Episode 146

What comes to mind when you think of nicotine?  For many people, it’s dirty smokers and lung cancer.

But as Dr. Neil Grunberg, Professor of Medical and Clinical Psychology at the Uniformed Services University, explained to us way back in Episode 22, if you uncouple nicotine from tobacco, it’s actually a pretty darn powerful cognitive enhancer.

In fact, nicotine is only one of between 500 – 700 chemicals in tobacco (which turn into more than 7,000 when tobacco is smoked).  So, before we get to the meat of the matter, let’s make one thing clear:  nicotine is not synonymous with tobacco.  And don’t smoke cigarettes – ever.

Nicotine as a Smart Drug

Nicotine is a very unusual drug – neither straight stimulant nor straight relaxant.  It keeps you alert when you’re tired, but is calming when you’re stressed.

It increases focus and alertness, helps sustain attention, and decreases distractibility.  It also controls hunger and reduces pain.  Researchers are even looking into therapeutic uses for nicotine in the fight against dementia and Alzheimer’s.

For more on taking nicotine as a smart drug, download our guide to getting started with nicotine.  Just enter your email address in bottom right corner of this page and we’ll hook you up.

Better Than Caffeine?

Let’s take the two most popular drugs in the world:  caffeine and nicotine.  If you need to get alert, should you drink a cup of coffee or take some nicotine?

Well, both are stimulants and will make you feel more alert and focused. Caffeine is a straight-forward stimulant — it stimulates you.  Nicotine, on the other hand, might be a better call if you’re stressed and tired, since it will wake you up, but also help calm you down.

But that’s not the only consideration.  The potential for addiction (“addiction liability” in official jargon) of caffeine and nicotine are hugely different.  Only about 15-20% of people will become physiologically addicted to caffeine.

Remember, that’s different than just relying on caffeine to get going in the morning or to stay up late.  Addiction in this sense means that you must have the substance to maintain normal physiological functioning.

Nicotine is much more addictive:  about 80-85% of people will become addicted to nicotine.  For comparison, that number is 50-60% for heroin.  So yeah, you probably will become addicted to nicotine if you take it regularly.  Anyone who’s tried to quit smoking knows just how addictive nicotine is.

But Is It Worth It?

There are two big concerns with taking nicotine:  addiction and vascular constriction.

Addiction

There’s no way around it:  nicotine is really addictive.  And once you become addicted, getting un-addicted is no walk in the park.  Your body will have begun to need nicotine to functional normally, so expect plenty of withdrawals and other unpleasantries.

Vascular Constriction

The benefits of nicotine are short-term, but the downsides are long-term.  Regular use of nicotine causes your blood vessels to constrict, causing heart problems.

If you’re young, Dr. Grunberg does not recommend regularly taking nicotine.  He doesn’t think the value is high enough compared to the potential danger to your heart over the decades.  That said, we don’t know how many years of nicotine exposure it takes to start negatively impacting your heart.  So if you’re in your 60s or 70s, the balance might tip the other way.

It’s up to you to weigh the potential risks.

Full disclosure:  Jesse does use nicotine patches, but not daily.

Could Nicotine Be Non-Addictive?

Nicotine works by binding to nicotinic acetylcholinergic receptors in the brain.  It turns out that there are actually multiple types of nicotinic receptors, some linked to the addictive quality of nicotine, and other to the other – calming, stimulating, appetite-controlling – effects of nicotine.

This discovery means that we could potentially create synthetic analogues that stimulate some receptors and not the addiction-related ones.  So we could get the benefits of nicotine without the potential for addiction.  That would be a remarkable drug, wouldn’t it?

Episode Highlights

0:31Nicotine - Part 2
1:47This Week in Neuroscience: Pollution particles 'get into brain'
5:35The audience interaction section
7:43Next #AxonChat - Wednesday, September 28 at 8pm Eastern Time with Dominic D’Agostino
8:33Re-introduction to Neil Grunberg
10:23What else does nicotine do?
12:11The dangers of tobacco have little to do with nicotine
13:23Nicotine: addictive, not evil
13:45The correlation between various routes to administration and addiction
19:22Tolerance increase due to exposure
21:40Nicotinic acetylcholine receptors and designer drugs
28:53Are there long-term upsides or downsides to nicotine use?
30:25A cost-benefit analysis for using nicotine
32:59Buying a new... heart?
34:46Staying alert into your 90s
35:42A future addiction episode
36:26Ruthless Listener-Retention Gimmick: Compulsive drinking in rats stopped cold by flipping neurons like switches

PS: Our weekly Brain Breakfast has a high potential for addiction, but is completely safe.

