Could Psychiatric Symptoms Be Hiding a Physical Illness? with Dr. Janet Settle

[00:57] Dr. Linda Bluestein: Welcome back, every bendy body, to the Bendy Bodies Podcast. I'm your host, Dr. Linda Bluestein, the Hypermobility MD, a Mayo Clinic-trained expert in Ehlers-Danlos syndromes dedicated to helping you navigate joint hypermobility and live your best life. Today's guest is Dr. Janet Settle, an integrative psychiatrist. I am so excited to have this conversation. I think I've shared before that I have lived with anxiety my whole life and also ADHD, and we are learning so much more about how mast cells can play a role in both of these conditions. This is going to be a great conversation that I think so many people are going to benefit from.
[01:36] Dr. Settle is a board-certified integrative psychiatrist with over 30 years of experience blending conventional and holistic approaches to mental health. Disenchanted with the limitations of traditional psychiatry early in her career, she pursued training in 5-element acupuncture and was among the first physicians board-certified by the American Board of Holistic Medicine in 2000. She later completed a fellowship in anti-aging, regenerative, and functional medicine and was board certified by the American Board of Integrative Medicine in 2016. Her practice focuses on identifying and treating the root causes of chronic medical and psychiatric conditions using functional medicine.
[02:13] Dr. Settle also specializes in trauma treatment, drawing on psychodynamic psychotherapy, EMDR, attachment therapy, and internal family systems, or IFS. She has worked on specialty inpatient trauma units and completed advanced psychotherapy training through the Denver Institute for Psychoanalysis.
[02:32] I am really excited about this conversation. As always, this information is for educational purposes only, and it's not a substitute for personalized medical advice. Stick around until the very end so you don't miss any of our special hypermobility hacks. Here we go.
[02:48] Well, I am super excited to be here with Dr. Janet Settle. It's so great to see you. I feel like it's been such a long time.

[02:55] Dr. Janet Settle: It has been a long time. It's nice to see you too.

[02:59] Dr. Linda Bluestein: I'm really excited to chat about this really important topic. What first drew you to study or treat patients with mast cell activation disorders?

[03:09] Dr. Janet Settle: As you might expect, it was sort of a long journey. I started my psychiatric practice, my private practice, in the early '90s, and pretty quickly got disillusioned with the tools that I was given in my residency training and just started grasping around at this, that, and the other — studied acupuncture for a while and took extra psychotherapy training. And then I got into holistic medicine. I got into treating people with supplements and fish oil and 5-HTP.
[03:36] And still, the more I identified as someone who was interested in holistic and integrative methods, the more and more people started coming to me with complex medical problems, sometimes not even psychiatric problems, but most often a combination of medical and psychiatric problems that were not being well addressed by conventional medicine. So it's like the drumbeat got louder and I kept searching — learned about doing hormone replacement, got fellowship trained in functional medicine, and then finally started hearing from some of my colleagues about mast cell activation.
[04:26] The first mast cell activation meeting I went to was the one held here outside of Denver in Broomfield in 2019. That's when I sort of thought, okay, now finally — it's 2019 — I finally have a finger on the pulse of what's maybe really going on. So it took me a long time, but I was motivated even before I was interested in holistic medicine, you know, just by the number of people who had intractable fatigue. In psychiatry, traditionally, we lump fatigue into depression. So everyone who has depression and low mood — which all people with chronic illness have — would all get assigned a diagnosis of major depressive disorder. Which may or may not be true, but it certainly is not what addresses the fatigue. And of course the low mood is oftentimes because of the daunting task of managing a chronic illness, oftentimes without enough help from the conventional medical establishment. So that's a long answer, but it's been a real journey.

[05:43] Dr. Linda Bluestein: And that's where we first met was in Broomfield. At that time, I didn't live in Colorado yet. In fact, my husband had wanted to move to Colorado, but I was not so sure. And then I came out for that meeting and I was like, oh wow, this is a beautiful place. I'd been here to ski a couple times, but I remember meeting you there. And then of course I met you in New York as well a few years later, which was great. We had lots of fun conversations there. How has your understanding of mast cell-related psychiatric issues evolved over time?

[06:15] Dr. Janet Settle: Really from zero to 60. When I first started learning about mast cell activation, I thought, oh, this is going to give me some tools to help these people with chronic illness and fatigue with their other symptoms. But I really didn't realize how much it was going to help their mental health symptoms. I was thinking of it like, oh well, I can still do my integrative psychiatry thing, but then I can add on these mast cell strategies. But then it turned out that the mast cell strategies treat a lot of the mental health symptoms. I wasn't expecting that.
[06:58] Beyond that, my conceptualization of what these mental health conditions are — what is major depression, what is bipolar disorder, what is panic disorder — has fundamentally shifted to the point that I now think some of what we call psychiatric illness is really mast cell activation that hasn't yet been acknowledged or put on the map. So it's been a pretty drastic change in my conceptualization.

[07:31] Dr. Linda Bluestein: I remember at that meeting, they had a microphone and we could go up and ask questions, and you went up and said you were a psychiatrist, and some of the things you said — I was like, wow, I hadn't thought about it that way. And I know there are now some papers that have come out talking about the role of mast cells in psychiatric conditions. So it's super fascinating. Maybe we can just back up a little bit and explain what mast cells are and what happens when they become overactive or dysregulated.

