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Psilocybin for Depression: Optimal Dosages for Antidepressant Effects (2023 Review)

Recent research has provided compelling evidence on the therapeutic potential of psilocybin, a naturally occurring psychedelic, in treating depression.

A systematic review and dose-response meta-analysis shed light on the optimal dosage of psilocybin for depression, revealing variations in effectiveness based on patient subgroups and associated risks.


  1. Psilocybin showed significant antidepressant effects, with optimal dosages varying for treatment-resistant, primary, and secondary depression groups.
  2. Higher psilocybin doses (ED95: 40 mg/70 kg) were more effective for treatment-resistant patients, whereas lower doses sufficed for secondary depression (ED95: 8.92 mg/70 kg).
  3. Psilocybin was generally well-tolerated, with adverse events being mostly transient and mild to moderate, including headache and nausea.
  4. Psychological support effectively managed panic reactions during psychedelic trips at higher doses, highlighting the importance of controlled conditions in psilocybin therapy.

Source: European Neuropsychopharmacology (2023)

Historical Use of Psilocybin for Healing

Psilocybin, a psychedelic compound, found in over 200 species of mushrooms, has a rich history that spans continents, cultures, and centuries.

The renaissance of interest in its potential to treat depression is not only a testament to its enduring appeal but also a bridge connecting ancient wisdom with the cutting edge of psychiatric research.

Ancient Rituals & Indigenous Wisdom

  • Pre-Columbian Mesoamerica: Psilocybin mushrooms were integral to the spiritual and medicinal practices of indigenous peoples in Mesoamerica. Aztec and Maya texts and iconography depict these “flesh of the gods” mushrooms, used in rituals to induce visions and commune with the spiritual world, suggesting an early recognition of their profound psychological effects.
  • Shamanic Healing: Across various indigenous cultures, shamans utilized psilocybin mushrooms in healing ceremonies, believing in their power to treat ailments of the mind and spirit. These practices, deeply rooted in a holistic understanding of health, highlight the early use of psilocybin as a tool for psychological and emotional well-being.

Twentieth-Century Rediscovery & Research

  • Western Discovery: The mid-20th century brought psilocybin into the awareness of Western science through the explorations of researchers like R. Gordon Wasson. His accounts of participating in indigenous mushroom ceremonies ignited scientific and public interest in the psychedelic experience.
  • Psychedelic Research Boom: In the 1950s and 1960s, figures such as Timothy Leary and Richard Alpert (Ram Dass) spearheaded research into the therapeutic potential of psychedelics, including psilocybin, for treating a range of psychiatric conditions, notably depression. Despite promising results, the sociopolitical climate of the time led to stringent regulations, stifling further research.

The Modern Renaissance in Psilocybin Research

  • Revival of Interest: The 21st century has seen a resurgence in research into psilocybin’s therapeutic potential, driven by growing disillusionment with conventional antidepressants and an increasing body of scientific evidence supporting its efficacy and safety in treating depression.
  • Clinical Trials & Neuroscientific Insights: Contemporary studies have begun to unravel the complex mechanisms through which psilocybin acts on the brain, offering hope for innovative treatments. Through neuroimaging and clinical trials, researchers are exploring how psilocybin disrupts entrenched neural pathways associated with depression, promoting cognitive flexibility and emotional insight.

How Psilocybin Treats Depression (Mechanisms)

The therapeutic potential of psilocybin, a naturally occurring psychedelic compound, in treating depression has garnered significant interest in recent years.

Psilocybin’s antidepressant effects are thought to stem from a complex interplay of pharmacological, neurobiological, and psychological mechanisms.

Pharmacological Mechanism: Serotonin 2A Receptor Agonism

Serotonin 2A (5-HT2A) Receptor Activation

Psilocybin and its active metabolite, psilocin, function as agonists at the 5-HT2A receptor, a subtype of the serotonin receptor family predominantly expressed in the brain.

This activation is considered central to psilocybin’s psychedelic effects and is hypothesized to underlie its therapeutic potential.

The 5-HT2A receptor plays a crucial role in regulating mood, cognition, and perception, making it a key target for psychedelic-assisted therapy.

Neurotransmitter Modulation

Beyond the 5-HT2A receptor, psilocybin influences various neurotransmitter systems, including dopamine and glutamate.

This broad modulation of neurotransmitter activity contributes to the compound’s complex psychopharmacological profile, potentially correcting dysregulated neurotransmitter systems implicated in depression.

Neurobiological Mechanisms: Brain Connectivity & Neuroplasticity

Enhanced Brain Connectivity

Imaging studies have shown that psilocybin induces increased connectivity between different regions of the brain, breaking down the rigid patterns of activity associated with depression.

