Psychedelic research has enjoyed somewhat of a renaissance over the past decade. A wave of studies in the US, UK and Australia have investigated the transformative potential of psychedelics in tackling conditions like depression, anxiety, anorexia nervosa, and post-traumatic stress disorder (PTSD). 

Imperial College London launched the world’s first ‘Centre for Psychedelic Research’ back in 2019. It was the first centre in the world to investigate the brain effects of LSD using modern brain imaging and is the first to study psilocybin (the active compound in magic mushrooms) for treating major depression. The small, phase two clinical trial results were released on Wednesday and are published in the New England Journal of Medicine

The trial suggests that psilocybin combined with psychological therapy is as effective a treatment as a leading antidepressant known as escitalopram (sold under brand names like Cipralex and Lexapro). While there is a clear need for greater research and for a more diverse sample of participants, the designer of the trial and the head of the Centre for Psychedelics Research at Imperial, Dr Robin Carhart-Harris, believes the results show that functional alternatives to depression treatment could exist alongside ‘selective serotonin reuptake inhibitors’ (SSRIs) – a widely used class of antidepressant drugs.

I spoke to Dr Carhart-Harris about the details of the trial, how psychedelics affect the brain, and how likely it is that psilocybin will become as common a treatment as antidepressants. The Q&A is followed by a look at how the UK’s drug laws are hampering psychedelic research.

Saffron Swire: What is psilocybin, and how does it affect the brain?

Dr Robin Carhart-Harris: Psilocybin is a naturally occurring chemical that was first detected in certain mushrooms in the late 1950s. Most people know these mushrooms as ‘magic mushrooms’, a term coined by journalists in the late 1950s. 

We give pure, synthesised psilocybin in our research. When it gets into the body and bloodstream, it makes its way into the brain, stimulating what we call the serotonin system. The main effect of this is to dysregulate brain activity and promote a hypersensitive and ‘plastic’ brain state, meaning psychological change is accelerated by the psychedelics. 

What does ‘microdosing’ mean?

Microdosing refers to the taking of very small doses of psychedelics two or three times a week. Microdosing is a phenomenon that has been much popularised by the media ahead of any convincing scientific evidence. In fact, the most evidence suggests that microdosing psychedelics is no more effective than a placebo – which is pretty effective, by the way! 

How are receptors in the brain affected by psychedelic drugs, and how could they help mental health conditions, or in this trial’s case, major depression? 

Psilocybin, like other psychedelics, work on brain serotonin 2A receptors in the cortex. The cortex (meaning ‘bark’ – like on trees) is the wrinkly outer layer of the brain that humans have so much of. There is increasing evidence that activating serotonin 2A receptors accelerates brain growth, both in utero, where they stimulate the proliferation of neural stem cells and in adulthood, where they promote the growth of synaptic connections, the ‘limbs’ of neurons via which they communicate with each other. 

If such accelerated ‘brain growth’ occurs in an ideally nurturing environment, i.e., with professional psychotherapists present, then (mal) adaptive ways of thinking and behaving such as occur in depression, can potentially be revised.

Why do you think there has been an increased interest in researching the potential of psychedelics in general?

Current mental health treatments are not very effective – they often have side effects. Also because rates of mental illness may be increasing, particularly in the young, and with the stresses of Covid-19. Furthermore, recent scientific evidence and its reporting are stoking optimism in its potential to be a breakthrough treatment. 

When did you first start the psilocybin trial, what has it involved, and what have been the main risks?

In a sense, this road began in 2012, when we won some funding to do a trial in treatment-resistant depression. This trial was completed and published in 2016, and after that, our full focus has been on this bigger, more rigorous trial now published. 

Depression is a risky disorder, in large part because of the massively increased suicide risk. Interestingly, we observed greater decreases in suicidality in this trial in the psilocybin group – which is especially interesting as there has been some controversy about anti-depressants like escitalopram in relation to suicide, specifically in younger people. 

It is unclear what the particular risks are with psilocybin. Still, we safeguard by carefully screening volunteers and excluding patients with a personal history or immediate family histories of any psychotic disorders. We are trying to be very careful here as cases exist where psychedelic use has been alleged to have triggered psychotic disorders. No such cases have been observed in modern controlled research, however. 

One extremely important safeguard is the psychological support we put in place for the psilocybin dosing sessions and afterwards. We believe this supervision and support is essential for minimising risk and increasing positive outcomes. 

