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Catherine Ulbricht, PharmD, MBA(C), Column Editor Lemon Balm (Melissa officinalis L.)An Evidence-Based Systematic Review by the Natural Standard Research Collaboration

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An evidence-based systematic review including written and statistical analysis of scientific literature, expert opinion, folkloric precedent, history, pharmacology, kinetics/dynamics, interactions, adverse effects, toxicology, and dosing.
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NATURAL STANDARD REVIEW
Catherine Ulbricht, PharmD, MBA(C), Column Editor
Lemon Balm (Melissa officinalis L.):
An Evidence-Based Systematic Review
by the Natural Standard Research Collaboration
Thomas Brendler, BA
Joerg Gruenwald, PhD
Benjamin Kligler, MD, MPH
David Keifer, MD
Tracee Rae Abrams, PharmD
Jen Woods, BS
Heather Boon, BScPhm, PhD
Catherine DeFranco Kirkwood, MPH, CCCJS-MAC
Ethan Basch, MD
Hope J. Lafferty, AM
Catherine Ulbricht, PharmD
Dana A. Hackman, BS
for the Natural Standard Research Collaboration
Thomas Brendler is affiliated with PlantaPhile, Berlin. Joerg Gruenwald is affili-
ated with Phytopharm Consulting. Benjamin Kligler is affiliated with Continuum Cen-
ter for Health and Healing. David Keifer is affiliated with the University of Arizona.
Tracee Rae Abrams is affiliated with the University of Rhode Island. Jen Woods is
affiliated with Northeastern University. Heather Boon is affiliated with the University
of Toronto. Catherine DeFranco Kirkwood is affiliated with the MD Anderson Cancer
Center. Ethan Basch is affiliated with the Memorial Sloan-Kettering Cancer Center.
Hope J. Lafferty is affiliated with the Memorial Sloan-Kettering Cancer Center.
Catherine Ulbricht is affiliated with Massachusetts General Hospital. Dana A. Hack-
man is affiliated with Northeastern University.
Natural Standard (www.naturalstandard.com) Copyright ©2005. Reprinted with
permission.
Journal of Herbal Pharmacotherapy, Vol. 5(4) 2005
Available online at http://www.haworthpress.com/web/JHP
doi:10.1300/J157v05n04_08 71
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ABSTRACT. An evidence-based systematic review including written
and statistical analysis of scientific literature, expert opinion, folkloric
precedent, history, pharmacology, kinetics/dynamics, interactions, ad-
verse effects, toxicology, and dosing.
KEYWORDS. Citronellae, English balm, Lamiaceae, Melissa officinalis
L., sweet balm
SEARCH STRATEGY
To prepare each Natural Standard review, electronic searches are
conducted in nine databases, including AMED, CANCERLIT, CINAHL,
CISCOM, the Cochrane Library, EMBASE, HerbMed, International
Pharmaceutical Abstracts, MEDLINE, and NAPRALERT. Search terms
include the common name(s), scientific name(s), and all listed syn-
onyms for each topic. Hand searches are conducted of 20 additional
journals (not indexed in common databases), and of bibliographies
from 50 selected secondary references. No restrictions are placed on
language or quality of publications. Researchers in the field of comple-
mentary and alternative medicine (CAM) are consulted for access to ad-
ditional references or ongoing research.
Selection Criteria
All literature is collected pertaining to efficacy in humans (regard-
less of study design, quality, or language), dosing, precautions, ad-
verse effects, use in pregnancy/lactation, interactions, alteration of
laboratory assays, and mechanism of action (in vitro, animal research,
human data). Standardized inclusion/exclusion criteria are utilized for
selection.
Data Analysis
Data extraction and analysis are performed by health care profes-
sionals conducting clinical work and/or research at academic centers,
using standardized instruments that pertain to each review section (de-
fining inclusion/exclusion criteria and analytic techniques, including
validated measures of study quality). Data are verified by a second re-
viewer.
72 JOURNAL OF HERBAL PHARMACOTHERAPY
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Review Process
Blinded review of reviews is conducted by multidisciplinary re-
search-clinical faculty at major academic centers with expertise in epi-
demiology and biostatistics, pharmacology, toxicology, complementary
and alternative medicine (CAM) research, and clinical practice. In cases
of editorial disagreement, a three-member panel of the Editorial Board
addresses conflicts, and consults experts when applicable. Authors of
studies are contacted when clarification is required.
Update Process
Natural Standard regularly monitors scientific literature and industry
warnings. When clinically relevant new data emerge, best efforts are
made to update content immediately. In addition, regular updates with
renewed searches occur every 3-18 months, variable by topic.
SYSTEMATIC AGGREGATION, ANALYSIS,
AND REVIEW OF THE LITERATURE
Synonyms/Common Names/Related Substances
Balm, balm mint, bee balm, blue balm, Citra, citronellae, citron-
melisse, common balm, cure-all, dropsy plant, English balm, folia
citronellae, folia melissae citratae, garden balm, gastrovegetalin,
hjertensfryd, honey plant, kneipp melisse pflanzensaft, Labiatae/
Lamiaceae (family), lemon melissa, lomaherpan, melissa, Melissa
officinalis,Melissa officinalis L., melissae, melissae folium, Melisse
(German and French), melissenblatt, melissengeist, sweet balm,
sweet mary, toronjil (Spanish), valverde boutons de fievre crème.
Natural Standard Review 73
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Selected Combination Products
Abdomilon, Abdomilon N, Absimed, Agua del Carmen, Aktiv
Nerven-und Schlaftee, Anevrase, Aponatura Beruhigungs, Aponatura
Einschlaf, Aranidorm-S, Arterosan Plus, Avedorm, Baldracin,
Baldrian-Elixier, Baldrian-Krautertonikum, Baldriparan, Baldriparan
Beruhigungs, Baldriparan stark N, Balsamo Branco, Befelka-Tinktur,
Beruhigungstee, Biocarde, Bio-Garten Tee zur Beruhigung, Bio-
Garten Tropfen zur Beruhigung, Camomila, Canad, Caramelos
Agua del Carmen, Cardalept, Cardiaforce, Colominthe, Cough
Drops, Cura, Digestol Sanatorium, Doppelherz Melissengeist,
Doppelherz Tonikum, Dormarist, Dormiplant, Dragees pour la de-
tente nerveuse, Elixir Bonjean, Emmenoiasi, Especies Calmante,
Euvegal Entspannungs-und Einschlafdragees, Euvegal forte, Euvegal
N, Euviterin, Fargestium, Fluxoten, Gastregan, Gastrol S, Gastrosan,
Gutnacht, Heumann Beruhigungstee Tenerval N, Herz-und Kreisl-
auftonikum Bioflora, Hyperiforce comp, Iberogast, JuDorm, JuNeuron
S, Klosterfrau Melissengeist, Kneipp Krauter Taschenkur Nerven
und Schlaf N, Kneipp Nerven-und Schlaf- Tee, Kneipp Nerven-
und Schlaf-Tee N, Krauterdoktor Beruhigungstropfen, Krauterdoktor
Entspannungs-und Einschlaftropfen, Krauterdoktor Magen-
Darmtropfen, Krauterdoktor Nerven-Tonikum, Krauterdoktor
Rosmarin-Wein, Krauterhaus Mag Kottas Babytee, Krauterhaus
Mag Kottas Magen- und Darmtee, Krauterhaus Mag Kottas Nerven-
und Schlaftee, Krauterhaus Mag Kottas Wechseltee, Krautertee Nr
1, Krautertee Nr 141, Krautertee Nr 16, Krautertee Nr 201, Krautertee
Nr 209, Krautertee Nr 9, Lindofluid N, Lo-701, Luvased-Tropfen
N, Mag Doskar’s Magentonikum, Mag Doskar’s Nerventonikum,
Mag Kottas Beruhigungstee, Mag Kottas Krauterexpress-Nerven-
