Estrogen Impacts the Effects of Psilocybin for Women

Pharmacy Times interviewed Jennifer Chesak, author of The Psilocybin Handbook for Women: How Magic Mushrooms, Psychedelic Therapy, and Microdosing Can Benefit Your Mental, Physical, and Spiritual Health, about the neurological effects of psilocybin, and how those effects can act differently on women’s biological systems, particularly in relation to menstrual cycles. Chesak also explains why it may be valuable for health care professionals, such as pharmacists, to be familiar with psilocybin and psilocin, and their impact on health.

Pharmacy Times: What does psilocybin do, and are its effects primarily neurological/cognitive?

Jennifer Chesak: Psilocin, which is a pro drug of psilocybin, binds to the serotonin receptors and sort of activates them. Psilocybin and psilocin are tryptamine alkaloids, essentially, and they mimic the serotonin neurotransmitter. They also increase something that is called brain-derived neurotrophic factor (BDNF), and that causes this growth of new synapses and neurons. It's a mix of cognitive functions and neurological or neurotrophic factors that happen.

The other thing that happens has to do with the default mode network, which is a network of brain regions, that work together in sort of a resting state and they're concerned with our self, a little bit of memory…and so, some changes happen during a psilocybin journey that impact that default mode network. There’s a mix of neurological and cognitive functions going on.

Researchers have a really great way of explaining why psychedelics work—which helps us understand why it has some beneficial effects for anxiety, depression, body image—and is called the relaxed beliefs under psychedelics (REBUS) model, which was created by Dr. Robin Carhartt-Harris and Dr. Karl J. Friston. This model explains that when we're children, our brains are much more flexible and malleable in terms of we haven't really formulated our beliefs about ourselves or how the world around us operates. They're really, really flexible. But as we get into adulthood, our brains become more rigid and we become much more solidified in those beliefs, and it's hard to change them. And so, when we are in normal states of consciousness—again, that brain is very rigid—think of that rigidity as your brain being like a frozen pond. Now, if you were to try to take a new belief to gain entry into that frozen pond, you take a rock and drop it on that frozen pond, it does not gain entry. So, in normal states of consciousness, we have a lot of trouble changing our own belief systems. When we're on a psychedelic, our brains become much more flexible, or entropic; we get back to that state of childlike wonder and awe. Now think of that brain as a thawed pond, if you take that belief and try to drop it in, now it gains entry and causes a ripple effect. I think that that shows a lot of promise in terms of how and why it seems like psychedelics are having some promise for PTSD, other types of trauma, depression, anxiety, negative beliefs about your body, all of these things are being studied right now…that is essentially why we have these beneficial effects.

When we're on a psychedelic, our brains become much more flexible, or entropic; we get back to that state of childlike wonder and awe. Image Credit: Adobe Stock - nataliaderiabina

Pharmacy Times: Why might it be valuable for health care professionals, such as pharmacists, to be familiar with psilocybin (and psilocin) and its potential impact on health?

Chesak: I think it is really important for pharmacists and other clinicians to be looking at this and gaining some familiarity, because over the next few years, the population that would be using psychedelics is going to grow exponentially. It's already growing very fast. I think it's important because patients have questions about things like, does it matter if you're on medications or what conditions people have, or if there’s going to be an issue with If you have an underlying condition if you're using psilocybin or another psychedelic. So, I think it's really important for people to feel safe asking their doctors and pharmacists about this, as well as discussing their usage. Clinicians and pharmacists should understand any reasons why someone maybe shouldn't be using it, and to be able to explain that to someone or give them advice on if they need to taper off of another medication. The problem right now is that we don't have FDA approval for psilocybin and other psychedelics like MDMA. It means that a lot of us are still using it in secret or not talking about it with our doctors. I really want to feel safe going to my doctor and saying, “Hey, I'm interested in this, I'm on these medications, is there an issue?”

Pharmacy Times: What is the difference between psilocybin and psilocin?

Chesak: Psilocybin is the compound in magic mushrooms, essentially, and there's a whole bunch of different species of psilocybin mushrooms. When you ingest psilocybin—whether that's in tea form, a capsule, or eating the raw mushroom—your body metabolizes psilocybin into psilocin, and that is really what causes the changes and psychedelic effects. People just keep talking about psilocybin, but it's really psilocin that's doing the work, but it's easier to just discuss psilocybin without explaining psilocin, but that is what is actually doing the having the beneficial effects. They're just two different tryptamine alkaloids. Essentially, psilocybin is a prodrug of psilocybin, meaning that's what it converts to and that's what causes thatchange.

