August 27, 2020

From podcast: https://bengreenfieldfitness.com/podcast/sleep-podcasts/modafinil/

[00:00:00] Introduction

[00:01:34] Podcast Sponsors

[00:04:07] Guest Introduction

[00:08:13] Interest In Sleep And Neuroscience

[00:13:36] What Exactly Modafinil Is

[00:19:29] Various Neurotransmitters Response To Modafinil

[00:23:18] Antioxidant And Neuroprotective Effects Of Modafinil

[00:28:03] Podcast Sponsors

[00:31:14] How Modafinil Use Can Go Wrong

[00:47:08] Whether Or Not Genetics Determine A Response To Modafinil

[00:49:42] How Modafinil Affects Sleep Cycles

[00:54:12] How Long Does Modafinil Stay In The Bloodstream

[00:57:53] Effects Of Combining Modafinil With Alcohol And Drugs

[01:05:50] Why Jonathan Has Never Used Modafinil Personally

[01:09:55] Closing the Podcast

[01:10:38] End of Podcast

Ben:  On this episode of the Ben Greenfield Fitness Podcast.

Jonathan:  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 is 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.

Ben:  Health, performance, nutrition, longevity, ancestral living, biohacking, and much more. My name is Ben Greenfield. Welcome to the show.

Boomshakalaka-laka. 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, 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 want to 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 synthesize maybe a gram of it on our own every day. 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 you can get. It's called Creapure, and five grams a day year-round, and it's amazing for cognitive function, but of course it's also a workout booster. So you kill two birds with one stone with one of the most heavily researched and safe supplements that's out there. And we have sourced the world's purest form of creatine that you can get your hands on. It is also completely plant-based as well, which is great. You can get it at getkion.com. It's the Kion Creatine, getkion.com, getK-I-O-N.com. You save 10% off of your first order if you use code BEN10.

This podcast is also brought to you by one of my favorite companies. They take bees and they harvest all of the goodness out of bees. They take great care of the little bees. They're actually devoted to be helped, but they're also on a mission to bring some of the best stuff from bees, the propolis, the royal jelly, the organic honey, all of the power that we find in the hive. These folks package and bring to you in things like handy-dandy nootropics immune system formulas, even bee pollen that you can sprinkle on granola, or smoothies, or avocado toast, or salads, or anything else. I love their bee pollen. It's crunchy, it's flavorful, it's low calorie, and it's chock-full of nutrients. So, the company I'm talking about is Beekeeper's Naturals. They're going to give 15% off of any of their bee products to any of my listeners, which means you. So, you go to beekeepersnaturals.com/ben. That's B-E-E-K-E-E-P-E-R-S, Naturals, N-A-T-U-R-A-L-S, dot com/ben, beekeepersnaturals.com/ben, and that gets you 15% off of any of the fine, fine Beekeeper's products.

Alright, let's go talk all things modafinil.

Well, folks, this is it. I've 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 of 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 dog 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 episode. 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 is 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 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 Pardi. And I said to Dan that I was very interested in interviewing someone on modafinil, who would he recommend? And he said there's this guy, Dr. Jonathan Wisor. 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?

Jonathan:  Mm-hmm.

Ben:  And–

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

Ben:  Yeah. Now, for you, is that because of the love for exercising in that environment, or are you one of those biohackers who's trying to increase brown fat conversion and take advantage of all these other elements that you get with cold thermogenesis?

Jonathan:  I mean, it's really about exercise and there is definitely an exhilaration, embracing experience and you feel the cold.

Ben:  Yeah, yeah. Well, I was showing you my cold tub, my Morozko out there by my office. And I've been turning to that more increasingly than coffee when I'm a little bit sluggish during the day or that afternoon tiredness sets in. Sometimes I'd even put my whole body in. I'll 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, and yeah. 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 Ph.D. in neuroscience from University of California in Los Angeles. I know you've done some research at Stanford University. And now, you're on the faculty at Washington State University.

Jonathan:  Yeah. Right in the Spokane.

Ben:  Yeah. And you also work with the medical education program.

Jonathan:  Mm-hmm.

Ben:  What is it? WWAMI, Washington–

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

Ben:  Okay. Alright. So, are you spending the lion's share of your time then lecturing or researching?

Jonathan:  It's about two-thirds research, one-third teaching at this point.

