Short-Acting Psychedelic Trial Reports Rapid MDD Symptom Reduction

Key Takeaways

• Blinded treatment with intravenous DMT fumarate was associated with greater depressive symptom reduction at 2 weeks, with separation from placebo also reported at 1 week.
• Response and remission were reported at 1 week, 2 weeks, and exploratory 6-month follow-up, while later open-label comparisons between one and two doses showed no significant differences at the reported post-second-dose time points.
• Most treatment-emergent adverse events were mild to moderate, transient blood pressure and heart rate increases were observed after dosing, and no serious adverse events, deaths, withdrawals for adverse events, or dose changes were reported.

Adults with moderate-to-severe major depressive disorder receiving intravenous DMT fumarate had a 2-week MADRS advantage of -7.35 points over placebo in a Nature Medicine phase IIa randomized trial. The double-blind, placebo-controlled study evaluated SPL026 as a single 21.5-mg infusion over 10 minutes with supportive psychotherapeutic support, and the primary endpoint was change in Montgomery–Åsberg Depression Rating Scale scores 2 weeks after the first dose.

Thirty-four participants were randomized, with 17 assigned to placebo-active and 17 to active-active before a second open-label DMT dose was offered 2 weeks later. The protocol included ward admission the day before dosing, discharge the next morning, a 90-minute therapist preparation session, and a brief readiness session on dosing day. Two therapists stayed present during dosing, a study psychiatrist remained on site, and integration sessions occurred on days 1, 2, and 15.

Follow-up included a remote assessment at 1 week, an in-person day 29 visit, remote 1-month and 3-month assessments, and exploratory 6-month follow-up. Participants had a mean age of 32.8 years, 29.4% were women, 88.2% identified as white, and depression duration averaged 10.5 years. Eligibility required at least two prior unsuccessful treatment attempts, and dosing and observation occurred in a controlled inpatient setting.

At 2 weeks, the between-group MADRS difference was -7.35 points, with a 95% CI of -13.62 to -1.08, P=0.023, and d=0.82. At 1 week, the secondary comparison was -10.75 points, with a 95% CI of -16.95 to -4.55, P=0.002, and d=1.09. Week 1 response and remission were 6% and 13% in placebo-active participants and 44% and 44% in active-active participants. At week 2, those measures were 12% and 12% in placebo-active participants and 35% and 29% in active-active participants. During the open-label phase, weeks 3, 4, 6, and 14 showed no significant single-dose versus two-dose differences, and pooled 6-month response and remission were 44% and 40%. Those later comparisons came from the open-label stage and were described as descriptive and hypothesis-generating.

Safety findings showed 47 possibly treatment-related adverse events in 25 participants, usually mild and sometimes moderate, most often infusion site pain, nausea, anxiety, headache, insomnia, or restlessness. Most events resolved during the dosing visit, and no serious adverse events, deaths, withdrawals for adverse events, or dose discontinuations or adjustments were reported. Blood pressure and heart rate increased transiently just after dosing, but laboratory tests, ECGs, physical examinations, and Beck Scale for Suicidal Ideation scores showed no concerning change.

The exploratory moderator analyses linked larger antidepressant changes with higher Mystical Experience Questionnaire scores, Ego Dissolution Inventory scores, feelings of unity, and general intensity ratings. Investigators also noted limited diversity, untested blinding, and unmeasured alliance and integration; the trial paired brief intravenous dosing with structured inpatient support and reported rapid improvement with mild-to-moderate adverse events.