topical steroid withdrawal symptoms

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I’ve discussed topical steroid withdrawal symptoms and TSW skin concerns extensively on the Healthy Skin Show, but there is still so much about this condition that isn’t well understood.

Partly because we don’t yet have much research on TSW.

So when I heard that Dr. Ian Myles was looking into topical steroid withdrawal symptoms, I had to get him on the show to break it down for you in layman’s terms (because his paper is complex).

Topical Steroid Withdrawal (aka. TSW and also sometimes called red skin syndrome online), is a condition triggered by the use of glucocorticoid steroids often used topically (and typically prescribed for chronic skin conditions like eczema and psoriasis).

Because topical steroids are the standard of care for these conditions, many people unfortunately end up using them for extended periods of time (sometimes without any breaks and with increasing potency). And some go on to develop TSW, which is a horribly debilitating condition with symptoms that can drag on for years after stopping all steroid exposure.

The research we’re discussing in this episode has yet to undergo peer-review, but is in the process. Either way, the ideas are fascinating, albeit complex (especially for those with little to no experience with nutritional biochemistry). So we’re hoping that this conversation helps you understand the ideas while also adding context to what’s next for TSW research.

My guest today is Dr. Ian Myles! He did his undergrad at Colorado State University, received his M.D. from the University of Colorado, then trained in internal medicine at The Ohio State University prior to beginning fellowship training in allergy and clinical immunology at NIH. He became a commissioned officer in the United States Public Health Service Commissioned Corps and has supported several US and international missions.

Dr. Myles received his MPH from George Washington University before becoming the head of the Epithelial Therapeutics Unit to evaluate the efficacy and safety of a topical, live bacterial treatment for eczema.

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In This Episode:

  • How Dr. Myles’s interest in topical steroid withdrawal and TSW skin began
  • Study about topical steroid withdrawal symptoms
  • Niacin and TSW connection
  • Topical steroids impact on your cells’ powerplants (aka. mitochondria)
  • Which type of steroids may be to blame
  • Treatment ideas for topical steroid withdrawal symptoms
  • What may be driving TSW symptoms in your brain
  • Thoughts on oral and topical berberine for TSW skin


“So we're saying… what distinguishes patients with TSW and patients with atopic derm? And you can say, what's too much, and then what's too little? And so the thing that's too much, like we said, was niacin, the nicotinic acid. And then what was too little was tryptophan.”

“Kynurenine shuts off your ability to sweat, and we hear a lot from the patients that during the height of it they would be beet red, they'd be flushed, they'd do all this, but they're not sweating. They'd be feeling super hot, but they wouldn't sweat.”


Find Dr. Ian Myles online here and on Twitter


Dr. Myles’s TSW deep dive on YouTube:

Healthy Skin Show episodes on Topical Steroid Withdrawal

Healthy Skin Show ep. 279: Chemical That Triggers Eczema (Oh My!) w/ Dr. Ian Myles

Healthy Skin Show ep. 328: Client Case Study: Severe Eczema On Feet + Body


344: ​​NEW RESEARCH On Topical Steroid Withdrawal Symptoms + TSW Red Skin Trigger w/ Dr. Ian Myles {FULL TRANSCRIPT}

Jennifer Fugo (00:08.996)

Ian Myles (00:10.59)

Thank you for inviting me.

Jennifer Fugo (00:14.882)

So I think the biggest question that probably everyone has is what made you care, or maybe be so interested, in Topical Steroid Withdrawal (TSW) in the first place to even want to study it?

Ian Myles (00:27.214)

I'd never heard of it until 2019. There was the More Than Skin Deep meeting, which is National Eczema Association. I came to it through Global Parents for Eczema Research. And just sitting there in the corner, and then Kelly Barta, who is a representative for ITSAN, came up to give a presentation and she started talking about TSW, and I'm thinking, never heard of this, this lady's nuts. And it became very clear that everyone else in the room had heard about it, and so I was quickly Googling it and you can see there's like a million, 10 million things on Google.

And then you go to PubMed, which is where all the scientific journals are, and I think at that point there may have been maybe 14 papers total. So it wasn't like she had a mountain of evidence against her. And again, my thought was, okay, well she must have had severe eczema and just wasn't treating it properly, right? And then she starts showing some of the photos, and you're like, oh, nevermind, whatever this lady has, it is clearly not normal atopic derm anymore. Maybe it was, but now it's not.

And you know, then the pandemic destroys the universe of science for a while there. And then when we came back around, she was still interested in doing a pilot study. And initially I had suggested the extramural world, which would be dermatologist offices getting money from NIH to do these kinds of research pockets. And then it became slowly apparent that any place that had the resources to do it just wasn't going to help her, or help ITSAN at all.

