Clinical TrialMajor Depressive Disorder (MDD)LSDCompleted

Assessing the effects of Lysergic acid diethylamide (LSD) microdosing in people experiencing depression (LSDDEP2)

Randomised, double-dummy, triple-blind, placebo-controlled, parallel groups trial (n=90) investigating sublingual LSD microdosing (2–20 µg, start 8 µg) twice weekly for 8 weeks versus active placebo (caffeine or methylphenidate) in people with MDD.

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Target Enrollment
90 participants
Study Type
Phase II interventional
Design
Randomized, triple Blind

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Compound research: LSDTopic research: Major Depressive Disorder (MDD)

Detailed Description

This Phase II randomised, triple-blind, double-dummy parallel trial enrols adults with moderate MDD (MADRS 18–35) to receive sublingual LSD microdosing or an active comparator (caffeine or methylphenidate) twice weekly for eight weeks; primary outcome is MADRS total score at 8 weeks.

Dosing is participant-titrated within predefined ranges (LSD 2–20 µg, caffeine 50–300 mg, methylphenidate 10–60 mg) with adherence monitored via participant video recordings; secondary measures include HAM-A and safety assessments.

Study Protocol

Preparation

sessions

Dosing

16 sessions

Integration

sessions

Study Arms & Interventions

LSD 8–20 µg

experimental

Sublingual LSD solution administered twice weekly for 8 weeks; starting 8 µg (range 2–20 µg) with participant-titrated adjustments.

Interventions

  • LSD8 - 20 µg
    via Sublingual• two doses per week for 8 weeks• 16 doses total

    Dose may be increased/decreased by 1–2 µg by participant if well tolerated; adherence monitored via participant video recordings.

Caffeine 100–300 mg (active comparator)

active comparator

Oral caffeine tablets as active comparator; twice weekly for 8 weeks.

Interventions

  • Compound100 - 300 mg
    via Oral• two doses per week for 8 weeks• 16 doses total

    Caffeine starting 100 mg (range 50–300 mg); doses adjusted by ±50 mg; adherence monitored via video; active comparator encoded as placebo reference with details in notes.

Methylphenidate 20–60 mg (active comparator)

active comparator

Oral methylphenidate (Ritalin) as active comparator; twice weekly for 8 weeks.

Interventions

  • Compound20 - 60 mg
    via Oral• two doses per week for 8 weeks• 16 doses total

    Methylphenidate starting 20 mg (range 10–60 mg); doses adjusted by ±5 mg; adherence monitored via video; active comparator encoded as placebo reference with details in notes.

Participants

Ages
21 – 65
Sexes
Male & Female

Inclusion Criteria

  • 1. Provision of signed and dated informed consent form.
  • 2. Stated willingness to comply with all study procedures and availability for the duration of the study.
  • 3. Any gender identity aged 21–65 years.
  • 4. Diagnosis of Major Depressive Disorder (MDD) as per the DSM-5 criteria for MDD.
  • 5. Have a MADRS score between 18–35 at the time of screening.
  • 6. Ability to take oral medication and be willing to adhere to the study intervention regimen.
  • 7. For persons of child-bearing potential: agree to use an effective or highly effective contraception.

Exclusion Criteria

  • 1. Current or past history schizophrenia or other psychotic disorders, or bipolar I or II disorder.
  • 2. Diagnosis of PTSD as assessed by clinical interview.
  • 3. Diagnosis of an eating disorder as assessed by clinical interview.
  • 4. Risk of suicide as determined by The Columbia-Suicide Severity Rating Scale (C-SSRS).
  • 5. Substance dependence in the previous 6 months.
  • 6. Problematic use of alcohol defined as a score on the AUDIT of 16 or greater.
  • 7. Stage II or higher treatment-resistant depression as defined by the Thase and Rush (1997) staging criteria for the current depressive episode.
  • 8. BMI <18 and >35.
  • 9. Planned or current pregnancy or lactation.
  • 10. Cardiovascular conditions including abnormal heart rate or blood pressure.
  • 11. Significant renal or hepatic impairment.
  • 12. Abnormal 12-lead ECG as judged by a study physician.
  • 13. Abnormal laboratory test findings as judged by a study physician.
  • 14. Use of monoamine oxidase inhibitors, methylphenidate (ritalin) or dexamphetamine.
  • 15. Excessive on-going medication burden as determined by a study physician.
  • 16. Any lifetime history of psychedelic microdosing.
  • 17. Use of serotonergic psychedelic drugs in the last year.
  • 18. Lifetime history of self-medicating with psychedelics to treat their depression.
  • 19. Daily caffeine use > 500 mg per day.

Study Protocol, Arms & Participants

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Study Details

  • Status
    Completed
  • Phase
    Phase II
  • Type
    interventional
  • Design
    Randomizedtriple Blind
  • Target Enrollment90 participants
  • Timeline
    Start: 2024-03-11
    End: 2025-11-26
  • Compound
    LSD
  • Topic
    Major Depressive Disorder (MDD)

Locations

Unknown facility — Australia

Recent activity

  • CompletedAssessing the effects of Lysergic acid diethylamide (LSD) microdosing in people experiencing depressio… (ACTRN12624000128594, lsd)
  • StartedAssessing the effects of Lysergic acid diethylamide (LSD) microdosing in people experiencing depressio… (ACTRN12624000128594, lsd)

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