This Podcast Will Kill You - Ep 157 Retinoids Part 2: …how it’s going

Episode Date: November 12, 2024

That same little bottle of retinol serum sitting on your bathroom counter - how does it work? Does it actually work? Those are the questions we’re taking on in part two of our retinoids two-parter. The answers, as you might expect, are complicated. Because as it turns out, “retinoid” is a catch-all term for a bunch of different types of compounds, all of which work in slightly different ways. And on top of that, the testing required to demonstrate efficacy isn’t exactly held to the highest of standards. But we do the best with what we have to get to the bottom of this retinoid puzzle. Tune in to learn everything you ever wanted to know about retinoids. Support this podcast by shopping our latest sponsor deals and promotions at this link: https://bit.ly/3WwtIAu  See omnystudio.com/listener for privacy information.

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This is a job for Indeed sponsored jobs. From the moment of birth, you begin to age. The changes are almost entirely internal and imperceptible. But by your 20s, the sun has probably left its first telltale marks on your most prominent feature, your face. You start to get tiny lines or wrinkles. Or as dermatologists put it, you experience photo aging. Usually by your early 30s and with each passing year, those first fine furrows begin to deepen and multiply. To some, the lines are signs of character or a merry disposition to be neither fretted over nor false.

against. To many others, though, they are scars, reminders of the disappearance of youth. Not surprisingly, then, eliminating wrinkles is a roughly $3 billion business in youth conscious America. In the past 15 months, however, we have been told that much of this energy and enterprise may have been rendered obsolete by a drug that purports to improve skin tone and erase wrinkles. Its scientific name is all trans-retinoic acid, but most of us know it by its brand name, Retinae. Once a popular acne cream marketed by ortho-pharmaceutical, a $600 million a year subsidiary of $9 billion Johnson and Johnson, retinae has been hailed by doctors and the press as the first drug, as opposed to a cosmetic, that shows promise not only in treating the symptoms of aging, but also in actually

reversing part of the process itself. Do you like my dramatic rendition there? I loved the dramatic rendition. I do want to know how big the industry is today because that's from that same money magazine, right? Okay, 1988. Can't wait. Three billion dollars in 1988. Wow. Wow. Yeah. So that quote was excerpted from the article that you quoted Aaron. Thank you for sending me this last episode, which was The Selling of Retinay by Leslie Vreeland in CNN Money Magazine published April 1st, 1989. 1989. Got it. Oh, I'm so excited for this episode.

It's going to be a good one. Hi, I'm Aaron Welsh. And I'm Aaron Elman Updike. And this is This Podcast Will Kill You. So last week, if you haven't listened to last week's episode, I recommend it. Must you before today? Not necessarily, but it's a good primer. Yeah.

No makeup. Term intended. Get it. Good one. Because last week we focused all about how retinae came to be and really the horrific backstory of the person, Albert Kligman, who was very much at the forefront of the development of retinae. And all of the horribly unethical experiments that went down in order to create this product that now is so ubiquitous. And today, we are going to talk about what retinae even is. what are all of the other retinoids that are out there? And what do they do? And do they actually work? And how? And why? How and why? Love it. I'm so excited because I, that's definitely something I didn't

come across in any bit of my research. I was like, I don't know if retinol works for anti-aging or whatever. And I know that I have my biases in terms of disbelieving any claim that any skin care products makes. in general, but yeah. Yeah. Yeah, it's going to be fun. We're going to get all into it, but first, we're drinking the same thing as last week. We are. Quarantini is skin deep, and it has carrot juice, again, vitamin A, blah, blah, blah, blah, beta carotene. I remember that. Beta carotene to vitamin A to Tritone. Yeah. That's the pathway. So we got carrot juice in there. We got ginger, lemon, vodka, you know, it's a hit. It's a hit. And the full recipe is up on our website, this podcast, we'll kill you.com, and our social media channels. If you're not following us,

you should be. And we've always got a non-alcoholic pussy burrito version as well. On our website, you can find great things. You can find transcripts. You can find the sources for each and every one of our episodes. You can find a contact us form if you want to hear a certain topic or you just want to say hi or if you say hey come say hi to us come to my uh organization and give a talk we've got a submit your first hand account forum we've got links to merch to patreon to music by bloodmobile to our bookshop.org affiliate account our goodreads list wow so many things on that one little website who could believe it oh um also rate review and subscribe. Okay, shall we get into, this is going to be a big one, so let's just take a break and get

started. That sounds great. Retinoids. Retenoids. So how I'm going to try and break down or organize this episode is we'll first talk about what the heck is a retinoid and what is vitamin A. And again, not a ton of detail because we're really going to focus on the uses of vitamin A or retinoids in skin and skin care. And then how and what the evidence is to actually support that. And then finally, we'll get into how that evidence has perhaps been extrapolated by the cosmetic industry to sell us all anti-aging products and whether or not there's any data to support such extrapolations.

