Why Psylocibin is a viable treatment for depression and anxiety

ABSTRACT

The resurgence of psychedelic research in the past two decades has produced compelling evidence for psilocybin-assisted therapy (PAT) as a potentially transformative treatment for depression, anxiety, and treatment-resistant depression (TRD). Unlike conventional pharmacological approaches, psilocybin operates through both neurobiological and psychological mechanisms, with emerging research suggesting that mystical and spiritual experiences serve as critical mediators of therapeutic outcomes. This paper synthesizes current clinical trial data demonstrating psilocybin’s efficacy compared to selective serotonin reuptake inhibitors (SSRIs), examines the role of spirituality in therapeutic outcomes, and addresses the limitations of conventional antidepressant pharmacotherapy. Evidence suggests that psilocybin-assisted therapy, when administered in controlled clinical settings with appropriate psychological support, produces rapid, sustained symptom reduction in depression and anxiety while facilitating significant positive changes in meaning, purpose, and psychological flexibility—outcomes not consistently achieved by SSRIs alone.

KEY FINDINGS:

Single-dose psilocybin therapy produces clinically significant reductions in depression and anxiety within weeks
FDA has designated deuterated psilocybin (CYB003) as breakthrough therapy for major depressive disorder
Mystical experiences during psilocybin sessions are significant predictors of therapeutic outcomes
SSRIs show modest effect sizes with 60-70% of patients experiencing incomplete response or non-response
Psilocybin facilitates lasting changes in psychological flexibility, openness, and sense of meaning
Combined psilocybin and spiritual practice produces enduring positive trait changes

I. INTRODUCTION

Major depressive disorder (MDD) remains one of the most significant global health challenges, affecting over 300 million individuals worldwide. Current first-line pharmacological treatment consists primarily of selective serotonin reuptake inhibitors (SSRIs) and related agents that target monoamine neurotransmitters. However, despite decades of refinement in conventional antidepressant pharmacotherapy, treatment response remains inadequate for a substantial proportion of patients. A meta-analysis published in The Lancet examining 21 antidepressant drugs found that while antidepressants showed superiority to placebo, effect sizes were modest, with significant numbers of patients experiencing treatment-resistant depression (Cipriani et al., 2018). Furthermore, concerns regarding long-term side effects, emotional blunting, sexual dysfunction, and withdrawal symptoms have prompted renewed investigation into alternative therapeutic modalities.

Concurrently, a renaissance in psychedelic research has emerged following decades of regulatory and institutional barriers. Leading academic institutions, including Johns Hopkins University, Yale University, and the University of California, have reestablished rigorous clinical programs investigating classical psychedelics—particularly psilocybin—for treating psychiatric conditions. The FDA has granted Breakthrough Therapy Designation to deuterated psilocybin for major depressive disorder (2024), signaling recognition of its potential to address significant unmet clinical needs.

What distinguishes psilocybin from conventional psychiatric medications is not merely its biochemical action but rather its capacity to facilitate profound shifts in consciousness, meaning-making, and psychological perspective. Accumulating evidence suggests that the therapeutic efficacy of psilocybin derives from a synergistic combination of neurobiological changes and what participants characterize as spiritually transformative experiences. This mechanism differs fundamentally from SSRIs, which primarily suppress symptoms through chronic neurochemical adjustment without necessarily addressing existential dimensions of psychological distress.

This paper examines the current empirical evidence supporting psilocybin-assisted therapy, explores the intersection of spiritual experience and clinical outcome, and contextualizes psilocybin efficacy within the broader landscape of conventional antidepressant limitations.

II. CLINICAL EFFICACY OF PSILOCYBIN FOR DEPRESSION AND ANXIETY

A. Recent Randomized Controlled Trials

Contemporary clinical research demonstrates substantial antidepressant efficacy for psilocybin when administered in controlled therapeutic settings with psychological support. A landmark 2022 study published in the New England Journal of Medicine by Goodwin and colleagues—the first large international multi-center randomized controlled trial—evaluated 233 adults with treatment-resistant depression. Participants received either a single 25 mg dose of psilocybin or placebo in combination with psychological support. Results demonstrated clinically significant superiority of psilocybin over placebo, with the 25 mg dose establishing the optimal balance between efficacy and tolerability.

