Lysine for Herpes Simplex and Cold Sores

Table of Contents

1. Herpes Simplex Virus: The Lifelong Latent Infection
2. HSV and Arginine in Cell Culture
3. The Proposed Lysine-Arginine Competition
4. Clinical Trial Evidence, 1978 to 1987
5. Doses Used in the Prevention Trials
6. Lysine During Outbreaks in Progress
7. Lysine Compared With Acyclovir, Valacyclovir and Famciclovir
8. Topical Lysine and Other Topical Treatments Studied
9. Limits of the Evidence and Safety Findings
10. Key Research Papers
11. Connections
12. Featured Videos

Herpes Simplex Virus: The Lifelong Latent Infection

Herpes simplex virus type 1 (HSV-1) is the usual cause of cold sores (herpes labialis); type 2 (HSV-2) is the usual cause of genital herpes. HSV-1 is very common: a 2020 WHO-supported analysis estimated that in 2016 about 3.7 billion people had HSV-1 infection at any site, a global prevalence of 66.6% in people aged 0–49, and that several billion had oral HSV-1 infection (James 2020). Recurrent cold sores are less common than infection; a 2001 trial report gives their occurrence as 20% to 40% of the US population (Sacks 2001).

After the first infection the virus stays in a latent state in sensory nerve ganglia — the trigeminal ganglia for oral herpes — and periodically reactivates to produce lesions at or near the original site. A 2022 narrative review notes that the usual antiviral therapies act on the virus during entry, replication and reactivation but do not reach it in its latent state (Pedrazini 2022). The 2015 Cochrane review describes cold sores as a painful blistering eruption that forms crusts, recurs periodically, and has no cure (Chi 2015).

Commonly described triggers for a recurrence include fever (the origin of the older name “fever blister”), psychological stress, local injury to the lip and sunlight. Ultraviolet light is the trigger that has been tested directly: in two randomized trials sunscreen prevented cold sores induced by experimental ultraviolet light, while a third found that sunscreen did not prevent cold sores induced by sunlight (Chi 2015). The valacyclovir prescribing information gives tingling, itching or burning as examples of the earliest symptoms of a cold sore.

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HSV and Arginine in Cell Culture

In 1964 Tankersley reported that in human cells in tissue culture, HSV produced neither cytopathic effects nor new virus when arginine was withheld, and that a prompt and extensive infection followed once arginine was replaced; lysine was not required by the virus and partially inhibited its multiplication (Tankersley 1964). Griffith, DeLong and Nelson reported in 1981 that arginine deficiency suppressed HSV replication in tissue culture and that lysine, acting as an arginine analogue, antagonised arginine's growth-promoting effect (Griffith 1981).

These are cell-culture (in-vitro) findings. People cannot simply do without arginine: it is used by the body to make nitric oxide, urea and creatine, so the idea tested in people was not to remove arginine but to raise lysine relative to it. Whether oral lysine at supplement doses changes arginine availability inside infected cells enough to matter is the question the human trials set out to answer.

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The Proposed Lysine-Arginine Competition

Lysine and arginine are both dibasic (positively charged) amino acids, and they share transporters: in the kidney, lysine shares the b0,+ transporter with cystine, ornithine and arginine; its two subunits are encoded by SLC3A1 and SLC7A9, the genes defective in the inherited kidney-stone disease cystinuria (Eggermann 2012). Griffith and colleagues' 1978 paper summarised tissue-culture work in which a ratio favouring arginine enhanced viral replication and a ratio favouring lysine suppressed it, and their 1981 paper proposed that limiting excess dietary arginine, and possibly adding lysine, might help people prone to herpes lesions.

A 2022 narrative review describes lysine as interfering with the formation of viral capsid proteins and DNA through competitive antagonism with arginine, and by increasing arginase, the enzyme that breaks arginine down (Pedrazini 2022). In one human trial the recurrence rate fell significantly when a participant's serum lysine exceeded 165 nmol/mL and rose when it fell below that level (Thein 1984).

