Modafinil: Is This Wildly Popular Smart Drug Safe And Effective? (& What It Can Do For Your Sleep Cycles & Brain Health).

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 Modafinil, your brain says, hey, everything's great. Your muscle's 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 physiologic price for that health.

Performance, nutrition, longevity, ancestral living, biohacking, and much more. My name is Ben Greenfield. Welcome to the show. Boom Chakalakalaka. I am not on any mind altering substances while I am 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 Modafinil today and if you've never heard of this wakefulness promoting smart drug that's sweeping the world by storm, or at least Silicon Valley, you're the Take a listen. I thought this was really interesting and I learned a lot from my guest. Well folks, this is it. I have gotten a ton of questions from you about this smart drug that seems to be increasing in popularity. For better or worse. It's called Modafinil, also known as Provigil, along with several other variants of it that are sold as online pharmacy variants and different isomers of it. But Modafinil or Provigil is probably the most popular version of it. It's the darling of the smart drug industry. It has been for quite some time. There's about 200 human clinical 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 not a host of addictiveness or excessive stimulation, although that's something that we'll explore on today's episod. It's used by a ton of notable figures. The myth or truth I'm not quite sure, is that nearly every president and vice president now is using this drug. Folks like Joe Rogan, anti aging people like Ray Kurzweil, Barack Obama, Definitely reported that he used it. So does 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 and air Force pilots for enhancing alertness and reducing battle fatigue. Lab studies have looked into it almost kind of similar to 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 I decided I wanted to just jump in 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 really 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 Pardee. And I said to Dan that I was very interested in interviewing someone on my Modafinil who would he recommend. And he said, there's this guy, Dr. Jonathan Weiser. 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.

All things cold for me. I love cross country skiing and I love cold water swimming as well.

Now, now for you, is that because of the, the love for exercising in that environment or are you one of those biohackers who's trying to increase, you know, 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, when you, a bracing experience when you feel the cold.

Yeah, yeah, I was well showing you my, my cold, my Morozco out there by my office and I, I, I've been increasingly than coffee. When I'm a little bit sluggish during the day or that afternoon, tiredness sets in. Sometimes I don't even put my whole body and I'll just get lazy, just take off my shirt, immerse my entire torso in there and just do a few dunks, towel off, go back in and keep jamming away on work. Cold is, of course, amazing for alertness, but that's not the drug that we're going to talk about today. So you have a PhD in neuroscience from University of California in Los Angeles. I know you've done some research at Stanford University and now you are a. You're on the faculty at Washington State University right here in Spokane. Yeah. And you also work with the medical education program. What is it, Whammy Washington?

Well, that's a prior iteration now with the College of Medicine at Washington State University in Spokane.

All right, so are you spending the lion's share of your time then lecturing or researching?

It's about 2/3 research, one third teaching at this point.

Gotcha, Gotcha. And what type of courses are you teaching?

Teach the basic cell biology of the nervous system, of muscles, of the immune system. Cell biology in the first year of the medical curriculum.

Gotcha. And 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 rhythmicity or things that might relate to modafinil?

Well, so back when I was an undergraduate, I knew that I wanted to study some aspect of 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.

Was that in high school or college?

No, this is college. Yeah.

Okay, this is crazy. I'm going to be a rabbit hole here because I worked at a bakery. Really in my, it would have been my, my junior and senior year of college in Moscow, Idaho. I worked at a, at a French bakery. And it was very funny because I would show up at the bakery at about 4am and yeah, just prepare everything and, and it was very French. They were, we're talking chocolate croissants. But, but done, done. Right. You know, and we had the croque monsoise that people come in for, for lunch. You know, the sourdough bread with the cheese and the tomato 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. And then I'd go off to school at about 8am and take all my courses. And then in the afternoon I worked as a personal trainer at the gym across the street from the French bakery. So I'd basically get people fat in the morning, train them to burn calories. It was a great business model. So 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. So, you know the fluffy, white, spongy bread that you could squeeze into a ball. Yeah, that's a good way to put it. Yeah. So same thing. I go to work at 4 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. It certainly kept me motivated and inspired to stay in school, but it also gave me focus to my interest in neuroscience. This sleep thing. If your sleep isn't good, things can really go wrong for you. And what is it about sleep? What is it that it does for us that is beneficial? And why is it that I can't just get up at 4am when I want to and be fully functional then? So that was. We're going back decades now, of course, and I'm still facing that same question with. We have a lot more details now than we did back then about how sleep is regulated and what sleep does for us that's beneficial. But that story continues to evolve. And so 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 coursework and your research since then?

