Policy considerations that support equitable access to responsible, accountable, safe, and ethical uses of psychedelic medicines

Abstract

There is mounting evidence suggesting psychedelic and entactogen medicines (namely psilocybin and 3,4-methylenedioxymethamphetamine [MDMA]), in conjunction with proper psychosocial support, hold the potential to provide safe, rapid acting, and robust clinical improvements with durable effects. In the US, both psilocybin and MDMA have been granted Breakthrough Therapy designations by the US Food and Drug Administration and are expected to receive full FDA approval within the next couple years with similar regulatory considerations occurring in multiple countries. At the same time, regulatory changes are poised to increase access to legal or decriminalized psychedelic use in various non-medical settings. This review provides a brief discussion on the historical use of psychedelic medicines, the status of the empirical evidence, and numerous significant policy considerations that must be thoughtfully addressed regarding standards of practice, consumer protection, development of data standards, safeguarding access, and community education which supports the responsible, accountable, safe, and ethical uses of these medicines in clinical, faith-based, and other contexts. We provide suggestions for how public health and harm reduction can be supported through a public-private partnership that engages a community of stakeholders from various disciplines in the co-creation and dissemination of best practices and public policies.

1. Introduction

Mental health conditions contribute significantly to the global burden of disease, across all geographic regions, ethnicities, and ages (Whiteford, Ferrari, Degenhardt, Feigin, & Vos, 2015). The globally shared stressor of the COVID-19 pandemic and increased social, civil, and political discord has led to an onset or worsening of stress- and trauma-related symptoms for many individuals, even further heightening the level of urgency in identifying and making available effective and rapid-acting interventions. The impairment experienced by individuals with serious psychiatric illnesses (e.g., PTSD, major depression, suicidality, or opioid or alcohol use disorders) may be chronic, treatment-resistant, and ultimately fatal (Stephenson, 2021). Around the globe, treatment for these conditions is often sought in both medical and non-medical (e.g., mutual aid or faith-based) settings, although there are significant limitations in both the accessibility to and effectiveness of conventional mental health interventions, especially among individuals with chronic and complex presentations (e.g., military veterans).

This special issue of Neuropharmacology consists of a collection of articles focused on the emerging science of psychedelics. While the clinical development of psychedelic medicines will undoubtedly progress over the coming years, mounting evidence suggests that significant regulatory changes expanding non-medical access to psychedelics are also on the horizon (Feuer, 2020; Webster, 2019). Clinicians, policy makers, and regulatory bodies must prepare for the broader public use of psychedelics and consider taking steps to support the safe, ethical, accountable, and equitable uses of these drugs. Below we present a brief review of the history of psychedelic drug use; highlights from modern clinical trials data on psychedelic medicines; the importance of session facilitators; and suggestions for several regulatory structures that could be advanced through a public-private partnership focused on psychedelic drug policies that address clinical and faith-based psychedelic use. Finally, we present various considerations that may determine if equitable access to psychedelic care will be possible.

In this article, we use the word “psychedelic” as a broad umbrella term for what is a diverse category of substances with respect to their chemical structures, pharmacology, benefits, and risks (Belouin & Henningfield, 2018; Johnson, Richards, & Griffiths, 2008; Nichols, 2016). For example, lysergic acid diethylamide (LSD) and psilocybin are classic psychedelics and serotonin receptor partial agonists with notable dose-related hallucinogenic effects with relatively low rewarding properties compared to prototypic drugs of abuse (Johnson, Griffiths, Hendricks, & Henningfield, 2018). Whereas, MDMA, classified as an entactogen or empathogen, typically elicits emotional openness, demonstrates serotonin- and dopamine-releasing activity, and has greater reinforcing effects, albeit generally lower hallucinogenic properties than classic psychedelics (Mithoefer, Grob, & Brewerton, 2016). It is likely that a growing number of psychedelic organic products and synthetic substances will be used and studied in the coming years (Belouin & Henningfield, 2018).

2. Centuries of lessons learned

The introduction of psychedelics to western medicine occurred in the late 1800s. Biomedical research with psychedelics did not substantively take hold until the late 1940s, which was then followed by their widespread non-medical use during the 1960s. This non-medical use contributed to the regulatory backlash that not only prohibited broader public use of psychedelics, but it also impeded their legitimate scientific study in clinical settings (Hofmann, 2013; Nutt, King, & Nichols, 2013). Yet, far before psychedelics spread throughout western societies, they were deeply rooted in numerous indigenous cultures’ ceremonial healing practices tracing back thousands of years (Guerra-Doce, 2015). In these settings, psychedelics may be understood as sacred medicines, tools to be used with great respect (Furst, 1972). Biomedical researchers of psychedelics frequently reference the use of psychedelics in traditional settings and have at times sought to understand and appreciate the ways that psychedelics are used, and then adapt concepts learned to their clinical protocols (Dyck, 2016; Grob et al., 1996). Policy makers who aim to create well-reasoned and thoughtful regulatory policies for psychedelics may seek to do the same by seeking consultation with communities that have been the traditional stewards of these substances.

