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The Science of Substance Abuse

The Science of Substance Abuse
Why do we derive pleasure from using substances that are not good for us? What's going on in our bodies and our brains that allows us to enjoy the effect of chemicals that can potentially kill us? And why in the world didn't evolution take care of this problem a long time ago? We'll talk to scientists about what happens to the body when you use cigarettes, alcohol and marijuana.

MAUREEN CAVANAUGH (Host): I'm Maureen Cavanaugh. You're listening to These Days on KPBS. People bemoan the fact that everything that feels good is either illegal, immoral or fattening, and now we might add bad for your health. There's a lot of moralizing that goes into the topic of substance abuse. Many psychological reasons are given. We hear about self-medication and addictive personalities, and we try to warn kids about the dangers of chemicals by telling them their brains will fry and their lives will be ruined. But the question remains: Why do we derive pleasure from using substances that are not good for us? What's going on in our bodies and our brains that allows us to enjoy the effect of chemicals that can potentially kill us? And why in the world didn't evolution take care of this problem a long time ago?

This morning, we'll be exploring how nicotine, alcohol and marijuana actually affect our bodies. How exactly they alter our moods and mental abilities. And what they are actually doing to our bodies while we're busy enjoying ourselves. Joining me are three researchers who specialize in examining the effects of chemical substances. I'd like to welcome Paul Kenny. He's an associate professor in the Department of Molecular Therapeutics at the Scripps Research Institute in Florida. Paul, welcome to These Days.


PAUL KENNY (Associate Professor, Department of Molecular Therapeutics, Scripps Research Institute): Thank you. Nice to be involved.

CAVANAUGH: Thank you. And Barbara Mason is staff scientist at Scripps Research in La Jolla. Welcome, Barbara.

BARBARA MASON (Research Professor, Scripps Research Institute): Hi, Maureen. Actually, I'm professor.

CAVANAUGH: Oh, so you're professor at Scripps Research in La Jolla.



CAVANAUGH: Okay. And Richard Clark is director of medical toxicology at the UCSD Medical Center. Richard, welcome to These Days.

RICHARD CLARK (Director, Medical Toxicology, UCSD Medical Center): Good morning.

CAVANAUGH: I'd like to welcome – I'd like to invite our listeners, that is, to join the conversation. If you have a question about the way certain chemicals affect you or problems with breaking an addiction, gives us a call, 1-888-895-5727, that's 1-888-895-KPBS. Let me start, if I may, with you, Paul, and we're going to be talking about nicotine. And, okay, so you light up a cigarette. The active ingredient in cigarettes is nicotine. How does that smoke get transported to your brain?

KENNY: Well, when you smoke, the smoke can enter the brain really in two ways. It can enter almost directly from the mouth through sub-buccal absorption into the blood system there and it can go almost directly into the brain from the mouth basically. Or the smoke enters the lungs and enters the general circulation that way. And you really begin to feel the effects of the nicotine in tobacco smoke within seconds. Usually within two, three, four seconds you have relatively high concentrations of nicotine within the brain.

CAVANAUGH: And what does nicotine do to the brain once it arrives there?

KENNY: Well, nicotine is special in the sense that its structure, its shape, actually fits very well into a type of protein that's in the brain called the nicotinic receptor. And that receptor is there in the brain to respond to natural chemicals that are produced in the brain. And nicotine just happens to mimic the shape of some of these chemicals, neurotransmitters, those are called, so the nicotine can artificially stimulate these proteins simply by its shape.

CAVANAUGH: I see. So what – what is it in the brain that actually makes the experience enjoyable?

KENNY: Well, the brain is made up of, I guess, many different parts and one part is the endogenous reward system or pleasure system. And the reward system is something that's concerned with evolution. Many – Basically, all organisms have it. And it serves the function of telling you that what you did was good and right and to help reinforce particular behaviors. And so nicotine can subvert or artificially activate that pathway, that reward system, by stimulating these nicotinic receptors that are located throughout that pathway. And so when you smoke and you absorb nicotine and stimulate these pathways, you feel good. You feel that what you did was good and by its very nature, it's reinforcing, which means you're more likely to do it again.

CAVANAUGH: Does this have something to do with the secretion of dopamine or serotonin?

