1. Practice

Two things to say out loud if you take one of these drugs.

Semaglutide and tirzepatide, sold as Ozempic, Wegovy, Mounjaro, and Zepbound, work by turning down appetite and slowing the stomach. That is the mechanism and it is the whole point. The part that has been slower to arrive: appetite is also how a body gets its vitamins. Turn it down and the vitamins go down with it.

Most of the time that is fine. Bodies carry reserves. But the reserves are not equal. The body stores years of B12 and months of iron. It stores about three weeks of thiamine, vitamin B1.

Thiamine is the vitamin the brain needs to burn sugar. Run out and the brain fails in a specific way: confusion, a walk that goes unsteady, eyes that will not track together. That is Wernicke's encephalopathy. Caught early, it is treated with a few dollars of thiamine. Caught late, the memory damage can be permanent. For a century medicine has taught it as an alcoholic's disease. It is a starvation disease. Alcohol is just the most common way to starve.

First thing to say out loud: the vomiting is the warning.

Nausea is expected on these drugs. Vomiting that goes on for weeks is different. In the case series below, every patient had weeks of gut symptoms and fast weight loss before the brain gave out. The gut trouble is the warning. The brain is the end of the story.

So split it in two.

If you are keeping food down but eating far less and losing weight fast, ask for a thiamine blood level at your next visit, and make sure some thiamine is coming in every day, from food or a multivitamin. A plain multivitamin covers it, which is the Product slot this week.

If you are vomiting most days and your thinking has gone soft, do not reach for a pill. Nothing you swallow is absorbing reliably. That is an emergency department visit. The treatment goes in through a vein. Do not wait for a level. In the hospital we treat on suspicion and let the test confirm us later, because the vitamin is cheap and the miss is permanent.

Four weeks ago I wrote about hospitalized veterans who did not drink. One in four was low on thiamine, and the most common sign was loss of appetite, not confusion (Diseases, 2026). A separate VA clinic checked thiamine in patients with obesity before any surgery. About a third were already low (Obesity, 2025). The people these drugs are prescribed to start the race behind.

Second thing to say out loud: tell the person holding the airway.

The same slowed stomach that keeps you full for hours does not empty on schedule for a procedure. Researchers pooled 13 studies and about 84,000 patients having an upper endoscopy, the camera exam of the stomach. After a standard fast, people on a GLP-1 were about four times as likely to still have food in the stomach, and more of their procedures were called off on the table (Clinical Gastroenterology and Hepatology, 2025). Food in a stomach under sedation can go into the lungs.

The guidance changed in late 2024. Five medical societies, the anesthesiologists among them, now say most people can stay on the drug before a procedure. People who are still climbing the dose, on a high dose, or having nausea, vomiting, or constipation get extra precautions. That can mean a day of clear liquids beforehand, a bedside ultrasound to check the stomach, or a different way of protecting the airway while you are asleep. The older 2023 rule, holding the weekly shot for a week, still shows up on some pre-op instructions.

None of that happens if the anesthesiologist does not know you take it. The scheduler and the surgeon's nurse are not enough. Tell the person holding the airway.

2. Publication

One paper worth reading, in three sentences.

Two researchers, one of them the Korsakoff's specialist in this week's Person slot, searched the medical literature for every published case of Wernicke's in a person taking semaglutide for weight loss, and found six (Bidesie and Oudman, Obesity, 2026). All six had weeks of gut symptoms and heavy weight loss before the neurological collapse, and the outcomes were poor in several, including permanent memory loss and death.

A separate group went through the FDA's side-effect reporting database this year and found 15 cases. Wernicke's was reported a little more than twice as often on these drugs as on other medications, and 7 of the 11 patients with follow-up had lasting neurological damage (Clinical Nutrition, 2026).

Six cases earn the slot because of what they share. Every one of them had a warning phase. Weeks of it. The drug did not cause a sudden collapse. It caused a slow starvation that a blood test could have seen and a few dollars of thiamine could have stopped. The authors' recommendation is the whole issue in one line: when someone on one of these drugs cannot keep food down or is losing weight fast, think thiamine early, and give it through a vein before the brain fails.

Millions of people take these drugs and the overwhelming majority are fine. Nothing here says the drug is dangerous. It says a drug that turns off appetite will run short on the things appetite was delivering. We have known how to prevent this particular shortage since the 1930s.

3. Product

This week's pick: a multivitamin. Unsponsored, no affiliate relationship, no brand.

After weight-loss surgery, a daily multivitamin for life is standard of care. The bariatric surgery society's guidelines say every post-surgery patient should take at least 12 milligrams of thiamine a day, about ten times the daily value (Surgery for Obesity and Related Diseases, 2017). The reasoning is simple. A stomach taking in a fraction of what it used to cannot be trusted to deliver every vitamin. The newer drugs produce surgery-scale drops in intake in some people, and nobody wrote the equivalent rule for the shot.

A review this year pooled six studies and about 480,000 adults on GLP-1s. Vitamin D deficiency rose from about 8 percent at six months to about 14 percent at a year. Iron stores ran roughly a quarter lower than in comparison patients on a different diabetes drug. More than 60 percent of users were eating less calcium and iron than they need, and thiamine and B12 deficits widened the longer people stayed on treatment (Clinical Obesity, 2026). These are observational data and cannot prove the drug did it. They do not need to. Eating less does it.

What to look for: thiamine, B12, iron, vitamin D, and calcium listed at or near 100 percent of the daily value. Skip the “proprietary blends.”

4. Person

One person worth following in this space.

Erik Oudman, a neuropsychologist at Utrecht University who works at the Slingedael Korsakoff Center in Rotterdam, and the senior author of this week's paper.

Korsakoff's syndrome is what Wernicke's becomes when nobody catches it: a permanent inability to form new memories. Oudman spends his working life with the people it happened to. From there he has spent more than a decade taking apart one sentence in every textbook, the one that says this is an alcoholic's disease. He has published systematic reviews of Wernicke's in people who do not drink: after bariatric surgery (2018), in the severe vomiting of pregnancy (2019), in anorexia (2018), in depression (2020), in schizophrenia (2021), in Crohn's disease and colitis (2021), in kidney disease (2024), and in children (2025). Now semaglutide.

Read them in order and a pattern appears. The trigger changes every time. The disease does not. Anyone who stops eating for long enough, for any reason, is on the same clock, and the clock runs about three weeks.

Most of medicine learned this disease on the alcohol ward and filed it there. Oudman documents everyone the filing system missed. His papers are on Google Scholar under his name, and the reviews are plain and free to read.

These drugs work. They lower weight, they lower blood sugar, and the outcome trials show fewer heart attacks. They also change how a person eats. That changes a hundred small things a month, like how the gut behaves and whether the nausea is a bad Tuesday or the third bad week in a row. Almost none of that gets written down. The prescriber sees a weight and a blood pressure every few months. The patient remembers the last few days.

Every case in this week's paper had a warning phase measured in weeks. The information existed. Nobody was holding it in one place.

That is what MeNome is for, our free app at menome.belly-md.com. It does not diagnose anything. It keeps the record, a minute a day, so that when the nausea has been there for three weeks you know it has been three weeks, and so does the person who can do something about it.

We wrote the rule for the surgery and forgot to write it for the shot.

That's the four. See you next week.

Rick

From BellyMD

MeNome is our free app for keeping your own record. A minute a day on your gut, sleep, mood, and energy, and over time it shows you what shows up together. It lives at menome.belly-md.com.

I also make MGB+, a small line of gut-brain supplement formulas: Clear, Cool, and Calm, at belly-md.com. Structure-function support, not a treatment for any disease.

If you want to talk through your own gut-brain picture with me directly, I offer a gut-brain consultation (educational, 500 dollars). Details at belly-md.com.

Not medical advice. This newsletter is for education and does not create a physician-patient relationship. Nothing here is a diagnosis or a prescription. Talk to your own physician before starting, stopping, or combining any medication or supplement, including over-the-counter ones.

1. Practice

A molecule you do not make, in four diseases you have heard of.

