Depressive DisordersAnxiety DisordersSubstance Use Disorders (SUD)Palliative & End-of-Life DistressNeuroimaging & Brain MeasuresImmunology & InflammationMedicinal Chemistry & Drug Development

Psychedelics as Medicines: An Emerging New Paradigm

This review (2016) by three prominent researchers looks back at the latest research on psychedelics and their psychological and anti-inflammatory effects.

Authors

  • Matthew Johnson
  • David Nichols
  • Charles Nichols

Published

Clinical Pharmacology and Therapeutics
meta Study

Abstract

Scientific interest in serotonergic psychedelics (e.g., psilocybin and LSD; 5-HT2A receptor agonists) has dramatically increased within the last decade. Clinical studies administering psychedelics with psychotherapy have shown preliminary evidence of robust efficacy in treating anxiety and depression, as well as addiction to tobacco and alcohol. Moreover, recent research has suggested that these compounds have potential efficacy against inflammatory diseases through novel mechanisms, with potential advantages over existing anti-inflammatory agents. We propose that psychedelics exert therapeutic effects for psychiatric disorders by acutely destabilizing local brain network hubs and global network connectivity via amplification of neuronal avalanches, providing the occasion for brain network “resetting” after the acute effects have resolved. Antiinflammatory effects may hold promise for efficacy in the treatment of inflammation-related nonpsychiatric as well as potentially for psychiatric disorders. Serotonergic psychedelics operate through unique mechanisms that show promising effects for a variety of intractable, debilitating, and lethal disorders, and should be rigorously researched.

Available with Blossom Pro

Research Summary of 'Psychedelics as Medicines: An Emerging New Paradigm'

Introduction

Interest in serotonergic psychedelics such as psilocybin and LSD has resurged after decades of minimal clinical research following regulatory restrictions in the 1970s. The extracted text summarises accumulating clinical evidence that single or a few supervised administrations of these agents, given with psychotherapy, produce substantial and sometimes long‑lasting improvements in anxiety and depression related to life‑threatening illness, as well as promising signals in addiction. In addition, preclinical work has identified potent anti‑inflammatory actions mediated by 5‑HT2A receptor activation, suggesting potential utility outside psychiatry. Nichols and colleagues position this article as a synthesis of recent clinical and preclinical developments and as an argument for a possible paradigm shift. They propose a mechanistic hypothesis to account for the broad therapeutic effects: psychedelics transiently destabilise key local brain network hubs and alter global functional connectivity by amplifying neuronal avalanches, creating an opportunity for networks to ‘‘reset’’ after the acute effects subside. The authors argue this mechanism, together with anti‑inflammatory actions, could underlie durable clinical benefit and warrant rigorous further study.

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 (21)

Papers cited by this study that are also in Blossom

Pilot study of psilocybin treatment for anxiety in patients with advanced-stage cancer

Grob, C. S., Danforth, A. L., Chopra, G. S. et al. · JAMA Psychiatry (2011)

Psilocybin with psychological support for treatment-resistant depression: an open-label feasibility study

Carhart-Harris, R. L., Bolstridge, M., Rucker, J. et al. · Lancet Psychiatry (2016)

1174 cited
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)

Validation of the revised Mystical Experience Questionnaire in experimental sessions with psilocybin

Barrett, F. S., Johnson, M. W., Griffiths, R. R. · 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)

389 cited
Antidepressant effects of a single dose of ayahuasca in patients with recurrent depression: a preliminary report

Osório, F. L., Sanches, R. F., Macedo, L. et al. · brazilian Journal of Psychiatry (2015)

420 cited
‘Hitting highs at rock bottom’: LSD treatment for alcoholism, 1950-1970

Dyck, E. · Social History of Medicine (2006)

90 cited
Lysergic acid diethylamide (LSD) for alcoholism: meta-analysis of randomized controlled trials

Krebs, T. S., Johansen, P. Ø. · Journal of Psychopharmacology (2012)

Pilot study of the 5-HT2AR agonist psilocybin in the treatment of tobacco addiction

