On this episode of the Ben Greenfield Fitness podcast.
That means that every time you get a puff of dopamine, it's going to stay there a little bit longer because you've got modafinil blocking that reuptake into the cell that produced and released the dopamine. Take your mode, a half, a nail your brain. Says, hey, everything's great, your muscles, getting a signal from cortisol that says this is fight or flight time. This is not time to store glucose. It's time to burn glucose. If you're going to try to use modafinil for cognitive enhancement specifically with the goal of
Restricting your sleep, you will pay a physiological price for
that. Performance nutrition. Longevity ancestral, living biohacking, and much more. My name is Ben Greenfield. Welcome to the show.
Boom, shaka-laka-laka. I am not on any mind-altering substances while I'm recording. Today's podcast introduction for you. Although this entire podcast is about one of the world's most popular mind-altering substances, namely modafinil, modafinil, the wonder drug, the Limitless drug, the drug that I believe inspired the movie Limitless, or Lucy or one of those smart drug movies. Anyways, we're going to talk all things mode death than ill today, and if you never heard of this wakefulness,
Smart drug. That's sweeping the World by storm or at least Silicone Valley, your take a listen. I thought this was really interesting and I learned a lot from my guest. Now. Of course, there is a nootropic that a lot of people don't realize is a nootropic, but it's very interesting and that would be creatine. Now, you've probably heard that creatine is good for improving athletic performance and muscle gains, but it also plays a pretty important role in cognitive function.
Especially for plant-based eaters who don't get a lot of creatine from their diet. Since creatine largely comes from meat. We sent the size, maybe a gram of it on our own everyday. All the rest needs to come from meat. They actually found that on young adult plant-based eater, six weeks of creatine supplementation. Had a significant positive effect on working memory and on intelligence. I use it every single morning. In my smoothie. I use the purest creatine gets called creapure and 5 grams a day year round and
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Increasing in popularity, For Better or Worse? It's called modafinil, also known as provigil along with several of our other variants of it that are sold as as as online, pharmacy variance and different isomers of it. But modafinil, or provigil is probably the most popular version of it. It's the darling of the smart dog and history. It has been for quite some time. There's about 200 human clinical.
Uncle studies that I've actually been able to come across on PubMed for the past 10 years, most of them generally reporting few side effects and you know, not not a host of addictiveness or excessive stimulation, although that's something that we rolled will explore on today's episode. It's used by a ton of notable figures the the myth or truth. I'm not quite sure is that nearly every president and vice president. Now is using this
God, folks, like Joe Rogan anti-aging, people like Ray Kurzweil Barack Obama definitely reported that he used it. So it was Hillary Clinton. Tim Ferriss is one of those notable biohackers that has reported using it in the past. It's the entire inspiration behind the smart drug movie Limitless and also Lucy, it is reported to increase resistance to fatigue, to improve mood. Reaction Time vigilance. They've tested it in military.
An Air Force pilots for enhancing alertness and reducing battle fatigue. Lab Studies have looked into it almost kind of similar to two ketones for example for its antioxidant and neuroprotective effects, the acute ingestion of it for you exercise, junkies out there. It may increase exercise, time to exhaustion and the list goes on and on. So what could go wrong? Is this stuff too good to be true and and I decided I wanted to just jump
And record an actual podcast for you on modafinil, so, I reached out to because this is so intimately tied to sleep. I mean, it's an off-label anti narcoleptic drug release is how it originated. I reached out to one of the Sleep researchers Who I Really respect a guy who's been on the podcast before Dan party and I said to Dan that I was very interested in interviewing someone on modafinil. Who would you recommend? And he said, there's this guy dr. Jonathan wiser, and it turns out that Jonathan lives about 15 minutes from
My house, so I am at my house on Saturday morning here and Jonathan drove up based on my invite to record a podcast. I have just met him, and I'm just getting to know him, but we do share a common passion for Cold, Water Swimming, correct. And all
things cold for me. I love cross-country skiing and I love Cold Water Swimming.
Now for you. Is that because of the the love for exercising in that environment or you,
Of those biohackers who's trying to increase Brown fat conversion and, and take advantage of all these other elements that you get with cold
thermogenesis. Yeah. It's, I mean, it's really about exercise and, you know, there is definitely an exhilaration when you bracing experience and you feel that cold. So
yeah. Yeah. I was well showing you my, my Colt, my marasco out there by my office and I'll, I've been turning to that more increasingly than coffee when I'm when I'm a little bit sluggish during the day or that you don't have to.
Soon, tiredness sets in sometimes, I didn't put my whole body and I'll just, you know, I'll get lazy. Just take off my shirt, immerse, my entire torso in there and just do a few. Do a few dunks, towel off. Go back in and keep jamming away. I'm work. And yeah, cold is, of course, amazing for alertness, but that's that's not the drug that we're going to talk about today. So you have a, you have a PhD in Neuroscience from from University of California in Los Angeles. I know you've done some research at Stanford.
And Purdue University and now you are a on the faculty as Washington State University radio manual can. Yeah, and you also work with the medical education program. What is it? Whammy Washington
that? Well, that's a prior iteration now with the College of Medicine at Washington State University in Sakai and it's all right.
So so are you spending the The Lion's Share of your time then lecturing or researching?
It's about two-thirds research, 1/3 t.
Teaching. Okay this point. Gotcha.
Gotcha. And what type of courses are you? Are you teaching
teach the basic cell biology of the nervous system of muscles of the immune system? Some cell biology first year of the medical curriculum,
gotcha teaching and what with regards to Neuroscience, particularly or sleep. What's your background in terms of your research or your interest in? Kind of the Neuroscience aspects of sleep or sleep or circadian rhythm?
The or, you know, things that might relate to
modafinil. Well, so back when I was an undergraduate. I knew that I wanted to study some aspect to the brain, but I didn't really have any specific leads when I started out. And so I was just thinking about what aspect of the brain interests me. Well, my first summer between my freshman and sophomore years, I worked in a bakery and I had a very odd shift work
schedule. It was on high school or
college. This is college. Yeah.
Okay. This is crazy. I'm gonna rub a hole here.