Histidine is an amino acid, one of the building blocks of protein. It is in eggs, meat, fish, dairy, beans, and whole grains, and you cannot live without it. Your own cells break it down one way. Some of the bacteria living in your gut break it down another way, and their version leaves behind a compound called imidazole propionate. ImP for short. You do not make it. Something living in you makes it, out of a nutrient you cannot stop eating.

For most of medical history that would have been trivia. Then people started measuring it.

In 2018, Ara Koh and Antonio Molinaro, working in Fredrik Bäckhed's lab in Sweden, found that people with type 2 diabetes carry more ImP in their blood (Cell, 2018). Then they showed why it matters. ImP jams the signal insulin uses to tell your cells to take up sugar. Fed to mice, it made their blood sugar control worse. A waste product from a gut microbe, interfering with a hormone.

In 2025, a team in Madrid moved the story to the artery wall. They gave ImP to mice prone to artery disease, kept them on ordinary food, and the mice built plaque anyway, with no change in their cholesterol (Nature, 2025). The damage ran through inflammation. ImP flips a switch on immune cells, and blocking that switch stopped the plaque from forming. Plaque, with a clean cholesterol panel, driven by a molecule no standard blood test will ever see.

Two weeks ago the human outcome data landed. Across roughly 7,000 patients with coronary artery disease in four European studies, people with high ImP died more, had more heart attacks, and had more strokes, even after accounting for every standard risk factor (European Heart Journal, 2026). In one group, the highest levels more than doubled the risk of dying.

And late last year, a lab at UCLA showed the molecule does not stop at the body. ImP gets into the brain and changes activity in the hypothalamus, the deep region that runs hunger and stress (Cell Host Microbe, 2025). Mice with more ImP showed more stress behavior. In people, higher levels went along with worse stress coping and more emotional eating.

That is diabetes, artery disease, cardiovascular death, and stress. One molecule, made by a tenant.

Now the part almost everyone gets wrong.

You cannot order this test. ImP is measured on research equipment after special sample handling. There is no version your doctor can order, and no home kit worth your money. Anyone selling you one is ahead of the science.

The answer is not to eat less protein. This is the first place everyone goes, and the data say no. In a study of nearly 2,000 Europeans, the people with high ImP were not eating more histidine than anyone else (Nature Communications, 2020). What set them apart was the rest of the plate: less fiber, fewer vegetables and nuts, more saturated fat, mostly from cheese. The signal is not how much histidine goes in. It is who gets to it first.

And the microbe does not need to be common. Federico Rey, one of the senior scientists on this week's paper, put it plainly: the bacteria that make ImP live in a large fraction of people, but in small numbers, and a microbe does not have to be abundant to matter. We tend to picture the microbiome as a census, as if the answer is in the percentages. Sometimes the answer is one rare organism running one chemical reaction nobody else in the room can run.

2. Publication

One paper worth reading, in three sentences.

Researchers at the University of Wisconsin measured ImP in the blood of 1,196 adults whose memory and thinking tested normal, average age 61, and the people with more of it scored lower on tests built to catch the earliest slipping, and carried more of two blood markers that rise when brain cells are being damaged (Vemuganti, Kang, and colleagues, Nature Communications, 2026). The paper added two more legs: a common gene variant that raises blood ImP has also been tied to Alzheimer's risk in large genetic studies, and in mice, ImP in the drinking water meant more amyloid plaque in one Alzheimer's model, more of the tangled tau protein in another, and a leakier barrier between the bloodstream and the brain in ordinary animals. Hold it honestly, because the authors do: this shows a link, not proof of cause, the volunteers were mostly white and mostly women, and when I asked the first author whether the kidney explanation behind that gene finding was backed by kidney data yet, he told me straight out that it is not, that it is a working hypothesis, and that better data is a year or more away.

That last answer is why this is the pick.

3. Product

This week's pick: a bag of mixed nuts. Unsponsored, no affiliate relationship, no brand, and obviously not a BellyMD product.

Vegetables and nuts were the two food groups most clearly missing from the high-ImP diet in that European study. Nuts are also the food group with a real randomized trial behind them. In Spain, the PREDIMED trial assigned 7,447 adults at high heart risk to a Mediterranean diet with olive oil, the same diet with mixed nuts, or a low-fat control diet. The nut group had about a 28 percent lower rate of heart attack, stroke, or death from heart disease (New England Journal of Medicine, 2018).

Two honest notes, and the first matters more than the pick. That trial was published in 2013, pulled back by its own authors in 2018 when they found enrollment problems at a few sites, reanalyzed the hard way, and republished. The result held. A trial that caught its own error and survived the correction is worth more than one nobody ever checked.

Second: nobody has shown that eating nuts lowers ImP. The pick stands on the diet pattern being the same one, the trial being real, and the downside being a bag of almonds.

4. Person

One person worth following in this space.

Vaibhav Vemuganti, a graduate student at the University of Wisconsin-Madison, and first author on the paper above. He works between two labs that do not usually share a hallway: Federico Rey's, which studies gut bacteria, and Barbara Bendlin's, at the Wisconsin Alzheimer's Disease Research Center, which has been collecting blood samples and memory tests from the same volunteers for years. Neither lab could have produced this paper alone.

The senior authors have the titles. Vemuganti gets this slot because of how he showed up. I made a short video about his paper, and he found it and wrote to me first, with a thank-you, his mentor copied in, and an offer to answer questions. He answered every question in under a day, sent me the exact page where the gene data lives so I could look for myself and then, unprompted, told me what people were getting wrong about his own work: readers were concluding they should stop eating protein, and the data do not say that.

One more thing, and it is the reason the slot stayed his. When he read a draft of this issue, he wrote back asking me to add other people's names. Jea Woo Kang, at the Wisconsin Alzheimer's Disease Research Center, led the work connecting ImP to memory and blood markers in living people. James Hilser and Hooman Allayee, at UCLA, brought the genetics behind the gene finding. And he wanted credit paid upstream, to Fredrik Bäckhed's group in Sweden, where Ara Koh and Antonio Molinaro did the original work that made anyone care about this molecule at all.

He had a blank slate to spread his message and he used it to name six other people.

He’s reachable, too. He is on LinkedIn at linkedin.com/in/vaibhav-vemuganti-a7b79a183, and he wants questions from anyone who reads this. Take him up on it. The first author of the paper you just read about is almost never someone you get to ask.

A scientist who tells you what his own paper does not show, and who hands the credit to other people, is worth ten who do neither.

Barbara Bendlin, the other senior scientist, described where she wants this to go, and it is the most useful sentence in all the coverage. If someone finds a drug that lowers ImP, this becomes cholesterol: a number, with a drug, and a decision.

We are not there. But notice what had to be true for anyone to even ask. ImP was named in 2018. The Wisconsin volunteers had been giving blood and taking memory tests for years before that, back when nobody knew this molecule existed, let alone that it was worth measuring. The discovery did not need a new study. It needed a record that already existed, sitting in a freezer, waiting for a question nobody had invented yet.

That is the entire argument behind MeNome, our revolutionary patient symptom tracking app. We cannot tell you what your daily symptoms will turn out to mean. Nobody can yet. That is exactly why the record has to start now…you cannot go back and measure a year you did not record.

That's the four. See you next week.

Rick

From BellyMD

MeNome is our free app for keeping your own record. A minute a day on your gut, sleep, mood, and energy, and over time it shows you what shows up together. It lives at menome.belly-md.com.

I also make MGB+, a small line of gut-brain supplement formulas: Clear, Cool, and Calm, at belly-md.com. Structure-function support, not a treatment for any disease.

If you want to talk through your own gut-brain picture with me directly, I offer a gut-brain consultation. Details at belly-md.com.

Not medical advice. This newsletter is for education and does not create a physician-patient relationship. Nothing here is a diagnosis or a prescription. Talk to your own physician before starting, stopping, or combining any medication or supplement, including over-the-counter ones.

1. Practice

The line that stopped being a measurement and became a diagnosis.

In 1569 Gerardus Mercator published a map that solved a problem sailors had been losing to for a century. Plot a course on it and a line of constant compass bearing comes out straight. Set the heading, hold it, arrive.

