It's been 27 years since the United States Food and Drug Administration (FDA) overturned a policy that banned women of childbearing age to be part of clinical trials, but the consequences of such exclusion are still clear to see.
Today, far too many drug prescriptions are based on dosage research conducted on male participants; sometimes, these larger dosages can be dangerous for women and people assigned female at birth.
A new analysis of 86 different drugs, encompassing more than 5,000 articles, reveals that the way the drug moves through the body - called pharmacokinetics - can predict sex differences in adverse drug reactions.
Even though participants were given the same dosage regardless of sex, in more than 90 percent of cases, female participants suffered worse adverse health effects from their medication than men did, including but not limited to nausea, headaches, drowsiness, depression, excessive weight gain, cognitive deficits, seizures, hallucinations, agitation, and cardiac anomalies.
Given the broad scope of FDA-approved drugs that were considered, the authors say their findings support the idea that women are routinely overmedicated.
One of the best examples of this is Ambien, a popular sleep medication that lingers longer in the blood of women; too much Ambien can lead to excessive drowsiness and substantial cognitive impairment, and in severe cases, an overdose of this drug can be fatal. After years of adverse health reports, officials only recently halved the dosage for women.
"When it comes to prescribing drugs, a one-size-fits-all approach, based on male-dominated clinical trials, is not working, and women are getting the short end of the stick," says psychologist and biologist Irving Zucker from the University of California Berkeley.
This gap between male and female participants became a gulf in the 1970s, when the poorly-researched morning sickness drug thalidomide tragically caused birth defects among newborn children.
The FDA took action by banning the drug from the market and also banning women of 'childbearing potential' from early clinical trials (even if they were practising abstinence or if their partner was infertile).
This ban has since been called paternalistic, and it was lifted by the FDA in 1993. Yet unfortunately, its consequences live on.
In 2011, a review of clinical trials found 75 percent did not report any outcomes by sex, including nine studies where less than 20 percent of participants were women.
And this isn't just an issue in the US; the drug dose gender gap, as it is known, has persisted the world over.
A cross-sectional study of over 43,000 published articles and over 13,000 clinical trials found female participants were substantially underrepresented, especially in international research on HIV/AIDS, chronic kidney diseases, and cardiovascular diseases.
"Neglect of females is widespread, even in cell and animal studies where the subjects have been predominantly male," says Zucker.
According to data published in 2018, in pre-clinical animal research on pain, cardiovascular disease, and diabetes, the majority of studies use only male animals, for fear of introducing unnecessary variability.
In surgical research, 80 percent of the studies are done on only male animals, and in neuroscience, only 20 percent of studies use both sexes.
Far from increasing variability, however, recent studies have shown that female models allow scientists to reveal marked differences in biological processes, such as pain processing or drug absorption and clearance.
And ignoring these crucial differences leads to poorer health outcomes for women.
Most of the FDA-approved drugs studies in this new analysis were strongly linked to sex differences in adverse drug reactions.
In fact, in 88 percent of cases, sex differences in pharmacokinetics predicted adverse outcomes that were also sex-biased. In other words, if the drug works differently in women, then there is an "overwhelmingly high probability" there will also be more adverse drug reactions impacting women.
What's more, the different ways in which women processed these drugs couldn't simply be explained by their body weight, which is known to affect drug absorption and distribution. Biological sex as a whole was a bigger determining factor.
"The common practice of prescribing equal drug doses to women and men neglects sex differences in pharmacokinetics and dimorphisms in body weight, risks overmedication of women, and contributes to female-biased adverse drug reactions," the authors write.
"We recommend evidence-based dose reductions for women to counteract this sex bias."
Today, the makeup of clinical trials should represent the overall patient population, and in 1998, another FDA rule stated that safety and efficacy data be explored among both sexes.
Since 2014, the US National Institutes of Health have put into place several policies that would encourage the use of both male and female humans and animal models in research. But there's still more we could be doing, especially when it comes to enforcing these rules.
In 2018, more than two decades after women were allowed back in clinical trials, a review found that of 107 NIH-funded trials, 74 percent did not bother including sex as a factor at all.
With so many drugs on the market, it's hard to say for sure if women are being routinely prescribed dangerously high doses of drugs, but preliminary results certainly suggest that could be the case.
Further research is needed, and in the meantime, the authors of this new study argue the FDA should publicly post peer-reviewed data on how male and female bodies process different drugs.
What's more, drug companies should have to provide credible evidence of sex differences on their labels, and provide dosage adjustments for different body weights as well, where feasible.
"Establishing sex parity in the drug approval process should be explicitly identified as a long-term goal of the Department of Health and Human Services," the authors conclude.
"The decades-long pattern of neglect of female animals in pre-clinical research and underrepresentation of women in clinical trials and research must be corrected, and the recent NIH oversight and vigilance must be maintained."
The study was published in Biology of Sex Differences.