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REVIEW ARTICLE

Meal-Time Supplementation with Betaine HCl for Functional

Hypochlorhydria: What is the Evidence?
Thomas G. Guilliams, PhD; Lindsey E. Drake, MS

Abstract
It is well established that the inadequate intake of clinical and subclinical signs and symptoms (though
key nutrients can lead to nutrient deficiency-related many nutrient insufficiencies are difficult to diagnose).
phenomena. However, even when the intake of nutrients Along with food matrix issues, the integrative and
is sufficient, the inadequate digestion and/or absorption functional medicine community has long considered
of macronutrients, micronutrients or other therapeutic inadequate levels of stomach acid, pancreatic enzymes
compounds from the diet (i.e., phytonutrients) can and/or bile acid secretion to greatly contribute to an
result in similar clinical consequences. These individual’s risk for maldigestion or malabsorption.
consequences include classic GI-related symptoms
related to malabsorption, as well as a broad range of

Thomas G. Guilliams, PhD, is a professor at the University Inadequate Stomach Acid Production
of Wisconsin School of Pharmacy and founder of the (Hypochlorhydria/Achlorhydria)
Point Institute. Lindsey E. Drake, MS, is a Research A variety of different methods can be used to measure
Associate at the Point Institute. gastric acid production and stomach pH
(e.g., gastric intubation, catheter electrodes, radio-
Corresponding author: Thomas G. Guilliams, PhD telemetric capsules and pH-sensitive tablets); therefore, a
E-mail address: [email protected] variety of different cut-off points have been used to define
hypochlorhydria and achlorhydria in the literature.
Generally, a fasting gastric pH less than 3.0 is considered
It is well established that the inadequate intake of key “normal,” while values above 3.0 are deemed to be
nutrients can lead to nutrient deficiency-related gradually more hypochlorhydric. True achlorhydria results
phenomena. However, even when the intake of nutrients is in a gastric pH above 7, which is characterized by very
sufficient, the inadequate digestion and/or absorption of limited acid production even when stimulated by gastrin
macronutrients, micronutrients or other therapeutic or histamine (e.g., chronic atrophic gastritis).1 Subjects
compounds from the diet (i.e., phytonutrients) can result taking proton-pump inhibitors will generally have a
in similar clinical consequences. These consequences fasting gastric pH between 5-7.
include classic GI-related symptoms related to Inadequate levels of stomach acid (regardless of the
malabsorption, as well as a broad range of clinical and root cause) can result in many nutritional and digestive
subclinical signs and symptoms (though many nutrient issues. For instance, a reduction in gastric acid secretion
insufficiencies are difficult to diagnose). Along with food prevents adequate denaturing of folded proteins resulting
matrix issues, the integrative and functional medicine in poor protein digestion and increased food allergenicity.2
community has long considered inadequate levels of Activation of pepsin (from pepsinogen) is greatest at a pH
stomach acid, pancreatic enzymes and/or bile acid of 2 or less and its protease activity is optimal at a pH of
secretion to greatly contribute to an individual’s risk for 1.8 to 2.3.3 A low-acid environment is linked to reduced
maldigestion or malabsorption. Indeed, routine mealtime absorption of key micronutrients such as calcium, iron,
“replacement” of one or more of these agents is commonly folic acid, vitamin B6 and vitamin B12.4,5 Also, since gastric
recommended by such practitioners to improve digestion acid helps to eliminate harmful ingested microorganisms
and absorption. In this paper, we outline the evidence for and hinders bacterial overgrowth in the stomach and
one of these common recommendations- the small bowel; low stomach acid can increase the risk for
supplementation of betaine HCl to support inadequate small intestinal bacterial overgrowth (SIBO) and specific
stomach acid production (hypochlorhydria)- while microbial overgrowth from organisms like Clostridium
exploring what is known about the prevalence of this difficile.6,7,8 While most of these consequences of low
condition. stomach acid are undisputed, there is much less agreement
on the prevalence of this condition in the general

32 Integrative Medicine • Vol. 19, No. 1 • February 2020 Guilliams—Betaine HCl for Functional Hypochlorhydria
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population, how to test for such a condition and, especially, Figure 1. Stomach pH during meal in younger and
whether there is an appropriate therapy for low stomach older subjects.
acid.