Absolutely.

Gotcha, Gotcha. How much now do you find yourself talking about sleep or the neuroscience of sleep 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 because the nervous system can next to the immune system. And so 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 it in as much as possible.

The list goes on and on. We could probably talk for two hours just on 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, a sleep disorder actually keeping someone awake when they have a disease that causes them to sleep during the day, this modafinil or Provigil, as it's also called, is quite commonly used and like I mentioned in our introduction, increasingly used now amongst biohackers and E gamers and poker players and college students. 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 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 wanted 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 that will 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 produced the dopamine and released it in the first place.

So kind of similar to what you'd see with, like, a selective serotonin reuptake inhibitor, which would be inhibiting the uptake of serotonin by that cell that released it. In the case of dopamine, it's a similar mechanism to where it's in this synaptic cleft, but then there's a reuptake mechanism back to the neuron from which it originated.

Exactly. Yeah. And so you mentioned. Yeah. So maybe by analogy. Yeah. We think of antidepressant drugs, selective serotonin reuptake inhibitors. Well, modafinil is a selective dopamine.

Dopamine reuptake inhibitor inhibitor, sdri.

Although that's not a term that is typically used. We just made it up by analogy. Yeah.

That's all right. We can make up shit.

Yes. Okay. So by analogy, that's. 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 and release the dopamine. So you're strengthening or enhancing this dopaminergic signal that tells us to focus and stay motivated.

Okay. And norepinephrine, similarly, from what I understand, is also affected by modafinil. And perhaps it's not just dopamine that's being acted upon in terms of actually, I guess, in a way flooding cells with dopamine or decreasing the actual reuptake of dopamine. But then is norepinephrine 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 if you block the reuptake of dopamine by the mechanism that I just described, those dopaminergic cells, some of the other cells that they will activate, contact and activate, will be cells that are producing norepinephrine. And so then those norepinephrine cells are like, oh, okay, we need to be recruited into this process too. Right. And so then we have an increase in norepinephrine release. So, yeah, so that's going to help also focus our attention.

Right? Focus our attention or in excess cause some of the pot that I know some people have reported when using Modafinil, especially in higher dosages, because dopamine, I wouldn't say, at least in my own personal experience, even just using a dopamine precursor like Mucuna, for example, it doesn't seem to produce any really pronounced anxiety effects. It's more like a feel good wakefulness type of effect. But then I think norepinephrine, it does kind of give you this anxious kind of jittery effect that.

Yeah, that makes sense. I think that's one of the things that norepinephrine can do. It's a central mediator of the so called fight or flight response, the sympathetic response. And so, yeah, anything that does boost norepinephrine could have that effect. And probably, you know, certainly that's not the case in everyone who takes Modafinil. And it probably has to do with individual variability in sort of neurochemistry.

I want to get to how tightly.

The dopamine links to the norepinephrine in that particular individual's central nervous system.

Yeah, yeah. And then in addition to that, and I do want to get into, and I think we will kind of variations in response to Modafinil. I have some of my own hypotheses regarding that. But then also, have you looked into histamine at all and a histaminergic response to Modafinil?

So, yes, there is definitely a histaminergic response as well. And again, we have to emphasize that all of these neurotransmitters talk with each other. 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 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, that's associated with cognitive enhancement. 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, but he was at grandma's house last week and he had an allergic reaction to pollen. He gets a little bit of seasonal allergy and she gave him Benadryl. And he has ever rarely, we're pretty natural at Our house. He's rare ever ingested a pharmaceutical and he was sleepy and his eyes were rolling over. He said, dad, what's going on? I said, well it's shutting down one of the excitatory compounds in your body, histamine, and you're probably gonna sleep pretty solid tonight and you're probably gonna have some bizarre dreams. But. Yeah, but histamine in excess or something that would block histamine seems to really produce this kind of wakefulness effect.

