Psychedelic Therapies Advance in Depression Trials with Mixed Results

Compass Pathways announced that its second pivotal trial for COMP360 psilocybin in treatment-resistant depression met its primary endpoint, making it the first classic psychedelic to produce two positive Phase 3 results. The company plans to submit a New Drug Application in the fourth quarter of 2026.

The randomized, fixed repeat dose, double-blind phase 3 COMP006 study evaluated the efficacy, safety, and tolerability of COMP360 psilocybin in patients aged 18 years and older with treatment-resistant depression. Study participants (N=581) were randomly assigned 2:1:1 to receive 2 administrations of COMP360 psilocybin in doses of 25mg (n=296), 10mg (n=142) or 1mg (n=143), taken 3 weeks apart. The primary endpoint was the change from baseline in Montgomery-Åsberg Depression Rating Scale (MADRS) total score at 6 weeks.

Findings showed COMP360 psilocybin 25mg statistically significantly reduced symptom severity, as measured by MADRS, compared with the 1mg dose at week 6 (mean difference, -3.8 points [95% CI, -5.8, -1.8]; P <.001). In the 25mg arm, 39% of patients achieved a clinically meaningful MADRS reduction of 25% or greater; improvements were seen as early as 1 day post-administration and were sustained through 6 weeks.

The results echo the company's first Phase 3 trial, COMP005, which tested a single 25 mg dose against placebo in 258 U.S. participants and produced a similar separation of -3.6 MADRS points (p<0.001). In that trial, 25% of participants in the active arm met the same 25% response threshold at Week 6. Compass Pathways has not disclosed remission rates for either Phase 3 study.

Updated Part B results from COMP005 demonstrated sustained efficacy for COMP360 psilocybin 25mg, maintaining symptom severity reductions through week 26 after just 1 or 2 doses. Greater than 40% of participants who achieved a clinically meaningful reduction in MADRS total score but remained not remitted by 6 weeks went into remission after a second dose.

Across more than 800 dosed participants in both Phase 3 trials, the most common treatment-emergent adverse events were headache, nausea, anxiety and hallucination. Most events occurred on the days of administration and were resolved within a day. Serious adverse events involving suicidal ideation occurred at a rate below 1%, and an independent safety monitoring board found no clinically meaningful imbalance in suicidality between treatment and control arms. There was one case of suicidal behavior, which occurred in the 1 mg arm of COMP006.

Separately, SPL026, a psychedelic compound containing dimethyltryptamine (DMT) developed by Helus Pharma, demonstrated antidepressant potential in a Phase IIa trial. During the trial, 34 patients with moderate-to-severe major depressive disorder were randomised to receive either a 21.5mg intravenous dose of SPL026 or placebo. All patients involved in this trial had received at least two unsuccessful rounds of treatment, which could include pharmaceutical and/or psychotherapy-based regimens.

One week after dosing, patients who received SPL026 experienced a significant 10.8-point drop in average MADRS scores compared with placebo. SPL026's antidepressant impact was also sustained at the two-week mark, with those given the drug demonstrating an average 7.4-point reduction in MADRS from baseline at this time point. SPL026 also reduced depression in some patients at both the three- and six-month mark post-treatment.

The second portion of the trial, in which both the placebo and treatment group received SPL026, also revealed that two doses of the drug offered no significant benefit over a single dose, suggesting that the drug could be effectively administered as a single dose in major depressive disorder. DMT is a naturally occurring psychedelic, which is the major psychoactive compound in ayahuasca. The drug experience lasts approximately 25 minutes, which is significantly shorter than other psychedelics in clinical trials.

The psychedelic was proven to be safe and tolerable, with no serious treatment-emergent adverse events or concerning changes in suicidal thoughts recorded within the study period.

The developments come as psychedelics have rapidly advanced from an academically marginal subject to a focus of mental health research. The FDA approved intranasal esketamine as an adjunctive treatment for treatment-resistant depression in 2019 and, in January 2025, extended approval for its use as monotherapy. Clinical trials of classic psychedelics for various other disorders, including substance use disorders, eating disorders, anxiety disorders, and posttraumatic stress disorder, are underway.

In 2024, an FDA Advisory Committee voted against approval of investigational MDMA-assisted therapy for PTSD, citing concerns about safety, data integrity, and functional unblinding, and requested an additional phase 3 trial.

Another biotech, AtaiBeckley, is planning to initiate a Phase III trial on its mebufotenin benzoate nasal spray for treatment-resistant depression in Q2 2026. This follows the positive results of a Phase IIa study, where two doses of BPL-003 decreased MADRS scores by 19.0 from baseline.

For the roughly 4 million Americans whose depression resists two or more treatments, the process often remains what it has been since the SSRI era began: try one drug, wait weeks, and if it doesn't work, try the next. That cycle can stretch for years. Several studies suggest that the intensity of a "mystical-type experience" during a psychedelic session predicts the degree of improvement in depression, anxiety or addiction.