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Page 512 Alternative Medicine Review ◆ Volume 7, Number 6 ◆ 2002
Arginine Review
Copyright©2002 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission
Abstract
Arginine, a semi-essential amino acid, is
involved in numerous areas of human
biochemistry, including ammonia detox-
ification, hormone secretion, and immune
modulation. Arginine is also well known as a
precursor to nitric oxide (NO), a key component
of endothelial-derived relaxing factor, an
endogenous messenger molecule involved in
a variety of endothelium-dependent
physiological effects in the cardiovascular
system. Because of arginine’s NO-stimulating
effects, it can be utilized in therapeutic
regimens for angina pectoris, congestive heart
failure, hypertension, coronary heart disease,
preeclampsia, intermittent claudication, and
erectile dysfunction. In addition, arginine has
been studied in the treatment of HIV/AIDS,
athletic performance, burns and trauma,
cancer, diabetes and syndrome X,
gastrointestinal diseases, male and female
infertility, interstitial cystitis, immuno-
modulation, and senile dementia. Toxicity,
dosage considerations, and contraindications
are also reviewed.
(Altern Med Rev 2002;7(6):512-522)
Introduction
Arginine is a semi-essential amino acid
involved in multiple areas of human physiology
and metabolism. It is not considered essential be-
cause humans can synthesize it de novo from
glutamine, glutamate, and proline. However, di-
etary intake remains the primary determinant of
plasma arginine levels, since the rate of arginine
biosynthesis does not increase to compensate for
depletion or inadequate supply.1,2
Jeremy Appleton, ND
Arginine: Clinical Potential of a
Semi-Essential Amino Acid
Arginine contains four nitrogen atoms per
molecule, making it the most abundant nitrogen
carrier in humans and animals (Figure 1). Although
it is not a major inter-organ shuttle of nitrogen,
arginine nevertheless plays an important role in
nitrogen metabolism as an intermediate in the urea
cycle, making it essential for ammonia detoxifi-
cation.3
Arginine Biochemistry
Arginine is synthesized in mammals from
glutamine via pyrroline 5-carboxylate (P5C) syn-
thetase and proline oxidase in a multi-step meta-
bolic conversion.4 In adults, most endogenous argi-
nine is derived from citrulline, a by-product of
glutamine metabolism in the gut or liver. Citrul-
line is released into the circulation and taken up
primarily by the kidney for conversion into argin-
ine.5
Supplemental arginine in enteral feeding
is readily absorbed.6 About half of ingested argin-
ine is rapidly converted in the body to ornithine,
primarily by the enzyme arginase.7 Ornithine, in
turn, can be metabolized to glutamate and pro-
line, or through the enzyme ornithine decarboxy-
lase into the polyamine pathway for degradation
into compounds such as putrescine and other
polyamines.
In addition to the above-mentioned meta-
bolic activity, arginine is a precursor for the syn-
thesis of proteins, as well as nitric oxide, urea,
Jeremy Appleton, ND – Department chair, National College
of Naturopathic Medicine; Director of Scientific Affairs,
Cardinal Nutrition; co-author, MSM: The Definitive Guide
(Freedom Press).
Correspondence address: NCNM, 049 SW Porter,
Portland, OR 97201 Email: jappleton@ncnm.edu
Copyright©2002 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission
Alternative Medicine Review ◆ Volume 7, Number 6 ◆ 2002 Page 513
Review Arginine
creatine, and agmatine.8 Arginine that is
not metabolized by arginase to ornithine
is processed by one of four other en-
zymes: nitric oxide synthase (to become
nitric oxide); arginine:glycine
amidinotransferase (to become creatine);
arginine decarboxylase (to become ag-
matine); or arginyl-tRNA synthetase (to
become arginyl-tRNA, a precursor to
protein synthesis). Arginine is also an
allosteric activator of N-acetylglutamate
synthase, which synthesizes N-
acetylglutamate from glutamate and acetyl-CoA.9
Mechanisms of Action
Arginine has significant effects on endo-
crine function – particularly adrenal and pituitary
secretion – in humans and animals. Arginine ad-
ministration has long been known to stimulate the
release of catecholamines,10 insulin and gluca-
gon,11 prolactin,12 and growth hormone (GH).13,14
Little is known, however, about the exact mecha-
nism by which arginine exerts these effects.
