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

NCT06746441 | Completed Phase 2 DMC

• 1 other identifier: KMU/DIR/CTU/2024/011
• Study Type: interventional
• Target: 60
• Locations: 1 country
• Sites: 1

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.

Conditions

Major Depressive Disorder

Keywords

Psilocybin; Cognitive Behavioral Therapy (CBT); Randomized Controlled Trial; Psychedelic Therapy; Inflammatory Markers

Outcome Measures

Primary Outcomes (4)

• Change in Depression Scores (Hamilton Depression Rating)

  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

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

• Change in Depression Scores (Montgomery-Åsberg Depression Rating Scale)

  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

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

• Change in Depression Scores (Beck Depression Inventory)

  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

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

• Change in Anxiety Scores (Beck Anxiety Inventory)

  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

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

Secondary Outcomes (5)

• Change in Brain-Derived Neurotrophic Factor (BDNF) Levels

  Baseline, Week 6, and Week 10

• Change in Oxytocin Levels

  Baseline, Week 6, and Week 10

• Change in Inflammatory Markers

  Baseline, Week 6, and Week 10.

• Deviation from Balanced Time Perspective (DBTP)

  Baseline, Week 6, and Week 10.

• EEG Pattern Changes

  Baseline, Week 6, and Week 10.

Study Arms (4)

Psilocybin Therapy Group

EXPERIMENTAL

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.

Drug: Psilocybin

Control Group

NO INTERVENTION

Participants will continue their routine antidepressant medications (e.g., SSRIs such as citalopram, escitalopram, or sertraline) without any additional intervention.

Cognitive Behavioral Therapy (CBT) Group

ACTIVE COMPARATOR

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.

Behavioral: Cognitive Behavioral Therapy (CBT)

Psilocybin-Assisted CBT Group

ACTIVE COMPARATOR

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.

Drug: Psilocybin; Behavioral: Cognitive Behavioral Therapy (CBT)

Interventions

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.

Also known as: Psilocin (the active form of psilocybin metabolized in the body)

Psilocybin Therapy Group; Psilocybin-Assisted CBT Group

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.

Cognitive Behavioral Therapy (CBT) Group; Psilocybin-Assisted CBT Group

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.
• 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).

Sponsors & Collaborators

• Khyber Medical University Peshawar: lead

Study Sites (1)

Lady Reading Hospital, Pakistan

Peshawar, Khyber Pakhtunkhwa, 25000, Pakistan

Location

Related Publications (5)

• Lee YJ, Lee GW, Seo WS, Koo BH, Kim HG, Cheon EJ. Neurofeedback Treatment on Depressive Symptoms and Functional Recovery in Treatment-Resistant Patients with Major Depressive Disorder: an Open-Label Pilot Study. J Korean Med Sci. 2019 Nov 4;34(42):e287. doi: 10.3346/jkms.2019.34.e287.

  PMID: 31674161 BACKGROUND

• MacCallum CA, Lo LA, Pistawka CA, Deol JK. Therapeutic use of psilocybin: Practical considerations for dosing and administration. Front Psychiatry. 2022 Dec 1;13:1040217. doi: 10.3389/fpsyt.2022.1040217. eCollection 2022.

  PMID: 36532184 BACKGROUND

• Dodd S, Norman TR, Eyre HA, Stahl SM, Phillips A, Carvalho AF, Berk M. Psilocybin in neuropsychiatry: a review of its pharmacology, safety, and efficacy. CNS Spectr. 2023 Aug;28(4):416-426. doi: 10.1017/S1092852922000888. Epub 2022 Jul 11.

  PMID: 35811423 BACKGROUND

• Mertens LJ, Wall MB, Roseman L, Demetriou L, Nutt DJ, Carhart-Harris RL. Therapeutic mechanisms of psilocybin: Changes in amygdala and prefrontal functional connectivity during emotional processing after psilocybin for treatment-resistant depression. J Psychopharmacol. 2020 Feb;34(2):167-180. doi: 10.1177/0269881119895520. Epub 2020 Jan 16.

  PMID: 31941394 BACKGROUND

• Goodwin GM, Aaronson ST, Alvarez O, Arden PC, Baker A, Bennett JC, Bird C, Blom RE, Brennan C, Brusch D, Burke L, Campbell-Coker K, Carhart-Harris R, Cattell J, Daniel A, DeBattista C, Dunlop BW, Eisen K, Feifel D, Forbes M, Haumann HM, Hellerstein DJ, Hoppe AI, Husain MI, Jelen LA, Kamphuis J, Kawasaki J, Kelly JR, Key RE, Kishon R, Knatz Peck S, Knight G, Koolen MHB, Lean M, Licht RW, Maples-Keller JL, Mars J, Marwood L, McElhiney MC, Miller TL, Mirow A, Mistry S, Mletzko-Crowe T, Modlin LN, Nielsen RE, Nielson EM, Offerhaus SR, O'Keane V, Palenicek T, Printz D, Rademaker MC, van Reemst A, Reinholdt F, Repantis D, Rucker J, Rudow S, Ruffell S, Rush AJ, Schoevers RA, Seynaeve M, Shao S, Soares JC, Somers M, Stansfield SC, Sterling D, Strockis A, Tsai J, Visser L, Wahba M, Williams S, Young AH, Ywema P, Zisook S, Malievskaia E. Single-Dose Psilocybin for a Treatment-Resistant Episode of Major Depression. N Engl J Med. 2022 Nov 3;387(18):1637-1648. doi: 10.1056/NEJMoa2206443.

  PMID: 36322843 BACKGROUND

MeSH Terms

Conditions

Depressive Disorder, Major

Interventions

Psilocybin; psilocin; Cognitive Behavioral Therapy

Condition Hierarchy (Ancestors)

Depressive Disorder; Mood Disorders; Mental Disorders

Intervention Hierarchy (Ancestors)

Indole Alkaloids; Alkaloids; Heterocyclic Compounds; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Tryptamines; Indolizidines; Indolizines; Behavior Therapy; Psychotherapy; Behavioral Disciplines and Activities

Study Officials

• Dr Mahvash Khan

  Hayat Abad Medical Complex, Peshawar

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: PARTICIPANT
• Masking Details: Randomized (Random allocation will be performed using a simple lottery method.)
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Parallel Assignment (The study has four distinct intervention groups: Control, Psilocybin Therapy, CBT, and Psilocybin-assisted CBT.)

Study Record Dates

• First Submitted: December 9, 2024
• First Posted: December 24, 2024
• Study Start: December 1, 2024
• Primary Completion: June 1, 2025
• Study Completion: July 30, 2025
• Last Updated: September 2, 2025

Record last verified: 2025-08

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR
• Time Frame: The IPD will become available one year after the completion of data analysis (anticipated November 2025). Data will remain accessible for a period of 5 years or until the data usage restrictions are lifted by ethical review.
• Access Criteria: The data will be accessible to qualified researchers who meet the following criteria: * Ethical approval for data usage from their institution. * A research proposal that justifies the use of the data and outlines the planned analysis. * Institutional support for data management and ethics review.

Locations

PA (1)