Psychedelic drug abuse potential assessment research for new drug applications and Controlled Substances Act scheduling

Henningfield and colleagues situate the paper in the historical and regulatory context of psychedelic research, emphasising that classic indoleamine psychedelics (for example, LSD and psilocybin) and certain phenethylamines (for example, MDMA) were placed in Schedule I of the US Controlled Substances Act (CSA) during the 1970s. They note that Schedule I status, coupled with international treaty obligations, has had lasting consequences for access to these compounds, for the conduct of basic and clinical research, and for the pathway to develop approved medicines that contain these substances. The introduction highlights that although decades of basic, clinical, and epidemiological research exist for some compounds, many regulatory questions remain unresolved — notably how abuse-potential evidence should be gathered and used to inform New Drug Applications (NDAs), rescheduling decisions under the CSA, product labelling, and post-approval risk mitigation strategies such as REMS (Risk Evaluation and Mitigation Strategies). This paper sets out to review how abuse-potential research applies to psychedelic medicines within the US regulatory framework. The authors examine the components and purpose of the CSA's eight-factor analysis (8FA), summarise FDA guidance on abuse potential (notably the 2017 guidance), discuss practical and scientific impediments posed by Schedule I for research, evaluate the suitability of standard human abuse-potential (HAP) study designs for strongly hallucinogenic compounds, and propose alternative or modified approaches to characterise abuse-related risks. Throughout, the focus is regulatory science: what evidence agencies will likely require, how that evidence might be generated safely and validly, and what the scheduling and REMS implications could be for potential psychedelic drug products.

The extracted text does not present a formal Methods section with a defined search strategy or inclusion/exclusion criteria; rather, the paper is a narrative, regulatory-science review that integrates legal/regulatory documents, agency guidance, historical and contemporary scientific literature, and illustrative case examples. The authors draw on U.S. statutory text and processes (the Controlled Substances Act and the scheduling/rescheduling process), FDA and DEA guidance and practice, NIDA and NIH reports, peer-reviewed empirical studies, and prior eight-factor analyses for specific substances (for example, published 8FAs of psilocybin and MDMA). Where relevant, they also cite clinical trial examples and classic human laboratory studies (for example, Griffiths et al., 2006) to illustrate methodological issues. Methodologically, the paper organises inquiry around several interlocking domains: (1) the legal and administrative mechanics of scheduling under the CSA and the role of FDA, NIDA, and DEA in the 8FA; (2) the conventional elements of abuse-potential assessment for CNS-active drugs (in vitro binding, animal assays such as intravenous self-administration and drug discrimination, and human abuse-potential [HAP] studies) as described in FDA's 2017 guidance; (3) practical impediments to Schedule I research, including DEA registration burdens summarised in NIH/NIDA reports; and (4) critical appraisal of how standard HAP designs perform when applied to strongly hallucinogenic drugs, with discussion of modified designs and additional outcome domains such as psycho‑socio‑spiritual (PSS) measures. The authors bring together regulatory requirements, historical data, animal and human research findings, and programmematic experience to generate recommendations rather than meta-analytic effect estimates. When specific study exemplars are discussed (for instance, the Griffiths et al. 2006 controlled comparison of psilocybin and methylphenidate, and recent modified HAP clinical studies), the authors summarise design features and outcomes to illustrate points about safety, validity, and the range of subjective and persisting effects that bear on abuse potential and therapeutic value. The narrative approach is used to identify gaps where standard methods may be inadequate and to propose collaborative development of modified HAP (mp-HAP) models involving FDA, NIDA, CROs, and an expert panel; however, the extracted text does not report a formal consensus process or empirical validation of such an mp-HAP model within this paper.