And we had a protocol in place for other reasons to look at quote-unquote normal eczema and just kind of normal healing. So I thought, all right, well, you cobble together some people and we'll plug them into this. And I warned her at the time, I said either it's going to be so similar to allergic inflammation that it would be very difficult to tease apart, or it will be so overwhelmingly obvious as to what the problem was that we'll all be upset that nobody looked earlier. And that's how we got started, and we started enrolling people less than a year ago when this whole protocol kicked off, and enrolled them and put them through the protocol phases to figure out what was going on. Because it was obviously a really severe disease and was clearly not being taken seriously by anyone with the resources to do the research.

Jennifer Fugo (02:58.399)

And now we have this preprint that, am I correct in saying it hasn't yet undergone peer review, but we are in the process of this happening. And the paper is called “Topical Steroid Withdrawal Is A Targetable Excess Of Mitochondrial NAD+”. And for the layperson, they might go, what? Mitochondrial NAD+. So, can you talk to us, maybe at a very high level, how you would maybe explain this to your wife? Well, your wife is in nutrition, so she probably knows a lot more than the regular person, but maybe a family member or a patient just from a high level. We'll start there because, don't worry folks, we got a lot of science coming at you. We're gonna make sure to put all the terms in the transcripts and everything, because we do want you to have some general understanding of this. It is complicated. So high level, what's the study about?

Ian Myles (04:03.82)

The highest level is that I think most people at least have an elementary school understanding of the mitochondria as the powerhouse of the cell, right? And it's kind of magical in the way it works, but the shortest version is it is just ripping energy out of the food that you consume, and it is processing it into a way that all your other cells can work on. And it is a chain of events, so food goes in one end, it gets broken down, it gets turned into energy on the back end. And all along the way, it's generating waste products that then have to be recycled and taken care of. CO2, you're blowing out, you need water, you're gonna urinate, oxygen, you need to breathe in and out. So that's how it's doing its job. And NAD is one of those waste products in the process, early in the process. So you’ve digested your food, it's going to the mitochondria, it starts to make NAD, which is one of those waste products that has all the downstream effects that we can get into the details of. But that's just kind of the top level, is that the mitochondria, in its process of making energy for your cells, generates a waste product that, if it builds up, can create a lot of pathology.

Jennifer Fugo (05:22.589)

So one of the cool things, and for those of you who recall, I got a master's degree in human nutrition and we had to study all of this different nutritional biochemistry. So I had to draw out all of these complex pathways and nerdy things that for many people, as I've tried to explain this to them, they start to kind of glaze over. So I hope that as people see this, and plus you've got a really great YouTube video on a deeper breakdown on this Topical Steroid Withdrawal paper, so we'll link to that in the show notes, where you talk about a lot of this stuff. And so we've got NAD+. And I think maybe the first place to start is the fact that you found higher levels of niacin, correct, in the TSW skin? Do you want to talk to us a little bit about the significance of that because that's a big deal, I think, for topical steroid withdrawal patients.

Ian Myles (06:24.427)

Yeah, when we put people through, we take their skin and we run it through mass spec, so we're looking for all the metabolites that are in the skin at a given moment. And the niacin pathway, so nicotinic acid, it's called vitamin B3, it also goes by that name, just leapt off the page as being just so overwhelmingly abnormal in the patient group.

And when you talk to the patients, you kind of get a sense of what, like I said, when they throw in the TSW pictures, you're like, well, that's not normal eczema. But when you talk to them, you get a sense of what some of the topical steroid withdrawal symptoms are, right? These TSW skin flushing symptoms that they're describing. They use the word zingers, these stabbing, the fancy term would be neuropathic pain, but it's like some kind of electrical shocks going through your body or whatever. And so when niacin shows up, the part that makes the most sense is like, well, there's your flushing. So niacin has fallen out of favor but it used to be used quite frequently for cholesterol abnormalities. In theory, it would take it and it would boost the ”good cholesterol”. That was what it was supposed to be used for. But the side effects of flushing were sometimes so profound and so common that's why nobody would ever realistically use it anymore. And so to see niacin being incredibly high in a disorder that we knew was marked by flushing kind of made us get a little, you know, some confidence that maybe we're on the right path.

Jennifer Fugo (07:56.473)

And there's that whole camp that says, well, the skin's getting red during Topical Steroid Withdrawal because of nitric oxide and entirely due to nitric oxide. Do you think that this perhaps may add nuance to the perspective that we have about what's causing this intense TSW skin flushing that happens?