Schlaf-Tee, Mag Kottas Magen-Darmtee, Mag Kottas Nerven-
Beruhigungstee, Mag Kottas Schlaftee, Mag Kottas Tee fur stillende
Mutter, Mag Kottas Wechseltee, Mariazeller, Mediflor Tisane
Calmante Troubles du Sommeil No 14, Mediflor Tisane Circula-
tion du Sang No 12, Mediflor Tisane Pectorale d’Alsace, Me-
lissa comp., Melissa Specie Composta, Melissa Tonic, Melissengeist,
Melissin, Nervendragees, Nerven-Tee Stada N, Nervifloran,
Nervosana, Nyrene, Oxacnt N, Oxacant-sedativ, Pascosedon,
Passedan, Passelyt, Passiflora Composta, Phytoberidin, Phytogran,
Phytonoctu, Plantival, Plantival novo, Presselin Blahungs K 4 N,
Pronervon Phyto, Relax, Resolutivo Regium, RubieSed, Salus
Nerven-Schlaf-Tee Nr.22, Salusan, Santane D5, Santane N9, Schlaf-
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und Nerventee, Sedacur, Seda-Grandelat, Sedantol, Seda-Plantina,
Sedariston, Sedaselect N, Sedasyx, Sedatol, Sedatruw S, Sedinfant
N, Seracalm, Sidroga Herz-Kreislauf-Tee, Sidroga Kindertee, Sidroga
Magen-Darm-Tee, Sidroga Nerven-und Schlaftee, Sirmiosta Nerven-
elixier N, Sol Schoum, Songha, Songha Night, Soporin, Species
nervinae, St Radegunder Beruhigungs-und Einschlaftee, St Rade-
gunder Fiebertee, St Radegunder Herz-Kreislauf- Tonikum, St
Radegunder Herz- Kreislaufunterstutzender Tee, St Radegunder
Magenberuhigungstee, St Radegunder Nerventee, St Radegunder
Nerven-Tonikum, St Radegunder Reizmildernder Magentee, St
Radegunder Rosmarin-Wein, Stullmaton, STW 5-II (bitter candy
tuft, matricaria flower, peppermint leaves, caraway, licorice root,
and lemon balm), STW-5-S (matricaria flower, peppermint leaves,
caraway, licorice root, and lemon balm), SX Valeriana comp,
Synpharma InstantNerventee, Teekanne Magen-und Darmtee, Teek-
anne Schlaf-und Nerventee, The Brioni, The Chambard-Tee, The
Franklin, Tisana Arnaldi, Tisana Cisbey, Tisana Kelemata, Tisane
antiflatulente pour les enfants, Tisane calmante pour les enfants,
Tisane des Familles, Tisane favorisant l’allaitement, Tisane Grande
Chartreuse, Tisane pour le coeur et la circulation, Tisane pour le
Foie, Tisane pour le sommeil et les nerfs, Tisane pour les enfants,
Tisane pour l’estomac, Tisane Purgative, Tisane relaxante, Tisane
Touraine, Vagostabyl, Valerina Day Time, Valerina Night- Time,
Valverde Dragees pour la détente, Wechseltee.
CLINICAL BOTTOM LINE EFFECTIVENESS
Brief Background
Lemon balm (Melissa officinalis) is an herb with a lemon scent na-
tive to southern Europe. Historically lemon balm has been said to
possess sedative/tranquilizing, anti-gas, fever-reducing, antibacte-
rial, spasmolytic, hypotensive, memory-enhancing, menstrual-in-
ducing, and thyroid-related effects and has been proposed by some
to be an herbal cure-all.1-3 The plant has been used for centuries in
various cultures internationally.4,5
Lemon balm has been used for its tranquilizing properties in Portu-
guese folk medicine and for anticancer properties in Cuban folk
medicine.1,6
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Lemon balm is member of the Lamiaceae family.7-10 Other mem-
bers of the Lamiaceae family include dittany, mint, sage, siderites,
and sweet marjoram.11
In vitro data suggest that lemon balm may contain high concentra-
tions of antioxidants.12
Lemon balm has been assigned to the FDA Generally Recognized
As Safe (GRAS) list in the United States. No serious side effects
have been reported, although there is limited research of long-term
effects. See Tables 1 and 2.
Evidence of harm is considered separately; the below grades apply
only to evidence of benefit.
Historical or Theoretical Uses Which Lack Sufficient Evidence
• Analgesic,13 anorexia, anticholinergic,14,15 anti-gas,16 antihista-
minic, antihypertensive, antisecretory,17 antispasmodic,18-20 anti-
ulcerogenic,17 antiviral,7,9,9,19,21-26 anxiolytic,19,27 aromatic, atten-
tion deficit and hyperactivity disorder,28 cancer,6,17,29,30 chronic
bronchitis, chronic fatigue syndrome, colic, coughs, depression,19
digestive aid, fever reduction, flatulence, flatulent colic, gastroin-
testinal disorders, Graves’ disease,31-33 heart conditions, high blood
pressure, HIV,26 influenza, insect bites, insomnia,19,34-36 irregular
menstrual periods,16 irritable bowel syndrome, intestinal relaxant,15
memory enhancer,4,5,14 migraine, nausea, nervous palpitations,37
nervous stomach,37 neuralgia,19 neurasthenia, promoting menstrual
flow,33,38 promoting sweating, restlessness, sedative,13,19,34-36
shingles, skin irritations, sleep disorders,19,34-36 tension headache,
toothache, tranquilizer, vasodilatation, vomiting, wound healing
(topical).
76 JOURNAL OF HERBAL PHARMACOTHERAPY
A
B
C
D
E
GRADING
SYSTEM
LINK
TABLE 1. Scientific Evidence for Common/Studied Uses
Indication Evidence Grade
Herpes simplex virus infections B
Agitation in dementia C
Anxiety C
Cognitive performance C
Colitis C
Dyspepsia C
Sleep quality C
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Expert Opinion and Folkloric Precedent
In Europe, lemon balm has been widely used as a topical antiviral
treatment for genital and oral herpes, applied at the first sign of a
herpes flare-up or regularly for prevention. In Germany, the essen-
tial oil placed on the temples has been used to relieve headaches or
sleeplessness.
The German Commission E recommends lemon balm for nervous
sleep disorders and functional gastrointestinal complaints. The
European Scientific Cooperative on Phytotherapy (ESCOP) rec-
ommends its use for tenseness, restlessness, and irritability. Lemon
balm has been placed on the FDA Generally Regarded As Safe
(GRAS) list.
Natural Standard Review 77
TABLE 2. Natural Standard evidence-based validated grading rationale™
Level of Evidence Grade Criteria
A(Strong Scientific Evidence) Statistically significant evidence of benefit from > 2 properly
randomized trials (RCTs), OR evidence from one properly
conducted RCT AND one properly conducted meta-analysis, OR
evidence from multiple RCTs with a clear majority of the properly
conducted trials showing statistically significant evidence of
benefit AND with supporting evidence in basic science, animal
studies, or theory.
B(Good Scientific Evidence) Statistically significant evidence of benefit from 1-2 properly
randomized trials, OR evidence of benefit from 1 properly
conducted meta-analysis OR evidence of benefit from > 1
cohort/case-control/non-randomized trials AND with supporting
evidence in basic science, animal studies, or theory.
C(Unclear or conflicting scientific evidence) Evidence of benefit from 1 small RCT(s) without adequate
size, power, statistical significance, or quality of design by
objective criteria,* OR conflicting evidence from multiple RCTs
without a clear majority of the properly conducted trials showing
evidence of benefit or ineffectiveness, OR evidence of benefit
from 1 cohort/case-control/non-randomized trials AND without
supporting evidence in basic science, animal studies, or theory,
OR evidence of efficacy only from basic science, animal studies,
or theory.
D(Fair Negative Scientific Evidence) Statistically significant negative evidence (i.e., lack of evidence
of benefit) from cohort/case-control/non-randomized trials, AND
evidence in basic science, animal studies, or theory suggesting
a lack of benefit.
