Source: Seynaeve et al., CNS Drugs 2026

Up to 60% of people with major depression take an SSRI antidepressant. Most psychedelic trials require stopping these first, which can bring withdrawal symptoms, worsening depression and even suicidality. There are also concerns that SSRIs could interact with psychedelics or blunt their effects. This small trial asked what happens when people with treatment-resistant depression stay on their SSRI and receive 5-MeO-DMT.

The study

Design: Phase 2a, open-label, single-centre, ascending-dose trial with 12 weeks of follow-up. This was Part 2 of a four-part study (NCT05660642).
Participants: 12 adults aged 31-55 (7 women, 5 men) with moderate-to-severe depression that hadn't responded to at least two antidepressants. Their depression was long-standing, with an average of more than 15 years since diagnosis. All had been on a stable dose of citalopram, escitalopram, sertraline or fluoxetine for at least 5 months. Two-thirds had a history of suicidal thoughts.
Screening: people with heart conditions sensitive to blood pressure spikes, or a history of psychosis, bipolar disorder or other severe psychiatric conditions, were excluded.
Dosing: a single intranasal dose of BPL-003 (Beckley Psytech's 5-MeO-DMT nasal formulation). Six people received 10 mg. A safety committee then reviewed the data before six more received 12 mg.
Support: three preparation sessions over roughly two weeks before dosing, and three integration sessions in the two weeks after, with a trained therapist using a standardized, non-directive approach.

What it found

Day 2: two-thirds of each group (4 of 6) were responders, meaning their depression score had halved.
Day 85 (about 12 weeks): 5 of 6 in the 10 mg group and 4 of 6 in the 12 mg group were still responders.
Core symptoms: sadness, inner tension, lassitude, inability to feel and pessimistic thoughts all dropped sharply. In the 10 mg group, the core symptom score fell from about 19 to 7 by day 2, and stayed near 6 at day 85.
SSRI interaction: the antidepressant effect didn't appear to be blunted by the ongoing SSRI.
Suicidal thoughts: none were reported during the trial.

Safety

Side effects: no severe or serious events. Drug-related side effects were mostly nasal irritation and stomach upset, and resolved on dosing day.
Blood pressure: it rose sharply for a short time, peaking about 10 minutes after dosing (on average from roughly 102/63 to 132/81 in the 10 mg group), with no heart symptoms. It returned to baseline within 90 minutes.
Recovery: people were ready to go home after about 96-102 minutes on average.
A next-day episode: one participant felt disoriented, dizzy and nauseous, with a brief out-of-body feeling, while reflecting on the experience and listening to music similar to the session music. It passed within 15 minutes and didn't recur.

Limitations

Only 12 participants and no control group
Mostly White participants
Only four specific SSRIs at stable doses, so the results may not apply to other antidepressants
Funded by Beckley Psytech, and the authors are company employees or consultants

What this means, and doesn't

This is an early, encouraging safety signal for a group usually excluded from psychedelic research. But it involved 12 carefully screened people, one specific product at specific doses, and close medical monitoring in a clinic. It doesn't show that 5-MeO-DMT is safe with every antidepressant, at every dose, or in other settings, and SSRIs remain an important part of screening in ceremonial work.

No one should stop or change a medication without their prescriber.

Two details are worth noticing. The trial built in preparation and integration sessions, close to the structure used in ceremonial practice. And the brief next-day episode shows that an experience can echo for a while afterwards, which is one reason ongoing support after a session matters.

Research summaries are for education, not medical advice. Considering 5-MeO-DMT yourself?
Start with Safety & Screening.