A short-acting psychedelic was tested alongside SSRIs, not after stopping them

Nearly every published psychedelic depression trial has required participants to taper off their antidepressants before dosing, largely out of concern that SSRIs might interact with the psychedelic or blunt its effect. A proof-of-concept trial published this week in CNS Drugs, funded and run by Beckley Psytech, tested the opposite approach: keeping patients on a stable SSRI dose while dosing them with intranasal 5-MeO-DMT, a fast-acting psychedelic [s1].

Why the SSRI question matters

Up to 60% of people with major depressive disorder are on an SSRI, and roughly a third don't achieve full symptom remission on that treatment alone [s1]. Discontinuing a stable SSRI to enroll in a psychedelic trial can itself trigger withdrawal symptoms, worsening depression, or suicidality — a real cost that has limited who can access psychedelic trials to date. Concerns about combining SSRIs with psychedelics — including QT-interval prolongation, serotonergic toxicity, or the SSRI blunting the psychedelic's subjective and therapeutic effects — have driven most trials to require a washout period instead [s1].

The design

This was a 12-week, open-label, single-center, ascending-dose trial (ClinicalTrials.gov NCT05660642) testing a single intranasal dose of either 10 mg or 12 mg of 5-MeO-DMT — the proprietary formulation BPL-003 — in participants aged 18–75 with moderate-to-severe, treatment-resistant major depressive disorder, defined as failing to respond to at least two adequately dosed antidepressants [s1]. Twelve participants, six per dose cohort, were treated between 22 February 2024 and 2 January 2025, all while remaining on a stable dose of one of four SSRIs — citalopram, escitalopram, sertraline, or fluoxetine — for at least five months prior [s1]. Participants underwent three preparatory psychological support sessions before dosing and three more afterward, with a trained therapist present, and were followed for 12 weeks post-dose [s1]. A safety review of the initial 10 mg cohort was required before dose escalation to 12 mg [s1].

What it found

No serious adverse events occurred [s1]. Drug-related side effects were concentrated on dosing day and included administration-site symptoms (irritation, pain, discharge) and gastrointestinal effects; one participant reported disorientation, dizziness, and a brief pseudo-hallucination the day after dosing, which resolved within 15 minutes and did not recur [s1]. Blood pressure rose transiently after dosing — from a pre-dose average of roughly 102/63 mmHg to a peak around 132/81 mmHg at 10 minutes in the 10 mg group, and similarly in the 12 mg group — before returning to baseline within 90 minutes, without accompanying cardiovascular symptoms [s1]. Participants were assessed ready for discharge roughly 100 minutes after dosing on average [s1].

On depression symptoms, measured with the Montgomery-Åsberg Depression Rating Scale (MADRS): in the 10 mg cohort, 66.7% of participants (4 of 6) were responders — at least a 50% score reduction — by the first post-dose assessment on day 2, rising to 83% (5 of 6) by day 85 [s1]. In the 12 mg cohort, 66.7% were responders at both day 2 and day 85 [s1]. No suicidal ideation was reported during the trial, despite 8 of 12 participants (67%) having a prior history of suicidal ideation [s1].

What this does and doesn't establish

This is a 12-person, open-label trial with no control group — every participant knew they were receiving the drug, and there was no placebo arm to separate a genuine drug effect from expectation, natural symptom fluctuation, or the substantial psychological support participants received before and after dosing. The population was predominantly white (11 of 12 participants), a diversity limitation the authors themselves flag as common across psychedelic trials and unresolved here [s1]. The finding is nonetheless meaningful within its narrow scope: it suggests that at these two doses, 5-MeO-DMT's safety profile alongside a stable SSRI resembles what's been reported for 5-MeO-DMT alone in healthy volunteers and in treatment-resistant depression, without evidence that the SSRI blunted the drug's psychedelic or therapeutic effects [s1].

What to watch

Randomized, placebo-controlled trials of the same concomitant-SSRI approach, which the authors describe as the necessary next step [s1], and whether the tolerability findings hold in a larger and more diverse group. 5-MeO-DMT is not approved for any indication; this article describes an early-stage investigational drug trial and is not medical advice.

Sources

1. Intranasal 5-MeO-DMT Concomitant with SSRI for Treatment-Resistant Depression: A Proof-of-Concept Trial — CNS Drugs, 24 March 2026