American Journal of Health-System Pharmacy
Copyright (C) 2001 American Society of Health-System Pharmacists, Inc.  All
rights reserved.

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Volume 58(4)             15 February 2001             p 298, 300, 304
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Lysine for management of herpes labialis
[Alternative Therapies]
Tomblin, Frankie A. Jr. Pharm.D.; Lucas, Kristy H. Pharm.D.
Degree Candidate (Tomblin)
School of Pharmacy; tomblin-fa@usa.net
Clinical Assistant Professor (Lucas)
Schools of Pharmacy and Medicine; Departments of Clinical Pharmacy and
Internal
Medicine
West Virginia University; 3110 MacCorkle Avenue; Charleston, WV 25304

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Section Description

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Lysine is one of 10 essential amino acids required for human nutrition.1
Dietary
sources of lysine include meat, cheese, yogurt, brewer's yeast, legumes, and
wheat germ.2 This article examines the literature in an attempt to determine
the
validity of claims that lysine is effective in reducing the frequency,
duration,
and severity of outbreaks of herpes labialis (cold sores) in patients prone
to
frequent recurrences.

Use. Lysine is marketed for use in the prevention and treatment of outbreaks
of
herpes, particularly herpes labialis. Although not curative, lysine is
advertised to decrease the frequency, severity, and duration of cold sores.
Lysine has also been used to aid in the treatment of rheumatoid arthritis,
heroin intoxification, and metabolic alkalosis and to increase the
absorption
and decrease the elimination of calcium.

Pharmacology. Herpes simplex virus (HSV) is highly dependent on the amino
acid
arginine for reproduction.3 Griffith et al.4 reported that high
intracellular
concentrations of lysine (50 ([mu]g/mL [342 [mu]M]) inhibit reproduction of
HSV
in tissue cultures by acting as a competitive inhibitor of arginine.
However,
Park and colleagues 5 found that alysine concentration of 200 [mu]M did not
impede replication. The contradictory findings of these two studies may be
due
to the different concentrations of lysine achieved intracellularly by
different
tissue types (the Griffith et al. study used Green monkey kidney cells, and
the
Park et al. study used trigeminal ganglion cells from albino mice). Thein
and
Hurt's study 6 of 26 volunteers with frequent recurrences of herpes labialis
showed that serum lysine concentrations greater than 165 [mu]M (24 mg/mL)
were
necessary to significantly decrease the recurrence rate. However, the exact
serum lysine concentration required is controversial. FIGURE

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Pharmacokinetics. Extensive pharmacokinetic data for lysine are lacking.
Lysine
is transported across cellular membranes by two transport systems.7 Studies
suggest that lysine is rapidly transported into muscle tissue 8 and that
lysine
concentrations in muscle exceed those of other amino acids, especially at
five
to seven hours after ingestion.9 Free lysine monohydrochloride is absorbed
from
dietary sources at the same rate as lysine, so supplementation would be
likely
to be effective in correcting lysine deficiency.10 Lysine is the most highly
conserved amino acid. This allows humans who consume a nitrogen-balanced
diet (a
diet consisting of 1 g of protein per pound of body weight daily) to have
very
low lysine requirements.11 Catabolism occurs primarily in the liver.

Clinical studies. Lysine's precise role in the prevention and treatment of
herpes labialis outbreaks is unknown. Of seven randomized, double-blind,
placebo-controlled studies reviewed, six showed lysine to be effective for
decreasing the frequency of outbreaks. Only two of the six studies found
lysine
to decrease the severity or duration of an outbreak, however.

The earliest study reviewed was conducted by Milman et al.12 in 1978 to
determine the efficacy of lysine in reducing the duration and severity of
lesions in patients with recurrent herpes labialis. At the screening visit,
patients were randomized to receive L-lysine monohydrochloride or placebo.
The
number of patients assigned to each group was not reported. The patients
were
given 11 500-mg tablets, along with a questionnaire for self-reporting the
duration and severity of lesions. The patients were instructed to take two
tablets at the onset of symptoms and one tablet each morning and evening
thereafter until the 11 tablets were gone. They were also told to record the
duration and severity of their outbreak on the questionnaire. Follow-up
visits
occurred only upon the completion of each 11-tablet treatment course. With
each
follow-up visit, a new packet containing 11 tablets and a questionnaire were
distributed. The number of visits served as a surrogate marker of the number
of
outbreaks occurring during the 48-week study period.