The bargain was area. His projection stretches the world as it climbs away from the equator, and at the top it is grotesque. Greenland looks about the size of Africa. Africa is fourteen times larger. Mercator knew this. He was solving a navigation problem, he solved it completely, and four and a half centuries later his map still hangs in classrooms where nobody is plotting a course.

Something close to that happened to the ECG.

Nobody explains this part to patients. When you arrive with chest pain, the tracing gets measured against a threshold: one millimeter of ST elevation in two neighboring leads. Clear it and you are a STEMI, the alarm goes off, and a team gets called in from home to open the artery now. Miss it and you are an NSTEMI, which is treated as the serious-but-not-emergent kind, and you get admitted, medicated, and scheduled.

That millimeter was not handed down from biology. It was drawn in the 1980s to decide who should receive a clot-dissolving drug that caused bleeding into the brain in close to one percent of the people who got it. With a risk like that, the diagnosis had to be near-certain before anyone reached for the syringe. The threshold was set high on purpose, and for that question it was the right answer.

Then we hung it on the wall. STEMI and NSTEMI stopped describing a tracing and started describing an artery.

The artery did not agree.

Researchers pooled 25 studies covering 60,898 patients who carried an NSTEMI diagnosis and looked at what the catheterization actually found. Thirty-four percent had a completely blocked culprit artery, and those patients had roughly 70 percent higher odds of dying and 66 percent higher odds of going into cardiogenic shock than the NSTEMI patients whose arteries were open (Hung et al., Crit Care 2018;22:34). One in three patients we file under not-blocked is blocked.

It replicates. An independent cohort of 1,128 NSTEMI patients in China found complete occlusion in 25.4 percent, and over 3.6 years those patients ran a 46 percent higher risk of death, another heart attack, stroke, or unplanned repeat procedure, after adjustment (Am J Cardiol 2025, published November).

Then there is the part that should be hard to read. In a study of 808 patients with suspected heart attack, the ones whose arteries were blocked but whose ECG never crossed the line had the same infarct size and the same mortality as the ones whose ECG did cross it. What they did not have was the same speed. They waited longer to get to the catheterization lab (Meyers et al., Int J Cardiol Heart Vasc 2021;33:100767). Same damage, same risk of dying, slower response, and the only thing separating the two groups was whether the injury happened to register above an arbitrary line.

The same paper showed the information was on the tracing the whole time. Blinded readers trained to look for occlusion patterns rather than millimeters caught 86 percent of the blocked arteries. The millimeter criteria caught 41 percent.

Hospitals measure door-to-balloon time. It is reported, benchmarked, and enforced, and it is the reason STEMI care in this country got dramatically faster over twenty years. There is no clock at all for the patient whose artery is shut and whose ECG stayed under the line. That delay produces no dashboard entry and no missed-metric report. To every quality system in the building, it looks like an appropriately managed NSTEMI.

The harm is not hidden. It is unmeasured, which is a far more durable condition, and it is how this survived two decades of quality machinery aimed directly at chest pain.

What to do with this.

"It's not a STEMI" does not mean "your artery is open." It means the tracing did not clear a threshold. Those are different sentences, and the second one is the one you want answered.

Ongoing pain is information, and it expires. Say it out loud, say it again when it does not stop, and ask for a repeat tracing. A single ECG is a still photograph of a moving process. If you or someone you are with is still hurting, that is worth saying every time somebody new walks in.

There is a question you can ask, and it is a fair one. Is anyone considering that the artery could be completely blocked even though the ECG doesn't meet criteria? In 2025, the American College of Cardiology, the American Heart Association, and the American College of Emergency Physicians jointly published a guideline naming several ECG patterns that call for emergency artery-opening even though they never reach the millimeter (Rao et al., Circulation 2025;151:e771-e862). The obligation has changed.

And one thing in fairness. The objection from the cath lab is legitimate. Every unnecessary activation means contrast, radiation, and a team driving in at three in the morning for something that turns out not to be a heart attack. The reading that caught 86 percent of blocked arteries gave up a few points of accuracy in the other direction to do it, and at national volume that is not free. The criteria were built to guarantee a floor, so that no reasonable cardiologist would argue with the call. Treating a floor as the ceiling is the error, and it belongs to those of us reading the tracing, not to the people answering the phone.

2. Publication

One paper worth reading, in three sentences.

Researchers searched three databases without language restriction, pulled every study of adults diagnosed with NSTEMI that reported what the angiogram showed, and pooled 25 studies and 60,898 patients to ask a question the diagnostic category had made it easy not to ask: how many of these people had a closed artery (Hung CS, Chen YH, Huang CC, et al., Crit Care 2018;22:34, doi 10.1186/s13054-018-1944-x). The answer was 17,212 of them, 34 percent, with a 95 percent confidence interval of 30 to 37, most often in the left circumflex, the vessel whose territory the standard twelve-lead ECG sees worst. Hold it honestly, because the authors do: these are observational cohorts rather than randomized trials, the individual studies varied in how they defined a culprit lesion, and the paper's own conclusion stops at whether these patients should be treated more aggressively "warrants further study" rather than claiming the case is closed. What makes it my pick is that the finding was always available. Nobody needed a new technology or a new trial. Somebody had to ask a question the category discouraged.

3. Product

This week's pick: a blood pressure cuff that has actually been tested. Unsponsored, no affiliate relationship, no brand, and obviously not a BellyMD product.

This issue is about a measurement determining a decision. The measurement you control at home is your blood pressure, and most of the devices sold to consumers have never been through a formal accuracy validation protocol. Not failed one. Never taken one.

There is a free public list. The American Medical Association runs the US Blood Pressure Validated Device Listing at validatebp.org, reviewed by an independent committee of physician experts. Search the model before you buy it. If it is not on the list, it has not been checked.

Use an upper-arm cuff. Wrist devices are not recommended for routine measurement except when an upper-arm cuff will not fit or cannot be used (Picone DS, Padwal R, Stergiou GS, et al., J Hum Hypertens 2022;37:108-114). And cuffless wearables, including the watch on your wrist right now, sit outside most validation programs entirely.

4. Person

One person worth following in this space.

Stephen W. Smith, MD, emergency physician at Hennepin County Medical Center in Minneapolis, and the author of Dr. Smith's ECG Blog.

He has spent well over a decade posting real tracings from real shifts, with the angiogram result at the bottom, for free, in public, to anybody who wants to get better at this. No paywall and no institutional imprimatur. He also put his name on the revised criteria for reading a heart attack through a left bundle branch block, which is the pattern that used to be treated as unreadable (Smith et al., Ann Emerg Med 2012;60:766-776).

What I want you to notice is the direction the change traveled. The occlusion argument did not come down from a guideline committee and get distributed to the bedside. It came up from clinicians reading tracings, publishing what they found, arguing about it in public for fifteen years, and eventually pulling the guideline toward them. The 2025 document is downstream of that, not upstream.

Medicine does not usually work that way. It is worth watching when it does.

Every specialty has a Mercator projection. Somewhere in its history, somebody drew a line for a specific and reasonable purpose, and everybody after them inherited the line without inheriting the purpose.

Mine is the one I work on now. The conditions I spend my time on, the disorders of gut-brain interaction, are diagnosed by symptom criteria that were built substantially so that researchers in different countries could agree on who belonged in which study. That was a real problem and the criteria solved it. Then they migrated into clinics, and a threshold designed to make studies comparable started being used to decide whether a person's suffering counted. You have met the result if you have ever been told your workup was normal, as though normal and fine were the same word.

That is why we built MeNome, our free tracking app at menome.belly-md.com. It does not replace a diagnosis. It keeps the part of you the threshold was never designed to capture.

The artery does not care what we call it.

That's the four. See you next week.

Rick

From BellyMD

I build MGB+, a small supplement line for gut-brain support: Clear, Cool, and Calm, each a magnesium and B-vitamin based formula meant to support the gut-brain axis as part of a broader routine. Structure-function support, not a treatment for any disease. If that is relevant to you, it lives at belly-md.com.

If you want to talk through your own gut-brain picture with me directly, I offer a gut-brain consultation. Details at belly-md.com.

