Episode Transcript
Harriet Carroll, Long COVID researcher, patient and advocate
[00:00:00] Jill Brook: Hello fellow POTS patients and super people who care about POTS patients. I'm Jill Brook, your hyperadrenergic host, and today I'm honored to speak with Harriet Carroll, PhD, who is a distinguished and highly published academic researcher in the UK with important contributions in the areas of hydration, thirst, blood sugar, metabolism, and a whole lot more.
She was ironically working on COVID vaccine research when she herself suffered a debilitating reaction to the COVID vaccine, which still affects her today. So she now works as a scientific consultant on long COVID and long VACs, helping these patients determine the best tests and treatment for their problems using her scientific background. Dr. Carroll, thank you so much for being here today on the POTScast.
[00:00:50] Harriet Carroll, Ph.D.: Thank you for having me.
[00:00:52] Jill Brook: So you are super unique because you had a career before COVID that made you an expert on some things very relevant to POTS and long COVID and chronic illness and I'm super excited to discuss that. But then you also had a life changing experience during COVID that made you a Maybe by necessity, apply your scientific background to really dig in to how to help patients like yourself.
And now you've made it a career, right, to help people in your same medical situation. So I'm hoping to cover all of that, or as much as possible, being mindful of your time and energy. But could we spend a few minutes talking about your career before COVID? I was just so appreciative of your amazing research about all these things that were relevant to us. So, yeah, if you don't mind, just kind of... talking about it
[00:01:49] Harriet Carroll, Ph.D.: Yeah, sure. Thank you for that lovely introduction. And it is a highly ironic illness that I've got, you know, working in COVID, getting vaccine injured, working in hydration, getting all my hydration stuff ruined. But yeah, my PhD, I was interested in blood sugar regulation and appetite, and particularly how these are affected by meal timing and nutrients.
So, I studied how these are affected by sugar at breakfast and my first post doc was looking at meal patterns and metabolic health using some fancy statistical methods and I then had an idea about hydration and the gut microbiome. My second postdoc was about the gut microbiome and fiber, so I could get some experience in analyzing poo. Sadly, I couldn't get funding for the idea, and then someone kind of stole the idea, so I spent a year studying poo for no reason, which is probably the most depressing sentence you can say in your life. I then got some funding with some collaborators at Lund University in Sweden and we were investigating various aspects of water intake in health epidemiology.
And within that, we're doing a project in astronauts. Now, I've not gone public with what the project is because I don't want someone to steal the idea again, but I will say that I think the particular angle that I'm taking is going to offer some pretty cool insights into POTS. And to give you a bit of background about space science, in space and microgravity models, astronauts get something called chicken legs where their legs lose about 1 and that gets shunted up to their head causing their forehead to expand by about 7%. And with that comes absolute chaos in their hydration regulation. But it doesn't end there, because once they've finished astronauting they then need to come back to earth and guess what happens when they come back to earth?
they get orthostatic intolerance and guess what space agencies try with them? hydration and other POTS interventions. So one of the most interesting studies I've read was looking at fludrocortisone and they found it successfully boosts their blood volume, but it doesn't alleviate their orthostatic intolerance. So I think there's quite a lot we can learn from that in a POTS context.
[00:04:10] Jill Brook: Can i just make sure i understood that correctly so you're saying they give them fludrocortisone and it helps their blood volume but it does not help their orthostatic tolerance so basically this humongous focus we have on boosting blood volume at least if you extrapolate From that research says we might not be solving the problem as assuredly as we think.
[00:04:33] Harriet Carroll, Ph.D.: exactly that, and I mean, I'm a great case study for that, I'm on fludrocortisone and salt, and when I started them, I had huge results, and then as time went on, my POTS is just as bad as if I wasn't on treatment, so yeah, I think we could learn quite a lot just from those kind of studies in astronauts.
[00:04:51] Jill Brook: Wow. Wow. Okay. So we, we want to get you back when this is published and you can talk about it.
[00:04:59] Harriet Carroll, Ph.D.: So yeah, it's been massively slowed down because of my health, but I'm trying to like dedicate at least one day a week to it, so I'm hoping in a year or so, I'll have something exciting to share. So yeah, then the other area that I'm interested in is the party drug ecstasy and specifically the active ingredient MDMA.
So I've been interested in this because it challenges all of our assumptions about hydration physiology. Now, when people take MDMA, they get incredibly thirsty, they pee less, and their pee is more concentrated. So on the face of it, they look very dehydrated. But on a cellular level, they're actually overhydrated and this mismatch has led to some pretty dangerous public health information encouraging fluid intake when people are on MDMA, despite overhydration being the number one cause of death and injury on the drug. So I once tweeted like a thread of Allegedly trusted sources who were saying that MDMA causes dehydration.
I tweeted them and emailed them. I offered them free advice and I don't think any of them took me up on it. So this mismatch in hydration physiology and hydration state, I thought can give us a really cool model about whether the physiology of dehydration could disrupt blood sugar regulation, which is what most of the literature says.
But that could be independent of body water status. So you're kind of uncoupling the physiology and the state of hydration. So that's about where I was when the pandemic hit.
[00:06:38] Jill Brook: So I just want to make sure everybody heard that you said the party drug ecstasy, not the POTSie drug ecstasy.
[00:06:44] Harriet Carroll, Ph.D.: Yes, the party. The party drug ecstasy.
[00:06:47] Jill Brook: Wow, so that, that kind of follows a trend of what it seems like with all nutrition research from the beginning of time, which is that everything is always more complex than originally thought.
[00:07:00] Harriet Carroll, Ph.D.: Yes, and hopefully we'll delve into a bit of the complexity of this.
[00:07:03] Jill Brook: Wow. Okay. So that's what you were up to when COVID came along. And if I could, I mean, I would just love to probe a little bit more. Like some of your nutrition articles that are, are relevant to this population are you know, you, like you mentioned, hydration and then blood sugar and thirst. Like we know that 70% of POTS patients are found to have low blood volume and that our POTSie kidneys might be throwing out too much salt and fluids.
