Psychiatric Effects of GLP-1s (What We Know So Far)

Margaret: [00:00:00] Shout out GLP-1. Thank you for letting me prescribe all sorts of atypical antipsychotics. 

Preston: Yes. Thank you. Not everyone needs you, okay? 

Margaret: Not yet. Like- Yeah ... get some studies and we'll see. 

Preston: Yeah. How to be safe And welcome back to How to Be Patient, a podcast of lot more patient talking and a lot less how-to. But today- and by patient talking, I mean patiently talking.

It's, the, adverb. So today we are- Nailed it ... gonna be talking about GLP-1s, the en vogue topic. I think this has been getting a lot of press recently. So we found it actually meandered over into psychiatry before. Psychiatry had a, desire to weigh in on this. So we're gonna be kind of talking about that intersection.

But before we get into that, this is our chance to check in on how things been going over the last [00:01:00] week. And I was thinking about what icebreaker I wanted to do today, and I was like, "I don't have anything GLP-1 related." And you can ask, like, "Well, what's your experience with GLP-1s been?" It's like, well, I don't, like, TMI if there is personal experience with it, but also, like, I don't know.

This, to me, is kind of like a vague question. So instead I was like, maybe we'll do rose, bud, thorn. But also that felt a little camp counselor-y, so instead I'm gonna do the thing that works for me, which is we're gonna name some stuff that we're grateful for, like, like around the Thanksgiving table. Damn it

Yeah. 

[music]: No, we're gonna, we're gonna sit down your ass down at this table and be grateful for 

Margaret: once. 

Preston: Exactly. Exactly. And so we're, I know Margaret and I are- And that's you too, 

Margaret: listener. 

Preston: Yeah. Whether you're sitting, like, on the couch or in the car or you're standing up, prepare to be grateful. You're in 

[music]: the OR.

Preston: And I- Yeah, and I want you to do this exercise with us. We're gonna go around robin. So I can, [00:02:00] start off. I am grateful for my cats. They are both crunching right now, and they're- What does that 

Margaret: mean? 

Preston: Oh, crunch, they're eating. Yeah. Oh, okay. I give them, some rocks, so that they can, you know, snack and then chill out during the podcast.

They'll probably still be around to check out the microphone later like they always do. It's, it was funny. The other day I was like, man, how can these cats eat rocks every day, you know, to be just as excited about it? Like, don't they want some variety? And then I pour my- 

Margaret: Actual rocks? 

Preston: like, like Meow Mix.

Margaret: Oh, okay. 

Preston: Not literal rocks. Yeah. 

Margaret: I've never had a cat- Oh, I see ... and so I don't really 

Preston: know. Yeah. It's, like, I guess it's the lingo, the vernacular to call, like- 

Margaret: Yes ... kibble. I'm not on cat TikTok- Kibble. Yeah ... except for the, like, really super weird cats I think get through. But I'm, like, I'm pretty allergic to cats actually.

Preston: Gotcha. Yeah, I am, I'm allergic too. 

Margaret: Not grateful for that. Yeah. Really? 

Preston: Mm-hmm. I mean, 20% of cat [00:03:00] owners are allergic to cats. Wow. You guys are like persevere. We just power through because why not? Yeah, so, so anyways, I'm like, man, they eat the same food every day. How can they do that and still be excited about it?

And then I pour my cereal of my Frosted Mini Wheats, which are essentially the human version of kibble. 

[music]: Your kibble , yeah. 

Preston: And I was like, you know what? Who am I to judge? So that's my first one I'm grateful for So you're 

Margaret: thankful for your cats and your, kibble- Mm-hmm ... your human kibble. 

Preston: Yeah, my human kibble.

Cereal aisle is just like human cat food. 

Margaret: I, something I'm grateful for, yesterday, I, paid off my WashU, like, private, l- like the loans that WashU ga- gives us for like parts of our med school debt. And so I still have my, like, federal loans, but I had a good chunky amount on my WashU loans, and I paid them off.

So now I only have federal loans- Wow ... which is a huge thing for me, and is why I've worked so many like extra weekends and extra shifts and stuff over the last three [00:04:00] years. so just federal loans now. But pretty soon I'm gonna be less than six figures of debt, which is- 

Preston: That's awesome ... 

Margaret: great. Especially- Yeah

'cause still in training. So that's something I am grateful for past me for soldiering through and pretending like I still had call every three weekends during fourth year and last year. 

Preston: Yeah, absolutely. I like how you phrase that, grateful for past me, not just being grateful for the outcome, but for- Mm-hmm

the older version of yourself to, or I guess, younger version of yourself to, to do that for you. 

Margaret: Yes. That's 

Preston: cool. 

Margaret: And to, you know, li- some listeners, but readers online of like my different, like, little digital journals I put out, you guys also helped me pay those off, so thank you. 

Preston: That's great. Yeah, it's a group effort really.

And 

Margaret: now I go to- Wash- ... to the wrap plan for my federal. 

[music]: WashU, yeah. 

Margaret: Me, you guys. 

Preston: All right. Now listener, it's your turn. What are some... What's something you're grateful for? [00:05:00] We're both gonna pause. Aw, that was really good. It's an important thing to be grateful for that, whatever it is. 

Margaret: I thought it's so unique.

Preston: I know. And just, it's just very you too. You, dear listener- 

Margaret: Such a you answer ... 

Preston: I'm grateful for you. 

Margaret: Oh, wait, I have one more. I got a new piercing last, this week- Ooh ... for no reason. I got a like, it's a conch, so it's like on the outside of the ear, and eventually- Mm-hmm ... I'm gonna have a, like, it's like a middle cuff.

But- Oh, that's sick ... I'm thankful for having a high pain tolerance because it was fine. 

Preston: Yeah. 

Margaret: Maybe you should get a piercing. You could really just lean into, like, an alt style this fall. 

Preston: You know, so, like, people in the military have, like, alt style, versions- Mm-hmm ... of themselves that they, you, have to do piercings that you can hide easily- Oh

in uniform. That's like- 'Cause you can't have any, like, facial piercings or stuff like that in uniform. So it's really common for someone to have, like, a septum piercing and they [00:06:00] flip it- Oh, and they can flip it up ... upside down. Yeah. 

Margaret: Yeah. 

Preston: During work hours. Yeah. But, like, you know, getting my ears pierced, it's kinda tough.

Can't do it. Kinda tough, yeah. It's not 

Margaret: allowed. It is kinda tough. All right, 10 years from now, you're gonna lock in. 

Preston: Yeah, it, when I, yeah, when I finish my s- active duty service commitment, it's just be prepared world, alt Preston is coming through. 

