Anyone who has waited out weeks of antidepressant trial and error knows how slowly hope can drain away, and it is against that long, familiar wait that a single spray of a psychedelic compound is now being measured. A randomised trial of 193 patients suggests that mebufotenin can lift treatment-resistant depression for eight weeks, with most people able to go home within hours, yet the improvement was partial, the trial was funded by its maker, and many participants could tell whether they had received the real dose. For patients in India, where psychedelics are banned, the more reachable path
A Single Psychedelic Spray Offers Hope for Patients Whose Depression Resists Two Antidepressants
Treatment-resistant depression affects roughly 31% of US adults treated with antidepressants, who face weeks of trial-and-error waiting and limited options.
One in three patients gets no relief from two antidepressants
Mark
Why does this trial matter, when psychedelics have been studied for years?
Mimi
Because of how fast it works. One spray, an effect that fades within the hour, most patients home within two hours, and symptoms stayed lower than the comparison group's for eight weeks.
Mark
And the alternatives are heavier?
Mimi
Yes. ECT needs weeks of sessions and can affect memory. Magnetic stimulation means a session every weekday for four to six weeks.
Luke
Before we get carried away: the average improvement was about 30%. Andrade called that incomplete.
Mimi
He did, and he suggested the dose or the number of doses may have been too low.
Luke
That's his interpretation, not something the trial showed. It's a hypothesis. Also, the company developing the drug paid for the study.
Mark
Does the blinding issue weigh on this one too?
Mimi
Yes. Many participants could tell whether they got the real dose, which is what troubled the FDA with MDMA in 2024.
Luke
And the trial excluded people with suicidal thoughts and anyone who had tried ketamine or ECT. We don't know how it performs in those groups.
Mark
What does this mean for India?
Mimi
Not much directly. No Indian patients took part, and psilocybin and DMT are banned there. Andrade points to oral ketamine instead.
Luke
Even that has limits. Long-term safety data are thin, which the Indian Psychiatric Society's guideline acknowledges.
Il Polso
- A patient who has already failed two antidepressants faces weeks more of waiting, and each new attempt tends to bring a smaller chance of recovery.
- A JAMA trial of a single mebufotenin spray has offered a rare fast alternative, with symptoms staying lower for eight weeks.
- The average benefit is only about 30%, and participants could often guess whether they had the real dose, which weakens the result.
- The trial was paid for by the company that makes the drug, leaving critics doubting how far the evidence can be trusted.
- In India, psychedelics remain banned, so attention is turning to oral ketamine and to a five-centre trial that could strengthen its case.
Anyone who has waited out weeks of antidepressant trial and error knows how slowly hope can drain away, and it is against that long, familiar wait that a single spray of a psychedelic compound is now being measured. A randomised trial of 193 patients suggests that mebufotenin can lift treatment-resistant depression for eight weeks, with most people able to go home within hours, yet the improvement was partial, the trial was funded by its maker, and many participants could tell whether they had received the real dose. For patients in India, where psychedelics are banned, the more reachable path may still run through oral ketamine, whose wider use awaits better evidence.
A patient who starts an antidepressant usually waits four to six weeks to learn whether it works. If it does not, the wait begins again with another drug. When two full-dose treatments have failed, psychiatrists call the illness treatment-resistant depression, and the odds of recovery shrink with every further attempt. Researchers estimate that around 31% of US adults treated with antidepressants meet that description.
A randomised trial published in JAMA this week tested something much faster. Its 193 participants received a single spray of mebufotenin, a psychedelic whose effects fade within an hour. Most were well enough to go home within two hours, and their symptoms stayed lower than a comparison group's for eight weeks. Existing options for this group, including electroconvulsive therapy, repeated magnetic stimulation and ketamine, are slow, demanding or short-lived.
The promise comes with caveats. Chittaranjan Andrade of Nimhans in Bengaluru, writing an editorial on the trial, noted that patients improved by only about 30% on average, and that many could tell whether they had the real dose. The trial was company-funded. Psychedelic research has long struggled with this blinding problem, and regulators have not approved a psychedelic for depression.