And a lot of us have difficult drinking enough. We on this podcast have discussed some findings from really small studies on POTS patients suggesting that we POTS patients have extra high insulin and maybe a greater risk for type 2 diabetes. And then just like on top of that, some of us are thirsty all the time. Like me, that's how I actually originally found you is that I was doing some research for someone else and for myself, trying to figure out what is going on. We are thirsty all the freaking time, can't get enough. My funny story about this is that when I actually went to the Mayo Clinic and got my POTS diagnosis, one thing they had me do was a 24 hour urine test because they were looking for the mast cell activation syndrome.
And so I was in Phoenix, Arizona on a hot, hot, hot day. And I had to carry around plastic buckets of my urine and I had to keep it cold. And they started out by giving me two, one gallon jugs. And it's so inconvenient and I just have to pee all the time and I was so thirsty and I was purposely drinking as little as possible.
because i didn't want to have to carry it around and i didn't know how i was going to keep it cold overnight i ended up putting ice in the bathtub over these jugs of my pee but even me trying my hardest not to drink i was just so out of control thirsty that i ended up with four gallons. And that stood out in my memory because of having to carry it around and keep going back and asking for more jugs.
And then you wrote, like, the all time greatest explanation of thirst. Like you found some fascinating reasons why people would be thirsty. I guess I'm inviting you to talk more about any of these findings as you see fit, just because all of them seem so relevant to us.
[00:09:47] Harriet Carroll, Ph.D.: I'm ironically getting very thirsty doing this. So I'm just going to take you on a little wild ride and hopefully it'll all come together at the end. So we'll start with a bit of background about my specific interest. So I'm interested in the hormone vasopressin. And that is a key hormone that regulates our body water.
So when we get hot or we get dehydrated or we have salt, vasopressin goes up. It tells the kidneys to stop excreting fluid so our pee becomes darker because there's less water in it. In turn, that water stays in our body, stays in our blood, and it stops our blood volume dropping so our blood pressure stays stable.
Now, high levels of vasopressin have been associated with worse health, for example, an increased risk of diabetes and the metabolic syndrome, and as you said, there's possibly a trend between POTS and diabetes, and maybe that's partly to do with our blood volume. This is a pretty consistent finding across epidemiology, animal models, underpinning theory and mechanisms that we understand about vasopressin's actions.
And as well as a couple of human studies. Now the other bit of background is about blood sugar regulation tests. So one of the tests we do is called an OGTT, where we give 75 grams of pure liquid glucose on an empty stomach in the morning and we measure the response. And honestly, it's a vile drink. Now this can tell us how well our liver in the fasted state and our cells in the kind of post sugar state are responding to the sugar challenge.
And we use this test a lot in metabolic research, but we also use it in clinical practice. So understanding anything that skews the O G T T or the fasted measure is very important. So I wondered, could hydration skew the O G T T particularly because we do OG TTS in the morning when we are theoretically most dehydrated.
So when I first suggested this to my PhD supervisor during my MRes, he didn't believe that such a study hadn't been done, so he actually sent me away twice to double check. He then searched and couldn't find anything. He then tweeted and he finally believed me when another guy, who ended up being a co supervisor, agreed that it hadn't been done and it should have been done.
First of all, we did a pilot study in five of us and we found quite remarkable results. So very clearly in all five of us, when we were dehydrated, we had higher blood sugar. But naturally, it was a small study, so we needed to repeat it in a larger sample and we also needed to make it a little bit more controlled. So that was my first PhD project.
[00:12:22] Jill Brook: Can I just ask a quick question? It kind of makes sense that when you measure blood sugar, it's based on concentration, right? So, dehydration means less blood, and so your sugar is spread out over less blood.
[00:12:37] Harriet Carroll, Ph.D.: Yeah, in theory, in this kind of model, so we, on average, induced about 2% dehydration. So it's actually... Dehydration sounds really scary but we actually are very good at maintaining our blood volume and our body water.
[00:12:53] Jill Brook: So it's not just, it's not just that. Okay, go ahead.
[00:12:56] Harriet Carroll, Ph.D.: It's not just an artifact of that. I mean that could be implicated. Stuffed up the measure to check that. So,
[00:13:03] Jill Brook: Oh,
[00:13:04] Harriet Carroll, Ph.D.: so I couldn't adjust for it in the end, which was frustrating. So yeah, so we repeat the study. So to my knowledge, this was the most well controlled hydration study in the literature. We successfully matched four days of diet and physical activity and 16 participants before they did the O G T T when they were either dehydrated or well-hydrated.
So we really took out a lot of bias in the study. So what we found was when participants were dehydrated, their vasopressin increased exactly as we would expect, but their glucose and insulin stayed remarkably the same. Honestly, I was shocked at how close these lines were. We also found that thirst increased when they were dehydrated and I'm really surprised that that groundbreaking research didn't make the headlines but when you're dehydrated you do get thirsty.
The interesting thing was that when participants were dehydrated they scored their thirst about 90 out of 100 on average so quite thirsty and that'd be expected. But what I didn't pick up on at the time, and in retrospect is really interesting, is that when they were well hydrated, they scored their thirst an average of 60 out of 100.
Now that sounds quite thirsty to me, so there's the first kind of clue that this isn't a simple relationship. Now we also measured a novel hormone in the hydration field called FGF21. Now FGF21 has some roles in metabolism and obviously lots of POTSies have things like hypersensitivity to low blood sugar.
So FGF21 I think might end up being important in POTS but we're kind of in the early days of it. In terms of the hydration work, animal studies have suggested that FGF21 is implicated in thirst and drinking behaviours. So in our study, we kind of looked at the reverse. Does hydration affect FGF21? And we found that it didn't, and you'll see a trend in my research, I tend to not find things.
[00:15:00] Jill Brook: That's how we know you're an honest researcher.
[00:15:02] Harriet Carroll, Ph.D.: Alongside this kind of a little side story is that there's that common myth that you can only live a few days without water. Now, I had a bit of lockdown boredom, so I wanted to test this myself. So I went three days with less than 50 grams of water, and that was just from the food that I was eating. I was eating dry food, but obviously it's got a bit of water in there.
[00:15:23] Jill Brook: Just for fun.
