Serotonergic psychedelics for depression: What do we know about neurobiological mechanisms of action?

Introduction Current treatment options for major depressive disorder (MDD) have limited efficacy and are associated with adverse effects. Recent studies investigating the antidepressant effect of serotonergic psychedelics—also known as classic psychedelics—have promising preliminary results with large effect sizes. In this context, we conducted a review of the putative neurobiological underpinnings of the mechanism of antidepressant action of these drugs. Methods A narrative review was conducted using PubMed to identify published articles evaluating the antidepressant mechanism of action of serotonergic psychedelics. Results Serotonergic psychedelics have serotonin (5HT)2A agonist or partial agonist effects. Their rapid antidepressant effects may be mediated—in part—by their potent 5HT2A agonism, leading to rapid receptor downregulation. In addition, these psychedelics impact brain derived neurotrophic factor and immunomodulatory responses, both of which may play a role in their antidepressant effect. Several neuroimaging and neurophysiology studies evaluating mechanistic change from a network perspective can help us to further understand their mechanism of action. Some, but not all, data suggest that psychedelics may exert their effects, in part, by disrupting the activity of the default mode network, which is involved in both introspection and self-referential thinking and is over-active in MDD. Conclusion The mechanisms of action underlying the antidepressant effect of serotonergic psychedelics remains an active area of research. Several competing theories are being evaluated and more research is needed to determine which ones are supported by the most robust evidence.

• Publication year

  2023

• Venue

  Frontiers in Psychiatry

• Publication date

  2023-02-10

• Fields of study

  Medicine, Psychology

• Identifiers
  DOI 10.3389/fpsyt.2022.1076459PMID 36844032PMCID 9950579
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Exposure to per- and Polyfluoroalkyl Substances and Markers of Liver Injury: A Systematic Review and Meta-Analysis

  2022cited by this paper
• Neural mechanisms underlying psilocybin’s therapeutic potential – the need for preclinical in vivo electrophysiology

  2022influential reference
• Increased global integration in the brain after psilocybin therapy for depression

  2022influential reference
• Harnessing psilocybin: antidepressant-like behavioral and synaptic actions of psilocybin are independent of 5-HT2R activation in mice

  2021cited by this paper
• Acute Effects of Psilocybin After Escitalopram or Placebo Pretreatment in a Randomized, Double‐Blind, Placebo‐Controlled, Crossover Study in Healthy Subjects

  2021influential reference
• Low doses of LSD reduce broadband oscillatory power and modulate event-related potentials in healthy adults

  2021cited by this paper
• Psilocin, LSD, mescaline, and DOB all induce broadband desynchronization of EEG and disconnection in rats with robust translational validity

  2021cited by this paper
• Effects of unilateral tDCS over left prefrontal cortex on emotion regulation in depression: Evidence from concurrent functional magnetic resonance imaging

  2021cited by this paper
• Anti-Inflammatory Effects of Four Psilocybin-Containing Magic Mushroom Water Extracts in vitro on 15-Lipoxygenase Activity and on Lipopolysaccharide-Induced Cyclooxygenase-2 and Inflammatory Cytokines in Human U937 Macrophage Cells

  2021cited by this paper
• Lasting effects of a single psilocybin dose on resting-state functional connectivity in healthy individuals

  2021cited by this paper
• Psilocybin-induced changes in brain network integrity and segregation correlate with plasma psilocin level and psychedelic experience

  2021cited by this paper
• Trial of Psilocybin versus Escitalopram for Depression.

  2021cited by this paper
• Hallucinogenic/psychedelic 5HT2A receptor agonists as rapid antidepressant therapeutics: Evidence and mechanisms of action

  2021cited by this paper
• Psilocybin therapy increases cognitive and neural flexibility in patients with major depressive disorder

  2021influential reference
• Psilocybin acutely alters the functional connectivity of the claustrum with brain networks that support perception, memory, and attention

  2020cited by this paper
• Changes in inflammatory biomarkers are related to the antidepressant effects of Ayahuasca

  2020cited by this paper
• Low Doses of LSD Acutely Increase BDNF Blood Plasma Levels in Healthy Volunteers

  2020cited by this paper
• Toxicity of ayahuasca after 28 days daily exposure and effects on monoamines and brain-derived neurotrophic factor (BDNF) in brain of Wistar rats

  2020cited by this paper
• Psilocybin Induces Time-Dependent Changes in Global Functional Connectivity.

