Clinical TrialMajor Depressive Disorder (MDD)PsilocybinPlaceboCompleted

The Effect of Psilocybin on MDD Symptom Severity and Synaptic Density

The effect of psilocybin on major depressive disorder (MDD) symptom severity and synaptic density - a single dose randomized, double blind, placebo-controlled Phase IIb positron emission tomography study.

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Target Enrollment
35 participants
Study Type
Phase II interventional
Design
Randomized, quadruple Blind

Detailed Description

Randomized, double-blind, parallel-group Phase 2b trial (n=35 actual) comparing a single 25 mg oral dose of psilocybin with a single 100 mg niacin active placebo in adults with MDD; primary outcome is change in MADRS score to Day 8.

Participants undergo MRI and PET with [11C]UCB-J to assess synaptic density at baseline and Day 15; one preparation session and three post-dose integration sessions are provided under a set-and-setting protocol with two facilitators present during dosing.

Safety measures and biological samples (CSF, blood) collected at baseline and Day 15; follow-up visits continue to Day 365 for clinical outcomes and safety.

Study Protocol

Preparation

1 sessions

Dosing

1 sessions

Integration

3 sessions

Therapeutic Protocol

support

Study Arms & Interventions

Psilocybin

experimental

Single oral 25 mg psilocybin dose

Interventions

  • Psilocybin25 mg
    via Oral• single dose• 1 doses total

Niacin (active placebo)

active comparator

Single oral 100 mg niacin active placebo

Interventions

  • Placebo100 mg
    via Oral• single dose• 1 doses total

    Niacin 100 mg active placebo to aid blinding

Participants

Ages
20 – 65
Sexes
Male & Female

Inclusion Criteria

  • Inclusion Criteria:
  • Individuals eligible to be randomized in this protocol are those who meet all of the following criteria:
  • 1. Are 20 to 65 years old at the time of written informed consent at the In-Person Screening visit
  • 2. Are able to read, speak, and understand Swedish
  • 3. Are able and willing to adhere to study requirements, including attending all study visits, preparatory and follow-up sessions, and completing all study evaluations
  • 4. Are able to swallow capsules
  • 5. Women of childbearing potential (WOCBP) must agree to practice an effective means of birth control throughout the duration of the study, from Screening through the Day 42 assessment
  • 6. Meet ICD-10 criteria for a diagnosis of remitting major depressive disorder and are currently experiencing a major depressive episode of at least 30 days and less than 5 years at time of Screening
  • 7. Have sustained moderate-severe depression symptoms at Screening and Baseline, as defined by a Screening MADRS total score ≥ 22 and ≤30% and ≤7 point improvement from web-screening to screening
  • 9. Have an identified support person and agree to be accompanied home after dosing

Exclusion Criteria

  • Exclusion Criteria:
  • 1. Women who are pregnant or nursing or intend to become pregnant during the study
  • 2. Current depressive episode lasting >5 years
  • 3. Unwilling or unable to discontinue formal psychotherapy
  • 4. Ongoing antidepressant drug treatment
  • 5. Prior DBS or VNS in current episode
  • 6. Currently receiving ECT or TMS
  • 7. Unable or unwilling to discontinue medications that are UDP or UGT modulators (eg valproate)
  • 8. Report psychedelic substance use ever (psilocybin, LSD, mescaline, DMT, 5-MeO-DMT, ibogaine, 2C compounds, MDMA, etc.)
  • 9. Specific cardiovascular conditions (coronary artery disease, prior MI, long QT, hypertrophy, ischemia, CHF), tachycardia (>100 bpm), clinically significant ECG abnormality (eg QTcF >450 ms), artificial heart valve
  • 10. Elevated blood pressure at Screening or Baseline per protocol thresholds
  • 11. History of stroke or TIA
  • 12. Moderate to severe hepatic impairment (Child-Pugh ≥7)
  • 13. Epilepsy
  • 14. Insulin-dependent diabetes or history of hypoglycaemia requiring intervention
  • 15. Inability to suspend certain medications/supplements (eg PDE5 inhibitors, niacin >20 mg) or positive urine drug test for specified substances
  • 16. Nicotine dependence preventing nicotine-free dosing period
  • 17. ICD-10 schizophrenia spectrum or other psychotic disorders, bipolar I/II or NOS
  • 18. Antisocial personality disorder
  • 19. Moderate or severe alcohol or drug use disorder within past 12 months
  • 20. Any psychiatric condition judged by PI to be more significant than MDD
  • 21. First-degree relative with schizophrenia spectrum/psychotic disorders or bipolar I
  • 22. Psychiatric condition incompatible with rapport or safe exposure to psilocybin
  • 23. Suicidal ideation per MADRS Item 10 ≥5 or any suicidal thoughts judged to present serious risk prior to randomization
  • 24. Any other physical or psychological condition making participant unsuitable

Study Protocol, Arms & Participants

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Study Details

Locations

Northern Stockholm Spychiatry Clinic — Stockholm, Sweden

Related Publications

Open AccessindividualPrimary

Short-Term and Late-Term Effects of Psilocybin on Symptoms in Major Depression: A Randomized Clinical Trial.

This double-blind placebo-controlled randomised clinical trial (n=35) found that a single 25 mg dose of psilocybin, given with psychotherapy, reduced depression symptoms in people with moderate to severe recurrent major depressive disorder within days and for more than three months on some measures. Most side effects were mild or moderate, but two participants had severe anxiety that needed medical attention.

Published
Journal
JAMA Network Open
Authors
Yngwe, H., Plavén-Sigray, P., Ekman, C. J., Henje, E., Berglund, A., Tiger, M., Beckman, M., Lundberg, J.
Open AccessindividualSecondary analysis

CSF galanin and noradrenaline downregulation by psilocybin therapy in major depressive disorder

This secondary analysis of a randomised, placebo-controlled trial found that psilocybin selectively reduced cerebrospinal fluid galanin and noradrenaline in people with major depressive disorder. The results suggest that changes in these two signalling chemicals may be part of psilocybin’s biological effect.

Published
Journal
Neuropsychopharmacology
Authors
Paslawski, W., Doyon, D., Ekman, C. J., Yngwe, H., Mamula, D., Zareba-Paslawska, J., Beckman, M., Xu, Z. Q. D., Hökfelt, T., Tiger, M., Lundberg, J., Svenningsson, P.

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