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NCT Number: NCT06746441

Effect of Psilocybin Only and Psilocybin Assisted Cognitive Behavioral Therapy in the Management of Major Depressive Disorder and Associated Metabolic, Immune, Inflammatory, Neuroplasticity and Electrical Activity Markers

This randomized controlled clinical trial evaluates the effectiveness of psilocybin and psilocybin-assisted cognitive behavioral therapy (CBT) in the management of Major Depressive Disorder (MDD). The study aims to compare the effects of psilocybin-only therapy, CBT, and psilocybin-assisted CBT on depression symptoms, neurochemical markers, inflammatory markers, and neuroplasticity in individuals with MDD. Participants will continue their routine depression medications and will be assessed for changes in depression scores, biochemical markers, and brain activity patterns using validated tools and tests.

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Key information

Conditions

Major Depressive Disorder Depressive Disorder Depressive Disorder, Major Mental Disorders Mood Disorders

Age range

18 year–70 year

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 2

Primary location

Lady Reading Hospital, Pakistan

Peshawar, Khyber Pakhtunkhwa, 25000, Pakistan

About this study

This single-masked randomized controlled trial investigates novel therapeutic interventions for Major Depressive Disorder (MDD). MDD is a leading cause of disability worldwide, with a significant proportion of patients being treatment-resistant or showing only partial response to conventional antidepressants. Emerging evidence suggests that psilocybin, a serotonergic psychedelic, has potential as a rapid-acting antidepressant.

The study will recruit 60 participants meeting DSM-V criteria for MDD, randomized into four groups:

Control group (Conventional therapy only), Psilocybin therapy group, Cognitive Behavioral Therapy (CBT) group, and Psilocybin-assisted CBT group. Participants will receive interventions over 10 weeks, with psilocybin administered in two heroic doses six weeks apart, and CBT delivered in 8-10 structured sessions. Biochemical and neurochemical markers such as CD4/CD8 ratio, TNF-α, IL-6, BDNF, and oxytocin will be measured, along with inflammatory markers (resistin and visfatin). Depression scores will be assessed using scales like HAM-D, MADRS, and BDI. EEG recordings will evaluate changes in brain activity pre- and post-intervention.

The primary objective is to assess improvements in depression symptoms, while secondary objectives include evaluating changes in immune, inflammatory, and neurochemical markers and EEG activity. Data will be analyzed using ANOVA with Tukey's post-hoc tests to determine statistical significance.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

Inclusion criteria

  • Individuals aged 18-70 years.
  • Diagnosed with Major Depressive Disorder (MDD) according to DSM-V criteria.
  • Active depressive symptoms as indicated by a score > 16 on the Hamilton Depression
  • Rating Scale (HAM-D) over the preceding two weeks.
  • Female participants of childbearing potential must be using a highly effective form of contraception and willing to maintain contraceptive use throughout the study period.
  • Participants must have been taking one SSRI antidepressant (e.g., citalopram, escitalopram, fluoxetine) for at least 6 weeks with at least 75% adherence.

Exclusion criteria

  • Resting blood pressure >140/90 (average of four separate measurements).
  • Risk of suicidal tendencies as indicated by a score of 3 or higher on item 3 of the HAM-D scale.
  • Use of multiple SSRIs or any antidepressant not specified in the inclusion criteria.
  • Presence of concurrent psychiatric disorders (e.g., bipolar disorder, schizophrenia).
  • Use of psychedelics or ketamine within the last 12 months.
  • Pregnancy, breastfeeding, or attempting to conceive.
  • History of substance abuse or alcohol use in the last 6 months.
  • Cardiovascular conditions (e.g., hypertension, stroke history).
  • History of seizures or epilepsy.
  • Diabetes (especially insulin-dependent).

Treatment and study plan

Psilocybin

Drug

Psilocybin is a naturally occurring serotonergic psychedelic compound found in Psilocybe mushrooms. It is metabolized in the body into its active form, psilocin, which has a high affinity for serotonin 5-HT2A receptors. This enables psilocin to bypass the default serotonin pathway, producing antidepressant effects.

For this study:

Psilocybin will be administered orally in a dose of 5-6 grams per session. Each participant in the Psilocybin and Psilocybin-assisted CBT arms will receive two sessions spaced six weeks apart.

The therapy will be conducted in a controlled hospital setting with medical monitoring during the session to ensure safety until the hallucination phase subsides.

Psilocybin will be added to routine antidepressant medication.

Other names: Psilocin (the active form of psilocybin metabolized in the body)

Cognitive Behavioral Therapy (CBT)

Behavioral

Cognitive Behavioral Therapy (CBT) is a structured, time-limited psychotherapy aimed at alleviating symptoms of depression. It involves addressing negative thoughts and behavioral patterns through the following steps:

Identifying troubling life situations. Recognizing thoughts, emotions, and beliefs about those situations. Identifying negative or inaccurate thinking patterns. Restructuring those thoughts into positive and realistic perspectives.

