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

Phase 2

Recruiting

• Conditions: Major Depressive Disorder
• Interventions: Drug: Psilocybin; Behavioral: Cognitive Behavioral Therapy (CBT)

• Registration Number: NCT06746441
• Lead Sponsor: Khyber Medical University Peshawar

Brief Summary

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.

Detailed Description

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.

Study Timeline

• Status Verified: 2024-12
• Study Start: 2024-12-01
• Study First Submitted: 2024-12-09
• Study First Submitted QC: 2024-12-20
• Last Update Submitted: 2024-12-20
• Study First Posted: 2024-12-24
• Last Update Posted: 2024-12-24
• Primary Completion: 2025-06
• Study Completion: 2025-07

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 60

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).

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Psilocybin Therapy Group	Psilocybin	Participants will receive two oral doses of psilocybin (5-6 grams per dose), administered six weeks apart. Each session will occur in a controlled environment with medical monitoring until the hallucination phase subsides. Participants will continue their routine antidepressant medications during the study.
Psilocybin-Assisted CBT Group	Psilocybin	Participants will receive both psilocybin therapy and Cognitive Behavioral Therapy. Psilocybin will be administered in two oral doses (5-6 grams per dose), six weeks apart, with medical monitoring during sessions. In addition, participants will undergo 8-10 CBT sessions over six weeks. Routine antidepressant medications will be continued.
Cognitive Behavioral Therapy (CBT) Group	Cognitive Behavioral Therapy (CBT)	Participants will undergo 8-10 structured sessions of Cognitive Behavioral Therapy over six weeks. Each session will last approximately 90 minutes, focusing on restructuring negative thought patterns and addressing depression symptoms. Participants will continue their routine antidepressant medications during the study.
Psilocybin-Assisted CBT Group	Cognitive Behavioral Therapy (CBT)	Participants will receive both psilocybin therapy and Cognitive Behavioral Therapy. Psilocybin will be administered in two oral doses (5-6 grams per dose), six weeks apart, with medical monitoring during sessions. In addition, participants will undergo 8-10 CBT sessions over six weeks. Routine antidepressant medications will be continued.

Primary Outcome Measures

Name	Time	Method
Change in Depression Scores (Hamilton Depression Rating)	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
Change in Depression Scores (Montgomery-Åsberg Depression Rating Scale)	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
Change in Depression Scores (Beck Depression Inventory)	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
Change in Anxiety Scores (Beck Anxiety Inventory)	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 Outcome Measures

Name	Time	Method
Change in Brain-Derived Neurotrophic Factor (BDNF) Levels	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.
Change in Oxytocin Levels	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.
Change in Inflammatory Markers	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.
Deviation from Balanced Time Perspective (DBTP)	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.
EEG Pattern Changes	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).

Trial Locations

Locations (1)

Lady Reading Hospital, Pakistan; 🇵🇰 Peshawar, Khyber Pakhtunkhwa, Pakistan