Current Drug Metabolism, 2005, 6, 15-22 15
1389-2002/05 $50.00+.00 © 2005 Bentham Science Publishers Ltd.
Effects of Betaine Intake on Plasma Homocysteine Concentrations and
Consequences for Health
and P. Verhoef
Wageningen Centre for Food Sciences and Wageningen University, Division of Human Nutrition, Wageningen, the
Abstract: High plasma concentrations of homocysteine may increase risk of cardiovascular disease. Folic acid lowers
plasma homocysteine by 25% maximally, because 5-methyltetrahydrofolate is a methyl donor in the remethylation of
homocysteine to methionine. Betaine (trimethylglycine) is also a methyl donor in homocysteine remethylation, but effects
on homocysteine have been less thoroughly investigated. Betaine in high doses (6 g/d and higher) is used as
homocysteine-lowering therapy for people with hyperhomocysteinemia due to inborn errors in the homocysteine
metabolism. Betaine intake from foods is estimated at 0.5-2 g/d. Betaine can also be synthesized endogenously from its
precursor choline. Studies in healthy volunteers with plasma homocysteine concentrations in the normal range show that
betaine supplementation lowers plasma fasting homocysteine dose-dependently to up to 20% for a dose of 6 g/d of
betaine. Moreover, betaine acutely reduces the increase in homocysteine after methionine loading by up to 50%, whereas
folic acid has no effect. Betaine doses in the range of dietary intake also lower homocysteine. This implies that betaine can
be an important food component that attenuates homocysteine rises after meals. If homocysteine plays a causal role in the
development of cardiovascular disease, a diet rich in betaine or choline might benefit cardiovascular health through its
homocysteine-lowering effects. However betaine and choline may adversely affect serum lipid concentrations, which can
of course increase risk of cardiovascular disease. However, whether the potential beneficial health effects of betaine and
choline outweigh the possible adverse effects on serum lipids is as yet unclear.
Key Words: Betaine, choline, homocysteine, health, human.
Betaine (N, N, N-trimethylglycine) is a quaternary amine
that occurs naturally in cells to protect them against osmotic
stress. Betaine can also be synthesized endogenously through
oxidation of excess choline. Choline is required for synthesis
of phospholipids in cell membranes, cholinergic neuro-
transmission and for methyl metabolism through betaine .
Betaine helps to maintain normal cell volume, e.g. in the
kidney, and it serves as methyl donor for the remethylation
of homocysteine into methionine, catalyzed by the enzyme
betaine-homocysteine methyltransferase (BHMT) (Fig. (1))
. Methionine is metabolized into homocysteine, via
demethylation of S-adenosylmethionine (SAM). High total
homocysteine (tHcy) concentrations may lead to cardio-
vascular disease , pregnancy complications , and
cognitive decline in elderly [5-7]. The most potent food
component that reduces thcy concentrations is the B-vitamin
folate: the vitamer 5-methyltetrahydrofolate is also a methyl
donor in the (re)methylation of homocysteine to methionine
. Additionally, supplementation with other B vitamins
such as cobalamin (vitamin B
) and pyridoxine (vitamin B
can also reduce tHcy concentrations, but to a much lower
extent than folic acid [9, 10].
Now that the US food supply is fortified with folic acid,
the interest in homocysteine-lowering nutrients in addition to
*Address correspondence to this author at the Wageningen Centre for Food
Sciences and Wageningen University, Division of Human Nutrition, PO box
8129, 6700 EV, Wageningen, the Netherlands; Fax: +31-317-483342;
folic acid will increase. Betaine and its precursor choline are
potential candidates. Large amounts of betaine are already
given as oral therapy to patients with inborn errors that lead
to very high thcy concentrations in blood, even though little
is known about the metabolism of betaine in humans.
