A randomized, placebo-controlled phase 2a trial evaluating SPL026, an intravenous formulation of dimethyltryptamine (DMT), met its primary endpoint in adults with moderate-to-severe major depressive disorder (MDD), demonstrating a statistically significant reduction in depressive symptoms at 2 weeks compared with placebo. The findings represent one of the first controlled trials of a short-acting psychedelic in MDD.
“We have shown that a single dose of SPL026 is safe, effective and durable, with treatment effects comparable to other promising interventional treatments often requiring much longer treatment sessions,” lead investigator David Erritzoe, MD, PhD, from Imperial’s Department of Brain Sciences, said in a statement, “Although such early trial results should always be interpreted with some caution, these data show the promise of DMT as a potentially more cost-effective treatment for clinical depression than related serotonergic agonists with longer psychoactive action due to the shorter dosing sessions.”
SPL026 is an intravenous formulation of DMT, a short-acting serotonergic psychedelic that acts primarily as a 5-HT2A receptor agonist. Unlike psilocybin, which typically produces psychoactive effects lasting 4 to 6 hours, intravenous DMT has a substantially shorter duration of acute subjective effects, often less than 30 minutes.
In the double-blind stage of the study, a single 21.5-mg intravenous infusion of SPL026 administered over 10 minutes resulted in a mean difference of –7.35 points on the Montgomery-Åsberg Depression Rating Scale (MADRS) at week 2 compared with placebo (95% CI, –13.62 to –1.08; P =.023). Treatment effects were detectable as early as week 1, with a mean difference of –10.75 points (95% CI, –16.95 to –4.55; P =.002). Response rates, defined as ≥5 0% reduction in MADRS score at week 2, were 35% in the SPL026 arm versus 12% with placebo. Remission rates (MADRS ≤ 10) were 29% vs12%, respectively.
The study enrolled 34 participants (mean age 32.8 years; 29.4% female; predominantly White) with a mean depression duration of 10.5 years. Participants were randomized 1:1 to receive SPL026 (n = 17) or placebo (n = 17) in conjunction with supportive psychotherapy that included preparation and integration sessions. The primary endpoint was the change in MADRS score from baseline to week 2.
In an open-label extension, all participants were eligible to receive SPL026 2 weeks after the initial dose, with antidepressant effects reported as persisting up to 3 months post–first dose. Some participants reportedly maintained benefits up to 6 months, although detailed long-term subgroup data were not announced. The therapy was generally well tolerated, with no reports of treatment-related serious adverse events.
Although SPL026 demonstrated proof-of-concept efficacy, Helus Pharma indicated it is not advancing the intravenous formulation in its current form. Instead, mechanistic and clinical insights from the trial are informing the development of HLP004, a proprietary novel serotonergic agonist under investigation for generalized anxiety disorder (GAD), with phase 2 topline data anticipated in the first quarter of 2026. The company is also advancing HLP003 in phase 3 development as adjunctive therapy for MDD; that program has received Breakthrough Therapy designation from the FDA.
“This publication represents an important validation of short-acting serotonergic agonists as a clinically meaningful approach in mental health treatments,” said Michael Cola, chief executive officer of Helus Pharma, in a statement. “The findings provide clinical proof-of-concept for short-acting serotonergic modulation and further support our conviction that our novel serotonergic agonist molecules, such as HLP004, can potentially deliver meaningful outcomes with greater consistency and commercial feasibility. We look forward to reporting topline data from our Phase 2 study of HLP004 in generalized anxiety disorder later this quarter.”
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