Lemon Balm (Melissa officinalis) for Treatment of Herpes Labialis
By Cydney E. McQueen, PharmD
Lemon balm (melissa officinalis) traditionally has been used as a carminative for gastrointestinal distress or as a mild sedative.1,2 The Greeks and Romans used lemon balm for wound dressings and to treat bites and stings. Investigations of its chemical constituents in various in vitro and animal studies reveal antibacterial, antiviral, anti-inflammatory, astringent, and sedative properties.2
Pharmacology
Melissa officinalis leaves have a range of chemical constituents; of primary importance are the tannins, polyphenols, glycosides, and rosmarinic acid.2-4 Early work with tannin and polyphenol components demonstrated activity against numerous viruses, including herpes simplex.3,5,6 Later investigations attribute antiviral effects more specifically to phenolcarboxylic acid.7 Two non-tannin components inhibit protein biosynthesis by blocking leucine incorporation and ribosomal activity.8
Mechanism of Action
Blockade of receptors used by the herpes virus for cell adsorption prevents viral entry into the cell, thereby interfering with viral replication.7
Clinical Trials
The earliest clinical trial examining topical melissa for herpes simplex infection was published in 1984.9 Only three other trials have been conducted, two of which are available in English.7,10,11 (For a review of clinical studies, see Table 1.)
| Table 1-Clinical trials of melissa extract for herpes simplex infections | |||||
| Trial | Subjects | Infection Site | Results | LOE* | Limitations |
| Koytchev7 | 66 | Labialis | ¯ Symptom severity | II | Major |
| Wölbling11 | 115 | All locations | ¯ Symptom severity | V | Major |
| Wölbling11 | 116 | All locations | ¯ Symptom severity | II | Major |
| Vogt10 | 116 | All locations | ¯ Symptom severity | Unknown | Unknown |
| Wölbling9 | Unknown | All locations | ¯ Relapse frequency | Unknown | Unknown |
| * LOE = Level of evidence | |||||
Koytchev’s study7 was a randomized, double-blinded controlled trial (RDBCT) of LomaherpanTM, a proprietary 1% cream of a lyophilized aqueous extract.3 The cream was applied qd for five days and compared to a placebo of identical vehicle. A priori calculations indicated 33 patients per group were needed for 80% power. Because of the irregularly recurring nature of herpes outbreaks, 120 patients who met inclusion criteria were given either melissa or placebo cream with instructions to begin treatment within four hours of prodrome symptoms and to return for a physician visit within 24 hours. Sixty-six patients (34 treatment, 32 placebo) complied and constituted the enrolled subjects. Patients must have had at least four episodes per year of clinically diagnosed herpes labialis with typical blister presentation and experienced prodrome complaints of itching, tingling, and burning. Physician visits occurred at days 1, 2, 3, and 5 after symptom onset. Complaints, number of blisters, and size of affected area were scored on a scale developed for acyclovir trials.
Primary endpoint was symptom score on day 2 (DS2), with a secondary endpoint of total scores (TS) of symptoms over five days of treatment. Both groups were similar in regard to demographics and baseline characteristics of time, duration, and severity of last episode, as well as time between current and last episodes. There was a significant difference (P = 0.042) between treatment and placebo groups for mean DS2 (4.03 and 4.94, respectively). The small difference between groups for symptom scores over the five-day treatment period was not significant (P = 0.16) and the physician assessment showed a trend toward improvement, but this also was not statistically significant (P = 0.083). Difference in number of blisters present was significant in favor of treatment when ratings were grouped (0 or 1 blister, and > 2 blisters, P = 0.047), but not when each rating was considered separately (0, 1, 2-3, > 3 blisters, P = 0.15). Investigators concluded that results for primary and secondary endpoints were "coherent" and demonstrated efficacy and "a significant reduction in each of the components" of the total score.
This well-designed study had validated primary endpoints; all statistical tests were used appropriately. Using DS2 as the primary endpoint is appropriate because presentations of herpes labialis symptoms are typically the worst on day 2 of an outbreak. Investigators did compare results to previous trials and discussed confounding factors. Major trial limitations include inadequate enrollment to meet power and overstated conclusions given the results presented. There is question as to whether the statistically significant difference between groups on day 2 is actually clinically significant. Other questions involve the lack of reporting of side effects, if any occurred, and use of concomitant medications. Level II, major limitations (See Figure 1 for an explanation of the evaluation standards and scales used in rating clinical studies.)
