Skip to content

Depression

One of the most-studied indications in psychedelic and consciousness research, from antidepressant mechanisms to assisted-therapy trials.

State of the evidence

Synthesized

Synthesized from 25 studies in the library · AI-generated, grounded in the abstracts below

Found by searching the library for Depression, major depressive disorder, MDD, depressive disorder, treatment-resistant depression, then ranked by relevance.

Psilocybin and ketamine/esketamine show rapid and often sustained antidepressant effects in treatment-resistant depression and cancer-related depression, with several randomized trials reporting large improvements within days to weeks. However, the evidence is tempered by small sample sizes, open-label designs in some studies, and mixed durability at longer follow-ups. Mindfulness-based cognitive therapy (MBCT) reduces relapse in recurrent depression, but the evidence for psilocybin and ketamine is still emerging and not yet definitive.

Confidence in the evidence

Moderate
  • Multiple RCTs (e.g., 25610, 25621, 16210, 2362) show consistent positive effects for ketamine and psilocybin, but sample sizes are small (18–79 per arm).
  • Several studies are open-label (16000, 8534, 27749) or have crossover designs, increasing risk of bias.
  • One head-to-head trial (15938) found no significant difference between psilocybin and escitalopram at 6 weeks, introducing some inconsistency.
  • Long-term follow-up data are limited; some studies show sustained effects (16210, 8534), but others (2362) report no sustained response at 12 weeks.
How we rate confidence

Confidence reflects the strength of the underlying evidence, not whether the result is favorable. It weighs the number and size of studies, their design (randomized trials count for more than observational or single-case work), how consistently they point the same way, and their risk of bias.

Tiers run from Insufficient to High. High is rare in this field: small, early, or open-label studies land lower even when their direction is encouraging.

Evidence by study

Direction is each study's finding relative to your question: Supports, Opposes, No effect, Mixed, or Unclear.

A Randomized Trial of an N-methyl-D-aspartate Antagonist in Treatment-Resistant Major Depression 2006
Supports

Ketamine produced significant improvement in depression within 110 minutes, sustained for 7 days, compared to placebo.

RCT · Sample size: 18

Psilocybin produces substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer: A randomized double-blind trial 2016
Supports

High-dose psilocybin produced large decreases in depression and anxiety, sustained at 6 months with about 80% showing clinically significant improvement.

RCT · Sample size: 51

Rapid and sustained symptom reduction following psilocybin treatment for anxiety and depression in patients with life-threatening cancer: a randomized controlled trial 2016
Supports

Psilocybin produced immediate, substantial, and sustained improvements in anxiety and depression, with 60-80% maintaining clinically significant reductions at 6.5 months.

RCT · Sample size: 29

Synaptic Dysfunction in Depression: Potential Therapeutic Targets 2012
Supports

Reviews evidence that ketamine rapidly induces synaptogenesis and reverses stress-related synaptic deficits, supporting a synaptogenic hypothesis of depression treatment.

theoretical

Psilocybin with psychological support for treatment-resistant depression: an open-label feasibility study. 2016
Supports

Psilocybin (10 and 25 mg) with psychological support was feasible and associated with reduced depressive symptoms up to 3 months.

open-label trial · Sample size: 12

Mindfulness-Based Cognitive Therapy for Depression: Replication and Exploration of Differential Relapse Prevention Effects. 2004
Supports

MBCT reduced relapse from 78% to 36% in patients with 3+ previous episodes, but was less effective in those with only 2 episodes.

RCT · Sample size: 73

Trial of Psilocybin versus Escitalopram for Depression 2021
No effect

Psilocybin did not show a significant difference in antidepressant effects compared to escitalopram at week 6 on the primary outcome.

RCT

Mindfulness-based cognitive therapy for depression 2006
Supports

Describes the development of MBCT, a theory-driven intervention incorporating mindfulness training to reduce relapse in recurrent major depression.

theoretical

Effects of Psilocybin-Assisted Therapy on Major Depressive Disorder 2020
Supports

Psilocybin therapy (20 and 30 mg/70 kg) produced significant antidepressant effects compared to a waiting list control in MDD.

RCT · Sample size: 27

Antidepressant Efficacy of Ketamine in Treatment-Resistant Major Depression: A Two-Site Randomized Controlled Trial 2013
Supports

Ketamine showed greater improvement than midazolam at 24 hours, with response rates of 64% vs 28%.

RCT · Sample size: 73

Mindfulness-Based Cognitive Therapy for Depression: A New Approach to Preventing Relapse 2003
Supports

Describes MBCT as a new approach to preventing relapse in depression.

theoretical

Single-Dose Psilocybin for a Treatment-Resistant Episode of Major Depression. 2022
Supports

Psilocybin 25 mg significantly reduced MADRS scores at week 3 vs 1 mg control, but sustained response at 12 weeks was not supported.

