60. Psychedelics Postpartum

Hi everyone, welcome to another episode of Mummy Brain Revisited. I'm your host, Dr. Jody Poluski. Today, we're going to be talking about psychedelics and the postpartum period. I'll be speaking with Dr. Danielle Stolzenberg, who is an associate professor in the Department of Psychology at the University of California Davis. We're going to be talking about her study looking at how psilocybin use in the postpartum period can affect mom and offspring in pre-clinical model. Stay tuned and enjoy. It's nice to see you. It's good to see you. I'm very excited to have you here and talk about psychedelics and postpartum depression. I think it's really interesting topic because there's already people using psychedelics during the postpartum period without research. Yours is really the very first study to look at what's going on. Maybe you can tell us about your study and why you did it. Sure. That's absolutely right within the scientific community and even within the popular media there have been many conversations about psychedelics as potential promising therapeutics for women's health and for postpartum depression. It's an exciting time because psychedelics are highly effective mood disorder treatments, at least with the preliminary information that we have. And I was excited about them as a possibility for postpartum depression because they're so fast acting. And we know in the postpartum period that miss of the essence bonding with the infant is a really important part. The other thing that makes them really exciting is that they can produce these long lasting effects, even with just a single dose. And again, when you think about some of the unique considerations within the postpartum period, you're concerned about chronic use of medication during lactation and complications associated with that. So a single dose treatment would be an ideal thing. And then what kind of shocked me is that there had been absolutely no research at all on whether or not psychedelics would be safe in the postpartum period. And when I say research, I guess I'm really talking about preclinically because that's of course my area of expertise and that's what I focus on. So I thought surely someone's looking at this in a mouse model or a rat model and that wasn't the case. So that's really what prompted us to start the experiment. What we wanted to do is really look at this in a way that would be most relevant translationally. So we wanted to think about the sorts of things that would be important for the postpartum period, including do psychedelic or psilocybin in particular, and transfer into the milk, could it possibly affect the offspring. We also wanted to incorporate maternal care into the paradigm to understand how it might affect moms while they're interacting with infants. So these were the sorts of things that we were thinking about when we decided to start these experiments. Yeah, and for clarification, there's no research in mothers on the use of psilocybin in the postpartum period, correct? In humans, in animal models, there's actually one article published that is a just a perspective, talking about how psychedelics could be really useful for postpartum depression. Yeah, and I find this really interesting because there are women and there are therapists who are working with the perinatal or postpartum population, who are using psychedelics as a treatment, even though we don't have any scientific evidence suggesting it's helpful or not. I agree with you, and I also think it speaks to how urgent the need for treatments, and that's what really shocked me. Read this article, start thinking about this, we're designing our experiment, and I'm googling on the internet to see what people are saying outside of the scientific literature. And I found a Facebook group where moms could basically guide each other to try to find where you can get psilocybin if you're really struggling with postpartum depression, and that really hit me hard because people are really struggling, which is something that I'm generally aware of. And so that really, I think fueled why we wanted to be so comprehensive and why we worked quite hard over the last couple of years to try to get this out as fast as we could. And I think this is a good point that it does speak to the need to have more options for treatment, prevention, intervention when it comes to mental health during pregnancy in the postpartum period. So then tell us because you did this in animal models, now I'm assuming you of course had a model for some aspects of postpartum depression, and maybe just tell us a bit about that because I'm a big believer in properly modeling some aspect of the human condition. That we're looking at when we're using animal models, sure, yeah, my lab had developed a mouse model for postpartum social stress. And we adapted this actually from a social stress paradigm that's been used to model behaviors related to major depressive disorder in rodents. And then in addition to that, we added a resource deprivation component. So in the resource deprivation, we removed nest materials from mom. She still has some nest materials, but not enough to build a nice big nest. And we did this because we know that in addition to psychosocial stress, low socioeconomic status is also a major risk factor for postpartum depression. And so those were the two pieces that we wanted to incorporate. And then in addition to