The 1971 UN Convention on Psychotropic Substances, which forms the basis of many national controlled substance laws today, allows individual nations to exempt from regulation the use of certain psychoactive drug-containing plants “which are traditionally used by certain small, clearly determined groups in magical or religious rites” (United Nations, 1971). Various countries (including Brazil, Canada, Mexico, Peru, Portugal, Spain, and the United States) have laws and regulations that permit the ritual and religious uses of psychedelic plants and their derivatives, such as peyote or ayahuasca, within certain social groups (Labate & Feeney, 2012). Despite the many differences between medical and faith-based uses of psychedelics, one common element often found in both contexts is ritual—a clear set of procedures that is reproduced, time and time again, with regards to how a psychedelic session is conducted, how facilitators are expected to act, and how participants are engaged with before, during, and after the session. In indigenous and other faith-based settings, such rituals are often informed by generations of practice in the art of carefully supporting people through psychedelic experiences.

While centuries-worth of wisdom regarding the proper uses of psychedelics has undoubtedly been generated from their uses in traditional settings, there still are important health questions that should be addressed with medical research, such as how risks change when a participant has an underlying health condition (e.g., serious mental illness or cardiac disease) or when they are taking certain concomitant medications (e.g., serotonergic antidepressants) (Bradberry, Gukasyan, & Raison, 2022; Lim, Wasywich, & Ruygrok, 2012; Malcolm & Thomas, 2021). These questions are even more urgent when considering the use of relatively novel psychedelics, like 5-methoxy-N,N-dimethyltryptamine (5-Meo-DMT), which does not have centuries-old traditions of use. One of many very important lessons about safe psychedelic use that the medical field can likely learn from traditional settings is the role of community in psychedelic integration. Community members may include individuals who facilitate sessions, people who have received psychedelic care, or friends and family members of such participants. Community members knowledgeable of psychedelics and their effects can help ensure good oversight and feedback to facilitators, provide guidance to participants seeking psychedelic care, and help report inappropriate facilitator behavior when it occurs, whether in medical or non-medical settings. How different models of psychedelic use can best incorporate community involvement as a means of promoting optimal outcomes is an empiric question that merits careful attention moving forward.

3. Thirty years of modern biomedical research

In the next couple years, the US Food and Drug Administration (FDA), the European Medicines Agency (EMA), and similar medical regulatory agencies around the world will evaluate new drug applications that would introduce MDMA, psilocybin, and related compounds to their respective prescription drug markets. Such regulatory approvals would lead to the reclassification of these controlled substances, making psychedelic medicines legally available to a large portion of the population for the first time. New controlled substance laws and policies might also make psychedelic use more prevalent through legalization or decreasing penalties for non-medical use. Much of the political momentum behind these regulatory changes stems from the progress that has been made in clinical investigations of these drugs as treatments for mood, trauma-related, and substance use disorders. Data from several phase 1 and 2 trials, and a single phase 3 trial, suggest that psychedelic drugs like MDMA, psilocybin, and LSD, when combined with psychosocial support in clinical settings, may produce rapid and clinically meaningful effects while also being relatively well-tolerated (Reiff et al., 2020). Until very recently, much of this research has been privately funded via philanthropic support. Federal funding in Australia, Brazil, Canada, the United Kingdom, the United States, and other countries is now available for academic studies of these drugs’ therapeutic potentials, and multiple companies have been founded in just the last few years with the aim of developing psychedelic therapies (Johns Hopkins Medicine, 2021; Phelps, Shah, & Lieberman, 2022).