Ben:  Okay. Gotcha. And what type of courses are you teaching?

Jonathan:  Teach the basic cell biology of the nervous system, of muscles, of the immune system. So, cell biology in the first year of the medical curriculum–

Ben:  Gotcha.

Jonathan: –is the teaching.

Ben:  And with regards to neuroscience, particularly, or sleep, what's your background in terms of your research or your interest in the neuroscience aspects of sleep, or sleep or circadian rhythmicity, or things that might relate to modafinil?

Jonathan:  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.

Ben:  Wait, was that in high school or college?

Jonathan:  No, this is college. Yeah.

Ben:  Okay. This is crazy. I'm going to rabbit hole here because I worked at a bakery–

Jonathan:  Really?

Ben: –in my–it would have been my junior and senior year of college in Moscow, Idaho. I worked at a French bakery. And it was very funny because I would show up at the bakery at about 4:00 a.m. and prepare everything, and it was very French. We're talking chocolate croissants, but done right, lots of butter. And we had the croque monsieur that people come in for lunch, that sourdough bread with the cheese and the tomato on them. But what's funny is I would be selling these extremely high carbohydrate, high-calorie breakfast items to people in the morning. And then, I go off to school at about 8:00 a.m. 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 basically get people fat in the morning and then train them to burn calories.

Jonathan:  They come in for their [00:10:46] _____.

Ben:  Yeah. It was a great business model.

Jonathan:  Yeah.

Ben:  So, you worked at a bakery?

Jonathan:  Yeah. Well, this is the opposite end of the spectrum in terms of bakery. This was a wonder bread bakery.

Ben:  Oh, my.

Jonathan:  The fluffy, white, spongy bread that you can squeeze into a ball.

Ben:  Yeah. Right. “Bread”.

Jonathan:  Yeah. That's a good way to put it. Yeah. So, same thing. I'd go to work at four o'clock in the morning, and it was not fun, it was brutal to have to do that week in, week out. 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 4:00 a.m. when I want to and be fully functional then?

Ben:  Yeah.

Jonathan:  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.

Ben:  So, you've woven this interest of sleep and the study of the neuroscience of sleep into your course work and your research since then?

Jonathan:  Absolutely.

Ben:  Gotcha. How much now do you find yourself talking about sleep or the neuroscience of sleep in your research or your teaching?

Jonathan:  All the time. I mean, I try to bring it into the teaching as much as I can because the nervous system connects to the immune system. And so, when 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 it in as much as possible.

Ben:  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 eGamers, 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 a 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.

Jonathan:  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 the 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 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 we'll 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.”

Ben:  Right.

Jonathan:  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 there 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.

Ben:  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?

Jonathan:  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 reuptake inhibitor.

Ben:  Dopamine reuptake inhibitor. SDRI.

Jonathan:  Sure, yeah.

Ben:  Okay.

Jonathan:  Yeah. Although that's not a term that is typically used–

Ben:  We just made it up.

Jonathan: –but by analogy, yeah.

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

Jonathan:  Yeah. Okay. So, by analogy, 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 released the dopamine. So, you're strengthening or enhancing this dopaminergic signal that tells us to focus and stay motivated.

Ben:  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 also affected in some way?

Jonathan:  So, I would say sort of yes and no. Yes, it is clear that if you measure norepinephrine in the brains–this would be in 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, 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?

Ben:  Right.

Jonathan:  And so then, we have an increase in norepinephrine release. So, yeah. So, that's going to help also focus our attention.

Ben:  Right. Focus our attention, or in excess, cause some of the potential anxiety 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 like 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 give you like this anxious, jittery effect.

Jonathan:  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, probably. Certainly, that's not the case in everyone who takes modafinil, and it probably has to do with individual variability in sort of neurochemistry.

Ben:  Yeah. I want to get to that. Yeah.

Jonathan:  How tightly the dopamine links to the norepinephrine in that particular individual's central nervous system.

Ben:  Yeah, yeah. And then, in addition to that–and I do want to get into, and I think we will, variations in response to modafinil. I have some of my own hypotheses regarding that.

But then also, have you looked into histamine at all, in a histaminergic response to modafinil?

Jonathan:  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, 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 anti-histamine, an allergy drug, you're going to be potentially in a fog, right?

