143 - David Joffe - Overcoming Sleep Challenges in Long Covid Patients

Unlock the secrets to better sleep and enhanced well-being in our latest episode featuring David Joffe, a leading expert in respiratory and sleep medicine. You'll gain valuable insights into the intricate roles of slow-wave and REM sleep, crucial for both physical restoration and cognitive functions like memory consolidation. David shares his extensive knowledge on how sleep deprivation and stress can wreak havoc on your immune system and metabolic health, drawing direct links to the challenges faced by those with Long Covid.

The probiotic mentioned in the episode is called AB-21

For more information about Long Covid Breathing courses & workshops, please check out LongCovidBreathing.com

(music credit - Brock Hewitt, Rule of Life)

Chapters

• 0:00 Sleep and Long-Covid Importance
• 19:11 Circadian Rhythms and Sleep Hygiene
• 37:36 Gut Microbiome and Dopamine Dysregulation
• 52:18 Effective Sleep Solutions and Diagnosis

Transcript

Jackie Baxter: 0:55

Hello and welcome to this episode of the Long Covid Podcast. I am delighted to be joined this morning by David Joffe, who is here to talk about sleep and all sorts of stuff around that. This is something that is affected by Long Covid quite a lot, so hopefully this is going to be a really interesting discussion. So a very warm welcome to the podcast this morning, thank you. Would you mind just saying a little bit about yourself before we get started and sort of what it is that you do.

David Joffe: 1:30

So I'm a respiratory and sleep specialist and many moons ago, when I was still doing research, my interests were in circadian rhythm and cognitive impairment, in obstructive sleep apnea. That was my PhD, and then later I developed interests in reflux and lung disease, neuromuscular disease, ventilation, non-invasive ventilation and, in a strange kind of way, because I also have thousands of veterans I developed an interest in dopaminergic pathways and PTSD. And then COVID came and it's pretty much all the things that I had had a long interest in, and so when I saw my first post in April 2020, with long COVID I started to read furiously and hadn't really stopped. I now write stuff and try and collaborate with much smarter people overseas. We don't have a huge depth of interest here.

Jackie Baxter: 2:39

Yeah, and one of the great things to come out of all of this is this kind of greater sense of connection and collaboration between you know, all of these people coming together from everywhere, yeah, that's really really cool. Um. So I suppose um sleep we, we all know that sleep is important. You, we know how rubbish we feel when we get a bad night's sleep. Probably most of us remember that from before we got unwell. So why is sleep so important? And I suppose for everybody, but particularly in that sort of healing process, and I suppose for everybody, but particularly in that sort of healing process.

David Joffe: 3:22

Sleep is the essence of you know. It's the most important eight hours of your life. Without sleep, animals perish. We've done those experiments. There's two distinct and important components to sleep. There's slow-wave sleep, which is restorative or recuperative sleep. It's the energy of sleeping less, it's what makes you feel tired and makes you want to put your head down, and it is, uh, an s-shaped curve, so it builds pressure over the day until you get to a peak. Obviously, if you start sleep deprived, you are simply starting at a higher peak and that peak just keeps building. It's more like an Australian mortgage than an American mortgage. It has to be paid back and it is when we drop our blood pressure, drop our heart rate, flush out our system, reduce our sympathetic tone, increase our parasympathetic tone.

David Joffe: 4:25

Rem sleep is a very different animal. Rem sleep is really about rebooting our PC, our brain, and so it's all about flushing out the RAM, if you will, so that we forget and dispense with all the input that we've had during the day. That is a little relevance. We don't want to store it. Keep it, remember it, and we store the bits that matter. So it's all about memory consolidation. But it also has some other remarkably important aspects beyond that. So it's deeply involved in new learning. It has a significant role in executive function. It's the kind of brain part of sleep, if you will. They are both essential, you can't do without them. But we separate them and have done forever, because that's you know how it just pans out and the pathology of covert associated sleep disruption is is similarly a little bit dependent on you which aspects of sleep are most affected. But one thing we know for sure is that if you sleep-deprived people and stress them enough, their lymphocytes will drop. They become more immune, dysregulated we recognise that. They're more prone to put on weight, they get more metabolic derangement. That's independent of whether they have sleep apnea or anything else. And so sleep is absolutely crucial to every bodily function and it's driven predominantly by circadian rhythm.