A 2024 dose-response network meta-analysis published in ScienceDirect, analyzing randomized placebo-controlled clinical trials through July 2024, confirmed that psilocybin produces significant antidepressant effects with time-dependent therapeutic action. The meta-analysis validated the 25 mg dose as optimal and supported the FDA’s recommended timing for efficacy evaluation. Importantly, effects were observed as early as day 2, with continued improvement through day 15 post-administration, in stark contrast to SSRIs which typically require 4-6 weeks to demonstrate efficacy.

A double-blind randomized clinical trial published in JAMA Network Open (2024) examining 30 frontline healthcare workers with depression found that a single 25 mg dose of psilocybin produced significant decreases in depression symptoms (Montgomery-Asberg Depression Rating Scale) by day 28, with sustained improvements maintained at later follow-up points. Notably, the effect size for psilocybin exceeded that of the active control condition (niacin), suggesting the specificity of psilocybin’s antidepressant mechanism.

B. Treatment-Resistant Depression

Particularly compelling evidence emerges from studies of treatment-resistant depression (TRD)—defined as failure to respond to at least two adequate trials of antidepressants. A 2024 study published in the Journal of Affective Disorders examined psilocybin-assisted psychotherapy in participants with high levels of treatment resistance, significant comorbidities, and complex illness presentations. This study is notable for including participants typically excluded from trials: those with baseline suicidality, bipolar II disorder, and multiple psychiatric comorbidities. Despite this higher-risk population, psilocybin-assisted therapy demonstrated significant antidepressant effects comparable to earlier trials conducted in more select populations, with safety profiles remaining adequate. Participants receiving multiple psilocybin sessions (two or three doses over 6 months) showed greater antidepressant effects than single-dose recipients, suggesting potential for dose escalation in complex cases.

British research (2024) examining psilocybin therapy for TRD documented treatment in 388 total participants across five clinical trials. Of these, 253 met criteria for TRD, many having endured 7-30 years of illness and failed 2-11 previous medications. Early findings demonstrated robust antidepressant response in this severely treatment-resistant population.

C. Anxiety and Existential Distress

Johns Hopkins research documented substantial reductions in cancer-related anxiety and existential distress. In a double-blind study, cancer patients receiving high-dose psilocybin (30 mg/70 kg) demonstrated significant decreases in death anxiety and existential distress that persisted for at least 6 months following a single administration—a duration far exceeding typical SSRI efficacy windows. Participants reported not merely symptom suppression but fundamental shifts in perspective regarding mortality, meaning, and quality of life.

Research from the University of Washington published in 2024 examined psilocybin therapy in clinicians with pandemic-related depression and burnout, similarly demonstrating rapid symptom reduction and sustained improvements in well-being.

III. NEUROBIOLOGICAL MECHANISMS OF ACTION

A. Serotonergic and Glutamatergic Systems

Psilocybin functions as a partial agonist at serotonin 5-HT receptors, particularly 5-HT1A, 5-HT1D, 5-HT2A, and 5-HT7 receptors. However, unlike SSRIs which produce chronic increases in synaptic serotonin through reuptake inhibition, psilocybin’s mechanism operates through acute activation of these receptors within circumscribed dosing sessions. This distinct pharmacological profile may explain the rapid onset of antidepressant effects and the durability of therapeutic benefits following single or limited administration—outcomes that do not align with SSRI pharmacokinetics.

Recent neuroimaging studies reveal that psilocybin reduces activity in the amygdala (involved in emotional reactivity), decreases synchronization in the default mode network (associated with rigid self-referential thinking), and increases activation in regions associated with cognitive flexibility and emotional processing. Particularly significant is psilocybin’s effect on the claustrum—a brain region implicated in attention and ego boundaries—resulting in decreased activity that correlates with subjective reports of ego dissolution and sense of interconnectedness. These neurobiological changes appear to persist beyond acute drug administration, suggesting neuroplastic adaptations that support lasting psychological change.

B. Neuroplasticity and Neurotrophic Factors

Research indicates that psilocybin may promote neuroplasticity through increases in brain-derived neurotrophic factor (BDNF) and activation of tropomyosin receptor kinase B (TrkB) signaling. This represents a fundamentally different mechanism from SSRIs, which show inconsistent effects on BDNF. The capacity to upregulate neurotrophic signaling may contribute to psilocybin’s observed effects on synaptic plasticity, cognitive flexibility, and long-term psychological restructuring.