Ben:  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 rarely ever ingested a pharmaceutical. And he was sleepy and his eyes were rolling over and 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 going to sleep pretty solid tonight and you're probably going to 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.

Jonathan:  Well, so let's be clear. What you just described is the effect of an antihistamine. So, something that blocks histamine.

Ben:  Right, antihistamine, yup.

Jonathan:  Right. So, modafinil, again indirectly, we think, is the opposite of that.

Ben:  Exactly. Yeah.

Jonathan:  It is, again, sending out a signal to the cells that produce the histamine that says, “Hey, it's time for your 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. So, this may be another aspect of the modafinil story. It's so critical for its cognitive enhancement properties.

Ben:  I saw one study that showed about 150% increase in histamine release [00:21:43] _____.

Jonathan:  Sounds about right, yeah.

Ben:  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?

Jonathan:  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 cell types that we've mentioned. So, modafinil is downstream from that. And people who have narcolepsy, they are lacking the orexin signal that would otherwise be there.

Ben:  It's basically like the wake drive signal, orexin.

Jonathan:  Right. That's right, yeah.

Ben:  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 be kind of like the opposite of adenosine in a sense when it comes to wake drive.

Jonathan:  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 the dopamine-producing cells, the histamine producing cells. 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.

Ben:  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'd even 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?

Jonathan:  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.

Ben:  Okay.

Jonathan:  And MPTP–and I mean, this is–like, okay, if you're an abuser of a poorly made synthetic opioids, please get help. 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 impurity 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 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'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.

Ben:  Okay.

Jonathan:  This is not to say that you wouldn't enhance cognition with modafinil in someone who has Parkinson's disease. 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. And I just don't think the data are there in terms of slowing the progression of the disease.

Ben:  Okay. Got it. It's interesting when you say that about Parkinson's because there's another very compound that's being used increasingly again amongst like the smart drug and the biohacking community, and that is nicotine, which suppresses the GABAergic activity on dopaminergic neurons. Meaning, it would keep inhibitory neurotransmitters 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 to modafinil, like 50 kilograms 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.

The other stack that people often use with this is just caffeine because–and I think the reasoning is basically 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 stacking caffeine, nicotine, and modafinil to hit cognition and awareness on three different levels. So, it's interesting what people are cooking up in their kitchens these days.

Hey, I want to interrupt today's show to tell you about one of the coolest places to shop for online healthy items that exist. It's way better than Amazon, way better. You can get organic groceries, like you can on Amazon, but you also get clean, beauty, safe supplements, non-toxic home supplies, ethical meat, sustainable seafood, clean wine. You can immediately filter everything by keto, paleo, gluten-free, vegan, non-GMO, Fair Trade Certified, BPA-free, you name it. It really helps you juggle and balance work, fitness, eating healthy, taking care of your family, and it's all this very convenient, kind of like Costco membership-based program that makes all this stuff incredibly affordable. You can't find a ton of the stuff on their website that you would find on Amazon, and it's also marked way down.

I'm talking about Thrive Market. They're going to give you $20 to go spend on anything you want, like a full-on shopping spree. So, $20 in shopping credit. And what's going to happen is to get up to 20 bucks in shopping credit. You go to the Thrive Market website. And if you sign up for the one-year membership, which comes out to, like, right around five bucks a month, it's barely anything, then you're going to get that prize up to $20 to use on anything you want. It's risk-free. You can cancel within 30 days and get a full refund. And it's a very, very great website if you like nut butters, dark chocolate, healthy granolas, anything, any healthy pantry item. It's my go-to. So, all you do is you go to thrivemarket.com/ben. That's T-H-R-I-V-E, thrivemarket.com/ben. You don't need a code, you don't need anything fancy, you just go to the website, get shopping away. You're going to love it. Your mouth is going to be watering, too.

In addition to that, one of the most intelligently formulated probiotics that exist for alleviating constipation, for easing bloating, for supporting gut barrier integrity, for maintaining regularity, for even modulating things like mood and even longevity is this so-called Synbiotic, S-Y-N, Synbiotic. It's made by the folks at Seed. They're incredibly smart. They have designed a probiotic that's actually able to survive the acidic nature of your stomach, that's able to make its way all the way to your colon. Right? You deliver these beneficial bacteria alive in your colon, which is actually where they matter the most. And it's the first probiotic ever to use what's called capsule-in-capsule technology. They nest the bacteria in an inner capsule that's protected by a prebiotic infused outer capsule, which provides the barrier to oxygen, and moisture, and heat. This Synbiotic is the fanciest, most hacked up biotechnological probiotic you're ever going to get your hands on, and they're going to give you 15% off. You just go to seed.com/ben. That's S-E-E-D.com/ben. If you go to seed.com/ben and use code BEN15, it's going to save you 15% off of anything from Seed. So, enjoy.

