Intranasal 5-MeO-DMT Concomitant with SSRI for Treatment-Resistant Depression: A Proof-of-Concept Trial

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This 12-week, open-label, single-centre phase 2a trial evaluated the safety, tolerability, and exploratory antidepressant effects of a single intranasal dose of 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT; BPL-003) administered adjunctively to stable selective serotonin reuptake inhibitor (SSRI) treatment in 12 adults with treatment-resistant depression (TRD). Participants aged 18–75 years with moderate-to-severe major depressive disorder, defined by a baseline Montgomery–Asberg Depression Rating Scale (MADRS) score of at least 24 and inadequate response to at least two prior antidepressants, received either 10 mg or 12 mg intranasal 5-MeO-DMT following preparatory psychological support, with post-dose integration and 12 weeks of follow-up. Safety assessments included adverse events, suicide risk, cardiac telemetry, vital signs, and discharge readiness. Treatment was generally well tolerated, with drug-related treatment-emergent adverse events limited mainly to transient intranasal and gastrointestinal symptoms occurring on the dosing day; no severe or serious adverse events and no suicidal ideation during the trial were reported. Transient increases in blood pressure resolved within 90 minutes, and participants were typically ready for discharge at around 2 hours post dose. Rapid and sustained reductions in depressive symptoms were observed in both dose cohorts, with 66.7% of participants meeting responder criteria by day 2 and similar response rates maintained through day 85. These preliminary findings suggest that intranasal 5-MeO-DMT administered concomitantly with SSRIs has an acceptable safety profile and may produce rapid, durable antidepressant effects in TRD, supporting the need for controlled trials in this population.