Proton Pump Inhibitors (PPIs) & Cognitive Impairment: Brain Not Working?

Over the past few months I’ve been taking a PPI (proton-pump inhibitor) called “Esomeprazole” (Nexium) to manage a condition called laryngopharyngeal reflux (LPR).

I take the Esomeprazole (Nexium) at a dosage of 20 mg twice daily (b.i.d.). The medication is partially effective in reducing some of my most severe symptoms of LPR including: ear pain; eustachian tube dysfunction (ETD); burning sensations (throat & eyes); and postnasal drip.

Although the medication has been very useful, the longer I’m on it – the dumber I subjectively feel. Do I have any evidence to support this feeling? Yes.

It takes me longer to solve puzzles; I need more time to complete work (lower efficiency); I often feel spaced out for no reason (brain fog/ADHD-esque vibes) – and none of this happened prior to using PPIs.

I legitimately feel like I’ve dropped to below average IQ from using a proton-pump inhibitor (PPI). That said, it could just be coincidence – maybe I’m getting dumber for other reasons…

How could PPIs cause cognitive impairment (Mechanisms)

Included below are hypothetical mechanisms by which proton-pump inhibitors (PPIs) may cause cognitive impairment in a subset of individuals.

I want to emphasize that these are hypothetical and not proven. At this time there’s no strong evidence to conclude that PPIs impair cognitive function.

It is known that ~15% of a single IV dose of omeprazole can reach the CNS and potentially affect cognitive function. (R)

Increasing Amyloid Beta Peptide & Fibrillar A Beta (?)

If we assume that: (1) PPIs (or certain PPIs) increase amyloid beta within the brain; and (2) increased amyloid beta causes cognitive impairment – then this could be a potential mechanism by which PPIs cause cognitive impairment.

PPIs & amyloid beta peptide/fibrillar A Beta: There’s preliminary evidence from cellular and mouse studies suggesting that PPIs can increase amyloid beta formation. (R)

  • Lansoprazole and other PPIs increase amyloid-beta levels in cellular and mouse models of AD – as well as “wild type” mice.
  • Lansoprazole and other PPIs may increase amyloid-beta levels by modulation (inhibition) of 2 proteases: Beta-secretase & Gamma-secretase.
  • Lansoprazole and other PPIs might increase BACE1 and Meprin Beta-protease activities.
  • PPIs can inhibit vacuolar proton pumps (V-ATPases) of lysosomes – and blocking V-ATPases may basify lysosomes to impair degredation of fibrillary A beta (fA beta). (R)

Amyloid-beta & cognition: There is significant evidence to suggest that amyloid-beta accumulation is associated with cognitive impairment/decline.

  • Presence of abnormal amyloid-beta among clinically normal older individuals is associated with future risk of cognitive decline. (R)
  • Individuals with greatest risk of cognitive decline seem to be those with evidence of amyloid-beta and findings suggestive of neurodegeneration. (R)
  • Cellular production of amyloid-beta rapidly increases in response to a physiological challenge and often diminishes upon recovery. (R) (If PPIs are increasing amyloid-beta formation – then this would be a sign of physiological challenge.)

Important notes:

  • There hasn’t been much research done looking into the effect of PPIs on specific markers (e.g. amyloid beta) within the brains of humans.
  • Cell and mouse studies suggest that lansoprazole specifically (not other PPIs) may increase amyloid beta by inhibiting beta/gamma-secretases.
  • Long-term studies examining the association between PPIs and dementia in humans are inconclusive – data are mixed (some suggesting no effect, others suggesting an effect, and some suggesting protection).
  • Whether increasing amyloid-beta is a legitimate mechanism by which PPIs (or specific PPIs like lansoprazole) cause cognitive impairment – remains unclear.

Neurochemistry modulation

It is well established that modulation of neurochemistry can induce cognitive impairment (e.g. antihistamines, benzodiazepines, etc.) – particularly if there’s a decrease in excitatory transmission and/or an increase of inhibitory transmission.

If we assume that: (1) PPIs can modulate neurochemistry to a significant degree and (2) PPIs modulate neurochemistry in ways that interfere with cognition – then it’s possible PPIs cause cognitive deficits via modulation of homeostatic neurochemistry.

It is known that PPIs effectively cross/penetrate the blood-brain-barrier (BBB). (R)

PPIs & neurochemistry: It appears as though common proton-pump inhibitors like omeprazole and esomeprazole may affect both peripheral and central levels of serotonin. (R)

  • Omeprazole inhibits tryptophan hydroxylase (TPH) isoforms TPH1 and TPH2 – both of which influence peripheral and central concentrations of 5-HT (serotonin), respectively.
  • Esomeprazole is understood to inhibit MAO-A (monoamine oxidase-A), the main enzyme responsible for 5-HT (serotonin) metabolism, albeit with lower potency compared to effects on TPH1 and TPH2.
  • High-dose omeprazole treatment (100 mg/kg) to CD-1 mice: (1) significantly increased 5-HT concentrations (brain & serum); (2) reduced time spent immobile in tail suspension tests relative to vehicle control.
  • Proton pumps (H+/ATPases) appear to the accumulation of neurotransmitters in synaptic vesicles of rats – influencing uptakes of glutamate, serotonin, and GABA. (R)

Serotonin & cognition: Evidence suggests that serotonin (5-HT), a neurotransmitter that may be influenced by some PPIs (e.g. omeprazole & esomeprazole) – can influence cognitive function.

  • Reduced 5-HT transmission negatively influences cognitive functions and normalization of serotonin (5-HT) activity may have beneficial effects. (R)

Important notes:

  • There hasn’t been much research done examining the effects of PPIs on neurotransmitter concentrations in the brain and periphery of humans.
  • Since serotonergic transmission should theoretically be “normalized” prior to PPI usage among individuals without preexisting neuropsychiatric conditions – PPI administration could alter serotonergic homeostasis and induce cognitive impairment.

Confidence in this mechanism: Low. Not much research has been done examining the effect of PPIs on neurotransmitter levels in the human brain.

Mitochondrial dysfunction

If we assume that: (1) mitochondrial dysfunction can cause cognitive impairment; and (2) PPIs may induce mitochondrial dysfunction – then it’s possible PPIs cause cognitive impairment (in part) via induction of mitochondrial dysfunction.

Mitochondrial dysfunction & cognition: Mitochondrial dysfunction is thought to cause cognitive deficits/impairment – as evidenced by a myriad of studies.

  • Cognitive impairment is associated with mitochondrial dysfunction in peripheral blood mononuclear cells of elderly population. (R)
  • Cognitive impairment may be a CNS manifestation of syndromic as well as non-syndromic mitochondrial disorders. (R)
  • Mitochondrial dysfunction underlies cognitive defects as a result of neural stem cell depletion and impaired neurogenesis. (R)
  • Mitochondrial dysfunction is a common pathogenic mechanism involved in the hallmark features of Alzheimer’s Disease brains. (R)
  • Systematic review: Adult mitochondrial disease is associated with cognitive impairment/decline in: visuospatial functioning; memory; attention; processing speed; and executive functions. (R)

PPIs & mitochondrial function: There’s some evidence to suggest that PPIs may modulate mitochondrial function – possibly resulting in dysfunction.