Cuz I worked at a bakery rely in my would have been my, my Junior and Senior year of college. Okay, Moscow, Idaho. I worked at a French Bakery, and it was very funny because I would show up at the bakery at about 4 a.m. And this is prepare everything and it was a very French. They were talking chocolate croissants. But done done, right, you know, a lots of butter and and we had the the croak months was that people come in for lunch. You know, that sourdough bread with the cheese and the tomato.
Go on them. What was funny is I would be selling these extremely high carbohydrate high calorie breakfast items to people in the morning and then in the afternoon, or the in that, I go off to school at about 8 a.m. And and take all my courses. And then, in the afternoon, I worked as a personal trainer at the gym across the street from French bakery. So I basically get people fat in the morning during the burn calories. It was a great business model. Yeah, you worked at a
bakery. Yeah. Well, this is kind of the opposite end of the
Spectrum in terms of Bakery. This was a Wonder Bread Bakery Soma, you know, the fluffy white spongy bread that you can squeeze into a ball and right, you know, so quote-unquote bread. Yeah. That's a good way to put it. Yes, so same thing, I go to work at four o'clock in the morning and it was not fun. It was, you know, it was brutal to have to do that week in week out. And I was in and it certainly kept me motivated and inspired to stay in school, but it also gave
Me Focus to my interest in Neuroscience. Like, you know, this this sleep thing. If your sleep isn't good, you know, things can really go wrong for you. And you know, what is it about sleep? Well, what is it that it does for its, that is beneficial. And why is it that I can't just get up at 4 a.m. When I want to and be fully functional. Then. Yeah, it's a, you know, that was dead. We're going back decades now, of course. And I'm still, you know, facing that same question with, you know, we have a lot more details now than we did back then about how sleep is regulated and what
it does for us, that's beneficial and but that, that story continues to evolve. And so that's, that's how I've gotten to where I am
today. So you've woven this interest of sleep and the study of the Neuroscience of sleep into your course work and, and your research since then absolutely gotcha. Gotcha. How much now are do you find yourself talking about sleep or the Neuroscience of sleep and you're in your research or your
teaching all the time? I mean I try to bring it into the teaching as much as I can and it's, you know, because it's the
System connects to the immune system. And so I'm talking about the immune system. I can bring it in there. If you look at like stress hormones and the danger posed to the cell by stress hormones. A lot of that is influenced by whether or not we get good sleep. Glucose utilization is affected by whether or not we get good sleep. So yeah, I try to bring in as
much as possible list goes on. And on we could probably talk for two hours. Just just on the the biological effects of sleep, or the lack thereof, but when it
Comes to either mitigating some of the tiredness, and fatigue, from lack of sleep or in some cases in a case, such as narcolepsy. For example, sleep disorder, actually keeping someone awake. When they have a disease that causes them to sleep. During the day, this modafinil is, or provigil as it's also called as is quite commonly used. And like, I mentioned, our introduction increasingly used out amongst biohackers and egain.
Hours and poker players and college students. And I've even seen some articles about. I believe it was Duke University was considering some type of doping monitoring type of system for students using smart drugs, like modafinil. And So, based on that, let's start here, describe to people. What modafinil actually is.
Okay. So modafinil is what we call a small molecule therapeutic. So it is a small molecule.
You'll that when you take it orally, it will enter through the digestive system into the bloodstream from there. It will go into the brain and it binds to a cellular molecule known as the dopamine transporter. Okay. So let's maybe take a step back from this. We've got various different neurotransmitters in the brain and probably I'm guessing your audience recognizes dopamine. Oh, this is a transmitter in the brain, the different transmitters.
Have different functions associated with them and we can say in general. I mean, we could talk about this for if we want to talk about it, you know, at a detailed scientific level. We could talk about this topic alone for hours, but for the level that I'm guessing the general public would want to understand it. We can associate dopamine with motivational States. And so when we need to focus and stay motivated on a task, we have cells in the brain that will produce dopamine and will release.
That dopamine throughout the brain that will convey to the rest of the brain. Okay. It's time to focus on this task. It's time to stay motivated by this task, right? Okay. So those cells will release dopamine. Now, their release of dopamine is highly regulated and highly controlled because these neurotransmitters like every other neurotransmitter, you've got to get, just the right amount of dopamine. They're signaling the other cells. And so the cells that release the dopamine have a mechanism that allows
Them to keep its concentration at the appropriate level and that is that they will actually take it as soon as they release it. It'll stimulate a receptor on the other cells, and then it will be taken back into that cell, that produce the dopamine, and released it in the
first place. So, it's kind of similar to what you'd see with, like, a selective serotonin reuptake inhibitor, which would be inhibiting the reuptake of Serotonin by that cell, that released it. In the case of dopamine. It's a similar mechanism.
In ISM to where it's in this synaptic cleft, but then it's, there's a reuptake mechanism back to the neuron from, which it
originated, exactly. Yeah. And so, you mentioned, yeah, so maybe by analogy you three. Think of an antidepressant, drugs, selective serotonin reuptake Inhibitors. Well, modafinil is a selective dopamine.
Don't like taking a SSD
RI, you sure? Yeah, although that's not a term. That is obviously, you just remained allergies. All right. Thank you.
Make up shit. Yes.
So by analogy, that's the yeah, that's what we're talking about. And so that means that every time you get a puff of dopamine that goes out there and conveys to the rest of the brain. Stay motivated, stay focused. It's going to stay there a little bit longer because you've got modafinil blocking that reuptake into the cell that produced the and released the dopamine. So you're okay strengthening or enhancing this dopaminergic signal. That tells us to focus and stay motivated. Okay, and, and
Norepinephrine. Similarly, from what I understand is also affected by modafinil. And and perhaps it's not just dopamine that's being acted upon in terms of actually, you know, I guess only flooding cells with dopamine or decreasing actual reuptake of dopamine, but then is norepinephrine also
affected in some way. So, I would say sort of yes and no. Yes, it is clear that if you measure norepinephrine in the brains of, this would be an experimental animals.