KENNY: That's – Those two neurotransmitters are certainly part of it. And I guess for a long time people believed that nicotinic and nicotine induced increases in dopamine in particular played an absolute central role, and this was how you experienced pleasure or reward when you smoked. And recently the picture's become a little bit more complex but dopamine is certainly considered one of the main players in drug addiction in general and it certainly plays a role in tobacco addiction. And serotonin systems are also certainly stimulated by nicotine and tobacco smoke, and that's considered to play an important role in the more mood related effects of tobacco smoking.

CAVANAUGH: Now what – one thing everybody who realize – who's around smokers or who has been a smoker realizes is that if there's a stressful situation, if there's something that comes up that really agitates somebody, the first thing a smoker needs is to have a smoke. What is it about that addiction to nicotine that triggers that immediate need for nicotine in a stressful situation?

KENNY: That is a critical question. Many people are trying to figure that one out, in particular George Koob at the Scripps Research Institute has spent a long time trying to understand the role of stress pathways in addiction and has made great headway there. It's really unclear at the moment. If you ask a smoker how they feel after they smoke, invariably they say that they have a reduced stress. They reduced anxiety, they feel better. And as you say, if people are stressed and they're smokers, they tend to want to smoke at that point. There's been lots of different explanations as to what is occurring and one explanation is that the stress hormones themselves may act on nicotinic receptors to alter the function and trigger a desire to smoke or to stimulate that receptor and to smoke. And what's interesting, though, is even though people report that they feel less stressed when they smoke, smoking and nicotine themselves may actually increase stress. So you can see a vicious cycle can be set up where you smoke because you think it alleviates stress yet the smoking process itself may actually ramp up your own stress pathways and lead to even more desire to smoke afterwards. So that's probably part of the addiction process.

CAVANAUGH: And what, if any, are the positive effects of nicotine on the body?

KENNY: Well, nicotine certainly has rewarding effects and mood-enhancing effects and that's part and parcel of the addiction. Nicotine's also thought to have mild cognizant enhancing effects so when people smoke, and it's almost like a cup of coffee, you feel that you function better.


KENNY: The other effects of nicotine that may contribute to this reinforcing effects is its appetite suppressing action. So a lot of people don't want to quit smoking because they think they'll gain weight. And a lot of people like the fact that they don't feel hungry when they smoke. So nicotine certainly has complex effects on the brain, hits many, many pathways.

CAVANAUGH: I want to come back to nicotine but I also want to move on to Barbara and talking about marijuana. And one thing that we know that marijuana does not have is an appetite suppressant. The active ingredient in marijuana is a chemical called THC, and I'm wondering how is that transported to the brain? Is it similar to nicotine?

MASON: Yes. Paul actually gave a very elegant description of how smoke products can enter either through the mouth, through the nose and very – through the lungs, very rapidly gain access to the central nervous system. THC is interesting because it can be present for a very long period of time in the system and all of these compounds with addiction potential have the immediate rewarding effects but in – after awhile, the body becomes tolerant and there may be a need to increase the amount that's taken in order to receive the desirable effect. For a smoker who's stopped and quit smoking, for example, and some stressful event occurs and it's just very natural to pick up a cigarette, the next thing they know, by the end of the week they're back up to a pack a day again. So it – it moves very quickly.


MASON: But with THC, as you described, the most psychoactive ingredient in marijuana, it has quite a long half life and so people didn't recognize the withdrawl symptoms of marijuana as quickly as they did with nicotine where you have to keep using on a fairly regular…


MASON: …interval to maintain the desired mood state, or even alcohol.

CAVANAUGH: That's interesting. And I want to go back to the idea that THC, the smoke in marijuana, is absorbed and affects the brain in a similar way as nicotine but the effects are quite different.


CAVANAUGH: Tell us about what THC does when it gets to the brain.

MASON: Well, the brain has an endogenous cannabanoid system.

CAVANAUGH: Oh, wow, what's that?

