Psychedelic nasal spray reduced treatment-resistant depression for 8 weeks

The primary outcome was the change in depression severity from baseline to day 29 between the 12-milligram and 0.3-milligram groups on the Montgomery-Åsberg Depression Rating Scale, which scores symptoms from 0 to 60, with higher scores indicating worse depression. Independent, blinded raters conducted these interviews by video call at baseline and every two weeks after dosing, including days 2, 8, 29, and 57. Staff assessed discharge readiness every 30 minutes starting 90 minutes after dosing, though participants had to stay at least four hours. Statistical models controlled for baseline depression scores, geographic region, and randomization schedule.

Baseline depression scores averaged about 32 across the three groups. The trial was designed with enough participants to detect a 6-point difference; the primary comparison at day 29 found an adjusted mean difference of 5.3 points (confidence interval 1.8 to 8.9), as scores dropped by 11.1 points in the 12-milligram group versus 5.5 points in the control group. The 8-milligram group improved by 12.5 points, an adjusted difference of 6.2 points (confidence interval 2.1 to 10.2). Whether a participant had tapered off antidepressants before the trial was not associated with the primary outcome.

Improvements appeared by day 2, when both active groups had dropped about 9 points versus 3.8 in the control group, and persisted to day 57, where active-group reductions averaged about 11 points versus 5.2. At day 29, response rates (at least a 50 percent score reduction) were about one-third in both active groups versus 12 percent in the control group; remission rates (a score of 10 or less) were 26 and 18 percent for the 8-milligram and 12-milligram groups versus 8 percent for the control group. Response and remission rates were reported descriptively, without confidence intervals or statistical tests.

Both active doses outperformed the control dose across all time points on clinician-rated illness severity and self-reported quality of life. On a self-reported depression scale, the 12-milligram group improved more than the control group at all visits, while the 8-milligram group improved more at days 2 and 8, though differences at days 29 and 57 were not statistically significant.

On day 1, the 8-milligram and 12-milligram doses produced higher scores on a 0-to-5 questionnaire measuring mystical-type experiences such as a sense of unity, transcendence of time and space, and ineffability (averaging 2.4 and 2.6, versus 0.4 in the control group). Those scores did not correlate with day 29 symptom reductions, a finding that runs against evidence from other psychedelics, which the authors note has suggested that the intensity of the subjective experience predicts therapeutic outcomes.

Most participants in the active groups (85 percent for 8 milligrams and 78 percent for 12 milligrams) met discharge readiness criteria within two hours of dosing, with two-thirds ready at 90 minutes. Those criteria required that the acute psychedelic effects had fully subsided and that vital signs, orientation, and coordination had returned to normal. This rapid turnaround is the feature the researchers argue sets the spray apart from psilocybin and LSD.

Side effects were common in all three groups, reported by roughly 73 to 85 percent of participants, and 99.7 percent of events were mild or moderate. The most frequent were headache, nausea, and pain at the spray site. Headache was about as common in the control group as in the active groups (29.5 percent overall), while nausea was far more common with the active doses (33 and 40 percent) than with the control dose (3 percent). Because the 8-milligram dose had comparable efficacy to the 12-milligram dose with fewer side effects like nausea and anxiety, the researchers selected the 8-milligram dose for Phase 3 trials, which will follow patients for longer to test how long the benefits last.

Most side effects in the active groups appeared on the day of dosing and resolved within 24 hours, though one participant in the 12-milligram group had two severe panic attacks related to the drug. Temporary increases in heart rate and blood pressure resolved within an hour. No suicidal behavior occurred during the trial. Eight drug-related reports of suicidal thoughts without intent were recorded: one in the 8-milligram group, four in the 12-milligram group, and three in the control group, all mild or moderate, and those in the active groups all occurred in participants with a history of such thoughts.

These results align with an uncontrolled, open-label study of 10 women with postpartum depression, which tested an inhaled formulation rather than a nasal spray in a different patient group, and similarly found rapid relief of depressive symptoms. The findings also parallel a 2019 observational study in which 42 people who inhaled vapor from dried toad secretion containing mebufotenin reported reduced depression and anxiety four weeks later, though that study had no control group and relied on self-reported symptoms.

As with all research, there are some caveats to consider. The trial was funded by Beckley Psytech, an AtaiBeckley company that is developing the nasal spray, and several authors are company employees or hold stock or patents related to the compound. Employees of the sponsor were involved in the trial’s design, data analysis, and the decision to publish.