Episode Transcript hideshow

— This Week in Neuroscience --

Jesse: So in the main interview for this episode, we’re going to be talking about nicotine, which famously is an inhaled drug—at least, typically that’s how people get it—that crosses the blood-brain barrier and winds up in the brain.  Which raises the question: what else that we breathe is making its way into our brains?  There is this nice physiological envelope, the blood-brain barrier that is there to protect us.  But no system is perfect, and some recent data has come out showing that air pollution is actually, in some cases, at least some types of air pollution, winds up making its way all the way into the recesses of our brain, there to do who knows what.  New research was conducted this year at Lancaster University in the UK, looking at brain tissue from 37 deceased people who died from a variety of causes, some natural, some not, but seeing what sort of compounds from their environment might have made its way into their brain tissue over the course of their life.  29 of these people came from Mexico City, which is a notorious hotspot for pollution.  They had ages ranging from 3 to 85, so, pretty wide range; and the other 8 came from Manchester, in the United Kingdom. 

Now, in particular, the researchers were looking at a particle called magnetite, which can be an airborne pollution particle that they suspected might make it into our brain as well as the rest of our body.  Now, magnetite can occur naturally within the brain in very small quantities, but the way that magnetite forms within the body is visibly different under a high-powered microscope.  It’s jagged when it forms naturally within the body, and by contrast, magnetite particles that are formed in vehicle engines or braking systems, they have smooth, rounded appearances.  And what the researchers found when looking at the brain tissue from these cadavers was that naturally-occurring or endogenous magnetite within the brains was only 1% as prevalent was magnetite that they’d brought in from their environment during their lifetimes.  How is it that these magnetite particles were getting past the blood-brain barrier?  Well, they are very, very small; less than 200 nanometers in diameter, which, in comparison, a human hair is 50,000 nanometers thick.  Which, according to the researchers, the way that this is getting to the brain, they think it’s going in through the nose, passing into what’s called the olfactory bulb, and then continuing through the nervous system, into the frontal cortex of the brain. 

Now, all this sounds pretty bad at first blush, and in fact the researcher’s paper uses the term "dreadfully shocking," which is quite emphatic terminology for a scientific paper… In fact, I’ll read you that little bit.  This is from the author, Professor Barbara Maher, who says, "It’s dreadfully shocking.  When you study the tissue, you see the particles distributed between the cells, and when you do a magnetic extraction, there are millions of particles, millions in a single gram of brain tissue.  That’s a million opportunities to do damage."  Now, as crummy as all this sounds, it’s not an open and shut case that this sort of environmental pollution making its way into the brain is actually leading to any bad downstream effects, although there are plenty of suggestive links.  Dr. Clare Walton of the Alzheimer’s Society says, "The causes of dementia are complex, and so far there hasn’t been enough research to say whether living in cities and polluted areas raises the risk of dementia.  Further work is in important, but until we have more data, people shouldn’t be unduly worried."  However, as the study’s author points out, these particles are made out of iron, and iron is very reactive, and so it’s almost certainly going to do some damage to the brain.  It’s involved in producing very reactive molecules called reactive oxygen species, which produce oxidative damage, and that’s very well-defined.  It can’t be benign. 

Last but not least, it’s probably worth mentioning that just living in a city doesn’t necessarily mean you’re clocking up the same amount of airborne damage year by year.  Certainly a person’s job and lifestyle habits will give a person more exposure, or less, to certain environmental toxins.  The highest level of magnetite pollution found in any of the brains that they sampled were from a Mexican man that was killed in a car accident.  He was only 32 years of age.  And there were people from Mexico City, the same city in this study, up to 85 years old.  So, he’d racked up more metal in his brain at 32 than some of the 85-year-olds.  So it just goes to show that living in a certain city doesn’t necessarily mean that you’re running the same pollution odometer as your neighbors. 

— Main Interview --

Jesse: So I don’t know if anybody remembers a couple years of ago when they made an Incredible Hulk movie, and then like two years later they made a brand-new Incredible Hulk movie with no reference to the other.  It wasn’t like a sequel, it was just basically a straight-up remake.  I don’t think either of them were very good.  But anyway, we’re doing something a little bit similar here with our coverage of nicotine; we had a nicotine episode very early on in the history of Smart Drug Smarts, but I thought it was an important and valuable enough discussion, I wanted to kind of take a second swing at it.  It’s such a well-known and popularly demonized drug, but it really does have some hidden upsides.  I’d also never tried nicotine myself before at the time that we did the original episode.  Since then, I’ve been using nicotine patches on various occasions. 