[00:15:24] Harriet Carroll, Ph.D.: It's just fun. This is the kind of person I am. So the result is I didn't die after three days. I stayed perfectly healthy. My wee got very dark. For the British listeners, it was very much like iron brew. I also got very thirsty, but I wasn't that thirsty. So there's another clue. Now when I was in my PhD, I was constantly testing dehydration protocols.
So I would come in, in the morning, put my joggers on, put my hood up, put sweatsuit on, sit in the heat tent, and then after that I would lose about maybe half a kilo of of fluid. And after that, I'd feel so thirsty and the first drink I took could be so refreshing. It would be absolutely amazing.
After three days of no fluid, I lost more body water than the heat tent. But I wasn't as thirsty and there's a great video on Twitter somewhere of me taking my first drink after three days. And it's just a big ball of disappointment. I wasn't at all refreshed. It was meh. So there's another clue. Now, just to give a bit of background about thirst, and again, this is slightly from my vasopressin perspective, but in brief, when we get dehydrated, our blood concentration increases.
So you can think of this like, I don't know if you have Ribena in the States or like a diluting squash. So you put your squash in a cup and you fill it with water. If you put loads of water in, you get a bigger cup of water and it's more diluted and that's like your well hydrated blood. Now if you put your juice in the glass and only put a little bit of water in, you've got a smaller glass and you've also got more concentrated drink and that's your dehydrated blood.
So when blood concentration goes up, we get thirsty, and this relationship between blood concentration and thirst is probably one of the most reliable biopsychological phenomenon that I've ever seen, and I think that's why in the hydration field we've got a bit fixated on it, because if you make someone's blood more concentrated, they get thirsty, it's nearly guaranteed.
Now, thirst is primarily regulated in the brain, and a quick fun fact on one of the first ways we learned about this was a man got kicked by a horse. He fell over and hit his head and got brain damage. And a side effect of that brain damage was he was excessively thirsty. Off memory, I think he was drinking about 18 liters of fluid a day.
[00:17:48] Jill Brook: Whoa, huh,
[00:17:50] Harriet Carroll, Ph.D.: what I note there is that a lot of long COVID and ME sufferers say they feel like they've been concussed. And they're also thirsty, so we're starting to get a bit of a picture here. Now, in the brain, we have special stretch sensitive channels, so in theory, when these stretch, they indicate you're well hydrated, and you no longer need to drink.
And when they shrink, it indicates you're dehydrated, and they trigger thirst. That all seems a little bit too simple. So during my PhD I asked a few hydration experts the following question, and I just got shrugs back. Why do marathon runners die of over hydration? They experience intense thirst, but they're over hydrated.
But they're thirsty, so they drink more, they get more overhydrated, they drink more, and then they die. That doesn't fit our current model of blood concentration and thirst. Now think back to my MDMA ideas, and you can see exactly the same thing going on. All the signs of dehydration, but drinking themselves to death.
And there's loads of other examples of this mismatch as well. So you get diabetes insipidus, which I think a lot of POTSies probably have, but they don't get tested for. There's a syndrome of inappropriate antidiuretic hormone secretion. In aging, all of our hydration just goes wild.
This isn't complex. In everyday life, you meet people who naturally drink a lot more than other people. And if it was all down to blood concentration, that wouldn't be the case. Now the other aspect it doesn't explain is why we get thirsty when we take certain medications like antidepressants, or why we get thirsty after certain activities, like during a hangover, which I don't think has anything to do with dehydration, and I'm hoping to write a paper about that soon. So, just take a drink.
[00:19:42] Jill Brook: yeah, no, this is also fascinating. And I was tested for diabetes insipidus at one point, which is a funny test because they basically just sit there and it's mostly about waiting, and they just wait for you to pee, a few hours later, pee, pee, pee, pee, and they watch what happens to the concentration of your pee.
And then they give you some of that vasopressin to see if it makes you stop peeing. And I remember feeling pretty good on that vasopressin, interestingly. But I'm curious to hear where this is going.
[00:20:16] Harriet Carroll, Ph.D.: Yeah, so what's going on with all of this is... I spent a month of lockdown reading papers spanning back to the 1800s, trying to understand thirst, and I created a model of thirst. Now it's incomplete, because honestly, if I went down every rabbit hole, the paper would never have got written. But there's loads of other things that I don't go into detail, like catecholamines and certain drugs and things.
But within this model, I propose there's at least four types of thirst. For the first one I call true thirst, which is the thirst I described above. It's regulated by things like your blood concentration, vasopressin, and the renin-angiotensin system.
The second type of thirst I called contextual thirst, and this is things like, if you're speaking, your saliva evaporates and it makes you thirsty, or you might be drinking for another reason, like the caffeine in a coffee, or the pleasant flavour of a sugar sweetened drink. Now, this contextual thirst is not regulated by your hydration physiology. But the act of drinking will change your hydration physiology, so it must be being regulated.
The third type of thirst I called pharmacological thirst, and I think this is the one that's most relevant to long COVID and POTS thirst. So a lot of drugs give us a dry mouth and they've got obviously a lot of things going on in these drugs but they've got a commonality. They all interfere with the cholinergic system. Acetylcholine is the main neurotransmitter in the cholinergic system and one of its roles is regulating body secretions including saliva.
Now, there is a blog on my website if you want to learn more about the cholinergic system, so I won't go into loads of detail here, but within pharmacological thirst, I propose there's two subtypes of thirst, I called true xerostomia, now, xerostomia just means dry mouth, you know what scientists are like, we need fancy words, so it just means a true dry mouth, so there's literally a reduction of saliva in your mouth and that makes you feel thirsty.
And I propose that's caused by local acetylcholine effects acting on the salivary glands. The second I called sensational xerostomia, which is the feeling of a dry mouth even though there's saliva in your mouth,
[00:22:32] Jill Brook: Oh,
[00:22:33] Harriet Carroll, Ph.D.: that is from central acetylcholine effects directly in the brain.
[00:22:37] Jill Brook: huh.
[00:22:38] Harriet Carroll, Ph.D.: The fourth type of thirst I called impulsive thirst, and this was trying to offer an explanation about everyday drinking behaviours, like why we start drinking, how much do we drink, and why do we stop drinking.
