[00:00] Start of Podcast
[01:20] Dr. Hill and truBrain
[05:20] Modafinil and Its Effects
[11:43] General Rules For Trying Smart Drugs or Nootropics
[15:26] Caffeine As a Stimulant
[23:58] Foods and Diet with Drug Compatibility
[30:30] What is in truBrain?
[40:26] End of Podcast
Ben: Hey folks, it’s Ben Greenfield and if today’s podcast sounds just a little bit different it’s because I am recording from my hotel room in Sacramento after having raced back-to-back Spartan obstacle racing events down here in Sacramento. But I did not want to wait ‘til I got back to my home office to record today’s podcast for you because the guy that I have on is pretty dang cool and a wealth of knowledge on something that I have a big personal interest in and I know that a lot of you are interested in too, and that is smart drugs and nootropics.
My guest today is Dr. Andrew Hill, and Dr. Hill is the lead neuroscientist at a company called truBrain and he actually has a PhD in cognitive neuroscience from UCLA and studies how attention operates in your brain. So he’s a lecturer at UCLA, he teaches courses on healthy brain aging, on neuroscience, on psychology, and he’s basically an expert on everything smart drug and nootropic-related; so we’re gonna be delving today into a variety of topics including a bunch of things that people kinda have the wrong idea about when it comes to smart drugs and nootropics and everything like that. So as you listen in to this podcast, if you wanna go access the show notes, if you wanna check out any of the resources that Dr. Hill and I talk about, the show notes for today’s episode are over at bengreenfieldfitness.com/braindrugs, that’s bengreenfieldfitness.com/braindrugs. Dr. Hill, thanks for coming on, man.
Andrew: Sure Ben, thanks for having me. Happy to be here.
Ben: So I’m curious, if we could jump right in here, coz this is one thing that you told me that you wanted to talked about and something I didn’t know about until you sent me an article that I’m gonna publish on the site along with our podcast episode today, and that’s that a smart drug is different than what’s called a nootropic. Can you kinda go in to what a smart drug actually is and what a nootropic is?
Andrew: Sure. So there’s a few different categories of things on the market, and smart drugs, prescription drugs, are typically prescribed to people to help cognition in some way; usually focus or alertness, wakefulness, and those are things like stimulants. And they’re used for attention problems as well as staying awake when you work night shifts, things like that. In contrast nootropic, N-O-O-tropic, that word comes from the Greek “nous”; the mind, and tropic; promoting growth. The strict definition of nootropics is supporting cognition or preventing against some risk or some damage long-term, but more importantly nootropics shouldn’t have any side-effects by definition. So if something has a side-effect and it has risks or interactions with other compounds that are adverse, then we would generally a sort of gray-area called a cognitive enhancer.
Andrew: Something like caffeine, it certainly has cognitive enhancing properties; it helps you focus, helps with reaction time.
Andrew: But because it has side-effects, it’s habit forming, makes you run to the bathroom a bit more often, caffeine wouldn’t really be considered a strict nootropic.
Ben: But it’s not a smart drug either; why wouldn’t caffeine be a smart drug?
Andrew: Well, it probably is to some extent.
Andrew: The definition we’re using for smart drugs is that they’re prescribed, generally.
Andrew: And they’re often designed or used in a medical context to address a specific problem.
Ben: What are some examples of smart drugs?
Andrew: Well, you know the brand names like Adderall, Ritalin, the sort of psychostimulants class of drugs is what most people think of; there are some other drugs being used for various cognitive issues including advanced issues in aging, Alzheimer’s, and things like that that have memory components. But most people will be familiar with the psychostimulant class and that includes methylphenidates like Ritalin and Concerta, as well as the mixed amphetamine salts including things like Adderall, as well as drugs of abuse like methamphetamine. Those are all psychostimulants.
Ben: What about Modafinil, which I’ve heard a ton about, that kind of what a lot of people I think originally classified as being similar to the pill from the movie “Limitless”, like the smart drug pill, a lot of folks talk about Modafinil. Does that fall into smart drug or nootropic category?
Andrew: Probably neither, I mean it’s definitely prescribed, typically, but it’s prescribed for wakefulness, for narcolepsy; and then off-label, people use it for attention. But I have some real issues with Modafinil, the cognitive enhancements you get from it are just not that dramatic, and certainly not dramatic compared to things that are really in the nootropic class of substances as well as interventions like mindfulness training and neurofeedback. Those are both much stronger and safer approaches than something like Modafinil, and Modafinil just doesn’t do all that much. There’s been some studies out there looking at side-effect profiles as well for Modafinil and its related compounds, and the side-effects aren’t that great. Not a lot of people have them but when you do have them, they are dramatic side-effects and life-threatening.
Ben: Like what?
Andrew: There’s two forms of things that tend to come with Modafinil. One is called erythema multiforme minor and then there’s a major form, and the minor form is essentially hives. It’s happened to me when I tried Modafinil, pretty low dose, daily prescription as prescribed and about two weeks in, I woke up and I was covered with hives and it was dramatic like for weeks I was in the hospital. And the more aggressive version is EM Major, which is also called Stevens Johnson syndrome. That’s where your skin sort of peels off and if you don’t get major medical intervention, you just die fairly quickly.
Ben: Why is it the skin that seems to be most affected by something like Modafinil?