Love it. Oh my gosh. I'm so excited. It's going to be really, really fun. I'm excited about it. So the term retinoid encompasses a pretty wide range of chemicals. Retinoids as a large group are essentially all either vitamin A derivatives or they function like vitamin A in our bodies or in our skin. So whatever their chemical structure may be, because especially with the development of more synthetic retinoids, they don't look the same as vitamin A looks. Whatever their chemical structure, the things that we classify retinoids are binding to specific receptors, retinoid receptors, and acting in a similar way to vitamin A. And vitamin A's other name is retinol, or all trans retinol. And again, there are a bunch of

different types or a bunch of different forms. And you might be familiar with some of these names. Retinal esters, retinaldehyde, tretanone, isotretanone, adapt. Apolline, there is a whole range of these chemicals, and they all, again, function at these retinoid receptors. And we're going to lump them, for the purposes of this episode, into two major buckets, prescription retinoids, and over-the-counter retinids. Cool. Cool. So what the heck do any of these retinids actually do? Vitamin A, which vitamin A is just call it like a, it cool. equivalent to all of these for the purposes of this. Okay? We're lumping it all. That's fine. Vitamin A is an essential nutrient. It's a fat soluble vitamin, so it dissolves in fat, and we can

store it in our fat. And like all vitamins, this is something that we need in our diets. We don't make it ourselves, and it is essential for life and survival. We need vitamin A from the very earliest stages of embryonic development all the way until our death. Vitamin A is essential. Vitamin A is a essential in the formation of our nervous system and the way that our bodies are built and patterned as an embryo, like the way that an embryo is literally built. And it's also essential for vision. And its role in vision is really well established and, again, worthy of its whole own episode. But that's not today. That's not today. We get vitamin A in our diet in the form of carotenoids like beta-carotene in our carrots.

And then also from eating, ingesting like preformed vitamin A in our foods. Like if you're eating meat, it probably has some vitamin A in it as well. Okay. But today we're going to focus on how we use retinodes specifically in our skin because they have become such a seemingly ubiquitous and essential part of skin care. So to understand how these retinoids work in our skin, let us first understand our skin a little bit better. Love it. So our skin is composed of three major layers, starting from the bottom, aka the inside of our bodies and going towards the outside.

We have the subcutaneous tissue. It's also called the hypodermis. And that's mostly just like fat and stuff. It's like your fluff, right? And then you have your dermis, which is like the bottom layer of what is really like skin, skin. And your dermis is made up of stuff like collagen and elastins, which are made by these cells that are called fibroblasts. Your dermis is also where all of the blood supply is to your skin. And your dermis is like the really strong part that really holds us together, like quite literally. And then on top of your dermis is your epidermis. And your epidermis is very, very thin. It ranges like on the soles of your feet and the palms of your hands. It's the thickest, maybe the width of like two credit cards stacked together.

All right. If you can imagine that. I don't know. Whenever I see those, I'm like, I don't know. the fancy credit cards now or like old school credit cards. I don't know. It's pretty thin. One of mine is metal and very thick, but I'll just say it's one of the, it's that. It's like that thick. I don't know. Dinner shows up every night, whether you're prepared for it or not. And with Blue Apron, you won't need to panic order takeout again. Blue Apron meals are designed

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And our epidermis, like specifically, this teeny tiny little layer is the number one protection that we have from the outside world. And despite how relatively thin it is, just like in general and also compared to the other layers, the dermis and our subcutaneous tissue, it still also has a whole bunch of layers within it. And we talked a little bit about the different layers of skin in our skin cancer episode. But it's, I almost imagine it like one of those really, really fancy cakes that they make on Great British Bake Off, where you have like a bunch of different layers that are like different compartments, but all together, they're like delicious cake.

Okay, like the really thin layers? Like, how many layers are we talking? So let's get into it. There's the basal cell layer, which is the bottom of our epidermis. This sits on top of a basement membrane that touches our dermis. And our basal cell layer is the cells that proliferate. So these are like stem cells. They proliferate.

They replicate. And as they replicate, they also migrate upwards towards the outside world, like towards the top of your eponymous. And as they migrate, they also differentiate. and the major cell that we have in our epidermis are called keratinocytes. And they're called this because they make keratin, which is the protein that we make in our skin and our hair and our nails, etc. And so this basal cell layer is the first, like the bottom layer. And then you have a bunch of these keratinocytes.

And then as they migrate upwards and continue to differentiate, they form from these like fat, chunky, juicy, I don't know, like a moose. layer of cake, yum, into something more flat and squat, like, say, I don't know, like a meringue layer, like something a little bit more firm. Marins like fluffy, right? Yeah, but not like a cooked meringue, something like a somewhere between super jelly and more firm. I'm losing it on the baking references here. My baking knowledge is much more limited than yours. Like a pudding layer?

No, not a pudding layer. Anyways, we're just going to ignore the baking. Okay. Well, it'll make sense again at the top. So then they get to be more squat and flat and stuck really close together. And then at the very top of our skin, the very first layer, like when you're touching right here, that layer is super keratinized. Basically, those cells no longer even really look like cells, they just look like layers of keratin because they're so smushed and stuck together. They no longer have a nucleus.

those are kind of like fondant that you put on top of the cake. Okay. All right. We're trying. That very important outermost layer, the fondant, is called the stratum corneum. And the stratum corneum is a really important part of our whole epidermis. It holds our water in, like fondant holds the rest of this jello cake together. It protects us against UV damage and oxidative stress.

It protects against infections and other environmental toxins. Just below this stratum corneum, all those other cells, they're still very keratinized, like the next layer down, but they have a little bit more room between them. There's a little bit more kind of like mortar holding the bricks together, more fatty stuff, and then you have just the rest of your kind of cell layers down to that basal layer. Throughout this, we also have other cells, right? we have melanocytes, which are pigment-producing cells. We also have hair follicles, sebaceous glands that produce sebum.