David Joffe: 6:18

So light enters your eye as long as you're not blind, and and sends a light message signal to your suprachiasmatic nucleus, which sits really above the eyes, and that sends a message to the pineal gland to release melatonin. And it does that in a to release melatonin, and it does that in a very monotonous way, depending on the time of day, the length of day, a few things. You know the speed with which you're actually moving around the sun, all that sort of stuff, but the essence of it is it is the atomic clock of your body, and so we know that alcohol dehydrogenase, which is what breaks down booze, rises in the evening. So if you drink at lunchtime you're more likely to get nicked for drink driving because, yeah, enzymes are not switched on. We recognise that HNG-CoA, which is the enzyme for lipid metabolism, switches on at night, which is why the oldest statins were always given at night, because they didn't have a long enough half-life, and that's when the hormone is active. We know that your cortisol bottoms out at 3 o'clock in the morning. We know that your cortisol bottoms out at 3 o'clock in the morning, and so your liver and adrenals can't see the sun. They don't know what time it is, so they take that message. But every other enzyme succinate dehydrogenase I mean every part of our metabolism and our metabolic system is kind of tied into timing. We don't use every enzyme all the time, or every hormone, and so that's kind of the fundamental backbone of it, and so it also correlates with the urgency of sleep and the drive for sleep, which is the S wave that I was describing to you that peaks at sort of 9pm, and so lining up your circadian clock is remarkably important for people with long COVID.

David Joffe: 8:30

There are many mechanisms. Some of it is ductus biosis there's a paper on that out today but a lot of it is to do with disturbance and senescence of dopamine and the obvious changes in serotonin, and we know that there is low serotonin. It's being demonstrated. Well, melatonin comes from serotonin. That's how you make it, and so if you don't have enough serotonin, you're not going to have enough melatonin and you're also going to be desynchronized. In addition to that, there are other things that play.

David Joffe: 9:06

People with long COVID are more likely inactivity and other things to put on weight. They may develop obstructive sleep apnea. If it's knackered their hearts, they may get central sleep apnea. If it's knackered their hearts, they may get central sleep apnea. But certainly some of the other dopamine-related abnormalities like restless legs. There's a 40-odd percent increase in women with restless legs and long COVID. That's a combination of iron state. For some, magnesium is important and it's all about dopamine.

David Joffe: 9:46

And restless legs is really distressing and prevents people from getting into sleep and staying asleep, and for some they get distressing, fidgeting and discomfort during the day.

David Joffe: 10:02

Some they get distressing, fidgeting and discomfort during the day, um.

David Joffe: 10:05

So for me a lot of it really revolves around dopamine regulation, um, and people have focused a lot on serotonin but have, I don't think, really caught on to how much dopaminergic injury there is with this condition and that's really part of what I'm seeing clinically More restless legs, more PTSD, more major depression, more narcolepsy, more REM behavior disorder and that's a biggie because that has implications for the future. So many of the long COVID patients I see have lost the normal paralysis of dream sleep so they may call out or shout out or may just move in their sleep in REM sleep. That's abnormal. In REM sleep you are within your voluntary muscles, you're paralysed, and so when you see muscle activity or people living out the violence of their dreams, we call that REM behaviour disorder. Now we've long recognised this as a condition generally of older men 60, 65, of whom 80% will get Parkinson's at around 14 years. That all goes badly. When you're seeing as many young people as I am who have laboratory-confirmed REM sleep without atonia, will they follow the same path?

David Joffe: 11:35

I don't know.

David Joffe: 11:36

We're four years in, but you would have to be concerned, particularly given what we know about the virus's ability to really crush your dopamine cells that are responsible for much of this.

Jackie Baxter: 11:52

It's interesting what you're saying about the dream sleep, because this is something that people do talk about. You see it as people saying that they're not dreaming or that they're having, you know, really crazy, vivid sort of dreams. So it seems to be a whole spectrum. But you know, as with everything with long COVID, you know, there's so much variation.

David Joffe: 12:15

Absolutely. I worry about those, to be honest, jackie, who have vivid dreams in it and reenact them. They're the ones that I worry about. Those, to be honest, jackie, who have vivid dreams in it and reenact them. They're the ones that I worry about because of REM behaviour disorder. So everyone I see with long COVID who has any kind of sleep disturbance, and certainly all of those who have brain fog I hate that word they all get a sleep study. Because I'm a sleep physician and I work in a lab and my registrar is sitting on 20 REM sleep without atonia studies just this year alone. He couldn't understand why I was doing all these special montages.

