In this episode, I’m speaking with Dr. Mark Cronshaw, a highly respected expert in the field of photobiomodulation (PBM) – what most people commonly think of as red light therapy.
This is the first of many podcasts with Dr. Cronshaw, who is one of the most brilliant and knowledgeable experts I’ve had the pleasure of connecting with on this topic. Our conversation goes deep into the science of photobiomodulation—there are some practical pearls that Dr. Cronshaw discusses, but be prepared for deep, nuanced, and technical scientific discussion about light therapy.
WARNING: Please be aware that this conversation with Dr. Cronshaw is NOT just a simple practical how-to guide of “go buy this device and use it this way.” This is a podcast series that intends to go deep into the scientific, technical, and theoretical nuances of PBM science. So it’s NOT for everyone. If you just want a simple practical how-to guide, we will eventually get there, but there are several hours of geeky technical science stuff before we get there. These podcasts with Dr. Cronshaw are for people who want to nerd out on PBM science. So please don’t say I didn’t warn you! 🙂
Table of Contents
In this podcast, Dr. Cronshaw and I discuss:
- Finding the “sweet spot” of PBM therapy, technically known as the biphasic response or the Arndt-Schultz law—how to deliver the energy, what amount of energy you have to deliver, and how best to deliver it
- How to use PBM therapy in different ways for different outcomes, such as increased energy and immune function or pain relief
- The incredible ways photobiomodulation interacts with your mitochondria, specifically the electron transport chain, as a beneficial hormetic trigger
- An evolutionary explanation for your cellular anatomy and why even your body’s deepest tissues are responsive to light therapy
- How Dr. Cronshaw’s opinions have changed as he shifted from his work with lasers to learning more about photobiomodulation
- Some foundational principles of photobiomodulation, including lasers versus LEDs, the optical window, and penetration depth
- How much light actually gets through your skin to positively impact deeper tissues?
- The fascinating connection between melanocytes, your nervous system, and why even diffuse LED light exposure may benefit specific areas of your body
- Why light therapy experiments conducted in vitro—in Petri dishes or just on cells—might lead us to erroneous conclusions about the real effects on humans
- The controversy of tissue heating associated with photobiomodulation and Dr. Cronshaw’s opinion on this “hot” topic
- The possibility of multiple layers of mechanisms of light therapy—photochemical, photothermal, photomagnetic, photofluorescent, photoacoustic, and photoelectrical!
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Transcript
Mark: First of all, thank you very much for inviting me. It’s my great pleasure to be here today, Ari. It’s always good when I meet someone who’s a fellow enthusiast for PBM because this is a subject that I’m very passionate about, as I know you are too. It’s been a journey for me, and it’s a journey which is continuing, which started off in my activities clinically because I’m an active clinical dentist. I’m involved in private practice.
I’ve been using lasers for surgery for many years, and I got very interested in the effects I was seeing because I saw how well things healed, how little pain patients were having afterwards. I wanted to develop my understanding. Then I formalized my studies by studying at the University of Genoa in Italy, which is one of the early world centers of excellence for the study for photobiomodulation. From that, ultimately, because I acquitted myself well, they took me on as a faculty.
To learn something, there’s nothing quite like having to teach it. I got really into depth into various aspects of how surgical lasers work, but also started digging more deeply into how photobiomodulation worked because I wanted to know how I could do this better, more reliably and predictably, and also how I could better teach it to my students. I’m involved in dental education.
This culminated in when I left Genoa in my signing up to do a doctorate because I realized there were many questions that I couldn’t answer based on the literature that I’d read or the many speakers I’d listened to, that there seemed to be the need for me personally to go through the literature and to reappraise it and to introduce some of my own thoughts so I could better understand the processes involved in doing this. The outcome is now five, six years on, I’ve now very recently published my thesis.
I think I’ve got a better understanding. This is a very exciting time to be involved in PBM and PBM research because we’re at the stage in which we’re now being able to take the science, the evidence base, and translate it into something which is going to be not only useful to clinicians like myself, but the target is to empower normal people to be able to do self-application of targeted PBM to start to treat some of the many ailments which are otherwise really quite difficult to manage medically.
My confident prediction is that within the next five to 10 years, everybody will have some sort of PBM device at home. Along with the Elastoplast and the Dettol, you’ll have your PBM device and it’s just going to be wonderful because this is going to open a whole new toolbox, which is the biggest single medical advance I’ve seen during the course of my career. I think the outcome of this is just going to be an absolute game changer in many things, not just in dentistry, but in medicine.
It’s my pleasure to be here today. I’ll be very happy to share with you the benefits of the research that I’ve done. We can have a great conversation. I very much look forward to continuing this conversation with you, Ari, and because we’ve got so much to talk about, we could talk for hours.
The biphasic dose response
Ari: Yes, absolutely, Mark. I’m very excited to dig into this with you. Mark, the last little segue there was– I remember when we started recording, you had just finished expressing some thoughts on the biphasic dose response, the Arndt-Schultz curve, and then you segued into another line of thinking. Do you remember?
Mark: Yes. Oh, I remember all that.
Ari: Can you give just a little segue into that?
Mark: Absolutely. When I first got interested in this, I decided that I’d have to look at the literature to see what the published science showed in regards to dissymmetry. How much energy do I need to use to produce an effect? The classical literature indicated that there was what was known as the biphasic response, something called the Arndt-Schultz law, where it was either too little, nothing happened, get into the sweet spot, and you got the happy stuff happening.
