Depressive DisordersPTSDSubstance Use Disorders (SUD)

Therapeutic mechanisms of psychedelics and entactogens

This review (2023) highlights the promising rapid and sustained therapeutic effects of psychedelics and entactogens based on recent clinical and preclinical evidence. To better comprehend their impact on mental health, the review emphasizes the importance of bridging the gap between human and rodent studies and shifting the focus to circuit modulation rather than individual molecular targets.

Authors

  • Boris Heifets
  • David Olson

Published

Neuropsychopharmacology
meta Study

Abstract

Recent clinical and preclinical evidence suggests that psychedelics and entactogens may produce both rapid and sustained therapeutic effects across several indications. Currently, there is a disconnect between how these compounds are used in the clinic and how they are studied in preclinical species, which has led to a gap in our mechanistic understanding of how these compounds might positively impact mental health. Human studies have emphasized extra-pharmacological factors that could modulate psychedelic-induced therapeutic responses including set, setting, and integration-factors that are poorly modelled in current animal experiments. In contrast, animal studies have focused on changes in neuronal activation and structural plasticity-outcomes that are challenging to measure in humans. Here, we describe several hypotheses that might explain how psychedelics rescue neuropsychiatric disease symptoms, and we propose ways to bridge the gap between human and rodent studies. Given the diverse pharmacological profiles of psychedelics and entactogens, we suggest that their rapid and sustained therapeutic mechanisms of action might best be described by the collection of circuits that they modulate rather than their actions at any single molecular target. Thus, approaches focusing on selective circuit modulation of behavioral phenotypes might prove more fruitful than target-based methods for identifying novel compounds with rapid and sustained therapeutic effects similar to psychedelics and entactogens.

Available with Blossom Pro

Research Summary of 'Therapeutic mechanisms of psychedelics and entactogens'

Introduction

Heifets and Olson place psychedelics and entactogens in the context of a clinical resurgence: controlled, therapist-supported administrations of compounds such as MDMA and psilocybin have produced rapid and sometimes sustained benefits across conditions including PTSD, depression and substance use disorders. Despite promising clinical signals, the authors note an important translational gap. Preclinical animal work tends to emphasise receptor-level actions and measurable neuroplasticity, whereas human studies highlight subjective-state, contextual and psychotherapeutic factors (commonly summarised as "set, setting and integration") that are poorly modelled in laboratory species. This disconnect has limited mechanistic understanding and the ability to optimise these agents for safety, scalability and efficacy. The review aims to synthesise clinical and preclinical evidence to clarify candidate mechanisms by which psychedelics and entactogens could produce lasting therapeutic effects, to compare competing conceptual models, and to identify how circuit-level approaches might bridge human and rodent studies. The authors argue that, because these drugs are pharmacologically diverse, their rapid and sustained actions are best understood in terms of the neural circuits they engage rather than a single molecular target, and they propose directions for animal experimentation and translational research that reflect this perspective.

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

Study Details

References (98)

Papers cited by this study that are also in Blossom

MDMA-assisted therapy for severe PTSD: a randomized, double-blind, placebo-controlled phase 3 study

Mitchell, J., Bogenschutz, M. P., Lilienstein, A. et al. · Nature Medicine (2021)

Durability of improvement in post-traumatic stress disorder symptoms and absence of harmful effects or drug dependency after 3,4-methylenedioxymethamphetamine-assisted psychotherapy: a prospective long-term follow-up study

Mithoefer, M. C., Wagner, M. T., Mithoefer, A. T. et al. · Journal of Psychopharmacology (2012)

346 cited
Effects of Psilocybin-Assisted Therapy on Major Depressive Disorder

Davis, A. K., Barrett, F. S., May, D. G. et al. · JAMA Psychiatry (2021)

1015 cited
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
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)

Rapid and sustained symptom reduction following psilocybin treatment for anxiety and depression in patients with life-threatening cancer: A randomized controlled trial

Ross, S., Bossis, A. P., Guss, J. et al. · Journal of Psychopharmacology (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
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
Safety, tolerability, pharmacokinetics, and pharmacodynamics of low dose lysergic acid diethylamide (LSD) in healthy older volunteers