David Joffe: 12:55

now he's going to write a paper with me, but the loss of dream sleep, yeah we've long known that if you give normal people with a normal mood 40 milligrams of Prozac prior to bed, the one thing that they will recall is an increase in dream intensity and colour and colour. It's actually a really old psychiatry trick and I guess I kind of overlap with psychiatry, so much with PTSD. I actually at one stage examined the quality of psychiatrists. As a physician, trust me, I'm not mad. But what struck me was they've always known that you know, the re-emergence of colorful, vivid dreaming is a pretty useful guideline to the fact that you're on the right antidepressant at the right dose. And so if I'm starting people on antidepressants often for insomnia or for other reasons ptsd etc. I always say to them when, when I see you in you know eight weeks, I'm going to ask you about your dreams and it's actually fascinating how they come. I'm dreaming again. I go yep, right, right, right, it does.

Jackie Baxter: 14:16

So it's a good sign that people are dreaming, because that means that they're in that REM sleep.

David Joffe: 14:23

Yeah, exactly, we just can't control the content of it. The trick is we actually have dreamlike meditation throughout the night. Our brains don't just shut down, but the colourful, intense stuff that you often recall on waking. We have most of our dream sleep in the second half of the night. So it's not uncommon to wake in REM, you know, and you go whoa took the brown acid last night because it's colourful and vivid and sleep is very structured. So all of your slow-wave sleep is largely in the first half of the night. The reason for that is because of that build-up of pressure, and so you then, at 9pm, switch it on and you basically decompress that sleep pressure is the word we use and then, as time allows and you've decompressed slow-wave sleep. It is the crucial bit. You will then have increasing chunks of REM sleep and so it is a kind of secondary. I mean, they're both important, but you will always go looking for slow-wave sleep. That's what your brain wants to do.

David Joffe: 15:32

The fascinating thing is that you know, having spent a lifetime on call, it depends when they call you as to how you are the next day If they find you in the first half of the night, out of slow-wave sleep. Well, the next day. If they find you in the first half of the night had a slow wave sleep, well, the next day you're tired. If they wake you in the second half of the night, at three or four in the morning, you're not that tired because you had your slow wave sleep. But, my god, are you grumpy. And so you know it's. You know fascination watching my colleagues because you can literally tell when they've got a phone, because if they, you know, are just exhausted, well it's probably first half of the night or, some of us, all night. But it really does alter what we do and how we feel. And you know sleep is the most essential part of what we do. It's what runs our brains. And so all this kind of American bullshit of you know lunches for wimps, you know Gordon, gekko stuff. Well, half the world goes to sleep at lunchtime. You know France, italy, they all do the right thing. They go home, have a glass of wine and a nap. I can tell you, around the equator no one's going hunting in the middle of the day. It's too damn hot. They're all lying under a tree asleep.

David Joffe: 16:48

And there is a second natural window of sleep that occurs around about 1 pm, and we should use that. And I always tell my long COVID patients don't ignore it, use it. You know, have that secondary nap, don't make it, use it. You know, have that secondary nap. Don't make it long 30 to 40 minutes at the absolute most and try and get some sleep. We know that if you go beyond 30 minutes you might sink into slow-wave sleep and then it's like you know, trying to float to the surface. It's awful, it's sleep inertia. But if you give people a 20 minute nap, so it's really just stages one and two sleep. We know from large studies we've done on airline pilots, uh, air traffic controllers, it actually improves performance, uh.

Jackie Baxter: 18:22

And so you know the stock market can wait for now it's really interesting because I think you know we've all kind of experienced those nights where we didn't get enough sleep. Or you know where we got woken up by something in the middle of the night or you know whatever that kind of disturbance was and I think you know we've all experienced. You know feeling grumpy the next day or just feeling off, you know not being able to concentrate enough. You know all those nights you know back at college where you pulled all-nighters, you know, and the next day you know you can sort of function when you don't get enough sleep. We know that we feel rubbish. We know that we feel rubbish but kind of understanding a bit more about why is just fascinating.

Jackie Baxter: 19:11

So you were talking about when the cortisol bottoms out in the middle of the night, about three o'clock in the morning. You said and you know cortisol comes up a lot when people are talking about all sorts of different aspects of long COVID. We hear about a lot of people kind of waking up in the middle of the night. Is that related?

David Joffe: 19:28

No, I don't think so. I think there's another explanation. So the finding of low cortisol is not always replicatable and it may simply be that their clocks are shifted forward. So three in the morning is when you measure their blood. It's seven in the morning, but biologically it's three in the morning is when you measure their blood. It's seven in the morning, but biologically it's three in the morning. So no one's done and I've spoken to Dave Petrino about this to do the time DMSO, which is basically melatonin saliva, to see whether it's just that and it's a circadian issue or, you know, is it actually a real metric. But I'll be honest with you when I read it and I've looked at it to me my first thought was that's circadian rhythm disturbance. It's not necessarily a mark of other things.

