This article is part of the 2018 NMJ Oncology Special Issue. Download the full issue.
To treat patients with sleep disturbances, it’s important to understand how neurotransmitters affect sleep and wakefulness. In this interview, NMJ’s Editor-in-Chief Tina Kaczor sat down with neurotransmitter expert and practicing naturopathic physician Robyn Kutka, ND, to learn more about how GABA, melatonin, histamine, acetylcholine, dopamine, serotonin and lesser-known neurotransmitters are involved in the circadian rhythm.
Kutka shared a wealth of clinically relevant knowledge about neurotransmitters, hormones, stress, and sleep that any practitioner who sees patients with sleep issues can put into practice.
Approximate listening time: 32 minutes
About the Expert
Robyn Kutka, ND, is an expert in naturopathic medicine, hormones and menopause. She uses this knowledge, coupled with her laboratory medicine experience and the latest in scientific research, to develop customized treatment plans designed to address the cause of health concerns. Kutka received her medical education from the National University of Natural Medicine, where she trained as a general practitioner and tailored her studies to receive more focused training in the field of women’s health, completing a 3-year women’s health clinical internship. She has spent more than a decade educating women on the topics of sexual health and romance enhancement in their relationships and continues to advance her knowledge in the field, studying with the International Society for the Study of Women’s Sexual Health and the American Academy of Anti-Aging Medicine.
In addition to practicing at Inspire Your Health in Portland, Oregon, Kutka is the director of clinical services and lead staff physician at Labrix Clinical Services. She serves as an educational resource for providers across the world on the topic of hormone balancing and bioidentical hormones and has shared her knowledge by speaking for organizations including the American Academy of Anti-Aging Medicine, the Association for the Advancement of Restorative Medicine and the Integrative Healthcare Symposium.
Transcript
Tina Kaczor, ND, FABNO: Hello, I'm Tina Kaczor, editor-in-chief here at the Natural Medicine Journal. I'm talking today about sleep and how various neurotransmitters are involved in the circadian pattern of wakefulness and sleep, and I'm talking with Doctor Robyn Kutka. Doctor Kutka is a practicing naturopathic physician in Portland, Oregon, with a focus on women's health, and in particular balancing hormones and neurotransmitters. Doctor Kutka, thank you so much for joining me.
Robyn Kutka, ND: Absolutely, thank you for having me. I'm excited for our topic today.
Kaczor: Me too, and I want to start with the most basic of questions, because we are diurnal beings, we are not nocturnal beings. My first question is basically what drives us to sleep at night?
Kutka: Great question. I think we think about our circadian rhythm, our circadian Process C, but it's actually a little bit more than that. When it comes to sleep, we have a couple of processes that work together to balance that out and promote our sleep patterns. So we have our Process C, which is our circadian process, that is mostly endogenous. So we think about our body temperature, our melatonin production, but it's adapted to our local environment and our external time cues, so things like daylight, timing of sleep, our timing of meals, work schedule, social interaction, so it can change based on those things.
But then the Process C is balanced with something called Process S, and think a lot of people aren't aware of that. That's our sleep homeostasis, our sleep pressure so to speak. It's this drive for sleep that builds as we wake and accumulates until we start our sleep, at which point it starts to decrease. When we have an imbalance in those 2 systems, that's where we start to see some sleep disruptions.
Kaczor: So when you say it's our drive for sleep, do you mean that's more of our habits and our lifestyle?
Kutka: No, it's more of an internal process regulated by things like some of our neurotransmitters. It's more of a biochemical process. I think a great example of disruption that maybe will help to explain it is when people drink alcohol. We drink alcohol and people think it's helping them sleep. What happens is it disrupts some of the chemical process of this Process S and actually shortens it at the end, and so we end up waking earlier. A lot of people will fall asleep nicely but then they wake up sooner than they want to and it's because we've disrupted our normal process with that.
Kaczor: Oh, okay. So yeah, let's dive right into that. What's going on with the ... What neurotransmitters, I should start there, are involved with sleep? I think the one thing we all know about is melatonin and perhaps serotonin by association, but what are the neurotransmitters involved in sleeping and wakefulness?
