Nicotine: impact on cognition, performance, mood, health risks, and more (AMA 70 sneak peek)

1. 0:00 – 1:38

   Intro

   1. PAPeter Attia0:00

      The safest things when it comes to anything other than nicotine are going to be the FDA-approved products in the form of patches and gums. Right beneath that is what we just talked about, the nicotine pouches, where, um, they are not tobacco derived. I think I would take a big step down and then talk about e-cigarettes.

   2. SPSpeaker0:21

      What do we know about how addictive nicotine itself can be?

   3. PAPeter Attia0:26

      Boilerplate answer here is that nicotine is highly addictive, and the discontinuation of nicotine will lead to withdrawal symptoms. The most prominent of these being irritability, anxiety, even anger, uh, difficulty concentrating, sleep disturbances.

   4. SPSpeaker0:40

      What do we know about other chemicals that can be present in these products and the health implications of those so people kind of understand why they would want to avoid them?

   5. PAPeter Attia0:50

      Most of the things that are added to nicotine replacement therapies, which have been approved by the FDA, are there to basically add flavor, texture, stabilization, um, and, and a- and adjust absorption. If your nicotine is tobacco derived as opposed to synthetic, uh, you are still probably assuming risk.

   6. SPSpeaker1:09

      So let's kind of now go from risks, downsides to potential benefits.

   7. PAPeter Attia1:16

      A lot of people will talk about how, "Hey, when, when I use this stuff, I feel better, I feel sharper." Yes, but as you're increasing your dependency, you may actually end up losing that, um, when you're deprived of nicotine. [upbeat music] Hey, everyone, welcome to "The Drive" podcast. I'm your host, Peter Attia.

2. 1:38 – 3:40

   Revisiting the previous AMA on microplastics: low-effort, high-impact changes to significantly reduce microplastic exposure

   1. SPSpeaker1:38

      Peter, welcome to another AMA. How you doing?

   2. PAPeter Attia1:42

      I'm, I'm doing really well. Thank you for having me back.

   3. SPSpeaker1:45

      I mean, we're always happy to have you whenever you would like. Um, and again, it'd be very awkward if you weren't here. I think we do need to follow up based on one of our recent AMAs is, do you still have a liquid of some form in front of you?

   4. PAPeter Attia2:00

      I do.

   5. SPSpeaker2:02

      What kind of, uh, cup is that in?

   6. PAPeter Attia2:06

      You know, I'm actually drinking it in a glass.

   7. SPSpeaker2:08

      [chuckles] Did you listen to our microplastics AMA, and that's why you made that change?

   8. PAPeter Attia2:15

      Nick, I have made several changes following the AMA on microplastics. Um, I believe that they are all in the spirit of eighty/twenty, right? So I'm, I'm, I'm really kind of low on the sigmoidal curve of, um, cost and energy with one exception. Um, and yeah, I think I'm just taking what I think are the relatively easy steps to hopefully mitigate eighty percent of my exposure, and I'm gonna spend no more time worrying about the last twenty percent, which, uh, A, I have no idea if it matters, and even if it does, I don't think I could live my life and be concerned with it.

   9. SPSpeaker2:58

      That's great to hear. Two things. First is by the time this comes out, we'll most likely have a short video on what those changes were, so we'll link to that. Um, if we don't have that video, something terribly went wrong, so we should have it. The second is, are you just so happy that you continue to join us for these AMAs? Otherwise, you would still be living so foolishly in your microplastic life.

   10. PAPeter Attia3:22

       [laughs] I am looking forward to the day when someone else hosts an AMA for me.

   11. SPSpeaker3:28

       Maybe an avatar.

   12. PAPeter Attia3:31

       That would be awesome.

   13. SPSpeaker3:32

       We could just have AI Peter, and it's just an ongoing AMA that never ends.