F(Strong Negative Scientific Evidence) Statistically significant negative evidence (i.e., lack of evidence
of benefit) from 1 properly randomized adequately powered
trial(s) of high-quality design by objective criteria.*
Lack of EvidenceUnable to evaluate efficacy due to lack of adequate available
human data.
* Objective criteria are derived from
validated instruments for evaluating study quality
, including the 5-point scale
developed by Jadad et al., in which a score below 4 is considered to indicate lesser quality methodologically
(
Jadad AR, Moore RA, Carroll D, Jenkinson C, Reynolds DJ, Gavaghan DJ, McQuay HJ. Assessing the quality of
reports of randomized clinical trials: is blinding necessary? Controlled Clinical Trials 1996; 17[1]:1-12
). See Table 4.
Listed separately in monographs in the “Historical or Theoretical Uses which Lack Sufficient Evidence” section.
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Brief Safety Summary
Likely Safe: When used topically or orally in recommended doses
(up to 30 days) in otherwise healthy adults34,39 and when con-
sumed in amounts found in foods. Lemon balm has been assigned
Generally Regarded As Safe (GRAS) status in the United States
with a maximum level of 0.5% in baked goods.
Possibly Unsafe: During pregnancy or lactation or in pediatric pa-
tients, and when used in patients with thyroid disorders or in com-
bination with sedatives (theoretical).
DOSING/TOXICOLOGY
General
Recommended doses are based on those most commonly used in
available trials, or on historical practice. However, with natural
products it is often not clear what the optimal doses are to balance
efficacy and safety. Preparation of products may vary from manu-
facturer to manufacturer, and from batch to batch within one man-
ufacturer. Because it is often not clear what the active components
of a product are, standardization may not be possible, and the clini-
cal effects of different brands may not be comparable.
Standardization
Investigations of lemon balm have suggested that the percentage
of essential oil from the leaves can range from 0.08 to 0.25 mL/100
grams, and 0.06 to 0.167 mL/100 grams in the herb.40 The content
and quality of essential oils from lemon balm also may differ de-
pending upon the height and location of the harvest cut of a partic-
ular plant, the vegetation period of the plant, and also between
different populations of the plant. For example, the oil content in
lemon balm appears to be highest in the top third of the plant, and
the percentage of the constituents may be highest when the plant is
cut in the basipetal direction.40-47 Clinical trial data suggest that
different preparations of lemon balm may result in products, which
exhibit different properties depending on the process used for the
sample preparation.2
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Lomaherpan®is a topical lemon balm extract (70:1) sold in Europe
that is standardized by bioassay.23,24 Herpilyn®, a topical prepara-
tion with equivalent standardization to the European products
(70:1), is sold in the United States. Doses used in other herbal
combinations are variable.
Studies have demonstrated that analysis of the different constitu-
ents of lemon balm may be achieved using methods such as gas
chromatography, mass spectroscopy, thin-layer chromatography,
plasma optical emission spectrometry and inductively coupled
plasma-source mass spectrometry, matrix solid-phase dispersion,
UV, 1R, 1H NMR, 13C NMR, and FAB MS.8,11,40,48-54 Several au-
thors have presented methods for identification,55-58 determination
of herbicide residues,59 and characteristics of adulterations.60 A
study of residue extraction from the whole leaves of lemon balm
by in vitro analysis by an isopropanol apparatus suggested that this
method is not appropriate for lemon balm.61
Adult Dosing (18 Years and Older)
Oral
Tea: A common dose of lemon balm is one cup of tea taken several
times per day as needed. Anecdotally, others have suggested 1.5 to
4.5 grams of lemon balm herb taken several times per day as a tea.
Tincture: A dosage of 2-6 mL three times per day (1:5 in 45% al-
cohol) has been used historically.
Liquid extract: Lemon balm extract in a dose of 60 drops per day
has been cited in research on patients with Alzheimer’s disease for
improvement in cognition.62
Leaves: A dosage of 8-10 grams per day has been used.
Combination products: The product Songha Night®, which in-
cludes 120 mg Valeriana officinalis extract and 80 mg lemon balm
extract, has been used as a sleep aid in a dosage of three tablets
taken nightly for 30 days.34 For anxiety, Klosterfrau Melissengeist®
[each teaspoonful (5 mL) contains essential oils of lemon balm (27
mg), orange peel (36 mg), cinnamon (16 mg), and myristica (4
mg)] has been taken as 0.23 mL/kg body weight, three times per
day for eight weeks.37 For dyspepsia, Iberogast®, a standardized
formula containing Matricata recutita,Iberis amara,Angelica
archangelica,Carum carvi,Silybum marianum, lemon balm,
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Chelidonium majus,Glycyrrhiza glabra, and Mentha piperita,
has been taken in a dosage of 20 drops, three times per day for a
minimum of four to eight weeks.63
Topical
Cream: Cream containing 1% of a standardized 70:1 extract, topi-
cally up to four times per day for 5 to 10 days has been studied for
the treatment of active viral herpes.22-24
Tea: Alternatively, a tea has been applied to herpes lesions with a
saturated cotton ball several times per day. The tea is prepared by
steeping 2-3 teaspoons (2-3 grams) of the finely cut leaf in 150 mL
boiling water for 5-10 min and then straining.
Pediatric Dosing (Younger Than 18 Years)
Insufficient available data.
Toxicology
Lemon balm preparations may contain trace amounts of lead. A
study evaluating metal dispersion in food crops suggested that the
soil in which some plants are grown may be contaminated by lead
from environmental pollution and therefore may cause the plant to
contain trace amounts of the element.64
The lack of genotoxic effects of aqueous or alcoholic extracts of
lemon balm on Aspergillus nidulans D-30 using a plate-incorpora-
tion assay has been noted.6
There are insufficient available data on chronic toxicity.
ADVERSE EFFECTS/PRECAUTIONS/CONTRAINDICATIONS
Allergy
Individuals with known allergy/hypersensitivity to lemon balm should
avoid its use. Hypersensitivity reactions have been reported, including
contact dermatitis.65 Lemon balm extract had a weak sensitizing effect
in guinea pigs.66
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Adverse Effects/Post Market Surveillance
General: Based on available research, oral forms have been reported
to be relatively well-tolerated when taken for up to 8 weeks.37 Evidence
for topical administration of cream suggested minimal side effects for
up to 10 days of application.22,24,39
Dermatologic: Contact dermatitis,65 local reddening, burning sensa-
tion, paresthesia, residual pigmentation,23 and dermal irritation24 on ap-
plication of cream have been reported. One case of irritation and one
case of exacerbation of herpes symptoms were reported when lemon
balm was applied topically.24
Neurologic: One clinical study reported the occurrence of head-
ache.37 One study cited that 1200 mg of lemon balm resulted in EEG
changes.67 One trial reported that 900 mg of lemon balm may reduce
alertness, so caution should be used when driving or operating heavy
machinery.20 In one clinical trial, the use of a Valeriana officinalis/
lemon balm combination was reported to cause mild adverse effects in
28.8% of patients, with sleep disturbances and tiredness cited as the
most common side effects (although sedative properties of Valeriana
officinalis alone are well-described and the additional effects of lemon
balm are not clear in this combination).13,34 AValeriana officinalis-
Humulus lupulus-lemon balm combination was reported to cause tired-
ness in isolated cases.68
Ocular/Otic: Anecdotal reports note the possibility of lemon balm
increasing intraocular pressure.
Cardiovascular: One randomized controlled trial reported the occurence
of palpitations.37
Endocrine: A pre-clinical study reported that constituents of lemon
balm may block the binding of thyroid-stimulating hormone (TSH) to
its receptor by acting both on the hormone and the receptor itself.69
Studies have suggested that patients with thyroid problems such as
Graves’ disease use caution due to the potential for thyroid hormone in-
hibition.27,31-33,38,69 Lemon balm may interfere with thyroid hormone
replacement therapy (theoretical).
