Abstract
New medicines containing classic hallucinogenic and entactogenic psychedelic substance are under development for various psychiatric and neurological disorders. Many of these, including psilocybin, lysergic acid diethylamide (LSD), and 3,4-methylenedioxymethamphetamine (MDMA) are Schedule I controlled substances of the United States Controlled Substances Act (US CSA), and similarly controlled globally. The implications of the CSA for research and medicines development, the path to approval of medicines, and their subsequent removal from Schedule I in the US are discussed. This entire process occurs within the framework of the CSA in the US and its counterparts internationally in accordance with international drug control treaties. Abuse potential related research in the US informs the eight factors of the CSA which provide the basis for rescheduling actions that must occur upon approval of a drug that contains a Schedule I substance. Abuse-related research also informs drug product labeling and the risk evaluation and mitigation strategies (REMS) will likely be required for approved medicines. Human abuse potential studies typically employed in CNS drug development may be problematic for substances with strong hallucinogenic effects such as psilocybin, and alternative strategies are discussed. Implications for research, medicinal development, and controlled substance scheduling are presented in the context of the US CSA and FDA requirements with implications for global regulation. We also discuss how abuse-related research can contribute to understanding mechanisms of action and therapeutic effects as well as the totality of the effects of the drugs on the brain, behavior, mood, and the constructs of spirituality and consciousness.
| Original language | English |
|---|---|
| Article number | 109220 |
| Journal | Neuropharmacology |
| Volume | 218 |
| Early online date | 17 Aug 2022 |
| DOIs | |
| Publication status | Published - 1 Nov 2022 |
| Externally published | Yes |
Bibliographical note
Jack Henningfield and Marion Coe are employees of PinneyAssociates, Inc. which provides scientific and regulatory consulting support for new drug applications (NDAs) and risk management programs for a broad range of CNS active substances and drug products including psychedelic substances, new chemical entities, and alternative formulations and routes of delivery, as well as dietary ingredient notifications, cannabinoid assessment, and noncombustible tobacco/nicotine products for FDA regulation. Drs. Henningfield and Coe received no external financial support for writing this article and no external commercial interests had any input.David Heal and Sharon Smith are shareholders and employees of DevelRx Ltd. DevelRx provides consultancy on drug discovery and development to treat psychiatric, neurological and metabolic disorders. They specialize in advising pharmaceutical companies on drug abuse and dependence evaluations and prepare regulatory submissions. DevelRx advises on the development and approval of cannabinoids and other natural products as novel foods or food additives. DevelRx, David Heal and Sharon Smith have received no external financial support for writing this article, and no external commercial interests had any input.
Allison Coker receives salary support for full-time employment with MAPS PBC, a wholly owned subsidiary of the MAPS, a 501(c) (3) non-profit organization conducting research and development of MDMA as a potential medicine.
Peter S. Hendricks, Ph.D. Department of Health Behavior, School of Public Health, University of Alabama at Birmingham. PSH is a paid scientific advisory board member of Bright Minds Biosciences Ltd., Eleusis Benefit Corporation, and Reset Pharmaceuticals Inc., and has received research funding from the Heffter Research Institute.
Funding
Peter S. Hendricks, Ph.D. Department of Health Behavior, School of Public Health, University of Alabama at Birmingham. PSH is a paid scientific advisory board member of Bright Minds Biosciences Ltd., Eleusis Benefit Corporation, and Reset Pharmaceuticals Inc., and has received research funding from the Heffter Research Institute . Psychedelic substances with abuse potential and no accepted therapeutic use are currently in Schedule I of the CSA. Developing therapeutic medicines for approval by the Food and Drug Administration (FDA), and rescheduling by the DEA prior to marketing, requires a broad range of research and evidence supporting efficacy and safety in the form of New Drug Applications (NDAs) consistent with the Federal FDCA, which provides the framework for NDA development and submissions (U.S. Food and Drug Administration, 2022a). NDA submissions require abuse potential assessments with CSA scheduling recommendations as required by the CSA (U.S. Drug Enforcement Administration, 2022a) and following FDA's 2017 Guidance, Assessment of the Abuse Potential of Drugs (U.S. Food and Drug Administration, 2017), hereafter referred to as “abuse potential guidance.” By “abuse-related,” this article follows the approach of FDA's 2017 abuse potential guidance when referring to all lines of scientific evidence, including chemistry, nonclinical in vitro and animal studies, physiological dependence and withdrawal, clinical trial adverse event reports, historical patterns of use, and surveys of current use patterns in the population. It is also important to keep in mind that abuse potential is “conducted as a component of its [the drugs overall] safety evaluation” by FDA (U.S. Food and Drug Administration, 2017), with other components like toxicity also playing a significant role. Although not specifically codified in the CSA, these lines of evidence mirror the requirements for the scientific and medical evaluation or “8 Factor Analysis” (8FA) required to be conducted by the US Department of Health and Human Services (DHHS) and DEA under the CSA prior to scheduling and rescheduling a drug or other substance (see the 8 factors in Table 1 and summary of the process in the Scheduling Process section).An ongoing point of discussion with FDA and among pharmaceutical developers is how many and what kinds of abuse-related studies will need to be conducted to support the approval of psychedelic medicines. Abuse potential research on psychedelic substances was conducted in the 1960s and 70s, however, methodological limitations noted in Bonson's overview of LSD regulation are important to keep in mind and bear careful consideration by today's researchers, because many of these studies are at best considered pilot or exploratory and not adequate to guide regulatory decision making (Belouin and Henningfield, 2018; Bonson, 2018; Calderon et al., 2018). At that time, all