No trial was found that tested a dietary lysine-to-arginine ratio against herpes recurrence. The trials measured recurrences, severity and healing time; none tested or claimed a cure, and latent virus in the ganglia is not reached by lysine or by the antiviral drugs. Foods described as high in arginine or in lysine are listed on the Herpes Prevention page.

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Clinical Trial Evidence, 1978 to 1987

Clinical interest followed Christopher Kagan's 1974 letter to The Lancet on lysine therapy for herpes simplex. The human studies of oral lysine, in date order:

• Griffith RS, Norins AL, Kagan C (1978), Dermatologica. 45 patients with frequently recurring herpes infection were given 312–1,200 mg of lysine daily in single or multiple doses. The authors reported that supplementary lysine accelerated recovery and suppressed recurrence. The abstract describes no placebo or control group.
• Milman N, Scheibel J, Jessen O (1980), Acta Dermato-Venereologica. A double-blind, placebo-controlled crossover study in 65 patients with recurrent cold sores: 1,000 mg of L-lysine monohydrochloride daily for 12 weeks, then placebo for a similar period. Overall, lysine had no effect on the recurrence rate, although significantly more patients were recurrence-free during lysine than during placebo (p = 0.05). Lysine had no effect on healing rate or on how the lesions looked at their worst.
• DiGiovanna JJ, Blank H (1984), Archives of Dermatology. A double-blind, placebo-controlled trial of 400 mg lysine hydrochloride three times a day in 21 patients with frequently recurring infection. The investigators found no substantial benefit, either as treatment for episodes in progress or as prevention of recurrences.
• McCune MA, Perry HO, Muller SA, O'Fallon WM (1984), Cutis. A randomized, double-blind, placebo-controlled crossover study in 41 patients. 1,248 mg a day of L-lysine monohydrochloride showed evidence of decreasing the recurrence rate; 624 mg a day was not effective. Neither dose shortened healing time compared with placebo.
• Thein DJ, Hurt WC (1984), Oral Surgery, Oral Medicine, Oral Pathology. 26 volunteers with frequently recurring cold sores completed a 12-month double-blind crossover study of 1,000 mg L-lysine daily. In most instances the lysine group reported significantly fewer lesions, and recurrence rose when lysine was withdrawn. Recurrence fell significantly when serum lysine exceeded 165 nmol/mL and rose when it fell below that level.
• Griffith RS, Walsh DE, Myrmel KH, Thompson RW, Behforooz A (1987), Dermatologica. A double-blind, placebo-controlled, multicenter trial of 1,000 mg L-lysine (as the monohydrochloride) three times a day for six months. 27 participants on lysine and 25 on placebo completed the trial. The lysine group had an average of 2.4 fewer HSV infections (p < 0.05), with significantly milder symptoms and shorter healing time.

Reviews reach cautious conclusions. Mailoo and Rampes (2017, Integrative Medicine: A Clinician's Journal) — a literature review, not a meta-analysis — concluded that lysine appears ineffective for prophylaxis or treatment at doses below 1 g/day without a low-arginine diet, that doses above 3 g/day appear to improve patients' subjective experience of the disease, and that longer controlled studies of doses above 1.2 g/day are needed to test its role definitively. The 2015 Cochrane review of interventions for preventing cold sores (32 randomized trials, 2,640 participants, 19 treatments) found no evidence of efficacy for lysine in preventing herpes labialis (Chi 2015).

Taken together, the trials are small and their results point in different directions; the review evidence does not establish that lysine prevents cold sores.