RCT · Sample size: 233

Psilocybin with psychological support for treatment-resistant depression: six-month follow-up. 2017
Supports

Psilocybin produced large reductions in depressive symptoms at 1 and 5 weeks, with effects remaining significant at 6 months.

open-label trial · Sample size: 20

A Randomized Add-on Trial of an N-methyl-D-aspartate Antagonist in Treatment-Resistant Bipolar Depression 2010
Supports

Ketamine significantly improved depressive symptoms within 40 minutes, with effects lasting through day 3.

RCT · Sample size: 18

Efficacy and Safety of Flexibly Dosed Esketamine Nasal Spray Combined With a Newly Initiated Oral Antidepressant in Treatment-Resistant Depression: A Randomized Double-Blind Active-Controlled Study 2019
Supports

Esketamine nasal spray plus antidepressant showed significantly greater improvement in MADRS score at day 28 compared to antidepressant plus placebo.

RCT · Sample size: 227

Trauma re-experiencing episodes during esketamine treatment in patients with treatment-resistant depression and comorbid PTSD: a retrospective case series. 2026
Mixed

Trauma re-experiencing occurred during esketamine sessions; in 72.7% episodes resolved, but 27.3% discontinued treatment; favorable outcomes when continued.

retrospective case series · Sample size: 22

Changes in anxiety, quality of life, and functioning following psilocybin-assisted therapy in veterans with treatment-resistant depression. 2026
Supports

Psilocybin produced sustained improvements in anxiety, quality of life, and functioning through 12 months, though effects were no longer significant after accounting for depression improvement.

open-label trial · Sample size: 15

Increased morning cortisol after ketamine treatment for suicidal depression: Exploratory report from a randomized trial. 2026
Supports

Ketamine increased morning cortisol 24 hours post-infusion, with a small correlation with decreased suicidal ideation, suggesting enhanced stress-resilience.

RCT

Prescribing bias and adverse outcomes of esketamine in major depression comorbid substance. 2026
Opposes

Esketamine users had higher risks of comorbid SUD and, within the esketamine cohort, SUD was associated with higher risks of self-harm, suicide attempt, and hospitalization.

retrospective cohort · Sample size: 30670

Comparing transcranial magnetic stimulation and esketamine treatment response trajectories in resistant depression. 2026
Supports

Esketamine showed faster time-to-response than rTMS over 90 days, but cumulative response rates were similar; suicidal ideation improved more rapidly with esketamine.

retrospective analysis · Sample size: 372

Effects of ketamine on sleep and circadian rhythmicity in major depressive disorder and bipolar disorder: A systematic review. 2026
Supports

Ketamine is associated with favorable effects on subjective sleep quality and preliminary evidence that sleep disturbances may predict antidepressant response.

systematic review · Sample size: 1694

Ketamine and esketamine for the prevention of postpartum depression: A systematic review and network meta-analysis, with an integrated evidence synthesis. 2026
Supports

Ketamine and esketamine may reduce risk of developing postpartum depression, but data quality was low to very low.

systematic review and network meta-analysis

Ketamine-related neural changes in treatment-resistant depression: A multimodal synthesis of fMRI and PET studies. 2026
Unclear

Ketamine-related neural changes were frequently reported in subcortical regions and default-mode, ventral attention, and visual networks, but results are hypothesis-generating due to heterogeneity.

systematic review

Clinical correlates of anhedonia non-response to ketamine in treatment-resistant depression. 2026
Mixed

47.1% of patients were anhedonia non-responders to ketamine; non-responders were more likely to be single and had fewer depressive episodes and lower prior substance use disorder.

retrospective analysis · Sample size: 34

The role of therapeutic alliance in psilocybin treatment for treatment-resistant depression: A post hoc path analysis. 2026
Supports

Therapeutic alliance had indirect effects on depression outcomes via psychedelic experience measures, but direct effects were not significant.

post hoc path analysis · Sample size: 79

Points of agreement

  • Both psilocybin and ketamine/esketamine produce rapid antidepressant effects, often within hours to days.
  • Multiple RCTs show that psilocybin and ketamine reduce depression in treatment-resistant populations.
  • Psilocybin's effects are often sustained for weeks to months, with some studies reporting benefits at 6 months.
  • MBCT reduces relapse in recurrent depression, particularly in patients with 3 or more prior episodes.

Conflicts

  • One trial (15938) found no significant difference between psilocybin and escitalopram at 6 weeks, while other trials show large effects for psilocybin vs placebo.
  • Sustained response at 12 weeks was not supported in one psilocybin trial (2362), whereas other studies report sustained effects at 6 months.
  • Esketamine was associated with higher risks of comorbid SUD and adverse outcomes in one retrospective study (28670), contrasting with its overall positive efficacy in RCTs.
  • Anhedonia non-response to ketamine was observed in 47% of patients in one study (28912), indicating variability in response.

