Latest / The XX Lab / What Women Should Know Before Taking Hormonal Birth Control | Dr. Nusa Faric #19

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What Women Should Know Before Taking Hormonal Birth Control | Dr. Nusa Faric #19 · The XX Lab

• speaker-0: Today on the XX Lab, I'm joined by Dr. Nusha Farage, a research fellow at the University of Edinburgh, whose work focuses on mental health, behavior change, and women. Dr. Farage recently conducted an important meta-analysis examining the relationship between oral contraceptive use and the risk of depression, a topic that impacts millions of women, but many people still feel confused, conflicted, or uncertain about. In this important conversation, we talk about what research actually shows regarding the links. Between hormonal contraceptive use and depression risk, who appears to be the most vulnerable to these effects, and why these experiences have historically been difficult to study and discuss openly. We also talk about what women can do if they suspect their hormonal birth control may be affecting their mood or mental health, how to think through the risks and trade-offs involved in contraceptive decision making, and some of the strategies that may help mitigate these effects for women who wish to remain on hormonal contraception. This is a nuanced, compassionate, and incredibly important conversation, and not just for women using hormonal birth control, but for anyone who's interested in women's mental health, hormones, and the complex ways that biology and lived experience intersect. This is the XX Lab. I'm Dr. Sarah Hill. Let's get started. Doctor Noosha Fadrich, welcome to the XX Lab. speaker-1: Thank you for having me, Sarah. speaker-0: Yeah, I'm so excited to have you here today because you have a new paper out where you conducted a broad meta-analysis looking at the relationship between hormonal birth control, in particular oral contraceptive pills, and the risk of depression. And I want to talk to you about that today. Before we like really launch into that, I I just want to know what got you interested in this topic. This, you know, you spent a lot of time. working on this meta-analysis and we'll spend some time talking about what that means for those of you who are listening who've never heard that word before. But it's something that takes a pretty long time to do and especially a really long time to do it well, which I think you've really done with this particular paper. And so what got you interested? speaker-1: ⁓ yeah, thank you for this question. So there was definitely a combination of factors that really motivated me to carry this through because it really felt like it was one of those very tough projects. One, because it's so time consuming, and two because it's kind of difficult to get these things funded. So I had to do it in you know in my sort of like free academic time with with my colleagues and also assemble the right type of people who could help me out. So this actually started in 2011, 2012 as my master's kind of systematic review. So I only sort of scratched the surface there. And, you know, I wrote what I could in a few weeks. And then I thought, ⁓ my goodness, there's so much more. And I also was taking birth control and I had some kind of quite debilitating side effects, which I noticed very early on. And I thought, That I can't really continue taking it as this is a common experience for women. And I knew that probably switching to something else wouldn't work for me because I tried several times with different pills, and I've always had the same, same side effects. And I I told some of my friends, and they just didn't believe me. And actually, that really fired me up. It really, it really made me feel well. as it would anyone when they're not believed. So just generally quite angry. And I got quite a lot of motivation from that spite, to be honest. Like not that I wanted to prove them wrong, but I wanted to know as a scientist, because I'm a very curious person, like whether there was actually any scientific base and biological base to what I was experiencing. So I then went to work in actually in regulatory medical writing. So I was actually producing documents for the Medicines and Healthcare Products Regulations Agency in the UK, so MHRA. And I learned a lot about how clinical trial data is taken and then written into patient leaflets and into, you know, materials the patients and clinicians and pharmacists receive. And I was still thinking about this project. And then I did my PhD and it was in my third year of PhD. there was an email that went round at UCL where I was based at the University College London and they were gathering project ideas and I could be a supervisor and I just jolted this project down thinking no one will pick it up anyway because people kind of don't believe there's an association. Like generally I feel like in research they go, yeah, but you know, but and they try and find ways to kind of talk you out of it. And actually a young researcher came forward. She's the first author on the paper, Madeline Davis Kalog, and she did an amazing job and actually won an award at UCL for the highest project thesis grade, which was kind of unheard of. She got 89%, which on like a master's thesis in the UK is exceptionally high. Like if you get 75 is is exceptional, but 89 is is sort of wow. And ⁓ we tried to publish it, and we tried to publish it in the BMJ, and we got back comments and reviewers' comments, and some of them were reasonable, but again, some of the comments were a little bit contentious and shocking. So, for example, we got a comment back saying one of the very well known side effects of hormonal contraception is loss of libido. How do you know that? Women are not depressed because they're having less sex. And, you know, sort of these kind of comments. And again, I work off spite, honestly. I was so upset about this that I decided enough is enough. We're gonna go and update this meta-analysis because of course there's time lapse. By the time you you finish writing the study and you submit it and you get it reviewed, sometimes it's considered outdated. So you need to update it. And it actually took us a number of years with coordinating everybody to update it. And we went carefully through every single paper and we made sure that we included only high quality trials and studies because we noticed quite a lot of methodological issues with the one and only other meta-analysis that exists on this topic. And yeah, it was just a journey and it was actually something that just didn't leave me alone and It felt almost quite cathartic to get it finished and to say to the world and to everyone who's experiencing similar things, y it's not just in your head. That you know, you're dealing with hormones. Hormones really affect you. They really change who you are, in your own words. So that was really how it all started. And it was a very, very long journey. speaker-0: Sounds like a long journey. So the the paper actually started out as did you say a thesis? speaker-1: Yeah, it started off as like a little systematic review that you have to do in a few weeks. And then it started off as a master's project f which is a the ⁓ the major like master's thesis of the first author of Madeline. It then actually we we said, Well, we need to update it now, also based on all the comments we got back from the journal. And of course the journal didn't accept it at the end. speaker-0: Yeah. And so so you were getting pushback from the reviewers. So for listeners who ⁓ are not familiar with the review process in academia, it's kind of a kind of a mess. Like I I mean, because you send a paper off to other experts in the field. It's usually three, sometimes four, sometimes two. And these other experts will read the paper and then give feedback based on their sort of understanding of the literature and then comparing their understanding of the literature to what's being submitted. And if you get reviewers who have a bias, so for example, if you have reviewers who are reading the paper who are, you know, have an incentive even to believe that hormonal birth control or oral contraceptives aren't related to depression, right? They're not going to be evaluating the paper fairly, right? They're going to be unduly scrutinizing the research. And since for such a long time, the party line in academia, in psychiatry, More in psychiatry, I think, than than neuroscience and psychology, but there's this like the party line is that you really can't demonstrate that there's a relationship between poor mental health outcomes and use of hormonal birth control. I mean, is is that your understanding too? Is that the way that you've sort of read the the party line of the field has been sort of this endorsement of this idea that you can't really sh you know, even though there's been this paper and that paper that have found a relationship that maybe it's because of something else? speaker-1: Yeah, I think it's often like lack of experience or having that personal experience and lack of understanding really how I suppose endocrinology works because if you speak to endocrinologists, they can tell you, ⁓ yeah, you know, I suppose because the contraceptives, hormonal contraceptives can increase the risk of thrombolytic events. plotting events and that's due to low grade inflammation, which is actually higher in in users and non-users, they would say, yeah, I mean that's there's an inflammatory cascade, you know, so the it's very it's very possible that inflammation, because there's something called inflammatory depression, which is actually studied at King's College and I believe at at Oxford University, you know, there's an actual term inflammatory depression, which comes from the increased level of cytokines, which is, you know, to do with Basically, yeah, just high levels, some bodies really respond quite ⁓ vigorously or vehemently to to just a slight change in in inflammation. And you also pointed out, you know, many times how you came across this research with the you know blunted stress response. There's so much that's gone on as a whole array of of changes. You know, your brain processes information differently. So your your sense of smell changes, your sense of even who you're attracted to because attraction is often chemical, of course. You know, you how you perceive facial attractiveness, body attractiveness. I mean, what changes, of course, is how much seebus is produced in your skin because a lot of girls are given ⁓ contraceptives to control their, you know, ⁓ it's more for aesthetic reasons