Johnson, M. W., Garcia-Romeu, A., Cosimano, M. P. et al. · Journal of Psychopharmacology (2014)

Long-term follow-up of psilocybin-facilitated smoking cessation

Johnson, M. W., Garcia-Romeu, A., Griffiths, R. R. · The American Journal of Drug and Alcohol Abuse (2016)

562 cited
Show all 21 references
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)

Assessment of addiction severity among ritual users of ayahuasca

Fábregas, J. M., González, D., Fondevila, S. et al. · Drug and Alcohol Dependence (2010)

222 cited
Human hallucinogen research: guidelines for safety

Johnson, M. W., Richards, W. A., Griffiths, R. R. · Journal of Psychopharmacology (2008)

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)

Mystical experiences occasioned by the hallucinogen psilocybin lead to increases in the personality domain of openness

Maclean, K. A., Johnson, M. W., Griffiths, R. R. · Journal of Psychopharmacology (2011)

The peak experience variable in DPT-assisted psychotherapy with cancer patients

Richards, W. A., Rhead, J. C., Dileo, F. B. et al. · Journal of Psychedelic Drugs (2012)

Implications for psychedelic-assisted psychotherapy: functional magnetic resonance imaging study with psilocybin

Carhart-Harris, R. L., Leech, R., Williams, T. M. et al. · British Journal of Psychiatry (2018)

202 cited
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)

Neural correlates of the LSD experience revealed by multimodal neuroimaging

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

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
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)

Cited By (80)

Papers in Blossom that reference this study

Cognitive and Subjective Effects of Psilocybin Microdosing: Results from Two Double-Blind Placebo-Controlled Longitudinal Trials

Prochazkova, L., Marschall, J., Lippelt, D. P. et al. · Neuropharmacology (2026)

Therapeutic emergence of dissociated traumatic memories during psilocybin treatment for anorexia nervosa

Peck, S. K., Knatz Peck, S., Brewerton, T. D. et al. · Journal of Eating Disorders (2025)

Mind over matter: the microbial mindscapes of psychedelics and the gut-brain axis

Caspani, G., Ruffell, S. G. D., Tsang, WF. et al. · Pharmacological Research (2024)

5-Methoxy-2-aminoindane Reverses Diet-Induced Obesity and Improves Metabolic Parameters in Mice: A Potential New Class of Antiobesity Therapeutics

Baraghithy, S., Gammal, A., Permyakova, A. et al. · ACS Pharmacology and Translational Science (2024)

Psilocybin pulse regimen reduces cluster headache attack frequency in the blinded extension phase of a randomized controlled trial

Schindler, E. A. D., Sewell, R. A., Gottschalk, C. H. et al. · Journal of the Neurological Sciences (2024)

27 cited
CCH attack frequency reduction after psilocybin correlates with hypothalamic functional connectivity

Madsen, M. K., Petersen, A. S., Stenbæk, D. S. et al. · Headache (2024)

36 cited
Serotonin-2 Receptor Agonists Produce Anti-inflammatory Effects through Functionally Selective Mechanisms That Involve the Suppression of Disease-Induced Arginase 1 Expression

Flanagan, T. W., Foster, T. P., Galbato, T. E. et al. · ACS Pharmacology and Translational Science (2024)

Set and setting predict psychopathology, wellbeing and meaningfulness of psychedelic experiences: a correlational study

Borkel, L. F., Rojas-Hernández, J., Henríquez-Hernández, L. A. et al. · Expert Review of Clinical Pharmacology (2023)

The relation between naturalistic use of psychedelics and perception of emotional stimuli: An event-related potential study comparing non-users and experienced users of classic psychedelics

Orłowski, P., Hobot, J., Ruban, A. et al. · Journal of Psychopharmacology (2023)

Overcoming the clinical challenges of traditional ayahuasca: a first-in-human trial exploring novel routes of administration of N,N-Dimethyltryptamine and harmine

Dornbierer, D. A., Marten, L., Mueller, J. et al. · Frontiers in Pharmacology (2023)

Show all 80 papers
The Potential of Psychedelics for the Treatment of Episodic Migraine

Schindler, E. A. D. · Current Pain and Headache Reports (2023)