  2020cited by this paper
• Effects of Psilocybin-Assisted Therapy on Major Depressive Disorder

  2020cited by this paper
• Intrinsic Connectivity Networks in the Self- and Other-Referential Processing

  2020cited by this paper
• Psychedelics in Psychiatry: Neuroplastic, Immunomodulatory, and Neurotransmitter Mechanisms

  2020cited by this paper
• Therapeutic mechanisms of psilocybin: Changes in amygdala and prefrontal functional connectivity during emotional processing after psilocybin for treatment-resistant depression

  2020cited by this paper
• Modulation of Serum Brain-Derived Neurotrophic Factor by a Single Dose of Ayahuasca: Observation From a Randomized Controlled Trial

  2019cited by this paper
• Attentional bias in depression: understanding mechanisms to improve training and treatment.

  2019cited by this paper
• Effect of Different Laser Wavelengths on Periodontopathogens in Peri-Implantitis: A Review of In Vivo Studies

  2019cited by this paper
• Psilocybin-assisted mindfulness training modulates self-consciousness and brain default mode network connectivity with lasting effects

  2019cited by this paper
• Classic psychedelics: An integrative review of epidemiology, therapeutics, mystical experience, and brain network function

  2019cited by this paper
• Hallucinogens and Serotonin 5-HT2A Receptor-Mediated Signaling Pathways.

  2018cited by this paper
• Rapid antidepressant effects of the psychedelic ayahuasca in treatment-resistant depression: a randomized placebo-controlled trial

  2018cited by this paper
• Psychedelics: Where we are now, why we got here, what we must do.

  2018cited by this paper
• A brain network model for depression: From symptom understanding to disease intervention

  2018cited by this paper
• Psychedelics as anti-inflammatory agents

  2018cited by this paper
• Psilocybin modulates functional connectivity of the amygdala during emotional face discrimination.

  2018cited by this paper
• A Single Dose of 5-MeO-DMT Stimulates Cell Proliferation, Neuronal Survivability, Morphological and Functional Changes in Adult Mice Ventral Dentate Gyrus

  2018cited by this paper
• Canadian Network for Mood and Anxiety Treatments (CANMAT) 2016 Clinical Guidelines for the Management of Adults with Major Depressive Disorder: Section 5. Complementary and Alternative Medicine Treatments.

  2018cited by this paper
• Changes in global and thalamic brain connectivity in LSD-induced altered states of consciousness are attributable to the 5-HT2A receptor

  2018cited by this paper
• Altered network hub connectivity after acute LSD administration

  2018cited by this paper
• Unifying Theories of Psychedelic Drug Effects

  2018cited by this paper
• Acute effects of LSD on amygdala activity during processing of fearful stimuli in healthy subjects

  2017cited by this paper
• Increased amygdala responses to emotional faces after psilocybin for treatment‐resistant depression

  2017influential reference
• Psilocybin for treatment-resistant depression: fMRI-measured brain mechanisms

  2017cited by this paper
• Rumination and Default Mode Network Subsystems Connectivity in First-episode, Drug-Naive Young Patients with Major Depressive Disorder

  2017cited by this paper
• How do antidepressants work? New perspectives for refining future treatment approaches.

  2017cited by this paper
• d-Lysergic Acid Diethylamide (LSD) as a Model of Psychosis: Mechanism of Action and Pharmacology

  2016cited by this paper
• Psilocybin produces substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer: A randomized double-blind trial

  2016cited by this paper
• Increased Global Functional Connectivity Correlates with LSD-Induced Ego Dissolution.

  2016cited by this paper
• Decreased mental time travel to the past correlates with default-mode network disintegration under lysergic acid diethylamide

  2016cited by this paper
• Antidepressant Effects of a Single Dose of Ayahuasca in Patients With Recurrent Depression: A SPECT Study

  2016cited by this paper
• Psilocybin with psychological support for treatment-resistant depression: an open-label feasibility study.

  2016cited by this paper
• Canadian Network for Mood and Anxiety Treatments (CANMAT) 2016 Clinical Guidelines for the Management of Adults with Major Depressive Disorder

  2016cited by this paper
• Neural correlates of the LSD experience revealed by multimodal neuroimaging

  2016cited by this paper
• Receptor interaction profiles of novel psychoactive tryptamines compared with classic hallucinogens.

  2016cited by this paper
• The Psychedelic State Induced by Ayahuasca Modulates the Activity and Connectivity of the Default Mode Network

  2015cited by this paper
• Hallucinogenic drugs in pre-Columbian Mesoamerican cultures.

  2015cited by this paper
• Psilocybin-Induced Decrease in Amygdala Reactivity Correlates with Enhanced Positive Mood in Healthy Volunteers.

  2015cited by this paper
• Hallucinogenic drugs in pre-Columbian Mesoamerican cultures☆

  2015cited by this paper
• Neuropsychological mechanism underlying antidepressant effect: a systematic meta-analysis

  2014cited by this paper
• Safety and Efficacy of Lysergic Acid Diethylamide-Assisted Psychotherapy for Anxiety Associated With Life-threatening Diseases

  2014cited by this paper
• The entropic brain: a theory of conscious states informed by neuroimaging research with psychedelic drugs

  2014cited by this paper
• Psychedelic N,N-Dimethyltryptamine and 5-Methoxy-N,N-Dimethyltryptamine Modulate Innate and Adaptive Inflammatory Responses through the Sigma-1 Receptor of Human Monocyte-Derived Dendritic Cells

  2014cited by this paper
• Exercise ameliorates depression-like behavior and increases hippocampal BDNF level in ovariectomized rats.