Kutka: Oh, definitely, there's several involved in sleeping and wakefulness and some I think we're really aware of and others are newer, they're things we don't typically think about. Just like all of our processes, it's a balance between our neurotransmitters that will help promote sleep. And so we have sleep promoters which are more of your inhibitory neurotransmitters, things like GABA and melatonin. GABA's probably your largest sleep promoter, and those are common to us. We know those, but then there's a couple others like adenosine and galanin that we probably aren't used to talking about.
When we think about wakefulness promoters that's more of our excitatory neurotransmitters, so histamine, acetylcholine, dopamine, serotonin like you mentioned. Serotonin's a little tricky. I think it can really be both a sleep promoter and wakefulness promoter, but then norepinephrine, epinephrine, and then one called orexin or hypocretin is another.
Kaczor: Okay, yeah, we'll definitely come back to the serotonin because that's definitely one that I can see how it can go both ways given what it looks like in the pathway and just feedback from patients from over the years. Let's talk about histamine some more, histamine as a neurotransmitter, because the reason I started here is because I think there's another kind of common knowledge out there, which is Benadryl puts you to sleep and Benadryl's an antihistamine, and so it's kind of nice to have that to hang our hats on, like we know an antihistamine puts us to sleep then histamine must keep us awake. So what's going on there?
Kutka: Yeah, I think you're right in that a lot of people are turning to the over the counter medications, most of which have the antihistamine in there and it's spot on. Histamine is probably our strongest contributor to arousal or staying awake. So using an antihistamine and really blocking that neurotransmitter can help promote sleepiness. But beyond that histamine, also plays a limited role in our muscle tone and control while we're sleeping as well. A lot of our major pharmacological treatments will actually work on histamine to promote sleep, not all but quite a few of them.
Kaczor: Okay, so yeah, let's circle back. Well I was going ask you this. Antihistamine diets are popular. So now they have someone who knows neurotransmitters well on the horn, I want to ask a question and that is, these antihistamine diets, are they helpful for people who have sleep issues, or are they linked at all to the histamine in the brain, or are we just talking more systemic?
Kutka: Great question. There aren't a lot of great placebo-controlled, double-blind studies out there using an antihistamine diet but people who have higher histamine levels, higher stress levels, things like that, there actually could be some breach of integrity to the blood-brain barrier. And so I do think it's worth trying, at least initially trying some form of antihistamine diet, and I'll get back to that. It's not necessarily because we're consuming so much histamine or we're making so much histamine. Maybe it's because we're not breaking our histamine down as well, you know, break down and testing first and seeing what neurotransmitters are dysregulated, but in somebody that for whatever reason has those higher levels of histamine, of course decreasing the amount of histamine that might be coming in per se could be beneficial.
That's more of beneficial I think too for people who are more sensitive to histamine from their foods and that's not going to be everybody. You know, there's a lot of, I don't want to use the hype but I'm going to, a lot of hype around the histamine food plans. I definitely have patients come in and say, "I'm sure I have a histamine intolerance." Well do we really have a histamine intolerance or maybe we have a variant in that enzyme in breaking it down, or maybe we have a nutrient deficiency so that enzyme isn't working at full capacity or as well as it could per se.
If we try a histamine or low histamine diet for people and it's working I wouldn't necessarily look at that as a histamine intolerance. It might be more diagnostic of that's the reason that's they're not sleeping but is it because, like I mentioned, not necessarily a histamine intolerance but maybe they need more of the nutrients to break it down to help support that enzyme.
Kaczor: Yeah, and I do want to get back around to testing but before we go there I just want to hit a couple more of these neurotransmitters that are wakefulness neurotransmitters like that serotonin that you mentioned, which I find interesting because a lot of people take a lot of supplements and drugs to increase their serotonin levels and those same folks can sometimes have sleep issues. How do we kind of tease this apart to know when serotonin should be supported and maybe shouldn't be pushed so heavily with substrates or cofactors?
Kutka: Well I do think that probably goes back to testing but also knowing where any implications that somebody might be lower in serotonin, I'm going to think about that in my postmenopausal women that might be a little lower in estrogen. That's one of estrogen's main roles is to promote serotonin. So if I know that, and I don't want to wait for testing maybe I'm just going to try it and try to get her some relief, you know, try promoting serotonin at that point and see if we can get some relief in the short term and then think about testing later so we don't have to wait for something.