So, I wanted to take a second look at nicotine, coming back for more, and we’re going back to our source, Dr. Neil Grunberg from the Uniformed Services University of the Health Sciences, where he specializes in military and emergency medicine, as well as medical and clinical psychology, and is also one of the world’s leading authorities on nicotine—especially one of the leading authorities found outside the tobacco industry, which is probably an important caveat, because his paycheck is paid by the US government essentially, not by any big vested interest in a tobacco conglomerate, the findings of which might be somewhat more subject to skepticism, but not so with Dr. Grunberg.  And I think we get a pretty fun and well-rounded conversation looking at both the pros and cons of nicotine, really trying to separate nicotine from tobacco.  Obviously nicotine is famous because of tobacco, but they are certainly dissociable ideas, and for the purpose of this conversation we’re going to be trying to talk about nicotine minus all of the tobacco baggage.  So, I kind of think of this as a "hooker with a heart of gold" sort of story, about this misunderstood chemical that has all these good things going for it but has this nasty reputation.  Dr. Grunberg, I think he would characterize it more as like a "hooker with a heart of gold who still might steal your wallet while you’re not looking, so you really have got to be careful."  But that’s probably more than enough preamble, so let’s jump in with Dr. Neil Grunberg. 

--

Dr. Grunberg: Nicotine has been well-known for a long time, and its role as the important addictive element of tobacco, cigarettes, and other tobacco products has been well-established now for decades.  But with the understanding of its importance has also become an analysis of what else does it do, or why does it appeal to people, and what has been referred to by some as beneficial effects.  These include some cognitive-enhancing effects, because nicotine is a stimulant.  But it’s interesting, because it is a drug, unusual in that it brings you up when you’re down and brings you down when you’re up, but I mean that in a positive sense.  It alerts you when you’re tired, it calms you down when you’re too stressed out.  It increases attentional focus and alertness, as well as the ability to attend to various stimuli, focus attention, sustain attention, decrease distraction.  And then it’s shown some promise in different medicinal forms when dealing with perhaps cognitive dementia, maybe Alzheimer’s, or other developing states that will lead to deterioration of mental function over time. 

Jesse: So they’re actually looking at therapeutic uses for nicotine now.  That sounds so counterintuitive. 

Dr. Grunberg: I don’t know, it’s funny that you say counterintuitive, because I actually think of it as something that it may be surprising, but it should not be counterintuitive.  Because if you wonder why did this drug become the most addictive, most used and valued drug in the history of the world… I mean, the only drug that’s used by a greater proportion of people historically were caffeine or alcohol.  But even then, in many societies nicotine exceeds even those.  So the question then becomes why do people use it?  Well, they’ve used it because nicotine helps with attention, as I’ve mentioned; it controls hunger, it also reduces pain, and it has a variety of these health-enhancing effects.  Now, the problem with tobacco is not largely the nicotine, although it’s why we crave and enjoy it.  The dangers of tobacco, which are enormous, are the thousands—I mean, literally thousands—of other chemicals that one inhales when you’re exposed to a tobacco product.  Nicotine is only one of 7,000 inhaled chemicals on each puff of a cigarette. 

Jesse: And I think you mentioned last time that we talked that the burning of tobacco, that magnifies the amount of chemicals that a person takes on by a factor of 10. 

Dr. Grunberg: You’re exactly right, the estimates are 500 to 700 chemicals that are in various processed and prepared tobacco.  But pyrolysis, where the heating and burning, converts chemicals, they break down, they also combine, they form other chemicals, and it does increase by approximately tenfold.  For most people, if they’re wondering, "What do you mean by that?"  The best example is toast.  If you take a piece of bread with all of its constituent elements, when it’s heated, it first gets warm.  But the browning of it, the development of the charcoal, and the brown and then black if you burn your toast, is actually new chemicals.  And similarly, when one heats or barbecues other foods, new chemicals are formed, some of which are very, very tasty, some which are fine or perhaps healthful, and some of which pose additional dangers.  So that’s exactly what happens in the heating of the tobacco column, increases by approximately a factor of 10 the number of chemicals you inhale.  But again, nicotine, which has gotten the most press because it is, indeed, addictive, gets mistaken as therefore that’s evil.  Well, a drug that’s addictive means that you need it to maintain normal physiological and psychological functioning.  That does not mean the same as it causes a health hazard. 

Jesse: I’m curious about the various routes of administration possible with nicotine and the ability to get people addicted.  Are all of them equally likely to addict, or are some better or worse than others in that regard? 

Dr. Grunberg: The various routes of administration of any drug into the body can include eating it, smoking it, snorting it, injecting it… And injecting it where?  Injecting it into one’s muscles, into one’s veins, into other parts of the body, even into one’s brain.  Now, of these different ways of taking drugs, many people presume that if a drug is addictive or has other actions in the brain as we’ve mentioned, such as cognitive alertness, then it must mean that if you’ve snorted it, that’s closer to the head, and therefore that must be more… Other people think the old expression, to "mainline a drug" that became popular in the ‘60s and ‘70s—mainlining means to put into the bloodstream directly.  People assume, "Okay, mainlining, that must be the way to really get nicotine or cocaine or heroin into me!" Well, that gets it into the body, the systemic circulation.  But mainlining—snorting, eating—are not the best ways to get it to the brain.  And this is something that is very surprising, is that the most effective way to get a drug to the brain, of course, would be injected directly into the brain, but let’s leave that as something that—we do that experimentally with animal models, but that’s just not done. 

