For a healthy adult with occasional herpes labialis, what L‑lysine dosage and regimen are recommended for treatment and prophylaxis, and what contraindications should be considered?

L-Lysine for Cold Sores

L-lysine supplementation is not recommended for the treatment or prevention of cold sores (herpes labialis) because high-quality evidence demonstrates no substantial benefit, and current CDC guidelines recommend proven oral antiviral therapy (valacyclovir, famciclovir, or acyclovir) as first-line treatment instead. 1

Why L-Lysine Is Not Recommended

Lack of Efficacy in Controlled Trials

• A double-blind, placebo-controlled trial of lysine 400 mg three times daily (1200 mg/day total) in 21 patients with frequently recurring herpes simplex infection found no substantial benefit for either treatment of active episodes or prophylaxis of recurrences when measuring episode frequency, duration, and severity. 2
• The evidence suggests that lysine supplementation is ineffective for prophylaxis or treatment of herpes simplex lesions at doses below 1 g/day, even when combined with low-arginine diets. 3

Conflicting and Low-Quality Evidence at Higher Doses

• One older study (1984) suggested that maintaining serum lysine concentrations above 165 nmol/ml with 1000 mg daily supplementation might reduce recurrence rates, but this finding has not been consistently replicated in rigorous trials. 4
• Doses exceeding 3 g/day may improve patients' subjective experience of the disease according to survey data, but this evidence comes from uncontrolled questionnaire studies rather than blinded clinical trials. 5, 6, 3
• A 2017 systematic review concluded that longer duration controlled studies of daily lysine doses exceeding 1.2 g/day are required to definitively test its role, indicating the current evidence base remains insufficient. 3

Proven First-Line Treatment Instead

For Acute Episodes (Treatment)

• Valacyclovir 2 g orally twice daily for 1 day (doses separated by 12 hours) is the first-line treatment, reducing median episode duration by approximately 1 day compared to placebo when initiated during prodrome or within 24 hours of lesion onset. 1
• Famciclovir 1500 mg as a single oral dose is an equally effective alternative with convenient single-day dosing. 1
• Acyclovir 400 mg orally five times daily for 5 days remains effective but requires more frequent dosing and may reduce adherence. 1

Critical Timing Principle

• Treatment must be initiated during the prodromal phase (tingling, burning, itching) or within 24 hours of lesion appearance because peak HSV-1 viral titers occur in the first 24 hours, making early viral replication blockade essential. 1
• Starting antiviral treatment after the first 24 hours markedly diminishes clinical efficacy, leading to longer lesion duration and reduced symptom relief. 1

For Frequent Recurrences (Prophylaxis)

• Daily suppressive therapy is indicated for patients experiencing ≥6 recurrences per year, reducing recurrence frequency by ≥75%. 1, 7
• Valacyclovir 500 mg orally once daily (can increase to 1000 mg once daily for very frequent recurrences) is the first-line suppressive option. 1
• Famciclovir 250 mg orally twice daily or acyclovir 400 mg orally twice daily are alternative suppressive regimens. 1
• Safety and efficacy have been documented for acyclovir for up to 6 years of continuous use; valacyclovir and famciclovir have documented safety for 1 year. 1, 7

Contraindications and Cautions for L-Lysine

• Patients with cardiovascular or gallbladder disease should be cautioned about the theoretical risks of lysine supplementation, though these risks are not well-defined in the literature. 3
• There are no established contraindications for the proven oral antivirals (valacyclovir, famciclovir, acyclovir) in immunocompetent adults, though renal dose adjustment is required for patients with impaired kidney function. 1

Common Pitfalls to Avoid

• Do not rely on lysine supplementation when proven oral antiviral therapy is available and substantially more effective. 1, 2
• Do not use topical antivirals as they provide only modest clinical benefit and are substantially less effective than oral therapy. 1
• Do not delay treatment beyond the first 24 hours of symptom onset, as efficacy decreases significantly when treatment is initiated after lesions have fully developed. 1
• Do not fail to consider suppressive therapy in patients with ≥6 recurrences per year who could significantly benefit from daily antiviral prophylaxis. 1

Preventive Measures That Actually Work

• Apply sunscreen (SPF ≥15) or zinc oxide to the lips before UV exposure to decrease the probability of UV light-triggered recurrences. 1
• Identify and avoid personal triggers including ultraviolet light exposure, fever, psychological stress, and menstruation. 1
• Provide patients with a prescription to keep on hand so treatment can be initiated immediately at first symptoms. 1