But you're right, I think serotonin's a tricky one where too little and we're not going to get great sleep and too much and that could actually promote wakefulness and decrease our REM sleep. If we think about it, a lot of people will try 5-HTP and when we're giving 5-HTP, that serotonin precursor, we're almost always giving it to people before bed. So clinically I think well, if we give it to them and it helps that's a pretty good indication that they need that serotonin support and maybe melatonin support because, down the road serotonin becomes melatonin, but if we give it to them and it causes them to have more sleep disruptions or irritability on waking or something along those lines I think we've missed the mark there and it probably isn't serotonin that's the issue.
Kaczor: Yeah, so testing might flush that out? Is that what I kind of heard you start with? If they have a high serotonin and low melatonin then obviously there's a conversion issue?
Kutka: Yeah, that would be, I would think of that as a conversion issue or somebody with lower serotonin levels on their testing. Then we'd want to support that. Somebody with higher serotonin levels we probably wouldn't want to support that and that wouldn't really get us where we wanted to go.
Kaczor: Okay, and let me ask you this, is there a role for any of the other neurotransmitters to control the serotonin at all? Is there any play with the others that is involved with controlling the serotonin output into the synapse? Do you know what I'm saying?
Kutka: Oh, I do, yeah, absolutely. I think GABA in general will help to decrease the activity of our wakefulness promoters, so histamine, serotonin, norepinephrine. GABA's going to come in and kind of combat that, whether it's not necessarily decreasing serotonin per se but blocking serotonin messaging in different parts of the brain.
Kaczor: Okay.
Kutka: I think that's ... yeah, GABA's really huge across the board.
Kaczor: Yeah, yeah, GABA's kind of that mellow you out neurotransmitter, right? That's what we all associate with being calm and the Valium effect.
Kutka: Exactly.
Kaczor: All right, so let's move on to norepinephrine. There was something that you mentioned in a lecture that you did, and it was that ... You mentioned norepinephrine levels increase most when focused cognitive effort is interrupted. I kept repeating that line in my brain going, "Boy, focused cognitive effort is interrupted." So anytime you're ... I kind of wondered, I went straight to all of our interruptions on a given day, you know, our phone goes off or notifications come up on the computer. It's just such a very busy world that we live in now as far as long we have to concentrate on only one thing. Is that what you mean by that? Is that relevant even?
Kutka: Yeah, no, I think it is. We think of serotonin being elevated as we sustain our cognitive concentration but norepinephrine is going to raise as we interrupt it. So it's kind of ... I call it shiny goldfish syndrome. If you guys have watched Finding Nemo and Dory's all over the place. That's what we're thinking about. And so another way to look at that is our ADHD meds or ADD meds. They're working on norepinephrine and raising and sustaining those levels so that people can concentrate. So we're watching something, we get interrupted and move on to the next thing and we get this increase in norepinephrine. It's really, I think, in a way our body trying to maintain that focused concentration that's lacking there. And so disruption in that system makes it difficult and we see that sustained with medication but I think there's other ways we could do it certainly, but yes, I think you got out of it what I intended there.
Kaczor: Okay, good, good. So basically maybe turning off our phones while we eat or whatever, when we're just trying to concentrate on one thing maybe we should intentionally almost like horses, put blinders on, just kind of focus and not-
Kutka: Oh, absolutely. I think we can extract this really ... I was thinking about it in preparation for today and really we can even extrapolate that to this ... We see a huge lack of mindfulness in our culture and this idea of we're so busy. We go from one thing, to the next thing, to the next thing, and as we're doing that it's keeping us in more of the sympathetic versus our parasympathetic state, and this is really just another way of looking at it doing the same thing. We move from one thing to another, we're increasing those norepinephrine levels. We're in this fight or flight mode all the time, and then that's causing a disruption in some of our neurotransmitters, and we see that extrapolated into our patient base on all those things we do to help them with whether it's deep breathing or 10 minutes a day on their own, or any of the herbs or things that we might be doing. What we're really doing is trying to promote more time spent in that parasympathetic state so we can lower some of these excitatory neurotransmitters and things. So it goes beyond sleep for sure.
Kaczor: Mm-hmm, so what should dopamine be doing in the daytime and in the nighttime? Is there a rhythm for the dopamine, ideal rhythm for it like there is some of the others?
Kutka: Well it's another wakefulness promoter. It doesn't necessarily decrease toward bedtime or anything like you see in some of the others that we talked about, but when we have disturbances in dopamine you'll see some disturbances in sleep. So I tend to think about commonly we see disturbances in REM sleep in our Parkinson's patients or increased sleep disturbances in people with schizophrenia where dopamine is associated. It can definitely help control sleep and wake and as we wake up it actually down regulates melatonin. So I suppose it does have its own little rhythm there. It'll down regulate melatonin just before waking allowing us to wake up and get out of that sleep state.
