Nicotine with Dr. Neil Grunberg

Boomer Anderson: [00:00:00]Welcome to decoding superhuman. This show is a deep dive into obsessions withhealth performance, and how to elevate the human experience. I explore thelatest tools, science and technology with experts in various fields of humanoptimization. This is your host Boomer Anderson. Enjoy the journey

today, we'll be talking about compounds of controversy andspecifically nicotine. My guest today is one of the world's leading experts onthe molecule and he has called it perhaps the most interesting molecule in theworld. Dr. Neil Grunberg is a professor of military and emergency medicine,medical and clinical psychology, and neuroscience in the uniform servicesuniversity.

He has been educating physicians, psychologists and nursesfor the armed forces and public health service and scientists for research andacademic positions. Since 1979, he has published over 200 papers, addressingbehavior medicine, drug use stress, traumatic brain injury and leadership. Dr.Greenberg has been recognized for his professional contributions by awards fromthe American psychological association centers for disease control andprevention, food and drug administration, national cancer Institute society forbehavioral medicine, us surgeon general and uniform services university.

And in 2015, dr. Greenberg was elected to be a presidentialleadership scholar. So when you get to interview somebody with a resume likethis, you get quite nervous, but you also have a lot of fun because with dr.Greenberg, I learned so much, we talked about the neurobiology of addiction. Weget into nicotine and what delivery mechanisms make.

You may make you more prone to addiction. We talk aboutpotentially the performance benefits of nicotine and. Finally, we get into aconversation around psychedelics and what dr. Greenberg thinks of the currentmovement in psychedelics. The show notes for this one are decodingsuperhuman.com/nicotine.

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This is an absolute pleasure. Welcome to the show.

Dr. Neil Grunberg: [00:04:34]Thank you so much, Boomer. Um, I'm really pleased at the opportunity to talkwith you and share some ideas and insights with your audience.

Boomer Anderson: [00:04:41]Wow. When I started delving into the world of nicotine. It's very hard to getinto that world scientifically, without stumbling across your name.

And so I I'm honored to have you here today, but it justbegs the question. How did you get so interested in nicotine and ended up doingquite a lot of research?

Dr. Neil Grunberg: [00:05:02]Well, that's very kind of you and your comments are generous, but, well, it'skind of a funny story. Actually, when I was growing up, I was a seriousmusician.

A drummer and growing up in the 1960s and I was a precociousdrummer. And I mentioned that not to brag, but because I was both, um, I hadthe opportunity and pleasure of playing in all sorts of bands with people whowere older. I mentioned that because I watched friend after friends start usingvarious drugs, say that the drug was expanding their mind, but then couldn't stop.

And one, after another destroyed themselves, So it puzzledme and I was too young to try, but the drugs and I was interested when I wentto college, I was at Stanford university. I was studying both biology andpsychology. I was studying genetics and I also was studying, uh, working in theStanford hypnotic research laboratory.

Again, I was interested in how does. Something, whether it'soneself or, or a drug manipulate or altered States of consciousness orunderstanding of music or art. And the, like from there, I went on to Columbiauniversity and, uh, to earn PhDs and a physiological psychology and socialpsychology and pharmacology.

But to your story. I actually, when I went to Columbia, Iexpressed to my mentor, uh, a famous psychologist named Stanley Schachter. Iwanted to study real drugs, drugs of addiction, like heroin and, and mindaltering drugs such as LSD. Well, they weren't studying that. And, uh,professor Schachter was studying something.

I had no interest in and that was cigarette smoke. It was adifficult decision because I had to decide which mentor to work with, whetherto work on the drugs that interested me or work with this great psychologist.And then I thought, unfortunately, I had the wherewithal or the, uh, the, thehumility to realize what did I know at 22 years old?

So I started working with professor Schachter. Basically,you know, metaphorically rolling my eyes. Why are we studying cigarettesmoking? Which my father, and essentially everyone I knew adult did that madethem well stunning with professor Schachter, we started stunning and readingabout some ideas with only a couple of laboratories in the world.

One in London, actually, a professor MIH, Russell, anotherUCLA and Marie Jarvik. We're arguing that there was something in tobacco,especially this drug, nicotine that was especially important. But what I didn'texpect was then as I got more and more into the biology and the psychology ofcigarette smoking and studying nicotine, I then started deciding we needed tofocus on it specifically.

And in graduate school, I developed an animal model, a ratmodel, so I could isolate and study the drug nicotine. In parallel studies towhat I did in human. It's not separating them. And that then ended up leadingto all sorts of discoveries. Um, that, that my laboratory, my grad students, myresearch assistants that I made throughout the 1980s, that was the beginning ofit.

And, and then we went into several of our discoveries aboutnicotine and food consumption, nicotine and bodyweight, nicotine, and hunger,and nicotine and attention, nicotine and stress. Nicotine alcohol interactionsand on and on and off.

Boomer Anderson: [00:08:40]Wow. There there's, this conversation could go on for hours, but in theinterest of protecting your time, uh, I want to just start to go into kind ofthe addictive aspects of nicotine, and maybe this is cigarette smoke ingeneral, but you can tell me if I'm wrong here is nicotine addictive foreverybody.

And is there something special about. Inhaling for instance,uh, that makes it more addictive. I know you've done some work around theneurobiology of this, so I'm very, very curious.

Dr. Neil Grunberg: [00:09:14]Yeah, that's a terrific question. As one would argue that you just asked me amulti barreled question.

Boomer Anderson: [00:09:20]I probably did.

Dr. Neil Grunberg: [00:09:24]So to start with, when one smokes in tobacco products, the drug nicotine is theprimary drug of addiction. But just to get that in perspective, when one takesan inhalation on a cigarette, one inhales, not one chemical or two or ahundred, one inhales, approximately 7,000 chemicals. And that's important tostart with because we need to separate the health hazards, the pathophysiologichealth hazards from the addiction aspects.

There are hundreds of chemicals. In cigarettes, but whenthey're burned by pyrolysis, it multiplies roughly by a factor of 10. So that'swhy there's 7,000 chemicals. The drug nicotine you asked about is highlyaddictive, arguably the most addictive drug known in the history of the world.And when I say that we have to consider what's called addiction liability,which is what you explicitly asked me about.

And that is, is everyone addicted to nicotine or not?Probably not, but the vast majority of people who are exposed to it, probablyon the order of 80%, do develop an addiction. Now just to make them comment,compare that to morphine and heroin and opiates, highly addictive drug,approximately 50% become addicted.