  • Omeprazole inhibits carnitine/acylcarnitine transporter within mitochondria in in liposomes. (R)
  • Pantoprazole induces mitochondrial apoptosis (programmed cellular death) and attenuates NF-kB signaling in glioma cells. (R) (It’s unknown as to whether its effect is similar in healthy, non-glioma cells).
  • Lansoprazole inhibits mitochondrial superoxide production and cellular lipid peroxidation induced by indomethacin in RGM1 cells. (R)

Important notes:

  • The effect of PPIs on mitochondrial function hasn’t been extensively examined in healthy humans.
  • The above studies involved: liposomes; glioma cells; and RGM1 cells post-indomethacin.
  • Furthermore, most of these studies suggest a potentially beneficial effect of PPIs on mitochondrial function – such that they might actually improve cognition.
  • However, all of the studies indicate that PPIs have potential to modulate mitochondrial function – leading some to speculate that this could result in mitochondrial dysfunction (via disruption of mitochondrial homeostasis).

Confidence in this mechanism: Low. I’ve seen zero strong evidence to suggest that PPIs cause mitochondrial dysfunction.

Tau protein modulation (?)

If we assume that: (1) tau protein accumulation can cause cognitive impairment; and (2) PPIs modulate accumulation rate of tau protein – then it’s possible PPIs cause cognitive impairment (in part) via modulating tau protein accumulation.

Tau protein & cognition: Evidence suggests that tau protein accumulation within the brain is strongly associated with cognitive impairment/decline and neurodegeneration.

Tau protein plays an important role as a microtubule-associated protein in neuronal axons, stabilizing microtubules and inducing their assembly. (R)

When tau protein is hyper-phosphorylated, it is unable to bind and stabilize microtubules, which leads to degeneration of affected neurons. (R)

  • Plasma tau levels are higher in mild-cognitive impairment (MCI) compared with cognitively normal (CN) among the elderly. (R)
  • Tau pathology may lead to cognitive deficits through a variety of mechanisms, including, but not restricted to, grey matter loss. (R)
  • Tau protein is associated with longitudinal memory decline in cognitively healthy subjects with normal CSF biomarker levels. (R)
  • Both CSF t-tau and p-tau concentrations are associated with mild cognitive impairment (MCI) and Alzheimer’s disease (AD).

PPIs & tau protein: PPIs may modulate tau protein in ways that cause cognitive impairment.

  • PPIs exhibit high binding affinity for tau protein – particularly lansoprazole. (R)
  • Lansoprazole has high lipophilicity and can cross the BBB and reach the brain within ~37 minutes post-administration – such that it’s useful as a radiotracer in PET scans. (R)
  • Lansoprazole’s interaction with tau NFTs (neurofibrillary tangles) does not fid the classical “one-sit” or “two-site” binding models.
  • It is unclear as to whether lansoprazole and other PPIs interact with, or modulate, tau protein in ways that could cause cognitive impairment – but this is a possibility.

Important notes:

  • It is known that PPIs like lansoprazole can bind to tau protein with high affinity, such that they’re useful radiotracers in PET scan neuroimaging.
  • However, no studies have examined whether PPIs modulate the accumulation of tau protein – or the activities of tau protein – within the brain.
  • Therefore, it’s premature to conclude that PPIs induce cognitive impairment via interactions with tau protein.

Confidence in this mechanism: Low. There’s no robust evidence from human trials demonstrating that using PPIs causes accumulation of tau protein – such as would impair cognition and induce neurodegeneration.

Indirect mechanisms (Possibilities)

There are a variety of indirect mechanisms by which PPIs may cause cognitive impairment.

Nutrient deficiencies (vitamins & minerals)

PPIs can sometimes interfere with the absorption, metabolism, and retention of various nutrients (vitamins & minerals) – particularly in high-dose, long-term, and elderly users.

If we assume that: (1) PPIs induce significant nutrient deficiencies and (2) nutrient deficiencies can impair cognition – then it’s possible and likely that PPIs can impair cognition via affecting vitamin and mineral status.

  • PPIs have been associated with an increased risk of vitamin and mineral deficiencies impacting vitamin B12, vitamin C, calcium, iron, and magnesium. (R)

Vitamin B12

  • Low levels of vitamin B12 are associated with neurocognitive disorders. (R)
  • Low vitamin B12 levels are “an underestimated cause of minimal cognitive impairment and dementia.” (R)

Iron

  • Iron deficiency can cause changes in neurotransmitter homeostasis, decreased myelin production, impaired synaptogenesis, and decline in the function of the basal ganglia – adversely affecting cognition and motor development. (R)
  • Iron deficiency with or without anemia can cause cognitive disturbances and behavioral changes. (R)

Magnesium

  • Total magnesium intake between the estimated average requirement and the recommended dietary allowances (RDAs) may associate with a lower risk of mild cognitive impairment and probable dementia in postmenopausal women. (R)
  • High magnesium intake alone may improve cognition in older adults. (R)
  • There’s a direct association between serum magnesium and cognitive function in adults – and low magnesium is associated with poorer cognitive performance. (R)

Calcium

  • Low serum calcium is a potentially associated factor for conversion of mild cognitive impairment to early Alzheimer’s disease. (R)
  • Lower serum calcium level predicts worse cognitive scores among those with Parkinson’s disease. (R)

Vitamin C

  • Systematic review: “Studies demonstrated higher mean vitamin C concentrations in the cognitively intact groups of participants compared to the cognitively impaired groups.” (R)
  • There may be significant associations between plasma vitamin C and performance on tasks involving attention, focus, working memory, decision speed, delayed/total recall, and recognition. (R)
  • Maintaining healthy vitamin C levels can have a protective function against age-related cognitive decline and Alzheimer’s disease – and avoiding vitamin C deficiency is likely more beneficial than taking supplements above the RDA. (R)

Important notes:

  • PPIs may interfere with the absorption and/or levels of nutrients other than those listed above.
  • Any major deficiencies in one or more essential nutrients could negatively impact cognitive function.
  • Even reduced levels of certain non-essential nutrients might affect cognition for some (relative to having higher levels of those non-essential nutrients).
  • Not everyone using PPIs experiences nutrient (vitamin & mineral) deficiencies.
  • Many studies showing that low levels of certain vitamins/minerals are associated with cognitive impairment do not prove causation (such that there may be other confounds explaining why vitamin/mineral levels are low – including diseases themselves.)
  • However, any significant nutrient deficiencies that develop while using PPIs could adversely affect cognition.

Confidence in this mechanism: High. Anyone with a significant deficiency in an essential nutrient will likely experience suboptimal cognitive performance and/or cognitive decline.

Gut microbiota dysbiosis

Assuming: (1) PPIs can negatively affect gut microbiota composition (causing dysbiosis) and (2) gut microbiota composition affects cognition – then PPIs could impair cognition via modifying the gut microbiome.