Kaczor: Okay, so the other one you mentioned that I wasn't familiar with was orexin. What is orexin?
Kutka: It's actually, it's not newer per se but it's newer to us in medicine. It's only been really studied since the late '90s. It's another neuromodulator/neurotransmitter that helps coordinate sleep. When we don't have enough of it, it actually is associated more with narcolepsy. That's what they've studied it in quite a bit of so it's again a wakefulness promoter and it's influenced by a lot of our main energy factors, things like our monoamines, so serotonin, dopamine, norepinephrine, nutrients, blood sugars, leptin, ghrelin. So we extrapolate that out and see that it also coordinates our regulation of energy balance, and sleep, and wakefulness. Our newer medications, not so popular yet, actually work on this system. There's 2 different receptors for orexin. The newer pharmaceuticals, suvorexant, that's actually what's working on this. So it's not necessarily a hypnotic like some of the other medications that we use.
Kaczor: Okay, okay, yeah, and I saw those hypnotics just got an FDA warning for sleepwalking recently, last week I believe.
Kutka: Mm-hmm (affirmative).
Kaczor: Yeah, so yeah, if we can work around them that would be ideal, right, for folks who have sleepwalking issues.
Kutka: Yeah, absolutely.
Kaczor: All right, so we've been talking about all of those neurotransmitters and you had mentioned in your lecture glutamate and how it is involved as an excitatory neurotransmitter but I think it's also involved in GABA production as well. Can you give us a little review about glutamate and how we can either assess and/or balance that?
Kutka: Yeah, absolutely. So glutamate, like our other neurotransmitters, can be looked at in neurotransmitter testing. Not all can but glutamate can be. Glutamate actually becomes GABA when we're thinking about our cycles there. So when glutamate is too high and it's not converting properly to GABA we can actually see some of those insomnia symptoms or even difficulty falling asleep. And so having proper conversion so we have adequate GABA levels to promote sleep is important there.
Glutamate might raise because people are ... I have seen it raised because people are supplementing it or maybe it's in their protein powders and they're not converting it properly, but some people are more sensitive to our glutamic acids in foods, not all but some people are and that could also be what's raising it for people. If they have an issue, again, converting it or don't have the right cofactors to do that then we're going to see imbalances there that are going to promote more of our insomnia versus sleep patterns.
Kaczor: Okay. Let me ask you this because I know you've worked for laboratories in the past and you've looked at a lot of these various neurotransmitter tests results. Is it your opinion that cofactors in larger quantities push these pathways such that so if glutamate was high and GABA was presumed to be low, can we push these pathways just by giving the cofactors or is that not-
Kutka: No, I think that's a fair assessment. In a perfect world where all enzymes work properly without any variance or maybe we don't have any SNPs in them—it's a great environment with low inflammation, low pollution, low toxicity, as long as people aren't malnourished if we work on the cofactors I think we can get a lot of good benefit and good outcomes there but I would always think about making sure cofactors are repleted and optimal before I give any of the amino acid precursors or building blocks otherwise we won't be able to simulate them. And so I think you're right in what you're kind of saying here is that cofactors being the priority. One great example of that is vitamin D. We need vitamin D to make the vast majority of our neurotransmitters, especially serotonin and dopamine. Yeah, here in the Portland area we live in a part of the country where almost everybody's vitamin D is insufficient unless they're supplementing it. So it's a great example of making sure that we replete that before we start giving people building blocks.
Kaczor: Yeah, yeah, and it's an interesting difference between say repletion and mega dosing where you're giving intentionally large doses of P-5-P, Pyridoxal-5-Phosphate, or some other cofactor to make the neurotransmitters. I think that everyone should be aware that's there's a very big difference between those 2, repletion and basically nutraceutical dosing of large amounts of any kind of vitamin.
Kutka: Yeah, absolutely. I think that's a great comment there. The other thing I think about is iron deficiency. You know, we're working with both women and men can be iron insufficient but women in particular if they're menstruating quite often are insufficient in iron. Depending on what labs we're looking at reference ranges aren't going to show that. They're going to look "normal" when really they're considered iron deficient in that we work on repleting. Obviously wouldn't mega dose any iron or anything but repleting that before we give the amino acid precursors as well.
