Depressive DisordersSubstance Use Disorders (SUD)Neuroimaging & Brain MeasuresDMTLSDPsilocybin

Synergistic, multi-level understanding of psychedelics: three systematic reviews and meta-analyses of their pharmacology, neuroimaging and phenomenology

This systematic review (2024) and meta-analysis (s=44) finds that medium/high doses of LSD yield higher ratings of visionary restructuralisation than psilocybin. It also reports that psychedelics strengthen between-network functional connectivity and diminish within-network connectivity, and that LSD induces more inositol phosphate formation at the 5-HT2A receptor than DMT or psilocin, while receptor selectivity differences remain negligible.

Authors

  • Robin Carhart-Harris
  • Katrin Preller
  • Morten Kringelbach

Published

Translational Psychiatry
meta Study

Abstract

Serotonergic psychedelics induce altered states of consciousness and have shown potential for treating a variety of neuropsychiatric disorders, including depression and addiction. Yet their modes of action are not fully understood. Here, we provide a novel, synergistic understanding of psychedelics arising from systematic reviews and meta-analyses of three hierarchical levels of analysis: (1) subjective experience (phenomenology), (2) neuroimaging and (3) molecular pharmacology. Phenomenologically, medium and high doses of LSD yield significantly higher ratings of visionary restructuralisation than psilocybin on the 5-dimensional Altered States of Consciousness Scale. Our neuroimaging results reveal that, in general, psychedelics significantly strengthen between-network functional connectivity (FC) while significantly diminishing within-network FC. Pharmacologically, LSD induces significantly more inositol phosphate formation at the 5-HT2A receptor than DMT and psilocin, yet there are no significant between-drug differences in the selectivity of psychedelics for the 5-HT2A, 5-HT2C, or D2 receptors, relative to the 5-HT1A receptor. Our meta-analyses link DMT, LSD, and psilocybin to specific neural fingerprints at each level of analysis. The results show a highly non-linear relationship between these fingerprints. Overall, our analysis highlighted the high heterogeneity and risk of bias in the literature. This suggests an urgent need for standardising experimental procedures and analysis techniques, as well as for more research on the emergence between different levels of psychedelic effects.

Available with Blossom Pro

Research Summary of 'Synergistic, multi-level understanding of psychedelics: three systematic reviews and meta-analyses of their pharmacology, neuroimaging and phenomenology'

Introduction

Serotonergic psychedelics — including DMT, LSD, and psilocybin — alter consciousness profoundly and have attracted renewed clinical interest for neuropsychiatric disorders, yet their mechanisms remain incompletely understood. Prior research has typically examined each level of analysis — subjective phenomenology, functional neuroimaging, and molecular pharmacology — in isolation, precluding meaningful cross-level synthesis. This paper aimed to resolve that limitation by conducting systematic reviews and meta-analyses at all three hierarchical levels simultaneously for the three classical tryptamine psychedelics, and integrating the findings using a common framework based on the seven canonical Yeo resting-state cortical networks.

Expert Research Summaries

Go Pro to access AI-powered section-by-section summaries, editorial takes, and the full research toolkit.

See Pro PlansAlready have an account? Sign in

Full Text PDF

Full Paper PDF

Pro members can view the original manuscript directly in the browser.

See Pro PlansAlready have an account? Sign in
Open PDF in new tab

Study Details

References (65)

Papers cited by this study that are also in Blossom

Psychedelic Psychiatry’s Brave New World

Nutt, D. J., Erritzoe, D., Carhart-Harris, R. L. · Cell (2020)

Treating Addiction: Perspectives from EEG and Imaging Studies on Psychedelics

Tófoli, L. F., De Araujo, D. B. · International Review of Neurobiology (2016)

Must Psilocybin Always “Assist Psychotherapy”?

Goodwin, G. M., Malievskaia, E., Fonzo, G. A. et al. · American Journal of Psychiatry (2023)

Psilocybin-occasioned mystical-type experience in combination with meditation and other spiritual practices produces enduring positive changes in psychological functioning and in trait measures of prosocial attitudes and behaviors

Griffiths, R. R., Johnson, M. W., Richards, W. A. et al. · Journal of Psychopharmacology (2017)

393 cited
Psychedelics and Consciousness: Distinctions, Demarcations, and Opportunities

Yaden, D. B., Johnson, M. W., Griffiths, R. R. et al. · International Journal of Neuropsychopharmacology (2021)

Psychometric evaluation of the altered states of consciousness rating scale (OAV)

Studerus, E., Gamma, A., Vollenweider, F. X. · PLOS ONE (2010)

Direct comparison of the acute effects of lysergic acid diethylamide and psilocybin in a double-blind placebo-controlled study in healthy subjects

Holze, F., Ley, L., Müller, F. et al. · Neuropsychopharmacology (2022)

169 cited
Comparative acute effects of mescaline, lysergic acid diethylamide, and psilocybin in a randomized, double-blind, placebo-controlled cross-over study in healthy participants