rather than health reasons. And that probably speaks to a lot of teenage girls. And of course it's completely understandable. speaker-0: I find it so funny that it seems like especially in the medical establishment, it's like people are willing to accept the fact that hormones have a whole cascade of influences on the body when they do the things that they want them to do. Right. So it's like the doctor will say, ⁓ you know, this is gonna improve your skin and ⁓ it's gonna decrease your menstrual cramps and ⁓ it's gonna dri decrease your risk of ovarian cancer. But then it like when it comes to, ⁓ well, it, you know, I I think that this might be related to ⁓ poor mental health outcomes. It's like, ⁓ no, no, no, it doesn't do that. Or like, I think that this might be related to changes in attraction. ⁓ no, no, it doesn't do that. It's almost like magical thinking, where where there's like, ⁓ you know, hormones aren't that important ⁓ except for all these other things that they do. And I think that there's a general downplaying of of just how important they are in terms of shaping the activities of the brain, and including, you know, through different pathways, all of which can potentially have a negative impact on mental health. As you noted, ⁓ inflammatory activity. Like we know that you get changes in inflammation in response to hormonal birth control use compared to ⁓ what we see in naturally cycling women. And as you noted, there's a lot of evidence that suggests that ⁓ inflammatory activity can predict depression and poor mental health outcomes. And in fact, you know, I'm I'm of the belief that, you know, 50 years from now, when we ⁓ sort of get more sophisticated in terms of understanding the mechanisms behind depression. I think that we're gonna find that inflammation and especially inflammation as a result of our sedentary lifestyles and and processed food and lack of social connection, all these other things that we know to be related to inflammation, I think are major drivers in the depression epidemic that we see in the industrialized world. I think that that definitely is a mechanism or a potential mechanism when it comes to hormonal birth control use. You talked about changes in the stress response that potentially can lead to changes in ⁓ depression. And ⁓ also ⁓ aren't there changes in neurotransmission that also happen in response to hormonal birth control use? Can you talk us through that? speaker-1: Yeah, ⁓ that or also cortisol levels, you know, ⁓ you you yourself noticed ⁓ in in the research that there's a blunted stress response, meaning that cortisol level is higher so you don't get an appropriate response, a physiological response to a stimuli that it's exciting, whether it's positive excitation or or negative excitation, you know, whether it's somebody's birthday or a surprise, or whether you're scared of something or you need to go on stage. So you can have an overdrive of of cortisol. And interestingly, you know, ⁓ in some research is noted that for example, lower socioeconomic population, you know, they're generally more stressed because of of course socioeconomic factors. And so they are more prone to exhibiting depression. And actually some of the studies that we needed to exclude did a very clever thing where they included a very high number of women in low socioeconomic status in in the, for example, non-user groups. And then, you know, that would level up the effect ⁓ of the stress or of the pill. So that's one thing. Now in terms of the brain, there are very different brain regions that have actually shown volumetric changes, so changes in gray matter volume. speaker-0: Can you tell us can you tell listeners what what is grey matter? speaker-1: gray matter is essentially ⁓ I would say like the new brain or the the part of the cortex that's like responsible for I suppose like well I don't actually know the the exact definition. I'm gonna have to look that up. So speaker-0: So okay, so with with gray matter it's like ⁓ essentially the it's like the information processing in information processing, yeah. speaker-1: Gray matter is essentially like information processing tissue. It's the tissue, but it also works via either chemical or electrical transference of information. And of course, hormones, they like you always say, Sarah, they're not just localized, even if you're using an implant or a patch or an intrauterine device, if you're using a a vaginal ring to deliver. So these are like hormone delivery systems. They Don't just enter your bloodstream locally and stay there. They actually travel and they they cross the blood-brain barrier and they affect very various neurotransmitters. So there have been a number of studies which we actually cite in our paper. So there is now increasing research into the underlying sort of biological mechanisms of how ⁓ oral contraceptors may influence mood, such as, for example, oral contraceptive. induced ⁓ changes to brain structure and activity in brain regions that are linked to emotional regulation and the development of certain psychiatric disorders. Also brain regions that are responsible for altered stress responses and the hypothalamic turretary axis, which is actually the beginning or the, you know, this is where your menstrual cycle begins. The pill actually starts working and then it tells the ovaries to stop producing or to halt production of certain hormones. So what's interesting is that some of the ⁓ studies have actually found that the effects of hormonal contraception can actually be so severe that it can be similar to some psychological stressors, like long-term stressors, such as for example, certain patients with PTSD. So it can in some women it can actually really cascade into an extreme form of ⁓ stress response. speaker-0: So before we get into the weeds with your meta-analysis and start to talk about what you found, I'm just wondering if you can orient listeners to a natural menstrual cycle and then how that changes with hormonal birth control. speaker-1: Well, really the hormones are quite leveled out. So during the menstrual cycle, you have ⁓ in the first ⁓ half the cycle, you have the rise in estrogen and then that fall around, you know, a drastic fall just just before violation, and then progesterone rises in the second half of the cycle. But with the pill, this is actually leveled out so that it's almost just continuously the same. And some ⁓ authors have argued that, you know. This is the pill or the appearance of hormonal contraception is one of the early biomedical interventions that stops a natural process. Because really, we have biomedical interventions to help us fix something that has gone wrong. Yet in a natural menstrual cycle, nothing has really gone wrong. It's a natural process. But what we're doing with biomedical intervention here is that we're that we're stopping or Altering that natural process. You still have a bleed when you ⁓ are on hormonal contraception, depends on what kind, but that bleed is similar to a period and it's not really a period, they call it a sham period. And that's because the lining of the uterus doesn't really thicken in the same way. It shows that it has a slightly different appearance also under a microscope. So because it's like it's grown by by almost like ⁓ propelled by different information because really hormones are agents of information. They travel from one part of the body and go to the other part of the body and tell it what to do and tell that tissue, ⁓ can you behave this way or can you do this? Can you release that? So it's really all communication and that communication is changed. It's altered. And of course that that then shows in our behavior. It shows in in many different ways, ⁓ how we think, how women relate to one another, how women relate to the world, because the brain really processes information very differently. speaker-0: Yeah, it's like the our brain is hormonal. You know, it's it's wired to be sensitive to our cycling sex hormones. And so when you take a naturally cycling woman who, as you noted, has these this big rise and then the fall of estrogen in the first half of the menstrual cycle, and then the big rise and fall of progesterone, and also some estrogen in the second half of the cycle, that creates a very different experience both from the neck down, like including the building and the differentiating of. Endometrial tissue. So you get that differs. And also what's happening psychologically, right? That you get these changes in the way that women experience themselves and the way that they experience the world around them. And for, you know, a long time there's been this debate about mental health and whether hormonal birth control use may be related to changes in mental health. And as you noted from your own experiences, it's like a hot button topic. Like people get really fired up about it, about with women who are like you, who've had experiences, like bad experiences with ⁓ mental health using hormonal birth control. I actually had, and I didn't write about this in my book, but ⁓ I for the most part, because I was on hormonal birth control for like about twelve years in total, and I didn't have any ⁓ bad mental health experiences except for on one. particular type of hormonal birth control. It was the hormonal birth control shot. And I was on it for one, you know, shot cycle, which I is about three months long. And it was, I cried every day. I bled and cried. Every day I cried and it was, it was just terrible. And the worst thing about that shot is that you can't undo it. Once you get it and and then I'm crying every day. And I knew exactly what was going on. And but there's nothing I could do. You know, so I just had for the next three months had to like cry my eyes out. And it was my spring semester in my freshman year of college. And I was actually traveling in ⁓ Paris with my boyfriend at the time, crying my eyes out all the way up and down the Champs-Élysées. It was really like you and I where you we've had this experience where we say, you know, we know that this. speaker-1: And so difficult. speaker-0: Is a result of this. And then you have ⁓ people who are very strongly, you know, no, you can't demonstrate that hormonal birth control is related to a greater risk of ⁓ developing depression. There's so much confusion around this issue, which is why I was so excited that you wrote this really beautiful paper that recently was published looking at a meta-analysis. And for those of you who don't know what that is, a meta-analysis is essentially a study of studies, is like a super study. Where