Andrew: Yeah, well you have to remember that developmentally speaking, when we’re a blob of cells in utero, one of the first things that happens is the tissue differentiates the three different layers: endoderm, ectoderm, and mesoderm. And the same layer ends up turning into the skin as the brain. They’re actually sort of developmentally almost a contiguous development, that’s why things that affect the brain often affect the skin. You see liver spots in the skin when you get a little bit older, very similar things happening inside neurons; a lipofuscin, a sort of sticky, fatty deposit with some phosphorus in it and some other things I believe.
You tend to have some parallels with skin and brain, and we’re still not 100% sure what Modafinil’s doing. The initial theories were that it was flushing a sort of timing signal on the hypothalamus called orexin. It may not be actually doing most of its work through that, it looks like the research at least partially hangs the results or the effects of Modafinil on histamine. And histamine is a major compound in the body, it’s not just an allergy symptom or an allergic system mediator; it’s, in the brain, used as a master valve or master control before several other neurotransmitters. So when you affect histamine you affect all sorts of other things, which is why it works to sort of shrug off sleep and suppress appetite and a few other things coz it’s doing those through downstream mechanisms of norepinephrine, probably dopamine and a few other things. There’s a lot of medical use, or at least in the literature, Modafinil is a successful drug if you’re trying to quit cocaine. It occupies some of the same dopaminergic site, probably, and allows you to quit cocaine more easily; that’s one of the things it’s been used for. And if you’re narcoleptic, go for…
Ben: I’ve heard some people talk about Modafinil in terms of its effect on the liver because it’s metabolized by the liver, that that might be an issue in addition to the effects that it has on the skin that you already talked about.
Andrew: I think that’s more about the individual, I mean all of these things were individualized. One paper that I’ve looked over or review article from Modafinil shows that people that have attention problems have a dramatically increased rate of side-effects. Liver stuff would be about which liver enzymes you have the most activity of, and so there will be some inter-individual variability of course on these things. Dramatically, I mean not everyone has side-effects; in fact it’s fairly uncommon to have side-effects on Modafinil. But the risks are there, and for me, you have to make a strategic decision about what you’re gonna risk putting in your body because the number of chemicals and powders and substances and herbs and supplements and vitamins, amino acids is multiplying and there’s all kinds of things out there. And you can’t try everything; not everything’s safe.
There’s lots of research chemicals out there with names like NSI and lots of other newer nootropics that are derived from the first class of nootropics that just haven’t been tested, they don’t have decades of safety history. And as a personal threshold, you have to decide where your risk acceptance is against what is gonna be some small gains. Nootropics don’t make you dramatically different. If you take stimulants, you are awake, you might even be sort of pushed by them; they’re gonna have other effects you may not want: aggression, mania, appetite-suppressive. But there’s definitely a feeling from stimulants; you are altered. Early on in the process of taking stimulants you get euphoria, they get you high to some extent.
Andrew: None of that is true for nootropics. You’re not altered, you’re not high, not euphoric. And so you’re trying to get a specific effect or trying to support performing longer throughout your day, performing better into your later decades in life.
Ben: Yeah, and I wanna ask you about some specific ingredients in nootropics that come in handy for things like that, but first, you talked about safety of smart drugs and I’m curious if you have some guidelines for people listening in in terms of what they can do as far as rules to follow when they’re looking into whether or not they’re going to try something, or kind of a way to vet a smart drug.
Andrew: Sure. So some general rules are: don’t take anything that’s super new. Things need to have gone through not only animal and human testing but they need to have been used by humans for many years for different things before I think they are a good candidate to swallow yourself. There’s lots of brand-new research chemicals out there, so don’t go after something that is brand-new, that came out last year that people are saying “oh this feels really good” because there’s just no safety, you don’t know what long-term risks are from research materials.
Ben: Yeah, that’s one of the things, we talk about ketosis a lot on this show and a lot of people ask me why I haven’t experimented a ton of liquid ketones like KetoForce for example, or beta hydroxybutyrate; I believe it’s called BHB salts, beta hydroxybutyrate salts that you would take to enhance cognitive performance during, for example endurance events. And one of the reasons I give is that a) it doesn’t taste very good, but b) there isn’t a ton of research yet on it, and that’s certainly something that I always look at because, just being in that state that I’m in as a health blogger and podcaster, I do get offered some of this stuff sometimes. I get packages that show up on my front doorstep sometimes, and often it is brand-new stuff and I’m a little bit cautious when it comes to these research chemicals with a bunch of numbers and letters for a name and no human studies.
Andrew: Yup, and a couple of other general rules: get your smart drugs/nootropics from a vendor, from a website or individual who provides some safety testing. A lot of stuff is sort of manufactured in bulk powder and overseas labs and then shipped into these countries, and the quality of chemistry is not necessarily equivalent in every lab, and you don’t want to end up with lead or arsenic or other heavy metals in your bulk nootropics from China, for instance, you wanna buy from a vendor who says “yes, we tested this batch, here’s the certificate.”
Ben: So you would know that based off of information that was printed on the label of the nootropic or the smart drug?
Andrew: Or just the vendor’s website. For a lot of sort of more novel compounds that are being manufactured and brought in, the responsible vendors will take every single batch that comes in and test it in a third-party lab and then share that certificate on their website. So when you’re buying your particular brand, you can ask them “hey where’s the testing certificate for this batch?” and they’ll share that with you, ideally.