Ley, L., Holze, F., Arikci, D. et al. · Neuropsychopharmacology (2023)

138 cited
Recreational Psychedelic Users Frequently Encounter Complete Mystical Experiences: Trip Content and Implications for Wellbeing

Qiu, X., Minda, J. P. · Psyarxiv (2021)

5 cited
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)

Show all 65 references
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)

Neural correlates of the psychedelic state as determined by fMRI studies with psilocybin

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

Psilocybin for treatment-resistant depression: fMRI-measured brain mechanisms

Carhart-Harris, R. L., Roseman, L., Bolstridge, M. et al. · Scientific Reports (2017)

Increased global integration in the brain after psilocybin therapy for depression

Daws, R. E., Timmermann, C., Giribaldi, B. et al. · Nature Medicine (2022)

Psilocybin therapy increases cognitive and neural flexibility in patients with major depressive disorder

Doss, M. K., Považan, M., Rosenberg, M. D. et al. · Translational Psychiatry (2021)

249 cited
Therapeutic mechanisms of psilocybin: Changes in amygdala and prefrontal functional connectivity during emotional processing after psilocybin for treatment-resistant depression

Mertens, L. J., Wall, M. B., Roseman, L. et al. · Journal of Psychopharmacology (2020)

155 cited
Increased amygdala responses to emotional faces after psilocybin for treatment-resistant depression

Roseman, L., Demetriou, L., Wall, M. B. et al. · Neuropharmacology (2018)

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)

The entropic brain - revisited

Carhart-Harris, R. L. · Neuropharmacology (2018)

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)

818 cited
Hallucinogens and Serotonin 5-HT2A Receptor-Mediated Signaling Pathways

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

211 cited
The fabric of meaning and subjective effects in LSD-induced states depend on serotonin 2A receptor activation

Preller, K. H., Herdener, M., Pokorny, T. et al. · Current Biology (2017)

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)

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

Vollenweider, F. X., Vollenweider-Scherpenhuyzen, M. F. I., Bäbler, A. et al. · NeuroReport (1998)

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

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

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

Pokorny, T., Preller, K. H., Kraehenmann, R. et al. · European Neuropsychopharmacology (2016)

103 cited
Psychological and physiological effects of extended DMT

Luan, L. X., Eckernäs, E., Ashton, M. et al. · Journal of Psychopharmacology (2023)

Acute effects of intravenous DMT in a randomized placebo-controlled study in healthy participants

Vogt, S. B., Ley, L., Erne, L. et al. · Translational Psychiatry (2023)

64 cited
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
The effects of the preferential 5-HT2A agonist psilocybin on prepulse inhibition of startle in healthy human volunteers depend on interstimulus interval

Vollenweider, F. X., Csomor, P. A., Knappe, B. et al. · Neuropsychopharmacology (2007)

Neural correlates of the LSD experience revealed by multimodal neuroimaging

Carhart-Harris, R. L., Muthukumaraswamy, S., Roseman, L. et al. · PNAS (2016)

The effect of lysergic acid diethylamide (LSD) on whole-brain functional and effective connectivity

Bedford, P., Hauke, D. J., Wang, Z. et al. · Neuropsychopharmacology (2022)

Psilocybin acutely alters the functional connectivity of the claustrum with brain networks that support perception, memory, and attention

Barrett, F. S., Krimmel, S. R., Griffiths, R. R. et al. · NeuroImage (2020)

Receptor interaction profiles of novel psychoactive tryptamines compared with classic hallucinogens

Rickli, A., Moning, O. D., Hoener, M. C. et al. · European Neuropsychopharmacology (2016)

Dynamic coupling of whole-brain neuronal and neurotransmitter systems

Kringelbach, M. L., Cruzat, J., Cabral, J. et al. · PNAS (2020)

238 cited
Transcriptomics-informed large-scale cortical model captures topography of pharmacological neuroimaging effects of LSD

Burt, J. B., Preller, K. H., Demirtaş, M. et al. · eLife (2021)

Emotions and brain function are altered up to one month after a single high dose of psilocybin

Barrett, F. S., Doss, M. K., Sepeda, N. D. et al. · Scientific Reports (2020)

Serotonergic psychedelic drugs LSD and psilocybin reduce the hierarchical differentiation of unimodal and transmodal cortex

Girn, M., Roseman, L., Bernhardt, B. et al. · NeuroImage (2022)

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)

Psilocybin-induced changes in brain network integrity and segregation correlate with plasma psilocin level and psychedelic experience

Madsen, M. K., Stenbaek, D. S., Arvidsson, A. et al. · European Neuropsychopharmacology (2021)

Altered network hub connectivity after acute LSD administration

Müller, F., Dolder, P. C., Schmidt, A. et al. · NeuroImage (2018)

142 cited
The effects of psilocybin and MDMA on between-network resting state functional connectivity in healthy volunteers