HOMOCYSTEINE, BETAINE AND FOLATE
Homocysteine is metabolized by two methionine con-
serving remethylation reactions (Fig. (1)): 1) by means of
methionine synthase (MS), with 5-methyltetrahydrofolate as
methyl donor; and 2) by means of BHMT, with betaine as
methyl donor. Methionine is important for protein synthesis,
and it is a source of methyl groups through formation of
SAM. SAM is a universal methyl donor in many reactions
catalyzed by methyltransferases . Homocysteine can
also be broken down into cysteine via the transsulfuration
Betaine is either consumed through foods, or formed
endogenously out of its precursor choline. Catabolism of bet-
aine provides 3 methyl groups to the one-carbon pool. One
of these methyl groups becomes available for remethylation
of homocysteine into methionine, in a reaction catalyzed by
BHMT. The other 2 methyl groups from betaine enter the
folate pool for formation of 5, 10-methylenetetrahydrofolate
in mitochondria [2, 12, 13]. The end-product of betaine cata-
bolism, glycine, is used as a methyl acceptor for S-adeno-
sylmethionine (SAM) when SAM concentrations become too
high. Glycine N-methyltransferase (GNMT) catalyzes this
16 Current Drug Metabolism, 2005, Vol. 6, No. 1 Olthof and Verhoef
Remethylation through the BHMT pathway is confined
to the liver and kidney . In contrast with that, remethyla-
tion of homocysteine catalyzed by MS occurs in all body
cells. Both remethylation pathways are metabolically
interrelated . Rats that were maintained on a choline-
deficient diet for 2 weeks have 31% lower hepatic folate
content . Moreover, rats maintained on a folate-deficient
diet also induced depletion of hepatic choline . This
suggests that limitation of one pathway increases remethyla-
tion via the other pathway. In line with this, we found that
supplementation with folic acid doses increases fasting
plasma betaine concentrations in healthy elderly (Melse-
Boonstra et al., unpublished). In addition, supplementation
with B-vitamins attenuates the initial inverse association
between plasma betaine concentrations and post-methionine
thcy concentrations in coronary patients . On the other
hand, 6 weeks of betaine supplementation does not affect
folate concentrations in adults with mildly elevated tHcy
concentrations supplemented with 6 g betaine per day . It
could be that, instead of the folate concentrations, the
concentration of the amino acid serine is increased through
betaine supplementation, but this was not measured. Serine
is the actual methyl donor in the synthesis of 5-
methyltetrahydrofolate, which makes folate more a methyl
carrier (Fig. (1)) . Overall, this indicates that increased
remethylation of homocysteine via MS down regulates the
remethylation through the BHMT dependent pathway.
BETAINE AND ITS PRECURSOR CHOLINE IN
Betaine is present in several plants as an osmolyte that
protects against unfavorable environmental conditions, such
as high levels of salt or low temperature. Betaine has similar
functions in some organs of mammals. As a result betaine is
present in various plant foods and in meat. Recently a
database with information on amounts of betaine and choline
derivatives in various foods became available . The
dietary intake of betaine is estimated at 0.5-2 g/d, and of
choline at 0.3-1 g/d [21, 22]. With the database it would now
be possible to determine daily intakes of betaine and choline
in different populations. However, it is unknown to the
authors whether this is currently being investigated.
Fig. (1). Schematic overview of the role of betaine, choline and folic acid in homocysteine metabolism.
Effects of Betaine Intake on Plasma Homocysteine Current Drug Metabolism, 2005, Vol. 6, No. 1 17
Foods rich in betaine are spinach, beets, shrimp and
wheat products. Interestingly, many wines contain betaine in
low levels, particularly less expensive wines because beet
sugar is used to increase the alcohol content . Betaine is
a by-product of sugar production from sugar beets and it is
used in food industry as food additive.
Foods rich in choline are in eggs, liver, soybeans and
pork. Choline is present in foods mostly as lecithin [21, 22].
Lecithin is actually a mixture of phospholipids and it con-
tains about 30% phosphatidylcholine. Lecithin is also added
to commercial foods as an emulsifying agent.
Betaine and choline are also available as dietary supple-
ments for several purposes, e.g. heart health through homo-
cysteine lowering, digestive aid, liver protection, cognition,
and physical performance. However their actual effective-
ness is questionable.
EFFECT OF BETAINE ON PLASMA HOMOCYS-
TEINE IN CLINICAL SETTING
In observational studies plasma betaine concentrations
are inversely associated with fasting homocysteine
concentrations in cardiovascular patients . In addition,
plasma betaine is a determinant of the increase in plasma
homocysteine after methionine loading .