that, one of the things that I don't think gets addressed as much in the pre clinical and even clinical literature in terms of symptoms associated with postpartum depression is the struggles that mom sometimes have like bonding. And so we also added a component of our dependent measures to focus specifically on maternal withdrawal or sort of maternal avoidance from infants. And what we did is we have a two cage system so we can look at active withdrawal and avoidance. So does mom spend more time in a completely different cage that's attached by a little PVC pipe to a cage where her litter is I think about it like leaving the room going into a different area. You're still technically you can still hear the moms can still hear and smell their infants, but there's actively moving away from them. And so we built that into the model as well. Okay, on a side note that reminds me of some of the research from Amanda Kentner that showed that moms who could get away from their babies are actually benefited and so did their offspring. Yes, so it's not necessarily that them being away is a bad thing. You're just looking at how it could change the interaction. If they've been exposed to the stress or paradigm or not. Yes, that's a really great point because actually years ago and some work where we called it our rats gone wild project and we had rats living in these large outdoor enclosures. And we had a very similar situation where moms could leave the nest box and yes, they spent lots of time without the pups. I think probably here one of the big differences is when our rat project they were you can imagine an enriched environment so when they're not with the pups they're engaged in climbing and foraging for food and things like that in this situation what we saw frequently when moms were retreating from pups is a serious stress related behavior. It's just like a lot of times when we were just sitting in the nest box related behaviors like digging agitatedly running around the cage or sometimes sitting immobile and just grooming excessively, which is a sign of stress in my. So I think it's that's such a great point because it's hard to get a full repertoire of behavior and I think it's absolutely natural for moms to spend a lot of time away from their litter and we probably have an artificial sense of how much time they spend with pups in the laboratory. And we did see a lot of stress related behaviors and of course the control animals were also in a two cage system. Yeah, so we had so we were able to see what what would moms do under non stressed conditions in this in the larger environment, but want to make sure everybody knows it's okay to be away from your kids. So tell us what was the main findings. Yes, so in complete contrast to our expectations, I just really want to emphasize that we were very excited about psilocybin when we started this and we thought that this was going to be game changing, but in complete contrast or expectations, we found that not only did psilocybin not alleviate the effects of postpartum stress in our model, but we also found that it produced adverse effects on maternal and stress related behaviors. For up to two weeks following treatment, I should also say just to be clear, we did what's called it to by two design, so we looked at mice that were exposed to the stress factors that I described. And mice that were exposed to no stress factors and then we looked at psilocybin or the sailing was our placebo control and we were able to basically ask, is there an effective psilocybin. And then regardless of stress, is there an effective stress regardless of psilocybin and then of course, is there an interaction between the two and that's what we were interested in. We did not find any interaction effects at all, so we found some effects of stress alone, but we found many effects of psilocybin alone, and that was really surprising to us. In addition to that, we also found that the offspring that had been reared by moms that were exposed to psilocybin when they were in adulthood. So we waited all the way into adulthood. This is one of the huge advantages of working with animals is that you can look at these long-term effects and you can really understand that those effects are related to early life environment. And we found when they were adults that they exhibited greater adonia, which is a whole mark of major depressive disorder. It's the sort of inability to experience pleasure. It's very easy to measure in rodents. And so we found the exhibited adonia and adulthood. And of course, any time that you're looking at a manipulation in the early life environment in a rodent model, there's always a major question of, okay, if they're showing adonia and adulthood, is it because they were exposed to psilocybin through the milk? Or is it because they were exposed to a mom who was treated with psilocybin who had some deficits in caregiving behavior? Or is it some combination of the two? And so what we actually did is we repeated the experiment, only injected the offspring directly. So we treated them directly with psilocybin. And then we looked once again in adulthood and we found that the phenotype was the same. So they were still exhibiting greater levels of adonia. And this is both male and female offspring. And so from now we were really able to into the causal conclusion that exposure to psilocybin developmentally altered their adult response to pleasurable