- Ketamine is currently the only psychedelic in widespread clinical use. MDMA for the treatment of PTSD is currently in Phase IIIb and is expected to be approved by 2023. Psilocybin for depression has just finished the data collection on a large Phase IIb trial, of which a total of 26 have been conducted or
are currently ongoing.
- Universities and hospitals commonly sponsor trials; companies have sponsored an average of 10 trials annually over the last three years, which will rise to 40 annually in 2024. More than 30 companies have indicated an intent to run clinical trials.
- We can expect MDMA-assisted psychotherapy for PTSD to be approved by the FDA in 2023. Psilocybin for depression, both major depressive disorder (MDD) and treatment-resistant depression (TRD), will probably be approved by 2025. Other approvals for ibogaine, LSD, DMT and ketamine could follow soon afterwards.
Author: Floris Wolswijk is the founder of Blossom. He started Blossom in 2019 to help translate psychedelic research to a wider audience. Since then he has grown the database to encompass over 1500 papers and hundreds of other valuable resources. Floris has an MSc in Psychology though don’t hold it against him.
Psychedelic research is pushing ahead at a pace never seen before. Where in the early 2000s, you were lucky to find a handful of researchers doing animal studies with mind-altering substances; nowadays, more than 100 exciting papers on psychedelics are published every month.
These papers detail the results of clinical trials, of which a new one is started every week, observational studies often in traditional settings, new hypotheses, and reviews that bring together what we currently understand about psychedelics as medicines.
Psychedelic Research Groups
The astronomical rise of research into psychedelics is a result of the work from several research groups that have found the balance between the multidimensional world of psychedelics and the rigorous demands of scientific inquiry. This work has also been made possible by foundations that have paid for much of the early research, specifically the Heffter Research Institute, the Beckley Foundation and MAPS.
The new wave of research arguably started with the study of DMT experiences by Rick Strassman in the 1990s. At that time, as far as we know, his group at the University of New Mexico was the only place doing research with psychedelics on humans. Although the study didn’t investigate psychedelics as medicines ‘per se’, it showed others that, with enough persistence against wider discourse, the research could be done.
The Johns Hopkins research group got permission in 2000 to reinitiate research with psychedelics, this time in patients who were psychedelic-naïve, not having taken psychedelics before. The Centre for Psychedelic and Consciousness Research at Johns Hopkins, founded in September 2020, marks the next phase of research intensification as the group expands and investigates psilocybin for many different mental health disorders
On the other side of the pond, the Imperial College London (ICL) team has been the first to study psychedelics with brain imaging techniques. After more than a decade of research, the Centre for Psychedelic Research at ICL was launched with the explicit goal to develop psilocybin-assisted therapy into a licensed treatment for depression.
These pioneering centres are not the only places where research is taking place. Everywhere from Maastricht University in The Netherlands to the University of São Paulo in Brazil, individual researchers and research groups have studied psychedelics, each through their unique lens. We can expect more research centres to join those already established.
In the last two years, many new research centres have joined the two original groups. Researchers, including the author Michael Pollan, have launched the UC Berkeley Centre for the Science of Psychedelics in September 2020 with the aim of educating the public, training therapists and conducting more research. Mount Sinai, which launched the Centre for Psychedelic Psychotherapy and Trauma Research at the start of 2021, will also research MDMA, psilocybin, and other psychedelics for the treatment of those with complex mental health issues.
In February this year, Mass General launched the Center for the Neuroscience of Psychedelics, where neuroimaging will be leveraged to better understand how psychedelics work. The University of California San Francisco (UCSF) has launched The Translational Psychedelic Research, which will investigate psilocybin for hard-to-treat mental health disorders such as bipolar depression. Finally, UCSF has also set up a psychedelic section within its Neuroscape laboratory, where Robin Carhart-Harris serves as a director.
Clinical Trials with Psychedelics
Of all the research that has been done with psychedelics, psilocybin and MDMA get to share the limelight. But it’s actually ketamine that has generated the most amount of research. As of July 2021, 140 clinical trials have been conducted with ketamine for the treatment of mental health and substance use disorders. As detailed earlier in the report, this had led to the approval of Spravato for TRD and for the widespread use of ketamine for the treatment of MDD and suicidal ideation.