We have nerves. We have other immune cells. But most of your skin are these keratinocytes. So being our largest organ by surface area, a lot of different things can go wrong in our skin, especially as it is constantly being insulted from everything in our environment. And as it turns out, retinoids are used medically by prescription to treat a pretty wide variety of skin conditions. So let's get into some of this. Focusing mostly on prescription retinoids here, we'll talk more about over-the-counter versions later. Prescription retinoids are often used to treat acne, which is, again, what you talked a lot about, Aaron, in last week's episode, one of the main first things that we figured out

that retinodes can do. So acne is what happens when pores and your hair follicles, which pores are kind of like hair follicles and no longer have a follicle in them. They're just little channels down to the lower layers of your skin. When these get stuffed with dead skin cells and bacteria that end up proliferating, they can eventually come to the surface and burst forth. And when that happens, you get a lot of inflammation, you get a lot of pain, and potentially a lot of scarring. We use retinoids very often to treat acne, especially to treat acne that can cause that kind of scarring, because not all acne does. Retinoids are also used to treat some kinds of psoriasis.

And psoriasis is something that can result in what are called hyperkeratotic, meaning there's a lot of, like, thick, disorganized keratin production. And it forms these plaques. And so retinoids can be used to help treat that. How do those plaques form? Oh my gosh, psoriasis is its whole own episode. Okay, I know. Is there like a TLDR?

TLDR is it's like disorganization of keratinization and like the sloughing of your skin. And it's an autoimmune disorder. So there's like a lot more detail to it. Did not read the instruction manual and we're just going to throw keratin everywhere? Right, right, right. Okay. Is that? Yeah.

It's like a lot more detailed than that, especially for psoriasis, because it's like autoimmune. So there's like your immune system in general not reading the manual. So yeah, in general, not reading manuals is accurate. Retinoids are also sometimes used to treat certain types of skin cancers, including Kaposi's sarcoma. And also other more rare forms of things that tend to be under this umbrella of like abnormal keratinization or what's called de-esarchomal. which is basically when your cells are not adherent to each other in your skin the way that they should be, right? Because they should be pretty well brick and mortar together. Like enclosed by this fondant is like one tight nug, right? Yeah. But disquamation means that

things are not well connected. So then you get a lot of flaking, a lot of itching. So these are things like ectheosis or dernier's disease. There's a lot of different things that can potentially benefit from retinine treatment. And of course, the big elephant, the wrinkly elephant in the room, retinuits are used for photo aging. Now, let's take a minute here, shall we? Aging, of course, is a completely natural process. And I don't mean natural in quote-unquote, the way that goop says the word natural. I mean that aging is not a disease state.

But it is characterized by visible changes in the architecture of our skin. Aging skin is characterized by things like a loss of hydration and like an inability to regulate hydration as well because of damage to that kind of outer layer of skin. It's also characterized by reduced collagen production, a loss of elasticity, and a delay in recovery after injury to the skin. And there's probably more. UV damage, like exposure to the sun, speeds up and exacerbates this aging process in a way. And that is the process that people are talking about when they say photo aging. And so photo aging looks like all of the things that I'm not going to say any brand names, but certain brand of skin care product commercials might tell you that you must

avoid at all cost, right? It manifests on your skin as things like fine lines, wrinkles, dispigmentation, things called solar lentigenes, which are those like spots, sunspots, loss of elasticity, blah, blah, blah, blah, blah. Histologically, we see a thinning of your epidermis so that those cake layers altogether are thinner. Okay. And disorganization of some of the connective tissue. So it's not like laid down in really nice sheets the way that it is in non-photo-damaged skin. Looks like a cake that I would make then. I think you can make a great cake, Karen, don't sell your shells short.

Thank you, but I beg to differ. Yes, a homemade cake, okay? Yes, okay. And so all of these changes are going to vary, not just with the amount of UV exposure that someone's exposed to, but also with things like the amount of melanin in your skin, because melanin, which is the pigment produced by our melanocytes, is protective against UV damage.

and it's just going to vary based on straight up genetics in ways that we don't fully understand, but there's a lot of genetics involved in both aging and photo aging. So how do retinodes then fit into these drugs? I said that we use them for these things. How exactly? Like what are they doing? Right. And how are they doing all of these different things? Because it sounds like the mechanisms of aging or the mechanisms of a condition like psoriasis, like acne, are different. So what is it, what is the unifying thing that is, yeah? Excellent question. Let's get into it.

Okay. So retinoids, I already said, are this group of a variety of different chemicals with different chemical structures that act on this common ground of these retinoid receptors. We have a bunch of these throughout our body, like six different kinds of retinoid receptors. There's a few of them, like three or four at least, that are present in pretty good numbers in our epidermis and our dermis. What retinoids do is they bind to these specific receptors, which are on our DNA. And what they do then is they modulate the expression of other genes.

So what does that mean? They are changing the way that our skin cells are interacting with our environment. So our skin, again, is the major barrier between us and our outside world. So we might think of it as just like a thing that just sits there, but it's not. It's an organ, and it's a very dynamic organ. It's constantly responding to changes, changes in light, in temperature, humidity, responding to pathogens, trying to fix all of the damage that UV rays are imposing on it. So topical retinodes, especially, bind to these retinoid receptors.

They turn some genes on and turn other genes off. And what it seems like they do is they turn on genes that produce things like growth factors, and they turn off genes that do stuff like chop up collagen into tiny little bits. And they also can turn on genes that help to induce that skin cell, those keratinocytes, to differentiate from that basal cell layer, and just increase turnover overall of cells. Okay. So that's a lot of different functions. Yeah, and this is both topical and oral retinoids.

