Advancing Psychedelic-Assisted Therapy in Missouri (MO-PAT): Innovation at the Speed of Safety

Abstract

The United States is facing a growing behavioral health crisis. Now more than ever, novel, safe and effective treatments are needed. Over the past decade, clinical trials of psychedelic-assisted psychotherapies (PAT) have shown promising results for treating a number of common behavioral health conditions with minimal adverse effects. This article provides a brief historical and sociopolitical context surrounding PAT, discusses unanswered questions related to the safety and quality of PAT, and charts a pathway forward through the complex policy, legal, and social barriers to uptake for the state of Missouri in its consideration of PAT as a behavioral health treatment. With careful consideration and proper infrastructure, PAT could represent a paradigm shift in how the field approaches the prevention, treatment, and potential recovery of behavioral health conditions. We outline how Missouri can be at the forefront of advancing the science and practice of PAT – cautiously.

Introduction

After decades of nearly dormant research due to federal restrictions, psychedelics (e.g., psilocybin) are returning to mainstream culture as medicines that hold promise to provide fast-acting and sustained relief from common but debilitating behavioral health conditions like depression, substance use disorders, eating disorders, anxiety and psychological distress associated with life-threatening illnesses (e.g., cancer), and post-traumatic stress disorder (PTSD) when paired with psychotherapy.^1–5 In a field where modest medication efficacy is the rule, greater efficacy is often at the cost of tolerability, and where few people achieve remission or lasting treatment effects, safe and effective treatment innovations such as psychedelic-assisted psychotherapy (PAT) are necessary.⁶

The resurgence of psychedelic research comes at a time when the United States is faced with a growing behavioral health crisis. Demand for behavioral health services has soared in recent years and has been further exacerbated by the COVID-19 pandemic, which has been associated with increased depression and anxiety symptoms.⁷ Overdose deaths and deaths by suicide in the United States are at record highs.^8,9 Despite the urgent need for fast-acting, long-lasting, effective behavioral health treatments, limited access to the available treatment options remains a persistent problem.¹⁰ The longstanding workforce shortage has been exacerbated by poor reimbursement rates, chronic underfunding of the behavioral health system, low compensation, and poor working conditions for clinicians,¹¹ and is projected to worsen given the current unmet need and continued increase in demand.¹²

The purpose of this article is to provide a brief historical and sociopolitical context surrounding PAT, discuss unanswered questions related to the safety and quality of PAT, and chart a pathway forward through the complex policy, legal, and social barriers to uptake for the state of Missouri in its consideration of PAT as a behavioral health treatment. As the behavioral health crisis worsens and PAT continues to show promise in clinical trials and real-world experiments such as those in Oregon, increasing access to PAT should be at the top of key stakeholders’ minds.¹³ Missouri is at an advantage: we have major research universities at the forefront of studying psychedelics, state lawmakers sponsoring legislation to increase access to PAT for veterans, and we can learn lessons from state legalization and decriminalization of psychedelics for medicinal purposes prior to federal rescheduling and approval by the U.S. Food and Drug Administration (FDA) approval.

History and Sociopolitical Context

While definitions of what constitutes a ‘psychedelic’ molecule may vary, they generally include ‘synthetic drugs (e.g., Lysergic acid diethylamide [LSD]),’ and naturally occurring ‘botanical’ compounds (e.g., psilocybin, Figure 1). When ingested, these psychoactive compounds can lead to altered states of perception and consciousness, changes in cognition, heightened emotion, and increased self-awareness.¹⁴ PAT is often described as a mystical and transformative experience in which the individual may undergo changes in consciousness, confront challenging and suppressed emotions, process and reframe difficult feelings, and find a renewed meaning.¹⁴ Classic psychedelics (N, N-Dimethyltryptamine (DMT), lysergic acid diethylamide LSD, and psilocybin) are hypothesized to exert these effects as 5-hydroxytryptamine (5-HT)^2A receptor agonists.¹⁵

Figure 1.

Synthetic and Naturally Derived Psychoactive Substances with Psychedelic Properties.