Then beyond that, nothing happens at all. I thought, “Well, okay.” When I looked in the literature, my interest is not only to see how to optimize healing but also how to inhibit pain as well as to manage inflammation, because clinically for me, that’s very important. As a dentist, I get to manage people who are in pain and with inflammation. I want to know how best to do it and how to treat it with my photobiomodulation therapies. I discovered that there are actually two dose windows.
There’s a low dose window, which is associated with increased cellular activity. Then there’s a higher dose symmetry, which is associated with analgesia and the inhibition of pain.
I then published a paper with colleagues Stephen Parker and Prabina Rani expressing these thoughts within the context of adopting an evolutionary model in regards to trying to understand the various ways in which cells communicate internally, from which later I then turn this into a thesis, which I’ve spent the last five, six years evolving into trying to understand exactly how to deliver the energy, what amount of energy you have to deliver, how best to deliver that energy in order to predictably and reliably produce the responses that we want, as well as to develop an overview of how is it that this thing works.
Now that I’m not at the end of that journey, because it’s still a continued journey, nobody knows it all, it’s exciting times to be able to share these thoughts with you. I think we could talk an awful lot more. It’d be really great if we could just show you some graphics as well. I think for an educational route, if you can see some images, it really does help, rather than just having to focus on the word. With your permission, maybe in one of our future conversations, I’ll show you some of my materials, because visually, I think sometimes it’s easier to understand complex subjects rather than just having to focus on the spoken word.
Ari: Yes, absolutely. I would love that. I only have a little less than an hour right now. We can absolutely do a series if we need to cover other topics that we don’t get to.
Mark: Excellent. Let’s hammer on in that case. All right?
Ari: Sweet.
Mark: The outcome of that Feeling the Heat review paper, I suggested that there’s a multi-phase response to PBM, that it wasn’t just good stuff or nothing. It would be a beneficial thing to have inhibition, because inhibition is associated with analgesia. We know what those dose windows are because from the literature reviews I’d done, I knew that there was a sweet spot between two through to about eight, nine joules per square centimeter at tissue level, which was associated with an increased rate of mitosis, increased ATP, and all the positive events associated with increased mobility and activity of the immune system, et cetera.
Above that, as soon as you get above about 10 joules per square centimeter, then you didn’t see any of that. You saw inhibition, but that inhibition was also associated with analgesia, because the review paper is on pain. I could quote and cite the papers if you wanted to. They all indicated that you needed a higher dissymmetry in order to achieve analgesia. I thought, “Great, this is useful. Clinically, I’ve now got two target doses.” I thought, “Well, what does that correspond to in terms of the mechanics of what’s happening? You know that photon’s coming into the cell, how is it it’s producing one effect as opposed to the other?”
I then theorized, and I realized that in the electron transport chain, there are checks and balances inherent to it because the mitochondria is like a chemical factory. It’s the most incredible, sophisticated thing, producing all these useful products, fatty acids, proteins, ATP, byproducts. It’s associated with nitrogen metabolism. The facility that mitochondria add to eukaryota, which are multicellular things, are just absolutely mind-blowing, but like all chemical factories, it’s dangerous because you’re getting a lot of reactive oxygen species produced, that can be highly toxic.
You’re also getting some heat generated because as a byproduct of any chemical process, you get some heat. If you overheat things, then you can start to damage part-formed proteins, and you can start to derail various enzymes so that they don’t work properly. If it’s left uncontrolled, that can kill the mitochondria, and it can kill the cell. This is all very strictly regulated. I then went looking to see what the regulators were for internal cellular metabolism for temperature control, and there are various ones.
When the temperature is elevated by two degrees centigrade, then you get an activation of some protective enzymes called heat stress proteins. There’s a whole cascade of these heat stress proteins, some of which are chaperones, which wrap up the part-formed proteins, prevent them getting damaged, and some of them have got specific effects which improve the ability of the cell to survive the heat stress.
Along the way, they shut down the electron transport chain. They activate ATPase, which is the thing which is driving the cell, the ATP that’s generating the ETC. There are associated effects with other protective gene sequences like p53, which just helps improve the stress resistance of the cell against cellular death caused by this stress. Then there are other things as well, such as—
Heat stress
Ari: Can I just add, for people who might be listening to that? Talking about heat stress proteins or heat shock proteins might sound like, “Oh, this is a bad thing,” but we have lots of evidence showing that the initiation of this heat shock protein response, which happens with exercise, which happens with sauna, is linked to a host of different beneficial physiological effects.
Mark: Absolutely. This is a process we refer to as hormesis. Hormesis is the technical term for the cell’s protective mechanisms, where the cell doesn’t just survive in consequence of the hormetic influence, the stressor. It’s actually more resilient. This is something which has been proven to be really important in the prevention of some of these awful complications that we’ve seen in cancer chemotherapy and radiotherapy where by preconditioning the tissues, you can increase the stress resistance of the tissues to withstand the next incoming stress.
This concept of preconditioning, I think, is really very important in the PBM story. Apart from the HSP cascades, there are others that I found. Now, inside the electron transport chain, adjacent to it in the mitochondria, there are some things called UCPs. These are uncoupling proteins. Now, uncoupling proteins were first discovered in brown fat cells. These are the things where, when you get cold, you start to shiver, and you’re getting heat generated.