So, yeah, all of them are going to work in the same way. Topical retinoids and oral retinoids, they're going to bind to the same receptors. They're binding to the same things. The oral ones are going to be much stronger, and they're going to be binding to additional receptors that are not only present in your skin, but other places as well, and reaching deeper down into your dermis that topical preparation. are not going to reach as well because your dermis is where the blood flow is, and it's actually really hard to get things that you apply topically all the way down deep.

Right. Too many layers of defense in there. Exactly. We've got such great skin. So all of this variety of functions, what does it end up doing? Like what do we see with retinoid application? We see a thickening of that epidermal layer. So the whole entire, from the basal layer to the top, we see a thickening of that, especially the moose section in the middle, those healthy growing keratinocytes in the middle. We also see an increase in collagen and elastin production. And so this is sometimes called like a regeneration of the extracellular matrix. This is the stuff that holds our skin together. And because retinoids are turning

off genes that are chopping up collagen, we see more collagen and elastin being made. And because it's also increasing cell turnover, what that means is that you're sloughing off skin. It's pushing from that basal layer up and up and up to that stratum corneum and being kicked off of our bodies. Okay. Into my carpet more rapidly. Okay. So that is one of the ways that it helps in acne because by pushing out cells more rapidly, you're also reducing the amount of sebum that's produced and sitting around.

which helps to reduce the formation of those, like, areas where you've got nuggets of dead skin cells that are being able to sit there, which means that you have less of a conducive environment for bacteria to grow and thrive. Yeah. It's also why you often see if someone has acne or even doesn't have that much acne and starts using a retinoid, you can often see this, there's a lot of different terms for it, like purging is not a very medical term. but you can see a worsening of your acne when you initially start using it. And that's because it takes time for that epidermal turnover to push all of what's already deep in your skin out to the surface. Okay. And I'm not done. There's more. The reason that this then ends up helping in things like pigmentation changes, like say sunspots,

is because in increasing that cell turnover, you're reducing how much time the keratinocytes, those skin cells, are in common. with the melanocytes, which is a fancy way of saying you just have less pigment that's getting built up in random little cells. And in doing all of this, retinoids also seem to help protect against further UV damage. And I find this point especially interesting because retinoids can actually make people much more sensitive to the sun. They can heighten photosensitivity. They can make you have rashes or have more easy sunburns. But on a large scale, part of what they are doing is turning on and off genes that are also getting turned on and off in the opposite direction from UV damage, if that makes sense. So they're kind of counteracting what ultraviolet light is

doing to our skin. Right. Okay. So if ultraviolet light says flips the switch to off, retinoids are flipping that to on. Exactly. Okay. Yeah. So that is all of what we know. And again, there's a lot more detail. I've got a bagillion papers if you want the like real deep deeds. But that is what we know about how these retinoids are working and why it is that they are used medically for the indications that they are often used for. Now, all of this data that we have is almost entirely exclusively from Tretanoin, aka retinoic acid, aka the stuff you can only get with a prescription. So prescription only is that because, like, I want to know more about this. Maybe this is a bigger question, but like, is that because strength? Is that because application? Like, why is it, why is that prescription only? Oh, Erin, we will get there. Okay. Okay. Okay. Okay. But that is kind of like the big picture of retinoids in general. Okay. Do you have any questions? I'm shocked. I mean, I do, but I know that you're going to get into a lot of it. And so I'm like, I want to be like, but how does that this? And how? Yeah. Yeah. What is.

Is it increased cell proliferation? Is that a thing all the time? Like, is that something that we should aim for? Or is that have potential consequences? Like, are there consequences to retinoid use? I mean, absolutely, yes. So there are definitely major side effects. The biggest side effect for topical preparations of any type of retinoid,

but especially the prescription retinoids, so tretnoin and other similar retinoids, because there are other ones as well. The biggest side effect tends to be skin irritation. And that's because it is doing all of the things that we said that it's doing, right? So it's increasing your cell turnover. It's like forcing your skin to be making a whole bunch more of what it's doing. And so especially depending on your skin type, depending on what you've been using before, depending on your sun exposure, some people have really strong negative reactions to various retinodes

and really can't tolerate them. The other big thing to know about retinodes is that they are also teratogenic. So teratogenic means potentially incredibly harmful to a developing fetus. Now, this is very true for isotretinoin, which is the form of retinoid that is used orally in the U.S. Okay. There are other forms of retinoids that are used orally in other places. So this is true for oral forms of vitamin A. while vitamin A is like an absolutely necessary part of human embryonic development,

like you can't make a brain or an embryo without vitamin A, it's concentration dependent. So if you have too much of it, you also are at risk for pretty severe developmental problems in a developing embryo. So with oral retinoids, we see very high rates of congenital defects, which can include anything from congenital heart malformations, neurologic malformations. So problems with your heart, problems with the nerves, problems with the way that the face is formed, and a whole range of really, really wide-ranging developmental problems because it tends to affect really early stages of embryonic development, as well as a very high rate of spontaneous abortion when people

are on oral retinids and get pregnant. Okay, I have a couple of questions. Give it to me. Why would you go on oral retinoids versus topical? Is it just to have more of these systemic or like deeper dermal effects? Great question. So the main indication medically for oral isotretinoin is severe acne that has been unresponsive to everything else. Okay. And then question two, you said that high doses of vitamin A can lead to congenital defects. is that something that you would encounter outside of oral trinotenoin? Like eating a lot of care. You know what I mean? Like, does our body have a way of, you know, excreting excess vitamin A that is taken, like, through dietary forms?