IV. SPIRITUALITY AS A MECHANISM OF THERAPEUTIC ACTION

A. Defining Mystical Experience in Clinical Context

One of the most distinctive aspects of psilocybin therapy is its capacity to reliably occasion what participants and researchers characterize as “mystical-type experiences”—subjective states sharing phenomenological characteristics with spontaneously occurring religious and spiritual experiences. These experiences are characterized by:

Unity and interconnectedness (sense of profound connection to all existence)
Transcendence of time and space (temporal and spatial boundaries dissolving)
Ineffability (difficulty expressing experience in ordinary language)
Noetic quality (sense of gaining deep insight or truth)
Sense of sacredness or meaningfulness
Positive affect (feelings of peace, joy, love)
Ego dissolution (temporary loss of ordinary sense of self)

Notably, these phenomenological characteristics are remarkably consistent across cultures, time periods, and spontaneous versus drug-occasioned contexts, suggesting they represent fundamental human experiences rather than artifacts of pharmacological manipulation.

B. Mystical Experience as Predictor of Clinical Outcome

Multiple studies demonstrate that the magnitude and depth of mystical experience during psilocybin sessions predicts therapeutic outcomes across diverse psychiatric conditions. A seminal 2022 study examining depression found that scores on the Mystical Experience Questionnaire during acute psilocybin administration significantly predicted improvements in depressive symptoms at 5-week follow-up (r = -0.49, p = 0.03). Similarly, measures of “spiritual experience” and “blissful state” during the session correlated with symptom improvement. Insight scores also significantly predicted depression reduction (r = -0.57, p = 0.01).

In smoking cessation studies, 80% of participants with mystical experiences during psilocybin sessions achieved sustained abstinence at 6-month follow-up—a success rate substantially exceeding that of the best available pharmacological smoking cessation aid (varenicline, ~35% efficacy) and cognitive behavioral therapy alone (<30% efficacy). Participants without mystical experiences showed lower cessation rates.

In cancer-related existential distress research, mystical experience during the psilocybin session predicted decreases in death anxiety and increases in life meaning, with these improvements persisting at 6-month follow-up. The correlation between mystical experience intensity and anxiety reduction was robust across multiple studies.

Long-term follow-up research (14 months post-administration) found that 58% of participants rated their psilocybin-occasioned experience as among the five most personally meaningful experiences of their entire lives, and 67% rated it among the five most spiritually significant experiences. These ratings correlated significantly with the magnitude of mystical experience during the session (r = 0.65 for personal meaning, r = 0.77 for spiritual significance).

C. Mechanistic Models: How Spirituality Produces Therapeutic Change

Contemporary theoretical models propose that mystical experiences produce therapeutic change through several interrelated mechanisms:

1. Psychological Flexibility: Mystical experiences temporarily disrupt rigid patterns of thinking and emotional reactivity. The sense of ego dissolution and fundamental interconnectedness may create psychological flexibility—the capacity to hold thoughts and emotions without rigid adherence to self-referential narratives. Research suggests that acute mystical experiences feed into increased psychological flexibility, which then predicts reductions in depression and anxiety.

2. Meaning and Purpose: Depression fundamentally involves loss of meaning and purpose. Mystical experiences, by definition, involve profound sense of meaning and significance. Participants report that insights gained during mystical states catalyze enduring shifts in how they understand their lives, relationships, and mortality. This restoration of meaning represents a psychological dimension largely unaddressed by SSRIs.

3. Ego Dissolution and Self-Referential Thinking: Depressive and anxious rumination involve excessive self-focus and rigid self-schemas. The ego dissolution occasioned by psilocybin—subjective sense of boundary dissolution between self and environment—may interrupt pathological self-focus, creating space for new self-understanding.

4. Cognitive Reappraisal: The insights and new perspectives gained during mystical states appear to facilitate lasting cognitive reappraisal of life circumstances, relationships, and existential concerns. Participants report that the clarity and emotional salience of insights during mystical states creates particularly powerful memory encoding and internalization.