Over the years, we can clearly see a strong upwards trend in the number of patients that have participated in clinical trials. Where an average of 1,100 patients per year were studied between 2016 and 2018, this more than doubled to 2,450 patients in clinical trials between 2019 and 2021. The average number of participants in each trial is 52, which is higher than one might expect. The numbers increase from 36 on average in phase I trials, up to 96 per phase III trial. Looking at the data, without ketamine trials, lowers the average in phase I trials to 30 patients per trial.
Clinical Trial Locations
Looking at geographic trial activity, America is the most active when it comes to running clinical trials, with Switzerland, mostly the Liechti Laboratory, coming in second place. The UK takes the fourth spot after Canada and has recently been ramping up the number of trials in the country. Surprising to note is a dozen trials in China, one of our profiled countries, where ketamine has been researched since 2012. China has also conducted a study on psilocybin for the treatment of migraines.
Not only are most of the studies in Western Educated Industrialised Rich Democratic countries but the patient populations are currently not that diverse. A review in 2018 found that 82% of patients are white and only 2% are of Asian origin – a startling discovery, given that this is where 60% of the world lives. Other ethnic groups are similarly underrepresented. Studies on dosing, efficacy, genetics and differing attitudes towards health services should be aimed at a more diverse and representative group for society to better generalise the results of the current body of research.
Number of Clinical Trials
The number of trials that have been sponsored has shot up in the last three years, with an average of ten trials being sponsored each year. Most of the current studies are being conducted by universities, which have recently also significantly increased their output.
The data for 2021 does include some trials that haven’t started yet, but we can expect some more to be registered before the year is over. At this time the biggest sponsors of research are COMPASS Pathways, MindMed, Johnson & Johnson, atai and its various subsidiaries.
Somewhat surprising is the number of trials already sponsored by governments. This is mostly done by the Veterans Affairs services in America. In the coming years, we expect this number to rise as psychedelic research becomes more mainstream, and more data is readily available. News from Germany and Australia indicate that more government funding is on the way.
Projecting the current numbers into the future, we can expect the number of trials to continue to rise quite quickly. Not only should many companies actually deliver on their plans to run trials, but we can also expect more studies to be sponsored by governments – such as the German government who is sponsoring the MIND Foundation’s psilocybin trial.
Psychedelic trials sponsored by industry
The commercial interest in research with psychedelics has only recently been ignited. There are more than 30 companies that are either running a clinical trial, have run a trial or have indicated that they plan to pursue a trial with a psychedelic. Although some of these press releases may not materialise as completed studies, many well-funded companies are on track to start clinical trials in the next few years.
There are currently tens of companies pursuing trials, of which the most certain are listed here. The duration to develop a psychedelic as medicine can vary widely. At this time, we only have Spravato for TRD and SI, and MDMA for PTSD as examples.
With the very short development cycle and because it was a known chemical entity, the cost of development for Johnson & Johnson most probably is way below their average of the US$5.8 billion that they’ve spent per newly developed drug. Presumably, it is also below the average of US$800 million that is the estimated cost to bring a single drug to market.
We do know that MAPS, although with a longer timeline, is following a far leaner approach, with their total costs still under US$100 million; they expect to spend an additional $100 million in further research expenses plus around $70 million in commercialisation expenses prior to launch. Although the expected approval has crept up over the years, 2023 seems to be a reasonable estimate.
The trials listed on the next two pages are sorted by either their start date or probable start date if the trial isn’t ongoing right now. As previously mentioned, much research is picking up in the UK, with Beckley Psytech, Awakn and Small Pharma being three of the companies running trials.
Notable Scientific Papers
Research is a cumulative process where later research papers build on the work that has come before. A new process is better understood, or a more controlled study is done to confirm the findings from an open-label trial. Some studies, however, are revolutionary and bring about a change in perspective that moves a field ahead to a new milestone, from which small new steps can be taken again.
Based on the database of more than 1.400 psychedelic research papers, we’ve highlighted some of the most influential, revolutionary papers on psychedelics below. These mark some of the moments that marked the age of psychedelics as medicines.