A phase 1/2 trial to assess safety and efficacy of a vaporized 5-methoxy-N,N-dimethyltryptamine formulation (GH001) in patients with treatment-resistant depression

Reckweg, J., van Leeuwen, C., Theunissen, E. L. et al. · Frontiers in Psychiatry (2023)

62 cited
Subacute effects of a single dose of psilocybin on biomarkers of inflammation in healthy humans: An open-label preliminary investigation

Burmester, D., Madsen, M. K., Szabo, A. et al. · Comprehensive Psychoneuroendocrinology (2023)

Optimizing outcomes in psilocybin therapy: Considerations in participant evaluation and preparation

Modlin, N. L., Miller, T. M., Rucker, J. J. et al. · Journal of Affective Disorders (2023)

Psychedelic-supportive psychotherapy: A psychotherapeutic model for, before and beyond the medicine experience

Wolfson, P. E. · Journal of Psychedelic Studies (2023)

A Multidisciplinary Hypothesis about Serotonergic Psychedelics. Is it Possible that a Portion of Brain Serotonin Comes From the Gut?

Császár, N., Bob, P., Bókkon, I. · Journal of Integrative Neuroscience (2022)

7 cited
Pharmacological, Neural, and Psychological Mechanisms underlying Psychedelics: A Critical Review

van Elk, M., Yaden, D. B. · Neuroscience and Biobehavioral Reviews (2022)

Psychedelics, Mystical Experience, and Therapeutic Efficacy: A Systematic Review

Knight, G., Rucker, J., Cleare, A. J. et al. · Frontiers in Psychiatry (2022)

Exploratory study of the dose-related safety, tolerability, and efficacy of dimethyltryptamine (DMT) in healthy volunteers and major depressive disorder

D’Souza, D. C., Syed, S. A., Safi-Aghdam, H. et al. · Neuropsychopharmacology (2022)

Using a MDMA- and LSD-Group Therapy Model in Clinical Practice in Switzerland and Highlighting the Treatment of Trauma-Related Disorders

Oehen, P., Gasser, P. · Frontiers in Psychiatry (2022)

Magic Mushroom Use: A Qualitative Interview Study of Post-Trip Impacts and Strategies for Optimizing Experiences

Shaw, L., Rea, K., Lachowsky, N. J. et al. · Journal of Psychoactive Drugs (2022)

11 cited
How Low-Doses Of Psychedelics Compliment High Dose Experiences: Observational Evidence In Naturalistic Settings

Ferenstein, G. · SSRN (2022)

Psilocybin Combines Rapid Synaptogenic And Anti-Inflammatory Effects In Vitro

Smedfors, G., Glotfelty, E., Papatziamos, C. et al. · Research Square (2022)

Neural Plasticity in the Ventral Tegmental Area, Aversive Motivation during Drug Withdrawal and Hallucinogenic Therapy

Vargas-Perez, H., Grieder, T. E., Van Der Kooy, D. · Journal of Psychoactive Drugs (2022)

Biochemical Mechanisms Underlying Psychedelic-Induced Neuroplasticity

Olson, D. E. · Biochemistry (2022)

95 cited
Knowledge, Perceptions, and Use of Psychedelics among Individuals with Fibromyalgia

Glynos, N. G., Pierce, J., Davis, A. K. et al. · Journal of Psychoactive Drugs (2022)

Models of psychedelic drug action: modulation of cortical-subcortical circuits

Doss, M. K., Madden, M. B., Gaddis, A. et al. · Brain (2021)

Psychedelic-Inspired Approaches for Treating Neurodegenerative Disorders

Olson, D. E. · Journal of Neurochemistry (2021)

The readiness of psychiatrists to implement psychedelic-assisted psychotherapy

Page, L., Rehman, A., Syed, H. et al. · Frontiers in Psychiatry (2021)

30 cited
Psychedelics as Tools for Belief Transmission. Set, Setting, Suggestibility, and Persuasion in the Ritual Use of Hallucinogens

Dupuis, D. · Frontiers in Psychology (2021)