Encouraging results have been published from four different phase 2 double-blind randomized control trials (DBRCT) of psilocybin-assisted therapy for mood and anxiety disorders (Carhart-Harris et al., 2021; Davis et al., 2021; Griffiths et al., 2016; Ross et al., 2016). Positive results were also found for MDMA-assisted therapy for severe PTSD in several phase 2 and one phase 3 DBRCT (Jerome et al., 2020; Mitchell et al., 2021). Relatively large phase 2 and 3 trials of psychedelic therapies are currently underway or in development for alcohol use disorder, major depressive disorder (MDD), treatment-resistant depression (TRD), PTSD, and other conditions (Siegel et al., 2021). To date, the US FDA has granted Breakthrough Therapy (BT) designations to MDMA for the treatment of PTSD (Multidisciplinary Assocation of Psychedelic Studies, 2017) and to psilocybin for TRD (COMPASS Pathways, 2018) and MDD (Khan, 2019). A BT designation facilitates and expedites the development and review of new drugs that have the potential to address unmet medical needs. This designation is given to medicines, which in early phases of research appear to be safe, to have limited concern for abuse, and to demonstrate substantial improvement over available therapies on clinically significant endpoints (US Food and Drug Administration, 2018).

Notwithstanding these promising clinical outcomes, accumulated safety data from clinical research and anecdotal reports from naturalistic use indicate that the use of psychedelic substances comes with potentially serious risks including medical harms (Leonard, Anderson, & Klein-Schwartz, 2018), psychiatric complications (Bender & Hellerstein, 2022), and interpersonal boundary violations (Anderson, Danforth, & Grob, 2020; Goldhill, 2020; Pilecki, Luoma, Bathje, Rhea, & Narloch, 2021). Many, though certainly not all, of these negative outcomes are reported in the context of non-medical use that lacked appropriate supervision or support.

4. Safety is in the hands of session facilitators

Many of the risks associated with psychedelics come not so much from the physiological effects of the drugs themselves, but from how and with whom they are used. Mitigating adverse outcomes due to the behavioral effects of psychedelics has long been recognized as a priority in assuring safe drug administration (Johnson et al., 2008). Beyond the training of prescribers who will provide psychedelics in medical settings, well-trained session facilitators are essential to work with participants using psychedelics in both clinical and faith-based contexts (Phelps, 2017). Facilitators anchor the integrity, safety, and ethical use of psychedelics, including during preparation, the dosing session(s), and integration, regardless of the setting. Facilitators support an unfolding and dynamic process, often aiming to accompany, and not guide, the psychedelic experience. Whether following a clinical protocol or participating in a faith-based ceremonial setting, some individuals can be expected to undergo challenging experiences while under the effects of a psychedelic. Facilitators ideally demonstrate the capacity to respond and tend to participants who then find healing through their own agency and their own inner-directed psychological work. The development of psychedelic facilitator best practice guidelines carries the complexity of engaging with regulations germane to controlled substances, the practice of medicine and professional counseling, and religious and cognitive liberties. To assure community support for, and practitioner adherence to such guidelines, a complex stakeholder engagement process is undoubtedly needed.

5. Policy development in the context of a public-private partnership

Public policies for the regulation of psychedelics entail engendering trust among multiple stakeholder groups, including those historically disenfranchised by, harmed by, or distrustful of government agencies that have enforced controlled substance laws over the past century. These policies require focus on risk mitigation, harm reduction, and safety monitoring strategies that can meaningfully be implemented amidst the regulatory structures being proposed for legal psychedelic use. In the case of the USA, establishing an interagency federal task force and public-private partnership would leverage the capabilities of governmental agencies and the contributions from a consortium of stakeholders from civil society that advances and informs these efforts. Such a public-private partnership would facilitate collaboration across an array of interests and communities so that large-scale consensus driven actions can be informed by democratic processes that are acceptable to a broad set of constituents. Whether in the US or other parts of the world, a public-private partnership would ideally include: federal/national departments and agencies; state and regional government officials engaged in implementing public policies; representatives of indigenous communities that traditionally use psychedelic substances in their healing practices; academic researchers; representatives from secular and faith-based groups of psychedelic practitioners; representatives of non-governmental organizations and patient coalitions (e.g., veterans, end of life, and addictions); for-profit and non-profit sponsors of drug development; and international regulatory partners (e.g., the UN Office of Drug Control and Policies and the World Health Organization). Such a consortium leverages stakeholder subject matter expertise to address the numerous complex safety, ethical, and regulatory issues, and to operationalize scalable cohesive real-world solutions.

The primary objectives of a public-private partnership include published guidelines that promote best practice standards for harm reduction, risk mitigation, safety monitoring and benefit maximization, as well as forms of recourse for individuals when harms are inevitably experienced by some. These standards must derive from actual practices already developed over time by experienced practitioners and be further informed by a critical assessment of the pertinent peer-reviewed evidence. As with any professional practice, protection from criminal and civil legal liability could serve as an incentive to practitioners for following these communally-generated guidelines. Operationalizing accountable, safe, and ethical use frameworks that mitigate risks elevates the use of psychedelic substances from below-ground to a transparent above-ground space, thereby protecting public health and offering a path to legal protection for conscientious practitioners.