This effect, often visualized as a more interconnected and synchronized brain network, is thought to facilitate a state of increased cognitive flexibility, allowing patients to escape depressive thought patterns and behaviors.


Psilocybin has been shown to promote neuroplasticity, the brain’s ability to form new neural connections and reorganize itself.

By enhancing synaptic genesis and dendritic growth, psilocybin may help to restore normal brain function in depressed individuals, potentially leading to lasting improvements in mood and cognitive function.

Psychological Mechanisms: Emotional Insight & Cognitive Flexibility

Altered Sense of Self & Emotional Breakthroughs

Psilocybin therapy often leads to profound emotional and perceptual experiences, including a temporary dissolution of ego or sense of self.

This altered state of consciousness can facilitate deep psychological insights and emotional breakthroughs, enabling individuals to confront and reframe negative thought patterns and emotional traumas that contribute to their depression.

Increased Cognitive Flexibility

The experience induced by psilocybin is associated with enhanced cognitive flexibility, allowing individuals to view their problems, life, and relationships from new perspectives.

This cognitive shift is thought to be a key factor in psilocybin’s therapeutic effect, enabling lasting changes in behavior and thought processes that are beneficial for individuals with depression.

Major Findings: Psilocybin Dosages in Depression (2023 Review)

The systematic review and dose-response meta-analysis on psilocybin’s use in treating depression has unveiled nuanced and compelling findings that mark a significant advancement in the field of psychedelic-assisted therapy.

By meticulously analyzing data from several high-quality studies, the research offers a detailed perspective on how varying doses of psilocybin affect patients with different types of depression.

1. Dose-Response Relationship & Efficacy

  • Treatment-Resistant Depression: For patients with treatment-resistant depression, the study identified a near maximal effective dose (ED95) at 40 mg/70 kg, indicating that higher doses are necessary to elicit a significant therapeutic response. This subgroup showed a robust dose-response relationship, suggesting that escalating doses up to a certain threshold could enhance therapeutic outcomes.
  • Primary vs. Secondary Depression: A striking differentiation was found between primary and secondary depression regarding the optimal dose. For primary depression, the ED95 was determined at 24.68 mg/70 kg, whereas for secondary depression, a significantly lower dose of 8.92 mg/70 kg was identified as nearly maximally effective. This distinction underscores the influence of the depression’s etiology on psilocybin’s effectiveness, suggesting that secondary depression may be more responsive to lower psilocybin doses.
  • Anxiety Symptoms: The analysis extended beyond depressive symptoms, revealing significant dose-response associations for the reduction of anxiety symptoms. This finding indicates that psilocybin’s therapeutic potential spans multiple dimensions of mental health, offering relief from both depressive and anxiety symptoms within certain dose ranges.

2. Safety & Tolerability

  • Adverse Events: The meta-analysis reaffirmed psilocybin’s generally well-tolerated nature, with most adverse events being transient and of mild to moderate severity. Headache and nausea were among the most common side effects, consistent with previous research on psilocybin’s safety profile.
  • Management of Psychological Discomfort: At higher doses, psychological discomfort, including panic reactions during psychedelic experiences, was noted. However, the study highlighted the effectiveness of psychological support in managing these reactions, suggesting that adverse psychological effects can be mitigated in a controlled therapeutic setting.
  • Dose-Dependent Side Effects: The findings also elucidated a dose-response relationship for various side effects, including physical discomfort and increases in blood pressure, further emphasizing the importance of dose optimization to minimize risks while maximizing therapeutic benefits.

(Related: Psilocybin for Depression in Adults – 2023 Review)

Psilocybin for Depression: Dose-Response Effects (2023 Review)

The study aimed to assess the effectiveness of psilocybin across different doses and to evaluate its safety and tolerability profile in treating both primary and secondary depression.


  • Study Design: The research team conducted a systematic review and a one-stage dose-response meta-analysis following the Cochrane risk of bias assessment guidelines. The review protocol was registered on PROSPERO.
  • Data Sources: Multiple electronic databases were searched from inception until February 2023, focusing on double-blind randomized placebo-controlled trials (RCTs) that evaluated fixed doses of psilocybin in adult patients with depression.
  • Data Analysis: A restricted cubic splines model was employed to analyze the dose-response relationship, allowing for the identification of 95% effective doses (ED95) for different patient groups. The analysis included subgroup investigations based on the type of depression (primary vs. secondary).