Margaret: Give it, give me a second gratitude for you also. 

Preston: okay.

I'm really grateful for, I just, wanna say, like, my legs. 

Margaret: Okay. 

Preston: And, by that I mean, like, that they, work, that I can go- Mm-hmm ... and play sports, that I can run, that I can be active. I think I've spent so much of my life maybe, like, dreading that I had to go do activity or I need to go on this run or I have to do something as a part of a team, but I, you know, I was out playing soccer last night and I thought how cool is it that I can get to go do this thing and that, like, my body works.

Yeah. And that I can play. So. [00:07:00] 

Margaret: Yeah. I feel like, ever since I started teaching a y- now it's been like a year of going back to teaching Pilates. I feel like I notice much more, like, it's not that I notice, like, how people walk or move, and I'm sure you have this as, like, someone who was, like, an athlete- Mm-hmm

in college. But because you, I, like, walk around the room and make corrections as I'm teaching classes, I just notice how people move more. And a lot of people at all sorts of ages have, like, it's not abnormal to have, like, a shoulder that is kinda funky and a knee that gives you trouble. Even, like, I think I, and I've never had, like, an injury.

So I've had, like, a hip kind of, like, labrum maybe, like, a little bit of a twinge before. But I've, like, not ever had to deal with something like that or broken a bone or had chronic pain for a long time. And so I think it, similarly to you, it just, like, it makes me aware. You know how everyone always says you, like you have 100 problems until you have a health [00:08:00] problem, then you have one problem.

Preston: Yeah. the one that I was thinking of- And we may have talked about on this podcast before is the invisible crown, which I think that comes from a- maybe a poem. Basically, the, the concept is, or, the way the poem goes is that health is a crown, but it's only visible to those that don't have it.

Oh. So when you're feeling sick, you see everyone else wearing this crown, but they can't see it themselves. Yeah. and then it's, all you can see when you're the one who's, who doesn't have it. So this is me trying to see my own crown. You know? That's sick. I have my health- That's funny. I'm gonna write it down

and I don't wanna wait until I lose it. Yeah. I'm like, I'm looking in the mirror like, "Invisible crown. Invisible crown. Invisible crown." And then, like, you know, shows like it's Bloody Mary or something. it doesn't, but I can just take a moment and be like, "Okay, I can play soccer. That's sick. Go running.

For, sure, dude," you know? "Get my cardio sesh on." 

Margaret: I do think that both you and I experienced a parent going through a significant loss of [00:09:00] that crown- Mm-hmm ... when we were teenagers, right? 

Preston: Yeah. 

Margaret: You were younger than that, but 

Preston: I was like- No, I was like, 16, 17. 

Margaret: Yeah, I think I was, like, 19 or maybe I was 20, but when my, like, dad first got sick.

And so I do think that there's... I don't know. we can move on from this, but I do think there's a sharpening of that awareness in some ways when that ha- like, you see someone so close to you be impacted- Mm-hmm ... so early, or if it personally obviously happens to you. 

Preston: Yeah. So to the listener too, I hope, you guys, if you have the crown, that you're, trying your best to look at it too.

Margaret: Nice. 

Preston: Well, let's, on, on that note, let's move on, talk about some GLP-1s. So we're gonna take a- ... a quick break, and when we come back, I wanna just real quick, and we're not gonna get too medicine-y, but go into some of the mechanisms of GLP-1s. And then we'll talk about actually maybe what are some of the, like, psychiatric effects that we're seeing or what's the [00:10:00] emerging evidence that's coming out.

See you soon.

Margaret and I are very excited to tell you about a healthcare news podcast that just came out called Medlines. 

Margaret: It's a quick weekly wrap-up of everything in our field, from breakthrough discoveries and research, to politics and, of course, medical pop culture. 

Preston: I think the best way to conceptualize this podcast is it's like NPR's Up First, but for medicine.

So they're short, to the point, with episodes no longer than 15 minutes. 

Margaret: And it's written and created by an amazing team, some of whom you might recognize: Dr. Glaucomflecken and Lady Glaucomflecken, as well as many people here at the Human Content Podcast Network. 

Preston: With thanks for their inaugural sponsor, the New England Journal of Medicine.

New episodes of Medlines are out wherever you get your podcasts, with new episodes out every Friday.

Okay. And we are back to talk about GLP-1s and maybe send you back to your GI block of [00:11:00] M- MS1, M2. So this was, always super fun for me. so When I was in med school, and I think it was probably the same for you, I remember studying all the diabetes drugs and like the, you know, like sulfonylureas and like metformin and, different variations of insulin.

And then GLP-1s were talked about there, but it was only, I only saw it in the context of diabetes. And they were saying like, "Yeah, the- these are relatively new. They work really well for diabetes, and some people are thinking about using them for weight loss." That's how it was, like, introduced to me. Was that kind of the same for you?

Margaret: Similarly. I remember distinctly being, like, on medicine, being with this, like, very fabulous attending, who I think is- was also, like, a GI attending, but would sometimes do a few weeks of hospitalist at the VA in St. Louis. I remember her teaching us about them and saying, like, similarly to you, I guess it would've been, like, a couple years before.

And so there was much more of an emphasis on, like, this is new and it's, like, [00:12:00] life-changing- 

[music]: Mm-hmm ... 

Margaret: for our patients with diabetes. And so there was, like, less of the mention of weight gain. Yet to the p- point that I, like, almost didn't put it together, like, three or four years ago when it started to be, like, really, you know, in the public eye and about weight loss.

so it's interesting. I just remember her being like, "The cardiovascular outcomes are so much better for our diabetes, our patients with diabetes who are on this." 

Preston: Mm-hmm. Yeah, and, it is making a big difference. So according to the CDC, of adults living with Type 2 diabetes right now, about a quarter of them are using some sort of a GLP-1.

So th- it's a large portion, and I would say for the other 75%, a good portion of those would be indicated or w- would be able to benefit from one, but it's cost-prohibitive still in some way. And I would say there's another portion that maybe won't, aren't, are unable to tolerate the medication for, whatever reason.

The [00:13:00] other thing that's interesting that, you know, we've seen a, a, a big rise in is current usage in general. So a recent Gallup poll, indicated that about 11% of all US adults are actively taking a GLP-1. 

Margaret: Wow. 

Preston: Yeah. And this is about a 3% rise in recent years. I don't think it indicated, like, whether or not it's specifically for, weight loss or diabetes, but essentially, you know, somewhere between, like, one in 10 and, one in eight.

[music]: Mm-hmm. 