5. Openness and Trait Change: Research demonstrates that high-dose psilocybin, particularly when accompanied by mystical experience, produces lasting increases in the personality trait of openness. Openness—characterized by curiosity, imagination, and receptiveness to new experiences—is associated with improved psychological functioning and reduced depression/anxiety. This represents a fundamental personality change rather than symptom suppression.

D. Integration of Spiritual Practice

Notably, research examining psilocybin combined with structured spiritual practice demonstrates amplified and more enduring effects. A Johns Hopkins study involving 75 healthy adults examined two high doses of psilocybin (20 mg and 30 mg) combined with either standard-level or intensive spiritual practice support. At 6-month follow-up, both high-dose groups showed large, statistically significant increases in measures of interpersonal closeness, gratitude, life meaning/purpose, death transcendence, and religious faith. The high-dose, high-support group (intensive spiritual guidance) showed the largest effects on all measures. Particularly striking were the effects on life meaning and trait forgiveness—dimensions not typically targeted by conventional psychiatric medications.

V. LIMITATIONS OF SELECTIVE SEROTONIN REUPTAKE INHIBITORS

A. Modest Efficacy and High Non-Response Rates

A comprehensive meta-analysis examining 21 antidepressant drugs published in The Lancet found that while SSRIs showed superiority to placebo, the effect sizes were modest. Importantly, 60-70% of patients with major depression do not achieve full remission on SSRIs, and 30-40% show minimal or no significant response. The clinical significance of SSRI superiority over placebo has been questioned in the literature, with some researchers arguing that a 3-7 point difference on depression rating scales falls below clinically detectable thresholds.

When examining effect sizes using standardized mean differences, SSRI effects typically range from 0.3-0.5—classified as small to modest effect sizes. By contrast, reported effect sizes for psilocybin-assisted therapy for depression range from 1.5 to 2.0 when compared to placebo—substantially larger effects achieved within a single to few sessions rather than chronic administration.

B. Incomplete Symptom Resolution

Even when SSRIs do produce response, many patients achieve only partial symptom reduction rather than remission. Furthermore, SSRI efficacy often reaches a plateau, with additional dose escalation producing minimal additional benefit. For patients with residual depressive symptoms or partial response, current guidelines recommend augmentation strategies (adding second medications), which further increases medication burden and side effect risk without guaranteed benefit.

C. Long-Term Side Effects

While acute side effects of SSRIs (nausea, sexual dysfunction, initial anxiety) are well-documented, growing evidence suggests concerning long-term effects including:

Emotional Blunting: Studies in patients taking SSRIs for several years document reduced capacity for emotional experience, decreased motivation, and sense of emotional dampening. This differs fundamentally from depression-related anhedonia, representing instead a medication-induced emotional flattening that some patients find more distressing than depressive symptoms.
Weight Gain: Chronic SSRI use is associated with metabolic changes and weight gain in substantial proportions of users, which may contribute to cardiovascular disease and reduced quality of life.
Sexual Dysfunction: 40-60% of SSRI users experience sexual dysfunction including reduced libido, erectile dysfunction, and anorgasmia—effects that frequently persist and can lead to medication discontinuation or relationship distress.
Withdrawal Symptoms: Upon discontinuation, a significant proportion of SSRI users experience withdrawal symptoms including dizziness, electric shock sensations, mood disturbance, and anxiety—sometimes severe enough to necessitate slow tapers over months and representing a barrier to discontinuation.
Apathy Syndrome: Some long-term users report decreased motivation and initiative despite being asymptomatic for depression—a state of neutral mood without positive engagement.

D. Efficacy Decreases with Long-Term Use

A 2024 meta-analysis examining enduring effects of antidepressants found evidence suggesting advantages of psychotherapy and combination treatment over pharmacotherapy alone in sustained response after 12 months, and extending to 24 months post-treatment. This finding suggests that while SSRIs may produce acute symptom reduction, they do not produce durable psychological change that persists after discontinuation.

E. Differential Response by Severity

Research indicates that SSRI efficacy appears to increase with baseline depression severity, yet even in severely depressed populations, response rates remain far from universal. Treatment-resistant depression—depression failing to respond to multiple SSRI trials—remains inadequately addressed by current pharmacological approaches, often requiring escalation to augmentation strategies with uncertain benefit or alternative modalities like electroconvulsive therapy.