Pharmacy Times: How does psilocybin affect women differently?

Chesak: We know that estrogen can affect binding at the serotonin receptor sites. We need more research on the trajectory of the menstrual cycle and when in the cycle to use psilocybin. It seems like we know that where we are in our cycles, and the level of estrogen in our body may matter in terms of if we're doing a deeper journey, or it may matter for microdosing as well.

Right now, researchers have dug into some case studies and they're getting anecdotal reports. Researchers at Johns Hopkins University did a case study on three women who used psychedelics, and two of the women used psilocybin. What they found, just based on these case studies, is that it may cause the menstrual cycle to come a little early. So, if you if you did a journey about midway through your cycle, you may end up getting your period just a little bit earlier.

What they also found was that it seemed to regulate menstrual cycles after a period of irregularity. Two of the women in the study—one had premenstrual dysphoric disorder and the other had polycystic ovarian syndrome—had some time where their periods had become irregular. In one case, one woman’s period had completely stopped, but after taking psilocybin, it came back. We need more research because all we have right now are these case studies and anecdotal reports, but it does seem like there is some type of effect on the menstrual cycle and the mechanisms of action do make sense from a scientific perspective.

Image Credit: Adobe Stock - Microgen

Our menstrual cycles occur along the hypothalamic-pituitary-gonadal (HPG) axis, so as one hormone kicks off, it tells another hormone what to do in this feedback loop and that's the trajectory of our menstrual cycles. We also have the axis that manages our stress response, the hypothalamic-pituitary-adrenal (HPA) axis. These two axes sort of overlap, and so they each impact one another. When we use psilocybin, we are at doing something along that stress response along the HPA axis. We already know from research outside of psychedelics, that these two axes do impact each other: our stress response can impact our cycle, and our cycles can impact our stress response. So, it's not a stretch to think that when we are using psilocybin, that something is going on with our stress response that then impacts the menstrual cycle, or where we are in our cycle matters for the type of trip that we have if we're journeying on a deeper dose. I hope researchers continue to dig into this because it seems like it really matters where we are on our cycles.

I talked to an indigenous wisdom expert, and I think it is really important that as we talk about science, we bring in indigenous wisdom, because psilocybin is a sacred substance that has been used for centuries in indigenous cultures. And so, they have been doing things over and over again to reproduce the same results. The indigenous wisdom expert that I spoke to, Mikaela de la Myco, noted that if you're thinking about journeying, that might be better done around the ovulation period as opposed to closer to getting your actual period. So, kind of before you enter the luteal phase of your cycle. Again, we need more research on that, but, I think that's good advice from a scientific perspective. The reason for that would be that as we get closer to our periods, our bodies do become a little bit more insulin resistant in that luteal phase. A lot of people do some type of fasting right before a journey, so that might be abstaining from food for just a few hours or that entire day that you’re journeying, or it might be that you've done some fasting leading up to the journey that's longer than that. Fasting during the luteal phase can be very difficult because of that insulin resistance that naturally happens in the luteal phase.

Again, we need more research, but I'm excited to see that that's that some of that research is in the works.

Pharmacy Times: How might using psilocybin impact certain menstrual symptoms, such as premenstrual dysphoric disorder (PMDD)?

Chesak: [Researchers] haven't done any clinical trials, but it's possible that re-regulation of the menstrual cycle may help with PMDD, and some other menstrual cycle symptoms. So, it could be effective and menopause, but it does appear that there's some potential for reregulating, I don't know that it's going to resolve a bunch of symptoms. It's possible, we just don't have the research there yet. Just making a cycle more regular could theoretically help with PMDD.

Pharmacy Times: What information is available around the dosing and dose schedule and the impact on these symptoms?

Chesak: Not as much as I would like to see, I think we're going to get some of that research. But from just from anecdotal reports of people, it seems like psilocybin tends to have some really good beneficial effects for about 6 months to a year. So, I think it really will just depend on the person and their individual needs in terms of how often you might do a journey. A lot of people do every 6 months, or once a quarter or once a year for that, that deeper dose. We do know that there's a period of neuroplasticity that lasts after a journey, and so, I think we're still looking at research in terms of how long that lasts in terms of having some beneficial effects.