David Joffe: 20:15

One of the reasons people may have arousals at night can be anything from their REM behaviour disorder to their restless legs. But for some there are several forms of POTS. I mean, pots is so complicated and you know for a sleep and breathing guy getting my head around it, but we recognise that there is certainly a hyperadrenergic form. So those who typically get much more tachycardia, new hypertension, much of that's driven in part by the endothelitis. So their vascular tree is stiff, but some of it is really just dysregulation and the fact that their parasympathetic system has been paralyzed and so there's more sympathetic tone.

David Joffe: 21:07

Again that comes back to my interest with reflux is this thing will absolutely monster your vagus nerve and so we are really starting to see people who have terrible poor gut motility. Their esophagus doesn't empty, their gut doesn empty. They are aspirating and inhaling Part of its mast cells. Stomach is just direct vagal injury all the way back to the brain. But it's the nerve of everything. It's what moves your voice box, it's what provides sensation to your lung, to your pleura, to your pericardium, it's what controls your heart rate. You know it's the nerve of everything, and so you know I had a long interest in the vagus and clearly when you clobber your vagus which is really about, to a large extent, heart rate control, parasympathetic you switch that off. Well, you've got sympathetic, and so in slow-wave sleep we're meant to be parasympathetic. Slow heart rate, drop in blood pressure, all of those good things. So if you can't achieve that, you're just going to thrash yourself and thrash your vascular system.

Jackie Baxter: 22:22

So actually, things like down regulating before sleep, you know, so important isn't it to help us get into that parasympathetic?

David Joffe: 22:31

Absolutely, and so I think we really haven't explored. I mean, I use a lot of slow release melatonin in all my long COVID people. The reason I do is because it's TGA approved, it's pharmacological prepared, so you know it's quality assured, it's script only and it's slow release so and it's a small dose. This idea that more is better is really silly. Two milligrams is all that is required, but if you take it at 7pm it peaks at 9pm, so it models what you're trying to do and resets that circadian clock.

David Joffe: 23:09

It also has some other added benefits. It can often be helpful in reducing the violence of people with REM behaviour disorder and you know you really don't want people smacking themselves around and falling out of bed. You know it can be really damaging. And, last but not least, at low dose the evidence, rather than at high dose, is it does provide some endothelial protection, like statins, and we recognise that this is very much a vascular bomb in endotheliitis and we're hoping very much that the paper that we've written, razia and Doug Kell and Dave Petrino and a whole bunch of us, will actually get to see daylight, because it's really good science.

Jackie Baxter: 23:56

Now, what about like morning people and nighttime people? And how does this kind of work? I mean, obviously this morning's a little extreme for me because of our time difference. It's 7am here, so my brain's a little sluggish this morning. Let's say, but um, you know, when we're trying to kind of get a sleep cycle going, there is a logic to that.

David Joffe: 24:17

You realize, don't you? Is that? Fundamentally, there are two clock cycle lengths there. There's a 25 and a 23-hour clock, and some dick divided the world in 24 hours. So there are early birds.

David Joffe: 24:29

I hate them. They're the guys who are up at the gym at 5, oh yeah, baby, yeah, pumping, pumping, except they have no social life because they have to be in bed at 8. And then there are guys like me who you do not want to talk to me in the morning. It's got to be too short blacks in culture, but I can write science at nine o'clock at night. I'm just the other side of it, and so we all have. You know, just the way we are.

David Joffe: 25:23

It's like men and women in terms of, you know, sleep arousal. I mean no blokes ever heard the car in the driveway or the key in the front door? No, that's. That's what mothers do. Mums sleep out the front of the cave listening out for bears, and we're down the back and nothing much wakes us. You know, that's just biology, and and you actually can't really change it in adoles that's why their clocks shift forward and universities need to adjust to that is that kids' clocks are delayed, so they actually want to go to bed at 2 in the morning and get up at 10 or 11. That's why they always grow on school holidays because parents let them sleep, growth hormone is released in slow wave sleep. That's why you're always buying new shoes at the end of the school holidays because they've grown.

Jackie Baxter: 26:18

And I guess you know this is just kind of reiterating how important that sleep is, you know, for growth, for healing, for all of these things. Absolutely, I suppose the question is how do we improve that sleep? How do we get into better sleep, longer sleep?