you're looking at and pooling together the results of different research papers that have already been published on a topic. So it's almost like a scoping review, but using data. So in addition to just reviewing things verbally, you're also going back and looking at the magnitude of the effects that they find. And you also are looking at the quality of the research. And what I really loved about your meta-analysis is that. It took all of this body of research where we have these conflicting results, where sometimes you find that hormonal birth control is related to a depression risk. Sometimes people say that it's not. And your paper also, in addition to just like pooling, you know, and looking at the patterns and the data, you also ⁓ stratified and and excluded papers that were of poor quality. And you tended to give more weight to those papers of high quality. So ⁓ I would love for you, first of all, just to talk to us about the different types of papers that you included in that. So like with you know, when you were looking at the literature, what was the amount of variability and the quality of the studies that were out there? And then what did you choose to include in your meta-analysis? speaker-1: Yeah, that's a really great question. That's literally like a whole universe in of itself. Like I could give a lecture on this. One thing I really wanted to say, you know, when you said when you were on Champs Elysee with your ex boyfriend, I cry I had a very similar experience with a friend of mine who I wasn't on hormonal birth control at the time because I can't really handle it for a very long time. But I didn't know my friend was and we went traveling, a group of us we went to Berlin and very similar to what you described, just kind of quite con we were so confused and then she told us and then we thought, okay, that's fine. So I think it's very important for women to find the right fit and to find like what really works for them and One of the things we noticed when we were screening ⁓ papers, you first of course have a look at what's out there already, like what kind of a systematic review or meta-analysis exists on this topic. So we came across, ⁓ you probably know about Cochrane Library. So Cochrane is this independent body, UK-based body that, you know, just kind of ⁓ is affiliated with a lot of institutions, produces systematic reviews on any topics. any topics whatsoever. Let's say that you're looking at like the effectiveness of tamoxifen on on breast cancer proliferation or something, you'll find it. You'll find anything. And so we we thought, okay, well let's see what sort of like systematic review is out there on any of the hormonal contraception. And we found one published in 2011 and that's the only one that's around on combined oil contraception. And it's called types of progestogens in combined oral contraception effectiveness and side effects. And it's a 99-page long review. And believe it or not, depression, anxiety, mood changes are not mentioned a single time. So that was a very big shock because it was almost masking. So it really it really paid attention to things like breast tenderness, headaches, nausea, vomiting, migraine. Dizziness, decreased libido, high blood pressure, other more minor effects like vaginal discharge, abdominal pain, acne, alopecia, but nothing on mental health effects. speaker-0: You know what's so crazy about that is that I mean, I've I've seen the research, and I'm sure that you have too, that I think it's like 50% of women who start hormonal birth control sto stop it within a couple of months because they can't stand the side effects. And like the number one side effect that causes women to discontinue hormonal birth control is is mental health-related side effects. And and they're so essential. You know, it's it's like vaginal you know, whatever changes. I mean, obviously that's something that that can create problems for a person, but it's not as essential of as like the way that you s experience the world, you know, like with your mental health. speaker-1: Exactly. Now what they did use as a term, and I've noticed that the more up-to-date patient information leaflets on hormonal contraceptive products, they instead of, you know, the ones maybe from sort of five years ago and older used depression, anxiety, mood changes. But sort of with the with kind of yeah, five years ago or so onward, they started to use this term nervousness. And I actually queried FDA, ⁓ MHRA, which is equivalent to FDA in the UK, and you know, these kind of British like medicines, compendiums, British medicines formularies to see, because usually when you conduct clinical trials, you need to have a list of possible side effects that you can report and the definition. But they don't even define what they mean by nervousness. So when this is now written into patient information leaflets that That you know, like for example, you would know in America with the introduction of O-Pill, over-the-counter pill, that's available in in so many places now, nervousness is actually listed as one in ten or like very common side effect. But really, what what would you say nervousness is? What would you say that you have inner tension, that you feel uneasy, that you feel afraid? I mean, how nonspecific is the term nervousness? speaker-0: To me, it also feels it minimizes it. Like nervousness sounds like the way they feel before test. It doesn't sound like not wanting to get out of bed or considering ending your own life, which is, you know, what we find in some cases with hormonal birth control. speaker-1: Yeah, the other thing that a friend of mine who works in clinical trials said what's possible is that they take various side report, like side effect reports and just like group them into one. So that that's a possibility. And that way they're not being so specific. But yeah, so so that was like the first thing that kind of stood out. And, you know, it kind of rang a little bit like, well, all the all the patient information leaflets state that. Depression on anxiety or so-called nervousness is very common. Why are you not even mentioning it? Type thing. That raised some eyebrows because it's a very trusted source. Actually, Gochin is supposed to bring, I mean, their mission and their vision is to bring very trusted evidence on any topic, on any decision making. That happens in healthcare so that people can and public and you know physicians and nurses can feel feel reassured and have a source to go to to check for sort of latest evidence. So that was one thing. So the second thing we had to look at was the existing meta-analysis on this topic. And that was performed in 2001. And really it was it was well written. It used some of the nice graded evidence because when you take papers you need to grade them for evidence and it was quite comprehensive. speaker-0: When you say grade them for evidence for people who are listening and don't know, like does that mean that you're essentially grading them for the quality? So it's like if if it's better, it gets a higher score. And if it's like lower quality, it gets a worse score. speaker-1: Yes, exactly. So you have a number of criteria. They're usually quite long, this criteria, so you have to go through them carefully. So there are things like are statistical methods appropriate for the type of data? What type of data is used? How many people are in the study? Is it like what type of study is it? Is it a small like cross-sectional or cohort study, which means that it's like a snapshot in time? Or is it going forward, so people taking people who've never taken anything and then measuring when they do take something. So, you know, maybe three months, six months, twelve months, and so on. So that would be a prospective study. Or is it asking people how they used to feel? And that could be self-report study or can be something like looking at their health data and trying to figure out if there's a relationship between a time when they weren't taking something and when they started taking something, now that's called a retrospective study. So, you know, you have all kinds of different criteria, things like how clearly is ⁓ are statistics reported? ⁓ you know, how have they dealt with noise, what's called noise in the data, which is data that's not explainable. How well did they deal with shortcomings? So actually you go through all this criteria to then give it an overall score of high quality, medium quality, or low quality. And so the previous meta-analysis did that very well. They also had a comprehensive electronic search. Their conclusions were again a little bit questionable because they looked at hormonal contraception. So they didn't just look at oral hormonal contraception. And they did find a positive effect on mood with oral contraception. speaker-0: So when you say when you say a positive effect on mood, meaning that women who are taking oral contraception had a better mood? speaker-1: Yes. And so they found that actually for all the other contraceptive options there was worsening of mood. But for the pill, there was, you know, ⁓ an improvement in mood. And so we wanted to have a look at what was really going on there. And there are a number of things that again we think that basically invalidates that meta-analysis or makes it makes it very questionable. So, first of all, they used a lot of very low quality studies. So, studies that had such a wishy-washy way of sort of using the data and scoring things together that there was just no reason to include them. Second of all, they had one larger trial and they really relied on that one single trial to draw conclusions because they used a certain type of meta-analysis. So when Sarah, you were talking to the, you know, and explaining to the listeners about Different, I mean, what meta-analysis is, there actually are different ways of how you can synthesize that data and make a big picture. So you can compare different types of studies or different types of populations, and you can come, you know, you can combine different kinds of outcomes. In this case, you can combine different types of pills and compare them against the placebo, but that's not what this meta-analysis did. This meta-analysis actually compared each pill with another pill. And then made sort of an overall assumption and conclusion. So it's called something called network meta-analysis. And I would, for the listeners, I will explain it this way. So you know what the relationship between A and B is, and B and C is, but then you make a calculation, or the computer makes a calculation, what the overall