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

The authors note that many people with major depressive disorder receive selective serotonin reuptake inhibitors (SSRIs), yet a substantial proportion do not achieve remission even with adequate treatment. They also highlight that stopping a stable SSRI can cause withdrawal symptoms, worsen depression, and increase suicidality. Although psychedelics have shown rapid antidepressant effects in earlier research, most clinical trials have required SSRI discontinuation because of concerns about interactions such as serotonergic toxicity, QT prolongation, or blunting of psychedelic effects. Seynaeve and colleagues therefore aimed to generate preliminary data on intranasal 5-MeO-DMT given to people with treatment-resistant depression who remained on stable SSRI therapy. The study set out to assess safety, tolerability, and effects on depressive symptoms after a single intranasal dose of 10 mg or 12 mg 5-MeO-DMT over 12 weeks. This was presented as a proof-of-concept, first phase 2a trial in this setting, with the practical goal of informing whether controlled studies of concomitant 5-MeO-DMT and SSRI use were warranted.

The researchers conducted a 12-week, open-label, single-centre, ascending-dose trial. Adults aged 18-75 years with moderate-to-severe major depressive disorder and treatment-resistant depression were eligible if they had a baseline Montgomery-Asberg Depression Rating Scale (MADRS) score of at least 24 and had failed to respond to at least two antidepressants at adequate dose and duration. Participants had to be on a stable, adequate dose of one of four SSRIs: citalopram, escitalopram, sertraline, or fluoxetine. Key exclusions included medical conditions that could be risky if blood pressure or heart rate rose transiently, and current or past schizophrenia, psychotic disorder, bipolar disorder, delusional disorder, schizoaffective disorder, or other severe psychiatric disorders. Eligibility was assessed with medical review, examination, ECG, laboratory tests, and psychiatric screening instruments. Before dosing, participants completed three preparatory psychological support sessions over about 2 weeks. They then received a single intranasal dose of 10 mg or 12 mg 5-MeO-DMT, with the 10 mg cohort reviewed first by a safety committee before dose escalation. Psychological support was standardised and nondirective, including preparation, support during dosing, and integration afterwards; three post-dose support sessions were delivered during the 2 weeks after treatment. Safety monitoring included adverse events throughout the trial, suicidality assessment with the Columbia-Suicide Severity Rating Scale, and cardiac telemetry plus vital signs during the dosing session. Readiness for discharge was checked every 30 minutes from 90 minutes after dosing. The main symptom outcome was change in MADRS score. Analyses were described as primarily descriptive, with no a priori hypotheses.

Twelve participants were treated between 22 February 2024 and 2 January 2025, six in each dose cohort. They were aged 31-55 years; seven were female and five male, and 11 of 12 were White. The mean time since MDD diagnosis was over 15 years in both cohorts, and the current depressive episode had lasted a long time in both groups. All participants had been on SSRI treatment for at least 5 months before dosing. A history of suicidal ideation was reported by 8/12 participants, including two with prior suicidal behaviour. No suicidal ideation occurred during the trial. Drug-related treatment-emergent adverse events were mainly intranasal administration-site symptoms and gastrointestinal effects on the dosing day. One participant reported transient disorientation, dizziness, nausea, and a brief pseudo-hallucination the day after dosing while reflecting on the experience; these symptoms resolved within 15 minutes. No severe treatment-emergent adverse events and no serious adverse events were reported. Transient blood pressure increases occurred after dosing without cardiovascular symptoms. Mean blood pressure rose from 101.6/63.2 mmHg before dosing to a peak at 10 minutes of 132/81.3 mmHg in the 10 mg cohort, and from 106/65.9 mmHg to 136/85.2 mmHg in the 12 mg cohort. Blood pressure returned to baseline by 90 minutes. Mean readiness for discharge was about 102 minutes in the 10 mg cohort and 96 minutes in the 12 mg cohort. Depressive symptoms improved rapidly and remained improved through follow-up. In the 10 mg cohort, 4/6 participants were responders, defined as at least a 50% reduction in MADRS score, at the first post-dose assessment, on day 2, and 5/6 were responders by day 85. In the 12 mg cohort, 4/6 were responders at day 2 and day 85. Reductions were seen across all MADRS items at all post-dose assessments. The MADRS-6 core symptom subscale fell from 19.2 at baseline to 7.3 on day 2 and 6.2 on day 85 in the 10 mg cohort, and from 21.0 at baseline to 10.0 on day 2 and 9.3 on day 85 in the 12 mg cohort.

The authors interpret these findings as showing that a single intranasal dose of 10 mg or 12 mg 5-MeO-DMT was acceptably safe and tolerable when given alongside SSRI treatment in people with treatment-resistant depression, with encouraging exploratory evidence of sustained antidepressant benefit. They state that the safety profile was consistent with earlier trials of intranasal 5-MeO-DMT in healthy volunteers and with monotherapy studies in treatment-resistant depression. They also suggest that the evaluated dose range did not show obvious attenuation of efficacy when 5-MeO-DMT was administered with SSRIs. In their view, the rapid discharge readiness at around 2 hours after dosing is in line with other intranasal 5-MeO-DMT studies, and short-duration psychedelics could have advantages for scalability and cost compared with longer-acting compounds. The authors emphasise several limitations. The sample was very small, there was no control group, and the participant pool was predominantly White with limited ethnic diversity. They note that such limited diversity is common in classical psychedelic trials but remains a problem for generalisability. They also caution that the findings may not apply to concomitant use with all SSRIs, especially given the long duration of illness and current episode in this sample. Overall, Seynaeve and colleagues argue that the study provides preliminary support for further controlled clinical trials of intranasal 5-MeO-DMT in people who remain on SSRIs, but that more data are needed before stronger conclusions can be drawn.

The authors conclude that concomitant administration of intranasal 5-MeO-DMT with SSRIs in treatment-resistant depression was well tolerated in this first phase 2a study and showed encouraging exploratory evidence of sustained improvement in depressive symptoms. They state that additional data are needed and that the results support the case for controlled clinical trials in this population.