Ian Myles (08:08.715)

Yeah, I mean if you took enough niacin as a pill you're gonna flush, and then with that flushing nitric oxide will be elevated, that is just part of how the human body flushes. And I have seen one paper that talked about higher levels of nitric oxide in patients with Topical steroid withdrawal symptoms, and I'm not refuting that. We didn't test for that and it's certainly possible that nitric oxide was also elevated in our cohort. But what we're saying is that nitric oxide would be one of the final dominoes to fall and niacin is way upstream. So it would be one of the first dominoes to fall and then you would end up with nitric oxide at the end. So I do not believe that blocking nitric oxide or trying to address the nitric oxide would be sufficient, because at that point you're too far gone down that pathway and you really need to focus on what to do about the niacin and, as we'll discuss later, some of the ways in which your body recycles that particular waste product generates waste products of its own, and that's why I think that's the thing that needs to be focused on.

Jennifer Fugo (09:26.167)

And that's one reason why I agree with you. I sort of struggled as a nutritionist, I work in the diet space and whatnot. There's this whole community of TSW people that are like, “do the low nitric oxide diet.” And I'm like, I have never really seen that work, to reduce those levels in food. And I think the niacin, when I saw that in the paper, I was like, that makes so much sense. It really, really does. It was an interesting point that then led you to start looking into, how on earth would we have this elevation of niacin in the first place in TSW? So do you want to talk a little bit about that production of niacin?

Ian Myles (10:23.18)

Yeah, because the way the detection systems work, you can ask, what do patients with Topical Steroid Withdrawal symptoms, and by the way, we were comparing to patients with eczema. So, you know, they weren't as severe in terms of overall skin disease, but that's to say that we're not just looking at TSW skin versus healthy. So we're saying, all right, what distinguishes patients with TSW and patients with atopic derm? And you can say, what's too much, and then what's too little? And so the thing that's too much, like we said, was niacin, the nicotinic acid. And then what was too little was tryptophan. And tryptophan is made into NADH, which then becomes NAD, but the idea is that you need tryptophan as part of that recycle system. So your body's making too much NAD, you need to recycle it somehow, tryptophan is part of that process. So that again stuck out to us to say that the one item that they have too little of is made into the thing that they have too much of. So really suggesting that that entire pathway had been upregulated.

And so then along the way, when you go from tryptophan to niacin, you have to go through these things called kynurenines. Each of those are neurotoxic at a particularly high enough level. So this really then starts to jump out at us to say okay, well you got flushing, you can now explain that with just niacin alone. And then all of these neuropathic pains and the tingles and the temperature dysregulation, patients will say like, an actual thermometer won't change, but they will feel too hot, or they will feel too cold, kind of like hot flashes and so forth that people would experience in menopause. So it would tell us that kynurenine should do all of that too. Kynurenine shuts off your ability to sweat, and we hear a lot from the patients that during the height of it they would be beet red, they'd be flushed, they'd do all this, but they're not sweating. They'd be feeling super hot, but they wouldn't sweat. And so that started to make sense. And so just that pathway alone really started to connect a lot of the dots between the symptoms that distinguished TSW from “regular eczema” and then the biochemistry that we were finding.

Jennifer Fugo (12:41.17)

So one question that I have for you, which I thought was interesting. So we have this kynurine pathway that starts with tryptophan, and then we've got the mitochondria itself. So how did you hone in on the mitochondrial impact of producing this excess NAD+ or niacin?

Ian Myles (12:44.492)

So there’s two different methods, the first one is metabolism, so you're just looking at the metabolite. Then there's a second method, which is RNA-Seq, or a fancier term is transcriptomics. So I think if you remember, got to go back to our biochemistry again, sorry, but you start with DNA, then it becomes RNA, and then it becomes a protein. And so that process has to play out for every protein your body makes. DNA, RNA, protein. And so in transcriptomics you're just looking at the RNA. You're trying to say, what is the body actively making at this second that I collected the sample from. So that's how you get to see bigger pictures and additional things that the metabolites alone aren't going to tell you.

And so then when you look at the transcriptomics to say, all right, what is the body actively making and how is it skewed, how is it thrown off? That's when the mitochondria showed up. And so that was far and away the most abnormal, really the only statistically significant abnormality, in TSW skin, by the transcripts, was the mitochondrial processes. So again, the mitochondria is what's churning through, generating the waste product of NAD, which gets replenished with, fed by tryptophan. And so everything's now pointing to the fact that the mitochondria have gone on overdrive, and they're spewing out waste products faster than the body is able to do anything with it and is beyond our capacity to recycle. And that buildup of waste products now can explain, at least, all the other downstream symptoms that we see.

Jennifer Fugo (14:48.56)

So one thing that was super fascinating, your paper came out and I was telling some of my community members yesterday, I spent like two hours combing through your paper. I had textbooks, I was on the floor. This was like grad school all over again. I'm trying, and I literally actually, I saved my drawing. I'm literally trying to draw out the pathway and everything, because I'm a visual learner, so it was really helpful for me to do that. And I think it's important for people to know that it is the fact that topical steroids, and is it more so that it's corticosteroids, that are up-regulating, or it's like putting the gas pedal on certain enzymes like tryptophan 2,3-dioxygenase, right? So, there is some impact from an enzymatic level that is happening here that drives this process. I think traditionally this has been thought of as, well, hydrocortisone is similar to cortisol, and so this must be entirely an adrenal issue, and I will admit that was my perspective for quite a long time. This is literally a revolutionary perspective.