   14. PAPeter Attia3:36

       [laughs]

   15. SPSpeaker3:39

       All right. Well,

3. 3:40 – 5:06

   Overview of episode topics related to nicotine

   1. SPSpeaker3:40

      today's AMA is not gonna be that. It will be you live, and it is on a single topic we get asked a lot about. There's so much more use of it. We initially did an AMA on it, I think like four years ago, and at the time, you didn't see as much use as you do now, and that's nicotine. So we are gonna talk all things nicotine today. This is gonna look at benefits, short term, long term, around everything from cognition, exercise, whatever it may be, risks of nicotine and things that people need to be aware of. We're gonna look at different ways and vehicles that people can use nicotine and what are the pros and cons. And then we're also gonna end this with something that we've-- get asked a lot about every now and then when it comes to smoking cessation. And I think we often say a lot of people in our audience most likely are not smoking, because if you are, you're probably not opting into this deep content, but some people are. But also we hear from people where it's, "Hey, my parents, significant other, like children, friends," whatever it may be, "are still doing this. How can I talk to them about quitting?" So we'll cover that as well. So all that said, anything you want to say before we get rolling?

   2. PAPeter Attia4:58

      Nope.

   3. SPSpeaker5:01

      That was a great insight that you added right there, so thank you for that.

   4. PAPeter Attia5:04

      [laughs]

   5. SPSpeaker5:05

      Um,

4. 5:06 – 7:18

   The current landscape of nicotine research

   1. SPSpeaker5:06

      all right. Start out, can you explain just where the field of nicotine research currently stands and kind of like even what's new and distinct from when we talked about this four years ago?

   2. PAPeter Attia5:18

      Yeah. So I think one of the things that we appreciated, meaning the, the team and I as we were kind of preparing for this, was, um, you know, trying to appreciate how much of the research on nicotine is based on, uh, tobacco and its first application through obviously cigarettes, but then also the idea of using tobacco to extract nicotine for non-smoke but tobacco-derived nicotine versus synthetic nicotine, um, which is honestly what a lot of people are thinking about in that context. And so s- s- so I think that's just sort of important to understand that it is not always easy to tease out the impact of nicotine. And I'll foreshadow one example that we're gonna talk about, which is infertility. Um, you would think, um, we would have legions of data that would explain the effect of nicotine on fertility, both for males and females. Um, it turns out that if you want to talk about it through the lens of smoking- That's true. But if you want to talk about it through the lens of vaping or nicotine pouches, that's not true. Um, and so I think that's, that's just kind of one of the issues that I think makes this difficult, um, uh, to talk about with complete clarity. Um, so, so anyway, I, I guess that, that's the first thing I would say. I think the second thing I would say is, and you alluded to this, four years ago we did an AMA on nicotine. Um, don't worry, those of you that listened to that, there's very little overlap. Um, I spent way more time talking about how nicotine worked, mechanisms of action. Um, today we're probably gonna, I think, answer a lot more of the practical questions that people have. Um, and I will also say that four years later, there's, there's frankly more research on some of the benefits of nicotine. Um, and, uh, again, to be sure, we're gonna talk about both the risks and benefits of nicotine today. Um, so anyway, I would say that's, uh, you know, that, that, that's probably a good place to start.

5. 7:18 – 11:12

   Addressing the common misconception that nicotine itself is the primary cause of tobacco-related health risks

   1. SPSpeaker7:18

      And I think it'd be really helpful for people double-clicking on kind of one thing you hinted at there, which is for a lot of people when they hear nicotine, there's just a negative connotation, right? And usually it's because they associate it with tobacco, cigarettes, and so their mind initially goes to nicotine as maybe a negative, harmful thing. So do you want to maybe quickly kind of disentangle for people the health risks of tobacco from the effects of nicotine specifically?

