David Nutt is a psychiatrist at the Edmond J. Safra Professor of Neuropsychopharmacology in the Division of Brain Science, Dept. of Medicine, Hammersmith Hospital, Imperial College London and is the Chair of the Scientific Advisory Board for COMPASS Pathways. His research area is psychopharmacology – the study of the effects of drugs on the brain, from the perspectives of both how drug treatments in psychiatry and neurology work, and why people use and become addicted to some drugs such as alcohol. To study the effects of drugs in the brain he uses state-of-the-art techniques such as brain imaging with PET and fMRI plus EEG and MEG. This research output has led to over 500 original research papers and a similar number of reviews and books chapters, eight government reports on drugs and 35 books, including one for the general public, Drugs: Without the Hot Air, which won the Transmission Prize in 2014.
You've been working in psychopharmacology for over 30 years. What first sparked your interest in the space and what psychedelic-based discoveries have you been most intrigued by?
I have been working in the field of psychopharmacology for over 40 years – much of it in the clinical arena with patients and human volunteers. I have probably given more different types of drugs to humans than anyone else alive. These have confirmed our theories that the brain is a complex chemical machine and that the best way of both studying its function and remedying disorders such as depression and anxiety and addiction is through psychopharmacology.
In the early 1980s the 5-HT2A receptor was becoming identified and the first selective antagonist [ritanserin] was developed by Janssen. In my PhD back in the early 1980s I had shown that ECT as well as antidepressants enhanced serotonin function which led to the antidepressant effects - the question was through which subtype of the 5-HT receptor? At that time before receptor cloning we thought there were just 5-HT 1 and 5-HT 2 receptors. We knew that psychedelics worked through the 5-HT 2 receptor and ECT had recently been shown to increase 5-HT 2 receptor function in rats but working with 5-HT 2 agonists in humans was prohibited so using an antagonist was the best we could do to explore the function of this receptor. We conducted a two week trial with ritanserin in healthy volunteers using psychological tests, endocrine measures and sleep polysomnography recordings. Subjectively, ritanserin had little effect other than a slight calming but on sleep it had the unexpected effect of enhancing the power in the slow wave [deep] sleep -range of EEG frequencies.
The question of what the agonists did wasn’t resolved until nearly 30 later when we overcame the regulatory hurdles and worked with psilocybin and LSD and found the opposite – that these drugs dramatically reduced EEG power across the whole spectrum- producing a state of increased brain entropy. Its this disorganised state that explains the psychological effects of psychedelics especially the hallucinations and altered sense of self. But more than that, these alterations in brain function we believe are the reason serotoninergic psychedelic drugs have therapeutic activity. By disrupting ongoing repetitive brain processes that underpin symptoms such as depressive ruminations depression can be lifted, and this effect seems to last for many weeks, probably because these 5-HT 2 receptors allow the learning of new – non depressed - ways of thinking
Can you tell us about some of your personal experiences with psychedelics and what perspective that gave you on the role they could potentially play in the world?
I don’t talk about me for several reasons. The main one being that whatever my own experiences with any drug might be, for many reasons [prior knowledge, expectation, etc] they are likely not to be typical so not scientifically useful. Also we know from the 1960s that personal experiences with psychedelics had far greater media impacts than research discoveries. These distorted the public debate about psychedelics and subsequently led to their suppression. The new renaissance of psychedelic research and clinical therapy needs to stay firmly grounded in scientific evidence, not personal anecdote
You were recently appointed to the board of directors at Psyched Wellness, a company focused on developing supplements from the Fly Amanita Muscaria mushroom. What is your history with Amanita Muscaria and what potential health and wellness benefits are you most excited about?
I have worked in the field of GABA for much of my research career. Along with the discovery that ECT accentuated serotonin function I also discovered it significantly impacted GABA function, and that the two might be related. One of the tools I used in this early work was the recently identified GABA-A agonist muscimol, and I published several papers in which it featured.
At that time though I knew that muscimol was a natural product from Amanita Muscaris I wasn’t aware of the historical use of this mushroom in social and shamanic interactions. Most of my subsequent publications on GABA receptors have focussed on ligands of the closely-related benzodiazepine receptor site.
It was only when I began to research psilocybin-containing magic mushrooms and other psychedelics that I came across muscimol containing mushrooms. What is now clear from millennia of use is that these do have significant positive effects on humans [as well as reindeer] as well as some unusual psychedelic effects especially in the visual system where it can change size perception [micro and macropsia]. There is also some evidence that the social-enhancing effects of Amanita Muscaris may have contributed to the development of shared religious experiences especially Christianity. This raises interesting questions about how muscimol might produce such a range of effects that I hope to explore as part of the Psyched Wellness program. The good news is that we now have much more developed research tools for human research than we did when muscimol was first discovered so we can more effectively explore its brain actions.
You are also on the scientific advisory board at COMPASS Pathways. What role do you play in their ongoing trials and what results and discoveries have you found most intriguing to date?
My role as chair of the scientific advisory board is to advise on current and future research plans and trials and to help develop a complementary pre-clinical research programme to underpin and further inform the clinical one. I have helped them identity and recruit a range of experts to both the clinical and pre-clinical board. Also I worked with some of their team and external experts to produce the definitive review of microdosing that we published last year in the Journal of Psychopharmacology.
What have you learned from the CMPS clinical trial, which is the largest clinical trial on psilocybin currently happening in the world?