Another big rule of thumb Ben, is there’s this tendency especially in flashier blends of compounds, to obscure or obfuscate what’s actually in there. And the most common way to do it is to say “we have a couple of grams of some proprietary blend” and they don’t tell you all of the individual ingredients, just list a whole bunch of what I call buzzword compliant compounds. And there’ll be some things in that list of ingredients that be great to take, some things that may not be great to take, but more importantly you don’t know how much of each, and a really expensive and high-end compound might not be in that blend in the effective amount. There term for this is fairy dusting in the industry, sprinkling in tiny little amounts just to give the appearance of efficacy. So know how much…
Ben: Interesting. Fairy dusting.
Andrew: Fairy dusting.
Andrew: You know, like Tinkerbell goes by and fairy dusts.
Ben: Right, interesting. Okay.
Andrew: So know your amounts of each ingredient. Also, if caffeine is doing the heavy lifting in the nootropic blend that you’re taking, it’s probably not worth it. Caffeine’s wonderful, coffee’s wonderful and I think the health benefits of drinking coffee are not to be understated.
Ben: I agree, and one of the reasons I agree with that is one of the things I use nootropics for personally, is speaking and going to events at night. And a lot of times, I know I’m gonna be going to bed after I’ve spoken at a conference or at 6 or 7 PM or after I’ve gone to a party and I plan on being whatever, back in my hotel room or back at home, by 10 or 11 PM, and I don’t necessarily wanna be up ‘til 2 AM because I slammed 100 mg of caffeine at 6 PM, which happens to me if I take a caffeine-rich smart drug. So that’s actually one of the things I look for when I’m looking at some of these nootropic blends is how much caffeine is added to them.
Ben: That is actually a big component in my decision of whether or not I’m gonna take something.
Andrew: Yeah and when Chris, my partner at truBrain, first produced the truBrain 1.L supplement nootropic stack, there was no caffeine; that was a very conscious choice not to rely on some subjective “feel it in the moment and then I crash.” Now Chris has brought out the functional beverages, the think drinks, and there is a caffeinated option for those coz people expect caffeine in their beverages, and some people rely on caffeine and add it in, but it’s about managing your own caffeine. We don’t wanna impose it on you from the point of view of a nootropic stack nor do you want to necessarily have to become dependent on caffeine to get the effects you’re looking for.
Ben: So I wanna ask you about some of the other ingredients that go above and beyond caffeine when it comes to things we might or might not see in cognitive blends or in nootropics. I just wanna ask you about a few of these that I know are pretty common.
Ben: Piracetam or things in the Aniracetam family, would those be considered as something that you would find acceptable in a smart drug or a nootropic?
Andrew: Yeah, those are sort of the poster childs for nootropics. In fact, Piracetam is the first one in that class which is, shortened to the “racetam” class; Piracetam is a derivative of a neurotransmitter, GABA I believe, it has pyrrolidine ring in it. And all of the other “racetams”, you mentioned one Aniracetam, Oxiracetam, Pramiracetam, there’re three or four others; they’re all used for different things, they have slightly different effects. Piracetam is the oldest, best studied, and apparently safest and most predictable results.
Ben: Now I thought, you said it was similar to the neurotransmitter GABA, but I thought that was an inhibitory neurotransmitter.
Andrew: It is, it is. It seems to bind to glutamate receptors but is derived from GABA chemically.
Ben: Okay, so it doesn’t make you tired like GABA would?
Andrew: Not at all, not at all. Although, GABA doesn’t just make you tired, it actually allows you to focus when you’re stressed.
Andrew: There’s a GABA-ergic nootropic L-Theanine, which is an amino acid found in tea leaves. And L-Theanine is often in a nootropic blend because it sort of balances the push you might get from caffeine or from other stimulating smart drugs.
Ben: That’s actually a really good point. That’s something I mentioned how I won’t use caffeine in isolation or more specifically in the absence of L-Theanine in the evening. But I have found, from what I understand researchers also shown this to be true, that when taken with L-Theanine, caffeine tends to not have that wakefulness effect and instead provides focus and then you’re able to fall asleep afterwards. When do you find caffeine in like green tea?
Andrew: Not the same degree of push from the caffeine, but it still has to go through its own elimination profile. And depending who you are, caffeine has a half-life of between three and six hours. So you have to figure these two half-lives before you can sleep on it. For most people, we’re talking about six to twelve hours potentially from caffeine dose to good sleep architecture that’s not disrupted.
Andrew: I think L-Theanine might shorten that a little bit. I certainly can sleep with caffeine in my system six to eight hours in. If there’s been some L-Theanine, I often…
Ben: It just might not be as high-quality sleep, huh?
Andrew: Exactly, it might be harder to fall asleep and it might not be as deep in the first half of the night.
Ben: Okay, now when you use something like Piracetam in a nootropic, one of the other things that I understand is that it somehow depletes choline in your brain, is that how it works?
Andrew: Well I’m not sure about depletion but we think, and this is not well established, because of these subjective effects and because of some of the hints in the research, that the “racetams” and other things that improve memory, focus, attention, are probably doing at least some of their job through acetylcholine, the neurotransmitter acetylcholine, which is involved with learning and memory. Because of that, people started co-administering a choline source with “racetams”, and it does seem like they work better; some people get sluggish or get a little bit headache-y when they don’t take choline. Choline by itself though, in certain forms, is a pretty nice nootropic. There’s a couple forms out there you’ll see in nootropic blends, citicoline been used for years as an aging supplement and it’s in many nootropic blends now including truBrain, and Alpha-GPC is also in a lot of nootropic blends.
Ben: Is it true that you shouldn’t take Piracetam or Aniracetam in the absence of choline?