Gastrointestinal: Cases of nausea and diarrhea have been reported.37)
Precautions/Warnings/Contraindications
Use cautiously in patients with thyroid problems such as Graves’
disease due to potential for thyroid hormone inhibition.27,31-33,38,69
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Use cautiously in patients with glaucoma as anecdotal reports have
suggested that lemon balm may increase intraocular pressure.
Use caution when driving or operating heavy machinery. Results
from one clinical study have suggested that lemon balm may re-
duce alertness at doses of 900 mg.20
Lemon balm preparations may contain trace amounts of lead. A
study evaluating metal dispersion in food crops suggested that the
soil in which some plants are grown may be contaminated by lead
from environmental pollution and therefore may cause the plant to
contain trace amounts of the element.64
Pregnancy and Lactation
Not recommended due to lack of sufficient data.27 Lemon balm
may elicit emmenagogic, antithyrotropic, and antigonadotropic ef-
fects (anecdotal).
INTERACTIONS
Lemon Balm/Drug Interactions
Alcohol: In theory, alcohol use with lemon balm may augment the
sedative effects of alcohol.20,27 However, no additive effects of al-
cohol were shown when combined with a Valeriana officinalis-
Humulus lupulus-lemon balm combination product.68
Barbiturates: Lemon balm has been reported to increase the hyp-
notic effects of barbiturates in animal studies.13,27
Sedative agents: Based on preclinical studies70 and initial human
research,20 combination use of lemon balm with sedatives may re-
sult in additive effects.
Glaucoma medications: Based on anecdotal accounts, lemon balm
may increase intraocular pressure, thereby diminishing effects of
glaucoma medications.
Thyroid agents: In euthyroid rats, the administration of freeze-
dried extracts of lemon balm was reported to reduce pituitary and
serum thyroid stimulating hormone (TSH) concentrations.31-33
One study suggested that constituents of lemon balm may block
the binding of TSH to its receptor by acting on both the hormone
and the receptor itself.69 Lemon balm may interfere with thyroid
hormone replacement therapy (theoretical).
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Nicotine and scopolamine: Lemon balm may displace drugs bound
to nicotinic and muscarinic receptors, as demonstrated in clinical
trials with the displacement of nicotine and scopolamine from
these receptors.2,14,20
Selective serotonin reuptake inhibitors (SSRIs): As demonstrated
in in vitro studies, lemon balm may inhibit concentrations of sero-
tonin and therefore may interact with drugs which affect concen-
trations of serotonin in vivo.15
Lemon Balm/Herb/Supplement Interactions
Sedative herbs and supplements: A study examining efficacy and
safety of herbal sedatives suggested that combination use of sed-
ative herbs with lemon balm may result in additive effects.70
Such herbs include ashwaganda root, calamus, calendula, Cali-
fornia poppy, capsicum, catnip, celery, cough grass, elecampane,
Siberian ginseng, German chamomile, goldenseal, gotu kola,
hops (Humulus lupulus), Jamaican dogwood, kava, sage, St.
John’s wort, sassafras, skullcap, shepherd’s purse, stinging net-
tle, valerian (Valeriana officinalis), wild carrot, wild lettuce, and
yerba mansa.
Herbs and supplements used for glaucoma: Anecdotal accounts
suggest that lemon balm may increase intraocular pressure, thereby
diminishing effects of glaucoma treatments.
Herbs that affect thyroid hormone: In euthyroid rats, the adminis-
tration of freeze-dried extracts of lemon balm was reported to re-
duce pituitary and serum TSH concentrations.31-33 One study
suggested that constituents of lemon balm may block the binding
of TSH to its receptor by acting both on the hormone and the
receptor itself.69
Lemon Balm/Lab Interactions
Thyroid Stimulating Hormone: In euthyroid rats, the administra-
tion of freeze-dried extracts of lemon balm was reported to re-
duce pituitary and serum TSH concentrations.31-33 One study
reported that constituents of lemon balm may block the binding
of TSH to its receptor by acting on both the hormone and the
receptor itself.69
Prolactin: In rats, prolactin serum levels and hypophyseal stores were
reduced by 40 mg/100 grams of a freeze-dried extract of lemon balm.33
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MECHANISM OF ACTION
Pharmacology
Constituents: The known major components of lemon balm are re-
ported to include hydroxycinnamic acid derivatives, particularly
rosmarinic acid, caffeic acids, chlorogenic acid, and metrilic
acid;11,38,49,71-73 tannins;7,9,21,74,75 flavonoids, including luteolin,
luteolin 7-O-beta-D-glucopyranoside, apigenin 7-O-beta-D-gluco-
pyranoside, and luteolin 3-O-beta-D-glucuronopyranoside;17,32,40,
45,48,52,76,77 monoterpene glycosides;78 sesquiterpenes, including
β-caryophyllene and germacrene;78 triterpenes;79 and volatile oils,
including citronellal, citral a (geranial), citral b (neral), methyl
citronellate, ocimene, citronellol, geraniol, nerol, β-caryophyllene,
β-caryophyllene oxide, linalool, and ethric oil.40,45,80-84 The vola-
tile oil comprises 0.5-0.1% of the plant by weight, and citronellal,
geranial, and neral constitute about 50-70% of this oil.80 Eugen-
ylglycoside has been isolated from lemon balm leaves.85 The
chemical composition of lemon balm tea yielded 10 mg/L of es-
sential oil (74% citral) and large amounts of polyphenol com-
pounds.86 Steam distillates of lemon balm callus cultures yielded
dehydroabietane and another diterpene hydrocarbon, with the rela-
tive proportion of those two compounds varying considerably dur-
ing cultivation passage.87
Antiviral effects: Studies have reported that aqueous extracts of
lemon balm exhibit antiviral effects against Newcastle disease vi-
rus, Semliki forest virus, influenza virus, myxoviruses, vaccinia,
and herpes simplex virus.7,9,21,25,51,74 Lemon balm extract and
rosmarinic acid have demonstrated antiviral properties against
HIV-1.26 Studies conducted to assess the antiviral effects of lemon
balm on Herpes simplex virus 1 have suggested that different ex-
tracts of the herb (M1, M2, M3, and M4) exhibit different effects
on the virus.51 Studies conducted to assess the antiviral effects of
lemon balm on Herpes simplex virus 2 suggest that the volatile oil
components of lemon balm inhibit replication of HSV-2.88 Lemon
balm’s antiviral effects are attributed to the tannin and polyphenol
constituents. Tannins are reported to possess antiviral proper-
ties7,9,21,25,74 as are rosmarinic, caffeic, and ferulic acids.7,51
Antibacterial/antifungal effects: The lemon balm constituent
rosmarinic acid was reported to impair in vivo activation of mouse
macrophages by heat-killed Corynebacterium parvum, as mea-
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sured by the decreased capacity of the activated macrophages to
undergo the oxidative burst.73 In vitro analyses of the antimicr-
obial properties of lemon balm suggested that at a concentration of
500 microg/mL, the herb completely inhibits the growth of all
yeast species including, Torulaspora delbrueckii,Zygosaccharomyces
bailii,Pichia membranifaciens,Dekkera anomala, and Yarrowia
lipolytica.(50,89) Data from in vitro analyses have suggested that
lemon balm may be effective as an antibiotic against anaerobic
and facultative aerobic periodontal bacteria including, Porphyromonas
gingivalis,Prevotella spp., Fusobacterium nucleatum,Capnocyto-
phaga gingivalis,Veilonella parvula,Eikenella corrodens,Pepto-
streptococcus micros, and Actinomyces odontolyticus.90 Lemon
balm oils have been reported to demonstrate highest activity against
S. enterica (BA50 range, 0.0044-0.011%).91 Antibacterial activity
was reported to be expressed on a multiresistant strain of Shigella
sonei.92
Antiinflammatory effects: The paucity of clinical evidence makes
the assessment of the antiinflammatory effect of lemon balm diffi-
cult to verify.73,93 Rosmarinic acid has been reported to reduce paw
edema induced by cobra venom factor in rats and to inhibit passive
cutaneous anaphylaxis in rats at doses of 1-100 mg/kg by mouth.