difference between A and C is. So it's in a way, it's a little bit of a guess. So network meta-analysis was very inappropriate method for the type of data that the authors were analyzing. And then also they had very few placebo-controlled studies. So that's that was a big issue. speaker-0: Just for ⁓ listeners, just in case there's people who don't understand that when you have a placebo controlled trial, that that means you've got an experiment. And it's it's it's only when we do an experiment that we're actually able to tell cause and effect with an outcome. So, you know, can if you have some a group taking ⁓ randomly assigned to take the pill and the other group is randomly assigned to take the placebo, and then you see changes in mental health ⁓ between those two groups, you can actually make the inference that the that the changes in mental health are the result of Taking the pill versus the placebo. Right. And so what you're saying is that in this other meta-analysis, that that they used very few of these and that they tended to rely really heavily on these network types of analyses where they're not really even comparing A and C, right? They're comparing A and B and then and then B and C and then making inferences about A and C. And so you were looking at this existing work and saying, I don't know about this. speaker-1: Exactly. And they also, for example, you have ways of measuring depression, right? So depression is measured either by self-rapports, which is women ⁓ scoring on a validated scale or a clinician doing that for them by interviewing them. So you get an overall score of how depressed you are. You have many different validated scales, but most famous one is BDR or bike depression inventory. And so what this meta-analysis did is it combined all kinds of different studies. And remember, these are low-quality studies without the placebo control. They might be comparing. Two different or three different hormonal contraceptives between each other rather than against the placebo. Some of the measures for depression, the higher the score, the higher the depression. But some of the depression scores are the lower the score, the higher the depression. So what they did is they didn't standardize this. So in a way, they their results could have nullified the results because they didn't even statistically take care of of of basically ⁓ standardizing measures, meaning that they, you know, in statistics it's called homoscedacity in statistical terms, when you just have to align the s the scores so that the positive on one and the negative on the other actually mean the same thing. And so they didn't they didn't do this. They they they just left it as it was without any explanation. They also say they used a particular mathematical model called Bayesian method, but they don't specify which one. And also, I was shocked the reviewers didn't pick this up, was when they said, for example, they actually make misleading and statistically inappropriate statements. So they would say, we provide quantitative evidence based on experimental data that hormonal contraceptive use is relatively safe regarding the effect of on depressive symptoms. But the authors didn't provide any safety data whatsoever. Yet they're making all these claims about safety. So it was really It was so far-fetched, and we thought, no, we need to repeat this. We have to do a meta-analysis like this, and we have to be more careful in what we're including. So when you were asking me about what we excluded, so we had some reference. We thought, okay, Cochrane Review mentioned depression sparingly to say the least. This meta-analysis didn't really use the best methodology. So how can we improve this? So we had ⁓ gone through the studies as you typically do as a researcher. You run your searches in major databases, you pull in into spreadsheet papers that you think are relevant, and then you have to screen them. You have to go through every single one of them and say, yes, this one belongs to my study, or it doesn't. So the reason why we excluded a lot of studies was because they, for example, did the following. They labeled Women as non-users of the pill, if they had used the pill for less than four months, three months, or six months. So not only did they exclude the women, they actually put them in non-user groups. I mean, that's essentially saying you become a user of the pill or of the medication the very first day you take it. That's when you become a user. But in these studies, somehow they were able to argue. That you have had to been using the pill for three months or four weeks, three months, or six months to be even be called a user. So during those times before you're not a user, you're you're a non-user. So when you when you do placebo controlled studies, when you do a a pill versus placebo or non-pill. you actually had in the placebo group, you actually had pill users, but they were forced into non users, even though they were using it because they haven't used it for a certain duration of time. speaker-0: Well, and I would think that that would unnecessarily bias that group to have bad mental health, right? Because if they so here's a group of people who was was on hormonal birth control and then discontinued it, presumably b for some reason, right? And oftentimes it it's is because of side effects. And so here's women who are sensitive to side effects. And one thing that we know about women who are more sensitive to mental health side effects tends to be women who have a ⁓ biological predisposition to depression. So now you're putting these groups of women in the control group, right? And that's going to bias that group by sort of tilting them toward being more likely to have poor mental health relative to users. So it's not really a fair comparison. It's not apples and apples, it's apples and oranges. speaker-1: Exactly. We also noticed that some studies said that the users would report depression and anxiety, and the study authors argued that they had to have either depression or anxiety, but not both combined. So if they had developed both depression and anxiety, they were excluded from the study. speaker-0: So again, so people who have the worst outcomes are excluded from the study. And by the way, folks, for those of you listening, th those two conditions are comorbid, meaning that they tend to co occur more frequently, oftentimes than they don't co occur. And so this is ⁓ this is also problematic. speaker-1: Yeah, especially in ⁓ younger women, you know, a lot of studies have suggested that younger women, so b when the brain is still still developing between sort of ages of thirteen to twenty five. So the the lowest age studies we found were thirteen years old. So ⁓ women starting the pill at thirteen. So that would be the lower cut of Cut off point, you know. So most studies run up to sort of ages 37, 38, maybe. But yeah, we found this is when the brain is still developing. And actually, in a lot of studies, ⁓ particularly with progestins, so artificial synthetic progesterones, or yeah, but they're called progestins, the effect of this mood worsening is is is really pronounced in in adolescents and in younger women. Because the brain is quite plastic. It's called plasticity. So it's very adaptable. The the brain is able to adapt itself if it has an injury or if it has some sort of changes going on. Usually goes back to baseline if you sort of don't play with it too much. But actually in adolescence, ⁓ the brain studies have shown that some for some reason the brain doesn't really go back to to ⁓ the same sort of wiring. So that this like there there may be this long-term change. And of course this this has actually been confirmed studies showing that younger women are more likely to stay on antidepressants if they had been taking hormonal contraception in in adolescence. speaker-0: Just to to stop on that for a moment, because that's very consistent with the the literature that I have been seeing, where there's now rodent models that show that, you know, it's essentially the rodent equivalent of ⁓ adolescence. If you put rodents on hormonal birth control during that time, that you get structural ch changes in the brain. Because of course the brain is developing during adolescence. You're going through the pubertal transition, your brain is Turning from the child version of itself into the grown-up version of itself. And ⁓ part of that means that it's being rewired, as you said. Like the brain is uniquely plastic during this time. And so that the developmental changes are happening that that sort of essentially re-remodeling itself into an adult version of itself. And that there's research now that finds that ⁓ girls who go on hormonal birth control during adolescence. That this may increase their risk of developing major depressive disorder that lasts throughout the lifetime. And and and now you're mentioning, and I actually wasn't familiar with that particular finding that you just told us about ⁓ that girls who go on antidepressants during adolescence or hormonal birth control use, that they tend to stay on it longer, which ⁓ is consistent with this other work that that seems to find that that it may lead to developmental changes that ultimately increase the risk of long-term. Major depressive disorder even after girls discontinue hormonal birth control use. speaker-1: Yes, precisely. And the reason why this is also important in this context that we've been talking about what has been excluded from our studies. I mean, we've also come across studies where they had deliberately excluded girls who started to take hormonal contraception before the age of fifteen. Because a lot of studies start off with thirteen. So essentially they would have cut out, you know, at the most at risk group, because we know that younger girls respond. to hormones just in a more in a more kind of intense in intense way. I don't know, they have much higher, kind of more negative responses to hormonal contraception. Maybe because their brain is still developing. But actually those users who start later, so after the age of 25, their depression doesn't seem to be ⁓ as so it's still statistically significant, but that difference isn't so large. So these were really the reasons why we excluded studies. They were either you know, really I badly designed. They were also ideologically driven. So they really excluded women who they should have really kept in. I mean, the fact that you were allowed to put a user into a non user group, I think should be forbidden. Not even a possibility because it's not true. Because you