In this study:

CBT will consist of 8-10 structured sessions, each lasting approximately 90 minutes.

Participants will attend therapy sessions twice weekly over a six-week period. The intervention will be delivered by trained psychotherapists in a controlled hospital setting.

Routine antidepressant medications will be continued alongside CBT.

Primary outcomes

  1. Change in Depression Scores (Hamilton Depression Rating)

    Time frame: Baseline, Week 6 (end of the first psilocybin session), and Week 10 (end of intervention).

    Assessment of changes in depression scores using the Hamilton Depression Rating Scale (HAM-D), a clinician-administered tool for evaluating the severity of depression.

    Unit of Measure: Points on the HAM-D scale. The HAM-D consists of 17 items, each assessing a specific depressive symptom. Each item is rated on a 0-4 or 0-2 scale, depending on the item. The total score ranges from 0 to 52. Higher scores indicate greater severity of depressive symptoms.

    0-7: Normal 8-13: Mild depression 14-18: Moderate depression 19-22: Severe depression

    • 23: Very severe depression

  2. Change in Depression Scores (Montgomery-Åsberg Depression Rating Scale)

    Time frame: Baseline, Week 6 (end of the first psilocybin session), and Week 10 (end of intervention).

    Assessment of changes in depression scores using the Montgomery-Åsberg Depression Rating Scale (MADRS), a clinician-administered scale for evaluating depressive symptom severity.

    Unit of Measure: Points on the MADRS scale.

    The MADRS consists of 10 items, each assessing a specific depressive symptom. Each item is rated on a 0-6 scale. The total score ranges from 0 to 60. Higher scores indicate greater severity of depressive symptoms.

    0-12: Normal 13-19: Mild depression 20-34: Moderate depression

    • 35: Severe depression

  3. Change in Depression Scores (Beck Depression Inventory)

    Time frame: Baseline, Week 6 (end of the first psilocybin session), and Week 10 (end of intervention).

    Assessment of changes in depression scores using the Beck Depression Inventory (BDI), a self-reported measure designed to evaluate the severity of depression symptoms.

    Unit of Measure: Points on the BDI scale.

    The BDI consists of 21 items, each assessing a specific depressive symptom. Each item is rated on a 4-point scale. The total score ranges from 0 to 63. Higher scores indicate greater severity of depressive symptoms.

    0-13: Normal 14-19: Mild depression 20-28: Moderate depression 29-63: Severe depression

  4. Change in Anxiety Scores (Beck Anxiety Inventory)

    Time frame: Baseline, Week 6 (end of the first psilocybin session), and Week 10 (end of intervention).

    Assessment of changes in anxiety scores using the Beck Anxiety Inventory (BAI), a self-reported questionnaire for evaluating the severity of anxiety symptoms.

    Unit of Measure: Points on the BAI scale.

    The BAI consists of 21 items, each assessing a specific anxiety symptom. Each item is rated on a 0-3 scale. The total score ranges from 0 to 63. Higher scores indicate greater severity of anxiety symptoms.

    0-7: Normal 8-15: Mild anxiety 16-25: Moderate anxiety 26-63: Severe anxiety

Secondary outcomes

  1. Change in Brain-Derived Neurotrophic Factor (BDNF) Levels

    Time frame: Baseline, Week 6, and Week 10

    Assessment of changes in serum BDNF levels from baseline to the end of the intervention.

    Unit of Measure: ng/mL.

  2. Change in Oxytocin Levels

    Time frame: Baseline, Week 6, and Week 10

    Assessment of changes in serum oxytocin levels from baseline to the end of the intervention.

    Unit of Measure: pg/mL.

  3. Change in Inflammatory Markers

    Time frame: Baseline, Week 6, and Week 10.

    Evaluation of changes in serum levels of TNF-α, IL-6, resistin, and visfatin to monitor systemic inflammation.

    Unit of Measure: pg/mL or ng/mL, depending on the specific biomarker.

  4. Deviation from Balanced Time Perspective (DBTP)

    Time frame: Baseline, Week 6, and Week 10.

    Measurement of deviation from a balanced time perspective using the Zimbardo Time Perspective Inventory (ZTPI).

    Unit of Measure: ZTPI score.

  5. EEG Pattern Changes

    Time frame: Baseline, Week 6, and Week 10.

    Analysis of changes in EEG activity patterns before and after the intervention, focusing on frequency bands (e.g., Alpha, Beta, Theta, and Delta waves) and their relative power across these bandwidths.

    Unit of Measure: Relative power (percentage or dB).

Sponsors and collaborators

Lead sponsor

Khyber Medical University Peshawar

Other

Registry information

Official study title

Effect of Psilocybin Only and Psilocybin Assisted Cognitive Behavioral Therapy in the Management of Major Depressive Disorder and Associated Metabolic, Immune, Inflammatory, Neuroplasticity and Electrical Activity Markers: a Randomized Controlled Trial

Important dates

Study start
2024
Primary completion
2025
Study completion
2025
First posted
Dec 24, 2024
Registry last updated
Sep 2, 2025

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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