Andrew: I’m not 100% sure, I don’t think that’s true for everyone. I helped Chris design truBrain so I put it in because I thought it would mean the effects and the experience would be much more consistent across people, but you might be somebody who has a lot of choline resources available, high choline diet anyway, and might not need it. It’s not a linear “you must take choline if you take Piracetam” and in fact, some forms of choline aren’t gonna do much; they don’t get past the blood-brain barrier. People take choline bitartrate often and it just doesn’t have much penetrance into the brain.
Ben: Which form of choline do you think is best?
Andrew: The two that I mentioned, citicoline and Alpha-GPC, I think those are the best ones in terms of cognitive support; they get into the brain, they seem to have slightly different effects on cognition, CDP choline or citicoline tends to have more of an effect, I think in the cell membrane metabolism.
Ben: Citicoline, that’s C-I-T-I-coline?
Andrew: Yes, exactly.
Ben: Got it.
Andrew: [phone rings] Sorry.
Ben: Okay, cool. There’s another one that I want to ask you about… we talked about L-Theanine, we talked about Piracetam, we talked about choline. Now there’s another ingredient called tyrosine that I’ve seen a lot in these, where does tyrosine fit in?
Andrew: So tyrosine is really used in most of these blends under the theory that it is providing raw material for dopamine. Tyrosine is an early chemical amino acid that is synthesized into dopamine, and dopamine is the neurotransmitter involved with salience, interest, reward, it helps you learn what’s important to do. Psychostimulants are a dopaminergic drug, they produce large amounts of dopamine so you’re very interested and very energetic. Bees, when they’re flying around and find a flower full of extra pollen get a huge dopamine hit, and that tells them that this is important to learn, important to pay attention to long-term. So we think that as you’re focusing, attending, working, a lot of attention resources are dopaminergic, and alterations in dopamine metabolism in differences across individuals do contribute to differences in attention performance and ability. People with ADHD have different dopamine receptors and different types and amounts of receptors than the average person. And so we’re sort of front-loading the dopamine system with raw materials when you include something like L-Tyrosine.
Ben: Are there certain foods that you can eat along with smart drugs to enhance their effects? I’ve heard of walnuts and fish and eggs and stuff like that, but I mean does that stuff really make a difference?
Andrew: I think it does, however you’re starting to get into what you touched on earlier, the ketogenic diets. The summary is that you really need to be avoiding almost all sugars and lots of starches and maximizing fats. And the foods you mentioned, walnuts, eggs, things like coconut, macademia nuts, pecans; those all have large amounts of omega-3 fatty acids. And so do deep-sea cold water fish, salmon, tuna, and animals, lamb and beef that have fed on grass, grass-fed animals: very high omega-3 profile in their meat; omega-3 fat. And the omega-3 fats that you eat, actually all the fats that you eat get incorporated into cell walls, pretty much. The body’s very greedy for fats and it’s one of the primary things we need to survive. If you don’t eat fats, you will die and die quickly. So eating lots of fats is good and the body will take them up and incorporate them into the cell walls, but if you’re eating lots of really low quality fats, omega-6 fatty acids, lots of saturated oxidized fats, small molecules of oxidized fats, this is gonna degrade the functioning of cell walls directly and degrade how well the cells work long term, as well as having secondary effects of inflammation, probably promoting atherosclerosis, interior blood vessel inflammation, plaques and things. So yes, I do suggest that people, for brain healthy diet, lean heavily towards fats, heavily towards grass-fed and sustainable meats; things that you could eat that are not heavily processed. And avoid sugar; in fact, in the absence of excess sugar and a dysregulated insulin system, it appears that fats, even saturated fats, are not unhealthy. And in the presence of sugar, almost any fat is gonna be a problem.
Andrew: So long-term, I think brain health is a lot more about managing insulin response and sugars than I think it’s about anything else. You can link a lot of the diseases of aging, diabetes, cancers, to insulinogenic processes.
Ben: Yeah, yeah. So don’t eat a banana with your Bulletproof coffee, right?
Andrew: Exactly, I have a rule of thumb: I try not to consume more than 20 grams of free carbohydrates in one sitting. For me as an adult male who’s relatively healthy and has a little bit insulin stuff but no dramatic dysregulation, 20 grams doesn’t seem to spike my insulin and I hold my daily consumption down to about 65-70 grams a day of carbs. At most days except when I cheat, which I do, that seems to be a low enough level of carbohydrate to reap all of the benefits that people get from a real hardcore paleo-primal ketogenic diet but without any of the real risks, you aren’t stressing the kidneys out so much, you aren’t really working that hard. 65 or 70 grams of carbs a day is not that dramatic. It means just not eating sugars.
Ben: Right, exactly. Another question for you, I hear a lot about the smart drugs or these nootropic blends that to get the maximum effect from them, that you need to take them frequently, like every day for example. Is that true?
Andrew: It seems to be, and the reason is, we talked about choline, when you swallow it can be taken up and turned into cell wall material and then converted eventually into things like phosphatidylcholine, phosphatidylserine; there’s really some basic cell wall processes. And your body is, in an ongoing fashion, rebuilding cells, so some of the components that are nootropics, on an ongoing way improve and change the cell’s metabolism. Another example is inside the cells we have mitochondria, they’re little powerhouses that pump out cellular energy in the form of ATP, and mitochondria become damaged after a while, and they eventually get old and in a perfect world they would send a signal that’s “hey you’re damaged” and they commit suicide and a new mitochondria or two is born in its place.