David Joffe: 26:38

you know the right sort of sleep obviously there's pharmacological aspects which I can touch on, but the essence is is of sleep hygiene and sleep anxiety. One of the problems is people start to worry about worrying about not sleeping, and that's your brain's way of making you hypervigilant, like PTSD. Fall asleep in a foxhole, coming home in a body bag, lie awake listening out for Sanchez in the jungle. You're going to come home. You're not the same guy. And so there is this. You know, hypervigilance and worry. That is part of PTSD and anxiety, and so for some, you need to address that pharmacologically. That's the value of sleep studies. But sleep hygiene is crucial. Is the room dark enough? Is it quiet enough? Are you hot? Are you too cold? There is an ideal temperature for sleeping which is around about 23, 24 degrees, and so you know people who you know wearing lots of heavy stuff, and sometimes, you know, weighted blankets can be useful for some people because they feel the comfort. But it's all about the timing, it's about maintaining a regular routine. So, you know, go to bed at 10, turn your light out, don't look at your phone, turn your clock radio around, make sure it's dark, make sure your pillow is not going to give you a bad neck.

David Joffe: 28:14

If you have a partner, get two doonas. Two doonas is a revelation. I always tell my patients get two doonas. You know, women have a different thermocouple to men and so they may need a different weight of their doona. And also, when they roll over, they don't pull and push, because every time your partner has an arousal and rolls over, you do too. So two doonas doesn't ruin intimacy, it just improves sleep hugely.

David Joffe: 28:46

We also recognise that it's important not to overheat. So there's some really interesting work that's now becoming incredibly important with global warming and climate change, which demonstrates that in places where the temperature really doesn't get below 32, 34 at night, there's 25% less slow-wave sleep. And so you know, we actually require one of the very first signals that we're going to go into sleep and it's in part related to melatonin is a drop in core body temperature. It's one of the signals of the cascade of prostacyclines and other brain chemicals that actually initiate sleep. And so if you can't drop your core temperature, you're going to struggle.

David Joffe: 29:36

And in truth, you know the wife's tale about warm milk. Well, milk has tryptophan in it, so that in some way may be a little bit a bit of sleaky stuff in it, but it's more about the fact that if you have a hot drink, well, what does your body have to do? It has to cool, because it's in your stomach, and so you then move the blood to your periphery because you're trying to cool your core, and that is probably one of the reasons warm milk helps uh is it's really to do with core temperature dropping and trying to get it down and so those sorts of things.

David Joffe: 30:14

The environment, you know, is it too bright? Do you need eye shades? Does your bloke snore? The steam train, so all of those things to make the environment as conducive to sleep as possible. But definitely, you know, phones, pads, those sorts of things there are definite no, no, as dark, as quiet, as temperature accurate and as temperature controlled as you can get it. And that's difficult in some places. I mean, every time I've been to the uk, oh my god, you can walk around in that house just in the places. I mean, every time I've been to the UK, oh my God, you can walk around in that house just in the underwear. Everyone heats their houses to 32 degrees but they can't open a window and then there's no air conditioning. So you know, whereas in Australia we think it's fabulous and sunny all the time, so we all have air conditioning, thank God they now reverse cycle because it gets cold in winter, we forget, and so we don't always heat our houses and they're not always necessarily built to contain the heat. So having that sleep environment ideal is crucial.

David Joffe: 31:26

Other things that I find helpful uh, meditation, meditation is remarkably good. There's some very good apps for meditation, some that are more about mindfulness, some are more about yoga, nidra, you know, checking your body. But what would then work in a somewhat similar way, they actually increase alpha rhythm in the front of the brain, which helps to trigger sleep onset. And so it also helps if you've got your earphones in and stuff to block out the tinnitus, which is bloody awful COVID. And so for some, doing a meditation with earphones in, with ocean in the background or whatever, blocks out the tinnitus, that can be helpful. And then there are some self-help courses that I sometimes use for people for behavioural strategies. You know how to stop your brain from thinking. You know, keep a pad and pen next to your bed If you want to worry about it, write it down, worry about it tomorrow. All of these things, they all work in various ways.

David Joffe: 32:39

The problem with long COVID is that for many the insomnia is novel. They were great sleepers and then whack, and so their long COVID comes with really a decimation of their sleep, and that's why for many of them they're so dysfunctional. It's like PEMS. You know, I always say to my long COVID patients that the sleep is the most important part of PEMS.