Preston: so, so it's, you know, you sit on a bus full of 30 people, you know, a couple people could be- Three are on GLP-1 ... on GLP-1. So just, kind of think about that as e- even just as you, like, talk about it at the water cooler or anything, like, like, it's very likely, like, someone around you that you wouldn't even know is, using it.

And I've had people disclose it to me that I, like, wasn't expecting. Like- 

[music]: Mm-hmm 

Preston: Like I'd, you know, like you're like talking to a neighbor or something and you're like, "Oh, how's it going?" And they'll just be like, "I'm on [00:14:00] that shot now." You're like, "Oh, good morning." They're like, "Yeah, feeling great." Okay, dude.

[music]: Okay, girl. You're like, "All right. I'm gonna go on my run now." Like, "I'm gonna... I'll be back." 

Preston: Yeah. Or like I was in, LA for the, the Figs shoot, and I was like chatting- with people. Oh, well, 

[music]: oh, the what? Where, oh- Mm-hmm ... I was in LA for a 

Preston: shoot? 

[music]: Yeah, the Figs shoot. Anyways, 

Preston: yeah, so, so I'm socializing and then, you know, someone goes, "Hey, I've been microdosing, oral GLP-1's.

What do you think about that?" 

[music]: Oh. And 

Preston: I'm like, "Whoa, yeah, yo, like, do you have diabetes?" 

[music]: You're like, "

Preston: What are we doing?" Just 

[music]: does not look like it. 

Preston: Yeah. It- so anyways, e- even, like outside of my like classic doctoring, I've like s- have been interacting with this a lot. a k- kind of quick review on what even a GLP-1 is supposed to accomplish.

So it stands for glucagon-like peptide 1, which it's a, it's an agonist of a receptor of [00:15:00] a, an actual endogenous hormone we have. So for everyone listening, you, have a homegrown version of GLP-1. it's released in the, L cells in your small intestine, and it's usually triggered by eating food. I think carbs trigger a stronger release of it than, other forms of macronutrients, but, uncertain.

I do know that it comes bimodally, so after you eat a meal you have an initial surge or release of GLP-1, and then it happens again around 30 or 45 minutes after you digest a little bit more. Now, where the glucagon-like receptors bind, that's, kind of like the important thing. So everyone knows about its relationship with GI stuff.

It binds to, the pancreas, which can control release of insulin, so it actually can like block release of glucagon in the alpha cells in the pancreas so it can like keep your blood sugar from spiking, but also promotes releasing insulin. And that's just in general [00:16:00] A good way to think about GLP-1 is it's helps put you in a fed state.

So it's like indicating to your body, like, "I've eaten food and I wanna chill out now." So the other ways we see it affecting people are their vagal nerve afferent, so the kind of the vagal nerve endings that tell the stomach to empty or to relax or to turn over, like it will slow those down because if you're fed, you wanna like slow your stomach down so you have time to digest.

It also has like some effects on the cardiovascular and renal system. Nothing that I wanna get in detail about, but it's just important to know that you have GLP-1 receptors everywhere in your body. Did I say everywhere in your body? That's right. It's also all over your central nervous system, which is the stuff that 

Margaret: we 

Preston: care about.

Brings us to 

Margaret: psychiatry. 

Preston: Yeah. So this paper that we're kind of bringing on board here, and for those of you who wanna read along, the, the DOI is gonna be in the show notes, but this is the psychiatric effects of GLP-1 [00:17:00] receptor agonists. This is a systematic review and emerging evidence by, Brianna S. A.

and colleagues And then you can just kind of copy the link and pull it up. But, one thing that they mention very early on in the introduction is that we have this plausibility mechanism for how GLP-1's gonna affect our mood and that's because we actually have a lot of GLP-1 receptors in the, the amygdala, the hippocampus and around like the nucleus accumbens which these all play large roles in kind of memory, fear, behavior, reward response.

Margaret: I'm just looking at the-- I'm looking at the paper and I'm seeing someone, it's not someone I know but it's someone from the Brigham so I'm like, "What's up? What's up?" 

Preston: That's cool. Yeah. 

Margaret: What's up? Hello residency. continue. Yes. 

Preston: Yeah. Yeah. So, 

Margaret: so it's reason- So they're there too. 

Preston: Yeah. The, the point is it's, reasonable to conclude that if you have receptors for this hormone somewhere in your central nervous system that there may be effects that modulate how it can affect your brain, [00:18:00] therefore your emotions, mood, behavior, everything like that.

And the, the, thing you may also be asking is w- but wait, won't the drug have to be able to get into your brain to do that? And the answer is yes. As far as we know or has been established like semaglutide and a lot of the other like mainstream GLP-1s do cross the blood-brain barrier and they do bind, with these receptors.

There-- I, I say that as a caveat because there are new versions and peptides of GLP-1s that are coming out constantly like, tirzepatide, retatrutide, like anything that ends in a T-I-D is gonna be like in that GLP-1 class but- 

Margaret: Is, 

this what people- ... 

Preston: not 

Margaret: all these are FDA approved ... refer to? I recognize like I should know this and I can look it up but like is this what people mean online when they're like pep- I'm taking peptides?

What the, what are people saying when they're saying they're taking or what do they think they're saying? 'Cause God knows what it actually is the t- they buy. What are people saying when they're like, "I'm taking a peptide"? 

Preston: that could be a totally different episode. Okay. And most of the time peptides [00:19:00] have to do with I think it's like, skin cell production.

So there's like a certain peptide that has to do with like your copper metabolism. But 

Margaret: aren't they taking it for like weight loss and muscle building? Oh. Yeah, 'cause there's some people who are like-- I'm like-- Hold on, I gotta find this. 

Preston: Let's- I mean, let's, do it live. Let's Google these. Okay. so I'm seeing like- Biohacking 

Margaret: peptides for...

I know the skin one. The skin one is less controversial. but it's like injectable peptides. Oh, 

Preston: like CJC im- imunoprenilin. Oh, okay, this is a peptide to stimulate natural growth hormone production. Okay Yeah. So when they, when you're saying peptides, they probably are referring to some GLP agonists, but there may also be like some growth hormone promoters in there too.

I was 

Margaret: like, "What are you guys talking about?" I like-- Now my phone is gonna start showing me these and be like, "I bet she wants it." I don't wanna know. 

Preston: Yeah. 

Margaret: Not until I'm [00:20:00] forced to know for patient care. Okay, sorry for that tangent. How interesting. But I was like, is this- 

Preston: no, it's important to know, yeah.