Gaps

  • Durability of effects beyond 6-12 months is not well studied for psilocybin and ketamine.
  • Most psilocybin studies have small sample sizes and many are open-label, limiting generalizability.
  • Comparative effectiveness against standard antidepressants is understudied, with only one head-to-head trial (15938).
  • Blinding is challenging in psychedelic trials due to subjective effects, potentially biasing results.
  • Optimal dosing, number of sessions, and long-term safety (e.g., trauma re-experiencing, SUD risks) require further investigation.
  • Mechanisms of action (e.g., neural changes, HPA axis effects) are not fully understood and need harmonized multimodal studies.
Browse these studies in the library
How we analyze this

This synthesis reads the 15 most-cited and 10 most recent studies whose primary subject is Depression, up to 25 in all. The most-cited set anchors the established evidence, and the recent set surfaces work that is too new to have gathered citations yet.

A study qualifies only when Depression or a known alias appears in its title or keywords, so broad reviews that mention it only in passing are left out. Each study is read from its abstract, strongest evidence first, and the summary reports the direction of the results along with any conflicts and gaps.

Ask your own question in the Research Synthesis Tool

4,818 articles · 2,301 from the last two years · 5,852,036 participants across 2,042 studies reporting sample size

Common study designs

review 913 systematic review 282 experimental study 180 observational cohort 185 randomized controlled trial 504

Research

Synthesize the evidence → Search all →

Unveiling the Sacred Plant: Reidentifying Soma, Haoma, and the Assyrian Sacred Tree

Milind Raskar

A multidisciplinary investigation combining textual analysis, fieldwork in India's Kutch region, and comparative ethnobotany identifies Vernonia cinerascens Sch. Bip. as a strong candidate for the sacred Soma plant of the Rigveda and its Iranian counterpart Haoma. The plant's woody stems, arrow-like shoots, tawny color, and leafy sprigs match ancient descriptions. Pressing its branches yielded a golden-tawny juice with a crackling sound noted in hymns. Experiential trials reported psychoactive and healing effects—relaxation, enhanced concentration, pain relief, calm joy—similar to those praised in the texts. The plant's known medicinal uses in African ethnobotany for mental disorders and depression further support the identification. Comparisons with Assyrian sacred tree iconography and Zoroastrian Barsom ritual suggest a broader Near Eastern continuity of sacred plant traditions.

DOI: 10.31235/osf.io/5sxaq_v1

Assessing the Impact of Ketamine-Assisted Multimodal Therapy on Depressive Symptoms: A Longitudinal Pre-Post BDI-II Study with Exploratory Follow-Up Analysis

Anja Frank, Mario H W Scheib preprint

A multimodal therapy combining ketamine-assisted psychotherapy, repetitive transcranial magnetic stimulation, neurofeedback, and additional psychotherapy sessions substantially reduced depressive symptoms in a Spanish clinic. Among 67 patients with various diagnoses who were screened for depression, Beck Depression Inventory-II scores dropped significantly from before to after treatment, with a large effect size. Exploratory follow-up of 28 patients indicated that improvements could be sustained for months or even years. The findings suggest that integrating multiple biological and psychological interventions may offer an effective approach for treating depression in a clinical setting.

DOI: 10.31219/osf.io/4smjr_v1

Psychedelic Therapy: A Primer for Primary Care Clinicians – Part VII. Ketamine

Viviana D. Evans, Alejandro Arenas, Kenneth Shinozuka et al. preprint

Ketamine, originally a dissociative anesthetic, is now used for treatment-resistant depression and major depressive disorder with suicidal ideation. A single intravenous infusion shows antidepressant effects within hours, with a large effect size on depression scores. It also reduces PTSD symptom severity and suicidal ideation in emergency settings. However, therapeutic effects often subside within weeks, requiring repeated doses. Risks include temporary or persistent memory impairment, cardiovascular issues, liver toxicity, and bladder inflammation. Ketamine's opioid-sparing effect improves postoperative pain management.

DOI: 10.31234/osf.io/dtb6a

Concurrent Changes in Self-Reported Sleep Disturbance During At-Home Ketamine-Assisted Therapy for Depression: A Retrospective Analysis of 13,963 Adults

Research Square • Jack Swain, Davis Carter, Leonardo Vando et al.

Among 13,963 adults with moderate-to-severe sleep disturbances who received at-home ketamine-assisted therapy for depression, 67.4% showed at least a 1-point improvement on a single sleep-related item from a depression screening tool after two sessions. By session six, 76.8% of completers met that threshold, and the average score dropped 48.8% from baseline. However, the study could not separate sleep changes from mood improvement because all participants were treated for depression and no control group was included. Side effects were reported by 3.7% to 5.0% of participants across sessions.