Kaczor: Yeah, that's a great point. Yeah, iron deficiency is pretty common in women's health, especially for cycling women. And it's so important for so many of these enzymes, isn't it, for these enzymes that create the neurotransmitters in the brain?
Kutka: Yeah, absolutely, for that initial step of conversion toward serotonin, toward dopamine. We need iron, we need vitamin D, we need B6, and actually biopterin, tetra biopterin, so we think about it as a methylation step as well.
Kaczor: Yeah, yeah, that's interesting because of course we think of fatigue as a low iron symptom but maybe sleep disturbance could be counted as a symptom as well or just any neurotransmitter disruption really.
Kutka: Yeah, absolutely.
Kaczor: Okay, so I have a question because I have a lot of women in my practice, especially if they're perimenopausal, postmenopausal, they tell me they have this wake in the night, say 1:00, 2:00, 3:00, and they've got a busy brain. One patient called it her monkey mind, turns on inexplicably. She starts worrying about stuff she knows she doesn't need to worry about but it kicks in and she can't turn it off and she can't get back to sleep of course because after that I'm guessing her cortisol kicks in and wakes her up, right?
Kutka: Mm-hmm (affirmative).
Kaczor: What's going on with these women who especially peri- and postmenopausally seem to have this middle of the night wakefulness and the brain just kind of kicks on and won't kick off?
Kutka: Yeah, great question. This is one of my favorite things to work with in practice because 97% of the time it's so easy to fix and get some really good symptom relief here. As we become perimenopausal we start having more anovulatory cycles and of course postmenopausally we're not cycling at all. So we have anovulatory cycles. We're not expecting that egg so then we don't have the tissue hanging around that would express a lot of progesterone.
Progesterone actually works at the GABA receptors, progesterone and its metabolite allopregnanolone. We have 2 different GABA receptors. So progesterone works at one and its metabolite works at the other. So as we become menopausal and we have much lower levels of progesterone overall, those GABA receptors aren't being stimulated as much as they have in the past. We talked about how important GABA is in that sleep promotion, probably the most important neurotransmitter we have there, and it's so calming. It's what things like most of our sleep medications and anxiolytics actually work at GABA receptors. And so for women in that period of life, their body's own anxiolytic has really decreased substantially.
When that happens they're going to have that what you called "monkey mind." They can't turn their mind off and they're thinking about all these things they know they don't need to think about. So as we promote, whether we're going to promote progesterone, or allopregnanolone, or utilize potentially some GABA. That's a tricky one because it's too large to cross the blood brain barrier but whatever we do, if we can promote working at those receptors they can get some excellent relief from their sleep symptoms.
Kaczor: So progesterone or allopregnanolone is usually how you would support those women through that process?
Kutka: Yeah, absolutely. Typically, when we swallow progesterone, we're straying from neurotransmitters a little bit, but when we swallow progesterone the vast majority of it, probably over 90%, is actually metabolized to allopregnanolone. So a tip for these women is to maybe utilize some oral progesterone or sublingual progesterone which will give them a little bit of progesterone and whatever is absorbed through the blood vessels under the tongue but what they swallow in their saliva will work like an oral progesterone. And so they'll get both progesterone and allopregnanolone at the GABA receptors. It can be so beneficial for sleep.
Kaczor: That's a great point because obviously a topical cream of progesterone is just not going to have that same effect.
Kutka: No, it's not, not for most women. Every now and then someone will get enough from that but that sublingual oral really helps, and what's really neat about that too is that it doesn't work as a hypnotic where a lot of the medications that work at those receptors work as hypnotics and they rob us from our deep restorative sleep that we need for muscle building, and hormone regulation, and things. Progesterone doesn't do that, and in studies with about 300 mg of oral progesterone they saw this return to sleep normalcy and the restorative sleep for the women who were suffering from it but it didn't negatively affect women who weren't suffering from insomnia when they took it. So it didn't make them excessively groggy or anything like that. There were no negative side effects with it.
Kaczor: And in interpreting the tests when you see them and women are taking that 300 mg of progesterone say orally, do you see any changes in downstream steroid synthesis? Do you see any more testosterone or anymore estrogens formed in those women?