So to do this, I used psychological appetite constructs and applied these to thirst appetites. And although these are psychological constructs, they are all regulated in the brain neurologically. So I won't go into detail on this, but I propose that the reason we start drinking, so imagine you're sitting in a thermoneutral office.
You've got a cup of water in front of you. Why do you randomly just pick up that glass of water and start drinking? I propose that is due to natural fluctuations in acetylcholine. Now, thinking back to my interest in ecstasy, I knew the study would be impossible to test. So, me and a colleague did the study ourselves. And again, this was highly controlled, but it was just two of us, so I don't want to make any wild generalizations.
[00:23:39] Jill Brook: Okay. Okay. We won't ask how you got the ecstasy.
[00:23:43] Harriet Carroll, Ph.D.: Obviously you're all above board. What was interesting is that we had vastly different responses. So my vasopressin got quite high about the levels you might see in metabolic diseases. And that's what we would tend to expect on ecstasy. But my collaborator didn't have a response, a vasopressin response. Now, this actually reflected our subjective experiences.
So, my collaborator, she had a bit of a buzz, but she was still a functioning scientist during the study. I, on the other hand, was cuddled up in a blanket cave, marvelling at how soft it was, trying to cuddle my collaborator. So, now despite this... So one of us had high vasopressin, which our model would predict would cause blood sugar to go high. The other didn't get a vasopressin response, so their blood sugar should have stayed normal. But despite this, both of us had blood sugar dysregulation, but it was both ways. We had high blood sugar and we had low blood sugar.
It was erratic, going everywhere. What was particularly notable was our high insulin and my insulin in particular. I have never seen anything like it, it's so high. So the theory that vasopressin drives blood sugar didn't quite add up because only one of us had high vasopressin, but both of us got high and low blood sugar, so it doesn't really fit the theory.
Now, both of us did get an elevated cortisol on MDMA, and that probably drove some of the blood sugar dysregulation. Now, when we did that study, I was starting to think a bit critically about thirst. So we measured two types of thirst. I just had a zero to 100 scale of your thirst and your dry mouth. Now, what was interesting is that these didn't always track exactly the same. So it does suggest there's different types of thirst that we can differentiate.
[00:25:38] Jill Brook: So you mean that when mouth was dry is not when people were always the most thirsty.
[00:25:43] Harriet Carroll, Ph.D.: yeah, and vice versa. So you might have been really, really thirsty, but your mouth wasn't dry. So when I did my three days of no fluid, that was after I'd written the thirst paper. So I did these zero to a hundred scales of my true thirst, my true xerostomia, and my sensational xerostomia. Now the latter two, so my true thirst and my true dry mouth, they correlated quite well.
And Both of these, I propose, are regulated in the brain, so it kind of fits my idea. The sensational xerostomia, so the feeling of dry mouth, was my dominant thirst. In other words, I had saliva in my mouth, but it felt dry, and that didn't track with the other two types of thirst all the time. So, how does any of that link to POTS and long COVID?
[00:26:34] Jill Brook: Yes. Tell us!
[00:26:36] Harriet Carroll, Ph.D.: Well...
[00:26:37] Jill Brook: messed up. No
[00:26:38] Harriet Carroll, Ph.D.: Well, as you said, a common complaint is thirst. So, first of all, we know that many, if not all POTS patients have low blood volume, so that in itself can be contributing. Think back to the stretch sensitive channels. They'll always be detecting low stretch. So that might be giving thirst signals, but that can't be all of it because even when we fix the low blood volume, we still get thirsty.
So that's just one part of the picture. We've also established that brain injury can cause thirst. Now, obviously, I don't want to scare or alarm anyone, but a lot of us have got rampant MCAS and mast cells regulate body water distribution so they've got a whole role of their own which I won't go
[00:27:24] Jill Brook: What? We have to talk about that sometime another time.
[00:27:27] Harriet Carroll, Ph.D.: I'll need
to do some reading first so yeah. But bar their direct role we've got rampant MCAS, neuroinflammation, clotting, hypoxia, hypoperfusion and all of that together probably means we have some level of brain injury that could be contributing to thirst. Now we also established that the cholinergic system is implicated in thirst and can maybe even give us different types of thirst.
And there's growing evidence of cholinergic dysregulation in long COVID and POTS. And indeed, one medication for POTS called pyridostigmine or mestinone. This acts directly on the cholinergic system by preventing the breakdown of acetylcholine, so you get longer acting neurotransmission. And a common comorbidity in POTS is things like Sjögren's disease which is an autoimmune disease that in part attacks the cholinergic receptors and one of the characteristics is dry eyes and dry mouth.
[00:28:27] Jill Brook: Oh, so that's why! It's attacking the cholinergic receptors and that's why you get dry eyes and dry mouth in Sjogren's. Never knew that, wow, cool.
[00:28:37] Harriet Carroll, Ph.D.: So another POTS medication you might have heard of and you've kind of already spoken about it is desmopressin. Now this is an artificial form of vasopressin. So there's different types of vasopressin receptors. And Desmopressin is selective for just the V two receptor. Now, the V two receptor is the one that's in your kidneys and it tells your kidneys to stop excreting water.
So when you take Desmopressin, you are peeing out less water and you're maintaining your blood volume. But Vasopressin has other actions through the V one receptors.
[00:29:09] Jill Brook: That desmopressin does not have, you're saying.
[00:29:10] Harriet Carroll, Ph.D.: exactly, yes. So V one receptors, one of their roles is acting on smooth muscle. So that encourages things like vasoconstriction and lots of POTSies have low vasopressin. So the low vasopressin in POTS isn't just a matter of low blood volume, but also a matter of inappropriate vasodilation.
[00:29:33] Jill Brook: so the blood pooling is worse.
[00:29:35] Harriet Carroll, Ph.D.: Exactly. We've also established that in most people M D M A increases vasopressin. So it might be if we could isolate whatever it is in M D M A that increases vasopressin. It might be quite a good POTS drug and it won't be replacing the hormone. It would just be encouraging natural production, which might have benefits over synthetic hormones. So there's a link to MDMA.
