The Food and Drug Administration (FDA) and the National Institutes of Health (NIH) communicated publicly about psychedelic drug development and current thinking around safety, therapeutic use, and research. The FDA Division of Psychiatry Products provided information in a workshop about how to design and efficiently study psychedelics for potential medical use.
In a historic presentation, representatives from the US Food and Drug Administration spoke about psychedelic drug development for the first time publicly at the American Society of Clinical Psychopharmacology (ASCP) annual meeting. The message was clear. The FDA will evaluate risk-benefit profile of psychedelic substances in the same way as other investigational drugs. With psilocybin and MDMA moving forward in phase 2/3 trials, the Division of Psychiatric Products of FDA talked about their current thinking of how best to conduct controlled clinical trials with substances that present novel challenges to current paradigms in drug development.
FDA Presentations at the ASCP Meeting
The panel opened with an introduction from Juliette Toure, BCPP, MBA, PharmD, Senior Policy Advisor at Center for Drug Evaluation and Research, FDA. This year for the special topic FDA workshop they chose to focus on psychedelics. Six speakers followed, each contributing specialized knowledge of the process psychedelic drug development and what criteria must be followed to gain approval.
The first talk by Sean Belouin, PharmD, Senior Policy Advisor at the US Public Health Service, gave an overview of the long history of psychoactive plants in indigenous cultures, the discovery of LSD by Albert Hoffman, PhD, and the series of events that lead decades later to the Controlled Substance Act in the 1970s. Prior to psychedelics being placed on the Schedule 1 list, several studies had tested LSD, with reportedly good outcomes, for treating various mental health disorders.
By the 1960s more than 1,000 papers had been published about LSD being investigated for depression, alcoholism, schizophrenia, and as an adjunct to psychotherapy. Trials in the 1950-60s, however, lacked the rigorous scientific approaches of today’s standards. Some of the methodology flaws highlighted were the lack of randomization of subjects to treatment groups, inconsistency of treatments applied within groups, the absence of control groups, the use of unvalidated outcome measures, the under reporting of adverse events, missing statistical analyses, and the determination of treatment response made solely by the investigator.
Unique Challenges for Psychedelic Drug Development
Next up, Katherine (Kit) Bonson, PhD, Pharmacologist in FDA’s Controlled Substances Staff, spoke to the unique challenges of studying Schedule 1 controlled substances. By definition, drugs in this category should have no accepted medical use and have a high potential for abuse. However, the classification of psychedelics does not reflect the currently available evidence from abuse liability studies in animals and humans.
If a drug gains FDA approval by showing adequate safety and efficacy data, the Controlled Substances Staff of the FDA, in consultation with NIDA, will review data and conduct an eight factor analysis of abuse potential. This analysis informs doctors about potential risks and appears in the drug label, specifically Section 9 Drug Abuse and Dependence. The Controlled Substances Staff sends results of this analysis to the Department of Health and Human Services, Office of the Assistant Secretary for Health, who then makes a recommendation for a new classification (Schedule 2-5) to the Drug Enforcement Administration (DEA). The DEA ultimately makes the final decision on the schedule category in which the drug will fall.
FDA Approval Path for Psychedelic Drug Development
The path to FDA approval requires first characterizing the toxicological profile of a drug in animal models before the drug can be tested in humans (phase 1 trials). Nancy Dickinson, PharmD, Senior Clinical Analyst at FDA, explained how information from scientific publications can be used to start initial studies (phase 1 and 2), but for a New Drug Application (NDA) the complete battery of nonclinical toxicology studies must be completed. The quality of nonclinical data from published literature and the dosing paradigm proposed for human trials (single vs. many, low dose vs. high dose) will inform the requirements and timing for toxicology testing. The FDA encourages sponsors to discuss psychedelic drug development plans with them early in the process to avoid delays and doing unnecessary work.
Drug Development Pathway for FDA approval of New Medications
Nonclinical – establishes toxicology and pharmacology profiles of a drug in animal safety studies to support human clinical trials and marketing authorization by FDA
Phase 1 – tests safety of an investigational drug in a small number of healthy individuals
Phase 2 – evaluates safety and efficacy of a drug in people with a disease or condition, providing initial information about whether the drug can reduce symptoms to a degree that out weighs adverse effects
Phase 3 – investigates a drug in a large number of people with a disease or condition at multiple study sites and must show significant benefit over a control group plus adequate safety; FDA evaluates results in a New Drug Application and then grants approval for marketing a new medication where appropriate
Phase 4 – collects data on long-term effectiveness, safety, and costs of treatment in post marketing surveillance trials after FDA approval
Bernard Fisher, MD, Clinical Team Leader at FDA, spoke about clinical trial designs for establishing safety and effectiveness in psychedelic drug development. Several questions must be addressed to write the content of the drug label to instruct providers on how to use the medicine.
