Lysine for Management of Herpes Labialis

Frankie A. Tomblin, Jr., Pharm.D. and Kristy H. Lucas, Pharm.D.


Am J Health Syst Pharm. 2001;58(4) 

In This Article

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 out-breaks 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 < 0.05). The researchers found significantly fewer recurrences when the serum lysine concentration exceeded 165 nmol/mL (24 µg/mL) (p < 0.05) but not when the concentration was less than 165 nmol/mL.

McCune et al.[14] enrolled 47 immunocompetent patients with recurrent herpes labialis outbreaks in a study to determine the efficacy of oral lysine for prophylaxis. This study compared two dosages of lysine versus placebo in a crossover fashion, with patients randomized into four groups. Group 1 (n = 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 out-breaks was significantly lower with lysine 1248 mg/day (0.89 outbreak per patient per 24-week period) than with placebo (1.56 outbreaks) (p 0.05); lysine 624 mg/day did not affect frequency (2.6 versus 2.76 outbreaks).

DiGiovanna and Blank [15] studied the ability of lysine to modify or prevent out-breaks of herpes. Twenty patients were randomly assigned to receive lysine 400 mg or identical placebo capsules three times daily. The patients were instructed to begin taking the capsules at the onset of their first outbreak after randomization and to record the number, severity, and duration of outbreaks. They were also asked their opinion about the effectiveness of the capsules they were receiving. The study was unable to detect an actual or perceived benefit of lysine therapy.

A study by Simon et al.[16] indicates that the lysine dosage studied by DiGiovanna and Blank [15] may have been too low. In a letter to the editor, Simon et al. suggested a dose-dependent effect of lysine on lesion recurrence. These authors randomized 31 patients diagnosed with herpes labialis or genitalis to receive either 250- mg lysine hydrochloride capsules (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 < 0.01). Healing time was reduced by a mean ± S.D. of 2.3 ± 0.7 days in the lysine group, versus 0.2 ± 0.6 day with placebo (p < 0.1). More patients in the lysine group than the placebo group reported their symptoms to be "milder" (74% versus 28%) (p < 0.01). The study concluded that lysine appeared to reduce the frequency, duration, and severity of outbreaks.

All of the randomized, double-blind, placebo-controlled studies were small (21-119 patients). Considering that an estimated 90% of the U.S. population has one or more outbreaks of symptoms related to HSV infection by five years of age, larger trials should be feasible and would provide more helpful information.[18] The only trial of a substantial size was an uncontrolled case study of patients with cold sores, canker sores, or genital herpes.[19] This study involved distributing a questionnaire and unspecified amounts of lysine to 4000 patients with recurrent herpes outbreaks when they visited a physician. After six months of lysine supplementation, 88% of the 1534 patients who returned the questionnaire considered supplemental lysine effective for herpes.

The older studies [6,12,13] used lower dosages of lysine than the newer studies.[14,15,16,17] The newer studies tend to support the claim that lysine reduces the frequency of out-breaks, but they do not seem to support claims regarding duration or severity. Most of the studies were small, with no mention of statistical power. Some were not double-blind or placebo controlled. Many did not report statistical analyses. Some of the older reports did not include information on study design, and some of the trials were reported as letters to the editor.


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