[00:30:02] Jill Brook: that is fascinating. So it's funny because you keep saying MDMA and I keep hearing ecstasy. So, there's nothing known besides this illegal party drug that increases vasopressin in your body naturally?
[00:30:19] Harriet Carroll, Ph.D.: Yeah, I'm sure there, there is things. But my interest is MDMA, so that's what I've
[00:30:24] Jill Brook: it. Okay. Put that on the list of things
[00:30:26] Harriet Carroll, Ph.D.: at, sorry about that, I don't have an answer.
[00:30:28] Jill Brook: that's fascinating.
[00:30:30] Harriet Carroll, Ph.D.: So the other thing is that there's a lot of talk about G-protein coupled receptor autoimmunity in long COVID and they're often targeted it at sort of cholinergic type G-protein coupled receptor autoimmunity. But the V one B, the vasopressin one B receptor is A G P C R and that one acts directly to stimulate the H P A axis and the HPA axis is where cortisol comes from.
[00:30:56] Jill Brook: Do you mind saying that in a little bit more basic terms for those of us that don't know all those terms? I think so. G coupled,
[00:31:07] Harriet Carroll, Ph.D.: G protein coupled receptor, yeah.
[00:31:09] Jill Brook: Yes.
[00:31:10] Harriet Carroll, Ph.D.: Okay. You want me to break that down a little bit?
[00:31:12] Jill Brook: Yeah. Would that be okay?
[00:31:13] Harriet Carroll, Ph.D.: Yeah, yeah. Let me just think. Okay. So there's a lot of talk about G protein coupled receptors, receptor autoimmunity in long COVID. Now, G protein coupled receptor is just a particular way a receptor works, essentially. So it's a type of receptor.
And the ones that are talked about a lot in long COVID are often related to things like the cholinergic system. Now, as I said, the vasopressin has lots of different receptors that it works on, and one of those receptors is the V one B receptor, and that is a G-protein coupled receptor. So if we're getting G-protein coupled receptor autoimmunity, it could be affecting one of the vasopressin receptors.
[00:31:55] Jill Brook: Okay. So then vasopressin can't work properly on the body.
[00:32:00] Harriet Carroll, Ph.D.: exactly, and the V1B receptor acts to stimulate the HPA axis, and the HPA axis is where cortisol comes from. And many long COVID patients have low cortisol, and increasing cortisol is one of the roles of vasopressin. So if you have high vasopressin, it will stimulate cortisol. So I wonder if the low cortisol in long COVID... It could be, at least in some people, a symptom of low vasopressin.
One of my studies, we did a sub analysis, so it's very preliminary evidence, we don't want to over exaggerate it at all, but we kind of showed the first human evidence of vasopressin acting directly on the HPA axis to stimulate cortisol and separately regulating hydration.
So there is evidence, starting to get evidence of this in humans now, not just animal models. So, whilst that was a bit of a tangential ride, I've been surprised at how relevant all my PhD work has been to long COVID and POTS, and I hope that all made sense.
[00:33:06] Jill Brook: Yeah, well, some of it's a little touchy here and go, but it's enough that I will listen a second time and catch all of it. But it's absolutely fascinating to just be reminded that everything in the body probably does more than just one job. And so we always hear about the vasopressin, for example, just, you know, helping your pee less.
The fact that it also affects cortisol and blood sugar,
[00:33:34] Harriet Carroll, Ph.D.: Yep,
[00:33:35] Jill Brook: that's just amazing. And you also mentioned something else that kind of caught my attention, because it's something that I think anecdotally I'm hearing, but I don't think I've ever heard any other researcher talk about it. You said In POTS or long COVID, we might be seeing some hypersensitivity to low blood sugar.
[00:33:57] Harriet Carroll, Ph.D.: yeah, and again, I'm basing that on anecdotes too, and I haven't really got direct ideas about it. I suspect, you know like with B12 deficiency, they're starting to find that you can get B12 deficiency specifically in the central nervous system. I suspect we might be a bit like that with the way our blood sugar is regulated.
In Alzheimer's, one idea about Alzheimer's is it's insulin resistant specifically in the brain so you can get these compartmental areas of dysregulation. So I wonder whether we've got some kind of nervous system dysfunction with how we're uptaking or using sugar and it, you know, some of that will link to some of the metabolic problems that we have.
So, yeah, I, I don't have an answer for it right now, but I think there's a lot of potential ideas that could all make sense, at least in some people.
[00:34:57] Jill Brook: That's fascinating because I keep hearing from people who are describing kind of exactly what you're saying, where they absolutely feel like they're hypoglycemic, they get shaky, they get weak, they get dizzy, they feel better if they eat. But when they do continuous glucose monitoring, Glucose stayed in the normal range and their doctors are confused and they don't know what's happening and that's pretty fascinating.
Can I ask one more thing? I am hearing from not a lot of patients, but enough that it's a little bit of a thing where POTS patients have said, there's something weird about my appetite. My appetite has become enormous since having POTS, do you know what's going on? And I always have to say, sorry, I... I have no idea, but it's getting to the point where I start saying, OK, you're not the first person to say that, though. Does that ring any bells in your head?
[00:35:53] Harriet Carroll, Ph.D.: I wrote a blog about it because in the long COVID sphere, I think the majority of patients lose their appetite, but some gain an appetite, and I'm definitely a gain appetite person. I wrote a blog about it.
[00:36:07] Jill Brook: And we will put links to your websites in the show notes.
[00:36:10] Harriet Carroll, Ph.D.: Oh, perfect, yeah.
[00:36:12] Jill Brook: can find that, because I've even had some physicians send me questions about that. So that's amazing. So obviously, your research life has been amazing and I could just read your stuff all day long. It's so wonderful and you ask such great questions and I just can't believe how relevant so much of it is.
And again, I think it's just cool that I'm getting to meet you because I was a fan before you were in the world of POTS. But if you don't mind, could you kind of tell us a little bit more about your experience during COVID.
[00:36:46] Harriet Carroll, Ph.D.: Yeah, so I was working on a UK HSA siren study, which was looking... Initially, how protective prior infection was against getting a second infection, then the vaccines appeared, so we started to look at vaccine effectiveness and a few other things too.