I want to get to, well, I guess like the dark side. If all these great things are happening that are going to keep you awake if you're sleep-deprived, or even arguably increase cognition, or as we've seen in a lot of these studies in the military and on fighter pilots, awareness or reaction time, or in athletes, increased time to exhaustion. What could go wrong?

Jonathan:  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, be patient with me. Modafinil is FDA approved for conditions in which someone is suffering from excessive daytime sleepiness. Okay?

Ben:  Narcolepsy.

Jonathan:  Well, yeah. I'm going to give you three categories of people or situations, 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.

Ben:  CPAP machine.

Jonathan:  The CPAP machine to make sure that 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, medical professionals, security guards, et cetera. 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 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.

Ben:  If you're breastfeeding.

Jonathan:  Yeah. You're going to have excessive–

Ben:  I'm just kidding. Don't take modafinil. I'm just kidding.

Jonathan:  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 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 that's how I'm going to live.” And 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 they have to get up at 5:00 a.m. because that's when the stock market opens on the east coast or whatever. So, now they're only getting five hours of sleep a night. 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, right?

Ben:  Right.

Jonathan:  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.”

Ben:  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.

Jonathan:  Exactly.

Ben:  Yeah.

Jonathan:  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 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 modafinil. I'm saying this not based on speculation, but based on observations in published scientific studies.

Ben:  Okay.

Jonathan:  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 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.

Ben:  Okay.

Jonathan:  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, 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, 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. 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 so I'm not going to deposit glycogen.” Okay?

Ben:  Right.

Jonathan:  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 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've 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. 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 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 is 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.”

Ben:  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–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. We can get into–

Jonathan:  Yeah. Low to moderate, I'd say.

Ben:  We can get into microdosing. 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 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 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 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.

Jonathan:  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 way of 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 of sleep and you're supplementing yourself with modafinil, that melatonin is still lost.

Ben:  Mm-hmm. Yeah.

Jonathan:  So, you're paying a physiological and hormonal price for your time spent a week.

Ben:  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 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.

Jonathan:  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. If someone takes methamphetamine, which methamphetamine boosts dopamine or dopamine production through somewhat different ways than modafinil, 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 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 effect.

Ben:  Have you looked into whether tolerance builds up over time if you need increasingly larger amounts of modafinil?

Jonathan:  I am not aware of any data on that.

Ben:  Okay. Alright, yeah.

Jonathan:  I think it's stable dosing works in the long term, I believe.

Ben:  I looked into it a little bit. There was one pretty large retrospective study that found in a bunch of patients who are 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 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 internets, pretty high dosages. Meaning, excess of 200 milligrams and up to 800 milligrams, which is a lot more than the standard 50- to 200-milligram dose.

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

Ben:  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 downregulated. In particular, there were two that I came across, one called Tari, T-A-R-I, another one called D2. And those are apparently two activators of the dopamine transporters that get downregulated 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 downregulated. So, there may be something to be said for cycling it.

Jonathan:  Yeah. That's a good point, yeah.

Ben:  Okay.

Jonathan:  That sounds legit to me, yes.

Ben:  Okay.

Jonathan:  This all sounds based on, not that I'm recalling specific studies, but knowing how the nervous system works, and again, how it will react to repeat exposures. That sounds like a very reasonable possibility to me.

Ben:  I also want to unpack something related to something you alluded to earlier, and that would 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're taking 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. 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.

Jonathan:  Yeah. These are the cytochromes, cytochrome P450.

Ben:  Yeah. Right, exactly. The cytochrome P450.

Jonathan:  Yeah.

Ben:  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 is the one you got to be really careful with–

Jonathan:  Right, right.

Ben: –because if you take that 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 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 assess whether or not that might be the case. And so, it seems there's almost like this metabolic tolerance to it, and then also this dopamine tolerance to it that could be hit in two different ways.

