SchizophreniaHealthy VolunteersPsilocybin

Psilocybin induces schizophrenia-like psychosis in humans via a serotonin-2 agonist action

This paper (1998) was one of the first to identify psilocybin/psilocin as working on the serotonin (5-HT2A) receptor and not only on the dopaminergic system. The direct comparisons as mentioned in the article are nowadays a bit more nuanced.

Authors

  • Franz Vollenweider

Published

NeuroReport
individual Study

Abstract

Psilocybin, an indoleamine hallucinogen, produces a psychosis-like syndrome in humans that resembles first episodes of schizophrenia. In healthy human volunteers, the psychotomimetic effects of psilocybin were blocked dose-dependently by the serotonin-2A antagonist ketanserin or the atypical antipsychotic risperidone but were increased by the dopamine antagonist and typical antipsychotic haloperidol. These data are consistent with animal studies and provide the first evidence in humans that psilocybin-induced psychosis is due to serotonin-2A receptor activation, independently of dopamine stimulation. Thus, serotonin-2A overactivity may be involved in the pathophysiology of schizophrenia and serotonin-2A antagonism may contribute to therapeutic effects of antipsychotics.

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Research Summary of 'Psilocybin induces schizophrenia-like psychosis in humans via a serotonin-2 agonist action'

Introduction

Earlier research has emphasised dopaminergic dysfunction in schizophrenia, but accumulating evidence implicates serotonin (5-HT) systems as well. Clinical observations include altered cortical serotonin receptor binding in schizophrenia, potent 5-HT2 antagonism among atypical antipsychotics, and the fact that classic indoleamine hallucinogens such as psilocybin and LSD can elicit syndromes in healthy people that resemble early stages of schizophrenia, including ego disturbances, affective changes, loosened associations and perceptual alterations. Animal studies suggest that hallucinogens act via 5-HT2 receptors, yet extrapolation to humans is uncertain and some hallucinogens also affect dopaminergic systems, leaving open whether human effects are mediated directly by 5-HT2 receptors, indirectly via dopamine, or both. To address this gap, Vollenweider and colleagues tested whether psilocybin’s psychotomimetic and cognitive effects in healthy volunteers are mediated by 5-HT2 and/or dopamine D2 receptors. Using a placebo-controlled, within-subject design, they examined how pretreatment with a selective 5-HT2 antagonist (ketanserin), a D2 antagonist typical antipsychotic (haloperidol), or a mixed 5-HT2/D2 antagonist atypical antipsychotic (risperidone) altered psilocybin-induced psychological and working memory effects, assessed chiefly with the Altered State of Consciousness (APZ-OAV) rating scale and a delayed response task (DRT).

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Study Details

  • Study Type
    individual
  • Journal
    NeuroReport
  • Compound
    Psilocybin
  • Topics
    SchizophreniaHealthy Volunteers
  • Author
    Franz Vollenweider
  • APA Citation

    Vollenweider, F. X., Vollenweider-Scherpenhuyzen, M. F. I., Bäbler, A., Vogel, H., & Hell, D. (1998). Psilocybin induces schizophrenia-like psychosis in humans via a serotonin-2 agonist action. NeuroReport, 9(17), 3897-3902. https://doi.org/10.1097/00001756-199812010-00024

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63 cited
Natural Psychoplastogens As Antidepressant Agents

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Therapeutic Use of LSD in Psychiatry: A Systematic Review of Randomized-Controlled Clinical Trials

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Characterization and prediction of acute and sustained response to psychedelic psilocybin in a mindfulness group retreat

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126 cited
Dynamical exploration of the repertoire of brain networks at rest is modulated by psilocybin

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183 cited
Psilocybin-assisted mindfulness training modulates self-consciousness and brain default mode network connectivity with lasting effects

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Carhart-Harris, R. L., Friston, K. J. · Pharmacological Reviews (2019)

Cytochrome P450 enzymes contribute to the metabolism of LSD to nor-LSD and 2-oxo-3-hydroxy-LSD: Implications for clinical LSD use

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34 cited
Psychedelic drugs-a new era in psychiatry?

