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Marco Leyton, PhD, assures me the cocaine he purchased was legal. Plus, it wasn’t for him. Definitely not. It was for recreational cocaine users who had answered Leyton’s ad in a local newspaper to do drugs and collect 500 Canadian dollars — for science.
Leyton had jumped through many hoops to get to this point — getting an okay from the Canadian equivalent of the FDA, exempting him from criminal prosecution, and clearing his own university’s ethics approval. “I wasn’t asking people to bring in their own cocaine,” Leyton, an addiction neurobiologist at McGill University in Canada, tells me. Now that could be unethical.
It was all in pursuit of one of the deepest questions that haunts us as individuals: “Why do we really care about some things and not too much about others?” as Leyton says.
Really: Why do we want what we want?
With the drugs in hand, Leyton ran a small study for some insight. It involved just eight participants, but it’s noteworthy because it’s a relatively rare human experiment in a field that more commonly tests rodents (which have found similar results as the human studies).
Plus, it’s just wild. I have never read these words in an academic journal before: Participants “were presented with cocaine paraphernalia consisting of a mirror, a razor, a straw, and a bag with 3.0 mg/kg of cocaine hydrochloride.”
The study took place over four days. And while the cocaine is the eyebrow-raising component of the study, a special protein shake was the actual key.
On any given day, half the participants were randomly assigned to ingest a shake that was missing a key ingredient called phenylalanine, an important amino acid that helps your body manufacture the neurotransmitter dopamine. That’s the chemical released when your brain is expecting, or sometimes demanding, a reward, like a sweet treat or, well, cocaine.
So, if you’re like these study participants, and had been fasting before this experiment, and then only given a food source without phenylalanine, your body chemistry would subtly change. Leyton thought the participants who consumed this weird breakfast would have less dopamine available in their brains.
After their shake, the participants were then invited to do blow. Or, as the study plainly states, the participants “used the razor to divide the powder into three equal lines.”
They snorted it.
But remarkably, on the phenylalanine-free shake days, Leyton says “they decreased their craving for cocaine.” They said they were less interested in taking it.
But it was more than that: The special shake “decreased the ability of the cocaine itself to produce more desire for the drug,” he says.
And strangely, “it had no effect on the drug-induced euphoria,” Leyton says. In other words, they still liked cocaine. They just didn’t want it as much.
While talking to Leyton about his cocaine study, I wondered: Why isn’t the phenylalanine-free shake The Answer to addiction, to overeating, to similar problems of compulsive consumption?
Well, for one, because it’s impractical. Phenylalanine is in just about all protein food sources. So unless someone wants to solely eat speciality lab-generated shakes their whole lives, that’s not going to work.
But also because Leyton would expect it to decrease the motivation to do anything. “So now the whole world becomes kind of blah,” Leyton says. And what fun is that?
The reason why this cocaine study is so interesting is because it reveals where and how desire hides in the brain.
And desire is important. It’s a fulcrum on which our well-being balances.
Desire — for food, companionship, fun, sex, whatever — can bring excitement, joy, and even purpose to life. It’s the Good Stuff! But too much craving is the seed of addiction, of unhealthy eating habits, of the shameful feeling of being torn between what’s good for us and what we crave.
We cannot live without wants, yet we cannot be overcome with them.
The solution that has eluded researchers for a long while is a trick to help people reset the balance. A trick that turns down the dial of desire enough to be effective, but not too much, preserving our motivation to find joy in the world. And one that could work for a wide array of issues, including substance use disorders and overeating.
Scientists are starting to see the potential for GLP-1 drugs like Ozempic to pull off this trick.
You may be more familiar with some of their brand names, such as Ozempic, Wegovy, or Mounjaro. Or their generic names: semaglutide and tirzepatide. This class of drugs was first approved for use in diabetes, then for weight loss, and it is growing in popularity. In the last three months of 2022, clinicians wrote more than 9 million prescriptions for these drugs in the US, according to the health care market research firm Trilliant.
The drugs have made headlines for their use among the glitterati, and have been provoking important conversations about how society views and treats people with higher weights.
