Antidepressants are the usual first treatment for depression, and they act slowly. A patient waits four to six weeks to learn whether a drug is helping. If it is not, the doctor changes the dose or the drug, and the wait begins again. Once two different antidepressants have failed, both taken at a full dose for long enough, psychiatrists call the illness treatment-resistant depression. Regulators such as the European Medicines Agency use the same two-drug threshold. The odds of recovery fall with every further drug: 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, but only about 13% on the third or fourth. In the US, researchers estimated in 2021 that about 31% of adults treated with antidepressants meet the definition.
Researchers are now testing whether a psychedelic could bring relief in a single visit. In a randomised control trial published in JAMA this week, they gave 193 such patients one 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.
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The trial is significant for both its design – it was a randomised control trial – and the findings. Patients in the drug-resistant depression group typically have few options and even those are slow or demanding. One is electroconvulsive therapy (ECT), in which doctors trigger a brief seizure under anaesthesia. About half of such patients go into remission, but they need several weeks of sessions, and some see some implications on their memory. Then there is magnetic stimulation of the brain, which usually means a session every weekday for four to six weeks, and about three in ten patients respond. A third option is the anaesthetic ketamine, which can ease depression within hours, but the effect fades. After all three, many patients relapse unless they keep taking an antidepressant.
Mebufotenin, then, is a promising candidate – but it might not be a panacea just yet. Chittaranjan Andrade, a psychopharmacologist at Nimhans in Bengaluru, wrote in an editorial alongside the mebufotenin trial that “the antidepressant effect was incomplete”: patients were about 30% better on average. None had tried ketamine or ECT, people with suicidal thoughts were excluded, and many could tell whether they had received the real dose. “If the benefit is only 30%, it means that you’ve either not given an adequate dose, or you’ve not given it on an adequate number of occasions,” he said. The company developing the drug paid for the trial.
{{/usCountry}}Mebufotenin, then, is a promising candidate – but it might not be a panacea just yet. Chittaranjan Andrade, a psychopharmacologist at Nimhans in Bengaluru, wrote in an editorial alongside the mebufotenin trial that “the antidepressant effect was incomplete”: patients were about 30% better on average. None had tried ketamine or ECT, people with suicidal thoughts were excluded, and many could tell whether they had received the real dose. “If the benefit is only 30%, it means that you’ve either not given an adequate dose, or you’ve not given it on an adequate number of occasions,” he said. The company developing the drug paid for the trial.
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Psychedelics have long been explored as potential therapies for mental health illnesses. But regulators have raised concerns about this class of chemicals. One, a blinded study – where the subjects of a study truly do not know whether they are being give the drug or a placebo – is difficult because patients can usually tell whether they received 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. Its sessions last hours, though, and that is 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 these trials, and psilocybin and DMT are banned under the Narcotic Drugs and Psychotropic Substances Act. Andrade expects psychedelics to stay “unavailable and unaffordable” here 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, who has led much of India’s research on oral ketamine, adds that its wider use “needs to be supported by more solid research than is currently available”.
People also misuse ketamine, at far higher doses than those used in treatment, and heavy recreational use can damage the bladder. In treated patients, reviewers have found few bladder problems, but most trials followed patients for only weeks. In a year-long study of esketamine, the nasal form, funded by its maker, researchers reported no bladder damage and no misuse. In its 2026 guideline, the Indian Psychiatric Society 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.
Vital explains the science and the conversations at the frontier of healthcare and wellness. It isn’t medical advice — what to do with it is a conversation for you and your doctor.