David Joffe: 33:08

To me, pems is like your mitochondria are no longer running on thermonuclear power. They've been dismantled and damaged and hijacked, so you're running on lithium, a bit like one of Elon's crappy Teslas, and the fact is that you're range limited. There's only so much lithium in a charge, and so if you do not charge your battery fully overnight, you will not have the distance, and that's what people find. It's also fair to say that how you use that battery is important. If you do too much physically, your brain will crash. If you do too much mentally, you have a physical crash, and so it's important for people to a get enough sleep and b to recognize what their envelope is or how much they can do before they're going to go off the cliff, and so you know. That's why things like braided exercise isn't going to fix that. It's's not functional, it's mitochondrial.

Jackie Baxter: 34:12

And I guess I mean you were talking earlier about the importance of the circadian rhythm and daylight and things like this. And you know, for people with long COVID-19, many are not active at all, you know.

David Joffe: 34:26

so if that must contribute, yeah, that's part of it, yep, and I was hoping you'd raise that. I mean, the truth is that you know, one of the biggest problems is, you know, there's a lot of long COVID in the UK and in the northern darker places. Some of that is probably in part related to the length of the day hours. But also, you know, know, if you've got really shitty long covid, well you're not going anywhere and so actually trying to, you know, wheel you over to a window, but then you're light sensitive, so that's a problem. The catch is, you know, it's a bit like bone health we need sunlight to make vitamin D.

David Joffe: 35:09

I do bone mineral density, even on young women like yourself with long COVID. Why, well, firstly, you ain't going anywhere. B, you're not seeing any sunlight, even if you're taking your vitamin D. And thirdly, we know that the virus itself upregulates bone cells that are actually eating you, and so it upregulates bone destruction versus bone making. And so you know these things are really important because you know it's the skeleton upon which your muscles work.

David Joffe: 35:44

So for me there are potentially I mean, we've used them little white lights and blue lights and things you know to try and re-regulate shift workers, and we have that science and so you know, I think, for seasonal affective disorder, which is people who get the glums and the long dark hours, we know that there are those tools and they've been validated in the sleep literature. Australia is in fact one of the leaders in that and you know, there's, there's science there, and so maybe for those who cannot get out using these things because it's about the intensity of the light, sun's very bright, screen not so bright, and the further you are from the light it actually decays at a really rapid rate. So flux, which is how much light is given off, decays enormously with distance and that's why the little glasses, ones with the lights on top, may be better for some people, particularly if they can't get outside and trying to get some sunlight, you know, I think's really important, but there's no question that the hems and the disability compounds the sleep.

Jackie Baxter: 37:08

Yeah, absolutely. Now, you mentioned just then vitamin D and you mentioned earlier I can't remember the context when you were talking about the gut and the motility and all of that, and there have been some connections made between sort of sleep, vitamin D, gut dysbiosis, all of that sort of stuff, for want of a better word. So is this related?

David Joffe: 37:35

Possibly so. The biggest reservoir of serotonergic sources is the gut dopamine. You know there's dopamine elsewhere in the body, but the biggest reservoir is the brain, and so that's why I talk about mast cells, because you know what we use to block mast cells are antihistamines. Well, histamine is serotonin. There just happens to be quite a lot of them, and so that's the bit that we really haven't got our heads around is the pharmacological ways to address it. But there's no question that the gut is a huge reservoir. There's no question, all the science shows that, and so correcting the dysbiosis, I think, is crucial. So all of my patients are on a very specific probiotic, and the reason I'm a scientist it's been probably the best studied probiotic done in a Mexican four-way blinded, quadruple crossover study I mean, it's rock hard science and what they showed was a substantial increase in viral shedding in the faeces. Now, if you assume that that's where this thing hangs out, then logically it makes sense to use the most you know studied probiotic, and so that's the one that I get my guys to order, and so I always tell new patients go there and find out where the cheapest place to buy it is. Someone usually knows, but it does make a difference. It does improve the PEMS, fixing the probiotic, you know, as best you can, and for some it really makes a difference to their constipation, which is also really important.

David Joffe: 39:33

So the gut has a two-way switch, again vagus. So if you have a, a large meal, there's a reflex to go and evacuate your bowel. That is the stomach telling the colon to make room there's more coming. The constipation is a really big deal in long COVID because it goes the other way. If you are fecally overloaded, and that can be for any number of reasons medicinal, lack of exercise, lack of movement, lack of fluids, because you can't drink enough then the gut, the bowel, sends a message to the stomach to say hang on, we're full, slow down, and so it just makes the gastroparesis and the bloating worse, which is a really common scenario.