PPIs & dysbiosis

  • PPIs, through long-term reduction in gastric acid secretion, can increase the risk of an imbalance in gut microbiota composition (i.e. dysbiosis). (R)
  • Evidence suggests that intestinal dysbiosis can occur secondary to proton-pump inhibitor use. (R)
  • The differences between PPI users and non-users observed in this study are consistently associated with changes towards a less healthy gut microbiome.
  • One paper suggests that PPIs could: exacerbate preexisting dysbiosis (in patients with cirrhosis). Exacerbated dysbiosis could then induce release of ammonia and endotoxins in the gut lumen and blood – causing hyperammonemia and subsequent hepatic encephalopathy (loss of brain function) via modulation of blood-brain barrier transport. (R)

Dysbiosis & cognition

  • Altered gut microbiota (dysbiosis) may cause cognitive dysfunction via: neural pathways (vagus nerve); inflammatory pathways (low grade inflammation); and biochemical pathways (short-chain fatty acids). (R)
  • Available evidence suggests that gut microbiota is linked to cognitive performance and that the manipulation of gut microbiota could be a promising avenue for enhancing cognition. (R)

Infection risk

Assuming that: (1) PPIs increase susceptibility to infections, (2) PPI users get more total infections (or more severe infections) than non-PPI users, and (3) infections can cause long-term and/or permanent cognitive impairment – then this is another indirect means by which PPIs could impair cognition.

  • PPIs use is associated with increased susceptibility to infections. (R)
  • Infections are associated with cognitive decline/impairment – likely due to the direct effects of the infection and/or immune responses (e.g. cytokine secretion). (R)
  • Some research suggests that infections leading to brain dysfunction may be more prevalent than appreciated. (R)

Depression risk

Assuming that: (1) PPIs cause depression (regardless of mechanisms); and (2) depression causes cognitive impairment – then induction of depression could be an indirect means by which PPIs cause cognitive deficits.

  • Use of PPIs might represent a frequent cause of depression in older populations; thus mood should be routinely assessed in elderly patients on PPIs. (R)
  • PPI use was associated with an increased risk of depression and anxiety in children. (R)
  • 94% of patients with major depressive disorder had cognitive complaints during acute depressive episodes. (R)

Note: There may be mechanisms by which PPIs cause cognitive impairment (directly or indirectly) other than what’s listed above.

PPIs & cognitive function (Research)

Included below are studies that specifically assessed the effect of PPIs on cognitive function. As you can see – there hasn’t been much research done in this specific domain. (There are a host of “associational” studies – but these are unable to prove causality.)

Gastric acid suppressants and cognitive decline in people with or without cognitive impairment (2022) (R)

Wu et al.: No evidence that PPIs cause cognitive impairment in cognitively normal adults. PPIs are less likely than H2RAs to cause cognitive decline among those with preexisting impairment.

  • Aim: Determine the risk of cognitive impairment associated with PPIs and H2RAs in people with or without cognitive impairment.
  • 11,605 participants who used an H2RA and/or PPI between 2005-2021 were evaluated.
  • 1,701 with mild-cognitive impairment (MCI) and 2,784 cognitively normal (CN) met inclusion criteria for analyses for progression to cognitive impairment or dementia.
  • Evaluation: Drug exposure (PPIs & H2RAs); cognitive outcomes (time to MCI or all-cause dementia).

What were the results?

Over ~2.7 years of follow-up, cognitively normal (CN) H2RA users (N = 547) and PPI users (N = 2,237) did NOT differ in 5-year risk for cognitive impairment due to MCI or dementia.

In the MCI group, over ~1.9 years follow up: H2RA users (N = 288) exhibited earlier progression from MCI to dementia within 5 years compared to PPI users (N = 1,413).

In mild-moderate AD, H2RA users (N = 157) exhibited faster memory decline than PPI users (N = 471).

Post hoc analyses found a trend indicating earlier MCI-to-dementia progression than PPI users – but this association wasn’t significant.

Exclusion of 68 participants with MCI who developed dementia without an AD diagnosis revealed that H2RA use (N = 275) was associated with earlier progression from MCI to AD over a 5-year period than PPI use (N = 1,349).

H2RA use was associated with ~40.2% higher dementia risk among those with MCI.

What can we conclude here?

PPI monotherapy is associated with lower risk of: (A) progression from mild-cognitive impairment (MCI) to dementia and (B) faster memory decline among those with mild-moderate AD (Alzheimer’s disease) – than H2RA monotherapy.

There were no relationships between H2RAs or PPIs and cognitive decline observed in cognitively normal participants.

Researchers think that there may be a dose-dependent relationship between H2RA use and dementia risk stemming from: (A) anticholinergic effects; (B) gut microbiome effects; and/or (C) nutrient deficiencies.

Limitations: Longitudinal/associational study (cannot prove causation); unknown confounds like: prescription vs. OTC meds, disease severity, ulcer diagnosis, socioeconomic status (may have affected results); permanence of H2RA cognitive effect unknown (perhaps cognitive impairment resulting from H2RA therapy is reversible via cessation/withdrawal from the drug).

Cognitive impact after short-term exposure to different PPIs (2015) (R)

Akter et al.: “The present study reveals for the first time that different PPIs have varying degrees of influence on different cognitive domains that have associations with AD.”

  • Aim: Investigate degree of neuropsychological association of each PPI with different cognitive functions.
  • 60 healthy volunteers (ages: 20-26) who: hadn’t used PPIs for at least 3 months prior to the study; followed a standard diet; and avoided alcohol, nicotine, and any type of medication (including caffeine) for at least 48 hours prior to each experiment session.
  • Volunteers were assigned at random into one of 5 treatment groups (different PPIs) or a control group – each group consisted of 10 volunteers.
    • Group 1: Omeprazole (40 mg/day)
    • Group 2: Lansoprazole (30 mg/day)
    • Group 3: Rabeprazole (20 mg/day)
    • Group 4: Pantoprazole (40 mg/day)
    • Group 5: Esomeprazole (40 mg/day)
    • Group 6: Control (placebo capsule)
  • Assessments: Series of 5 computerized neuropsychological tests (CANTAB Dementia Battery).

Motor screening test: Purpose of test is to relax the subject and introduce subject to computer/touch screen. Test also screens for difficulties with vision, movement, and comprehension.

  • Increased errors: Significant increases in mean error from baseline to 7 days of treatment with omeprazole and esomeprazole groups – with a large effect size.
  • Increased latency: Significant increases in mean latency time for both lansoprazole and pantoprazole groups – with a large effect size.
  • Post-treatment effect of PPIs and placebo (control) showed no significant changes, except for the esomeprazole and pantoprazole groups, with large effect size.
  • However, one-way ANOVA showed no significant differences in mean latency score or mean error score among PPI users.

Paired associates learning test: Tests visual memory and new learning. Sensitive primarily to changes in temporal and frontal lobes.