[07:56] Dr. Janet Settle: Mast cells — I describe them as sentry cells. They're in everybody. They're at the interfaces between the inside world and the outside world: the lining of the gut, the lining of the bladder, the lining of the lungs, the blood-brain barrier, the skin. They're sentry cells. They're kind of primitive in a way because they're kind of binary — they're either calm, or they're dumping all their alarm signals. They're full of hundreds of different inflammatory chemicals and other kinds of alarm signals. Histamine is the one that's sort of a household word, but there are literally hundreds of others that aren't household names and weren't even in med school curricula.
[08:51] When these mast cells get triggered, they dump their signal load. Those signals travel around locally to the area where the cells are living, but they can also get into the bloodstream and travel through the rest of the body. They're alarm and alert signals. What happens in mast cell activation syndrome is that the mast cells become more sensitive, more easily activated, and harder to calm down.
[09:13] Mast cells are born in the bone marrow and have a lifespan of months to years. The reason that's important is because sometimes it can take some time — it's a project to try to get a person's mast cells calmed back down again, because once they've gotten overactivated, it's hard to get the genie back in the bottle.

[09:44] Dr. Linda Bluestein: Definitely. And we know that so many people go for so many years without being properly evaluated or diagnosed. How do you normally describe the link between mast cell disorders and psychiatric or neuropsychiatric symptoms?

[10:00] Dr. Janet Settle: I think one of the reasons this really isn't on the map yet for conventional medicine — or only in a very limited way — is because we sort of thought histamine is only about allergies, that it should only be about allergens. But one of the things that happens because these mast cells are located in so many different parts of the body is that if you line up 10 people with mast cell activation syndrome, they might have 10 different clinical pictures. Some people have the gut issue, like an IBS picture. Some people have chronic pain, joint pain. Some people have migraines, or asthma, or bladder symptoms like interstitial cystitis. Some people have hives and anaphylaxis. Or some people have a couple of those, but not the rest. So if somebody looks at a laundry list of symptoms, they might think, oh, I don't have all of that.
But often missing from those comprehensive symptom lists are the mental health symptoms and psychiatric symptoms that, in my experience, definitely go right along with this. Most often, the histamine and other mast cell mediator types of mental health symptoms are any kind of activation — panic, anxiety, hypomania, people feeling revved up, racing thoughts, irritability, insomnia, and brain fog. Maybe some kinds of things that people think of as being more like ADHD, I think, can be related to histamine and mast cell mediators. That's a whole bunch of symptoms that are bread and butter for most psychiatrists, conditions we treat all the time.
[11:58] One interesting thing I was always wondering: why did we all get, nationally and globally, fixated on serotonin and never on histamine? Well, it turns out that the stains that allowed scientists to study the tracks and projections in brain samples — if you take a postmortem brain and you're studying neurotransmitters — the stains they had for norepinephrine, dopamine, and serotonin came around about 20 years earlier than the stains for histamine. Histamine is such a small molecule, it didn't stain well. They couldn't track it down. So really all these other neurotransmitters were stained in brains and studied starting in the '50s and '60s, whereas it really wasn't until the late '70s and early '80s that they could study what was going on with histamine in the brain. And by then, of course, the '80s is when Prozac came out. The world was already on a gigantic love affair with SSRIs. Nobody was thinking about histamine except in the context of allergies. So I think that was a converging circumstance that slowed us down in terms of understanding histamine and its effect on the brain.

[13:14] Dr. Linda Bluestein: That's super interesting — you don't normally think of things like that. I've never heard that before, but it makes a lot of sense. So that's really fascinating. I know that mast cell mediators like histamine, tryptase, and cytokines can affect the brain and mood, but we don't normally think of that — like you said, we normally think of serotonin and dopamine. How do those mast cell mediators affect the brain and mood?

[13:38] Dr. Janet Settle: There are a couple of ways. The mast cell mediators live right on the surfaces of the brain and the blood-brain barrier. There's some controversy about to what extent they live completely inside the brain, but they definitely communicate back and forth — these chemical mediators, these cytokines and histamine and other activation chemicals — with the immune cells of the brain. The macrophages inside the brain are called microglia, and there's crosstalk back and forth between the mast cells and the microglia. It also looks like mast cells can sometimes cross the blood-brain barrier and get into the brain, although that's more cutting-edge research.
[14:24] So those chemicals go in like any other neurotransmitter and activate parts of the brain. Histamine is a neurotransmitter, but people don't think of it as one. There are histamine-producing neurons in the brain — they live in the limbic system. There aren't that many of them compared to other neurotransmitters, which may be another reason they were discovered later. But there's a group of histamine-secreting neurons in the limbic system, and they spray their projections all over the entire brain.
[15:07] Histamine itself can act in a typical synaptic way, sending a message across the synapse from one neuron to the next, but it also can diffuse through the brain tissue to have a more localized message — which I suspect is part of what's going on in a panic attack, although I can't prove it.

[15:28] Dr. Linda Bluestein: Interesting. So if someone — given how safe antihistamines are — would it be a reasonable thing to try for a panic attack, knowing that it's not going to take effect within seconds or a few minutes, but you might see some benefit in 15 to 30 minutes depending on the medication?