This paper, published in 2000, is the most cited paper in our database and one of the first to investigate ketamine for depression in a double-blind randomised-controlled trial (RCT). The study found improvements in depressive symptoms for patients three days later.
Ten years later, in 2010, this RCT investigated the effect of psilocybin on anxiety in those battling life-threatening cancer. It found reductions in anxiety and depression which later studies found helped up to five years later. The study was conducted only with 12 patients; a 2016 study with 51 patients found similar results.
It is hard to believe that it is already seven years ago that, in 2014, an open-label trial showed that 80% of patients were smoking-free six months after undergoing two sessions of psilocybin-assisted therapy. Five years later, 60% were still free from smoking. Unfortunately, no other research papers on smoking, which kills eight million people per year, have been published.
The safety and efficacy of ±3,4-methylenedioxymethamphetamine-assisted psychotherapy in subjects with chronic, treatment-resistant post-traumatic stress disorder: the first randomised controlled pilot study
The first RCT that studied MDMA for PTSD was published in 2010. The study was incredibly successful and showed that 83% of participants who received MDMA did not qualify for PTSD anymore; this was only 25% in the control group. Many studies, after this one, have been finding similarly spectacular results. A follow-up four years later found that, of those treated with MDMA, only two, out of the 16 contacted, had relapsed.
Many hypotheses existed around what happens when psychedelics are administered; in 2012, we get a first glimpse at what lies below the hood. The ICL team finds that blood flow decreased in several hub regions of the brain, something that was quite surprising at that time. Although more fMRI studies have been done since that time, there are still many open questions about how psychedelics influence brain processes.
A bridge between the neuroscience and the psychology of psychedelics was built with the publication of ‘the entropic brain’. The paper proposes two different forms or states of cognition where one is more ‘critical’ and unconstrained; the psychedelic state. Several revisions since the publication in 2014, such as the relaxed Beliefs Under Psychedelics model, have continued refining this framework.
Psychedelics were studied in patients with life-threatening diseases not only because of their need for help but also because regulators were more likely to approve the study if patients had a shorter life to live during which they could be negatively impacted by the use of psychedelics. Studies like this survey of nearly 22,000 people show that these concerns may not be valid, as it found a slightly lower rate of mental health problems for those who used psychedelics than the general public.
Through which mechanisms psychedelics have long-term positive effects, when the molecules have long since left the body, is hotly debated. One line of thought finds that the more intense the mystical experience, the better the effects on mental health. Since the publication of this paper in 2006, many others have found similar correlations. Other processes such as long-lasting neurological changes have also been identified that may (together) underlie the therapeutic effects of psychedelics.
Less exciting than other studies, the guidelines for safety that were published in 2008 have served a critical role in the development of psychedelic research. The ‘set’ and ‘setting’, knowledge of dosing, and developing trust with the participants, are key elements to facilitating a good research protocol.
Contrary to the other papers indexed here, this RCT was only published in April 2021. The study pitted psychedelics directly against an antidepressant (escitalopram). The study found that the psilocybin group had better results, but unfortunately, the main measure was not statistically different. Still, this marks a seminal moment where a direct comparison against one of the most widely used antidepressants was made.
Psychedelics making it to market
The timeline presented here is our best, arguably optimistic estimate, for when the different psychedelics or their second-generation equivalents could be approved for medical use.
This is based on the current drugs under development, such as MDMA for PTSD, and drugs that are just now going into clinical trials. There is good anecdotal evidence for many compounds and health indicators, and we expect many to pass through the trials successfully.
Based on research from Biotechnology Innovation Organisation, QLS Advisors and InformaUK from this year, the chances of developing a novel compound as a medicine are below 10%. Repurposing a drug, for a new health indicator, faces somewhat better odds and has about a 25% chance of getting approved.
Will this be different for psychedelics? Possibly. For many, we know the safety profile from earlier research and a lot of evidence is pointing towards effectiveness. But enthusiasm and personal transformation stories may not always translate to success in phase III trials. Novel psychedelics will also have to prove their efficacy against those already approved; something that will turn out to be difficult if real-world data supports the effectiveness found in trials conducted with classical psychedelics. Off-label use of psychedelics could also be expected in the future, much as it has been with ketamine.