Excellent question. It's not. It's a fat soluble vitamins. So we're not excreting it. Okay. So it absolutely can build up in our tissues. It would be very difficult to get vitamin A toxicity just from eating something like carrots. because, again, those are precursor vitamins that you're getting in the form of, like, carotenoids and things like that.

So in that way, it's not impossible, but very difficult. Certainly, if you're taking a bunch of supplements that aren't isotretanone but are other vitamin A supplements, then yes, you definitely could see similar effects. Okay. So what I want to mention, because I do think that this is an important part of the story, is that because of the risk of birth defects and spontaneous abortion, but mostly because of the risk of birth defects, when someone is on something like isotretanone or acutane is one of the brand names for it, there are very extensive restrictions on the prescribing of this medication in the U.S. and in most other countries.

In a lot of places, it's only dermatologists or other specialists that can prescribe it at all. And almost universally, anyone with a uterus, who is considered of childbearing age, has to read through a really extensive document that outlines the risks and guidelines of use. They have to sign a pledge committing to using two forms of contraceptive therapy, starting one month prior to the medication and continuing for at least one to three months after they're done using iso-dentin. And in some cases, they have to take monthly pregnancy tests before they can get each prescription, which also means you can only get your prescriptions 30 days at a time. And despite all of this rigamarole, from what I have read,

there is no real evidence that this has actually decreased the risk of fetal exposure to isotretinoin. Wait, why, though? Because, I mean, I think because there are so many layers to this, right? Like, A, not all birth control. is perfect. B, signing a pledge is not the same thing as doing it. See how much are these risks actually being explained versus, oh, just sign here and do this and then you'll get your medicine. Yeah. Right? Like there's, there's a lot, a lot, a lot of different layers to it. Okay. There's also a registry in the U.S. that you have to sign up for. And like every person involved has to sign the prescribing provider, the, the pharmacist who's dispensing it, the patient. And so it's

all on a registry in the U.S., which is a country that has restrictions on access to birth control and is banning abortions and criminalizing pregnancy? Ah, okay. Yeah. Yeah. Yep. Yep. Yep.

So it's important to know it is, it can be a very effective medication for severe scarring, like cystic acne that hasn't responded to things like topical preparations. It has the potential for serious side effects like breath defects. It also has some other side effects. It can increase your liver enzymes. It can increase your cholesterol. Most of those are transient. And so they tend to get better as soon as somebody stops the medication.

And in some cases, this medicine also can make people feel really bad, like cause things like depression to worsen, anxiety, and things like that. And we don't really understand the mechanisms of any of that. Okay. But it's not a medication that is easily prescribed, just like bloop. Mm-hmm. But anyways, let's get back to wrinkles. Yeah, yeah.

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All right. So I told you everything about what we know about something like retinae. Yeah. Or even a dappoline, which I will say is now over the counter. You can get a dappoline. It's different. It's one of the brand names in the U.S. And that used to be only available with a prescription,

but now some concentrations of it are available without a prescription. Just real quick, because I feel like maybe you'll go down this road, but the different formations of this, do they have just like different effects, or they target different genes, or what's the deal? Yeah. I'm so glad you asked, Aaron. So the prescription strength retinoids are all either retinoic acid, which is trinotin, retinae, or they are synthetic versions of a retinoid that are active when you put them on. That is the biggest difference between over-the-counter retinols that you can buy at CVS or wherever target. Costco, anywhere, sacks, if you want to buy expensive versions, right? All of those types,

which have names like retinol, retinaldehyde, and a whole bunch of these retinal esters, all of those types of retinoles are not the active form. Retinoic acid, trinotenoin, retinae, is the active form of a retinoid. That's what's binding to your receptors. That's what's doing the thing. Okay. The other ones that are available through a prescription, like adapylene, there's also, like I mentioned already, isotrotrinoin, there's a newer one called tazerotene. There's a whole variety of these. These are synthetic versions.

They look different than retinoric acid, but they are binding to the receptors themselves. So they, again, they work when you put them on. Everything that you can buy over the counter has to be converted. It is a derivative and isn't the thing. that is binding to the receptor. Okay. So if you put on an over-the-counter retinol, it says retinol on the bottle, it has to be converted through a two-step process before it becomes retinoric acid and is doing a thing to your skin.

Okay. So like what then is that process or like how is it? Yeah. It's oxidation by enzymes in your skin. You basically, your skin has to see it and be like, oh, I know what this thing is. It's like a vitamin A. I'm going to use it. Boop, boop, boop.

then it converts it, and then it uses it. But, like, ultimately, then how is it, like, is it just, like, the strength, the power, like the concentration? Okay. Okay. Yeah. So what the, here's the, here's the bottom line, because I feel like one of the big questions that I had in doing this episode is, like, there's these prescription strength versions and there's these over-the-counter versions. We use the prescription strength for a lot of stuff. We have good data for Tretnoen that it's doing most of the things that we're prescribing it for. There's less data for the photo aging effects of the other ones. Okay. Because they don't need to do that study. We'll get there.

Yeah, I'm excited for that. But what about all of these other ones, right? Because you can get so many else. And the bottom line is that while we have evidence that some of these might work, we don't have the type of evidence that you would expect from a drug. And we will probably never have that kind of evidence. So what it ends up being is that all of the over-the-counter retinoids are substantially less potent than tretinoin. So it's often, like the number that cited is that retinol, which is one of the most common over-the-counter versions, is about 10 times less potent than trinin, the prescription strength. Okay. So they put it in your bottle, in theory at 10 times higher concentration.

