Why PPIs Lead to Increased Appetite
Proton pump inhibitors do not directly cause increased appetite through a well-established mechanism, but certain PPIs (lansoprazole and rabeprazole) may activate the hypothalamic-pituitary-adrenal (HPA) axis, which could theoretically influence feeding behavior. 1
Potential Mechanism Through HPA Axis Activation
The only direct evidence linking PPIs to appetite changes comes from a small study examining hormonal effects:
- Lansoprazole and rabeprazole significantly increased plasma ACTH and cortisol levels in healthy volunteers under fasting conditions, with lansoprazole raising ACTH at 60-120 minutes and cortisol at 180-240 minutes post-administration 1
- Omeprazole had no effect on ACTH or cortisol levels, suggesting this is not a class effect of all PPIs 1
- The HPA axis is known to relate to energy homeostasis and regulation of appetite and food intake, leading researchers to hypothesize these specific PPIs might promote feeding behavior 1
Important caveat: This was a single small study (5 healthy male volunteers) and remains theoretical—there is no robust clinical evidence that PPIs actually increase appetite in practice 1
Rebound Acid Hypersecretion: A Different Phenomenon
What is well-established is that PPI discontinuation (not ongoing use) causes rebound acid hypersecretion (RAHS), which could be confused with appetite changes:
- Chronic PPI use causes hypergastrinemia, which promotes proliferation of parietal cells and enterochromaffin-like cells, increasing the stomach's acid-producing capacity 2, 3
- When PPIs are stopped, this increased parietal cell mass produces excessive acid, potentially causing upper GI symptoms that patients might interpret as hunger 2
- This rebound phenomenon can persist for weeks to months after discontinuation, though parietal cell mass typically regresses by 6 months 2
Clinical Reality
In standard clinical practice and major gastroenterology guidelines, increased appetite is not recognized as a significant side effect of PPI therapy. The American Gastroenterological Association's comprehensive 2022 clinical practice update on PPI de-prescribing does not list appetite changes among concerns for long-term PPI use 2
The primary documented effects of PPIs relate to:
- Acid suppression lasting up to 36 hours 3, 4
- Risk of rebound symptoms upon discontinuation 2
- Potential associations with infections, fractures, and other complications with chronic use 2
Bottom line: If a patient reports increased appetite on PPIs, consider alternative explanations such as symptom relief allowing better food intake, or investigate whether they are experiencing early rebound hypersecretion if doses are being missed.