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Doses Used in the Prevention Trials

The trials above gave L-lysine by mouth, mostly as L-lysine monohydrochloride, at these doses (each as the trial reported it):

• 312–1,200 mg/day — Griffith 1978 (no control group; benefit reported).
• 400 mg three times a day — DiGiovanna & Blank 1984 (no substantial benefit).
• 624 mg/day and 1,248 mg/day — McCune 1984 (the lower dose was not effective; the higher dose showed evidence of fewer recurrences).
• 1,000 mg/day — Milman 1980 (no overall effect on recurrence rate) and Thein & Hurt 1984 (fewer lesions, linked to serum lysine above 165 nmol/mL).
• 1,000 mg three times a day for six months — Griffith 1987 (2.4 fewer infections on average than placebo).

Trial reports differ in whether the stated dose is milligrams of lysine or of the hydrochloride salt; how each study reported its dose is set out on the Lysine Doses Used in Studies page. No trial was found that compared timing (with or without meals, single or divided doses), and no trial was found that tested how long benefit takes to appear or whether recurrences return after stopping, beyond the Thein & Hurt observation that recurrence rose when lysine was withdrawn.

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Lysine During Outbreaks in Progress

Several of the trials measured lysine during outbreaks as well as between them. DiGiovanna and Blank (400 mg lysine hydrochloride three times a day) found no substantial benefit for episodes in progress. Griffith 1987 (1,000 mg L-lysine three times a day for six months) reported milder symptoms and shorter healing time. Milman 1980 and McCune 1984 found no effect on healing at 1,000 mg, 624 mg or 1,248 mg a day.

No trial was found that gave a short, higher “outbreak” course of oral lysine starting at the first symptoms, or that compared such a course with a lower daily dose. Outbreak schedules that circulate in popular sources, such as 3 g a day for 5–7 days, do not come from a published trial identified for this page. No trial of lysine combined with acyclovir, valacyclovir or famciclovir was found either, so whether the two together differ from either alone is unknown.

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Lysine Compared With Acyclovir, Valacyclovir and Famciclovir

Acyclovir, valacyclovir and famciclovir work by a different mechanism from the one proposed for lysine. The US prescribing information for valacyclovir describes it as rapidly converted in the body to acyclovir, which the viral thymidine kinase of HSV phosphorylates inside infected cells; the resulting acyclovir triphosphate inhibits viral DNA replication by competitively inhibiting the viral DNA polymerase, by being incorporated into and terminating the growing viral DNA chain, and by inactivating the polymerase. Famciclovir is a prodrug of penciclovir, another nucleoside analogue.

• Treating a cold sore — the valacyclovir prescribing information lists treatment of cold sores among its adult indications, at 2 grams twice daily for 1 day taken 12 hours apart, started at the earliest symptom; its efficacy when started after a papule, blister or ulcer has formed has not been established. In a randomized, placebo-controlled trial in 701 patients who started treatment within 1 hour of prodromal symptoms, median healing times were 4.4 days with a single 1,500 mg dose of famciclovir, 4.0 days with 750 mg twice for 1 day, and 6.2 days with placebo (Spruance 2006). No trial of a short course of lysine for an outbreak was found (see above).
• Preventing cold sores — the 2015 Cochrane review concluded that long-term use of oral antivirals can prevent herpes labialis but that the clinical benefit is small; in one trial long-term oral acyclovir reduced clinical recurrences from 1.80 to 0.85 episodes per participant over four months. Evidence for short-term (one month or less) use of oral acyclovir was inconsistent across doses. The same review found no evidence of efficacy for lysine (Chi 2015).
• Genital herpes — the CDC's sexually transmitted infections treatment guideline states that suppressive therapy reduces the frequency of genital herpes recurrences by 70–80% among patients who have frequent recurrences. The suppressive regimens it lists are acyclovir 400 mg twice a day, valacyclovir 500 mg or 1 g once a day, and famciclovir 250 mg twice a day. The guideline does not mention lysine.
• Side effects — the valacyclovir prescribing information lists headache, nausea and abdominal pain as the most common adverse reactions. Its warnings include acute kidney failure and central nervous system effects (agitation, hallucinations, confusion), more likely in older adults and reported in people with kidney disease given doses too high for their kidney function, with dose reduction recommended in kidney impairment; and thrombotic thrombocytopenic purpura/hemolytic uremic syndrome in specific immunocompromised groups given 8 grams a day in trials. Safety findings for lysine are in the last section below.
• Head-to-head — no trial comparing lysine with an antiviral drug was found.