So can you just talk to us a little bit, just so people who maybe are a little more curious and nerdy, or physicians who are listening to this, understand that there is something that these steroids are acting upon in the body that causes this, especially if they've forgotten that all of these things happen under the surface.

Ian Myles (16:17.544)

Yeah, so one of the collaborators on it is named Dr. Luis Franco, and he also works at NIH. And his entire lab is dedicated to studying what steroids do. And the official term, if you want to get nerdy, and if you are somebody who's combing through biochemistry journals, you want to look for the word glucocorticoids. That's what we're talking about when we're talking about clobetasol and hydrocortisone and whatever. They have different effects, but glucocorticoid is the fancy term that you would look for.

And when I met him for the first time and you know, hey what do you work on, blah, blah, blah. And so he was like, I'm trying to figure out how steroids work. And coming from a place of ignorance at the time, I was like, we can't possibly not know that. How do you have an entire lab dedicated to that? And he starts outlining how incredibly ignorant we are about what these drugs do, how they work, what cells they work on, and so there's really an entire universe there that we don't appreciate how they work. And so his group took healthy controls and they brought them into the lab in a setting, they took one biopsy, and then they slathered them with topical steroids – very high potency, higher than even would be realistic – but then they just came back four hours later and took another biopsy. So they want to see like, all right, what do steroids do in a four-hour period? And there are massive changes in the skin in just four hours. And in those four hours, you see this massive uptick of mitochondrial activity.

Now that would beg the question, why doesn't everybody get topical steroid withdrawal then? And we don't have an answer for that. Is there some other factor? Is it all about length and how potent the steroids would be? Was there a predisposition? Is the microbiome involved? I don't have any idea. But this tells you that the understanding of the full scope of what some of these drugs do isn't there, and shouldn't just be assumed. Because before I met Dr. Franco, I would have reflexively said, they're anti-inflammatory, and that would have been the extent of my understanding of that. But now you step back and say, wow, they do all kinds of things. Even beyond the obvious side effects that we know about, glaucoma and cataracts and growth stunting and so forth. But even just, they have a lot of off-target effects that you don't appreciate.

Jennifer Fugo (19:02.219)

And with this study, and I don't know if you can answer this, do you think that this is just from topically applied steroids or do you think that it could be any type of, say, glucocorticoid, or from prednisone, for example?

Ian Myles (19:06.609)

I can't imagine that the oral steroid would make it better, but I will note that when we started, various groups had put together a large survey that was geared toward patients with TSW skin but was open to anybody with some kind of skin disorder. And they just kind of asked, all right, what are your symptoms or how long have you had steroids? Which type of steroids did you have? And people said, yes, whatever, they had topical steroid withdrawal or they didn't. And what that allowed us to do then is to go back and say, if I was trying to use that survey to predict, which answers would you say that would make me think you're going to end up telling me you have TSW? Oral steroids was a pretty small player in predicting topical steroid withdrawal symptoms.

The things that were much bigger were if you were using topical steroids for months and months and months and months and not seeing any benefit. So if it's, I got a rash and I keep using steroids and the rash keeps spreading, or I had the rash and I'm using my steroids and now I'm developing new symptoms like that burning sensation, like the temperature sensation problem. Or, they started me on a low-dose steroid, it's not working, we just keep ramping up higher and higher and higher and higher, and now I'm on long-term, highest-dose steroids and I'm not seeing any control of my disease. So those were the big red flags which kind of speak to length of topical steroids. Again, most people in that group eventually will get exposed to oral steroids as a, well, let's just try this and see if it takes it away.

I don't know. I would say, you don't find too many people in this day and age that are going to be on oral steroids for months in a row. In the COPD world, the emphysema world, they give out steroids, oral steroids like candy because people have an exacerbation and they need to get the inflammation under control, but they're not doing it for four months. So at least we could probably say that I don't think there's anybody who gets an oral steroid for 10 days who ends up having TSW. I really think that there probably has to be some element of the topicals involved, but it's hard to say because you don't have anybody who's on steroids for such a prolonged period of time orally.

Jennifer Fugo (21:39.559)

Do you think this overproduction of NAD+ or Niacin is happening while you're using the medication, or is it once you stop using the medication?