Statistical adjustments for multiple comparisons were applied to the primary outcome and three key secondary outcomes; the remaining comparisons were not adjusted. The smaller size of the 8-milligram group after the randomization change may also have limited statistical power to detect differences on the self-reported depression scale at later visits.

Difficulty maintaining blinding is a recognized problem across psychedelic trials, and the authors cite it as an inherent limitation, noting that most participants and on-site clinicians guessed their treatment assignment. Blinding was better preserved among the centralized remote raters who scored the primary measure; that measure is scored through an interview in which participants describe their own symptoms. Pre-treatment expectations did not correlate with day 29 outcomes, though those expectations were measured before the first preparation visit, prior to dosing and to any knowledge of group assignment; post-dose expectancy was not measured.

In addition, the two-hour discharge figure describes an assessment rather than an actual discharge. No one was discharged at two hours because the protocol required a minimum four-hour stay. Average times to readiness were just under two hours in the active groups, with the longest cases running past four.

In an editorial published alongside the trial in JAMA, Chittaranjan Andrade of the National Institute of Mental Health and Neurosciences in Bangalore, India, called two findings striking: that a single dose given on its own kept depression scores roughly a third lower for eight weeks, and that most patients were ready to leave within two hours rather than the four to twelve hours that psilocybin and LSD require.

At the same time, Andrade noted that the average patient improved only about 30 percent, and that the response and remission rates fall below those typically seen with ketamine and electroconvulsive therapy. In his reading, either the 8- to 12-milligram dose or the single-dose approach is insufficient, and he suggests testing higher or escalating doses, or a course of treatments as is standard with ketamine and electroconvulsive therapy.

Both the study authors and Andrade note that the trial population may underrepresent more severely treatment-resistant patients. Participants had failed a median of two antidepressants, which Andrade describes as not markedly refractory depression. The protocol also excluded people with PTSD, bipolar or psychotic disorders, any personality disorder, a first-degree family history of schizophrenia or bipolar disorder, suicidal ideation with intent in the prior year, or prior nonresponse to ketamine or electroconvulsive therapy. Because active suicidal intent was an exclusion, Andrade notes that the trial could not examine whether the drug reduces suicidal thinking, as ketamine and electroconvulsive therapy have been shown to do.

Other constraints affect how the findings might translate to clinical care. Participants had to discontinue antidepressants so the spray could be tested on its own, which the authors note can cause withdrawal symptoms or a return of depression and may not reflect how the drug would be used in practice. Andrade adds that the trial offers no guidance on when or how patients would transition to a conventional antidepressant afterward. In addition, the study did not evaluate how much the structured psychological support contributed to the improvements, and the trial population lacked racial and ethnic diversity, as nearly 90 percent of participants were white.

Andrade argues that psychedelic research points toward a broader rethinking of how depression is treated, not just treatment-resistant depression. He questions whether it is justifiable to put patients in severe distress through antidepressants that take four to eight weeks to work when faster-acting options exist, and notes that current Canadian guidelines do not list ketamine and esketamine as third-line treatments for depression, naming them only as second-line add-ons for difficult-to-treat depression.

He also raises a point about access: in low- and middle-income countries, where newly approved psychedelics are likely to be unavailable or unaffordable, generic ketamine can be given orally at negligible cost, though he notes the evidence base for that approach needs strengthening. Andrade has published several studies on oral ketamine and cites his own work in making this argument.

He adds that psychedelics have not yet been approved by regulators and will need to be evaluated for long-term safety, including the risk of hallucinogen persisting perception disorder, a condition in which visual disturbances continue after the drug has worn off. He also calls for more detail on what the mebufotenin experience is actually like, including difficult experiences, whether patients found it unpleasant or frightening, and whether they would undergo it again.

The study, “Single Intranasal Administration of the Psychedelic Mebufotenin for Treatment-Resistant Depression: A Randomized Clinical Trial,” was authored by David Feifel, Mathieu Seynaeve, Wiesław Jerzy Cubała, Fiona Dunbar, Gerhard Gründer, Rosa María Dueñas Herrero, Chandni Hindocha, Paul Liknaitzky, Sean M. McGuigan, Sejal Mehta, Mimi Pierce, Dimitris Repantis, Claire Roberts, Frank Wiegand, and Robert Conley.

The accompanying editorial, “Treatment Approach to Major Depressive Disorder: It’s Time for a Paradigm Shift,” was authored by Chittaranjan Andrade.

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