Rosmarinic acid has been reported not to inhibit t-butyl
hydroperoxide-induced paw edema in the rat, indicating selectiv-
ity for complement-dependent processes.73
Antioxidant effects: In vitro data suggest that lemon balm contains
high concentrations of antioxidants (greater than 75 mmol/100
g).8,11,12,17,72,94 Lemon balm has been reported to demonstrate high
phenolics content and antioxidant properties (TEAC 4.06+/0.31
mM/QE 1370.09+/41.38 microM).95 Lemon balm extracts and
rosmarinic acid have both been reported to demonstrate antioxi-
dant properties in vitro,8,11,72 and rosmarinic acid and caffeic acid
have demonstrated significant antioxidant and immune modulat-
ing activities.10, 11, 72,73,93 During linoleic acid autoxidation and its
EDTA-mediated oxidation, lemon balm showed antioxidant activ-
ity.96 An in-vitro cytotoxicity assay demonstrated that lemon balm
oil was very effective against a series of human cancer cell lines
(A549, MCF-7, Caco-2, HL-60, K562) and one mouse cell line
(B16F10). Further antioxidant activity of lemon balm has been
reported as evidenced by the reduction of 1,1-diphenyl-2- picryl-
hydrazyl (DPPH).97 Studies have demonstrated that the cytopro-
tective effect of lemon balm extracts seen in rats was due in part to
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free-radical scavenging properties.10,17 Immunostimulating effects
of a lemon balm extract were also demonstrated.98 Inhibitory ef-
fects of rosmarinic acid from lemon balm on porcine pancreatic
amylase were reported in vitro.99
Antiprotozoal effects: Essential oils, monoterpenes, and sesquiterpenes
from lemon balm were tested on bloodstream forms of Leishmania
major and Trypanosoma major. These constituents were reported
to be about 50- to 80-fold more toxic to T. major than were human
HL-60 cells. None of the essential oils or terpenes were reported to
be more toxic to L. major than HL-60.78 Monoterpene and sesquiter-
penes may possess antiprotozoal effects (anecdotal).
Antithrombotic effects: Rosmarinic acid has been reported to dem-
onstrate inhibitory effects on both the classical pathway convertase
and the alternative pathway convertase. One study reported that
rosmarinic acid inhibited 70% of the immunohemolysis of anti-
body-coated sheep erythrocytes by guinea pig serum via possible
inhibition of the C3 convertase of the classical complement path-
way. However, higher concentrations of rosmarinic acid were less
effective.73 Rosmarinic acid was also reported to inhibit C5 con-
vertase in the classical pathway.73,93
Antithyroid effects: Studies have shown that freeze-dried extracts
of lemon balm were reported to inhibit the binding of bovine TSH
to human thyroid plasma membranes and adenylate cyclase. In rat
liver microsomes, lemon balm aqueous extract was reported to in-
hibit the extrathyroidal enzymatic T4-5-deiodination to both T3-
and T4-5-deiodination.31,32 The thyroid-stimulating immuno-
globulin G (IgG) found in patients with Graves’ disease has been
reported to resemble TSH in its ability to bind to the thyroid
plasma membrane and to activate the thyroid gland. Freeze-dried
extracts of lemon balm were reported to exhibit antithyrotropic ac-
tivity by forming adducts with TSH that bound weakly, if at all, to
the TSH receptor. When IgG was incubated with extracts of lemon
balm, a dose-dependent decrease was reported in the TSH-binding
inhibitory activity. As a result of this reported decrease, adenylate
cyclase activity was stimulated (thyroid-stimulating immunoglob-
ulin activity) and thyroid iodine release was enhanced in the
McKenzie assay system. Cinnamic acid has been reported to in-
hibit the binding of TSH to human thyroid membranes.31,32 In
euthyroid rats, the administration of freeze-dried extracts of lemon
balm was reported to reduce pituitary and serum TSH concentra-
tions.33
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Emmenagogic effects: One study suggested that freeze-dried ex-
tracts of lemon balm inhibited binding of 125I hCG to rat testis
membranes.38 In rats, prolactin serum levels and hypophyseal
stores were reported to be reduced by 40 mg/100 grams of a
freeze-dried extract of lemon balm.33
Spasmolytic effects: Due to lack of clinical data, lemon balm has
not been recommended for use as a spasmolytic agent.18-20 Using
histamine and acetylcholine as spasmogens in guinea pig ileum, no
significant antispasmodic activity resulting from lemon balm ex-
tracts were reported.(18) Studies on isolated duodenum of rat have
reported antispasmodic effects of lemon balm in vitro.100
Sedative effects: In mice, an aqueous alcoholic extract of lemon
balm was reported to produce dose-dependent sedation, inducing
sleep and potentiating sub-hypnotic and hypnotic doses of pento-
barbital. On the other hand, in the same study the essential oil of
lemon balm was reported to have no sedative effect.13 With high
doses, a peripheral analgesic effect was noted.13 In tests on Wistar
strain rats and on laboratory mice, lemon balm dried extract was re-
ported to exert influence on CNS in evoking antiaggressive activity.
CNS studies of rat reported sedative, hypnotic, and analgesic effects
of lemon balm in vivo.100 An ethanolic extract of lemon balm was
tested for affinity to the GABA(A)-benzodiazepine site, and moder-
ate activity was reported.101 However, a study of a volatile oil-free
hydroalcoholic extract reported sedative activity in mice.
Cardiovascular effects: One study demonstrated that aqueous ex-
tracts of lemon balm provoked a significant reduction in the car-
diac rate in isolated rat hearts, while the contractile force remained
unchanged. This was reported to be caused by the stimulation of
cardiac muscarinic receptors.102
Pharmacodynamics/Kinetics
Insufficient available data.
HISTORY
Lemon balm is a delicate, low-growing (1-2 foot) perennial herb
with lemon-smelling, pointed, heart-shaped or oval leaves, and
small white or yellow flowers. The leaves are used medicinally.
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Lemon balm is native to the Mediterranean region, and now is also
grown in western Asia, the United States, and Europe.
Lemon balm is commonly planted in gardens to attract bees. The
name comes from the Greek word “melissa” which means “bee,”
and “balm,” a short form of “balsam.” The medicinal use of lemon
balm has been documented since Ancient Greek and Roman times.
Condition
Refers to the medical condition or disease targeted by a therapy.
Study Design
Common types include:
Randomized controlled trial (RCT): An experimental trial in which
participants are assigned randomly to receive either an interven-
tion being tested or placebo. Note that Natural Standard defines
RCTs as being placebo-controlled, while studies using active con-
trols are classified as equivalence trials (see below). In RCTs, par-
ticipants and researchers are often blinded (i.e., unaware of group
assignments), although unblinded and quasi-blinded RCTs are
also often performed. True random allocation to trial arms, proper
blinding, and sufficient sample size are the basis for an adequate
RCT.
Equivalence trial: An RCT which compares two active agents.
Equivalence trials often compare new treatments to usual (stan-
dard) care, and may not include a placebo arm.
Before and after comparison: A study that reports only the change
in outcome in each group of a study, and does not report be-
tween-group comparisons. This is a common error in studies that
claim to be RCTs.
Case series: A description of a group of patients with a condition,
treatment, or outcome (e.g., 20 patients with migraine headache
underwent acupuncture and 17 reported feeling better afterwards).
Case series are considered weak evidence of efficacy.
Case-control study: A study in which patients with a certain out-
come are selected and compared to similar patients (without the
outcome) to see if certain risk factors/predictors are more common
in patients with that outcome. This study design is not common in
the complementary & alternative medicine literature.
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Cohort study: A study which assembles a group of patients with
certain baseline characteristics (for example, use of a drug), and fol-
lows them forward in time for outcomes. This study design is not
common in the complementary & alternative medicine literature.