Yeah, so when I got the vaccine, I started to get like the flu like side effects about six hours after, and they probably lasted about 30 hours, and I would say it was... It was probably worse than the actual flu I had a few years ago. And then the flu like symptoms disappeared but a whole bunch of accompanying symptoms remained so like I had numb hands, small handwriting which is actually a sign of Parkinson's so that's a real neurological symptom that often just gets brushed off.
My sleep got weirder, I had really intense fatigue, brain fog, slowness, weakness, I could barely speak. Obviously I had a huge increase in my appetite, and some strange appetite changes. My sense of taste changed a little bit too, and although I was really really ill, the scientist in me was like, this is fascinating. I got very light and sound sensitive, I got headaches, which I just never get headaches, so that was weird. I had tinnitus, pulsatile tinnitus. body temperature dysregulation. I dip into hypothermia. Really dizzy, really nauseous, my period came a little bit early and it was one of the most painful periods I've ever had. And then I'd get these what I call incapacity episodes and they're like As close to paralysis as you could be without actually being paralysed, so you'd just have to lie still until it passed, and it might be 10 minutes, but the worst one was 6 hours of just lying still on my living room floor, and I'm sure there was other stuff too, but I was initially pretty much bed bound for about 2 or 3 weeks. And then things gradually started to improve, particularly after I had my first lot of bloods done.
And in the long COVID sphere, there's a lot of talk about therapeutic phlebotomy. And obviously me being me, I've decided to run a blinded study on myself. So my friend takes blood, but I don't know if she's actually taking the blood or just jabbing me with a needle and pretending to take blood.
[00:38:59] Jill Brook: Good for you.
[00:39:00] Harriet Carroll, Ph.D.: And I think I can actually tell when blood's been taken. So. Yeah, we'll see how that experiment goes.
[00:39:06] Jill Brook: Interesting.
[00:39:08] Harriet Carroll, Ph.D.: So yeah, I was improving, I was still struggling, but I was gradually getting better. And then I had a head CT scan and I reacted to the dye and that was my first read up. So I was back in bed for about three or four weeks. And then a few weeks later, I had a wisdom tooth removed and that didn't go well.
And at that point I stopped feeling like I was improving and I started to feel like I was fluctuating but overall declining. And then after about seven months, I started to get pins and needles in my legs, breathlessness started, I got a weird whole body rash just generally falling apart. And I guess 'cause we're talking about vaccines, I should add, I had a P C R like two days before my vaccine.
I had a P C R, like one or two days after my vaccine. I was getting my antibodies measured. There was no evidence of COVID. It was a vaccine reaction.
[00:39:53] Jill Brook: Wow. And so with having all of this happen to you, were you able to get any good treatment? Like did doctors know what to do with you? Did they? Take you seriously, hopefully?
[00:40:07] Harriet Carroll, Ph.D.: Yeah I guess like based on what other people have gone through I've definitely had it a lot easier I've had my share of gaslighting like I got rejected by neurology six months after my vaccine because apparently dizziness and nausea are expected after a vaccine. Occupational health told me anxiety can manifest in many different ways.
I obviously got FNDed by a neurologist. My GP said it was medically unexplained. Haematology was the most interesting. So obviously talking to someone who understands the type of clotting we get after the vaccine. Very well. My D dimer has consistently been elevated and they did eventually find multiple pulmonary emboli. So haematology tested me for antiphospholipid syndrome, now that's an autoimmune clotting disorder which causes relapsing remitting symptoms that are pretty much identical to long COVID. So when then those tests came back negative, he then said, I just don't understand how you're attributing your symptoms to clotting after he's just tested me for a clotting disease that causes my symptoms. So I just found that completely bizarre.
[00:41:17] Jill Brook: Wow, and you had the high D dimer, which suggests the clotting, and you said you did have blood clots in your lungs?
[00:41:25] Harriet Carroll, Ph.D.: Yeah, lots of little ones.
[00:41:28] Jill Brook: Oh, wow.
[00:41:29] Harriet Carroll, Ph.D.: But, on the flip side, I have had a lot of privilege, and I always feel a bit ashamed, because it's not fair that you shouldn't get treated differently, but it is what it is, so after 10 days of being pretty much bed bound, and my GP just saying, wait and see, wait and see, and not doing anything, no one had seen me, and my boss wasn't happy, and I was obviously working in the NHS at the time, So my boss very kindly arranged for me to see a consultant, and that's just my privilege.
I don't know how long the GP would have left me in bed. The doctor who helped me the most, I'll give him a shout out, Dr. Kevin Deans, absolute legend. I only got into his care because I was working with him on the siren study. So I don't think if I was working, I would have had that contact. So that was, again, more privilege.
And then I think the other aspect of privilege and treatment is I've participated in a lot of research studies and I've also got my own plasma from a year before the vaccine stored in my freezer.
[00:42:29] Jill Brook: Oh my
[00:42:29] Harriet Carroll, Ph.D.: so
[00:42:30] Jill Brook: how
[00:42:30] Harriet Carroll, Ph.D.: I can get pre and post vaccine measures. So I can see that my cortisol, my vasopressin, are lower after my vaccine.
My cell trend autoantibodies were higher before my vaccine, which was a bit weird. My lactate is higher after the vaccine so there's something metabolic going on. So yeah, I can see all of this pre and post change which is a privilege and I'm really lucky to be able to do that.
[00:42:56] Jill Brook: Wow, that is fascinating. By any chance, did anyone else ask for samples of your blood before and after? Is this causing interest in other people to study it?
[00:43:05] Harriet Carroll, Ph.D.: It's more me pestering people I know who can measure things and luckily a lot of my collaborators are very kind and they will measure things for me.
[00:43:15] Jill Brook: Yeah. Well, so how are you doing now? And can you tell us about your new career, helping people in your same medical situation?
[00:43:26] Harriet Carroll, Ph.D.: Yeah, so I guess I'm actually having a good few days, but overall, I would say I'm still declining, but, you know, very fluctuant, and I know it could be much worse. I'm definitely grateful for the ample days where I'm functional, even though I'd like to be more productive.
