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) for heartburn or acid reflux, you might be unaware that these two medications are working against each other. It’s not a matter of side effects-it’s about absorption. Your body can’t properly absorb levothyroxine if your stomach isn’t acidic enough, and that’s exactly what PPIs do: they shut down acid production. The result? Your thyroid hormone levels drop, even if you’re taking your pill every morning like clockwork.

Why Levothyroxine Needs Acid

Levothyroxine isn’t like most pills. It doesn’t dissolve well in a neutral or alkaline environment. For it to be absorbed into your bloodstream, your stomach needs to be highly acidic-ideally with a pH between 1 and 2. That’s the natural state of your stomach before you eat. The acid helps break down the tablet and convert levothyroxine into its absorbable form. Without it, up to 30% of your dose can pass right through your system without being used.

Proton pump inhibitors-drugs like omeprazole (Prilosec), esomeprazole (Nexium), and pantoprazole (Protonix)-block the final step of acid production in your stomach. They don’t just reduce acid temporarily; they suppress it for hours, sometimes up to 72 hours after a single dose. This means even if you take your levothyroxine four hours before your PPI, your stomach is still too neutral for proper absorption. Studies have shown that timing separation doesn’t fix the problem. The acid suppression lasts too long.

What Happens When You Take Them Together

The clearest sign that this interaction is happening? Your TSH levels rise. TSH, or thyroid-stimulating hormone, is the body’s way of saying, “We need more thyroid hormone.” When levothyroxine absorption drops, your pituitary gland pumps out more TSH to try to compensate. A rise in TSH-even if it’s just from 2.5 to 5.0 mIU/L-can mean you’re not getting enough medication.

A 2021 systematic review of seven clinical studies found that patients taking both levothyroxine and PPIs had significantly higher TSH levels compared to those taking levothyroxine alone. In one study, patients who were previously stable on levothyroxine saw their TSH jump after just six weeks of taking 40 mg of pantoprazole daily. Their symptoms returned: fatigue, weight gain, brain fog. Many were told their hypothyroidism was “worsening,” when in reality, their body just couldn’t absorb the drug.

According to data from the Mayo Clinic, about 15-20% of people on long-term PPIs need a higher levothyroxine dose-often by 12.5 to 25 mcg per day-to get back to normal thyroid levels. That’s not a small adjustment. For someone on 75 mcg, that’s a 17-33% increase. Without testing, you’d never know.

Who’s Most at Risk

You’re more likely to experience this interaction if:

• You’ve been on a PPI for more than three months
• You’re taking a high-dose PPI (like 40 mg omeprazole or pantoprazole)
• You’re older or have other conditions that affect digestion
• You’re on generic levothyroxine (brand-name formulations may be slightly more consistent, but the interaction still occurs)

Approximately 18% of people taking levothyroxine in the U.S. are also on a PPI. That’s nearly 2.7 million Americans who might be under-treated for hypothyroidism without realizing it. Reddit communities like r/Hashimotos have thousands of posts from people who noticed their fatigue got worse after starting PPIs-and only improved after switching medications or adjusting their levothyroxine dose.

What to Do Instead

There are better options than just increasing your levothyroxine dose.

Switch to Liquid Levothyroxine

Tirosint-SOL is a liquid form of levothyroxine that doesn’t need stomach acid to be absorbed. It’s made with glycerin and comes in softgel capsules you swallow whole. Because it bypasses the stomach’s acidity requirement, it works just as well whether your stomach is acidic or neutral.

A 2019 study in the Journal of Clinical Endocrinology & Metabolism confirmed that patients on Tirosint-SOL had stable TSH levels even when taking PPIs. The catch? It costs about $350 a month, compared to $15-$25 for generic tablets. Insurance doesn’t always cover it, and many doctors don’t know about it. But if you’re on long-term PPIs and struggling with symptoms, it’s worth asking your endocrinologist.

Try an H2 Blocker Instead

Another option is switching from a PPI to an H2 receptor antagonist like famotidine (Pepcid). Unlike PPIs, H2 blockers don’t shut down acid production completely-they just reduce it temporarily. A 2018 study in Pharmacotherapy showed no significant change in TSH levels when famotidine was taken with levothyroxine.

Famotidine works well for occasional heartburn or nighttime reflux. But if you have severe GERD or Barrett’s esophagus, it may not be strong enough. Still, for many people, it’s a safer alternative.

Reevaluate Whether You Need the PPI

Most people take PPIs for way longer than they should. Guidelines say PPIs should be used for no more than 4-8 weeks for most conditions. Yet many stay on them for years. Ask your doctor: Could you try lifestyle changes? Lower your portion sizes? Avoid eating 3 hours before bed? Cut out caffeine, alcohol, or spicy foods?

If you can reduce or stop the PPI, your levothyroxine absorption may return to normal without any dose changes.

How to Monitor and Adjust

If you’re taking both medications, here’s what you need to do:

1. Get your TSH checked before starting the PPI. This is your baseline.
2. Test again at 6-8 weeks after starting the PPI.
3. If your TSH is up by more than 1.0 mIU/L, your doctor should consider increasing your levothyroxine dose by 12.5-25 mcg.
4. Recheck TSH 6-8 weeks after the dose change.
5. Repeat every 6 months if you’re on long-term PPIs.

According to Cleveland Clinic data, 43% of patients stabilize within 12 weeks of adjusting their dose. That means most people can get back to feeling normal-once they know the problem isn’t their thyroid, it’s their stomach.

What’s Coming Next

Researchers are working on new formulations of levothyroxine that don’t rely on stomach acid at all. Enteric-coated tablets, designed to dissolve in the small intestine instead of the stomach, are currently in phase 3 clinical trials. If approved, they could change how millions of people manage their thyroid medication.

Also, the FDA is updating labeling requirements for thyroid drugs to clearly warn about PPI interactions. That means in the near future, pharmacists will be required to flag this when you pick up your prescription.

And while Tirosint-SOL’s patent expires in 2025, generic versions may still be hard to make. The formulation is complex, and simply copying the ingredients doesn’t guarantee the same absorption profile. So even when generics arrive, they may not be cheaper or better.

Bottom Line

Levothyroxine and PPIs don’t mix well-not because they’re dangerous together, but because one stops the other from working. If you’re on both and still feel tired, gaining weight, or struggling with brain fog, don’t assume your hypothyroidism is getting worse. Ask for a TSH test. Talk to your doctor about alternatives. Consider liquid levothyroxine or switching to famotidine. And question whether you even need the PPI anymore.

This isn’t just about pills. It’s about making sure your body gets what it needs to function. Your thyroid doesn’t care if you’re taking a pill for heartburn. It just needs the hormone to be absorbed. And that starts in your stomach.