Right? I feel like you're going to tell me that it's not right. Well, Aaron, when I tell you how many papers I read for this to try and really get a sense of all of these other types of retinodes, do they work or do they not? I still don't have a clear answer. All of the data that exists for these over-the-counter versions of retinoids are suburb. to major industry bias, because nearly every study is funded by industry. Most of them are pretty small studies. None of them are really great studies. But there is a really big amount of data

out there that is a conglomeration of data on histologic samples. So like you cut skin, you apply stuff, you look at it under a microscope. Animal studies, so you put it on a mouse and see what happens to their cute little wrinkles. And human studies, which some of them are well designed and some of them are really not well designed, but they're human studies on face skin, on arm skin, on butt skin, on a whole bunch of different kinds of skin. And overall, the conclusion that I come to is that there is a preponderance of evidence that some of these retinoles work in a similar way to tretanoin. Mostly retinaldehyde, there's maybe stronger evidence for, and this is a type of retinol

that only has to be converted one time in your skin before it's active. Okay. And to a lesser extent, retinol, which is one of the more common kinds, and has to be converted twice. At certain concentrations, these seem to be effective for treating photo aging, which is the only thing that people are studying them for. So I just, that's what they're studying them for. Okay.

Effective meaning what? Effective meaning when you test them, they reduce the appearance. I'm putting all of this in air quotes. Uh-huh, uh-huh. They reduce the appearance of fine lines. They reduce the appearance of sunspots, solar lentigenies. And in some cases might improve things like skin roughness or brightness or evenness or things like that.

Again, these are not well-designed studies. And I want to now remind ourselves of a really important part, because what I said is that there is evidence for some of these types of retinoids that at certain concentrations, they may be similarly effective to trinone. So let's remind ourselves of our supplements episode. If you haven't listened, please do. It's one of my favorites. So cosmetics or cosmaceuticals, which is when a cosmetic product is actually supposed to be doing something to your skin, anything that you're buying over the counter are regulated entirely differently than drugs that you get from the pharmacy. And much like supplements, which are also not regulated, cosmeaceuticals are not regulated, essentially at all.

which means that just like for supplements, skin care companies can make a huge variety of claims about what their products can or can't do. But they do not have to do any research to prove these claims. They do not have to get any kind of approval from the FDA. And they don't have to even tell the FDA what's in any of their bottles of anything. really? Like there's no even a ingredient quantity list? You have to have ingredients on your bottle, you don't have to tell the FDA anything about what it is before you sell it to consumers. Uh-huh. Yep. Mm-hmm. Which also means that these companies have absolutely no reason to waste their money doing how much work it would take and spending how much money it would require.

to do good, well-researched, well-designed, side-by-side, randomized controlled trials where you're actually testing things the way that you need to to get something approved as a drug. Rather than ensure, like an actual double-blind or like, instead of just ensuring that the data will fall the way you want it to fall. Because just going back to all the different measures that you said, reduce the appearance of wrinkles, reduce the appearance of solar lentigenes. increased skin elasticity. I know that you said some of this was histologic changes, but I feel like two things are important to remember. One is that some of those observations

seem to be just that, like subjective, does it look less wrinkly? Like how do you measure that quantitatively? But then number two, even if you do measure it quantitatively in some capacity, you could say reduce the appearance, even if it's the most minor reduction. And so is there actually meaning in that reduction? Oh my gosh, Aaron. I mean, that's even like a whole other level because drugs don't even necessarily have to show that, right? Like, if you have statistical significance, that's not the same as clinical significance.

That's something that's true in all of medicine and not just, definitely not just skincare products, but like especially in skincare products. And like, I mean, yeah, bottom line is not at any single cream or anything prescription or otherwise that you rub on your face is going to make you look like, I don't know, who doesn't have any wrinkles. A baby? A baby. Yeah, a baby. There you go. I'm going to try and say a famous person. I can't think of any. But yeah, so 100% that is definitely true. I will say there are ways to quantify things like hyperpigmentation or the depth of wrinkles and things like that. And some studies do that, but a lot of studies don't. And that's the point. I have so many sources that you guys can go and read through. And some of these studies are fine. Some of these studies are halfway decent, but a lot of them aren't.

And so it's really like you have to look at all of the evidence, right? And there isn't an incentive to do better studies. And so here's the other thing that becomes so problematic with the way that these cosmetics and cosmeticals are regulated. There is no good way as a consumer to sort through these thousands of products that are available. And because labeling laws are essentially non-existent, you have no idea what it is that you're actually getting, much less what percentage of these various retinoles that you're getting. So as an example, I did a Google search. I googled best over-the-counter retinoid. That's what I googled. I found a bunch of these top 10 lists, you know, like US World News is like best ones. And like health.com, click on my affiliate link, Allure.