are Yeah, you're a user the very first moment the the moment you take you you take the drug. You're a user of the drug. So speaker-0: Right, yeah. speaker-1: That was quite shocking. So we stuck to better design studies and we made sure that the studies that we included were good quality studies. So that the picture we also used a different way of synthesizing the data. So when I was talking and we were talking about meta-analysis of the big picture and how the previous study compared A's and B's and B's and C's and then tried to make this calculation of what the relationship between A and C is, we didn't do this. We We actually did an analysis based on when the changes were reported in women's cycles, so that we had a very kind of same measurement across all the studies, and then we compared non-users to users. So we we performed a very different type of big picture analysis, which is more appropriate for that type of data. speaker-0: And so what were the different outcomes that you looked at when you were measuring depression? Did you just look at depression diagnoses? Did you look at ⁓ probability of being prescribed antidepressants? What were the different endpoints that you explored in your in your study? speaker-1: So the endpoints were as typically the studies do, one is the actual depressive score and the psychotropic drug use. So that would be the use of antidepressants. Some studies also controlled for things like anxiolytics and other types of like psychotropic drugs, but mostly it's just all antidepressants, different types of antidepressants. So antidepressant initiation. And then the third thing we looked at was being diagnosed with depression in the first place. So it's not just what your score is and how high your depressive score is, but are you being diagnosed? So how many people get diagnosed with depression? And usually when you get diagnosed with depression, it is it must be pretty serious. So it could be ⁓ mild to severe. So it's more of a clinical depression rather than just, you know, I'm I'm feeling a little bit, you know, under the weather today type thing. So th these were the three outcomes we had, yeah. speaker-0: And tell us, ⁓ let's get to the punchline. What did you find in your meta-analysis when it came to probability of being diagnosed with depression? ⁓ so having clinical levels of depression, depression scores, and the probability of being on in antidepressant medication. speaker-1: We had to group studies into different categories because not all studies looked at antidepressant initiation, not all studies looked at the depressive scores. So this is the breakdown. Drum roll across five studies, which ⁓ totaled 1.6 million women. Pill users had a 31% higher relative risk of being diagnosed with depression than non users. And then in the three larger Cohort studies, which actually combined 2.15 million women. Pill users were 25% more likely to start antidepressants than non-users. And then we had eight smaller studies that measure symptom scores directly, and those only kind of combined 2,500 women. Pill users had a slightly higher depression score, so a statistical, statistically significant score. And this would have equated, we actually did a calculation, this would have equated to zero point eight points difference on a depression inventory. So on the particularly BEC depression inventory or BDI, which is the most common or well known depression measurement scale. speaker-0: Yeah, for those for those of you who aren't familiar with this, the BDI, the back depression inventory is the you is the usual suspect. Like if you go to the doctor's office and they give you a little test that's measuring your mental health, that's usually what they're using, is the back. speaker-1: Yes, exactly. We also had some studies that use MADRS, which is Montgomery Osbour depression rating scale, but and ⁓ and but but we have standardized it so that it aligned with the Beck measurements. So this is something that the previous meta-analysis didn't do. It had so the depression scores ⁓ were statistically significant, but we had to say that they were clinically modest or clinically small because The 0.8 score difference on a depression score sometimes can make a big difference, but sometimes it doesn't. So actually that difference can go either way. So those are the three main findings. speaker-0: What I think is so interesting is that, you know, when you look at the literature, and there's a lot of messiness in in terms of like this paper finds this, and then this paper finds that, and this paper finds that there is a relationship between hormonal birth control use and depression, and this one doesn't. That usually the pill, the combined oral contraceptive pill, is the one that kind of comes out smelling like a rose. Because when you look at a lot of the, you know, the the papers, like ⁓ they they find that, you know, the non-oral products generally tend to have a worse risk profile when it comes to mental health. And that this tends to be true for both teenage users. So again, these adolescent users who may be on a greater risk of developing depression throughout their lifetime. But then also with the adult users in that the the the hormonal IUD and the shot and you know and the patch ⁓ that that they tend to do worse and that the combined oral pill tends to kind of blink in and out of the danger zone, right? Some papers finding that there's no link Between oral contraceptives and only non-oral products, and then other product, you know, then other papers finding that they do. And so with your project, what you found is that with these combined oral contraceptive pills that oftentimes come out looking better than many of the other options in terms of their mental health risk profile, that when you look specifically at the best done studies and looking ⁓ specifically at, you know, things that use experimental methods. Large samples don't include users in the control group and do some of these ⁓ things that other researchers weren't doing. That in this case, when you look at things this way, that you do find this pattern. So, do you think that we're finally going to be at a place where clinicians and people alike are willing to say that using hormonal birth control? Including combined oral contraceptive pills, which tend to again have the lower mental health-related risk profile compared to a lot of the other products out there. When you look at all of the different studies that have been published, do you think that we're finally at a place that people are going to actually start to acknowledge the fact that at least for some women, right? Because this isn't saying that everybody who takes these products is going to experience a negative mental health side effect, because we just we know that that's not true, but that instead that that we're going to get to a place where People are gonna acknowledge the fact that for some women that this might be bad news for mental health. speaker-1: I think so. I mean, I've done my due diligence. I've written to ⁓ you know, various newspapers and I've given ⁓ the paper to my GP. So my GP's actually such a interested doctor. He really takes care of new evidence and he was really interested and he said, I'll tell my colleagues. I also told my ⁓ gynecologist, and he said, when this is published, I really want to see it. So some people are taking an interest, and I'm just generally that sort of person who's like, Listen, I have this new cool study out. I've been working on it for so long, and it means the world to me and to the women. You know, this is really for all the women out there, for anyone who actually Did make an effort to look for evidence and found that inconclusive evidence. And now they're able to read in our review as well that why ours is different to the one that already exists with the, you know, the big picture. I'm yet to write to Cochrane to ask them what this is all about. And yes, I mean. I really think that people are waking up also because women are becoming more vocal. They're also becoming a little bit more aware. You probably know about the lowdown, the sort of online repository of side effects to all things contraception. speaker-0: For those of you who are listening who don't know what this is, you should check out the you should check out their website. But it's essentially a database. It's it's like a crowdsourced database that's been put together where people you can log in and look at people's reports of what they experience when they're on different forms of hormonal birth control. ⁓ and then you can also put in your own experiences and then read from other people's experiences and see how people review that. Very cool. So if you have you talked to them about this, have you told them about your paper? speaker-1: I know that, you know, just when basically what I mean is women are waking up in terms of having this ⁓ these sort of ⁓ you know, it's kind of like trip advisor put but for contraception. I think that's how they like to describe themselves, right? So essentially I think women can go to these platforms and read up I'm and I I really feel that the younger generation especially are so curious about what they're taking, what they are putting in their bodies. They're very Good at really evaluating is this the right thing for me or not? Do I and I think there's a lot of information out there, and it's very sincere because of course it's people's genuine sort of reports and the lowdown really group symptoms into different categories, and you can see very clearly that depression and mood changes are some of the, you know, most common side effects and reasons for discontinuation or for the change. And often you can also read very positive reviews, people saying. That after trying many different pills or different hormonal contraceptive options, they finally settled on something and the and it really agrees with them. So, you know, they're it's definitely worth exploring. So there's information out there. I'm also gonna update Wikipedia pages. So I'm gonna make sure that the study's cited on Wikipedia. And yeah, that just generally people take this a little bit more seriously. We used to have a high school teacher, yeah, in in my biology class, and she ⁓ She always said, girls, girls, this is hormones we're talking about. You're taking hormones. Just remember that. That is serious. So I thought that was that was very poignant. She didn't, she didn't tell us off and she didn't tell us don't take it. She just said, girls, girls, you know, just think. These are hormones. This is not a joke. speaker-0: