Clinical TrialParallelMajor Depressive Disorder (MDD)PsilocybinRecruiting

Effect of Psilocybin and Structured Integrated Reframing Therapy on Gut-Brain Axis Biomarkers and Depression in Major Depressive Disorder

This Phase III, randomised, parallel-group trial (n=60) will evaluate psilocybin and Structured Integrated Reframing Therapy (SIRT) in adults aged 18-60 years with trauma-related major depressive disorder and post-traumatic stress symptoms who are receiving a stable selective serotonin reuptake inhibitor (SSRI). The study will compare conventional therapy, psilocybin therapy, SIRT, and psilocybin-assisted SIRT, with the main aims of assessing depression, trauma-related symptoms, anxiety, and gut-brain axis biomarkers. Participants in the psilocybin-containing arms will receive oral psilocybin under medical supervision in a controlled clinical setting during two supervised dosing sessions over the 8-week intervention period, while all groups continue stable SSRI treatment. SIRT will be delivered once weekly for 8 weeks and combines cognitive behavioural therapy, dialectical behaviour therapy, mindfulness, cognitive reframing, emotional regulation, coping skills training, and communication-focused techniques. Outcomes will be measured at baseline, week 4, week 8, and week 12, using the TADE tool together with HAM-D, PCL-5 and GAD-7, alongside serum biomarkers including short-chain fatty acids, IL-6, IL-10, zonulin, occludin and GDNF.

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Target Enrollment
60 participants
Study Type
Phase III interventional
Design
Randomized

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Compound research: PsilocybinTopic research: Major Depressive Disorder (MDD)Research in Pakistan

Detailed Description

Trauma-related Major Depressive Disorder (MDD) is frequently associated with poor response to conventional antidepressants, persistent psychological distress, and alterations in gut-brain axis function. Existing assessment tools primarily diagnose depression or PTSD but provide limited guidance for integrated clinical management. This study aims to develop and validate the Trauma Anxiety Depression Emotion (TADE) management tool while simultaneously evaluating the effectiveness of psilocybin-assisted Structured Integrated Reframing Therapy (SIRT) in improving clinical and biological outcomes.

This prospective, four-arm randomized controlled trial will compare conventional therapy, psilocybin therapy, SIRT, and psilocybin-assisted SIRT. Participants will undergo assessment using the newly developed TADE tool together with established psychometric scales including HAM-D, PCL-5, and GAD-7. Biological outcomes will include serum gut-brain axis and inflammatory biomarkers, including Short-Chain Fatty Acids (SCFAs), Interleukin-6 (IL-6), Interleukin-10 (IL-10), Zonulin, Occludin, and Glial Cell Line-Derived Neurotrophic Factor (GDNF). Assessments will be performed at baseline, during treatment, and at 12-week follow-up. The study aims to determine whether combining psilocybin with SIRT provides superior clinical improvement and favorable biological changes compared with either intervention alone while establishing the validity and clinical utility of the TADE management tool.

Study Arms & Interventions

Treatment as usual

active comparator

Participants will receive standard conventional treatment for trauma-related Major Depressive Disorder, consisting of a stable selective serotonin reuptake inhibitor (SSRI) regimen prescribed by the treating psychiatrist. No psilocybin or Structured Integrated Reframing Therapy (SIRT) will be administered. Treatment will continue for 8 weeks with routine clinical follow-up.

Interventions

  • Compound
    via Oral• stable regimen throughout the study

    Unmatched intervention: Selective Serotonin Reuptake Inhibitor (SSRI)

Psilocybin

experimental

Participants will continue standard SSRI therapy and receive oral psilocybin administered under medical supervision in a controlled clinical setting. Two supervised dosing sessions will be conducted during the 8-week intervention period according to the study protocol. No SIRT will be provided.

Interventions

  • Psilocybin
    via Oral• two supervised dosing sessions during the 8-week intervention period• 2 doses total
  • Compound
    via Oral• stable regimen throughout the study

    Unmatched intervention: Selective Serotonin Reuptake Inhibitor (SSRI)

Structured integrated reframing therapy

experimental

Participants will continue standard SSRI therapy and receive Structured Integrated Reframing Therapy (SIRT), a trauma-informed psychotherapy integrating Cognitive Behavioral Therapy (CBT), Dialectical Behavior Therapy (DBT), mindfulness, cognitive reframing, and communication-focused therapeutic techniques. Therapy will be delivered once weekly for 8 weeks by trained therapists.

Interventions

  • Compound
    via Other• once weekly for 8 weeks• 8 doses total

    Unmatched intervention: Structured Integrated Reframing Therapy (SIRT)

  • Compound
    via Oral• stable regimen throughout the study

    Unmatched intervention: Selective Serotonin Reuptake Inhibitor (SSRI)

Psilocybin + structured integrated reframing therapy

experimental

Participants will continue standard SSRI therapy and receive both supervised oral psilocybin administration and Structured Integrated Reframing Therapy (SIRT). Psilocybin will be administered in two supervised dosing sessions during the 8-week intervention period, while SIRT will be delivered once weekly for 8 weeks. The combined intervention is intended to evaluate the synergistic effects of psychedelic-assisted psychotherapy on clinical outcomes and gut-brain axis biomarkers.

Interventions

  • Psilocybin
    via Oral• two supervised dosing sessions during the 8-week intervention period• 2 doses total
  • Compound
    via Other• once weekly for 8 weeks• 8 doses total

    Unmatched intervention: Structured Integrated Reframing Therapy (SIRT)

  • Compound
    via Oral• stable regimen throughout the study

    Unmatched intervention: Selective Serotonin Reuptake Inhibitor (SSRI)

Participants

Ages
18 – 60
Sexes
Male & Female

Inclusion Criteria

  • Adults aged 18-60 years.
  • Diagnosis of Major Depressive Disorder (MDD) according to DSM-5 criteria.
  • Trauma-related depression with clinically significant trauma symptoms.
  • Hamilton Depression Rating Scale (HAM-D) score \>16.
  • PTSD Checklist for DSM-5 (PCL-5) score \>33.
  • Generalized Anxiety Disorder-7 (GAD-7) score \>10.
  • Receiving a stable single SSRI antidepressant regimen for at least 6 weeks before enrollment with adequate treatment adherence.
  • Able and willing to provide written informed consent.
  • Willing to comply with all study procedures and follow-up visits.
  • Women of childbearing potential must agree to use effective contraception throughout the study.

Exclusion Criteria

  • Significant cardiovascular disease.
  • Clinically significant hepatic or renal impairment.
  • Significant neurological disorders.
  • Current or past psychotic disorder or bipolar disorder.
  • Current substance or alcohol use disorder, including ketamine or psychedelic drug use.
  • Use of more than one antidepressant medication.
  • Pregnancy, planned pregnancy, or breastfeeding.
  • Known hypersensitivity or contraindication to psilocybin.
  • Participation in another interventional clinical trial within the previous 30 days.
  • Inability or unwillingness to provide informed consent.
  • Any medical or psychiatric condition that, in the investigator's opinion, would interfere with safe participation or study assessments.

Study Protocol, Arms & Participants

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Study Details

Study Team

Sponsors & Collaborators

Locations

Institute of Health Science, Khyber Medical University — Islamabad, Capital, Pakistan
Hayatabad Medical Complex Peshawar — Peshawar, KPK, Pakistan
Khyber Medical University — Peshawar, KPK, Pakistan

Recent activity

  • StartedEffect of Psilocybin and Structured Integrated Reframing Therapy on Gut-Brain Axis Biomarkers and Depre… (NCT07703722, psilocybin)

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