Judith Grisel on Addiction, Neuroscience and Choice

Judith Grisel: Three things I guess. One is that we are really in a time in history where we’re very interested in the brain and in science. So, seventh graders appreciate things about the brain that we didn’t even know 30 years ago, and I think there’s a neurophilia going on. Second, addiction is so widespread, practically everybody is touched by it. And third, I also think on my part, being at a liberal arts university and having to speak to students about complex ideas on a daily basis, I must be able to mine the minutiae of scientific inquiry and translate and explain its general principles in a way that people can understand.

JG: My hope is that the readers who aren’t scientists will learn about and be able to appreciate the core principles of brain adaptation—how it adapts to every single drug-related repeated experience that alters the way we feel. Seatbelts and sunscreen were not considered life-saving before the research taught us differently. Now, we understand the risks of not wearing seatbelts or using sunscreen, and both are seemingly simple, but most definitely life-saving practices. I want people to develop that kind of understanding about the brain’s adaptive capacity and drug use. My secondary hope is that scientists who read it will come closer to appreciating what it’s like to be an addict. My hope is that I was able to explain that in a way that made sense to both audiences.

JG: Well, the first thing I would say—even though I’m not a therapist (and neuroscientists don’t understand it all that well, themselves) is that there’s a difference between understanding the implications for people suffering with addictions and simply collecting piles of data. I think that there’s definitely a place for all voices and insights to come together and try to work on this problem. It’s certainly not as if neuroscientists have made any great strides. So, that should alleviate some fear.

I also think that scientists like me who are working at a chemistry bench top or with laboratory mice, are looking at little trees or even particular leaves on particular trees. In contrast, I think clinicians are more trained to see the big picture—the psychological and social factors beyond the brain chemistry. I think we need a lot more communication and interaction between the neuroscientists and social scientists and the clinicians actually working day to day with addicts. 

JG: I’d first define addiction, even though there is some controversy over that, and the definition changes quite frequently as anybody who looks at the DSM would know. I would say that there are five characteristics of addiction: Tolerance, dependence, craving, the drug use or the activity needs to be detrimental to the person and to their community, and denial. Those five things coming together are what I’m interested in understanding better. And the tolerance, dependence and craving are due to the brain’s adaptive capacity.

Any experience or drug that alters our neutral or baseline affective state—and this is a little different for each person, forces the brain to adapt to try to bring the chemistry in the brain, and associated behavior, back to that neutral baseline. Some people are naturally lighthearted and happy and some are naturally a little depressive and melancholy. Whatever their particular neutral is, it is the brain’s business to try to figure that out and return to its neutral position. The pathology arises when that neutral baseline is going up and down like wild all the time because of constant ingestion of drugs, because, in part, the brain is unable to sort what’s happening and do something about it.

I drink coffee every day, and what is going on in my brain is a good example. I am completely addicted to coffee. The only good news is it doesn’t cause any problems for me, so you can say maybe I’m not addicted; I’m just dependent. When I wake up in the morning, I am unable to really think or communicate until I get the coffee. I don’t wake up like my 16-year-old does, hopping out of bed and ready to go. I wake up like I’m in a coma. I get a big cup of coffee, and then I feel normal. That is true for every drug. If you take benzodiazepines regularly to deal with anxiety, your brain produces tension and anxiety so that now the benzos make you feel okay and without them you’re a wreck. The brain does something similar, but in the other direction with opiates.

Opiates affect our neutral or baseline affective state. They make us feel great. The brain makes us feel crappy to counteract that and bring us back to an affective neutral. When we take away the opiates, then we just feel bad and miserable. And that’s true for any drug: alcohol, stimulants, marijuana. I think, if I were working with clients, I would want them to understand that their using has diminishing returns as the brain adapts. 

JG: That’s right. It’s necessary for survival.

JG: Let's start with the most complicated drug, which is also the smallest molecule—alcohol. Because it's so small and can go anywhere, it diffuses easily through membranes, and acts very promiscuously throughout the brain, including making us sedated, euphoric and less anxious.

At the other end of the spectrum are the stimulants; the class of drugs that includes methamphetamine, amphetamine, MDMA. They act in particular spots in the brain to enhance the amount of monoamines—dopamine, norepinephrine, and serotonin—in the synaptic spaces. By acting locally that way, they do two things. They make you more active behaviorally, so that's why they're stimulants, and they also make you euphoric, because dopamine works more directly in the mesolimbic system.

