To whom it may concern,

This letter intends to notify stakeholders of an upcoming analysis, conducted by the Dysphoric Project. This analysis will be focused to better understand U.S. policies and guidelines in regard to women in psychedelic clinical trials, and the psychedelic drug approval process.

BACKGROUND– A large body of scientific literature now exists, showing that the serotonergic system plays a key role in psychedelic drug effects. A large body of scientific literature also shows that the menstrual cycle plays a key role in the serotonergic system function.

In a preliminary analysis, our team has found a significant lack of integration between these two bodies of research. So far, we can provide only one example of the menstrual cycle as a variable in psychedelic research, conducted in 1995. These preliminary findings are alarming, from a scientific, safeguarding, and regulatory standpoint. Women are now required by law to be included in clinical trials to account for and understand the effect of treatment alongside cyclical female biology. Investigating, understanding, and reporting outcomes by sex, is vital to better understand psychedelic efficacy and safety for both men and women.

NIH REVITALIZATION ACT OF 1993 - The NIH Revitalization Act of 1993 was passed to promote equality in research, ensuring the inclusion of women and accounting for female-specific variables in clinical research. After the NIH Revitalization Act was signed into law, numerous policies and guidelines were enacted to ensure women are adequately represented in research, including the Evaluation of Gender Differences in Clinical Investigations which states the following:

“The guideline identifies three specific pharmacokinetics issues to be considered when feasible: (1) effect of the stages of the menstrual cycle; (2) effect of exogenous hormonal therapy including oral contraceptives; and (3) effect of the drug or biologic on the pharmacokinetics of oral contraceptives.”

It’s unclear at this point if there are any psychedelic trials considering these factors, however, numerous trials have reached both Phase 3 and breakthrough designation - meaning they could be available as FDA-approved treatments in the near future. The lack of sex focused understanding in this drug development is a significant issue because psychedelic research has been largely funded by private investors, who may not be subject to the NIH Revitalization Act. Drug approval applications, however, are subject to the related FDA guidelines.

SPECIAL PROTOCOL ASSESSMENT– This letter will be shared with the Food and Drug Administration to request updates to the Special Protocol Assessment – Guidance for Industry, under the procedural update provision which states the following:

“The SPA agreement may only be changed through a written agreement between the sponsor and the FDA, or if the FDA becomes aware of a substantial scientific issue essential to product efficacy or safety.”

We hope that updates made to this guidance will include clear and binding provisions that incorporate the FDA’s own initiatives on Sex as a Biological Variable in Research. We also hope that the reference to the Evaluation of Gender Differences in Clinical Investigations will be removed from the footnotes and incorporated into the main text of the document to promote increased clarity and visibility.

ANALYSIS SCOPE - As part of our analysis, we will address the following:

STAKEHOLDER LIST - The general public - including U.S taxpayers, Hystelica, Institute for Clinical and Economic Review, U.S Department of Defense, U.S Department of Health and Human Services, Center for Drug Evaluation and Research, Center for Biologics Evaluation and Research, National Institute on Drug Abuse, FDA Office of Women’s Health, NIH Office of Research on Women’s Health, Department of Veterans Affairs Office of Women’s Health, University of Texas at Austin, John Hopkins University, University of Alabama, University of Arizona, Harvard University, Stanford University, Yale University, Oregon Health and Science University, New York University, University of Washington in Seattle, Washington University School of Medicine in St. Louis, University of Minnesota, Columbia University, Duke University, Emory University, University of Wisconsin - Madison, Mount Sinai, University of California Davis, University of Michigan, University of California at Berkeley, University of California at San Diego, Felicity Pharma, MindMed, Compass Pathways, Cybin, Multidisciplinary Association for Psychedelic Studies (MAPS), Alvarius Pharmaceuticals, F.I.V.E, Atai LifeSciences, Tryp Therapeutics, Natural MedTech, Clairvoyant Therapeutics, Ninnion, MindBio Therapeutics, Terran Biosciences, Mynd Life Sciences, NeonMind, XPhyto Therapeutics, Sensorium Therapeutics, Psychae Institute, Ceruvia Lifesciences, M2Bio, Wake, Beckley Psytech, Mindset Pharma, PharmaTher, Silo Pharma, Entheon Biomedical, Delix Theraputics, BetterLife Pharma, Elusis, Oscillate, Empath Ventures, Psych Capital, Neo Kuma, Leafy Tunnel, JLS Fund, Moetic.

STAKEHOLDER WEBINAR– An online webinar for stakeholders will be held on May 1st. Dr. Grace Blest-Hopley from Hystelica will present preliminary findings from a scoping review to highlight what is known currently from a scientific perspective on psychedelics and female biology. The Dysphoric Project will present an overview of our preliminary analysis on U.S policy and guidelines. We hope that this webinar will be a productive, cross-functional conversation focused on enhancing the safety of psychedelic clinical trials, and strengthening study design for psychedelic research.

Details for joining the webinar will be posted publicly on our website, dysphoricproject.org/open-letter-to-the-fda... for the general public. If a stakeholder or representative cannot attend the webinar, a recording will be provided.

Questions or comments regarding this letter can be sent via email to info@dysphoricproject.org. We hope to balance a collaborative approach with the need for immediate action to ensure female biology is considered in psychedelic research and the psychedelic drug approval process.

Best regards,

Tina A. Williams

U.S Army Veteran, OIF Campaign

Director, Dysphoric Project

Hailey Llewellyn

Menstrual Health Researcher, Consultant

Director, Dysphoric Project