Recent advances in the neuropsychopharmacology of serotonergic hallucinogens

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.

Keywords: 5-HT2A receptor; Head twitch; Prefrontal cortex; Psychedelic; Visual effects.

Figure 1

Chemical structures of indolealkylamine, phenylalkylamine, and ergoline hallucinogens.

Figure 2

Chemical structures of conformationally-restricted hallucinogens.

Figure 3

Structure of serotonin.

Figure 4

Signaling pathways coupled to the 5-HT_2A receptor. Abbreviations: AA, arachidonic acid; 2-AG, 2-arachidonoylglycerol; ARF, ADP-ribosylation factor-1; DAG, diacylglycerol; DGL, diacylglycerol lipase; ERK1/2, extracellular-regulated kinases 1 and 2; GRB, growth factor receptor-bound protein 2; IP₃, inositol triphosphate; p38 MAPK, p38 mitogen-activated protein kinase; MEK1/2, mitogen/extracellular signal-regulated kinases 1 and 2; MKK3/6, MAPK kinases 3and 6; MKK4, MAPK kinase 4; MEKK, MAPK kinase kinase; PA, phosphatidic acid; PC, phosphatidyl choline; PIP₂, phosphatidylinositol 4,5-biphosphate; PKC, protein kinase C; PKN, protein kinase N; PL, phospholipids; PLCβ, phospholipase Cβ; PLD, phospholipase D; SHC, Src homology 2 domain containing transforming factor; SOS, son of sevenless homolog.

Figure 5

Subjective effects of psilocybin as measured by the 5-Dimension Altered States of Consciousness instrument (5D-ASC). The values reported by Grob et al. (2011) were reanalyzed using the 11 new homogenous APZ subscales developed by Studerus et al. (2010). Values are the mean (SEM) percentages of the total possible score. The placebo was niacin.

Figure 6

Chemical structure of lisuride.

Figure 7

Effect of pretreatment with the selective 5-HT_2A antagonist M100907 on the head twitch response induced by 0.3 mg/kg 25I-NBOMe in C57BL/6J mice. Data are presented as group means ± SEM for 20-min test sessions. **p < 0.01, significant difference from 25I-NBOMe alone. Data from: Halberstadt and Geyer, 2014.

Figure 8

Distribution of 5-HT_2A receptors in neurons in layer V of the prefrontal cortex. 5-HT_2A receptors are expressed by glutamatergic pyramidal neurons and GABAergic basket cells and chandelier cells. Hallucinogens increase the frequency of spontaneous EPSCs and IPSCs in layer V pyramidal neurons by enhancing recurrent glutamatergic and GABAergic network activity.