The Big Story
GLP-1s are reshaping our neural circuitry
The internet is awash with anecdotal reports of patients on Ozempic and Wegovy suddenly losing their desire to drink, smoke, bite their nails, gamble, or compulsively shop. Now, the hard science is finally starting to catch up to the Reddit threads.
A major piece in the Washington Post this week detailed how scientists are discovering that GLP-1 receptor agonists are actively reshaping the brain. Alongside this, the Journal of Clinical Psychiatry outlines the evidence-based case for prescribing GLP-1s for persons with mental disorders.
Major Findings
It’s not just the gut: The drugs are acting directly on the central nervous system, dampening the brain’s reward circuitry and modulating dopamine release.
University of Colorado Anschutz researchers imaged the brains of 13 young women with PCOS before and after starting GLP-1 therapy. Within months, connectivity in the salience network — the brain system that decides what gets your attention and how rewarding it feels — had multiplied.
Psychiatric applications: The JCP commentary establishes “aspirational targets” for GLP-1s, suggesting they could soon be frontline treatments for specific mood disorders and cognitive impairments associated with psychiatric conditions.
A solution to the plateau problem: Meanwhile, researchers at the NIH have identified the mechanism behind the dreaded GLP-1 weight-loss plateau, successfully using roflumilast in animal models to rescue the weight-loss effect by targeting cellular pathways in the brain.
Access remains a massive hurdle: Patients with severe eating disorders — who could theoretically benefit from the metabolic and psychiatric stabilization of GLP-1s — are finding access practically impossible due to restrictive prescribing guidelines and insurance walls.
Our Thesis
Time for psychiatry to undergo a well-deserved existential crisis
The medical establishment is built on distinct, rigid silos. Psychiatrists deal with the brain. Endocrinologists deal with hormones. Bariatric doctors deal with fat.
Following this artificial delineation, the standard of care in psychiatry has been SSRIs and atypical antipsychotics — drugs notorious for causing massive weight gain, metabolic dysfunction, and emotional blunting.
Much of western medicine has long operated under the illusion that the brain sits in an ivory tower, largely divorced from the rest of the body. Of course physicians would prescribe psychiatric medications that directly target the brain — the notion that chemicals produced in the gut could influence patient psychology seems patently absurd.
But this model began to break down when physicians started realizing the most effective psychiatric drug of the decade is a diabetes medication (turned obesity medication, turned longevity medication).
It’s the food, dummy
Many in the psychiatric establishment have historically ignored — or been heavily incentivized by Big Food and Big Pharma to suppress — the undeniable link between what we consume and how our brains function.
To be blunt: we are being metabolically poisoned by an ultra-processed food supply, and that systemic damage is manifesting as psychiatric illness.
Turns out that by prescribing GLP-1s, an obesity medicine specialist at your local med spa might accidentally do more good for your mental wellbeing than an army of Harvard-trained psychiatrists.
We are already seeing endocrinologists and primary care docs inadvertently treating depression and substance use disorder simply by fixing their patients’ metabolic health. Psychiatrists are going to have to learn metabolic medicine, and fast.
It’s still an uphill battle
Because GLP-1s aren’t FDA-approved for psychiatric indications, insurers won’t currently cover them for mood disorders.
We are looking at a lost decade where millions of patients could be freed from compulsive behaviors and debilitating mental illnesses, but will be denied care simply because the mechanism of action isn’t well-understood (after all, why would a drug designed to fix the pancreas fix the brain?).
Plus the billing codes don’t match up — and isn’t that the most egregious sin of all?
Other News You Should Know
The VA steps up on psychedelics: The VA is moving forward with psychadelic medicine trials. They just launched a clinical trial for MDMA-assisted therapy targeting dual-diagnosis veterans with both PTSD and Alcohol Use Disorder. (VA Press Room / Marijuana Moment)
Taking the daily pill out of addiction recovery: A new study shows that monthly injectable buprenorphine cuts return-to-use rates by an astonishing 3.5x (or more — up to 8.1x) compared to daily oral dosing. (GlobeNewswire)
Turns out that simply removing the daily friction of forcing a patient to actively choose their medication over a high is the ultimate behavioral hack for dramatically improving recovery outcomes.
The Supreme Court ghosts Meta: SCOTUS refused to hear Meta’s appeal against Vermont’s social media addiction lawsuit. (Reuters)
This means the tech giant can’t hide behind Section 230 to protect its deliberately addictive design features (like infinite scroll and autoplay). The floodgates for litigation remain open.
The Techlash finally hits the classroom: The Los Angeles Unified School District passed a resolution banning all digital devices, including laptops and tablets, for students through the second grade. (Fortune)
EdTech is facing big headwinds as administrators finally realize that handing a glowing dopamine dispenser to a six-year-old is terrible for learning (and terrible for building productive future citizens).
Opioid analogs, now at your local gas station: A kratom-based beverage called “Feel Free” is popping up in convenience stores, heavily marketed as a natural wellness and productivity drink. Users are ending up in five-week inpatient rehabs with severe withdrawals. (CBS Chicago)
It’s a classic “American Addiction Economy” story: highly addictive, unregulated, psychoactive compounds sold next to the beef jerky at the corner store.