It's only 50.

Boomer Anderson: [00:10:50]I thought it was much higher.

Dr. Neil Grunberg: [00:10:51]It's approximately . Now it depends on exactly. Fentanyl, for example is muchdifferent from morphine in the life. But when I look at opiates broadly,alcohol addiction liability serious for many people is probably on the order of10 to 20%. So if we take 80% for nicotine, 50% for opiates, 15 or 20% foralcohol.

So just start with on your first question. No, every one isnot, does not become addicted, but the vast majority do now with regard to theaddiction, if you'd like we could get into how and why it works well, letlet's,

Boomer Anderson: [00:11:34]if you're okay with it, I would love to go into just sort of why it works andlike are certain people predisposed to it.

Dr. Neil Grunberg: [00:11:41]Okay again. Great questions. You double back. You also asked about inhalation.So with regard to a drug, one has to consider again, whether we're talkingabout nicotine cocaine, opiates, and on and on various drugs of addiction,those drugs that are addictive, basically as, as I've argued, cross circuitneurochemical pathways in the brain that are the basis of appetitive.

Or appetite based, uh, addictive behaviors. So the bodycomes to need the drug as if it's a foodstuff in the way we need fruits andhave hungers in the life. Now with regard to something else you mentioned,that's important besides the drug itself is going to be the form of the drugand how, or the drugs taken into the body, which you asked about smoking orroute of administration.

So let's take that as well. That's also very important. Manypeople think the closer you put a drug to the brain, the more likely it'sgetting into the brain. Well, that's not true because the brain is protected bya metaphorical cellophane wrap. The blood-brain barrier, which protects ourbrain from bacteria and viruses, except in particular subset of cases and keepsa lot of dirt out of our brain.

Many drugs that we take into our bodies systemically to dealwith, um, uh, illnesses or antibiotics, and like do not do not cross the bloodbrain barrier. So do not get into the brain. However, for something to beaddictive, it must get into the brain and affect the brand. And the case ofroute of administration, one could take a drug by eating it, snorting it,smoking it.

Plenty of it in the body and injecting it in various ways,intravenously intramuscularly, when you can take it, you know, in other waysthrough a suppository in the life, but what's really important is the best orthe most effective way to get a drug to the brain is to inhale it. If that drughas a physical chemistry, That allows it to cross the blood-brain barrier.

So in the case of nicotine, when nicotine's inhaled, what'simportant, is it cross? It goes from the lungs into a particular part of thecardiovascular system. So the cardiovascular system has basically two circuits.One's called the systemic and the other pulmonary. So all the heart. Pumps thebloods, of course, to our limbs, to throughout our body.

There is another circuit that, that actually moves bloodfrom our lungs. And the reason is oxygen needs to get to the brain directly.The reason it's important is nicotine and it's true of cocaine and opiates. Ifthey're in certain forms, if they're smoked, if they're smoked, they pass. Intothe pulmonary circuit, the cardiovascular system, and they get to the brain isless than 10 seconds without being broken down or metabolized.

If the drug, however, is mainlined or IB administration, itgoes to the heart. Then it goes through the systemic parts of the bodymetabolize in the liver research-related before it gets to the brain. So it'stime course. And concentration and the form it's in is different. So any dry,and this is why crack cocaine is so much more addictive than snorting cocaine.

This is why in fact heroin can be smoked. It's calledchasing the dragon lights up and put on aluminum foil and it lights up likemagnesium, you know, just flares that if a drug comes that way, and that's whynicotine, when taken in this format into the lungs, medially gets into thebrain in the brain.

Then there's certain parts of the brain we could get into,particularly the ventral tegmental area and different addictive parts of thebrain. Nicotine like other drugs of addiction, similar neurobiological mechanismsset off a cascade of release of a variety of, of chemicals. Colludingcatecholomines most famous being Delta beam epinephrin nor epinephrin centrallyperipherally.

The indole means the most famous or well known beingserotonin. And the endogenous opioid peptides, including leucine and methaneand Kathlyn and dynorphins and, and a variety of effects. So we'll have thebiological action, but addiction, as we may get into also involves theinterrelationship between psychological processes and biological learningmechanisms, which include.

Paired association, ism, classical conditioning and operantconditioning. All these, if you want, we can get into, or we can get into themolecular biology of how it acts in the brain.

Boomer Anderson: [00:16:49]Give me two very, very good choices. Uh, if you don't mind, let's go down themolecular biology route because I think some of the paired association stuff isvery, very interesting.

We may get to that later, but I want to, I want to touch onthe molecular biology a little bit.

Dr. Neil Grunberg: [00:17:02]Sure. Sure. So nicotine is really an interesting drug. I've actually referredto it, to look up my name as the most interesting drug in the world. And I saythat because it has a high addiction liability, as I said, about 80%.

But in addition, unlike any other drug that we know of inits natural form, nicotine brings you up when you're down and down, when you'reup. That's really interesting. It responds bringing one to an optimalphysiological arousal. Now, when it does that, this nicotine itself is a very,very small molecule.

So it has  ring. Ifany of your, your, your audience knows the physical chemistry of this, thesmall particle, then when it gets to the brain nicotine acts. At a series ofreceptors in the brain called nicotinic acetylcholine synergic receptors moreshortly briefly, people just say nicotine or nicotinic receptors.

These receptors are very, very interesting. The molecularbiology, if we really look using electron microscopy to blow them up arepentameric structures. That means they have five units. It looks very much theway I usually describe it. If you picture a navel orange that you've peeledsegments of an orange, the nicotinic receptor looks like five segments, roughlyof navel oranges with a, you know, with the let's call, the navel or the holein the middle, the molecule, the nicotine will attach to the molecule.

Causing it to open a transport of certain ions or chargedparticles, which will then have a cascading effect in neuro-transmitters. Nowwhat's also important because you've asked about the microbiology and Iunderstand that you're dealing with a very sophisticated audience. There arenow identified quite a few different kinds of nicotinic receptors, reason.

This is so important. Is from an intellectual and scholarlylevel. It helps us understand why nicotine has so many effects. I alreadybriefly listed a few before, but it jazzes you up. It can calm you down. It canaffect your appetite. It can modulate your stress. It can affect your cognitiveprocess, making you more alert.