Nutt, D. J. · Dialogues in Clinical Neuroscience (2019)

Psilocybin lacks antidepressant-like effect in the Flinders Sensitive Line rat

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60 cited
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Dyck, E. · Journal of Psychoactive Drugs (2019)

Recreational use of psychedelics is associated with elevated personality trait openness: Exploration of associations with brain serotonin markers

Erritzoe, D., Smith, J. M., Fisher, P. M. et al. · Journal of Psychopharmacology (2019)

Psychedelic effects of psilocybin correlate with serotonin 2A receptor occupancy and plasma psilocin levels

Madsen, M. K., Fisher, P. M., Burmester, D. et al. · Neuropsychopharmacology (2019)

Trait Openness and serotonin 2A receptors in healthy volunteers: A positron emission tomography study

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9 cited
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Carhart-Harris, R. L. · Current Opinion in Psychiatry (2019)

Current perspectives on psychedelic therapy: use of serotonergic hallucinogens in clinical interventions

Richards, W. A., Garcia-Romeu, A. · International Review of Psychiatry (2018)

LSD modulates effective connectivity and neural adaptation mechanisms in an auditory oddball paradigm

Timmermann, C., Spriggs, M. J., Kaelen, M. et al. · Neuropharmacology (2018)

The Varieties of the Psychedelic Experience: A Preliminary Study of the Association Between the Reported Subjective Effects and the Binding Affinity Profiles of Substituted Phenethylamines and Tryptamines

Zamberlan, F., Sanz, C., Pallavicini, C. et al. · Frontiers in Integrative Neuroscience (2018)

Dimensions of consciousness and the psychedelic state

Bayne, T., Carter, O. · Neuroscience of Consciousness (2018)

106 cited
Psychedelics, meditation, and self-consciousness

Milliere, R., Carhart-Harris, R. L., Roseman, L. et al. · Frontiers in Psychology (2018)

Psychedelics as anti-inflammatory agents

Flanagan, T. W., Nichols, C. D. · International Review of Psychiatry (2018)

Double-blind comparison of the two hallucinogens psilocybin and dextromethorphan: effects on cognition

Barrett, F. S., Carbonaro, T. M., Hurwitz, E. et al. · Psychopharmacology (2018)

78 cited
DARK Classics in Chemical Neuroscience: Psilocybin

Geiger, H. A., Wurst, M. G., Daniels, R. N. · ACS Chemical Neuroscience (2018)

The abuse potential of medical psilocybin according to the 8 factors of the Controlled Substances Act

Johnson, M. W., Griffiths, R. R., Hendricks, P. S. et al. · Neuropharmacology (2018)

Psychedelic use and intimate partner violence

Walsh, Z., Bird, B. M., Lafrance, A. et al. · Journal of Psychopharmacology (2018)

Unifying theories of psychedelic drug effects

Swanson, L. R. · Frontiers in Pharmacology (2018)

Neuroendocrine Associations Underlying the Persistent Therapeutic Effects of Classic Serotonergic Psychedelics

Schindler, E. A. D., Wallace, R. M., Sloshower, J. A. et al. · Frontiers in Pharmacology (2018)

Dark Classics in Chemical Neuroscience: Lysergic Acid Diethylamide (LSD)

Nichols, D. E. · ACS Chemical Neuroscience (2018)

The Experience Elicited by Hallucinogens Presents the Highest Similarity to Dreaming within a Large Database of Psychoactive Substance Reports

Sanz, C., Zamberlan, F., Erowid, E. et al. · Frontiers in Neuroscience (2018)

Psilocybin disrupts sensory and higher order cognitive processing but not pre-attentive cognitive processing-study on P300 and mismatch negativity in healthy volunteers

Bravermanová, A., Viktorinová, M., Tylš, F. et al. · Psychopharmacology (2018)

Altered network hub connectivity after acute LSD administration

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Interactions of hallucinogens with the glutamatergic system: permissive network effects mediated through cortical layer V pyramidal neurons

Marek, G. J. · Current Topics in Behavioral Neurosciences (2018)

Psychiatry & the psychedelic drugs. Past, present & future

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Connectome-harmonic decomposition of human brain activity reveals dynamical repertoire re-organization under LSD

Atasoy, S., Leor, R., Kaelen, M. et al. · Scientific Reports (2017)

The serotonin hallucinogen 5-MeO-DMT alters cortico-thalamic activity in freely moving mice: Regionally-selective involvement of 5-HT1A and 5-HT2A receptors

Riga, M. S., Llad O-Pelfort, L., Artigas, F. et al. · Neuropharmacology (2017)

LSD Increases Primary Process Thinking via Serotonin 2A Receptor Activation

Sumiyoshi, T., Kraehenmann, R., Pokorny, D. et al. · Frontiers in Pharmacology (2017)

Psilocybin with psychological support for treatment-resistant depression: six-month follow-up

Carhart-Harris, R. L., Bolstridge, &. M., Day, C. M. J. et al. · Psychopharmacology (2017)

Double-blind comparison of the two hallucinogens psilocybin and dextromethorphan: similarities and differences in subjective experiences