Not medical advice. This newsletter is for education and does not create a physician-patient relationship. Nothing here is a diagnosis or a prescription. If you are having chest pain, call 911. Talk to your own physician before starting, stopping, or combining any medication or supplement, including over-the-counter ones.

That was the whole trip. Flights, a hotel, a long drive, weeks of planning. All of it for about two minutes of the moon covering the sun.

No one I met there thought the math was strange. Not one person asked whether two minutes was worth the effort. We all just went.

I have been thinking about why that felt so easy.

Here is one answer. We knew it was going to happen.

Not “probably.” Not “in most people.” We knew the date. We knew the minute. We knew the second. Someone could have told you that number two hundred years ago and it would have been the same number.

So the waiting was not really waiting. It was a countdown. There is a difference.

Now think about how medicine asks you to wait.

A doctor tells you to try something for six weeks. Maybe twelve. Maybe longer. You ask if it will work, and you get an honest answer, which is that it works for a lot of people and we will find out if you are one of them.

That is a fair answer. It is also a terrible thing to hold onto at week three.

So people stop. They stop the medication. They stop the diet. They stop the therapy. A lot of them stop about two weeks before the thing would have started working.

I see this constantly. And the thing that bothers me the most?

The person who stopped almost always thinks it is their fault. They tell me they are bad at sticking with things. They say it about themselves like it is a flaw in their character.

It is not a flaw in their character. It is the difference between a countdown and a maybe.

Nobody quits an eclipse. You never hear about someone driving eleven hours, checking their watch at hour nine, and deciding it probably was not going to get dark anyway. That does not happen. The finish line is on the calendar.

Medicine almost never gives you that. It gives you the odds, and then it goes quiet.

I think the quiet is the real problem. And I think the quiet is fixable, even when the uncertainty is not.

Because here is something your doctor usually does know, even when they cannot tell you whether a treatment will work for you.

They know roughly when you would find out.

They know this one tends to show up in a week and that one takes two months. They know which symptoms move first. They know what an early sign of progress looks like, and it is often not the thing you are watching for.

That is a timeline. It is not a promise. But it turns a maybe into something closer to a countdown, and that turns out to be most of what a person needs to keep going.

So ask for it.

Ask when. Ask what the first sign would be. Ask what point means it is not working, so you know you are allowed to stop then, and not before.

A good answer sounds like this. Give it eight weeks. If this is going to help you, the first thing you will notice is that the bad days are less bad, not that they are gone. If you get to week eight and nothing has moved at all, we try something else.

That is not a cure. It is just a date.

But a date is what lets a person stand in the cold for two minutes and call it worth it.

Which it was, by the way.

The light goes strange before it goes dark. Colors flatten out and turn wrong in a way your body notices before your brain does. Then it drops. And every person around you makes the same sound at the same moment, which is the part I was not ready for.

Then it is over. You get your two minutes. And nobody asks whether it was worth the trip.

They knew what they were waiting for.

1. Practice

One broken gene, four organ systems, and the most useful sentence you can say before anesthesia.

In 2004, the year I graduated high school, a strange little trial ran in Anesthesiology. Ten natural redheads and ten dark-haired women, desflurane (an inhaled anesthetic) titrated against a standardized noxious stimulus, and the redheads needed nearly 20 percent more anesthetic to stop responding. Nine of the ten carried loss-of-function variants in a single gene, the melanocortin-1 receptor, MC1R (Liem et al., Anesthesiology 2004;101:279-283).

The follow-up landed a year later: subcutaneous lidocaine underperforms in redheads too. Which recasts a fact every dentist already knew and misfiled. Red-haired patients are about twice as likely to fear and avoid dental care, and for generations that went in the chart as nerves. It was pharmacology the whole time. They feel the drill because the drug is failing, not because their courage is.

Now the part that shouldn't make sense. These are the patients we cannot numb, and yet their baseline pain thresholds run higher, not lower. In 2021 the Fisher lab at Mass General worked out why: melanocytes with broken MC1R put out less of a hormone called alpha-MSH, and losing it tips the body's standing balance toward its own opioid tone. Mice carrying the redhead variant tolerate more before they flinch, and naloxone, the overdose reversal drug, erases the advantage (Robinson et al., Science Advances 2021). The threshold is real and it is opioid-shaped.

One honest caveat before the tour continues. Human pain testing in redheads is messy and depends on the modality; in the same lidocaine work, sensitivity to cold and heat actually ran higher. The clean, replicated, bedside-relevant facts are the ones above: more volatile anesthetic, less local anesthetic effect, and a mechanism that runs through the opioid system.

Everybody thinks this gene is about hair color. In the skin, MC1R is the switch between brown-black pigment and the red-yellow pigment called pheomelanin, and a broken switch means red. But the receptor does not stop at cosmetics.

In the skin, the red pigment itself is dangerous. Red hair carries up to three times the melanoma risk, and not just from sun. When researchers deleted the red pigment from red-haired mice, melanoma risk dropped, with the damage tracing to oxidative stress from the pigment pathway itself (Mitra et al., Nature 2012). That pigment does oxidative damage in the dark.

In the brain, the same receptor shows up in Parkinson's. In 131,821 Harvard-tracked adults, risk climbed step by step as hair color lightened, redheads at the top of the gradient, and pooled analyses since put their odds roughly 70 percent above everyone else's (Gao et al., Ann Neurol 2009). Mice carrying the redhead variant progressively lose dopamine neurons and prove more vulnerable to the toxins we use to model the disease (Chen et al., Ann Neurol 2017). The neurons at stake live in the substantia nigra, a structure named, literally, for its pigment. A pigment gene, killing dopamine neurons.

Even aging reports to it. In a genome study of thousands of faces, people carrying two variant copies of MC1R read as much as two years older than their birth certificates, independent of sun damage and skin tone (Liu et al., Current Biology 2016).

So here is the bedside translation. If you are a natural redhead: say so to your anesthesiologist, expect your dentist to reach for a second cartridge and ask for it without apology, and keep your dermatology appointments even if you never burn, because your pigment works in the dark. If you are a clinician: budget roughly a fifth more anesthetic agent, and when infiltration fails in a red-haired patient, reach for more drug before you reach for a psychological explanation. The failure has a phenotype.

2. Publication

One paper worth reading, in three sentences.

In the 1980s, researchers enrolled 20,863 Finnish men into a vitamin trial and, almost as an afterthought, wrote down their hair color; a quarter century and 1,982 prostate cancers later, someone finally asked the file a question, and the red-haired men had roughly half the risk of everyone else, hazard ratio 0.46 (Weinstein, Virtamo, Albanes, Br J Cancer 2013;109:747-750, doi 10.1038/bjc.2013.385). Honest cards: the redheads were few, the confidence interval is wide, and the whole cohort smoked, so this is a more hypothesis-generating than fixed scientific fact. What makes it my pick is the economics, because nobody ran a new trial, nobody recruited a single patient, and the marginal cost of the discovery was asking a different question of data that had been sitting in a drawer since the Cold War.

3. Product

This week's pick: sunscreen you will actually reapply. Unsponsored, no affiliate relationship, and obviously not a BellyMD product.

The evidence here is better than most people assume. In the Nambour trial, 1,621 Australian adults were randomized to daily sunscreen or use-it-when-you-feel-like-it, and a decade after the trial ended the daily group had half the melanomas and roughly three quarters fewer invasive ones (Green et al., J Clin Oncol 2011;29:257-263). Modest trial, wide intervals, and still one of the only times a cancer has been prevented in a randomized study with something you can buy at a pharmacy.

Two honest notes. The bottle matters less than the habit, so the right sunscreen is broad-spectrum, SPF 30 or higher, and pleasant enough that you use it daily; EltaMD UV Clear is the dermatology-office workhorse if you want a name. And if you are a redhead, remember what the mouse study showed: sunscreen buys off the ultraviolet half of your risk and does nothing about the pigment working in the dark, which is why the skin check keeps its place on your calendar either way.

4. Person

One person worth following in this space.