Family, N., Maillet, E. L., Williams, L. T. J. et al. · Psychopharmacology (2019)

Hallucinogens in Mental Health: Preclinical and Clinical Studies on LSD, Psilocybin, MDMA, and Ketamine

Hibicke, M., Gobbi, G. · Journal of Neuroscience (2020)

145 cited
Show all 98 references
Psychedelic Agents in Creative Problem-Solving: A Pilot Study

Harman, W. W., McKim, R. H., Mogar, R. E. et al. · Psychological Reports (1966)

Updated cost-effectiveness of MDMA-assisted therapy for the treatment of posttraumatic stress disorder in the United States: Findings from a phase 3 trial

Marseille, E., Mitchell, M. J., Khan, J. G. · PLOS ONE (2022)

Entactogens: How the Name for a Novel Class of Psychoactive Agents Originated

Nichols, D. E. · Frontiers in Psychiatry (2022)

Psychological and cardiovascular effects and short-term sequelae of MDMA (“ecstasy”) in MDMA-naıve healthy volunteers

Vollenweider, F. X., Gamma, A., Liechti, M. et al. · Neuropsychopharmacology (1998)

450 cited
The prosocial effects of 3, 4-methylenedioxymethamphetamine (MDMA): controlled studies in humans and laboratory animals

Kamilar-Britt, P., Bedi, G. · Neuroscience and Biobehavioral Reviews (2015)

Differences Between the Mechanism of Action of MDMA, MBDB, and the Classic Hallucinogens. Identification of a New Therapeutic Class: Entactogens

Nichols, D. E. · Journal of Psychoactive Drugs (1986)

536 cited
Pharmacological effects of methylone and MDMA in humans

Poyatos, L., Pérez-Mañá, C., Hladun, O. et al. · Frontiers in Pharmacology (2023)

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

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

Constructing drug effects: a history of set and setting

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

389 cited
Human hallucinogen research: guidelines for safety

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

The Subjective Effects of Psychedelics Are Necessary for Their Enduring Therapeutic Effects

Yaden, D. B., Griffiths, R. R. · ACS Pharmacology and Translational Science (2020)

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

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

Psychoplastogens: A Promising Class of Plasticity-Promoting Neurotherapeutics

Olson, J. A. · Neuroscience Insights (2018)

Changes in global and thalamic brain connectivity in LSD-induced altered states of consciousness are attributable to the 5-HT2A receptor

Preller, K. H., Burt, J. B., Adkinson, B. et al. · eLife (2018)

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)

Structure-based discovery of nonhallucinogenic psychedelic analogs

Cao, D., Yu, J., Wang, H. et al. · Science (2022)

A non-hallucinogenic psychedelic analogue with therapeutic potential

Cameron, L. P., Tombari, R. J., Lu, J. et al. · Nature (2020)

70 cited
An analog of psychedelics restores functional neural circuits disrupted by unpredictable stress

Lu, J., Tjia, M., Mullen, B. et al. · Molecular Psychiatry (2021)

Bespoke library docking for 5-HT2A receptor agonists with antidepressant activity

Kaplan, A. L., Confair, D. N., Kim, K. et al. · Nature (2022)

Pharmacological Mechanism of the Non-hallucinogenic 5-HT2A Agonist Ariadne and Analogs

Cunningham, M. J., Bock, H. A., Serrano, I. C. et al. · ACS Chemical Neuroscience (2022)

A non-hallucinogenic LSD analog with therapeutic potential for mood disorders

Lewis, V., Bonniwell, E. M., Lanham, J. K. et al. · Cell Reports (2023)

102 cited
Novel psychopharmacological therapies for psychiatric disorders: psilocybin and MDMA

Grob, C. S., Mithoefer, M. C., Brewerton, T. D. · Lancet Psychiatry (2016)

MDMA enhances emotional empathy and prosocial behavior

´dric, C., Hysek, M., Schmid, Y. et al. · Social Cognitive and Affective Neuroscience (2013)

Direct comparison of the acute subjective, emotional, autonomic, and endocrine effects of MDMA, methylphenidate, and modafinil in healthy subjects

Dolder, P. C., Müller, F., Schmid, Y. et al. · Psychopharmacology (2017)