F. Lack of Meaning and Purpose Restoration

Fundamentally, SSRIs address neurochemistry but do not directly address existential dimensions of depression: loss of meaning, purpose, and sense of connection. While reduction of depressive symptoms may secondarily facilitate engagement with meaningful activities, SSRIs do not directly restore sense of meaning or produce the psychological transformation characteristic of spiritual or mystical experiences.

VI. COMPARATIVE EFFICACY: PSILOCYBIN VERSUS SSRIs

A. Effect Size Comparisons

When comparing effect sizes across methodologically comparable studies:

Psilocybin-assisted therapy for major depression demonstrates effect sizes ranging from 1.5-2.0 (Cohen’s d) in randomized controlled trials, achieved within single to few dosing sessions.

SSRIs in randomized controlled trials demonstrate effect sizes of 0.3-0.5 (Cohen’s d), requiring 4-6 weeks of daily administration to achieve response.

Psilocybin shows approximately 4-6 fold larger effect sizes than SSRIs in controlled comparisons, though direct head-to-head randomized trials comparing psilocybin to SSRIs remain limited.

B. Speed of Onset

Psilocybin: Symptom improvement frequently observed within days to weeks following single or limited doses. Peak effects typically evident by 1-4 weeks post-administration.

SSRIs: Typical lag of 4-6 weeks before symptom improvement; some patients require 8-12 weeks for meaningful response.

C. Durability of Effect

Psilocybin: Single-dose or limited-dose therapy produces effects persisting weeks to months following cessation of administration. Long-term follow-up studies (6-12 months post-therapy) document sustained improvement in majority of responders without ongoing medication.

SSRIs: Symptomatic relapse frequently occurs upon discontinuation. Chronic administration is typically required to maintain benefit, necessitating indefinite medication adherence.

D. Psychological Transformation

Psilocybin-assisted therapy: Produces measurable, durable changes in personality traits (particularly openness), sense of meaning and purpose, prosocial attitudes, and psychological flexibility. These changes reflect fundamental psychological reorganization rather than symptom suppression.

SSRIs: Do not typically produce lasting trait changes. Upon discontinuation, personality and attitudes generally revert to baseline.

VII. SAFETY CONSIDERATIONS

A. Acute Adverse Effects

Psilocybin-assisted therapy under controlled clinical conditions demonstrates favorable safety profiles. Common acute adverse effects include:

Nausea (4-22% of participants)
Headache (15-50% of participants)
Transient anxiety or emotional distress during sessions

Importantly, these effects are typically mild and self-limited, managed through psychological support and reassurance. Rescue medication (benzodiazepines) is required in <1% of cases.

Serious adverse events in clinical trials are rare. Acute substance-induced psychotic disorder is exceptionally uncommon (reported in 1 of 89 healthy volunteers in one trial), resolving completely within 24 hours.

B. Contraindications and Risk Mitigation

Psilocybin-assisted therapy requires careful patient selection and monitoring. Relative contraindications include:

Personal or family history of psychosis or bipolar I disorder
Current active suicidality (though recent evidence suggests carefully monitored psilocybin therapy may benefit some suicidal individuals)
Current substance dependence
Certain medical conditions and medications

However, recent research examining complex populations—including those with bipolar II disorder, baseline suicidality, and significant comorbidities—documents feasibility and adequate safety when administered with appropriate clinical oversight.

VIII. MECHANISTIC MODELS EXPLAINING PSILOCYBIN’S SUPERIORITY

A. Multi-System Engagement

Unlike SSRIs, which primarily target monoamine reuptake, psilocybin engages multiple biological and psychological systems simultaneously:

Serotonergic agonism (distinct acute mechanism from SSRI reuptake blockade)
Glutamatergic system modulation
Neuroplasticity and neurotrophic factor upregulation
Disruption of pathological neural networks (default mode network, rigid self-referential patterns)
Psychological insight and cognitive restructuring
Spiritual transformation and meaning-making
Enhanced psychological flexibility and openness

This multi-level engagement may explain why psilocybin produces broader and more durable improvements than SSRIs, which operate primarily on a single neurochemical dimension.