[00:43:42] Jill Brook: When you say that I know when I email you, I get an automated response saying that you have a work schedule that gives you enough time for your pacing, right? So is pacing a big part of your life?
[00:43:54] Harriet Carroll, Ph.D.: Yeah, obviously pacing is, and I'm not very good at it, but I try, and obviously staying horizontal, that's a real trigger for PEM, so I have to stay sort of horizontal a lot, but that's a double edged sword with POTS, because it can make your POTS worse, so it's kind of weighing up, do I want to function this week, or do I want POTS to get worse long term?
[00:44:17] Jill Brook: Yeah. Yeah.
[00:44:18] Harriet Carroll, Ph.D.: So,
[00:44:19] Jill Brook: But you work a few days a week helping other patients?
[00:44:23] Harriet Carroll, Ph.D.: Yeah, yeah, so my new kind of venture... Basically, when I was working, I would get inundated with messages from patients asking for help, but I needed my non work days to recover, so I couldn't really keep up with everyone. And then my NHS contract came to an end, so I thought, let's just try and make this a career.
So, the premise is that I remember spending a ton of time trying to work things out, and I just wish I had someone to talk to who just got it. And now we know a lot more but patients are still like confused or not sure about things or that you know they should get drugs thrown at them by their doctor and they don't really know is that the right thing, is there something better.
So my aim is to just kind of try and bring a bit of clarity to everything. So I'm not selling a protocol, I think we're all different and I obviously have my biases but I try and just be open minded and impartial as possible. So like the typical appointment would be things like it sounds like you might have POTS or MCAS, here's how to test for it, here's the treatment options, here's what you might want to ask the doctor for, here are the risks of treatment.
I've got a service where I do kind of more long haul projects where I might interpret or find research for people. For one person I'm scrolling through their medical records to see if there's something that might have been missed. And then just kind of giving... The advice that you only really know about if you're in the community, so like, obviously beta blockers are very common in POTS, but a lot of doctors don't know that they aggravate mast cells, so if you've got MCAS, it's probably not a good thing to start with beta blockers.
So it's not giving medical advice, I'm just a scientist, and I just want to support patients in whatever way I can within my remit, and that's the premise of the business.
[00:46:10] Jill Brook: Yeah, yeah. Do you have any general advice for long haulers or long vaccine patients?
[00:46:18] Harriet Carroll, Ph.D.: Yeah, I think my first bit of advice would be to find a support group that suits your needs, and we've all obviously got different needs, so my favourite support group is a UK vaccine injured support group called UK CV Family, and their ethos is all about empathy, you know, we've all got different opinions, But it never gets political, it never gets nasty.
We all just love each other like a family. And they've also got a family and friends group to offer support to those who are standing by us on this journey. It's tough for them too. But you might want a group that's all about research or you might want a group that's all about the politics. Find what you need and use it.
And then I think really trust your body. It's something that I think a lot of doctors and most people underestimate is how well we can sense that things are going wrong. So just don't let anyone make you doubt your reality. And then I think my final bit of advice would just be to be kind to yourself. Like this is a really rough journey and the last thing we need is to be angry at ourselves for not performing, not keeping up, missing things, and I think just think of your rest and your needs just as you would your medication, they're absolutely essential for your recovery.
And I think particularly in the ME kind of side of things, we see how severe that can get. And we see our comrades who are in dark rooms 24 7 not being able to talk to anyone. And I think for me personally, that's just given me a greater appreciation of the things I can do rather than the things I can't do.
So like, I appreciate now when I go home, I can spend time with my niece and nephews. Even though I'm not running around with them, they're playing, but I'm with them, and I can appreciate that more. Because I know at any moment, that could just be ripped away from me, and that might not even be feasible in the future.
[00:48:03] Jill Brook: Yeah. In addition to that, is there anything that you wish you had known sooner about dealing with a vaccine injury?
[00:48:12] Harriet Carroll, Ph.D.: I just think there should be more discourse about unrecognised side effects and I think being vaccine injured is a very political position to be in, so you're not only not getting medical support, you're also getting the whole of society telling you that you're not vaccine injured and they're trying to justify away your being and they're trying to tell you that you're collateral damage or you're rare. And I think the mental toll of that is probably the most difficult part of vaccine injury.
I imagine it's the same with most iatrogenic harms, that there's just an added level of denial. And that, I think, makes vaccine injury uniquely difficult. Not necessarily more difficult, it's just uniquely difficult because you've got that added level of denial of almost... Hatred from society in some ways. The government certainly don't want to acknowledge you because they rolled the vaccine out.
[00:49:12] Jill Brook: Right, right. Oh, I can't even imagine. And that's why we're just all the more grateful that you're willing to talk about this with us because we know there's other people out there who, you know, who aren't... Doing as well as you are doing with all of this. Do you have any other favorite resources for people in this situation?
[00:49:36] Harriet Carroll, Ph.D.: Yeah I think for all its flaws, Twitter can be a beautiful place and probably the same for for most social media platforms they can be beautiful they've got algorithms and you can train those algorithms. And if you train them right, you'll come into contact with the most kind, caring, and informed people on the planet.
So I think use it to your advantage, remember you don't have to reply to everyone, you don't have to get into these arguments, you can block people. If you use it right, I think that can be a really great resource. And then there's great charities, I think the group that gets forgotten most about in all of this is children.
So like there's a great charity in Scotland, Long COVID Kids Scotland, that's just for children and their family to help deal with long COVID. POTS UK they've got a list of POTS friendly doctors and they've got resources for doctors. If you're vaccine injured, React 19 in the US, they've got a ton of resources and they've also got a page, if you're not from the US, about international support groups.
And then more generally, Facebook has some really amazing support groups for specific conditions like MCAS or B12 deficiency. And the patients in those groups are just an infinite fountain of knowledge. They can be so helpful in the face of dismissive and non responsive doctors. So I think there's loads of resources out there and you kind of sometimes just need to find them or post on other support groups and someone will be able to go, oh yeah, have you joined this group? And then you found it.