Of the 198 patients accepted for study participation, 79 were excluded
because
they did not return their first questionnaire or returned it incomplete.
Information from the remaining 119 patients was included in the analysis.
The
total number of patients using the first 11 tablets (initial treatment) was
53
and 51 in the lysine and placebo groups, respectively. The total number of
treatments needed in each group was 97 (lysine) and 93 (placebo). The median
recurrence-free interval was 57 and 53 days for the lysine and placebo
groups,
respectively. No statistical analysis was reported, but the study showed no
apparent difference in the duration or severity of herpes labialis outbreaks
between lysine therapy and placebo.

A second trial conducted by the same authors looked at the possible
prophylactic
effect of lysine on outbreaks of herpes labialis.13 This study included data
from 65 patients initially receiving either L-lysine monohydrochloride 500
mg (n
= 31) or placebo (n = 34) twice daily. After 12 weeks, patients were crossed
over without interruption to the alternative agent. The patients used a
questionnaire to record the duration and course of outbreaks. Seventy-nine
patients were admitted to the study, but after 14 (unexplained) withdrawals
and
exclusions, 65 patients remained for analysis. An intention-to-treat
analysis
was not completed. There was no difference in the number of recurrences
during
lysine treatment (91) and during placebo treatment (104) and no difference
in
the frequency or severity of new lesions. Statistical analysis was not
reported.

A 1984 study found conflicting results regarding the efficacy of long-term
lysine supplementation and dietary arginine reduction for decreasing the
frequency of herpes labialis outbreaks.6 The study also examined the
relationship
between serum lysine and arginine concentrations and the frequency of
lesions.
This crossover study compared L-lysine monohydrochloride 1000 mg/day with
placebo. Group A (n = 15) received lysine for the first six months, followed
immediately by six months of placebo. Group B (n = 11) received placebo
followed
by lysine. During the first six-month period there was no significant
difference
in the number of lesions between the two groups (2.6 versus 2.8 lesions per
patient). However, during the second six months the lysine recipients had
significantly fewer new lesions than the placebo recipients (1.8 versus 2.9
lesions per patient) (p pn = 11) received L-lysine monohydrochloride 1248 mg
(four 312-mg tablets) per day for six months and then placebo for six months
without interruption. Group 2 (n = 9) received the same regimen with placebo
first, then lysine. Group 3 (n = 11) received lysine 624 mg (two 312-mg
tablets)
per day for six months and then placebo for six months. Group 4 (n = 10)
received the same regimen with placebo first, then lysine. Of the 47
patients
enrolled, 6 withdrew (1 moved and 5 were eliminated for noncompliance). No
intention-to-treat analysis was performed. This study found no significant
difference between lysine and placebo for either dosage with respect to
healing
time. However, the frequency of outbreaks was significantly lower with
lysine
1248 mg/day (0.89 outbreak per patient per 24-week period) than with placebo
(1.56 outbreaks) (p n = 16) or mannitol capsules (n = 15). The patients took
two
capsules twice a day for three months (1000 mg/day). Eighteen of the
patients
then continued taking one capsule every morning and two every evening for a
total of 750 mg per day for three more months; the other 13 subjects
withdrew
for unexplained reasons. The lysine group had fewer recurrences than
predicted
while taking 1000 mg/day (17 recurrences versus 42.6 predicted). The placebo
group also had fewer recurrences (26 recurrences versus 33.0 predicted).
During
the second three-month period (750 mg/day or placebo) there was no
significant
difference between actual and predicted recurrences (17 recurrences versus
16.8
predicted in the treatment group and 16 recurrences versus 21.8 predicted in
the
placebo group). The clinical significance of the results is unclear, since
this
small study did not compare actual recurrences with lysine against actual
recurrences with placebo. Also, the researchers did not report their method
of
predicting recurrences.