The effect of betaine and choline supplementation on
lowering of plasma concentration of thcy has mainly been
studied in clinical settings [25-30]. Betaine is considered a
safe and effective therapy to lower thcy in patients with
inborn errors in the enzymes involved in homocysteine
metabolism, e.g. diminished activity of cystathionine beta-
synthase (CBS), who are not responsive to pyridoxine treat-
ment . Generally, large amounts of betaine are added to
the regimen to lower thcy because low doses were not
effective . Betaine doses of up to 20 g per day (the most
commonly used dose was 2 x 3 g betaine/day) drastically
lower fasting and post-methionine plasma thcy levels to
near-normal levels. The onset of homocysteine-lowering is
within several days and long-term supplementation with
betaine remains effective for years . In contrast to the
effects of betaine in the patients with genetically caused
hyperhomocysteinemia, supplementation with 4-6 g/d of
betaine in addition to folic acid therapy (1-5 mg/d folic acid)
for 1 week to 3 months does not affect fasting or post-
methionine loading thcy concentrations in hemodialysis
patients (Table 1). The authors concluded that higher
dosages of betaine or folic acid might be needed to
normalize plasma thcy concentrations in these patients [33,
34]. McGregor et al.,  also found that 4 g/d of betaine in
addition to folic acid and pyridoxine therapy for 3 months
has no additional effect on fasting plasma thcy in patients
with chronic renal failure. However, in their study betaine
supplementation does suppress the increase in thcy concen-
trations following methionine loading by 18%, relative to
folic acid and pyridoxine treatment alone. Thus the effect of
betaine on thcy lowering is not consistent in these clinical
studies. Moreover, all these studies are done in patients with
fasting thcy concentrations far above normal. Recently data
became available about the effects of betaine supplemen-
tation in healthy subjects with normal thcy concentrations.
EFFECT OF BETAINE ON PLASMA HOMOCYS-
TEINE IN THE GENERAL POPULATION
In healthy volunteers with normal thcy concentrations
supplementation with 6 g/d of betaine for 6-12 weeks lowers
fasting thcy concentrations up to 20% relative to placebo
(Table 1) [18, 36, 37]. In addition, taking betaine together
with a methionine loading test (100 mg/kg body weight)
reduces the increase in thcy after a methionine load by up of
50%, whereas folic acid has no effect [18, 37] (Fig. (2)). This
implies that adding betaine to foods that potentially increase
thcy concentrations, (e.g. protein-rich foods, which are high
in methionine) helps to attenuate homocysteine rises after
meals. Consequently, the risk of cardiovascular disease
might be reduced since the increase in plasma thcy after
methionine loading is a risk indicator for cardiovascular
disease independent from fasting thcy concentrations [38,
39]. The lack of an effect of folic acid on post-methionine
plasma homocysteine might be due to the rise in SAM after
methionine loading, which suppresses activity of 5, 10-
methylenetetrahydrofolate reductase (MTHFR), and thereby
production of 5-methyltetrahydrofolate . Hence, the
remethylation pathway via folate is hindered. The
concentration of SAM does not seem to influence the
remethylation via the betaine remethylation pathway.
The dose of 6 g/d of betaine used in the intervention
studies and in therapeutic settings cannot be easily attained
through normal food consumption. Normal betaine intake is
estimated at 0.5-2 g/d. A betaine dose of 6 g is in ~0.8 kg of
cooked spinach or ~2.6 kg of wheat bread . We therefore
investigated the effect of betaine doses lower than 6 g/d on
plasma homocysteine concentrations. In a parallel study we
gave 1.5 g/d, 3 g/d, 6 g/d of betaine, or placebo to 19 healthy
subjects per dose group for 6 weeks. We measured fasting
plasma homocysteine at baseline, and after 2 and 6 weeks of
intervention. We also measured plasma homocysteine
responses after methionine loading at baseline, and on day 1,
and after 2 and 6 weeks of intervention. We found that there
is a dose-response relation between betaine doses up to 6 g/d
and plasma thcy responses (Fig. (3)) . The dose of
betaine in the dietary range (1.5 g/d) lowers fasting thcy by
12% and plasma thcy concentrations 6 h after methionine
loading by 23% in healthy volunteers. In addition, a single
dose of 0.75 g of betaine together with a methionine load on
the first day of supplementation acutely reduces the increase