Jonathan:  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.

Ben:  Yeah, exactly, exactly. Okay. And I have all sorts 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 the next day at a very early time, very early time. And you take modafinil, let's say at 7:00 a.m. one morning, and then suddenly without changing anything else in your life, you wake up about 4:00 or 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. Can you theorize on that at all or that?

Jonathan:  Wow. This is one I have not heard of before that when you sleep–

Ben:  Yeah. I'm thinking maybe it has something to do with that orexin and the change in wake drive, potentially, like if you're shifting wake drive later in the night. 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 shifting your orexin and–

Jonathan:  Yeah. That would be what I've [00:50:49] _____, yeah.

Ben: –shifting yourself to sleep. So, 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 maybe you're waking up at 8:00 a.m. and not at your normal 6:00 a.m., 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.

Jonathan:  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 our internal clock that controls the time of day at which we wake up. It is responsive to some of these various neurotransmitters that we've talked about. And again, we've talked about how when you modify the dopaminergic signaling with modafinil, you can potentially modify these various other neurotransmitters. 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.

Ben:  Right.

Jonathan:  And so, you may have been doing that with–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.

Ben:  Yeah.

Jonathan:  So, that's my best hypothesis about that one.

Ben:  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–even during this recent COVID epidemic, it came up because some people are using melatonin as a way to 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?

Jonathan:  Yeah.

Ben:  And so, I put on blue light blocking glasses when I woke up.

Jonathan:  Smart.

Ben:  It's going to keep my body thinking, because I just can't lay in bed for two hours from 4:00 to 6:00 a.m. and just drive me nuts. So, I get up, but I keep things dark. Don't turn off the light–or turn on 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.

Jonathan:  Yeah.

Ben:  But I thought it was really odd. I would have expected I would want to sleep in the day after taking modafinil, but it was just the opposite.

Jonathan:  Yeah. I suspect there's some feedback going on to the clock and, yeah.

Ben:  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 this 100- to 200-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 anything along those lines?

Jonathan:  Well, there are two different enantiomers, and an enantiomer 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 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 R one, in fact, has been marketed as R-modafinil as a distinct–

Ben:  R-modafinil, I haven't used it, but I've heard it's a lot stronger.

Jonathan:  So, yeah. Well, this one is the one that's metabolized very slowly.

Ben:  Okay.

Jonathan:  Yeah. So, it's got a much longer half-life than the S-enantiomer.

Ben:  Interesting.

Jonathan:  And I mean, that might be good or bad depending on exactly what indication you're using it for.

Ben:  Right. Or I suppose that you could theoretically, if you were using the R-enantiomer, throw in one of those tricks like grapefruit juice and slow down–

Jonathan:  Go 24/7.

Ben:  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 neutralize modafinil or slow its release, which if you're using that R version could come in handy. This is kind of related to theanine. Some people will use theanine to take the edge off of a stimulant. Many people who use modafinil will use theanine to take the edge off 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– cellulose. Some of the things people are using to feed good bacteria in their gut, those also slow the release or the uptake of modafinil.

Jonathan:  Oh, that's interesting.

Ben:  And so, that'd be another hack if you were using like the really strong version, like the R version of modafinil. So, I thought that was interesting how many different things can tweak 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'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 10:00, you'd 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 like 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.

Jonathan:  Yeah. No doubt there is. Yeah.

Ben:  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. It 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. 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.

Jonathan:  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. I don't think there are concerns with modafinil harming the liver, but with all these other things that you're talking–

Ben:  Modafinil a combination, I think that's where you [00:58:51] _____.

Jonathan:  Exactly. Yeah. That's what I was going to say. If people want to start tweaking their liver enzymes, all bets are off.

Ben:  Right, right. Exactly. The other one in addition to the liver, because alcohol is metabolized by that CYP 450 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'd probably enhance the effect, but alcohol would actually put undue stress on the liver.

Jonathan:  Yeah.

Ben:  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 downregulated 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 combine with modafinil, I would imagine.

Jonathan:  Yeah. I'm wondering if this is one of these desensitization processes going on.

Ben:  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 describe that modafinil works earlier is almost the same way that cocaine works in terms of its effect on dopamine and norepinephrine.

Jonathan:  Yeah. So, 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 transporters to some extent, and noradrenaline transporters to some extent.

Ben:  Okay.

