ental illness is the 21st century’s leading cause of disability, affecting an estimated billion people across the world. Depression is the number one contributor: more than 250 million people have this condition globally. The number of people prescribed antidepressant medications, the first-line treatment for depression, increases each year, and the market for them is valued at approximately $15bn (£11bn). Yet depression prevalence rates have not decreased since accurate record-keeping began. One reason for this paradox is the failure of science to adequately explain how and why depression occurs. Psychiatry has long sought and failed to find a compelling biomedical explanation for depression. One popular idea, the “serotonin hypothesis”, was inspired by the observation that drugs that increase the activity of this naturally occurring brain chemical have antidepressant effects. First produced in the mid-1980s, Prozac (chemical name fluoxetine) is the most famous selective serotonin reuptake inhibitor (SSRI) antidepressant. Of these, Cipralex (escitalopram) is one of the newest and best performing. While the serotonin hypothesis has some scientific foundation, it has been massively oversold by the pharmaceutical industry. This has stoked scepticism about one-sided, neurochemical explanations for depression, which suggest, for instance, that people are depressed because their serotonin levels are too low. The latest evidence indicates that SSRIs such as escitalopram are only marginally more effective at treating depression than a placebo, with response rates tending to average around 50-60%. Other limitations of SSRIs include poor compliance, symptoms when people stop taking them, unpleasant side-effects and a sluggish onset of antidepressant effects. I began investigating an alternative to antidepressant medicines about 15 years ago as part of my PhD. Psilocybin, a constituent of “magic mushrooms”, is a classic psychedelic. When taken in high doses, it profoundly alters the quality of one’s conscious awareness, producing complex visions and releasing suppressed memories and feelings. After completing a series of studies involving psilocybin, including an earlier trial of its effects among people with treatment-resistant depression, I set out to design a more rigorous test that might help to contextualise the drug’s therapeutic promise. The resulting trial was completed last year, and its findings have now been published in the New England Journal of Medicine. It was a double-blind, randomised, controlled trial involving 59 people with moderate to severe depression. They were randomly allocated to one of two treatment groups: one in which the main treatment was a six-week course of the conventional SSRI antidepressant, escitalopram, and another in which the main treatment was two high-dose psilocybin therapy sessions. Those in the escitalopram group did about as well as one would expect, based on previous SSRI trial data and the relatively short, six-week course. Across four different measures of depressive symptoms, the average response rate to escitalopram at the end of the trial was 33%. In comparison, psilocybin worked more rapidly, decreasing depression scores as early as one day after the first dosing session. At the end of the trial, the average response rate to psilocybin therapy was more than 70%. While we suspected that psilocybin might perform well compared to the SSRI, we had not expected it to perform as well as it did. In fact, the initial main hypothesis for this trial was that the psilocybin therapy would have superior effects on psychological wellbeing, but not on depression severity scores. This prediction was generally supported, but people in the psilocybin group also showed evidence of greater improvements across most depression measures, as well as anxiety symptoms, work and social functioning, suicidal feelings and the ability to feel emotion and pleasure. Both groups experienced similar levels of side-effects, but the escitalopram group experienced worse drowsiness, dry mouth, sexual dysfunction and anxiety. In the psilocybin group, the most prevalent side-effect was a mild to moderate headache one day after dosing. Six-month follow-up work is now under way to test our prediction that the positive effects seen in the psilocybin group will be longer lasting. So why does psilocybin appear to be a more successful treatment for depression than a typical antidepressant? Brain imaging data from the trial, alongside the psychological data we collected, appears to show that while SSRIs dampen emotional depth by reducing the responsiveness of the brain’s stress circuitry, helping to take the edge off depressive symptoms, psilocybin seems to liberate thought and feeling. It does this by “dysregulating” the most evolutionarily developed aspect of our brain, the neocortex. When this liberation occurs alongside professional psychological support, the most common outcome is a renewed breadth of perspective. Psychedelic therapy seems to catalyse a type of psychological growth that is conducive to mental health, overlapping in many respects with spiritual growth. The most exciting aspect of this trial is a sense that we are on the verge of a paradigm shift in mental healthcare linked to an improved understanding of the origins of depression, and how we can most effectively treat it. In my view, this shift will take us away from an outdated and myopic “drug-alone” perspective that has dominated psychiatry for several decades, and towards a multi-level “biopsychosocial” model. This model sees the symptoms of depression as an adaptive response to adversity, with decipherable – albeit complex – psychosocial causes. Psychedelics can treat depression by activating powerful brain states that have evolved in humans to catalyse deep psychological change. When these “hyper-plastic” states are combined with a nurturing environmental context, defensive habits of mind and behaviour can undergo a healthy, potentially enduring revision. These ideas aren’t confined to the academy. Since I wrote about developments in psychedelic medicine for the Guardian last year, the US state of Oregon has voted in favour of legalising psilocybin therapy, a senate bill has been introduced to decriminalise psychedelic drugs in California, and policies are also being reviewed in New York, Washington DC, New Jersey, Florida, Canada, Australia and the UK. The Australian government has pledged A$15m (£8.5m) to psychedelic research, while two new research centres dedicated to studying psychedelic medicine have been announced at major US universities. Of course, our study certainly isn’t a licence for people to self-medicate. But these are exciting developments – and show that governments are recognising the benefits of psychedelic therapies. Many obstacles have already slowed the progress of psychedelic medicine, and there will doubtless be more, from litigation issues to moral objections. If we’re to achieve a population-level improvement in psychological wellbeing, this road won’t be easy. Despite the recent landmark trial, I do sometimes wonder if we will make it at all. One thing I am more certain of, however, is that we must try. Robin Carhart-Harris is head of the Centre for Psychedelic Research at Imperial College London In the UK, the charity Mind is available on 0300 123 3393 and Childline on 0800 1111. In the US, Mental Health America is available on 800-273-8255. In Australia, support is available at Beyond Blue on 1300 22 4636, Lifeline on 13 11 14, and at MensLine on 1300 789 978