MASON: It has receptors for substances that the body makes naturally and Mother Nature didn't put them there so we could get high. Mother Nature put them there for a functional purpose. And that work is going on right now, clarifying the purpose of that system in the brain and it seems to be to modulate other activity. Like if the stress system or arousal systems are high, the body's own endocannabinoid system will kind of bring them back down. So if we use a chemical like marijuana to artificially stimulate that system, you feel very mellow. And it also tends to enhance perception so that food, for example, you'd mentioned how marijuana doesn't seem to have the appetite suppressant effects of nicotine, the pleasurable aspect of eating might be enhanced but in high doses perceptions can get so enhanced that you start having perception distortions and even possibly hallucinogenic-like effects. So it – There's definitely a dosing issue in marijuana and also the individual's vulnerability, but it's an enhancing of the more mellow effects and at the same time people seem to want help in getting off of marijuana when they notice that they are not functioning in the way they desire. Like in a college environment, when kids get really caught up in the cannabis culture, they may have worked really hard in AP classes in high school to get into medical school but then find they're only getting Cs in college because there's this amotivational syndrome that's part of the…


MASON: …the mellowness that…

CAVANAUGH: I don't mean to interrupt you but I was – I want to – because we did talk a little bit about dopamine and serotonin when we talked about nicotine and that sort of relationship is now seemingly unclear. But what about THC? What – does that also release dopamine in the brain? Is that where the euphoria comes from?

MASON: You know, the systems are not so discreet. It's more like a plate of spaghetti with systems influencing each other. And the endocannabinoid system and the opioid system seem to have a close working relationship.

CAVANAUGH: I see. Let – I think that I understood that. Let's move on to Richard Clark and talk a little bit about alcohol, the other mood enhancing, mood altering drug that we're talking about. The active ingredient in alcohol is ethanol, is that correct?

DR. CLARK: Pretty much so, that's – they're almost synonymous terms, ethanol could be alcohol whenever you refer to alcohol in general, yeah.

CAVANAUGH: And, of course, alcohol, you drink it and so it doesn't have the smoke effect that we've been talking about. So how is alcohol transported to the brain?

DR. CLARK: Well, alcohol actually gets into the body pretty quickly, more quickly than most people would think. You may even absorb some from the mouth but it's one of the few drugs that we take that's well absorbed from the stomach and that's probably why people start to feel a glass of wine, for instance, within minutes probably of starting to drink it, much more quickly than most other drugs that are absorbed in the small intestines of the body. So because of that property, we start to feel effects from it relatively quickly compared to when we're drinking it even though it's not quite as fast as a drug such as nicotine or THC that you're smoking that can get in within seconds.

CAVANAUGH: Right. Why is it so easily absorbed by – through the stomach?

DR. CLARK: Well, it's got properties that make it move through the acid medium of the stomach a little quicker than most drugs do. So it enters the bloodstream very rapidly. Alcohol's been in the environment for millennia and so our bodies are very used to it and, as you know, we have enzymes that are especially there to break down alcohol. And so it's – it may even be necessary in some of the chemical processes that go – undergo in the body in very, very small amounts. And so the body needs a bit of it or gets a bit of it very quickly and then processes it very fast as well.

CAVANAUGH: And so when it does – when it is absorbed and it goes to the brain, what actually – How does it affect the brain?

DR. CLARK: Well, like the other drugs we've talked about, it's probably not as simple as a one sentence answer.

CAVANAUGH: Is it the plate of spaghetti again?

DR. CLARK: Oh, yeah, it – That's probably a good – a good analogy for things. There are different kinds of channels in the brain that transmit different ions like chloride, and alcohol is one of many chemicals that can affect that transmission of chloride and other molecules in the brain. And as it either enhances or stops or slows down that transmission, it causes us to feel a whole bunch of different things, and the most obvious thing is sedation when you get higher and higher amounts of it. But it's not quite that simple. And as we know, as our alcohol levels are going up in our bodies, we feel almost a euphoric effect. Many people do. And, in fact, there's really good evidence now that a lot of these great researchers that are also on the line now are doing, that this euphoric effect is what keeps people coming back to alcohol even in an addictive or a dependent sort of sense. And that's what we like the most. That's what most people like in that first glass of wine that kind of asks us to get a second glass of wine. But the long term effect and the higher and higher concentration of alcohol effect is really sedation. And, again, there's many drug that'll do that but alcohol's the easiest obtained one that we have without a prescription or anything else that you can get today.

CAVANAUGH: Now is that, that concept, that function of sedation, does that – is that what is affecting our motor functions and the fact that our inhibitions are relaxed when we overindulge in alcohol?