In my opinion, for a deeper dose you would have to do some trial and error to see what works for you. With microdosing there are a bunch of different protocols out there, but my indigenous wisdom expert recommended that if you are considering microdosing to follow whatever protocol that you choose for 3 months and keep track of some of the effects that are happening, if you're having a change in symptoms, or just how you generally feel. It’s best to try that before deciding if it is or isn’t working or just continuing on…it will give you more knowledge than if you just a 3 week microdose session and then quit.

Pharmacy Times: How have you recommended navigating the intersection of using psilocybin for health benefits and being a parent?

Chesak: I see a lot of promise for psilocybin within the realm of parenting. Some parents are actually using psilocybin to better connect with their kids, for example, a parent might do their own solo psilocybin journey, then later, the brain becomes more entropic during a psilocybin journey—and then there's some beneficial effects for entropy after a psilocybin journey—that makes your brain more flexible when getting back to that state of childlike wonder and awe. Then parents come back together with their kids and are finding that they are enjoying play a little differently in terms of, “Yeah, I want to get down on the floor and put those Legos together, I want to do some art with my kid.” It can be a challenge when you've got so many things going on in your life and you're busy to get to that state of childlike wonder and really focus on being present and having fun playing with your kids. So, there's some potential there, I've heard from parents that that's what they're doing.

The other thing that I think psilocybin has a lot of promise for ending cycles of generational trauma, if you will. To throw some statistics out there, adverse childhood experiences—ACEs for short—essentially, are any trauma that might have occurred in childhood. So, it might be abuse and neglect, systemic racism in one's community, or parent that was incarcerated, a divorce, surviving like a natural disaster like wildfires or tornadoes…These things can be very traumatic and that changes your stress response as a child and it there’s some lasting effects from these aces that last into adulthoods. 1 in 6 adults have had 4 or more ACES, and when you have them, your children are threefold more likely to also have ACES. If we have traumas, there can be this passing down of trauma through the generations. And so, I think a lot of parents are thinking about psilocybin in the context of, “How can I heal some of my own traumas so that I am not continuing cycles of trauma with my children, their children, and passing that down from generation to generation?” I see a lot of promise there simply because psilocybin does so much potential for helping with trauma. I do see down the road that as more parents decide to use psilocybin, that we may be benefiting children with this effect that we pass down by healing ourselves.

Pharmacy Times: What would you recommend around dosing for different health conditions that psilocybin is particularly indicated for, such as anxiety, depression, or PTSD?

Chesak: I think when we're dealing with trauma and trying to resolve it, there's not necessarily going to be a full resolution of trauma…what I think is that a deeper dose—something like 3 or 3.5 grams—is going to be really beneficial for tackling deeper traumas, or having a beneficial effect for anxiety and depression and supplementing with microdosing after your deep journey…Choosing a microdosing protocol—there's the Fadiman protocol and there are others—and then following that for a while to see how it affects you. Or you could also use microdosing very intuitively, you don't necessarily have to follow these protocols. For example, you could decide that one week, you’re struggling with some anxiety, and might just take a couple of microdoses, that's an option that people can try.

But I do find that people are using microdosing, in many cases in lieu of selective serotonin reuptake inhibitors (SSRIs). That's not to say that I'm encouraging people to go off their SSRIs and microdose instead, but it is an option that's worth discussing with your doctor because as we know, SSRIs they tend to blunt moods, and not only not only do they blunt your lows, but they also blunt some of your highs. There's a study where researchers found that with psilocybin, instead of blunting those highs and lows, it just makes people feel more okay with their highs and lows, which is actually really kind of cool. So, when do you do these things, or how often and what dose? It's going to depend person to person, I would suggest deeper doses in a very therapeutic setting for managing depression, trauma, anxiety, and body image issues, then exploring microdosing thereafter and then determining when you might want to do a deeper journey again, which again, might be 6 months out, or it might be a year out.

Pharmacy Times: What are known counterindications for psilocybin use?

Chesak: What has become a guideline is looking at the counter indications for what would exclude you from participating in a psilocybin clinical trial, meaning what conditions and medications would exclude you. I think that's a good guideline in terms of saying, “Oh, hey, if I have one of these conditions, or I'm on one of these medications. I need to stop for a second, I need to think about this, I maybe need to talk to my doctor and then formulate a plan.”

