Clinical TrialMajor Depressive Disorder (MDD)PsilocybinPsilocybinCompleted

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

Single-masked, randomised controlled trial (n=60) comparing psilocybin (two high-dose oral sessions, 5–6 g each, six weeks apart), CBT (8–10 sessions), psilocybin-assisted CBT, and routine care in adults with MDD.

Target Enrollment
60 participants
Study Type
Phase II interventional
Design
Randomized, single Blind

Detailed Description

This randomized, single-masked, parallel-group trial will randomize 60 adults with DSM‑V major depressive disorder to one of four arms: routine care, psilocybin only, CBT only, or psilocybin-assisted CBT. Psilocybin is given in two oral sessions six weeks apart; CBT comprises 8–10 structured 90‑minute sessions.

Outcomes include change in depressive symptoms (HAM‑D, MADRS, BDI), immune and inflammatory markers (CD4/CD8, TNF‑α, IL‑6, resistin, visfatin), neuroplasticity markers (BDNF, oxytocin) and EEG measures; analyses will use ANOVA with Tukey post‑hoc tests.

Study Protocol

Preparation

sessions

Dosing

2 sessions

Integration

10 sessions
90 min each

Therapeutic Protocol

cbt

Study Arms & Interventions

Psilocybin Therapy

experimental

Two oral psilocybin sessions (heroic doses) administered six weeks apart in addition to routine antidepressant medication.

Interventions

  • Psilocybin6000 mg
    via Oral• two sessions, six weeks apart• 2 doses total

    Dose reported as 5–6 g per session; upper value used (6000 mg). Participants continue routine antidepressants; medical monitoring during sessions.

Control

no intervention

Continuation of routine antidepressant medications without additional intervention.

Interventions

  • Compound
    via Other• routine care

    Continuation of routine antidepressant medications (e.g., SSRIs) only.

CBT

active comparator

8–10 structured CBT sessions delivered over six weeks alongside routine antidepressant medication.

Interventions

  • Compound
    via Other• 8–10 sessions over six weeks• 10 doses total

    CBT sessions ~90 minutes each; behavioural intervention.

Psilocybin + CBT

active comparator

Two oral psilocybin sessions plus 8–10 CBT sessions; participants continue routine antidepressants.

Interventions

  • Psilocybin6000 mg
    via Oral• two sessions, six weeks apart• 2 doses total

    Psilocybin 5–6 g per session (upper value used). Medical monitoring during sessions.

  • Compound
    via Other• 8–10 sessions over six weeks• 10 doses total

    CBT sessions ~90 minutes each.

Participants

Ages
18 – 70
Sexes
Male & Female

Inclusion Criteria

  • 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 use a highly effective form of contraception and maintain use throughout the study.
  • Participants must have been taking one SSRI antidepressant (e.g., citalopram, escitalopram, fluoxetine) for at least 6 weeks with ≥75% adherence.

Exclusion Criteria

  • 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 Details

Locations

Lady Reading Hospital, Pakistan — Peshawar, Khyber Pakhtunkhwa, Pakistan

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