  2014cited by this paper
• Monoamine neurocircuitry in depression and strategies for new treatments.

  2013cited by this paper
• Inflammatory cytokines in depression: neurobiological mechanisms and therapeutic implications.

  2013cited by this paper
• Broadband Cortical Desynchronization Underlies the Human Psychedelic State

  2013cited by this paper
• Effects of psilocybin on hippocampal neurogenesis and extinction of trace fear conditioning

  2013cited by this paper
• Functional connectivity measures after psilocybin inform a novel hypothesis of early psychosis.

  2013cited by this paper
• Fluoxetine-Induced Cortical Adult Neurogenesis

  2013cited by this paper
• Use of the Classic Hallucinogen Psilocybin for Treatment of Existential Distress Associated with Cancer

  2013cited by this paper
• Activation of Serotonin 2A Receptors Underlies the Psilocybin-Induced Effects on α Oscillations, N170 Visual-Evoked Potentials, and Visual Hallucinations

  2013cited by this paper
• Pharmacology of ayahuasca administered in two repeated doses

  2012cited by this paper
• Neural correlates of the psychedelic state as determined by fMRI studies with psilocybin

  2012cited by this paper
• Short-term SSRI treatment normalises amygdala hyperactivity in depressed patients

  2012cited by this paper
• Serum BDNF levels before treatment predict SSRI response in depression.

  2011cited by this paper
• Optimizing the technological and informational relationship of the health care process and of the communication between physician and patient. The impact of Preventive Medicine and social marketing applied in Health Care on youth awareness–Preliminary study

  2011cited by this paper
• A meta-analysis of cytokines in major depression.

  2010cited by this paper
• Prevalence and predictors of recurrence of major depressive disorder in the adult population

  2009cited by this paper
• What did STAR*D teach us? Results from a large-scale, practical, clinical trial for patients with depression.

  2009cited by this paper
• National patterns in antidepressant medication treatment.

  2009cited by this paper
• From inflammation to sickness and depression: when the immune system subjugates the brain

  2008cited by this paper
• The molecular neurobiology of depression

  2008cited by this paper
• Low plasma BDNF is associated with suicidal behavior in major depression.

  2007cited by this paper
• Decreased plasma BDNF level in depressive patients.

  2007cited by this paper
• The immune-mediated alteration of serotonin and glutamate: towards an integrated view of depression

  2007cited by this paper
• Continuity of antidepressant treatment for adults with depression in the United States.

  2006cited by this paper
• Dysfunction in the neural circuitry of emotional self-regulation in major depressive disorder

  2006cited by this paper
• The effect of chronic antidepressant treatment on serum brain-derived neurotrophic factor levels in depressed patients: a preliminary study.

  2005cited by this paper
• Randomized, placebo-controlled trial

  2004cited by this paper
• A randomized double-blind trial

  2003cited by this paper
• Pharmacological treatments

  2003cited by this paper
• Requirement of Hippocampal Neurogenesis for the Behavioral Effects of Antidepressants

  2003cited by this paper
• Alterations of serum levels of brain-derived neurotrophic factor (BDNF) in depressed patients with or without antidepressants.

  2003influential reference
• Topographic pharmaco-EEG mapping of the effects of the South American psychoactive beverage ayahuasca in healthy volunteers.

  2002cited by this paper
• Modulation of neopterin formation and tryptophan degradation by Th1‐ and Th2‐derived cytokines in human monocytic cells

  1999cited by this paper
• Psilocybin induces schizophrenia‐like psychosis in humans via a serotonin‐2 agonist action

  1998cited by this paper
• LSD and the phenethylamine hallucinogen DOI are potent partial agonists at 5-HT2A receptors on interneurons in rat piriform cortex.

  1996cited by this paper
• Regulation of central 5-HT2A receptors: a review of in vivo studies.

  1995cited by this paper
• Immunological consequences of in vitro exposure to lysergic acid diethylamide (LSD).

  1994cited by this paper
• A functional anatomical study of unipolar depression

  1992cited by this paper
• Parachlorophenylalanine reversal of tranylcypromine effects in depressed patients.

  1976cited by this paper

• The effects of psilocybin on psychological distress in cancer patients: a systematic review and meta-analysis

  2026cites this paper
• Psychedelics in Multiple Sclerosis: Mechanisms, Challenges, and Prospects for Neuroimmune Modulation and Repair

  2025cites this paper
• The Role of Psychedelics in Contemporary Psychological and Interdisciplinary Inquiry

  2025cites this paper
• Changing your mind: neuroplastic mechanisms underlying the therapeutic effect of psychedelics in depression, PTSD, and addiction.