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Topical Lysine and Other Topical Treatments Studied

Topical products containing lysine are sold for cold sores, but no controlled trial of lysine alone applied to the skin was found. Singh and colleagues (2005, Alternative Medicine Review) ran a small open-label pilot study in 30 participants using an ointment that combined L-lysine with zinc and herbal ingredients, with no placebo comparison. The authors reported full resolution in 40 percent of participants by the third day and in 87 percent by the end of the sixth day, and no adverse effects. Because the product was a combination and the study was uncontrolled, the contribution of lysine itself cannot be separated out.

Other topical treatments that have been tested in trials:

• Lemon balm (Melissa officinalis) cream — Wölbling and Leonhardt (1994) reported an open multicentre study in 115 patients and a placebo-controlled double-blind study in 116 patients of a dried lemon balm leaf extract applied to the skin; the authors concluded that it protected against herpes simplex infections and that starting treatment early in an episode was most effective. In a later double-blind, placebo-controlled trial in 66 patients with recurrent cold sores, a cream containing 1% dried lemon balm leaf extract, applied four times daily for five days, produced a lower combined symptom score on day 2 than placebo (Koytchev 1999).
• Docosanol 10% cream — in two identical double-blind, placebo-controlled trials, median time to healing was 4.1 days with docosanol applied 5 times daily, 18 hours shorter than with placebo (Sacks 2001). A 2004 review describes docosanol as acting by inhibiting viral fusion and as the first topical antiviral approved in the US for over-the-counter use in recurrent herpes labialis (Leung 2004).
• Topical acyclovir 5% cream — for prevention, the Cochrane review found moderate-quality evidence from 2 trials that it probably has little effect on preventing recurrence (Chi 2015).
• Zinc — a laboratory study found that zinc salts inactivated clinical HSV isolates in vitro (Arens 2000); this is a test-tube finding, not a human trial. Zinc is covered on the Zinc page.

No trial was found that tested oral lysine together with any of these topical treatments.

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Limits of the Evidence and Safety Findings

What the trials leave open:

• Small, old trials — the six human studies were published between 1978 and 1987 and enrolled between 21 and 65 participants each; one had no control group.
• Dose — the lower doses tested (624 mg a day in McCune 1984; 400 mg three times a day in DiGiovanna 1984) were not effective, and the Mailoo and Rampes review describes doses below 1 g/day as appearing ineffective without a low-arginine diet. Results at 1,000 mg a day were mixed (Milman 1980 versus Thein & Hurt 1984).
• Diet — the review notes that the low-dose trials which found no benefit did not combine lysine with a low-arginine diet; no trial tested the diet itself.
• Who was studied — the Cochrane review covered immunocompetent people only; no trial of lysine in people with weakened immune systems was found.
• Not a cure — the trials measured recurrences, severity and healing time; latent virus persists in the ganglia regardless of treatment.

Safety findings on oral lysine:

• Stomach and bowel symptoms — a 2019 systematic review of 71 human studies, at doses from 16.8 mg to 17,500 mg a day, found the adverse events to be mainly stomach and bowel symptoms and set a provisional no-observed-adverse-effect level of 6,000 mg a day (Hayamizu 2019).
• Kidney — a 1996 case report describes a 44-year-old woman who developed Fanconi's syndrome and severe tubulointerstitial nephritis, progressing to chronic kidney failure, in association with oral L-lysine taken as a supplement (Lo 1996).
• Cardiovascular and gallbladder disease — the Mailoo and Rampes review states that people with cardiovascular or gallbladder disease face theoretical risks from lysine supplementation.
• Pregnancy and breastfeeding — no safety data on supplemental lysine doses in pregnancy or breastfeeding were found.
• Antiviral drugs — no study of lysine taken with acyclovir, valacyclovir or famciclovir was found.