David E. Fisher, MD, PhD, chief of dermatology at Massachusetts General Hospital and director of its Cutaneous Biology Research Center. Most labs pick an organ. Fisher picked a receptor and let it drag him across the body: his group produced both the 2012 paper showing red pigment drives melanoma without ultraviolet light and the 2021 paper explaining redhead pain thresholds through opioid tone. That is the same gene, followed honestly for a decade, from skin cancer to pain pharmacology. He is not a social media presence; following him means reading what the lab publishes, and it is worth the effort, because wherever MC1R turns up next, he will already be there.

Red hair is the easy one. It is visible from across a room, it has been sitting in plain sight for two hundred years of modern medicine, and it still took until 2004 to explain why these patients feel the drill. You carry a thousand traits nobody can see from across a room: how you sleep, how you flush, how your gut moves, what the 3 p.m. crash does to you. No chart holds them in one place, so nobody gets to ask the Finnish question of them. That conviction is why we built MeNome, our free tracking app, at menome.belly-md.com. The pattern was never hiding. Nobody was looking.

That's the four. See you next week.

Rick

From BellyMD

I build MGB+, a small supplement line for gut-brain support: Clear, Cool, and Calm, each a magnesium and B-vitamin based formula meant to support the gut-brain axis as part of a broader routine. Structure-function support, not a treatment for any disease. If that is relevant to you, it lives at belly-md.com.

If you want to talk through your own gut-brain picture with me directly, I offer a gut-brain consultation (educational, 500 dollars). Details at belly-md.com.

Not medical advice. This newsletter is for education and does not create a physician-patient relationship. Nothing here is a diagnosis or a prescription. Talk to your own physician before starting, stopping, or combining any medication or supplement, including over-the-counter ones.

Then we wrote one sentence into every textbook: this happens to alcoholics. That sentence stopped being a description and became a filter. If a patient does not drink, the level does not get sent. And because the level does not get sent, the case does not get counted, and the absence of cases keeps confirming that the file was right to close.

Eighty years later, somebody finally counted.

PRACTICE

Send both assays, draw them fasting, and treat before they come back.

If you decide to work a patient up for thiamine deficiency, three things about the mechanics matter more than they should.

Send plasma and whole blood. They disagree, and the disagreement is informative rather than annoying. In the study below, plasma flagged 26.4% and whole blood flagged 2.7% in the same patients on the same draw. The commercial ranges are 8 to 30 nmol/L for plasma (Quest) and 66.5 to 200 nmol/L for whole blood (LabCorp), both by LC-MS. Plasma low with whole blood normal is the pattern that improved with repletion in this cohort. Both low is straightforward. Both normal with a convincing picture still does not exclude it.

Draw it fasting. The standard criticism of plasma thiamine is that it reflects recent intake. For staging body stores that is a weakness. For us it is a handling instruction: draw it after breakfast and you can wash out a real deficiency. These were early-morning fasting draws. Samples also need careful handling and shipping, so a mishandled specimen is its own false result.

Do not wait for the number. Turnaround was 7 to 10 days, which is longer than the window in which the answer would have changed anything. Replacement is inexpensive and has an excellent safety profile. A missed Wernicke's ends in Korsakoff or death. That asymmetry is the entire argument for treating on suspicion and letting the level confirm you later.

PUBLICATION

Mates EA, Kilgore-Gomez A, Phibbs C. Thiamine Deficiency in Hospitalized Veterans Without Alcohol Use Disorder: Prevalence, Biomarker Assessment, and Clinical Characteristics. Diseases 2026;14(8):275. Open access (doi 10.3390/diseases14080275).

286 hospitalized veterans. Alcohol use disorder excluded by protocol. Anyone already taking a B-complex or thiamine supplement excluded as well, so the cohort could not be padded by people who were already being treated.

26.4% had low plasma thiamine. Of the patients with clinical data, all but one had signs or symptoms. This was not an incidental laboratory abnormality hunting for a story.

The symptom rank order:

Decreased appetite, 88%. Nausea or vomiting, 60%. Constipation, 58%. Mental confusion is sixth, at 48%. Memory loss is seventh. Double vision is 13%.

We were taught to find this disease by its neurology. In these patients it announced itself through the gut, and it did so more often and more loudly than it did through the brain.

It also rarely arrived alone.

GI beriberi in 60%. Two or more concurrent syndromes in 77%. One clean syndrome in 19%. Whatever this is, it is not an organ-specific disease, and the habit of looking for it one system at a time is part of why it stays hidden.

Then there is the figure that should change a reflex.

Of 35 patients meeting criteria for Wernicke's, four had the classic triad. Twenty-two had exactly one finding. Altered mental status was present in 94%, ophthalmoplegia in 29%, ataxia in 26%.

Every one of us was trained to recognize this by a triad that showed up in one patient out of nine.

On repletion, among 32 low-plasma patients who returned: MOCA improved a mean of 1.9 points (p = 0.0093), composite motor strength 2.5 points (p = 0.0417), and 27 of 32 reported feeling better.

Two more things: Total body stores are 25 to 30 mg. Two to three weeks of poor intake empties them, or 72 hours in someone acutely ill, which means a hospital admission is long enough to produce this rather than merely reveal it. The screen we would reach for does not find it, which is a fair description of how a disease stays invisible for eighty years.

The honest ceiling. One VA center. Mean age 70.6, 96% male, 90% white. An underpowered exploratory pilot with no signal on length of stay, readmission, or 90-day mortality. The authors also note that 86.6% of enrollees met clinical criteria for some deficiency syndrome, a number they call implausibly high without biomarker confirmation, and they say plainly that clinical criteria alone overcall it. Their conclusion is not that everyone is deficient. It is that nobody knows, because nobody had looked.

PRODUCT

Better-absorbed B1, for the people already asking.

For a diagnosed deficiency, plain thiamine is the answer and it costs pennies. That is what was used in the study and there is no reason to reach past it.

For daily use the calculus differs, because plain thiamine hydrochloride absorbs less and less efficiently as the dose climbs. Two derivatives do measurably better in human comparisons.

Benfotiamine is an S-acyl derivative. It is frequently described as fat-soluble, which is technically wrong: Volvert's 2008 work found it practically insoluble in water, oil, and organic solvents alike, and the authors said directly that it should not be called lipophilic. Its advantage is absorption, not solubility…technically.

Allithiamine is a disulfide, and the disulfides are the lipid-soluble ones. Both out-absorb thiamine salts in head-to-head human studies.

Buy either from a manufacturer that publishes third-party testing and prints the dose on the label. Neither is a treatment for deficiency, and if you think you have one, the answer is a level and a physician, not a bottle.

PERSON

Michael Donnino, Beth Israel Deaconess.

An emergency physician with thirty-one thiamine papers to his name. He is the one who named gastrointestinal beriberi, in the Annals in 2004, and he has spent the twenty years since running randomized trials on thiamine in septic shock, after cardiac arrest, and in diabetic ketoacidosis. He was still publishing on it this year. I think he follows me on Twitter, too!

This man ran controlled trials on this for two decades while the field treated the question as closed. If you want a single argument that this was dismissed rather than disproven, his bibliography is it.

Rick Pescatore, D.O. is an emergency physician and Editor-in-Chief of Emergency Medicine News. He is the founder of BellyMD, which makes MGB+, a line of gut-brain formulas built around well-absorbed B1 and magnesium.

1. Practice

The treatment with some of the best evidence in IBS, and the reason almost nobody is offered it.

Start with the sentence that ends most of these appointments: "there's nothing wrong, it's probably stress." Patients hear an accusation. They hear that the pain is invented, that they are the problem, and that the visit is over.

The anatomy in that sentence is wrong, and getting it right is the most useful thing I can hand you this week.

Your gut is always talking. Stretch, pressure, acid, the ordinary mechanics of a meal moving through, all of it generates signal traveling up to the brain constantly. Almost none of it reaches awareness, because the brain sets the gain. Think of a volume knob sitting between the gut and consciousness. In disorders of gut-brain interaction, the umbrella term Rome V uses for IBS, functional dyspepsia and their relatives, that knob is turned up. Normal signals arrive loud. The pain is entirely real, it is being generated by real nerves carrying real traffic, and the amplification is the pathology.