Kutka: No, and I think 300 mg is probably higher than I would do. It's just what was in the study. But progesterone doesn't become estrogen, or testosterone, or anything like that. So we don't see any either increase in those. It also won't inhibit production of those. The pathways are so different, especially in our postmenopausal population, where they're making those hormones. So no negative or positive effects on other hormones really.
Kaczor: Okay, okay, and so we've mentioned the word testing several times during our talk today but I just ... There's a couple different types of patients, right? There's the ones who don't want to test, and there's people who want to test everything you can possibly test because they really want to see the objective information, and then there's the people in between where as a clinician you're like, "Well, let me just test a couple things and make sure I'm right," or you take a couple shots and you were wrong, and then you test. There's so many different ways of doing this. What I want to know is two-fold, one, what's the basic least amount of testing that's going to get you the most bang for your buck, because a lot of people are paying out of pocket, and then what would be on the flip side those folks who are just all in and they want to go no-holds-barred, they're just like, "Give me the whole package." What can you test and I'm talking saliva, urine, blood? What are the 2 routes to go as far as testing?
Kutka: Mm-hmm (affirmative), oh, great question. I think basic wise there's some serum, blood tests that we want to do really on the vast majority of people who are going to come in with some of these symptoms. At that point we're looking at nothing new but maybe looking at it with a new lens so to speak. So we're looking at somebody's ferritin, their vitamin D levels, we're looking at their CBC, and maybe B12, and folate to really get an idea of how they're using those really important cofactors here. Of course with sleep disturbances I'm thinking about potential thyroid imbalances too, so I would look at those in serum for people and that would be really my absolute minimum. Starting there, maybe doing some stress management techniques and repleting any nutrient deficiencies that we find, and optimizing I should say. I'm sure you and most of the listeners realize that our reference ranges aren't necessarily set to optimal for many things, and so we want to optimize those, not just make them look okay. Then they can better utilize and assimilate what else is going on in their body and whatever else we give them.
But then beyond that, we can look at neurotransmitters in urine, almost all of them. Acetylcholine we don't have a great assay for, some of those newer ones like orexin or adenosine we're not really monitoring that but our main ones that we know that promote sleep and wakefulness can be utilized in an easy spot urine test. It's super simple and the studies that we have on that correlated well to central spinal fluid. You know, yes, we're looking at full body levels there but it's still a reflection of the imbalances in the body and that is correlated well from the literature that we do have at this point correlating that.
And then, of course, from there if we wanted to get an idea on how we're breaking it down there's another test that will look at the metabolites of neurotransmitters. I don't use it a ton but for somebody who wanted to do absolutely everything, you know, we're looking at organic acid testing, and neurotransmitters, and all of their metabolites. But I would also think about hormones in these people as well, particularly our cortisol levels and finding any dysregulations in the HPA axis, so the brain telling the adrenals to work. Those imbalances with cortisol levels will absolutely lead to sleep disturbances and not just having elevated cortisol levels at night but even people with flat line or lower cortisol levels will actually be the ones that typically will report more nighttime wakenings than others.
But then we can look at sex hormone imbalances in our salivary testing as well and get a great look at all of the neuroendocrine influencers that can be resulting in sleep disturbances. That's really the imbalances there that we're seeing that's causing that, not necessarily one thing over the other but an imbalance of those sleep promoters and wakefulness promoters.
Kaczor: So would it be fair to say that if someone was testing hormones they're going a little bit more upstream because the hormones are having such a profound effect on neurotransmitters, so if they had to pick one or the other? Is that accurate?
Kutka: Yeah, I think that is pretty accurate but particularly in I think about it more in women in that period of postmenopausal group or even younger women who are having menstrual cycle disruptions because it's that estrogen promotes serotonin, it promotes dopamine; progesterone promotes GABA. And so our really big players are promoted by our main sex hormones. Yeah, I think that's a fair statement there for sure.
Kaczor: Okay, great. Well we didn't get in the HP axis so now we have something to talk about next time we have an interview. And of course this was great. I really appreciate your time and your expertise. Neurotransmitters can be a pretty confusing topic for a lot of folks so thank you for all the clinically relevant information.
Kutka: Yeah, absolutely. Thanks so much for having me. I hope that it helps with some patients' interactions in the future.
Kaczor: I'm sure it will and next time maybe we'll talk about the HPA axis, and sleep and wakefulness, and until then, take care.
Kutka: Thank you, you too.