This is a pivotal three arm multi-centre trial of 3 different doses of psilocybin [1,10,25 mg] in patients with resistant depression. So far we have learned that recruitment of research patients is difficult even in a disorder as common as major depression, especially when other medications are not allowed so have to be withdrawn before the psilocybin is administered. Also there are relatively few centres in the world that have staff trained in psychedelic therapy so these have to be set up in anticipation both of clinical research and later clinical role out. The good news is that there are many psychiatrists and psychologist interested in this new approach to mental illness who are wanting to be trained. Other good news is that both the FDA and EMA have granted COMPASS Pathways psilocybin research fast track status, showing that they too believe in the need for innovation in psychiatry medicines and that psilocybin may fulfil this.
In your own research, what kind of discoveries have you made in using Psilocybin with treatment-resistant depression?
The first point to be aware of is that when we started out psychedelic research with psilocybin our ambition was to use brain imaging to find the neural correlates of the psychedelic state. We didn’t expect that psilocybin would turn out to be a new approach to treating depression. This came because of the neuroscience findings, in particular, our discovery that psilocybin depressed activity in the subgenual cingulate cortex a key node in the brain circuit that drives depression. Before our discovery with psilocybin many other treatments of depression from ECT and SSRIs to psychotherapy and even placebo had revealed that improvements in mood were associated with – and likely driven by – reduced activity in this brain region. Also we found that psilocybin completely disrupted the brain network called the DMN [default mode network]. This is the recently discovered network in which our sense of self is produced. Imaging research from other groups had showed the DMN to be overactive in depression and related to the amount of rumination. So we thought that disrupting excess DMN activity might lead to a reduction in depressive thinking. These two neuroscience ideas coupled with evidence from psilocybin effects when it was used in a psychotherapeutic study from Roland Griffiths’ group at Johns Hopkins were sufficient to get us our first [and last] funding from the UK government. With this we conducted the first ever modern-day trial of psilocybin in resistant depression. We used a dose of 25mg – the same as in our imaging studies and the Johns Hopkins one – which produces a powerful 4-5 hour trip. The next day all patients reported improvements in mood and these reached maximal statistical significance at 5 week. Some became depression-free i.e. entered remission and a few of these have stayed well ever since, however most relapsed over the next 6 months which was disappointing though given most had been depressed for over ten years not surprising. This is why in our current study we are giving two doses of psilocybin 2 weeks apart to see if we can get a more prolonged action. This psilocybin treatment study is the first head to head RCT comparison with a standard antidepressant [the SSRI escitalopram] and will report early in 2021.
What do you believe is the biggest misconception about the use of psychedelics today?
A perception of danger. I think this is that because they are still Schedule 1 drugs under the UN Conventions and no country has yet removed them from this Schedule, then people assume they are as harmful as other drugs in Schedule 1 such as fentanyls and crack cocaine. Also, most people think that psychedelics are addictive because they are so heavily controlled and yet they are not – indeed research shows repeated use leads to tolerance within a few days. Moreover they don’t lead to craving for more. Indeed one of the most promising areas of therapeutic interventions with psychedelics is in the treatment of addiction. Before the UN Conventions ban there were 6 trials of LSD for alcoholism which a recent meta-analysis has shown had an effect size twice that of any treatment for alcoholism since. More recently this anti-alcoholism effect has been demonstrated in a small trial with psilocybin and a few treatments with psilocybin have also been shown to have remarkable impact to reduce smoking
Where do you see psychedelic medicines in the future and how much of an impact do you think they will make on psychopharmacology as a whole?
I see psychedelics as potentially one of the great breakthroughs in psychiatry. There have been few major advances in psychiatry in recent years. Most of the medicines we use are derivatives of drugs that were discovered in the 1950s or 1960s. With the exception of ketamine no antidepressant treatments work quickly and this is an area where psychedelics offer a powerful new treatment modality especially as a single dose has more enduring efficacy than ketamine. What is especially exciting for psychedelics is their potential utility in disorders other than depression. Our group and others are setting up studies in OCD and anorexia and several addiction trials are being developed. Though these disorders seem quite different in symptoms, they share the common feature of being internalising disorders – i.e. all these patients engage in repetitive thoughts about themselves. In depression, its negative self-referential thinking; in OCD, it's about contamination etc; in addiction its about the drug of choice, and in anorexia it's about weight and body image. We believe all these involve overactivity of the DMN that psychedelics can disrupt. Time will tell if we are right!
Who is someone you think is doing important work in the world of psychedelics that more people should be aware of?
The field is still too small, due to the UN Conventions Schedule 1 constraints impeding university and commercial research. In the USA the Johns Hopkins and NYU groups have led the way with innovative clinical trials and are now bringing imaging into their clinical studies. In Europe, apart from U.S, research has been very limited except in Switzerland where they have a more research-sympathetic regulatory approach to human psychopharmacology. This has allowed the groups of Vollenweider and Liechti to do a significant amount of work with LSD and psilocybin in depression and anxiety that brings confidence in others findings of efficacy. This body of work has given the Swiss health authority the confidence to allow compassionate use of these psychedelics. This is something I would dearly like other countries particularly the UK to adopt. The only distressing aspect of our clinical experiences so far is the fact that so many of the patients in our research study responded to psilocybin but then relapsed and want another dose. But I can only give it in a research study and we don’t have any that accept people who have had previous psilocybin treatment. So they suffer even more knowing that there is a treatment that could help them that they are denied for outdated and indefensible reasons – the worse possible situation.