111 cited
Effects of 3,4-Methylenedioxymethamphetamine on Conditioned Fear Extinction and Retention in a Crossover Study in Healthy Subjects

Vizeli, P., Straumann, I., Duthaler, U. et al. · Frontiers in Pharmacology (2022)

REBUS and the Anarchic Brain: Toward a Unified Model of the Brain Action of Psychedelics

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

Effect of lysergic acid diethylamide (LSD) on reinforcement learning in humans

Kanen, J. W., Luo, Q., Kandroodi, M. R. et al. · Psychological Medicine (2020)

Separating the agony from ecstasy: R(-)-3,4-methylenedioxymethamphetamine has prosocial and therapeutic-like effects without signs of neurotoxicity in mice

Curry, D. W., Young, M. B., Tran, A. N. et al. · Neuropharmacology (2017)

MDMA as a Probe and Treatment for Social Behaviors

Heifets, B. D., Malenka, R. C. · Cell (2016)

3,4-Methylenedioxymethamphetamine facilitates fear extinction learning

Young, M. B., Andero, R., Ressler, K. J. et al. · Translational Psychiatry (2015)

A randomized controlled trial of 3,4-methylenedioxymethamphetamine (MDMA) and fear extinction retention in healthy adults

Maples-Keller, J. L., Norrholm, S. D., Burton, M. et al. · Journal of Psychopharmacology (2022)

42 cited
Psychedelics promote neuroplasticity through the activation of intracellular 5-HT2A receptors

Vargas, M. V., Dunlap, L. E., Dong, C. et al. · Science (2023)

330 cited
The neural basis of psychedelic action

Kwan, A. C., Olson, D. E., Preller, K. H. et al. · Nature Medicine (2022)

Trial of Psilocybin versus Escitalopram for Depression

Carhart-Harris, R. L., Giribaldi, B., Watts, R. et al. · New England Journal of Medicine (2021)

927 cited
Percentage of Heavy Drinking Days Following Psilocybin-Assisted Psychotherapy vs Placebo in the Treatment of Adult Patients With Alcohol Use Disorder

Bogenschutz, M. P., Ross, S., Bhatt, S. R. et al. · JAMA Psychiatry (2022)

497 cited
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)

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)

Biochemical Mechanisms Underlying Psychedelic-Induced Neuroplasticity

Olson, D. E. · Biochemistry (2022)

95 cited
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
The Effects of Hallucinogens on Gene Expression

Martin, D. A., Nichols, C. D., Nichols, Á. C. D. · Current Topics in Behavioral Neurosciences (2017)

Psychedelics promote structural and functional neural plasticity

Ly, C., Greb, A. C., Cameron, L. P. et al. · Cell Reports (2018)

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)

Prolonged epigenomic and synaptic plasticity alterations following single exposure to a psychedelic in mice

De La, M., Revenga, F., Zhu, B. et al. · Cell Reports (2021)

167 cited
Repeated lysergic acid diethylamide (LSD) reverses stress-induced anxiety-like behavior, cortical synaptogenesis deficits and serotonergic neurotransmission decline

De Gregorio, D., Inserra, A., Enns, J. P. et al. · Neuropsychopharmacology (2022)

Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo

Shao, L-X,, Liao, C., Gregg, I. et al. · Neuron (2021)

5-HT2ARs Mediate Therapeutic Behavioral Effects of Psychedelic Tryptamines

Cameron, L. P., Patel, S. D., Vargas, M. V. et al. · ACS Chemical Neuroscience (2023)

86 cited
Harnessing psilocybin: antidepressant-like behavioral and synaptic actions of psilocybin are independent of 5-HT2R activation in mice

Hesselgrave, N., Troppoli, T. A., Wulff, A. B. et al. · PNAS (2021)

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)

Psychedelic Resting-state Neuroimaging: A Review and Perspective on Balancing Replication and Novel Analyses

McCulloch, D. E-W., Knudsen, G. M., Barrett, F. S. et al. · Neuroscience and Biobehavioral Reviews (2022)

Subjective reports of the effects of MDMA in a clinical setting

Greer, G. R. · Journal of Psychoactive Drugs (1986)