People have done this, if you measure changes in norepinephrine, when an animal is given modafinil, you do see an increase in norepinephrine as well. Now, it's probably indirect and one of the things that we know about neurotransmitters is that they're all talking with each other simultaneously. It's just this cocktail of chemicals in the brain. And so if you block the reuptake of dopamine by the mechanism that I just described, right? You're going those dopaminergic cells, some of the other cells that
That they will activate contact and activate, will be cells. That are producing norepinephrine. Right? And so then those norepinephrine cells are at, okay, we need to be recruited into this process to, right? And so then we have an increase in norepinephrine release in, right? So, yeah, so that's going to help. Also focus our attention, right?
Focus our attention or an excess cause some of the, you know, potential anxiety, that. I know some people have reported, you know, when using modafinil, especially in higher dosages. Because, you know, do,
I mean, I wouldn't say at least in my own personal experience, even just using a like a dopamine precursor, like, mucuna. For example, it doesn't seem to produce any, any really pronounced anxiety, affects. It's more like a feel-good, wakefulness, type of effect. But then, I think norepinephrine, it does kind of give you like this anxious, kind of jittery effect
that. Yeah, that, that makes sense. I think that's one of the things that norepinephrine can do. It's, you know, it's a central mediator of the cell.
Called fight or flight response, the sympathetic response. And so yeah. Anything that does Boost norepinephrine could have that effect on. Probably, you know, certainly that's not the case in every one who takes modafinil. And it probably has to do with individual variability in sort of
neurochemistry. I want to get out
tightly the dopamine, links to the norepinephrine in that particular, individuals, central nervous
system. Yeah. Yeah, and then, in addition to that and I do want to get into and I think we will
All kind of variations in response to modafinil. I've some of my own hypotheses regarding that but then also have you looked into histamine at all and a histamine, allergic response to modafinil.
So yes, there is definitely a histamine Urgent Response as well. And again, you know, we have to emphasize that all of these neurotransmitters talk to talk with each other, you know, and so For Better or Worse, you're going to when you try as selectively as you might try to
Activate one, you're messing with the whole system and in some way or another, which may ultimately be therapeutic for you or it may not be. But yes, histamine is another one that is the histamine producing cells. And so histamine is another type of cell that's associated with arousal. This is associated with cognitive enhancement. Right? And so, and the way to think about that is if you take an antihistamine, an allergy drug, you're going to be potentially in a fog,
right? My son, I wasn't happy about this.
Is that grandma's house. And, and he last week and he had a, an allergic reaction to pollen. He gets little bit of seasonal allergy and she gave him Benadryl and he has ever rarely, you know, we're pretty natural at our house. He's rarely ever, you know, ingested, a pharmaceutical, you know, he was sleepy and his eyes are rolling over. He's a dad was going on. And said, well, she had shutting down one of the excitatory compounds in your body histamine and you're probably going to, you know, sleep pretty solid tonight. You probably have some bizarre dreams, but, but yeah, but histamine and
Excess or something. That would block. Histamine seems to really printout produce those. This this kind of wakefulness
effect. Well, so let's be clear that that's what you just described. Is it at the effective and antihistamines or something right blocks to his mean? Yeah, right. So modafinil again indirectly. We think is the opposite of that. So answer put it is again sending out a signal to the cells to produce the histamine that says, hey it's time for you, histamine cells to be more active and release more histamine and the histamine.
Again, as opposed to an antihistamine, the histamine itself is in general associated with improved cognition cognitive enhancement. Yeah. So this may be another aspect of the modafinil story. They are so critical for its it's a cognitive enhancement
properties. I saw one study that showed about a hundred fifty percent increase in histamine release
sounds about right once we got out right dopamine
and norepinephrine and we've got histamine and then there's also this interesting molecule called orexin.
Have you looked into how that ties into
modafinil? Yeah, Rex in is sort of an upstream regulator of all of these neurotransmitters that we've talked about. And so it the orexin producing cells will feed into and potentially activate. All of these different cells types that we've mentioned. So modafinil is Downstream from that and in people who have narcolepsy, they are lacking the orexin
That would otherwise be there. It was basically like the Wake Drive sick, right? That's right.
Yeah, it says you you'd see a drop in orexin as nighttime approaches Rand and then an increase in adenosine, which, which coffee or caffeine would would decrease the stimulation of or at least, it would fill those receptors that identity would normally interact with so Rex and would almost become like the opposite of adenosine in a sense. Right? Comes
awake Drive. Yeah, so Rex. And yeah, it's it's kind of a master orchestrator of the wake.
Promoting Drive in the hypothalamus. One of the most basic functional areas of the brain and it in turn will project to and activate these other the dopamine-producing cells, the histamine producing cells. But so in narcolepsy for instance where they lack or Exon, you need this pharmaceutical way of boosting, those Downstream signals and modafinil works very effectively in that context. Okay. Got it.
Another question that I wanted to ask because
You know, when we look at modafinil, it has this wakefulness producing a fact, but then, you know, when you look at some of the literature and I even sent you one study that showing like an antioxidant effect or a kind of almost like a neuroprotective effect, and have you seen anything like
that? Yeah. So the, the neuroprotective effect, I do not put a whole lot of weight onto that. So, here's my understanding of where this alleged antioxidant order or
Neuroprotective effect comes from. I think it's this. There's an impurity in certain synthetic, opioids, called mptp. Okay, and mptp and I mean, this is like, okay, if you're an abuser of poorly made synthetic opioids, you know, please get help. But if you're not a what I'm about to tell you, if you're not an abuser or user of poorly, made synthetic opioids, this alleged antioxidant effect. It's not relevant to you.
Okay, and here's the deal mptp. This impurity that people will unintentionally take. It gets taken up by the dopamine transporter into dopamine-producing cells. And then there's a metabolic process within those. Dopamine-producing cells that produces a toxin and kills the dopamine-producing cells again, all of this is only if you're taking this impurity in peer opiate, okay, mixture including mptp. Well, if you block the do.
Dopamine, transporter with modafinil, you're going to prevent that mptp from being taken up into back into the dopamine-producing cells. And so it's protective against the dopaminergic neurotoxins in that context. Specifically, there's some speculation that dopamine itself because the path. That generates these toxins that I just described that that's involved in the metabolism of dopamine itself and but whether or not there's any potential law,
Term sort of neuro degenerative process that relates to this pathway in the absence of these. Artificial toxins is highly debated. And furthermore. If you just look at this empirically, like in people who have Parkinson's disease, a condition where we have a known degeneration of the dopamine-producing cells does modafinil protect those cells in the Parkinson's population, the data that I'm aware of are not particularly strong.