I looked at all of these. I went through every single one of these top 10. By the way, they're all different, which tells you something. Yeah, it does. I read through the ingredients on every single one of these bottles that they recommended as top 10. Most of them had absolutely no concentration listed. Most of these used retinol, which, again, has some data to support its use. A lot of them used retinal palmitate, which is a type of retinal ester that actually has data that shows it

doesn't work. It doesn't do anything. In fact, very few of them use retinolthehyde, which again is another one that has some data. And I will say it's the one that people are the most hyped up out, which you just again have to take with grains of salt. This is the newest iteration or like... Exactly. And all of these products that you're buying are also chalk full of things like a bunch of other B vitamins, hyaluronic acids, all of these other things that skincare companies are claiming are also going to help your skin, whether or not it's true, whether or not they have any data to show for it. And by putting all of these products in combination, you have no idea if any effect that you're seeing is from the retinoid that's in there or from anything else

in that formulation, right? And, and I just keep going, Erin, because it's ridiculous. The formulation really matters for retinids, because retinids are not stable in light and in oxygen, they break down very easily. So if you don't know how long your bottle has been sitting on the shelf, you don't know if it's still active. Drugs, pharmaceuticals, are tested in their entirety, right? Drugs are tested by the entirety of the formulation. So no matter what brand, whether it's generic, whether it's brand name retinae, if you're getting something that says it's 0.1% Tretanoin, then you are getting a formulation that has been tested to at least be non-inferior to every other version of Tretnoan that's available with a prescription. There is robust studies,

at least now, because they've been forced to do it after that lawsuit, apparently. And there's safety data to back all of this up. With cosmetics, sure, they can do a bunch of tinkering and add a bunch of stuff in that makes it go on smooth, it makes it feel nice, right? But that doesn't mean that it's doing anything. Yeah. And just like with supplements, when independent organizations have gone through and actually tested off the shelf a whole bunch of different retinoids, that's exactly what they found is that they either don't contain what they claim they do, or they don't contain it at the concentrations they claim, or at, like, ridiculous concentrations that were nothing like the randomized control trials that the company funded to do anyways,

Right. Or when they put them on their shelves, they degrade far more rapidly than they should. Therefore, they're not effective by the time your bottle's gone. So would robust, randomized control trials be really helpful? Yeah, they would. Where's the incentive? It doesn't exist. You asked, Erin, what is the anti-aging market?

Let me tell you. In 2021, it was estimated to be valued at $63 billion. Did the article from 1989 say $3 billion? $3 billion in 1989. $63 billion in 2021. And most numbers that I saw, and this was from a number of different websites, because this information is not like conglomerated into studies yet. Most numbers said between $68 and $72 billion today.

And it is rapidly growing. Like it just keeps growing. Who needs research? You've got marketing. I mean, okay. And I just like, here's the little. devil's advocate here, where I'm thinking, okay, well, if the pharmaceutical companies aren't going to do this research, then who would do the research?

Universities, researchers, research organizations, is that the best use of funding? No, it absolutely isn't, right? Because we're talking about wrinkles on your skin. Now, I will say acne is a totally different thing. Totally different thing. We should do a whole episode, but that is part of why the FDA agreed to make a dappoline or like what is different gel is the brand name in the U.S. over the counter in the U.S. in 2016 is because it was so restrictive to be able to get it. And it really works.

And acne can be very problematic. It can cause a lot of scarring. It can cause a lot of psychosocial distress. It can cause like it's painful. Like acne is a very big deal. What we're talking about are wrinkles on your skin. Photo aging. Yeah.

Photo aging. Like I'm sorry. It's not the same thing. So no, it's not. And here's the other thing. It's not that this research is not being done, right? These companies invest heavily in R&D, but they are absolutely not going to be incentivized to publish that and let everyone else get their formulations. Why would they? Right. They're going to keep it in-house. It's, I mean, it's a, it's, of course, it's capitalism. I mean, it's capitalism. I mean, so the answer to the question, does it work for anti-aging is so layered, right? You could say yes. And you could say this study indicates that this, but you have to consider the effect size. How much does it actually reduce the appearance of wrinkles? You could consider how, oh, well, this study showed it, but it did a different test. You could show that, yes, it was statistically significant, but the sample size was 10

individuals. There are so many different challenges in getting to a answer that is not with a million in different layers of qualifiers. A hundred percent. I will say looking at all of the evidence from all of the things, Tretnoan has evidence that has good evidence overall, that it can reduce some signs of photo aging. But yes, the question of like, what does that mean to one person versus another?

Right. Does it matter to you? Does it not? Like, you know? Well, and then a follow-up question that I would have to Tretto Tretnawan and yes, okay, if there is evidence, that is in support of reducing the signs of photo aging, how long do those effects last? If you use Tretano, like, how long does it take for Tretanoin to have that impact?

And then if you stop using Tretanoin, do the effects go away? It's a good question. Most of the evidence I saw is that it takes at least weeks. You also mentioned something about the FDA put a caveat on there, that there's no histological changes. So it is interesting. the histologic changes that we see with Tretanoin max out at a certain number of weeks and then seem to go back to being like less histologic changes. But the visible changes when they do like, I forget the names of the fancy photographs and things where they take things and measure

things, those changes, like the visible changes remain and continue to improve. But the histologic changes seem to be more transient. So people are still trying to figure out what does that mean? Does that mean that the histology is not necessarily like what is driving the visible changes? Anyways, that's a little bit too detailed. But what was your question? How long do the effects last? Oh, yeah. So they take weeks to months to see an effect.

But they do seem to last pretty long. And you are also going to continue to age for your entire life. So like if you stop using them, you will go back to photo age. after a few months to a year, it seems like they last for at least a little bit of time. But if you use them forever, you are also still going to photo age. To some extent. Yeah. But significantly less than if you hadn't ever used them.

How significant. Well, statistically significant, Erin. I know. Clinically significant depends on the person. I mean, it is. Because all of this is for cosmetics. Right. It's for how you look, how you appear.

