National Institutes of Health Psilocybin Research Speaker Series: State of the Science, Regulatory and Policy Landscape, Research Gaps, and Opportunities

Abstract

The U.S. National Institutes of Health (NIH) convened a seminal first ever psychedelic drug substance-focused speaker series, from April 22 to June 10, 2021, titled the “NIH Psilocybin Research Speaker Series.” This speaker series provided evidence-based scientific information to the public and the scientific community. Its aims were to assess the current state of the science and the regulatory and policy landscape, as well as to identify gaps in knowledge and understanding, ultimately serving to define future research needs. The highlights of the lectures and discussion from 26 national and international distinguished experts served as the basis for this special issue of Neuropharmacology.

Background

Psilocybin is a naturally occurring alkaloid found in more than 200 species of fungi, more commonly referred to as “magic mushrooms.” Psilocybin, converted by the body to psilocin, has psychoactive hallucinogenic activity in the central nervous system (CNS). Naturally occurring mushrooms have been historically used as sacred sacraments by Indigenous cultures worldwide for centuries in the context of religious or spiritual healing ceremonies. Psilocybin is currently a Schedule 1 substance under the 1970 Controlled Substances Act (CSA), where Schedule 1 classification is defined as substances that currently have no accepted medical use and have potential for abuse (U.S. Drug Enforcement Administration [DEA], 2022). Ongoing clinical research trials are exploring psilocybin for its potential medicinal application in treating a range of psychiatric disorders such as: major depressive disorder (MDD), treatment resistant depression (TRD), post-traumatic stress disorder (PTSD), opioid use disorder (OUD), and additional substance use disorders (SUD), as well as anorexia, among other indications. To date, the U.S. Food and Drug Administration (FDA) granted two breakthrough therapy designations (BTDs) for psilocybin, one for TRD in 2018 (COMPASS Pathways, 2018), and a second for MDD in 2019 (Khan, 2019), as well as MDMA for PTSD (Multidisciplinary Association of Psychedelic Studies, 2017). A BTD designation is a process designed to facilitate and expedite the development and review of new drugs that have the potential to address unmet medical needs. This designation is given to drugs that are intended to treat a serious condition where preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over available therapies on clinically significant endpoint(s) (FDA, 2022). Currently, the FDA has not made a safety or efficacy determination, and BTDs are not considered a substitute for marketing approval. The FDA has not found these substances to be currently safe and effective for any indication.

With the intent to provide timely evidence-based research education to clinicians, researchers, policymakers, and the public, the Trans-NIH Integrative Medicine Course Organizing Committee sponsored the “NIH Psilocybin Research Speaker Series” from April 22 to June 10, 2021 (NCI Event, 2021). This speaker series brought together scientists, physician-scientists, clinical psychologists, oncologists, pain and palliative care specialists, pharmacists, patients, as well as experts in jurisprudence and public policy. The series garnered more than 900 registrants and covered a robust variety of topics, including those in the realm of drug discovery, preclinical mechanisms-of-action, clinical research, patient perspectives, health disparities, ethics, and public policy. The topics were arranged within five themes: Regulation, Policy and Ethics; Clinical and Human Research; Preclinical Research and Drug Discovery; Patient Perspective and Disparity; and Final Panel Discussion (Table 1). The presentations and final panel discussion illustrated the current research, gaps in knowledge and understanding, the challenges involved with both advancing and broadening the scope of research with psychedelics, and the numerous complex service delivery issues that will need to be addressed if psychedelic substances, like psilocybin, were to receive potential FDA approval for one or more clinical indications. The series also served to bring together several federal agencies including: the NIH institutes represented on the Trans-NIH Integrative Medicine Course Organizing Committee (i.e., The National Cancer Institute [NCI], the National Center for Complementary and Integrative Health [NCCIH], and the NIH Clinical Center Pain and Palliative Care Department), the National Institute of Mental Health (NIMH), the National Institute on Drug Abuse (NIDA), the FDA, and the Substance Abuse and Mental Health Services Administration (SAMHSA).

Table 1.