423 cited
Reduction in social anxiety after MDMA-assisted psychotherapy with autistic adults: a randomized, double-blind, placebo-controlled pilot study

Danforth, A. L., Grob, C. S., Struble, C. et al. · Psychopharmacology (2018)

196 cited
First study of safety and tolerability of 3,4-methylenedioxymethamphetamine-assisted psychotherapy in patients with alcohol use disorder

Sessa, B., Higbed, L., Durant, C. et al. · Journal of Psychopharmacology (2021)

Inhibition of serotonin transporters disrupts the enhancement of fear memory extinction by 3,4-methylenedioxymethamphetamine (MDMA)

Young, M. B., Norrholm, S. D., Khoury, L. M. et al. · Psychopharmacology (2017)

Psychedelics reopen the social reward learning critical period

Nardou, R., Sawyer, E., Song, Y. J. et al. · Nature (2023)

Dark Classics in Chemical Neuroscience: 3,4-Methylenedioxymethamphetamine

Dunlap, L. E., Andrews, A. M. · ACS Chemical Neuroscience (2018)

Psychedelics and Psychedelic-Assisted Psychotherapy

Reiff, C. M., Richman, E. E., Nemeroff, C. B. et al. · American Journal of Psychiatry (2020)

Classic psychedelics: An integrative review of epidemiology, therapeutics, mystical experience, and brain network function

Johnson, M. W., Hendricks, P. S., Barrett, F. S. et al. · Pharmacology and Therapeutics (2019)

Psychedelic-Assisted Psychotherapy-A Systematic Review of Associated Psychological Interventions

Cavarra, M., Falzone, A., Ramaekers, J. G. et al. · Frontiers in Psychology (2022)

Psychedelics and Psychotherapy: Cognitive-Behavioral Approaches as Default

Yaden, D. B., Earp, D., Graziosi, M. et al. · Frontiers in Psychology (2022)

Psychedelics and the essential importance of context

Carhart-Harris, R. L., Roseman, L., Haijen, E. C. H. M. et al. · Journal of Psychopharmacology (2018)

Synthesizing the Evidence for Ketamine and Esketamine in Treatment-Resistant Depression: An International Expert Opinion on the Available Evidence and Implementation

Mcintyre, R. S., Rosenblat, J. D., Nemeroff, C. B. et al. · American Journal of Psychiatry (2021)

Blinding and Expectancy Confounds in Psychedelic Randomised Controlled Trials

Muthukumaraswamy, S., Forsyth, B., Lumley, T. · Expert Review of Clinical Pharmacology (2021)

Great Expectations: Recommendations for improving the methodological rigor of psychedelic clinical trials

Aday, J. S., Heifets, B. D., Pratscher, S. D. et al. · Psychopharmacology (2021)

Adverse events in clinical treatments with serotonergic psychedelics and MDMA: A mixed-methods systematic review

Breeksema, J. J., Kuin, B. W., Kamphuis, J. et al. · Journal of Psychopharmacology (2022)

Positive expectations predict improved mental-health outcomes linked to psychedelic microdosing

Kaertner, L. S., Steinborn, M. B., Kettner, H. et al. · Scientific Reports (2021)

112 cited
Long-term Follow-Up Outcomes of MDMA-assisted Psychotherapy for Treatment of PTSD: A Longitudinal Pooled Analysis of Six Phase 2 Trials

Jerome, L., Feduccia, A. A., Wang, J. B. et al. · Psychopharmacology (2020)

143 cited
Transformative experience and social connectedness mediate the mood-enhancing effects of psychedelic use in naturalistic settings

Forstmann, M., Yudkin, D. A., Prosser, A. M. B. et al. · PNAS (2020)

Psychedelics and connectedness

Carhart-Harris, R. L., Erritzoe, D., Haijen, E. C. H. M. et al. · Psychopharmacology (2017)

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)

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)

Psilocybin and LSD Have No Long-Lasting Effects in an Animal Model of Alcohol Relapse

Meinhardt, M. W., Güngör, C., Skorodumov, I. et al. · Neuropsychopharmacology (2020)

Psilocybin targets a common molecular mechanism for cognitive impairment and increased craving in alcoholism