But they are also part of an emerging story that’s potentially much bigger: There are faint, early glimmers that they could be used for drug addiction, too.
We don’t fully understand how these drugs work. But they seem to be tapping deep into the brain’s wanting system and shining a light on a silent aspect of what it means to be human: What we want, and why we want it, is often not in our conscious control.
What is want?
After talking to several researchers for this story, I realized the English word “want” is imprecise to describe the psychological phenomenon Leyton has been describing.
“It’s not your desire for world peace,” says Kent Berridge, a neuroscientist at the University of Michigan. “It’s not my desire to exercise or lose weight.” Those are “real desires,” he assures. But they are not behind the sort of behavior that is facilitated by the dopamine system in the brain. “They don’t give you that kind of urge.”
Imagine this scenario. You’re at a house party, sitting on a sofa. In front of you is a bowl of peanuts. Humble, roasted, salted peanuts. Not a super exciting snack. And you’re not that hungry. But in a moment of fidgetiness, you take a peanut. A few moments pass. You take another. And then another. Do you even like peanuts? You know more food — tastier food — is coming when dinner is served. You don’t really want to eat these, but now, half the peanut bowl is gone. Still, there’s something inside you — wordless, noiseless, unceasing — compelling you to reach for more.
That’s want.
It’s a manifestation of our mesolimbic system, the reward pathway in the brain that’s facilitated by dopamine. It’s a system that’s trained, over time, to influence our decisions. It’s the system that compels you toward the peanut and also toward other things, like scrolling through endless TikToks or Instagram reels.
Leyton’s cocaine experiment highlights another key, unintuitive, way to define wanting — by showing that wanting is not the same as liking.
You might find this idea confusing. Scientists were once confused by it, too. “When I started in the field decades ago, we thought they were basically the same two words for the same psychological process,” Berridge says.
It made sense to conflate the two. In daily life liking and wanting ”go together really well,” Berridge says. We want things because we like the way they taste or how they make us feel.
It just seems so obvious that liking and wanting should go together. So it’s interesting to see the studies in which they can, indeed, be pulled apart. First, there were animal studies. Starting in the late 1980s, Berridge and colleagues surgically or chemically diminished lab rats’ ability to produce dopamine.
Without dopamine, “those rats won’t eat voluntarily, they won’t drink voluntarily, they won’t pursue any reward voluntarily,” Berridge says. “And it was thought that they had lost all pleasure.” But, studies concluded, they apparently did not.
There’s convincing evidence that this split between liking and wanting happens in humans, too. That’s what Leyton’s cocaine study demonstrates — the liking of cocaine and the wanting of cocaine can be disentangled.
Leyton has repeated the dopamine-reducing experiment with other drugs, “with alcohol, tobacco,” he says. When he puts people in a low dopamine state, they don’t just say they crave their drugs less, but they’re less willing to work on a tedious computer task to obtain them.
He’s even done a version of this study with money. “It’s not a drug,” he says, “it’s not even delicious!” But when Leyton put them into a low dopamine state, participants “were less willing to sustain the effort to obtain $5 bills.”
And in all these experiments with the dopamine-reducing protein shake, the same pattern emerged. “The motivation to seek out a reward was diminished, even though the pleasure was the same,” Leyton says. “The alcohol still tastes delicious,” he says. The cigarettes are “enjoyable as usual.” Extra money in your pocket is still great.
Another key thing about the wanting system — and arguably, its most frustrating aspect — is that it often exists beyond our conscious awareness.
“Many people would argue that we have very little [conscious] access to our motivational processes,” Leyton says. (Though he didn’t formally measure it in his studies, Leyton says his participants have a hard time guessing if they received the dopamine-reducing shake or a placebo shake. The low-dopamine days don’t seem all that abnormal. On the low dopamine days, it’s as though the participants just say “I’m just going to quit early today. That’s enough. I’m done.”)
With food, says Alexandra DiFeliceantonio, a nutritional neuroscientist at Virginia Tech, you could seek out a particular food because of conscious choice. “I think I’m going to want this because I’m trying to eat healthy,” she says as an example. Or we can like the flavor, texture, or memory the food conjures.