B. Addressing Biological Heterogeneity of Depression

Depression represents a heterogeneous condition with multiple biological and psychological etiologies. SSRIs assume a monoamine deficiency hypothesis, which is oversimplified and inconsistent with contemporary neuroscience. Emerging evidence implicates inflammation, glutamatergic dysfunction, neuroplastic deficits, and existential/spiritual factors in depression pathophysiology.

Psilocybin’s multi-system effects address multiple hypothesized depression mechanisms simultaneously, potentially explaining its efficacy across diverse depression subtypes and etiologies.

IX. FUTURE DIRECTIONS AND REGULATORY LANDSCAPE

A. Current Regulatory Status

As of January 2025, psilocybin remains a Schedule I controlled substance in the United States; however, regulatory momentum is building:

FDA Breakthrough Therapy Designation granted to deuterated psilocybin (CYB003) for major depressive disorder
Oregon legalized psilocybin services in licensed facilities (2020)
Colorado passed legislation establishing psilocybin services (2022)
Multiple countries (Australia, Switzerland, Canada) permit psilocybin use for treatment-resistant depression in clinical settings
Phase III clinical trials are ongoing for FDA approval

B. Anticipated Clinical Implementation

If psilocybin clears Phase III trials and receives FDA approval, experts recommend reclassification from Schedule I to Schedule IV—similar to prescription sleep aids—reflecting recognition of legitimate medical utility while maintaining controlled distribution to regulated clinical settings.

Clinical implementation will likely involve:

Specialized training for psilocybin-assisted therapy practitioners
Standardized protocols for preparation, dosing, and integration sessions
Careful patient selection and screening
Insurance coverage and healthcare system integration
Ethical frameworks addressing accessibility and equity

X. SYNTHESIS AND CONCLUSIONS

Contemporary evidence establishes psilocybin-assisted therapy as a viable, evidence-based intervention for major depression, treatment-resistant depression, and anxiety—with compelling data supporting superiority over SSRIs in multiple clinically relevant dimensions:

Effect sizes are substantially larger for psilocybin than SSRIs
Onset of therapeutic benefit is more rapid
Durability of benefit extends beyond active administration
Psychological transformation and trait changes are more profound
Mechanisms address multiple depression etiologies simultaneously
Safety profiles are favorable under clinical supervision
Long-term side effect burden is lower than chronic SSRI use

Perhaps most significantly, psilocybin-assisted therapy operates through mechanisms fundamentally different from SSRIs: rather than suppressing symptoms through chronic neurochemical adjustment, psilocybin facilitates psychological and spiritual transformation that addresses existential dimensions of depression and anxiety. The strong predictive relationship between mystical experience and therapeutic outcome suggests that meaning-making, transcendence, and spiritual insight represent legitimate psychological mechanisms of healing—dimensions recognized across human cultures and spiritual traditions but largely neglected by conventional psychiatric pharmacotherapy.

The role of spirituality in psilocybin-assisted therapy is not tangential or incidental but rather central to therapeutic mechanisms. Experiences of ego dissolution, interconnectedness, and spiritual significance appear to catalyze lasting psychological reorganization, sense of meaning, and openness to new perspectives—outcomes that correlate with and likely mediate clinical improvement in depression and anxiety.

While SSRIs represent important pharmacological advances and continue to benefit substantial numbers of patients, they address only a fraction of depression’s multifaceted etiology and do not produce the durable psychological transformation documented with psilocybin-assisted therapy. The limitations of SSRIs—modest effect sizes, incomplete response rates, emotional blunting, sexual dysfunction, and lack of sustained benefit after discontinuation—highlight the necessity of pursuing alternative approaches.

As regulatory barriers diminish and clinical implementation becomes feasible, psilocybin-assisted therapy promises to represent a paradigm shift in psychiatric treatment—one that integrates neuroscience with recognition that humans are fundamentally meaning-making creatures whose psychological wellbeing depends on spiritual dimensions as much as neurochemistry.

REFERENCES

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AUTHOR NOTE: This research paper synthesizes evidence from peer-reviewed clinical trials, meta-analyses, and systematic reviews conducted through January 2025. The conclusions reflect consensus emerging from rigorous clinical research conducted at leading academic institutions. As regulatory landscapes evolve and additional clinical data accumulate, some findings may require revision. This paper is intended for educational and scholarly purposes and does not constitute medical advice.

Ariel Cook