From Psychiatry to Neurology: Psychedelics as Prospective Therapeutics for Neurodegenerative Disorders

Nichols, C. D., Wiatr, K., Figiel, M. et al. · Journal of Neurochemistry (2021)

63 cited
Psilocybin for End-of-Life Anxiety Symptoms: A Systematic Review and Meta-Analysis

Yang, F., Yang, S., Tseng, P. et al. · Psychiatry Investigation (2021)

Psychedelics for Brain Injury: A Mini-Review

Khan, S. I., Carter, G. T., Aggarwal, S. K. et al. · Frontiers in Neuroscience (2021)

Safer Tripping: Serotonergic Psychedelics and Drug Checking. Submission and Detection Rates, Potential Harms, and Challenges for Drug Analysis

Hirschfeld, T., Smit-Rigter, L., Van Der Gouwe, D. et al. · Current Addiction Reports (2021)

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)

Does psychedelic therapy have a transdiagnostic action and prophylactic potential?

Kočárová, C., Horacek, J., Carhart-Harris, R. L. · Frontiers in Psychiatry (2021)

73 cited
Naturalistic Entheogenics: Précis of Philosophy of Psychedelics

Letheby, C. · Psyarxiv (2021)

2 cited
Relational Processes in Ayahuasca Groups of Palestinians and Israelis

Roseman, L., Ron, Y., Saca, A. et al. · Frontiers in Pharmacology (2021)

30 cited
Clinical and biological predictors of psychedelic response in the treatment of psychiatric and addictive disorders: a systematic review

Romeo, B., Hermand, M., Pétillion, A. et al. · Journal of Psychiatric Research (2021)

60 cited
Psychedelic Communitas: Intersubjective experience during psychedelic group sessions predicts enduring changes in psychological wellbeing and social connectedness

Kettner, H., Rosas, F. E., Timmermann, C. et al. · Frontiers in Pharmacology (2021)

157 cited
The Subjective Effects of Psychedelics May Not Be Necessary for Their Enduring Therapeutic Effects

Olson, D. E. · ACS Pharmacology and Translational Science (2020)

Psychedelics as an emerging novel intervention in the treatment of substance use disorder: a review

DiVito, A. J., Leger, R. F. · Molecular Biology Reports (2020)

Long-term Amelioration of OCD Symptoms in a Patient with Chronic Consumption of Psilocybin-containing Mushrooms

Lugo-Radillo, A., Cortes-Lopez, J. L. · Journal of Psychoactive Drugs (2020)

25 cited
MDMA-induced changes in within-network connectivity contradict the specificity of these alterations for the effects of serotonergic hallucinogens

Holze, F., Dolder, P. C., Ley, L. et al. · Neuropsychopharmacology (2020)

Acute dose-dependent effects of lysergic acid diethylamide in a double-blind placebo-controlled study in healthy subjects

Holze, F., Vizeli, P., Ley, L. et al. · Neuropsychopharmacology (2020)

192 cited
Psychedelics as a Novel Approach to Treating Autoimmune Conditions

Thompson, C., Szabo, A. · Immunology Letters (2020)

Transient Stimulation with Psychoplastogens Is Sufficient to Initiate Neuronal Growth

Greb, A. C., Vargas, M. V., Duim, W. C. et al. · ACS Pharmacology and Translational Science (2020)

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)

Psilocybin as a New Approach to Treat Depression and Anxiety in the Context of Life-Threatening Diseases-A Systematic Review and Meta-Analysis of Clinical Trials

Vargas, A. S., Luís, Â., Barroso, M. et al. · Biomedicines (2020)

Psychedelic Treatments for Psychiatric Disorders: A Systematic Review and Thematic Synthesis of Patient Experiences in Qualitative Studies

Breeksema, J. J., Niemeijer, A. R., Krediet, E. et al. · CNS Drugs (2020)

Ethics and ego dissolution: the case of psilocybin

Smith, W. R., Sisti, D. · Journal of Medical Ethics (2020)

Psilocybin: from ancient magic to modern medicine

Nichols, D. E. · Journal of Antibiotics (2020)