[15:53] Dr. Janet Settle: Absolutely. I've heard lots of people — a couple people this week, in fact — say, well, this or that medication for anxiety never did anything for me, until I tried Benadryl. And Benadryl can be a perfectly good anti-anxiety medication. Ketotifen, which I'm sure we both prescribe regularly — compounded as a mast cell stabilizer — is great used as needed for anxiety and panic or other kinds of anxiety. Especially people like the sublingual form when it's compounded into a dissolving tab, or something you stick on your tongue or inner cheek. That's very popular among my patients as a PRN for anxiety.

[16:53] Dr. Linda Bluestein: I usually start people at half a milligram or 1 milligram. Is that the kind of dose you would use?

[17:00] Dr. Janet Settle: Yeah, the same kind of dose. Usually I start with half a milligram in case it's sedating, but if people are anxious, they're usually not very easily sedated.

[17:12] Dr. Linda Bluestein: And I know hydroxyzine can also be used for a similar purpose, right?

[17:17] Dr. Janet Settle: Yes, hydroxyzine is super convenient because it comes in the 10 milligram commercial size in addition to the 25. Sometimes if 25 milligrams is too sedating, I'll have people take 10 milligrams as needed for daytime anxiety, and that works pretty well. I think ketotifen probably works better, but hydroxyzine is definitely good.

[17:40] Dr. Linda Bluestein: And if cost is a factor, you can often get that covered by insurance. And with Benadryl, of course, you can get children's Benadryl in the liquid drops and titrate a smaller dose if 25 milligrams is too much.

[17:48] Dr. Janet Settle: Exactly. And doxepin is available as a liquid — I know you've used that before in low doses.

[18:01] Dr. Linda Bluestein: Is hydroxyzine available as a liquid also? I feel like maybe it is.

[18:09] Dr. Janet Settle: I haven't used it that way.

[18:11] Dr. Linda Bluestein: I'll look into that. Okay, great. What about neuroinflammation, the gut-brain axis, and the vagus nerve? What kind of role do they play?

[18:29] Dr. Janet Settle: Neuroinflammation is very influential in all of these conditions, and mast cells are driving neuroinflammation again through that crosstalk with the macrophages. It's sort of a two-way street. If you have inflammation for some other reason — because you've had an infection, an accident, an injury, a stressor, even any kind of emotional stress, or dental work — I can't tell you how many people come to me and say, I was fine, I was cruising along stable on my meds, and all of a sudden the last week or two I'm just anxious, I can't sleep, I can't function. We go through the list: did this happen, did that happen? And they've had dental work or dental surgery, and it really kicks that up. That's an inflammatory signal that activates the mast cells, then the mast cells go back and activate more inflammation, and it turns into a kind of spiral.
[19:33] I'm very interested in the new information coming out about neuroinflammation. The vagus nerve is a superhighway of information going in both directions between the brain and all the organs in the body, but I think 70 or 80% of the information is going from the body to the brain. So anything that happens in your body — whether it's stress, injury, accident, illness — is sending those signals up the vagus nerve: signals of injury, illness, trauma, up to the brain, activating the brain and contributing, I think, to that inflammatory state.
[20:15] Of course, an inflammatory state is a good thing if you have to heal an injury. If you break your arm, you need inflammation; you need your body and your brain working together to set up all the conditions for that to heal. But in some people, it seems to turn into a vicious cycle where it's hard to turn that inflammation off. I think that's one of the factors that drives fatigue — I think of fatigue as a symptom of inflammation, whether it's in the brain or the body.
The gut-brain axis is also really important. We have as many neurons in the gut as we do in the brain, so they call the gut the second brain. We have all kinds of expressions in our language that acknowledge this — you get a gut feeling, or I knew it in my gut. All the neurotransmitters working in your brain are also working in your gut, so they really mirror each other. Taking care of imbalances and root cause conditions in the gut is equally important to treating mental health.
[21:40] And part of what I do in the functional medicine part of my practice involves that pentad of conditions we talk about: mast cell activation, Ehlers-Danlos, POTS and dysautonomia, autoimmunity, and the GI piece — SIBO, dysmotility-type conditions in the gut. All of these things run in a pack together. They're probably not 5 distinct things; they're probably offshoots of one or a couple of things.

[22:23] Dr. Linda Bluestein: That makes sense. I was curious — we don't want people to not go to the dentist, of course, which I know you're not advocating. What do you think about pre-treating before going to the dentist — taking some extra antihistamines or mast cell stabilizers? Is that something you ever advise?

[22:42] Dr. Janet Settle: Absolutely. I do recommend that people who know they have some mast cell activation or even sensitivity pre-treat for any known stressor — pre-treat for travel if they're going to have a rigorous travel schedule, for stressful exams, dental work, or if someone in their household has a cough and their body's going to be fighting that off. I tell people to have a very low threshold for adding on items from their rescue kit.
[23:22] In my thinking, people have a maintenance plan with things they take regularly, and then they have a rescue kit, which might mean doubling up on or adding higher doses of things from the maintenance plan. I tell people to have a low threshold for jumping on the rescue remedies at the first sign of trouble — or if you know about the trouble in advance, that's even better.
[23:58] And I definitely want people to go to the dentist, because untreated dental issues are another source of mast cell activation.