David Joffe: 40:18

So I rely very heavily I have two wonderful gastroenterologists who I've kind of trained by sending them papers over the last three years, so they kind of get it to to help me manage the constipation. And interestingly, one of the better drugs that we've used is a drug called recitrans, which is a histamine blocker. It's a 5-HT4 blocker, and so not only does it improve constipation, so it's designated for chronic constipation, but we know it helps move the fall gut as well, and so we're becoming more inventive about what we're using now we've talked a lot about you, about all sorts of great strategies.

Jackie Baxter: 41:07

You were talking earlier about dopamine being a big thing in sleep. Can we go down that rabbit hole a little bit?

David Joffe: 41:17

So dopamine has lots of functions. I could spend hours talking about it, but the essence of it is that dopamine is everything from the hormone of movement so Parkinson's, no dopamine. We recognise that that pathway begins down at the blue body, which is actually the centre for flight and fight and fright is actually the centre for flight and fight and fright. We recognise that we put unpleasant memories with dopamine into part of the brain called the amygdala. And the reason we do that is basically because it's the fastest route. And so for my veterans, if a car backfires, they don't stand around thinking, oh, it sounds like an AK-47 in Kandahar, they have to get off the pavement. It's the fastest route home, it's a survival advantage. And so dopamine has many components to it. It's also the drug of addiction, and that's really crucial.

David Joffe: 42:31

So in the 50s, big tobacco worked out that if you put ammonia in cigarettes it binds more avidly to the nicotine receptors. How good are we? So you know, that's one of the reasons why, you know, nicotine is such a ferociously addictive substance. And it's again dopaminergic. We realise that excess dopamine is associated with schizophrenia, and so most of the antipsychotic drugs are antidopaminergic in one form or another. And so and we know I mean from the early days in New York that there were Long Island Jewish psych hospital and a whole plethora of young people with no family history, no drug addiction, turning up with new onset psychosis. The only thing they had in common was COVID turning up with new onset psychosis. The only thing they had in common was COVID. And so it's pretty obvious that you know that was really the message about dopamine dysregulation and it's going to be really important to try and work out.

David Joffe: 43:42

You know how that actually plays out because dopamine and mood are also very related. So if you can imagine that serotonin and dopamine like to be, the brain likes them in balance, how do we know that? Because if people are depressed, in other words their serotonin is low, they will often get restless legs. If you put them on an antidepressant, sometimes their restless legs will get better. That's fine. But what is really common is that the dose that people need for their antidepressant means that their mood's fine.

David Joffe: 44:23

But again there's this dysregulation, disconnect between dopamine and serotonin, and so we use dopaminergic drugs to relieve their restless legs. How do we know some of this? Well, nature gave us the perfect experiment. It's called Parkinson's disease their. Dopamine just goes kaboom. Parkinson's disease their dopamine just goes kaboom. The problem is, if you look at the literature, 50% of those with Parkinson's have really nasty organic depression. So these are not people who are just feeling sorry for themselves because of a little bit of Parkinson's. Now these people are really profoundly organically depressed and need serious firepower to bring them out of it. And often they are more anxious and dopamine, I think because of the amygdala, is part of anxiety. So you know there's lots of things that dopamine does and I think that you know in the fullness of time. I think that you know in the fullness of time we will start to better understand how dopamine interacts with.

David Joffe: 45:35

You know all of these things, because it certainly does, and we certainly know from those with pre-existing cognitive impairment and early Parkinson's. It puts it on steroids, and so there's a lot of literature around people who you know, the older group, who are just starting to lose it a little bit. They're pretty good, they get COVID and absolutely, absolutely stuff them, and so you know, it accelerates that pathway, and so you know, I think we need to be very mindful about just how, um, you know, brain injuring, uh, this thing can be.

Jackie Baxter: 46:19

I suppose, for for me, the elephant in the room that we haven't haven't touched upon really is my wheelhouse and also yours of breathing. So you mentioned sleep apnea and a lot of sort of breathing disturbances in sleep. Now, I think we both know how important breathing is to sleep, but I feel like we should maybe touch on this a little bit.