It’s because of the activation of the UCP1, which opens up the gate inside of the mitochondria, and it allows the protons, which are the little hydrogen ions that have been pushed across into the inner mitochondrial matrix, back into the matrix. When you get a lot of protons there, then it really is like a big party. There’s lots of molecular vibration, and that generates heat. It’s the natural mechanism [unintelligible 00:12:50]. There are other UCPs as well.
There are about five sorts that have been identified. These are present in all organs and tissues. In the brain, in the kidneys, in the liver, and muscles. Anywhere where there’s high metabolic activity, you’ve got these UCPs. These UCPs, when they open, it’s like pulling the plug on the bath. The bathwater drains out, the bathwater being the proton gradients. If the proton gradient’s gone, then the way the electron transport chain works, it’s like a hydrodynamic dam, because it’s driving this little molecular rotor as this stream of protons is coming down.
As it’s going along, it’s taking an electron, and it combines it with the phosphate. Then you’ve got ADP going to ATP. If you turn off that flow of protons, you’re not getting that ATP generated. As a result, the amount of energy available in the cell is gone. UCPs are another regulator, which is associated with temperature because when you have an elevation of temperature, you also get an increase in the amount of reactive oxygen species because two key enzymes, which Praveen Arany has identified in a very nice study he did with his Harvard colleague, Khan, where if you heat things above 42 degrees centigrade, there’s two enzymes.
One’s called catalase, and the other one’s called glutathione reductase. These are very important at deactivating reactive oxygen species because reactive oxygen species can react with nitrogen, which is present in proteins, and produce reactive nitrosyl species, and they’re deadly poison to the cell. They kill the tissues.
Ari: Sorry, go ahead. Complete the thought, and then I’d like to just add one thing.
Mark: You want to avoid RNS. Now, small amounts of ROS, which is a normal byproduct of what we call aerobic metabolism, oxidative phosphorylation, this wonderful enzymic chain present in the mitochondria, are actually stimulatory. They help activate some gene transcription sequences associated with beneficial things like an increase in mitosis as well as the production of some very important growth factors to do with blood vessels called vascular endothelial growth factor and a whole host of other things.
There’s activation nuclear factor kappa-B. It’s alphabet soup, this sort of stuff. When you first look at it, you think, “Oh my goodness, how am I ever going to understand this?”
Ari: When you get into all the different cascades from heat shock proteins, from all these different growth factor cascades, from reactive oxygen species, scavengers.
Mark: At first sight, you look at it and you think, “How can I possibly understand this?” That’s why I got interested in that first study because out of that, I came up with the concept that the cell really has got three compartments. There’s the mitochondria, there’s the cell body, and then there’s the nucleus. In terms of evolutionary terms, the cell nucleus is a descendant of a virus. The mitochondria, they’re descendants of Alphaproteobacteria, which have become combined inside of the chassis of the cell, which is a different genus again, which is called an archaeon.
The evolutionary biologists think that this is a one-off event. Out of that ménage à trois, the marriage of these three things, out come the eukaryotes because then suddenly you’ve got multicellular organisms which are endothermal, they’re able to generate their own heat so you can move away from solar energy, you can move away from deep sea vents where they’re getting their heat, and they’re also able to manufacture prodigious amounts of all these useful biomolecules like ATP, which is just incredible because then you’re able to move out of your immediate area and start to colonize, and out of that emerge all the biodiversity which we identified today.
With this understanding of this three-way switching system, I then had a way of looking at that alphabet soup and looking at it thinking, “Okay, now some of these things are going to be located in the outer membrane, they’re membrane-activated things.” There’s crosstalk between the mitochondria, the cytoplasm, which is the cell chassis as it were, and then also the nucleus. I can start to see a roadmap there which helps me sieve the wheat from the chaff because otherwise, it’s just so mind-boggling and complicated.
My brain just switched off and I thought, “I’ll never understand this.” With that frame, I was then able to start to decipher some of the processes which I associate with positive and negative activation of the mitochondria, because mitochondria are indeed very important in regards to photobiomodulation as a mechanism, but they are far from the whole story. Over the past five, six years, it’s been incredibly exciting because we’ve had lots of fresh thinking coming in from all sorts of things.
In my small way, I’ve contributed, but there are other great people out there like Anne Liebert and Brian Bicknell and people like this who’ve come up with some astonishing stuff related to photosensitivity of things in the heart, the kidneys, the brain, and deep tissues, related to materials called opsins as well as TRPVs, and there are all these photosensitive reactive molecules. You’re thinking, “Well, why? These are in deep tissues. I think this is quite remarkable. There’s this photosensitivity.”
Then I twigged that this is an inherent thing which is built in from our evolutionary origin because in terms of the single-cell precursor to Eukaryota, they were all incredibly photoreactive. The fact that that’s a retained feature suggests that it’s an important retained feature. In PBM, we’re selectively activating a whole series of ancient switches, which are the keys to the kingdom, because from this, you’ve got some activation of switches associated with important enzymes like COX-2, which is like oxygenase, which is the active site for the production of PGE2, which is a steroid, which is like the master switch for inflammation.
Then there’s a whole host of other key aspects related to photon transduction as a process where you can then start to selectively affect, in a targeted manner, certain pathways. I thought, “Oh, this is all great. It’s all starting to make sense.”