[24:01] Dr. Linda Bluestein: Yeah, having untreated gum disease or whatever can contribute to inflammation in the body. I really like the maintenance plan and rescue kit framing — I think those terms are very clear. A lot of people talk about flares versus dips. I kind of like the term dips because I feel like flares — I don't know. Whatever works for people, of course. But I think the words we use matter a lot.

[24:39] Dr. Janet Settle: I like that word dip. I haven't heard that. That's good.

[24:45] Dr. Linda Bluestein: In terms of psychiatric symptoms or diagnoses that might be mast cell related — you've talked about depression, panic, anxiety, ADHD. What about things like PTSD, mood instability, personality disorders? Can those things be mast cell related?

[25:05] Dr. Janet Settle: Super interesting questions. With mast cells, I'm looking at anything that's intermittent and episodic. Whether it's hives or an attack of IBS or an attack of migraines or a panic attack or a mood swing in one direction or another — anything that's recurrent but intermittent, I think of as a potential mast cell symptom. I do see a lot of mood swings that I find are responsive to mast cell stabilizing strategies and also strategies for reducing neuroinflammation.
[25:44] I haven't thought as clearly about PTSD, but of course stress is such a clear and tangible trigger for mast cells that it would make sense that it plays a role in PTSD. I haven't done a systematic analysis of how many of my patients with PTSD also have mast cell activation. I'll have to think about that.
[26:25] I have thought quite a bit about personality disorders, and I do have a pet theory — without too much evidence behind it yet — that the state of systemic and neuroinflammation that people get into and sometimes have to live in really does change a person's coping strategies, styles for living, styles for coping with life. When you're sick, it's a regressive experience. It doesn't pull on the most mature coping mechanisms or the most advanced level of functioning we've ever reached in our lives. So you could make an argument: is the way someone's functioning personality-wise with a chronic illness really their personality, or is it a side effect of their inflammation or the level of pain they have to live with? I think that's going to be a super interesting question for the future.

[27:43] Dr. Linda Bluestein: Definitely. And I have one more question before we take a quick break, and it's kind of a big question. How can clinicians distinguish between primary psychiatric disorders and psychiatric symptoms driven by physiologic inflammation or mast cell activation?

[28:03] Dr. Janet Settle: That is the million-dollar question — the zillion-dollar question. You can't. They look the same. And that's the trick. The trick is to look for it. The trick is to test for it. The trick is to have mast cell mediators and histamine on your internal differential when you see someone with almost any psychiatric symptoms, and then go ahead and do the investigation.
[28:46] Sometimes it's easier because someone will give me the history and say, oh yeah, I have interstitial cystitis and I have hives and I've had anaphylaxis. Then it's like, okay, this is starting to come together — these may well be psychiatric symptoms of mast cell activation. But the strange thing is sometimes there's none of that and it's just purely psychiatric symptoms, but it's still mast cell driven. And so then you just have to try. You say, well, why don't you try the usual things? Why don't you try a little Benadryl? Why don't you try ketotifen? Under supervision, of course.
[29:32] So sometimes it's more obvious. It would be great — when mental health providers and psychiatrists start asking more of those questions about the comorbidities, they can put that picture together. Just like you might see a patient and think, I'm not sure if that's more of a dopamine issue or a serotonin issue — people don't yet think, I wonder if that's a histamine issue. But I think they will.

[30:11] Dr. Linda Bluestein: Okay, great. We're going to take a quick break, and when we come back we're going to talk about treatments for mast cell-related psychiatric symptoms. We'll be right back.

[31:44] Dr. Linda Bluestein: We are going to jump into treatment in just a minute, but I have a couple of questions first. I wanted to ask — are there other medical causes that can be missed as causes of psychiatric symptoms? Metal toxicity, for example. Is there something we should be aware of that's rarely discussed?

[32:06] Dr. Janet Settle: I'm so glad you asked. There is a long list of things I hope people will look for. Everyone knows, I think, that we should check thyroid for any kind of psychiatric conditions. And interestingly, I've found quite a small number of people where the parathyroid hormone was elevated, and identifying that and then having surgery allowed people to get off antidepressants entirely — which I didn't learn well enough in residency. So I'm a stickler for checking both thyroid and parathyroid. And of course with anxiety, you want to check for an adrenal tumor, pheochromocytoma — though in 30-plus years I've never identified one of those myself.
[33:10] I think yeast overgrowth is under-recognized and undertreated. With people taking antibiotics and steroids for this and that, yeast and fungus can really get going. I get some good traction for more nonspecific physical and psychiatric symptoms — fatigue, brain fog especially, itching, GI symptoms, bladder symptoms, acne — with that kind of picture, sometimes testing for fungal overgrowth. It's hard to test for, but there are various ways to try. Sometimes just treating presumptively, if the clinical picture looks convincing enough, I may give someone a course of an antifungal.
[34:24] In terms of metal toxicity — mercury and Candida help each other. They're like little partners in crime. When you find one, you oftentimes find the other. I do some metal testing and sometimes prescribe some detox strategies that may help with heavy metals, though I don't do IV chelation. Usually I'm working on other things first; heavy metal toxicity isn't at the top of my list to address.
[35:00] I think parasites are underrecognized and undertreated, just because we can't find them very well. They're so smart about staying hidden, and everything you try to do to test for them comes back negative. There's also this presumption that, oh, we're living in a developed country, we don't have parasites — but that's just not true. My thinking is still evolving there. I've been reading some of the work of Dr. Simon Yu, and that's been informative.
[35:53] And of course we were talking about dental — did you have a conversation about cavitations on your podcast?

