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

Disclosures

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

Conclusion

In this article, we sought to compare and contrast hallucinations in SCZs and under psychedelics. We identified several interesting common features: both experiences are related to a reduced integration and stability of functional networks, as well as a distorted anti-correlation between resting-state and task-positive networks. Furthermore, both experiences are afforded a strong metaphysical meaning. We also highlighted various crucial differences: First, psychedelics over-engage primary sensory cortices, hallucinations in SCZs, on the other hand, are mostly related to overactivation of associative networks. Furthermore, while drug-induced psychosis mostly encompasses VH (often geometric) with preserved insight, SCZs is characterized by AH (mostly voices) and poor reality monitoring. Additionally, we pointed out a number of topics that need further investigation, more particularly the role of serotonin in SCZs, the prevalence of MMH in both experiences and the potential cultural impact on hallucinations in SCZs. Finally, we suggested that psychotic experiences, regardless of their diagnostic categorization, might be underlain by the same computational mechanisms that tie together subjectivity and neural implementation, namely altered predictive processing. Future studies will have to clarify whether the same (eg, strong priors) or different (eg, climbing vs descending loops) impairments underscore these different psychotic experiences.

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Acknowledgments
We would like to dedicate this work to the memory of our beloved friend and colleague, Martin Fortier-Davy.

Funding
D.D. was supported by a Wellcome Trust Grant (WT108720). A.L.H. was supported by the National Institute on Drug Abuse, USA [grant number 5R01 DA041336]. Y.Z. and E.K. were supported by the Internal Grant Agency of the Ministry of Health of the Czech Republic [grant number AZV 17-32957A]. K.H.P was supported by the Heffter Research Institute, USA [grant number 2020-03-01]. T.N. was partially supported by Junior Research Fellowship COFUNDed between Durham University and the European Union [grant number 609412].

Table 1. The pharmacology of psychedelics
	Drug Discrimination (DD)	Head-Twitch Response (HTR)	Prepulse Inhibition (PPI)	Exploratory and Investigatory Behavior
Behavioral effect	Rats can be trained to discriminate hallucinogens from vehicle.	Rats and mice treated with hallucinogens express the HTR.	Hallucinogens reduce PPI in rats.	Hallucinogens reduce exploratory and investigatory behavior in rats.
Receptor mechanism for phenylalkylamine hallucinogens (eg, mescaline)	Selective 5-HT_2A receptor antagonists (eg, M100907 and MDL 11,939) block the effect.	Selective 5-HT_2A receptor antagonists (eg, M100907 and MDL 11,939) block the effect.	Selective 5-HT_2A receptor antagonists (eg, M100907 and MDL 11,939) block the effect.	Selective 5-HT_2A receptor antagonists (eg, M100907 and MDL 11,939) block the effect.
Receptor mechanism for indoleamine hallucinogens (eg, LSD and psilocybin)	The mechanism for the DD effects for tryptamine hallucinogens often mediated by both 5-HT_1A and 5-HT_2A receptors. The mechanism for the effect of LSD is time-dependent; at short intervals between injection and testing (eg, 15–30 min), the effect of LSD is blocked by selective 5-HT_2A antagonists; however, if the interval is increased to 90 min then the effect of LSD is blocked by antagonists of D₂-like receptors.	Selective 5-HT_2A receptor antagonists (eg, M100907 and MDL 11,939) block the effect.	Selective 5-HT_2A receptor antagonists (eg, M100907 and MDL 11,939) block the effect.	Indoleamine hallucinogens act through both 5-HT_1A and 5-HT_2A receptor mechanisms.
Sensitivity to lisuride	Lisuride produces hallucinogen-like effects in some DD studies but not in others.	Lisuride does not induce the HTR in rats or mice.	Lisuride reduces PPI in rats but the effect is mediated by D_2/3 receptors rather than the 5-HT_2A receptor.	Lisuride does not produce LSD-like effects on exploratory or investigatory behavior in rats.

Table 2. Comparison of the brain-imaging markers of psychotic and serotonergic hallucinations
	Schizophrenia Spectrum	5-HT_2A Agonists	Comparison
Major networks a) During rest b) During task	a) DMN hypoactivation Decreased connectivity within and (mostly) between RSN b) Lack of DMN suppression during tasks—decreased DMN and CEN anticorrelation	a) DMN hypoactivation Decreased connectivity within—increased connectivity between RSN Decreased DMN and CEN anticorrelation b) Not enough evidence	a) Partially similar Differences in changes in connectivity between RSN
Hallucinations a) Symptom capture b) Resting-state analysis	a) Activation of hippocampus and modality-specific secondary cortex with deactivation of DMN and activation of SN and CEN b) Thalamic connectivity with prefrontal cortex lowered—thalamic connectivity with somatosensory cortex increased	a) Not available b) Increased activity in primary visual areas—decreased activity in associative areas Preserved thalamic connectivity with DMN—increased thalamic connectivity with CEN	a) Directly incomparable—mostly primary cortices in psychedelics—mostly associative cortices in SCZs
Link with experience	AH altered resting-state connectivity in left temporal areas VH increased RS connectivity between visual cortex and amygdala in SCZs (AH and VH)	VH/imagery expanded connectivity and activity of V1—VH/imagery correlated with CEN activation

RSNs, resting-state networks; DMN, default mode network; CEN, central-executive network; SN, salience network.

Table 3. Comparison of the phenomenology of psychotic and serotonergic hallucinations
	Schizophrenia Spectrum	5-HT_2A Agonists	Comparison
Sensory modalities	Mainly AH (multimodal in some cases)	Mainly VH (multimodal in some cases)	Different
Content	No geometric hallucinations Complex hallucinations (mostly ordinary entities)	Geometric hallucinations Complex hallucinations (ordinary and extraordinary entities)	Different
Meaning	Strong existential/metaphysical meaning	Strong existential/metaphysical meaning	Similar
Reality monitoring/insight	Poor reality monitoring and insight	Reality monitoring and insight often preserved	Different
Duration	Recurrent psychotic episodes; they can last from several weeks to several months. Hallucinatory episodes during psychotic episodes can last several seconds or minutes; continuously present in some individuals.	Transient states, lasting a few hours. Long-term perceptual effects are rare.	Different