Well, so let's be clear, that's what you just described is the effect of an antihistamine.

So something that blocksamine.

Right. So modafinil, again, indirectly, we think is the opposite of that. So it is again sending out a signal to the cells that 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 anti histamine. The histamine itself is in general associated with improved cognition, cognitive enhancement. So this may be another aspect of the modafinil story that is so critical for, for its cognitive enhancement properties.

I saw one study that showed about 150% increase in histamine release.

Sounds about right.

So we've got dopamine, we've got norepinephrine, we've got histamine. And then there's also this interesting molecule called orexin. Have you looked into how that ties into modafinil?

Yeah, orexin is sort of an upstream regulator of all of these neurotransmitters that we've talked about. And so 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 signal that would otherwise be there.

It's basically like the wake drive signal. That's right, because you'd see a drop in orexin as nighttime approaches and then an increase in adenosine, which coffee or caffeine would decrease the stimulation, or at least it would fill those receptors that adenosine would normally interact with. So orexin would almost become like the opposite of adenosine in a sense when it comes to wake drive.

Yeah, so orexin, yeah, 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 orexin, 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 when we look at Modafinil, it has this wakefulness producing effect. But then when you look at some of the literature, and I sent you one study that's showing like an antioxidant effect or kind of almost like a neuroprotective effect. Have you seen anything like that?

Yeah. So the neuroprotective effect, I do not put a whole lot of weight onto that. So here's my understanding of where this alleged antioxidant 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, what I'm about to tell you, if you're not an abuser or user of poorly made synthetic opioids, this alleged antioxidant effect is 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 impure opiate mixture, including mptp. Well, if you block the dopamine transporter with Modafinil, you're going to prevent that MPTP from being taken up, up 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 these, the path that generates these toxins that I just described, that's involved in the metabolism of dopamine itself. But whether or not there's any potential long term sort of neurodegenerative 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. So, and 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 Parkinson's as a motor disorder, but there are cognitive effects as well. 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. I don't think the data are there in terms of slowing the progression of the disease.

Okay, got it. It's interesting when you say that about Parkinson's, because there's another very common compound that's being used increasingly again amongst the smart drug and the biohacking community, and that is nicotine, which suppresses kind of the GABAergic activity on dopaminergic neurons, meaning it would keep inhibitory neurotransmitters from. From essentially shutting down some of the response to dopamine, which we know is an issue in Parkinson's, and seems to increase the acetylcholine activity. And so actually, a lot of people are combining like a milligram of nicotine with what would be considered like a microdose of modafinil, like 50 milligrams 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 stack that people often use with 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 know, you'll see people stacking caffeine, nicotine and modafinil to kind of hit cognition and awareness on three different levels. So it's interesting what people are cooking up in their kitchens these days. 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 in a lot of these studies on the military and on fighter pilots, you know, awareness or reaction time, or in athletes, increased time to exhaustion, what could go wrong?

Okay, so I think we need to consider this broadly at first, and then I'll get a little bit more specific in 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 or klepsy. Well, yeah, so. And we could. I'm gonna. I'm gonna give you three categories of people or situation, circumstances 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 mentioned, 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 Modafinil, 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 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. The CPAP machine, to make sure that you have your breathing continues 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 will ameliorate that excessive daytime sleepiness. So sleepiness 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 shift work, people who undergo shift work. And of course, this is inevitable in many cases, you know, medical professionals, security, 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 shift work. 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 that you're caring for at home and you have disrupted sleep at night, if you're breastfeeding, yeah, you're going to have excessive.

I'm just kidding. Don't take Modafin if you're breastfeeding.

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 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 Modafinil 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. I want 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 things related to the stock market until like, midnight, and then they have to get up at 5am because that's when the. The stock market opens on the east coast or whatever. So now they're only getting five hours of sleep a night. You know, that's an example. Or a gamer or somebody who's just like, obsessive about checking Twitter or something. 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. Most of us cannot pull that off without pharmaceutical enhancement, at least in the long term, more than a few days at a time. Okay? And so that person, they can go to their 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, like, I'll be sitting at my computer And I'll fall asleep. And they'll say, okay, you have excessive daytime sleepiness. Here's your prescription for Modafinil.