Carbonaro, T. M., Hurwitz, E., Johnson, M. W. · Psychopharmacology (2017)

102 cited
Psilocybin with psychological support improves emotional face recognition in treatment-resistant depression

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88 cited
Acute LSD effects on response inhibition neural networks

Schmidt, A., Müller, F., Lenz, C. et al. · Psychological Medicine (2017)

Increased thalamic resting state connectivity as a core driver of LSD-induced hallucinations

Lenz, C., Dolder, P. C., Lang, U. E. et al. · Acta Psychiatrica Scandinavica (2017)

Serotonin and brain function: a tale of two receptors

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Dreams and psychedelics: neurophenomenological comparison and therapeutic implications

Kraehenmann, R. · Current Neuropharmacology (2017)

68 cited
Effects of LSD on music-evoked brain activity

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Effect of psilocybin on empathy and moral decision-making

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155 cited
Looking for the Self: Phenomenology, Neurophysiology and Philosophical Significance of Drug-induced Ego Dissolution

Millière, R. · Frontiers in Human Neuroscience (2017)

Modern clinical research on LSD

Liechti, M. E. · Neuropsychopharmacology (2017)

The therapeutic potential of psychedelic drugs: past, present, and future

Carhart-Harris, R. L., Goodwin, G. M. · Neuropsychopharmacology (2017)

Dreamlike effects of LSD on waking imagery in humans depend on serotonin 2A receptor activation

Kraehenmann, R. ;., Pokorny, D. ;., Vollenweider, L. ;. et al. · Psychopharmacology (2017)

138 cited
Acute effects of LSD on amygdala activity during processing of fearful stimuli in healthy subjects

Mueller, F., Lenz, C., Dolder, P. C. et al. · Translational Psychiatry (2017)

The psychological and human brain effects of music in combination with psychedelic drugs

Kaelen, M. · Imperial College London (2017)

Pharmacokinetics of Escalating Doses of Oral Psilocybin in Healthy Adults

Brown, R. T., Nicholas, C. R., Cozzi, N. V. et al. · Clinical Pharmacokinetics (2017)

Ayahuasca dimethyltryptamine, and psychosis: a systematic review of human studies

Dos Santos, R. G., Hallak, J. E., Bouso, J. C. · Therapeutic Advances in Psychopharmacology (2017)

Tripping up addiction: the use of psychedelic drugs in the treatment of problematic drug and alcohol use

Morgan, C. J. A., McAndrew, A., Stevens, T. et al. · Current Opinion in Behavioral Sciences (2017)

Pharmacology and Toxicology of N-Benzylphenethylamine (“NBOMe”) Hallucinogens

Halberstadt, A. L. · Current Topics in Behavioral Neurosciences (2017)

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Constructing drug effects: a history of set and setting

Hartogsohn, I. · Drug Science Policy and Law (2017)

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Hallucinogens and Serotonin 5-HT2A Receptor-Mediated Signaling Pathways

López-Giménez, J. F., González-Maeso, J. · Current Topics in Behavioral Neurosciences (2017)

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Phenomenology, Structure, and Dynamic of Psychedelic States

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The Challenging Experience Questionnaire: Characterization of challenging experiences with psilocybin mushrooms

Barrett, F. S., Bradstreet, M. P., Leoutsakos, J. M. S. et al. · Journal of Psychopharmacology (2016)

The serotonin 5-HT2C receptor and the non-addictive nature of classic hallucinogens

Canal, C. E., Murnane, K. S. · Journal of Psychopharmacology (2016)

Psilocybin for treating substance use disorders?

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Clinical Applications of Hallucinogens: A Review

Garcia-Romeu, A., Kersgaard, B., Addy, P. H. · Experimental and Clinical Psychopharmacology (2016)

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Receptor interaction profiles of novel psychoactive tryptamines compared with classic hallucinogens

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Measuring the subjective: revisiting the psychometric properties of three rating scales that assess the acute effects of hallucinogens

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42 cited
Inhibition of alpha oscillations through serotonin-2A receptor activation underlies the visual effects of ayahuasca in humans

Valle, M., Maqueda, A. E., Rabella, M. et al. · European Neuropsychopharmacology (2016)

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The current state of research on ayahuasca: A systematic review of human studies assessing psychiatric symptoms, neuropsychological functioning, and neuroimaging

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LSD acutely impairs fear recognition and enhances emotional empathy and sociality

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Modulatory effect of the 5-HT1A agonist buspirone and the mixed non-hallucinogenic 5-HT1A/2A agonist ergotamine on psilocybin-induced psychedelic experience

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103 cited
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Nichols, D. E. · Pharmacological Reviews (2016)

Lysergic acid diethylamide: a drug of ‘use’?