  • Effective Doses: The study found distinct ED95 values for different populations, suggesting that treatment-resistant patients respond better to higher doses of psilocybin (ED95: 40 mg/70 kg), whereas patients with secondary depression showed a favorable response to much lower doses (ED95: 8.92 mg/70 kg).
  • Safety & Tolerability: Psilocybin was generally well-tolerated across studies, with most adverse events being transient and of mild to moderate severity, such as headache and nausea. Psychological discomfort during psychedelic experiences was noted at higher doses but could be managed with appropriate psychological support.
  • Dose-Response Relationship: Significant dose-response associations were observed for both the antidepressant effects and various side effects of psilocybin, indicating a correlation between the dose administered and the outcomes experienced by patients.


  • Heterogeneity of Studies: There was considerable heterogeneity in the study populations, dosing regimens, and outcome measures across the included trials, which could influence the generalizability of the findings.
  • Limited Data on Long-term Effects: The long-term safety and efficacy of psilocybin remain uncertain due to the lack of extended follow-up in the reviewed studies.
  • Variability in Depression Types: The distinction between primary and secondary depression among study participants adds complexity to interpreting the optimal dosing recommendations, as the underlying pathophysiology and response to treatment may differ.

Using Psilocybin in Depression Treatment (Evidence-Based Ideas)

Based on the comprehensive findings of the systematic review and dose-response meta-analysis on the use of psilocybin for treating depression, several key recommendations can be formulated to guide clinical practice.

1. Optimal Dosage

  • Treatment-Resistant Depression: For individuals with treatment-resistant depression, higher doses of psilocybin (ED95: 40 mg/70 kg) are recommended. This dosage has shown to be effective in eliciting significant therapeutic responses, marking an important consideration for this subgroup.
  • Primary Depression: Patients with primary depression may benefit from a dose of approximately 24.68 mg/70 kg. This dosage strikes a balance between efficacy and minimizing potential adverse effects, suitable for inducing meaningful therapeutic outcomes.
  • Secondary Depression: For those with secondary depression, notably lower doses (ED95: 8.92 mg/70 kg) are suggested. This reflects the subgroup’s sensitivity to psilocybin and the potential for effective treatment at reduced doses.

2. Ideal Candidate Selection

  • Screening for Suitability: Ideal candidates for psilocybin therapy should be carefully selected through comprehensive psychological and medical screening. This process should identify any contraindications, such as a history of psychosis or bipolar disorder, and ensure that psilocybin is a suitable treatment option.
  • Informed Consent: Patients must be fully informed about the nature of psilocybin therapy, including potential experiences during the session and possible side effects, to ensure informed consent.

3. Therapeutic Setting & Support

  • Controlled Environment: Psilocybin sessions should be conducted in a controlled, therapeutic environment under the supervision of trained professionals. This setting ensures patient safety and supports the management of any adverse reactions.
  • Integration Therapy: Integration sessions post-psilocybin administration are crucial for helping patients process their experiences and apply insights gained to their daily lives. Ongoing support and psychotherapy should be provided to maximize therapeutic outcomes.

4. Monitoring & Safety Protocols

  • Adverse Events Management: Establish protocols for managing both psychological and physical adverse events during and after psilocybin sessions. Immediate access to medical and psychological support should be ensured.
  • Follow-up Care: Regular follow-up assessments are essential to monitor the patient’s progress, evaluate the long-term efficacy and safety of the treatment, and provide additional support as needed.

5. Ethical & Legal Considerations

  • Regulatory Compliance: Ensure that the use of psilocybin for depression adheres to all relevant local laws and regulations, recognizing the varying legal status of psilocybin across jurisdictions.

Conclusion: Psilocybin Appears Effective in Depression

The systematic review and dose-response meta-analysis on psilocybin’s use in treating depression represent a pivotal step forward in understanding its therapeutic potential.

By identifying specific effective doses for various subgroups of depression, the study highlights the importance of personalized treatment approaches in psychedelic-assisted therapy.

The findings suggest that psilocybin is not only effective in reducing depressive symptoms but also demonstrates a favorable safety and tolerability profile, with manageable adverse effects.

Crucially, the study underscores the necessity of a controlled, therapeutic setting and professional support to maximize the benefits of psilocybin treatment while ensuring patient safety.

Furthermore, the distinctions in optimal dosing between primary and secondary depression underscore the complexity of depression as a disorder and the nuanced role psychedelics can play in its treatment.

As we advance, this research lays the groundwork for future clinical trials and the development of guidelines to integrate psilocybin into mainstream psychiatric practice, offering new hope to those for whom conventional treatments have fallen short.


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