Right. Which is more likely to be able to get your doctor to write your prescription for Modafinil than 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 19 hours a day, 19 hours sleep, get their 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 Modafinil. And this is based. I'm saying this not based on speculation, but based on observations in published scientific studies.

Okay? Okay.

So now we need to know what goes on physiologically when we restrict ourselves 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 five hours of sleep a night. So what that means is the 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 that they can take that glucose, convert it 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 Modafinil 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? So, and that's. This is scientific. This is published. This is something that's been studied systematically. Other things. Cortisol is our stress hormone, right? It's our Fight or flight hormone. Under normal circumstances, if you're getting 8, 9, 10 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 that you have stored up glycogen in the previous night. 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 responsive 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. Some glucose. And that's what they do. People who are restricted to five hours of sleep a night, either voluntarily or under 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 five hours of sleep, that increase in cortisol in the evening, that will occur whether or not you're taking Modafinil. Take your Modafinil. Your brain says, hey, everything's great. Your muscle's 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.

One thing I should throw in there that's related to this exercise piece is I would say about half a dozen times, because we scheduled this interview about. About. I guess it was maybe about a month, a 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 modafinil and I took about 100. I vary between 100 and 200 milligram dosage, which is pretty common, low to moderate. We can get into micro dosing. And also 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, 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 the benefits of sleep that go beyond simply allowing you to have better cognition 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 used 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 muscular recovery that should occur during sleep to the extent to where I, I had a notable increase in soreness that I usually wouldn't experience the next day. I was fine as far as wakefulness the next day when 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 our deep slow wave sleep in order for us to have that surge of growth hormone that occurs at night. If you restrict someone to five hours of sleep, they don't have that surge in growth hormone. That's true whether or not they are taking modafinil at the time. Finally, melatonin. I think people are a little more excited about melatonin than I think the data 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 hours of sleep and you're supplementing yourself with modafinil, that melatonin is still lost. 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 insensitivity, in which things that would normally elicit 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. Maybe sex might become less enjoyable. Any of these things that rely upon dopamine. If you need more and more Dopamine, and this is just a theory. I haven't seen literature on this. It would seem that constantly flooding the receptors with dopamine like that might induce some kind of dopamine insensitivity or tolerance to dopamine itself.

Yeah, I guess I'm not aware of anything like that happening with Modafinil. That's a good question for you to pursue and that's probably something I will look up myself later. But I'm not aware of anything like that happening with modafinil. Certainly that kind of mechanism exists in the nervous system. There's no doubt that it does. So like that's often if someone takes methamphetamine, which methamphetamine boosts dopamine production through somewhat different ways than modafinib, we have to discriminate them. 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, 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 affect.

Have 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. 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 rep retrospective study that found in a bunch of patients who were taking Modafinil 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 was over several months to the end. It was still effective. And then most of the reports to tolerance are in places like Reddit or forums or kind of like the underground biohacking type of type of comments on blog sessions where people are like, yeah, I need more and more over 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 off label use, 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 milligram dose.

Now I believe 200 is pretty much the standard? I think so, yeah. If you're pushing it beyond that, good luck.

Another few thoughts that I had would be the desensitization tolerance, meaning there are the receptors that activate the dopamine transporters, and apparently those can be down regulated. In particular, there were two that I came across, one called tari, T A R, I, another one called dt, and those are apparently two activators of the dopamine transporters that get down regulated when you are using modafinil. And I did find some literature showing that 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 weekends off, that the dopamine transporters do not actually become down regular. So there may be something to be said for cycling it.

Yeah, that's a good point. Yeah, 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 again, how it will react to repeated exposures, that sounds like a very reasonable possibility to me.

I also want to unpack something related to something you kind of alluded to earlier. Now be different people responding in different ways. And when I was thinking about this, I began to think about it the same way as one would think about coffee. We know, for example, and many people are aware, if they've taken a 23andMe test, they're reported to be a fast coffee oxidizer versus a slow coffee oxidizer based on these CYP genes. And these would be related to liver enzymes responsible for breaking down certain compounds. And we know that modafinil is processed in the liver and some people have a higher activity of those genes and some people a lower activity.

Yeah, these are the Cytochrome, Cytochrome PCs, Cytochrome P450.