Wrong. Okay, so and I'm this is not to say that you wouldn't enhance cognition with modafinil in someone who has Parkinson's disease. And there are we think of it, Parkinson's is a motor disorder but there are cognitive effects as well. Yeah, some of those are treated by modafinil, but we have to make a clear distinction between having a cognitive enhancing effect, which it does and being somehow neuroprotective, meaning that it would actually slow the progression of the disease, right? And I just don't
think the data are there in terms of slowing the progression of the
disease. Okay? Got it is interesting when you say that about Parkinson's because there's another very common compound that's being used, increasingly again amongst like the smart drug and the bio hacking community. And that is nicotine, which suppresses kind of the gabaergic activity on on dopaminergic neurons meaning, it would, it would keep inhibitory neurotransmitters from from essentially shutting down some of the response to dopamine, which
Gina was an issue in Parkinson's and seems doing increase the acetylcholine activity. And so, actually, a lot of people are, are combining like a milligram of nicotine with what would be considered like a microdose. I'm going to have to know like 15 grams of modafinil, and that's kind of, like a stack that's being used because you're getting a little bit of a dopaminergic protective effect with the nicotine, and then a further dopamine release with the modafinil. And, you know, the other the other stack that people often use
This is just caffeine because, you know, and I think the reasoning is basically, you know that adenosine I talked about earlier. So you've got three different mechanisms of action. Really, you've got the decrease in the gabaergic, stimulation of those dopaminergic, receptors with nicotine. You have the increase in dopamine norepinephrine, histamine, and orexin from the modafinil. And then you've got the blockage of the adenosine receptors from the caffeine. And so you'll see people
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I want to get to, well, I guess like the dark side, you know, if all these great things are happening that are going to keep you awake, if you're sleep deprived or even, you know, arguably increase cognition, or as we've seen a lot of these studies on, on the military and on fighter pilots, you know, awareness or reaction time or in athletes increase time to exhaustion, what could go
Okay, so I think we need to consider this broadly at first and then I'll get a little bit more specific and answering that. So let's so be patient with me. Modafinil is FDA approved for conditions in which someone is suffering from excessive daytime sleepiness. Okay Wubbzy. Well, yeah, so and we could. I'm going to I'm going to give you three categories of people or situations.
Come stances in which one would experience. Excessive daytime sleepiness. So the first is that you have some sort of sleep disorder that prevents you from having good quality sleep at night, or getting a sufficient amount of sleep at night. And so if your sleep is poor or you have insufficient sleep at night as a result of a sleep disorder, you will have excessive daytime sleepiness. And as you mention narcolepsy, that's the classic example, so they never go into really deep sleep at night. They're never fully awake. During the day. They take
Daffodil and that will very effectively address that excessive daytime sleepiness other examples people have insomnia. And for whatever reason it's intractable. Insomnia. They're going to have excessive daytime sleepiness. They can take modafinil and improve their, their daytime, functioning sleep. Apnea. Sleep apnea is another one. Now, the most important aspect of sleep apnea treatment is something called continuous positive airway pressure or CPAP machine, the CPAP machine to make sure that you have your breathing continues.
Is while you're asleep, but even then you will suffer from residual, daytime sleepiness with sleep apnea. And so there's another perfect example of where modafinil is Will ameliorate that excessive daytime sleepiness. So sleep sleeping a secondary to a sleep disorder. The second category I would give you is what I would call situational Sleep Disorders or situational daytime, sleepiness and situational would
refer to the fact that you have some sort of obligation that prevents you from getting good quality sleep at night. So one of them, we've already mentioned, shiftwork. People who are, who undergo shift work, and of course, this is inevitable. In many cases, you know, medical professionals security guards, Etc. It's unavoidable that tens of millions of people, have to experience shift work. Some of them experience excessive daytime sleepiness as a result of that, you know disruption of their nighttime.
Sleep with with shiftwork, modafinil is approved and is very effective for excessive daytime sleepiness in that kind of situational. Another situation. Might be a personal situation. If you have an aging parent that you're caring for at home, or if you have a young child or a few young children are caring for him and you have disrupted sleep at night or you breastfeeding. Yeah, you're going to have it, assesses killing, don't take no damage. So, if you're in one of these situations and you can't get quality sleep at night or
Enough sleep at night, modafinil is is recommended and will be effective for your excessive daytime sleepiness. Now, I'm going to give you a third category and based on the kind of people you're describing who are using what happened L for, you know, Gamers for cognitive enhancement or whatever. I would say the third category of excessive daytime. Sleepiness might be what I would call motivational daytime sleepiness. And what I mean by that is that someone is intentionally because they have some motivation. They
Are restricting, their nighttime sleep. They have decided for whatever reason. I want to get five hours of sleep, going to get four hours of sleep, a night every night. And I want to that's how I'm going to live, you know, and it's because maybe it's because they live here on the West Coast and they have to monitor a things related to the stock market until like midnight and they have to get up at 5 a.m. Because that's right in the the Stock Market opens on the East Coast or whatever. So now they're only getting five hours of sleep at night, you know, that's an example, or a gamer or somebody who's just like obsessive.
About checking Twitter or something. Right? The point is, this is a motivational State. You have decided. I want to get five hours of sleep a night. That's what I'm going to do. And if you do that, there's a vanishingly small percentage of the population who can pull that off without pharmaceutical enhancement. Right? Most of us cannot pull that off without pharmaceutical enhancement, at least in the long, long term more than a few days at a time, right? Okay. And so that person they can go to the doctor and say I have excessive daytime sleepiness.
The doctors may or may not even ask them why they might just say well when you say that, what do you mean? Well, yeah, it's like I'll be sitting at my computer and I'll fall asleep. Right? And I'll say okay you have excessive daytime sleepiness. Here's your prescription for modafinil, right?
Jude, which is more likely to be able to get your doctor to write a prescription for my death and all of them telling them that League of Legends is really appealing to you
right now. Exactly. Yeah, and there's a person with excessive daytime sleepiness. Well, they take the modafinil and great. Now, they can actually stay up 90 now.