Arginine is the
biologic precursor of ni-
tric oxide (NO), an en-
dogenous messenger
molecule involved in a
variety of endothelium-
dependent physiological
effects in the cardiovas-
cular system15 (Figure 2).
As the precursor to nitric
oxide, many of arginine’s
clinical effects are
thought to be mediated by
its effects on endothelial-
derived relaxing factor.
An immense quantity of
research has explored the
biological roles and prop-
erties of nitric oxide,16,17
which appears to be of
critical importance in
maintenance of normal
blood pressure,18 myocar-
dial function,19 inflamma-
tory response,20 apoptosis,21 and protection against
oxidative damage.22 Arginine is also a critical com-
ponent of vasopressin (anti-diuretic hormone).
Arginine is a potent immunomodulator.
Supplemental arginine appears to up-regulate im-
mune function and reduces the incidence of post-
operative infection. A significant decrease in cell
adhesion molecule and pro-inflammatory cytokine
levels has also been observed. Arginine can posi-
tively influence aspects of immunity under some
circumstances and influence cytokine balance.
Figure 1. Structure of Arginine
HN
H2N
CNH(CH2)3CH(NH2)COOH
Figure 2. Synthesis and Functions of Nitric Oxide
NADPH
+H+
NADP+
NO Synthase
O2
NO
Nitric oxide
Relaxes
smooth muscles
Inhibits platelet
aggregation
Functions as CNS
neurotransmitter
Mediates tumoricidal and
bactericidal activity
of macrophages
L-Arginine
L-Citrulline
Adapted from: Champe P, Harvey R. Lippincott’s Illustrated Reviews: Biochemistry, Second
Edition. Philadelphia, PA: J. B. Lippincott Company; 1994.
Page 514 Alternative Medicine Review ◆ Volume 7, Number 6 ◆ 2002
Arginine Review
Copyright©2002 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission
Arginine supplementation (30 g per day for three
days) has been shown to significantly enhance
natural killer (NK) cell activity, lymphokine-acti-
vated killer cell cytotoxicity, and lymphocyte mi-
togenic reactivity in patients with locally advanced
breast cancer.23,24
Clinical Applications of Arginine
Human Immunodeficiency Virus
(HIV) and Acquired
Immunodeficiency Syndrome (AIDS)
Arginine may be of benefit in individuals
with HIV/AIDS. In a small pilot study of arginine
supplementation in persons with HIV, 11 individu-
als were given 19.6 g per day arginine or placebo
for 14 days. NK-cell cytotoxicity increased 18.9
lytic units, compared to +0.3 lytic units with pla-
cebo. This was not statistically significant, most
likely due to the small number of patients.25
The combination of glutamine, arginine,
and hydroxymethylbutyrate (HMB) may prevent
loss of lean body mass in individuals with AIDS
cachexia. In a double-blind trial, AIDS patients
with documented weight loss of at least five per-
cent in the previous three months received either
placebo or a combination of 3 g HMB, 14 g L-
glutamine, and 14 g arginine given in two divided
doses daily for eight weeks. At eight weeks, sub-
jects consuming the mixture gained 3.0 ± 0.5 kg
of body weight, while those supplemented with
placebo gained only 0.37 ± 0.84 kg (p = 0.009).
The weight gain in the supplemented group was
predominately lean muscle mass, while the pla-
cebo group lost lean mass.26
A six-month, randomized, double-blind
trial of an arginine/essential fatty acid combina-
tion was undertaken in patients with HIV.27 All
patients received a daily oral nutritional supple-
ment (606 kcal supplemented with vitamins, trace
elements, and minerals). In addition, half of the
patients were randomized to receive 7.4 g argin-
ine plus 1.7 g omega-3 fatty acids per day. Body
weight increased similarly in both groups and there
was no change in immunological parameters.
Clinical trials evaluating the effect of arginine as
monotherapy for AIDS patients have yet to be
conducted.