Yeah. So there's one involved with Modafinil. Cytochrome P2C19 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's where I suspect perhaps 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 CYP enzymes. They're 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 or for you to feel it more. And so I looked up all these CYP inhibitors and grapefruit's the most common. Grapefruit's the one you gotta be really careful with, because if you take that at the same time as a pharmaceutical, you can actually inhibit the breakdown of that pharmaceutical to a 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. Berberine was another. And then there's California poppy and chaste tree. So it turns out that there are certain things that if you weren't really feeling the Modafinil or you felt like you were a 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.

I think that's true. I would just offer a significant level of caution to somebody who wants to mess with their liver enzymes.

Exactly, exactly. Okay. And I have all sorts of kind of fun little things I want to delve into too. 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, up the next day at a very early time, very early time. And you take modafinil, let's say 7am One morning, and then suddenly, without changing anything else in your life, you wake up about 4 or 5am 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?

Wow. This is one I have not, not heard of before.

That it would actually, I'm thinking maybe it has something to do with that Orexin, you know, and, and the change in wake drive potentially if, like, if you're shifting wake drive later in the night. But, but the, 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 erection. Yeah, that would be what I, you know, if you're shifting your, your sleep drive to start to kick in at like 10pm 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 maybe you're waking up at 8am and not at your normal 6am but instead it seems to occur. And I talked with a couple other folks who had experienced this idea where you wake up a lot earlier when you're on Modafinil.

Well, the one possibility I can offer is that everyone has a circadian clock. And I don't know if that means anything, but this is, you know, our internal clock that 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. In particular, if we engage in exercise early in the morning and simultaneously expose ourselves to light as part of that exercise process, that will push the clock to an earlier wake up time. And so you may have been doing that with, you know, 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, that's going to shift the clock to a little bit earlier in the day. So that's my best hypothesis about that one.

Yeah. Yeah. 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 mimic, manage, I believe, the potential for Covid to attach to receptors. And there's some other literature that could potentially suggest melatonin may have some type of antiviral activity. Then there's also some people who use high, high dose melatonin for circadian rhythmicity, for example, when traveling 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 coffee or. I don't know what Modafinil would do. I would imagine modafinil would probably help out quite a bit. But it's light like Just staring at sunlight or getting exposure or even just 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 then, and then so I put on blue light blocking glasses when I woke up.

Smart.

Kind of keep my body thinking because I just can't lay in bed for two hours from 4 to 6am and drive me nuts. So I get up, but I 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 or 7am or around, I'd take all that off and just blast myself with light. And it seemed to shift my circadian rhythm back into cycle. But I thought was really odd. I would have expected I would want to sleep in the day after taking Modafinil, but it was just the opposite.

Yeah, I suspect there's some feedback going on to the clock.

Yeah. So I have a few notes here about a few other things that I wanted to ask you about. One would be, do you know, I mentioned that I guess the, this 100 to 200 milligram dose seems to last about 12 to 15 hours. But have you looked into time spent in the bloodstream, if it's still in the bloodstream for a longer period of time than that or anything along those lines?

Well, there are two different enantiomers. And an enantiomer refers to the fact, refers to a molecule that can have two different shapes. And so the analogy that you can think of is that your two hands, they're shaped very similarly, but. But they're actually symmetrical to each other 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 enantiomer and an S enantiomer. And the R1 in fact has been marketed as Armodafinil as a distillery.

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 enantiomer Interesting. And that, I mean that might be good or bad depending on exactly what indication you're using it for, right?

Or I suppose that you could theoretically, if you were using the R and antimir, throw in one of those tricks like grapefruit juice and slow down go 24 7. Actually, it's interesting, just the total rabbit hole here. Side comment. In addition to 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 R version could come in handy. This is kind of related to theanine. Some people use theanine take the edge off of a stimulant. Many people who use modafinil will use theanine to take the edge off of the anxiolytic effects. Coffee is another one. Many people will put about 100 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 prebiotic compounds like marshmallow root and inulin, what's called it, 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.

Oh, that's interesting.