So, so it would be encompassed in the peptide argument- Okay ... or discussion. Okay. So, basically established it does affect the-- it, it can mechanistically affect the CNS. We know there are receptors in certain parts of your brain. We know it crosses the blood-brain barrier. So the, kind of the-- Now the purpose of this article is actually to dive into a couple different domains where we might possibly see these effects.

And- Mm-hmm ... this isn't contained, but the, this specific systematic review is looking at depressive symptoms, substance use disorder symptoms- Okay ... eating disorder symptoms, suicidality psychosis, and I don't know why I'm blanking on the last one. Yeah ... anxiety, which I was, like, prepared to lump in with the other ones.

So it's, interesting because they actually did w- what I thought was a pretty good job of pulling some pretty true, like, [00:21:00] meta-analyses that looked at randomized controlled trials for specifically depressive symptoms. And surprisingly, they didn't get much consensus, which maybe I shouldn't say surprisingly.

Like, even when you do gold standard randomized controlled trials with seemingly, like, large groups, I f- it's, often... Or, like, I'll see more than I would expect conflicting data. 

Margaret: Yeah. I mean, I think that we're-- My, my impression of where we're at in general with some of the GLP-1 agonist stuff with, like, mental health is that it is falling to, like, the natural reasoning fallacy in terms of where we actually are scientifically versus where people want us to be or, like- Mm-hmm

industry would like us to be, or, you know, our patients would like us to be and we would like to be. But, like, that, like, so in the paper they... Not, this is not me dragging the paper, but I feel like you see stuff like this in news [00:22:00] articles or, like, on social media where people take a paper like this and they say, you know, obviously like GLP-1 agonists work because there's central activation of preproglucagon expressing neurons and the stimulation of corticotrophin-released- Mm-hmm

hormone in the- That sounds really science-y. It must work ... HPA axis. And it's like someone can be relatively smart and be like, "Yeah, that does sound like it would make someone not depressed." And then to your point that like, well, when the people who are really actually doing the research and are, like, doing semi-decent studies on this, like, we're actually not getting that this thing is true just 'cause it sounds like it aligns with our understanding of a hypothesized mechanism.

But hypothesizing will take the internet and the wellness industry, it will kick its ass every time and- 

Preston: It 

Margaret: really 

Preston: will ... 

Margaret: just... So I think it, it's interesting and I-- 'Cause I don't, know, I feel like there's many things that you could say in theory this is why it would work, but that it looks [00:23:00] like the studies so far are pretty mixed except for in the case of people with Type 2 diabetes.

Preston: Yeah, exactly. So, just to, read this off really quick. "A meta-analysis of 80 randomized clinical trials including 107,860 participants found no significant association between GLP-1RA use in either se- serious psychiatric adverse events or non-serious events compared to placebo. No significant change in depressive symptoms was observed."

And, they- basically ran through consistency in these findings among groups not in the, the diabetes group. So what you're saying is that for most people, there's no change in depressive symptoms, but it actually may have a benefit for people that have diabetes and are already taking the medication.

And this wasn't true for depression, but for anxiety, it was almost the, not necessarily- Yeah ... the opposite, but there was a specific group where they [00:24:00] had a negative effect. So in most people- Mm-hmm ... there wasn't a big change in anxiety symptoms, but for people taking it specifically for weight loss- Mm-hmm

noticed an increase in anxiety effects. 

Margaret: Which, I mean, when we have the data, we can hypothesize, again, hypothesize. Like, I feel like if you think about anxiety and weight loss, like weight loss can be somewhat stressful from like a homeostatic per- view of like the body's sense of safety. And so it doesn't necessarily surpri- like I, I feel like we see lots of people come in with like super high blood sugar, but then when they come in low blood sugar, you're like, "Something is off," right?

Yeah. There's like much less wiggle room for how that appears and looks. 

Preston: My interpretation of that hypothesis was that it's- it's almost like your, please skills are completely depleted. Like when someone's taking a, a GLP-1 to stabilize their blood sugar and diabetes, [00:25:00] it's not causing the same shock to the system as someone who's losing 50 pounds over the course of like several months.

Margaret: Yeah. 

Preston: And I made a post talking about this on Instagram a little while ago, and some people were saying, and I don't have an answer to this too, by the way. Some of these comments were saying, "Is it actually the GLP-1 causing anxiety, or are they just responding to all the symptoms of feeling hungry, but they don't actually- Right

feel the hunger?" 

Margaret: Right. 

Preston: And, I, think it, it's a great point and I'm not sure it's one or the other and, it may be both, which I feel like is just- Mm-hmm ... like the cheeky shortcut answer to a lot of these questions, but it's probably both. 

Margaret: Or it's the intellectually honest one of like- Yeah ... we don't know.

I, I think an, like we could have a million hypothesis at this point. Mm-hmm. But like for the anxiety one too, I would be curious like, and I would need to look more into the, that study in particular that we're talking about, like what was the protocol for how quickly the weight loss was and what was the pers- like the average starting weight [00:26:00] and like height and BMI change?

'Cause like from- Mm-hmm ... the eating disorder perspective, not that would necessarily be that, there's certainly a like limit to pace of weight loss that Is more or less likely to cause anyone to be kind of more perturbed and have, like, anxiety, depression, whatever. And so I would also be curious about that.

And think, like, I don't think that we think that GLP-1 agonists are so comprehensive that they, like what you were saying or what your commenters were saying, would totally get rid of the systemic impacts of malnutrition. 

Preston: Mm-hmm. And, I think it, it makes me think of almost like those... like when you can take medications that suppress a single feeling but nothing else, like, comes through.

Like, you ever, like, have a bunch of caffeine and it suppresses your appetite? You can still, like, be hangry or, like, be like, "I'm having trouble focusing." Like, "Why am I having trouble focusing? I had all this caff- oh, yeah, I haven't eaten today." 

[music]: Mm-hmm. 

Preston: Yeah. Like, the-- Like, you can, like, suppress your [00:27:00] response to it.

Or almost like how when you take a beta blocker and- Mm-hmm ... you become hypoglycemic, it suppresses your, like, natural response to that hypoglycemia. 

[music]: Mm-hmm. 

Mm-hmm ... 

Preston: so, and that's actually something they, counsel diabetics on to be, like, careful about taking beta blockers because it will mask your hypoglycemia.

So, and then just to kind of furnish this too, this is actually when they studied anxiety, that was with roughly, I guess, 100 times, the population. So a large scale observational study using over 11 million adults with obesity found that GLP-1, users had a significant increase in, anxiety disorders, demonstrating a 100%...

108% increase, 

Margaret: which is 

Preston: significant. 