Chronic pain and psychedelics: a review and proposed mechanism of action

Castellanos, J. P., Woolley, C., Bruno, K. A. et al. · Regional Anesthesia and Pain Medicine (2020)

101 cited
Reviewing the potential of psychedelics for the treatment of PTSD

Krediet, E., Bostoen, T., Breeksema, J. J. et al. · International Journal of Neuropsychopharmacology (2020)

Classic psychedelics as therapeutics for psychiatric disorders

Nichols, C. D., Hendricks, P. S. · Handbook of Behavioral Neuroscience (2020)

Twenty percent better with 20 micrograms? A qualitative study of psychedelic microdosing self-rapports and discussions on YouTube

Andersson, M., Kjellgren, A. · Harm Reduction Journal (2019)

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

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

126 cited
Acute effects of lysergic acid diethylamide (LSD) on resting brain function

Felix, M., Stefan, B. · Swiss Medical Weekly (2019)

Cessation and reduction in alcohol consumption and misuse after psychedelic use

Garcia-Romeu, A., Davis, A. K., Fire Erowid et al. · Journal of Psychopharmacology (2019)

211 cited
Psychedelic medicine: The biology underlying the persisting psychedelic effects

Kuypers, K. P. C. · Medical Hypotheses (2019)

Chronic, Intermittent Microdoses of the Psychedelic N, N-Dimethyltryptamine (DMT) Produce Positive Effects on Mood and Anxiety in Rodents

Cameron, L. P., Benson, C. J., Defelice, B. C. et al. · ACS Chemical Neuroscience (2019)

Ayahuasca and Public Health: Health Status, Psychosocial Well-Being, Lifestyle, and Coping Strategies in a Large Sample of Ritual Ayahuasca Users

Ona, G., Kohek, M., Massaguer, T. et al. · Journal of Psychoactive Drugs (2019)

A systematic study of microdosing psychedelics

Polito, V., Stevenson, R. J. · PLOS ONE (2019)

197 cited
Psychiatry might need some psychedelic therapy

Johnson, M. W. · International Review of Psychiatry (2018)

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

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

Predicting responses to psychedelics: a prospective study

Haijen, E. C. H. M., Kaelen, M., Roseman, L. et al. · Frontiers in Pharmacology (2018)

339 cited
Awe: a putative mechanism underlying the effects of classic psychedelic-assisted psychotherapy

Hendricks, P. S. · International Review of Psychiatry (2018)

143 cited
Psychedelics as anti-inflammatory agents

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

Psychedelic-Assisted Psychotherapy: A Paradigm Shift in Psychiatric Research and Development

Schenberg, E. E. · Frontiers in Pharmacology (2018)

Psychedelics promote structural and functional neural plasticity

Ly, C., Greb, A. C., Cameron, L. P. et al. · Cell Reports (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)

Out of the box: A psychedelic model to study the creative mind

Kuypers, K. P. C. · Medical Hypotheses (2018)

Effects of N, N-Dimethyltryptamine on Rat Behaviors Relevant to Anxiety and Depression

Cameron, L. P., Benson, C. J., Dunlap, L. E. · ACS Chemical Neuroscience (2018)

The Meaning-Enhancing Properties of Psychedelics and Their Mediator Role in Psychedelic Therapy, Spirituality, and Creativity

Hartogsohn, I. · Frontiers in Human Neuroscience (2018)

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

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

Altered network hub connectivity after acute LSD administration

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

142 cited
Psychedelic Drugs in Biomedicine

Kyzar, E. J., Nichols, C. D., Gainetdinov, R. R. et al. · Trends in Pharmacological Sciences (2017)

Potential Therapeutic Effects of Psilocybin

Johnson, M. W., Griffiths, R. R. · Neurotherapeutics (2017)

Psilocybin-Assisted Therapy: A Review of a Novel Treatment for Psychiatric Disorders

Thomas, K., Malcolm, B., Lastra, D. · Journal of Psychoactive Drugs (2017)

Modern clinical research on LSD

Liechti, M. E. · Neuropsychopharmacology (2017)

Your Personal Research Library

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

See Pro PlansSign in