Wölbling’s 1994 publication described two studies, both using the same 1% extract cream.11 The first was an open-label pilot with 115 patients who had skin and transitional mucosa herpes simplex infections. The subjects were directed to use the cream five times daily until lesions were healed, but for no more than 14 days. Symptoms were assessed at days 0, 4, 6, and 8. On day 8, 96% of patients had completed the healing process, which the authors note, has a normal range of 10-14 days. Level V
The second study in Wölbling’s article was a RDBCT using the same melissa cream against placebo in 116 patients. Patients must have had prodrome symptoms for no more than 72 hours, could have either skin or transitional mucosa infections, and could not be on any antiviral treatment. Patients were to apply cream two to four times daily for at least five but no more than 10 days. Patients were assessed on a 1-4 symptom scale for redness, swelling, vesicles, scabs, pain, and healing; lesion size was measured; and a global assessment of efficacy (GAE, 1-5 scale) was carried out by the patient and physician at trial end. Groups were similar after randomization for all characteristics (duration of prodrome, prestudy treatments, and sites of infection) and demographics except for age, because of the inclusion of three children in the placebo group. At day 2, there was significantly greater improvement in the melissa group for redness (P < 0.01) and swelling (P < 0.05), but not other symptoms. Melissa patients had less scabbing, but this did not reach significance. A significant difference (P = 0.037) favoring melissa was also found in planar area on day 2. Melissa was also favored in GAE ratings by both physicians and patients (P = 0.031, P = 0.022, respectively). Reported side effects included irritation (two in the placebo group, one in the melissa group) and burning (in two placebo patients). Of three dropouts, one melissa patient withdrew because of symptom exacerbation and one did not follow up; the placebo patient withdrew secondary to persistent itching. A subgroup analysis performed on the herpes labialis patients (n = 67) showed a faster decrease in lesion area in the treatment group that was significant on day 5 (P = 0.012), but not on day 2.
Outcome measures were appropriate. Investigators discussed a possible bias against the treatment group; patients had a longer duration of symptoms (4.5 hours on average) before beginning treatment than the placebo patients. This explanation is not clear and conflicts with earlier text stating mean prodrome symptom durations were the same in both groups. A primary trial limitation is the variable dosing; there was no explanation of why this was permitted, especially considering results of the open-label study. Another primary limitation is inclusion of various types of herpes infections, leading to difficulties in comparing characteristics such as lesion size and area. The authors concluded that treatment must be "started in the very early stages of the infection" in order to be effective, yet there are no conclusive data regarding differences in outcome compared to timing of treatment start to support this statement. Level II, major limitations
Adverse Events
Used topically for herpes labialis, adverse events are limited to irritation. There has been one report of exacerbation of symptoms.11,12
Contraindications
Patients with hypersensitivity to Melissa officinalis or preparation components should be counseled against use.
Pregnancy and Lactation
There are no known concerns or documented warnings against the use of topical preparations.
Interactions
No interactions are known for topical administration.12
Formulation and Dosage
The proprietary concentrated preparation used in the trials is made with a 1% lyophilized aqueous extract that is applied two to five times daily. Melissa brews or teas used as poultices, although recommended in some references, are unlikely to be effective.13
Conclusion
Results of the two Level II trials available for analy-sis demonstrated statistically significant differences in resolution of some herpes labialis symptoms in a comparison of Melissa officinalis extract cream and placebo. However, only one of these trials limited the herpes infections to labialis, and both have major limitations affecting clinical applicability. The extent to which melissa speeds healing of cold sores has not been well quantified and comparisons to antiviral treatments such as topical acyclovir are needed. Claims that melissa, when administered during the prodrome, will prevent full development of an outbreak also need to be tested.
Recommendation
Despite the positive results of these two Level II trials, there is still not enough evidence to state with certainty that melissa extract is an efficacious treatment for herpes labialis. However, considering that herpes labialis is normally a self-limiting condition, that reported adverse events for melissa are minor, and that topical pharmaceutical preparations also are not highly effective, topical melissa extract can be considered an option for treatment. Patients should be counseled that although some controlled studies demonstrated benefit the effects may be minor, are not known with certainty, and may vary according to product. Grade B
References
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2. DerMarderosian A, ed. Lemon balm. In: The Review of Natural Products. St. Louis, MO: Facts and Comparisons; 1999.
3. Mellissae folium. In: European Scientific Cooperative on Phytotherapy. Monographs on the Medicinal Use of Plant Drugs. March, 1996.
4. Chlabicz J, Galasinski W. The components of Melissa officinalis L. that influence protein biosynthesis in-vitro. J Pharm Pharmacol 1986;38:791-794.
5. Kucera LS, Herrman EC. Antiviral substances in plants of the mint family (Labiatae). I. Tannin of Melissa officinalis. Proc Soc Exp Biol Med 1967;12:865-869.
6. Herrman EC, Kucera LS. Antiviral substances in plants of the mint family (Labiatae). II. Nontannin polyphenol of Melissa officinalis. Proc Soc Exp Biol Med 1967;12:869-874.
7. Koytchev R, et al. Balm mint extract (Lo-701) for topical treatment of recurring herpes labialis. Phytomedicine 1999;6:225-230.
8. Englberger W, et al. Rosmarinic acid: A new inhibitor of complement C3-convertase with anti-inflammatory activity. Int J Immunopharmacol 1988;10:729-737.
9. Wölbling RH, Milbradt R. Klinik und Therapie des Herpes simplex. Vorstellun eines neuen phytotherapeutischen Wirkstoffes [abstract]. Therapiewoche 1984;34:1193-1200.
10. Vogt HJ, et al. Melissanextract bei herpes simplex. Der Allgemeinarzt 1991;13:382-841.
11. Wölbling RH, Leonhardt K. Local therapy of herpes simplex with dried extract from Melissa officinalis. Phytomedicine 1994;1:25-31.
12. Lemon balm. Natural Medicines Comprehensive Database [online version]. Therapeutic Research Faculty; Stockton, CA. Available at: http://www.naturaldatabase.com. Accessed February 17, 2000.
13. Balm: All-purpose soother. Available at: http://www.healthyideas.com/healing/herb/970930.herb.html. Accessed February 17, 2000.
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