Margaret: So was this a, a-- Was this an associative study? 

Preston: It was an observational study. So- 

Margaret: Okay. 

Preston: So- They followed 11 million obese individuals, observed them, and then saw, I'm assuming on a GAD s- like, GAD-7 screeners, about 100% [00:28:00] increase in their scores. 

Margaret: I'm just trying to see if, like, if that's an observational study.

Preston: Oh, like if it's a cohort or if it's a trans-transsectional- 

Margaret: Yeah, like, 

Preston: well, 

Margaret: if 

Preston: it's like- ... or like a cross-sectional analysis ... 

Margaret: yeah, from over 11 million adults found that users had a significantly increased risk of developing psychiatric conditions. but that-- If that's associative, yeah, these associations remain consistent across demographics.

But we already know that from some of the, kind of population level studies on people, like, living with diabetes or people living with obesity or chronic pain have an increased risk- Mm-hmm ... of anxiety and depressive disorders as well. And so I guess my question would be, like- Can we separate that out?

Because that would actually change clinical decision-making. Yeah. You know what I 

Preston: mean? So, just I actually pulled up the study. Yeah. It said that they, everyone enrolled in the study had a BMI over 30, and the cohorts- were either GLP-1 or no GLP-1. 

Margaret: Okay. And so then how long did they follow them for?

Preston: And then I [00:29:00] don't think they actually followed them. I think they assessed, their psychiatric symptoms within the last year. So- Interesting ... they looked at 11 million people, Mm-hmm ... all, with di- all with obesity, divided them into two co- cohorts, one on a GLP- 1, one not, and said, "What have your psychiatric symptoms looked like in the last year?"

And the people on GLP-1s- Yeah ... had 100% higher reported levels of anxiety. 

Margaret: Interesting. And 195% higher of depression. But- 

Preston: Mm-hmm ... 

Margaret: the kind of confounding variable there could be who advi- like, these people ended up on this medication at that time. Maybe it was a newer medicine. Like, is it reality, one, that being on that medicine impacted development of these psychiatric conditions?

Or is it possibly this other option that's like- 

[music]: Mm-hmm ... 

Margaret: having a higher likelihood or kind of a phenotype for these ones made you advocate more, made your presentation look different, that prompted more of a likelihood to be put on a [00:30:00] GLP-1? 

Preston: It, yeah- Who knows? Exactly. Like, we, like, we assume you wanna assume it's causal because that makes sense in your brain.

It, could be very possible that anxious people advocate more to be put on GLP-1s. 

Margaret: Yeah. 

Preston: I'm not-- I don't know if I believe that. And I say 

Margaret: that as an anxious person. Like- 

Preston: Yeah 

Margaret: As an anxious person myself, I know my own shit. Not that it's good or bad. Some people should-- Some depressed people, like, can't advocate and can't see a hopefulness, so like- 

Preston: Mm-hmm.

Margaret: yeah, no, it's just, it's interesting and, again, I think underscores... This whole paper, I think, does a really good job of saying, like, this is where we are without jumping or trying to reduce the things that we know and the things that we don't know. 

Preston: Exactly. and then I also, kind of moving forward, I wanna touch on suicidality, and then we'll take a quick break and kind of come back and talk about, Let's actually talk about suicidality and, psychosis. Then we'll-- when we come back, we'll talk about the eating disorders and substance use, 'cause I think that's an interesting path [00:31:00] forward. So, psy- like anything, in psychiatry, our biggest safety concern is suicide, so that's the one we care the most about Very o- or it takes the highest priority 'cause it's the most lethal.

The most large cohort studies don't actually show any kind of statistically significant, increase in suicide risk. And- Okay. Which is 

Margaret: good to know. 

Preston: It is good to know. And there, there's a possible exception, that it might be higher reported in people that are already on antidepressants or benzodiazepines.

So something to keep in mind, but remember, like, it's correlational. and we don't have enough to say, like, this contributes... It, has any sort of causal relationship with, increased suicidality. 

Margaret: Well, and that, like, compared to the population of, like, people who are on these and are not on antidepressants or benzos, like, if you have depression, you also have a higher risk of suicidality [00:32:00] than someone without depression.

Preston: Mm-hmm. 

Margaret: and so it's hard to say. I think it's similar to, like, kind of the conversation we have with antidepressants, where it's like And t- like the black box warning that happened in the early 2000s with antidepressants in adolescents, that it's like there are people who are depressed that we give some medicines, and then it does something with the depression, and they already have a risk of suicidality, and so it impacts them possibly differently than people who don't already have a risk.

And, you know, certainly there are cases where medications could be the first unmasking of suicidality that never existed before. But I think often what we're talking about is like a baseline risk that is impacted secondary to a medication. And- Mm-hmm ... GLP-1 agonists may not be, an exception to that rule either.

Yeah ... and then the other thing, I looked-- I didn't-- the, they use the w- the phrase pharmacovigilance, which I think is just like side effect reporting, for medications, w- in the suicidal ideation part, [00:33:00] which is where this kind of possible increased odds ratio for people on antidepressants or benzos for the suicidality- Mm-hmm

which is interesting as a way of clumping. I do. 

Preston: I, hadn't seen that term before, and I like it. 

Margaret: Yeah ... 

Preston: pharmacovigilance. 

Margaret: Just vigilante shit, like 

Preston: Exactly. Pharmaco- sa- yeah, salient reporting of pharmaco-related symptoms. Finally, with regard to schizophrenia spectrum and other psychotic disorders, happy to report that there is so far no evidence that GLP-1s worsen psychotic symptoms.

Margaret: Right. And would you- Hooray. And- As time goes on, you should think about collaborating with primary care p- on, for GLP-1s because of the psych- antipsychotics they're on, and because there's a 20 to 25 year- Mm-hmm ... especially cardiovascularly mediated risk. So help your patients. If you're advocating for metformin, some of them you need to also be advocating for GLP-1s if you're not [00:34:00] gonna prescribe it, someone else will, so.

Preston: Exactly. 

Margaret: Good to know it doesn't hurt anything so far- 

Preston: Right ... 

Margaret: that we 

Preston: know. So, and, that means like all the more reason that if someone's on olanzapine, on a second-gen antipsychotic, on any kind of chronic antipsychotic, that, yeah, get the ball rolling. Okay. So let's, take a, a quick break, and when we come back, we'll talk more about, eating disorders, substance use, and actually potential possible primary uses of GLP-1s for psych conditions.

So I'm gonna do dealer's choice. Would you rather talk about substance use first or eating disorders first? Let's do 

Margaret: substance use first, I think. Okay. 

