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Introduction and Background¹

Psychiatric illnesses—such as major depressive disorder, anxiety disorder, substance use disorder, and posttraumatic stress disorder (PTSD)—are widely prevalent and represent a substantial health burden worldwide (GBD 2019 Mental Disorders Collaborators, 2022). According to the National Alliance on Mental Illness (NAMI), nearly one in five Americans live with a diagnosed mental illness.² Yet, conventional medications for mental illnesses often fail to relieve patients of disruptive and disabling symptoms.

It has long been known that the classic psychedelics (namely, lysergic acid diethylamide [LSD] and psilocybin) and entactogens (namely, 3,4-methylenedioxymethamphetamine [MDMA])³ can facilitate profound and

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¹ The planning committee’s role was limited to planning the workshop, and the Proceedings of a Workshop was prepared by the workshop rapporteurs as a factual summary of what occurred at the workshop. Statements, recommendations, and opinions expressed are those of individual presenters and participants; have not been endorsed or verified by the Health and Medicine Division of the National Academies of Sciences, Engineering, and Medicine; and should not be construed as reflecting any group consensus.

² To learn more about the prevalence of mental illness and the National Alliance on Mental Illness, see https://www.nami.org/mhstats (accessed June 12, 2022).

³ In these proceedings, the term “psychedelics” refers to hallucination-inducing drugs with a mechanism of action that is thought to be primarily mediated through 5HT receptor agonism. These so-called serotonergic hallucinogens induce an altered state of consciousness characterized by profound alterations in mood, thought process, and perception (De Gregorio et al., 2021a; Vollenweider and Kometer, 2010). This pharmacological category is also referred to as the “classic psychedelics.” The term “entactogens” (sometimes referred to as “empathogens,” but with “entactogens” predominating in usage) refers to a pharmacological class of drug that induces feelings of empathy, connectedness, and well-being through a mechanism of action involving carrier-mediated serotonin release from neuronal stores. This drug class includes 3,4-methylenedioxymethamphetamine (MDMA) and other substances with a similar psychopharmacological effect (Kyzar et al., 2017; Vollenweider, 2001).

persistent changes in cognitive, sensory, and psychoemotional states (Rucker et al., 2022). However, existing and emerging evidence suggesting that these substances may also be useful as tools to alleviate mental illness has sparked a renaissance of interest by investigators, clinicians, drug developers, and patient advocates in recent years. In response to this renewed interest, the National Academies of Sciences, Engineering, and Medicine’s Forum on Neuroscience and Nervous System Disorders (Neuroscience Forum) convened a workshop on March 29 and 30, 2022, to explore the use of psychedelics and entactogens as treatments for psychiatric disorders.⁴

“There’s such tremendous excitement about these agents and their potential to represent a paradigm shift in psychiatric therapeutics, in which we have the hope of rapidly acting and long-lasting treatments,” said Sarah H. “Holly” Lisanby, director of translational research at the National Institute of Mental Health (NIMH), and professor emeritus of psychiatry at Duke University.

While optimism about the use of psychedelics and entactogens is warranted by the data available, Gerard Sanacora, Gross Professor of Psychiatry at the Yale University School of Medicine and workshop co-chair, said this optimism must be balanced with concerns about the complexity, ethics, licensing, regulatory oversight, public health, and health equity. “We still have a long way to go,” he said, cautioning against letting the excitement surrounding potential clinical benefits get too far ahead of actual clinical efficacy and safety data. He added that the anecdotal reports of clinical benefit and the limited clinical trials that have been completed have “spurred a tremendous [number] of back-translational efforts to further understand the potential mechanisms of action.”

THE NATIONAL INSTITUTES OF HEALTH EXAMINES RESEARCH OPPORTUNITIES AND GAPS

A surge in scientific and public interest in the therapeutic potential of psychedelics prompted the National Institutes of Health (NIH) to convene a workshop⁵ in January 2022 to examine the challenges, opportunities, and research gaps that need to be addressed to advance this therapeutic

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⁴ To learn more about the workshop, go to https://www.nationalacademies.org/event/03-29-2022/exploring-psychedelics-and-entactogens-as-treatments-for-psychiatric-disorders-a-workshop (accessed June 22, 2022).

⁵ For information on the NIH Workshop on Psychedelics as Therapeutics: Gaps, Challenges and Opportunities, see https://nida.nih.gov/news-events/meetings-events/2022/01/nih-workshop-psychedelics-therapeutics-gaps-challenges-opportunities (accessed July 6, 2022).

paradigm, said Nora Volkow, director of the National Institute on Drug Abuse (NIDA). As shown in Figure 1-1, both clinical trials and non-clinical research studies have accelerated rapidly over the past two decades, particularly in the past 5 years. However, Volkow noted that most clinical trials have small sample sizes and are non-randomized.

Volkow added that the recreational use of hallucinogen-inducing drugs among college-age adults also increased between 2019 and 2020 (Schulenberg et al., 2021), which she attributed both to increased media attention and the stress of the COVID-19 pandemic.