[36:09] Dr. Linda Bluestein: I don't think we really went into cavitations significantly. No.

[36:15] Dr. Janet Settle: Cavities are infections in teeth, and cavitations are infections in the bone underneath the tooth. People can have a cavitation — a silent, hidden infection underneath a tooth. Most often it's underneath a root canal tooth or a wisdom tooth extraction site where the tooth was removed but maybe not completely. With a root canal, they kill the nerve so it's painless, but you have this hidden infection.
[36:52] So when people have chronic mysterious symptoms, I will refer them to get what's called a cone beam CT — a special CT scan of the roots of the teeth where you can see the cavitations. Sometimes people have very dramatic results getting those things cleaned out, including improvement in depression. I've seen that. I've seen depression really respond to getting cavitations treated.

[37:33] Dr. Linda Bluestein: That's fascinating. Are there certain things, specifically with cavitations, that would make you more suspicious?

[37:44] Dr. Janet Settle: Certainly someone who has chronic facial pain — something that looks like trigeminal neuralgia, or a chronic facial pain, or migraines — would make me suspicious. But in the case I was thinking about where the depression clearly responded, there was none of that as a tip-off. So mostly I'm just asking people how many root canals they have. Another tip-off would be something like, I had this crown replaced and it's still achy and hurts 8 years later, or a root canal they've gone in a couple of times to redo, and the person still has pain. That would be a tip-off.

[38:36] Dr. Linda Bluestein: Okay. And what other treatments have you found most effective for psychiatric symptoms in patients with MCAS or related conditions like EDS or dysautonomia?

[38:51] Dr. Janet Settle: All of the usual mast cell treatments apply and do help with psychiatric symptoms, just like they help with non-psychiatric symptoms of mast cell activation. So the usual antihistamines — the H1 blockers we talked about, the H2 blockers like Pepcid and Tagamet — ketotifen, low-dose naltrexone. Supplements like luteolin, quercetin, nettles, PEA — all those things apply, but they aren't specifically psychiatric treatments.
[39:27] In terms of psychiatric treatments I use in this setting, they probably fall into two different categories. One category would be psychiatric medications that also have some antihistamine activity. Things like Seroquel or Remeron come to mind, and of course Benadryl, hydroxyzine, and doxepin.
[40:01] The other group would be things that reduce neuroinflammation but aren't essentially antihistamine in nature. That would be things like lamotrigine — Lamictal — or lithium, which is very anti-neuroinflammatory. And one of my favorites is an SSRI that nobody's heard of called fluvoxamine. It once had the brand name Luvox, but it's only generic now. It was the last of the whole line of SSRIs, so everyone said, oh, another SSRI. But it turned out to be a special one. The last one was maybe one of the most special ones, but it never got any attention.
[40:55] Fluvoxamine works as an SSRI, but it's also anti-inflammatory at something called the sigma-1 receptor — and that effect is throughout the body, not just the brain. For example, during COVID, when people were hospitalized, fluvoxamine was used as an anti-inflammatory for people who had no psychiatric symptoms whatsoever, and there was at least one study showing improved outcomes at discharge. So it's very anti-inflammatory. I really like fluvoxamine as an antidepressant — it's also pretty good for sleep, since it's sedating in low doses. The low dose would be like 25 or 50 milligrams, maybe up to 100. The label says the full dose is 300 milligrams; I have some people on 300, but the typical dose range is something like 100 to 300 milligrams at bedtime because of the sedation.
[42:12] I want to back up, though, because one of the categories of symptoms that is really related to neuroinflammation is obsessive anxiety — the looping thoughts, the rumination, the intrusive thoughts where you can't get something out of your mind and you're going over and over it again. Some people have obsessive anxiety and also have compulsive behaviors. An obsession is an unwanted intrusive thought, and a compulsion is an unwanted intrusive behavior designed to neutralize the thought — so someone has obsessions about cleanliness and the compulsion is hand washing, or someone has obsessions about safety and the compulsion is not leaving the house or not driving on the highway.
[43:12] Some people have that full-blown picture with both obsessions and compulsions. Some people just have the obsessive anxiety as part of their depression or even their bipolar picture. And fluvoxamine is really effective for this — it's FDA approved for OCD, but it also works for regular depression and obsessive anxiety. I really believe that obsessive anxiety is biochemically different from garden-variety anxiety and that it responds to anti-inflammatory strategies like low-dose naltrexone.

[44:04] Dr. Linda Bluestein: That's so interesting. And I did prescribe fluvoxamine for a while during COVID — was there someone at WashU in St. Louis doing a lot of research around that? I feel like I was reading about it in a lot of different places. Is it hard to come off of, like a lot of other SSRIs?