Cardiovascular Conditions
Angina Pectoris
Arginine supplementation has been effec-
tive in the treatment of angina in some, but not
all, clinical trials. In an uncontrolled trial, seven
of ten people with intractable angina improved
dramatically after taking 9 g arginine per day for
three months.28 A significant decrease in cell ad-
hesion molecule and pro-inflammatory cytokine
levels was also observed. A double-blind trial in
22 patients with stable angina and healed myo-
cardial infarction showed oral supplementation
with 6 g arginine per day for three days increased
exercise capacity.29
In men with stable angina, two-week oral
supplementation with arginine (15 g per day) was
not associated with improvement in endothelium-
dependent vasodilation, oxidative stress, or exer-
cise performance.30 In patients with coronary ar-
tery disease, oral supplementation of arginine (6
g per day for three days) did not affect exercise-
induced changes in QT-interval duration, QT dis-
persion, or the magnitude of ST-segment depres-
sion;31 however, it did significantly increase exer-
cise tolerance. The therapeutic effect of arginine
in patients with microvascular angina is consid-
ered to be the result of improved endothelium-
dependent coronary vasodilation.32
Congestive Heart Failure
Patients with congestive heart failure
(CHF) have reduced peripheral blood flow at rest,
during exercise, and in response to endothelium-
dependent vasodilators. Nitric oxide formed from
arginine metabolism in endothelial cells contrib-
utes to regulation of blood flow under these con-
ditions. A randomized, double-blind trial33 found
six weeks of oral arginine supplementation (5.6-
12.6 g per day) significantly improved blood flow,
arterial compliance, and functional status com-
pared to placebo. Another double-blind trial found
arginine supplementation (5 g three times per day)
improved renal function in people with CHF.34
Alternative Medicine Review ◆ Volume 7, Number 6 ◆ 2002 Page 515
Review Arginine
Copyright©2002 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission
Atherosclerosis and Coronary Heart
DiseaseImpairment of the NO synthase pathway
may be one of the earliest events in atherogen-
esis.35 Animal studies have suggested anti-athero-
genic effects of supplemental arginine, including
improved endothelium-dependent vasodilation,
inhibition of plaque formation,36 and decreased
thickening of the aortic tunica intima.37 In humans,
arginine supplementation normalized platelet ag-
gregation in hypercholesterolemic adults.38 How-
ever, increased dietary arginine has not been con-
sistently associated with decreased mortality from
coronary heart disease,39 and arginine supplemen-
tation (a single intravenous dose of 16 g) failed to
affect maximal working capacity, indices of myo-
cardial ischemia, or blood flow in hypercholes-
terolemic patients.40
Hypertension
Administration of arginine prevented hy-
pertension in salt-sensitive rats, but not in sponta-
neously hypertensive rats.41 If arginine was pro-
vided early, hypertension and renal failure could
be prevented. In healthy human subjects, IV ad-
ministration of arginine had vasodilatory and anti-
hypertensive effects.42 In a small, controlled trial,
hypertensive patients refractory to enalapril and
hydrochlorothiazide responded favorably to the
addition of oral arginine (2 g three times per day).43
Small, preliminary trials have found oral44 and IV45
arginine significantly lowers blood pressure in
healthy volunteers.
Intravenous infusion of arginine (15 mg/
kg body weight/min for 35 min) improved pul-
monary vascular resistance index and cardiac out-
put in infants with pulmonary hypertension.46
Intermittent Claudication
Intravenous arginine injections signifi-
cantly improved symptoms of intermittent clau-
dication in one double-blind trial. Eight grams of
arginine, infused twice daily for three weeks, im-
proved pain-free walking distance by 230 ± 63
percent and the absolute walking distance by 155
± 48 percent (each p < 0.05) compared to no im-
provement with placebo.47 To date, this is the only
trial of arginine for intermittent claudication.