Now, is, especially as women, is that something that we are judged on constantly? Absolutely. I have a lot of feelings. I think that's why I have so many resources and sources for this episode. It's because I have a lot of feelings about this. But I'm trying to not dive into my feelings and just talk about the data. Conceal don't feel. Thank you.

Just kidding. Never take that advice. That was the villain song. It is. It is. It's true. But yeah, so I mean, it's, it is a really, really interesting, frustrating area. And it's also, it is very, very hard to get good data. There are so many people out there who are trying to break it down in ways that are understandable for people, which I appreciate, but almost always at the end of it, they are also being paid by skincare companies. And so it's very difficult to then take, all of that information as non-biased, right? Right. So. And we all have our biases.

We do. In general, but it is different when there's like monetary support for those biases, I think. Yeah. Yeah. So I'm not going to tell you any brands. I mean, I did mention the brand names of some things, just so people know what I'm talking about. But you can get generic. But do you use?

Do you use retinae there? No, because it made me break out. I have like, I had, yeah, I had a little thing of retinol, and I don't know what happened, but I started to use it and it made me break out. And I was like, you know, I'm not doing this. Probably because it made you purge. Yeah, probably. And I just don't really, you know.

That's fair. I have two different bottles. I just bought a new one. During the episode? During researching for this episode. I was like, I'm going to try it. I still have never used prescription strength, which I think is especially funny because, like, I could have had a friend calling a prescription for me at any point.

I mean, I still could, but I just, I've never used the prescription, which is like the one that has the most evidence. It's all just, you know, I don't know, Erin. I know. It's complicated. And I think I struggle a lot to articulate how I feel about aging and wrinkles and the freckles on my face and the fine lines and this and that. And I don't know.

I will say all of the studies that I read and I read a lot, they all look at like, these areas, like near your eyes and near your mouth. And I'm like, I don't even care about those wrinkles. What about this one? There's nothing. There is nothing that will touch this between my eyebrows except Botox. Botox. We already did that episode.

But yeah, Erin, that's, I don't know what my conclusion is. There's some evidence for some things, but it is almost impossible to know if, any of the things that you can buy over the counter are going to work. And so there are a lot of people whose stance is absolutely don't waste your money. They're a complete waste of money. And I think that that might be a slightly unfair stance because for some people, they might work because, again, there is some evidence that they work in some cases. But it's also not okay to say, oh, these totally work because there's such a huge range. And it's just so difficult. As a consumer, like, nobody is looking out for us to help us sort through this, essentially. So once again, the consumer

just has to waste our money. It's, it is, it is supplements, Redux. Like, we're doing the same thing, where it's like, what's the harm? Well, you're spending your money on stuff that may or may not do anything. Yeah. And you might get a really bad reaction to it because even though over-the-counter retinoles, because they're less potent, tend to be, have less side effects of like the peeling and the irritation, the redness. They're not without side effect. Right. Yeah. And yeah, I don't know. It's a lot, Erin. It's a lot. It is a lot. If you want to read more, I have, I don't know, two and a half entire pages of citations. So let me tell you about some of my favorite ones. A couple textbooks that I read in cosmetic dermatology textbooks, if you want some more detail on, like,

the skin and just like big picture stuff. My two favorite review papers that looked at like the overall evidence for these over-the-counter versus prescription strength retinoles were one by Levin at all from 2010. That was titled, How Much Do We Really Know About Our Favorite Cosmaceutical Ingredients? I liked that one. I also really liked one by Tatali at all from 2020. That was titled Popular Over-the-Counter Cosmaceutical Ingredients and their Clinical Efficacy. I thought those were like pretty well-balanced reviews, but I also have a whole bunch of actual data papers if you want to get real deep dive in. I've got some on the evidence just for tretnoin and then also some on the teratogenicity of retinols. So one thing I should mention that I did not mention earlier is that when I was talking about the increased risk of birth defects and spontaneous abortion with the use of retinoids, that applies to oral retinoids. Recommendations from every single medical society are to,

not use any kind of retinoid, including over-the-counter, including topical just for your skin products at any time while you're pregnant, no matter what. All of the data that we have on the risks of birth defects is for oral medications of retinodes. We don't have strong data that shows that topical retinodes that you put on your skin increase the risk of birth defects. but out of an abundance of caution, the recommendation still stands to not use any kind of retinoid product. So just to clarify if anyone was wondering why. So I got all those sources. And there's a whole bunch more. And we'll post the list of all of them on our website. This podcast will kill you.com under the episodes tab. We will. Thank you to Bloodmobile for providing the music for this episode

and all of our episodes. Thank you to Tom Brifogel and Leanna Squillacchi for the audio mixing. Thank you to everyone at exactly right. And thank you to you, listeners. I hope you enjoyed this two-part deep dive. Yeah. Do you use retinoles? Do you use prescription retinels?

Do you not use any retinoles? Do you use over-the-counter retinels? I really want to know. Do you have feelings about retinoles? Do you have feelings? I have a lot of feelings. Yeah. Should we do a whole episode about wrinkles?

Oh, yeah. I thought you were going to say, should we do a whole episode about feelings. Yes. Yes. Yes. And a big thank you, of course, to our wonderful, lovely, generous, fantastic patrons. We appreciate your support. It means the world to us. It really does. Thank you so, so much. Well, until next time, wash your hands. You filthy animals. Truck month is going on now at your local ram dealer. Hurry in for great deals and exceptional offers on a powerful selection of ram trucks. And right now, purchase and get zero percent financing for. for 60 months on 2026 Ram 1500 Big Horn and Laramie models. Don't miss this great offer. See your local RAM dealer.

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