But for a human, surprisingly the most effective way to get the drug to the brain is to actually smoke it, presuming one additional assumption: that the chemical itself passes from the lungs, is picked up in what’s called the circulatory or the pulmonary circuit, the lung portion of the bloodstream, it’s carried to the brain, and then—this is important—that the chemical structure is such that it passes what’s called the blood-brain barrier.  Now, the blood-brain barrier I liken to a piece of naturally-occurring cellophane wrap or plastic wrap, with tiny, tiny little perforations.  It protects the brain, so that’s why it’s rare for the brain to get infected with bacteria, viruses, other problems.  Many chemicals cannot pass the blood-brain barrier, so they’re blocked, they don’t get in.  But nicotine is one of many that does.  So if you smoke a cigarette, and nicotine is in the cigarette of course, it’s taken up into the lungs.  The part of the bloodstream that picks up the oxygen from the lungs also picks up the nicotine, and in less than 10 seconds—estimates are 5 to 8 seconds—after you inhale a cigarette puff, the nicotine is picked up in the lungs and gets into the brain very rapidly, passing the blood-brain barrier, making it highly addictive for two reasons.  One is that it gets to the brain, and the other that it gets to the brain in close temporal proximity, in close time course, from the behavior of using it. 

Jesse: Yeah, that reminds me of the B. F.  Skinner behaviorism experiments and how the things that were easiest to train animals on were the things that had the really rapid feedback. 

Dr. Grunberg: That’s exactly right, it has to do with the time course between the stimulus, the response, the reinforcer.  Now, the other thing that’s interesting—so, if you take the nicotine and let’s say you were to snort it, you’d think, well, that’s near the brain.  But no, when you snort a chemical, it goes through the nasal passage and then into the gastrointestinal tract.  Very little is absorbed across the buccal mucosa.  Some is, but not much.  A really good example maybe your listeners will find familiar, (not as if they’ve done this, but they’ll find it familiar), is marijuana.  If one smokes marijuana, the tetrahydrocannabinol, the active ingredient THC in marijuana, also passes the blood-brain barrier and gets there rapidly to have its euphoric effect on the brain.  If you eat marijuana in a cookie, in a brownie, in a foodstuff, it has a much, much lower effect, because when it’s eaten it goes into the stomach, is broken down in the stomach, in the GI tract, ground up, and then is metabolized or broken down further in the liver, and then the bloodstream picks it up.  And so if you eat any material with a drug, whether it’s marijuana, THC, nicotine, cocaine, heroin, other things, it takes much longer to get to the brain, building on the point you just made about Skinner and others, reinforcement, but also the amount of the drug is markedly reduced. 

So to smoke a drug that passes the blood-brain barrier is the most effective way to get it there and therefore is the most addictive.  That’s followed by some other kinds of mainlining.  But even then, if you inject something into the bloodstream, if I inject something into my arm, into a vein, it goes to the heart, and then that goes throughout all systemic circulation.  It takes quite a while and is broken down substantially before it gets to the brain.  So this is a very important point and that’s why one uses—another way of getting a drug is transdermally, across the skin.  Nicotine passes across the skin, and that’s why nicotine patches work.  But it’s a much lower dosage than if it’s smoked. 

Jesse: What is the approximate ratio there as far as what actually winds up in the brain from a standard nicotine patio, which I think is like an inch, maybe an inch and a half by an inch and a half?  How much nicotine is actually crossing transdermally and winding up in the bloodstream vs.  if somebody were to smoke an equivalent amount of cigarettes?  What would the equivalent amount of cigarettes be? 

Dr. Grunberg: I guess the range would depend on a lot of characteristics of the person.  But I would say 10 to 30-fold less.  So, that’s why the patch is intended to be a smoking cessation aid, recognizing that the individual smoker has come down dramatically from, say, two packs a day, which would be 40 cigarettes, to a pack, 20 cigarettes, to 10 cigarettes, and then maybe the patch over the course of the day would be like a few cigarettes. 

Jesse: That’s really interesting, because in the time since we’ve talked, there have been many, many, many days that I’ve used the patch for cognitive purposes.  But I wound up finding that even a whole patch was too strong for me, so now I’ll cut it in half with scissors before I put one on.  But to think that that’s 30 to 50 times less than an honest-to-goodness smoker might be getting, that says a lot. 

Dr. Grunberg: That’s a really interesting observation.  And for the record, I did not tell you to do such a nasty thing…

Jesse: No, no, no, no, not at all.  This was on my own recognizance. 