Ian Myles (21:56.106)

I think it's happening the whole time, as evidenced by the fact that in four hours you see this massive uptick in the mitochondria. But what I think happens is that the steroids, while they are putting your mitochondria in overdrive, they're shutting off all of the downstream effects. So the kynurenine pathway and the pro-inflammation and all of that, there are studies that will show you that, at least from what we know about glucocorticoids, they will shut that part off. And so I think you are basically amassing a dam so to speak, that you are just building up this mitochondrial abnormality, and then the steroids are preventing any downstream effect of that, and then once the steroids stop, for some people, obviously for some people, their mitochondria must quiet down quickly enough that they are able to then recycle the backlog, so to speak. But for others, it's clear that it doesn't happen and then I think that the floodgates open and you start to see this downstream effect.

Jennifer Fugo (22:59.589)

So one really cool thing that I learned from doing my little carpet deep dive into your paper was that really the niacin that's probably showing up in the skin predominantly is being formed or made in the liver. Whereas there's this whole brain pathway, the kynurenine pathway is found in the brain. And unfortunately, like you already shared, a lot of the metabolites, or steps essentially, in that pathway are inflammatory towards the brain. In fact, some of the research that I'm very well versed in, because I literally learned this in grad school, was that one of the steps is quinolinate, that elevated levels of that actually can create a state of neurotoxicity. And there are admittedly a lot of neurologic impacts. And one thing that you had also shared with me is that there's this anti-cholinergic effect going on. So can you talk a little bit about what's going on from the brain perspective?

Ian Myles (23:46.442)

Yeah, so most people probably get fight or flight, and so that's their sympathetic nervous system. So the opposite of that is rest and relax, which is the parasympathetic nervous system, and the parasympathetic nervous system is run effectively through choline and your vagus nerve. And so this comes up a lot in regular eczema. I will say the cholinergic pathway is involved, at least by our studies, in what we would consider to be regular atopic derm, and I've always had, in the back of my head, some questions about the anxiety and the mental stress of atopic derm. Obviously anybody who has a disorder that you're scratching all the time, and you're distracted, and now you can't sleep, and your kid’s awake, and you're not finding good relief from the drugs, that's gonna be mentally taxing. That's gonna be anxiety-provoking.

But some part of me always felt like, well, all of these pathways are in that anxiety marker too. So is there a biochemical reason that their brain is being flushed with the very chemicals you would want if you wanted to generate anxiety in somebody. So I think that cholinergic suppression and all of these intermediaries would very much go into the brain and induce anxiety and some of these other mental stresses.

Jennifer Fugo (25:34.241)

Do you think it could also play a role in causing the elephant skin effect? Do you think that there's anything from your research that could possibly explain that, or we still don't know?

Ian Myles (25:43.593)

I mean, the true answer is I don't know. The only part that I think would make any sense is it upregulated a pathway known as Wnt/Beta-catenin. This is a pathway that you need to make, there's no human that doesn't have this pathway because you won't make it past the two-cell zygote stage if you don't have this. So this is just how your body replenishes new cells and how you really grow. And so, in theory, if you were to kick that pathway into overdrive, now, I'm not making a comparison with cancer on this, because I don't think they have cancer, but that's one outcome, is a neoplasm. The other one would be, you just have a proliferation of cells that is not well-controlled. And so when you hear the stories from TSW skin patients, where they're not just talking about skin sloughing off like you hear from an eczema patient, they're talking about just an absurd, massive amount where, one of the patients said she took a bra off at night and like a cup of cells would fall out at a time, just this overwhelming amount of skin cells.

And so if you did that long enough and you weren't replacing them, there'd be no you, right? You would just, you would erase yourself cellularly. And so the Wnt/Beta-catenin pathway is the only way to replenish all of that. And so what I think is happening is that if that just got ramped up out of control, if it happened to the fibroblasts and the elastic cells, you might see this kind of proliferating skin, like the elephant skin that they're talking about, and you'd also expect this kind of massive sloughing. Why it would only happen on the joints, I don't really have a great answer for you. That's my best interpretation for that. If it ends up being something else, I don't know.

Jennifer Fugo (27:28.638)

Do you think that there could be any involvement, from what you've seen so far, in how it interplays with the adrenals and cortisol at all?

Ian Myles (27:35.881)

We didn't see that. Well, let's take that back, we saw a little hint of it in the blood where there was some steroid metabolism abnormality. They had a lot of lipid abnormalities, the type of lipid abnormalities you would expect in a patient with skin atopic derm, so it was kind of like skin repair lipid abnormalities. But there was one type called C21 steroid, which includes cortisol. It's hard for me to sort that out, only because if you just had anybody who has a chronic disorder who's stressed and is upset all the time, I would anticipate that their cortisol would be slightly elevated. So I don't know how to implicate the adrenals independent of all the stress and pain that these guys are going through. It would be interesting to start collecting samples before somebody stops steroids and follow people through the whole process. That might give you your answer, but I don't know yet.