Hours a day, 19 hours, straight get the five hours of sleep. Wake up, take their modafinil, the next morning and everything's great at the cognitive level. That's all true. That's all well and good. But there are some things that are going to go on physiologically, even if you're taking out a phenol and this is base, I'm saying this not based on speculation, but based on observations and published scientific studies. Okay? Okay. So now we need to know what goes on physiologically when we restrict
Cells to five hours of sleep a night. And there's there's a lot of really good, really solid data out there. And I'm going to do my best to summarize it in just a couple of minutes here. Okay. So what happens when we get eight, nine, ten hours of sleep. That doesn't happen when we get five hours of sleep. Well, let's see. First of all, when we restrict ourselves to five hours of sleep, we lose our insulin sensitivity. Okay, we undergo a state of insulin resistance, if we have 5 hours of sleep a night.
So what that means is that muscles, you know, if you think if anyone's listening and is interested in athletic performance, if you're going to have good athletic performance, you've got to have good glucose absorption into the muscles so they can take. That glucose is converted into glycogen. Use it later for your athletic performance. If you have five hours of sleep a night, the muscles lose the ability to store that glucose. They become insensitive to insulin, okay? If you take mode,
Methanol to help keep you awake. When you are undergoing, only five hours of sleep a night that loss of response to insulin still occurs. Okay, so you may be wide awake, your brain says, hey, I'm great. I'm feeling fine. Your muscles are saying, I'm not going to pick up any glucose. I'm not going to deposit glycogen. Okay, right. So and that's this is scientific. This is published is something that's been studied systematically other things. Cortisol is our stress hormone, right?
Our fight, or flight from hormone under normal circumstances. If you're getting eight, nine, ten hours of sleep a night. You're going to get a burst of cortisol in the morning and that's good. I mean, this is preparing you for the day. This is preparing you to use those muscles that you have used the previous that you have stored up glycogen, and the previous night. And so, and so you had that burst of cortisol and then in the evening, the cortisol goes down and it disappears. And the cortisol actually will inhibit the response of muscles to insulin.
Right. And so this is why it's good in the evening. The cortisol drops, you get the insulin signal that the muscles can detect both the absence of cortisol and the presence of insulin. They say okay time to store some glucose. And then that's what they do. People who are restricted to 5 hours of sleep, a night either voluntarily or under a, you know, a research protocol will have that cortisol continuing into the night and the cortisol being there, suppresses the response to insulin.
And so, again, you have that reduced muscle mass building of muscle mass. If you're restricted to 5 hours of sleep that increase in cortisol, in the evening that will occur whether or not you're taking modafinil, take you mode. A fantail, your brain says, hey, everything's great, your muscles, getting a signal from cortisol that says this is fight or flight time. This is not time to store glucose. It's time to burn
glucose. Okay, I should throw in there. That that's related to this. This exercise piece is I would say.
About half a dozen times because we scheduled this interview about, I guess it was maybe about a month to month and a half ago. So about half a dozen times between now and then because I always like to do a bit of immersive journalism. I took them to ethanol and I took about a hundred. I vary between a hundred and two hundred milligram dosage, which is, which is pretty common. We can get in low to moderate and getting a micro dosing and also something that some people are actually using it as a hallucinogenic to it at higher dosages which we can get into if we have time and
I noted The increased time to exercise fatigue, for sure. Like, it definitely enhanced workouts. However, what I also noticed, was that the morning after the day on which I took modafinil. I was remarkably more sore from my workouts and I would theorize that based off what you're describing about about the benefits of sleep, that go beyond, simply allowing you to have better cognitive.
Ignition. The next day that there was a remarkable decrease in neuromuscular or musculoskeletal recovery due to the impact on Sleep Quality because I also measured my sleep. I use this this ring to measure my sleep, and my deep sleep levels, particularly were remarkably low, the night after, which, I had taken modafinil, although, I took just a standard dosage in the morning, which should be out of the body in 12 to 15 hours. It impacted the quality of the
Kuehl mother, the muscular recovery that should occur during sleep to the extent to, where I had a notable increase in soreness that. I usually wouldn't experience the next day that by, you know, I was fine. As far as wakefulness the next day with my body
was sore. Yeah. So these are things that we have to watch out for. If you're going to try to use modafinil for cognitive enhancement specifically with the goal of restricting, your sleep. You will pay a physiological price for that growth hormone. It's the same thing. We need are deep slow-wave sleep, in order for us to have that surge of
A hormone that occurs at night, if you restrict someone to 5 hours of sleep, they don't have that surgeon growth hormone. That's true whether or not they are taking one Avenue at the time. Finally, melatonin. I don't, I think people are a little more excited about melatonin than I think the data often often supports, but we have an increase in melatonin at night. When we get eight, nine, ten hours of sleep, that increase is blunted when we have five hours of sleep, and if you have five hours of sleep and your
Letting yourself with modafinil that melatonin is still
lost. So, yeah, so
you're paying a physiological and hormonal price for your time, spent awake. And there's one thing you
didn't mention, which I'm actually interested in, and that would be this idea that if you are consistently flooding, The receptors with dopamine, could you create a state of? I guess what? I might call dopamine in sensitivity, in which things that would
Normally a list of the dopamine response become less enjoyable or require more of them to become as enjoyable. Like could you theoretically or have you seen in the literature? For example, increased susceptibility to overeating because food isn't as rewarding or you know, I would theorize perhaps even appetite Cravings or more snacking because you're looking for more dopamine. Hits during the day, you know, maybe sex might become less enjoyable, you know any of these things.
Rely upon dopamine if you need more and more dopamine. And then this is just a theory. I haven't seen literature on this. It would seem that that constantly flooding The receptors of dopamine like that might induce some kind of dopamine insensitivity. Your tolerance to dopamine itself.
