Whole-body hyperthermia as a treatment for depression: sauna, hot yoga and exercise | Charles Raison
Scientists exposed patients to high heat using an infra-red device or hot yoga and found both modalities to have anti-depressant effects. Heat stress causes the release of beta-endorphins as well as dynorphin, an endogenous opioid. Exercise produces similar results by releasing anti-inflammatory cytokines that may contribute to an anti-depressant outcome. In this clip, Dr. Charles Raison describes how whole-body hyperthermia has the potential for real-world clinical efficacy as a tool in the fight against major depression.
- Rhonda: I’m super interested in the study that you published where you had used whole body hyperthermia to treat major depressive disorder, or at least a single bout of it seemed to have a lasting effect for six weeks. Whole body hyperthermia, to me, it sounds very similar to using something like a sauna, would you say it is?
- Charles: Oh yeah, yeah. It’s just the heat.
- Rhonda: Okay.
- Charles: I mean, the machine is fancy, it’s like a $50,000 machine. It uses infrared lights. It kind of cooks you from the inside out, and that allows you to get hotter, with less misery, you know. Because saunas, I mean, you know, you’re getting that heat on your skin. It’s hard, right?
- Rhonda: It’s definitely hot.
- Charles: Yeah. I mean, I’m a big steam room sauna fan. But the box is very different. So I put myself in this machine to see what I was doing to people. I’ve never been so... So to back up, yes, you’re right, we did do a study, and we treat people to a core body temperature of 38.5 centigrade, which is 101 point something or other, which is unbelievably hot if you don’t wanna be that hot. I mean, I’d never been that hot in my life. I mean, sweat was just pouring off my body, and I was huffing and puffing. I felt like I’d been running for 10 miles out in the desert summer, you know. It’s really hot. It’s mild hyperthermia, but it’s hot. Now we have colleagues, David Mischoulon and Maren Nyer at Harvard that have joined us in hyperthermia work, and she especially is interested, and has a grant to study hot yoga, and convincing people to wear a rectal probe when they’re doing hot yoga. And hot yoga, which also, you know, makes people sweat like pigs, elevates core body temperature too, interestingly, exactly the same place, 38.5.
- Rhonda: Oh, wow.
- Charles: Right. You know, a lot of people when I talk about hyperthermia, and I give talks to folks. A lot of people, if it’s a crowd, will come up afterwards and say well, “You know, hot yoga.” And like, a lot of people are hooked on hot yoga, and it’s because, I’m convinced it’s because it’s an anti-depression strategy. That they are essentially doing something very similar to what we do in the box. And, you know, most people, it took about an hour, hour and a half, for most people to get up to that 38.5. And then when that happened, we turned off the heat, but we left people in the box because it stayed warm and their core body need to be elevated for at least another hour. So even the timing of hot yoga is probably consistent with sort of our hyperthermia machine.
- Rhonda: So the hot yoga, sauna, I mean, maybe a hot bath, like if you say, so basically anything that’s...
- Charles: It’s the heat.
- Rhonda: Yeah.
- Charles: Yeah, that’s true. There’s some interesting data on hot baths improving autistic symptoms, right? There’s people looking at this in New York, right? So yeah, there’s a story there.
- Rhonda: Yeah. There’s a personal story for me in terms of the sauna. One of the reasons why I got so into using the sauna was because in graduate school, I lived across the street from the YMCA, and they had a sauna there and so I was just, you know, using the sauna. I’d go into this, I’d use the sauna before I would go into the lab and do my experiments for the day.
- Charles: Yeah.
- Rhonda: And, you know, as you know, graduate school is extremely stressful, failed experiments sometimes setting you back six months, and lots of stress.
- Charles: Your career going up in smoke.
- Rhonda: Yeah. I mean, just 16-hour experiments you have to do, and you’ve got to publish and they’re new, and you’ve got to publish... Well, you know, so it’s very stressful. And what I started to notice was for whatever reason, the sauna, using the sauna, really, really lowered my anxiety, and my ability to deal with the stress. Like I was so much...
- Charles: More chilled out.
- Rhonda: Yeah. It’s so much easier for me to deal with all the stress. And it was extremely noticeable, enough for me, you know, to start to go, “Something’s going on here.” So I started looking at the literature. Of course, my husband, Dan, was doing the same thing, and he had definitely noticed the same thing. So what was really interesting, I looked in the literature and found, you know, that using, that heat stress in general, increases...you dump a bunch of beta endorphins. Well, that’s obvious. That happens with exercise. I think part of the, like you mentioned, you know, you’re when you’re running or exercising vigorously, your core body temperature is elevated and that’s sort of part of that endorphin response. But what was really interesting to me was like at the same time, a friend of mine who was doing some research on the opioid pathway and he was looking at the kappa opioid pathway, so mu opioid receptors bind endorphins, and kappa opioid are sort of the opposite of endorphins, is sort of the dysphoric.