  • PPI ingestion was associated with difficulties in choosing the correct location of the pattern and a greater number of trials to choose a correct location.
  • Omeprazole, Lansoprazole, Pantoprazole – all increased mean values within each group before treatment and after treatment.
  • Omeprazole: Significant increases in PAL total error adjusted score and PAL total error six-shapes adjusted score with 95% Cis and a large effect size.
  • Lansoprazole & Pantoprazole: Showed significantly different error scores among the groups before and after treatment.
  • Rabeprazole & Esomeprazole: Increased mean value but this was not statistically significant.
  • Comparing all PPI groups with the control group – only the participants in the omeprazole and lansoprazole groups scored significantly.
  • One-way ANOVA of the 5 PPI groups revealed no differences among them in increasing PAL total error adjusted score or PAL total error 6-shapes adjusted score.

Reaction time test: Evaluates the speed of the subject’s motor and mental responses.

  • RTI movement time score increased significantly from baseline to post-treatment with near significance for omeprazole, pantoprazole, lansoprazole, and rabeprazole.
  • Change in reaction time among esomeprazole users was not significant.
  • None of the PPIs were associated with significant increases in RTI reaction time.
  • Among the PPI vs. control group – researchers found significant increases in movement times for the Omeprazole, Rabeprazole, and Pantoprazole groups – with 95% CI values and large effect sizes.
  • Worth noting was that the Rabeprazole group exhibited a significant decrease in reaction time relative to the control group.
  • However, all of the treatment groups exhibited similar increases in reaction and movement times.

Rapid visual information processing test: Measures visual sustained attention and working memory. Sensitive to the activity of the fronto-parietal lobe.

  • All treatment groups exhibited significant decreases in RVP “A” scores (omeprazole, lansoprazole, rabeprazole, pantoprazole, esomeprazole).
  • Compared to within-group mean variations, no effects were found among the treatment groups and the control group.
  • Participants receiving drug treatment showed similar decreases in RVP “A” scores as suggested by ANOVA among the treatment groups.

Spatial working memory test: Measures retention and manipulation of visuospatial information and examines heuristic strategy. Sensitive measure of executive dysfunction of the frontal lobe.

  • Comparatively profound results for the SWM (spatial working memory) test relative to the other 4 cognitive assessments performed – in terms of change from baseline among the 5 PPI groups.
  • Omeprazole & Rabeprazole: Significantly increased SWM between errors scores and SWM strategy scores.
  • Lansoprazole, Pantoprazole, Esomeprazole: Made significantly more errors in the SWM strategy test.
  • None of the treatment groups’ scores differed significantly from the control group.
  • One-way ANOVA over the 5 treatment groups did not reveal any significant differences for SWM between error and SWM strategy scores within the PPI groups.

What are the main takeaways from this study?

Omeprazole

  • More errors in the MOT & PAL tests; more time to move on RTI test; failure to identify correct RVP sequences; more errors in SWM strategy – relative to baseline.
  • Significant change on PAL test and significant result in SWM between error test.

Researchers: “Findings indicate that omeprazole is one of the major contributors to impaired cognitive function leading to deterioration of visual and episodic memory, new learning, motor and mental response speed, short-term and sustained attention, retention and manipulation of visuospatial information, and strategy development.”

Overall: “The data suggest that omeprazole resulted in both statistically and clinically significant impairment of cognitive performance.”

Lansoprazole

  • Significant cognitive impairments observed in lansoprazole group before and after treatment.
  • Increased error score in at least one of the MOT, PAL, RTI, SWM subtests – and decreased probability of detecting correct sequence in RVP “A” subtest.
  • SWM strategy test revealed lansoprazole significantly impaired executive function more than any of the other PPIs.

Researchers: “Results indicate that lansoprazole not only hampers motor functioning, visual memory, alertness and attention – but also deeply limits retention of spatial information and the capacity to manipulate remembered memory to develop a strategy and execute a complex task.”

The findings also agree with prior research of amyloid-beta increases in mouse brain – indicating lansoprazole might impair cognition more than other PPIs.

Rabeprazole

  • Rabeprazole appears to have no significant effect on episodic memory or new learning (evidenced by lack of MOT & PAL score changes within or between groups – compared with the control group).
  • RTI, RVP “A”, and SWM tests revealed significantly different scores relative to baseline scores – indicating the negative effect of rabeprazole on the ability to retain and manipulate spatial memory and planning a task to execute.

Pantoprazole

  • Significant changes in at least one of the subtests on MOT, PAL, RTI, and SWM.
  • MOT mean latency, RTI movement time (within & between groups), and SWM strategy scores significantly decreased.
  • RVP visual attention test scores significantly changed as well.

Researchers: “Not conclusively, we might say that participants taking pantoprazole would be at high risk of attention deficit with impaired motor and mental response speeds.”

Esomeprazole

  • Little evidence that might support the negative effect of esomeprazole on cognitive performance.
  • MOT mean error (within & between groups); RVP “A”; and SWM strategy scores significantly changed – suggesting users might be at high risk of difficulties in: sustaining attention; retaining and manipulating spatial memory; and planning strategy.
  • No effect of esomeprazole on visuospatial memory, new learning, motor/mental response speed, response accuracy, and impulsivity.

Researchers: “We postulate that omeprazole has the highest impact on cognition and esomeprazole has the least.”

What can we conclude here?

Akter et al.: “It is evident that all the PPIs have some exacerbated effects on cognition. In most of the cases, these negative effects may remain unnoticed, but in the long run they may take part in the development of AD.”

The effects of PPIs on cognitive function may be contingent upon the specific PPI utilized.

Certain PPIs may have unique deleterious effects on distinct aspects of cognitive function – relative to other PPIs, despite a shared primary mechanism of action (inhibition of proton pumps).

Additionally, some PPIs (e.g. esomeprazole) appear less likely to cause cognitive impairment than others (e.g. omeprazole).

Limitations… (Critical thinking)

  • Small sample size: This study had an extremely small sample size (50 PPI users vs. 10 controls). This means that there’s low statistical power, inflated false discovery rate, and inflated effect size estimation. In other words, the result may have been due to complete random chance.
  • Short duration: This study was carried out over a 1-week period. It’s possible that there’s some sort of a multi-week period of physiological adaptation to PPIs after treatment initiation wherein cognitive function is slightly impaired initially – followed by normalization over a longer-term.
  • Uneven treatment vs. control group size: The number of individuals receiving a “treatment” (50) was not equal to the number of those in the control group (10). This may be problematic in terms of comparing the cognitive effects of “PPI users” to “controls” in that there’s imbalance.
  • Too many different PPIs: Some might argue that the combination of an extremely small sample (60 participants) coupled with the division of these participants into smaller subgroups – each assigned to a distinct PPI or control, means we cannot get much useful information about any specific PPI. For this reason, it may have been better to concentrate efforts on one (perhaps the most popular PPI – omeprazole) and compare this to a placebo control.
  • Dosing: Some might argue that the dosing for these PPIs was higher/lower than necessary. Perhaps it would’ve been beneficial to evaluate lower doses – or much higher doses (e.g. 80 mg esomeprazole per day). Assuming PPIs affect cognition, higher doses might be better for detecting this effect.
  • Cognitive tests: Some might argue that the total number of cognitive assessments performed (baseline & post-PPI) might be insufficient to detect significant meaningful change in cognition associated with PPIs.
  • Confounds: Authors acknowledged that factors such as: age, sex, APOE4 allele, CYP2C19 allele, and depression were not taken into consideration.
  • Caffeine withdrawal (?): It’s possible that individuals participating in this study were experiencing caffeine or stimulant withdrawal. Many young adults consume caffeine on a regular basis. Assuming some ingested caffeine up until 48 hours prior to cognitive assessment – they’d experience a withdrawal reaction which may have caused a dip in cognitive function below baseline.
  • Nocebo effects: Some individuals may have experienced “nocebo effects” – expecting that the substance they were taking would negatively affect cognition (such that physiology changed in ways to make this happen).
  • Performance anxiety: It’s possible that a subset of individuals experienced significant performance anxiety while undergoing CANTAB screening for a scientific study. Some may have felt pressure to perform well such that they made more errors.

