A single dose of a fast-acting psychedelic nasal spray may offer rapid and sustained relief for people with treatment-resistant depression, according to a study published in JAMA. The findings suggest that intranasal mebufotenin benzoate could reduce depressive symptoms while allowing many patients to leave the clinic within two hours of treatment. Unlike conventional psychedelic therapies, which can require several hours of medical supervision, this nasal spray produces relatively brief psychedelic effects. Researchers investigated whether the treatment could combine rapid antidepressant benefits with a shorter clinical recovery period.
Nasal Spray May Address Challenges in Depression Treatment
Approximately one-third of people with major depressive disorder do not respond adequately to standard antidepressant medications. This condition, known as treatment-resistant depression, can significantly affect quality of life and increase emotional distress. Although psychedelic compounds such as psilocybin and LSD have shown potential for treating difficult-to-manage depression, their effects can last several hours. Consequently, patients often require prolonged supervision in a clinical setting, creating practical barriers to treatment. To address these challenges, researchers investigated mebufotenin benzoate, a short-acting psychedelic formulated as a nasal spray. The study involved 193 adults aged 18 to 75 with moderate-to-severe major depressive disorder across 38 clinical sites in the United States, Australia and Europe. Participants had previously tried between two and five antidepressant treatments during their current depressive episode without achieving adequate relief.
Researchers Evaluate Three Nasal Spray Doses
Researchers randomly assigned participants to receive a single dose of mebufotenin benzoate at one of three levels: 8 mg, 12 mg or 0.3 mg. The lowest dose served as a control to help maintain blinding. Neither the participants nor the clinical staff and researchers assessing treatment outcomes knew which dose each participant received. Mebufotenin benzoate acts on two serotonin receptors in the brain, 5-HT1A and 5-HT2A, which are involved in regulating mood and perception. By targeting these receptors, the compound may help produce rapid changes in depressive symptoms.
Most Participants Met Discharge Criteria Within Two Hours
One of the study’s key findings was the relatively short duration of the nasal spray’s psychedelic effects. Clinical staff began assessing participants for discharge readiness 90 minutes after administration and continued assessments every 30 minutes. They evaluated recovery and safety criteria to determine whether participants could leave the clinic. The results showed that 85% of participants in the 8 mg group and 78% in the 12 mg group met the required criteria for discharge within two hours. These findings suggest that the treatment could reduce the time patients need to remain under clinical supervision compared with psychedelic therapies that produce longer-lasting altered states of awareness.
Antidepressant Benefits Persisted for Weeks
Beyond its short-term effects, mebufotenin benzoate also demonstrated potential for sustained relief from depression. Participants who received either the 8 mg or 12 mg dose experienced improvements in depressive symptoms within a day of treatment. The improvements persisted during the follow-up period. At four weeks, the 12 mg dose reduced clinician-rated depression scores by approximately five points more than the low-dose control group on a 60-point scale. The 8 mg dose also demonstrated a similar benefit. Furthermore, approximately one-third of participants who received either higher dose experienced a reduction of at least 50% in their depression symptom scores. The findings indicate that the antidepressant benefits may continue long after the immediate psychedelic effects have subsided.
Further Research Needed to Confirm Long-Term Benefits
The study offers promising evidence that a brief psychedelic experience may produce sustained improvements in treatment-resistant depression without requiring prolonged clinical supervision. However, researchers need longer follow-up studies to determine how long the benefits last, whether patients require repeat doses and how the treatment compares with existing therapies. The findings also do not establish that the nasal spray is suitable for unsupervised use. As reported by Medical Xpress, mebufotenin benzoate could represent a potential new approach to treating difficult-to-manage depression. If further clinical trials confirm its effectiveness and safety, the treatment may help expand options for patients who have not responded adequately to conventional antidepressants.