Henningfield and colleagues synthesise regulatory, preclinical, clinical, and epidemiological evidence to make several practical findings relevant to abuse-potential assessment and scheduling of psychedelics. First, Schedule I placement imposes substantive administrative and logistical barriers to research: DEA registration is described as time-consuming and resource intensive, with each substance requiring a substance-specific application, possible site inspections, and potentially lengthy delays for initial registrations and amendments. The NIH/NIDA report to Congress is cited to support these process-barrier observations. Second, the CSA's mandated eight-factor analysis (8FA) is presented as the core construct used by DHHS/FDA and DEA for scheduling and rescheduling decisions. The authors explain that FDA leads in guiding sponsors during drug development and prepares an 8FA with NIDA input; DEA issues the final scheduling rule. Since 2016 the timeline for DEA to issue an interim final scheduling rule, after FDA's approval decision and recommendation, is typically 90 days unless compelling reasons for delay exist. The paper emphasises that for FDA-regulated NDAs the abuse-potential assessment is one component of the overall safety evaluation. Third, with respect to typical abuse-potential studies, the authors outline the conventional evidence hierarchy: in vitro binding profiles, animal behavioural assays (intravenous self-administration, conditioned place preference, drug discrimination), and human abuse-potential (HAP) studies in recreationally experienced volunteers using bipolar liking scales (0–100), pharmacokinetic measures, and supratherapeutic dosing (commonly 2–3 times the intended therapeutic dose) to probe rewarding effects. They note that HAP findings are influential for FDA scheduling recommendations but that the HAP paradigm presents safety and validity challenges when applied to classic hallucinogens because therapeutic-range doses can produce strong perceptual changes, anxiety, and dysphoria. Fourth, the review highlights that long histories of research and population surveillance for certain agents (MDMA, LSD, psilocybin) reduce the need for new, dedicated animal and human abuse-potential studies in some cases. The authors report that sponsors developing MDMA for PTSD were told by FDA that a new HAP study would not be necessary, and they argue similarly that FDA should not routinely require new HAP studies for well-studied classic psychedelics. Nonetheless, for new chemical entities (NCEs) or novel routes/formulations (for example, intranasal or intravenous delivery), the paper indicates that additional studies would likely be required to characterise altered pharmacokinetics or tamper‑susceptibility. Fifth, clinical studies that capture a broad array of subjective outcomes — exemplified by Griffiths et al. (2006) — show that psilocybin produces strong mystical-type and personally meaningful experiences that persist weeks after dosing, and that while euphoriant (abuse-related) effects can occur, they are often tempered by dysphoria and anxiety. The Griffiths study (randomised, double-arm with 30 healthy subjects) found time courses of acute physiological effects (for example, increased heart rate and blood pressure) with return toward baseline within about six hours, and divergent subjective profiles between psilocybin and methylphenidate: both increased some ARCI (Addiction Research Center Inventory) scales, but only psilocybin produced strong LSD-scale effects (interpreted as dysphoric/qualitatively distinct). The authors also cite recent mp-HAP-style studies (small healthy volunteer trials) that limited psychedelic doses to therapeutic ranges, used personal monitors, and included consciousness measures; these trials reported dose-related increases in positive and negative subjective effects and were manageable in safety terms. Lastly, the authors survey public-health and epidemiological data suggesting relatively low prevalence of hallucinogen use disorders: DSM-5 prevalence estimates cited are 12‑month prevalence of 0.5% among 12–17-year-olds and 0.1% among adults for 'other hallucinogen' disorders. They also summarise population studies that associated lifetime classic psychedelic use with lower likelihood of some adverse mental-health outcomes in cross-sectional analyses, though they acknowledge limitations to such epidemiological inferences. Taking the totality of evidence together, Henningfield and colleagues argue that for well-studied classic psychedelics the weight of evidence does not support placement in the most restrictive schedules and that Schedule III or IV would be more consistent with observed abuse-related pharmacology and public-health data, while noting that final determinations rest with FDA and DEA.

The authors interpret their synthesis to mean that abuse-potential assessment of psychedelic substances proceeds under the same statutory and regulatory framework used for other CNS-active drugs, but that classic hallucinogens present distinctive methodological and practical challenges. From a regulatory-science perspective, they stress that abuse-potential assessment requires integrating pharmacological equivalence (Factors 1–3 of the 8FA), public-health data (Factors 4–6), and evidence of dependence/withdrawal potential (Factor 7), and that FDA-driven NDA review is the focal point for assembling this evidence. Because Schedule I status restricts access and raises administrative burdens, the paper emphasises the need for pragmatic regulatory engagement early in development to avoid unnecessary delays. Regarding HAP studies, the authors caution that standard HAP designs emphasising acute drug liking and supratherapeutic dosing may be unsafe or of limited validity for strongly hallucinogenic compounds. They therefore recommend that FDA not automatically require new HAP studies for psychedelics that have an extensive evidence base (for example, psilocybin, LSD, MDMA). Instead, where HAP studies are needed — especially for novel chemical entities, new formulations, or non-oral routes — they propose developing and validating a modified HAP (mp-HAP) model that limits supratherapeutic dosing where unsafe, incorporates personal monitors and set-and‑setting precautions, and expands outcome measurement to include domains such as prolonged 'afterglow', mystical or spiritual experiences, and PSS (psycho‑socio‑spiritual) measures that may influence non-medical use and sustained wellbeing. On scheduling and public-health balance, Henningfield and colleagues conclude that the long history of research and surveillance for classic psychedelics supports rescheduling to less restrictive categories than Schedule I if FDA approves a drug product, suggesting Schedule III or IV as plausible options based on current evidence. They note, however, that FDA and DEA determinations may differ and that international treaty obligations add complexity to national scheduling choices. The paper also stresses that REMS will likely be required for many psychedelic products to manage specific safety risks and diversion, and that REMS design should strike a balance between minimising harms and not unduly restricting therapeutic access — especially given concerns about healthcare disparities. Finally, the authors acknowledge uncertainties and limits: the paper is a narrative regulatory review rather than a systematic meta-analysis, the historical literature includes methodological limitations, and some evidence (for example, long-term epidemiological associations) is observational and subject to confounding. They call for collaborative efforts among FDA, NIDA, researchers, CROs, and an external expert panel to develop validated mp-HAP protocols and to generate the evidence needed for responsible approval, rescheduling, labelling, and REMS development so that both patient safety and access considerations are addressed.