But there are likely also unconscious processes going on that train the brain’s reward system. For instance, it’s hypothesized there is a nervous system pathway that connects our guts to our brains, which tells the brain’s reward system about the nutrient content of food, creating a want for it. Why do you reach for the cocktail peanuts? You could tell yourself a narrative like, “I’m just feeling fidgety.” But maybe it’s because your want system has learned to associate the nuts with a lot of nutritious calories.
“There’s actually two pathways that bring rewarding signals to the brain,” says Dana Small, a neuroscientist at Yale University who studies the food choices we make. “One pathway is what you normally think about when you think of food reward — the taste, the smell, maybe how it looks. Then there’s another pathway — the signals that are generated during digestion that you’re never aware of.”
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To illustrate the subtle power of this unconscious pathway, she tells me about a type of study (done in both animals and humans) where researchers take two similarly flavored beverages, but surreptitiously infuse one with more calories than the other. In these studies, “the dopamine circuits really respond more to the flavors that were paired with calories compared to the ones that weren’t,” Small says.
A lot of our thoughts about why we want food, DiFeliceantonio argues, “is the narrative that we put on top of a subconscious process.” Stories like: “I like that meal because it reminds me of my grandmother’s cooking.” But that narrative isn’t necessarily correct or complete. You also might like that food because of its caloric content.
Sure, wanting can start off as a conscious liking, I’m told. Addiction, in a simplified sense, is the wanting system’s most extreme manifestation. And “addiction ... usually it starts with liking,” says Mehdi Farokhnia, a physician-scientist who studies addictive behavior at the National Institute on Drug Abuse. You do a drug because it’s pleasurable, you like it. But as the addiction progresses, “that liking aspect goes down.” You can detest a thing you crave. Or crave it not for pleasure, but to prevent something uncomfortable, like withdrawal.
Addiction reveals another of the wanting brain’s secrets: What we want doesn’t always reflect a physiological need.
“Older views presumed that our feeding, drinking, and other primary motivated behaviors were closely calibrated to our moment-to-moment physiological needs,” Leyton explains. But it’s not the case that if you miss a meal, you’re going to instantly die of malnutrition. “The great majority of food-seeking behaviors are unrelated to nutritional needs,” Leyton says.
Instead, the want system anticipates and preempts our physiological needs. But it can easily overshoot, or even choose targets seemingly without reason. For instance, sometimes patients with Parkinson’s disease, whose brains struggle to produce dopamine, will often go on dopamine replacement therapy. With these therapies, weird side effects can pop up. Sometimes, the want systems focus intensely on sex, binge eating, gambling, or shopping. “It’s like an addiction has developed,” Berridge says.
But why shopping, why gambling? What makes a person compelled toward one over the other? “We just do not have a clear understanding of how that happens in the brain,” Berridge says.
Turning down the dial of want
Sometimes wants seep into the conscious portion of our brains, shouting intrusive thoughts. But conscious does not mean the same as “in control of.”
“The messages I get from my brain are ‘you’re dying, you’re starving, you’re dying’ and they are constant,” says Sara, who was recently telling me about her “food noise” — i.e., intrusive thoughts about food — and whose last name I’m withholding for privacy reasons. Whenever she’d make progress in losing weight, the “food noise” in her brain would intensify.
“When I’m trying to do anything,” she says, there would be constant thought about food.
It’s not a pang of hunger, per se. “I think it’s more of an urge,” she says. “Like my body tells me ‘I need this.’”
Sara explained to me it was impossible to ignore. It was very hard to sleep when her brain was telling her “you need food right now” — even when she wasn’t hungry.
Stories like Sara’s underscore why asking people to engage in sheer willpower to subdue strong urges is a recipe for failure. Just look around. The US drug and opioid crisis continues unabated. Studies consistently find dieting and exercising are, in practice, ineffective solutions for weight management. It’s not that diet and exercise can’t work. There are success stories. But, arguably, if you were to evaluate the effectiveness of diet and exercise as a prescription for weight loss alone, you’d find they don’t help a lot of people.
