Investigating Insomnia: Closing the Gender Gap in Clinical Pharmacology

Clinical Researcher—October 2025 (Volume 39, Issue 5)

PEER REVIEWED

Diane Heart, BNS, RN

 

 

 

Historically, women’s health has been marginalized in medical research—often as part of a phenomenon trivialized by the term “bikini medicine.” Under this approach, practitioners narrowly focused on obvious anatomical differences between the sexes rather than more meaningful health differences and, as this exclusionary perspective deepened, women of reproductive age were systematically excluded from clinical trials for decades. Seemingly, this was done under the pretext of safeguarding both women and their offspring; however, this practice left male physiology as the default in medical research and drug discovery.{1}

Although international and national clinical guidelines eventually required the inclusion of women in clinical trials, the implementation of these mandates faced significant challenges. Many researchers either failed to adhere to these guidelines or neglected to analyze results by sex, thereby undermining the effectiveness of various policies. Furthermore, preclinical research has mirrored these biases by excluding female cells and animal models, which perpetuates inequities in pharmacological studies.{1}

This systemic oversight has led to profound consequences.{1} A review revealed that a significant number of prescription drugs withdrawn from the market were due to greater adverse effects in women than in men.{1,2} Although researchers are now required to consider sex as a biological variable, the field of sex-based biology and medicine remains underdeveloped and often mischaracterized as peripheral.{1,3}

This article investigates gender disparities in clinical trials and pharmacology, focusing on adverse drug reactions (ADRs) and highlighting critical areas where differences in drug tolerability between genders are most significant, particularly in the management of insomnia.

The Problem

Women are nearly twice as likely as men to experience ADRs across all drug classes and are disproportionately hospitalized due to these reactions. Approximately half of commonly used drugs exhibit sex-related differences in ADRs, with women experiencing these reactions earlier in their treatment. Examples are biological factors such as weight, gastric activity, hormone fluctuations, and renal conditions such as reduced liver function.{2,4}

Biological differences between men and women significantly affect how drugs are processed in the body (pharmacokinetics, PK) and how they produce effects (pharmacodynamics, PD). Key biological factors include, but are not limited to:

• Lower body weight and higher body fat percentage: Women have a higher proportion of body fat, which can affect how drugs are distributed and stored.
• Slower gastric emptying: This can lead to differences in the rate at which drugs are absorbed.
• Hormonal fluctuations: Changes in hormone levels, such as during menstruation, pregnancy, or menopause, can alter drug metabolism.
• Reduced renal clearance: Women typically have lower kidney function compared to men, which can lead to slower drug elimination from the body.

Biological and physiological factors often lead to higher drug exposure in women, especially when medications are dosed based on averages that don’t account for sex or body composition differences.{2,5} This is particularly risky for drugs with narrow therapeutic indices; for example, drugs in which the difference between therapeutic and toxic doses is small, as it can lead to toxicity in women.

A study examining 86 drugs found that 76 of them had higher PK values in women, predicting sex-specific ADRs in 88% of cases.{2} These findings suggest that standard dosing practices often result in women being overmedicated. Adjusting doses for women could reduce side effects without affecting therapeutic results.{2,5}

However, despite clear evidence of sex-based differences in drug metabolism and response, clinical trials often do not have enough female participants, and sex-specific PK data are rarely included in drug labels. This creates a gap in what scientist know about PK and PD for women and for healthcare providers when prescribing medications, leading to suboptimal treatment and potential harm.{2}

Zolpidem

An example of how little is known about drug metabolism between men and women is found in the insomnia medication Zolpidem. In 2013, the U.S. Food and Drug Administration (FDA) reduced the recommended dose of zolpidem for women after data showed higher risks of excessive sedation and impaired driving due to slower metabolic clearance. Additionally, tests showed that women had higher morning blood levels of the drug compared to men, further highlighting the need for sex-specific dosing adjustments.{6,7}