   2. PAPeter Attia7:47

      Yeah, this is something I think I didn't-- Uh, maybe I didn't do a good job of this four years ago, or maybe I did, and at the end of the day, people just, uh, don't appreciate nuance. But I remember being very surprised at how, A, people thought that the takeaway from the podcast four years ago was we should all be using nicotine, and B, people were like, "How can you advocate for this as a doctor?" So, uh, my hope is to sort of untangle all of that for people. So nicotine is one of many compounds found within the leaves of the tobacco plant. Um, as such, it is in nicotine-- Uh, pardon me, tobacco-based products. Um, but the major health concerns that are associated with tobacco, which are primarily cancer and cardiovascular disease, for reasons we can talk about another time and we're not gonna talk about today, are not caused by nicotine per se, uh, but instead they are caused by several other components of tobacco itself and tobacco smoke, such as, you know, e-everything from toxic metals, formaldehyde, things called polycyclic aromatic hydrocarbons. These are actually the, um, the, the, the things that are causing the harm. Now, there are byproducts of nicotine, um, that are produced in processing tobacco, um, and they can be carcinogenic. So that means, and this is a very important point, I wanna make sure if you're, you know, trying to pay attention to the key points, this is one of them. This means that any tobacco-derived nicotine product may contain carcinogens. This was actually something I did not appreciate prior, okay? I thought that you could extract nicotine from tobacco and be completely free and clear of carcinogens. That is not the case. Now, I, I, I wanna be clear. It might be that, and it likely is, in fact, it almost undoubtedly is, that smoking tobacco is a much higher level of risk. Um, but I wanna make sure people understand that if your nicotine is tobacco derived as opposed to synthetic, uh, you are still probably assuming risk. So the level of these compounds depends on the processing technique, um, and the tobacco variety, of course, right? So they're found in the highest concentrations in products that actually still look like tobacco. Um, so I think that's kind of a nice way to think about it, right? So if you-- Everybody can imagine what a cigarette looks like. Well, if you take tobacco chewing leaves, right, people chew tobacco, that's going to have a lot of the negative properties. So the, the m- the more closely you are to tobacco, the worse things are. So obviously, if you're sticking it in a cigarette or a cigar or pipe, yep, you're getting plenty of it there. Um, if you're chewing it or taking it in snus, also a, a big problem. So this is why e-- And again, uh, I don't think I fully appreciated this four years ago. When you take a tobacco, uh, when you take nicotine out of tobacco directly, um, you're still assuming some of that, uh, that, that risk, that risk that comes in curing and fermentation of the tobacco itself.

6. 11:12 – 13:50

   Peter’s Marlboro-branded apparel is a nostalgic tribute to the Formula One era & not a sign of support for smoking

   1. SPSpeaker11:13

      And before we move on, uh, we should just address something because I forget sometimes people get confused by it. And even earlier this week, we got an email to the website, which is, "Peter, for someone who cares so much about their health, why did I see an Instagram or YouTube video of you where on your hat or your T-shirt there was the Marlboro logo? Do you support cigarette smoking?" So while we have people, do you just wanna explain why sometimes your clothing has that and how you're not sponsored by Big Tobacco and that is not a you should be going and smoking Marlboro Reds on the regular?

   2. PAPeter Attia11:56

      Yeah. Boy, that's-- Okay. So, um, this is a philosophical issue, but as people, some people, uh, listening to this podcast know, I am an enormous fan of Formula One, um, and that goes way back for a long period of time. And up until 2005, tobacco was a major sponsor of Formula One. In fact, the largest sponsor, uh, would have been Marlboro, and they were in the early 2000s all over the Ferraris, um, and in the era that is my favorite era of Formula One in the, in the 1980s, uh, and the early '90s, they were all over the McLaren car. And so you are correct. From time to time, you will see me wearing something, uh, or memorabilia that I have that is, uh, a throwback to that era of Formula One, and I believe in the original livery of those vehicles. In other words, I believe in era-appropriate, uh, nods to things that we pay attention to. And so yes, if you're looking at, um, a hat or a shirt or, uh, a car that is, is a, is a replica or pays homage to, to something of that era, you're going to see the livery of the sponsors of the time, and that would have been Hugo Boss, uh, Nacional, uh, Marlboro. And so, um, again, you know, uh, I, I'm not, you know-- Anyway, I don't-- There's nothing else I can say about it other than, uh, it has nothing to do with, with, uh, a tacit or otherwise approval of these products. I want to be unambiguously clear. I think smoking, uh, is an absolute error, the arguably the single biggest unforced error you can make with respect to your health. Uh, and fortunately, Big Tobacco does not sponsor, uh, motorsport anymore, um, and you know, that's, I think, I think they're better for it.