Jennifer Fugo (28:40.668)

It sounds like, and I think this is an important reminder, is that this is a stepping stone in the right direction. It's not all the answers. I think that's always important to ground people, because sometimes I also find, you know, everybody wants an answer. They want the answer, the solution. And I think, would you say we're still in the process of understanding this?

Ian Myles (29:01.033)

For sure. Even with our treatments that we tried, it was effective in 11 of 14, excuse me, 12 of 14. So that tells you not 100%, even in a small number, it won't be 100% if that got upscaled to hundreds of thousands. And I have, again, I'm not a TSW skin expert, I might end up being one very quickly, I guess, but just seeing the social media posts of people who say, you know, #TSW, you know, the physical appearance of the rashes that people are labeling can be just wildly different. And for all I know, that's all legitimate, right? Maybe all of it is TSW presenting in different ways, maybe they all have the exact same molecular problem. Or they have maybe Topical steroid withdrawal symptoms manifesing in different ways in different people, maybe for some people it's a mitochondrial abnormality, for some it will be something else.

But I think to go from a disorder where the vast majority of the biggest names in the field would either say it's not real at all, or it's just inflammation, they need to take a different drug, to okay, at least you got a hint, you can at least go run your study and see what you can find. I think that would be the next big, definitely a step in the right direction.

Jennifer Fugo (30:28.89)

So you just mentioned the potential treatment suggested in your paper. Can we talk a little bit about that? What did you use, or what did you come up with options-wise, for what may be a helpful solution?

Ian Myles (30:51.817)

Yeah, so in the mitochondria, like I said, it goes wild, it upregulates, starts making this NAD as a side product. The specific part of the mitochondria that does that is called Complex I. There's five of them. There's YouTube videos to educate yourself on the electron transport chain. Again, it's a wild world where it's ripping electricity out of your food and using it to build a hydroelectric dam to eventually make chemical energy for you. But to block Complex I, there are lots of chemicals you could use to do that, but the only drug, the primary drug that we know will block Complex I is metformin. So I thought, alright, we're going to try metformin. Well established, I mean it was created in the 20s, it's been around forever, you kind of have a sense of the complication rate, so remember we've got to keep safety in mind, it's not a cohort of people who are geared up to take additional drugs.

And then the other one we looked into was, there was two papers on Topical steroid withdrawal treatment in the entirety of the literature. Dr. Peter Lio has one on dupilumab, which makes some sense because we did find elevations of IL-4 and IL-13, which is what dupilumab would block. And then this traditional Chinese medicine. And it seemed to work, so looked that one up and said, all right, what's in it? And it looks like the dominant chemical in that traditional Chinese mix is berberine. Turns out berberine is known as herbal metformin. It is also currently being sold as herbal Ozempic, which I'm not buying, I've seen the data, I am not convinced that it is. No, thank you.

Jennifer Fugo (32:11.994)

No, me neither.

Ian Myles (32:33.482)

But in terms of glucose control, there's some data for it. And in terms of blocking Complex I, it was well established that this is a Complex I blocker. And we actually took both metformin and berberine to the lab, and we can show that berberine is much better at shutting off the mitochondrial abnormalities than metformin is. Whether that has any statement on glucose control, I have no idea. But it's good at blocking the mitochondrial abnormalities. So we mention it to patients, and another important thing is that there's a lot of things out there that have the word berberine on the bottle that do not have any berberine in the bottle. And so we leaned on Consumer Labs, which is a subscription service a normal, average person would never buy.

But we could find the exact brands that were vetted, and shown to be contaminant-free, and had the amount that they said that they had.

And the one that we ended up testing in the lab was made by Solaray. This is not a commercial endorsement of them, but it's a statement of fact that this is the one that had the amount they said they had. And so the topical steroid withdrawal patients took that. We suggested that people take maybe one pill a day just to see how their body reacts, because none of them had diabetes. So you don't want to throw any meds at people just to see, and then if they did okay for a week, we say all right, now go to two pills a day. Eventually a few of the patients took three pills a day and didn't notice any additional benefit.  And I do know that we discussed that in the naturopathic world there can be crazy, incredibly high doses of berberine out there, so I don't know, but we had people go up to twice a day. And at the time, at this time of our study, people had been on it for four to six months at this point.

So either metformin, three people with TSW tried it, I gotta say it was a little weak. I mean, one did really well on it. One was kind of like, eh. And one didn't respond well. And the guy who didn't respond well actually switched to berberine and started doing much better, for whatever it’s worth. And then out of the berberine, one person just didn't get any better, so that did not seem to work for that individual. And everybody else was in the 80 to 90% improvement, which is pretty good, but I would caution that people still had flares for the types of things they had flares to before. So if cold weather was bad for them or humidity, they would still notice that. So I wouldn't say anybody with TSW is cured by any means, but everybody, other than those, again, few who didn't respond, were very happy, at least they kind of felt like the edge was taken off and like, all right, now I'm feeling like I'm close back to where they were before TSW. Not symptom-free, if they came into it having symptoms, but they're at least back to where they were, and feeling pretty good.