Preston: Substance use for, 300. When looking at things that help with substance use disorders, we have a huge variety of stuff. I think what I've noticed, at least in the literature for like alcohol use disorder and, nicotine [00:35:00] use disorder, is that we've been kinda throwing the kitchen sink at it, and I think this is just another, another iteration, but, that actually has some promising results.

So in, a randomized control trial, exenatide was found to reduce neural reward response to alcohol cues but did not lead to significant overall reduction in alcohol consumption. I think that's a really interesting, phenomenon, something we kind of, see consistently with, GLP-1s. So I wanna kind of take a sidestep here to talk about, reward-driven behavior.

So I've been reading a little bit more about the kind of like neuroscience, mechanisms around this and I kinda wanna divide it into two buckets. So the first bucket is like reward drive or like the desire to even pursue the stimulus. And then the second one is actually behavioral action [00:36:00] towards the reward.

And you can... Actually, you can kind of separate them. So that first one, reward drive, it's through the ventral tegmental area and it's mostly just dopamine mediated. But the behavior part actually has a really large component of glutamate, that modulates it. So it's, important to kind of see these two pathways differently and, s- a lot of like medications that treat addiction may actually target one side or the other side.

Margaret: Can you, give an example of like what you think of as like the... I know you can't totally separate them, but like reward drive versus behavior drive, like maybe in the case of like alcohol. Like would it be the actual intoxication with alcohol molecules versus like dr- like drinking it? Or what do you think?

Preston: So it would be like the reward drive is that like feeling of euphoria you get or maybe relief you get when- Okay. 

Margaret: So like the chemical part 

Preston: of- When the chemical hits your brain ... an al- alcohol. Yeah Right. And then the behavior activation is like your [00:37:00] ability to control or to decide to act on going to get a drink.

[music]: Okay. Got it. 

Preston: So like for me, you know, if I'm feeling hungry and I want a snack, like even just the desire to go seek out a snack, that's the reward drive. And then I think for a lot of people just kind of at a basal level, like most people are like, "Oh, I could go for a snack," just kinda like throughout the day.

but then like whatever, whenever that reward drive gets up to a certain threshold then, I behaviorally I act on it. So it's-- You think about like adjusting levels, like, okay, how high is the threshold for me to break the ceiling to act on it? Like if that's really low, I may just be like going to get a snack constantly even if the re- the reward drive isn't that high.

[music]: Right. 

Preston: But then 

[music]: if the re- Gotcha. 

Preston: Yeah ... if the reward drive gets even lower because of like, maybe I feel nothing when I eat, you know, like, like maybe I have COVID and I can't taste anything, now actually the reward drive is less from the food. Now I don't have a desire to eat. Like that- 

[music]: Yeah ... 

Preston: it's not gonna lead to the [00:38:00] behavior itself.

[music]: Gotcha. Okay. 

Preston: So th- so those are kind of the two levers I think about It, in both pathways there are GLP-1 receptors. Mm-hmm. So it's very likely that the reward drive is reduced, or actually we can observe that there's less dopamine signaling. And I think this is mostly in rat models when you stimulate GLP-1 receptors in the, like, mesolimbic reward pathway.

Margaret: Mm-hmm. 

clinically it makes me think about the conversation we con- consistently have in, like, alcohol use disorder treatment that, like, some treatments impact, like we'll say similar to this because this paragraph in this paper goes on to say, though it was not-- they reduced the neural reward responses.

It didn't lead to significant overall reduction con- alcohol consumption. however, the participants did experience a significant reduction in heavy drinking days. Like, I feel like that's a common conversation we're having when we're talking about, like, [00:39:00] sometimes maybe it's, this is more like when we're learning about these meds, I feel like reality is there's much more Vivitrol than there is other things.

But, like, this medicine on studies is shown to be good at, like, reducing cravings and maybe it's less good at maintaining total sobriety, but it is good at reducing binge drinking days. And so I don't know. I feel like this language is very familiar in terms of these GLP-1 studies and substance use to things that we already use.

Preston: Yeah, exactly. And, the binge drinking reduction, it's still a big meaningful difference because when, people have reported about the, the most deleterious effects of alcohol i- is the binge drinking that, is more likely to cause neurotoxic effects, carcinogenic effects like, s- and strain on your liver Not promoting alcohol.

Any amount of alcohol is carcinogenic. Who am I [00:40:00] to be above a glass of wine every now and then? But it is, is- a reduction in binge drinking is still a significant reduction harm. 

Margaret: Probably a good 

Preston: thing. Yeah. 

Margaret: Yeah. There's some discourse online right now that's like people being like ev- and I don't disagree with part of it, but it's like, "Oh, the wellness industry is making everyone, like, not drink at all and everyone's losers, and this is just like another, like, this is a pathway in our pipeline to, like, conservativism and ma- like MAHA.

And I'm like, "Listen, not everything is one thing." not... Some- sometimes it's just like the divas learned like, oh, damn it. Like, any alcohol is probably not great for you. Doesn't mean we're gonna do none. But like, I don't know. I- there's been a lot of discourse about that in the last year of like, blah, blah, blah.

And it's just like, well, no, actually America's had a drinking problem. So like 

Preston: Yeah. Or, or- 

Margaret: Maybe some of this is okay. 

Preston: Or then like some, some article from The American or whatever weird offshoot journal will say like, "Gen Z is killing the alcohol [00:41:00] industry because-" Can't play it ... they're refusing to drink.

[music]: How dare they? Like, what? 

Preston: Imagine writing that like 60 years ago, like, "Gen X is killing the cigarette industry because they're refusing to smoke." How dare they? Literally. These- Literally ... these poor execs. 

Margaret: Come on, 

Preston: guys.

Margaret: It's just like these, the shareholders are losing money every day, you guys. Every day you don't drink, j- do your part. Do your part for the poor shareholders- I'm doing my part ... of America. I'm doing my part to fight. 

Preston: So- 

Margaret: Anyway, I'm not gonna say anything more- Yeah ... 'cause I'll start saying too dark things.

Preston: speaking of binging though, when- Gosh ... kind of as a segue into, to eating disorders, it does also have a similar effect. A systematic review of five studies reported significant improvement in body weight, body mass index, waist circumference, and the binge eating scale scores among individuals treated with GLP-1s.

Yeah. Particularly dul- dulaglutide and semaglutide. 

Margaret: Which this to me was also more impressive in ter- I, think. [00:42:00] I need to double-check it with the other study but, like, if you look at... So, right, we know this from our other journal clubs that we've had and also 'cause a lot of our listeners are in their own journal clubs around things.

