Levothyroxine and Proton Pump Inhibitors: How They Interfere with Absorption

If you're taking levothyroxine for hypothyroidism and also use a proton pump inhibitor (PPI) like omeprazole or pantoprazole for heartburn, you might be unaware that these two medications are working against each other. This isn't just a theoretical concern-it’s a real, documented interaction that can leave you feeling tired, gaining weight, or wondering why your thyroid levels won’t stabilize, even when you take your pills exactly as prescribed.

Why Levothyroxine Needs Acid

Levothyroxine isn’t like most pills. It doesn’t just dissolve in your stomach and get absorbed. It needs an acidic environment-specifically, a pH between 1 and 2-to break down properly and enter your bloodstream. That’s why doctors tell you to take it on an empty stomach, first thing in the morning, at least 30 to 60 minutes before eating. But if you’re also taking a PPI, you’re basically turning your stomach into a neutral pond instead of a strong acid bath.

Proton pump inhibitors block the acid-producing pumps in your stomach lining. That’s great if you have chronic GERD or ulcers. But for levothyroxine, it’s a problem. Without enough acid, the tablet doesn’t dissolve correctly. The hormone stays locked inside the pill, passes through your gut mostly unchanged, and gets flushed out. Your body doesn’t get the dose it needs.

What the Science Shows

A 2021 systematic review in the Journal of General Internal Medicine looked at seven studies involving over 1,200 patients taking both levothyroxine and PPIs. The results were clear: TSH levels rose in nearly every group. Higher TSH means your thyroid isn’t getting enough hormone signal from your brain, which is your body’s way of saying, “We’re still hypothyroid.”

One 2023 study published in PubMed (PMID: 37259094) gave patients 40 mg of pantoprazole daily for six weeks-just a standard dose-and saw TSH jump significantly, even in people who had been stable on levothyroxine for years. And here’s the kicker: it didn’t matter whether they took the PPI in the morning with levothyroxine or at night. The acid suppression lasted too long for timing to fix it.

That’s the key point most people miss. You can’t just space them out by a few hours. PPIs don’t wear off after 4 or 6 hours. They shut down acid production for up to 72 hours in some cases. So even if you take levothyroxine at 6 a.m. and the PPI at 8 p.m., your stomach is still too neutral for proper absorption.

Who’s Affected and How Much

About 15 million Americans take levothyroxine regularly. Around 18% of them-roughly 2.7 million people-are also on a PPI. That’s a huge number of people potentially underdosed on their thyroid medication. The Mayo Clinic Proceedings found that 15 to 20% of these patients need their levothyroxine dose increased, usually by 12.5 to 25 micrograms per day.

But it’s not just about the numbers. Real people feel it. On Reddit’s r/Hashimotos subreddit, a review of 147 posts from late 2023 showed that 68% of users taking long-term PPIs reported needing higher levothyroxine doses. The most common complaints? Fatigue (72%) and unexplained weight gain (58%). These aren’t just side effects-they’re signs your thyroid isn’t getting what it needs.

What You Can Do

There are three real options if you’re taking both medications.

1. Adjust your levothyroxine dose. If you’re on a PPI and your TSH is high, your doctor should increase your levothyroxine by 12.5-25 mcg. Retest your TSH in 6 to 8 weeks. Most patients stabilize within 12 weeks, according to Cleveland Clinic data.
2. Switch to liquid levothyroxine. Tirosint-SOL is a liquid formulation that doesn’t rely on stomach acid. A 2019 study in the Journal of Clinical Endocrinology & Metabolism confirmed it’s absorbed just fine even with PPIs. The catch? It costs about $350 a month-15 to 20 times more than generic tablets. Insurance doesn’t always cover it, and generic liquid versions aren’t widely available yet.
3. Try an H2 blocker instead. Famotidine (Pepcid) reduces acid too, but not as strongly or as long as PPIs. A 2018 study in Pharmacotherapy showed no significant change in TSH levels when famotidine was taken with levothyroxine. If you don’t need full PPI-level acid suppression, this might be a safer alternative.

What Doesn’t Work

Many people try to fix this by taking levothyroxine and the PPI hours apart. You’ll hear advice like “take your thyroid pill at 6 a.m., and the PPI at 10 p.m.” But the science says it won’t help. PPIs don’t just reduce acid for a few hours-they shut down the pumps for days. Even if you space them out, your stomach remains too neutral for levothyroxine to absorb properly.

And short-term PPI use? If you’re only on it for two or three weeks-say, after a bad bout of gastritis-you probably won’t see any effect. But if you’ve been on it for three months or longer, you need to assume the interaction is happening and act on it.

What’s Coming Next

The FDA is working on new labeling rules for thyroid medications that will explicitly warn about PPI interactions. That’s a big step forward. Meanwhile, researchers are testing new enteric-coated levothyroxine tablets designed to dissolve in the small intestine, bypassing the stomach entirely. Early trials are promising, but they’re still in phase 3.

Also watch for the 2025 patent expiration of Tirosint-SOL. Once that happens, generic manufacturers may finally be able to make affordable liquid levothyroxine. Right now, formulation challenges have slowed things down. But if they crack it, this interaction could become much easier to manage.

What to Do Now

If you’re on levothyroxine and a PPI:

• Don’t stop either medication without talking to your doctor.
• Ask for a TSH test if you haven’t had one in the last 3 months.
• If your TSH is high and you’ve been on a PPI for more than 3 months, discuss dose adjustment or alternatives.
• Consider switching to famotidine if your acid reflux isn’t severe.
• If cost isn’t an issue and your symptoms persist, ask about Tirosint-SOL.

This isn’t a rare edge case. It’s a common, well-studied problem that affects millions. If your thyroid levels keep being off, and you’re on a PPI, this is probably why. Don’t assume it’s just your body being stubborn. The science is clear. Your medication is fighting itself. Time to fix it.