It can cause craving. It can. How can it do all thesethings? Well, as we now know, there are a variety of different. Nicotinicreceptors. So they have different subunits of these five pieces. And we nowhave we've referred to them by alpha and beta and other sub units. So certainnicotinic receptors are primarily responsible for the need, the dependence thatdevelops needing the drug for normal function.

Now addiction or needing a drug needs to be distinguishedfrom psychedelic effects. That's a confusion. Perhaps the most famouspsychedelic drug is LSD  or LSD or inJohn Lennon's words, Lucy, but Ella it's D is not addictive. It has a profoundpsychedelic alters perception. So. The addiction part is different fromperceptual changes.

Other nicotine receptors are responsible for its contentalerting effect effect that doesn't answer. Yeah. For other parts of itsaction. The reason I mentioned that this is beyond intellectual, you know,argument or discussion is now. With this understanding that's developed overroughly the last 30 years, pharmaceutical companies have cleverly developingnicotine analogs, nicotine like drugs, but which can affect certain subreceptors and not others.

So let's say if you have a nicotine analog and nicotine likedrug that can turn on the cognitive enhancing, that increases selectiveattention. Sustained attention and decreases distraction, improving cognition.This could be a phenomenal drug. If it does not affect the addiction. Receptorwould be a great treatment to enhance cognition in general, as well as peoplewith cognitive problems or attentional deficit disorder or with dementia.

So now the developments are in various novel nicotine. Typedrugs that may be used to treat cigarette smoking addiction, the health hazardsof those thousands of chemicals to prevent nicotine from being addicted and byblocking it, and the development of novel, innovative pharmaceuticals to havesome of the positive enhancing effects, stress reduction, weight management,appetite management interaction on cognitive processing.

So that starts to get us more into molecular. If you want,we could get into the. After the receptor, we then get into the neuroanatomyand the neurochemistry that cascades down.

Boomer Anderson: [00:22:20]I, I want to just, this is fascinating, cause I, I could definitely go downthat wormhole, but I wanna, I want to take us a little bit more towards, uh,just different, uh, ways that people take intake, nicotine.

So the gums, uh, the, I have a spray over here, right? Um,When you're using those versus let's say smoking, I'm assuming that yourabsorption rates are different. And I'm just kind of curious if we can gothrough the absorption rates. And also, is there less of a chance of anaddiction as a result of using those alternatives?

Dr. Neil Grunberg: [00:23:03]Terrific question. So the addiction will be, of course, as I've alreadymentioned, but now I'll flesh out more based on what you asked the route ofadministration, the form of nicotine, which, which I hadn't talked about yet,as well as the dosage of nicotine, but with regard to the ways that are mostlikely to be addictive, we've mentioned smoking, but it's not just McGee.

It's what do you smoke? So cigarettes over the last. Centuryor so have been manipulated, created, adjusted to optimize, optimize theiraddiction liability. That's by changing what other chemicals are in thecigarette itself, the cigarette or tobacco column, as well as changing thingssuch as what's called the pH or the relative acidity, because this will affectwhether nicotine's in what's called a bound or a free form and its likelihoodof getting to receptors.

The reason I bring that up is cigarettes are also created sothat their tastes, they have sweeteners and sugars and others so that they canbe deeply inhaled and a deep inhalation as based on what I explained beforeincreases the likelihood, the nicotine, particularly if it's in a certainchemical format, gets to the brain in contrast, consider we also, people alsosmoke cigars.

Cigars are made very differently. The majority of people whouse cigars puff on cigars rather than inhale cigars. Now, people who had beenheavy cigarette smokers, and then switched to cigars, you will see those whoinhale now. How do you know easy by watching? If I'm watching someone smoke acigarette or smoke a marijuana joint or smoke a cigar, if they're deeplyinhaling, when they take the first inhalation, the chest goes up.

And then after a couple of several seconds, a thin stream, athin stream of smoke, but it doesn't look smoky. It looks very thin and evenslightly bluish will come out of their nose. Usually that's a deep inhalationif someone is solely puffing. So again, pictures of cigar, pardon me, is onetakes the inhalation and then.

Soon after a big puff of smoke, it looks like a cloud comesout. Then the installation was not deep. So the various cigarettes, cigarettes,cigars, all can be smoked and whether they're inhaled or not, and what's inthem is the first answer to your question. Now we move to the other products.Many of them, some of the products you mentioned were created.

To ideally be used as nicotine replacement products to helpwith smoking cessation or to satisfy the smoker again in place of smokingnicotine gum was the first that was developed or more accurately is callednicotine polychronic scum. It was developed in Sweden. In the 1960s,approximately the pharmaceutical company that developed it was based on achemist named obey Ferdo pheno.

A Swedish chemist really believed in some early work in somearguments that nicotine per se was important. So we started developing thedrug. Other pharmaceutical companies found we're not interested in latervarious documents that came out in tobacco litigation revealed the tobaccoindustry. Was well aware of the properties and power of nicotine dating back atleast to the 1950s, if not 1940s different story, but with a development andnicotine pilot probably cried like scum.

It was developed. It was marketed originally in Sweden andtested in Europe as a smoking cessation device. This is where we first startgetting some confusion. The gum, when it came out, it was very hard. Didn'ttaste good, but people who were motivated to quit smoking would use it invarious clinical trials.

When that same gum in the 1980s came to the United Statesfor FDA approval. Ironically, the FDA did not approve, did not approve thedosage of the gum. That was effective in the European clinical trials. Thedecision ironically was based on, wait, if this drug nicotine is so addictive,we better use a much lower dosage.

So as a result, there was a lot of excitement in the lateeighties in the United States. Whew, this drug nicotine might work, but itended up the dosage of the gum use in the U S was half the dosage that inEurope, And the gum purposely was poor tasted, bitter, and was hard to chew. Wemove on because things happened with the gum over the years, but you askedabout other products, nicotine, nasal spray, nicotine inhaler, nicotinelozenge, nicotine lollipops, and on and on and on a whole variety, nicotinewater.

Actually, all of these things were developed, especiallyafter the 1988 report. And I don't know if your viewers will see this. But thiswatershed report is very important in the history of nicotine because of, ofthe EDA report, which explained it. I'm very proud of it. Cause I was a cosenior scientific editor put together

Boomer Anderson: [00:28:41]and we'll link to it in the show notes for those listening.

