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

Jack E. Henningfield, Marion A. Coe, Roland R. Griffiths, Sean J. Belouin, Ann Berger, Allison R. Coker, Sandra D. Comer, David J. Heal, Peter S. Hendricks, Charles D. Nichols, Frank Sapienza, Frank J. Vocci, Farah Z. Zia

Research output: Contribution to journalReview articlepeer-review

15 Citations (SciVal)


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 languageEnglish
Article number109220
Early online date17 Aug 2022
Publication statusPublished - 1 Nov 2022
Externally publishedYes

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.


  • Abuse liability
  • Clinical study design
  • Consciousness
  • Controlled substance regulation
  • Drug scheduling
  • Psychedelics

ASJC Scopus subject areas

  • Pharmacology
  • Cellular and Molecular Neuroscience


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