THC also acts all over the brain, like alcohol, but unlike stimulants it has a unique mechanism of action. THC mimics the endocannabinoids which can swim upstream across a synapse—it's a really unique pharmacology. The presynaptic cell sends a message to the postsynaptic cell, which on occasion makes these endocannabinoids tell the presynaptic cell, "What you just told me was really important." It can do that all over the brain, because we never know which circuits are going to be responsible for keeping track of important things. And when it does that with THC, then the whole brain thinks things are important, which is why Rice-A-Roni is delicious when you’re stoned.

And then there is LSD and the psychedelics—mescaline, peyote, and DMT, or the stuff in ayahuasca; and those four chemicals are unbelievably selective. They're agonists, so they mimic serotonin at the serotonin 2A receptor, and that action causes the serotonin filter to turn off. So, we can think of serotonin normally as kind of dampening or inhibiting most of the neural activity in the cortex. It's like a widespread filter. And when the filter comes off, things go wild. And so, there's it's kind of unfiltered cortical activation.

The benzodiazepines and the barbiturates are basically alcohol in a pill. The difference between benzos and barbiturates is that the barbiturates can be lethal, and the benzodiazepines cannot, although they both make a mean dependence.

JG: Placebos work for everything, though it's very hard to sort the science from the hype, and I think people are completely lost. On the other hand, CBD is not dangerous, as far as we know, and if anything, it inhibits the effects of THC, which has been linked to psychosis. There is also some evidence that CBD can inhibit psychosis. So, CBD is not addictive and it's an antagonist to THC. There is great evidence that CBD blocks certain seizures in children. I think overall that the evidence for THC is 10 times messier than for CBD. And one important way it's messy is that we can see that acutely, it helps somebody sleep or it helps anxiety. But because you develop tolerance, my strong prediction is that those returns are going to diminish with time and, in fact, the drug will create anxiety and insomnia, which is what regular users say. They cannot sleep without it. They cannot get through a day without it.

JG: I first want to point out that this is a terrific example of what we were just saying—that we need both sides. We need the information that neuroscience provides at the molecular level but also the broader perspective that your observation implies. Your broad perspective suggests that all addictive disorders can fall under the umbrella of obsessive-compulsive disorders. Maybe obsessive-compulsive disorders, in turn, are under the umbrella of self-regulation. So, I really think it’s helpful because we’re focusing on some little, tiny detail and missing the big landscape.

I do want to say that we’re absolutely clear in neuroscience that everybody’s innate capacity for self-regulation is not the same. So, some people are fortunate with metabolism of monoamines, for instance, in a way that makes them a little more cautious and less impulsive. Impulsivity certainly counteracts self-regulation. So does frontal-lobe capacity. If you have a large frontal lobe, you’re better able to do it. I think community support and teaching can contribute to that, so I think everybody’s capable of it. I’m still working on it, myself. It’s not easy for me.

I’m somebody who tends toward extremes right away. I think, just to point out another big-picture view of this, it makes sense from an evolutionary perspective that some of us would be tending toward self-regulation and conscientiousness and careful thought and consideration before acting, and some of us would be more likely to swim to the other shore right away without even considering the implications—whether it’s good for the population—because you need both extremes. So, I think if everybody were reserved or everybody was impulsive, it would be detrimental for the whole group.

I do think in certain conditions, like the ones that you alluded to now of our current social institutions, we definitely value more highly the ability to pause, and you’ll do better if you’re not too impulsive, especially with all these drugs widely available. They are high potency and easy to administer. It’s not a good time and place for people who are poor at self-regulation, that’s for sure. 

JG: I really love that question. It’s really out of my expertise, so it’s going to be my opinion that I give here, and I can do that best from my own experience. I really did suffer for no good reason as a child. I think I was overly sensitive and tuned in to other people’s plights and confused by the values that seemed to be expressed around me. I don’t know, but I think if I had had an opportunity to talk about this kind of existential confusion, maybe I wouldn’t have found marijuana and alcohol such a sell.