Dr. Grunberg: Alright, I just wanted to be sure I don’t get in trouble here.  But that’s an interesting point, because what you’ve also stumbled on is that there’s also a marked increase in tolerance with exposure to the drug, meaning that it takes larger and larger amounts to have the same effect and over time people respond to the drug less and less.  Which is why the cigarette smoker who first tries a cigarette is overcome with coughing and nausea and vomiting, and a few puffs of one cigarette is too much.  And then they work their way up, usually during adolescence, to a few cigarettes, to half a pack.  But really if you think about the smoker, they’ll go from coughing and sick and nausea and vomiting over one cigarette to a point where they’re smoking sometimes 2-3 packs a day.  Of all the smokers I’ve studied, which are many, the heaviest smoker I ever studied claimed that he smoked 100 cigarettes a day, 5 packs.  I frankly didn’t believe him when he told me that until I brought him into the laboratory and I saw that he literally was a chainsmoker, in which he lit each cigarette on the cigarette that was not quite out in his mouth.  Yeah, sometimes he would have two cigarettes in his mouth at once, so that from the moment he woke until he went to bed, he’d have a cigarette in his mouth.  Think about that.  If you were sensitive to a patch, which is like a few cigarettes, yet depending on the brand, maybe it was the same as 5 cigarettes, but probably it was more like a couple, and this guy’s smoking like a hundred a day.  Incredible. 

Jesse: Yeah, you could totally imagine where somebody, if they’re doing that from the time they wake up to the time they go to sleep, they might very well have withdrawal symptoms during the time that they’re sleeping, and it’s maybe disrupting their sleep as a result of that. 

Dr. Grunberg: That’s absolutely correct.  In fact, one of the ways of estimating the extent of someone’s biological addiction is how long it takes from when they wake up in the morning, or in the middle of the night, until they light that first cigarette.  The person who feels compelled, must light the cigarette in less than five minutes from waking, is usually heavily addicted.  The person who wakes up and waits an hour or two before they have the cigarette after breakfast is responding to it but is not showing as powerful a biological addiction.  And then the person who’s called a "chipper," who smokes when they’re in a bar or when they’re with friends casually, but can go days or a week without smoking, that person does not display a biological addiction. 

Jesse: So, one thing that I learned since the time that we first talked is that our brains have inside them something called nicotinic receptors, which makes me wonder, is nicotine an exogenous analog, something in the outside world that reminds our brain of something that would normally be there anyway.  For most of human history, people didn’t have access to tobacco.  I mean, certainly I guess it was a plant from the new world that people in the old world wouldn’t have had access to before the time of Columbus.  So, what is it that’s naturally there within our brains that nicotine is reminding our brains of? 

Dr. Grunberg: What’s been casually referred to as nicotinic receptors are more accurately called nicotinic acetylcholinergic receptors.  But I’ll refer to them as nicotinic or nicotine receptor for the moment.  We now know that there are many, many subtypes.  They have a similar structure but with some variations.  These occur throughout the brain and they respond to acetylcholine and they respond and also are stimulated to the release of other natural chemicals called dopamine.  So the nicotinic or nicotine receptors get their name because, interestingly enough, they respond to this endogenous material, acetylcholine.  But there’s two large categories of types of these receptors, many in the brain, others in the peripheral nervous system, others in the part of the nervous system that interacts with our muscles.  And back in the 19th century, it was discovered that when one took extracts of tobacco, later to be understood to be nicotine, and you stimulated these receptors, some were stimulated by nicotine, these acetylcholine receptors; some responded to another chemical called muscarine.  And so the name of the receptors had to do with the fact that it was a subgroup of naturally-occurring receptors that responded to the nicotine.  Since those discoveries and the explosion in what’s molecular biology, studying the molecular structure of these proteins that are in our brain, over the last 40-50 years, it’s been discovered that there are nicotinic receptor subtypes that underlie the addictive part of nicotine’s effects; there are different nicotine subtypes that underlie the cognitive-enhancing effects we’ve briefly discussed; there are different nicotine subtypes that probably underlie the other effects of nicotine, to calm you down vs.  to jazz you up, to control your appetite vs.  to be addictive. 

The reason this is so important is that pharmaceutical companies can now design and synthetically create what are called nicotine analogs, designer drugs, to stimulate certain nicotine receptors and not others.  So you can see this is where the medicinal or the medical developments are very, very exciting.  If we can have drugs that, like nicotine, make us more alert, more attentive, better memory, calmer, control our appetite, but are not addictive—that’s a remarkable drug. 

Jesse: Is nicotine a chemical that is easily synthesized, or is it something that the best way to get it is still to extract it from a tobacco plant? 

Dr. Grunberg: Well the easiest way is to extract it from a tobacco plant.  But it can be synthesized today, as well. 

Jesse: Yeah, I was just wondering if it was something where the big tobacco companies are actually going to be moving into the pharmaceutical space for this, or if it’s something that big pharma can do on its own. 