Does the frequency matter
Ari: Hold on one second, Mark. I have to interject my excitement at this because I have this feeling like you’re the person that I’ve been wanting to speak with for years now because one of my biggest frustrations in health science more broadly is people who try to look at physiology, look at human biochemistry, and try to understand the picture of human health without coming from an evolutionary frame.
I find that it just ends up in a lot of confusion and a lot of counterproductive and misguided or very myopic and reductionistic ideas when human health and physiology is looked at through that frame. This is also specifically a frustration of mine in the field of photobiomodulation, where I feel there is often very much a lack of evolutionary context. As you know, most of the research has historically been on lasers.
I feel like so much of this body of knowledge and the people who are involved in what’s now called photobiomodulation, what used to be called low-level laser therapy, have really not looked at all of this from an evolutionary frame. I’m hearing you describe everything that you have just laid out over the last five or 10 minutes, and basically, you are presenting the evolutionary context to properly understand what’s really going on in photobiomodulation. As you’re talking, I’m going, “This is exactly what is needed in this field.” You are the person I’ve been wanting to talk to.
Mark: It just gets better because I certainly wouldn’t claim to know. I know a lot and I’ve got my theories and my ideas and I can explain to you how I’ve come to those. I can describe to you the evidence that I’ve used as expressed in my thesis, as well as my current and future publications in order to demonstrate scientific provenance of this. Essentially we’ve got the bones of an understanding where we can then start to think selectively how we might then approach tackling clinical problems, because then as opposed to thinking about, “Okay, this is a particular enzymic sequence, which wavelength are we going to use?”
There’s a whole heritage thing there. “Oh, you have to use the 632.5 helium-neon.”
Ari: Exactly. “
Mark: No, no, no, no. You want a 1064. It’s great. It’s a gorilla. It really gets–“
Ari: That’s exactly the kind of thinking that I’m describing that just doesn’t really make any clear sense from an evolutionary context.
Mark: A photon is a photon is a photon. A photon is a little bundle. It’s not even a particle of electromagnetic radiation. According to the frequency cycle, it’s either a very short frequency cycle, in which case it’s got a lot of energy, or it’s a longer wavelength and it’s got less energy. All this business about different colors for different effects, there’s a little bit of truth in there, but that’s more to do with the electron volt, which is the amount of energy that that photon’s got, rather than being a magic bullet.
You have to fire the 632.5 in order to get that CCO activated. All I can say is now that’s all being comprehensively debunked because a lot of the early studies very much focused on red wavelengths, but now we know we can produce these effects with blue wavelengths. We know we can produce it with mid-infrared, even far-infrared wavelengths.
Ari: I want to jump in with something, and this might lead us down a big path too early to go into all of this. Everything that you just described is maybe true, but is also not true in the sense that wavelength largely dictates penetration depth or penetration depth potential. Even if technically blue, or let’s say UV, or let’s say far-infrared wavelengths activated, let’s say identical mechanisms, I don’t think that’s true. Maybe there’s certainly some overlap as you’re implying, but–
Mark: Hey, we’re going to have a good conversation tonight. I’ve got some really interesting thoughts [crosstalk], but I’ll listen to you.
Ari: Hold on one second. Even if, let’s say– let’s just imagine a scenario where they all activated identical mechanisms at the cellular level, there would still be an enormous difference in the degree to which red and near-infrared wavelengths can penetrate beneath the skin versus let’s say blue, or UV, or far-infrared.
Mark: Absolutely. That’s right. Now then, let’s see if I can really upset you now, Ari.
Ari: You’re not likely to upset me. I don’t have very strong opinions on this.
Mark: I came from this from the direction of being a laser guy, and lasers are amazing things. All the photons are entrained in the same space and time. It’s a very intense beam. Even on very low power, with a little laser pointer with a milliwatt, you can point it across the room with a little lens and it will hit the opposite direction. It doesn’t lose its energy as it were. It’s such an intense thing that–
To take the line from James Bond, as he’s lying there waiting to undergo gender transformation by laser as Goldfinger is saying, “With this thing, I can put a spot on the moon,” he says, and indeed you can. The early pioneers in laser research were even thinking about this might be useful for interstellar communication because it’s such an intense energy. I have this very strong belief that if you wanted to reach subsurface targets, you needed to use a high-intensity energy source because otherwise it’s just not going to touch sides. [crosstalk]
Ari: Did you say surface targets or subsurface targets?
Mark: Subsurface targets. [crosstalk]
Ari: In other words, for listeners, if you want the light to go beneath the level of the skin.
Mark: That’s right. Then you needed to use something which has got what we call the coherence, which is this property of all the photons being the same in phase and time so it’s energetically having a very different effect. The difference between that and a non-coherent source, such as a light bulb or an LED, for instance, is there. It’s a chaotic source. It’s like the difference between picking up a rock and throwing it at a window and taking a little handful of sand, which may weigh the same, and then just vaguely scattering it at the window.
The impact in terms of the molecular substructure of being hit by this really intense coherent wave, which is what you got when the laser’s going in there, it produces an effect. Whereas if you’re just dribbling it with little bits of energy that’s arriving chaotically and not simultaneously because it lacks the spatial and temporal coherence of a laser beam, then it’s going to produce a very different effect. That can also be reflected in how deep it starts to penetrate. I had this very strong conviction that if you want to get beyond a centimeter or more into tissues, it just takes forever with a non-coherent light source. [crosstalk]
Ari: Can I ask you really quick, Mark? Is this the current perspective that you have that you’re articulating or this is what you believed when you were a laser guy?