Barroso Flores, J., Hoffmann, R., Wagner, K. et al. · Science Advances (2021)

Psilocybin sex-dependently reduces alcohol consumption in C57BL/6J mice

Alper, K., Cange, J., Sah, R. et al. · Frontiers in Pharmacology (2023)

Systemic enhancement of serotonin signaling reverses social deficits in multiple mouse models for ASD

Walsh, J. J., Llorach, P., Cardozo Pinto, D. F. et al. · Neuropsychopharmacology (2021)

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

Jefsen, O., Højgaard, K., Christiansen, S. L. et al. · Acta Neuropsychiatrica (2019)

60 cited
Effects of Setting on Psychedelic Experiences, Therapies, and Outcomes: A Rapid Scoping Review of the Literature

Golden, T. L., Magsamen, S., Sandu, C. C. et al. · Current Topics in Behavioral Neurosciences (2022)

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)

Subtypes of the psychedelic experience have reproducible and predictable effects on depression and anxiety symptoms

Nikolaidis, A., Lancelotta, R., Gukasyan, N. et al. · Journal of Affective Disorders (2023)

Tripping on nothing: placebo psychedelics and contextual factors

Olson, J. A., Suissa-Rocheleau, L., Lifshitz, M. et al. · Psychopharmacology (2020)

A placebo-controlled study of the effects of ayahuasca, set and setting on mental health of participants in ayahuasca group retreats

Uthaug, M. V., Mason, N. L., Toennes, S. W. et al. · Psychopharmacology (2021)

Antidepressant effects of a psychedelic experience in a large prospective naturalistic sample

Nygart, V., Pommerencke, L. M., Haijen, E. et al. · Journal of Psychopharmacology (2022)

46 cited
Prevalence and associations of challenging, difficult or distressing experiences using classic psychedelics

Simonsson, O., Hendricks, P. S., Chambers, R. et al. · Journal of Affective Disorders (2023)

Increased global integration in the brain after psilocybin therapy for depression

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

Sensitization to the prosocial effects of 3,4-methylenedioxymethamphetamine (MDMA)

Curry, D. W., Berro, L. F., Belkoff, A. R. et al. · Neuropharmacology (2019)

A retrospective analysis of ketamine intravenous therapy for depression in real-world care settings

Mcinnes, L. A., Qian, J. J., Gargeya, R. S. et al. · Journal of Affective Disorders (2022)

43 cited
Clinical Effectiveness of Intravenous Racemic Ketamine Infusions in a Large Community Sample of Patients With Treatment-Resistant Depression, Suicidal Ideation, and Generalized Anxiety Symptoms: A Retrospective Chart Review

Oliver, P. A., Snyder, A. D., Feinn, R. et al. · Journal of Clinical Psychiatry (2022)

The effects of ketamine on symptoms of depression and anxiety in real-world care settings: a retrospective controlled analysis

Hietamies, T. M., Mcinnes, L. A., Klise, A. J. et al. · Journal of Affective Disorders (2023)

Ketamine psychedelic therapy (KPT): a review of the results of ten years of research

Krupitsky, E. M., Grinenko, A. Y. · Journal of Psychoactive Drugs (1997)

Cited By (4)

Papers in Blossom that reference this study

Psychedelics as a potential treatment for borderline personality disorder: A narrative review

Artna, E., Sandhu, G., Chisamore, N. et al. · Psychiatry Research (2026)

Therapeutic-Like Context and Relational Support During Psychedelic Use Moderate Links Among Stress, Challenging Experiences, and Psychological Outcomes

Cherniak, A. D., Granqvist, P., Mikulincer, M. et al. · Journal of Psychoactive Drugs (2026)

Efficacy and Safety of the Neuroplastogen TSND-201 for the Treatment of PTSD A Randomized Clinical Trial

Jones, A., Warner-Schmidt, J., Kwak, H. et al. · JAMA Psychiatry (2026)

Structure-activity relationships of serotonergic 5-MeO-DMT derivatives: insights into psychoactive and thermoregulatory properties

Puigseslloses, P., Nadal-Gratacós, N., Ketsela, G. et al. · Molecular Psychiatry (2024)

Your Personal Research Library

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

See Pro PlansSign in