The NIH workshop addressed the need for better categorization of psychedelic drugs,⁶ including the classic psychedelics (namely, LSD and

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⁶ There are ongoing discussions in the field about when to use the term “psychedelic.” The designation has meant different things since coined in the late 1950s. In this 2022 NIH Workshop, “psychedelics” was used in an inclusive umbrella fashion to refer collectively to the classic psychedelics (e.g., LSD and psilocybin), dissociative anesthetics (e.g., ketamine and PCP), and entactogens (e.g., MDMA). In contrast, this workshop proceedings designates “psychedelics” as the classic psychedelics (serotonergic hallucinogenic drugs), and treats dissociative anesthetics and entactogens as distinct pharmacological categories with overlapping effects on behavior and mind. For more information, see https://www.nimh.nih.gov/news/events/2022/psychedelics-as-therapeutics-gaps-challenges-and-opportunities (accessed June 12, 2022).

psilocybin), dissociative anesthetics such as ketamine and phencyclidine (PCP or “angel dust”), and entactogens such as MDMA. Volkow suggested that clustering drugs according to their molecular targets and mechanisms of action, rather than by the highly variable subjective experiences of people taking these substances, will facilitate advances in research, clearer communication, and ultimately a shared understanding of psychedelic drugs and their effects, both positive and negative. The role of neuroplasticity in psychedelic therapy was discussed extensively at the workshop, including in animal models where neuroplasticity changes have been linked with therapeutic effects, enabling the ability to potentially tailor interventions to maximize effects. In addition, the apparent low toxicity and low addiction liability of these drugs, although not across all classes (e.g., Johnson et al., 2018), was another topic of discussion. Some of the drugs like ibogaine (a non-classical psychedelic with dissociative effects) block cardiac calcium channels in the heart, potentially leading to cardiotoxicity (Corkey, 2018). In addition, recreational MDMA use has been associated with subclinical heart valve disease (Droogmans et al., 2007). Although rare, in certain instances, recreational use of these drugs can lead to adverse outcomes like overdose or suicidality. As it relates to addiction liability, “they can lead to repeated misuse and negative consequences, but this is distinct from the enhanced motivational drive that you see with the classical addictive drugs,” said Volkow.

Characteristics of psychedelics such as neuroplasticity changes, low toxicity, and addiction liability suggest potential therapeutic benefits for depression and several other psychiatric disorders, including PTSD, obsessive-compulsive disorder (OCD), anorexia, autism spectrum disorder in adults, and substance use disorders. However, Volkow noted that major knowledge gaps exist related to safety, efficacy, dosing regimens, and concomitant therapies. While some evidence suggests that a greater mystical experience during psychedelics therapy correlates with higher efficacy (e.g., Griffiths et al., 2016), further investigation is needed, she said.

Sessions at the NIH workshop also focused on the challenges of conducting clinical trials and the need for objective surrogate outcome measures, as well as translation of the controlled conditions of psychedelic trials into real-world practice, said Volkow. Harmonized protocols for trials, including common inclusion criteria and methods for characterizing participants, are needed so that studies can be compared with one another, she said. Longer follow-up studies are needed to better understand long-term benefits and risks of psychedelic therapies. In addition, for therapies that demonstrate efficacy in clinical trials, a risk evaluation and mitigation strategy (REMS) will be needed to maximize the benefits and minimize the adverse effects of these therapies, said Volkow. Other outstanding questions discussed included who will pay for these trials and how to ensure that

diverse populations have access to the research and any new treatments that emerge from it, she said.

WORKSHOP OBJECTIVES

The goals of this workshop are to follow up on the January 2022 NIH workshop to develop a deeper understanding of both the promise and the pitfalls of these agents, and the potential next steps that might be taken to realize their therapeutic potential, said Lisanby (see Box 1-1). The therapeutic benefits of ketamine, a dissociative anesthetic with psychedelic properties, was discussed in a prior National Academies workshop proceedings, and was therefore not addressed again here.⁷

ORGANIZATION OF THE PROCEEDINGS

Recognizing the ongoing debate in the field regarding nomenclature, for the purposes of this workshop and proceedings, “psychedelics” is used to refer to hallucination-inducing drugs with a mechanism of action that is thought to be primarily mediated through 5HT receptor agonism. These so-called serotonergic hallucinogens are substances that induce an altered state of consciousness that is characterized by profound alterations in mood, thought process, and perception (De Gregorio et al., 2021a; Vollenweider and Kometer, 2010). This pharmacological category is also referred to as the “classic psychedelics.” The term “entactogens” (sometimes referred to as “empathogens,” but with “entactogens” predominating in usage) refers to a pharmacological class of drug that induces feelings of empathy, connectedness, and well-being through a mechanism of action involving carrier-mediated serotonin release from neuronal stores. This drug class includes 3,4-methylenedioxymethamphetamine (MDMA) and other substances with a similar psychopharmacological effect (Kyzar et al., 2017; Vollenweider, 2001) psychoactive drugs that induce feelings of empathy and/or a desire for contact with others (Vollenweider, 2001).

Chapter 2 discusses the history of the use of psychedelics and entactogens (i.e., MDMA) for the treatment of psychiatric disorders from more than 7,000 years ago to the present time, including the personal experiences of two individuals who participated in clinical trials. Chapter 3 explores the varied mechanisms of action of the different classes of psychedelics and entactogens as well as key knowledge gaps, including the question of whether the subjective mystical experience is essential for a therapeutic

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⁷ To read those workshop proceedings, see https://nap.nationalacademies.org/catalog/26218/novel-molecular-targets-for-mood-disorders-and-psychosis-proceedings-of (accessed June 12, 2022).

effect. The unique challenges for clinical development posed by these agents, as well as current clinical trial evidence for the efficacy of MDMA and psilocybin, are explored in Chapter 4. Considerations to ensure equitable access to psychedelic treatment are discussed in Chapter 5. Chapter 6 provides a summary of the workshop and the thoughts of leaders in the

field regarding potential key themes to navigate the future of psychedelic treatment. References cited throughout this proceedings are listed in Appendix A, and the workshop agenda is in Appendix B.

During the workshop, public attendees were able to ask questions and submit comments via an online chat platform, which were later posed by session moderators in the open panel discussions. These discussions are captured throughout this proceedings.

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