I love that. And I mean, I honestly, like that was really the message I was trying to write with my book was just that, you know, this is your brain on birth control was about getting people to recognize that like we've been really cavalier about this, you know, and and that hormones really are a big deal. I mean, they they signal to all of the different Cells in our body from head to toe, including so many in our brain, that of course it's gonna have the effect of changing the way that we experience ourselves and experience the world. It's been treated so, you know, lightly by the medical establishment with, you know, in in the United States, of course, they give them to young girls as soon as they get their periods to, you know, regulate their menstrual cycles or to decrease acne or decrease menstrual cramping without even thinking about the fact like what actually happens to a young girl. whose brain is still developing and whose whose reproductive, you know, axis is still developing, what happens when you shut down her hormone production? Like nobody's nobody's asking those questions, or very few people are asking those questions. And it's and it's because I think we've we've been so so cavalier with women's hormones. speaker-1: Yeah, and I I think also it's interesting, you know, how many women report lower libido on hormonal contraception and that's the point of it. It's kind of the, you know, sexual liberation. So you kind of think, now how does that make sense? speaker-0: Yeah, I I always say that it's like one of the biggest ironies in modern medicine, right, is the fact that going on hormonal birth control, which a lot of women take to help facilitate sex, can oftentimes lead to total sexual break like shutdown. speaker-1: Yes, exactly. But some women are are lucky. They don't they don't get much of any or any side effects and it's always worth exploring, listening to your body. That would be my kind of take-home message, you know, listen to yourself, know your truth. And just to clarify for those listeners who may think that I'm a spiteful person, since I was saying how I get motivated by spite, I get motivated, I think, by that kind of injustice and like knowing that something is not quite right and then, you know, not being believed or something like in this in this sphere I knew, ⁓ no, no, this this this this is a genuine thing. This is not just in my head. So I really wanted to explore it. It was just something that, you know, completely didn't leave me alone. But no, I'm not a very spiteful person at all. speaker-0: Right. Well, no, it's you're ⁓ you're suitably fired up for all of the women who've been told that that these experiences that they're having were all in their head. Right. And ⁓ and that, ⁓ no, you know, all this research finds that there's no link between hormonal birth control and mental health related side effects. And I mean, honestly, like even before the time of your paper, and I think their paper is like so nice and you did such a really great job on. ⁓ on your meta-analysis and really spotlighting the the papers that have been done, like using really good experimental methods and the way that you homogenize the data in order to make sure everything's on the same playing field. Even before that, I feel like you'd have to be completely naive in some ways to look at the literature and say there's nothing there. You know, because even if you have effects that are blinking in and out, like as a scientist, I look at that and say, okay, there's something moderating this effect. Right. Meaning that sometimes you find it in some people and then other times you don't find it in other people. And then our job as scientists is to like go and try to figure out what that is, right? Like why is it like who are the people that this is having this effect on? And then who are these other people that it's not having this effect on? But to even look at the state of the literature where you have some, you know, papers finding effects, other people's not finding effects, to to have the audacity to say, ⁓ no, there's there's nothing there. You know, because their favorite paper finds that there's no relationship. I mean, has has always bothered me. Like where it's like like you can't you can't look at the state of of the research literature at that point and conclude that women are making this up. speaker-1: Exactly. And it's cherry picking, isn't it? Sometimes it's cherry picking or like just being, you know, n being naive or a little bit like, well, just not informed. And sometimes I think I've learned to sort of brush off the comments. You know, I've I've also heard a comment like, ⁓ a little pill like this couldn't possibly do that to you. And you go, No, no, it really could, you know. speaker-0: Yeah, that's yeah. It's like this little bit of cyanide couldn't possibly kill you. Like it couldn't kill you. So it's like, why don't you try? And we'll find out. speaker-1: I think having a network of women, like having you know, having a platform like low the low down or similar, where women can talk to each other, discuss this and feel heard, that's also very important. And then just knowing that, you know, the world is still to catch up with sort of the, you know, the effects, the nuance effects that the pill has, and the you know, some women even like wro wrote books and discuss how the pill changed. the workforce and how it changed our parenting and how it changed our relationships and our relationship to sex and our values. So like people, people write all sorts of literature. I mean literature like that comes a lot from you know LSE, London School of Economics. So you can go to their thesis section and find all sorts. So people really discuss this and I I yeah, good for you. Discuss it. speaker-0: Do you w based on your read of the literature, d are there certain groups of women? So imagine that we have listeners who are have never used hormonal birth control and they're considering going on it. And are there particular groups of women who tend to be more at risk of developing the mental health related side effects than others? Yeah. Up to ⁓ interesting. speaker-1: Yes, ADHD up to like fivefold. Meaning like it's it's amplified by I mean like by five times. Yes, ADHD. There are a number of studies that show that women who take hormonocontraception and have and have ADHD symptoms, depending on what type of preparations or what type of ⁓ hormonocontraceptive they take, but some are really, you know, the the effects, ⁓ the negative effects on mood and anxiety particularly are skyrocketing. So they I mean, as you know, ADHD already is about n nervous system regulation. You have to really regulate your nervous system. That's where you start to then be able to build because actually ADHD can be a huge advantage. It's just the way you process information. You have a very creative brain. But it is it it doesn't function well with overstimulation. It just starts like shutting down. It just just shuts down. And it it kind of you have so many things you would like to achieve and you know how to do it, but you can't you can't do it. So actually I would imagine with what we were talking about earlier with the, you know, inflammatory cascade and with the cortisol levels and how that actually then crosses the blood-brain barrier and changes the activation and functionality of certain brain regions. would probably be the culprit behind this. So yeah, there are I can also refer the listeners to to this if they're interested, you know, I c I can link this in the description. speaker-0: Yeah, we can definitely include this in the show notes. So that's really interesting about women with ADHD. I've I've heard and I've seen papers that have looked at history of depression and they tend to find that those women tend to have a greater probability of experiencing negative mental health related side effects. I've also seen women who have a personal or family history of experiencing mental health side effects with hormonal birth control. That they may be at a greater risk of developing mental health side effects. And then also, sort of on the flip side, and I guess it's sort of it's it's it's a half flip side because I've also seen the research that that some women who've been diagnosed with PMDD respond to hormonal birth control use by feeling a lot better, ⁓ just simply because you're minimizing hormonal fluctuation. And women who have PMD, PMDD oftentimes have sensitivity to hormonal fluctuation. And their body just isn't as able to adapt quickly to rapid hormonal changes, and that that's responsible for their symptomology. And ⁓ for those women, when they go on hormonal birth control and level out their hormone production, they feel a lot better. But then there's some women who, when they're using hormonal birth control and they have PMDD, it actually gets a lot worse, making this a population of women that just needs to really be working with somebody who's willing to listen to them. ⁓ and work with them and has experience treating women with PMDD. speaker-1: Yeah, I could chime in to that because ⁓ we actually wrote in our paper toward the end in the discussion, we have found a couple of studies that show a protective mental health effect ⁓ in the for pill users. So definitely is something to be acknowledged that for some women the you know, there's a mood stabilizing effect when taking hormonal contraception. Well, we found particular studies with oral contraceptives, but it could be for for other preparations. That surely is a possibility. speaker-0: If have any of these types of conditions or any of these risk factors, it's just make worth making note of that and then including that in conversations with your doctor. So that way you can help, you know, make sure that you're being monitored if you go on something to make sure that it's working for you and make sure that it's, you know, having the effect that you want it to. ⁓ another thing that I wanted to talk to you about, and you mentioned this a little bit in your paper, ⁓ but you didn't systematically measure it, but just simply I'm guessing for the fact that a lot of studies aren't careful in terms of comparing different types of formulations of combined oral contraceptive pills. ⁓ and you know, as as I noted earlier, when you look at the the research and the the Different studies that have been conducted looking at the links between hormonal birth control use and mental health outcomes. Generally, they find that the non-oral products they do a worse job on your mental health than the combined products. And your