The psychedelic compound found in magic mushrooms can help alleviate severe depression when combined with psychotherapy, according to a trial that raises hopes for people failed by existing antidepressants. Nearly a third of patients with severe depression went into rapid remission after a single 25mg dose of psilocybin followed by therapy sessions, which aimed to help patients identify causes and potential solutions to their depression, researchers said. The results from the largest clinical trial yet into psilocybin and depression were described as “exceptional” by Prof Guy Goodwin, the chief medical officer at Compass Pathways, the mental healthcare firm that led the trial conducted at 22 sites across the UK, Europe and North America. An estimated 100 million people worldwide have treatment-resistant depression, defined as a major depressive disorder that has not responded to at least two antidepressant treatments. About half of those affected are unable to perform routine daily tasks. “Response rates in this group with treatment-resistant depression are usually between 10 and 20%,” Goodwin said. “We are seeing remission rates at three weeks of about 30% … that is a very satisfactory outcome.” Dr James Rucker, a consultant psychiatrist at South London and Maudsley NHS foundation trust, who worked on the trial at King’s College London, said treatment-resistant depression placed a “staggering” burden on patients and those around them, with a total cost to the UK of £3.9bn a year. The phase 2b clinical trial recruited 233 patients with resistant depression and randomly assigned them to receive a single capsule of either 1mg, 10mg or 25mg of synthetic psilocybin called Comp360. Patients listened to a calming playlist and wore eye shades to turn their attention inward for at least six hours while the psychedelic took hold. A therapist was present throughout to ensure the patients were safe and well. The volunteers went on to have therapy sessions the day after having the drug and one week later. Results published in the New England Journal of Medicine show that depression scores, measured on the standard Montgomery-Åsberg depression scale, improved immediately after treatment in all three arms of the trial. The most significant impact was in those on the highest 25mg dose of psilocybin. Three weeks after having the drug, 29% of this group were in remission, compared with 9% and 8% of the 10mg and 1mg groups respectively. At 12 weeks, benefits persisted in a fifth of those in the high-dose group, compared with one in 10 in the lowest-dose group. Psilocybin is the main active ingredient in magic mushrooms. Inside the body, it is broken down into a substance called psilocin, which releases waves of neurotransmitters in the brain. MRI scans show that brain activity becomes more chaotic on psilocin, with different regions of the brain talking to each other more than usual. “That may seem like a bad thing but it isn’t,” said Rucker. “That happens every night: when you dream your brain becomes more plastic, slightly more chaotic, and it’s when new connections are formed.” Patients on the trial spoke of being in a “waking dream” when they took psilocybin, a short-lived experience that wore off before they returned home. The increased connectivity in the brain appears to be a more enduring effect, however, lasting a few weeks and potentially making the brain more open to therapy. “When the brain is in a more flexible state it opens what we consider to be a therapeutic window of opportunity,” Rucker said. David Nutt, a professor of neuropsychopharmacology at Imperial College London, who was not involved in the trial, said the rapid effect of psilocybin suggested it was disrupting negative cycles of rumination in the patients, in effect acting as a “reset” on the brain. Despite the apparent benefits, many patients reported side-effects in the trial, the most common being headaches, nausea, dizziness and fatigue. One person had a bad trip and was given a sedative to help their anxiety. As is common with treatment-resistant depression, a number of patients in different arms of the trial reported self-harm and suicidal thoughts. Suicidal behaviours were seen in three patients who did not respond to the 25mg dose of psilocybin at least one month after taking the drug. According to Nutt, these cases were probably random events and unrelated to the dose of psilocybin, which would have been fully cleared from the patient’s bodies. A larger phase 3 trial that will explore the effects of two doses of psilocybin is due to start later this year.