So

Dr. Neil Grunberg: [00:28:45]well, we can discuss it, but before the late 1980s, it was not understood,widely accepted or even known. That nicotine was addictive again, although thetobacco industry had decades of internal research and documents that didn't getrevealed until many, many decades later, based on lawsuits pulling together allthe world literature started to understand these products.

As we understood the role of nicotine in getting people toself administer a product cigarettes, that's deadly. I mean, thinking about howdeadly it is. Um, example the U S alone. We all think of the horrors of nine11. Thousands of Americans killed in a terrorist attack each year since comingup, actually in a couple of days, September 11th.

When we think of it, we each year were concerned that theremight be another terrorist attack. Well, cigarette smoking does not kill. Thesame number of the U S is terrorist attack. In fact, let's think it kills somany more. It's staggering. So in the U S alone cigarette smoking is as if nine11 occurs not once a year, not once a month, not once a week.

What's the equivalent to the nine 11 tragedy happening threetimes a week. Wow. All year round for the last 40 years, 400, almost half amillion Americans die of cigarette smoking, but it's not nicotine that killsthem, but it's nicotine and why they're smoking and what keeps them smoking. Soto separate all these products you mentioned are being developed.

As I mentioned, ideally, to help people not smoke or get offcigarettes or substitutes. But there's also now a movement and someunderstanding should some of these products be developed as treatments forother things that contain has shown some positive value to treat depression,perhaps to treat it's afraid to treat thought disorders and life

Boomer Anderson: [00:31:07]at a high level. If I'm just looking at those various products and. Well,eventually I want to get into the benefits of nicotine. So, uh, but beforethat, it just, so I looked at those various products in terms of absorption,um, you know, smoking down to maybe even two lozenge slash Buechel absorptionsslash um, you mentioned inhaler, uh, What is sort of the rough absorptiondifferences of each, if you're able to.

Dr. Neil Grunberg: [00:31:36]Very good question. So the absorption, if one is, if nicotine is inhaled andit's in a chemical format that does plastic pass the blood brain barrier, as itis in cigarettes, which has to be a certain what's called salt form. Sonicotine itself. Is a viscous material, like an oily material. If left as thatoil, it won't move across the blood-brain barrier, but it's converted to,what's called a salt that turns it into a solid, but a solid that is soluble.

And water aqueous soluble as well as in lipids or fats. Sovarious salt forms of nicotine. As again, it appears in tobacco and otherproducts. If it's in a salt form than any inhalation smoking, particularlypowerful for poor it's absorption of the brain because of the passage and thepyrolysis, the heating, the heating helps second would be inhalation.

Not heated. So for example, a nicotine inhaler, the way I'man asthmatic would take a medication or any other kind of inhaler we have forbronchial expansion or invasive or dilation, that would be number two. Now,after that is a big drop off because all of the other forms will be consumed,which means they'd go through the GI, the gastrointestinal system, get into thesummit stomach where they'd be broken down.

Get into the liver broken down even more. And now it willdepend again on the chemical constituent of the chemical format, as well as thepH of the medium that's carrying it, whether or not when it gets down to thekidneys, it's reabsorbed and recirculate it, or whether it's leaves the bodyimmediately.

So here, for example, um, to best explain that. When we,when humans are under stress, um, any kind of stress, so plausible or negativestress, one of the effects in our body is there's an acidification of certainfluids in the body. When nicotine is in an more acidic environment in thekidneys, more of it is extruded from the body.

So one of the important reasons, people who are addicted.Smoke more under stress is not because nicotine is reducing stress is they'relosing more from the body. It's like you open the drain on your bathtub andwhen you want to keep the water lineups. So they smoke more to replenish. Theopposite is if one takes food stuffs that are Apple at NYCERS.

Like, um, tomato juice is an appetizer. RSUs is an acidifiercertain foodstuffs change the drug flow through the body. Again, it's true.Nicotine. It's true of opiates. And these are other important when we takemedications, you'll notice your pharmacist or physician. It's always importantto say, should this food, this drug be taken with food or not, and are therecertain foods to avoid or not?

And that's because certain drugs are sensitive to thechemical constituents of the foodstuffs. So all these, again, inhalation, heat,inhalation without hate, and then everything else. Snorting would probably benext. If we use like a nasal spray, then the next after that would beconsumption. Anything that we would consider swallowing or eating.

Boomer Anderson: [00:35:10]And so intermediaries, there are the spray and I guess, uh, laws in genderBuechel absorption.

Dr. Neil Grunberg: [00:35:18]If the logic, if it's kept in the vehicle, like it's kept the way, um, uh, um,like a skull bandit or something as if it's kept in the mouth a long time.Versus it's like a lollipop or lodge it's, you know, some people chew theirlodgings and swallow it right away, but you're absent.

You're absolutely right. You got the order from inhalationto, to nasal spray, to Buechel absorption, to, to GI absorption.

Boomer Anderson: [00:35:42]Uh, I want to go, go a little bit into the positive effects of nicotine. Causeyou, you did dabble when you're going through, uh, the addiction and in termsof giving us little teasers and I want to double-click on those teasers becausenicotine, you know, I do use it sort of, I don't use it every day, but I do useit in certain instances.

And I have noticed this knock on impact to things likeverbal fluency, for instance, um, And I'm just curious if we can run throughsome of these positive effects of nicotine, because as you said, it's this mostfascinating, most amazing drug. And I want to understand more about thepositives. A lot of health technologies run their course.

You use them for a distinct purpose and then. You can kindof put them aside for awhile case in point is my aura ring. I used it toidentify problem areas with my sleep. And now that I've a really remediedthose, I took it off and put it to the side, but there's one gadget that Icontinue to use every other day.

And that's the Vielight. The Vielight neuro alpha helps mesleep better. It helps me relax. It helps me meditate better. I enjoyed it somuch that I recommended to pretty much everybody that I know. And what I do isI stick this red light up my nose and on my brain and I experienced what iscalled transcranial and intra-nasal photo biomodulation.

The end result is relaxation, which is a high value for anentrepreneur like me. If you want yours head on over to vielight.com. And usethe code boomer and you're going to get yourself a nice little discount of 10%.That's V I E L I G H t.com/boomer. Let's get back to the show.

Dr. Neil Grunberg: [00:37:38]No, that's yeah. Or we'll call it the beneficial effects of smoking.

Now I understand. It's a very good question to understand itcurrently, just a little bit of history. So when we go back to tobacco was, wasindigenous indigenous plant in North America and parts of South America. Sobased on the history of, of tobacco, we understand that Christopher Columbushimself wrote in his journal about native Americans or the Indians drinking thesmoke of the tobacco.