Griffith and colleagues 17 conducted a trial of L-lysine monohydrochloride
1000
mg three times daily for the prevention and treatment of recurrent symptoms
of
HSV infection (either genital or orofacial herpes lesions). Of the 136
subjects
who volunteered, 22 were excluded because they reported fewer than two
outbreaks
in the six months before the study. The remaining 114 subjects were
randomized
to take lysine 1000 mg three times daily (n = 62) or placebo (n = 52). The
patients were asked to record the number, duration, and severity of
outbreaks.
At six months, complete data were available for 34 lysine-treated patients
and
25 given placebo. Seven patients were excluded from the lysine group because
of
concomitant acyclovir use. An intention-to-treat analysis was not performed.
The
number of outbreaks, compared with expectations based on the patients'
experiences in the previous year, was smaller in the lysine group than in
the
placebo group (p p p Dosage. Lysine is usually given orally in the form of a
tablet or capsule. Dosages used for HSV infection in the studies reviewed
ranged
from 250 mg every morning and 500 mg every night to 1000 mg four times a
day.16,20

Adverse effects. Six to 10 g of lysine is consumed daily in the average
adult
diet. Thus, it has been hypothesized that supplementation with 3000 mg/day
will
not cause serious adverse effects.11 Information on lysine's safety is
limited
but serious adverse effects have been reported. In one case, a 44-year-old
woman
developed Fanconi's syndrome, manifested as tubulointerstitial nephritis,
after
taking 3000 mg of lysine daily for five years.21 Abdominal pain and diarrhea
occurred in patients who received 10 g/day for five days.22 Other reports
either
do not provide safety information or state that no adverse effects were
observed.

Contraindications. Lysine supplementation is contraindicated in patients
with
renal disease or hepatic impairment.2 Patients with renal or hepatic disease
may
not be able to eliminate the large amounts of nitrogen produced upon
breakdown
of the supplemented amino acid. No data support the use of lysine in
children or
in pregnant or breast-feeding women.

Interactions. Studies indicate that concomitant use of lysine and calcium
can
increase the absorption and decrease the elimination of calcium.23 Large
doses
of lysine have been reported to increase the toxicity of aminoglycosides by
an
unknown mechanism.2

Conclusion. Lysine's efficacy for herpes labialis may lie more in prevention
than treatment. Studies do not support the use of lysine for decreasing the
severity or duration of outbreaks. Most patients tolerate the supplement
well.
Larger trials are needed to conclusively determine lysine's role in the
treatment of herpes labialis.

Frankie A. Tomblin, Jr., Pharm.D.

Degree Candidate

School of Pharmacy; tomblin-fa@usa.net

Kristy H. Lucas, Pharm.D.

Clinical Assistant Professor

Schools of Pharmacy and Medicine; Departments of Clinical Pharmacy and
Internal
Medicine

West Virginia University; 3110 MacCorkle Avenue; Charleston, WV 25304

1. Hansen M, ed. Pathophysiology: foundations of disease and clinical
intervention.
Philadelphia: Saunders; 1998:51.

2. Lysine. In: Burnham TH, Short RM, eds. The review of natural products.
St.
Louis: Facts and Comparisons; 1998.

3. Tankersley RW. Amino acid requirements of herpes simplex virus in human
cells. J Bacteriol. 1964; 87:609-13.

4. Griffith RS, DeLong DC, Nelson JD. Relation of arginine-lysine antagonism
to
herpes simplex growth in tissue culture. Chemotherapy. 1981; 27:209-13.
Bibliographic Links

5. Park NH, Pavan-Langston D, Declercq E. Effect of acyclovir,
bromovinyldeoxyuridine,
vi-darabine, and L-lysine on latent ganglionic herpes simplex virus in
vitro. Am
J Med. 1982; 73(1A):151-4. Bibliographic Links

6. Thein DJ, Hurt WC. Lysine as a prophylactic agent in the treatment of
recurrent herpes simplex labialis. Oral Surg. 1984; 58:659-66.