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The paradoxical psychological effects of lysergic acid diethylamide (LSD)

Carhart-Harris, R. L., Kaelen, M., Bolstridge, M. et al. · Psychological Medicine (2016)

253 cited
The serotonergic hallucinogen 5-methoxy-N,N-dimethyltryptamine disrupts cortical activity in a regionally-selective manner via 5-HT1A and 5-HT2A receptors

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New World Tryptamine Hallucinogens and the Neuroscience of Ayahuasca

McKenna, D., Riba, J. · Current Topics in Behavioral Neurosciences (2016)

Serotonergic Hallucinogen-Induced Visual Perceptual Alterations

Kometer, M., Vollenweider, F. X. · Behavioral Neurobiology of Psychedelic Drugs (2016)

Receptor interaction profiles of novel N-2-methoxybenzyl (NBOMe) derivatives of 2,5-dimethoxy-substituted phenethylamines (2C drugs)

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Acute effects of lysergic acid diethylamide in healthy subjects

Schmid, Y., Enzler, F., Gasser, P. et al. · Biological Psychiatry (2015)

Psilocybin-induced decrease in amygdala reactivity correlates with enhanced positive mood in healthy volunteers

Kraehenmann, R., Preller, K. H., Scheidegger, M. et al. · Biological Psychiatry (2015)

Acute Biphasic Effects of Ayahuasca

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Psilocybin-induced spiritual experiences and insightfulness are associated with synchronization of neuronal oscillations

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Restructuring consciousness -the psychedelic state in light of integrated information theory

Gallimore, A. R. · Frontiers in Human Neuroscience (2015)

Finding the self by losing the self: Neural correlates of ego-dissolution under psilocybin

Lebedev, A. V., L€ Ovd En, M., Rosenthal, G. et al. · Human Brain Mapping (2015)

Peak experiences and the afterglow phenomenon: when and how do therapeutic effects of hallucinogens depend on psychedelic experiences

Majic, T., Schmidt, T. T., Gallinat, J. · Journal of Clinical Psychopharmacology (2015)

Psilocybin-assisted treatment for alcohol dependence: a proof-of-concept study

Bogenschutz, M. P., Forcehimes, A. A., Pommy, J. A. et al. · Journal of Psychopharmacology (2015)

LSD-assisted psychotherapy for anxiety associated with a life-threatening disease: a qualitative study of acute and sustained subjective effects

Kirchner, K. · Journal of Psychopharmacology (2014)

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Halberstadt, A. L. · Behavioural Brain Research (2014)

Pharmacology of Hallucinations: Several Mechanisms for One Single Symptom?

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Classical hallucinogens as antidepressants? A review of pharmacodynamics and putative clinical roles

Tracy, D., Baumeister, D., Barnes, G. et al. · Therapeutic Advances in Psychopharmacology (2014)

The entropic brain: a theory of conscious states informed by neuroimaging research with psychedelic drugs

Carhart-Harris, R. L., Leech, R., Shanahan, M. et al. · Frontiers in Human Neuroscience (2014)

Psilocybin - Summary of knowledge and new perspectives

Tylš, F., Páleníček, T., Horacek, J. · European Neuropsychopharmacology (2013)

Serotonergic hyperactivity as a potential factor in developmental, acquired and drug-induced synesthesia

Brogaard, B. · Frontiers in Human Neuroscience (2013)

Broadband Cortical Desynchronization Underlies the Human Psychedelic State

Muthukumaraswamy, S. D., Carhart-Harris, R. L., Moran, R. J. et al. · Journal of Neuroscience (2013)

427 cited
Acute effects of ayahuasca on neuropsychological performance: differences in executive function between experienced and occasional users

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Effects of Schedule I drug laws on neuroscience research and treatment innovation

King, C., Nichols, D. E. · Nature Reviews Neuroscience (2013)

Studying the Effects of Classic Hallucinogens in the Treatment of Alcoholism: Rationale, Methodology, and Current Research with Psilocybin

Bogenschutz, M. P. · Current Drug Abuse Reviews (2013)

Use of the Classic Hallucinogen Psilocybin for Treatment of Existential Distress Associated with Cancer

Grob, C. S., Bossis, A. P., Griffiths, R. R. · Preprints (2013)

Psilocybin biases facial recognition, goal-directed behavior, and mood state toward positive relative to negative emotions through different serotonergic subreceptors

Kometer, M., Schmidt, A., Bachmann, R. et al. · Biological Psychiatry (2012)