Mark: This is what I believed when I was a laser guy. This is something where I put a lot of time and effort and work. I was using a machine called a beam profilometer. A beam profilometer, basically it’s a special camera which looks at the amount of power emerging across a plane. I’d have a camera up here, say, and then I’ve got my sample in between, and then I’d have a laser underneath here. I could then look to see what the profile of the energy was going through different thicknesses of the sample.
I did this for all the different wavelengths, different spot sizes, and different parameters associated with peak power and all this stuff, trying to unravel.
Ari: What was the sample? It was a tissue sample?
Mark: Yes, it was a tissue sample. Basically, I just bought some lean pork muscle from the local pig farm.
Ari: Did it have skin on it or no skin?
Mark: No skin. It was just lean muscle. I’m just looking, just to get an idea of what happens when photons enter into tissues at different thicknesses, producing different wavelengths, different optic spots, and different parameters of one form or another to do with peak power as opposed to average power and stuff like this. From that, I then published a paper which was looking at the effects of different wavelengths, which was consistent with the literature that showed that if you want to really go deepest into the tissues, you’re looking at round about an 800 to an 810-nanometer near-infrared laser.
There was this thing they referred to as the optic window, which is shaped a little bit like this, where on one end, you got around about 600, and on the other end, it’s around about 1,100 because it’s got relatively poor absorption inside of the tissue, although there’s difference in scattering, which is where it’s bouncing off the various substructures of the tissues, but because it was so poorly absorbed, you could go deeper, and the 810 was right in the sweet spot, right in the deepest bit.
I thought, “Yes, great. Okay. So an 810. This is really going to help, but all these other wavelengths can still be having beneficial effects.”
Ari: Mark, let me let me just interject one thing for listeners. Mark is touching upon a few really foundational topics in photobiomodulation here in rapid succession. One is there’s a big, contentious, very controversial area of lasers versus LEDs. This has been argued over by different experts and researchers for literally decades now. It’s still quite contentious.
There are some people who say LED-based light versus laser light are fundamentally different, and others who argue that at similar parameters, they create similar effects. Then you’ve talked about the optical window, how different wavelengths penetrate the tissue differently. That’s this funnel that he was just describing there, 600-ish nanometers up to about 1100-ish nanometers. This is the red and near-infrared part of the spectrum that penetrates deeply into the tissue, whereas most other wavelengths, blue, greens, UV, far-infrared energy is absorbed very much at the surface.
Then you also mentioned penetration depth into the tissue, talking about different wavelengths and spot sizes. You can think of it as the thickness of the beam of the light. How deeply those factors, and I assume irradiance also, influence the degree of penetration into the tissues, which is also another big area of controversy in photobiomodulation. Anyway, I just wanted to help listeners understand you’re touching on a lot of really critical foundational and contentious [inaudible 00:31:52] in PBM science.
Mark: Absolutely. That’s a very nice prossy of it. Thank you. Now, the question then arises, “Okay, well, in that case, how is it that LED can work?” I was reading studies that showed blinded, randomized, well-designed studies, and with my science hats on, I know what to look for. There was one involving a device called the Nova4, which is a flat 840-nanometer LED bed for full body irradiation for the treatment of fibromyalgia, which is a very unpleasant muscular inflammatory disorder.
They showed in a good study over a period of about six to nine months that this very clearly produced a highly beneficial, statistically significant effect in those people, yet these are LEDs. I’m thinking, “Well, it’s a muscle, that’s subsurface.” I know from the science that when you expose tissues to an LED, you may be getting at the centimeter depth between 0.2% to 0.6% of the surface energy being received at depth. Now, if you’re applying, say, 500 milliwatts at the surface of the tissues for the amount of energy that is actually reaching that muscle, you’re down to maybe 2 to 6 milliwatts, which is really quite low.
It’s going to take a long time before you can start to get it up to the 6 joules plus that you may then need to reduce the positive effects or the inhibitory that you’re seeking.
Ari: Was that 2 to 6 milliwatts per square centimeter?
Mark: Yes.
Ari: I’m curious of the numbers you just gave, because in writing the relevant section for my updated book, I cited some research that was talking about 10% of the light being present at 1 centimeter of depth, and then another reduction of– In other words, a 90% loss of the light by the time you get to 1 centimeter deep below the skin. Then to go down to 2 centimeters was basically another 90% loss. By the time you get 2 centimeters deep in the tissue, you’ve lost 99% of the surface light.
Obviously, I would imagine that differs depending on the specific light device and the radiance, how it’s applied and the spot size and the wavelength, and things of that nature. Just curious how those numbers line up.
Mark: When I did my literature review for my doctorate, I found that in the wavelengths that we’re looking at, in the red to near-infrared, which are most commonly used for PBM, that you have depending the way length and the consistency of the tissues, between 2% to 10% with a laser. Not with an LED, with a laser. If you look at the LED studies, and I could show you the study, there’s a study by a group funded by James Carroll, who’s behind THOR, with a group with Anna Yaroslavsky.