   3. SPSpeaker13:47

      Perfect. Back to the regularly scheduled

7. 13:50 – 20:36

   The limitations of current research on the health risks of nicotine itself

   1. SPSpeaker13:50

      program. Nicotine. Are there any harms associated with nicotine itself, kind of based on what we just talked about then?

   2. PAPeter Attia13:58

      Well, we're going to go into this in some detail, but I would say that clearly the biggest risk of pure nicotine, and now I'm just talking about it through the lens of synthetically acquired nicotine, so you're getting rid of all the tobacco-related processing, is, uh, in its addictive nature. And make no mistake about it, nicotine is highly addictive. Um, there are some other areas where, depending on the dose, there may actually be a harm. Again, I think this is very important to understand. Um, there are some mechanistic insights that suggest a negative, uh, impact on the endothelium. And it's certainly plausible that anything that negatively impacts the endothelium could increase the risk of cardiovascular disease. Um, but, um, these are not studies that have been-- you know, these are not large studies. These are not studies that have been done in humans, and these are extrapolations typically from other animal, um, uh, models. So, um, let-- I guess we should probably just maybe spend a minute kind of talking about nicotine again. Um, and again, I go into-- If people want more detail on this, I think it's covered four years ago. But, um, nicotine, uh, activates-- So nicotine is a molecule, and it activates something called a nicotinic acetylcholine receptor. Now, these receptors are not just in the brain where we most frequently talk about them, but they can actually exist throughout the body. And if you look at certain mouse models and rodent models, such as other rodents like, like rats, um, it's been demonstrated that n- high doses of nicotine can actually increase tumor growth and even foster metastases, um, in addition to increasing atherosclerotic plaques. Now, uh, that sounds, you know, pretty devastating. Um, I, I just want to always point out when, whenever we're talking about these rodent models, um, there are, there are, you know, there, there's lots of daylight typically between what happens in that model and what happens in, in humans. Um, and I, I think it's important to kind of look at, um, uh, other ways to triangulate upon the answer. So we're, we'll link to those studies in the show notes. Um, but the closest thing that we could find in, um, in humans was a twenty twenty-four Mendelian randomization. I know we talk about these a lot, but I always think it's worth explaining what an MR is. So a Mendelian randomization says, let's look at, um, genes in a population which we can assume are randomly assorted. That's the randomization part. And let's ask the question, will these genes be a proxy for a behavior that I want to study or something that I want to study where I can now use effectively observational tools to see if there's a difference? So again, you know, one example is, um, Mendelian randomization consistently shows that LDL cholesterol is causally associated with heart disease. Why? Because LDL cholesterol is highly genetic, and you can look across a population and see different levels of LDL even in people who are, you know, otherwise healthy, and you can examine the cardiovascular outcomes of these people, which would be the dependent variable, um, and that's how you can infer causality. By extension, by the way, HDL cholesterol turns out to be not causally related in the inverse. Nevertheless, so if you look at this Mendelian randomization, they wanted to look at the relationship of nicotine by itself on compromised lung function, lung cancer, COPD, CH-- um, ASCBD, et cetera. Okay. So, um, the only-- So, so I want to be clear. I don't think this was the world's best, um, MR. I think it was clever, though. So what did they look at? 'Cause, like, what genes would you try to parse out to understand how much tobacco someone is consuming, which is what you actually want to be able to do. So what they looked at was they looked at genes that spoke to nicotine metabolism. And so just as caffeine, we've talked about this in the past, caffeine, uh, metabolism is highly genetic, right? So people like me are wickedly fast at metabolizing caffeine, um, and therefore I seem to be able to drink it later in the day without a negative impact. Um, someone who's a very slow metabolizer is going to feel it more. Well, similarly with nicotine, you have high and low levels of nicotine, um, metabolism. And what the authors of this study, uh, postulated was people who are, um, faster nicotine metabolizers are gonna have lower levels of circulating nicotine and therefore less nicotine exposure. Now, that's possible. I, I-- technically, you could also argue that maybe someone who's a faster nicotine metabolizer would smoke more or consume more nicotine. So a-again, put that aside for the moment. But nevertheless, uh, the authors used these genetic variants associated with nicotine metabolism to adjust for basically smoking heaviness. And again, we're not interested in the role of smoking, we're interested in the role of nicotine. Okay. So, um, disease risk was increased with slower nicotine metabolism, but the added risk was abolished when adjusted for smoking heaviness, 'cause of course, if you do this, you have to ad-adjust for smoking, indicating that the main drivers of the outcomes, um, are the non-nicotinic components of cigarette smoke. Let me state that again. This is a complicated MR, but it is the closest thing I think we have to looking at humans, and it's looking at how much people smoked, how quickly they metabolize nicotine, trying to do an overlay of that to, to, to appreciate the nicotine exposure, and it came away basically saying that the harm of smoking is due to the tobacco and tobacco-related products, not due to the nicotine. I want to be clear, this is way, way far away from what you would want to be able to say is level one evidence, right? If you wanted to do this in a level one fashion, you would actually have to randomize people to a whole bunch of different tobacco-free nicotine products and study the outcomes of interest. Now, of course, nobody's going to do that for hard outcomes like mortality, uh, but I certainly think people could do that for softer outcomes. Um, uh, and, and, and my hope is that, that somewhere along there, people, people do that.

