This perspective paper (2021) argues that we should supplement confirmatory trials with other data points such as pragmatic trials, real-world data, and digital health solutions to optimise the outcomes of psychedelic therapy.

Abstract

“Favourable regulatory assessments, liberal policy changes, new research centres and substantial commercial investment signal that psychedelic therapy is making a major comeback. Positive findings from modern trials are catalysing developments, but it is questionable whether current confirmatory trials are sufficient for advancing our understanding of safety and best practice. Here we suggest supplementing traditional confirmatory trials with pragmatic trials, real-world data initiatives and digital health solutions to better support the discovery of optimal and personalised treatment protocols and parameters. These recommendations are intended to help support the development of safe, effective and cost-efficient psychedelic therapy, which, given its history, is vulnerable to excesses of hype and regulation.“

Authors: Robin L. Carhart-Harris, Anne C. Wagner, Manish Agrawal, Hannes Kettner, Jerold F. Rosenbaum, Adam Gazzaley, David J. Nutt & David Erritzoe

Summary

Close to one billion people are affected by mental illness and substance misuse worldwide. Mental illness is more common, impactful and costly than other health conditions, and is a core component of overall health.

Although psychiatric medication prescription rates have increased, the prevalence of mental illness is not reducing and may well be increasing in certain populations, such as the young. There is scope for improved tolerability and access to mental health interventions.

The Research Domain Criteria (RDoC) initiative is a biological initiative that aims to translate mental illness into ‘brain illness’ for the purpose of discovering candidate brain biomarkers and treatment targets.

Initiatives towards innovation in psychological health care include efforts to improve the cost-effectiveness, access to, and reach of psychotherapy through utilisation of technological advances, social and familial networks, and third wave psychotherapeutic approaches.

Positive findings from modern trials are catalyzing developments, but more pragmatic trials, real-world data initiatives and digital health solutions are needed to advance our understanding of safety and best practice.

There is growing appreciation of the value of both psychological and neurobiological accounts of mental illness and its aetiology, and of how environment, mind, brain and body interface and interact – consistent with the ‘biopsychosocial’ model.

Psychedelic therapy is a quintessentially biopsychosocial intervention, defined by its pharmacology as agonist action at the serotonin 2A receptor. It is a particularly promising and progressive mental health care solution.

Psychedelic therapy has shown promise for treating a range of mental health conditions, including depression, end-of-life anxiety, addiction, and obsessive compulsive disorder.

Two independent multi-site double-blind randomised controlled trials have been granted breakthrough therapy status by the Food and Drug Administration, while related work is currently underway across Europe.

Psychedelic therapy has a putative transdiagnostic utility, a rapid and enduring therapeutic impact, a favourable toxicity profile, and negligible addiction potential. However, there are rare cases of putative iatrogenesis.

Psychedelic therapy’s mechanism of action may involve a drug-induced period of heightened cortical plasticity, and the ability to relax and recalibrate cognitive and behavioural biases.

Here we advocate pragmatic considerations, the utilisation of basket protocols, and digitally aided data registries to advance the science of psychedelic medicine.

Developers may be right to adhere to convention in delivering confirmatory trials, but explorative study designs may offer greater benefits.

If studies and data registries are designed with careful consideration of data quality and fitness, pragmatic research could create significant value for various different stakeholders, such as scientists, clinicians, regulators, health care systems, payers and investors.

Data registries and pragmatic trials will collect data from broad and diverse samples, and digital tools, such as cellphone apps, could be used to generate large data pools that could be mined to inform on patient screening and treatment optimisation.

Data registries annexed to legal-access psychedelic therapy or approved pragmatic research trials, or both, can serve the agenda of identifying transdiagnostic treatment targets, and the RDoC initiative pays selective attention to phenotypes associated with pathology, neglecting parameters associated with wellness.

Collecting large sample sizes will enable better prediction-of-response modelling, which will help mitigate risk and inform the potential customisation of care.

Confirmatory trials constrain important treatment parameters, whereas pragmatic psychedelic trials may exercise flexibility in these areas. This is particularly true given the nascent nature of the treatment model.

A pragmatic trial model implemented under a basket protocol could advance our understanding of psychedelic therapy. Policy changes are needed to actualise the proposed approach.

The data derived from DB-RCTs will continue to sway sceptical opinions and aid progress with regulators, but pragmatic trials may be able to teach us more about how best to deliver the treatment.

Exploration is important early-on in a learning process, and should be given consideration in the context of psychedelic therapy. This will help mitigate risks associated with a too hasty scale-up of access.

Modern psychiatry is ripe for a radical ‘new’ treatment model, and psychedelic therapy offers a multi-level paradigm-challenge. Pragmatic trials, data registries and electronic data capture will aid advances in psychedelic medicine.

Pragmatic trials, data registries and digital and biometric data collection can interface well with single-subject designs, which allow participants to serve as their own comparison over time, thus decreasing the number of participants required to determine a causal relationship between intervention and outcome.

Single-case approaches also bear relevance to ‘citizen-science’ initiatives, in which individuals are invited to increase the rigour of their ‘self-experimentation’.

There is appetite for citizen-science-type engagement among users of psychedelics, and smartphone apps can be used to collect data on self-medicative psychedelic use in a convenient and efficient way. This data could be analysed using Bayesian statistics and multi-level regression and post-stratification analyses.

A pragmatic trial of psychedelic therapy should be started now, as policy changes are already afoot and could ‘get ahead of the data’, as occurred with cannabis. Large-scale datasets from naturalistic sampling could have considerable harm reduction potential.

Policy changes on psychedelic medicine will likely have trickle down effects on research, innovation and investment in psychedelic medicine, particularly in the implicated geographical locations. Digital data collection could lessen this burden.

Mainstream, institutional-level funding has still not come into psychedelic science, and philanthropy and commercial investment are its main drivers. Innovative, pragmatic and exploratory research can help safeguard this promising, yet vulnerable, approach to mental health care.