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Repurposing Famotidine for post-COVID Brain Fog, Antipsychotic-Induced Weight Gain, etc.

Mnemonic for famotidine (Pepcid) for Covid brain fog

Famotidine (PEPCID)

Pronounced:  fam OH ti deen / PEP cid

Mnemonic: “Pepsi Family tidings”

U.S. prescription rank: #57

Mechanism: H2 antihistamine

FDA-approved for:

❖ Gastroesophageal reflux disease (GERD)

❖ Gastric or duodenal ulcer

❖ Hypersecretory conditions (e.g., Zollinger Ellison Syndrome, multiple endocrine neoplasias)

❖ Preventing ulcers with ibuprofen (DUEXIS fixed-dose combo)

Off label uses:

❖ Urticaria (often in combo with an H1 antihistamine) 

❖ Prevention of stress ulcers in critically ill patients

❖ Prevention of aspiration pneumonitis during surgery

❖ Schizophrenia (investigational)

❖ Acute COVID-19 (investigational)

❖ Post-COVID-19 neuropsychiatric symptoms (investigational)

❖ Cardiac protection post-myocardial infarction 

The mnemonic: 

Do not misassociate the mascot with caffeine. “Tidings” means news or information, here referencing the Christmas carol lyric “Good tidings we bring to you and your kin. We wish you a merry Christmas and a happy new year”. 

What it is:

Famotidine (Pepcid) is a selective histamine H2 receptor (H2R) antagonist used for gastric ulcers and reflux. It is available by prescription (20 mg, 40 mg) or over-the-counter (20 mg). 

Mechanism of famotidine:

Famotidine blocks H2 receptors (H2R) on parietal cells in the stomach thereby inhibiting secretion of gastric acid. H2 receptors (as well as H1 and H3) are present in the brain. 

histamine mechanism Stahl
Antihistamine mechanism Stahl ballicule
Famotidine (Pepcid) mechanism of action

Comparison with other H2R antagonists: 

Famotidine is the most potent and selective H2-receptor antagonist. Ranitidine was a popular alternative H2 blocker but it was removed from market in 2020 due to contamination with NDMA. Less popular H2 blockers are cimetidine (Tagamet) and nizatidine (Axid). Cimetidine has antiandrogenic effects and is an inHibitor of several CYP enzymes. Nizatidine has prokinetic action by suppressing acetylcholine esterase, which increases salivation and may make it more effective than famotidine for preventing recurrence of erosive esophagitis.

Comparison with proton pump inhibitors (PPIs): 

Available PPIs include pantoprazole (Protonix), omeprazole (Prilosec), esomeprazole (Nexium), lansoprazole (Prevacid), dexlansoprazole (Dexilant), and rabeprazole (Aciphex).  PPIs are more effective for GERD than H2R blockers. PPIs, but not H2R antagonists, are associated decreased bone mineral density (Alanazi et al, 2024) and possibly dementia (Pourhadi et al, 2023).

H2R antagonists for allergic conditions:

The combination of H1 and H2 receptor antagonists can improve outcomes of acute allergic syndromes compared with the use of either H1 or H2 antagonists alone. 


Onset of antacid effect with famotidine is ~90 minutes and duration is 9+ hours, which is a 30% longer duration than either ranitidine or cimetidine. With IV administration peak effect is within ~30 minutes. 65–70% of famotidine is excreted unchanged in the urine. 

Side effects and risks:

Famotidine has an excellent tolerability profile (Howden & Tygat, 1996). In a first post-marketing study, the number of patients with side-effects was only 0.43%. Famotidine may cause agitation (14% of infants but less than 1% of adults), headache (5%), and dizziness (1%). According to Beers Criteria, famotidine should not be administered to older patients experiencing delirium due to weak anticholinergic effects (1 point on anticholinergic burden scale). Rare cases of famotidine-induced thrombocytopenia have been reported. See Cardiac Effects, below.  No irreversible adverse effects are known (Schunack, 1987).

Famotidine for COVID-19: 

Famotidine appears to improve the course of COVID-19 by attenuating the cytokine storm (Brennan CM et al, 2022). Proposed mechanisms include blocking histamine release by mast cells or activating a brain-integrated vagus nerve mechanism that inhibits inflammation (Yang & George et al, 2022). Famotidine also appears to boost the immune response against COVID-19 (Ghosh et al, 2020). Reported doses for acute COVID-19 ranged from 60 mg to 240 mg daily.