NIH Psilocybin Research Speaker Series Themes and Topics

Theme 1: “Regulation, Policy and Ethics”
“Psychedelics–What’s at Stake, Strategic Science Policy Considerations for Advancing Public Health through Dynamic Regulatory Frameworks (CAPT Sean Belouin, United States Public Health Service, and Substance Abuse and Mental Health Services Administration)
“Psychedelic Medicine and Ethics” (Paul S. Appelbaum, Columbia University; Mason Marks, Gonzaga University; William Smith, University of Pennsylvania)
“Abuse Potential Related Science and Regulatory Perspectives for Psychedelic Drug Product Development” (Jack Henningfield, Johns Hopkins University, and Pinney Associates)
Theme 2: “Clinical and Human Research”
“Psilocybin at the End of Life” (Charles Grob, University of California Los Angeles)
“Psilocybin: Neuropsychopharmacology and Implications for Therapeutics” (Roland Griffiths, Johns Hopkins University)
“Psilocybin in Cancer Patients with Depression—The Experience at Aquilino Cancer Center” (Manish Agrawal, Aquilino Cancer Center)
“Self-blinding Citizen Science to Explore Psychedelic Microdosing” (Balázs Szigeti, Imperial College London, England)
“Psilocybin and Group Therapy: Implications for Safety and Efficacy” (Brian Anderson and Alicia Danforth, University of California San Francisco)
“Psychedelics in Headache Medicine: Historical, Neuropharmacological, Neuroanatomical, and Clinical Evidence” (Emmanuelle Schindler, Yale University)
“Psilocybin-Assisted Psychotherapy for Advanced Cancer-related Psychiatric and Existential Distress” (Stephen Ross, New York University)
Theme 3: “Preclinical Research and Drug Discovery”
“Low Doses of Psilocybin Enhance Motivation and Attention in Poor Performing Rats” (Edward Sellers, University of Toronto, Canada)
“New Insights into the Mechanism of Action of Psilocybin” (Bryan Roth, University of North Carolina)
“Antidepressant-like and Anti-inflammatory Effects of Psychedelics in Rodent Preclinical Models” (Charles Nichols, Louisiana State University)
“Harnessing Psilocybin To Fight Depression: Insights and Provocations From Preclinical Studies” (Scott Thompson, University of Maryland)
“Synthesis, Characterization, and Preclinical Pharmacology of Psilocybin Analogs and Related Tryptamines” (Grant Glatfelter, NIDA, NIH)
Theme 4: “Patient Perspective and Disparity”
“A Breast Cancer Patient’s Perspectives on the Uses of Psychedelics in Medicine” (Erica Rex, Journalist and Writer for Scientific American and The New York Times)
“Special Considerations for Evaluating Psilocybin-facilitated Treatments in Vulnerable Populations” (Peter Hendricks, University of Alabama at Birmingham)
Theme 5: “Final Panel Discussion”
“What We Have Learned and Future Research Needs” (All speakers and additional invited experts: Sharmin Ghaznavi (Massachusetts General Hospital); Michael Silver (University of California Berkeley); Stephen Xenakis (Retired U.S. Army); Marta Sokolowska (Center for Drug Evaluation and Research, FDA); Frank Weichold (Office of the Commissioner, FDA); Susan Weiss (NIDA, NIH); Steve Zalcman (NIMH, NIH))

Event Recording Links: https://events.cancer.gov/nci/psilocybinresearch/agenda

April 22, 2021 Recording; May 27, 2021. Recording; June 4, 2021 Recording; June 7, 2021 Recording; June 10, 2021 Recording

Subsequent to this NIH Speaker Series, the National Institute on Alcohol Abuse and Alcoholism (NIAAA), NIDA, and NIMH convened an NIH workshop on January 12 and 13, 2022, on “Psychedelics as Therapeutics,” to further the discussion on the current state of understanding with psychedelics’ mechanisms-of-action and potential efficacy signals being observed in clinical trials conducted in different patient populations. Despite recent advances in the state of the science on psychedelics, the discussions from both of these NIH events made clear that more research is needed to address the research gaps identified.

Following both the speaker series and workshop, U.S. Senators Brian Schatz and Corey Booker sent a letter to NIH and the FDA in May 2022 inquiring about the state of psychedelic research. They notably mentioned chronic pain in their letter, which stated: “The Biden-Harris Administration recently announced support for expanding research on Schedule 1 substances to inform and advance evidence-based public policy, and how this research relates to addiction and overdose, chronic pain, and mental health conditions. It is important that federal research agencies continue to assess the efficacy of potential alternatives to drugs with high misuse potential” (Press Release from Senator Schatz’s Office, 2022). In fact, NCCIH expressed during the 2021 speaker series significant interest in supporting research on the therapeutic potential of psilocybin for treating chronic pain. The NIH Psilocybin Research Speaker Series Organizing Committee is hopeful that this first-of-its-kind event will encourage continuing discourse among the scientific community, the public at large, and policymakers, with the intention to accelerate research efforts by leveraging multiple streams of public, philanthropic, and private funding. This, in turn, would expand the research spectrum of potential therapeutic uses of psychedelics for treating those diseases and conditions where currently available evidence-based treatment modalities have failed for numerous people, and in some cases, carried unintended consequences, as with over-reliance on opioids for chronic pain.