meta-analysis finds that the combined products do also seem to have a an increased risk prof profile. But one of the things that we know about combined oral contraceptive pills is that they differ. Not only in the types of progestines that they have, and for readers of this is your brain on birth control, or just people who do their own own research or scientists who are listening, ⁓ we know that these progestines tend to fall into these four different generations, right? So these four different categories of progestine based on sort of when they arrived on the market. And each one is structurally a little a little bit different and tends to have different types of effects on the brain. ⁓ and in particular, there's a big difference between Whether or not the progestins are androgenic, meaning that they stimulate testosterone receptors, or whether they're non-androgenic, meaning they don't stimulate testosterone receptors, or are anti-androgenic, meaning that they actually have the effect of preventing testosterone receptors from being ⁓ stimulated at all. Given the molecular differences between these and the different types of receptors that they stimulate or don't stimulate, chances are It's gonna have some different effects on the way that women experience mental health outcomes, right? Like like we might expect to see that some types of progestins are going to be worse than others. And we also might expect that the different dosages of ethanol estradiol that's in these, because you have different things that range from, I think that it's is it like point one zero micrograms? I don't remember exactly what the the dosages are, up to like point three. So they they vary like. 300% difference between these different types of formulations. Like what what do you know based on what you've read in terms of the different types of effects that you might get depending on the type of progestin that you're on and depending on the dosage of estradiol? speaker-1: So for the ⁓ papers that were included in our meta-analysis, we actually conducted something called ⁓ sensitivity analysis, which is when you s look at the big so you do you analyze it, you analyze the data, you get a big picture, and you go, ⁓ actually, what if there's certain factors that influence the result here? So you kind of give the computer the command. To have a look at this. We did several subgroup analysis based on study type, so what type of study it was. It was mostly either an RCT or cohort prospective study. Follow-up length, so how long women were followed for, and the type of progestogen. And we actually didn't find any evidence that these factors changed the association, but that's due to something called heterogeneity. So heterogeneity literally means like the quality of being of different kinds. So it means that the studies were so different from one another that the computer said, look, it's it's showing no effect, but that's because the studies are different, right? It actually could be an effect. And we ⁓ I remember in some of the earlier drafts of the paper, we have actually focused a little bit in the discussion about different types of progestines having ⁓ worse mental health effects. And yes, ⁓ that's again particularly true for adolescents. I don't remember because we we do have a an appendix with all the pills that we have included. But again, it's something that I would need to go back to because my memory just doesn't doesn't hold that information. But you're right in pointing that progestins in particular have because of being of different generations of being of different kinds, basically molecularly and mimicking certain naturally occurring hormones, they metabolize differently in different bodies and then produce different effects. And that also shows in the severity of mental health effects. speaker-0: Yeah, one of the things that I always recommend to women is if they're on something that they think is causing or creating mental health related side effects and they want to be on hormonal birth control is to try switching it up and and as in particular switching up the progestin first because ⁓ they really do have different effects and it does seem to suggest, I mean, at least my understanding of the literature and everything that we've done with the the research that we've done in my lab, where it seems like some women just respond differently. Two different types of progestines. And for some women, it might be like they feel really great on this type of progestin that makes me feel really terrible. And then this one that I really love can make them feel terrible. And that there's just so much variability in the way that our bodies metabolize things, and the way that our, you know, receptors for hormones, like the their density and their action and all of that, that can really Create very different experiences for women depending on what they're on and who they are. speaker-1: Yeah, exactly. And that you know, they also work in tandem with estrogen. And we have estrogen receptors all over our body, literally on like almost every organ, even in the gut. And the gut has its own nervous system. It's called the enteric nervous system. It has it has about 100 million neurons. And so that's w it's called the second brain. That's why we say, you know, the gut. So it certainly is possible that. metabolism of estrogen rather than so but with introduction of progestins actually changes the way the second brain or the gut works, which then in effect, because it communicates with the with the main central nervous system, with the brain and the spine, it could have that kind of a relational effect. So so this is you have to think systemically. This is not just happening in one part of the body, even though you want to maybe influence a certain part of the body, it's actually systemic. It's everywhere. Going back to my high school teacher, girls, this is hormones we're talking about. speaker-0: Yeah, they they influence everything. And they and they do. So if there is a woman who who's listening to this conversation right now and she has been using hormonal birth control for a while now and she's also being treated for depression, what would your guidance be? Do you do you think that it's worth like taking a pause and like asking yourself like, when did this happen? Did this co-occur? Is this you is this me? speaker-1: Yes, they do. speaker-0: Is this my is this my birth control? Do you think that the results of your research, your meta-analysis, and your understanding of the relationship between oral contraceptive fill use and a depression risk makes it? I mean, you know, if she has an alternative way to prevent pregnancy, that it that it's would it warrant investigation? speaker-1: I think it would. Some women experience the effect of the pill more as just a flattening of the mood. Not so much the, you know, the extreme of what anxiety and depression can be. It's almost a spectrum. So I've definit I've for example, I had a friend and we were discussing my research. It really inspired her to try go off the pill. She was she's been on the pill since she was a teenager, and it was No joke, it was exactly what you said, Sarah, in so many of your podcasts and in the book. It was like this veil lifted. It's like she just didn't really realize how dampening the that effect of of the pill was, or how, in a way, almost everything was just okay, but it was flat. But then suddenly the world just became more colorful, more interesting. She had developed new interests. It was exactly what you said. So I think when you say, you know, if someone is going through depression and is taking the pill, is that worth investigating? I think it's always worth asking yourself, how do I really feel? You know, and and is this really worth? And what is the alternative? So explore the alternative. It's never too late to explore the alternative. You can still go off the pill and come back on it. So it's not forever. We luckily have these choices. We have, you know, ⁓ freedom to to choose and to try. So I would say definitely there is a possibility and sometimes some women have unfortunately quite severe mental health effects. So it's it's worth considering that it may be hormonally driven. speaker-0: Yeah, it's it's so interesting because that was very much I mean, minus the hormonal birth control shot, which had me crying up and down the Champs lysees when I was on the the other one, 'cause I used it a combined oral contraceptive pill most of my my life when I was on hormonal birth control. I mean, I would never have told you that there was anything wrong with me because I never felt upset. Like I didn't feel depressed. I didn't feel, you know, I I always thought I was a little bit anxious, maybe, but I I certainly didn't think that it was problematic. And then when I went off of it and had been off of it for a couple of months, I was just like, what have I been missing out on? Like I everything just felt so much more three-dimensional and I just felt more alive and and and like your friend, you know, developed new interests. I was like downloading music again for the first time in years. And it was just like I had no idea what I was missing because it did have that sort of homogenizing of my experiences. And years later I also realized that I really am not an anxious person. ⁓ because that was something I thought was part of my personality that ended up ⁓ you know, ten years. After being off of it, I realized like, you know, I'm actually not an anxious person. That was probably also ⁓ a byproduct of using hormonal birth control. And I think that, you know, for anybody who is listening who's on it, or if you're off it and thinking about going on it, or you're on it and thinking about going or off and on, whatever it is, it's worth keeping some sort of a journal, right? And also including just like asking other people to look after you. ⁓ if you're transitioning on to a new prescription or you're transitioning onto the pill from being off of it, or you're transitioning from on it to off of it, just let other people know what you're up to so that way they can help let you know whether or not they're starting to see storm clouds in the horizon. Because I I do think that one of the things that ⁓ I've really come to appreciate in my research career ⁓ as a psychologist is that our brain tells ourselves stories all the time. You know, it's like our brain creates stories and explanations for what's happening in in our own internal landscape as well as what's going on around us. And oftentimes it can prevent us from seeing reality