rewarding stimuli. Okay. So I'm hearing the outcome was completely different than anticipated because there was a hope that this would be beneficial for moms and thus beneficial for offspring. And that you saw the psilocybin effects in the control animals the ones that weren't stressed. And you saw the same thing in the stress animals or nothing in the stress animals. It was a main effect of psilocybin. It was a main effect. It was a gross regardless of the stress. Reads of the stress. Yeah. So regardless of this stress condition psilocybin is having this effect on the offspring. But now tell us a bit more about the moms exactly what happened with the psilocybin. So moms that were exposed to psilocybin, we saw acute effects. So shortly following psilocybin exposure, we saw disrupted maternal care. And then we looked two weeks later after the infants are weaned. So this is when the infants are no longer in the cage with mom. They're old enough to eat and drink on their own. And we conducted a behavioral test battery. So we looked at multiple different tests that would get at anxiety behaviors. So how do they respond in a situation where they're put into a stressful environment? We looked at how do they respond on measures of depressive like behavior. And what we found is overall across the entire test battery, we found an increase for behavioral risk. So we did something called an integrated Z-score where essentially we were able to look at variation across all of those tests and integrate it together. And so on that measure we saw an overall increase in risk. So they were performing with what we would consider an impairment on those tests relative to controls. And then specifically we found in two of our tests that were meant to get at anxiety like behavior. We used to test all the open fields and the elevated plus me is where essentially you put them into risky environments and see how they behave. In both of those measures we found increased anxiety like behavior in the mice that were exposed to psilocybin. Again, regardless of the stress. Okay. So this was the mother mice. If they've been exposed to the psilocybin, regardless of the stress exposure, that increases their anxiety like behavior in particular and increases their risk of having anxiety or depressive like behaviors in general. Like it kind of increases their risk of poor adaptation or mental, poor mental health, we could say. But of course these are animal models, but we're just looking at depressive or anxiety like behaviors. And when we finished, this is the I guess what I'm going to call the first part of the experiment because this is before we looked at the offspring, we thought to ourselves, wait a minute, is this, what if this is just related to sex because very few studies include female rodents. So if you look at, and just sorry, I'm going to interrupt sex. Imagine the sex gender, whether you're male or female, not whether someone's had sex or a male sex sex of the offspring, right? I was talking about sex of the mom. So in other words, I think what I'm what I was trying to say is we found these, this increase in anxiety like behavior are two weeks later in female mother mice. Our first question, this is so different than what's been published preclinically with psilocybin. Our first question was, wait a minute, is this because their moms or is this because they're females? Okay, that's how I should have said it. I'm highly aware that few preclinical studies of psychedelics have included male and female rodents, but I went back to try to find, okay, who's included females has anybody looked to see if there's differences between males and females and there's been just a couple of studies given that there had been so few studies. We thought, okay, let's repeat the experiment with female mice that have not given birth and that have not had any reproductive experience and will do the same timeline will inject them with psilocybin, treat them with psilocybin, and then two weeks later, we will run them through this exact same test battery and the same equipment, the same people, the same parameters will make sure that this isn't just due to their sex, their female sex. And so we did that in this experiment because at this point we knew that the effect was related to psilocybin, we didn't include any stressors for the female mice, so we just looked at female mice exposed to psilocybin or exposed to saline. What we found is that there was really no effects of psilocybin on the behavioral measures, which again, was not surprising because there was no stress component. Usually when you see therapeutic effects of psilocybin in preclinical studies, it's because there's been a stressor, but we actually did find a reduction in anxiety like behaviors. This is what I find really interesting, which is a little bit of research out there looking at reproductive state. Being female is one thing, but being female and having given birth is another thing. So you really found almost, it sounds like the opposite then in anxiety like behavior where it reduced anxiety like behavior in the virgin female age matched, whereas it increased in the postpartum females, the psilocybin. Correct. What do you think about that? I have a lot of questions as always arises from experiments like this. And I think could be, of course, many different things, more monolithy experience that the postpartum females is quite different than what would