[44:27] Dr. Janet Settle: I haven't thought of it as being particularly difficult to stop. It's not in my mind as a front runner of trouble with withdrawal the way Paxil is, for example. And of course Effexor is the worst, but it's not an SSRI.

[44:51] Dr. Linda Bluestein: I've heard terrible things about trying to come off of that.

[44:53] Dr. Janet Settle: Yeah. Usually my strategy works pretty well. If somebody wants to taper off whatever they're taking — whether it's an SSRI or an SNRI — I switch them over to Prozac, fluoxetine, because it has a long half-life and it kind of self-tapers. We write a 6-month taper, which is pretty simple and straightforward, and it usually works great.
Because Prozac lasts so long, you don't have to take it every day. You can take it 7 days a week for a month, then 6 days a week for a month, then 5 days a week for a month, then 4 days a week for a month, and on and on down you go. It usually is kind of a non-event. So that's my secret tip about SSRI withdrawal.

[44:55] Dr. Linda Bluestein: I love that, because I've had a couple of patients — I'm not a psychiatrist, obviously, but a lot of my patients are on psychiatric medications — and they'll share that they tried to wean off of whatever the medication was, and it was really difficult. So that's a great tip. When you do that crossover, how long do you have to wait after starting the Prozac before you start weaning the other one? Or can you stop it right away? I'm sure it depends on the medication and a variety of other factors.

[46:20] Dr. Janet Settle: Usually you can cross over pretty simply. You need someone who can help you find the equivalent dose, and then you make sure you've gotten close to that equivalent dose by looking for symptoms — either side effects of too much or withdrawal symptoms of too little — to dial it in. Then you can go ahead and start the taper.
Sometimes people are more robust and they just roll with anything, and you can change them over directly. But some people are more sensitive, and maybe I do a cross-taper for 2 or 3 weeks to get them from one to the other.

[47:08] Dr. Linda Bluestein: And you and I have talked about ketamine on a number of occasions. I prescribe ketamine sublingually. I don't normally prescribe it nasally, although I have done that before. What are your thoughts about ketamine?

[47:24] Dr. Janet Settle: I most often send people for IV ketamine — the 6 IV treatments for depression, which has been shown in the literature to really help pull people out of the ditch from a major depressive episode. That's been the most common thing I've done with ketamine. I've also referred people for ketamine-assisted psychotherapy. I sometimes prescribe the sublingual tabs for use with a trained therapist in a 90-minute psychotherapy session. I think it turns off the left brain so that the right brain can tell you important things and make connections.
[48:19] Are you talking about prescribing it for daily home use?

[48:22] Dr. Linda Bluestein: Yes — when I prescribe it, I'm prescribing it for persistent pain, and I'm aiming for taking the edge off the pain without the psychoactive effects, or with minimal psychoactive effects. Especially for people with a lot of central sensitization, or maybe they're coming off opioids. I was just curious what your thoughts were about the different ways to use it.

[48:53] Dr. Janet Settle: I'm usually prescribing it in larger doses for depression and referring people who use it daily for certain conditions — I don't usually prescribe it for pain. But that's interesting. What dose do you usually find takes the edge off the pain without being psychoactive?

[49:17] Dr. Linda Bluestein: So I write for 25 milligrams for their first script, and I say take a half to a whole. I tell them we're looking for just another tool to have in the toolbox — some reassurance that if things are bad, you have something you can do. Some people say, well, 25 milligrams really seems to help. Then usually I'll write the next script for 50 milligrams so they can take a half, which is less expensive since it has to be compounded. We're looking for the lowest effective dose.
[49:52] I did have a patient once — a tall, really big guy — who did not take it as prescribed. He took one, and then a few minutes later took another one, and ended up taking 6 total — 150 milligrams — and said he had psychoactive effects but didn't find the sweet spot he was looking for. Then I have other people who say, I take my 25 milligrams at night and it just helps me relax, and I don't escalate the dose. I know it's a really low dose, but I'm usually hoping to keep them way, way below the dose associated with ketamine cystitis — though nobody really knows what the magic threshold dose is for that.

[50:50] Dr. Janet Settle: Right. I've heard of a compounding pharmacist who really believes in using low-dose ketamine for depression. Have you seen antidepressant effects at that dosing?

[51:02] Dr. Linda Bluestein: That's a great question, because if you're making the pain better, oftentimes they're sleeping better and the depression is better too.

[51:09] Dr. Janet Settle: Sure.

[51:10] Dr. Linda Bluestein: I should start asking that more specifically. When you're doing the sublingual ketamine for psychotherapy, what kind of dose would you be looking at for the average adult?

[51:26] Dr. Janet Settle: I prescribe the 100 milligram dissolving tabs and have them work together with the therapist to find the right dose. It's usually around 250 milligrams — I would say 250 is the average for that. We're looking for a dose where there's some sedating, dissociative effect, because that's what unplugs the left brain so the right brain can talk. It's usually between 200 and 300, something like that. I have occasionally had people say it takes 400 or 450, but that's the outlier.

[52:12] Dr. Linda Bluestein: I have a patient who's young and takes 175 milligrams every night — that's her dose from a psychiatrist. And then I have other patients where a psychiatrist has prescribed 500 milligrams and they're taking it at home. Very interesting how that medication is used in so many different ways. Okay, are there certain psychiatric medications or treatment strategies that you find to be most problematic or potentially harmful for people with mast cell activation?