Association between proton pump inhibitor use and cognitive function in women (2017) (R)

Lochhead et al.: “We did NOT observe a convincing association between PPI use and cognitive function.”

  • Aim: Examine associations between PPI use and performance in tests of cognitive function.
  • 13,864 participants in Nurses’ Health Study II who had completed a self-administered neuropsychological test battery.
  • Measures: Psychomotor speed and attention; learning and working memory; overall cognition.

What were the results?

Modest association between PPI use and scores for psychomotor speed and attention (mean score difference for PPI use of 9-14 years vs. never users: -0.06 & -0.11).

However, after controlling for use of H2 receptor antagonists (HR2As) – there was no significant difference in psychomotor speed and attention.

HR2As were associated with poorer cognitive scores – with strongest association in learning and working memory (relative to never users).

What can we conclude?

PPIs, when used as a standalone, do NOT appear to significantly alter cognitive function in female nurses (ages 25-42).

H2RAs, when combined with PPIs or administered as a standalone, may impair cognitive function – particularly learning and working memory.

Limitations… (Critical thinking)

  • Modest cognitive impairment: Researchers admitted that PPI use may be associated with a modest reduction in cognitive function – such that power was lacking to detect it.
  • Female-only: This study examined female nurses – no males. It’s possible there are sex-specific effects of PPIs (such that they might impair cognition more in males than females).
  • Associational study: This type of study is unable to determine whether PPIs cause cognitive changes.
  • Single test: It’s possible that multiple rounds of neuropsychological examinations is necessary to detect significant cognitive changes among PPI users relative to non-users.

Lack of association between PPI use and brain aging (2021) (R)

Ahn et al.: “The present study does not support a relationship between PPI use and brain aging.” (It does suggest that PPI use might modestly impair aspects of cognition.)

  • Aim: Investigate associations between PPI use, brain volumes, estimated brain age, and cognitive function in the general population.
  • 2,653 participants underwent brain MRI and were divided into 2 groups based on PPI intake.
  • Measures: Brain volume (grey matter, white matter, total brain, hippocampus); estimated brain age; cognitive function.

What were the results?

There was zero association between PPI use and brain volumes or estimated brain age.

Verbal Learning and Memory Test (VLMT) scores were: (A) 1.11 lower in immediate recall and (B) 0.72 lower in delayed recall – among PPI users relative to non-users.

What can we conclude?

Although PPI use doesn’t seem to induce significant changes in brain volume or brain age – as evidenced by MRI scans, PPIs might impair aspects of verbal learning and memory such as immediate recall and delayed recall (as was observed on the VLMT).

However, there were no differences observed between PPI users and non-PPI users in immediate recall and delayed recall when using the NAI for cognitive assessment instead of the VLMT.

Additionally, the “delayed verbal recall” scores on the VLMT were modified by statin intake (PPIs + statins had a 0.51 higher delayed verbal recall score than those who took PPIs without statins).

Lastly, although PPI users had lower VLMT scores – the effect sizes were small (Cohen’s d = 0.13 for immediate memory & 0.17 for delayed recall).

Limitations (Critical thinking)

  • Associational study: Because this was an associational study, we cannot conclude that PPI usage caused impairment in aspects of verbal learning and memory (immediate recall & delayed recall). Perhaps other confounders such as obesity correlated with PPI use and better contributed to poorer cognitive function (rather than the PPI itself).
  • Cognitive tests: The cognitive tests utilized for this study may not have been comprehensive enough to detect certain cognitive changes that occurred while using PPIs. Tests that check for overall cognitive function (including visuo-spatial processing, executive function, attention, recall, orientation, abstraction, language, etc.) may have provided better detail.
  • Participant characteristics: There were some differences between groups (PPI users vs. non-PPI users) that may have fully explained the poorer cognition among the PPI users.
    • Ages: The average ages of participants were ~51 (non-PPI users) and ~60 (PPI users). The difference in average age of ~9 years between non-PPI and PPI users could explain the slight cognitive impairment in PPI users.
    • Brain lesion & vascular risk factors: 31.8% of PPI users had a brain lesion/vascular risk factor – relative to 26.3% of non-PPI users. This might’ve explained the poorer cognition among PPI users to some extent.
    • Co-administered drugs: The PPI users more frequently used anticholinergics (7.7% vs. 1.9%); antidepressants (8.2% vs. 4%); antihypertensive drugs (64.7% vs. 30.8%); etc. Many of these co-administered drugs can impair cognition and may have been the primary reason for poorer cognition among PPI users.
    • Education: 26.5% of the PPI users had completed less than 10 years of education – whereas only 14.8% of the non-PPI users had completed less than 10 years of education. It’s possible that total education, IQ, or innate cognitive abilities explain the observed poorer aspects of cognition among PPI users.
  • Duration of PPI treatment: The cumulative duration of PPI administration by users was unavailable. Researchers only knew that the PPI users had administered a PPI for at least 7 consecutive days leading up to the MRI scan. It’s possible that a significant percentage of PPI users had only been treated for a short-term, which may have influenced results. (Perhaps the strongest cognitive impairment shows up after a longer-term of use such as 1-3+ months.)
  • Prevalent user bias: Could’ve attenuated true effect sizes (according to researchers).
  • Reverse causation: Researchers stated that they cannot rule out possible reverse causation (i.e. cognitive decline may predispose to gastric problems and ultimately PPI intake).
  • Unknown PPI dosing: It may have been useful to know the relative strength of PPI therapy that each PPI user was administering. Why? Perhaps there’s a dose-dependent effect wherein only high-dose users exhibit significant change in brain volume or cognition.
  • VLMT & statin intake: Individuals that took PPIs plus statins had a 0.51 higher delayed verbal recall score than those who took PPIs but no statins.

Proton Pump Inhibitors & Risk for Mild Cognitive Impairment and Dementia (2018) (R)

Goldstein et al.: “PPI use was associated with a decreased risk of decline in cognitive function and decreased risk of conversion to MCI or dementia due to Alzheimer’s disease (AD).”