Multiple regulatory mechanisms and structures can be effectively developed through a public-private partnership. Medical product regulators benefit from engagement with stakeholder experts in the crafting of both drug product labels and guidance for industry documents that shape the future of psychedelic regulatory science. Regulatory programs, such as the US FDA’s Risk Evaluation and Mitigation Strategy (REMS) programs may be desired, which at first, may limit patient populations psychedelic medicines can be prescribed (US Food and Drug Administration, 2021). Despite their inherent restrictive nature, REMS programs are adaptable and have inbuilt mechanisms intended to prevent them from being “unduly burdensome on patient access to the drug” (Barlas, 2016; United States Code, 2022). Notably in the case of controlled substances, the US FDA has been able to structure REMS for both medication-assisted treatment (MAT) using buprenorphine for opioid use disorder (OUD) and intranasal esketamine for TRD. Both REMS require that patients who are administered these controlled substances also receive counseling by specially trained staff.¹ For countries that do not use REMS-like programs, other control mechanisms may be available to assure a gradual rollout of these medicines in a manner that allows the prescriber community time to learn from, and improve upon, its use in clinical settings.

Public health can be protected in the case of both medical and non-medical contexts if safe drug supplies can be assured, and diversion can be prevented through adequate monitoring (US Drug Enforcement Administration, 2022). Regulators can learn from countries with experience overseeing the distribution of non-psychedelic controlled substances, like cannabis, through dispensaries or other facilities that serve as an alternative to conventional pharmacies (Government of Canada, 2022) and yet are still subject to regulations meant to protect public safety.

Coordinated Registry Networks (CRNs) are proven effective mechanisms for amassing real-world evidence (RWE) that support expanded medical product safety evaluation (Pappas et al., 2019). CRNs are a mechanism for fulfilling many medical safety requirements in the post-approval period. Through the accumulation of real-world safety data, a CRN can potentially support the expansion of allowable clinical indications. Importantly, CRNs can potentially capture data from compassionate use cases that will shed light on a drug’s effects in patients with serious medical illness, who, because of their complicated health status, may be unfit for enrolling in clinical trials (US Food and Drug Administration, 2017). Prescription drug monitoring programs (PDMPs) and nationally representative surveys like the US National Survey on Drug Use and Health (NSDUH) allow for the capture of population-level data on the use of controlled substances, and they can provide healthcare providers and public health authorities with timely information about emerging trends in prescribing and patient behaviors that could lead to harms from drug use. The data compiled can help identify the extent of substance use and mental illness among different subgroups, estimate trends over time, and aid in determining the need for treatment services (Substance Abuse and Mental Health Services Administration, 2022).

The predicted wide-spread use of psychedelic substances necessitates pharmacovigilance (US Food and Drug Administration, 2005) as a cornerstone of good safety monitoring. Individuals experiencing psychedelic therapies should be aware of the potential for adverse events and be able to report them. Pharmacovigilance reporting improves the safety of psychedelic drug use with expedited reporting, aggregation of data, and identifying potential safety signals that can collectively inform public health responses. Likewise, knowing that individuals can become highly vulnerable during psychedelic sessions, stakeholders also need to consider ethical vigilance reporting, meaning the reporting of professional and interpersonal violations so that these can be appropriately investigated, and the violators held accountable for their actions. The emergence of regulated and sanctioned forms of psychedelic use will ideally allow for open dialogue of various safety concerns, thereby avoiding the further perpetuation of stigma and secrecy around use that denies the public transparent reporting of harms and ethical abuses when victims fear recrimination for coming forward.

Public education about psychedelics and their effects must be transparent, collaboratively curated, and comprehensive - touching on psychedelics’ potential benefits, limitations, risks, as well as useful strategies for mitigating harm. Public education on psychedelics must be responsive to the questions that are emerging from communities of users and potential users, as well as informed by an evidence base that is objectively assessed and widely disseminated by individuals with scientific, clinical, and practical expertise in the use of these substances. Public education that leads to improved social and self-regulation of psychedelic use is perhaps the most potent public offering that could come from a public-private partnership created to address the public health impacts from the growing psychedelic movement.

6. Scaling-up quality care while prioritizing equitable access

Stakeholders representing multiple communities and perspectives influence key policy decisions and impact equity and access to psychedelics. Safe and effective forms of psychedelic care require considerable personnel effort, societal infrastructure, and time. Key questions for consideration:

• How should psychedelic providers best engage with insurance and other healthcare payer programs to cover these costs in medical settings?