DOI: 10.21203/rs.3.rs-9553669/v1

MDMA Assisted Psychotherapy Decreases PTSD Symptoms, Dissociation, Functional Disability, and Depression: A Systematic Review and Meta-Analysis

medRxiv • W. M. Green, S.b. Raut, F.l.j. James et al. • 4 citations preprint

MDMA-assisted psychotherapy improves dissociation, depression, and functional impairment in people with post-traumatic stress disorder (PTSD), but does not improve sleep quality. A systematic review and meta-analysis of randomized controlled trials found that the therapy reduces core PTSD symptoms and enhances quality of life. The evidence is limited by small sample sizes in available trials, but supports further development of MDMA-assisted psychotherapy for PTSD.

DOI: 10.1101/2023.08.17.23293955

PHARMACOKINETICS OF N,N-DIMETHYLTRYPTAMINE FUMARATE IN HUMANS

Meghan Good, Tiffanie Benway, Zelah Joel et al. • 4 citations

DMT (N,N-dimethyltryptamine) is being developed as a treatment for major depressive disorder. In a phase I trial, 24 healthy adults received escalating intravenous doses of DMT fumarate (SPL026) that were safe and well-tolerated. DMT exposure increased proportionally with dose over the 9–21.5 mg range. Peak plasma concentration occurred at about 10 minutes, and the mean elimination half-life was 9–12 minutes. In vitro experiments showed that DMT is cleared by monoamine oxidase A (MAO-A) and modified by the enzymes CYP2D6 and CYP2C19. The unbound fraction of DMT in plasma was approximately 70%. These findings support the development of DMT infusion regimens for treating major depressive disorder.

DOI: 10.22541/au.165237523.39763980/v1

Microdosing Is More Than Placebo In Some Individuals: A Critical Re-examination of ‘Self-blinding citizen science to explore psychedelic microdosing’

preprint

A reanalysis of Szigeti et al.'s (2021) self-blinding citizen science study on psychedelic microdosing partially supports the original conclusions but identifies specific conditions where microdosing produces positive effects compared to placebo. Positive effects were found for participants who received both placebo and treatment during their trial (affective benefits), felt some level of intoxication, correctly identified placebo from treatment, and had at least mild depression. The findings add to evidence that certain benefits may exist for psychedelic microdosing under particular circumstances.

DOI: 10.31219/osf.io/sf75q

Intron retention, a novel method for evaluating the response to ketamine in patients with treatment-resistant depression

Research Square • Norihiro Okada, Kenshiro Oshima, Akiko Maruko et al.

Non-responders to ketamine treatment for depression show elevated viral infection markers based on intron retention (IR) gene analysis of RNA-seq data. Several IR genes associated with viral infection returned to healthy levels after ketamine regardless of responder status, suggesting non-responders are not resistant to ketamine but rather have an extremely high inflammatory state that the drug's effects cannot overcome. Excluding one transcriptomic outlier with extreme viral infection did not change IR gene conclusions but did alter differentially expressed gene (DEG) results, supporting the authors' claim that IR genes may be more useful markers of depression than DEGs.

DOI: 10.21203/rs.3.rs-5823020/v1

Ketamine treatment safety and tolerability in treatment-resistant depression with somatic comorbidities: focus on dissociation and psychotic symptomatology.

Research Square (Research Square) • Adam Włodarczyk, Wiesław J. Cubała, Maria Węgielnik-gałuszko et al.

In hospitalized patients with treatment-resistant depression (major depressive or bipolar disorder), intravenous ketamine treatment was associated with changes in psychotic symptoms over time among those with epilepsy, but not among those with other somatic conditions. The study, which included 49 participants and was limited by a small, unblinded, single-site design, suggests that careful monitoring for psychotic symptoms is needed when using ketamine in patients with epilepsy, and that somatic comorbidities may influence dissociative side effects.

DOI: 10.21203/rs.3.rs-42473/v1

Can we change depressive beliefs? Modulation of belief updating by ketamine in treatment resistant depression

Hugo Bottemanne, Orphée Morlaàs, Anne Claret et al. • 4 citations preprint

Ketamine infusion makes people with treatment-resistant depression more optimistic about the future by changing how they learn from good and bad news. After a single infusion, patients updated their beliefs more after favorable information and less after unfavorable information, compared to healthy controls. This shift toward optimism was driven by learning more from positive surprises than negative ones. This change in belief-updating predicted early clinical improvement at one week, seen in 19% of patients. The findings suggest ketamine's antidepressant effects involve altering cognitive biases, which could enhance psychotherapy for depression.

DOI: 10.31234/osf.io/zx5vr

Clinical trials

All Depression trials →