Famotidine for post-COVID neuropsychiatric symptoms:

Famotidine was trialed for treatment of COVID-related brain fog.  Famotidine 40 mg BID showed improvement in cognition, depression, and anxiety versus placebo at 6 and 12 weeks without side effects (Momtazmanesh et al, 2023).

Famotidine for schizophrenia:

High dose famotidine was studied as an adjunct to antipsychotic medication, started at 100 mg BID without titration. Significant improvement was found versus placebo at 4 weeks (Meskanen et al, 2013).  It is unclear whether the apparent benefit is a direct effect of blocking H2 receptors in the brain, because famotidine was effective in augmenting clozapine, which itself is a potent H2R inverse agonist (super-antagonist). 


Not all trials of famotidine for schizophrenia showed significant efficacy. Andrade (2013) argued that famotidine is unlikely a serious candide for schizophrenia, noting that alprazolam and many antidepressants block H2R receptors without providing antipsychotic benefit.  Also, asenapine is a potent H2R inverse agonist (as is clozapine) but efficacy of asenapine in schizophrenia is far below that of clozapine. 

Ma & Jiang et al (2023) theorized that H2R agonists (opposite effect of famotidine) may hold greater potential in treatment of schizophrenia than H2R blockers. NMDA receptor-mediated glutamatergic transmission deficiency is thought to be the leading factor in the etiology of schizophrenia.  Functional deficiency of H2 receptors on glutamatergic neurons (medial prefrontal cortex, mPFC) may be crucial for the pathogenesis of schizophrenia. No H2R agonist is currently available for clinical use. 

Famotidine to ameliorate weight gain from olanzapine: 

H2 histamine receptors are involved in the regulation of feeding behavior and weight. Famotidine 40 mg once daily significantly reduced weight gain with olanzapine for schizophrenia (Ghaffari et al, 2016). Although it is no longer available, ranitidine was more extensively studied for amelioration of antipsychotic-induced weight gain, also showing benefit (Xiao-Jing Gu et al, 2017).

Cardiac effects of famotidine:

The heart harbors histamine, which exerts significant physiological effects on cardiac chronotropy and inotropy via H1 and H2 receptors. By blocking H2R, famotidine decreases force of cardiac contraction. Famotidine 40 mg/day was found to prevent left ventricular dilation post-myocardial infarction (Mujtabi et al, 2012). Many studies have demonstrated that H2R antagonists improve the outcome of heart failure (Kou & Zhang et al, 2024). Famotidine 40 mg benefitted CHF by decreasing stroke volume and cardiac output similarly to quinidine 1000 mg (Kirch et al, 1992). Famotidine is well-tolerated in individuals with cardiac conditions (Howden & Tygat, 1996). IV famotidine produced little acute hemodynamic effect in critically ill patients (Omote et al, 1990). 

Dynamic interactions:

  ❖ Anticholinergic (weak, 1 point)

Kinetic interactions:

 ❖ Increases gastric pH

  ➤ May interfere with drugs dependent on gastric pH for absorption including cefuroxime (Ceftin, antibiotic), dasatinib (Sprycel for leukemia), delavirdine (Rescriptor for HIV), neratinib (Nerlynx for breast cancer), pazopanib (Votrient for renal cancer), and risedronate (Actonel for osteoporosis).

 ❖ 1A2 inHibitor (weak)

  ➤ Minimal if any clinically significant drug interactions—in a box—although the label instructs to avoid with tizanidine (super-sensitive 1A2 substrate) because tizanidine levels may escalate to toxic range.

 ❖ Renal excretion

   ➤ The label defines renal dosing, although decreasing the dose from the standard GERD/ulcer is likely unnecessary.

famotidine interactions

Dosing: For GERD or gastric/duodenal ulcers 20 mg BID or 40 mg HS is the typical dose. For hypersecretory conditions the label instructions starting 20 mg q 6 hr (80 mg/day) with max of 160 mg q 6 hr (640 mg/day, which is #4 of 40 mg tabs QID = #16/day). Doses up to 200 mg QID (800 mg/day) have been tolerated (Howden & Tygat, 1996). For heartburn OTC 20 mg tablet should be taken 10–60 minutes before consuming offending food. Renal dosing adjustments are defined. For COVID-19 and psychiatric dosing, see above.

Copyright 2024, CaferMed Publishing. Intended for prescribers.

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