• What constitutes the essential educational background and supervision requirements for session facilitators?

• How can different practitioner disciplines collaborate in providing these therapies to maximize affordability and accessibility?

• Can formal partnerships be established between medical and non-medical settings to capitalize on the strengths each has to offer?

The potential outsized public demand for psychedelic care points to the need for practitioners across medical, counseling, faith-based, and peer-support disciplines to serve as facilitators. With time, the demand is projected to grow for experienced facilitators not only to provide care, but to educate and supervise future generations of facilitators. Institutions of higher education are positioned to coordinate with state and national boards in the creation of interdisciplinary training, credentialing, and licensing programs. While possibly cost-effective in the long-term (Marseille, Kahn, Yazar-Klosinski, & Doblin, 2020), providing psychedelic therapies may come with significant up-front costs. More regulatory requirements will contribute to greater costs for practitioners, and eventually participants. If the expense of these therapies is such that only affluent communities or those with generous insurance plans have access, then the disadvantaged and underserved communities who may most need access to these potentially highly effective interventions are shortchanged. An effective public-private partnership of stakeholders addresses, and ideally prevents the perpetuation of, disparities in health and well-being that too often are based on income, age, gender, race/ethnicity, sexual orientation, and disabilities.

Faith-based and other non-medical models have been proposed as a means of limiting costs while increasing access to psychedelic care. However, even highly trained psychedelic facilitators who work in non-medical contexts will encounter situations where the safety of their participants would benefit from consultation with licensed healthcare personnel. Knowing when such consultation is indicated, or how to access urgently needed medical care, may not be readily apparent to many non-medically trained psychedelic facilitators. Without the proper attention to health and safety, the personal and financial consequences of psychedelic use gone awry (in any setting) could be costly to society. Importantly, many structures already exist for professional training, accountability, and self-regulation within non-medical, faith-based settings (Board of Chaplaincy Certification Inc., 2022). It should be noted, unlicensed, faith-based practice with psychedelics is not necessarily unregulated practice.

Public policies that proactively recognize the need for engaging with faith-based and other non-medical psychedelic practitioners can be prepared to handle petitions for exemptions from the controlled substance laws (Dennis, 2022). While faith-based exemptions involving psychedelics should not be used as mere convenient detours around regulations meant to protect public health, governing bodies can nevertheless take as seriously requests for faith-based exemptions involving psychedelics as they do faith-based exemptions not involving psychedelics. How these situations are ultimately decided depends on religious freedom statues, which vary from country to country.

Finally, the implications of patents and other intellectual property protections for the psychedelics field require close examination (Gerber et al., 2021). Decades of research with psychedelics have led to thousands of peer-reviewed publications documenting how psychedelic medicines have been used to heal and explore the human psyche, both in medical contexts and, long before that, in indigenous traditional practices. The way that scientific knowledge of psychedelics has openly been shared among academic researchers who were financially supported by both philanthropy and government resources has led to the resurgence of psychedelic science today (Council on Spiritual Practices, 2021). Patents that are granted and enforced for intellectual property claims tied to tried-and-true procedures, rituals, and forms of care commonly used with psychedelic medicines, may have far-reaching legal ramifications including infringing on the practice of medicine, constitutionally protected faith-based traditions, scientific research, and, most importantly, potentially impeding affordable access to these medicines (Love, 2021).

7. Summary

This is a unique historical moment in mental health, exacerbated by a global pandemic, with momentum toward FDA and EMA approvals for two psychedelic therapies, and various locations that are decriminalizing or legalizing non-medical psychedelic use by adults. The use of psychedelics may soon be far more prevalent than it is today. Regarding strategic public policy, this is a rare opportunity for a “do-over” – a second chance, to learn from the past and avoid repeating the mistakes that ultimately derailed more than two generations’ worth of biomedical research on psychedelic medicines. The current science establishes that psychedelic substances are powerful tools with significant potential for alleviating human suffering. While the data indicate that psychedelics are largely safe and well-tolerated when used in appropriate settings, these drugs do nevertheless come with potential for serious risks. With cooperative stakeholder engagement and respectful, interdisciplinary teamwork, a short window of opportunity opens for the creation of both medical and non-medical frameworks that assure safe, ethical, accountable, and equitable access to psychedelic medicines and assisted therapies.

Highlights.

• Psychedelics carry notable promise and risk when used as mental health therapies;

• Public education and facilitator training are essential for risk mitigation;

• Public policies must prioritize harm reduction and best practices;

• Successful scaling up of psychedelic therapies requires equitable access.