DR. CLARK: Yes, more or less, that's right. I think in lay terms that's probably the easiest way to describe it. It's a disinhibition effect, which is still the early parts of sedation. And that's what affects our driving ability, our coordination, our speech and virtually everything else that goes on.

CAVANAUGH: And a lot of people, like cigarettes and marijuana, take alcohol before they have to go into a situation that's going to cause them anxiety. Before – Lots of people have a drink before they go to a party, let's say, or a social situation that they don't want to deal with. How does it help deal with that anxiety?

DR. CLARK: Well, it takes the edge off. Most of us get a little nervous when we're getting ready to go on an airplane or going to a party and that disinhibition effect, for instance, for a party, would allow you to perhaps go in and speak to people that you normally wouldn't speak to or not to be worried about talking to somebody about a topic that might stress you out under normal circumstances. So not only does it take the edge off by making you just perhaps a little bit drowsy, but it also causes you to be more euphoric and feel like you can talk easier.

CAVANAUGH: And it – But it's different than anti-anxiety medicine, right? If you were to take some sort of a calming pill. It – Does it have the same action in the brain? Or is alcohol different?

DR. CLARK: Well, it probably has a little combination thing so it will eventually have the same sedating effect but there's other factors that go in, probably mediated with dopamine and serotonin, like you've mentioned, and with opiates in the brain that cause you to feel good and to be less stressed and calmer.

CAVANAUGH: We will continue talking about the mood altering substances that we are talking about and talk about how they affect the rest of our bodies while they are affecting our brains. I'm speaking with Paul Kenny, Barbara Mason, and Richard Clark, and we will be taking your calls as These Days continues in just a few moments here on KPBS.

CAVANAUGH: I'm Maureen Cavanaugh. You're listening to These Days on KPBS. And I'm speaking with Paul Kenny, associate professor in the Department of Molecular Therapeutics at Scripps Research Institute in Florida, Pearson Family Professor Barbara – at Scripps Research in La Jolla, Barbara Mason. And Richard Clark, director of Medical Toxicology at the UCSD Medical Center. We are talking about how nicotine, alcohol and marijuana actually affect our bodies. And we are taking your calls at 1-888-895-5727. Let's go to the phones and speak with Greg in Poway. And good morning, Greg. Welcome to These Days.

GREG (Caller, Poway): Good morning. Good morning. Thanks. Just curious because I know that psychiatrists, psychologists deal with addictions a lot – alike, and I'm wondering other things like chocolate, oh, I don't know, gaming, video gaming, pornography, do they all operate on the same kind of principle, the same part of the brain? Your panel, do they know anything about that?

CAVANAUGH: Let's find out. Thank you for the call, Greg. Would anyone like to take that question? Other addictions?

KENNY: Yeah, maybe I could jump in there if that's okay?

CAVANAUGH: Sure, Paul.

KENNY: We've been looking at exactly that question. We're looking at that at the moment. We've very interested in it because these systems, as Barbara said earlier, they're not put there on purpose to make you addicted, they serve a natural purpose. So we've been trying to frame obesity as perhaps an addiction to high fat, high sugar food and to see if those same systems that appear to be corrupted in drug addiction may also be corrupted in individuals that compulsively seek these high value foods. And, indeed, that's what we're finding, that the same types of corruption that we see in the brains of addicts occur in – during the development of obesity. You get very clear neuroadaptations that appear to be a hallmark for addiction that occur as obesity develops. So I would say, yeah, in many cases it is possible to develop an addiction to natural rewards. And also with that in mind, there's a phenomenon that appears to be emerging in Parkinson's patients and other people who seem to be on dopamine replacement therapies that when they're treated with certain types of drugs that can stimulate dopamine receptors in the brain, they can develop compulsive type behaviors even though they haven't actually consumed an addictive drug. And so you can induce a compulsion or an addiction towards a natural reward by stimulating these same pathways that are stimulated by addictive drugs. So my view is that, yes, many of these natural reinforcers can ultimately develop. You can develop a dependence on a more addiction-like state toward them.

CAVANAUGH: So, Paul, getting back to nicotine, so this corruption, this addictive thing that's going on in the brain…

KENNY: Yeah.

CAVANAUGH: …does that – is that the key to the enjoyability of cigarettes?