[52:48] Dr. Janet Settle: I don't think so. The thing that comes to mind is the issue of excipients — people having their mast cells flared by excipients in medications. But I don't have a sense of certain psychiatric treatments or medications that need to be specifically avoided in people with mast cell activation. It's more about paying attention to individual sensitivity.
[53:21] And especially if somebody comes in and doesn't know anything yet about mast cell activation, that can be a very confusing time. It seems like everything is making them worse. You're like, I don't tolerate this, I don't tolerate that, nothing is helping. Before I knew as much about mast cell activation, you could run someone through 12 different meds and nothing helped, and you feel terrible because you haven't helped the person.
[53:49] Now I know to slow it down and really lean into the cromolyn — and the H1 blockers and H2 blockers — because if somebody has mast cell activation, the thing that really helps is to turn the baseline down so that people can see their dips or their flares. Once that baseline is turned down, we can reassess the psychiatric symptoms and see: is there anything left to treat? Sometimes there's not. Sometimes with cromolyn and Benadryl, people say, oh thank you, I'm done.

[54:33] Dr. Linda Bluestein: Wow.

[54:33] Dr. Janet Settle: It's amazing. But other times, with less noise, there's more room to then use whatever else might be needed. I was going to say I lean more toward lamotrigine and lithium in this group. The mood symptoms people tend to present with look bipolar-ish. I hope they change the DSM in my lifetime so we have better labels. I say bipolar-ish because it looks like bipolar, probably responds to meds for bipolar — but do I really think it's bipolar? No, I really think it's mast cell activation. Anyway, it's not uncommon for people with mast cell activation in my practice to not respond as well to SSRIs, and to respond better to lamotrigine and lithium, which are antidepressants, mood stabilizers, and anti-anxiety agents. I say, well, we're just using this non-specifically, we don't need to put a label on this. But it can make people uncomfortable — why are you recommending bipolar meds for me? And I say, don't think about that; let's just think about what helps.

[56:19] Dr. Linda Bluestein: Yeah, that's an interesting point about the potential stigma — having lithium, for example, in your records. I even thought about that before I started low-dose naltrexone. Are people going to look at that? I've had patients ask me that when I suggest it, and I of course talk to them about the off-label uses for chronic pain and things like that. It's tricky. What about low-dose lithium for cognitive function? Do you ever recommend that?

[57:00] Dr. Janet Settle: All the time. I love lithium orotate in doses between 5 milligrams and 20 milligrams. I use it in a couple of different scenarios. I might even use it for insomnia, irritability, or mood swings if someone has a subtle kind of mood swings or low mood. I'll have them try a week each of 5, 10, 15, and 20 milligrams of lithium orotate at bedtime and then compare and contrast — see which week feels best and stay on that dose.
[57:45] If somebody has a more robust bipolar picture and would like to replace prescription lithium with lithium orotate, I might have them use 30 or 60 milligrams. But you're asking about cognitive function — I think the data is pretty good. And the new stuff that's just come out about lithium and the possibility of dementia prevention is exciting. So when someone comes in and says, I'm worried about dementia, I'm worried about my cognition, I say, well, this is safe and easy — just take 5 milligrams of lithium orotate. You don't have to follow levels. If you tried to check a blood level, it would be undetectable. It doesn't carry the same risks as prescription lithium for the kidneys and the thyroid. I don't want to call it a no-brainer, because what we want here is a full-brainer.

[58:48] Dr. Linda Bluestein: Right, right, right. Absolutely. This has been such a great conversation. I have so many other questions I want to ask you, but I'm going to try to wrap up and fit a couple more things in. What are the non-pharmacologic things that you find most helpful in this population?

[59:19] Dr. Janet Settle: Some people respond to the low-histamine diet, so I usually have people try that. Some people — it makes no difference, and I think, well, they must have a different population of mast cells in a different part of their body. They're not the people who get flushing or tachycardia after meals. So I have people try the low-histamine diet and then decide if it helps them.
[59:45] I think stress management, sleep hygiene, and awareness about triggers are important — so that you can be proactive, be prepared, have your kit with you. As people mature further into their course of mast cell activation, they get better at that and it can really improve their quality of life.
[1:00:13] I think psychotherapy to help address the stubborn emotional buttons that can get people riled up is important — because if your buttons get pushed, your mast cells are getting pushed. Understanding your buttons and finding compassion and healing for your inner buttons is an important step.
[1:00:47] I'm a huge fan of Internal Family Systems therapy. I don't offer it myself, but I'll give a shout out to IFS because it's one of the fastest psychotherapy techniques I've come across in 30 years. The people who do somatic IFS are listed on Susan McConnell's website, which I think is embodiedself.net, but I might be wrong. She treats different parts of the body as different parts of the self, so you can actually have a dialogue between your own higher self and, say, your mast cells, and ask: what do you want me to know? What are you doing for me? How are you protecting me? The idea is that every part of your body is doing something it has learned to do, thinking it's helping you or responding to something. I think that can be really powerful.

[1:01:52] Dr. Linda Bluestein: That's really cool. And I know you have a new business offering. If you could tell us about that and where people can learn more about you.