When people engage in self-control to curb behaviors, they are fighting to use their conscious brain against their unconscious one. That’s never been a fair fight.
Remarkably, GLP-1 drugs could be leveling the playing field.
These drugs are called “GLP-1” because they mimic a naturally occurring hormone called Glucagon-like peptide-1. This hormone does a lot in the body, but in circuitous ways.
Primarily, it works on the pancreas to stimulate insulin, which lowers blood sugar. From there, it suppresses appetite through a few proposed mechanisms, including increasing the amount of time it takes for the stomach to empty, leading to feelings of fullness. “What they are doing is producing a sense of early satiety,” Small says.
These drugs aren’t perfect when it comes to weight loss. Many people struggle with side effects, such as nausea, or see their progress plateau. So far, GLP-1 drugs have mostly been studied in people with diabetes, heart disease, and obesity, so less is known about their effects on other populations.
Like any drug, they come with some risks. They’re known to increase the risk of developing thyroid cancer, for instance; they shouldn’t be taken during pregnancy; and despite more than a decade’s worth of safety data from diabetes patients (which show these drugs are, for the most part, very safe), scientists still don’t precisely understand how they work.
But a curious piece of the puzzle resides in the brain. GLP-1 drugs appear to work directly in the brain as a neurotransmitter, influencing neurons in the brain’s reward system, and in the hypothalamus, which regulates the body’s metabolism. The drugs are “probably not acting primarily on dopamine neurons per se,” Berridge says. “But they’re acting on the neurons that dopamine neurons are talking to.”
So, it’s complicated. But however the drugs are working, they seem to pull off a neat trick. They seem to tap into the wanting system, dialing it down while leaving liking intact.
“I still like food,” says Sara, who was prescribed the GLP-1 drug Mounjaro a few months ago after learning she was prediabetic. “Food tastes great to me. I just get to experience it in a way that I haven’t before.”
Most importantly, she gets to experience eating without that cruel voice in her head.
“About 24 hours after I took the first dose, there was just a calmness in my body and in my brain,” she says. “I wasn’t thinking about food.”
Finally, she was able to eat at mealtimes and not have intrusive thoughts in between. “That’s a very different way of living than I have been living for most of my life,” she says. Sara has lost 65 pounds with the medication. “And that is wonderful. But the peace part of it — that’s the best part of it.”
Researchers are now exploring whether this quieting of the wanting mind on GLP-1 drugs extends beyond food. Remarkably, this class of drugs has been showing promise in reducing cravings for other substances — like alcohol, nicotine, cocaine, and even opioids.
Theoretically this makes sense. “We only have one reward system,” DiFeliceantonio says. “There’s not a special reward system for food, and a special reward system for sex, and a special reward system for drugs.”
So, tapping into the reward system via appetite ought to impact cravings for other things. “There really isn’t a universe where we can impact food motivation and nothing else,” she adds. (Indeed, scientists have shown that the reverse is also true. Being hungry “increases motivation for drugs in many animal studies,” Berridge says.)
A lot of the evidence that GLP-1 drugs reduce cravings for drugs and alcohol is anecdotal. “There have been a lot of medical reports from patients,” Farokhnia, the NIH physician-scientist says. “People who took these GLP-1 drugs ... for their diabetes, obesity, other indications.” He says he’s heard reports from patients and colleagues that “they completely or almost completely lost their desire to drink alcohol or use drugs.”
Stories like this are starting to filter into scientific journals reporting on cases. Users have also taken to social media, where they marvel at their reduced cravings for alcohol.
The anecdotes are supported by evidence in animal studies, going back to the early 2010s. Rats on GLP-1 drugs seek out drugs and alcohol less than similarly addicted controls. Monkeys on GLP-1 also drink less. But human studies are starting to trickle out. One randomized control trial funded by Novo Nordisk (the maker of Ozempic and Wegovy) found that the GLP-1 drug exenatide decreased heavy drinking days, but only in obese patients.
At the recent American Association for the Advancement of Science conference in Denver, Colorado, researchers from Penn State presented unpublished data on a very small randomized control study (just 20 participants) using the GLP-1 drug liraglutide in an in-patient opioid withdrawal clinic.