Naturally occurring psychedelic compounds such as psilocybin have been used for spiritual ceremonies (as a means of healing, gaining spiritual insights, facilitating life transitions) and in other traditional rites in some indigenous groups for millennia.¹⁶ Beginning in the early 1900s, synthetic psychedelics such as 3,4-Methylenedioxy methamphetamine (MDMA), LSD, and ketamine were synthesized, and eventually, their medicinal properties were tested. In the 1950s and 60s, hundreds of research studies of varying quality were conducted on naturally occurring and synthetic psychedelics, especially LSD, documenting the unique ability of these compounds to aid in treating a variety of behavioral health disorders.¹⁷

However, the recreational use of psychedelics in the 1960s helped to shepherd in the counterculture, where influential social figures like Dr. Timothy Leary encouraged young people to “turn on, tune in, and drop out” of society, seen by many as an existential threat to prevailing social norms at the time.¹⁸ Under the Controlled Substance Act of 1970, psychedelics were categorized as Schedule I drugs, the most restrictive class of drugs considered to have ‘no accepted medical use,’ and research on psychedelics was halted for decades.¹⁹

Although federal research stalled, the ‘psychedelic renaissance’ is now upon us. The use of psychedelics is shifting from counterculture to mainstream with a heightened focus on their healing benefits. The FDA has acknowledged the therapeutic potential of psychedelic drugs. For example, in 2017 MDMA-assisted therapy received breakthrough therapy designation for the treatment of PTSD, and in 2018 and 2019, psilocybin-assisted therapy received breakthrough designation for treatment-resistant depression (TRD) and major depressive disorder (MDD), respectively.²⁰ In March of 2024, LSD received breakthrough designation for the treatment of generalized anxiety disorder.⁸ Although FDA does not regulate or comment on efficacy of behavioral therapies, psychedelic treatments uniquely work to rapidly promote nerve cell growth, differentiation, and connectivity, a process broadly referred to as ‘neuroplasticity.’ The rapid onset necessitates careful attention to both the mental and physical contexts (‘set and setting’) immediately surrounding exposure to psychedelic drugs to optimize the effects of the drugs for healing, as well as to promote safety. In August of 2024, the FDA rejected MDMA as a treatment for PTSD, requiring that the industry sponsor, Lykos, conduct more research, in turn setting back the approval timeline for this medicine.²¹ Psilocybin-assisted therapy is anticipated to be reviewed in 2026. Increasing access to PAT for individuals with behavioral health conditions, especially veterans, has garnered bipartisan support. However, even with legislative reform at the state level, until rescheduling occurs, PAT remains illegal at the federal level.

Over the past decade, clinical trials of PAT have shown promising results for treating behavioral health conditions and symptoms beyond PTSD, MDD, and TRD; these include anxiety associated with life-threatening illnesses (e.g., cancer), chronic pain syndromes, eating disorders, and substance use disorders.^2,22–25 A meta-analysis on the safety of psychedelics in a supervised medical context found nine serious adverse events were reported (i.e., acute transient anxiety and delusions) for more than 1,000 administrations of psychedelic substances, and the majority of side effects (e.g., nausea, headaches, increased heart rate and blood pressure) were moderate and occurred only in the hours following intake.²⁶

Despite the potential benefits and relatively safe risk profile of psychedelics for the treatment of behavioral health conditions, there remain several challenges and unanswered questions related to biological and psychological mechanisms of action, risks, safety, tolerability, short and long-term effectiveness, dose-response relationship, identification of populations that would benefit most, legality, implementation (administration, cost/reimbursement, equitable access), and policy (Figure 2). Addressing these questions now is especially important as the FDA contemplates approval of the use of PAT before federal legalization and several states (Oregon and Colorado) have approved the use of PAT for medicinal purposes.

Figure 2.

Outstanding Research Questions in Psychedelic-Assisted Therapy (PAT).