But, like, there is statistically significant results and then there is clinically significant or significant to our patients results. And the depression study, like, I think at most it was like a First of all, it was hard to read 'cause they had different depression report- Scales. Yeah ... scales. I don't know if you have that pulled up.

I, like, but it was negative .12, which I can't tell if that's like 10% of illness burden or whatever. Like, I can't-- It was hard for me to figure out what that, like even in looking back at the original papers. I don't know if you figured that out. 

Preston: Mm-hmm. No, 

Margaret: I didn't 

Preston: either, but I remember clocking it as like, this probably isn't that great of an ex- effect size.

Yeah. 

Margaret: But then this one is 8.14 on, again, on a sc- on a score, and I don't think this, the binge eating disorder score thing is like out of 1,000 or something. Hold on, let me find that, though. Yeah, 

Preston: let's pull up [00:43:00] the binge eating scale. Let's pull it up, 

Margaret: chat. 

Preston: It's to f- it's to 46, so- 

Margaret: Okay, so that's higher.

So then what is the- 

Preston: Well, that's the difference between moderate and severe binge eating, or between- Right ... moderate and minimal. So if you're, at a 20 s- like let's say you're at a 25 and it brings you down to- Mm-hmm ... a 17, you've entered like an entirely different like category of the disorder.

It's a, it's a- Right ... significant difference. 

Margaret: Which I would argue does, yeah, like you're saying, does matter. Whereas I'm still trying to figure out for the depression one. So for depression it looks like for most scales you need, I mean, it's gonna depend by scale, but like a 13 to 14-point change. 

Preston: Mm-hmm. 

Margaret: And so I can't tell-- Again, this is my one gripe with the depression study they cited is like it's kind of hard to tell like...

So it did, it varies, but this is why this is confusing because it's like they're all like in the 10, 20s, 30s, 40s for the depression scales they use, but it, I was like, where do I find I know it's, I'm [00:44:00] sure it's somewhere in there," but it was just difficult to figure out. 

Preston: Yeah, so what I'm seeing in that other paper is like negative .9 on a, PHQ9.

Okay, so that's like not- You know, neg-

negative- ... super 

Margaret: clinically ... .

Preston: 2 or negative two on a PHQ9. Yeah, this is small. It's very small. 

Margaret: Yeah. It's not necessarily changing clinical categories. Whereas to wrap this back, in binge eating disorder it is significant enough to take you down a level in the disorder, take you from mild to moderate down to mild or not clinically scoring anymore.

Yeah, 

Preston: exactly ... 

Margaret: which when you think of the core, like why we use GLP-1s anyway, like controlling hunger cues and appetite, especially if we think about the set point model for weight, which I think more and more people with some slight differences agree with, that like once your body gets to a certain weight, it tends to fight you to stay there.

And so I think the like yo-yoing that is often happening is often what's happening in like binge, eating disorder, although it doesn't have to, is [00:45:00] this kind of going back and forth from restricting, trying to change weight or change body habitus or health or whatever, and then binging.

Although some people do-- Like you wouldn't reach the level of bulimia necessarily in binge eating disorder, so you wouldn't be restricting so much that you're Starting to like lower the weight or purging or anything like that, but just like trying to eat like normal, quote unquote, or eat healthier and then go up into a binge.

Mm-hmm. And so it makes sense that this would be the place where this would be clearly effective in it being helpful because appetite regulation is a huge part of binge eating disorder. 

Preston: Yeah. And, also the ability to control the behavior towards the reward stimulus, which like controlling your behavior in the binge, like part of it is like a sense of a loss of control during the, binge itself.

So that also may like have some benefit on, that side. Now, interestingly [00:46:00] For the kind of like behavioral activation part of reward-seeking behavior, if you modulate glutamate, that can have some benefit. so we actually had a journal club last week where we were studying-- They were-- They looked at N-acetylcysteine or NAC- 

[music]: Mm-hmm

Preston: for specifically modulation of alcohol use disorder, and it had a, a similar effect where it reduced binge drinking episodes but didn't necessarily reduce the amount of alcohol intake. So, I don't know. Just, thinking out loud, like that could be a fascinating thing to combine with this or to, to look, more into glutamate effects on things like, binge eating disorder.

Margaret: I think, the other thing clinically to think about with this kind of thing for people is to remember that eating disorders-- The DSM is sort of behind or, I, guess doesn't-- It's not necessarily behind in terms of categorization as much as we are-- the field is evolving in terms of understanding what weight [00:47:00] represents and what eating behaviors represent.

Because like to have anorexia in the DSM-5, you have to have a certain low BMI, right? Even if you are like doing the things that categorize you as most people would think of behaviors for bulimia. And so the reason I say that, though, with this conversation is to just recognize that there are-- is probably a subset of people within-- who would identify as like having binge eating disorder, that often people who have binge eating disorder may also have a p- a history of restriction.

They may have a history of purging. They may have other disordered eating behaviors. And so I think the thing I'm harping on is while this can be helpful in these populations, I do think like a thorough-- It doesn't have to be like a psychologist or a psychiatrist exam, but like a really thorough understanding of their eating history and not just assuming it's like just binging, even if like...

And I think people can make the kind of biased assumption that is also not factual, that like if someone's in a larger body, then you don't [00:48:00] have to worry about an eating disorder being reactivated and like as long as their weight is above a certain number on the BMI, then it'll be fine, which is like not true in terms of like number of days you need to be at risk for refeeding, like if someone just stops eating for days at a time.

And so-- Or just any in general like risk in terms of if purging restarts. Like there have been times where like if a medication-- If there's like a shortage, like there has been for these medicines and they can't get it for a month or if their insurance does something funky, like that's a real risk for-- It's annoying for probably anyone, but it's-- it, would-- could represent a real risk for someone who has kind of latent eating disorder behaviors that exist alongside the binge, symptoms.

Preston: Mm-hmm. 

Margaret: Does that make sense? 

Preston: Yeah. I think I had trouble following towards the end about- 

Margaret: Well, listeners, you'll tell me if it made sense. 

Preston: Yeah. 

Margaret: I think it made sense, but 

Preston: Yeah, I guess like my, my takeaway is that like not giving someone access to the medication [00:49:00] or, using it too much particularly for weight loss is, a real risk even in people that don't meet criteria on the BMI scale.

Margaret: Yeah. Well, and I think just that like people are busy. A lot of people want this medication. A lot of people really want to and/or need to lose weight, and primary care doesn't always have time to do a full screen of like disordered eating history. And I think that more people have struggled with To pretty significant disordered eating than we capture or that we have-- than we have the capacity to capture when we're being forced to work in like twenty-minute visit clinics.