KENNY: Well, in fact, it's probably the complete opposite. You have, you know, the nicotine that's contained in tobacco smoke is a pharmacological agent and it stimulates proteins in the brain and you get this acute feeling of pleasure and reward. But the brain is very plastic and adapts to its environment very readily so when you consume these type of drugs, the brain wants to adapt and go back to the way it should be.


KENNY: And it's probably these adaptations, the brain's struggling to cope with being bathed in an excess chemical that shouldn't be there that results in the addiction. Basically, the brain adapts to having nicotine on board or having cocaine on board and such that when you take the drug away, what you're left with is the adaptation. So it goes from a state where you like having the drug to almost where you need to have the drug just to function normally. So – And, you know, when you take the drug away, what you undergo is a withdrawal process and that reflects the development of these adaptations that have occurred. So it's probably the mirror image. The good associated with the drug helps establish the habit but the bad associated with taking the drug away after a period – a long period of exposure, is probably – reflects the manifestation of an addiction.

CAVANAUGH: Now the way that I understand nicotine is that it, in itself, is not the thing that's most harmful about cigarettes. What is happening within the body of a smoker that causes diseases like lung cancer or emphysema?

KENNY: Well, nicotine itself, I mean, the most – Obviously, the most harmful thing about nicotine really is the fact it can cause addictions but nicotine has other beneficial effects. I mean, there's some literature to suggest, of course, that it's a cognitive enhancer, that it can improve cognitive ability. And there's epidemiological evidence suggesting that people who smoke are less likely to develop Alzheimer's disease or Parkinson's disease and other neurodegenerative disorders. And also various psychiatric illnesses may actually benefit from exposure to nicotine. So although nicotine is very damaging in that it can induce an addiction, it also has beneficial effects. So if you can develop nicotine-like substances that are – that don't have these addictive properties, they may actually make very useful drugs. But the fact that you can become addicted to nicotine means that you're very likely to consume high quantities of other chemicals that are contained in tobacco smoke, which can be very damaging and really have no beneficial effects. A lot of the plant alkaloids are contained in the tar and tobacco smoke are, as every one knows, very cancerous. They have high carcinogen value so in order to obtain nicotine, you expose yourself to these very nasty powerful substances and that's the downside of nicotine, unfortunately.

CAVANAUGH: And Barbara, researchers are finding that marijuana may lead to worse longterm problems than they previously thought. What are those longterm problems?

MASON: Well, Maureen, it's important to realize that all of the substances we're talking about today have been used by many people. Marijuana has been used by about 14 million Americans in the last month. Alcohol is widely used and even cigarettes are still widely used despite all the social sanctions. But of all those users, there are only a certain proportion, 10% marijuana, maybe 8% alcohol, I'm not sure what the percent is for nicotine, who will become addicted, whose brains will actually change in response to their use of that substance. And, as Paul alluded to, a lot of it is based on the quantity that the brain is exposed to but also individual vulnerability so that the individual is no longer using the substance for the pleasurable effects but rather to feel normal. And if they don't use, they feel anxious, dysphoric, trouble sleeping, you know, all like the complete opposite of all the desirable effects for using. So that really keeps you locked into a 'must use' state. And even like the caller inquired about the more behavioral types of addiction like gambling, Paul gave a nice explanation for the biological basis. And in keeping with that, a medication that has been studied for alcohol was actually found to be effective for gambling. So if a medication can influence the brain of a gambler and change that behavior, that's another piece of evidence that the brain is involved in even the behavioral forms of addiction.

CAVANAUGH: Let me ask you, though, if you were one of the 90%, let's say, of people who have used marijuana and are not addicted to it, is marijuana bad for your health?

MASON: Well, you have the same problems that – with nicotine where you're taking in other material in addition to the marijuana that can be as carcinogenic for the lungs and esophagus, etcetera, as cigarettes, at least that's what the majority of studies have shown, although not all studies show the same thing. So you have that down side. And for people who particularly have a vulnerability, I described how the sensory perceptions can be affected. There's some suggestion that marijuana use may result in a higher incidence of schizophrenia, and you can see the linkage with the perceptual distortions that occur, particularly in the high doses. And nobody's really clear about the chain of causality but we do know that there's a higher incidence of schizophrenia in cannabis users, you know, epidemiologically. And you can – and science is now starting to form some links in the chain. Of course, this is a 1% prevalence overall, so obviously not all cannabis users go down that road.