Missouri Call to Action

We are at a critical crossroads to harness the potential of PAT to alleviate suffering in often hard-to-treat, disabling behavioral health conditions. The increasing commercial availability and direct-to-consumer marketing of psychedelic products (e.g., ketamine) juxtaposed with the long and costly process of conducting large clinical trials for FDA approval creates a complex and rapidly evolving legal and regulatory landscape that will be difficult for clinicians and patients to safely navigate, especially when we are experiencing a protracted behavioral health crisis. Stories of the profound and rapid transformational effects of psychedelics, for those who are suffering and cannot access appropriate care, offer a seductive beacon of hope. However, stories of significant harm when psychedelics are ingested without the proper medical supervision and therapeutic support can literally be life-threatening. These stories highlight the potential for significant dangers and underscore the urgency of identifying solutions for overcoming implementation challenges and addressing unanswered questions related to the use of psychedelics for the treatment of behavioral health conditions. With PAT, we face an incredible opportunity to re-imagine behavioral health service delivery—with careful consideration and proper infrastructure, it could represent a paradigm shift in how the field approaches the prevention, treatment, and potential recovery of behavioral health conditions.²⁷ Missouri has the opportunity to be at the forefront of advancing the science and practice of PAT —cautiously.

What is needed is a coordinated effort to adopt and scale PAT for marginalized populations in Missouri. In Figure 3, we provide a roadmap that gives an iterative framework for the development and implementation of PAT in Missouri. A variety of inputs exist to ground this work. First, we must begin by acknowledging and respecting the historical knowledge, indigenous wisdom, and practical experience with medicinal use of naturally-occurring psychedelics since antiquity.^28,29 Scientific exploration of PAT evolved slowly following the introduction of the Controlled Substances Act in the 1970s and 80s, but has exploded in the past three decades, building a robust literature that should be expanded to now generate and test hypotheses regarding safety, quality, and equity (Figure 2). We can learn from implementation experiences in Oregon, California and Colorado, where psychedelics have been decriminalized or legalized for medical use. Next, we must look to innovation to generate tools and solutions that can be used to address remaining gaps in knowledge, using rigorous methodologies such as precision clinical trials and hybrid effectiveness/implementation studies to discover, test, refine, and implement PAT.^30,31 Finally, the outputs of this work should address three key components: access (ensuring that those who need and want treatment can get it in a timely and affordable manner), equity (ensuring that those who need it the most get it first), and quality (ensuring that PAT achieves its intended outcomes of improving participants quality of life and reduced symptomology). To achieve these goals, we recommend the use of 1) personalized clinical care and 2) implementation strategies to support the uptake, implementation, and sustainability of PAT in routine clinical practice [Adams DR, Allen H, Nicol GE, Cabassa LJ. Moving psychedelic-assisted therapies from promising research into routine clinical practice: Lessons from the field of implementation science. Translational Behavioral Medicine. 2024 Oct 17:ibae053]. Throughout each of these stages, the processes will be impacted by culture and society at large (e.g., the destigmatization of psychedelics), ethics and law (e.g., state and federal level regulations related to PAT), as well as advancements in science and medicine (e.g., advances in science catalyze new treatment paradigms or research methodologies).

Figure 3.

Knowledge, Experience & Iterative Innovation for PAT Implementation in Missouri.

Missouri has long been at the forefront of psychedelics research. For example, the Department of Psychiatry at Washington University (WashU) School of Medicine in St. Louis conducted one of the first clinical trials of LSD in the early 1950s.³² In that study, LSD was given to a total of 29 patients, mostly those hospitalized with psychosis or mania. The investigators observed that following their LSD exposure:

“…some of the patients were then able to re-evaluate the emotional meaning of some of their symptoms and improved. Most were better able to organize their ideas in relation to real rather than fancied problems and were seen to experience and express relevant emotion. Two of the patients [both psychoneurotic] … were improved sufficiently to discontinue treatment.” ³³

In 2023 WashU Medicine completed the first modern clinical trial of psilocybin in humans in the state of Missouri since the 1950s, using precision functional brain mapping, a neuroimaging approach pioneered by WashU researchers.³⁴ In the study, a single 25 mg dose of psilocybin caused global desynchronization of the connections between brain networks in healthy volunteers. Though network synchronization reestablished itself over a period of a few hours or days, small differences in the brain’s connections between the default mode network and other brain networks persisted for weeks, indicating there may be a window of optimal neuroplasticity that can be harnessed for targeted transformational psychotherapeutic healing.³⁴

Now, WashU is home to the Center for Holistic, Interdisciplinary Research in Psychedelics (CHIRP), a Transcend Initiative supported by WashU’s Here & Next Strategic Plan.³⁵ In addition to supporting university-wide, translational pilot research projects, the Center, jointly led by the Department of Psychiatry and the Brown School of Social Work, also incorporates private-public collaboration through the conduct of clinical trials for FDA approval of psilocybin for MDD and TRD, and community-based participatory research methods in planning the next phase of effectiveness and implementation research with psychedelics.