Preeclampsia
Endothelial dysfunction appears to be in-
volved in the pathogenesis of preeclampsia.48 In
an animal model of experimental preeclampsia,
IV administration of arginine (0.16 g/kg body
weight/day) from gestational day 10 until term
reversed hypertension, intrauterine growth retar-
dation, proteinuria, and renal injury.49 Intravenous
infusion of arginine (30 g) in preeclamptic women
has reportedly increased systemic NO production
and reduced blood pressure.50 Clinical trials are
needed to validate the role of supplemental argin-
ine in prevention and treatment of preeclampsia.
Growth Hormone (GH) Secretion
and Athletic Performance
In rats, NO stimulates secretion of growth
hormone-releasing hormone (GHRH) and thereby
increases secretion of GH. However, GHRH then
increases production of NO in somatotroph cells,
which subsequently inhibits GH secretion. In hu-
mans, arginine stimulates release of GH from the
pituitary gland in some populations, but the
mechanism is not well understood. Most studies
suggest inhibition of somatostatin secretion is re-
sponsible for the effect.51
At high doses (approximately 250 mg/kg
body weight), arginine aspartate has increased GH
secretion,52 an effect of interest to body builders wish-
ing to take advantage of the anabolic properties of
the hormone.53 In a controlled clinical trial, arginine
and ornithine (500 mg of each, twice per day, five
times weekly) produced a significant decrease in
body fat when combined with exercise.54 Acute, low-
dose arginine (5 g taken 30 minutes before exercise)
did not increase GH secretion, and may have im-
paired release of GH in young adults.55 Longer-term,
low-dose supplementation of arginine and ornithine
(1 g each, five days per week for five weeks) yielded
higher gains in strength and enhancement of lean
body mass when compared with controls receiving
vitamin C and calcium.56
Growth hormone has been observed to be
lower in older males than young men; however,
data suggest oral arginine/lysine (3 g each per day)
is not a practical means of enhancing long-term
GH secretion in older men.57
Page 516 Alternative Medicine Review ◆ Volume 7, Number 6 ◆ 2002
Arginine Review
Copyright©2002 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission
Burns and Critical Trauma
Burn injuries significantly increase argi-
nine oxidation and fluctuations in arginine re-
serves. Total parenteral nutrition (TPN) increases
conversion of arginine to ornithine and propor-
tionally increases irreversible arginine oxidation.
Elevated arginine oxidation, coupled with limited
de novo synthesis from its immediate precursors,
make arginine conditionally essential in severely
burned patients receiving TPN.58 Several trials
have demonstrated reduced length of hospital stay,
fewer acquired infections, and improved immune
function among burn59 and trauma60 patients
supplemented with various combinations of fish
or canola oil, nucleotides, and arginine.
Cancer
Animal research has shown large doses
of arginine may interfere with tumor induction.61
Short-term arginine supplementation may assist
in maintenance of immune function during che-
motherapy. Arginine supplementation (30 g per
day for three days) reduced chemotherapy-induced
suppression of NK-cell and lymphokine-activated
killer cell cytotoxicity, and lymphocyte mitoge-
nic reactivity in patients with locally advanced
breast cancer.23,24 In another study,62 arginine
supplementation (30 g per day for three days prior
to surgery) significantly enhanced the activity of
tumor-infiltrating lymphocytes in human
colorectal cancers in vivo. Arginine, RNA, and fish
oil have been combined to improve immune func-
tion in cancer patients.63-65
On the other hand, arginine has also pro-
moted cancer growth in animal and human re-
search.66 Polyamines act as growth factors for can-
cers. In several types of cancer, drugs are being
investigated to inhibit ornithine decarboxylase
(ODC), and hence inhibit polyamine formation.
The possibility of arginine stimulating polyamine
formation might be a concern in chronic adminis-
tration, since both arginase and ODC appear to be
up-regulated in some cancers.