hallucinogens with abuse potential were placed in Schedule I since they were determined to have no accepted medical use in the US, whereas opioids, stimulants, sedatives, and other substances with abuse potential but which were recognized to have medical use were placed in Schedules II, III, IV, or V commensurate with their recognized level of abuse potential.2 There is increasing pressure from researchers and from NIH (National Institute on Drug Abuse, 2021) to find ways to streamline the process and increase the diversity of researchers and institutions to participate.4 NIDA Director Nora Volkow also testified to Congress on the impediments to Schedule I research and advocated for modification of registration procedures to support broader participation of researchers and more timely progress (Volkow, 2020). In October 2021, the Office on National Drug Control Policy (ONDCP) Acting Director, Regina LaBelle, included the following recommendation in a letter to congressional leaders that was primarily focused on FRS but had clear implications for other areas of Schedule I research. She wrote, “Establish a simplified process that would align research registration for all Schedule I substances, including FRS, more closely with the research registration process for Schedule II substances.” (Jaeger, 2021a, 2021b, The White House, 2021). Such recommendations have been informed by researchers who routinely conduct Schedule II research, We do not expect rapid or radical change in Schedule I research requirements. We encourage researchers interested in conducting Schedule I research to contact NIDA, FDA, and DEA for advice as to what they might do to minimize delays and unnecessary costs and burdens, and to be clear on what could be done to make such research less burdensome and more efficient. In this area of research and regulation, it is apparent that NIH, FDA, and DEA are all making efforts to facilitate research and development as illustrated by the NIH-led lecture series that is the basis for this special issue and introductory commentaries and editorials to the special issue by various DHHS staff.5 Whereas until the early 2000s one HAP study was generally sufficient to support NDAs, in recent years it has become more common for sponsors to conduct more than one HAP study to enable evaluation of a broader range of doses and multiple comparator drugs than can generally be accomplished in a single HAP study (U.S. Food and Drug Administration, 2020a). Table 4 shows the main elements of a typical HAP study as employed to assess most categories of CNS active drugs and as recommended in FDA's 2017 abuse potential guidance.To mitigate the risk of serious adverse events, and increase the likelihood of a positive healing experience, study participants and patients are typically screened for potential contraindications (e.g., cardiovascular illness or a personal or family history of psychosis) and prepared for challenging experiences such as anxiety and panic and how to manage them. Participants often meet with their assigned study monitors prior to testing to develop rapport and trust and then during test sessions, a staff monitor (“guide” or “counselor”) is seated next to the participant to provide comfort and assistance as needed (Griffiths et al., 2006; Johnson et al., 2008). Thus, the emerging practices which are thought to contribute to therapeutic experiences, might also reduce the validity of HAP studies which have been designed over decades to minimize the impact of expectation and bias, supporting the rationale for HAP studies being conducted outside the context of a therapeutic study.Two recent studies support the viability of modified HAP study designs in which both limited the doses of the psychedelic to those under exploration for potential therapeutic use, used personal study monitors, and used a variety of instruments to assess various states of consciousness (Carbonaro et al., 2020; Holze et al., 2022). The Carbonaro et al. study compared 10, 20, and 30 mg/70 kg psilocybin to 400 mg/kg dextromethorphan, and placebo, in 20 healthy participants. Holze et al. compared 100 and 200 μg LSD to 15 and 30 mg psilocybin, and placebo, in 28 healthy participants and included a drug liking scale typical of HAP studies along with the States of Consciousness Questionnaire. Both studies found dose-related increases in ratings of positive and negative effects, as well as alterations in various measures of states of consciousness that appear to contribute to nonmedical real-world use in the community. The designs appeared acceptably safe and dysphoric effects were managed.Table 6 provides a few examples of potential REMS elements that may be considered by FDA in discussion with a drug sponsor and with input from external FDA Advisory Committees that will likely be convened to advise FDA on the approvability of psychedelic medicines and other issues that may be posed by FDA. Every one of these elements are influenced by the evidence-based abuse related risks of concerns, e.g., how to manage them (first element), concerns about medication diversion (second element),and long term abuse related risks including potential psychedelic substance use in patients that had no such prior histories (third element).For psilocybin, although some abuse-related data are yet to be collected based largely on adverse event reporting in ongoing clinical trials, we do not expect that this will substantially alter the characterization of psilocybin from the preliminary 8FA that was published in 2018. In that review Johnson et al., concluded as follows: “All 8 factors and other lines of evidence taken together indicate the profile of a substance that is characterized by some level of abuse potential and potential risks. However, the findings do not support placement more restrictively than Schedule IV.” (Johnson et al. (2018), p. 19). Whether FDA and DEA agree with this assessment will not be known until FDA approves a psilocybin-containing product and makes its scheduling recommendation. Regardless of FDA and DEA's determination, other countries that approve psilocybin containing products are not obliged to follow the US scheduling approach.Peter S. Hendricks, Ph.D. Department of Health Behavior, School of Public Health, University of Alabama at Birmingham. PSH is a paid scientific advisory board member of Bright Minds Biosciences Ltd., Eleusis Benefit Corporation, and Reset Pharmaceuticals Inc., and has received research funding from the Heffter Research Institute.
Keywords
- Abuse liability
- Clinical study design
- Consciousness
- Controlled substance regulation
- Drug scheduling
- Psychedelics
ASJC Scopus subject areas
- Pharmacology
- Cellular and Molecular Neuroscience