Jonathan:  So, that's one thing that will discriminate modafinil from cocaine. The other I think has to do with what we call the pharmacokinetics. You've already made reference to the pharmacokinetics like its initial effect will be 45 to 60 minutes after administration peaks at two hours, remains for [01:01:20] _____. So, that's a very slow pharmacokinetic response, that response that you get to modafinil. Cocaine. Cocaine's kind of an experiment of nature. So, you can take coca leaves, you can chew on them. Typically, people do it with like a rock. And this is what [01:01:36] _____.

Ben:  I did that a couple of times. It was actually, I hear cocaine and I think addicted people going crazy vacuuming their living room for eight hours. But yeah. I tried a little bit of coca leaf. One of my friends gave me some. It's mixed with baking soda because, apparently, the baking soda causes a little bit of breaking of the capillary 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 the system.

Jonathan:  Right. 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, take it orally, it's going to be the same. You can actually get some through your stomach, and again, it'll be a slow rising. You'll just have sort of a general alertness 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–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, the negative reaction to that concept was like, “Wait. Cocaine blocks 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 leaf 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.

Ben:  It 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 doing intranasal NAD, intranasal CPE, intranasal oxytocin.

Jonathan:  Yeah.

Ben:  I don't know if it'd work.

Jonathan:  No. I would say this, probably it's been tried. And if somebody's tried it by now, the news would be out, that's my guess.

Ben:  Yeah.

Jonathan:  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.

Ben:  Yeah. The reason I ask about the cocaine is apparently, 800 milligrams of modafinil in people who have used cocaine and also used 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 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–

Jonathan:  I'm glad that you say that.

Ben: –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 BenGeenfieldFitness.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?

Jonathan:  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 excessive daytime sleepiness, but it's very rare for me. I have two children. Once in a while, they'll be sick and you need 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. Right? And so, yeah, I never have.

Ben:  Yeah, yeah. 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 200 milligrams. And with 100-milligram dosage, and I did try 200 once and I was up until midnight after taking a 7:00 a.m. 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 try 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 8:00 a.m. And by the time I get to my hotel and get to bed, it's like 2:00 a.m. and I got to get up at 7:00 00 to give the talk. I could see myself using it 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 that giant bottle of modafinil tablets now in my pantry and I would say it'd be that type of thing that I would probably turn to base 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 have crossed multiple time zones and still got to operate so to speak.

Jonathan:  Yeah. I mean, that sounds to me like a reasonable and healthy approach, actually. I'm just thinking by way of analogy 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 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. But don't be a motivational–don't make yourself suffer from motivational daytime sleepiness and then use modafinil as a day-to-day thing for that purpose.

Ben:  Jump into cold water instead.

Jonathan:  Yes. That's right, yeah.

Ben:  Okay. So, here's the deal. I've just met you, but we're definitely going to have to cold water swim sometime.

Jonathan:  Alright.

Ben:  Now that I know that you're into it. There's not a lot of people are going to hunt down and just jump into 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.

Jonathan:  You're very welcome. Yeah. No, this is–

Ben:  A lot of fun.

Jonathan:  A lot of fun, yes.

Ben:  Alright, cool. Well, thanks for listening in, folks. I'm Ben Greenfield along with Dr. Jonathan Wisor signing out from BenGreenfieldFitness.com. Have an amazing week.

Well, thanks for listening to today's show. You can grab all the shownotes, the resources, pretty much everything that I mentioned over at 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 hormone, 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, helped to make this podcast happen and to generate income that enables me to keep bringing you this content every single week. When you listen in, be sure to use the links in the shownotes, use the promo codes that I generate, because that helps to float this thing and keep it coming to you each and every week.

 

 

Modafinil (also known as “Provigil”)…

It's the darling of the smart drug industry and has been for quite some time.

With over 200 human clinical studies in the past 10 years, it is reported to have few to no side effects, to not be addictive, and to not be excessively stimulating.

It's used by notable figures like Joe Rogan, Ray Kurzweil, Barack Obama, Hilary Clinton, Tim Ferriss, and many others.

It's the entire inspiration behind the smart drug movie Limitless with Bradley Cooper.

It may increase resistance to fatigue and improve mood, reaction time, and vigilance, while simultaneously reducing bad decision making.

Laboratory studies have even shown that it may have potent antioxidative and neuroprotective effects.