  • Aim: Evaluate volunteers over 50 with 2-6 annual visits.
  • 884 regular PPI users (taking PPIs at every visit); 1,925 intermittent PPI users; 7,677 never PPI users.
  • Analysis: Multivariable Cox regression analyses determined association between PPI use and annual conversion of baseline normal cognition into MCI or dementia.
  • Confounds that were controlled for: Demographics, vascular comorbidities, mood, anticholinergics, and H2RAs.

What were the results?

PPIs were NOT associated with greater risk of dementia or Alzheimer’s disease.

Continuous (ongoing) PPI use was associated with reduced risk of cognitive decline and reduced risk of conversion to MCI or dementia due to AD.

Intermittent PPI use was associated with decreased risk of decline in cognitive function and reduced risk of conversion to MCI or dementia due to AD.

Findings applied to both cognitively normal (CN) and those with mild cognitive impairment (MCI).

Takeaway: PPI usage among individuals above age 50 either: (A) has no significant impact on cognition OR (B) protects against age-related cognitive impairment/decline via unclear mechanisms.

Limitations (Critical thinking)…

  • Self-reported PPI use: Researchers relied upon self-reports from patients to determine whether they regularly (always) used PPIs; sometimes (intermittently) used PPIs; or never used PPIs.
  • Ages: All participants were over the age of 50. Results may not be generalizable to younger populations.
  • PPI specifics: Perhaps it may have been useful to control for: (A) specific PPIs (certain PPIs may carry higher risk of cognitive impairment than others) and/or (B) relative PPI dosage (certain doses of PPIs may cause greater impairment than others).

Other potentially relevant studies…

There are a variety of associational studies that examined the effect of PPIs on dementia risk. Many of these studies do not evaluate aspects of cognition.

Nonetheless, since dementia is associated with cognitive impairment: (1) if PPIs increase dementia risk – then (2) PPIs cause cognitive impairment via: (A) the actual dementia onset or (B) specific physiological changes.

Keep in mind that an association between PPI use and dementia does NOT prove causality (or lack thereof) – as there are many other potential reasons PPI cohorts may be at higher risk of dementia (e.g. obesity, sleep disorders, metabolic syndrome – all of which are associated with PPI use).

Gomm et al. (2016): “The avoidance of PPI medication may prevent the development of dementia.” (R)

  • 73,679 participants (ages 75+) and free of dementia at baseline.
  • Comparison: 2,950 PPI users vs. 70,729 non-PPI users.
  • PPI users were at significantly increased risk of dementia compared with non-users.

Liao et al. (2018): “No correlation was found between PPI use and Alzheimer’s disease (AD) in older adults.” (R)

  • 428 patients with AD vs. 1,712 controls without dementia
  • 115 patients with AD & 542 controls had used PPIs

Gray et al. (2019): PPI use was NOT associated with increased dementia or Alzheimer’s disease (AD) risk, even for people with high cumulative exposure. (R)

  • 3,484 participants (65+ years old) screened for dementia every 2 years.

Khan et al. (2020): “We found no evidence to support the association between PPI use and an increased risk of dementia.” (R)

  • Meta-analysis of 11 observational studies (ranging 5-10 years).
  • 642,949 subjects (158,954 PPI users vs. 483,995 non-users).
  • 10/11 studies were of “high” quality and 1 study was of “moderate” quality.

Cooksey et al. (2020): “This study, using large-scale, multi-center health data was unable to confirm an association between PPI use and increased dementia use.” (R)

  • Compared 183,968 PPI users vs. non-PPI users (ages 55+ & mean age: 69.9 years)
  • Main outcome was a diagnosis of dementia.
  • Confounders among PPI users such as cardiovascular disease and/or depression – and associated medications may be responsible for induction of dementia.
  • There appears to be a ~30% reduced risk of dementia from gastro-protectants (possibly mediated by anti-neurotoxic effects).

Torres-Bondia et al. (2020): “We did NOT find higher incidence of Alzheimer’s disease among PPI users – but a weak increase in the risk of non-AD dementias among PPI users was observed.” (R)

  • PPI users = 36,360 vs. non-PPI users = 99,362 (45+ years old)
  • PPIs analyzed: omeprazole; lansoprazole; pantoprazole; rabeprazole; esomeprazole
  • PPI users divided into 3 subgroups: very low exposure (<28 DDD); low exposure (28-83 DDD); high exposure (>83 DDD).
  • No dose-response relationship was found after comparing higher doses with lower doses.
  • Researchers failed to adjust for: APOE4 allele, alcoholism, smoking, BMI, osteoporosis, or polypharmacy.

Azhar et al. (2021): “At present, the evidence on PPIs and dementia suggests more reassurance than alarm.” (R)

Based on all of the available literature, what can we conclude re: PPIs & cognition?

There’s ZERO strong evidence to suggest that proton-pump inhibitors (PPIs) cause cognitive impairment, cognitive decline, or dementia (e.g. Alzheimer’s disease).

Wu et al. found: (A) no association between PPI use and development of cognitive impairment among cognitively normal individuals – and (B) lower rates of cognitive with PPIs than H2RAs.

One small study by Akter et al. (50 healthy adults) found that PPIs may impair cognitive function in specific ways that are contingent upon the specific PPI administered.

Interestingly, esomeprazole was the only PPI in this study that was NOT associated with cognitive impairment – whereas omeprazole, rabeprazole, pantoprazole, and lansoprazole were associated with distinct (drug-specific) cognitive impairments.

Lochhead et al. reported zero association between PPI use and cognitive function (13,864 female nurses).

Ahn et al. reported modest impairment in both: “immediate recall” and “delayed recall” on a Verbal Learning Memory Test (VLMT) among PPI users – but: (1) no differences in these categories were observed on other cognitive tests (e.g. NAI); and (2) “delayed recall” deficits disappeared after adjusting for statin use.

Goldstein et al. found that PPI administration decreases risk of cognitive decline in both regular (i.e. daily) and intermittent users.

Nearly all large-scale associational studies report zero correlation between PPI use and dementia.

One paper reported that PPIs may increase risk of dementia and another reported PPIs may increase risk of non-Alzheimer’s disease dementias (but the association was weak).

Conversely, a separate paper reported a ~30% decrease in dementia risk as a result of PPI administration – suggesting there may be some sort of protective effect.

Moreover, nearly all of the papers reporting “cognitive impairment” from PPIs have significant limitations such as: small sample size; associational design; uneven group numbers and/or characteristics; etc.

Did the PPI really cause cognitive impairment? (Consider other factors)

Many people likely misattribute cognitive impairment to usage of proton-pump inhibitors (PPIs) – when they’ve been: getting insufficient/poor sleep; experiencing high stress; using drugs that modify neurotransmitters (e.g. antidepressants; anticholinergics; antihistamines; benzodiazepines; etc.).

