Clinical TrialMajor Depressive Disorder (MDD)LSDPlaceboPlaceboNot yet recruiting

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.

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

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 microdose

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

active comparator

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

Interventions

  • Placebo100 - 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

active comparator

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

Interventions

  • Placebo20 - 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 Details

Locations

Unknown facility — Australia

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