When mitochondria get old and damaged, they actually don’t receive this signal to self-destruct very well. Taking Piracetam appears to do a whole bunch of things in the body, and a lot of them are involved with cell membrane metabolism and flexibility and fluidity. They also appear to help mitochondria receive this signal; “hey, self-destruct, you’re pumping out free radicals, you aren’t pumping out ATP anymore, you’re pumping out some ATP but mostly free radicals, you’re not helping.” And then they clean up some of the interior metabolism of the cell as well; there’s another neuroscience primarily here for your audience. A lot of our cells that do their job in terms of changing activity is driven by the membrane of the cell, and we have receptor proteins that pass through the membranes that are channels in and out. We also have lock and key sort of receptors embedded in the cell wall that change how the cell behaves, and to a large extent, how the cell regulates what those receptor proteins do is by changing how fluid or how flexible or how stiff the raft of proteins is right around the cell’s membrane protein. So by changing flexibility and fluidity, you’re changing all kinds of very long downstream effects on the cell’s health and metabolism. So yeah, daily basis, you will continue to provide support as your cells rebuild each other, and that’s probably especially true for the good fats, the DHA, the dietary stuff from Piracetam [0:30:17] ______ to neurotransmitters as well like L-Tyrosine and things like that.
Ben: So tell me about this truBrain blend.
Ben: What exactly is in it? And just to back up here, you guys have sent me some of the truBrain and it seems like I’ve gotten three different kinds of iterations of it from you over the past years that thing was formulated.
Andrew: [laughs] Okay.
Ben: What’s kind of the final product right now?
Andrew: So there’s the capsule version and a liquid. The liquid we call a think drink or a functional beverage, a focus drink, little one ounce bottles with tear off tops. The formulation’s slightly different but it’s pretty similar and in both cases, the capsules or drinks, we made a strategic decision to only include a few ingredients. There’s seven or eight things in the product, not some absolutely absurd long list of miniscule amounts of things, and we tell you exactly what’s in it; follow the rules that I laid out at the beginning of the segment. But what’s in the capsules right now is magnesium, and that’s a buffer, it sort of helps cells fire when they’re not firing as well and calm down when they’re firing too much. We include citicoline, we include Piracetam, tyrosine, acetyl L-carnitine; carnitine’s a protein that’s found in meat, it’s involved with cell metabolism and energy as well, helps your mitochondria pump out more energy.
L-Theanine, for the GABA-ergic effects, calming and buffering; and then there’s some DHA, some fish oil. DHA is profoundly better for the brain than many other types of fats; DHA is an omega-3 fatty acid, people may get it already in fish oil, although after using fish oil for a while in truBrain, we decided to get our DHA from algae and a lot of folks don’t realize this but the DHA that you get from fish, well the fish get it from algae. They’re eating algae, or most fish are eating krill, small little shrimp, the shrimp are eating algae, and there’s a sort of food chain effect, that as you go up the food chain, you get more of the potential things that the animals are eating. So by going very low the food chain, we avoid any risks of metal contamination from the fishes as well as getting a version that is vegan. People don’t want fish oil if they’re vegetarian or vegan often, and we were able to sort of drop down to the lowest level and find a DHA source that was algae. Chris jokes about cutting out the middle-man and straight to the sea floor for the algae.
Ben: Yeah, cool. And it’s a good vegan absorbable DHA too.
Andrew: Yeah, exactly. And that’s the capsules.
Ben: That’s the capsule, and what’s the drink?
Andrew: The drinks are almost the same. There’s no DHA in the drinks, shelf life was a much bigger issue when talking about a liquid product instead of a powder. And so we wanted to get at least six months or more of shelf stability, and the flavor of the DHA also wasn’t that great and it wasn’t dissolving well with all the powders we were trying to incorporate, so we changed things up a little bit. The drinks have a flavor that the capsules don’t have, obviously; I think there’s a cranberry flavor and there’s a pomegranate flavor. There’s a little bit of sugar, just a little bit but plain-old generic cane sugar, and then I think each beverage has 1-2 grams of sugar; it’s not much at all. And then we use a combination of Stevia, blue agave and monk fruit to get a better flavor profile because I’m guessing a lot of your listeners will have tried nootropics or heard about them, and one of the things you’ll discover very quickly is all of these powders taste absolutely horrible. Some are between battery acid and baby poo; they’re just really vile substances for the most part. And masking those flavors in a liquid drink was actually an engineering challenge that we found non-trivial, and we ended up being really excited with the final product. Garette, our chemist, spent a long time in a sort of mad scientist lab; we locked him in, threw in some samples and flavors and let him out once he had a relatively okay tasting product.
Andrew: But we dropped the DHA out and I believe Chris is going with Oxiracetam instead of Piracetam in the final version of the drink as well.
Ben: Why’s that?
Andrew: They’re very similar. The Oxi right now is in the boost. Both the drinks and the capsules have a boost packet for a little different effect on days we need more of an effect or working on a weekend like you are right now. And the boosts would always have a different “racetam”; in the powders the boost is Pramiracetam just to mix it up a little bit and give a little bit more of a push on days where you’re trying to get more done, and then the drinks it’s the Oxiracetam. And the flavor profile of Oxi is significantaly better than Piracetam, but they’re also fairly similar in many ways, so I think we’re eventuall gonna shift everything over to Oxi because of the flavor profiles.