   3. SPSpeaker20:35

      And

8. 20:36 – 23:45

   The most common side effects of nicotine

   1. SPSpeaker20:36

      what do we know about potential side effects of nicotine?

   2. PAPeter Attia20:40

      Thank you for listening to today's sneak peek AMA episode of The Drive. If you're interested in hearing the complete version of this AMA, you'll want to become a premium member. It's extremely important to me to provide all of this content without relying on paid ads. To do this, our work is made entirely possible by our members, and in return, we offer exclusive member-only content and benefits above and beyond what is available for free. So if you want to take your knowledge of this space to the next level, it's our goal to ensure members get back much more than the price of the subscription. Premium membership includes several benefits. First, comprehensive podcast show notes that detail every topic, paper, person, and thing that we discuss in each episode. And the word on the street is nobody's show notes rival ours. Second, monthly Ask Me Anything or AMA episodes. These episodes are comprised of detailed responses to subscriber questions, typically focused on a single topic and are designed to offer a great deal of clarity and detail on topics of special interest to our members. You'll also get access to the show notes for these episodes, of course. Third, delivery of our premium newsletter, which is put together by our dedicated team of research analysts. This newsletter covers a wide range of topics related to longevity and provides much more detail than our free weekly newsletter. Fourth, access to our private podcast feed that provides you with access to every episode, including AMAs, sans the spiel you're listening to now and in your regular podcast feed. Fifth, the Qualies, an additional member-only podcast we put together that serves as a highlight reel featuring the best excerpts from previous episodes of The Drive. This is a great way to catch up on previous episodes without having to go back and listen to each one of them. And finally, other benefits that are added along the way. If you want to learn more and access these member-only benefits, you can head over to peterattiamd.com/subscribe. You can also find me on YouTube, Instagram, and Twitter, all with the handle peterattiamd. You can also leave us a review on Apple Podcasts or whatever podcast player you use. This podcast is for general informational purposes only and does not constitute the practice of medicine, nursing, or other professional healthcare services, including the giving of medical advice. No doctor-patient relationship is formed. The use of this information and the materials linked to this podcast is at the user's own risk. The content on this podcast is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Users should not disregard or delay in obtaining medical advice from any medical condition they have, and they should seek the assistance of their healthcare professionals for any such conditions. Finally, I take all conflicts of interest very seriously. For all of my disclosures and the companies I invest in or advise, please visit peterattiamd.com/about where I keep an up-to-date and active list of all disclosures. [outro music]

Episode duration: 23:45