be happening in an emergency state. One of the things I think about a lot is that there's huge plasticity changes in the brain. Of course, I don't have to eat this is your area of expertise, but huge plasticity changes. And I think one of the reasons why psychedelics can produce these long lasting effects is that they produce really fast and long lasting changes in plasticity. In the few administer psilocybin during a period where the brain is being reorganized from a plasticity standpoint to begin with, you may have quite different effects. And that's what we're trying to understand now. I think there's a lot of important questions to ask with females specifically. And then how does reproductive state change things? Yeah. And remind me though, because psilocybin acts on the search in a genetic system to some degree, is that right? Because I'm wondering, okay, because I'm also wondering if it's not necessarily the hormone changes, but the neurotransmitter changes, which we haven't studied in detail at all across pregnancy and postpartum. But those systems, search in a genetic system, the dopaminergic system, those are also important for pregnancy and postpartum. And they also are changing. I think we sometimes gravitate towards hormones because we know we've done more research on them, but I would be curious then to look at these other systems, especially the search in a genetic system, which is less studied during pregnancy and postpartum period to understand what's going on. Yes, it's very interesting. And I think they're not separate. All connected. And we know that ovarian hormones directly regulate the expression of receptors that serotonin binds to you as well as enzymes involved in serotonin synthesis. And that's true for dopamine as well. They regulate dopamine receptors. So I think there's so many questions related to that. We did find it. So I should say we think that psilocybin produces its antidepressant effects through the activation of the serotonin to a receptor. And just as a preliminary question about whether or not that particular receptor is differentially expressed by reproductive state, we did find differences in the receptor expression. in the frontal cortex between postpartum, my virgin female mice and virgin male mice. So that being said, what are the take-homes that people should be aware of? I think that we're studying mice and mice are not tiny humans by any means, but I do think that we don't know a lot about how treatments affect the postpartum brain. And I think there hasn't been a lot of research that's been done, and this is an incredibly vulnerable period. We know this is a period of great, greatly increased risk for mental health. The main finding of this study I think is maybe that we need to proceed with caution. And I don't think that means we shouldn't proceed, as a matter of fact, I think it's the opposite. If anything, my hope is that these findings will inspire more research, because I think we need to be asking questions. Clearly there's an urgent need for this, but I think maybe a main finding is to consider the postpartum period is going to be a physiologically distinct period relative to other periods of the lifespan, and that we really need to be considering that when we design drugs, first of all, and when we study the effectiveness of drugs, and when we consider administering drugs in this period. Absolutely. I 100% agree. We need more to do more. And I think careful. Absolutely. And I also think thinking about medication during lactation, I think one thing I hope this study will inspire is more preclinical research on this, because there are advantages to using animal models. And I think here what we were able to do is we were able to go beyond asking about the amount of transfer of psilocybin. So we certainly did for this psilocybin could transfer through the milk. We found it in the brains of the offspring. We were able to do a sort of a time course. So within 30 minutes and hour, two hours, we were able to see psilocybin, sorry, salosin, which is the active metabolite. But then we were able to go beyond that to say, does it matter that they were exposed? And I think that's a really challenging question that you really cannot ask directly in a human model, but you can ask that question in a preclinical model. So my hope would be that this paper inspires other folks to ask these kinds of questions. I was surprised at how many papers I've read looking at exposure, maternal exposure, to various drugs in mice and rats that haven't actually looked at whether or not the metabolite reached the brain of offspring or produced long-term effects. So I think there's a lot of research that we can do in that area to provide some basic answers. More research needed. Always. Thank you for telling us a bit about this research. I would recommend people to go directly to the paper for the details. Because there's a lot in there and it's an important area of research. But like you said, I hope more research in this area starts, we start to ask more questions and have some answers that are important and can impact women's health today. So thank you. Thank you, Shari. Questions, comments, suggestions, get in touch at Mummy Brain Revisited on Instagram, Twitter, or Facebook. You can also contact me on my website at jodipoluski.com. That's j-o-d-i-p-a-w-l-u-s-k-i.com. Looking forward to hearing from you. [Music] [Music] [Music] Soundstripe.