Okay. Now, to understand that there, cause this will berelevant to your point, why. Why were they using it? Cause it certainly had notbeen processed in the way. Is that tobacco industry developed processing over,you know, over decades and decades? Well, some of it was used for religious orritualistic reasons.

So if, when thinks about various peace pipes, peace pipes interms of their history, and if look at the anthropo, the cultural anthropology.Sometimes when a very, very, very high concentrations of tobacco and nicotine,perhaps with some other mind altering payout day or something else. But if youthink about this, we moved back the centuries.

If I. So let's say this works well. I have the old shopping,which I am compared to you, the young buck coming up, you want to challenge me,you know, in my, my role as a, you know, as a shaman or more locally, whichtalk to, or achieve before we fight let's smoke from the pipe. So what would Ido? I would pack that pipe as intensely as I could.

Because I've developed a habituation to all the nicotine. Sotherefore it would just jazz me up. I have used smoke the same amount at wahigh concentrated, some nicotine duty. You too. What naive body? It would throwyou into spasms and convulsions lying on the ground. Just richer. When I dothis with you look like you're 30 years or so younger than me, you're on theground.

You're bigger, you're stronger. And I've done this now, yourwarriors or your supporters say, Oh my God, Neil, what have you done to boomer?I say, if you're nice to me, I'll do a dance and I'll get them back up andknowing time course. So I'm bringing this up because. The nicotine also whencombined with others, what would it do?

Well, it gave energy. It gave power, especially if onechoose on tobacco, just like if one, choose on a Coca leaf and get a low, lowconcentration of what later cocaine let's move now forward as this isprocessed, we start to see. So what are some of the benefits? Well, itenergizes, it stimulates now. Why is that important?

In terms of any kind of work or labor, whether it's physicallabor or you're a business person, or I believe in a previous life, boom, oryou did some investment work famously wall street, or if you were on wallstreet in New York or other places, you worked insanely long hours and you hadto be up. And as you probably know, a lot of very high powered lawyers,high-powered business people, particularly in the 1980s and nineties.

Got very interested in one particular drug that gave him asense of power and up, and that was cocaine. Okay. And abuse was just rampantin LA and New York and other cities around the world for a variety of reasons.Nicotine isn't as powerful as cocaine and causing that stimulant, but it doescause a sense of alertness and energy.

It also decreases appetite. So we think about this. If Iwant to work really long, hard hours without interruption, this drug nicotinein various dosage in various forums will make me feel more stimulated. Bring meup, focus my attention, increase my ability to maintain attention thatsustained attention and vigilance as well as select what I want.

Selective attention. Decrease decrease distractors that Idon't want to interfere with my thoughts, control my appetite, make me feel,bring up my mood. And then if I'm feeling bad or in the dumps decrease my antidepression, decrease any feelings of depression. So in addition, now, thosefeelings of energy and empowerment and, and reduce depression and increase thesense of power and energy and focus, cognitive ability and decrease, needing totake a break, to have a meal.

This is incredible. Now take all those things I said, whichare the direct effects. And those are called the, the, the, the, the positive reinforcingeffects. Nicotine also has something this term I need to explain callednegative reinforcement negative. It does. I'm sorry about the double negativesdoes not mean bad negative in psychology terms or behavior.

It means the removal of something positive means to givesomething so positive reinforcement means taking something increases areinforcement negative reinforcement means removing something. Increases thebehavior before he enforced the opposite, his punishment, and there wassomething called positive punishment, hitting, hurting, and negativepunishment, taking away something.

I prefer a children, a child getting a time, reduces abehavior by removing something they like back to nicotine. So the person whonow has been exposed regularly to nicotine has started to develop. A need forit. So a dependence early dependence, maybe it's not quite a deep craving,which will become addiction, biological, psychological addiction, but as thebody quickly develops dependence.

So you say you periodic use of nicotine products, perhapsyou have some low level of dependence. If that's true, then in addition to thepositive effects I mentioned. Talking to him and has been appetite, control,energy, et cetera, mood, uh, raising one mood. When one is abstaining fromnicotine, if you develop dependence, all the opposite happens.

Feel bummed. You feel tired, you're hungry and you'recraving you. Can't focus attention. So you'll notice now if you've done, onceyou've developed dependence and presentation of the drug. Is both positivelyreinforcing, but also negatively reinforced, you know, immediately removes allthe unpleasantness.

It immediately removes everything that got you down. Now, ifyou will exaggerating or potentiating the reinforcement, this is one of thereasons we've talked about it just briefly, so far today. Why the developmentof nicotine analogs in the pharmaceutical industry. It has multiple values. Oneof course, to help those tens of millions of people in the U S and hundreds ofmillions worldwide, who are still using the deadly drugs, deadly exposure tocigarettes in there, and their various noxious States.

But in addition, if one can develop a nicotine analog thathas all these other positive effects and either is zero dependents. Or really minimaldependence. Now you have an appetite control, a cognitive enhancer, a moodenhancer, you know, a focus attention, something that might even help withdealing with stress.

Alleviator we have, uh, Substantial important areas wherethis drug can really, uh, uh, add to the, uh, to the, the, the availability ofpharmaceuticals that can do a lot of positive things.

Boomer Anderson: [00:45:54]You think it's an analog per se, that can do that? Or could you get that with,uh, Let's say low dose, nicotine over a spread out period.

So it's not,

Dr. Neil Grunberg: [00:46:07]no, I have to tell you that's a surprise. You've all asked all your questions,but Murban good. That's a superb question. And I don't know the answer to that.There's been speculation. I'm trying to think. I don't know of, I can, I canspeculate. I don't know of any definitive evidence that would speak to it, butI can give you one piece of evidence.

Why? I think the extremely low dose would do some but notothers. And that is okay. We all, we know that what are called Bola or bolusinfusions of nicotine are important to get various peaks. So if we were tomeasure blood levels or plasma levels of nicotine, it's the rapid line, the upsand downs that appear to be necessary for some of the most marked positiveeffects of nicotine.