They did a study where they used an LED on the cheek, and they were using one of James’s LED clusters, which is a– I think it’s an 850-nanometer source. They were measuring directly on the inside of the cheek using a power meter how much energy was getting through.
They also did some very sophisticated mathematical analysis using something called the Monte Carlo simulation, which is a mathematical tool where if you know the thickness of the different layers, the epidermis, the amount of fat that’s present in the tissue, and this sort of stuff, then you can do an approximation which will then tell what you could expect in view of the optical parameters of that wavelength and those particular tissues because this has all been measured by the optical physics groups in the work associated with optical imaging.
They found that there was a correlation there that they were accurate to within about 10% using the two different methods, the power meter, as opposed to the Monte Carlo simulation. When I did my sub-analysis looking at the amount of power that was actually arriving, it was between 0.2% and 0.6% of the surface energy that was arriving at depth.
Ari: At 1 centimeter of depth? Is that through the cheek?
Mark: Yes, through the cheek. They were looking at using this potentially as a tool for treating cancer patients extraorally because sometimes these people can’t open their mouths properly because they’re so sore. They thought maybe an extraoral approach would work using these LEDs. That gave me pause for thought because I then thought, “Okay, I know that from studies such as some of the transcranial PBM stuff related to the treatment of Parkinson’s disease as well as other conditions like depression and traumatic brain injuries that there are evidence-based papers there and sufficient of them to indicate that this is something which can work with an LED.”
In Australia, you even have people who are building their own lampshades and using LEDs because they’re so desperate to get access to care to treat their Parkinson’s and they were getting a positive result.
Ari: This again, may be a digression, but some of these people, these bucket hats that you’re referring to are using just basic LED strips, which have, I think, maybe around 2 or 5, maybe up to 10 milliwatts per square centimeter in irradiance that should be too low to deliver any meaningful amount of light through the skull into the brain.
Mark: Exactly. There’s a neurologist in Colorado called Theodore Henderson who did some studies where he was measuring in cadavers, where he had some skulls and he was measuring directly using high-powered lasers as opposed to LEDs. He did a paper and it was saying, “These things just don’t get through to the dermis. How can these things possibly work?” It was an open question, yet we know we’ve got this growing evidence base showing that LEDs could just work great.
I thought, “Okay. I have what I would describe as my PBM road to Damascus moment because I spent all these years studying lasers and working out different parameters and different wavelengths and optical spot sizes and things to do with the beam profile for a laser and how to deliver those photons to depth, and yet, apparently that’s not necessary.” I thought, “That just really perplexed me.” I then had to go right back to the drawing board again. I thought, “I’m getting [crosstalk] seriously wrong here.”
How PBM works
Ari: I’m curious where you’re going with this because, in my mind, I’m curious if you agree with this or you are going to go a different direction, the big confounding variable in those topics, basically what you’re describing here, this scenario, and there’s some research in humans and animal research where they’ve, for example, looked at altering brain health parameters by either trying to shine light directly on the brain or shining it, let’s say, on the legs and the abdomen, where no light is [inaudible 00:40:00] have shown similar results both in animals and humans which implies that the big confounding variable here is systemic effects of irradiating the bloodstream where you don’t necessarily need to deliver any light directly to that target tissue.
Mark: This is developing into a good conversation because I think I can offer you a number of different routes which are different in the sense that we’ve– You see, In science, there are multiple pathways of knowledge and different groups of scientists tend to group together and do their thing but they don’t necessarily cross information. You can end up over-specialized. When you start to look outside of those boxes and see what other people are doing, it’s surprising what you discovered.
I discovered this guy called Iyengar an Indian man. He’d done some quite nice studies.
Ari: A teacher of yoga.
Mark: Yes. He did some stuff looking at the effects on melanocytes of photoirradiation. Now sites–
Ari: [crosstalk] I was talking about the originator of a whole field of Iyengar yoga. I think you’re referring to– Not that person.
Mark: He’s a man. He’s a different person. He’s a scientist.
Ari: Got it.
Mark: Now, it may be related. You never know. Now, melanocytes– of course, you live in California. I can see you’ve got gorgeous sunshine out the window there. You’re quite used to the idea that photoradiation results in melanocytes producing melanin to protect your dermis against the harmful effects of ultraviolet light. Melanocytes are incredibly interesting because the melanocytes are actually, in terms of developmental embryology, of the same cell lines that produce the whole of the peripheral nervous system. It’s something called neural crest.
Neural crest derivatives form all of the peripheral nervous system, but they also do two things, one of which is very close to my heart because they’re involved in producing teeth in that dentine is a neural crest derivative. No wonder it hurts, because it’s like a specialized form of nervous tissue. Then the melanocytes, which are a different cell line, they don’t just produce melanin. On photoirradiation, they also produce, now get this, serotonin, dopamine, noradrenaline, adrenocorticotrophic hormone, and luteinizing hormone.
Ari: All of that comes from melanocytes?
Mark: All that comes from melanocytes.
Ari: Oh, I didn’t know that.
Mark: When you irradiate the melanocytes, then you’re getting all these very important neurotransmitters and hormones that are being released. Now serotonin, as you know, that’s the happy drug, which is why on a bright sunny day you feel good.
Ari: All of that, is it still UV-specific or are there other wavelengths that act on melanocytes as well?