in plasma thcy 6 h after methionine loading by 16%. The
acute effect of betaine on homocysteine is in line with the
pharmacokinetics of betaine in humans. Betaine is very
rapidly absorbed, distributed and metabolized into dimethyl-
glycine, indicated by an increase in dimethylglycine concen-
tration after intake of betaine [41, 42]. This suggests that
exogenous betaine is quickly available as methyl donor after
Because betaine is also endogenously formed out of
choline, choline supplementation could influence the produc-
tion of betaine, the flux through the BHMT-remethylation,
and homocysteine concentrations [43, 44]. However data on
effects of choline intake on plasma thcy concentrations in
humans are limited. We investigated the effect of choline
supplementation for 2 weeks on fasting and post-methionine
plasma homocysteine in a cross over study in 26 male volun-
18 Current Drug Metabolism, 2005, Vol. 6, No. 1 Olthof and Verhoef
teers. Preliminary results show that choline supplementation
can lower plasma thcy responses in men (Olthof et al.,
Thus, low thcy levels can be achieved through specific
betaine and/or choline (en)rich(ed) foods. Whether low
homocysteine concentrations are beneficial for health is still
not sure. On the other hand, betaine might adversely affect
EFFECT OF BETAINE ON SERUM LIPIDS
In contrast to the potential beneficial homocysteine-
lowering properties of betaine, human studies show that
betaine supplementation adversely affects serum lipid
concentrations. Supplementation of 4 g/d of betaine in
addition to B-vitamins for 3 months in patients with chronic
renal failure increases total serum cholesterol, LDL, HDL
and triacylglycerol concentrations up to 10%, relative to
treatment with B-vitamins alone . Supplementation of 6
g/d of betaine for 12 weeks in obese subjects who are on a
weight loss diet increases serum total cholesterol and LDL
cholesterol up to 14% relative to the placebo group. Serum
triacylglycerol concentrations increased by ~12%, but this
was not statistically significant . Our own studies
confirm that betaine supplementation for 6 weeks increases
serum total cholesterol, especially LDL, in healthy humans
(Olthof et al., unpublished). Unfortunately there are no data
on changes in cholesterol concentrations in hyperhomo-
cysteinemic patients who are on betaine treatment. Probably
in these patients the benefits of the drastic reduction in thcy
will outweigh the adverse effects on plasma cholesterol
concentrations. However, it might be important to monitor
serum cholesterol concentrations in patients on betaine
treatment, and treat them if their cholesterol concentrations
The precursor of betaine, choline is also involved in lipid
metabolism. Choline in the form of phosphatidylcholine
plays an important role in the maintenance of normal lipid
transport. Choline deficiency in humans decreases serum
cholesterol by 15%, and increases fat accumulation in the
liver . In addition, patients receiving long-term paren-
teral nutrition without choline had very low total cholesterol
concentrations, especially LDL cholesterol . Adding
choline to the diet reversed liver problems in these patients
on parenteral nutrition and in healthy humans.
Table 1. Intervention Trials Investigating the Effect of Betaine on Plasma tHcy in Humans
Reference Subjects Design Effect on tHcy
v. Guldener et al.
Parallel, intervention for 12 weeks:
1. placebo (n=18)
2. 4 g/d betaine (n=17)
All subjects received 5 mg/d folic acid +
50 mg pyridoxine during the study
Fasting tHcy decreased from 48.4 µmol/L to 17.4
Post-methionine tHcy decreased from 94.3 µmol/L to
Betaine had no additional homocysteine-lowering
Mc Gregor et al.
Cross over, n=36, intervention for 3 months:
2. 4 g/d betaine
All subjects received 5 mg/d folic acid +
50 mg pyridoxine during the study
Fasting tHcy decreased to the same extent with both
treatments relative to baseline.
Post-methionine tHcy decreased with both treatments,
but was 18% lower on betaine than on placebo.
Schwab et al.
Obese men and
Parallel, intervention for 12 weeks:
1. placebo (n=20)
2. 6 g/d betaine (n=22)
All subjects were on a weight loss diet
Fasting tHcy decreased by ~11% (from 8.76 to 7.93
µmol/L) in the betaine group relative to the placebo
Steenge et al.
Healthy men and
Parallel, n=12 per group, intervention for 6 weeks:
2. 800 µg/d folic acid
3. 6 g/d betaine
Fasting tHcy decreased by 11% (from 12.2 to 10.9
µmol/L) in the betaine group and by 18% (from 13.0 to
10.7 µmol/L) in the folic acid group.