However, There is certainly a speculation that perhapsthere's a way to get a very, very low dose. I've actually argued myself that Ido believe in extremely low dose of nicotine can give some of the stimulatingproperties and have effects. But I have to admit readily that's fear when wespeculative. I know of no evidence,

Boomer Anderson: [00:47:22]but I mean in theoretical is fascinating to me because I I'm a unique humanGuinea pig and myself,

Dr. Neil Grunberg: [00:47:30]but extreme to an extent, I hope

Boomer Anderson: [00:47:33]only, uh, I, I try not to hurt myself too often, but when we're looking atextremely low doses, For instance, like the spray is one milligram.

Is that considered an extremely low dose? Are we evenlooking at sub one milligram in terms of

Dr. Neil Grunberg: [00:47:49]that's low? Um, that's a low dose, especially, it depends on what you'retalking about. A nasal spray or an

Boomer Anderson: [00:47:58]entire spray

Dr. Neil Grunberg: [00:48:02]that's low. Um, depending on the form of nicotine, that's still could bedependence producing. Okay. Okay,

Boomer Anderson: [00:48:09]so good. So if it's a non salt per se, uh, that would be a better choice thangoing with assault as far as looking at the addiction properties. Good. Justgoing back to what you said,

Dr. Neil Grunberg: [00:48:21]but then that was very, you know, you understand it well, but then realize someof the other prop, the effects that you use that are desirable, that I agreewith benefits.

So also would not happen unless it gets to the brain. It'snot going to get there. So, so. Estimates are that five to eight milligrams ofnicotine per day is the addictive range. So actually, as an example, um,decades ago, cigarettes for a long time, all were delivering between one and aone and a half milligrams in a given cigarette per day.

So even one cigarette deeply inhaled, uh, uh, I'm sorry,five cigarettes or six cigarettes easily could be addictive. Then there was aperiod late 1970s or eighties, lower nicotine cigarettes came out. They wererunning at about 0.7 milligrams. So about half I and other study those drugs inthe seventies and eighties.

And I found that many people who were smokers thinking thatwould be safer, could get down to about seven or eight cigarettes a day. Itstill gave them five milligrams a day. There were then other nicotine levelscigarettes dropping to 0.2 and 0.1. Some people argue that they weren't enoughto satisfy the smoker arguments go that's because they were on the market atthe same time as medium and high nicotine cigarettes were on the market.

No one ever tested, only low NICs seen cigarettes. Soarguably I've actually argued. That nicotine delivery in cigarettes should beless than 0.05. And the reason I've come up with that as all of the hundreds tothousands, thousands of smokers I've studied over the years, the heaviest,regular smoker I ever had in a study claimed a smoke, a hundred cigarettes.

Wow. Wow. I didn't believe him when he told me at first,because heavy smokers smoke two or three packs. Until I had him in lap and thisgentleman literally did what was literal chain smoking. He literally lit eachcigarette from the one in his mouth. So he never was without a cigarette fromthe moment he woke up mom and he went to bed at sometimes.

He'd have two cigarettes, well

Boomer Anderson: [00:50:43]functioning in society. Yeah.

Dr. Neil Grunberg: [00:50:46]I don't know how long he lived, but I studied him. He was in his forties. And Idon't mean to make that as a joke or in any way. I mean, I just don't know. Ididn't follow him. I mentioned that because, so when, when assumes that that'sthe absolute upper limit and tough.

If cigarettes were less than 0.05 milligrams, it would takea hundred cigarettes to get into the addictive range. However, it would take apack or so of cigarettes to get enough. To have some of these stimulatingeffects and therefore it could provide some of the beneficial effects withoutthe addiction making cigarette, smoking what the tobacco industry claimstotally a choice.

Although currently it's not totally a choice because it's soaddictive that I would carry over to what, what you've raised is that the sametypes of studies. Some are being done more need to be done on these otherdelivery systems to determine what range, what dosage and what amount to, tosuggest to a consumer.

So let's say you use a inhaler. Should you use one a day?Could you inhale 20 times a day? That type of, I don't know that details of thatsort have been available. Um, Again, the movement because you know, there's,there's such a confusion, you know, nicotine itself to me is absolutelyfascinating and drugs.

Yeah. It's addiction liability. However, although powerful,does that make it evil or morally bad? I do not believe that addiction ismorally bad. It's a psychobiological process where the human being becomes. Ifyou will enslaved to the pharmaceutical agent. That said many, many people actas if nicotine and tobacco or nicotine and cigarettes are one in the same,which is not true.

So I agree with your line of questioning that the nicotinedelivery products are very important to develop and many might have modest tosubstantial benefit. But then we get into the dangers of electronic cigarettes.Also originally introduced a smoking cessation AIDS, but then unfortunatelythey evolved or were developed in a variety of ways that make them as, or evenperhaps more dangerous than cigarettes.

So we're dealing with a powerful drug, but it depends onwhat's the container, what's the delivery system. What's the purpose.

Boomer Anderson: [00:53:26]And I guess that kind of leaves me with, we have a lot of people listening tothis show that come from an executive background, high performers, and prettywell versed, or at least have seen people experimenting with the positiveeffects of nicotine.

Is there. Uh, phenotype, if you will, uh, that should nottouch it. I E you know, is there somebody listening to this that could crossnicotine off their list because they check certain boxes?

Dr. Neil Grunberg: [00:53:59]Yeah, that's a terrific question. And that was very clever the way you framedthat. So again, if we consider the phenotype and the, and the genotype, perhapssome of the best research on.

Genetic differences would be the genotypical differences.And nicotine has been done by a professor, Rachel Tyndale at a university ofToronto. I believe she still is. And dr. Tyndale has really examined with someof her colleagues and learn that people differentiate in terms of their speedof metabolism of nicotine.

Yeah. This is very important and something, I think we'regoing to see more of in the next decade is our pharmacogenomics, how our bodyhandle pharmaceuticals should powerfully, I think should be part of ourinformation, our medical information that would help develop what drugs wetake, something I've argued to the FDA and to others.

But with regard to your question, the G the genotype wouldshow up at the, at the phenotype. So. Hmm, let me use this, this parallel inthe same way as different individuals, largely genotype, but also related toother genetic. And in fact, racial differences has to do with metabolism ofalcohol and whether or not alcohol metabolism, which is in several steps, stalls.

At the first step, which causes something called the alcoholflush. So for example, in general, the ginger genes have changed. We havedifference from. Agents, uh, other parts of Europe, Western Europe, even therehas been argue if you take different, um, culture of subgroups, why, forexample, you, um, people of Ashkenazi Jewish heritage, which I am tend to beless likely to drink alcohol.