For India the picture is different. No Indian patients took part, and psychedelics are banned there. Andrade expects them to stay out of reach, and he points instead to oral ketamine, which doctors can already prescribe off-label. Its wider use, he says, needs more solid research, and a five-centre trial funded by the Indian Council of Medical Research is the next piece of evidence to watch.
A patient with depression who starts an antidepressant usually has to wait four to six weeks to find out whether it is working. If it is not, the doctor changes the dose or the drug, and the wait begins again. When two different drugs have each been taken at a full dose for long enough and both have failed, psychiatrists call the illness treatment-resistant depression. Regulators such as the European Medicines Agency use the same two-drug threshold.
The odds worsen with each further attempt. In STAR*D, the largest US study of patients moving through successive treatments, about 37% recovered on the first drug and 31% on the second. On the third or fourth, only about 13% did. Researchers estimated in 2021 that about 31% of US adults treated with antidepressants meet the definition of treatment-resistant depression.
A randomised controlled trial published in JAMA this week tested a much faster approach. Researchers gave 193 such patients a single spray of mebufotenin, a psychedelic whose effects wear off within an hour. Most patients were fit to go home within two hours, and their symptoms stayed lower than those of a comparison group for eight weeks.
The existing options for this group are slow or demanding. Electroconvulsive therapy, in which doctors trigger a brief seizure under anaesthesia, brings about half of such patients into remission, but it takes several weeks of sessions and can affect memory. Magnetic stimulation of the brain usually means a session every weekday for four to six weeks, and about three in ten patients respond. Ketamine, an anaesthetic, can ease depression within hours, but the effect fades. After all three, many patients relapse unless they keep taking an antidepressant.
The result is promising but not conclusive. Chittaranjan Andrade, a psychopharmacologist at Nimhans in Bengaluru, wrote in an editorial alongside the trial that the antidepressant effect was incomplete: patients improved by about 30% on average. None of the participants had tried ketamine or ECT, people with suicidal thoughts were excluded, and many could tell whether they had received the real dose. Andrade said a 30% benefit suggests the dose was inadequate, or that it was not given on enough occasions. The company developing the drug paid for the trial.
The blinding problem has long dogged psychedelic research, because patients can usually tell when they have taken the drug. In 2024 the US Food and Drug Administration rejected MDMA for post-traumatic stress disorder, citing problems that included patients knowing which treatment they had received. Psilocybin, from magic mushrooms, has since passed two large trials by a modest margin, but its sessions last hours, one reason researchers turned to the shorter-acting mebufotenin. No regulator has approved a psychedelic for depression. Outside trials, people smoke mebufotenin at retreats as dried toad secretion, without medical screening.
No Indian patients took part in the trials, and psilocybin and DMT are banned under the Narcotic Drugs and Psychotropic Substances Act. Andrade expects psychedelics to remain unavailable and unaffordable in India even if the US approves them. He points instead to ketamine, which Indian doctors can already prescribe off-label and which, taken by mouth, requires little training and carries negligible costs. Andrade has led much of India's research on oral ketamine, and says its wider use needs more solid research than currently exists.
There are open questions on safety. People misuse ketamine at far higher doses than those used in treatment, and heavy recreational use can damage the bladder. Reviewers have found few bladder problems in treated patients, but most trials followed patients for only weeks. A year-long, maker-funded study of esketamine, the nasal form, reported no bladder damage and no misuse. The Indian Psychiatric Society's 2026 guideline recommends ketamine for treatment-resistant depression wherever available, noting that long-term data are limited. Andrade said the Indian Council of Medical Research has funded a five-centre trial of oral ketamine as a first treatment for depression, the next piece of evidence to watch.
Citazioni salienti
The antidepressant effect was incomplete.— Chittaranjan Andrade, psychopharmacologist at Nimhans, Bengaluru
Oral ketamine requires little training and carries negligible costs, but wider use needs more solid research.— Chittaranjan Andrade (paraphrased)
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