"Ozempic may be reshaping the brain, scientists say"

From the Washington Post, May 28:

GLP-1 drugs may be rewiring circuits involved not only in appetite but in emotion, desire and beyond. 

Ozempic was supposed to be a gut story. Then Allison Shapiro looked at the brain scans.

An assistant professor at the University of Colorado Anschutz, she was part of a team studying 13 teens and young women with a hormonal disorder affecting the ovaries who were put on GLP-1 drugs. As part of testing to catalogue the effect of the medication on their bodies, Shapiro took snapshots of their brains before and after.

She was astonished to find extensive changes.

Within only a few months, the brain connections in the salience network, which helps target attention, had multiplied.

“We didn’t expect to see this effect, and we really don’t know what it means,” Shapiro said.

Ozempic and other GLP-1 drugs were initially understood as a metabolism breakthrough: medicines that act like hormones to control hunger, blood sugar and weight. But as researchers probe deeper into how the drugs work, early evidence suggests that GLP-1s may also be reshaping parts of the brain.

Tens of millions of people are now taking the medications worldwide, turning what began as an obesity and diabetes treatment into what could be modern medicine’s largest unplanned neuroscience experiments.

Scientists are studying GLP-1 drugs — medications that mimic the hormones involved in appetite, blood sugar and digestion — for how they affect not only eating behavior, but also addiction, cognition, neurodegeneration and even motivation and pleasure. The category includes older diabetes drugs that researchers have studied for decades; newer medications such as Ozempic and Wegovy, which contain semaglutide; and Mounjaro and Zepbound, which contain tirzepatide — a newer compound that targets both GLP-1 and a second metabolic hormone known as GIP, a distinction some scientists believe may matter neurologically.

The emerging research on GLP-1s is part of a larger scientific shift away from treating brain and physical health as separate domains. Increasingly, researchers see them as tightly intertwined.

Exercise is associated with sharper cognition, stronger memory and better executive function across a person’s lifespan, probably because it enhances neural activation and plasticity — the brain’s capacity to adapt and reorganize itself. Diet exerts its own influence; eating balanced, nutrient-dense foods has been linked to greater gray matter volume and improved mental well-being.

But not all of the reported mental effects of GLP-1 drugs have been positive. On social media and at doctor’s offices, some users have reported a type of brain fog and others something broader and harder to define: a strange emotional flattening. People describe less pleasure, less motivation, diminished interest in hobbies and even reduced sexual desire.

Those accounts are beginning to raise deeper questions about what, exactly, these drugs are changing. If GLP-1s alter the brain systems involved in reward, craving and motivation, researchers wonder, where is the line between quieting a person’s destructive impulses and reshaping personality itself?

The mystery of the mechanism
The hormones and receptors targeted by GLP-1 drugs form a vast communication network that stretches far beyond the stomach. Naturally activated after eating, the system helps regulate hunger, blood sugar and digestion — but its receptors are also scattered throughout the body, including in the heart and deep within the brain.

Scientists are still in the early stages of investigating how GLP-1 drugs affect neural networks. Because the medications are relatively large molecules, researchers remain uncertain how much of them can cross the blood-brain barrier, a protective membrane that shields the brain from the bloodstream.

That uncertainty has raised a larger question: Are the drugs acting directly on the brain, or are they reshaping the nervous system more indirectly by reducing inflammation, improving metabolism and easing stress on the body?

Researchers suspect that both may be true. Some studies suggest the drugs help reduce inflammation that can damage neurons over time, while other research indicates the medications may help brain cells survive and function more effectively.

More on GLP-1s

• 13 surprising ways GLP-1s may benefit the body, according to science
• If you aren’t losing weight with GLP-1 drugs, this may be one reason why
• People with eating disorders are taking GLP-1s, and doctors are alarmed

One leading theory is that GLP-1 drugs may reduce inflammation in the brain. Researchers think the medications could quiet overactive immune cells that, when repeatedly triggered, may contribute to damage and cognitive degeneration over time. Other scientists suspect the drugs may act more directly on brain cells themselves, helping them function more efficiently and resist stress. These two effects may be happening simultaneously.

Researchers are also investigating whether this process originates in the gut rather than the brain. Naturally occurring GLP-1 hormones communicate with the brain through the vagus nerve, the long signaling pathway connecting the digestive system and brain stem that guides sensations of hunger and fullness. Scientists suspect those same gut-brain circuits may also influence mood, craving and cognition.

Rewiring addiction and desire
Long before Oprah Winfrey and social media influencers helped popularize GLP-1 drugs, physician-scientist Lorenzo Leggio was studying them as a possible addiction treatment.

After seeing a 2013 study in Sweden showing that rodents given a GLP-1-like medication consumed less alcohol, Leggio — the clinical director and deputy scientific director at the National Institutes of Health’s National Institute on Drug Abuse — replicated the findings and has been investigating ever since.

Leggio and his team have built a mock bar where participants are exposed to alcohol-related cues — smells, sights and other triggers associated with craving — while their physiological and behavioral responses are measured in real time. Participants also move through virtual-reality environments, including a cafeteria simulation in which they are asked to choose foods, allowing scientists to study how desire and decision-making may shift under the drugs’ influence.

Researchers have long known that addiction is associated with hyperactivity in brain circuits connected to reward, craving and reinforcement. Scientists suspect GLP-1 drugs may dampen the brain’s dopamine-driven reward systems that determine what feels pleasurable and worth repeating — which could lessen these urges. They are also investigating whether the drugs affect the amygdala, which helps regulate fear, stress and emotional processing.

Eli Lilly, which manufactures tirzepatide under the brand names Mounjaro and Zepbound, has launched a large clinical trial expected to conclude by the end of this year or early next year examining whether the drug could help treat alcohol-use disorder.

Several major studies examining GLP-1 drugs on nicotine dependence, opioid- and cocaine-use disorders, gambling addiction and binge eating are also underway.

“It’s very exciting times, but we don’t fully understand how it works,” Leggio said.

Many patients have described a quieting of “food noise” — the constant mental pull toward eating that many had lived with for years. But the same mechanisms that curb destructive cravings could also suppress healthy desires, a shift some on the medication have reported.

“If you think about it from a survival standpoint, some of the foundational behavior such as eating and sex could be impacted,” Leggio said. Still, he noted, the Food and Drug Administration has repeatedly reviewed available safety data and has not concluded that this is a widespread problem....

....MUCH MORE 

 So we're running a giant, unplanned, neuroscience project.

Let's hope it all works out.