Magic mushrooms might sound like an unlikely depression drug. Associated more with the 1960s' counterculture than with modern medical science, the mind-altering fungus has been banned in most parts of the world since 1971. With tight regulatory restrictions in place, what had once seemed like a promising avenue of research came to an abrupt dead end.

In recent years, however, we have seen a quiet revival of interest, with a number of researchers pondering whether psilocybin (the active component of magic mushrooms) might have purposes beyond the illicitly recreational. Along with other psychedelic substances like LSD (synthesised from ergot) and DMT (from ayahuasca), it has been touted as a possible treatment for depression, anxiety, addiction and post-traumatic stress disorder (PTSD).

Most recently, a team of scientists at Imperial College London trialled the substance on 12 depressed volunteers. The participants – six men and six women aged between 30 and 64 – had previously tried at least two different classes of depression medicine without success. Following this intervention, however, all saw their symptoms alleviate: all 12 were less depressed after three weeks, and five maintained the improvements for three months.

Due to limitations in size and design, the study did not offer conclusive evidence of efficacy. However, it has fuelled hopes that psilocybin might be able to treat depression where other drugs have failed.

"This was quite a rich study, and we learnt a lot in the process," says lead author Dr Robin Carhart-Harris, from the Department of Medicine at Imperial. "I think the main message from the study is that psilocybin seems well tolerated, and there are suggestions of efficacy here that require a better controlled, more rigorously done and bigger study."

A peak experience

Following extensive screening and baseline psychiatric testing, each volunteer received 10mg of psilocybin (a relatively low dose) within a therapeutic context. This was far removed from the typical recreational 'trip': the clinical research room had been transformed into a supportive space, with music playing through headphones and a trained mental health professional on site.

A week later, volunteers returned to the research facility for a second, higher dose of 25mg.

"This is the kind of dose that can produce quite a profound psychological experience; what Abraham Maslow called a 'peak experience', and others have framed as a mystical or spiritual experience," says Carhart-Harris.

"It's not uncommon for the patients to report an encounter with a divine being, a feeling of boundlessness, or a connection to the deeper scheme of things – and these kinds of experiences seem to be predictive of therapeutic outcomes."

"It's not uncommon for the patients to report an encounter with a divine being, a feeling of boundlessness, or a connection to the deeper scheme of things."

The next day, volunteers received a follow-up fMRI scan and a chance to discuss their experience with the team. While they underwent 'integration' work the following week, helping them make sense of their experience, for the most part the patient was left to process what had happened with minimal intervention.

"It's more about holding them in this safe place, such that they can go as deep as they can into the inner terrain of their own minds," says Carhart-Harris. "The therapists are there to support them, but things play out in this natural, autonomous sort of way."

The participants' depression levels were assessed through various metrics, primarily through the 16-item Quick Inventory of Depressive Symptoms (QIDS), but also through testing their autobiographical memory and ability to detect specific emotions in faces (both of which are impaired in depression). On average, their QIDS scores were significantly reduced from baseline one week and three months post-treatment, with the maximum effect after two weeks.

A catch 22

Although these results are certainly encouraging, Carhart-Harris says we should be careful not to over-interpret the findings: as a proof of principle trial, the study lacked a placebo group. A larger trial will be necessary if psilocybin is ever to gain approval as a drug to treat depression.

Unfortunately, further research may prove to be a convoluted process. Faced with legal restrictions and ethical objections, this study alone took years to complete, with the regulatory approvals taking a staggering 32 months. It was also expensive: while funding (from the Medical Research Council) was assured, it cost £1,500 to dose each person.

"It was difficult because it felt like some of the stigma around psilocybin and similar compounds was hampering our progress," says Carhart-Harris. "Getting approval from the ethics committee was drawn out and difficult, and the biggest delay was around obtaining the drug. There are only a small number of companies around the world that even synthesise psilocybin, and it wasn't enough to have it synthesised, it needed to be made to GMP [good manufacturing practice] standards."

He points out that, while a number of companies are licensed by the Home Office to work with Schedule 2 compounds, very few have a license to work with Schedule 1 compounds, such as psilocybin.

"They're not looked at as potential medicines by their very definition," he says. "It's a little bit of catch 22 – you can't do the research because you don't have a license, and you don't have a license because the research hasn't been done to challenge the scheduling."

Design challenges

Moving forward, there will be a further challenge in the form of study design. Due to the very pronounced subjective effects of psilocybin, it will be harder than normal to conduct a randomised controlled trial (RCT) with a placebo group who don't know what they're getting.

"It's a conundrum," says Carhart-Harris. "You can go with an inert placebo, but in that case the blind is ineffective and it's obvious when you get the active treatment. Or an alternative is to go with an active placebo – a very small dose of psilocybin – but then you don't have an inert placebo to know whether your very low dose has actually been active. So you can have a three-armed trial, but these are difficult to power, you need a big group, and they're expensive. It's difficult at the moment to get money for such trials."

"At the moment, the team is hoping to go ahead and conduct a double blind RCT."

At the moment, the team is hoping to go ahead and conduct a double blind RCT. Around 30 people would receive a single dosing session with psilocybin and another 30 would receive an inert placebo, while the psychological support received would be standardised.

Because the blinding would most likely be ineffective, the researchers would then go on to conduct a comparative efficacy study using a naturalistic design. For instance, they might compare psilocybin with a standard antidepressant, giving participants a choice about which course of action they would prefer.

Mounting evidence

Despite the sizeable obstacles, and presumed expenses ahead, Carhart-Harris is broadly optimistic about the future.

"The evidence is accumulating now," he says. "As well as our little study, there are bigger studies about to be published, and they've got better controlled conditions. A body of evidence will accumulate that will really challenge the scheduling of psilocybin as Schedule 1. This will get more and more people interested in its potential and move it along."

Of course, it goes without saying that Carhart-Harris does not recommend that depressed patients self-medicate, nor does he endorse the full-scale legalisation of psilocybin. However, with the appropriate caveats in place, he is excited about its therapeutic potential.

"It could be that psilocybin is available off-label, given legally as a treatment, as part of an adaptive protocol that's approved by the relevant people, within the next ten years."