The Guardian Australia

Psychedeli­cs are transformi­ng the way we understand depression and its treatment

- Robin Carhart-Harris

Mental 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, ithas 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 “drugalone” 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 selfmedica­te. 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

 ?? Photograph: Misha Kaminsky/Getty Images ?? ‘When taken in high doses, psilocybin [derived from magic mushrooms] profoundly alters the quality of conscious awareness, releasing suppressed memories and feelings.’
Photograph: Misha Kaminsky/Getty Images ‘When taken in high doses, psilocybin [derived from magic mushrooms] profoundly alters the quality of conscious awareness, releasing suppressed memories and feelings.’

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