clearly. And that a lot of times, like if we're starting to feel depressed, we don't think that, you know, ⁓ I'm taking the pill and now I'm feeling depressed. Instead, we think, like, wow, you know, my job is just really not stimulating anymore. Like I and my boss doesn't like me. And I don't have a lot of friends. And it's just like you start to, you know, you externalize the the problem. Your brain interprets it as problems that are around you instead of internal problems. Is that your sort of experience in understanding human nature as well? speaker-1: Yeah, definitely. I think some of it is also bias, like cognitive bias. You know, we like to fill in the blanks or tell ourselves the stories and ⁓ kind of you know, there's so many different like biases, cognitive biases that we have. And yeah, I think often we also have a view that health establishment wouldn't possibly, you know, give us something that could harm us or change us or produce these kind of effects. So I think it it's really up to an individual to know themselves. Like for example, the way I feel on the pill is so significantly different to when I'm off the pill or any other hormonal ⁓ contraception that for me it is, you know, I don't have to keep a diary to know the difference. But then there are women who do because you know they their partners would say I've noticed you're so tearful, you're so sensitive that you cry very often and you cry for things that are not really that significant. What is going on? So yes, I think it's important what you said, keeping that check in with yourself. speaker-0: So what do you think right now are some of the biggest unanswered questions in this field of research? Like what are some things that you really wish that we knew that we don't yet know? speaker-1: One I think is what genes may be responsible for having more kind of more pronounced or stronger mental health effects than f you know in women that that have them versus like women who don't really react or don't really have any potentially like, yeah, debilitating side effects. So that's an interesting question. I think a few research teams have tried to answer this but found nothing really conclusive. speaker-0: Yeah, I've seen a few. I think I saw like one where it was like some SNP related to a certain mineral corticoid receptor was related to like how a specific group of women responded to a fourth generation progestin. That was like one study that I found that actually found an effect. speaker-1: Okay, well that's interesting. I don't think I've seen that one. I've found, you know, really like epidemiological genetic studies, like looking at what and really like going into the details about different types of parts of the genome and you know, all about these strands. ⁓ I mean, they're just at the end of the day, they have names, you know, locations of different of different chromosomes. Have I get well of genes in the chromosome, they have like different different names, right? In the in the in the sequence. So yeah, it it was all like familiar to me, but also it there wasn't a clear, clear evidence. So that's one. The second thing that I would like to see done is, you know, people say, well, why don't you just switch or put this responsibility onto men and get them to take the pill? And I I don't think that's an answer either, because you at the end of the day you're then playing with their hormonal profiles and with their hormones. So it's not just like, well, okay, the ball is in your court right now. speaker-0: Yeah, like I I I I completely agree. I've been asked that question more times than I can count. And like you, I'm like, well, on the one hand, I'm glad that there is some research into this so that way we can both have to shoulder the burden, right? So we can actually have choices about whose hormones are gonna get messed up, but that's not the answer because then you're just shifting the burden of of of blunting hormone production onto your male partner, and that's not the answer. speaker-1: The third thing is why hasn't there been more research in trying to devise or develop non-hormonal contraception? So there, you know, I've seen a few things developing, but they're they're just not having much funding. I don't know what's happening, whether it's, you know, kind of lobbies or pressures from certain groups, but surely we can do better. I mean, we're we're so innovative. innovative we're you know we have a lot of engineers we can talk to engineers we can we can really come up with something that's non-invasive not hormonally so not biologically invasive but that's actually effective ⁓ in allowing us to basically have that sexual freedom and so yeah I I really want to see more research being done in this area. How about you Sarah actually? speaker-0: No, I I I completely agree. I think that we're very aligned when it comes to like kind of where I hope that the field goes. I mean, one is finding alternative methods of fertility regulation for women in particular, because we're the ones who ultimately have the larger cost of of an unanticipated pregnancy. So it's like we're always going to be the ones who shoulder the burden primarily of hor of birth control. And so I'd like to see options that are for women that don't mess up their hormones that allow them to be able to safely and effectively regulate their fertility and easily to the same extent that they do with hormonal birth control. And so I'd love to see something whatever that is. And then also, as you noted, I mean, I think that we've come so far. Like if you look in the world of psychiatry, for example. I'm when you look at their research, we we've kind of come a long way with antidepressants, ⁓ even in just like identifying people who are gonna respond to different types of treatments. So these people are gonna respond really well to SSRIs, and these people are gonna respond less well based on things like their serotonin transporter genes and so on and so forth. And I feel like we should be there with hormonal birth control. I mean, it feels kind of crazy to me. That I mean, especially given that there's a lot of these SNPs that are related to like the different types of progesterone receptors that you have, the different types of glucocorticoid receptors you have, the different types of estrogen receptors that you have, you know, your estrogen clearance rate. There's a lot of these things where we actually know and and have identified where these SNPs are. And ⁓ and I'm not seeing the research. ⁓ out there, like that's looking at these things as target SNPs that impact how women respond to different types of formulations of hormonal birth control. And I would really like to see these studies being done because I I do think that we have the technology now. And if we just could get the funding together ⁓ to get some of these studies out there to make better predictions about, you know, how individual X is going to respond to, you know, any type of hormonal birth control, because I I think that. You know, ⁓ it's like on the one hand, I want innovation, I want more options, but then also given how slow that is in sort of developing, I also want to see ways to make women's experiences on what we have available better. And so yeah, so a very similar, I feel very similar to you in terms of where I want the research ⁓ to go. And I wanna last, like, what do you, as we're sort of closing things up, what do you want listeners ⁓ to take away from this conversation and from the results of your paper. speaker-1: Yeah, so the results of the paper are very clear. I think, you know, it's not just in your head. It can be happening. It can be happening to your sister, to your neighbor, to your colleague, just anyone really who's taking this. It can be I think a takeaway and and of course a takeaway message is. Yeah, it's it it's real, it's happening. And we need to do something about it. I think we're t we're in a time. Where we really don't need interventions that can cause that much kind of grief or uncertainty for women. I think we really are in the time when we have a lot of knowledge and tools, hopefully funding and actually appreciation and love for not just science, but for women and for communities that take, you know, that take hormonal contraception that We can say, okay, maybe, maybe we can try something new, maybe we can put our heads together. And I don't think it's just up to, you know, gynecologists or endocrinologists. I think it's a real team effort. I think it's gonna be product designers, it's gonna be engineers, it's gonna be people who really understand. So biologists, chemists, like people who really understand the nuances. And I really think that the the future is. more of a sort of a device that you know just I don't know whether it sits there, it does something, but it doesn't create this these like systemic effects and it's still effective ⁓ in contraception. I don't know what that looks like. I tried to think about this and you know I'm I'm a big fan of Seinfeld, the series of course there was a episode about the sponge. And yeah, I wonder if the sponge can make its way back and why it's actually been removed. I don't I don't know anything about this. And I thought, well, why not? You know with the contraceptive option that clearly is it's a barrier method. It may, I mean, for some women it may be, you know, an issue ⁓ wearing something in your vagina when you want to have sex, but I mean men do it too, right? So Yeah. So that's that's I think the direction and the message, the take home messages. It's not just in your head, it's real, it's true and we need to do something about it. speaker-0: Excellent. Well, Dr. Noosha Farrick, thank you. This was a really wonderful conversation. And I'm gonna put for listeners, I'm gonna put the paper, the meta-analysis in the show notes, as well as some other papers, other reading for you that if you're interested in understanding more about the lay of the land when it comes to the research on hormonal birth control and ⁓ mental health-related ⁓ side effects. And lastly, where can listeners learn more about you? Do you have a website? Can they find you on social media? Where can we learn more from you? speaker-1: on LinkedIn or, you know, university websites. I'm not actually on social media. speaker-0: I think that's great. I think that that's perfect. So I'll have I'll have links where where we can hunt you where we can hunt you down, even though you're not on social media. Thank you so much for your time. speaker-1: Message Sarah, you get some message for me. Thank you for having me. Thank you.