[1:02:07] Dr. Janet Settle: Yes, the new thing I'm launching is a medical intuitive reading practice. I got certified through a certification group led by Wendy Coulter called The Practical Path as a certified medical intuitive. What I do in those readings is connect with the person's higher self in order to read an energetic representation of the physical body.
[1:02:37] I believe that we all have traumas — they might be individual traumas or even collective traumas or lineage, ancestral traumas, beliefs, emotions, things that are stuck in the energy body. We're all made up of an energy body and a physical body, which is organized around that energetic scaffolding. You can look into the kidney or the mast cells or the brain and see what's going on on an energetic level — is there some stuck hidden trauma that came down the family line or from earlier in life? It can give people a wonderful sense of either validation — oh yes, I knew that was it — or direction: oh, I didn't realize that was it, let me go after that.
[1:03:44] The reading includes recommendations for things to do on the physical level and maybe also on the energetic or emotional level to address issues that might be underlying physical conditions. I'm launching a new website — the business is called Gateway 2 Healing, with the number 2 — and it's gateway2healing.com. It should be up in about the next month.
I'm excited to add that to what I'm doing. Everybody has their own comfort level with this, but I believe that spiritual healing — finding a connection with one's own higher self, or whatever connection a person feels comfortable with, whether it's the universe, the divine, Mother Earth, whatever you want to call it — is really healing. It can be healing literally in terms of the body, but also in terms of hope, context, resilience, and not feeling alone.
[1:04:57] One of the things that's been a real motivation for me on this long journey is gradually seeing more and more how people appear to have been fairly betrayed by the medical system. The feeling of loneliness and medical trauma that comes from being dismissed, devalued, kicked out of ERs, eye-rolling — all of that can come from the stigma of having psychiatric meds and psychiatric diagnoses on your chart. But I think it's almost even worse for people who have chronic fatiguing illnesses in this cluster that includes mast cell activation, EDS, and POTS. That's tragic. And I think there's real healing to be found in finding a connection not only with peers and other people around you, but with whatever spiritual resources you feel comfortable accessing.

[1:06:17] Dr. Linda Bluestein: That's really cool. And you may know that we always finish every episode with a hypermobility hack. Do you have a hack to share with us?

[1:06:25] Dr. Janet Settle: Yes. The hack is: don't stop looking for the deeper root causes, because there's so much research going on right now into new things. Don't let people tell you, oh, you just have this and done, case closed, you just have to live with it. I disagree 100%. Keep learning and keep looking, because there's new stuff coming out every day — like about dental cavitations, like about parasites, about heavy metals. There's so much on the horizon that I think will go beyond even calming the mast cells and address a deeper level. Don't forget that there's a lot more coming down the pipeline. And I think there's more openness — I hope there's more openness, or else I'm living in my own bubble.

[1:07:30] Dr. Linda Bluestein: No, I definitely think there is. And that's why I really started getting more into educating people about pain long before I had the podcast, because I would go to anesthesia conferences, go to lectures about pain, and it felt like there was such a disconnect between researchers sharing what they're doing and people thinking, well, there is nothing. Part of the problem, of course, is the amount of time it takes for information to go from the bench to the bedside, which is a huge issue and something we need to work on. But I think it's really important for people to be aware that there are people working on these kinds of things. This conversation has made me feel really hopeful, because psychiatric problems are really pervasive and so many people are suffering and struggling. This has been really, really helpful, and I'm so grateful to you for taking the time to chat with me today.

[1:08:35] Dr. Janet Settle: Thank you so much for having me. It's been really fun to connect about this and to share information that I hope will be helpful for people.

[1:09:10] Dr. Linda Bluestein: Well, I really enjoyed that conversation with Dr. Settle. I feel like these psychiatric problems are just so difficult to navigate sometimes, and it gives me a lot of hope to think about all of the possible stones that we can unturn and really try to find the root causes of a lot of these symptoms. So thank you so much for listening to this week's episode of Bendy Bodies with the Hypermobility MD podcast.
[1:09:35] I hope you'll check out my other resources, including my newsletter, the Bendy Bulletin. You can check that out on Substack at hypermobilitymd.substack.com. You can help us spread the word about joint hypermobility and connective tissue disorders by leaving a review and sharing the podcast. This really helps raise awareness about these complex conditions.
[1:09:53] Did you know that I also offer one-on-one support for both clients and healthcare professionals? Whether you're living with a connective tissue disorder or caring for people who are, I've got your back. Check out my coaching and mentorship options on the services page at hypermobilitymd.com.
[1:10:08] You can find me, Dr. Linda Bluestein, on Instagram, Facebook, TikTok, and LinkedIn at hypermobilitymd. You can find Human Content, my amazing producing team, at humancontentpods on TikTok and Instagram. You can also find full video episodes up every week on YouTube at Bendy Bodies Podcast.
[1:10:25] As you know, we love bringing on guests with unique perspectives to share. However, these unscripted discussions do not reflect the views or opinions held by me or the Bendy Bodies team. Although we may share healthcare perspectives on the podcast, no statements shared on Bendy Bodies should be considered medical advice. Please always consult with a qualified healthcare professional for your own care.
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