- Charles: The kind of depressorgens.
- Rhonda: Yeah, dysphoric feeling. You don’t feel great. And he was telling me about some research with if you agonize that receptor, the kappa opioid receptor, what ends up happening is the feedback where you have the mu opioid receptors much more sensitive to endorphins, and you basically are having more of the receptors and they’re more sensitive. So then I started to look in the literature and found that something that we make in our brain endogenously, called dynorphin, is up regulated when you’re exposed to heat, because it cools your body down. So I started to go, “Wow, I wonder...” You know, so for example, there are studies where you expose rats to heat stress and they increased their dynorphin. I thought, “Well, what if the dynorphin binding to the kappa opioid receptor does actually sensitize mu opioid receptors to beta endorphins?” So I thought, “Oh, maybe that’s a possible mechanism why I’m feeling so good, like a lasting effect, where it’s like later on, you know, weeks later, I’d still feel really good.” So that’s sort of an interesting personal story for me. I’m not sure if you’ve ever looked into the dynorphin or beta-endorphin.
- Charles: Well, so this is a fascinating thing. Yes, indeed. So it turns out, you know, that almost certainly, within the next, sort of in the next six months, there’s going to be a major FDA approval for a very novel antidepressant that does the opposite of what you’re talking about. It antagonizes the kappa receptor, so it’s exactly opposite. Now interestingly though, and I have an interest in psychedelic medicines, something called ‘Salvinorin A’ is a kappa agonist, and is also of some significant interest at lower doses as an antidepressant, right? So here’s an example of this phenomenon. It’s a meta issue, and I don’t mean like meta like the Buddhist meditation, but meta, M-E-T-A, that opposites sometimes do the same thing. It’s interesting, there’s thing called an enantiodromia, goes all way back to Heraclitus, back in the... That right, sometimes you can get the same effect by doing opposite things. So right, the fact that hyperthermia stimulates kappa receptors, and the fact that blocking them could maybe also have an antidepressant effect, it’s fascinating but it’s consistent with this sort weird, again maybe kind of U-shape thing or the fact that opposites can sometimes do the same thing. We don’t know, from our studies, we don’t know the role that the opioid system played in our outcomes. This is something that, you know, we’re going to look at down the road. We looked at a bunch of immune stuff.
- Rhonda: And what did you find with the hyperthermia?
- Charles: Well, we found that hyperthermia does exactly same thing that exercise does.
- Rhonda: Okay.
- Charles: Which is not so surprising, right, but which is quite interesting. So to kind of want to kind of nerd out on the inflammatory pathway, right? When you get sick, what happens is you get activation of these two primary pro-inflammatory cytokines: interleukin one beta and the tumor necrosis factor, so IL1 Beta and TNF. They get activated, they do all sorts of stuff. They’re really pro inflammatory. They secondarily activate another cytokine called interleukin 6, or IL6. Now, IL6 is a bad guy, I think. It’s the one that’s most consistently elevated, somewhat, in depression. There’s all sorts of evidence that if it’s elevated, if you’re a Western person hanging around, if I measure your IL6, and if it’s up, bad. You’re going to get heart attacks, you’re going to get strokes, you’re going to get cancer, you’re going to get... You know, it’s a bad deal to have your IL6. It’s going to shrink your hippocampus. We know a lot of stuff about that. So it’s a bad boy. It’s activated by IL1, but it’s a sort of secondary. We’ve also known for years that, I see it sometimes as a Janus-faced cytokine. It faces two directions, because it also has anti-inflammatory effects, it activates IL10. So what you see with bad infection, IL1, TNF, they shoot up, IL6 goes up and you’re sick and that’s how it is, right? What exercise seems to do is it activates IL6 like crazy, but it doesn’t activate IL1 or TNF. In the blood, if you really, really exercise, like a maniac, yeah, you can get slight increases. If you look at sort of maybe less horrible killer exercise, you see this big increase in IL6. If you pull out people’s blood cells and stimulate them, you actually see reduced release of TNF and IL1. That’s anti-inflammatory thing you’re talking about, right? So you get this IL6 response, and then you get the sort of IL10 coming along, which is powerful anti-inflammatory. That’s what we see with hyperthermia.
- Rhonda: That’s so cool.
A hormone produced in the brain that blocks the sensation of pain. Beta-endorphin is released in response to a wide range of painful stimuli and stressors, including heat . Beta-endorphin exhibits morphine-like activity, but its effects are up to 33-times more potent than morphine. Both morphine and beta-endorphin act on the μ-opioid receptor.