It’s almost a knee-jerk reaction among otherwise sober, sane people to suppress and deny and minimize and escape any feelings of discomfort. Maybe I’m too heavy handed here, but as someone who couldn’t afford to do that anymore, I really think my suffering was the very thing that led to the not so much happy, as the well person. I think it’s impossible to be well if you can’t face darkness. We don’t have a lot of ways—I know I didn’t find any—to help people face the darkness. If you’re not taking medicinal alcohol, you’re taking medical marijuana. And if you’re not taking either of those, you’re taking prescriptions. If we look at the percentage of people in western societies who are medicating their existence, we are not talking about a physical malady, so much as a psychological malady. I think it’s hard to find people who are models for walking through it. I think that might be a dead end. I have gotten a lot of notes and letters from young people who say, “This is so hypocritical. My parents say, ‘Don’t smoke weed’, My parents say, ‘Don’t do this,’ but they do these things.” I even had a therapist the other day tell me, “Well, alcohol’s not really a drug.” I think that we’re all in denial, I guess. Not maybe you, but many of us. 

JG: So true. If there was ever a time not to check out, maybe you could say this at any time, but I’m saying it now. This is not the time to escape our reality.

JG: I’ve gotten a fair amount of pushback about that. We were so bad at solving addiction and the NIH and NSF were funding all this research on addiction and Congress, probably about 15 or 20 years ago, said, “What’s wrong with you guys? Fix it.” At that time, we didn’t understand how the brain works. Like the “No Child Left Behind,” they thought if they made an edict, it would solve the problem.

So, scientists realized, “Well, we’re not going to fix it if our criterion is that people are well.” So, we’ve said, now, that you can minimize the harm—reduce the harm—and that’s partly strategic to say, “Look. We are being successful.” Suboxone is better than overdosing on fentanyl. I completely agree. So, I’m not dualistic about this; that you’re either clean or you’re not and too bad. I really think every single strategy should be employed.

I think we’re diminishing our potential by capitulating to this quasi-existence where we’re not really engaged with reality but we’re also not dying. So, I think short-term strategies are terrific, but I object to giving someone a prescription for a substitute drug and sending them on their way. The causes of their excessive use, I think, need to be looked at. For me, it was a really hard, multipronged effort on my part and on the part of a fair number of professionals before I was willing to take responsibility.

This may sound trite, but in order to be free, you have to take responsibility. I think, in some cases, people don’t want that. Initially, I sure didn’t want that. I’m so grateful for it today, because sometimes I have a really rough period or day and it does occur to me, “Oh, my gosh. I would just like a brief—” 

JG: Escape. I go to the movies or take a hot bath. That’s my option. I think that surviving that, awake, looking at the factors in me that contributed to that discontent, or those things I can’t control, I think that’s powerful.

JG: What I meant comes from my experience. When I was using, occasionally I would think, "Mm, it's probably not a good idea to use today." Like, I was going to my grandfather's funeral or I was going to be traveling on a plane, or I had a final exam, or something pretty big, you know. So, the thought would come to my head, "I should not do this." And then I would compulsively steer right for it, recognizing for a moment that it was going to be bad. It was going to hurt, cost me, but I couldn't stop. So, I think the obsession to use is still occasionally in my brain. But what's different is I have some space now between the thought and the act. And I guess what I meant was that having that space is the opposite, because addicts often don't want to use but it’s just inevitable because they don’t have that space.

JG: Are you kidding? No, I counted to 10 many, many times, and also walked around the block and, you know, chewed on spaghetti sticks and just kind of disconnect that habit part of my brain, the striatal part, which by the time you become an addict, you might as well be a rat in a cage, because it's just press the bar, press the bar, press the bar. Even if nothing is coming out.

JG: Yeah, or disappointment, which is a huge trigger for people like me, because disappointment is sort of low dopamine, you know? But I think that a therapist can have a great role here. Instead of trying to avoid the obsessions, to experience the obsessions with somebody who helps us get that distance would be useful. I remember it slowly dawning on me, wow, just because it occurs to me doesn't mean I have to do it, and that was a novel thought.

JG: I am not against drug use. I am really against addiction. I don’t think there’s good evidence that people who are addicted can manage a controlled use, ever. Sometimes, they grow out of it, if they’re young enough, so that can happen if they get stopped really early like before they’re 20. The way I think of controlled use is being on a perpetual diet at a holiday party. It’s just miserable because—and for me, it really would be. How can I control myself? There are all these tasty things. So, it’s just the cost—I think the goal should be freedom. I think that’s hard for most people like me to imagine if I was trying to manage my drug use. I’ve heard a million creative ways of doing it and they all look miserable.

JG: I guess I would ask you a question about that. When I was in abnormal psychology—and this is in the ‘80s—I thought that my teacher told me that the understanding of pathology was qualitative. So, you’re either sick or you’re well, basically. I thought that seemed surprising, but it was a great relief because I was among the well, I thought, for most things. My understanding of the way it is now is that we see most disorders as spectra and at some point, normal functioning becomes pathological.