7. Christensin HN. Relevance of transport across the plasma membrane to the
interpretation of the plasma amino acid pattern. In: Leathem JH, ed. Protein
nutrition and free amino acid patterns. New Brunswick, NJ: Rutgers Univ.
Free
Press; 1968:40-52.

8. Longenecker JB, Hause NL. Relationship between plasma amino acids and
composition of the ingested protein. Arch Biochem Biophys. 1959; 84:46-59.

9. Uhe AM, Collier GR, O'Dea K. A comparison of the effects of beef, chicken
and
fish protein on satiety and amino acid profiles in lean male subjects. J
Nutr.
1992; 122:467-72. Bibliographic Links

10. Flodin NW. Lysine supplementation of cereal foods: a retrospective. J Am
Coll Nutr. 1993; 12:486-500. Bibliographic Links

11. Flodin NW. The metabolic roles, pharmacology, and toxicology of lysine.
J Am
Coll Nutr. 1997; 16:7-21. Bibliographic Links

12. Milman N, Scheibel J, Jessen O. Failure of lysine treatment in recurrent
herpes simplex labialis. Lancet. 1978; 2:942. Letter.

13. Milman N, Scheibel J, Jessen O. Lysine prophylaxis in recurrent herpes
simplex labialis: a double-blind, controlled crossover study. Acta Derm
Venereol. 1980; 60:85-7. Bibliographic Links

14. McCune MA, Perry HO, Muller SA et al. Treatment of recurrent herpes
simplex
infections with L-lysine monohydrochloride. Cutis. 1984; 34:366-73.
Bibliographic
Links

15. DiGiovanna JJ, Blank H. Failure of lysine in frequently recurrent herpes
simplex infections. Arch Dermatol. 1984; 120:48-51. Bibliographic Links

16. Simon CA, Van Melle GD, Ramelet AA. Reply. (Failure of lysine in
frequently
recurrent herpes simplex infection.) Arch Dermatol. 1985; 121:167-8. Letter.

17. Griffith RS, Walsh EW, Myrmel KH et al. Success of L-lysine therapy in
frequently recurrent herpes simplex infection. Dermatologica. 1987;
175:183-90.
Bibliographic Links

18. Black JM, Matassarin-Jacobs E. Medical-surgical nursing: clinical
management
for continuity of care. 5th ed. Philadelphia: Saunders; 1997:667-2211.

19. Walsh DE, Griffith RS, Behforooz A. Subjective response to lysine in the
therapy of herpes simplex. J Antimicrob Chemother. 1983; 12:489-96.
Bibliographic
Links

20. Wright EF. Clinical effectiveness of lysine in treating recurrent
aphthous
ulcers and herpes labialis. Gen Dent. 1994; 42(1):40-2. Bibliographic Links

21. Lo JC, Glenn MC, Rennke H et al. Fanconi's syndrome and
tubulointerstitial
nephritis in association with L-lysine ingestion. Am J Kidney Dis. 1996;
28:614-7. Bibliographic Links

22. Lysine. Natural medicines comprehensive database.
www.naturaldatabase.com
(accessed 2000 Feb 17).

23. Civitelli R, Villareal DT, Agnusdei D et al. Dietary L-lysine and
calcium
metabolism in humans. Nutrition. 1992; 8:400-5. Bibliographic Links

Section Description

The Alternative Therapies column features short reviews of herbals and other
"nutraceuticals" for which there is some scientific evidence of
effectiveness.
The contributing editor for Alternative Therapies is Joseph Pepping,
Pharm.D.,
Complementary Medicine Consultant, Kaiser Permanente, Honolulu, HI. Readers
are
invited to send ideas for the column to AJHP at 7272 Wisconsin Avenue,
Bethesda,
MD 20814 (301-657-3000) or ajhp@ashp.org.

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Accession Number: 00043627-200102150-00009
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