So that'd be another, that'd be another hack if you were using like the really strong version, like the R version of modafinil. So I thought, I thought that was interesting. How many different things can kind of, kind of tweak its, its absorption. And so in terms of the actual onset or the duration, what I found, I'm going to read this graphic that I found to you. It says onset. And this would be for like a standard 100 to 200 milligram dosage. Onset would be 45 minutes to two hours, where you really start to feel it. The time until peak effects, one to two hours. The peak effects occur at about two to four hours from intake. So arguably, if you, if you're taking this so that you can go crush it at a conference or a board meeting or something like that, and the board meeting's at 10. You'd actually want to take it like 7 or 8am 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 a standard dosage like that, 100 to 200 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.

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 a popular hangover remedy. And this concerns me again, because we know that alcohol needs to be neutralized by the liver. Modafinil needs to be neutralized by the liver. 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 alcohol obviously is putting the stress on the liver. 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. Reasons I don't think there are concerns with Modafinil harming the liver, but with.

All these other things, Modafinil combination. I think that that's where. That's where you.

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 the liver, because alcohol is metabolized by that CYP450 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. I talked about mixing with something like nicotine or caffeine or something like that. It probably enhanced the effect. But alcohol would actually put undue stress on the liver. 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 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. And so it looks like based on that, like if you were a weed smoker, you're turning to weed for the enjoyment effects, that Modafinil could actually blunt some of that effect. So that'd be another one. Probably not to compare combined with Modafinil would imagine.

Yeah. I'm wondering if this is one of these desensitization processes that's 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, 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 that modafinil works earlier is almost the same way that cocaine works in terms of its effect on dopamine.

Yeah, so there are some norepinephrine. 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 blocking that dopamine transporter, cocaine has effects mediated by blockade of the dopamine transporter, just like Modafinil, but also serotonin transportation 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 45 to 60 minutes. After administration peaks at two hours, you know, remains for 60. So that's a very slow pharmacokinetic response. That response that you get to modafinil cocaine. You know, cocaine's kind of an experiment of nature. So you can take coca leaves, you can chew on them. Typically people will do with like a rock. And this is what, you know, in the Andes.

I did that a couple of times.

Did you?

It was actually, you know, I hear cocaine and I think, you know, addicted people going crazy, you know, vacuuming their living room for eight hours, hours. But I tried a little bit of coca leaf. One of my friends gave me some. It was mixed with baking soda because apparently the baking soda kind of causes a little bit of breaking of the capillaries in the lower lip. And I just put a little bit in the lower lip with baking soda and it felt like I just had a little coffee kind of slow bleeding the system.

So if you look at the pharmacokinetics of cocaine getting into the brain when you take it in that manner, when you chew on a coca leaf and it's slowly absorbed 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 kind of that. You can actually get some through your stomach. And again, it'll be a slow rise and you'll just have sort of a general alert, improving and focusing effect. If you inject cocaine into your veins, that will get into the brain faster. Now we're starting to get into the world of 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 experiencing the euphoria and then having the difficulties with dose escalation and everything else that goes on 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 when you have cocaine in a form that is chewing on the coca leaf or swallowing the coca leaves that has the similar pharmacokinetic profile, you have a similar experience. And it's only when you change the pharmacokinetics. And with Modafinil, there's no way to change the pharmacokinetics. You can't smoke it. You can't really put it in a form that's injectable very effectively. So it is very different from cocaine in that respect. But 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 intranasal, nad, intranasal cbd, oxytocin. I don't know if it'd work.

Yeah, no, I would say this. Probably it's been tried, and if somebody tried it, by now the news would be out. That's my guess. It's a very funny compound in terms of its physical properties. It's very difficult to work with. And so there's. Yeah, as far as I know, there's no way to get a direct shot to the brain.

Yeah, yeah. The reason I ask 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 cocaine when they take 800 milligrams of modafinil, which I would suspect presents a whole host of issues for both the liver and the dopamine sensitivity based on what we've discussed. But apparently it produces some kind of a hallucinogenic effect. And I am in no way endorsing the off label use of a pharmaceutical drug in very high dosages to get the same effect as cocaine.

But I'm glad to hear you say that.

