Recent Advances in the Neuropsychopharmacology of Serotonergic Hallucinogens, Adam L. Halberstadt, 2015

Recent Advances in the Neuropsychopharmacology of Serotonergic Hallucinogens

Adam L. Halberstadt

Behavioral Brain Research, 2015, 15, 277, 99–120.

doi : 10.1016/j.bbr.2014.07.016



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.

Keywords : psychedelic; 5-HT2A receptor; head twitch; prefrontal cortex; visual effects


1. 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 (Hollister, 1968; Grinspoon and Bakalar, 1979). 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 (Glennon et al., 1982) and act as agonists of the serotonin-2A (5-HT2A) receptor (Glennon et al., 1983). Therefore, it has been proposed (Glennon, 1999) 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.

2. Pharmacology of hallucinogens

2.1. Receptor interactions

Classical hallucinogens can be divided into two main structural classes: indoleamines and phenylalkylamines (Nichols, 2012). 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 used in the Caribbean and in South America. It is also a component of ayahuasca, an infusion or decoction prepared from DMT-containing plants in combination with species of Banisteriopsis containing β-carboline alkaloids that act as monoamine oxidase inhibitors (McKenna et al., 1984). Psilocybin and its metabolite psilocin are the active components of hallucinogenic teonanácatl mushrooms belonging to the genus Psilocybe. The phenylalkylamines can be subdivided into phenethylamines, such as mescaline from the peyote cactus (Lophophora williamsii), 2,5-dimethoxy-4-bromophenethylamine (2C-B), and 2,5-dimethoxy 4-iodophenethylamine (2C-I); and phenylisopropylamines (“amphetamines”), including DOM, 2,5 dimethoxy-4-iodoamphetamine (DOI), and 2,5-dimethoxy-4-bromoamphetamine (DOB). Although N-alkyl substituted phenylalkylamines are usually inactive as hallucinogens, the addition of a N-benzyl group to phenethylamines can dramatically increase their activity, and N-benzylphenethylamines are a new class of potent hallucinogenic compounds (Braden et al., 2006). Examples of N-benzylphenethylamine hallucinogens include N-(2-methoxybenzyl)-2,5-dimethoxy 4-iodophenethylamine (25I-NBOMe) and N-(2-methoxybenzyl)-2,5-dimethoxy 4-bromophenethylamine (25B-NBOMe). The chemical structures of many of these hallucinogens are illustrated in Figure 1. Nichols and colleagues have also developed conformationally-restricted derivatives of phenylalkylamine hallucinogens: bromo-DragonFLY (1-(8-bromobenzo[1,2-b;4,5-b]difuran-4-yl)-2-aminopropane; Parker et al., 1998); TCB-2 (4-bromo-3,6-dimethoxybenzocyclobuten-1-yl)methylamine; McLean et al., 2006); and 2S,6S-DMBMPP ((2S,6S)-2-(2,5-dimethoxy-4-bromobenzyl)-6-(2-methoxyphenyl)piperidine; Juncosa et al., 2012). Likewise, lysergic acid 2,4-dimethylazetidide was developed as a rigid analogue of LSD that shows similar in vivo potency (Nichols et al., 2002). Figure 2 shows examples of rigid hallucinogen analogues.