Diabetes and Insulin Resistance
Endothelium-dependent relaxation is im-
paired in humans with both type 1 and type 2 dia-
betes mellitus (DM), as well as in animal models
of diabetes. Endothelial nitric oxide deficiency is
one likely explanation.67 Diabetes is associated
with reduced plasma levels of arginine,68 and evi-
dence suggests arginine supplementation may be
an effective way to improve endothelial function
in individuals with diabetes. An intravenous (IV)
bolus of 3-5 g arginine reduced blood pressure and
platelet aggregation in patients with type 1 diabe-
tes.69 Low-dose IV arginine improved insulin sen-
sitivity in obese and type 2 DM patients as well as
in healthy subjects.70 Arginine may also counter-
act lipid peroxidation and thereby reduce
microangiopathic long-term complications of
DM.71
A double-blind trial found oral arginine
supplementation (3 g three times per day) signifi-
cantly improved, but did not completely normal-
ize, peripheral and hepatic insulin sensitivity in
patients with type 2 diabetes.72 In young patients
with type 1 DM, however, oral arginine (7 g twice
per day for six weeks) failed to improve endothe-
lial function.73
Gastrointestinal Conditions
Gastritis and Ulcer
Preliminary evidence suggests arginine
accelerates ulcer healing due to its hyperemic,
angiogenic, and growth-promoting actions, pos-
sibly involving NO, gastrin, and polyamines.74,75
No clinical trials have yet explored the safety or
efficacy of arginine supplementation as a treat-
ment for gastritis or peptic ulcer in humans.
Gastroesophageal Reflux Disease (GERD)
and Sphincter Motility Disorders
A small, double-blind trial76 found oral
arginine supplementation significantly decreased
the frequency and intensity of chest pain attacks,
as well as the number of nitroglycerin tablets taken
for analgesia, in patients with esophageal motil-
ity disorders. However, in another study,77 argin-
ine infusions (500 mg/kg body weight/120 min)
failed to affect lower esophageal sphincter motil-
ity. No studies have yet explored the efficacy of
arginine supplements for GERD.
Alternative Medicine Review ◆ Volume 7, Number 6 ◆ 2002 Page 517
Review Arginine
Copyright©2002 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission
Genitourinary Conditions
Erectile Dysfunction (ED)
In a small, uncontrolled trial, men with
ED were given 2.8 g arginine per day for two
weeks. Forty percent of the men in the treatment
group experienced improvement, compared to
none in the placebo group.78 In a larger double-
blind trial, men with ED were given 1,670 mg argi-
nine per day or a matching placebo for six weeks.79
Arginine supplementation was effective at improv-
ing ED in men with abnormal nitric oxide me-
tabolism. However, another double-blind trial of
arginine for ED (500 mg three times per day for
17 days) found the amino acid no more effective
than placebo.80 Further double-blind research in
large groups is needed to confirm the efficacy of
arginine for ED.
Infertility, Female
Supplementation with oral arginine (16 g
per day) in poor responders to in vitro fertiliza-
tion improved ovarian response, endometrial re-
ceptivity, and pregnancy rate in one study.81
Infertility, Male
Arginine is required for normal spermato-
genesis. Over 50 years ago, researchers found that
feeding an arginine-deficient diet to adult men for
nine days decreased sperm counts by approxi-
mately 90 percent and increased the percentage
of non-motile sperm approximately 10-fold.82 Oral
administration of 500 mg arginine-HCl per day to
infertile men for 6-8 weeks markedly increased
sperm counts and motility in a majority of patients,
and resulted in successful pregnancies.83 Similar
effects on oligospermia and conception rates have
been reported in other preliminary trials.84-87 How-
ever, when baseline sperm counts were less than
10 million/mL, arginine supplementation pro-
duced little or no improvement.88,89
Interstitial Cystitis
In an uncontrolled trial,90 10 patients with
interstitial cystitis (IC) took 1.5 g arginine orally
daily for six months. Supplementation resulted in
a significant decrease in urinary voiding discom-
fort, lower abdominal pain, and vaginal/urethral
pain. Urinary frequency during the day and night
was also significantly decreased. In a five-week
uncontrolled trial, however, arginine supplemen-
tation was not effective, even at higher doses of
3-10 g per day.91 In a randomized, double-blind
trial of arginine for IC, patients took 1.5 g argin-
ine per day for three months. Twenty-nine per-
cent of patients in the arginine group and eight
percent in the placebo group had clinical improve-
ment (i.e., decreased pain and urgency) by the end
of the trial (p = 0.07). The results fell short of sta-
tistical significance, most likely because of the
small sample size (n = 53).