Which means there are two ends to treat. You can work on the gut, which is what diet and most drugs do. Or you can work on the amplifier.

Gut-directed hypnotherapy is the best-studied way of working on the amplifier, and the name does it no favors. This is not stage hypnosis, and nobody is unconscious or suggestible in the way the word implies. It is a structured protocol, roughly fifteen minutes a day for six to twelve weeks, of focused attention and specific suggestion aimed at gut sensation. Same category as the breathing protocol a cardiac rehab program teaches. Boring, repetitive, and effective.

How effective is the part that surprises people. In a head-to-head trial from Monash, gut-directed hypnotherapy performed about as well as the low FODMAP diet for gastrointestinal symptoms, and better on the psychological measures, with the benefit holding at six months. The low FODMAP diet is the most famous dietary intervention in gastroenterology. Hypnotherapy matched it, without asking anyone to eliminate a food group.

Two honest caveats, because this is where enthusiasm usually outruns the data. You cannot blind a patient to whether they received hypnotherapy, so expectation is baked into these effect sizes in a way it is not for a drug trial with a matching placebo capsule. And the trials are mostly modest in size. This is good evidence for a symptom-based condition. It is not the same grade of evidence as a large cardiovascular endpoint trial, and anyone selling it that way is selling.

So why has almost nobody reading this been offered it?

Not because of the evidence. Because of arithmetic. The clinicians formally trained to deliver these therapies are called GI psychologists, and estimates put the worldwide number in the low hundreds. Millions of patients, a few hundred providers. There is no version of that math where referral is the answer. The treatment is not being withheld out of skepticism. It mostly does not exist within driving distance.

That gap is why Rome V, published this year, did something quietly significant. Its stepwise model for psychosocial care places digital, self-directed brain-gut behavioral therapy at Level 2, sitting between the education a physician gives in the room and the personalized therapy of a specialist you probably cannot find. Not a consolation prize. A recognized tier of care. An app is now a legitimate answer to a real access problem, which brings us to the product pick.

2. Publication

One paper worth reading, in three sentences.

The Rome V biopsychosocial chapter (Elsenbruch et al., Gastroenterology 2026;170:1205-1223) lays out the stepwise model for psychosocial care in DGBI and is the document that formally elevates app-delivered behavioral therapy to a recognized tier. The line I keep returning to is its treatment of resilience, which it describes as the ability to cope with and respond positively to stress, and which it associates with lower symptom severity and better quality of life, with the recommendation that clinicians ask about it early. That is a guideline telling physicians to inquire about a patient's capacity to recover, not just their capacity to hurt, and I think it is the most quietly radical sentence in the chapter.

3. Product

This week's pick: Nerva, an app-delivered gut-directed hypnotherapy program. Unsponsored, no affiliate relationship, and deliberately not a BellyMD product.

Nerva is a self-paced six-week program built on the Monash protocol, the same lineage as the trial above, running about fifteen minutes a day. A randomized trial published last year in the American Journal of Gastroenterology compared it against an active control rather than a do-nothing group, which is the harder and more honest comparison, and found meaningful improvement in symptom severity, abdominal pain and anxiety.

Two things to know before you decide. It is a subscription, so check the current price yourself and treat it like any other recurring cost. And there is a prescription alternative worth asking your physician about: Mahana's program, authorized by the FDA in 2020 as the first prescription digital therapeutic for IBS, delivering cognitive behavioral therapy rather than hypnotherapy on the back of a 558-patient trial. Different technique, same target, and it may be covered when a consumer subscription is not. The two companies have since combined, which is worth knowing so you understand they are not fully independent options.

Neither one is a cure, and neither one is a reason to skip a workup you have not had. What they are is the first genuinely accessible version of a treatment that has been sitting in the literature for thirty years while almost nobody could get to it.

4. Person

One person worth following in this space.

Laurie Keefer, PhD, a clinical health psychologist at the Icahn School of Medicine at Mount Sinai, where she directs psychobehavioral research in the Division of Gastroenterology. She describes herself as a GI psychologist, which is roughly the point, because she is one of the people who built that job into a real thing with a name and a training pathway. She led the Rome Foundation working team report that gave brain-gut behavior therapies their shared vocabulary, and her research program centers on resilience and self-regulation as treatment targets rather than as personality traits you either have or you do not.

If this issue landed, her work is where the field's actual thinking lives, and she is considerably easier to read than most people at her level.

That's the four. See you next week.

Rick

From BellyMD

I build MGB+, a small supplement line for gut-brain support: Clear, Cool, and Calm, each a magnesium and B-vitamin based formula meant to support the gut-brain axis as part of a broader routine. Structure-function support, not a treatment for any disease. If that is relevant to you, it lives at belly-md.com.

If you want to talk through your own gut-brain picture with me directly, I offer a gut-brain consultation (educational, 500 dollars). Details at belly-md.com.

Not medical advice. This newsletter is for education and does not create a physician-patient relationship. Nothing here is a diagnosis or a prescription. Talk to your own physician before starting, stopping, or combining any medication or supplement, including over-the-counter ones.

Low is reassuring. Low sends people home.

She also takes a high-dose biotin supplement for her hair, and biotin breaks that test.

Most blood tests that hunt for one specific molecule are built around a chemical hook, and the hook is biotin. Flood the system with biotin from a supplement and the test stops reporting what is actually in the tube. Troponin comes back falsely low. The FDA warned about this in 2017, updated the warning in 2019 after the reports kept coming, and still keeps a list of troponin tests known to be vulnerable.

The vitamin did nothing to her heart. It corrupted the instrument we use to ask about her heart, and a falsely low troponin looks exactly like a low troponin.

We did not learn this from a study. We learned it from a body.

Nobody ran a trial of biotin in chest pain. There was no regulator who anticipated that a hair supplement would end up standing between a physician and a heart attack. The finding arrived the way these findings arrive. People took the supplement. Their results came back wrong in the direction that kills. Reports piled up until a signal rose out of the noise, and in the agency's own accounting of why it finally acted, that signal included a patient who died.

Old cartographers left unsurveyed territory blank and wrote terra incognita across it. Unknown land. They were honest about the limits of where they had actually walked.

Our maps are not.

What the list actually is

You have been handed a few of these warnings in your life. Grapefruit and cholesterol drugs. Blood thinners and salad. They arrive sounding like a complete list of what is dangerous.

They are a list of what somebody had a reason to check. A regulator required a study. A manufacturer needed an approval. Or people got hurt loudly enough to force a review.

Look at what gets checked.

There is one international rulebook for how drug interactions are studied. It was adopted in 2024, it is called ICH M12, and anyone can read it. It limits itself to interactions that work through the liver enzymes and cellular pumps that process medication. That is where one prescription collides with another, and it is a defensible place to spend the money.

Then it names what falls outside its borders. Interactions that work through absorption are out of scope, and the examples it gives are stomach acid, gut movement, and chelation.

Chelation is when a mineral clamps onto a drug in your gut and refuses to let go, so the drug never reaches your blood. It is how the calcium in your morning supplement disables your thyroid pill. It is how magnesium and zinc disable common antibiotics. The rulebook for studying drug interactions declares that entire mechanism to be someone else's problem.

Supplements appear in that document once. Researchers are told to exclude anyone using dietary supplements, herbal supplements, tobacco, alcohol, and certain foods and juices, so the data stay clean.

Read that again. In the design of the study, you are contamination. People who take supplements get removed from the room so the drug can be seen clearly.

Four places we did look

Thyroid medication. Calcium and iron clamp onto levothyroxine in the gut and cut how much of your dose actually gets absorbed, which is why the label says keep them four hours apart. It happens anyway, every morning, because swallowing all your pills at once is what a responsible person does. The thyroid tests stay abnormal, the dose gets raised, and the gland was working fine the entire time.

Metformin. The diabetes drug depletes vitamin B12 over years, and the label now says measure B12 every two to three years in everyone taking it. Low B12 causes numbness, burning, and unsteady walking. That is exactly the nerve damage everyone already blames on diabetes, so the symptom fits the disease and nobody thinks about the pill.