You mentioned Aniracetam and there was Oxiracetam as well, and that’s the one your listeners may enjoy trying, there’s some others… Ani is fairly different than Oxi or Piracetam or Pramiracetam in that Ani tends to have an anxiolytic effect; it tends to be very calming. Personally, it’s too calming for me; I get almost a little bit depressed or blue on Aniracetam. And Ani also has a window effect that’s probably 90 minutes or less, and so given the slightly more variable response on Ani and how short acting it was, we decided against that for truBrain and we used Piracetam for the first. The product’s been on the market for about 18 months and it’s been classed based because primarily that’s the “racetam” and all the other ingredients that I came to myself over many years of [0:36:30] ______ over the literature and doing some self-experimentation and experimenting on my friends and family actively [laughs] to some extent.
Andrew: Giving them things to try. We’re sort of in the decade of the brain. We’re actually down the second decade of the brain so being a neuroscientist, if you’re a medical doctor and you’re gonna throw a party and people find out you’re a medical doctor, they want you to look at all their weird moles, right? Well if you’re a neuroscientist, people want to ask you their interesting brain questions and it’s usually what they are experiencing.
Andrew: And so over many, many years, the second half of my PhD program when I was getting into nootropics and trying out these different things; people were coming to me and saying “oh I have a risk of Alzheimer’s, I have a risk of Parkinson’s, I’m not as sharp as I wanna be, I can’t hit on stimulants” and I work in areas of peak cognitive performance and I work in quantified-self areas as well, QBEG and neurofeedback clinician. So I help you retrain your brain actively in a very quick, aggressive way, but my mom can’t fly to California from Florida for neurofeedback sessions, so she wanted to know what she could take. And I helped her design a blend of nootropics, then eventually I got tired of writing down the list of ingredients for people or sourcing them, and that’s about when I met Chris and we decided to instantiate that blend with a few minor tweaks into truBrain 1.L.
Ben: Cool, cool. Well you also wrote an article, for people who wanna dig in this even more on smart drugs versus nootropics, and that article is over at bengreenfieldfitness.com. It’s at bengreenfieldfitness.com/braindrugs if you wanna check out the article that Dr. Hill wrote. The other thing is that if you want to try this truBrain stuff for whatever, 30 days or experiment with it for a week, truBrain, it’s T-R-U-brain, you can get it at bengreenfieldfitness.com/trubrain, T-R-U-brain. They’re giving all of our listeners a 20% off discount with code BEN20.
Andrew: That’s actually great. Chris, for the past 18 months, getting a 5 or 10% discount from Chris was about all you can get, and 15 was rare. I was giving out 15% discount coupons on podcasts in the past. So the fact that he’s giving you a 20% discount Ben, he must really like you.
Ben: I guess so, I don’t know. But that’s what he sent over so…
Andrew: That’s great.
Ben: We’ll take at what we can get it. Alright, so cool. So go to bengreenfieldfitness.com/braindrugs if you wanna read the article that Dr. Hill wrote; it’s really good. And go to bengreenfieldfitness.com/trubrain, that’s T-R-U-brain if you want to grab a discount on truBrain with code BEN20.
So Dr. Hill, thanks for coming on the call today; this is cool stuff.
Andrew: Yeah, my pleasure.
Ben: And I’m hoping that I am that much smarter now after I go find my choline and my Oxiracetam, my magnesium, my DHA, all this other stuff so…
Andrew: Sounds good.
Ben: Alright man, I’ll talk to you later.
Andrew: Okay, take care.
The following is a guest post by Dr. Andrew Hill, Lead Neuroscientist at truBrain. Click here for a fascinating audio podcast that accompanies this article. featuring Ben Greenfield and Dr. Hill.
Dr. Hill received his PhD in Cognitive Neuroscience from UCLA in 2012, studying how attention operates in the brain. He has been employed as a Lecturer at UCLA over the past few years, teaching multidisciplinary courses on both Healthy Brain Aging and courses in Neuroscience and Psychology. Dr. Hill has published chapters on measuring and modulating human attention, and continues to research self regulation.
Prior to UCLA, Dr. Hill obtained extensive experience working with both psychiatric and developmental populations as well as gaining experience in high technology areas. He received his B.S. in Psychology/Neuroscience from UMass Amherst, and is a key adviser in the formulation of the truBrain’s cognitive blend (get 20% off on your purchase with the code BEN).
The Limitless Pill
In the 2011 movie Limitless, Bradley Cooper’s character gets his hands on a smart drug (NZT-48) that enables him to be cognitively super human.
The only known side effect is that his eyes change color while he is on the drug, but that changes over the course of the movie as side effects, including withdrawal symptoms, begin to get worse and worse. It’s a sci-fi thriller with a not-so-feel-good message about addiction and performance enhancing substances. And goons chasing you.
Makes smart drugs sound dangerous, right?
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Like any good sci-fi , this movie questions our assumption on the limits of science. And some of what it is suggesting is not science fiction today. Smart drugs and nootropics are a current reality, being used more and more not to treat or remediate any active condition or complaint but towards boosting already typical or superior performance, in colleges, board rooms, military theatres, and by forward thinking gerontologists.
With the wide variety of compounds available today that have some research support for cognitive effects, it is important for you to understand the risks and benefits associated with usage, or at least how to choose smarter, when choosing things that affect your brain.
For example, one of the most popular misconceptions about smart drugs is that they are the same as nootropics. This may be due to similar benefits that people use them for, but ultimately they do not share the same range of effects, mechanisms of action, safety and side effects.