Perioperative Nutrition
Arginine is a potent immunomodulator.
Evidence is mounting for a beneficial effect of
arginine supplementation in catabolic conditions
such as sepsis and postoperative stress. Supple-
mental arginine appears to up-regulate immune
function and reduce the incidence of postopera-
tive infection.92 Two controlled trials have dem-
onstrated increased lymphocyte mitogenesis and
improved wound healing in experimental surgi-
cal wounds in volunteers given 17-25 g oral argi-
nine per day.93,94 Similar results have been obtained
in healthy elderly volunteers.95
Preterm Labor and Delivery
Evidence from human and animal studies
indicates nitric oxide inhibits uterine contractility
and may help maintain uterine quiescence during
pregnancy.96 Intravenous arginine infusion (30 g
over 30 min) in women with premature uterine
contractions transiently reduced uterine contrac-
tility.97 Further research is needed to confirm the
efficacy and safety of arginine in prevention of
preterm delivery.
Senile Dementia
Arginine (1.6 g per day) in 16 elderly pa-
tients with senile dementia reduced lipid
peroxidation and increased cognitive function.98
Page 518 Alternative Medicine Review ◆ Volume 7, Number 6 ◆ 2002
Arginine Review
Copyright©2002 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission
Side Effects, Potential Toxicity, and
Contraindications
Significant adverse effects have not been
observed with arginine supplementation. How-
ever, long-term studies are needed to confirm its
apparent safety. People with renal failure or he-
patic disease may be unable to appropriately me-
tabolize and excrete supplemental arginine and
should be closely monitored when taking argin-
ine supplements.
It has been postulated, on the basis of older
in vitro data99 and anecdotal reporting, that argin-
ine supplementation is contraindicated in persons
with herpes infections (i.e., cold sores, genital
herpes). The assumption is that arginine might
stimulate replication of the virus and/or provoke
an outbreak; however, this caution has not been
validated by controlled clinical trials.
Bronchoconstriction is reportedly inhib-
ited by the formation of NO in the airways of asth-
matic patients, and a bronchoprotective effect of
NO in asthma has been proposed.100 Airway ob-
struction in asthma might be associated with en-
dogenous NO deficiency caused by limited avail-
ability of NO synthase substrate (i.e., arginine).
However, oral arginine (50 mg/kg body weight)
in asthmatic patients triggered by a histamine chal-
lenge produced only a marginal, statistically in-
significant improvement of airway hyper-respon-
siveness to histamine.101 In fact, it is unclear
whether NO acts as a protective or a stimulatory
factor in airway hyper-responsiveness. Current
data suggest modulating NO synthesis by giving
oral arginine supplements has no significant ben-
efit on airway response to exercise in asthmatic
subjects,102 and may even induce
bronchoconstriction when nebulized and in-
haled.103 Until more is known, arginine should not
be used to treat asthma.
Since polyamines act as growth factors for
cancers, and arginine may stimulate polyamine
synthesis, chronic administration of arginine in
cancer patients should probably be avoided until
information arises regarding the safety of this prac-
tice.
Recommended Dosage
Doses of arginine used in clinical research
have varied considerably, from as little as 500 mg
per day for oligospermia to as much as 30 g per
day for cancer, preeclampsia, and premature uter-
ine contractions. Typical doses fall into either the
1-3 g per day range, or the 7-15 g per day range,
depending on the condition being treated.
Conclusion
Arginine appears to be a safe and effec-
tive therapy for many health conditions, particu-
larly cardiovascular diseases responsive to modu-
lation of endothelial-derived relaxing factor. Al-
though double-blind trials of arginine have been
conducted to evaluate its efficacy (i.e., for AIDS
cachexia, congestive heart failure, endothelial
function in type 1 diabetes, and erectile dysfunc-
tion), more studies are needed to confirm the effi-
cacy of this semi-essential amino acid in the treat-
ment of other health conditions. Healthcare prac-
titioners should exercise caution in recommend-
ing arginine to any patient with a history of geni-
tal or oral herpes, asthma, or cancer. Otherwise,
the amino acid is safe in typically recommended
doses of 1-15 g per day.
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