Mark: No, there are many different wavelengths that are– It tends to be more the bluer, whiter, as it were, lights that are the prime chromophores for this action, but it is a broader-band effect. Melanocytes are really photosensitive, and when you activate those melanocytes, they increase and peak in their production of these very important neurotransmitters at about three to four hours post-irradiation. Now, that’s something which can produce a systemic effect.
I then began to think, “Well, okay, so that’s one possible pathway because maybe melanocytes may be involved because the melanocytes are present in the epidermal-dermal boundary so they’re right in the superficial layer and an LED will activate the melanocytes.” I thought, “Okay, maybe melanocytes are involved,” and I thought, “Well, what else is there in that?” I came across to this amazing paper in SPI, which was just a short, and they were talking about how myelin, which is the outer sheath of the axon, can act like an optic probe.
Now, an optic probe, to me as a dentist, is familiar, because I have this LED curing light, and I switch it on, it’s got a glass probe at the end where the energy gets directed through towards the tooth, and then it activates the chemical inside of the composite, which then sets. Myelin, the sheath around myelinated nerves, that is an optic conductor. It can transport photons along the length of the axon, including across what’s known as the nodes of Ranvier, which are the junctions where there’s synaptic plates.
It goes across this. Now, we know that axons generate things called biophotons. This is something that Ann Liebert’s group have written quite a bit about. These are naturally generated photons where, by virtue of enzymic processes in the release of the energy as things are degraded, they can also release some almost– not quite subatomic, but tiny packets of photons which have been measured and identified. These photons then travel down the myelin sheath.
They thought that these have then started to activate transcription changes in other parts of the cell. It’s the natural mechanism.
Ari: Has this been validated, that this effect occurred?
Mark: Yes.
Ari: Wow. This is amazing.
Mark: I can give you some studies. This then started me thinking, “Well, okay, so when you start to apply an extrinsic light source to the skin, what’s happening with those nerve fibers?” If you look at the anatomy, and I could show you some great graphics, I’ve got a presentation I could show you in this, then you can see that some of the nerve endings are actually in the epidermis as well as in the immediate vicinity of the epidermal-dermal boundary.
These are myelinated fibers. These may be acting as photo pathways where you’re actually helping to transmit photons into deeper layers. Then I started thinking about, “Well, maybe this could explain acupuncture.” As you know, when you start to stimulate it, it’s superficial, and maybe that’s related to the generation of biophotons because it’s traveling at the speed of light, and it’d be reaching very far distance targets transmitted through the spinal column up to the central nervous system, and what have you.
That’s my wild speculation. When I thought about other pathways, then Iyengar also wrote about– He didn’t talk about the myelin stuff. He was just looking at melanocytes. He also talked about optic transmission by hair. Now, if you’ve got blonde hair, or what’s known as vellus hair, which are like little short baby hairs, these act just like photo-optic guides, and it carries the light into the dermis. The hair follicle, which is like a little bulb which is growing hair, that’s richly innovated.
Then you’ve got a little pool of light going into the dermis. Now, this is something which is very important in animal behavior, because in some parts of the world, according to the season, the animals change the color of their fur, and it’s a photon-induced response. As opposed to the fur being a block–
Ari: We would expect clearer or whiter hair to transmit photons better than darker hair.
Mark: If you’ve got some shorter days, then there’s going to be less activation of the production of pigments inside of the dermis because there’s less light being transmitted there. Also, it could be also affecting the manufacturing and production of these natural neurotransmitters, such as serotonin, or adrenaline, dopamine, and what have you, which then affects the activity of the animal, which is why they start to hibernate. Some people suffer from SAD, Seasonal Adjustment Disorder.
In winter, they get the winter blues, and they buy these panels, blue light, in order to see if they can maintain a more active central nervous system physiology. When I go skiing, I get a really intense blast of light, and it’s a tonic. I feel great in the winter months because it helps activate all these natural sequences. We’ve got melanocytes, we’ve got hair, we’ve got the potential that myelin itself may be a pathway. I thought, “Well, what else?” I thought, “Well, maybe we’re just looking at this from the wrong perspective.”
All the work on PBM is based on tissue culture in small animal studies, and they’ve been looking at things in the Petri dish, and they’re saying, “Oh, yes, this photon at this particular parameter at this particular wavelength is generating this response,” which is correct.
Ari: Just a quick side note, what you just mentioned, the fact that so much research has taken place in vitro experiments in cells in a Petri dish also has, I think– I’m curious to get your thoughts on this. Maybe we’ll get into this probably in the next conversation in greater depth, but I think it’s also led to a very distorted picture of proper irradiance and dosing parameters because cells in a petri dish are likely to be vastly more photosensitive than cells in a living human body.
Mark: Also, they’re in isolation. It’s a monoculture as opposed to a tissue. If you’re looking at it in terms of an isolated cell group, the effect is going to be very different than if it’s in a mixed tissue where there’s an immune system and then you’ve also got some circulation and all sorts of extrinsic influences are operating because the human body is highly complex in the sense that you have multiple overlays of systems.
You’ve got your endocrine system, you’ve got your central nervous system, you’ve got local regulators, some of which are temperature sensitive, and then there are other factors to do with the nature of the tissue itself. Yet this beautiful machine, it just works incredibly well. There’s this communication system. This may, in part, explain why you can start to produce distant effects. Again, Ann Liebert’s group have done, as you mentioned earlier, some work where they’ve been irradiating the gastric and intestinal tract externally and producing effects, which–
Ari: Is that in animals or humans?