MASON: But, you know, there – anything that's used in excess, there's no free ride.


MASON: You know, there's always some price to be paid.

CAVANAUGH: Let me talk about the price people pay in overindulgence in alcohol. Everyone knows that alcohol is bad for your liver and I'm wondering why is it bad for your liver?

DR. CLARK: Well, alcohol kills cells and the liver detoxifies alcohol and in the detoxification process of breaking it down, it can damage cells. The liver, most people realize, is one of the few organs in the body that can regenerate itself and during the process of damage from alcohol and then regeneration is where we get that situation called cirrhosis. And although in cirrhosis in people who drink too much alcohol the liver is regenerated, there's scarring that occurs throughout the liver that affects the way the liver processes things and it affects liver blood flow. And in that scarring process of cirrhosis, the liver doesn't work like it should and the rest of the body's functions, therefore, don't work like they should either and that leads to all kinds of other problems like increase in size of blood vessels in parts of the esophagus that can hemorrhage, and retaining fluid in the body, and eventually, as the liver deteriorates more and more, you don't clot your blood like you're supposed to and it can lead to death.

CAVANAUGH: Isn't it interesting, though, as you, yourself, said, Richard, that there's – we've been drinking alcohol as a species for millennia and we actually have an enzyme in our stomach that helps us break down the alcohol, so why would it still – why would the liver still have so much trouble in detoxifying the body from alcohol?

DR. CLARK: Well, it's an excess thing.


DR. CLARK: Just like every one of these substances we're talking about, small amounts may be beneficial, as we've already heard. And I think almost everybody's familiar with the studies showing that small amounts of alcohol may be beneficial to certain things, maybe less heart attacks, maybe less strokes. And in those small amounts, which like has already been mentioned, maybe 90% of the population would be not consuming more of on a normal circumstance, it's okay and that's why we have that enzyme. And there's alcohol naturally in foods that we will eat, and so the body has to be able to break those down. But it's that 10% of people that don't know when to say I've had enough that overwhelms the body's capabilities of detoxifying it and leads to all this longterm damage.

CAVANAUGH: And in the final minutes that we have, I do want to address one more thing that you said and the idea that alcohol kills brain cells. What's going on there?

DR. CLARK: Well, it probably does in – especially in excess. I mean, alcohol can essentially kill many different cells in the body and brain is one place that can be damaged. It probably isn't regenerated in the brain and we know that there's really good studies that longterm excess drinkers will damage especially parts of the back parts of the brain called the cerebellum that will never be replaced again. And they may have less coordination than somebody. And essentially with what you look like with intoxication is what you can look like with that type of longterm damage. Your memory's not the same as it used to be. Your coordination's not the same as it used to be. But in a person who drinks the standard glass of wine a day, that's really not a problem. And you've really got to consume quite a bit every day…


DR. CLARK: …in order to get there.

CAVANAUGH: Paul, in about the minute we have left, I wonder, it sounds from what you said, the answer to a previous question, that researchers may be going down the road that there could be one form of medication that would help people, relieve them of all types of addictions. Do you see that day coming?

KENNY: Well, that's a point that was brought up by Barbara where I guess that a single pharmacological agent could stretch across various different types of addictions, and I could see something being effective for many different types of addictions but it'd probably have to be combined with different types of therapies, either cognitive behavioral or other types of pharmaco-therapies to be really effective but, sure, I think there certainly could be developed drugs that could keep you off other drugs if you know what I mean.

CAVANAUGH: Well, I want to thank you all so much for talking with us today because I think you've really broken it down for us. We know what these things do to us now and it's up to us. Okay, well, thank you so much Paul Kenny for speaking with us.

KENNY: Thank you.

CAVANAUGH: Barbara Mason and Richard Clark, thank you so much.

DR. CLARK: You're welcome, Maureen.

KENNY: Thank you.

MASON: Thank you.

CAVANAUGH: I want to let everyone know when they called in, we couldn't get to your questions. If you want to post your comments online, we'll be happy to read them at Stay with us for the second hour of These Days coming up in just a few minutes right here on KPBS.