The NIH response to the Senators’ letter indicated that “NIH has several open funding opportunities to encourage research on the development and testing of novel pharmacological interventions (including, but not limited to, the use of psychedelic drugs) for mental health and substance use disorders.” The response also reiterated NCCIH’s interest in supporting psilocybin research in the area of chronic pain. Support for research in treating chronic pain is cross-cutting among different patient populations, especially with veterans, where there is broad evidence that suggests veterans struggle with chronic pain at higher rates than non-veterans (Nahin, 2017). NIH further noted several currently active NIH-funded projects that focus on studying psychedelic drugs with potential benefit for behavioral health. NIH institutes that currently support research in this area include: NIMH, NIDA, the National Institute of General Medical Sciences (NIGMS), the National Institute of Neurological Disorders and Stroke (NINDS), the National Center for Advancing Translational Sciences (NCATS), and NCCIH (NIH response to Senators Schatz and Booker, June 2022). In addition, in 2021, NIDA awarded nearly $4 million dollars in a grant to Johns Hopkins University to lead a 3-year, multisite study to investigate the potential efficacy of psilocybin in treating tobacco addiction (Johns Hopkins Psychedelic Grant). Subsequently, more studies including clinical trials with psilocybin were then funded by NIH in 2022, such as “Cellular Basis of Psilocybin Actions in Frontal Cortex” and “Circuit Mechanisms of Psilocybin Following Chronic Stress” by NIMH, “Potentiating Psilocybin” by NCCIH, and “Psilocybin Therapy for Advanced Cancer-Related Psychiatric Distress” by NCI. A complete listing of NIH-supported research grants focused on psychedelic drugs can be found at https://reporter.nih.gov/search/OLY6nh0Edk2G0dN6odbgMw/projects. A listing of psychedelic clinical trials can be found at https://clinicaltrials.gov/ct2/results?cond=&term=psychedelic&cntry=&state=&city=&dist=#. Additionally, an evidence brief on research on psychedelic medications for mental health and substance use disorders can be found on the U.S. Department of Veterans Affairs website at https://www.hsrd.research.va.gov/publications/esp/psychedelics-mh-brief.cfm.

While NIH is supporting research in this arena, the Psilocybin Research Speaker Series demonstrated the critical need to continue stimulating rigorous, high-quality, relevant, public health serving research with psychedelics, where the evidence can withstand the scrutiny of peer review and contribute to informing public health policy.

Scientific Discussions, Future Research Needs, Cross-cutting Recommendations

It is the hope of the organizing committee, that the NIH Psilocybin Research Speaker Series, as well as this Neuropharmacology special issue, will catalyze and prioritize publically and philanthropically funded research with psychedelics for the treatment of depression, PTSD, addiction, palliative care issues, and chronic pain, acknowledging that many psychedelic substances (e.g., psilocybin) have been in the public domain for decades, such that these compounds no longer hold patent protection, thus often disincentivizing venture capital investment in research (Belouin and Henningfield, 2018). Additionally, even though the speaker series purposely was not intended to provide public policy recommendations, the presentations and panel discussion demonstrated the need to address numerous complex service delivery issues associated with psychedelic use, where broad stakeholder engagement through a potential public-private partnership (PPP) might provide collective thoughtful guidance when it comes to informing regulatory and public policy decision making. Moreover, if psychedelics such as psilocybin, were to receive FDA regulatory approval in the future for a specific clinical indication(s), any licit use should be guided through a responsible, accountable, safe, and ethical use real-world framework, where “prescribed procedures” are followed through consensus driven protocols that maximize potential therapeutic benefits while simultaneously protecting the public through collectively agreed-upon harm reduction strategies (Belouin et al, 2022). In conclusion, several cross-cutting recommendations surfaced from the NIH Psilocybin Research Speaker Series covering several topical areas:

• Conduct public health and epidemiological studies evaluating patient and population usage to assess the long-term therapeutic benefits or detriments to the overall population, including the quality and sourcing of synthetic and organic psychedelic products (e.g., psilocybin).

• Accelerate clinical research designed to establish the safety and effectiveness of psychedelics in treating a range of psychiatric disorders and chronic health conditions, including investigating potential influences from external factors such as session facilitators, differing therapy settings, and characterizing the role of music during therapy sessions.

• Conduct clinical trials addressing the spiritual and existential improvements that can occur with psychedelics.

• Determine the impact of psychedelics on tumors and the immune system including in the context of cancer therapeutics or cancer outcomes.

• Encourage the FDA to work with a consortium of stakeholders to draft Guidance for Industry, outlining what are considered well-designed clinical trials (e.g., agreed upon clinical trial methodologies, outcome measures, and standardized data collection and reporting from randomized-controlled trials) to accurately assess therapeutic effects on depression, PTSD, chronic pain, OUD, SUD, and cancer/end-of-life existential distress and demoralization.

• Assess the potential effects from chronic psychedelic use and/or microdosing.

• Assess drug-drug interactions and abuse potential liability.

• Determine how psychedelics might be integrated in clinical care settings and how best to develop a sufficient real-world practitioner workforce that can support individuals undergoing psychedelic sessions.

• Developing national survey/data collection strategies that can best inform standards-of-practice when implementing real-world service delivery programs.

• Develop harm reduction strategies that include substance use prevention, risk mitigation, and safety and ethical monitoring, to include addressing the potential for intimate ethical violations that may occur with the use of psychedelics in vulnerable populations.

• Leveraging the state of the science to engage communities in transparent educational outreach.

• Conduct assessments that address health disparities in underserved populations and barriers to equitable access.

• Support basic research using human relevant preclinical models to further explore mechanisms of action.

• Develop new imaging technologies to better characterize psychedelics’ mechanisms of action.

• Focus on biomarker discovery that may inform patient stratification.

• Investigate the effects of host genetics, epigenetics, gender, lifestyle, environmental factors, and/or comorbidities that may impact safety and efficacy.