Therapeutic mechanisms of classic hallucinogens in the treatment of addictions: from indirect evidence to testable hypotheses

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Psilocybin dose-dependently causes delayed, transient headaches in healthy volunteers

Johnson, M. W., Sewell, R. A., Griffiths, R. R. · Drug and Alcohol Dependence (2012)

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Carhart-Harris, R. L., Erritzoe, D., Williams, T. et al. · PNAS (2012)

Psilocybin-Induced Deficits in Automatic and Controlled Inhibition are Attenuated by Ketanserin in Healthy Human Volunteers

Quednow, B. B., Kometer, M., Geyer, M. A. et al. · Neuropsychopharmacology (2011)

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Van Amsterdam, J., Opperhuizen, A., Van Den Brink, W. · Regulatory Toxicology and Pharmacology (2011)

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74 cited
Multiple receptors contribute to the behavioral effects of indoleamine hallucinogens

Halberstadt, A. L., Geyer, M. A. · Neuropharmacology (2011)

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Vollenweider, F. X., Kometer, M. · Nature Reviews Neuroscience (2010)

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Halberstadt, A. L., Nicholas, C. R. · Handbook of Behavioral Neuroscience (2010)

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González-Maeso, J., Sealfon, S. C. · Trends in Neuroscience (2009)

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Wallach, J. V. · Medical Hypotheses (2009)

Serotonin research: contributions to understanding psychoses

Geyer, M. A., Vollenweider, F. X. · Trends in Pharmacological Sciences (2008)

Investigation of serotonin-1A receptor function in the human psychopharmacology of MDMA

Hasler, F., Ludewig, S. · Journal of Psychopharmacology (2008)

Mystical-type experiences occasioned by psilocybin mediate the attribution of personal meaning and spiritual significance 14 months later

Griffiths, R. R. · Journal of Psychopharmacology (2008)

Effects of varied doses of psilocybin on time interval reproduction in human subjects

Wittmann, M., Hasler, F., Vollenweider, F. X. · Neuroscience Letters (2008)

70 cited
Psilocybin links binocular rivalry switch rate to attention and subjective arousal levels in humans

Carter, O. L., Hasler, F. ;., Pettigrew, J. D. et al. · Psychopharmacology (2007)

The behavioral pharmacology of hallucinogens

Fantegrossi, W. E., Murnane, K. S., Reissig, C. J. · Biochemical Pharmacology (2007)

Hallucinogens recruit specific cortical 5-HT(2A) receptor-mediated signaling pathways to affect behavior

Gonza ´lez-Maeso, J., Weisstaub, N. V., Zhou, M. et al. · Neuron (2007)

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Wittmann, M., Carter, O., Hasler, F. et al. · Journal of Psychopharmacology (2007)

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Safety, Tolerability, and Efficacy of Psilocybin in 9 Patients With Obsessive-Compulsive Disorder

Moreno, F. A., Wiegand, C. B., Taitano, E. K. et al. · Journal of Clinical Psychiatry (2006)

Psilocybin can occasion mystical-type experiences having substantial and sustained personal meaning and spiritual significance

Griffiths, R. R., Richards, W. A., Mccann, U. et al. · Journal of Psychopharmacology (2006)

Using Psilocybin to Investigate the Relationship between Attention, Working Memory, and the Serotonin 1A and 2A Receptors

Carter, O., Burr, D. C., Pettigrew, J. D. et al. · Journal of Cognitive Neuroscience (2006)

Psychological effects of (S)-ketamine and N,N-dimethyltryptamine (DMT): a double-blind, cross-over study in healthy volunteers

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Hallucinogens

Nichols, D. E. · Pharmacology and Therapeutics (2004)

Effects of the 5-HT2A Agonist Psilocybin on Mismatch Negativity Generation and AX-Continuous Performance Task: Implications for the Neuropharmacology of Cognitive Deficits in Schizophrenia

Umbricht, A., Vollenweider, F. X., Schmid, L. et al. · Neuropsychopharmacology (2003)

Effects of ayahuasca on sensory and sensorimotor gating in humans as measured by P50 suppression and prepulse inhibition of the startle reflex, respectively

Riba, J., Rodríguez-Fornells, A., Barbanoj, M. J. · Psychopharmacology (2002)

70 cited
Acute psychological effects of 3, 4-methylenedioxymethamphetamine (MDMA,“Ecstasy”) are attenuated by the serotonin uptake inhibitor citalopram

Liechti, M. E., Baumann, C., Gamma, A. et al. · Neuropsychopharmacology (2000)

262 cited

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