People perhaps of Irish or other heritage can drink more.Well, it ends up, there are metabolic differences and I'm not looking togeneralize across these ethnic groups, but the reveal, there are manyindividual differences within as well as between, well, we're learning. Thesimilarly alcohol is the most studied of that.

Same as true with nicotine. So if you're a fast or a slowmetabolizer, this could affect. And you can see it can break either way. Solet's say you're a very fast nicotine metabolizer. If I'm a fast nicotinemetabolizer. Great. That would suggest if it burns out of my body quicker, lesslike you'd get dependent.

However, if I'm a past metabolizer and I'm even slightlydependent, well, I need more or less. I would need more if I'm a very, you seewhere I'm going. Very slow metabolizer. That'd be the genetic revealingphenotypically. I might need much less to get the benefit or the, what I wantedfrom smoking. And so actually, even though there'd be a lot more in the system,maybe I only need this monk a few cigarettes a day or these other alternativeforums.

So in terms of the phenotype, which would go along with thegenotype, it's not as if there are personality differences. Man decades ago,there was an argument that extroverts were like it's.

Boomer Anderson: [00:57:19]So you can just going to ask this question. Extroverts are dopamine drivenpeople.

Dr. Neil Grunberg: [00:57:23]Yeah. It ends up well, that's it?

Yeah. That's interesting. As the extroversion introversionargue and it was actually, uh, proposed by, um, um,  a professor at university of London back inthe 1960s, just cause there was a correlation with people who would go toparties and the like, but nothing has stood up in terms of. Personalitydifferences.

Now you've gone to a deeper question whether or not thoughpeople. Okay. So there, there is an underlying relationship between arousal andhow we respond that has been described by something called a Yerkes Dodsonfunction. Now, in my opinion, the Yorkie Dotson function is the only true lawof psychology.

And I just think swish. There's concepts, a thesis, littleconcepts, hypo thesis, or hypothesis. Many hypotheses confirmed become athesis. Confirmation of thesis becomes a theory. Confirmation of theory becomesa law. Even Darwin's theory of evolution. You'll notice it's a theory. It's nota law only.

Individual scientist who has more than one law attributed tohis name is sir Isaac Newton who had three laws of moving. And one could argueof gravity, the Uruk C Dotson relationship, which was established bypsychologists in 1908, argues that there's an inverted U shape relationship likethat between arousal or stress and performance.

And the performance can be behavioral or emotional orhedonic. So if you think about it, if we're not aroused at all, you're asleep,you don't care. Is there zero motivation? You do a pretty crappy job. You don'tdo well. And you know, feeling pretty good, but there's a sweet spot when we'rekind of jazzed up and ready to go.

That's when we do our best, but if we're super jazzed up.Our performance deteriorates. Now that general curve, although existence for allpeople, either shifts right or left depending on the individual or flattens ornot, depending on personality and training. So for example, I work in militarymedicine.

We and we select, we train our doctors under stress to notdeteriorate their function under huge stress so that they're ready foremergency rooms. And it's critical. We select Navy seals and Rangers andspecial ops and other people doing high risk, high performance, high stressjobs in a way that they don't deteriorate until it gets in.

Almost Beyonce. So now we can get back to your point. Arethere individual differences in the Yorkie Datsun? Absolutely. Therefore,because of that, the person who needs a lot of arousal to reach your peak andperhaps boomer, you're one of those, or you may need a moderate amount, whetheryou need more caffeine or whether you need more nicotine.

Or whether you need, um, something that was psychologicallyjazz you up. Uh, you know, I can't see what you're looking at besides themonitor now, but whether you need pictures, do you need pictures, right. Ofsomething. Do you need to go on a rollercoaster or do you prefer on vacation togo to the mountains or the beach personally?

I'm somebody who's so up all the time that I need to bringmyself down. So I, I love going to the mountains, both because of thetranquility and frankly, the thinner oxygen. I actually think clearer if I takea hot bath or I'm in a high altitude,

Boomer Anderson: [01:01:07]you can get into a hypoxia discussion too.

Dr. Neil Grunberg: [01:01:11]Yeah, no, exactly.

And it's relevant. Other people. My wife for example, is alawyer, super lawyer, and very calm. She needs to get herself jazz up theworksheets. Otherwise she's always calm. Like I mentioned this because here'sthe phenotype you were asking about, where are you? You're a really jazzed upperson. Well, whether you use the nicotine to calm you down tonight mentionedit brings you down, but might it be a pretty high dose if were very relaxed andneeds to be boosted?

What a very small amount in a small amount of the drug wouldbe less dangerous. So sorry for the convoluted answer. No, that you're kind ofvery guy

Boomer Anderson: [01:01:58]dr. Grunberger. I want to be cognizant of your time because I know, and. I justwant to kind of round off because the book I could talk to you for hours, but Iwant to round off with something you said earlier about one of your firstinterest before you started studying nicotine was other drugs likepsychedelics.

And I'm just kind of curious if you're willing topontificate about it. Uh, what do you think about what's going on, particularlyin the U S right now with things like maps and psychedelic assisted therapy.

Dr. Neil Grunberg: [01:02:31]That's a really good question. Actually, I've lecture on this as well. So, uh,briefly when we look at the history of psychedelics, I won't go into theheavily, uh, as you may know, or this audience may know, you know, SigmundFreud and others actually believed that they could be used in various psychoticcases.

When, uh, on Hoffman, who was the chemist who originallydeveloped LSD Hoppin actually developed it to treat psychosis and then. Freudargued that cocaine. And then other of psychedelics could be used for, uh,epiphanies and intellectual breakthroughs, waxed and waned for a variety ofreasons, you know, and I think you're in Amsterdam.

I blame first time I was in Amsterdam, which in the, let'ssee what year, 1970, 71, you know, it was a place that, you know, thatobviously was, was quite different about how openly people use particularlymarijuana versus in the U S you know, we had different views. There has beenthough a resurgence in the last five to 10 years, particularly in potentiallyusing some psychedelics to treat PTSD post-traumatic stress disorder.

Um, also some other mental health cases. I believe thisresearch is valuable and worthwhile and should be pursued. But to add to that,I also believe that there are other fascinating drugs. That should be pursuedunder carefully study conditions. The one in particular, um, uh, is PCP, forexample, phencyclidine so PCP, fascinating drug originally, and one of hisstreet names and the original was elephant tranquilizer.