Prevalence of Low Stomach Acid

A large variance in the reported prevalence of
hypochlorhydria is noted in the literature. While aging is
regularly associated with decreased gastric acid production,
fasting hypochlorhydria is reported to be less common
(~10% or less) in elderly American subjects, while it is
reported to be more common (>60%) in elderly Japanese
subjects, and as high as 80% in a small cohort of Norwegian
subjects in their eighth and ninth decades of life (average
age: 84 years, range: 80-91).8-11 These studies illustrate the
lack of consensus in the literature for the prevalence of
fasting hypochlorhydria and achlorhydria in the aging
population as many factors are likely to affect fasting gastric
pH (e.g., gender, testing method and cutoff values, number
of parietal cells to produce HCl, coincident disease states
such as H. pylori infection and overall health, etc.).12
Nevertheless, while fasting gastric pH is likely an Note: Meal-time stomach acid pH, measured by
important marker for achlorhydria, especially when this Heidleberg capsule, is shown for a typical older and
condition is related to chronic atrophic gastritis, the younger subject (see text for details). Note that while the
gradual “functional” decline in gastric acid secretion pH of the stomach re-acidifies after the meal rapidly in
during and after consuming a meal (a biomarker rarely the younger subject, there is a >4-hour delay in reaching
reported in the literature) may be a much more important pre-meal stomach acid levels in the older individual (i.e.
measure of acid-related digestive issues. Interestingly, functional hypochlorhydria). Figure modified from
studies performed by researchers at the University of Berardi et al. with permission.
Michigan nearly two decades ago give us some clues to
investigate this phenomenon. They reported on the and old subjects (5.0 and 4.9, respectively), the time it took
fasting, mealtime and postprandial stomach pH levels in to re-acidify the stomach to a pH of 3.0 was 42 minutes in
healthy young and elderly subjects.13,14 Gastric pH levels the younger subjects and 89 minutes in the older subjects,
were measured using a tethered radio-telemetric capsule averaging nearly an hour longer to reach a pH of 2.0
(Heidelberg) in 15-second intervals. After 12 hours of (16.4% of the elderly subjects did not return to pH of 2.0
fasting, gastric pH was measured for one hour before a within four hours).
“standard meal”i and continuously for another four hours These data suggest that a diminution of gastric acid
once subjects commenced eating the meal. In the fasted secretion may gradually worsen with aging, which cannot
state, the average gastric pH was similar in both the be readily detected in the fasted state (i.e., independent of
younger (mean age 25 years) and the older (mean age 71 atrophic gastritis/achlorhydria). This extended mealtime/
years) subjects, with a slight statistical trend toward lower postprandial hypochlorhydria may contribute to poor
pH (more acid) in the elderly subjects (See Figure 1). protein digestion, reduced micronutrient absorption,
However, it should be noted that while none of the increased risk of dysbiosis, SIBO, or other symptoms
younger subjects had a fasting pH > 5.0 (the study’s associated with functional dyspepsia. Therefore, based
definition of achlorhydria), 11% of the elderly subjects had upon this progressive “functional” hypochlorhydria in
a fasting gastric pH >5.0, similar to the prevalence noted older subjects, it is not unreasonable for integrative and
above in US elderly subjects. Using this fasting data alone, functional medicine clinicians to consider oral
one might conclude that ~90% of elderly subjects have supplementation of “gastric acid” in the form of betaine
similar gastric acid production compared to younger HCl (often with pepsin) to help reduce meal-time stomach
subjects. However, while both groups saw an expected rise pH; but what is the evidence for this approach?
in stomach pH upon consumption of the meal, the time
required to re-acidify the gastric contents was much Supplementing “Acid” to Improve Digestion: What
slower in the older subjects. For instance, while the is the Evidence?
average pH after consuming the meal was similar in young The debate about the utility of supplementing acid is
related to the debate about the relationship between
i. The “standard meal” used in this early 1990s report was a 6 oz.
hamburger, 2 slices of bread, 2 oz. of hash browns, 1 oz. of tomato, endogenous stomach acid production and gastrointestinal
some lettuce, mayo and ketchup and 8 oz. of milk (1000 calories). outcomes. While conventional medical literature routinely

