Hallucinations Under Psychedelics and in the Schizophrenia Spectrum

An Interdisciplinary and Multiscale Comparison

Pantelis Leptourgos; Martin Fortier-Davy; Robin Carhart-Harris; Philip R. Corlett; David Dupuis; Adam L. Halberstadt; Michael Kometer; Eva Kozakova; Frank LarØi; Tehseen N. Noorani; Katrin H. Preller; Flavie Waters; Yuliya Zaytseva; Renaud Jardri


Schizophr Bull. 2020;46(6):1396-1408. 

In This Article


At the synaptic level, SCZs has been linked to dopaminergic (DA) alterations, while classical psychedelic drugs, such as LSD, mescaline, and psilocybin, are serotonin (5-HT) receptor agonists. Psychedelics can be divided into three main structural classes: phenethylamines, tryptamines, and ergolines. The phenethylamines are relatively selective for 5-HT2 subtypes, whereas the tryptamines bind to a larger number of sites, including most 5-HT receptors and σ 1 sites. Ergolines, by contrast, are even less selective and interact with serotonergic, dopaminergic, adrenergic, and histaminergic receptors. There is now a consensus that the 5-HT2A receptor is the primary target for serotonergic hallucinogens in the brain. The first evidence linking the 5-HT2A receptor to hallucinogenesis was derived from animal behavioral models (see Table 1). For example, Glennon and colleagues found that 5-HT2A antagonists, such as pirenperone and ketanserin, block the effects of psychedelics in drug discrimination (DD) studies conducted in rats.[4] Those investigators also found that the potencies (ED50 values) of hallucinogens in the DD paradigm are robustly correlated with their 5-HT2A affinity.[5] The head-twitch response (HTR) assay is another behavioral paradigm that has been used in mechanistic studies of serotonergic hallucinogens. The HTR is a rapid reciprocal head movement that occurs in rodents after administration of serotonergic hallucinogens.[6,7] Similar to the DD paradigm, selective 5-HT2A receptor antagonists such as M100907 also block the HTR induced by hallucinogens.[8,9] Likewise, LSD and other hallucinogens do not induce the HTR in 5-HT2A knockout mice.[10,11] The HTR paradigm has become increasingly popular in recent years because it is one of the few behavioral effects produced by hallucinogens that are not observed when animals are treated with non-hallucinogenic 5-HT2A agonists such as lisuride, an LSD analog.[10,12,13] There is also a robust correlation between the ED50 values of hallucinogens in the HTR paradigm and their potencies in humans and rat DD studies.[7] Therefore, although the HTR assay does not directly model the psychedelic effects produced by hallucinogens, it serves as a behavioral readout of 5-HT2A receptor activation that has considerable cross-species translational relevance.

In addition to DD and HTR, several other behavioral paradigms are commonly used to study the effects and pharmacology of hallucinogens in rodents. Prepulse inhibition (PPI) of the startle reflex is one example. PPI refers to the phenomenon where a weak prestimulus will inhibit the response to a subsequent startle-inducing pulse. This effect is commonly used as an operational measure of sensorimotor gating. LSD and other hallucinogens inhibit PPI in rats, an effect that can be blocked by pretreatment with selective 5-HT2A receptor antagonists (eg, M100907 and MDL 11,939).[11,14] Although lisuride also reduces PPI in rats, its effect is blocked by DA D2/3 receptor antagonists but not by MDL 11,939. Similar findings have also emerged from studies of exploratory behavior in rats. Although hallucinogens reduce exploratory locomotor activity in a novel environment via 5-HT2A receptor activation,[15,16] lisuride produces a qualitatively different behavioral profile similar to the effect of DA receptor agonists.[17] Hallucinogens also alter timing behavior in rats and mice via 5-HT2A receptor activation.[18–20]

Although the 5-HT2A receptor was first linked to the mechanism of action of hallucinogens in 1984, it took more than a decade to generate relevant evidence in humans. In 1998, a clinical study conducted by Franz Vollenweider and colleagues confirmed that ketanserin can block the subjective effects of psilocybin.[21] The 5-HT2A/D2 receptor antagonist risperidone can also block the subjective response to psilocybin, whereas the D2 antagonist haloperidol was not effective.[21] More recently, similar findings were reported for LSD. Although there has been speculation that D2 receptor activation may contribute to the psychopharmacology of LSD, ketanserin seems to have little effect on D2 sites but is capable of blocking the subjective and neural response to LSD.[22–24] Notably, it was also reported recently that the intensity of the subjective response to psilocybin is correlated with the level of central 5-HT2A receptor occupancy.[25]