Dr. Grunberg: There’s also genetic hybrids and the like of tobacco plants that have various concentrations and different amounts of nicotine.  But it’s the pharmaceutical companies, even more than the tobacco companies, that are working on the pharmaceuticals or the medicines that are based on nicotine.  I mean, that’s an interesting question you raise and this is what gets into a big debate… For the purposes of your program, I promise to stay focused on the science rather than the health policy, but your listeners will readily be able to see where I’m going with this.  Because indeed we understand there are different kinds of nicotine receptors, some which will have beneficial effects, others will enslave through the addictive drug…

Jesse: Hah, that’s not a politically-loaded term. 

Dr. Grunberg: That’s not politically-loaded term.  That’s an accurate word of the derivation of the word "addiction," which is actually from a latin root meaning to be enslaved. 

Jesse: Wow. 

Dr. Grunberg: But if the pharmaceutical companies can design nicotine-like drugs, then why can’t tobacco companies also design products that are feel-good, taste good, are rewarding, pleasant but not addictive.  And you can imagine that’s where the health policy arguments go, because intellectually they should be able to.  But then that gives free choice to the consumer rather than lack of choice once you become addicted. 

Jesse: Very interesting. 

Dr. Grunberg: And this is where the various nicotine medications—back to your point about routes of administration, there’s nicotine gum, but there’s nicotine lozenges, there’s nicotine nasal spray, there’s even nicotine water and aerosol.  But based on what I said before to get the listener to realize which will be the most effective to get the nicotine to the brain, well, of course the nicotine aerosol, the nicotine spray, that’s a much more potent way of getting it to the brain than drinking a nicotine water.  If you’re using it to get you off the tobacco, this is good.  But then we’re having maybe ethical or moralistic judgement, as well as a health judgement.  "Should I be drinking nicotine water for the rest of my life?  Is that bad?  What’s wrong with addiction if you’re addicted to something that’s healthy and not dangerous?"  But it becomes an interesting debate. 

Jesse: Yeah, it makes me think of the general public consensus, I guess, towards marijuana that we’ve seen and how much that’s changed over the course of the past 10-15 years, kind of getting the door open with some of the treatment and therapeutic uses.  Bringing people on board, "Oh, maybe this stuff isn’t so bad."  It makes you wonder, if there’s somebody sitting there, like a marketing company, thinking about the sequential steps of how to un-demonize nicotine in the public consciousness.  What are those dominoes?  Is it medicinal nicotine or something like that? 

Dr. Grunberg: That’s a really good point.  I’m surprised—at least, I’m not yet aware of—that someone hasn’t even gone to some kind of hybrid names.  Instead of medicinal marijuana, why aren’t we calling it Medi-Marijuana, or Medi-Juana or something?  From a marketing point of view, that’s the next step.  And then, you know, is nicotine—it’s kind of scary, but is it going to be Nico-Med?  Is it going to be Cogni-Tine?  Good marketing people will see what they can do.  You raise an interesting point about medical marijuana.  Where are we going with it?  What’s it route of administration?  But see, with routes of administration you get, also, into this tricky business.  What comes to mind now, listening to you and thinking about it, is the electronic cigarettes.  People often ask me, "Oh, isn’t this better?"  Well, theoretically an electronic cigarette should be much less dangerous than a cigarette because you’re getting hundreds of chemicals instead of thousands, right?  So that sounds great.  Also, if the electronic cigarette is used the way it’s marketed, and from what I understand it was initially intended as a smoking cessation aid, then of course that’s much better than continuing to be a tobacco smoker until you’re sick or dying.  But we still don’t have enough careful information or evidence about how dangerous e-cigarettes are.  But even more concerning than that have been the recent practices, almost since the e-cigarette was introduced, instead of nicotine capsules, people are putting in meth capsules, they’re putting in THC capsules, and they’re actually using the device with various mixes of chemicals, incredibly dangerous, in remarkably high concentrations, and then inhaling it and getting it into the body and brain in this very effective way. 

Jesse: It just goes to show that once the technology is out in the public sphere, you never know how people are going to wind up using it. 

Dr. Grunberg: It’s like the development of the syringe, the development of the patch.  There’s this remarkable drug delivery device, when used appropriately, is truly impressive, very valuable, but also easily abused. 

Jesse: So we talked about some of the cognitive benefits of nicotine earlier in this conversation, and most of those that we discussed seemed to be acute, short-term spikes.  And there’s also some long-term downsides that are worth talking about—vasoconstriction and I think some changes in the heart muscle.  But what I’m wondering about is are there any long-term upsides to nicotine?  Anything good from continued prolonged use? 