Yeah, I guess I'm not aware of anything like that happening with modafinil. That's a, that's a good question for for you to pursue and that's probably something that will look up myself. Later. I'm not aware of anything like that happening with modafinil, certainly that kind of mechanism exists in the in
nervous system. There's no doubt that it does, it sound like that's often. If someone takes methamphetamine, which methamphetamine boosts dopamine or dopamine production, through somewhat different ways than modafinil. We have to discriminate them. They both while they both act on dopamine. It's by quite distinct mechanisms, but like with methamphetamine users, they will often undergo dose escalation and it's probably because of what you're describing here. Like you're sort of desensitizing the system. You need to crank it more and more to have a positive
You looked into whether tolerance builds up over time. If you need increasingly larger amounts of modafinil,
I am not aware of any data on that. All right? Yeah, I think it's stable dosing works in the long term. I believe I looked into it a little bit. There's one pretty large
retrospective study that found in a bunch of patients, who are taking modafinil for some, for some of the labeled uses that you were talking about earlier like narcolepsy. For example, they didn't need any significant difference in their dosage from the
start of their prescription. This is over several months to the end. But yeah, it was. Yeah, it was still effective. And then most most of the reports that tolerance are in places like Reddit or you know our forums or kind of like the underground, biohacking type of type of comments on blog sessions with people like yeah, I need more and more we're time. But in actual research, they haven't found that to be the case. And perhaps, that could also be due to the fact that many of these people who are using it for for off-label use there.
They're using from what I've seen as far as like the chatter on the internet. Pretty high dosages, meaning excess of 200 milligrams, and up to 800 milligrams, which is a lot more than the standard kind of 50 to
200 milligrams. Yeah. Now I believe 200 is pretty much the standard, I think so. Yeah, if you're pushing it beyond that,
good luck. Another few few thoughts that I had would be the, the desensitization tolerance. Meaning. There are The receptors that activate the dopamine.
In Transporters, and apparently, those can be down regulated in particular. There were two that I came across one called tar ETA RI and other one called D2. And those are apparently to activators of the dopamine Transporters that get down regulated when you are using modafinil and I did find some literature showing that if you, if you cycle it. Like if you do like three days on one day off or three weeks on one week off or just take it on the weekdays and the
Hands off that the dopamine Transporters do not actually become down regulated. So there may be something to be said for cycling it.
Yeah that that's a good point. I mean that sounds legit to me. Yes. Okay. This all sounds based on not that I'm recalling specific studies, but knowing how the nervous system works and how it will react to repeated. Exposures. That sounds like a very reasonable cost ability to me. I
also want to unpack something related to something, you kind of alluded to earlier.
ER, now be different people responding in different ways. And when I was thinking about this and I began to think about it the same way as one would think about coffee. All right, we know for example and many people are aware if they'd taken a 23andMe test, you know, they're reported to be a fast coffee oxidizer versus a slow coffee oxidizer. Based on these. These cyp genes and these would be related to liver enzymes responsible for breaking down certain compounds. We know that that modafinil is processed in the liver and some people have a higher activity.
Buddy of those genes and some people a lower
activity. Yeah. These are the cytochrome side. Yeah,
exactly. Cytochrome p450. Yeah. Yeah. So there's one of all the modafinil cytochrome P to c19 is the name of it and apparently people who would have a higher activity of those enzymes would break down modafinil more quickly and potentially feel it less than the people with lower activity of those enzymes. And so that that's where I suspect. Perhaps the the
The difference in the way that certain people would feel when taking modafinil would lie. And so, then I got to thinking, well, okay, so we know that in people who are for example, a fast coffee oxidizer. There are certain things that can slow down the activity of those, those cyp enzymes that are their cyp Inhibitors. And that would actually allow you to if you're breaking it down too quickly for it to remain in your bloodstream for a longer period of time.
Timer for you, feel it more. And so, I looked up all these cyp Inhibitors and grapefruits. The most common great. First one. You gotta be really careful. Right? Right. Because if you take that same time as a pharmaceutical, you can actually inhibit. The breakdown of that pharmaceutical do certain extent, but bacopa, a common. Something else that's kind of used as a smart drug for memory. That's another one that seemed to inhibit it. Bear Berean was another and then there's a California, poppy and chaste tree. So it turns out that there are certain things.
Things that if you weren't really feeling the modafinil or you felt like you are non-responder, you could take one of these cyp Inhibitors at the same time and kind of assess whether or not that might be the case, you know, so it seems there's almost like this metabolic tolerance to it. And then also kind of this dopamine tolerance to it. That could be hit in two different
ways. Right? I think that's true. I would just offer a significant level of caution to somebody who wants to mess with their liver enzymes.
Okay, so and I have all sorts of kind of fun little things. I want to. I want to delve into two. I don't know if you've looked into sleep cycles, and I couldn't find a lot about this. But the reason that I want to delve into this was because when I used it, I noticed that I woke up the next day at a very early time. Very early time. In you take modafinil. Let's say 7:00 a.m. One morning and then suddenly without changing anything else in your life you wake up about
4:00 5:00 a.m. For one or two days. Afterwards, making me think that there's something going on in terms of the actual impact on sleep cycles. You theorized on that at all
or wow that I love. This is one. I have not heard of before that. Yeah, actually,
I'm thinking maybe it has something to do with that orexin, you know, and the change in Wake Drive potentially, if like, if you're shifting wake Drive later in the night, but but the deal with that is you'd think if you were to shift, wake drive forward, then you'd wake.
Later, not earlier, right? So if you're if you're shifting your rear exit, yeah, that would be whatever. He's up to sleep. So, you know, if you're shifting, your sleep drive to start to kick in at like 10:00 p.m. And you fall asleep at midnight, you'd think very logically that then the Wake drive would kick in again at a later time. Like at, you know, maybe you're waking up at 8 a.m. And not at your normal 6 a.m., But instead, it seems to occur. And I talked with another with it with a couple of other folks who had experienced this idea where you like wake up a lot earlier when you're on
modafinil. Hmm. Well,
The the one possibility I can offer is that we everyone has a circadian clock and I don't know if that means anything, but this is, you know, the our internal clock, right? The controls the time of day, at which we wake up, it is responsive to these. Some of these various neurotransmitters that we've talked about. And again, we've talked about how when you, you modify the dopaminergic signaling signaling, with modafinil, you can potentially modify these various other neurotransmitters. Yeah, they could be providing feedback to that. Circadian clock ever.