Post-methionine tHcy decreased by 49% in the betaine
group, whereas folic acid had no effect.
Olthof et al.
Healthy men and
Parallel, n=19 per group, intervention for 6 weeks:
2. 1.5 g/d betaine
3. 3 g/d betaine
4. 6 g/d betaine
Fasting tHcy was 12%, 15% and 20% lower in the 1.5
g/d, 3 g/d and 6 g/d betaine groups than in the placebo
Post-methionine tHcy was 23%, 30% and 40% lower
than in the placebo group after subjects had ingested 1.5
g/d, 3 g/d, and 6 g/d betaine for 6 weeks respectively.
The homocysteine-lowering effect of a single dose
(which was half the daily dose) of betaine after
methionine loading was similar to the effect after 6
Effects of Betaine Intake on Plasma Homocysteine Current Drug Metabolism, 2005, Vol. 6, No. 1 19
Supplementation with choline in rats increases serum
cholesterol concentrations [47, 48]. The effects of supple-
mentation with choline, on serum lipid concentrations in
humans are uncertain, but an increase in serum lipids is
expected . We found in a cross over study in 26 healthy
men that choline supplementation for 2 weeks increases
serum triacylglycerol concentrations, but had no effect on
serum cholesterol concentrations (Olthof et al., unpublished).
However, 2 weeks supplementation of choline might have
been too short to find the effect of choline on serum
The mechanism by which betaine and choline may
increase serum lipid concentrations probably involves
increased transport of lipids from the liver into the serum.
Lipids are exported from the liver in the form of Very Low
Density Lipoproteins (VLDL). Betaine or choline supple-
mentation might increase the synthesis of VLDL through an
increase in phosphatidylcholine synthesis, which is an
Fig. (2). Plasma thcy responses in humans after the ingestion of 100 mg methionine/kg body mass A) before and B) after 6 weeks of
treatment. Treatments consisted of the ingestion of 3 g of betaine (n = 12), 400 µg folic acid, (n = 12) or 3 g of placebo (n = 9) twice each
day. Values are means ± SEM. Adapted from Steenge et al. .
Fig. (3). A) Mean fasting plasma thcy concentrations (µmol/L) at baseline, and after 2 and 6 weeks of treatment with different betaine doses
in 19 healthy volunteers per dose group. B) Mean increase in plasma thcy concentrations (µmol/L) from 0-6 h after methionine loading at
baseline, on the first day, and after 2 and 6 weeks of treatment. Treatments consisted of ingestion of 0.75 g of betaine, 1.5 g of betaine, 3 g of
betaine, or 3 g of placebo twice each day. All subjects ingested half of the daily dose of betaine together with the methionine load .
20 Current Drug Metabolism, 2005, Vol. 6, No. 1 Olthof and Verhoef
essential component of VLDL . Consequently, more
VLDL will lead to increased transport of lipids from the liver
into the serum, whereby concentrations of lipids in the liver
decrease accordingly . Phosphatidylcholine synthesis can
be influenced through 2 pathways. Betaine and choline can
affect either pathway (Fig. (4)). Choline can be directly
metabolized into phosphatidylcholine. Secondly, betaine and
choline might increase availability of SAM via increased
remethylation of homocysteine into methionine. SAM is the
methyl donor for the formation of phosphatidylcholine via
sequential methylation of phosphatidylethanolamine .
The hypothesis as stated above could mean that other
dietary methyl donors that increase SAM potentially might
increase serum lipids as well, but no data are available on
this. In conclusion, betaine and choline supplementation
might lead to increases in serum lipid concentrations, which
is not beneficial for health.
BETAINE AND CARDIOVASCULAR OUTCOMES
A high plasma homocysteine is a potential risk for
cardiovascular disease. Betaine supplementation lowers
fasting plasma thcy in healthy subjects by 15-20%, and
plasma thcy after methionine loading by 20-40% [18, 37].
For example, a person who consumes a diet rich in
betaine (~2 g/d of betaine) has ~12% lower plasma thcy than
a person who consumes a diet poor in betaine (0.5 g/d) .