Notice how that instruction arrived. Metformin has been in wide use since the 1950s, and B12 sat in its labeling for decades as a suggestion, worth checking in people thought to be at risk. Only in recent years did the suggestion harden into a direction covering every patient. The interaction never changed. Our willingness to write it down did.

Orlistat. The weight-loss drug blocks fat absorption, which is the entire point, and vitamins A, D, E, and K travel through your body in fat. So the label tells you to take a multivitamin containing them and to separate it from the drug by two hours. Losing those vitamins is not a malfunction. It is the drug doing precisely its job to a molecule nobody was thinking about.

Warfarin. People on this blood thinner get told to avoid leafy greens, and that advice is wrong. The dose can be built around a steady amount of vitamin K in your diet. It cannot be built around an erratic one. The instruction is consistency, not avoidance.

The blank spaces

A drug and a supplement that appear together in no database have not been cleared. In the overwhelming majority of cases they have never been examined at all. Nothing is known about the pair.

Nothing known is a different condition from known to be safe. From where you stand, the two look identical.

So absence of evidence gets filed as evidence of absence, and the mistake stays invisible, because an interaction does not announce itself when it happens. It gets charged to something else. The disease is progressing. The treatment stopped working. You are getting older. You are anxious.

What to do

Know what is in the bottle, not just its category. "A multivitamin" is not information. Calcium, iron, zinc, magnesium, vitamin K, and five thousand micrograms of biotin is information. Bring the actual bottle to your appointment, or a photograph of the panel on the back.

Know the hour. Timing fixes more of this than quitting anything does. Four hours of separation rescues your thyroid pill. Two hours rescues the vitamins around orlistat. You do not have to give up the supplement, and moving it costs nothing.

Say it before your blood is drawn. If you take biotin, and it is in nearly every hair and nail product on the shelf, tell whoever is drawing the blood. If you are ever in an emergency department with chest pain, say it out loud even if nobody asks.

And when something new goes wrong, ask one question before accepting the obvious answer. Could this be the medication rather than the disease. That question is the one that costs people years, because the symptom usually fits the diagnosis they already have, and a thing that fits never gets examined.

Terra incognita

The list of known interactions will keep growing. It will grow the way it always has, one harm at a time, arriving years too late for the people it was about.

None of this is a reason to fear vitamins, and none of it says they are uniquely hazardous. It says they are biologically active, which is the entire reason you swallow them. A compound cannot be powerful enough to change how you feel and inert enough to ignore everywhere else.

The old mapmakers wrote terra incognita and meant it. Unknown. Unvisited. Not safe, not dangerous, simply unentered.

A blank space on the map has never meant the territory is empty.

Sources. Biotin interference with troponin: the FDA maintains a list of troponin assays subject to biotin interference; the underlying safety communications, issued in 2017 and updated in 2019, have since been archived off fda.gov. Scope of interaction studies: ICH M12, Drug Interaction Studies, adopted 2024, which superseded FDA's 2020 guidances. Levothyroxine, metformin, and warfarin prescribing information via DailyMed. Orlistat labeling via FDA Access Data.

1. Practice

The patient who’s full after four bites, and the workup that comes back clean.

This one shows up constantly. Someone eats a normal meal, or less, and feels uncomfortably full within minutes. Sometimes it’s burning or gnawing pain in the upper abdomen instead, unrelated to meals. Endoscopy is normal. Bloodwork is normal. They get told it’s stress, or acid, or nothing at all.

Most of the time it’s functional dyspepsia, and “functional” here doesn’t mean not real or psychological. Rome V retired that word almost everywhere else in the gut-brain vocabulary, replacing it with DGBI, disorders of gut-brain interaction. Functional dyspepsia is one of the few terms it kept. It has earned the name: a specific, mechanistically defined diagnosis, not a placeholder for “we didn’t find anything.”

Most people get the mechanism backwards, physicians included. Functional dyspepsia is not the stomach digesting slowly. That’s gastroparesis, a different diagnosis defined by measurably delayed gastric emptying on a scan. The two overlap, but plenty of FD patients have entirely normal emptying studies. Speed isn’t the problem. Two other things are.

Gastric accommodation is the first. The stomach is supposed to relax and expand when food enters, a vagally-mediated reflex that makes room without raising pressure. In FD that reflex is blunted, so a normal meal registers as a full stomach. Visceral hypersensitivity is the second, the same story as Issue 001, different organ. Normal stretch and normal acid exposure get relayed by the enteric nervous system and read by the brain as pain that has no business being there.

Clinically this splits into two overlapping patterns. Postprandial distress syndrome is early fullness, meal-triggered. Epigastric pain syndrome is burning or gnawing pain, not necessarily tied to eating. Most patients straddle both. Guidelines recommend testing for H. pylori and treating it before settling on an FD diagnosis. In a subset of patients, clearing the infection ends the problem outright.

Treatment stays incomplete. PPIs help some. Low-dose tricyclics help some. Prokinetics help some. Nothing crosses the finish line for everyone, which is exactly why the product pick below carries more evidence than most people expect from something sold over the counter.

2. Publication

One paper worth reading, in three sentences.

The Rome V pharmacology and nutraceuticals chapter (Camilleri et al., Gastroenterology 2026;170:1152-1170) reviews the trial evidence for non-prescription options in DGBI, including peppermint oil alone in IBS and a peppermint-plus-caraway-oil combination specifically in functional dyspepsia. The FD combination trials land at a number needed to treat of about 3, which is a genuinely strong effect size for a symptom-based GI condition. It’s the paper behind this week’s product pick, not a separate tangent, so if you only read one section, read the nutraceuticals chapter.

3. Product

This week’s pick: enteric-coated peppermint oil and caraway oil, combined. Unsponsored.

Sold in the US as FDgard and under a few other names, this is the combination the Rome V pharmacology chapter is citing when it reports that NNT of about 3 for functional dyspepsia. The enteric coating matters more than people assume. Plain peppermint oil, uncoated, can relax the lower esophageal sphincter and cause reflux, which is a strange failure mode for something meant to calm the stomach. A coating that survives the stomach and releases in the small intestine avoids that problem and is what the trial data actually used.

This isn’t a cure and it isn’t for everyone with upper GI symptoms. It’s a low-risk, reasonably evidenced option worth knowing about before reaching for a prescription, and worth mentioning to your own doctor if postprandial fullness or epigastric burning is the pattern you’re dealing with.

4. Person

One person worth following in this space.

Nicholas Talley, MD, PhD, a gastroenterologist and one of the central figures behind the Rome criteria as they’ve evolved from Rome II through Rome V. Based in Australia, longtime editor-in-chief of the American Journal of Gastroenterology, and one of the researchers most responsible for functional dyspepsia being treated as a defined, mechanistically-grounded diagnosis rather than a wastebasket term. If this issue was useful, his body of work on PubMed is where the FD and IBS overlap literature actually lives.

That’s the four. See you next week.

Rick

From BellyMD

I build MGB+, a small supplement line for gut-brain support: Clear, Cool, and Calm, each a magnesium and B-vitamin based formula meant to support the gut-brain axis as part of a broader routine. Structure-function support, not a treatment for any disease. If that is relevant to you, it lives at belly-md.com.

If you want to talk through your own gut-brain picture with me directly, I offer a gut-brain consultation (educational, 500 dollars). Details at belly-md.com.

Not medical advice. This newsletter is for education and does not create a physician-patient relationship. Nothing here is a diagnosis or a prescription. Talk to your own physician before starting, stopping, or combining any medication or supplement, including over-the-counter ones.

If cheap jewelry gives you a rash, you are sensitive to nickel. Nickel is also in food. Oats, whole wheat, chocolate, soy, canned beans. In people who are sensitized, the same metal that reddens your wrist can stir up the gut, and it can wear the costume of irritable bowel syndrome for years before anyone thinks to say the word nickel out loud.

React to latex gloves? Your immune system may not be able to tell latex apart from avocado, banana, and kiwi. The proteins look close enough that it treats the fruit like the glove.

Poison ivy wrecks your skin? Be careful with a mango. The peel carries an oil from the same chemical family, and it can raise a blistering rash around the mouth of someone who has met poison ivy before.