Meta-analysis: A pooling of multiple trials to increase statistical
power (often used to pool data from a number of RCTs with small
sample sizes, none which demonstrates significance alone but in
aggregate can achieve significance). Multiple difficulties are en-
countered when designing/reviewing these analyses; in particular,
outcomes measures or therapies may differ from study to study,
hindering direct comparison.
Review: An author’s description of his or her opinion based on per-
sonal, non-systematic review of the evidence.
Systematic review: A review conducted according to pre-specified
criteria in an attempt to limit bias from the investigators. System-
atic reviews often include a meta-analysis of data from the in-
cluded studies.
Author, Year
Identifies the study being described in a row of the table.
N
The total number of subjects included in a study (treatment group
plus placebo group). Some studies recruit a larger number of subjects
initially, but do not use them all because they do not meet the study’s en-
try criteria. In this case, it is the second, smaller number that qualifies as
N. N includes all subjects that are part of a study at the start date, even if
they drop out, are lost to follow-up, or are deemed unsuitable for analy-
sis by the authors. Trials with a large number of drop-outs that are not
included in the analysis are considered to be weaker evidence for effi-
cacy. (For systematic reviews the number of studies included is re-
ported. For meta-analyses, the number of total subjects included in the
analysis or the number of studies may be reported.)
Statistically Significant?
Results are noted as being statistically significant if a study’s authors
report statistical significance, or if quantitative evidence of significance
is present (such as p values).
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Quality of Study
A numerical score between 0-5 is assigned as a rough measure of
study design/reporting quality (0 being weakest and 5 being strongest).
This number is based on a well-established, validated scale developed
by Jadad et al. (Jadad AR, Moore RA, Carroll D, et al. Assessing the
quality of reports of randomized clinical trials: Is blinding necessary?
Controlled Clinical Trials 1996;17[1]:1-12). This calculation does not
account for all study elements that may be used to assess quality (other
aspects of study design/reporting are addressed in the “Evidence Discus-
sion” sections of reviews).
A Jadad score is calculated using the seven items in the table be-
low. The first five items are indications of good quality, and
each counts as one point towards an overall quality score. The
final two items indicate poor quality, and a point is subtracted
for each if its criteria are met. The range of possible scores is 0
to 5.
Magnitude of Benefit
This summarizes how strong a benefit is: small, medium, large, or
none. If results are not statistically significant “NA” for “not applica-
ble” is entered. In order to be consistent in defining small, medium, and
large benefits across different studies and reviews, Natural Standard de-
fines the magnitude of benefit in terms of the standard deviation (SD) of
the outcome measure. Specifically, the benefit is considered:
90 JOURNAL OF HERBAL PHARMACOTHERAPY
Jadad Score Calculation
Item Score
Was the study described as randomized (this includes words such as randomly, random, and
randomization)?
0/1
Was the method used to generate the sequence of randomization described and appropriate (table of
random numbers, computer-generated, etc)?
0/1
Was the study described as double blind? 0/1
Was the method of double blinding described and appropriate (identical placebo, active placebo, dummy,
etc)?
0/1
Was there a description of withdrawals and dropouts? 0/1
Deduct one point if the method used to generate the sequence of randomization was described and it was
inappropriate (patients were allocated alternately, or according to date of birth, hospital number, etc).
0/1
Deduct one point if the study was described as double blind but the method of blinding was inappropriate
(e.g., comparison of tablet vs. injection with no double dummy). 0/1
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Large: if > 1 SD;
Medium: if 0.5 to 0.9 SD;
Small: if 0.2 to 0.4 SD.
In many cases, studies do not report the standard deviation of change
of the outcome measure. However, the change in the standard deviation
of the outcome measure (also known as effect size) can be calculated,
and is derived by subtracting the mean (or mean difference) in the pla-
cebo/control group from the mean (or mean difference) in the treatment
group, and dividing that quantity by the pooled standard deviation (Ef-
fect size = [Mean Treatment Mean Placebo]/SDp).
Absolute Risk Reduction
This describes the difference between the percent of people in the
control/placebo group experiencing a specific outcome (control event
rate), and the percent of people in the experimental/therapy group expe-
riencing that same outcome (experimental event rate). Mathematically,
absolute risk reduction (ARR) equals experimental event rate minus
control event rate. ARR is better able to discriminate between large and
small treatment effects than relative risk reduction (RRR), a calculation
that is often cited in studies [(control event rate experimental event
rate/control event rate)]. Many studies do not include adequate data to
calculate the ARR, in which cases “NA” is entered into this column.
Number Needed to Treat
This is the number of patients who would need to use the therapy un-
der investigation, for the period of time described in the study, in order
for one person to experience the specified benefit. It is calculated by di-
viding the absolute risk reduction into 1 (1/ARR).
Comments
When appropriate, this brief section may comment on design flaws
(inadequately described subjects, lack of blinding, brief follow-up, not
intention-to treat, etc.), notable study design elements (crossover, etc.),
dosing, and/or specifics of study group/sub-groups (age, gender, etc.).
More detailed description of studies is found in the “Evidence Discus-
sion” section that follows the “Evidence Table” in Natural Standard
reviews.
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EVIDENCE DICUSSION
Herpes Simplex Virus Infections
Summary: Rigorous clinical data are lacking. Preliminary clinical
studies demonstrate promising effects. See Tables 3 and 4.
Evidence: Vogt et al. investigated the efficacy of a cream contain-
ing lemon balm extract in a randomized, placebo controlled, dou-
ble-blind trial in 116 patients with Herpes simplex infections.103
Patients were treated with either Lomaherpan Creme or placebo
two to four times per day over a period of up to 10 days. Symptoms
were documented after day two and at the end of the treatment pe-
riod (average five days). Symptoms investigated were reddening,
swelling, blisters, erosions, scab, pain, and healing. Severity of
symptoms was expressed in a score from one to four. Overall eval-
uation used a score from one to five. Regression of reddening and
reduction of swelling were reported as statistically significant vs.
placebo. Overall evaluation of efficacy was reported as signifi-
cantly positive vs. placebo both by patients and doctors. The au-
thors suggested that Lomaherpan proved effective in the treatment
of Herpes simplex infections. Efficacy was greater, the earlier treat-
ment commenced.
A placebo controlled, double-blind trial was conducted to evaluate
the efficacy of lemon balm in the treatment of herpes simplex skin
or mucosa infections in 116 patients.24 To be included into the trial,
patients must have had symptoms for no more than 72 hours, could
have either skin or transitional mucosa infections, and could not be
on any antiviral treatment. Patients could apply placebo or topical
Lomahephan®(1% dried lemon balm extract) 2-4 times per day for
5-10 days. Outcome measures assessed redness, swelling, scabs,
pain, healing, and vesicles on a one to four point symptom scale,
lesion size, and efficacy (globally assessed by patients and physi-
cians). Results reported that at day two, redness and swelling were
significantly improved in the lemon balm group (p = 0.0055 and
p = 0.25, respectively) compared to the placebo group. Global as-
sessment of efficacy by patients (“very good” rating 24 times in
the treatment group vs. 11 times in the placebo group, p = 0.022)
and physicians (“very good” rating in 25 times in the treatment
group and 10 times in the placebo group, p = 0.031) were reported
as significantly higher in the lemon balm group vs. the placebo
group. Reported side effects included irritation in one patient tak-
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ing lemon balm and in two patients taking placebo. Two patients
taking placebo also reported a burning sensation. Subgroup analy-
sis of 67 patients demonstrated a quicker decrease in lesion area in
the lemon balm group, which was not significant on day two but
was significant on day five (p = 0.012). One limitation of this trial
is the flexibility in dosing regimen.