Roseman, L., Leech, R., Feilding, A. et al. · Frontiers in Human Neuroscience (2014)

229 cited
Psilocybin Induces Aberrant Prediction Error Processing of Tactile Mismatch Responses-A Simultaneous EEG-FMRI Study

Duerler, P., Brem, S., Fraga-González, G. et al. · Cerebral Cortex (2021)

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

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

Serotonergic Hallucinogen-Induced Visual Perceptual Alterations

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

Single-Dose Psilocybin for a Treatment-Resistant Episode of Major Depression

Goodwin, G. M., Aaronson, S. T., Alvarez, O. et al. · New England Journal of Medicine (2022)

656 cited
Single-Dose Psilocybin Treatment for Major Depressive Disorder: A Randomized Clinical Trial

Raison, C. L., Sanacora, G., Woolley, J. D. et al. · JAMA (2023)

375 cited
Single-dose psilocybin-assisted therapy in major depressive disorder: A placebo-controlled, double-blind, randomised clinical trial

Schindowski, E. M., Jungwirth, J., Schuldt, A. et al. · EClinicalMedicine (2023)

Increased global functional connectivity correlates with LSD-induced ego dissolution

Tagliazucchi, E., Roseman, L., Kaelen, M. et al. · Current Biology (2016)

Embedding existential psychology within psychedelic science: reduced death anxiety as a mediator of the therapeutic effects of psychedelics.

Moreton, S. G., Szalla, L., Menzies, R. E. et al. · Psychopharmacology (2019)

47 cited
Ego-dissolution and psychedelics: validation of the ego-dissolution inventory (EDI)

Nour, M. R., Evans, J., Nutt, D. J. et al. · Frontiers in Human Neuroscience (2016)

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)

LSD alters dynamic integration and segregation in the human brain

Luppi, A. I., Carhart-Harris, R. L., Roseman, L. et al. · NeuroImage (2021)

141 cited
The psychedelic state induced by ayahuasca modulates the activity and connectivity of the default mode network

Palhano-Fontes, F., Andrade, K. C., Tófoli, L.F. et al. · PLOS ONE (2015)

Subacute Effects of the Psychedelic Ayahuasca on the Salience and Default Mode Networks

Pasquini, L., Palhano-Fontes, F., Araújo, D. B. · Journal of Psychopharmacology (2020)

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

Smigielski, L., Scheidegger, M., Kometer, M. et al. · NeuroImage (2019)

Functional connectivity measures after psilocybin inform a novel hypothesis of early psychosis

Carhart-Harris, R. L., Leech, R., Erritzoe, D. et al. · Schizophrenia Bulletin (2012)

241 cited
The Acute Effects of the Atypical Dissociative Hallucinogen Salvinorin A on Functional Connectivity in the Human Brain

Doss, M. K., May, D. G., Johnson, M. W. et al. · Scientific Reports (2020)

Functional imaging studies of acute administration of classic psychedelics, ketamine, and MDMA: Methodological limitations and convergent results

Linguiti, S., Vogel, J. W., Sydnor, V. J. et al. · Neuroscience and Biobehavioral Reviews (2023)

11 cited
LSD modulates music-induced imagery via changes in parahippocampal connectivity

Kaelen, M., Roseman, L., Kahan, J. et al. · European Neuropsychopharmacology (2016)

Psilocybin modulates functional connectivity of the amygdala during emotional face discrimination

Grimm, O., Kraehenmann, R., Preller, K. H. et al. · European Neuropsychopharmacology (2018)

Differential contributions of serotonergic and dopaminergic functional connectivity to the phenomenology of LSD

Lawn, T., Dipasquale, O., Vamvakas, A. et al. · Psychopharmacology (2022)

40 cited
Whole-brain multimodal neuroimaging model using serotonin receptor maps explains non-linear functional effects of LSD

Deco, G., Cruzat, J., Cabral, J. et al. · Current Biology (2018)

Effects of classic psychedelic drugs on turbulent signatures in brain dynamics

Cruzat, J., Perl, Y. S., Escrichs, A. et al. · Network Neuroscience (2022)

19 cited
Quality of acute psychedelic experience predicts therapeutic efficacy of psilocybin for treatment-resistant depression

Roseman, L., Nutt, D. J., Carhart-Harris, R. L. · Frontiers in Pharmacology (2018)

Cited By (2)

Papers in Blossom that reference this study

Psychedelic medicine: mechanisms, evidence, and translation to practice

Jacobs, E., Zahid, Z., Hinkle, J. et al. · BMJ (2026)

Network control energy reductions under DMT relate to serotonin receptors, signal diversity, and subjective experience

Singleton, S. P., Timmermann, C., Luppi, A. I. et al. · Communications Biology (2025)

Your Personal Research Library

Go Pro to save papers, add notes, rate studies, and organize your research into custom shelves.

See Pro PlansSign in