Prescriptive Answers Needed for Psychedelic Drug Development
The ones notable for psychedelics were: how psychedelics work in a particular setting, timing of administration, structured approach or will multiple approaches work, how fast does symptom reduction occur and how long are symptoms decreased, do people relapse and if so can the drug retrieve them from relapse. All of these variables must be carefully assessed when planning studies.
For example, a study may fail if a selected outcome measure does not measure the symptoms most affected by the drug or is given at the wrong time after treatment. Measures of depression usually assess symptoms after weeks or months and may not be suitable to detect rapid antidepressant effects. Adaptations to study designs are often needed to accommodate the unique properties of psychedelics.
While methods vary in protocols of MDMA and psilocybin, they all employ common elements important for both safety and treatment outcomes. Current protocols investigating MDMA utilize a two-person co-therapy team to deliver psychotherapy while someone undergoes an 8-hour session with MDMA. The providers of this therapy undergo specialized training and must have credentials in mental health, particularly with a therapeutic orientation.
Psilocybin trials also use a two-guide model to facilitate sessions. Training is required, but professional credentials are less advanced since the approach is typically more about supporting an internal process rather than providing verbal therapeutic interventions.
Michael Davis, MD, PhD, Clinical Team Leader at FDA, described how the FDA regulates the approval and marketing of drug products, but does not regulate the practice of medicine or how doctors prescribe medications, including off-label prescriptions. This delineation presents a dilemma as to how the FDA will regulate the non-drug factors that accompany psychedelic-assisted therapies.
Will the FDA require drug labels to entail the physical details of the clinical space – sofa, art, and low-wattage lightening? Or, how about how many therapists/guides are needed and what type of therapeutic modalities can be used? These features are thought to contribute to positive outcomes and reduce psychological adverse events, yet the FDA has little precedent on how to handle regulating the milieu of psychedelic medicine to maintain quality and safety.
Dr. Davis did point to a few example drug labels which entail therapeutic guidelines. Naltrexone’s label for opioid use disorders recommends a comprehensive management program that includes psychosocial support, and Bupropion’s label for smoking cessation describes the importance of patients receiving counseling and support throughout treatment.
The label for Buprenorphine for opioid use dependence says that all trials used the drug in combination with psychosocial counseling as part of an addiction treatment program. No clinical studies were done to assess the efficacy of Buprenorphine as the only component of treatment.
Risk Evaluation and Mitigation Strategy
An FDA drug safety program known as the Risk Evaluation and Mitigation Strategy (REMS) is employed to ensure benefits outweigh risks for medications with safety concerns. REMS may specify criteria for provider training and certification, patient monitoring, medication dispensation, and settings or use conditions. If safety and efficacy is established for psychedelics, REMS will likely be required as part of the marketing application for a psychedelic drug.
Javier Muniz, FAPA, MD, Associate Director of Therapeutic Review, addressed perhaps the stickiest of issues for studying psychedelics – how to adequately blind participants and investigators to understand the true effect of the drug. Expectations about drug effects and delivery of care can significantly alter a treatment response. When a person knows they received the active drug under study, this knowledge effectively “unblinds” the study and thus confounds the objective measurement of the pharmacological drug effects.
Currently no straightforward solution to this quandary exists. By definition, psychedelics induce non-ordinary states of consciousness and often bring about mystical states which cannot be concealed from clinical trial participants. Some researchers have tried active placebos – drugs with some noticeable effects such as niacin, Benadryl, stimulants, or low doses of MDMA – as the comparator treatment group, but for the most part participants can easily discern the difference.
The FDA panel recommended using blinded independent raters who are not present during the drug sessions to administer the study outcome measures that assess symptom severity. They also suggested playing with the expectancy factor by telling some participants that they have 25% chance of receiving the active drug and others that they have a 75% chance. While this may alter the expectancy a bit, the design still does little to negate the issue of a person being able to tell whether or not they received a mind-altering drug.
Lastly, another idea tossed around was anesthetizing a person and then administering a psychedelic while the person is sedated. Would the treatment outcomes be comparable? Possibly there are neurobiological effects that are purely related to the drug’s interaction with receptors in the brain, but most people think the positive outcomes of psychedelic therapy are due to a combination of the psychological AND biological effects within the context of supportive environments. Studying psychedelics while under anesthesia is interesting for addressing mechanistic questions but does not translate to real world applications of psychedelic medicine.
Lastly, Dr. Muniz referenced federal code stating that two dose-response trials are considered adequate and well controlled trials for FDA approval. A dose-response trial tests various doses of a drug without a placebo to show a treatment response at certain doses but not at other doses. An example of a positive dose-response trial would be more participants achieving a response at 20 and 30 mg of psilocybin, but not at 10 mg.
This approach may be useful for psychedelic drug trials, however a growing number of anecdotal reports of microdosing or ‘museum dosing’ (low doses with some perceptual changes) suggests that some psychedelics may be biologically active at small doses and capable of producing tangible behavioral effects, albeit different mechanisms than those of ego-dissolving experiences more typical of higher doses. Innovative approaches to the challenges presented were encouraged by drug developers, as was discussion of plans with the FDA early on in the process.