Ambien

Another sleep aid example includes the drug Ambien. Between 1997 and 2000, eight of the 10 drugs removed from the market for various reasons posed greater risks to women than men.{8} Notably, in 2013, the FDA reduced the recommended dosage of Ambien for women by half, 21 years after its initial approval.{8} This decision underscored significant sex differences in the drug’s PK and PD, with women exhibiting 35% lower clearance rates than men in a disparity unrelated to body weight.{6,8}

Recommendations

By adopting a vigilance-based strategy in clinical trials and a knowledge growth mentality focused on women’s health, researchers can address sex-based differences more effectively, ensuring equitable, personalized care that improves outcomes for all patients. Some examples of what this looks like in action are:

• Ongoing Professional Development: Strengthen scholarly literature through research publications regarding findings of sex differences in health and disease.
• Individualized Evaluations: Note sex-based risk factors during patient assessments, including hormonal changes, pregnancy, and menopause.
• Monitor Side Effects: Closely monitor women for ADRs especially for medications with narrow therapeutic indices and report during safety meeting follow up.
• Strengthen Knowledge: Read broadly and consult international government literature guidelines that account for sex differences in drug metabolism and efficacy.
• Advocate for Diverse Trials: Support clinical trials that include adequate representation of women and analyze data by sex.
• Monitor Effectiveness: Regularly assess the impact of sex-specific approaches on patient outcomes and include in team safety meeting follow ups.
• Encourage Reporting of ADRs: Foster a culture where adverse reactions, particularly those that may affect women disproportionately, are reported and studied.

Conclusion

The historical neglect of sex differences in medical research has had significant consequences, particularly for women’s health. The examples of Zolpidem and other drugs like Ambien highlight how systemic oversights in drug development and clinical trials have led to undeveloped knowledge and increased ADRs in women compared to men. Despite policy shifts to address these disparities, such as the FDA’s reduction in Ambien’s dosage for women, many of these changes came far too late and often lacked comprehensive data to support safer and more effective dosing practices for women.

A better understanding of sex-based differences in drug metabolism and response is crucial for improving the safety and efficacy of treatments. The underrepresentation of sex-specific data has contributed to increased knowledge gaps that put women at risk. To address these issues, future research must prioritize the inclusion of women in clinical studies and analyze results based on sex, ensuring that drug labels and dosing guidelines reflect these crucial differences.

By closing the gender gap in medical research, we can create a more inclusive healthcare system that takes into account the unique biological needs of all individuals, ultimately leading to better outcomes and reducing health disparities. This shift is not only necessary for advancing women’s health, but also for ensuring that healthcare interventions are effective, safe, and equitable for everyone.

References

1. Mauvais-Jarvis F, Berthold HK, Campesi I, Carrero JJ, Dhakal S, Franconi F, … Rubin JB. 2021. Sex-and gender-based pharmacological response to drugs. Pharmacological Reviews 73(2):730–62.
2. Zucker I, Prendergast BJ. 2020. Sex differences in pharmacokinetics predict adverse drug reactions in women. Biology of Sex Differences 11:1–14.
3. Regitz-Zagrosek V, Gebhard C. 2023. Gender medicine: effects of sex and gender on cardiovascular disease manifestation and outcomes. Nature Reviews Cardiology 20(4):236–47.
4. Franconi F, Brunelleschi S, Steardo L, Cuomo V. 2007. Gender differences in drug responses. Pharmacological Research 55(2):81–95.
5. Schwartz JB. 2003. The influence of sex on pharmacokinetics. Clinical Pharmacokinetics 42(2):107–21.
6. Greenblatt DJ, Harmatz JS, Roth T. 2019. Zolpidem and gender: are women really at risk? Journal of Clinical Psychopharmacology 39(3):189–99.
7. Woloshin S, Schwartz LM, Dejene S, Rausch P, Dal Pan GJ, Zhou EH, Kesselheim AS. 2017. Media coverage of FDA drug safety communications about zolpidem: a quantitative and qualitative analysis. Journal of Health Communication 22(5):365–72.
8. Harrison K. 2016. A drug for women, tested on men. Yale School of Medicine. https://medicine.yale.edu/news-article/a-drug-for-women-tested-on-men

 

Diane Heart, BSN, RN, (1heartofheart@gmail.com) is a Remote Clinical Research Associate based in Australia.