Oral LSD Drug Hits Phase III Endpoints in Anxiety, Depression

DT120, an investigational orally disintegrating tablet (ODT) formulation of the psychedelic lysergide (LSD), met the primary endpoints in a pair of phase III trials for generalized anxiety disorder (GAD) and major depressive disorder (MDD).
In the 214-participant Voyage study, patients with GAD who received a single 100 µg dose of DT120 achieved an 11.6-point improvement in Hamilton Anxiety Rating Scale (HAM-A) score from baseline to week 12 (P<0.0001), reported Dan Karlin, MD, chief medical officer of drug developer Definium Therapeutics, and colleagues.
Statistically significant improvements were observed as early as week 1 (-11.9 points from baseline; -7.7 vs placebo) and were sustained through week 12, yielding a 5.4-point placebo-adjusted reduction at the end of the 12-week double-blind phase (P<0.0001).
Similarly, among 149 participants in the Emerge trial, DT120 led to an 8.1-point placebo-adjusted improvement in Montgomery-Åsberg Depression Rating Scale (MADRS) total score at week 6 (P<0.0001), maintaining a 7.3-point placebo-adjusted benefit through week 12 (P<0.0001).
Both trials were presented at the Neuroscience Education Institute (NEI) Fall Congress in Colorado Springs, Colorado.
“Seeing a clinically meaningful improvement in patients with this level and duration of disease gives us hope that DT120 could offer a new treatment option for people who have been suffering for years and are still in need of better outcomes,” Karlin told MedPage Today.
“As a practicing psychiatrist, I see firsthand the profound toll depression and anxiety take on people and their families. I know clinicians need options that can provide substantial relief for patients living with two of the most common mental health disorders,” he continued.
“Too many patients face a treatment journey that involves daily medication, managing side effects, waiting weeks to determine whether a treatment is working, and ongoing adjustments to sustain benefits. Innovation in mental healthcare has simply not kept pace with the need,” said Karlin.
GAD Trial
At baseline, Voyage participants had a mean HAM-A score of 27.9 (entry criterion ≥20) and an average age of 42, while 64% were female. Approximately 21% had previously used any psychedelic, and 9% had past LSD experience. Over a third (36%) had tried two or more prior medications for GAD.
DT120 was administered during a single supervised session. Mean time to End-of-Session Checklist (EoSC) discharge clearance was 6.4 hours, with 90% cleared by hour 8.

“This represents a different treatment paradigm, not only in its potential therapeutic benefit but also in the patient experience: a dedicated treatment day, supported by appropriately trained clinical personnel, rather than the ongoing commitment of daily medication or recurring maintenance treatments,” said Karlin.
Secondary outcomes included:

• 11.9-point improvement in HAM-A score from baseline at week 1 (P<0.0001)
• 1.0-point improvement in Clinical Global Impressions-Severity (CGI-S) score at day 2 and week 12 (P<0.0001)
• Response & remission at week 12: Significantly higher response (≥50% HAM-A reduction; 43% vs 16% with placebo) and remission (HAM-A ≤7; 14% vs 4%)
• Efficacy was consistent across subgroups, including patients with ≥2 prior medications

DT120 was generally well-tolerated, with no serious adverse events (SAEs), suicidality signals, or self-injurious behaviors reported.
All AEs on DT120 were mild to moderate; the most common were illusion, nausea, and euphoric mood, predominantly occurring on dosing day. Headache was the most frequent AE reported following dosing day. One participant discontinued DT120 due to a treatment-emergent AE.
MDD Trial
In Emerge, participants had a baseline mean MADRS score of 34.5 (entry criterion ≥26) and CGI-S score of 4.8 (entry criterion ≥4), with active depressive episodes lasting between 8 weeks and 24 months. The mean age was 44, 54% were male, and 53% had previously received two or more antidepressants. Mean EoSC clearance time was 5.8 hours, with 100% of participants meeting discharge criteria by hour 8.
Additional findings included:

• A 17.6-point reduction from baseline in MADRS score by week 1 (P<0.0001; 14.2 points placebo-adjusted)
• Reductions from baseline in CGI-S of 1.0 at day 2, 1.2 at week 6, and 1.0 at week 12 (P<0.0001)
• Response & remission at week 6: Superior rates of MADRS response (≥50% improvement; 35% vs 7%) and remission (MADRS ≤12; 24% vs 3%) compared to placebo, maintained across subgroups including those with ≥2 failed prior lines

DT120 was well-tolerated, with no SAEs, suicidal behaviors, or discontinuations due to AEs. Also, 99% of reported AEs were mild to moderate in severity. The most frequent treatment-emergent AEs were illusion, euphoric mood, and nausea on dosing day, and headache thereafter.
“Patients with GAD and MDD need meaningfully differentiated treatment options that can offer them sustained relief, rather than just transient symptom relief,” Karlin said. “Our hope is that we may be able to move beyond simple symptom management to fundamentally reroute the course of serious mental health disorders.”