Closing remarks made by Dr. Charles Grob, Professor and long-time psychedelic investigator, solidified the impression of collaboration between FDA and psychedelic drug developers to work unhindered towards any possible cure to intractable mental illnesses. Dr. Grob and researchers from John Hopkins University had met with the FDA a few weeks prior after an unexpected invite to come talk about psychedelic research. Everyone has the same goal in mind, delivering a safe and proven treatment to the public. The cross sharing of information will undoubtedly help to advance the field.
The FDA presentations mark a significant moment in the history of psychedelics. By setting aside stigma and the political opinions that arose in 1960s to suppress psychedelic use and research, the FDA has very likely altered the course of mental health care of the future. However, not all government agencies have embraced a new stance on psychedelic research, much less psychedelic drug development. This despite all the rigorous scientific evidence coming from multiple University researchers and pharmaceutical companies.
National Institutes of Health at ASCP Meeting
A few hours before the FDA panel at the conference, George Koob, PhD, Director of the National Institute on Alcohol Abuse and Alcoholism (NIAAA), said the Institute would not award grants investigating psychedelics because these drugs were not safe, even in controlled medical settings. The incongruent perception of safety and risks by FDA and NIH created a situation where the agency charged with evaluating the safety of investigational drug products is at a conference to promote well-designed psychedelic trials, while the agency responsible for funding research to ‘enhance health and reduce illness’ refuses to provide critically needed money to carry out investigations for therapeutic use of psychedelics. Until then, research will proceed by nonprofits and pharmaceutical companies. But, at what cost to our society?
Amendment to Make it Easier to do Research Rejected
This issue is now reaching the ears of policy makers. Just a few weeks following the ASCP conference, Rep. Alexandria Ocasio-Cortez (D-NY) introduced an amendment to remove a section of a large-scale appropriations bill that restricts federal dollars from being spent on “any activity that promotes the legalization of any drug or other substance in Schedule I.” In a word- psychedelic drug development.
The goal of the amendment was to remove barriers for academics and scientists to pursue research of substances such as psilocybin, MDMA, and cannabis. After being approved in a voice vote and cleared by the House Rules Committee, the drug reform measure was vetoed in a 91 to 331 roll call vote by nearly all Republicans and many Democrats (148 voted against). Some speculate that the amendment failed due to a lack of information about the topic, and Democratic leaders failing to give any directive to members on whether to support or veto it.
To gain a better understanding of what efforts had been made by NIH and FDA relating to psychedelic drug development research for treatment of mental health conditions, Senator Brain Schatz (D-HI) wrote a letter on April 9, 2019 requesting information about agency agendas, gaps to understanding potential medical applications, safety and abuse potential, and scheduled drug classifications.
FDA Response to Psychedelic Drug Development
In a 6-page response dated June 13, 2019, the Acting Commissioner of FDA, Dr. Norman Sharpless, and the Director of NIH, Dr. Francis Collins, briefly answered the questions asked by Senator Schatz. Overall the reply was encouraging, “research on other psychedelic drugs holds promise for uncovering mechanisms of illness and possible interventions, ultimately leading to novel treatments with fewer side effects and lower abuse potential.”
NIMH and NIDA have funded an increasing number of grants over the last 10 years, mostly for ketamine and basic science research (not in humans) for LSD and ibogaine. But none have been funded to directly investigate potential therapeutic benefit of classical psychedelics or empathogens in humans (not explicitly stated). Notably, there was no mention of NIAAA funding or lack there of.
Moreover, the letter goes on to say, “Further research is needed to examine the efficacy and long-term safety of psychedelic drugs, including with repeated exposure and potential interactions with existing treatments.” A very brief safety summary was given for ketamine, LSD, psilocybin, MDMA, ibogaine, however the cited information comes mostly from non-medical use of these substances (except esketamine, an FDA-approved medication) and did not reflect safety profiles from research in clinical settings. Finally, they outline the process for drug rescheduling if FDA approval is achieved, as described earlier in this article by Dr. Bonson.
Decriminalization of Plants
On more local levels, two landmark events in the last month have brought reform of criminal policies related to psilocybin and some other naturally occurring psychedelic substances. Psilocybin decriminalization was voted in by residents of Denver, and the Oakland City Council unanimously passed a measure to decriminalize psilocybin-containing mushrooms and plant-based psychedelics, like ayahuasca, ibogaine, and mescaline-containing cacti.
Above all, collective efforts are propelling a movement forward for evidence-based decision making for psychedelic research and governance, allowing for a shift from archaic policies rooted in stigma and misinformation. After several decades of prohibition and suppressed research, the wheels of change are in full motion. Psychedelic drug development will make substantial progress within this decade.