Koytchev et al. conducted a randomized, placebo controlled, dou-
ble-blind trial to examine the effects of lemon balm in 66 patients
with a history of recurrent herpes labialis.22 Patients must have ex-
perienced at least four episodes per year to be included in the
study. Patients received either placebo or Lomaherpan®(1% cream
of freeze-dried lemon balm extract) and were treated topically on
the affected area four times per day for five days. The patients
were instructed to start the application within four hours of symp-
toms and return for a physician visit within 24 hours. Symptoms
including bother, number of blisters, and size of affected area were
scored on a scale developed for acyclovir trials. The primary out-
come measure was a symptom score on day two, and secondary
endpoints included total scores of symptoms over five days of
treatment. Results revealed a symptom score on day two of 4.03 in
the lemon balm group vs. 4.94 in the placebo group (p = 0.042).
According to the authors, the difference between total scores was
not significant (p = 0.16). Physician assessment was also reported
as not significant. Limitations include lack of reporting of side ef-
fects and tolerance of treatment.
A case series was conducted to study the efficacy of lemon balm in
the treatment of 115 patients with cold sores. To be included on the
study, patients experienced symptoms for less than 72 hours.
Cream containing 1% dried lemon balm extract was applied to ar-
eas of herpes simplex infection as needed up to five times per day,
up to 14 days.23,24 The primary endpoint was the complete healing
of the lesion. Healing was completed in 60% of the patients by day
four, 87% by day six, and 96% by day eight. According to the au-
thors, these results suggested that the benefit from using lemon
balm was dubious. The effect attributed to lemon balm was re-
ported as no shorter than that of the natural course of the disease.
The rate of adverse effects was 2.6% (three patients) and included
reddening of the skin, burning sensation, paresthesia, and in one
case, residual pigmentation. This study is limited by its lack of a
placebo control group.
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94 JOURNAL OF HERBAL PHARMACOTHERAPY
TABLE 3. Evidence Table
Condition Study
Design
Author,
Year
N Statistically
Significant?
Quality of
Study
0-2 = poor
3-4 = good
5 = excellent
Magnitude
of Benefit
ARR NNT Comments
Herpes
simplex
Randomized,
double-blind
trial
Vogt,
1991
116 Yes 4 Medium 26% 4 Cream with
1% lemon
balm (70:1)
used bid to
qid x 10
days. Side
effects less
than 1%;
early
treatment
improved
efficacy.
Herpes
simplex
Randomized,
placebo
controlled,
double-blind
trial
Wölbling,
1994
116 Yes 3 Small 24.9% 4 Cream with
1% lemon
balm (70:1)
used bid to
qid x 5-10
days.
Herpes
simplex
labialis
Randomized,
placebo
controlled,
double-blind
trial
Koytchev,
1999
66 No 2 NA NA NA Cream with
1% lemon
balm (70:1)
applied within
4 hours of
symptoms,
then qid x 5
days.
Herpes
simplex
Case series Wölbling,
1984;
Wölbling,
1994
115 No 1 NA NA NA Cream with
1% lemon
balm used 5
times per day
x 14 days.
No placebo
control group.
Agitation in
dementia
Randomized,
placebo
controlled,
double-blind
trial
Ballard, 2002 72 Yes 3 Small Reduction
in Cohen-
Mansfield
Agitation
Inventory
(CMAI): 24%
4 Lotion with
lemon balm
applied to
patients’ face
and arms bid.
Anxiety Randomized,
placebo
controlled,
double-blind
trial
Büchner,
1974
102 Yes 4 NA NA NA Combination
product used
at 0.23 mL/kg
body weight.
Anxiety Case series Lagoni,
1998
92 NA 2 NA NA NA Combination
product used.
Anxiety Case series Schmidt,
1992
1599 NA 2 NA NA NA Combination
product used.
1395 patients
evaluated.
Cognitive
performance
Randomized,
controlled
trial
Akhondzadeh,
2003
42 Yes 3 Small NA NA Lemon balm
extract used
at 60 drops/
day.
Cognitive
performance
Randomized,
placebo
controlled,
double-blind
trial
Herberg,
1996
48 Yes 2 Small NA NC 2 tablets of
combination
product used.
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Natural Standard Review 95
Condition Study
Design
Author, Year N Statistically
Significant?
Quality of
Study
0-2 = poor
3-4 = good
5 = excellent
Magnitude
of Benefit
ARR NNT Comments
Cognitive
performance
and mood
Randomized,
placebo
controlled,
double-blind
crossover
trial
Kennedy,
2001
20 NA 2 NA NA NA 3 00, 600, and
900mg of
standardized
extract used
on
alternating
days.
Cognitive
performance
Randomized,
crossover
trial
Kennedy,
2003
20 NA 2 NA NA NA 600, 1000,
and 1600mg
dried leaf
capsules
used at 7-
day intervals
by healthy
volunteers.
Dyspepsia Multicenter,
randomized,
placebo
controlled,
double-blind
trial
Madisch,
2004
120 Yes 3 Medium Relief from
gastro-
intestinal
symptoms:
40%
2.5 Combination
product
used.
Dyspepsia Double-blind,
placebo
controlled
trial
Madisch,
2001
60 Yes 3 Medium NA NA Combination
product
used.
Dyspepsia Multicenter
case series
Borho,
1991
152 NA 1 NA NA NA Combination
product used.
Sleep quality,
well-being,
and
tolerability
Multicenter,
randomized,
placebo
controlled,
double-blind
trial
Cerny,
1999
98 No 4 NA 23.9% 4 Healthy
volunteers
used
combination
product,
three tablets
qd, half-hour
before
bedtime.
Sleep quality Randomized,
placebo
controlled,
double-blind
trial
Dressing,
1996
68 Yes 3 Medium 40% overall
evaluation
3 Combination
product
used.
Sleep quality Randomized,
controlled,
double-blind,
crossover
trial
Lindahl,
1989
27 Yes 2 Small NA NA Combination
product
used, short
study
duration.
Sleep quality,
mild to
severe
insomnia
Randomized,
placebo
controlled
trial
Widy-
Tyszkiewicz,
1997
50 Yes 2 Medium NA NA Combination
product
used.
Sleep quality Controlled,
double-blind
trial
Dressing,
1992
20 Yes 1 NA NA NA Healthy
volunteers
used
combination
product; not
randomized.
Sleep quality Case series Orth-Wagner,
1995
225 Yes 1 NA NA NA Combination
product
used.
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Agitation in Dementia
Summary: Limited data are available supporting the use of lemon
balm as a treatment of agitation in dementia patients. Additional
study is necessary before a conclusion can be drawn. See Table 3.
Evidence: Ballard et al. conducted a randomized, placebo con-
trolled, double-blind trial to determine the value of aromatherapy
with essential oil of lemon balm for agitation in 72 patients with
severe dementia.39 Patients with clinically significant agitation in
the context of severe dementia were included in the study. Lotion
enriched with either lemon balm essential oil or placebo oil was
applied to patients’ faces and arms twice per day. Measurements of
effectiveness included agitation [Cohen-Mansfield Agitation In-
ventory (CMAI)] and quality of life indices (percentage of time
spent socially withdrawn and percentage of time engaged in con-
structive activities, measured with Dementia Care Mapping). Sixty
percent of the active treatment group and 14% of the placebo-
treated group reported a 30% reduction of CMAI score, with an
overall improvement in agitation (mean reduction in CMAI score)
of 35% in patients receiving lemon balm essential oil and 11% in
those treated with placebo. Quality of life indices were also re-
ported to improve significantly more in patients receiving the ac-
tive treatment. No significant side effects were reported. Although
the results of this trial are promising, this trial is limited due to a
small sample size.
Anxiety
Summary: Preliminary human evidence has been published that
supports the use of lemon balm for anxiety, commonly referred to
in the literature as psycho-vegetative disturbances. Further re-
search is needed to confirm these results. See Table 3.
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TABLE 4. Explanation of Columns in Natural Standard Evidence Table
12345 6 78910
Condition Study
Design
Author,
Year
N Statistically
Signifi-
cant?