Overdoses are dropping — unless you’re in the southwest: National street drug deaths are continuing to drop, with Oregon seeing a massive plunge in opioid fatalities. But some Western states (particularly in the southwest) are bucking the trend and experiencing a deadly surge of fentanyl overdoses. (NPR / MindSite News)
Eli Lilly’s $4 Billion hedge: What do you do when your obesity drug cash cow is printing money but you’re afraid the milk will run dry? You buy three vaccine companies for $4 billion, of course. (STAT)
Lilly is aggressively diversifying its GLP-1 cash hoard before the weight-loss market inevitably commoditizes.
Unfiltered
Anti-Microdosing Hysteria Hurts Patients
A Harvard MD took to STAT News this week to sound the alarm on a “““terrifying””” new epidemic sweeping the nation: GLP-1 “microdosing.”
Dr. Jody Dushay, an endocrinologist at Beth Israel Deaconess, penned an op-ed warning patients against taking fractional doses of semaglutide or tirzepatide. Her argument hits all the standard establishment talking points:
Microdosing is a cosmetic vanity project
It’s only being peddled by direct-to-consumer telehealth startups
Compounded semaglutide and tirzepatide have no clinical utility
Potential applications of microdosing are completely unsupported by clinical trials
Her solution? Stop taking compounded or titrated doses, take only the FDA-approved heavy doses, or wait until pharmaceutical companies publish rigorous data on smaller doses.
This is a classic example of medical paternalism, especially when it comes to promising new applications like addiction treatment.
1. Microdosing is about treating patients without starving them
Dr. Dushay assumes anyone taking a fraction of a dose is just trying to shed three pounds before a beach vacation. But there’s a substantially more interesting application of microdose GLP-1s beyond weight loss.
As we saw in The Washington Post this week, GLP-1s directly restructure the brain’s salience network, blunting the dopamine hit of alcohol, cocaine, or junk food. Most excitingly, these neurological effects can occur at much lower concentrations of GLP-1s versus what’s needed to acheive a 20% reduction in body mass.
If an addiction clinician is treating a normal-weight patient for alcohol use disorder, hitting them with a maximum 2.4mg dose of Wegovy is a terrible idea. It causes severe nausea, rapid muscle loss (sarcopenia), and malnutrition. Microdosing delivers just enough of the molecule to quiet the brain’s reward circuitry without carpet-bombing the patient’s gut.
2 & 3. The compounding “boogeyman” is a critical lifeline for patients
Dr. Dushay waves away compounded GLP-1s as unregulated snake oil sold by Instagram clinics. The reality is that compounding pharmacies (both 503As and 503Bs) are highly regulated by state boards and the FDA.
More importantly, they are the only functional mechanism for precision dosing in addiction treatment today. Brand-name auto-injectors dispense rigid, massive doses designed strictly to maximize weight loss. Compounded vials allow a physician to titrate a dose down to the exact microgram needed to extinguish a patient’s cravings.
Furthermore, since US insurers categorically refuse to cover brand-name GLP-1s for off-label addiction treatment, cash-pay compounded microdoses are the only way the vast majority of substance use disorder patients can afford the drug.
Demanding they stop means telling patients to buy a $1,200 brand-name pen they don’t need, to inject a dose that is too high, to treat a condition the pen wasn’t designed for.
4. The “no clinical data” argument is too dismissive
Dr. Dushay pretty heavily implies that microdosing is “unsupported by rigorous clinical trials.”
On the safety front, this is highly misleading. Novo Nordisk and Eli Lilly have already spent billions proving that smaller doses (like 0.25mg and 0.5mg of semaglutide) are incredibly safe. They are the FDA-approved titration steps for Wegovy and the baseline maintenance doses for Type 2 diabetes. Millions of people take them weekly.
Meanwhile, the data on GLP-1s for addiction is undeniable. A recent Lancet RCT proved semaglutide cuts heavy drinking days by 41% in AUD patients. Massive cohorts (including 95,000 patients in Sweden and 600,000 US veterans) show GLP-1s slash overdose rates and SUD-related mortality by nearly half.
Once an RCT proves a molecule successfully treats the brain, titrating the dosage down to the lowest effective threshold to minimize severe GI side effects is the rational clinical next step. And unlike weight loss, addiction treatment shows much more promise at smaller doses.
Many patients don’t have the luxury of time
Dr. Dushay acknowledges that smaller doses might eventually prove useful for targeted treatments but demands patients wait for the pharmaceutical companies to run the trials and the FDA to grant permission.
For a patient currently drinking themselves into liver cirrhosis, waiting five years for a clinical trial that pharma has zero financial incentive to run is an obvious death sentence. They’re not going to wait for permission.
Patients (and frontline clinicians) are taking greater ownership of their health. They are experimenting with different doses, managing their own side effects, and breaking their addictions using compounded GLP-1s.