Prescription drugs & sex differences; let’s learn from the past!
Written By Dr Lindsey Block -
“Sex bias persisted, even after research reported sex differences in diagnostic test results, disease progression, treatment response, drug metabolism, and surgical outcomes. Studies have associated this lack of female inclusion with suboptimal health care and adverse medical outcomes” [1].
A lot of drugs on the market were not adequately tested in the female population, which can result in drugs not working well or having adverse side effects in the female population. Despite higher disease burden than males, females were underrepresented in clinical trials in the fields of oncology, neurology, immunology, urology, cardiology, hematology, and psychiatry [1-3]. It should be noted that White people are also overrepresented in clinical trials, especially when disease prevalence is taken into account [4]. Importantly, even when females and minorities are included at a high rate, data analysis does not always take these groups into account (termed data stratification) [5].
Drug effectiveness is based on pharmacokinetic and pharmacodynamic properties. Pharmacokinetic properties include the absorption, distribution, metabolism, and excretion of a compound [6]. Pharmacodynamic properties include the mechanism of action the drug works through in the body [6]. Due to differences in male and female physiology (such as lower body weight and slower gastrointestinal motility), drug recommendations should be altered by gender for safety and efficacy as these differences can impact drug bioavailability [7]. However, despite these known differences, women are still 50-75% [6] more likely to experience an adverse effect [7]. A comprehensive study on angiotensin converting enzyme (ACE) inhibitors, important drugs used for cardiovascular and hypertension treatment, found that women experience 1.31 fold higher adverse drug reactions compared to men [8]. In addition, some diseases, such as cataracts, depression, and irritable bowel syndrome, impact women more than men [6]. Despite these known differences, women were either not included at a higher rate in clinical trials for these or data was not sex/gender-stratified [1, 7].
Lack of females in clinical trials can not only have severe consequences on those who take specific drugs, but lack of females in clinical trials can result in females missing out on drugs that could help them.
Sildenafil citrate, known widely as Viagra, is used to treat erectile dysfunction in males. Although the clinical trials initially focused on using sildenafil citrate as a blood pressure medication, a consistent side effect was erection [9]. Published information on the sex ratio for the initial clinical trials for Sildenafil citrate are lacking[10]. However, based on the strong male-centric finding of sildenafil citrate to treat erectile dysfunction, it is safe to conclude that males were the primary participants of these early trials.
In 2013, a clinical study showed positive effects of sildenafil citrate on primary dysmenorrhea (PD) in women [11]. However, the study was not sufficiently funded which resulted in too small of a sample size for a conclusive finding [11]. Estimates suggest that the economic impact of PD in the United States is $2 billion annually due to the 600 million lost work hours [11]. Despite the social and economic effect of PD, there are few effective treatments and insufficient funding available. Due to a lack of female enrollment during the initial clinical trials for sildenafil citrate, it was never tested/considered for menstrual relief. Although this drug may be useful for female menstrual symptoms, the industry is apparently not interested in pursuing this route.
Why haven’t women always been included? In the 1970s, the United States National Institute of Health (US NIH) and Food and Drug Administration (FDA) supported policies that excluded women of child bearing age from partaking in Phase I and II drug trials [12]. One outcome of this global stance had a horrific effect on newborns. Many pregnant women in Europe and Canada who took Thalidomide during pregnancy gave birth to fetuses with limb deformities [12, 13]. If animal studies included females and pregnant females as well as if women and pregnant people were allowed to enroll in Thalidomide clinical trials, this effect of Thalidomide would have been noted sooner.
In 1993, the US NIH mandated that women be enrolled in federally funded phase III clinical trials. Although this was an important step, there are many steps before a drug reaches phase III. A 2022 review found that women are still grossly underrepresented in Phase I clinical trials [14]. One result is that drugs that fail in male animals pre-trial and fail in men during phases I and II never have the opportunity to be tested in a female body. Since extensive data show drugs impact the sexes differently, it is highly probable that some drugs that do not make it past male bodies could succeed in female bodies. This can also hold true for drugs that did not reach a significant difference compared to placebo but showed a positive effect. In addition, even when women are included in clinical trials the data is often not stratified by sex, which can result in insufficient analysis and overdrawn conclusions [15]. Known differences in male and female physiology (as expressed above) and knowing that adverse drug reactions occur more frequently in women, support stratifying clinical trial data by sex [15].
Approximately half of the population experiences a menstrual cycle, which can impact the body’s physiology. Interestingly, one study found that alcohol consumption and the desire to consume alcohol fluctuate based on the menstrual cycle [16]. This study supports the need of thorough research that includes details on the menstrual cycle.
In summary, Females have historically been excluded from clinical trials due to the variability in their menstrual cycles. Male physiology should not be considered the “standard” and female physiology the “other.” Both exist and differences between them are complementary, allowing us to reproduce. Simply excluding females, especially those of reproductive age, is only a disservice to the ~50% of the population who has a menstrual cycle. Something to note is that while females experience fluctuations in hormone levels over a long period of time (28–35-day cycles), males also experience hormone fluctuations on a 24-hour basis and over their life span [17]. By not including females in studies on pharmaceuticals, female health has been lessened. Let us learn from the past and strive to not repeat these same mistakes when researching psychedelics.
The purpose of this article is to raise awareness of this issue with the goal of acknowledging our shortcomings to ensure our future is more equitable.
Moving forward. Not only do both sexes need to be included in clinical trials but data analysis needs to be sex stratified.
Questions for the field:
How may the menstrual cycle impact the effect of psychedelics? Should dose or frequency be altered based on the menstrual cycle?
How does menopause impact the metabolism of psychedelics?
How do changes in male hormone expression impact the effect of psychedelics? Since one dose can last many hours, is there a better time of day for males to take a dose?
As male hormones change with age, how may psychedelics impact a “younger” male brain compared to an “older” male brain?
References
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