Mark: In humans, where they’ve been producing some of the similar effects in terms of the benefits that you would see for a transcranial device. Now, that is something else, and I think, “Well, this must be a systemic effect, or maybe it’s working through the vagus nerve, I don’t know.” Having had this kind of thinking, I was thinking, “Okay, well, it’s not to say that the other mechanisms are wrong. Far from it, but there’s obviously a lot more happening.” Let me carry on with the story, Ari, because it’s a great story.
PBM and heating of tissue
Ari: Mark, I just want to let you know I have about five minutes, and this conversation is fascinating. I feel like I want to talk to you for the next five hours. I suspect that I’m still waiting for the part, by the way, that you’re going to upset me. I don’t know if you’ve gotten to that yet, but you have not upset me at all. I’m fascinated by this conversation. I’m very, very excited to talk to you. I feel like this is probably going to have to be at least a three or four-part series to get to all these layers of knowledge that it’s very obvious that you have. Fascinating stuff. Please continue. I have about five more minutes before I got to go.
Mark: You wanted to know about temperature. Let’s talk about temperature. Now, in certain circles, this is heresy. Photobiomodulation is not a photothermal response. I’m in agreement with Mike Hamblin there, and I’ll say, “Well, no, that’s not true. You see, if you go for this multiphasic response by triggering off this inhibitory mechanism inside the cell to switch off axonal activity, which is what happens when you elevate the tissue temperature by two degrees centigrade with the HSPs and the UCPs and what have you, which mothballs cellular activity, that’s a highly useful event.”
I would regard that as much photobiomodulation as the excitatory things. It’s semantics. The other thing is, “Well, okay, but can you have too much of a good thing?” Praveen says 42 degrees centigrade. Actually, above about 42 degrees centigrade, two key enzymes are deactivated, and then there is an ascending risk, but then this morning, first thing, I had a really hot cup of coffee, and my lips are still there. It’s to do with time and duration as well as the temperature.
This, again, is very well described in literature from other parallel fields. We know exactly how long you can expose tissues to at certain different temperatures before you start to see signs of tissue damage, and Praveen actually did a study on this. By virtue of the fact that in any phototransduction process, particularly with near-infrared, you’re going to get some heat, then it is an inherent property. I’ll finish by saying that there is a world of difference between the effects of a heat source and PBM.
At that point, I’m not going to say anything more, because I’m going to hold you on tenterhooks until we meet again, because there’s a lot [crosstalk]
Ari: I think everything you just said, I follow it, but I think you’re speaking on such a high level that it will probably be over listeners’ heads as far as exactly what you’re referring to, and there’s a whole controversy around– I’m just explaining to the listeners now. There’s a whole controversy around tissue heating during photobiomodulation and that’s what Mark was just speaking to here. Some people have put forth the idea that photobiomodulation should be non-thermal or is by definition non-thermal.
It’s mechanisms that are active in the cells in response to light that don’t involve heating the tissues. Further, some people have put forth the idea that increasing the temperatures of tissues to the degree that there is a thermal heating effect happening during photobiomodulation, that means it’s not true photobiomodulation.
Then another layer of this story is the idea that heating the tissues not only is– In terms of semantics, is not true photobiomodulation, but is harmful to the cells and above a certain temperature, what Mark was just referencing there is something that was discussed in the podcast I did with Praveen Arany, where he talked about his research on heating during photobiomodulation and above 42 degrees Celsius, you start to get deactivation of free radical reactive oxygen species scavengers.
Hopefully, you guys follow that, but basically, there’s a contentious issue around heating of the tissues during photobiomodulation, and there are some somewhat differing perspectives on that issue. That’s what Mark was speaking to there.
Mark: Absolutely. The long and short of it is that when that photon interacts with your biological target, you’re producing a variety of effects. One is going to be photochemical, another it can be photothermal, another it can be photomagnetic, it can be photo-fluorescent, and it can be photoacoustic or it can be photoelectrical. It’s an electromagnetic force. The effects on the target will depend on the resonance frequency of the particular target it hits, as well as the intensity of the energy that you’re applying.
You can start to produce multiple effects. It’s not just single hitting that magic switch to turn on CCO to produce more ATP, you’re producing multiplanar effects within the context of a 3D entity, which can be quite a big creature like myself, and you yourself. There’s all these other interplays of an endocrine system and a nervous system.
I think this oversimplified concept of PBM as being a 2D-planar cellular event, you’ve got to take a much bigger and wider perspective on it because when we start to think about high energy PBM, which is a really exciting area in PBM research at the moment, which I’m involved in, you can then start to think, “Well, what are the safety features of it? What can you safely achieve? Is this going to improve outcome?” That’s for a whole different conversation. We’ve got a long road ahead of us, Ari, I’m sorry. [crosstalk]
Ari: I see that. That’s exactly my thought. I feel like we have a very long road. You have so many layers of knowledge that I’m very excited to dig into with you. I feel like you’re just scratching the surface of this whole landscape of all this mind-blowing stuff. You have me very, very intrigued and very excited to continue this conversation.
Show Notes
00:00 – Intro
00:36 – Guest intro
19:12 – The biphasic dose response
26:17 – Heat stress
35:31 – Does the frequency matter
55:02 – How PBM works
1:07:41 – PBM and heating of tissue
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