Elsevier

Behavioural Brain Research

Volume 277, 15 January 2015, Pages 99-120
Behavioural Brain Research

Review
Recent advances in the neuropsychopharmacology of serotonergic hallucinogens

https://doi.org/10.1016/j.bbr.2014.07.016Get rights and content

Highlights

  • Serotonergic hallucinogens are classified as phenylalkylamines and indoleamines.

  • The two classes of hallucinogens produce similar subjective effects in humans and show cross-tolerance.

  • Hallucinogen effects are primarily mediated by the serotonin 5-HT2A receptor.

  • Many effects of hallucinogens are mediated in the prefrontal cortex.

Abstract

Serotonergic hallucinogens, such as (+)-lysergic acid diethylamide, psilocybin, and mescaline, are somewhat enigmatic substances. Although these drugs are derived from multiple chemical families, they all produce remarkably similar effects in animals and humans, and they show cross-tolerance. This article reviews the evidence demonstrating the serotonin 5-HT2A receptor is the primary site of hallucinogen action. The 5-HT2A receptor is responsible for mediating the effects of hallucinogens in human subjects, as well as in animal behavioral paradigms such as drug discrimination, head twitch response, prepulse inhibition of startle, exploratory behavior, and interval timing. Many recent clinical trials have yielded important new findings regarding the psychopharmacology of these substances. Furthermore, the use of modern imaging and electrophysiological techniques is beginning to help unravel how hallucinogens work in the brain. Evidence is also emerging that hallucinogens may possess therapeutic efficacy.

Introduction

Hallucinogenic drugs have been used by humans for thousands of years, but western scientists only became interested in these substances beginning in the late 1800s. These agents produce profound changes in consciousness. Because other drug classes can sometimes produce effects that overlap with those of the hallucinogens, it has been important to develop a formal definition for these compounds. This has turned out to be a difficult and contentious task. Hallucinogens have been defined as agents that alter thought, perception, and mood without producing memory impairment, delirium, or addiction [1], [2]. However, this definition is overly broad because it fails to exclude a wide-range of agents that are generally not classified as hallucinogens, such as cannabinoids and NMDA antagonists. It is now recognized that hallucinogens produce similar discriminative stimulus effects [3] and act as agonists of the serotonin-2A (5-HT2A) receptor [4]. Therefore, it has been proposed [5] that in addition to having the characteristics listed above, hallucinogens should also bind to the 5-HT2A receptor and produce full substitution in animals trained to discriminate the prototypical hallucinogen 2,5-dimethoxy-4-methylamphetamine (DOM). For this reason, hallucinogens are often categorized as classical hallucinogens or serotonergic hallucinogens. This article will review the pharmacology of hallucinogens, including their mechanism-of-action, their effects in animals and humans, and recent findings regarding how they interact with specific brain regions.

Section snippets

Receptor interactions

Classical hallucinogens can be divided into two main structural classes: indoleamines and phenylalkylamines [6]. Indoleamines include the tetracyclic ergoline (+)-lysergic acid diethylamide (LSD) and the chemically simpler indolealkylamines, which includes N,N-dimethyltryptamine (DMT), N,N-dipropyltryptamine (DPT), 5-methoxy-DMT (5-MeO-DMT), and psilocybin (4-phosphoryloxy-DMT) and its active O-dephosphorylated metabolite psilocin (4-hydroxy-DMT). DMT is found in several hallucinogenic snuffs

Subjective effects

Despite having different chemical structures, phenylalkylamine, tryptamine, and ergoline hallucinogens produce remarkably similar subjective effects [35], [36], [37], [38], [39], [40], [41], [42]. It is very difficult for hallucinogen-experienced subjects to distinguish between psilocybin and LSD if those substances are administered in a blinded fashion, with the only apparent difference being the duration of action [41]. Similar findings have been reported when mescaline, LSD, and psilocybin

Evidence from human studies

Multiple, converging lines of evidence point to 5-HT2A receptor activation as the unitary mechanism responsible for mediating hallucinogenesis. Indoleamine and phenylalkylamine hallucinogens bind to 5-HT2 sites with moderate to high affinity [80], [81], [82], [83]. Although indoleamine hallucinogens show relatively promiscuous binding profiles, phenylisopropylamine hallucinogens such as DOM and DOB are highly selective for 5-HT2 receptors [13], [15] and therefore it is likely that their effects

Locus coeruleus

The locus coeruleus (LC), located in the dorsal pons, is the source of almost all noradrenergic projections in the CNS. LC neurons are responsive to sensory stimuli, especially of a novel or arousing nature, and the firing of LC neurons is markedly increased by noxious stimulation (reviewed by: [230]). Intravenous administration of mescaline (2 mg/kg), LSD (5–10 μg/kg), DOM (20–80 μg/kg), DOB (50–100 μg/kg), or DOI (16–50 μg/kg) profoundly enhances the responses of LC neurons to sensory stimuli

Summary

Despite the complexity of hallucinogen effects, we are beginning to understand how these substances work in the brain. The 5-HT2A receptor was first identified about thirty years ago as a possible site of action of hallucinogens. It is now clear that most of the effects of hallucinogens are mediated by 5-HT2A activation. Although the vast majority of this evidence was derived from studies in animals, the resumption of human studies with hallucinogens has provided additional support.

Recent

Acknowledgements

This work was supported by grants from NIMH (K01 MH100644), NIDA (R01 DA002925), and the Brain and Behavior Research Foundation.

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