For addiction, I think that, at some point, the reward pathway—this mesolimbic dopamine pathway that mediates the pleasure we get from addictive drugs–becomes altered. For some people controlled, moderate use—making other things like your children’s wellbeing, for instance, more important than your getting high—those kinds of things become impossible. I guess I see that in my own life. What happened is all I really cared about was drugs. There was nothing—no consequence—that I wasn’t willing to pay. I basically gave it all away so I could have this momentary escape. I think that is so compelling for some of us, either at birth or as a result of experience or probably both, that it’s a point of no return. I think age might influence that. 

I’m really concerned for kids. We know 80 percent of substance abusers—people who have addictions—start before they’re 18. Using moderation or avoiding excessive use before their brain is done developing around 23 or 25 might be the way for them to avoid addiction. I think it’s possible, then, to grow out of it, if you can back away. Maybe addictions that develop in adulthood might be neurologically different than the ones that come on early.

JG: The one thing I didn’t understand was: since when do adolescents worry about death? Don’t they think they’re immune to it? Isn’t their ability to self-regulate naturally and appropriately diminished? Isn’t this the time in life when they’re supposed to be taking risks?

I just want to say to the psychotherapists working with adolescents that this seems to me to be incredibly important. For children growing up today, it is, as you say, unbelievably confusing and drugs are everywhere. You can smoke pot now in school right in your seat where you’re taking your math test with no one knowing it. I think that it’s a treacherous time to try to find yourself and a place for yourself in such a confusing world. I think that our future depends on these kids.

JG: I think that the kids in my town are very interested in neuroscience and I think most kids are interested in information. One of the things that’s really had a big impact, surprisingly, because they don’t worry about their own death so much or their own mortality, is this idea of the transgenerational effects from epigenetics. There was pretty alarming data piling up and we don’t understand it so well.

We understand the mechanism but it just seems incredibly inconvenient that if an adolescent is exposed to a drug like marijuana or alcohol and then grows up normally—doesn’t get any more of the drug, the offspring of that adolescent partier are prone to anxiety and depression and higher self-administration of drugs of abuse. I have to wonder if the epidemic of anxiety and depression is in part due to what our parents were doing in the 60s and ‘70s. Talk about a complicated, systemic way of understanding suffering, so that you reap what you sow. Also, most of the blame has been on the mothers, on the women who, somehow, were crappy. In fact, we know that the pathway for the sperm through the epididymis is marked by these experiences. We have a mechanism for how this can happen. Fathers to sons and grandsons is clear in the lab. Another analogy for even younger people that I talk about—and I don’t know if this will impact them or not—but it’s almost like you have a bank. You start out with a certain amount of money in your bank and that’s your affective state. When you use a drug to feel great, you’re withdrawing from that. It is always the case that you have to pay it back; quickly or slowly. 

So, a hangover is a little payback of the great time you had last night but there is no influx of funds coming from any place else. They have to come from us, so that’s why, if you withdraw a little bit at a time and you put money in, maybe, by learning the kinds of self-regulation and purposeful nourishing of yourself and your goals, having a little treat every now and then isn’t going to cause bankruptcy. 

JG: If we had a perfect world, I would say nobody would overdo it.

I think kids don’t listen to parents making rules so that’s not a great strategy because you cannot enforce this. They do what they do. I hesitate to say, “Help them do it at home,” or, “help them learn moderation,” because, really, any time the brain gets a big enough taste of a drug to feel great, especially in adolescence, that’s likely to have a lasting impact in the opposite direction.

So, I’m quite convinced that my brain is less sensitive to pleasure and reward, so that when I got married or had my daughter or any other kind of peak experiences, which were good, they might have been even better if I hadn’t dampened my sensitivity to that. While we know this to be the case, I agree with you, though, that coming down hard and fast is a waste of time.

It’s impractical. In general, I tried to bribe my children. I said, “If you can not get wasted until you’re 21, I’ll buy you a plane ticket anywhere.” That’s what I would like. I don’t think it worked but I do think they’ve, in some way, taken it to heart. I mean, we talk about it an awful lot. 

JG: I put different pictures of the brain impacted by drugs in the book, by the way, because I think those pictures have an impact on kids. So, seeing how chronic pot smoking decreases the number of brain receptors that respond to pot, I think that might help.