How did participants respond to the psilocybin therapy, and what was your most intriguing finding?

Participants have responded very well, indeed. We observed response rates of at least 70 per cent, which are on par with previous clinical trials of psilocybin for depression. This is much higher than the approximately 50 per cent response rate associated with anti-depressants like escitalopram; indeed, consistent with prior literature, response rates to escitalopram in this trial reached a high of 48 per cent. 

Was there a risk of a placebo effect, and how did you manage this in your trial?

The question should be, “how much of the positive effect of psychedelic therapy is due to positive expectations?” There we suspect and have some evidence to suggest that the answer is “a considerable amount.” However, this is not the placebo response, as that is the response to something inert. 

As psychedelics enhance sensitivity to contextual conditions, both inside and outside the individual, as well as during the psychedelic ‘trip’ and afterwards, the likelihood of being affected, in a positive way, by the participant’s positive expectations and the positivity and therapeutic efforts of the participant’s guides or therapists, is extremely high. In brief, harnessing such useful and important psychological factors is part of the psychedelic therapy model.

In my view, research with psychedelics may help to expose some myths about the assumed scientific rigour of placebo-controlled trials and related procedures. It may be that they are not as rigorous as many would like to believe, even when assessing less potent medications such as conventional anti-depressants. 

How has the ban on psychedelics affected scientific research in the field?

It has made it much harder to do the research. It affects the stigma surrounding these compounds, and I suspect this has made it more difficult for research institutions and mainstream funding bodies to support research with psychedelics. 

The licenses required to do the research are expensive, and the stipulations they make on how to store and manage licensed compounds are pragmatically challenging to implement. This has put off many research teams in the past, but many others are also now seeing that it may be worth it.

I hope that steps are taken in the future to make it easier to do scientific and medical research with psychedelics. 

How hard will it be to translate clinical research, like Imperial’s, into actual treatments? What are the obstacles?

The main obstacle is financial. Our trial is what you call an investigator-led and university-sponsored trial, meaning it was not funded or sponsored by a commercial entity. However, the road to medical licensing is an incredibly expensive one and is typically only taken on by commercial entities with sufficient bankroll to see the process through. A phase three licensing trial costs an average of $20m but can easily be ten times as high, particularly if further phase two work is required, as has been the case with the development of psychedelic medicines. 

How likely do you think it is that magic mushrooms could one day replace anti-depressants? 

“Replace” is probably the wrong word here. It is good for patients, their families and their clinicians to have a bigger repertoire of effective treatments than we have presently, particularly when the present treatments are not performing well enough. 

What do you think is the future of psychedelic therapy?

My hope and belief is that psilocybin therapy can be developed into a licensed mental health intervention. Some may prefer it over conventional anti-depressants, but for others, perhaps anti-depressants might actually be the better option. 

However, I suspect that if psilocybin therapy does become licensed, it will prove to be more effective and popular than conventional anti-depressants, not because the experience is pleasant but because the depth of healing is greater. 

Depression is a social disease affecting more than 264 million people worldwide, with close to 800,000 people dying by suicide every year. This tumultuous past year has taken no prisoners, and we can expect to see a rapid escalation of mental health-related problems. 

But while the US has embraced drug law reform, the UK still has a ‘zero-tolerance’ policy, meaning that psychedelics are still illegal and classified as a ‘Schedule 1’ (the most severely restricted category) drug under the UK Misuse of Drugs Act and UN conventions. This schedule is reserved for drugs that are ‘dangerous’ and have ‘no special medical utility’, a category that is increasingly inappropriate for psychedelics which have been continually proved to be both safe and effective (if microdosed and controlled).

If control was eased, research into the power of psilocybin could greatly accelerate. For example, medical cannabis was moved down to Schedule 2 in 2018, which has led to far greater treatment and research. 

 Professor David Nutt, a doctor and expert in neuropsychopharmacology, believes that policy on drugs, and psilocybin specifically, should be reformed: “They should reschedule psilocybin from ‘Schedule 1’ to Schedule 2,” he said. “This would allow it to be researched more easily so we can accelerate knowledge in both clinical and bench lab settings.” 

Alternative treatments – that are safe and effective – could have enormous potential for those with severe depression. From what we’ve seen, patients who have taken psilocybin can feel less suicidal, feel more supported and report fewer side effects. Yet as long as current laws in the UK block vital medical research, the likelihood of psilocybin reaching the same medical mainstream as SSRIs will continue to be about as realistic as a trippy illusion.