A 25% reduction in thcy concentrations is associated with
11% lower risk of ischemic heart disease, and 19% lower
risk of stroke . Based on this, a betaine-rich diet would
reduce cardiovascular disease risk by 5-10% relative to a
Whether homocysteine lowering indeed lowers risk of
cardiovascular diseases is not yet established, but evidence
for a causal relationship is accumulating [52-54]. In a meta-
analysis Klerk et al.,  found that subjects with the
MTHFR-TT genotype have a 16% higher risk of coronary
heart disease. The MTHFR 677C-->T polymorphism is a
genetic alteration in an enzyme involved in folate meta-
bolism that causes elevated thcy concentrations. Because a
relationship between a genotype and disease cannot be
confounded by lifestyle, this study provides strong evidence
for a causal relationship between high homocysteine and risk
of cardiovascular disease. In contrast, two secondary preven-
tion trials show no reduction of coronary heart disease or
stroke after ~2 y homocysteine-lowering treatment 
Baker et al., 2002]. In several years from now there will be
data from about 50.000 patients that were allocated to B
vitamins or placebo . However, all treatments in these
trials with B-vitamins include folic acid, which will make it
impossible to distinguish between the effects of folic acid
itself and the effects of homocysteine lowering per se. Only
intervention studies with homocysteine-lowering agents
other than folic acid, for example betaine, will help to
investigate the effect of homocysteine lowering per se on
disease risk. We used this approach in two studies in order to
investigate the effects of homocysteine-lowering per se on
endothelial function in healthy volunteers (Olthof et al.,
unpublished). Endothelial function can be considered a
surrogate endpoint for cardiovascular risk [58-61]. In our
studies we compare the effect of homocysteine-lowering via
folic acid supplementation with that via betaine supplemen-
tation on endothelial function in healthy volunteers.
The effects of betaine or choline intakes on cardio-
vascular morbidity or mortality are unknown. Observational
studies are now possible with the available database with
contents of betaine and choline in various foods .
However, it is unknown to the authors whether this is
currently being investigated. It will be important to realize
that a potential health benefit of betaine and choline through
thcy lowering might vanish, since betaine and its precursor
choline potentially increase serum lipids.
The interest in betaine and its precursor choline as
homocysteine-lowering agents is increasing. We have shown
that betaine doses in the range of normal dietary intake can
lower fasting plasma thcy as well as plasma thcy after
methionine loading in healthy volunteers. The unique
properties of betaine relative to folic acid are that betaine
suppresses the increase in thcy after a methionine loading,
Baker, F., Picton, D., Blackwood, S., Hunt, J., Erskine, M., Dyas, M., Ashby, M.,
Siva, A. & Brown, M.J. (2002) Circulation 106 (suppl II), 741 (abstract).
Fig. (4). The potential role of choline and betaine in phosphatidylcholine metabolism. Phosphatidylcholine is necessary for synthesis of
VLDL, which exports lipids from the liver.
Effects of Betaine Intake on Plasma Homocysteine Current Drug Metabolism, 2005, Vol. 6, No. 1 21
and that this occurs acutely. Therefore betaine is a promising
agent to suppress increases in thcy after meals. Betaine and
choline occur naturally in various foods. If betaine and
choline prove to be beneficial for health it might also be
interesting to produce foods high in betaine or choline by
adding these compounds, or through genetic engineering
techniques. For betaine, these techniques are in principle
already available to produce plants, such as spinach and
barley, with high amounts of betaine to improve growth of
these plants under high stress conditions worldwide . A
diet rich in betaine and choline could be beneficial for health,
if homocysteine proves to be a causal factor in the
development of cardiovascular disease. However, there are
indications that high betaine and choline intakes increase
serum lipid concentrations, which of course increases risk of
cardiovascular disease. Because the overall impact of betaine
and choline on health is unclear, ingestion of extra betaine or
choline through foods rich in these compounds, or through
supplements is not recommended. Studies on the effects of
betaine and choline on risk of cardiovascular disease are
needed before we can judge the health effects of betaine and
BHMT =Betaine-homocysteine methyltransferase
HDL =High Density Lipoproteins
LDL =Low Density Lipoproteins
MS =Methionine synthase
MTHFR =5, 10-methylenetetrahydrofolate reductase
tHcy =Total homocysteine
VLDL =Very Low Density Lipoproteins
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