Dr. Grunberg: That’s a really good question, and as you were asking it, I’m trying to think if I know of any.  I actually cannot think of any evidence of which I’m aware of a long-term upside of using nicotine.  But I need to readily admit that I also cannot think of many long-term downsides of nicotine per se, except that nicotine, a substantial dose over time, will cause vasoconstriction, a constriction of blood vessels, and may also lead to problems with heart and muscles.  We did some studies on that many years ago, a study on rabbits, and it was consistent with some other evidence.  And we were just looking at nicotine, and we saw changes in the heart muscle, what was called cardiomyopathy, over time.  Again, the heart muscle problems, the vascular problems, I cannot think of a long-term benefit.  Now, again, with full disclosure, to be intellectually honest, I don’t know how many years of nicotine exposure it would take to have a dangerous effect, so I certainly would never advocate that a child or young adult use the drug for a long time.  But whether someone in their 50s, 60s, 70s might use it, it might provide a beneficial effect, I’m open to that possibility. 

Jesse: So, sometimes I’ll do these mental trade-offs.  Like in the case of nicotine, you mentioned long-term for your heart, probably not a great idea.  But then I’ll find myself thinking, well, you know, I exercise, I eat really well, I kind of do all the right heart stuff.  Knock on wood, my heart probably has much better odds going forward than your average person.  Maybe I can afford a couple of cardiac demerits from using a nicotine patch; sort of the upside of the cognitive benefits counterbalances the wear and tear I might be doing on the heart.  Does that sound like wishful thinking?  Fanciful? 

Dr. Grunberg: I wouldn’t say it’s wishful thinking.  It’s a really interesting question.  What comes to mind is cocaine users over the years—and various other stimulants, amphetamines.  But as I recall, many years of cocaine use also would have tremendous problems on the heart.  We’ve seen this with various other stimulants and performance-enhancing drugs of different sorts.  So there’s been obviously a lot of debate and discussion particularly with sports figures and better drug screening.  There’s a lot of drugs now that are screened for and they’re avoided as PEDs, or performance-enhancing drugs, both because they give an unfair advantage to the athlete but also because they pose a tremendous risk particularly to the heart.  So, whether or not there’s a cost-benefit analysis, I suspect that, at least with regard to nicotine, as we understand it now and how we administer it, I cannot imagine that it would be ever of value compared to its potential danger, over decades. 

I had a colleague, a friend, many years ago, was someone I had known and the person whom, at the time, was in their mid-80s, and was very disturbed that their memory was lapsing.  No Alzheimer’s, but senile dementia.  Mid to late 80s.  They kept asking me, "Is there anything that can be done?"  I basically finally said—at the time, this was about 20 years ago, there was no obvious answer, and I told the person about the literature and the growing evidence about nicotine.  I said, "I don’t know if nicotine gum or the nicotine patch might help with your memory problems."  Again, a case of one, self-reported, self-aware, placebo or real effect, but the person reported to me when they did start using nicotine gum periodically, it was energizing, alerting, posed no health hazards that they were aware of, and it helped with their memory.  The person went on to live another decade.  Only case I’m aware of directly. 

Jesse: So, you personally, with everything that you know about nicotine, it is not something in your personal medicine cabinet, your personal supplement drawer? 

Dr. Grunberg: To be honest, it is not in my medicine cabinet currently.  I’m 63 and I believe I still have all my marbles and everything else.  Whether or not it will be in my cabinet in 10 years or 20, you’ll have to ask me when you and I do this podcast again in 10-20 years. 

Jesse: One last speculative question, and I might be trying to justify my own leanings here, but I’m a big believer that medical technology is already awesome and we’re going to continue to see more and more of the same, more and more improvements.  I find myself thinking if the cognitive benefits of nicotine are there, are real or assured, and if the long-term physiological downsides are essentially a weakening of the heart, I can’t help but think that 15-20 years from now I’m going to be able to go on Amazon Medical and drop $5,000 and get a brand new heart.  I’m being a bit facetious here, but not really.  But I’m just wondering if the cognitive benefits that I might accrue in the meantime might not be worth the trade if the medical technology to undue the stresses I might have been putting on my heart, my circulatory system, would be there for me by the time I need it in this medically-enhanced quasi-utopia future.  Am I being lunatic fringe here?  Do you buy any of that? 

Dr. Grunberg: I don’t think you’re being lunatic fringe, but Jess, again, based on such a speculative question, it’s an amusing hypothetical.  And on this one, whether it’s my age, being more than 20 years older than you, or maybe it’s my age and therefore I can’t really believe such science fiction, I’m still an advocate that people should be as healthy as possible in as natural ways as possible, through healthy eating, healthy exercise, various psychological techniques, whether it’s listening to music, doing art, meditation… I would lean to being as natural as possible.  Now, I turn to medications whenever needed, whether if for severe illness or perhaps for cognitive enhancement.  But right now, I personally am not an advocate of taking any risk with these vital organs I was fortunate enough and blessed to be born with.  So, I’m not quite ready to join you yet.  I find it an interesting speculation.  You might be right in a decade or two, I don’t know. 