Guilliams—Betaine HCl for Functional Hypochlorhydria Integrative Medicine • Vol. 19, No. 1 • February 2020 33
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suggests that the amount of stomach acid production is measured in milligrams; however, some recommendations
more than adequate for the purposes of digestion in still use “grains” to measure this compound. One grain of
healthy subjects, meal-time “functional hypochlorhydria” betaine HCl is equal to 65 mg.
may be much more common in older subjects. In addition, Within the integrative medicine community, the most
the rampant use of drugs to suppress acid production common recommendation for the use of betaine HCl
increases the frequency of mealtime hypochlorhydria in supplements is usually implemented using an empirical
many subjects. Therefore, it is common within the test for low stomach acid whereby increasing doses of
functional and integrative medicine community to betaine HCl are given during sequential meals until such
recommend supplementing agents that directly or time as an uncomfortable sensation is noticed by the
indirectly increase stomach acid during a meal. patient (see sidebar for a typical protocol). Along with
improvements in symptoms of dyspepsia (or laboratory
Agents Suggested to Indirectly Increase Stomach Acid analysis of improved protein digestion), the lack of
Bitter-tasting plants or plant extracts (bitters), have side-effects acts is an empirical confirmation that low
been commonly used in many herbal medicinal traditions gastric acid production was contributing to poor digestion
to promote digestion and/or to relieve digestive complaints, and/or dyspeptic symptoms. At this time, we are unaware
and mechanisms have been studied in in vitro models for that this popular protocol has been rigorously tested in a
the potential role of bitters in acid secretion; however, research setting, though thousands of clinicians follow
there is little in the way of systemic research in humans to such recommendations with positive anecdotal outcomes.
suggest specific preparations and dosages.15-18 Further,
in vitro research has identified several compounds in Supplementation with Betaine HCl and Stomach pH
brewed coffee that stimulate gastric acid secretion, some While betaine HCl supplementation is widely
of which are altered by the roasting process, with one recommended, there is limited published data evaluating
study suggesting this gastric acid stimulation may be the effects of this agent on stomach pH and, subsequently,
signaled via bitter taste receptors.19-22 Interestingly, cola digestive outcomes. However, recent published data that
beverages (e.g., Coca-Cola, pH 2.5) have been used to specifically investigates how betaine HCl supplementation
increase gastric acidity in clinical trials aiming to lower alters stomach pH may be helpful to the clinician
stomach pH to increase the absorption of some recommending this therapy. These researchers investigated
pH-dependent pharmaceutical drugs (e.g., ketoconazole, the ability of betaine HCl to re-acidify the gastric
itraconazole, etc.); however, the use of cola beverages to environment in subjects taking proton pump inhibitors,
promote low stomach pH for drug absorption (or nutrient with a specific goal to improve the solubility and efficacy
absorption) is not a healthy option.23-25 Instead researchers of specific pH-sensitive drugs.25,26 Using six healthy
and clinicians have turned to the supplementation of volunteers with normal fasting gastric pH (pH < 2),
betaine HCl for its direct ability to reduce stomach pH as hypochlorhydria (defined by the study as a pH > 4) was
it can be delivered in a tablets or capsules while avoiding induced by giving 20 mg of rabeprazole sodium (PPI)
contact with the oral cavity and esophagus.25-28 twice daily with food for four days prior to the study day.
On the fifth day, radio-telemetric Heidelberg capsules
Supplementing Betaine HCl were positioned in the stomach and each subject was given
Betaine HCl is the hydrochloride salt of betaine, a an additional 20 mg of rabeprazole. When the subjects’
different but important supplemental compound. It is gastric pH remained above 4.0 for a minimum of
important to distinguish between betaine HCl and betaine 15 minutes, they were given 1,500 mg of betaine HCl (two
(or trimethylglycine (TMG)) as these agents have very capsules, 750 mg each) with 250 ml of water and monitored
different chemistry and clinical indications. The non-acidic for changes in gastric pH for several hours in the fasted
betaine is used primarily as a methyl donor, especially to state. Gastric pH in all subjects fell rapidly from an average
treat homocystinuria (for which it is approved as a pH 5.2 in the half hour prior to the ingestion of betaine
prescription drug). In contrast, betaine HCl readily HCl to an average pH of 0.6 thirty minutes after
releases H+ in an aqueous environment (approximately supplementation. While the gastric acidification was
0.65 mmol/100 mg). Confusion between these two rapid, averaging 6.25 minutes to reach pH < 3, the total
compounds is common, even noted recently in a duration of re-acidification lasted just longer than one
medication error report when a pharmacy dispensed hour (average time to rebound to pH > 3 was 73 minutes,
anhydrous betaine (Cystadane) instead of the physician- rebound to pH>4 was 77 minutes, though there was a wide
prescribed betaine HCl (which was intended to help the inter-individual range [±30 minutes] for rebound). They
patient absorb another prescription drug while taking a later showed that, indeed, betaine HCl co-administered
PPI drug; see below).29 Because betaine HCl readily with a pH-sensitive drug (dasatinib) greatly enhanced
donates H+ in an aqueous environment, it is important solubility and absorption during PPI-induced
that betaine HCl supplements are in the form of capsules hypochlorhydria. It is important to note that these
or tablets when ingested. Betaine HCl is most often dramatic results occurred in the fasted state, whereas