So, there are some conditions that we do know and might make you want to pause and think about and discuss this. In general, psilocybin is a relatively safe substance in terms of toxicity, but there are some concerns. The things that might be an issue would be a cardiovascular of heart condition, if you have high blood pressure, coronary artery disease…I would say stop and talk to your doctor. That's simply because psilocybin does work on the sympathetic nervous system a little bit, so your heart rate could increase, your blood pressure might increase during a journey. So, if you if that would be a concern for you, I would say hold off and talk to someone before you try that.

Diabetes is exclusionary for a clinical trial, and the reason for that is when you're in an altered state of consciousness, you may have trouble managing a chronic condition, like managing your blood sugar, so that's not to say that you couldn't do a journey with some mental health professional, and they are managing that helping you manage that for you. It's just something to stop and say, “Okay, hold on, I need to think about this.”

Liver conditions, seizure conditions, and there are mental health conditions that are exclusionary. For example, having existing psychotic symptoms, some personality disorders, and conditions like that are exclusionary for clinical trials. However, some clinical trials are actually studying psilocybin in these populations. Borderline Personality Disorder, for example, would generally be exclusionary for a clinical trial, but some clinical trials are focusing on these conditions. In that case, then that person would be included. Ultimately, we just don't need more research about underlying conditions, and psilocybin. So, if you have any of those, it's just kind of a thing you want to pause for.

In terms of medications that you might be on…there is some concern that if you're on a medication that blocks the serotonin receptors, that psilocybin just might not work for you, or you might need a deeper dose. If you are on medications—such as a dopamine receptor antagonist that might exacerbate some anxiety or unease when you're doing a journey—that's something to stop and consider and say, “Oh, wait, I need to talk to a doctor, or I need to think about this a little bit more.” Researchers also looked into SSRIs and how that affects someone using psilocybin because there has been some concern about serotonin syndrome—where you have too much serotonin in your in your body—but it doesn't seem like psilocybin actually increases serotonin, instead it just activates those receptors. In terms of any type of medication that you're taking for mental health conditions, typically clinical trials have you taper off in a very safe and controlled way. Researchers are still studying whether that's even necessary. Do we need to taper off SSRIs? Preliminary research suggests that probably not if you're just on one SSRI, but it seems like that is a concern. We still want to be very, very careful. But if people are on more SSRIs, or if they're on multiple medications, like a mood stabilizer, then that's something where we need to stop and think about whether the person needs to taper and whatnot. It's just something to think about in terms of, “What would exclude me from a clinical trial? And then is there a workaround if there is an exclusion?” So, if someone is on an SSRI and another medication, is it possible for them to safely taper off that medication before trying psilocybin.

Pharmacy Times: What else should pharmacists understand about the different ways that psilocybin can impact different sexes based on biology?

Chesak: I think it's so important for pharmacists, and other clinicians to know that women have had a lot of difficulty in the mainstream medical system—and that's not to say that I have a problem with the mainstream medical system—however, there is a history of women being gaslit at the doctor's office for chronic pain and other conditions. What we're finding in research is that women in some cases are using psychedelics more frequently than men, and when you dig a little deeper into that research, you wonder what differences there are in how we tend to use psilocybin or psychedelics. More women are using psychedelics to self-treat a condition, and that is because—this is my opinion—that a lot of times we're left behind in science. I mean, women weren't even included in early-stage clinical trials until the 1990s, and that has had some dramatic ramifications for women's health. So again, women are turning to psychedelics to self-treat, and I hope that if a woman were to go to her pharmacist and talk about this with them, the pharmacist would be receptive to having a conversation, and same thing if a woman goes to her doctor. But it seems like we're not there yet, there's not this acceptance of psychedelics. I think that everyone really needs to understand where women are coming from. For example, I have endometriosis, this is a condition that affects 1 in 10 people assigned female at birth—and in rare cases, it can affect men—but it takes on average 10 years to get a diagnosis for this really serious chronic pain condition that can really affect quality of life. The National Institutes of Health in 2020 to dedicated less than point 1% of research to funding research for endometriosis, and that's really frustrating to me. We are left behind in mainstream medical system and so when you when we want to discuss these things with our pharmacist, I think we just really need to have an open mind and understand where women are coming from.