Jennifer Fugo (35:12.982)

And so when you say that, because I think it's important that we're very clear, that means that they went back to the state of say, eczema that they had. I think that's an important distinction because a lot of times people get so married to the idea that they only have topical steroid withdrawal, that the eczema was still there, yes?

Ian Myles (35:17.354)

Correct. For those who had eczema coming in. So a couple of patients had never had eczema, they got steroids for reasons they probably should not have gotten them for in the first place, and that launched them down this pathway. So for them, they got back to a state of symptom-free because they didn't have, they clearly had some contact derm or something like that before they came in. But for those who had underlying disease beforehand, I don't anticipate this would fix that. And there's been one trial that tried to use metformin for atopic derm and it's pretty weak. And let's be honest, if berberine was the cure for genuine eczema, the eczema community would have figured that out 200 years ago at this point, so I don't think that it's going to make that big of a dent in their underlying disease.

Jennifer Fugo (36:21.012)

I wanted to ask you, I noticed in the paper there was the suggestion of maybe using a diluted berberine in a bath for TSW skin. Can you talk a little bit about that?

Ian Myles (36:42.44)

One patient just had eczema, basically, just on the hand. And so it's kind of like, well, should you be taking a systemic exposure if you only have disease on the back of your hand? But if you take a capsule of it and dump it into water, it is very, very orange-yellow. And so if this individual put her hand in the water, it's too discoloring. And so that doesn't work. But that concentration is far higher than you need in at least a cell culture model to kind of turn off some of the defects.

And this might be a good time to bring up the stem cell angle of it. Because one of the things that I found the most perplexing when TSW was presented to me the first time is, why on earth would it take so long to go away? Because you have, based on some of the surveys that are out there, at minimum you're talking three to six months, and then about 25% of patients have three years or more. And in my head I thought well if it's a contact derm-type situation that's not gonna last for three years. You don't have poison oak that lasts for years on end. Especially if you start avoiding the product that was the problem. And if it were some kind of inducing an autoimmune disorder, which sometimes happens, so rheumatoid heart disease is if you induce a disorder where the body is now attacking the heart valves. If it was anything like that in the skin it should never go away. So that's weird.

So then the thing that clued us in for that was that the TSW skin flushing tends to spare the nose, not always, but mostly spares the nose, the palms of the hands, and the bottom of the feet. And those are the only parts of the body that don't have hair follicles. And so this kind of started to make sense that, well, maybe if you messed up the hair follicle stem cells, the stem cells, the way your body makes new skin is you have stem cells that just hang out at the bottom of every hair follicle, and then they crawl up the hair and then spread out and make new cells. So that's how your body is turning over new cells all the time, the stem cells from the hair follicles go up and then spread out from there. And If you corrupted those, then every cell that came after that would carry the same abnormality.

And so that would explain, at least to me, why it might take years for it to go away, because basically, if you imagine every cell that comes after it is a photocopy of the stem cell, and so if you break the photocopy, every single copy is now abnormal, and it might take time to go back, if at all, I don't know yet. And so again, there's no hair follicles on the places where they're not presenting, we did mouse studies to verify some of that. And so if it's true that the root of the problem is in the skin, on the stem cells and hair follicles, that then I think lends itself to asking the question, should we do it topically?

And that might be a next TSW follow-up study to have people soak in a level of berberine. We put it in the paper how one would calculate that, but it would be one capsule in a liter of water. It'll be super colored, you won't be able to use that. But then if you did a quarter to a half a cup and put it into a full bathtub, that should not generate any discoloration. But as long as you started with a legitimate berberine when you started, it should be that much in the liquid in your bathtub. And if you soak in that, again, we've been very blunt with some of the patients in the group, there's a lot of this that we are making up on the fly. And so, if it was just me, if you're like, what are you gonna tell your mom if she was going through this? I would say, soak in that 10 to 15 minutes at a time, three times a week, and let's just see what happens, right? Because I don't anticipate, that dose of berberine would be so dilute, that I don't think it would have any possibility of creating any problem in the body. And then if you just soak in that, let's see what happens.

Jennifer Fugo (40:31.437)

I do feel like I need to mention, just as a clinical nutritionist, for anybody listening, if you have been diagnosed with blood sugar issues and diabetes and you're on blood sugar medication, you should check with your provider before you ever start supplementing orally with berberine, because you can have major issues as a result. So again, just check with your provider before you start taking supplements because everybody likes to think that, because it's an herb, and because it's natural, it can't cause any harm. And you can absolutely, especially when you have blood sugar issues and you're on blood sugar meds, if you take berberine, it can actually drop your blood sugar too low, which is not safe. So I just wanna make sure to reiterate that. And obviously, if you're pregnant or breastfeeding, you also probably don't wanna take it either.