34 Integrative Medicine • Vol. 19, No. 1 • February 2020 Guilliams—Betaine HCl for Functional Hypochlorhydria
This article is protected by copyright. To share or copy this article, please visit copyright.com. Use ISSN#1945-7081. To subscribe, visit imjournal.com

subsequent research by this group suggests that food can Basic Protocol for using Betaine HCl
alter the re-acidification dynamics.27 (For empiric testing of mealtime hypochlorhydria and for
Using a similar study design as their previous work, supplementing gastric acid)
Faber et al. evaluated whether betaine HCl supplementation
could affect the absorption of a different pH-dependent This protocol involves giving patients increasing doses of
drug (atazanavir) in healthy subjects (N = 8) in whom betaine HCl at mealtimes until such time as noticeable
hypochlorhydria was induced using a PPI drug discomfort is reported. Patients who have exceeded
(i.e., rabeprazole, 20 mg twice daily).27 This study differed the necessary dose will experience tingling, heartburn,
from their previous work with dasatinib in that this drug diarrhea, or any type of discomfort including a feeling
was taken with a standardized light meal containing of unease, digestive discomfort, neck ache, backache,
336 kcal, 5.1 g fat and 9.3 g protein. The meal was headache, or any new odd symptom. Upon experiencing
administered at T0 followed by betaine HCl (1500 mg) ten tingling, burning, or any uncomfortable symptom,
minutes later (T10) and five minutes later the drug was patients can neutralize the acid with 1 tsp baking soda in
given (T15). In this study, 1500 mg of betaine HCl was not water or milk.
shown to significantly improve the absorption of atazanavir
in subjects with PPI-induced achlorhydria given a meal, 1. Patients with suspected mealtime hypochlorhydria
though interestingly, betaine HCl supplementation did should begin by taking one (1) capsule containing 350–
decrease the gastric pH. However, compared to the 750 mg (~5-12 grains) of betaine HCl with a protein-
containing meal† (Capsules containing betaine HCl with
previous study performed in the fasted state, it took nearly
added pepsin can also be used and may be superior for
three-times longer to reduce the pH below 1.0 in the fed overall benefit).
state. It is possible that consuming the betaine HCl just 2. If no discomfort or burning sensation is noted, the
prior to the meal (rather than 10 minutes after starting the patient can begin taking two (2) capsules with each
meal) could have diminished the time for re-acidification. protein-containing meal.
Nonetheless, these studies (along with the mealtime pH 3. If a burning sensation or any discomfort is noted after
studies in the young and old mentioned previously) allow taking this (or any) dose, the patient can neutralize the
us to make some clinical observations. acid with 1 tsp baking soda in water or milk and reduce
First, these data clearly show the potency of betaine the dose of betaine HCl to a previously tolerated dose at
subsequent meals or discontinue the protocol.
HCl to quickly acidify gastric pH in achlorhydric subjects
4. If there are no noticeable reactions to the betaine HCl
using a dose of 1500 mg (~23 grains), as well as the safe use after two days, patients should increase the number of
of betaine HCl in subjects treated with proton pump capsules with each meal to three (3).a
inhibitors. The rebound time to higher gastric pH reported 5. Continue increasing the number of capsules every two
in these subjects is, however, confounded by the fact that days (maximum 3,000 mg of betaine HCl) with each
these subjects were fasting in addition to taking meal if necessary, until a dose results in tingling, burning,
acid-suppressing therapy. Even when given 1500 mg of or any other type of discomfort. At such point, the
betaine HCl, most subjects had returned to their patient should decrease the dose by one (1) capsule per
PPI-induced gastric hypochlorhydria in less than 75 meal. If the discomfort continues, they should be instructed
to discontinue the betaine HCl supplementation and
minutes on an empty stomach. Since 1500 mg of betaine
consult with their healthcare professional.
HCl was less potent when a small (336 kcal) meal was 6. Once a dose is established, continue this dose at
consumed 10 minutes prior, this suggests that higher doses subsequent meals.
of betaine HCl dosed just before the meal may be needed to 7. With smaller meals, less betaine HCl is needed, so a
compensate for the average meal (600-1000 kcal). These reduced dose may be adequate.
same researchers have conducted a similar study using 8. Individuals with very moderate HCl deficiency generally
1500, 3000 and 4500 mg of betaine HCl in their attempt to show rapid improvement in symptoms and have early
overcome the mealtime suppression of drug absorption signs of intolerance to the acid. This typically indicates a
noted when using only 1500 mg of betaine HCl; however, return to normal acid secretion.
the results of this trial have not yet been made available.30
While limited in scope, these results generally agree Precautions: Administration of HCl/pepsin is contraindicated
with the empirical supplementation of meal-time betaine in peptic ulcer disease. HCl can irritate sensitive tissue and
HCl and suggest that the dose(s) of betaine HCl may need can be corrosive to teeth; therefore, capsules should NOT be
to be taken minutes prior to the meal or divided and taken emptied into food or dissolved in beverages.
throughout the meal. Furthermore, these data strongly
suggest that supplemental mealtime betaine HCl may be
a
It is important that this be done with a meal of sufficient
safe and appropriate (and necessary) in subjects on PPI size (500 calories or more) containing adequate protein.
therapy, in order to decrease common PPI side-effects Betaine HCl should not be given on an empty stomach
(e.g., protein/micronutrient/drug malabsorption, unless it is followed immediately by consuming a meal.
food-borne microbial survival, or slow gastric emptying).