It is of high interest to the US military for enhancing alertness and reducing battle fatigue.

Acute ingestion significantly increases exercise time to exhaustion.

So what could go wrong? Is this stuff too good to be true? Surely there must be some dark biological side of this supposed super-smart drug. On today's podcast, I host a guest who knows more about the science of modafinil than anyone I'm aware of—and who, conveniently, happens to live just a few miles from my house: Dr. Jonathan Wisor.

Dr. Wisor received a bachelor of science degree in psychology from Pennsylvania State University, a Ph.D. in neuroscience from the University of California, Los Angeles, then served as a postdoctoral fellow and subsequently as a research associate at Stanford University School of Medicine. From 2004 through 2008 he was a staff scientist at SRI International, a non-profit research institute in Menlo Park, California. Dr. Wisor has served on the faculty of Washington State University and the WWAMI (Washington, Wyoming, Alaska, Montana, Idaho) Medical Education Program since December of 2008.

During this discussion, you'll discover:

-How Jonathan became interested in sleep and neuroscience…8:05

• Professor at WSU teaching cell biology of the nervous system, muscles, immune system, etc.
• Worked at a bakery as an undergraduate, which caused erratic sleep patterns; This spawned an interest in neuroscience and sleep
• Sleep and neuroscience are recurring themes in his research and teaching
• Immune system and nervous system are connected
• Stress hormones, glucose utilization, etc. are influenced by the quality of sleep

-What exactly modafinil is…13:40

• “Small molecule therapeutic”
• Enters through the digestive system into the bloodstream, then into the brain
• Binds to the “dopamine transmitter” in the brain
• We associate dopamine with motivational states (focus on a single task)
• Cells' release of dopamine is highly regulated; stimulates a receptor on the other cells
  • Cells that release dopamine have a mechanism that allows to keep them to keep the concentration at a certain level, then take back the dopamine
• Modafinil is a “selective dopamine reuptake inhibitor” (not a precise scientific term)
  • It blocks dopamine when it attempts to reenter the cell from which it originated

-How various neurotransmitters respond to modafinil…19:30

• Norepinephrine is affected by modafinil indirectly
  • Central mediator of the sympathetic (fight or flight) response
• Histamine promotes alertness (anti-histamine drugs put you in a fog)
  • All these neurotransmitters talk with each other and, for better or worse, trying to selectively activate one is messing with all of them, which may be therapeutic or may not be
  • Histamine is associated with arousal, cognitive enhancement
• Modafinil has the opposite effect
• Orexin promotes wakefulness in the hypothalamus; modafinil helps fill in the gaps with an orexin shortage
  • People with narcolepsy are lacking the orexin signal

-Antioxidant and neuroprotective effects of modafinil…23:20

• Modafinil prevents 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), an impurity in synthetic opioids, from being taken up by the dopamine transporter into the dopamine-producing cells; a metabolic process that produces a toxin that kills those dopamine-producing cells
• Need to make a distinction between a cognitive effect and being neuroprotective (slows progression of a disease)
• For Parkinson's disease, a condition with a known degeneration of the dopamine-producing cells, data is weak as to whether modafinil protects those cells
  • Parkinson's is not only a motor disorder, it also has a cognitive aspect as well
• Data does not support modafinil as being neuroprotective
• Nicotine and caffeine can act as a neuroprotective (stacked with modafinil)

-How modafinil use can go wrong…31:15

• Modafinil is FDA approved for excessive daytime sleepiness
• 3 situations that cause daytime sleepiness:
  1. A sleep disorder that prevents quality sleep at night (narcolepsy, insomnia, sleep apnea); sleepiness secondary to a sleep disorder; modafinil addresses daytime sleepiness
     1. Sleep apnea treatment: continuous positive airway pressure machine (CPAP) machine
  2. Situational sleep disorders (nighttime work, newborn children, aging parents, etc.)
  3. Motivational daytime sleepiness (intentionally restricting nighttime sleep)
• Very few people can sustain excessive daytime sleepiness for long
• Physiological effects of sleep deprivation (even with modafinil):

