying these particular compounds, perhaps due to their unfortunate association with somewhat less than rigorous research techniques. In Nichols’ recent review [14], for example, prominent clinicians are quoted as stating that the effects of hallucinogens transcend pharmacology, are unpredictable, and border on the mystical. Nevertheless, the state of hallucinogen research is now approaching something of a high water mark. Selective antagonists are available for relevant serotonergic receptors, the majority of which have now been cloned, allowing for reasonably thorough pharmacological investigation. Animal models sensitive to hallucinogen-like effects have been established and exploited to yield a wealth of largely concordant data. Along similar lines, sophisticated genetic techniques have enabled the development of mutant mice, which have proven useful in the study of hallucinogens. Finally, the capacity to study post-receptor signaling events has lead to the proposal of a plausible mechanism of action for these compounds. The tools currently available to study the hallucinogens are thus more plentiful and scientifically advanced than were those accessible to earlier researchers studying the opioids, benzodiazepines, cholinergics, or other centrally active compounds. Those interested in hallucinogen research should thus be encouraged by all of these recent developments, and it is hoped that the perceived “scientific respectability” of the field will continue to increase.