So – what are smart drugs? What are nootropics? How do we know if something is safe or effective? What are these drugs actually doing to my brain? Why am I asking so many questions without answering them? Keep reading to get this and more information you need to understand these questions, and start formulating your own answers – and your own strategies for selecting nootropics.
Smart Drugs vs. Nootropics
A smart drug is generally a prescribed medication or off-label drug used primarily to treat some kind of mental or cognitive disorder.
The most common are drugs such as Adderall (dextroamphetamine) or Ritalin (methylphenidate) in the stimulant class used to treat symptoms related to ADHD – although legal and illegal off-label use is rampant. And while they may promote focus and energy in some people, others have dramatic side effect, to body and brain. Smart drugs in the stimulant class also tend to be reinforcing, producing spikes in dopamine and norepinephrine.
This leads to tolerance and habit formation, including adverse effects on appetite, mood stability, cardiac function, stress levels and possibly many other unwanted effects – especially on younger brains such as teens and young adults. Irritability and mood swings, anxiety, sleep issues, and other forms of emotional or cognitive regulation problems can crop up over time with stimulant use, as well.
A popular atypical stimulant “smart drug” includes the narcolepsy agents Modafinil / Adrafinil, although their effects on cognition beyond wakefulness are unproven, and side effects – while rare – can be life threatening. If attention problems are already present the side effect risk appears to be significant increased, as well. (Kumar, (2008), Approved and Investigational Uses, Drugs. 68(13):1803-39.).
In contrast to a smart drug, a nootropic is generally a non-prescribed compound, including vitamins, herb, other supplements, natural or synthetic compound that may increase or protect cognition in some way. The preponderance of research in the past 40 years shows some effects on focus, attention, effects on aging, and possibly cellular metabolism.
To paraphrase the definition of “nootropic” as initially coined in this article by the researcher Girugea in 1972, it is something that improves cognition without appreciable side effects, or provides from protection to the brain.
In a modern context we think of nootropics as something used not to treat any mental condition or pathology directly, but instead to provide support to peak function, protect against long term risk, and provide daily boost. Across the field, true nootropic ingredients and full blends can now be found largely sourced from natural ingredients. Nootropic blends are designed to leverage synergy effects suggested in the research and subjective experiences. The goals with nootropics should always be to allow for greater and more consistent cognitive effort and flow, without the side effects of a stimulant or other harsh substance.
How Do I Know If A Smart Drug Is Safe?
As a rule of thumb, it is the nature of science to be wrong at times.
We’ve come a long way since we accepted that the theory behind the Earth being the center of the universe was wrong. We understand that new research may overturn old knowledge. So how can we truly know the risks and benefits of long term use of nootropics or smart drugs?
A red flag in understanding the harm of a substance is the body’s ability to handle an overabundance of this substance. Small amounts of toxic substances may be beneficial in the short term, but the magic happens when we look at what is happening in the body when we get too much. Something as simple as a cup of coffee may seem harmless, but caffeine in high amounts can cause dizziness, anxiety, and even cardiac arrest or death. Caffeine mimics the action of the neuromodulator adenosine in the body. This leads to higher adrenaline and cortisol levels.
Even in typical doses caffeine can deeply affect our sleep and cause heart arrhythmias for some people. Alcohol has even worse short and long term toxicity symptoms at non-moderate doses, and some people struggle to keep their dosing moderate. In better doses – perhaps a couple cups of coffee a day (without sugar) and a drink or so per day on average, these substance are actively health promoting, and reduce risk for many brain and cardiac diseases. When you are picking substances and compounds, dosing should be cautious at first.
From this, a couple rules come out –
1) don’t take any compounds, substance, or blends of substances that don’t list all their ingredients out in plain amounts.
Proprietary blends with lump-sum amount hiding buzzword-compliant list of magical ingredients known as “fairy dusting” in the supplement industry.
Don’t be fooled.
Read the ingredients.
Figure out why and what is in there, and if you want it.
2) don’t chase suspicious research chemicals without much history of use or safety profile.
Experiment on yourself if you like, but you only have one brain – make rational and cautious choices. There are nootropic, smart drug, and cognitive enhancers that have been around for decades – something released last week as a “Research Chemical” with a bunch of numbers and letters for a name and no human studies isn’t worth the risk to you. Not for years.
What About Adderall & Modafinil Safety?
Smart drugs such as Adderall can cause dangerous lows, psychosis with extreme use, rebound fatigue, and depression, even at lower use levels. As an amphetamine, Adderall can act as a reuptake inhibitor, meaning that it can compete with other neurotransmitters for reuptake.
Specifically it is thought to block the uptake of dopamine and norepinephrine, which are associated with reward behaviors and our nervous system functions, respectively. This causes a flood of these neurotransmitters onto multiple receptors, causing neurotransmitter depletion and overexcited receiving neurons. This large “signal” is the reason for the focus, but also responsible for some of the side effects that go along with this class of prescription drugs. Existing research is also a bit weak on any improvement that Adderall or other stimulants may have on short term memory or cognitive function, and some actually may impair function.
Modafinil, also known as Provigil, is an example of a smart drug that has been used like a nootropic. Modafinil is prescribed to treat sleep disorders, but when combined with a normal functioning brain, can potentially cause increases in cognition and awareness.
Just like Adderall, the use of these drugs outside the medical field does not make them a nootropic. Modafinil is also a reuptake inhibitor for dopamine, causing the same type of neurotrasmitter flood as Adderall. However, Modafinil may also affect the histaminergic pathway, which deals with wakefulness and the delicate immune response of the body. Histaminergic neurons in the brain are more active during wakefulness and slow their firing pattern as we rest or sleep.