Yes, it's very interesting. And by the way, for any of you listening in right now, I'm going 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 or your thoughts regarding it. If you go to BenGreenfieldFitness.com Modafinil that's BenGreenfieldFitness.com modafinil if you don't know how to spell Modafinil, good luck. Use Google. Okay, so just a couple final things to touch on here. In closing, have you used or would 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 it's not that I have never experienced excessive daytime sleepiness, but it's very rare for me. I have two children. Once in a while they'll be sick to be up at night because of them or my pet dog being sick or something. But that's so rare that the excessive daytime sleepiness is the next day and then it's gone. I never have.

And I also wanted to comment on my own experience with it because I got a prescription from a physician for 200 milligram modafinil tablets and I cut those with a razor blade in half because I really didn't want 200mg and with 100mg dosage and I did try 200 once and I was up until midnight after taking a 7am dosage and didn't like it at all. I noticed that I did indeed have complete resistance to falling asleep on days for which I was sleep deprived. But it was a very annoying feeling, as though I was sleepy and a little bit irritable, but couldn't sleep if I tried to sleep, couldn't tuck away for a nap if I tried to tuck away for a nap and felt as though there was some definite low level irritability or anxiety that accompanied it. I did not trust the L theanine trick that supposedly works quite well in that scenario, but my own experience with it would dictate that it would be something that I would have on hand. For example, sometimes I'll fly to Japan or fly overseas, jet over to Seattle and I'll get in at midnight and have to give a talk at 8am and by the time I get to my hotel and get to bed it's like 2am and I gotta get up at 7 to give the talk. I could see myself using it for, for a scenario like that. I could also see in a military scenario or a scenario in which one was having to operate under very stressful conditions, sleep deprived, that it could come in handy. But for me personally, because I know people are going to ask, based on the literature I've seen and the metabolism by the liver and the effects on dopamine, that made me suspect there could be some dopamine insensitivities that could kick in with long term usage. I have the, that giant bottle of Modafinil tablets now in my pantry and I would say it'd be that the type of thing that I would probably turn to based on my lifestyle, maybe once a month on some really hefty days in which I'm sleep deprived or some big travel engagements where I just cross multiple time zones and still got to operate, so to speak.

Yeah, I mean that sounds to me like a reasonable and healthy approach actually. And I'm just thinking by way of analysis to insomnia medications, because people who experience insomnia periodically, infrequently, generally respond quite well to insomnia therapeutics, which are typically agents that either increase the signaling of gaba, the inhibitory neurotransmitter, or shut off the signaling of orexin, the one the master orchestrator of wake that we talked about earlier. So it seems that periodic use of insomnia medications is a very effective approach. And it's only when you start having to take it every night that it just. Things can really go haywire. So I would suggest it's probably a very healthy way to think about Modafinil as well. If you have excessive daytime sleepiness, situationally very specific and very infrequent situations, then take it in those situations, patients. But don't be a motivational. Don't, don't make yourself suffer from motivational daytime sleepiness. And then use Modafinil as a day to day thing for that purpose.

Jump in the cold water instead.

Yes, that's right.

So, so here's the deal. You know, I've just met you, but we're definitely gonna have to cold water swim. All right, now that I know that you're into it, there's not a lot of people I can hunt out. I like to go check to the cold river and splash around. So we'll do that. And in the meantime, you guys, for those of you listening in who have questions for Jonathan or myself, just go to BenGreenfieldFitness.com modafinil and I'll put links to everything that we talked about and research studies and you can jump into the discussion over there. And in the meantime, Jonathan, thanks for coming on the show, man.

You're very welcome. Yeah, no, this is a lot of fun. A lot of fun. Yes.

All right, cool. Well, thanks for listening in, folks. I'm Ben Greenfield along with Dr. Jonathan Weiss signing out from BenGreenfieldFitness.com have an amazing week. Well, thanks for listening to today's show. You can grab all the show notes, the resources, pretty much everything that I mentioned over@BenGreenfieldFitness.com along with plenty of other goodies from me, including the highly helpful Ben Recommends page, which is a list of pretty much everything that I've ever recommended for, for hormones, sleep digestion, fat loss, performance, and plenty more. Please also know that all the links, all the promo codes that I mentioned during this and every episode help to make this podcast happen and to generate income that enables me to keep bringing you this content every single week. So when you listen in, be sure to use the links in the the show notes, use the promo codes that I generate because that helps to float this thing and keep it coming to you each and every week.