Others may be drinking alcohol – or going through withdrawal from caffeine (due to the fact that caffeine can cause acid reflux). Caffeine is a well-known cognitive enhancer and even after withdrawal – some people never regain the same level of cognitive function that they had with caffeine.

Some people with reflux conditions have other health conditions like obesity, hypertension, insomnia, hypercholesterolemia, etc. – which could impair cognition directly or via medications used to treat these conditions.

Worsening of any preexisting medical condition(s) may be fully or partially culpable for cognitive impairment while taking PPIs – such that even if PPIs are causing some cognitive deficits (the worsening of a preexisting condition may be a stronger factor).

Anyone who thinks that PPIs caused cognitive impairment should do a self-audit and reflect upon things other than the PPIs that might’ve caused and/or contributed to changes in cognitive function.

Even something as simple as stopping an exercise routine (due to reflux) might result in some mental sluggishness that wasn’t present prior to the PPIs.

Could PPIs enhance cognitive function? (Worth considering)

It’s possible that, for some individuals, using PPIs (proton-pump inhibitors) might enhance or preserve cognitive function. For example, one large-scale study found that PPI use was associated with reduced risk of cognitive decline in both normal and intermittent users.

Treatment of reflux condition: Excessive stomach acid might impair cognition via the gut/vagus nerve; symptoms may be inherently distracting (e.g. constant burning sensation); symptoms may interfere with sleep (e.g. nasopharyngeal inflammation & apnea); symptoms may have caused anxiety/depression (both of which improve once managed); etc.

  • Sleep enhancement: Individuals with LPR/NPR (extra-esophageal reflux) can experience intranasal inflammation as a result of the reflux – which may cause upper airway resistance and/or sleep apnea (poor sleep quality). Treating the reflux may reduce acid-mediated intranasal inflammation and thus improve breathing during sleep to improve sleep quality – which could massively improve cognition.
  • Anxiety & mood improvement: Some individuals become anxious and/or depressed about symptoms associated with reflux. Effectively treating symptoms with a PPI may reduce anxiety and enhance mood – whereafter cognition might improve.
  • Less burning/pain sensation: Reduction in burning sensation and/or pain in the esophagus/larynx might make it easier to focus.
  • Vagus nerve normalization: Some cases of reflux may have vagal nerve dysfunction as a result of chronic acid exposure. Reducing the acid exposure might help the vagus nerve heal and regain normal function – which could improve cognition.

Neuroprotective effects: There’s some evidence to suggest that PPIs may actually be neuroprotective (protecting the brain against neurotoxicity and thus preserving cognitive function when faced with insult).

  • Proton-pump inhibitors exert anti-inflammatory effects and decrease human microglial and monocytic THP-1 cell neurotoxicity. (R)
  • Proton-pump inhibitors reduce IFN-gamma-induced neurotoxicity and STAT3 phosphorylation of human astrocytes. (R)
  • Gastroesophageal reflux may damage hearing – which could ultimately affect cognition – and some studies suggest PPIs may protect against hearing loss. (R)
  • Pantoprazole treatment protects against the effects of neurotoxicity resulting from drug-induced seizures in rats and human cell lines. (R)

Reduced oxidative stress & inflammation: There’s some evidence to suggest that PPIs might reduce oxidative stress – which might improve cognitive function among those with elevated concentrations of reactive oxygen species (ROS) and/or reactive nitrogen species (RNS).

  • Esomeprazole dose-dependently reverses the inhibitory effect of indomethacin on glutathione (GSH) levels. (R)
  • Lansoprazole inhibits mitochondrial superoxide production and cellular lipid peroxidation induced by indomethacin in RGM1 cells. (R)
  • PPI induces autophagy as a survival mechanism following oxidative stress in human melanoma cells. (R)

Modulation of neurotransmission: PPIs may directly and/or indirectly (such as via the gut & vagus nerve) modulate neurotransmission within the peripheral and central nervous system. Any significant modulation of neurotransmission could potentially enhance cognition in a subset of individuals relative to homeostatic baseline.

In vitro & in vivo (mice) investigations found: (R)

  • Omeprazole & esomeprazole may inhibit TPHs (tryptophan hydroxylases) TPH1 & TPH2 – which could decrease serotonin in the peripheral and central nervous system.
  • At high doses, omeprazole & esomeprazole can inhibit MAO-A (monoamine oxidase-A), the primary enzyme involved in serotonin metabolism – which could increase serotonin concentrations.

Note: Researchers discovered significantly different relative potencies against TPH1, TPH2, and MAO-A with different PPIs – so the magnitude of serotonergic modulation via PPIs will depend on the specific PPI.

My experience: PPI-induced cognitive deficits OR other variables OR both?

Although I suspect that PPIs (omeprazole & esomeprazole) may have caused cognitive impairment and an ADHD-like syndrome characterized by: “brain fog,” memory impairment, poorer focus, poorer & slower information processing, and feeling “spaced out” – I cannot be 100% certain that it’s from the PPI.

There are numerous confounds in this scenario, including: dietary changes; fat loss (which can alter hormones); sleep problems (maintenance-insomnia); bouts of high stress; usage of antacids (magnesium carbonate, calcium carbonate, etc.); administration of Gaviscon Advance UK; intermittent use of low-dose alprazolam or diphenhydramine; nightly use of melatonin (6-20 mg); quitting caffeine; giving up intense cardio; and stopping most supplements.

Of the confounds listed above, sleep problems; bouts of high stress; intermittent use of low-dose alprazolam or diphenhydramine; and nightly melatonin – could negatively impact cognitive function. That said, these were present well before PPI therapy started – and never previously impacted cognitive function.

Additionally, in the past I’ve: intentionally lost fat; given up caffeine; stopped intense cardio for months; stopped all supplements for months; etc. – and my cognitive function was subjectively great, such that I don’t think these confounds are too relevant.

It is possible that PPIs interact with other substances (alprazolam, diphenhydramine, melatonin) pharmacokinetically and/or pharmacodynamically to induce significant cognitive impairment – but I don’t use alprazolam or diphenhydramine regularly (maybe once or twice weekly at a low dose).

What I know is that my brain was always subjectively “quick” and thoughts were clear prior to PPI use. When I initially began PPIs, I didn’t notice much of a change in mental status or cognitive function.

However, continued usage of PPIs (twice daily dosing) from January 2022 to May 2022 (~4 months) is correlated with onset of what I’d call mild-to-moderate cognitive deterioration.

It took a couple of months for me to notice/perceive this deterioration… it emerged in March 2022 and I thought it was transient/would improve. I noticed a bit more decline in April 2022 – followed by more substantial perceived decline in May 2022 (current).

Subjectively, my brain feels as though it’s completely “empty” or “blank” most of the time – almost as if it’s stuck in idle; thoughts are less organized and more chaotic; and reading stuff that I was formerly able to efficiently/quickly comprehend now seems like a foreign language (I end up re-reading the same sentences over and over – hoping that the information will eventually “register”).