Now think about it when I talked about the Yogi Dodson,because PCP was an animal tranquilizer, huh? Knocks you out? Well, that's veryhigh doses, very big animals PL over in the 1980s, nineties, et cetera, becameto known as a wildly dangerous, wildly, dangerous truck. Giving people, quote,superhuman strength, guy I'm small, I'm five foot six, a guy, my size beingable to fight off six, eight guys, you know, larger than me guy, my size.

Reportedly, anecdotally being able to turn over a car. Okay.There I've dealt enough with PCP, uh, with people who've dealt with PCB withlaw enforcement, but I've lectured to law enforcement, uh, people over thedecades about it. The reason I'm bringing up PCP scientists are not allowed tostudy PCP that was stopped many years ago, but a variety of people includingmyself, say, wait a minute.

What is it in this drug that gives a huge superhumanstrength. Therefore, is there a potential to isolate that effect to deal withvarious serious degenerative musculoskeletal problems to deal with multiplesclerosis or others? You're saying so in my mind, any and all of the drugs thatwe've you and I've referred to in many more are worthy of investigation becausethey may have a tremendous benefit.

Could they be used again, as my older friends said back inthe sixties in a more careful and controlled way to give, um, spiritualinsights to, uh, enhance, um, artistic. Vision again, you know, we go back tothe, you know, the, the late great John Lennon, you know, and, and what's sointeresting about LSD or Lucien sky with diamonds reportedly.

If one follows the words, the lyrics that Lennon put to thatsong, and they're bizarre, you know, picture yourself on a board, on a river,et cetera. Some people have interpreted it and argued. Unfortunately we can'task led into affirm in or not that it was the music he played. Those were theimages he got because LSD caused something called synesthesia synesthesia.

You seem familiar is a fascinating phenomenon where oneperceives. In a sense through a set, one of the senses, that's not the one thatwas obviously stimulated. We see sound sound makes us see a taste, makes ushear auditory stimulate. It makes us, you know, uh, um, you know, it makes ussee and, and on and on and on how does synesthesia work?

There are a subset of people, very small that actuallyexperienced some station. They're not well-treated today. So long story toyours. I, part of my personal philosophy is as well is, you know, a quote,Socrates, the unexamined life is not worth living and that we both have theblessing and the responsibility.

As well as the opportunities, if we have them to explore inorder to work and seek to improve the human condition, we should seek whereverit is, whether it's in Western medicine, Eastern medicine, whether it's in, in,in, uh, uh, plants and chemicals that appeared in the Amazon jungle of whichthere's countless, or whether it's in synthetic drugs.

As we understand the complexity of the brain, you know, Ifthere are ways to then use these medic, these drugs as medications to helppeople cope with horrific, horrific, uh, uh, limited lives because of mentalhealth problems, it should be explored and go further if it's a way to makelife more enriching, but in a way that doesn't destroy it, I believe it shouldbe explored.

But that's a personal philosophy in no way affiliated with myuniversity or any institution I've worked with. Well,

Boomer Anderson: [01:08:19]dr. Greenberg, this has been an absolute pleasure. If you have time. I justwant to ask one, one quick question.

Dr. Neil Grunberg: [01:08:26]Tell him is yours. You're you're a delight. You're you're a great

Boomer Anderson: [01:08:28]hubs. Just go into my final, rapid fire questions.

If you will. What excites you most about the health worldright now?

Dr. Neil Grunberg: [01:08:43]What excites me most about the health world is that with the seriousness of thepandemic, I'm hoping that many people at a large scale globally will come toappreciate the importance of health. Physical mental, emotional, spiritualhealth, and that we can, and that we all recognize the importance of spendingmore time to find the balance of this multidimensional aspect of health.

That's that's the most exciting part. The other part,probably in terms of innovations. Is something I imagined beforepharmacogenomics custom tailoring medications based on our genetic differencesin which our individual genetic differences are much greater than those thatappear phenotypically based on race or ethnicity.

Boomer Anderson: [01:09:40]What's the book that has most significantly impacted your life.

Dr. Neil Grunberg: [01:09:45]Eugene, Harigel actually a Dutch author, uh, Zen and the art of archery.

Boomer Anderson: [01:09:53]What's your top trick for enhancing focus.

Dr. Neil Grunberg: [01:09:56]I didn't hear top

Boomer Anderson: [01:09:58]trick for enhancing focus

Dr. Neil Grunberg: [01:10:01]personally, or for

Boomer Anderson: [01:10:02]others for you. I mean, I actually given some of the you're the people that youwork with, I would love to hear the others ones.

Dr. Neil Grunberg: [01:10:09]Well that, okay. High altitude. Both in terms of less oxygen, as well as themagnificence and grandness of nature. And, and, and to realize that ourselvesand our problems or issues that they're grains of sand. So that to me is whatgives me the greatest perspective.

Boomer Anderson: [01:10:35]Where can people find out more about you?

Dr. Neil Grunberg: [01:10:39]Uh, well, if one is interested, but that's probably boring. One can simplyGoogle my name and look at my websites or my work, or I've, you know, I've hadthe privilege of published about 200 papers, many on nicotine, others ontraumatic brain injury and post-traumatic stress. And the last chapter of mycareer now for the last five years, my team and I are focusing on.

The enhancement of leadership and followership forhealthcare teams and for people in general, trying to pull all these piecestogether. And that's probably the most rewarding and challenging part of mycareer, how to help people relate to each other more effectively. Beautiful,

Boomer Anderson: [01:11:21]beautiful dr. Greenberg.

This has been, wow. This is such a pleasure. I would love tojust continue the conversation, but thank you so much for your time.

Dr. Neil Grunberg: [01:11:29]Thank you Bomer. And again, congratulations on your interesting and importantpodcast. I hope to meet you in person someday.

Boomer Anderson: [01:11:36]Where are you going to make it happen to all the superhumans listening outthere have an Epic day.

There are a few podcasts of my own that I listened to againand again. And when I review research on nicotine, this is the first thing I goto. Dr. Greenberg is such an expert and I am so grateful for having his time.If you enjoyed the episode, please share it on all your social medias. Let me knowwhat you think of it.

Email me podcasts@decodingsuperhuman.com. And if you reallyenjoyed the episode, head on over to iTunes and leave a five-star review,actually it's called Apple podcast now, but regardless those five star reviewsreally help the show notes. Again for this one are decodingsuperhuman.com/nicotine. And thank you superhumans from the bottom of my heart.