Killer, if we engage in exercise early in the morning and and simultaneously expose ourselves to light as part of that exercise process, that will push the clock to an earlier wake-up time. Right? And so you may have been doing that with, you know, and when you take modafinil, you're suddenly this big arousing signal, you're increasing your exercise level, you're probably increasing your exposure to light and that's going to shift the clock to a little bit earlier in the day. So,
So that's my best hypothesis
about that one. Yeah. Yeah, there's a light is so fascinating, in terms of it being able to, it seems override or mitigate the issues with a lot of these compounds. Melatonin being another high dose. Melatonin is something that, you know, even during this recent covid epidemic, it came up because some people were using melatonin, as a way to manage. I believe the potential for for Koba, too attached to her scepters. And there's some other literature that, that
Could potentially suggest. Melatonin may have some type of antiviral activity. Then there's also some people who use high dose melatonin for circadian. Rhythmicity. For example, we travel across multiple time zones and wake up groggy and the same can be said for CBD, for example, many people use CBD, they'll wake up groggy and one of the best ways to eliminate that grogginess even better than than coffee. Or, you know, I don't know what modafinil would do. I would imagine my death and would probably help out quite a bit, but it's
Right, like just staring at sunlight or get exposure to play or even you're staring at a backlit LED of a computer screen like any Hefty, exposure to light in the morning, seems to throw off some of those effects. And so what I did based on that was when I began to wake up early. I kept myself from Light. I kept myself from light until the time arrived at, which I wanted to start waking up, right? And that and that's why I put on Blue Light blocking glasses. When I woke up smart. I keep my body thinking because I just can't lay in bed for two hours from 4 to 6 a.m.
Is driving me nuts, so I get up but to keep things dark. Don't turn off the light or turn to turn on the lights in the house. Keep the computers with the red light mode, on the computers, wear blue, light blocking glasses. And then when 6:00 or 7:00 a.m. Rolled around, I'd take all that off and just blast myself with light, and it seemed to shift my circadian rhythm back into cycle. Yeah, it's always really odd. I would have expected. I would want to sleep in the day after taking modafinil, but it was just the opposite. Yeah, and I suspect.
There's some feedback going on to the clock. And yeah.
Yeah, so I have a
Have a few notes here about a few other things that I wanted to. Ask you about one would be do you do you know, you know, I mentioned that I guess this, you know, a hundred or two hundred milligram dose seems to last about 12, to 15 hours. But have you looked into like time spent in the bloodstream. If it's still in the bloodstream for a longer period of time than that, or, or anything along those lines. So, well, there
are two different enantiomers in an enantiomer refers to the fact refers to a molecule that can have two different shapes. And so the analogy
You can think of is that your two hands, they're shaped very similarly, but they're actually, you know, symmetrical each other, right? Because the thumbs are pointing inward, right? So that's how it is with modafinil molecules. There are two different shapes of modafinil molecule and they are metabolized differently. And so it turns out that there's an r and an Timur and an S enantiomer, and the are one. In fact.
It has been marketed as armodafinil as a distinct ethanol for. I
haven't used it. But I've heard it's a lot
stronger. So yeah. Well, this one is the one that's this metabolized very slowly. Okay? Yeah, so it's got a much longer Half-Life than the S and an Timur interests. And I mean that what might be good or bad depending on exactly what indication you're writing
it for, right? Or I suppose that you could theoretically if you were using the are and Auntie mayor throwing one of those tricks like grapefruit juice and yeah and slow down.
Go 24/7, your the other access is interesting. There's just the total total Rabbit Hole here side, comment, you know, in addition to those those cyp Inhibitors I was talking about there were some other compounds. I came across that appears to actually kind of neutralize modafinil or slow, its release, which, if you're using that, that our version could come in handy. This is kind of related to to theanine. Some people will use theanine to take the edge off of a. Stimulant many people use modafinil will use the inning to take the edge off the the anxiolytics.
This coffee is another one, many people will put about a hundred milligrams of theanine in with their coffee. Especially these so-called slow, coffee oxidizers. And it takes some of the edge off of coffee. Well, it turns out that these, these Prebiotic compounds like, you know, marshmallow root and inulin, what's wrong with cellulose, you know, some of the things people are using to like feed good bacteria in their gut. Those also slow the release or the uptake of modafinil that's installed so that
Another, that'd be another hack if you were using like the really strong version like the our version of modafinil, so I thought I thought that was interesting, how many different things can kind of kind of tweaked its absorption. And so in terms of the actual onset, or the duration, what I found I'm going to, I'm going to read this graphic that I found to you. It says on set and this would be for like a standard hundred to two hundred milligram dosage on set. Would be 45 minutes to 2 hours. Where were you really start to feel?
It the time until Peak effects one to two hours. The peak effects occur at about 2 to 4 hours from intake. So, you know arguably if you're taking this so that you can go Crush at a conference or a board meeting or something like that and the board meetings at 10. You actually want to take it like 7:00 or 8:00 a.m. A couple hours prior the tapering off. Like I mentioned is like 12 to 16 hours with the total duration, being 16 to 22 hours for for like a standard dosage.
A hundred to two hundred milligram dosage obviously. Based on what we've talked about already. Probably a pretty big amount of variation with that.
Yeah, no doubt. There is. Yeah.
The other thing that I came across that was interesting, was this idea of the use of modafinil, as a way for people to get over, hangovers seems to be popular hangover remedy. And This concerns me again, because we know that alcohol needs to be
Realized by the liver, modafinil needs to be neutralized by the liver. I would imagine and I don't know what your thoughts on. This would be that if you're using modafinil regularly as a hangover remedy, you're putting some pretty undue stress on the liver.
Well, I think the the alcohol obviously is putting the stress on the liver, you know, and how would that affect modafinil? I mean, I think this is certainly at the periphery of my expertise, but the FDA is pretty sensitive about things. Harming the liver for obvious reasons.
Don't think there are concerns with modafinil, harming the liver. But yeah, with all those other things
- accommodation. I think that
that's where that's where exactly. Yeah, that's what I was going to say. If people want to start tweaking their liver enzymes, all bets are off. Right?
Right. Exactly. The other one in addition to liver because because alcohol is metabolized by that, Cy p450 enzyme, and then modafinil is metabolized by a cyp enzyme. And so I would imagine that would be not so great for the liver versus stacking modafinil, you know, I talked about
out mixing with something like nicotine or caffeine or something like that. It probably enhance the effect but alcohol would actually put undue stress on the liver. Yeah. Yeah, if you have that in your system at the same time as modafinil, another one that I found interesting, obviously we both live in Washington state where marijuana is legal is they actually did a study on marijuana and modafinil and they looked at the the combination of THC and modafinil and what they found was that the normal euphoric effect of THC seems to be down regulated.