Objectively, my work performance is less efficient (more time to achieve same result), problem solving skills are down (as evidenced by difficulty/time it takes to solve things like crossword puzzles), and social skills are impaired (brain doesn’t feel “primed” to have a conversation – minimal wittiness, etc.).

Risk factors for cognitive impairment from PPIs

  1. High-dose PPIs: If PPIs cause cognitive impairment, then there might be a dose-dependent effect wherein high doses generate greater impairment than lower doses.
  2. Long-term daily PPI administration: Long-term daily PPI administration may be more likely to induce cognitive impairment than infrequent use or short-term treatment sessions (e.g. 2-week cycles).
  3. Old age: Older adults (ages 65+) may be more susceptible to cognitive impairment from PPIs due to preexisting age-related cognitive impairment/decline (such that PPIs might exacerbate it). Older adults are more likely to use other medications which may interact with PPIs in ways that impair cognition. Older adults are more likely to have kidney/liver impairment which could affect PPI pharmacokinetics to exacerbate cognitive deficits.
  4. Nutrient deficiencies: PPIs can directly interfere with the absorption of critical nutrients such as: vitamin B12, vitamin C, magnesium, calcium, iron, etc. Any significant nutrient deficits resulting from PPI use could obviously cause significant cognitive impairment.
  5. Organ function: Impaired liver and/or kidney function may cause higher blood-levels of PPIs and/or delayed elimination for a longer effect. One paper hypothesized that PPIs may exacerbate dysbiosis in patients with cirrhosis – which could alter the blood-brain-barrier and cause loss of brain function.
  6. Substance use: Administration of substances that are known to impair cognition (e.g. benzodiazepines, non-benzodiazepines, antidepressants, antipsychotics, anticholinergics, antihistamines, etc.) with PPIs may cause cognitive deficits (in part because the PPI may interact pharmacokinetically).
  7. Medical conditions: Any medical conditions [distinct from the condition for which the PPI is used] (e.g. obesity/overweight; diabetes; hypertension; diabetes) – could induce cognitive impairment or decline which might be exacerbated by the PPI.
  8. Non-esomeprazole PPIs (?): One study found that omeprazole, lansoprazole, rabeprazole, and pantoprazole – caused cognitive decline but not esomeprazole. (Whether this is accurate remains unknown.)

How to minimize likelihood of PPI-induced cognitive impairment (Possibilities)

  1. Minimal effective dose: Use the lowest effective dose of a PPI to manage an indicated medical condition.
  2. Minimal necessary duration of use: Use PPIs for as short of a duration as necessary to treat the indicated medical condition.
  3. Optimize nutrient status: Long-term PPI users should get proper bloodwork/labs to check for nutrient deficiencies (particularly: B12; magnesium; calcium; vitamin C; iron; etc.). It may be worth supplementing with B vitamins, magnesium carbonate, calcium carbonate, calcium ascorbate, etc. – if you’re unable to get sufficient levels via diet.
  4. Non-refluxogenic cognitive enhancers (?): Using non-refluxogenic drugs/supplements (i.e. substances that won’t increase acidity and/or alter esophageal sphincter function to cause reflux) to enhance cognitive function may be useful – particularly if they effectively attenuate or override PPI-related cognitive deficits.
  5. Avoid cognitive impairers: Many substances are understood to transiently impair cognition (e.g. alcohol, benzodiazepines, nonbenzodiazepines, anticholinergics, antihistamines, etc.). It’s possible that certain cognitive impairers may interact with a PPI either pharmacokinetically or pharmacodynamically to exacerbate the impairment.
  • For example, omeprazole can increase blood levels of diazepam (a benzodiazepine) by reducing plasma clearance via CYP450 enzymes – such that it could indirectly potentiate diazepam-related cognitive impairment.
  • (Note: At standard doses, pharmacokinetic interactions between benzos and PPIs is less likely with pantoprazole, lansoprazole, and rabeprazole – than with omeprazole.) (R1, R2)
  1. Consider different treatments: If a PPI is causing significant cognitive impairment, consider other treatment options.
  • Different PPI: Some people may find that switching to a different PPI results in less significant cognitive impairment than their current PPI. (There’s preliminary evidence to support the idea that type/magnitude of cognitive impairment depends upon the specific PPI used.)
  • H2 blockers: Some studies report H2 blockers are associated with cognitive deficits and PPIs aren’t. In theory, it makes sense that H2 blockers would be more likely to cause cognitive deficits due to an antihistamine effect in the brain.
  • Alginate suspension: Some people can manage reflux conditions with alginates alone. These aren’t going to significantly alter cognitive function.
  1. Lifestyle modifications: Head-of-bed elevation; weight loss; smaller meals; low acid diet; etc. – may all help reduce reflux such that a person can reduce PPI dose and/or discontinue altogether (thus averting any cognitive impact).
  2. Use esomeprazole (Nexium) (?): One study found that esomeprazole was the only PPI that did NOT cause cognitive impairment after 7 days of administration. (The study was very small and had significant limitations – but it may be worth considering the findings since there’s not really downside to using esomeprazole other than potentially slightly increased cost.)

Final thoughts on PPIs & cognitive impairment…

I realize that persistent symptoms of acid reflux conditions (e.g. GERD, LPR, etc.) can cause cognitive impairment due to: (1) the pathophysiology associated with the disease; and/or (2) symptoms of the conditions (which may cause distress, pain, distraction, poor sleep, etc.).

One study found that PPIs can cause cognitive impairment – and that the specific impairments that ensue could be contingent upon the specific PPI administered (such that omeprazole impairs cognition differently than lansoprazole, etc.).

However, most of the studies that reported cognitive impairment with PPIs had significant limitations (e.g. small sample sizes, confounds, etc.) – to such an extent that the strength of these findings is weak and the evidence quality is poor.

Most individuals who use PPIs for a short-term probably won’t experience any significant cognitive impairment attributable to the PPI.

Long-term users (assuming no significant nutrient deficits from PPI use) probably won’t experience cognitive impairment/decline – and there’s a small chance they could experience a neuro-preservation or protective effect (such as to delay/prevent cognitive decline).

In fact, PPIs may even enhance cognitive function (relative to a state of uncontrolled acid reflux) because they’ll reduce symptoms and/or symptom severity (such that symptoms become less distracting and less likely to interfere with sleep).

That said, PPIs like all drugs affect people in unique ways based on genetics, physiology, etc. – therefore it’s generally smart to trust your own experience.

If your cognition consistently: (A) worsens when using PPIs and (B) improves when off of PPIs (in lockstep) – this is a pretty good indicator that the PPI is causing or exacerbating cognitive deficits.

Have you experienced cognitive impairment from proton-pump inhibitors (PPIs)?

  • How confident are you that the PPI is to blame for your cognitive deficits?
  • Which PPI did you take?
  • What was the dose of your PPI? (per day)
  • Why do you think you experienced cognitive decline on a PPI?
  • Have you considered other variables that might have affected your cognition? (e.g. usage of other substances; high stress/poor sleep; medical conditions; etc.)
  • Have you checked for vitamin/nutrient deficiencies while using the PPI?
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