 Ježová, Daniela, et al. "Rise in plasma β-endorphin and ACTH in response to hyperthermia in sauna." Hormone and Metabolic Research 17.12 (1985): 693-694.  Loh, Horace H., et al. "Beta-endorphin is a potent analgesic agent." Proceedings of the National Academy of Sciences 73.8 (1976): 2895-2898.
A broad category of small proteins (~5-20 kDa) that are important in cell signaling. Cytokines are short-lived proteins that are released by cells to regulate the function of other cells. Sources of cytokines include macrophages, B lymphocytes, mast cells, endothelial cells, fibroblasts, and various stromal cells. Types of cytokines include chemokines, interferons, interleukins, lymphokines, and tumor necrosis factor.
A critical element of the body’s immune response. Inflammation occurs when the body is exposed to harmful stimuli, such as pathogens, damaged cells, or irritants. It is a protective response that involves immune cells, cell-signaling proteins, and pro-inflammatory factors. Acute inflammation occurs after minor injuries or infections and is characterized by local redness, swelling, or fever. Chronic inflammation occurs on the cellular level in response to toxins or other stressors and is often “invisible.” It plays a key role in the development of many chronic diseases, including cancer, cardiovascular disease, and diabetes.
Interleukin 10 (IL-10)
IL-10, also known as human cytokine synthesis inhibitory factor (CSIF), is an anti-inflammatory cytokine with multiple, pleiotropic, effects in immunoregulation and inflammation. It downregulates the expression of Th1 cytokines, MHC class II antigens, and co-stimulatory molecules on macrophages. It also enhances B cell survival, proliferation, and antibody production. A study in mice has shown that IL-10 is also produced by mast cells, counteracting the inflammatory effect that these cells have at the site of an allergic reaction. IL-10 is capable of inhibiting synthesis of pro-inflammatory cytokines such as IFN-γ, IL-2, IL-3, TNFα and GM-CSF made by cells such as macrophages and Th1 T cells.
Interleukin-1 beta (IL-1 beta)
A proinflammatory cytokine produced by macrophages. IL-1 beta is an important mediator of the body’s inflammatory response. It is involved in a variety of cellular activities, including cell proliferation, differentiation, and apoptosis.
Interleukin 6 (IL-6)
A pro-inflammatory cytokine that plays an important role as a mediator of fever and the acute-phase response. IL-6 is rapidly induced in the context of infection, autoimmunity, or cancer and is produced by almost all stromal and immune cells. Many central homeostatic processes and immunological processes are influenced by IL-6, including the acute-phase response, glucose metabolism, hematopoiesis, regulation of the neuroendocrine system, hyperthermia, fatigue, and loss of appetite. IL-6 also plays a role as an anti-inflammatory cytokine through inhibition of TNF-alpha and IL-1 and activation of IL-1ra and IL-10.
One of four related receptors that bind opioid-like compounds in the brain. Opioid receptors are responsible for mediating the effects of these compounds, which including altering pain, consciousness, motor control, mood, stress, and addiction. Agonism of this receptor produces a transient feeling of dysphoria but also causes an upregulation and sensitization of mu opioid receptors, which interact with beta-endorphin.
Salvinorin A is the main active psychotropic molecule in Salvia divinorum, a Mexican plant which has a long history of use as an entheogen by indigenous Mazatec shamans. Salvinorin A can produce psychoactive experiences in humans with a typical duration of action being several minutes to an hour or so. It is structurally distinct from other naturally occurring hallucinogens, acting on the k-opioid receptor instead of the 5-HT2A (serotonin) receptor.
Tumor necrosis factor-alpha (TNF-alpha)
A proinflammatory cytokine. TNF-alpha is produced by a wide range of cells, including macrophages, lymphocytes, glial cells, and others. TNF-alpha signaling inhibits tumorigenesis, prevents viral replication, and induces fever and apoptosis. Dysregulation of the TNF-alpha signaling pathway has been implicated in a variety of disorders including cancer, autoimmune diseases, Alzheimer’s disease, and depression.
The mu-opioid receptor is responsible for mediating the effects of agonists such as morphine and beta-endorphin, an endogenous mu-opioid agonist released. This opioid may also be involved in the body’s thermoregulatory response to hypothermia.
 Xin, Li, Ellen B. Geller, and Martin W. Adler. "Body Temperature and Analgesic Effects of Selective Muand Kappa Opioid Receptor Agonists Microdialyzed into Rat Brain." Journal of Pharmacology and Experimental Therapeutics 281.1 (1997): 499-507.
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