Preston: Mm-hmm. Yeah, 

Margaret: absolutely. Or getting it online and meeting with someone like twice for fifteen minutes and then being sent it in the mail. 

Preston: Yeah. And I think that's the, the unfortunate reality. A lot of people are get- I guess, getting like back alley treatment for their eating disorders or, exacerbations of their eating disorders.

[music]: Yeah. 

Preston: The kind of one last thing that I wanted to talk about is like anhedonia as a specific [00:50:00] symptom. So this is something- Mm-hmm ...that is not mentioned in the paper but is brought up pretty f- I would say, relatively frequently to me, by patients that are on it, and I've just kind of noticed this coincidentally with like my care.

So like someone will be taking their antidepressant, they're feeling like they're getting better, like the treatment's successful, and then they start on a GLP-1 for weight loss, and they start complaining of anhedonia. And it's not always picked up on the depression screeners. And I think this may be like one of the reasons why we get confused when we look at the conflicting evidence in depression because there are like very specific symptoms that may change with depression.

Basically, someone can-- someone's depression can get better, and their anhedonia can get worse, and the scale may not detect that. 

Margaret: You know what it almost reminds me of even though they're totally different mechanisms and they're not exactly the same, but it almost feels like I need the same language that I use when talking to people about different [00:51:00] antidepressants and them feeling numbed out.

Again, not the same, mechanism, but it feels like I end up reaching for the same words of just like, "I'm not enjoying," or, "It's just like not sparking." And it's like I'm not unhappy, but I feel like I'm- But I don't feel excited ...looking through like a fuzzy wall. Yeah. 

Preston: Mm-hmm. I'm taking Spanish lessons, and the word for excited is emocionado.

So I'd say, no me siento emocionado. I don't know what anhedonic is in Spanish. This is, my last random rabbit hole, and then we'll wrap up the episode. Okay, anhedonic in Spanish. It's actually a good thing for you to know. Okay, anhedónico. Te sientes

anhedónico. That's, what I'm gonna, remember for next time. Okay. Well, this is-- it's kind of a, this is a fun journal club. I-I'm glad that like there's new emerging evidence coming out. And also, I feel like the [00:52:00] biggest summary, kind of going through the paper is that depression's a mixed bag, not a large effect size.

Anxiety is worse in people that are trying to lose weight. suicidality It's a wash. no increased risk, but keep high pharmacovigilance on it. Psychosis, it's not negative. nothing we- no evidence has many things worse, so- But our meds 

Margaret: side effects are 

Preston: so- Those, are very real- Those are real

so counteract those best you can for... And then for alcohol use disorders and for binge eating disorders, it may be beneficial, at least in some areas and, like in the future might be a part of like, more expansive randomized controlled trials and actually may be a part of the treatment someday.

Margaret: Yeah. I think especially for binge eating disorder. I do think just to end on like a hopeful note already, this medication is a huge boon for psychiatry, just even just in the psychosis population [00:53:00] alone. Medications before this medicine didn't really work that well for weight loss and like some worked, you know, for sort of for diabetes health.

But like I think we lose it in all the discourse and all the like overuse and Hollywoodification of Ozempic. But like for us as psychiatrists and for some of our sickest patients and for family members of our sickest patients, like GLP-1s are so much more effective and they can be given in a shot, right?

Like they don't have to be remembered every day that they make Some of our medicines that are the most important to help psychosis more tolerable in the long run and can be giving back years of life. So this is just to say, among all the discourse with this, this medication, even if it never is fully on evidence for, like, treating primarily our illnesses, is helping a lot of our population that I, don't think we talk enough about in pop culture, which is people really struggling with very active psychosis, their families and in community.

So shout out GLP-1 agon- receptor [00:54:00] agonists. Thank you for letting me prescribe, all sorts of atypical antipsychotics and be able to help a little bit with this. 

Preston: Yes. Thank you. And also, stay away. Don't... Not everyone needs you, okay? 

Margaret: Not yet. Like- Yeah ... get some studies and we'll see. 

Preston: Yeah. That was a good, positive note to end it on.

I'm grateful- Gratitude. ... for GLP-1's. they make a good difference. well, thanks again for listening, guys. how's the show? We always wanna hear what you think. shout out to our Spotify commenters. Someone in the last episode said, "Had to pause the episode for glutamate." So please keep pausing for glutamate.

Actually, hit play for glu- glutamate. Hit 2X speed- What does that mean? ... for glutamate. I don't know. I think it's just they wanted to see glutamate again. 

Margaret: Oh, okay. I was 

[music]: like, "What?" They wanna hear more about glutamate, 

Preston: and I too wanna hear more about glutamate. I love to, [00:55:00] spend each day understanding it a little bit more.

If you want to watch our full video episodes, you can find them on my YouTube @itsPresro. There's also the video version on Spotify. If you wanna see more from me, I'm @itsPresro on, TikTok, Instagram, and YouTube. Margaret's @BadArtEveryDay on Substack and TikTok and Instagram, or you can find us on, Instagram at How to Be Patient with our, like, little kind of shared account.

Either Margaret or I will message you back. It depends on who's in the mood- It depends ... and what day. Yeah. But most of the time if it's a poll, it's probably Margaret. She's, I love a poll ... she's big on the polls out 

Margaret: there. Yeah. I love a democracy. 

Preston: Exactly. 

Margaret: I love an oligarchy that pretends to be a democracy.

we'll see you in the Spotify comments. 

Preston: Thanks again for listening. We're your hosts, Preston Roche and Margaret Duncan. Our executive producers are me, Preston Roche, Margaret Duncan, Will Flanary, Kristin Flanary, Aron Korney, Rob Goldman, Shahnti Brooke. Our editor and engineer is Jason Portizo. Our music is by Omer [00:56:00] Ben-Zvi.

To learn more about our program disclaimer and ethics policy, submission verification and licensing terms, and our HIPAA release terms, go to howtobepatientpod.com or reach out to us at howtobepatient@human-content.com with any questions or concerns. How to Be Patient is a Human content production.

Thank you for watching. If you wanna see more of us, or if you wanna see... This is Lilac, she's my cat. She's gonna be waving her hand at one of the floating boxes, which will lead to more episodes. Lilac, point to the other episodes. Lilac doesn't know what the internet is, but I swear they're there. They pr- they probably exist for real.

But in the meantime, I'm just gonna pet Lilac, and then I'm gonna go dance in the [00:57:00] background