Modafinil’s “beneficial” side effects may come from this heightened histaminergic neuronal activation, but too much activation can cause apoptosis, or cell death. In addition, this has been shown to cause adverse skin reactions that required hospitalization since the histamine pathway also deals with our immune system. Modafinil may increase your intelligence, but can be extremely dangerous to the health of your brain and body.
Nootropics, like truBrain’s cognitive blend, and a few other products on the market, have dose-toxicity levels much lower than salt, caffeine, and especially Adderall.
There doesn’t seem to be any neurotransmitter depletion, tolerance or habit forming potential, adverse body side effects, or impaired brain function, from most true nootropics, by Girugea’s definition. The mechanisms for nootropics lie within the structural connectivity of the brain, the optimization of blood flow and oxygenation, and the fortification of brain regions over long term consistency. Nootropics act more as a super supplement to protecting the brain. Girugea’s own first synthesized nootropic (in 1964) is still in use today and has been shown to have effects on mitochondrial metabolism, cell membrane fluidity, and functional connectivity in the brain.
Piracetam is this poster child for nootropics, and one of the main ingredients in truBrain nootropic blends. It is one of the only compounds used in that formulation that can not be found in nature, however it was originally derived from – and has structural similarities to – the neurotransmitter GABA.
Since Girugea bought piracetam to light in 1964, there has been lots of research to support the benefits of piracetam. It has been shown to positively affect our cell membranes and to have neuroprotective and pro-metabolism effects on cells. The fluidity in our membranes changes with stress and old age, as well as moment to moment as one method of regulating receptor activity. By keeping our membranes healthy we can promote the cells ability to communicate.
For example, truBrain combines other membrane oriented supplements – including choline. The cell membrane – especially in the brain – relays ongoing control signals and messages from other cells to the inner processes of the cell. Neurons’ membranes in the axon (wiring) and soma (cell body) help generate and propagate electrical signals, sum distant signals, and even have computational and complex learning functions related to changes in membrane function. Healthier and more active cell membranes bring us increased activity and cell communication, and hopefully better cognition.
Piracetam along with other truBrain ingredients such as magnesium, choline, and DHA, increases in brain plasticity and are designed to improve cognition and efficiency under processing load – or peak performance, versus remediation. Nootropics may support increased cognitive potential as well as long term protection. The truBrain team added L-Theanine and L-Tyrosine to support neurotransmitters of GABA and Dopamine, respectively.
You can use a similar or different strategy when building your own nootropic regimen, but use a strategy. Know why you are putting an ingredient in, know how it might interact with the others, and be sure that dosing is safe.
When you are planning your nootropic or nutraceutical regimen, think in terms of nutrition support to cell metabolism and function, amino acids, natural or near-natural compounds, and avoid bad fats and harsh chemicals that give a momentary boost at the cost of later crashing or having other more serious side effects, such as excess sugars and caffeine.
And don’t forget what else you put in your mouth – additional DHA and other omega-3 fatty acids (in grass fed meats, deep sea fish) are excellent for brain health. Craft your diet like you craft your brain supplement regimen – or have both catered / curated for you in a high end product. If you do create your own blend, think precise selection, not shotgun approach, and add slowly to your regimen.
The Problem With Instant Gratification
As a culture, we often hear false marketing claims or create mindsets about what is possible with our health.
We see ads that advertise a pill that gets rid of “stomach fat fast”. Truthfully, fat is lost uniformly in the body and the fastest and healthiest way to lose weight it about 1-2 pounds uniformly a week. So we eat poorly and don’t exercise for 2 years and then criticize our healthy workout plans and diet 1 month in when we don’t get the results we want.
The healthiest and most effective things in life are often the ones that we do routinely. Consistency is key. This is true if you are talking about athletic performance, academic or intellectual training, or nutrition and supplement support. While not “necessary” like supplements or medicines, nootropic use follows this principle as well. There is another rule, emerging.
If something is strongly “felt” dose to dose – if it gets you high, or wired, or sedated…it’s a smart drug, recreational drug, or something that may enhancing some aspect of performance (perhaps at the expense of another), but is definitely not a nootropic. And finally, nootropics should be sustainable.
With some nootropics there is an initial loading phase followed by a maintenance phase, and while subtle, results can be felt fairly quickly on the timescale of a few days. The contrasting quick highs / crashes of coffee, alcohol, smart drugs, and even quickly digesting carbs are definitely experienced more immediately, but have consequences that make them unsustainable for many people.
So in summary – here are a few initial rules to help select your own nootropic or cognitive enhancing blend:
- Know your ingredients, and their amounts.
- Don’t spend your money on obfuscate fairy dusting or expensive blends that are full of caffeine or random research chemicals.
- It’s not a nootropic if it has side effects.
- Your nootropic solutions should focus on mild nutritive and metabolic support, for long term gains and protection. Break the cycle peak and crash that you get with too many stimulants, and avoid the more serious side effects that you risk with smart drugs.
- Nootropics don’t get you high, altered, or wired.
And don’t forget the other accessible and evidence-based brain and cognition improving methodologies we have at our disposal today: meditation, yoga, and other contemplative (attention training) practices, biofeedback and neurofeedback, diets high in good fats, and other modifiable behaviors you can implement to take control of your brain health and performance.
So take care of your brain – the tools are out there, to support health and shift performance.