Case Study: Sex-Based Drug Effects of Ambien

The sleep medication Ambien, one of the most prescribed drugs in the U.S., was not thoroughly tested in women prior to its release. (Photo by Jb Reed/Bloomberg via Getty Images)

Overview

As described in our posts The Hidden History of Gender-Based Medicine and The Gender Gap in Drug Metabolism, women are consistently underrepresented in clinical trials. For this reason, most drugs on the market have not been specifically assessed in women, and dosing guidelines are based only on age or weight, not sex.

However, increasing amounts of evidence have shown that men and women metabolize drugs differently, usually leading to stronger effects in women. When the dosing guidelines are not adjusted accordingly, women end up taking higher than necessary amounts of medication, resulting in increased side effects. One high-profile case in which this issue occurred was in the development and prescription of the sleep drug Ambien.

Zolpidem (Ambien)

Zolpidem (the generic name of Ambien) was developed to help patients fight insomnia and sleep better. Both fast-acting and slow-acting versions of Zolpidem were developed, in an effort to help people who both had trouble falling asleep and had trouble staying asleep. After its release, Ambien became one of the most prescribed drugs in the United States.

The most severe side effects of Zolpidem occur when the drug effectively keeps its users asleep, even as they begin to act awake. Cases have been reported of users sleep-eating, sleep-walking, sleep-driving, and falling asleep while driving after taking Zolpidem, which all pose a danger to the person taking the drug and sometimes to others.

Lack of Sex-Based Testing

Ambien was released in 1992, one year before the ban on women’s participation in clinical trials was lifted. Furthermore, at the time, the reproductive system was considered the only notable difference between men and women, and Ambien was not intended to have any effects on the reproductive system. For this reason, women were not included in the initial testing phases for Ambien. In later stages, higher blood concentrations of the drug were noticed in women, however, a full sex-based analysis was not completed, due to a lack of female participants, and the results were not considered significant.

When the drug was released to the market, dosing guidelines were based solely on weight, meaning that male and female users of the same weight were prescribed the same dose.

Negative Effects

In the 20 years following the release of Ambien, some users experienced negative side effects, and at least 25 legal cases were related to Ambien usage. Most of these legal cases involved women, and emergency room visits associated with Ambien usage were found to be twice as common among women.

Sex-Specific Dosing

In 2013, in light of these side effects and with the assistance of additional data available from testing of a new formulation of Zolpidem, the U.S. Food and Drug Administration decided to halve the recommended dose for women. Later research revealed that women metabolize Zolpidem differently than men and clear it from their blood more slowly. Women had therefore been overdosing on the drug since its release, leading to increased and stronger side effects.

Upon this adjustment in dosing guidelines, Zolpidem became the first drug class with sex-specific dosing for every formulation.

In 2021, the percentage of adults taking prescription medication was lower among men than among women overall, in the 18-44 age group, and in the 45-64 age group. (Source: National Center for Health Statistics; National Health Interview Survey, 2021.)

Looking Forward

Although women are more likely than men to use two or more medications concurrently and to use more unique medications per year, women are still underrepresented in clinical trial populations. Additionally, even when women are included in studies, sex-based data analysis is not always completed.

Drugs act differently in women for physiological and temporal reasons (for more details, read our post The Gender Gap in Drug Metabolism). Women have a lower body weight and organ size but a higher percentage of body fat than men. Metabolic and digestive processes, blood composition, and flow patterns, and total body water percentages also differ. Furthermore, drug effects may vary based on a woman’s life stage (puberty, perimenopause, menopause, etc.) due to hormonal balances.

Without proper testing, creating appropriate dosing guidelines is more difficult, which may contribute to the fact that women experience adverse drug reactions nearly twice as often as men. Even in common over-the-counter drugs, like acetaminophen (Tylenol), women typically see elevated blood concentrations and longer elimination times, indicating that a lower dose would be equally effective with fewer side effects.

Summary

The case of Ambien illustrates the importance of sex-based drug testing and reveals some notable gaps in research from the past half century. Very few drugs currently on the market have sex-based dosing guidelines, even though they may be acting differently in men and women. In the future, it is important to thoroughly test new drugs in both sexes, and it may be worth reassessing dosing guidelines in existing drugs to ensure safety for all users.

Sources

• “Ambien Dosage for Women Adjusted in 2013, But Sex Bias in Drug Trials Persists to This Day”. Sleep Review. Sleep Review, 2020.

• Armstrong, E. (2018). The Gender Gap in Pharmaceutical Research. Voices in Bioethics, 4.

• Henderson L. “20 Years Later, Drugs Do Act Differently in Women.” Applied Clinical Trials. MJH Life Sciences, 2014.

• Johnson PA, et al. Sex-Specific Medical Research: Why Women’s Health Can’t Wait. Brigham and Women’s Hospital, 2014.

• Zhao, H, et al. Making a ‘sex-difference face’: Ambien dosing at the interface of policy, regulation, women’s health, and biology’. Social Studies of Science 00(0): 2023.

• Zucker I and Prendergast BJ. Sex differences in pharmacokinetics predict adverse drug reactions in women. Biology of Sex Differences 11:32(2020).