• • Lose insulin sensitivity (resistance)
  • Muscles lose the ability to store glucose for athletic performance
  • Staying awake with modafinil does not mitigate this negative effect
  • Cortisol levels get screwed up (inhibits the response of muscles to insulin)
• Ben reports an enhanced workout with modafinil, but much more soreness the morning after, as well as low amounts of deep sleep
• Growth hormone surge occurs at night
• Melatonin increase is blunted by lack of sleep
• You pay a physiological and hormonal price
• Cycling modafinil use may regulate dopamine transporters such as Tari and D2

-Whether or not genetics determine a response to modafinil…47:05

• Modafinil is processed in the liver; some people have higher CYP genes (which affect the liver)
• People with certain enzymes break down modafinil quicker and feel its effects less
• High CYP inhibitors: Grapefruit, bacopa, berberine, California poppy
• Take these with modafinil and perhaps assess your body's response to it
• Obviously use caution when toying with liver enzymes

-How modafinil affects sleep cycles…49:50

• Ben reports that he woke up significantly earlier 1-2 days after using it
• Perhaps has to do with the change in orexin levels and wake drive being shifted
• Our circadian clock is responsive to neurotransmitters discussed earlier (dopamine, serotonin, melatonin, cortisol, etc.)
• Other factors such as exposure to light, the time you exercise will also affect the circadian clock
• Sunlight exposure will help reset the circadian clock during multiple time zone changes
• Blue light blocking glasses
• Limit exposure to light until the time you want to wake up

-How long modafinil stays in the bloodstream after taking it…54:15

• Modafinil molecules are enantiomers, molecules that are a mirror image of itself (like two opposing hands)
• R and S enantiomers are metabolized differently
• R enantiomer (Armodafinil) metabolizes slower (much longer half-life) than S enantiomer
• Theanine is used to take the edge off a stimulant like modafinil or coffee
• Prebiotics such as marshmallow root and inulin slow the uptake of modafinil
• Onset or duration of a standard 100~200mg dose:
  • Onset is 45 min to 2 hrs
  • Time to peak effect is 1-2 hours (before it becomes effective)
  • Peak effect is 2-4 hours
  • Tapering is 12-16 hrs
  • Total duration of the cycle is ~16 hours
• Modafinil can remain in the body for 4 days

-Effects of combining modafinil with alcohol and drugs…57:55

• Both alcohol and modafinil are synthesized by the liver
• Modafinil itself is not harmful to the liver; a combination of the two may be
• Tweak your liver enzymes at your own risk
• The typical euphoric effect of THC may be down-regulated when combined with modafinil
• Similarities and differences between the effects of modafinil and cocaine on neurotransmitters
  • Cocaine blocks more than just the dopamine transporter, also the serotonin and noradrenaline transporters while modafinil blocks only the dopamine transporter
  • The pharmacokinetic response is slower in modafinil than cocaine
  • Snorting, smoking, injecting cocaine into veins brings on euphoria
  • How you use cocaine makes a difference in its effect on the body
  • No way to change the pharmacokinetics of modafinil (no direct shot to the brain)

-Why Jonathan has never used modafinil personally…1:05:50

-And much more!

Resources from this episode:

– Jonathan Wisor

– BGF podcast with Dan Pardi

– Gear and supplements:

• Morozko Forge (use code BENFORGE to save $150)
• Blue light blocking glasses
• Melatonin
• Grapefruit seed extract
• Bacopa
• Berberine
• California poppy
• Theanine
• Marshmallow root
• Inulin

– Other studies and articles:

• Modafinil Studies
• Mechanisms of modafinil: A review of current research
• Effects of acute modafinil ingestion on exercise time to exhaustion
• The safety of modafinil in combination with oral Δ9-tetrahydrocannabinol in humans

Episode sponsors:

–Kion Creatine: Fuel your performance, energy, and strength with Kion Creatine, made with 100% Creapure®. You can grab your own Kion Creatine now at getkion.com and save 10% off your first order with discount code BEN10.

-Beekeeper's Naturals: A wellness company specializing in innovative nutraceuticals made from healing hive compounds and plant-based ingredients. Get 15% off your order when you use discount code BEN.

–Thrive Market: Organic brands you love, for less. Your favorite organic food and products. Fast and free shipping to your doorstep. Receive a gift card worth up to $20 when you begin a new membership.

–Seed Daily Synbiotic: A formulation of 24 unique strains, each of which included at their clinically verified dose, to deliver systemic benefits in the body. Save 15% off your order when you use discount code BEN15.