JG: I have heard, though, from dozens, maybe hundreds, of kids, 15, 16, 17, 18 who completely identify with the lost, empty feeling that they cannot get enough of a drug. If these kids can stop early, their brain is much more capable of restoring things than it would be if they wait ‘till their 30. So, on the other hand, just because they have an increased risk of developing addiction, they also have an increased aptitude for recovering. Maybe this is a unique opportunity for them to begin to understand that these drugs really are so potent and so widely used, that it really is a dead end.

JG: Absolutely.

JG: For me and for many pot smokers, what that looks like is that everything is just completely boring and flat and uninteresting. I mean, I remember not caring about anything unless I was stoned. That is profoundly painful. It’s a big deal.

JG: I’m interested that you say battle it. I guess I wouldn’t expect that. Is it that we want them to battle the pains or do we want them to negotiate the pains?

JG: Yeah, and one way that’s helped me a lot is to realize it’s overwhelming if I look at everything. If I just pick something that’s important to me, one thing that’s important to me, and live my life to show that, then that’s enough. I don’t have to get overwhelmed by what’s going on in Yemen or what’s going on with the rising water—these are things that are beyond my scope, but I can do a little bit and that is, I think, maybe a message that’s lost to them right now. That there’s a place for each of us.

JG: Then, you point out the incredible irony, which is that they’re aware of all of this, and how do they deal with it? They completely erase it all by getting high, and by becoming withdrawn into themselves and their own private mental state which is being further manipulated by the drugs they are using. It’s simply not functional or adaptive.

JG: I think so. Connection! I mean, this is probably, blatantly obvious, but requires another side. Others who need us. I don’t think we can do it outside of the support of wise people. Connecting to art. Connecting to our bodies. Connecting to the earth. Connecting to mentors.

JG: Absolutely.

JG: Every new drug, when it comes out, has all kinds of promise and no side effects and that turns out to be true for a few months, until we get some data. I think it’s absolutely clear that the existing pharmacological treatment we have for depression is largely useless, and if nothing else, is really benefiting drug companies.

JG: I don’t think we have good pharmacological interventions, going back to what you said earlier. I think we are a society always looking for a quick fix. I’m not against this. What I like about this new drug is it’s finally a novel mechanism of action. It’s also not something you take every day. The chemical esketamine, though, is a little bit of a baloney because the drug that it’s copying, ketamine, is cheap and old. What do they have to do, because the patent’s out on that? They have to develop a fancy version on that, which is no more efficacious, but it’s going to earn a lot more money.

I think people are desperate for treatment for depression. There are so many people who are pleading, “Please, let me have brain surgery to alleviate my depression.” So, we clearly need something. I don’t think that it’s going to be a magic bullet, but maybe it’s good to see some movement in that area. 

JG: You know, it’s possible. It’s a dissociative anesthetic. It’s Special K, basically, which is abused.

JG: Oh, my gosh. That is worth an hour in itself. I think it’s critical. We basically did 96 percent of our research until the turn of the century on white males. They are not the default population, so it turns out—especially with drugs of abuse,but much more than anybody suspected—women respond differently. That’s evident in the clinic because women progress toward addiction and to toxic side effects much more quickly than men.

Women need lower doses. I think the reasons for using are different. I suspect—and it’s borne out by some data that’s accumulating—women use drugs more to cope and men use more to get off—to enjoy it. Those are really two different things. I think for men anger and resentment are big precipitating factors. For women, anxiety and insecurity are the precipitating factors. 

JG: I think the conversation was really enriching for me because I think we are both interested in the same goals but from different perspectives. I think it’s important to have these conversations, these bridges between what I know and what you know and our shared experiences from these different sides. So, I think that was really pleasant and novel for me because everybody only wants to talk about the brain molecules, evading these big, important, systemic, and social and spiritual questions.

JG: I hope so.

JG: Can I tell you, lastly, why I think you don’t have to worry about that? The neuroscience is not yielding answers. So, it’s going to be the data itself or the lack of data—the lack of understanding, the lack of impact—that brings us back to the wider community—to these connections outside of ourselves. As I say in the book, we thought that the brain was acting like Oz behind the curtain. Now, we realize, “Oh, the brain is just a way that the environment influences us.” We are coming full circle, I think, and we will, eventually, get to the same place where we realize everything’s social, psychological and biological.

JG: I would say they don’t understand it. I guess they’re selling something but it’s not understanding. It’s not wisdom.

JG: Absolutely.

JG: Thank you.