Could psychedelics revolutionise mental health treatments?

Could psychedelic drugs revolutionise mental health treatments? The Founders Pledge research team recently investigated this question and found promising results. Our research focused on the use of psilocybin, the active ingredient of magic mushrooms, as a treatment for depression and MDMA-assisted psychotherapy as a treatment for post-traumatic stress disorder (PTSD). Read the full report here.

What are psychedelics?

Psychedelics are drugs that cause altered states of consciousness. Humans have used psychedelics for thousands of years, from magic mushrooms, whose active ingredient is psilocybin, to ayahuasca, which contains the psychedelic DMT, to a variety of mescaline-containing cacti. Perhaps the most well-known psychedelic, LSD, was first synthesised in 1938 and, until it was banned in the 1960s, enjoyed decades of psychiatric use to treat pain, as well as a wide range of mental health problems, such as anxiety, depression and social anxiety.

Psilocybin and LSD are examples of classic psychedelics, which work through similar biological mechanisms and have similar effects on the body. Classic psychedelics primarily work through their effects on serotonin receptors in the brain. Another drug of interest to psychedelic-assisted mental health treatments, MDMA (known as ecstasy), differs from the classic psychedelics. For example, it rarely causes visual perception changes and affects dopamine and norepinephrine levels as well as serotonin levels. MDMA produces a gentler, more euphoric state than classic psychedelics; it increases feelings of empathy and bonding, relieves depression (while active) and helps users to process emotional trauma.

Psychedelic-assisted treatments have the potential to help reduce the mental health burden and lack of adequate treatment around the world. They are currently being tested as treatments for a variety of mental health problems, including depression, end-of-life anxiety and depression, post-traumatic stress disorder (PTSD), obsessive-compulsive disorder, tobacco dependence and alcohol dependence. These treatments involve the ingestion of a psychedelic substance in a safe setting, supervised by trained therapists, and are often combined with preparatory sessions in advance of treatments and integratory sessions afterwards. Integratory sessions don’t involve taking psychedelics, instead, they aim to address any problems that came up during or following treatment and to integrate learnings from the sessions into the patient’s daily life.

The psychedelic substances most commonly used for therapeutic purposes include psilocybin, LSD, DMT and MDMA.

How effective are psychedelic-assisted mental health treatments?

It’s still too early to judge with a high degree of confidence how effective these treatments are because no large studies have been carried out so far. However, initial studies of psilocybin for depression reported larger effects than existing treatments, while initial studies of MDMA-assisted psychotherapy for PTSD have found its effectiveness to be similar to existing PTSD treatments. In both cases, many patients had treatment-resistant forms of the condition – meaning they had not responded to previous treatments – but improved after the psychedelic-assisted treatment.

We should interpret these initial findings with caution. Studies in psychology and psychiatry – especially those that rely on self-reporting from participants – are often misleading. Perhaps as many as 40 percent of social science studies fail to replicate their results in large-sample, high-quality studies and those that do often see effects reduced by approximately 50 percent. Relatedly, there is evidence that large-scale replications of psychology studies tend to find significantly smaller effect sizes than meta-analyses (perhaps as much as three times smaller), which in turn find smaller effect sizes than single studies.

Overall, we think the evidence suggests that there’s a good enough chance that these psychedelic-assisted treatments are more effective than existing treatments for them to warrant further study through drug development processes. However, the evidence is still relatively sparse and we wouldn’t be surprised if these treatments turn out to be much less effective than originally claimed.

Finally, we note that psychedelics are not without risk but that controlled usage in a medical setting does not pose significant risks. Classic psychedelics are among the safest drugs we know of if used sparingly and with the right precautions, with minimal risk of physical harm or addiction. There could, however, be mental health risks for patients with a personal or family history of psychotic or bipolar disorders.

The physical safety of MDMA is not as clear as it is for classic psychedelics: there is evidence that frequent use of MDMA can cause neurotoxic damage, though this is difficult to verify due to confounding factors, and the potential for dependence on MDMA is not entirely clear. Controlled use of MDMA in a clinical setting does not pose significant risks as the purity, dose and frequency of MDMA sessions can be controlled. Outside such settings, though, use of MDMA could pose significant risks to users. There is a risk that clinical use of MDMA could prompt patients to self-medicate in unsupervised settings where the risks cannot be adequately controlled.

Funding opportunities

Within the space of psychedelic-assisted mental health treatments, we think that drug development is the most promising intervention. Drug development is a process that covers everything from the discovery of a brand-new drug to the drug being approved for medical use. Drug development is the most straightforward and potentially the only way to make psychedelic-assisted mental health treatments available at scale; it involves high-quality clinical trials that will teach us more about the benefits and costs of psychedelic-assisted mental health treatments and it will likely unlock other progress in psychedelic-assisted treatments.

Our investigation led us to recommend Usona Institute’s psilocybin drug development programme in the US as highly as our other top recommendations in the mental health and subjective wellbeing space. We also evaluated the Multidisciplinary Association for Psychedelic Studies (MAPS)'s MDMA-assisted psychotherapy drug development programme in the US, Canada and Israel, which we estimated to be similarly cost-effective. However, MAPS’ funding gap has since been filled through their successful Capstone Challenge. Following the completion of the Capstone Challenge, we evaluated MAPS’ European drug development programme. We think that the European programme presents a good funding opportunity for donors with a special interest in psychedelic-assisted mental health treatments but we judge it to be less cost-effective than Usona’s drug development programme and MAPS’ drug development programme in the US, Canada and Israel (which is now fully funded). As a result, we would recommend it only in certain circumstances.

At this point, it is important for us to emphasise the difference between evaluating funding opportunities and nonprofits. Our research conclusions do not imply that one nonprofit does more important work than another, or that a particular cause is more worthy of support than another. They instead reflect our overall view of which funding opportunities at nonprofits could currently use extra funds most effectively. In the case of this research project, our current best guess is that both MAPS and Usona are doing high-impact work. However, due to MAPS’ excellence at fundraising, they have less need for additional donations.

What’s next?

If these treatments prove effective, then we’ll be very excited to see them adopted in more countries around the world. Already, MAPS is working to bring MDMA-assisted psychotherapy to Europe and has plans to use data from the initial and European Phase 3 studies to gain approval in other countries.

More speculatively, these (or similar) treatments might prove effective for treating a range of other conditions. Of particular interest are anxiety and substance use disorders (including alcohol use disorder), due to their very large disease burden. Measuring the burden in disability-adjusted life years (DALYs), anxiety and substance use disorders account for about half of the global DALY burden due to all mental health and substance use disorders and almost twice as much as the global DALY burden due to depressive disorders. Initial studies into the use of psychedelic-assisted treatments for these conditions have been promising but the evidence here is even more speculative than for psilocybin and MDMA-assisted psychotherapy. We eagerly await further research.

For the full analysis of the effectiveness of psilocybin and MDMA-assisted psychotherapy and the full funding opportunity evaluations, see our psychedelic-assisted mental health treatments research report.