Jesse: No, I appreciate your candor and being the voice of reason. 

Dr. Grunberg: But part of it is, rather than nicotine, I think the more likely medication that, in your lifetime for sure and I think likely in my lifetime, may actually make a big difference, are the great number of pharmaceutical companies that are working on various cognitive enhancers, whether they’re nicotine analogs—that is, nicotine-like drugs—and others.  This is a very exciting area, because as we’re living certainly well into our 80s and many people into their 90s… My mom, for example, is at a remarkably healthy 93, shows very, very minimal cognitive effects.  But a lot of it is 30 years ago she asked me, "What do you think I can do to stay really healthy?"  I said, "Okay mom, we’ve got to really get on a regular aerobic exercise, even though mild.  Watch what you eat, no unhealthy behaviors," and she was religious about it.  30 years later, the woman is alert, could be in on this conversation, and is dancing.  It’s truly remarkable. 

--

Jesse: So, thank you so very, very much to Dr. Neil Grunberg for taking the time for that conversation.  I think maybe among the most interesting things mentioned there was how likely one compound vs.  another is to get a person physiologically addicted, and how nicotine comes out as the reigning champ in that regard by a wide margin, trouncing heroin, which everybody kind of conceives of as being like the addictive drug to end all addictive drugs.  Sometime in the not terribly distant future here, I would like to do sort of a deep-dive episode into addiction itself, kind of the general concept, because I think that’s a really interesting and misunderstood and, in some ways, counterintuitive concept.  Kind of like the word "drugs" itself, we’ve got all these moral overtones that get cross-pollinated with the physiological definitions of what goes on in an addictive state, and it’d be nice to kind of put that idea under the magnifying glass and really look at it.  But that’ll be in a future episode.  But actually, kind of keeping on theme with that, an inadvertent segue, we’ll keep talking about out of control drug-related behavior in the Ruthless Listener-Retention Gimmick. 

— Ruthless Listener-Retention Gimmick --

Jesse: What’s the difference between a binge-drinking rat and an alcohol-dependent rat?  Sounds like it’s the lead-in to a joke, but it’s actually a legitimate question, and researchers at the Scripps Research Institute, which is a US medical research non-profit group, have actually been doing a study recently that has, in addition to a control group of rats that are only drinking sugar water, other rats which are binge-drinking alcohol or are made alcohol-dependent—so, not necessarily giant amounts of alcohol all at once but a continuous steady supply, enough to induce the rat equivalent of human alcoholism.  Now, first, as with all animal studies, it’s worth putting the caveat that just because we see certain things in animals, doesn’t mean that those findings will necessarily translate up to humans. 

But this does seem like a really promising finding, what they’ve come up with, which is essentially an exogenous drug treatment, which in these alcohol-dependent and binge-drinking rats, has completely stopped in its tracks the learned behavior of whatever alcohol abuse the rats are doing.  So, previous studies had already established that there are a number of neurons in the central amygdala that scientists believe are related to the learned associations between alcohol and reward in alcoholic rats.  They’ve observed that the more that a rat drinks, the more activation they see in a neuronal ensemble that seems to reward and then reinforce future alcohol drinking, which essentially becomes the slippery slope towards addiction.  So after training these rats in their various drinking behaviors, the alcoholics, the binge-drinkers, and the teetotaling sugar water rats, the researchers injected them with a drug called Dawn 02, which has the ability to change these activated neuronal pathways that get turned on as a learning behavior is formed, and revert them back to an inactive state.  In doing this, in the two groups of alcohol-abusing rats, it seemed to revert them to what appears to be a normal relationship to alcohol.  They didn’t stop drinking, but they didn’t continue drinking habitually. 

The study's first author, Giordano de Guglielmo, said, "We’ve never seen an effect that strong that has lasted for several weeks.  I wasn’t sure if I believed it."  So, not even trusting their own findings, the scientists ran the experiment a second and then a third time, getting the same result each time, that the dependent rat would stop their compulsive drinking when these neurons were switched back to an inactive state.  Said another colleague, "It’s like they forgot they were dependent."  The rats whose learning was switched off in this way also showed no physical symptoms related to alcohol withdrawal.  Importantly, the rats all still showed motivation to drink sugar water, indicating that the scientists had affected only the alcohol-related neurons, not the brain’s overall reward system.  The next pieces of research the scientists hope to accomplish is to carefully track the formation of these neuronal alcohol reward circuits and then, of course, seeing if they can find a way of translating their findings to humans, and if these pretty striking results will be able to make a jump across species. 


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Written by Hannah Sabih
Hannah believes there's nothing 8 hours of sleep and some kale can't cure (yes, she's from California). She's an avid runner, reader, and traveler, who brings you the latest and greatest in neuroscience via our social media channels.