Spring pollen leaves you miserable, and then one day raw celery makes your mouth itch. Same misread, different tissue.

None of that is exotic. Every one of those connections is documented, sitting in a guideline somewhere, taught once and then filed. The knowledge is not missing. That is the part worth sitting with for a second. The knowledge is not missing. It has been found, written down, and published. It just never made it to the one person it was about.

Here is the thing I want to be fair about, because the easy version of this essay picks a villain and I do not think there is one. Medicine is built in silos for a good reason. You do not want a generalist doing your neurosurgery. Depth is expensive, and the only way to buy it is to narrow. Specialization is the reason medicine can do anything at all. It is not a bug. It is the whole engine.

But depth is bought with breadth, and somebody pays the difference. The allergist sees the jewelry. The gastroenterologist sees the bloating. The dermatologist sees the rash. Each of them is looking at a clean, true slice of you, and each of them is right about their slice. The sentence that connects the slices, the one that says these are the same event showing up in three different rooms, does not belong to any of them. It falls in the gap between two correct diagnoses. And a gap has no owner.

There is exactly one person who sits in all of those rooms. You were at the allergist in March. You were at the GI doctor in July. You are the one who remembers the mango from last summer and the earrings you stopped wearing in college. The pattern was never going to surface in a chart, because no single chart contains it. It can only surface in the one place that holds the whole record, which is the person the record is about.

I have watched people manage a label for a decade, rearrange their diet and their travel and their sense of their own body around it, when a real through-line was sitting in plain sight the entire time. Not because anyone failed them at the bedside. Every individual encounter was competent. The failure was structural, and structural failures are the hardest kind, because there is no face to be angry at. Just a system doing exactly what it was designed to do, cleanly, in pieces.

So I am not going to tell you the system is about to fix this. It is not. The incentives point the other way and the appointment is still fifteen minutes long. What I will tell you is that the work is real, and it has an owner now, and the owner is you. Your gut, your skin, your allergy history, the food you quietly stopped eating and never mentioned because it seemed too small to matter. That is one story. Reading it as one story is not paranoia and it is not a hobby.

Your body always kept one file. You are the only one who can read the whole of it. That is the most important job nobody ever assigned you.

Sources, via PubMed. Nickel and IBS-like gut symptoms: Rizzi 2017 (doi 10.5056/jnm16027) and D’Alcamo 2017 (doi 10.3390/nu9020103). Latex-fruit syndrome: Blanco 2003 (doi 10.1007/s11882-003-0012-y). Mango and urushiol cross-reactivity: Oka 2004 (doi 10.1111/j.0105-1873.2004.00451.x). Pollen-food, or oral allergy, syndrome: Bucher 2004 (doi 10.1111/j.1398-9995.2004.00626.x).

1. Practice

The antihistamine pairing people are quietly asking about.

Here is a question I get more than you would expect: "My doctor mentioned taking Claritin and Pepcid together for my stomach. Is that crazy?"

It is not crazy. It is also not a cure. Let me walk through why the idea exists, because the reasoning is more interesting than the pills.

Histamine is not just an allergy molecule. Most people meet it through hay fever and hives, but histamine is a signaling chemical the body uses in a lot of places, and one of the busiest is the gut. Your intestinal wall is packed with mast cells, which are immune cells that store histamine and other mediators and release them when triggered. When mast cells in the gut fire, they can irritate the dense web of nerves in the intestinal wall, sometimes called the enteric nervous system, which is why people describe it as a "second brain." That nerve network talks constantly to the actual brain. Turn up the volume on the gut nerves and the brain starts reading normal digestion as pain, urgency, or nausea. That amplified signaling is what clinicians mean by visceral hypersensitivity, and when the whole pain-processing system gets turned up over time, we call it central sensitization.

This matters for disorders of gut-brain interaction, or DGBI. That is the current term (not "functional GI disorders") for conditions like irritable bowel syndrome (IBS), cyclic vomiting syndrome, and cannabinoid hyperemesis syndrome (CHS). What ties these together is not a broken organ you can see on a scan (a “hardware problem), but a miscommunication between gut and brain (a “software problem). And histamine and mast cells appear to be part of the wiring in at least a subset of patients.

So where do the two drugs come in? Histamine acts on different receptors, which are the docking stations on cells. The H1 receptor is the one classic allergy pills target (loratadine, brand name Claritin, is a common over-the-counter, or OTC, H1 blocker). The H2 receptor is the one heartburn drugs target (famotidine, brand name Pepcid, is a common OTC H2 blocker). Both receptor types show up in the gut and in pain and nausea pathways. The logic of blocking both at once is simple: if histamine is contributing to the problem through more than one door, close more than one door. That is why some clinicians discuss combining an H1 and an H2 blocker in patients with IBS, cyclic vomiting, CHS, or prominent visceral hypersensitivity, often the ones whose symptoms have an allergic or histamine-flavored quality (flushing, itch, food reactivity, hives alongside the gut trouble).

The agents involved are ordinary and familiar. Loratadine and famotidine are both sold over the counter at standard doses most people have taken at some point for allergies or heartburn. That accessibility is part of why the combination gets talked about at all.

Full dislocure, though…this is largely mechanistic reasoning plus small studies and clinical experience, not large randomized controlled trials. The mast-cell-and-histamine story in IBS is real and supported by tissue studies, and mast-cell-directed treatments (including antihistamines and mast-cell stabilizers) have shown promise in small trials for subsets of patients. But "biologically plausible and helpful for some people in small studies" is a very different claim from "proven treatment for everyone with these conditions." It is not a guaranteed fix for IBS, but it is a reasonable, safe, low-cost thing to consider, especially if your picture has that histamine flavor.

2. Publication

One paper worth reading, in three sentences.

Work from the Leuven group in Belgium (Guy Boeckxstaens and colleagues) has been central to showing that mast cells and histamine signaling drive abdominal pain and visceral hypersensitivity in IBS, not just as a bystander but as part of the mechanism. Their line of research includes evidence that histamine acting through gut sensory nerves sensitizes them, and that blocking the H1 receptor can reduce that sensitization and improve symptoms in a subset of IBS patients. If you read one thing to understand why the antihistamine idea has legs, look at this group's work on histamine, TRPV1, and visceral pain in IBS (their other studies are widely cited and easy to find in PubMed under Boeckxstaens IBS histamine).

3. Product

This week's pick: a plain, well-built symptom journal. Unsponsored, obviously.

If you are going to have the antihistamine conversation (or any conversation) with your doctor, the single most useful thing you can bring is data. Not a vague "my stomach's been bad." A dated log of symptoms, foods, cannabis use if relevant, sleep, stress, and what you took and whether it helped.

My editorial pick is any simple, undated daily symptom and food journal, the kind sold as a small softcover notebook with a line for date, meals, symptoms, and severity. Brands matter less than the format. Look for one page per day, a 1-to-10 severity scale, and a notes line. The "undated" ones are better because you can skip days without guilt. A five-dollar notebook you actually fill in beats a fancy app you abandon in a week. Pattern recognition is where DGBI treatment lives, and you cannot see a pattern you never wrote down.

4. Person

One person worth following in this space.

Guy Boeckxstaens, MD, PhD, a gastroenterologist and researcher at KU Leuven. If the mast-cell and histamine thread in this issue interested you, he is one of the people who built the scientific case for it. His group's work is the reason "histamine and visceral hypersensitivity" is a serious research area and not a fringe idea. You will find him through his publication list on PubMed. Not flashy on social media, which is fine, the work speaks.

That's the four. See you next week.

Rick

From BellyMD

I build MGB+, a small supplement line for gut-brain support: Clear, Cool, and Calm, each a magnesium and B-vitamin based formula meant to support the gut-brain axis as part of a broader routine. Structure-function support, not a treatment for any disease. If that is relevant to you, it lives at belly-md.com.

Not medical advice. This newsletter is for education and does not create a physician-patient relationship. Nothing here is a diagnosis or a prescription. Talk to your own physician before starting, stopping, or combining any medication or supplement, including over-the-counter ones.