The study found a 40 percent reduction in cravings among the participants taking the GLP-1 compared to people who did not (all participants in the study were also offered other medication for withdrawal, such as buprenorphine). Patricia Grigson, the Penn State scientist presenting the data, emphasized that reduction of craving is usually equivalent to 14 days of treatment as usual, which would cost around $15,000 in her clinic. “We do need to evaluate it in a larger population, but it’s very hopeful,” Grigson said.
Some words of caution: these data are not conclusive. But it is hopeful and could be huge if validated.
More clinical trials in humans are underway for a variety of substances — including alcohol and nicotine. And while scientists in this space feel these drugs can be a breakthrough, they urge caution. “I think it’s one of the most promising medications and targets we have had in the addiction field,” Farokhnia says. “But to make a conclusion, we do need to wait until data from clinical trials come out.”
Until then, the emerging picture is this: Though working primarily on appetite, GLP-1 drugs are potentially able to turn down the overall volume on the most intense wants.
GLP-1 drugs aren’t reducing wants for everything. The evidence suggests they are just tweaking the volume on the dial of desire.
“I’m looking at the preclinical data [i.e., animal studies], that’s how I interpret them,” Elizabet Jerlhag Holm, a pharmacology researcher who has conducted animal studies on GLP-1 and addiction behavior, says. GLP-1s tend to work on the most intense urges and cravings — perhaps even in areas like sex addiction, Holm notes.
Berridge agrees. “It may not be turning down the amplitude of all wants,” Berridge says. Instead, he thinks, “it’s sort of lowering the ceiling. Particularly strong wants, urges like addictive cravings and things, they might be blunted a bit.”
Are our desires purely chemical?
I asked Sara, the Mounjaro user, if she felt like a different person since starting the drug. “100 percent,” she said.
There’s already a pathway for GLP-1 drugs to become some of the most prescribed medicines in the US. They help with obesity and heart disease — each impact millions of people. Further research might see them more commonly used for people with substance use disorders, making the potential prescription pool for these drugs even larger. JP Morgan projects these drugs might reach 30 million US users by 2030.
In that case, how might they change our wants, collectively?
Might many people be nudged into feeling like a slightly different person, with different wants? Might they make a mark on society, economies? Already there’s evidence GLP-1 users are buying different products at the grocery store. Anecdotal reports abound on the drugs changing compulsive behaviors in subtle ways: users stop biting their nails, stop picking their skin. (As these drugs are tested in wider populations, Farokhnia says he’ll be looking out for instances of anhedonia — or a lack of interest and enjoyment in life.)
In all my conversations about wanting and liking, I couldn’t help but think about free will. If we’re so impacted by subconscious forces, so silently influenced by pharmaceuticals, are we just the sum of these chemical interactions?
“If you and I go for a drink together tonight, maybe I would answer that,” Leyton jokes, saying the question of free will is beyond his pay grade.
“Certainly we can exert free will over these processes,” he says when pressed. “When we walk by the fridge, and we find ourselves opening believing that we’re not hungry, we can stop ourselves. As an amateur, I think there is such a thing as free will even though much of our behavior, even though many of our tendencies, reflect preconscious phenomena. We can control things.”
Yes, we can control things, but when you have a voice in your head telling you you’re starving, like Sara did, you have to engage in that sense of control all the time, and it grows exhausting.
“I had kind of given up,” she said of her weight challenges. “I had decided if I don’t live a long life, then I don’t, because this is too painful.”
Sara told me that being on Monjouro changed that for her.
Too many people have been put in an unfair battle against their wants. They’ve been told to somehow exert willpower over a system they have little conscious awareness of and control over. This might be the most remarkable thing about GLP-1 drugs: At least in the realm of appetite, they can potentially tip this battle, giving people a dependable dial to turn down the wanting noise in their brain.
“It’s not just about our willpower,” Sara says of obesity. But the sentiment ought to be the same for people with addictions. “This is a disease that requires treatment, and there’s treatment that can now help us. And I think for a lot of people, that is really liberating.”