Guilliams—Betaine HCl for Functional Hypochlorhydria Integrative Medicine • Vol. 19, No. 1 • February 2020 35
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15. McMullen MK, Whitehouse JM, Towell A. Bitters: Time for a New Paradigm.
Does the Betaine (TMG) portion of Betaine HCl Evidence-based complementary and alternative medicine : eCAM.
Benefit Digestion 2015;2015:670504.
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Journal of agricultural and food chemistry. 2018;66(26):6762-6771.
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Cells in Culture. Journal of agricultural and food chemistry. 2018;66(10):2295-
outcomes are currently lacking. However, a 2018 animal 2300.
study in rats found that high salt stress decreased the 19. Boekema PJ, Samsom M, van Berge Henegouwen GP, Smout AJ. Coffee and
gastrointestinal function: facts and fiction. A review. Scandinavian journal of
activities of amylase, lipase, trypsin and chymotrypsin gastroenterology Supplement. 1999;230:35-39.
(P < .05) and that anhydrous betaine (TMG) 20. Rubach M, Lang R, Hofmann T, Somoza V. Time-dependent component-
specific regulation of gastric acid secretion-related proteins by roasted coffee
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enzymes under these conditions.31 High salt stress also 21. Rubach M, Lang R, Bytof G, et al. A dark brown roast coffee blend is less
effective at stimulating gastric acid secretion in healthy volunteers compared
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Author Disclosure Statement betaine HCl in healthy volunteers with rabeprazole-induced
Thomas G. Guilliams, PhD, is a medical advisor for Ortho Molecular Products. hypochlorhydria. Molecular pharmaceutics. 2013;10(11):4032-4037.
27. Faber KP, Wu HF, Yago MR, et al. Meal Effects Confound Attempts to
Counteract Rabeprazole-Induced Hypochlorhydria Decreases in Atazanavir
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36 Integrative Medicine • Vol. 19, No. 1 • February 2020 Guilliams—Betaine HCl for Functional Hypochlorhydria