Decisions about medicines and supplements belong with a clinician.

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Key Research Papers

1. Griffith RS, Walsh DE, Myrmel KH, Thompson RW, Behforooz A (1987). Success of L-lysine therapy in frequently recurrent herpes simplex infection. Treatment and prophylaxis. Dermatologica 175(4):183-90. — PubMed PMID: 3115841
2. Tankersley RW Jr (1964). Amino acid requirements of herpes simplex virus in human cells. Journal of Bacteriology 87(3):609-13. — PubMed PMID: 14127578
3. Thein DJ, Hurt WC (1984). Lysine as a prophylactic agent in the treatment of recurrent herpes simplex labialis. Oral Surgery, Oral Medicine, Oral Pathology 58(6):659-66. — PubMed PMID: 6438572
4. DiGiovanna JJ, Blank H (1984). Failure of lysine in frequently recurrent herpes simplex infection. Treatment and prophylaxis. Archives of Dermatology 120(1):48-51. — PubMed PMID: 6419679
5. Griffith RS, Norins AL, Kagan C (1978). A multicentered study of lysine therapy in Herpes simplex infection. Dermatologica 156(5):257-67. — PubMed PMID: 640102
6. Griffith RS, DeLong DC, Nelson JD (1981). Relation of arginine-lysine antagonism to herpes simplex growth in tissue culture. Chemotherapy 27(3):209-13. — PubMed PMID: 6262023
7. Mailoo VJ, Rampes S (2017). Lysine for Herpes Simplex Prophylaxis: A Review of the Evidence. Integrative Medicine (Encinitas) 16(3):42-46. — PubMed PMID: 30881246
8. Pedrazini MC et al. (2018). L-Lysine: its antiherpetic action effect — review and update. Acta Odontologica Scandinavica. (Editorial note, 2026-10-14: no record of this paper was found in PubMed or Crossref; it is kept here for transparency, and no statement on this page rests on it. These authors' 2022 review is listed below. Its former search link is listed under PubMed Topic Searches.)
9. Tomblin FA Jr, Lucas KH (2001). Lysine for management of herpes labialis. American Journal of Health-System Pharmacy 58(4):298-300, 304. — PubMed PMID: 11225166
10. Singh BB, Udani J, Vinjamury SP, Der-Martirosian C, Gandhi S, Khorsan R, Nanjegowda D, Singh V (2005). Safety and effectiveness of an L-lysine, zinc, and herbal-based product on the treatment of facial and circumoral herpes. Alternative Medicine Review 10(2):123-7. — PubMed PMID: 15989381 (Editorial note, 2026-10-14: this entry previously gave the journal as Alternative Therapies in Health and Medicine; corrected against PubMed.)
11. Wölbling RH, Leonhardt K (1994). Local therapy of herpes simplex with dried extract from Melissa officinalis. Phytomedicine 1(1):25-31. — PubMed PMID: 23195812
12. Spruance SL, Bodsworth N, Resnick H, Conant M, Oeuvray C, Gao J, Hamed K (2006). Single-dose, patient-initiated famciclovir: a randomized, double-blind, placebo-controlled trial for episodic treatment of herpes labialis. Journal of the American Academy of Dermatology 55(1):47-53. — PubMed PMID: 16781291 (Editorial note, 2026-10-14: this entry previously gave the year as 2003; corrected against PubMed.)
13. Milman N, Scheibel J, Jessen O (1980). Lysine prophylaxis in recurrent herpes simplex labialis: a double-blind, controlled crossover study. Acta Dermato-Venereologica 60(1):85-7. — PubMed PMID: 6153847
14. McCune MA, Perry HO, Muller SA, O'Fallon WM (1984). Treatment of recurrent herpes simplex infections with L-lysine monohydrochloride. Cutis 34(4):366-73. — PubMed PMID: 6435961