The medicinal use of psychedelics is gaining popularity among the Missouri veteran community, and bipartisan bills legalizing compounds like psilocybin are being proposed in the state. The veteran suicide rate in Missouri is significantly higher than the national rate,³⁶ and Missouri politicians of all political affiliations are taking note. In 2022, Missouri lawmakers began an effort to pass legislation related to making psilocybin available to veterans in research settings, though bills were struck down in 2022 and 2023. A 2024 Missouri House Bill 1830 and Senate Bill 768 led by Republicans would have allowed military veterans who are at least 21 years old and are diagnosed with a qualifying condition such as PTSD or substance use disorders to access laboratory-tested psilocybin in a research setting legally, but the House Bill ultimately died in the chamber.^37,38 Meanwhile, a separate budget proposal that would spend $10 million from state opioid settlement funds to study the use of psilocybin to treat opioid use disorder passed the full House but was ultimately cut in the Senate committee.³⁹ While there has been no formal legislation passed in Missouri related to the use of psychedelics for behavioral health treatment, it is encouraging to see Missouri lawmakers spearheading the effort to increase the availability of these treatments for veterans.

Missouri is in an advantageous position to learn about implementation processes from states that have already begun the process of decriminalizing the therapeutic use of and legalizing psilocybin. In 2020, Oregon became the first state to legalize and decriminalize the use of psilocybin through regulated service centers.¹³ Oregon Psilocybin Services, housed within the Oregon Health Authority Public Health Division’s Center for Health Protection directs the Oregon Health Authority to license and regulate the manufacturing, transportation, delivery, sale, and purchase of psilocybin products and the delivery of psilocybin services.⁴⁰ An Advisory Board comprised of experts across disciplines was appointed in 2021 to make recommendations on the requirements, specifications, and guidelines for licensing, regulating and providing psilocybin services in Oregon.⁴¹ Colorado, which passed a law decriminalizing and legalizing psilocybin, ibogaine, mescaline, and DMT for medicinal uses, is also on the verge of creating state-licensed “healing centers” where individuals can pay for a supervised PAT experience.⁴² Other states, such as Maryland, Utah, Alaska, and Minnesota have passed legislation to create a task force to study and advise on legalizing certain psychedelic substances in the use of behavioral health treatments.³⁸

Missouri would also benefit from the creation of a task force as a first step to engage necessary stakeholders. This task force, composed of key stakeholders including experts in behavioral health intervention development and testing, behavioral health services delivery, health equity research, large-scale multisite clinical effectiveness trials, implementation science, and policy, as well as representatives from indigenous communities, community providers (e.g., social workers, primary care physicians, psychiatrists, etc.), regulatory leaders, policymakers, representatives from advocacy organizations, and patients and caregivers with lived experiences of behavioral health conditions and psychedelic use, would be responsible for advising on policies for access, use, and conduct of research. Academic leaders are well positioned to effectively lead this type of task force as they are responsible for upholding the scientific integrity of PAT. Community-based participatory research principles and ethical principles that honor and are informed by indigenous medicine traditions should be infused throughout to integrate stakeholders’ perspectives and wisdom, ensure equity and access, and inform implementation strategies.^43,44

Missouri will also need to establish monitoring programs to track outcomes relevant to public safety, such as drug diversion and crimes related to illicit distribution, and public health concerns, such as exposures during pregnancy and ingestion by minors. Any FDA approval for the clinical use of psychedelics will almost certainly require risk evaluation mitigation strategy (REMS), a program that monitors medications with a high potential for serious adverse effects.⁴⁵

To proactively facilitate the safe and effective implementation of PAT for Missourians, it is paramount to develop the infrastructure and stakeholder partnerships necessary to support the accessibility and quality of this promising new treatment. Further, throughout the regulatory and legislative process, PAT stakeholders must prioritize equity, centering the voices of Black, Brown, and Indigenous communities that have been impacted by the devastating “War on Drugs” era. A cohesive, community-engaged, and comprehensive approach will help to shape policy and regulations and ensure safe and equitable implementation of PAT in real-world settings throughout Missouri.