David Joffe: 46:46

Well, I mean, mean, apart from apnea and apart from other things, uh, you know, if your foregut's not working and you're lying on your back, you're much more likely to aspirate. If you, you know, gone to bed early with a reasonable meal, it's much more likely to come back up at you. And it will contribute to changing voice horse voice, loss of voice, uh, it can get anywhere and get into your station tubes, cause your station tube dysfunction and if you inhale it, uh, it can certainly worsen your asthma, can even give you asthma, uh, and certainly it will contribute to whatever lung damage is going on down there, because the lung is not a particularly clever organ, but there's more to it than that. I mean, the vagus is what drives your diaphragm, and there is already data that clearly shows that people with long COVID have got reduced diaphragmatic inspiratory muscle power, and so stand alone whether there's anything to see on the ct or not.

David Joffe: 47:52

Um, not everything that is breathlessness is lung disease. Yes, it may be, but it may be neuromuscular, it may be upper airway people whose cords are not moving properly have to try and suck through a straw or cardiac, and you know that's a biggie. We're seeing a lot more of that, and so you know, to me breathlessness is it is a very alarming symptom because it really makes me want to look for reflux. It certainly makes me want to treat it. It always makes me want to do a CAT scan, exclude other things and, of course, evaluate their heart.

David Joffe: 48:43

But you know, the problem is that the technology and I am actually engaged with a radiology engineering company is that the resolution of things like CT scans and, you know, vq scans they'll find biggish clots or sometimes smallish clots. They're not going to find the micro clots and that's one of the big deals for people is that they are what we call shunting. There's areas where there's underperfusion, and so the lung will move air around to avoid that and that creates a change in our lung sensation. But we also know that the virus itself disturbs the carotid body, which is really the hypoxic drive centre. That's why we were seeing, uh, happy hypoxics, people who's sitting there with you know, terrible looking lungs and appalling just chatting to you. Well, that's because that mechanism of alarming to low oxygen has been damaged and for some, um, the mechanisms for CO2 are also damaged and so they have trouble initiating sleep because their breathing cycles are out of range. There is so much more to it than that.

Jackie Baxter: 50:20

Yeah, and this sort of dysfunctional breathing pattern which is also then triggering our nervous system and stopping us from getting into that parasympathetic state which, as you said earlier, is so important for getting into and staying asleep.

David Joffe: 50:37

That term dysfunctional breathing. I mean, that's just, that's a Mickey Mouse term that people use to describe things they can't explain. So they'll do lung function tests and the CAT scan go well, you're normal. Well then tell me why I'm breathless?

David Joffe: 50:55

Well, you know, the kind of evaluation that you need to look at people's gas exchange, to look at their respiratory muscle power, to look at all of those things is quite daunting and difficult, and so the last thing you want to do is give people with POTS or PEMS a cardiopulmonary exercise test, because you'll crush them. So you know there is actually a protocol that Mark Faith and Darby has put together for us, a two-day protocol to try and spread it out. But you know, when you look at those studies, there's clearly a significant mismatch between you know, when you do it safely I mean, you can clearly see that there's tissue mismatch. There's, you know, much more peripheral extraction of oxygen when you deliver it. Yeah, it's complicated. You know there's not a one test fits all, and a lot of the the best tests are invasive, and so we don't really want to be doing those on people, if you can avoid them.

Jackie Baxter: 52:07

So I think what people find is oh, oh, my goodness, okay, right, I've just listened to this guy talk about sleep and there's, you know there's a lot there and I'm feeling a little bit overwhelmed. So what would be your kind of like top tips? Where would someone who's got rubbish sleep and is really struggling? Where would they start?

David Joffe: 52:25

For me, I would start by getting the environment right and if you're on your melatonin, you slow release and take it at the right time. Use the simple tools box, breathing, meditation, all of those things that actually have science that validates them, of those things that actually have science that validates them. But ultimately, for many, they're going to need help, they're going to need polysomnographic evaluation, and the problem is it depends where you are as to what the access to that is, and so you know home sleep studies. Well, that's just a kind of apnea no apnea thing. Most of them are kind of scored by robots and somewhere else, so they're not very helpful. You really need a laboratory study with all the right electrodes in all the right places and video camera and other stuff to find the sorts of things we're looking for.

David Joffe: 53:27

But for me it's the most useful tool when you see people who've got marked reductions in slow wave sleep or REM sleep. That's a fabulous biomarker of misery, and so you know, sometimes it's a lot easier to hear that you're miserable from a sleep physician than it is from you psychologist or psychiatrist or someone else. It's also irrefutable because it's neurobiology. You can fake most things, including elections. You just can't fake sleep.

Jackie Baxter: 53:59

Absolutely, and that's maybe quite a poignant thing to finish on. Thank you so much for giving up your time to come and speak to me.

David Joffe: 54:11

that's an absolute pleasure, thank you.