LSD microdosing reduces depression scores without major side effects, clinical trial finds

University of Auckland researchers report that an 8-week, twice-weekly LSD microdosing regimen for major depressive disorder was feasible and well-tolerated, with Montgomery-Åsberg Depression Rating Scale (MADRS) scores reduced by 59.5% at the end of treatment and sustained to six months.

Major depressive disorder affects about 5% of the global population and existing antidepressants can have slow onset, variable tolerability, side effects, and show limited efficacy for many patients. Interest in classic serotonergic psychedelics as potential treatments for depression and related conditions has been increasing.

Previous controlled work describes acute mood and energy changes from LSD microdoses in healthy volunteers and notes user-led microdosing practices at levels below substantial alterations in consciousness. Safety questions have included anxiety or overstimulation and a theoretical risk of heart valve disease linked to 5-HT2B receptor activity.

What the team set out to test

In the study, “LSD microdosing in major depressive disorder: results from an open-label trial,” published in Neuropharmacology, researchers conducted a Phase 2A open-label investigation to evaluate tolerability and feasibility for a Phase 2B randomized controlled trial. Objectives also included descriptive changes in depression severity and other mental health outcomes, along with cardiac safety, including echocardiography and electrocardiography (ECG).

A total of 19 participants enrolled and received the intervention. The mean age was 41.52 years. Fifteen participants were male. Baseline MADRS averaged 23.7 with SD 6.72, indicating moderate depression. Fifteen participants were taking antidepressants at entry, including SSRIs in 10, SNRIs in 2, tetracyclics in 2, and one taking both an SNRI and a tetracyclic.

Tolerability was defined by withdrawal due to adverse events. Feasibility was defined by attendance at scheduled clinic visits. Safety assessments included adverse events, laboratory tests, 12-lead ECG, and transthoracic echocardiography before and after the intervention.

Depression was assessed with the clinician-rated MADRS at baseline, weeks 2, 4, 6, and 8, with follow-ups at 1, 3, and 6 months. Additional measures included HAM-A, RRS, DASS, DARS, and WHOQOL-BREF at baseline and week 8.

Dosing and oversight

Participants took 16 sublingual doses over eight weeks, beginning with 8 μg in the clinic, then 6–20 μg at home twice weekly with titration guided by a study app capturing end-of-day subjective effects. Instructions asked participants to avoid potentially risky activities for 6 hours post-dose and to refrain from dosing after 2 p.m. to limit sleep disruption.

A custom smartphone app supported compliance, activity prompts on dosing days, and dose-response reporting. Video logs verified administration.

What participants experienced

Two participants discontinued for reasons unrelated to the trial and one withdrew due to anxiety on dosing days. The mean titrated dose was 14.61 μg with a range from 6 to 20 μg. A total of 342 doses were taken, with 319 self-administered at home and verified, indicating 100% compliance with home dosing.

Adverse events did not include any serious or severe cases. Headaches were most common on dosing days, reported three times across two participants. Anxiety leading to withdrawal occurred at 6 μg in a participant with high baseline anxiety, and symptoms resolved after withdrawal.

Was it safe?

Echocardiography before and after the intervention was completed by 15 participants in the main phase, with four continuing into an extension for a total of 32 doses over 16 weeks. No clinically significant echocardiographic abnormalities were identified by the end of treatment.

ECG readings that reflect how long the heart’s electrical system takes to recharge between beats were 408.84 ms at screening, 408.49 ms at end of the main phase, and 413.58 ms at the extension measure. One participant recorded a QTc of 460 ms at the measure visit after a baseline value of 434 ms.

Positive changes in symptoms

All measures moved in directions consistent with improvement by the end of treatment. Baseline MADRS averaged 23.7. End-of-treatment MADRS averaged 9.59, a 59.52% reduction. Nine participants met criteria for remission and clinical response at the end of treatment.

HAM-A decreased by 51.9%, indicating less anxiety. DASS subscales decreased for stress by 34.9%, anxiety by 59.1%, and depression by 40.6%.

Rumination decreased by 14.7% on the RRS, with fewer repetitive, problem-focused thoughts. DARS scores increased by 14.8%, signaling a greater ability to experience interest and pleasure.

WHOQOL-BREF scores increased across physical, psychological, social, and environmental domains, as well as overall quality of life and general health, a sign of broad gains in perceived quality of life.

What the findings mean

Findings support the feasibility of home-based, titrated LSD microdosing in moderate depression under clinical oversight. Safety monitoring identified no clinically significant changes.

Authors describe preliminary antidepressant signals and improvements across related measures. Plans to follow up with a Phase 2B randomized controlled trial are noted to evaluate superiority of LSD versus placebo as a continuation of this program.

© 2025 Science X Network