  2025cites this paper
• Efficacy and Safety of Psychoactive Tryptamines in Addiction: A Systematic Review

  2025cites this paper
• Restoring Oscillatory Dynamics in Alzheimer’s Disease: A Laminar Whole-Brain Model of Serotonergic Psychedelic Effects

  2025cites this paper
• Neuropharmacological potential of Mimosa tenuiflora in adult zebrafish: An integrated approach to GABAergic and serotonergic neuromodulation.

  2025cites this paper
• A unified pathogenic hypothesis for mental disorders based on schismogenesis

  2025cites this paper
• Ritual to relief: ethical frontiers in repurposing psychoactive substances

  2025cites this paper
• Intravenous psilocybin induces dose-dependent changes in functional network organization in rat cortex

  2025cites this paper
• Psychedelic interventions for major depressive disorder in the elderly: Exploring novel therapies, promise and potential

  2025cites this paper
• Psychedelics in the Treatment of Neurologic and Psychiatric Disorders: Coincidence or a New Point of View

  2025cites this paper
• Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Subcutaneous RE104

  2025cites this paper
• Tabernanthalog, a Non-Hallucinogenic Psychedelic, Alleviates Cancer-Induced Cognitive Deficits via Serotonergic Pathways

  2025cites this paper
• Effect of psilocybin therapy on suicidal ideation, attempts, and deaths in people with psychiatric diagnoses: a systematic review and meta-analysis

  2025cites this paper
• Temporal dynamics in neuroimaging as correlates of therapeutic response to psilocybin in major depressive disorder: A systematic review and critical appraisal.

  2025cites this paper
• The effects of psychedelic-assisted therapy on illness and death anxiety: A systematic review and meta-analysis.

  2025cites this paper
• From antidepressants and psychotherapy to oxytocin, vagus nerve stimulation, ketamine and psychedelics: how established and novel treatments can improve social functioning in major depression

  2024cites this paper
• Who Are You After Psychedelics? A Systematic Review and a Meta-Analysis of the Magnitude of Long-Term Effects of Serotonergic Psychedelics on Cognition/Creativity, Emotional Processing and Personality.

  2024cites this paper
• Novel rapid treatment options for adolescent depression.

  2024cites this paper
• Psilocybin induces dose-dependent changes in functional network organization in rat cortex

  2024cites this paper
• Spirituality as a Therapeutic Approach for Severe Mental Illness: Insights from Neural Networks

  2024cites this paper
• Psilocybin therapy and anorexia nervosa: a narrative review of safety considerations for researchers and clinicians

  2024cites this paper
• Is Use of Psychedelic Drugs a Risk or Protective Factor for Late-Life Cognitive Decline?

  2024cites this paper
• [Neuroimaging correlates of classical psychedelics effects: A systematic review].

  2024cites this paper
• Psychedelic therapy in depression and substance use disorders

  2024cites this paper
• Beyond the serotonin deficit hypothesis: communicating a neuroplasticity framework of major depressive disorder

  2024cites this paper
• Serotonergic Neuromodulation of Synaptic Plasticity.

  2024cites this paper
• The Therapeutic Potential of Psychedelics on Reducing Rumination: A Mini-Review

  2024cites this paper
• Lost in translation? Qualitative interviews with Australian psychedelic-assisted therapy trial clinicians.

  2024cites this paper
• Psychedelics: A review of their effects on recalled aversive memories and fear/anxiety expression in rodents.

  2024cites this paper
• The Algorithmic Agent Perspective and Computational Neuropsychiatry: From Etiology to Advanced Therapy in Major Depressive Disorder

  2024cites this paper
• Psychedelic Research for Alcohol Use Disorder with Comorbid Major Depressive Disorder: An Unmet Need

  2024cites this paper
• Psychoactive substances 25H-NBOMe and 25H-NBOH induce antidepressant-like behavior in male rats.

  2023cites this paper
• Biomarkers of Affective Dysregulation Associated with In Utero Exposure to EtOH

  2023cites this paper
• Classic Psychedelics for the Treatment of Depressive Disorders: An Update for Psychiatrists in Training

  2023cites this paper
• Gβγ subunit inhibitor decreases DOM-induced head twitch response via the PLCβ/IP3/Ca2+/ERK and cAMP signaling pathways.

  2023cites this paper
• Psychedelics as Therapeutics-Potential and Challenges.

  2023cites this paper
• Psilocybin for treatment-resistant depression without psychedelic effects: study protocol for a 4-week, double-blind, proof-of-concept randomised controlled trial

  2023cites this paper