Again, I know sometimes there's this tendency to want to do something, but you really have to be judicious to decide if this is appropriate for you, especially considering other factors that might make your case different than somebody else's. I just want people to be safe and make smart choices, obviously. So with that being said

Ian Myles (41:37.354)

Don't take it if you're pregnant. Just don't take it if you're pregnant.

Jennifer Fugo (41:57.483)

Yeah, don't take it if you're pregnant. So that being said, we have this study. It was a small group of participants with topical steroid withdrawal symptoms. I think that's important for people to realize this wasn't like a thousand people. It's a small start. What do you think is next?

Ian Myles (42:05.033)

What I'd love to see is an interest percolating out through the community where anybody should be able to do their follow-up study. I still would like to see, just personally, what would topical do, is that a better option? We also mention in there, this is just pure speculation, dry heat, not sunlight necessarily because of the UV aspect of it, but dry heat, actually, is also a Complex I inhibitor. So if you had just a space heater, that might be intriguing to see, you know, just these non-pharmaceutical ones. But I think anybody who has a clinic now who sees patients who say they have topical steroid withdrawal, we have in there proposed criteria, like how you would distinguish this from “severe eczema” and just kind of regular eczema. And what we would like to see is people taking that up.

And I don't think you're going to be able to do the same kind of placebo-controlled trials for berberine, because it is a spice kind of, I guess, but it has a scent to it and it is a very potent color, and so I don't think you'd be able to generate a placebo that would genuinely mask any of that. But I think if you just had patients and say, well let's just see what happens, and start to track people, we're going to put more people on berberine. If a handful of clinics out there did this in a controlled manner, they'd need IRB approval and all that, which has a little bit of a price tag on it, but the drug itself, I mean, the herb is obviously very inexpensive. If you chose metformin, it's very inexpensive, those drugs. I would love to see kind of follow-up studies on this to see how, because like I said, it is not gonna work in 100% of people.

And so then the next step after that would be, okay, well, why didn't it work in, let's just be cautious and say 25%. So let's say it’s 75% of people think wow this is wonderful, the greatest thing ever, and 25% are like, this guy's an idiot who doesn't know what he's talking about, it didn't work. Fine, right? But then what is it, why didn't those 25% get better? Do they have a different version? Do they not have a mitochondrial problem at all? Do they have some accessory pathway that needs to be blocked in addition? Those kinds of things would be the next steps.

Jennifer Fugo (44:22.76)

Yeah, and we also talked before this about generating some diagnostic tools to help identify TSW, so hopefully that could help. Whether it's through some lab, unfortunately, as far as I know, you can't really test for niacin levels in labs. There's organic acid testing.

Ian Myles (44:28.138)

You can, but it's worthless. We did all kinds of stuff in the blood, hoping to find something.

Jennifer Fugo (44:50.312)

Yeah, I think this is an amazing discovery. I'll say too, I think this goes to show you that it's not just time that's going to fix things, or there is something legitimately going on here that is distinctly different from atopic dermatitis. And I hope that, especially for all of the healthcare providers that listen to the show, that you will take a look at this study. We'll make sure to link everything up. I also want to link up your topical steroid withdrawal symptoms explanation and deep dive from YouTube about this, because you really do, I mean I was like, 45 minutes! And I watched the whole thing, I was like, my gosh. Okay. I understand more of it now than I did with my two-hour deep dive. So I think that there's a lot here to unpack. So if you feel like you're overwhelmed and that this is confusing, don't worry, you're probably not alone. But I think there's a lot of wisdom that we can pull out of this.

And Dr. Myles, I'm sure that many of the listeners would love to meet you in person and shake your hand, and just show you gratitude. I know I am extremely grateful for the fact that not only you did this, but also that you came here to talk about it so that we can share this with everyone. Do you have any final thoughts you'd love to share with listeners?

Ian Myles (46:49.223)

I think for the clinician listeners, I would say keep an open mind. If you're gonna take a stand, make sure you have a good amount of evidence to stand on. Because like I said, when I had first heard of Topical steroid withdrawal, my initial reaction was this is not a legitimate issue, not a thing. There wasn't any evidence for which I could have pointed to in the research that would have backed that up. So I think keeping an open mind. Also I hope the grandest take home from this, even if it's a small study, is that we need to have a better system in place for kind of tracking long-term complications for drugs that are safe for most, but clearly not for all. It'd be nice to see that flushed out. No problem, thank you.

Jennifer Fugo (47:55.496)

Well, thank you so much for joining us. I really, really appreciate it.

Ian Myles (47:55.897)

No problem, thank you.

topical steroid withdrawal symptoms