Let’s learn from the past!
Contributed by Hystelica Researcher Dr Lindsey Block
Sex Bias and Female Underrepresentation in Clinical Trials
Sex bias has persisted in biomedical research, even after studies reported sex differences in diagnostic tests, disease progression, treatment response, drug metabolism, and surgical outcomes. Research shows that the lack of female inclusion contributes to suboptimal healthcare and adverse medical outcomes [1].
Historically, many drugs on the market were not adequately tested in women, leading to reduced effectiveness or increased adverse effects. Despite women often carrying a higher disease burden than men, they have been underrepresented in clinical trials across multiple fields including oncology, neurology, immunology, urology, cardiology, hematology, and psychiatry [1-3]. White participants are also overrepresented, especially when disease prevalence is considered [4]. Even when females and minorities are included, data stratification—analyzing results by sex and minority status—is frequently overlooked [5].
Pharmacokinetics, Pharmacodynamics, and Gender Differences
Drug effectiveness depends on pharmacokinetics (absorption, distribution, metabolism, and excretion) and pharmacodynamics (mechanism of action) [6]. Differences in male and female physiology, such as lower body weight or slower gastrointestinal motility, can significantly impact drug bioavailability, necessitating sex-specific dosing recommendations [7].
Despite these differences, women are 50–75% more likely to experience adverse drug reactions [6,7]. For example, studies on angiotensin-converting enzyme (ACE) inhibitors found women had 1.31-fold higher adverse reactions than men [8]. Certain diseases, including cataracts, depression, and irritable bowel syndrome, disproportionately affect women [6], yet clinical trials often exclude women or fail to stratify data by sex [1,7].
Case Study: Sildenafil Citrate
Sildenafil citrate (Viagra) was initially tested as a blood pressure medication, but its effect on erectile function led to male-centered approval [9,10]. Early trials largely included men, and female participation data is scarce.
In 2013, a small clinical study suggested sildenafil citrate could reduce primary dysmenorrhea (PD) pain in women [11]. However, limited funding prevented a large-scale, conclusive study. This is significant given PD’s estimated $2 billion annual economic impact in the U.S., due to 600 million lost work hours [11]. The lack of female-focused research means potential treatments for women, like sildenafil citrate, remain underexplored.
Historical Context and Regulatory Changes
In the 1970s, the US NIH and FDA supported policies excluding women of childbearing age from Phase I and II trials [12]. One tragic outcome was the Thalidomide disaster, where pregnant women gave birth to infants with limb deformities [12,13]. Early inclusion of women in trials could have prevented such outcomes.
In 1993, the NIH mandated female enrollment in federally funded Phase III trials, but women remain grossly underrepresented in Phase I trials [14]. Drugs failing in male-focused early trials never have the chance to be tested in women, potentially missing therapeutics that may benefit female physiology. Furthermore, even when women are included, sex-stratified data analysis is often neglected, risking insufficient conclusions and overgeneralizations [15].
Menstrual Cycle and Female Physiology
Approximately half the population experiences menstrual cycles, which influence physiology and can impact drug or substance response. For example, studies indicate that alcohol consumption and cravings fluctuate based on the menstrual cycle [16]. This highlights the need for clinical research that incorporates menstrual cycle details.
Female physiology should not be treated as secondary to male physiology. While females experience hormonal fluctuations over a 28–35 day cycle, males also have daily and lifelong hormonal changes [17]. Excluding women from clinical trials reduces female health outcomes and limits understanding of sex-specific drug effects.
Implications for Psychedelic Research
The historical exclusion of women underscores the importance of inclusive psychedelic research. Key questions for the field include:
How does the menstrual cycle affect the efficacy and metabolism of psychedelics? Should dosing or frequency be adjusted?
How does menopause influence psychedelic metabolism?
How do male hormonal fluctuations impact psychedelic effects? Is there a better time of day for dosing?
How might psychedelics affect younger vs. older male brains as hormone levels change?
Moving forward, it is critical that both sexes are included in clinical trials, with sex-stratified data analysis, to ensure safe and effective treatments for all.
References
Steinberg JR et al. JAMA Netw Open 2021;4:e2113749.
Kardie Tobb MK et al. Am Heart J Plus 2022;13.
Sosinsky AZ et al. Contemp Clin Trials 2022;115:106718.
Samantha M. Improving Health Equity Across the Pharmaceutical Industry, 2021.
Bierer BE et al. Cell Rep Med 2022;3:100553.
Whitley H, Lindsey W. Am Fam Physician 2009;80:1254-1258.
Zucker I et al. Cold Spring Harb Perspect Biol 2022;14.
Bots SH et al. JAMA Netw Open 2022;5:e228224.
Jourdan JP et al. J Pharm Pharmacol 2020;72:1145-1151.
Galiè N et al. N Engl J Med 2005.
Dmitrovic R et al. Hum Reprod 2013;28:2958-2965.
NIH Inclusion Outreach Toolkit.
Kim JH, Scialli AR. Toxicol Sci 2011;122:1-6.
Cottingham MD, Fisher JA. Soc Probl 2022;69:492-509.
Zucker I, Prendergast BJ. Biol Sex Differ 2020;11:32.
Warren JG et al. Compr Psychoneuroendocrinol 2021;5:100022.
Law BM. Hormones & Desire, 2011.