High-dose birth control pills linked to elevated fear in safe contexts

A new study published in Neuropsychopharmacology suggests that the use of oral contraceptives may influence how the brain regulates fear responses in safe environments. The research indicates that women who use birth control pills, particularly those with higher doses of synthetic estrogen, may experience elevated fear in safe contexts compared to women who have never used hormonal contraception. The findings also imply that these alterations in fear processing could persist for a significant period after an individual stops taking the medication.

Anxiety disorders and post-traumatic stress disorder are nearly twice as prevalent in women as they are in men. Biological factors likely contribute to this disparity, with sex hormones acting as potential mediators. Specifically, the hormone estradiol plays a significant role in how the brain manages fear and memory.

Effective fear regulation requires the ability to distinguish between a threat and a safety signal based on the surrounding environment. For example, seeing a snake in a forest might require a fear response, while seeing a snake in a zoo enclosure should not. This process is known as contextual fear regulation.

Failures in this regulation process can lead to maladaptive fear, where a person feels threatened even when they are in a safe place. This inability to inhibit fear in safe contexts is a hallmark of anxiety-related conditions. While scientists know that natural estradiol helps extinguish fear associated with specific cues, animal research suggests a different effect regarding the context.

Studies in rodents indicate that high doses of externally administered estradiol can cause fear to generalize to safe contexts. This means the animals display fear behavior in environments that should be recognized as safe. Because combined oral contraceptives deliver a daily dose of synthetic estradiol, researchers aimed to determine if similar effects occur in humans.

The authors behind the new study sought to investigate whether hormonal status and the history of contraceptive use influence contextual fear responses. The researchers also wanted to examine if the dosage of the synthetic hormone ethinyl estradiol creates different outcomes.

“Women are about twice as likely as men to develop anxiety, which is linked to heightened fear levels, even in safe contexts and/or situations,” said study author Lisa-Marie Davignon, a PhD student at the Université du Québec à Montréal. “Some recent studies suggest that the contraceptive pill could play a role in anxiety. Our study explored whether pill use is linked to heightened fear in safe situations, which might help explain why anxiety is more common in women.”

The research team recruited 147 healthy adult participants for a comprehensive two-day experiment. The sample consisted of men, women with natural menstrual cycles, current oral contraceptive users, and women who had used the pill in the past but had stopped at least a year prior. This diverse sample allowed for comparisons across biological sex, current hormonal status, and history of use.

The study participants underwent a fear conditioning and extinction protocol. On the first day, they entered a virtual environment, such as an image of an office, which served as the “threat context.” In this context, specific visual cues were paired with a mild electric shock to the fingers.

Later on the same day, the participants underwent a procedure called extinction learning. They viewed a different background, such as a library, which served as the “safety context.” In this environment, the previously dangerous cues were presented without any electric shocks, allowing the participants to learn that the cues were now safe.

On the second day, the researchers tested the participants’ memory of these safety signals. They presented the cues again in both the threat context and the safety context. The primary goal was to measure “fear return,” or how much the fear response reappeared when the participant was placed back in the safe environment.

To measure these fear responses objectively, the team recorded skin conductance responses. This physiological measure tracks the electrical conductivity of the skin, which changes based on sweat gland activity controlled by the nervous system. Higher skin conductance indicates a stronger physiological arousal or fear response.

In addition to skin conductance, the researchers used functional magnetic resonance imaging (fMRI) to observe brain activity. They focused on specific regions known to be involved in fear and memory. These included the hippocampus, the ventromedial prefrontal cortex, and the anterior cingulate cortex.

The results showed that biological sex and natural endogenous estradiol levels were not related to contextual fear responses. Men and women with natural cycles showed similar patterns of fear regulation in the safe context. However, significant differences emerged when analyzing the groups based on contraceptive use history.

Women who were currently using oral contraceptives showed higher fear returns in the safety context compared to women who had never used them. This suggests an impairment in retrieving the safety memory associated with the context. The fear response remained elevated even though the environment signaled safety.

A parallel finding emerged regarding women who had used the pill in the past. Past users, who had discontinued use for more than a year, also exhibited higher fear returns in the safe context compared to never-users. This indicates that the modulation of fear regulation associated with contraceptive use may have lasting residual effects.

The researchers also analyzed the impact of hormone dosage among the current users. They divided the current users into low-dose and high-dose groups based on the amount of ethinyl estradiol in their pills. The analysis revealed a dose-dependent effect on fear regulation.

Women taking high-dose ethinyl estradiol formulations showed significantly greater fear returns in the safe context than never-users. Those taking lower-dose formulations did not differ significantly from the never-users, though they also did not differ from the high-dose group. This suggests that the quantity of exogenous hormones may be a relevant factor in the degree of fear generalization.

The brain imaging data provided a neural correlate for these physiological findings. Across all participants, lower activity in the hippocampus and the ventromedial prefrontal cortex was associated with higher fear returns in the safe context. These brain regions are essential for processing contextual information and inhibiting fear responses.

The hippocampus is particularly sensitive to estrogen and is central to distinguishing between different environments. The ventromedial prefrontal cortex helps suppress the amygdala, the brain’s fear center, when a situation is deemed safe. The reduced engagement of these areas aligns with the observed difficulty in suppressing fear within the safe context.

There were no significant differences found between the groups regarding fear responses in the threat context. The differences were specific to the safe context. This implies that the issue is not a general increase in fear, but rather a specific difficulty in recognizing or using safety signals from the environment.

“In our study, higher-dose contraceptive pills were linked to differences in how the brain processes fear, such as showing excessive fear in safe situations compared to women who have never used the pill,” Davignon told PsyPost. “Interestingly, women who stopped using the pill over a year ago also showed stronger fear in safe situations than women who never used it. This research helps women understand how the pill may be connected to anxiety and mental health, how some effects could last even after stopping the pill, and how hormone dose might play an important role.”

These findings align with previous animal models showing that high levels of exogenous estrogen can disrupt the hippocampus. This disruption leads to an inability to separate neutral contexts from threatening ones. The current study provides evidence that a similar mechanism may be at play in humans taking synthetic hormones.

It is important to address potential misinterpretations of this research. The results do not imply that oral contraceptives are unsafe or that women should discontinue their use. The study highlights a specific neurobiological effect that may be relevant for understanding anxiety susceptibility.

“Our study is not meant to encourage women to stop using the pill, as this research area is still too new to draw firm conclusions,” Davignon said. “Instead, our results highlight the importance of continuing to study associations between pill use and mental health, so that women can make more informed contraceptive choices.”

There are also some limitations to consider. The sample consisted of healthy individuals without a history of psychiatric disorders. It remains unknown whether these effects would be more pronounced or different in women with diagnosed anxiety or PTSD.

The experimental setup used brief exposures to static images to represent contexts. Real-world environments are more complex and immersive. Future research could utilize virtual reality to create more realistic contextual experiences.

“These results were found in a highly controlled lab experiment, and it will be important to see in the future whether they also appear in more real-world situations,” Davignon explained. “Moreover, our sample was composed of women without any psychopathology – reproducing such experiment in populations where anxiety levels are higher or even clinical could provide important clinical insight.”

Future investigations could explore the role of progestins, the other hormone component in birth control pills. Progestins vary widely in their chemical structure and effects, and they may also contribute to the observed changes in fear regulation. Understanding the combined influence of synthetic estrogen and progestin is essential.

The study, “Lasting effects of oral contraceptives on fear responses to a safe context,” was authored by Lisa-Marie Davignon, Alexandra Brouillard, and Marie-France Marin.