15. Chi CC, Wang SH, Delamere FM, Wojnarowska F, Peters MC, Kanjirath PP (2015). Interventions for prevention of herpes simplex labialis (cold sores on the lips). Cochrane Database of Systematic Reviews (8):CD010095. — PubMed PMID: 26252373
16. Pedrazini MC, da Silva MH, Groppo FC (2022). L-lysine: Its antagonism with L-arginine in controlling viral infection. Narrative literature review. British Journal of Clinical Pharmacology 88(11):4708-4723. — PubMed PMID: 35723628
17. Kagan C (1974). Letter: Lysine therapy for herpes simplex. The Lancet 1(7848):137. — PubMed PMID: 4130340
18. James C, Harfouche M, Welton NJ, Turner KM, Abu-Raddad LJ, Gottlieb SL, Looker KJ (2020). Herpes simplex virus: global infection prevalence and incidence estimates, 2016. Bulletin of the World Health Organization 98(5):315-329. — PubMed PMID: 32514197
19. Sacks SL, Thisted RA, Jones TM, Barbarash RA, Mikolich DJ, Ruoff GE, Jorizzo JL, Gunnill LB, Katz DH, Khalil MH, Morrow PR, Yakatan GJ, Pope LE, Berg JE (2001). Clinical efficacy of topical docosanol 10% cream for herpes simplex labialis: A multicenter, randomized, placebo-controlled trial. Journal of the American Academy of Dermatology 45(2):222-30. — PubMed PMID: 11464183
20. Leung DT, Sacks SL (2004). Docosanol: a topical antiviral for herpes labialis. Expert Opinion on Pharmacotherapy 5(12):2567-71. — PubMed PMID: 15571473
21. Koytchev R, Alken RG, Dundarov S (1999). Balm mint extract (Lo-701) for topical treatment of recurring herpes labialis. Phytomedicine 6(4):225-30. — PubMed PMID: 10589440
22. Arens M, Travis S (2000). Zinc salts inactivate clinical isolates of herpes simplex virus in vitro. Journal of Clinical Microbiology 38(5):1758-62. — PubMed PMID: 10790094
23. Hayamizu K, Oshima I, Fukuda Z, Kuramochi Y, Nagai Y, Izumo N, Nakano M (2019). Safety assessment of L-lysine oral intake: a systematic review. Amino Acids 51(4):647-659. — PubMed PMID: 30661148
24. Lo JC, Chertow GM, Rennke H, Seifter JL (1996). Fanconi's syndrome and tubulointerstitial nephritis in association with L-lysine ingestion. American Journal of Kidney Diseases 28(4):614-7. — PubMed PMID: 8840955
25. Eggermann T, Venghaus A, Zerres K (2012). Cystinuria: an inborn cause of urolithiasis. Orphanet Journal of Rare Diseases 7:19. — PubMed PMID: 22480232
26. Centers for Disease Control and Prevention. Sexually Transmitted Infections Treatment Guidelines, 2021: Genital Herpes. — cdc.gov
27. Valacyclovir tablets, US prescribing information (generic label, DailyMed). — DailyMed

PubMed Topic Searches

1. PubMed: Lysine herpes prophylaxis
2. PubMed: Arginine-lysine antiviral mechanism
3. PubMed: Valacyclovir single-day cold sore
4. PubMed: Lemon balm for HSV
5. PubMed: Docosanol for cold sores
6. PubMed: Pedrazini lysine antiherpetic review (former link of entry 8)

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Connections

• All Amino Acids
• Lysine Overview
• Lysine Benefits Hub
• Collagen Synthesis
• Lysine-Arginine Ratio
• Dosing and Forms
• Lysine Amino Acid
• L-Arginine (Counterpart)
• Herpes Labialis (Cold Sores)
• Herpes Zoster (Shingles)
• Lemon Balm (Melissa)
• Zinc
• Vitamin C
• Immune Boosting
• Eggs (Lysine Source)
• Yogurt (Lysine Source)
• History
• Sources

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