By combination with modafinil. So it looks like it looks like based on that. Like, if you were a weed smoker, you're turning to weed for the, the enjoyment effects, that modafinil could actually blunt some of that effect. So, you know, that'd be another one. Probably.
Yeah, I got to take a bite with modafinil. Would imagine. Yeah. I'm wondering if this is, you know, one of these desensitization process going on.
Yeah. Yeah, and then here's what's interesting. I know I'm throwing a lot of stuff out there, but I just, you know,
In leading up to chatting with you. I just started to dig into all these different off label uses of modafinil. So, apparently, the way that you described at modafinil Works earlier is almost the same way that cocaine Works in terms of its effect on
dopamine. Yeah, so there are some norepinephrine if there are definitely some parallels, but there are some important differences and one of the differences is that while modafinil appears to act pretty much exclusively by
Locking that dopamine transporter. Cocaine has effects mediated by blockade of the dopamine transporter, just like modafinil but also serotonin Transporters to some extent and noradrenaline Transporters to some extent. Okay. So that's one thing that will discriminate, modafinil from cocaine. The other I think is has to do with what we call the pharmacokinetics. And this is you've already made reference to the pharmacokinetics, like, you know, its initial effect will be 40.
Five to sixty minutes after Administration Peaks at two hours or, you know, remains for 16 point. So that's a very slow pharmacokinetic response that response that you get to modafinil cocaine. Cocaine is kind of an experiment of nature. So you can take coca leaves you can chew on them. Typically, people will do with it like a rock and this is what, you know, in the
Andes. Where did that a couple of times did you do? It was actually, you know, I I hear cocaine and I think, you know, addicted people.
On going crazy, you know, vacuuming their living room for eight hours, but I tried a little bit of coca leaf. One of my friends gave me some is mixed with baking soda because apparently the baking soda, cannae causes a little bit of breaking of the captain, right in my lower lip, and and I just put a little bit of lower lip with baking soda and it felt like, I just had a little coffee kind of slowly
right system. So if you look at the pharmacokinetics of cocaine getting into the brain, when you take it in that matter, when you chew on a coca leaf, and it's slowly
And through the gums and works its way through the bloodstream up to the brain. The pharmacokinetics are largely similar to those of modafinil. It's going to creep up slowly over a period of hours and it's going to drop over a period of hours. And as you just said, the cognitive experience is not dramatically different from modafinil. If you take cocaine and you inject it, do it take it orally. It's going to be the same one that you can actually get some through your stomach. And again, we slow rise and you'll just have sort of a general alertness improving and
Thing effect, if you inject cocaine into your veins, that will get into the brain faster. Now, we're starting to get into the world. You have Euphoria, right? Or if you snort it, or if you smoke it, then it gets right into the brain. And that's when you see people, having these issues of, you know, or are experiencing the Euphoria, and then having the difficulties with dose escalation, and everything else that goes on with, with cocaine abuse. So when we published our data originally saying that this is a dopamine transporter,
blocker. And here's our evidence. And here's why, and I believe those data have stood the test of time, but a lot of the reaction to that negative reaction to that concept was like, wait, cocaine blocks, the dopamine transporter. This is nothing like cocaine. Well, it's only the, when you have cocaine and a in a form that is chewing on the coca leaf or swallowing the coca leaf that has the similar pharmacokinetic profile. You have a similar experience and it's only when you change the pharmacokinetics and with modafinil
A way to change the pharmacokinetics. You can't smoke it. You can't you can't really put it into a form that's injectable very effectively. So it is very different from cocaine in that respect. But they our concept has withstood. The test of time. It is binding to the dopamine transporter, the same site as
cocaine begs. The question about whether or not there's like an intranasal spray version of modafinil just because I know a lot of people now are like doing Enter nasal NAD, intranasal
Oxytocin. Yeah, I don't know if it'd work. I yet. No, I think I would say this probably it's been tried and if somebody's mad right by now, the news would be out. That's my guess. Yeah, it's a very funny compound in terms of its physical properties and very difficult to work with and so interest. There's yeah, as far as I know, there's no way to get the as direct shot to
the brain. Yeah. Yeah. The reason I asked about the cocaine is apparently 800 milligrams.
Of modafinil in people who have used cocaine. And also use modafinil these folks report that they get a very similar effect as using cocaine. When they take 800 milligrams of modafinil, which I would suspect presents a whole host of issues for both the liver and the the dopamine sensitivity based on what we've discussed. Yeah, but apparently produces some kind of a hallucinogenic effect and I am in no way endorsing the the off-label use of a pharmaceutical drug in very high dosages to
get the same effect as cocaine,
but I'm glad he's right.
Yes. It's very interesting. And by the way, for any of you listening in right now, I'm going to to link to Jonathan's research website, as well as links to any of the studies mentioned during today's podcast. And also, this is where you can go to ask your own questions, or leave your own feedback about your use, of modafinil, your thoughts regarding it. If you go to Ben Greenfield fitness.com, / modafinil, let's
In Greenville fitness.com modafinil, if you don't know how to spell modafinil, good luck use Google. Okay, so just just a couple final things to touch on here in closing, have you used a word you ever use modafinil yourself knowing what you know about it.
I have never used it because I do not experience excessive daytime sleepiness. I mean, one of the things that I've always done with my research is try to apply it to my own life, to the greatest extent possible. And so, it's not that I have never experienced it.
Excessive daytime sleepiness, but it's very rare for me. I have two children once in a while. They'll be sick and you know right to be up at night because of them or my pet dog being sick or something, but that's so rare that you know, the the excessive daytime sleepiness is, you know, the next day and then it's gone. Yeah, right. And so yeah, I never
have. Yeah. Yeah, and I also wanted to comment on my own experience with it because I got a prescription for
Position for 200 milligram modafinil, tablets and I cut those with a worth of razor blade in half, because I really didn't want 200 milligrams and with a hundred milligram dosage. And I did try 200 watts. And was,