[00:51:00] Jill Brook: Yeah, well, and you mentioned Twitter, and I would just say that I started following you on Twitter. I think your handle is at AngryHackademic. I got a good laugh the other day because I woke up to one of your tweets that said something to the effect of, it must be frustrating for doctors to go to school for eight years just to learn that everything is caused by anxiety. And so I appreciated that and got a good laugh. What do you wish more doctors understood about long haul COVID and or a long haul vax?
[00:51:36] Harriet Carroll, Ph.D.: I wish they understood that you don't need studies to be able to do their job. You know, you can investigate this yourself and my doctor did just that. We looked at the limited research, we looked at my clinical case, and we were like, this might be a problem, and this might be a problem, and this might be a problem.
Let's see if they are problems. And they were, and then we could treat all of those pathologies as we went on. A part of it is like the legal and ethical framework they have to work within, but I think there just needs to be more flexibility to think outside the box, and to actually think more like a scientist, and explore what is wrong with this patient, believe the patient.
They're not making it up and also I wish doctors would understand that when you're this ill, you read a lot and you connect with everyone and a doctor, if they're lucky, they might get a lecture on POTS. A patient will have read hundreds and hundreds of patient papers about POTS. They know the physiology, they know the biomarkers 20 years before they are biomarkers in the clinical guidelines. And I wish doctors would just appreciate patient expertise a little bit more.
[00:52:59] Jill Brook: That's a great answer. So I know you have that scientist's mind that is so curious and always asking such good questions. If you had infinite funds for research, do you have any studies that you would like to see done right now?
[00:53:15] Harriet Carroll, Ph.D.: Well, if I had infinite funds, I would just buy a lab with everything, any scanner, we'd get the greatest minds to create assays, to find novel proteins, I would just run everything and I think I would... Change the paradigm of how clinical trials are run, because at the moment they're run in groups. And if, for example, you find X drug, it helps 20% of patients, they'll go, oh, well, it didn't work because it didn't reach statistical significance.
But instead of that, we should be going, okay, it helped these 20% of patients. Those are the ones it could be effective for. We need to find why is it effective for those patients. Then see if that criteria can be broadened out and find other patients who are gonna respond to that drug. Instead, they just dismiss it.
And then I think the other thing would be polypharmacy in trials and, and multi treatment, because they often just go, okay, well, you know, like in the UK the biggest long COVID study is the I C P trial. And they're testing like an single anticoagulant, two antihistamines, colchicine, and something else.
And I think, well, if you've got M C A S and POTS. And you're given colchicine. You're not targeting the pathology. Like this is just a terrible study design. Like if I went to a study about broken legs and they put a cast on my arm, you'd be, that's a terrible study design. You don't need to test the cast on the arm.
And that's what they're kind of doing in long COVID. And I tweeted last night that they're missing the trees for the forest to kind of butcher an expression. They're just seeing this long COVID and ME umbrella. and going you're all the same we need to find one biomarker, one treatment and we need to have one definition when actually you know one person with long COVID you know i've got MCAS, POTS, coagulopathy, endocrine dysfunction, possibly some metabolic issues and someone else with with long COVID is going to have myocarditis, they're going to have organ damage, they might have demyelination, they might have GBS, you know, we can't just clump this all together. So if I had a lab, it would all be about finding what commonalities subgroups have, and we'd be testing everything.
[00:55:37] Jill Brook: Yeah, absolutely. And I guess this would be a whole nother conversation, but sometimes it frustrates me when studies will consider every different autoimmune response differently in a separate category, as opposed to lump them together and allow that to reach statistical significance. Because obviously all autoimmune conditions are different, but then they do have aspects that are similar.
And a lot of, I think, significant results go away when you decide that you don't have a hundred autoimmune disorders, you have one or two of each of 50 different things, but they're all autoimmune disorders.
[00:56:17] Harriet Carroll, Ph.D.: Exactly. And it's the same for the way they monitor vaccine risks. If we're saying we've kind of got this long COVID like group who get this long COVID like reaction from a vaccine, but within that, we've got 2% who've got ME, 10% who've got MCAS, 10% who've got clotting, and now, and that's how they look at it. They look at all the individual problems that we've got, and then they go, well, all of a sudden these numbers are very low, so there's no signal and that won't be a thing, but if they put them all together and said, actually, all of these things could be classed as long COVID. They might then start to find some signals, which is their very myopic way of determining causality is to just look at population signals. So
[00:56:57] Jill Brook: Mm hmm,
[00:56:58] Harriet Carroll, Ph.D.: This big picture view of things, it just limits so much of science. In certain contexts, we need to know the average.
We need to know if I give a patient with diabetes metformin, what can I expect? And the trials will tell us, this is what you should expect, but they don't tell us anything about that individual and why would that individual respond or not respond? Why would they get this side effect and not that side effect?
And that's what we need to start to understand. And as well, like with side effects, the amount of times I've tried to look up, why does this side effect happen? And it's just like, no, this is a side effect of the medication. Well if we understood why that was a side effect,. We would learn a lot about how that drug works and we would learn a lot about who that drug is going to be effective for and not effective for. And we might also learn about other places where that drug might be effective in other conditions. So yeah I think there's a bit of a fight between individualized medicine and this kind of current paradigm but it doesn't have to be either or they've both got uses and we should utilize them both.
[00:58:01] Jill Brook: yeah, agreed, agreed. Well, Dr. Carroll, is there anything else you'd like to say on this topic before we let you go?
[00:58:11] Harriet Carroll, Ph.D.: I just hope that was interesting and I thank you for having me and also thank you for everything you do for POTS and related conditions.
[00:58:20] Jill Brook: Well, thank you so much for sharing your wisdom and your research and your insights with us today and for all the work that you do to help patients, for the tweets you write that keep us informed and make us laugh. I know that everyone listening also wishes you the best. Personally for your own recovery.
And so thank you for using so much of your precious energy on us today. We really appreciate it.
[00:58:45] Harriet Carroll, Ph.D.: Thank you.
[00:58:46] Jill Brook: Okay, listeners, that's all for now. We'll catch you again next week. But in the meantime, thank you for listening. Remember, you're not alone, and please join us again soon.
