For people living with depression who have found no relief despite trying several medications, the possibility that a single treatment could produce lasting improvement offers new hope. A study published in the medical journal JAMA found that a single dose of mebufotenin, a psychedelic substance administered through a nasal spray alongside psychological support, reduced depressive symptoms in patients who had not responded to previous treatments. Improvements were evident as early as the day after treatment, and the difference compared with the low-dose control group persisted throughout the eight-week follow-up period.
The trial involved 193 adults with moderate to severe depression who had failed to respond to two to five antidepressant treatments during their current depressive episode. After four weeks, about one-third of patients who received the active doses experienced a reduction of at least 50% in the severity of their symptoms, compared with 12% in the control group.
“Mebufotenin, also known as 5-MeO-DMT, is a psychedelic substance that acts on the brain’s serotonin system,” explains Dr. Itamar Cohen, a researcher specializing in psychedelics and author of the Hebrew-language book A Guide to Drugs. “One of its interesting characteristics is that the psychedelic experience lasts less than an hour, unlike substances such as psilocybin.”
One feature the researchers wanted to examine was how quickly patients recovered from the immediate effects of the drug. Most participants who received an active dose were assessed as ready for discharge within two hours. However, the trial protocol required them to remain at the treatment center for at least four hours.
The study was conducted at 38 medical centers across six countries, including the United States and the United Kingdom. Participants had an average age of 41, and approximately 59% were women. On average, they had been diagnosed with depression about 13 years before the study, while their current depressive episode had lasted approximately two and a half years.
Participants were randomly divided into three groups. Two received the psychedelic substance at doses of 8 or 12 milligrams, while the third received a very low dose of 0.3 milligrams and served as the comparison group. The low dose was intended to avoid producing a noticeable psychedelic experience.
Dr. Itamar CohenPhoto: Zohar ShitritThe experimental nasal spray, known as BPL-003, contains a synthetic form of mebufotenin, a substance that acts on serotonin receptors in the brain. A trained clinician administered a single spray into one nostril while the participant was in a private room, with a physician nearby. The treatment also included preparation and psychological support before, during and after administration.
To assess the effects of the spray without additional antidepressant medication, participants who were taking such drugs discontinued them under medical supervision at least two weeks before treatment. However, 12 participants began taking antidepressants during the eight-week follow-up period.
Researchers measured changes in depression severity four weeks after treatment using the Montgomery-Åsberg Depression Rating Scale, a standard clinical tool for assessing depressive symptoms. Both groups receiving active doses showed greater improvements than the low-dose comparison group. Among participants receiving 12 milligrams, depression scores fell by an average of about 11 points, while those receiving 8 milligrams recorded a decline of approximately 12.5 points. The comparison group showed an average reduction of about 5.5 points.
The researchers also examined how many participants achieved remission, defined as reaching a low level of depressive symptoms on the assessment scale. After four weeks, approximately 26% of those receiving 8 milligrams and 18% of those receiving 12 milligrams had achieved remission, compared with about 8% in the comparison group. These figures reflect participants’ condition at the time of assessment and do not establish that their depression had disappeared permanently.
“The results are certainly encouraging,” Cohen says. “This is a significant difference, especially when we are talking about people who have already tried other treatments without success. However, it is still too early to conclude that this treatment is more effective than existing options such as esketamine or transcranial magnetic stimulation.” The study did not directly compare the nasal spray with those treatments.
The improvement relative to the comparison group was apparent as early as the day after treatment and remained evident throughout the eight-week follow-up. At the end of that period, approximately 28% of participants receiving 8 milligrams and 32% of those receiving 12 milligrams had achieved at least a 50% reduction in symptom severity, compared with about 11% in the comparison group. Improvements in quality of life were also observed. However, on an additional questionnaire completed by participants themselves, the improvement in the 8-milligram group was not large enough relative to the comparison group to be considered statistically significant at either four or eight weeks.
During follow-up, approximately 76% of participants receiving 8 milligrams and 85% of those receiving 12 milligrams reported adverse events following treatment, compared with about 73% in the comparison group. Nearly all were mild or moderate and included nausea, headaches, anxiety, and pain or discomfort in the nose. Temporary increases in heart rate and blood pressure were also recorded, with readings returning to the normal range within an hour.
One participant who received 12 milligrams experienced two severe panic attacks, which researchers attributed to the treatment. No participants withdrew from the study because of adverse events. No suicidal behavior was documented, although reports of suicidal thoughts were recorded. Among those receiving active doses, these thoughts occurred without any reported intent to act on them and involved participants who had previously experienced suicidal ideation.
“People with conditions such as psychosis or bipolar disorder may face particular risks, and the safety of this treatment for them has not yet been established,” Cohen says. “That is why it requires careful medical and psychological screening.”
Both active doses produced similar improvements in depression symptoms, but some adverse effects were more common at the higher dose. According to the researchers, the 8-milligram dose offered a better balance between therapeutic benefit and side effects. It was therefore selected for evaluation in phase 3 clinical trials, the next stage of research.
One of the main challenges in the study was that participants and clinical staff were often able to guess who had received an active dose. “When someone experiences an intense psychedelic effect, it is very difficult to conceal the fact that they received an active substance,” Cohen explains. “That knowledge can influence their expectations and the results.” Independent clinicians responsible for assessing depression severity were more successfully kept unaware of participants’ treatment assignments. The study also did not separately examine how much of the improvement could be attributed to psychological support.
The researchers found no correlation between the intensity of the mystical experience reported by participants and the degree of improvement in their depression. However, they noted that the questionnaire used may not have fully captured the experience produced by the substance. Most participants were white, and the study may not have included enough people with particularly severe treatment resistance. It therefore remains unclear how well the findings apply to other populations.
The research was funded by Beckley Psytech, a company within the AtaiBeckley group that is developing the treatment. Company employees were involved in designing and conducting the trial, analyzing the data and writing the scientific paper.
“The encouraging news is that the therapeutic benefit persisted throughout the eight-week follow-up,” Cohen says. “But will it last six months or a year? Will repeated doses be necessary, and will they be safe? Those are questions we still do not have answers to.”