Quality of
study
0-2 = poor
3-4 = good
5 = excellent
Magnitude
of Benefit
Absolute
Risk
Reduction
Number
Needed to
Treat
Comments
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Evidence: Büchner et al. conducted a randomized, placebo con-
trolled, double-blind trial to examine the efficacy of lemon balm in
102 patients with anxiety and somatic complaints.37 Subjects were
assigned to take either placebo or Klosterfrau Melissengeist®at a
dose of 0.23 mL/kg body weight three times per day for eight
weeks. Outcome measures included psychological tests, which
were taken before and during the eight-week trial. Results reported
a significant improvement of the clinical state, including improve-
ments in symptoms of “vegetative disturbances,” including “inner
restlessness,” blushing, palpitation, and headache (p < 0.05). The
PF 16 Cattell test demonstrated a significant difference for dimen-
sion C = Ego Strength vs. Ego Weakness (p < 0.05). Significant
differences between the experimental and the control groups were
also reported in the FPI test for the dimensions of nervousness (p <
0.01) and excitability (p < 0.02). The FPI dimension of emotional
lability also demonstrated significant differences between the two
groups (p < 0.05). Pronounced effects were reported in female sub-
jects (p < 0.01). Eight patients in the treatment group reported side
effects including slight nausea, diarrhea, headache, and palpita-
tions, and five patients in the placebo group reported nausea, diar-
rhea, and headache. The major limitation of this trial is that it
assessed the efficacy of a combination product. Further random-
ized, controlled trials assessing lemon balm monotherapy are war-
ranted.
In a multicenter, four-week study involving 92 patients, the herbal
compound Seda-Plantinag was tested as an alternative to prescrip-
tion sedatives.104 According to the study results, Seda-Plantinag did
not lead to any signs of fatigue during the day. Patients reported a
clear decrease in the degree of their states of agitation or excite-
ment, as well as improvements with regard to their power of con-
centration and social efficiency. The authors suggested that a
combination of single herbal agents with sedative, psychotropic
effects proved to be well tolerated and may serve as an alternative
for synthetic tranquillizers, even if prescribed regularly in the
practice.
In a large case series, 1599 patients with symptoms of anxiety
were treated with Euvegal coated tablets (a combination product
with Valeriana officinalis and lemon balm).105 Patients reporting
nervousness, fatigue, and sleep disturbances were included in the
study. Patients were given one to two tablets of Euvegal twice per
day over a four-week period. After week two and week four, sever-
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ity of symptoms and possible adverse effects were documented. A
total of 1395 patients completed the observation. In two-thirds an
almost complete regression of symptoms was observed. Over 90%
of patients reported an improvement. Mild adverse effects were re-
ported in 32 cases. Limitations of this study are that it assessed the
efficacy of a combination product and that it was not a random-
ized, controlled trial.
Cognitive Performance
Summary: Clinical data suggest that the use of standardized lemon
balm extract has some effect on particular self-reported measures
of mood and cognition through cholinergic activities.4,5,14 More
rigorous studies need to be conducted using patient-relevant out-
comes to better assess the validity of these results as they apply to
patient care. See Table 3.
Evidence: Akhondzadeh et al. conducted a randomized, controlled
trial to assess the efficacy and safety of lemon balm extract in 42
patients with Alzheimer’s disease.62 The study included patients
with mild to moderate Alzheimer’s disease. Patients were given a
fixed dose of 60 drops/day of lemon balm extract. The primary
outcome measures were changes in the cognitive subscale of an
Alzheimer’s disease assessment scale and on the clinical dementia
rating. At four months, the results demonstrated that lemon balm
extract produced a significantly better outcome on cognitive func-
tion than placebo. No significant differences in the two groups in
terms of observed side effects were reported, except agitation,
which was more common in the placebo group. The authors sug-
gested that from these results lemon balm may be beneficial in the
treatment of patients with mild to moderate Alzheimer’s disease.
Further research is needed to confirm these results.
In a randomized, placebo controlled, double-blind trial, Herberg et
al. investigated the everyday safety of a Valeriana officinalis-
Humulus lupulus-lemon balm combination in 48 adults aged 30 to
60 years old. Subjects received two tablets (95 mg Valeriana officinalis,
15 mg Humulus lupulus, and 85 mg lemon balm per tablet) or pla-
cebo three times per day for two weeks. Cognitive performance
was assessed using a computerized test battery. The combination
with alcohol (mean 0.5%) was also investigated. No inhibition of
cognitive performance was reported. According to the authors,
statistically significant differences vs. placebo concerned improve-
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ment of general well-being and cognitive skills only. No signifi-
cant side effects were reported. The authors reported that the
Valeriana officinalis-Humulus lupulus-lemon balm combination
did not affect the effect of alcohol consumption.
Kennedy et al. conducted a randomized, placebo controlled, dou-
ble-blind, crossover trial to examine effects of three doses of
lemon balm on cognition and mood in 20 participants.35 Partici-
pants received either 300 mg, 600 mg, or 900 mg of a standardized
extract of lemon balm or placebo, on different days, each separated
by a seven-day washout period. Outcome measures included the
cognitive performance as assessed by Cognitive Drug Research
(CDR) computerized test battery and subjective mood rating as as-
sessed by Bond-Lader visual analogue scales. The results demon-
strated a sustained increase in “accuracy of attention” after
ingesting 600 mg and reductions in “secondary memory” and
“working memory” that were time- and dose-dependent. Patients
reported reductions in “alertness” after the administration of 900
mg and reported that “calmness” was elevated after the adminis-
tration of 300 mg. A limitation of this study is the small sample of
young, healthy subjects not representative of the population of pa-
tients with dementia who may benefit from lemon balm.
Kennedy et al. conducted a randomized, placebo controlled, dou-
ble-blind, crossover study which investigated the acute effects on
cognition and mood of a standardized extract of lemon balm in 20
healthy adults.2Participants received single doses of 600 mg, 1000
mg, and 1600 mg of lemon balm (Pharmaton) or a matching pla-
cebo at seven-day intervals. Cognitive performance was assessed
using the Cognitive Drug Research (CDR) computerized test bat-
tery and two serial subtraction tasks. A sustained improvement in
“accuracy of attention” following 600 mg of lemon balm and time-
and dose-specific reductions in both “secondary memory” and
“working memory” factors were demonstrated in the treatment
group. Self-rated “calmness,” as assessed by Bond-Lader mood
scales, was reported to be elevated at the earliest time points by the
lowest dose, and “alertness” was reported to be significantly re-
duced at all time points after the highest dose. A limitation of this
study is the small sample of young, healthy subjects not represen-
tative of the population of patients with dementia who may benefit
from lemon balm.
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Colitis
Summary: Limited clinical evidence is available supporting the
use of lemon balm for the treatment of chronic colitis. See Table 3.
Evidence: In a case series, 24 patients with chronic non-specific
colitis were treated with a combination of Taraxacum officinale,
Hypericum perforatum, lemon balm, Calendula officinalis, and
Foeniculum vulgare.106 Primary outcome measures included de-
crease in symptoms. Results demonstrated the disappearance of
spontaneous and palpable pains along the large intestine in 95.83%
of the patients by day 15 of treatment, and daily bowel movements
in the patients with obstipation syndrome. Although these results
are promising, lack of randomized, controlled trials with an ade-
quate sample population prevents meaningful extrapolation of
these results to clinical practice.
Dyspepsia
Summary: Clinical evidence of varying quality suggests that lemon
balm may help reduce dyspepsia as a component of combination
products. However, further research is necessary before a conclu-
sion can be drawn.
Evidence: Madisch et al. conducted a multicenter, placebo con-
trolled, double-blind trial using the commercially available, herbal
combination preparation Iberogast®, which contains lemon balm,
with and without the ingredient bitter candy tuft in 60 patients with
functional dyspepsia.63 Patients discontinued all medications for
seven days and then received either of the Iberogast®preparations
or a placebo for four weeks. Gastrointestinal symptom (GIS) score
and total scores consisting of ten dyspeptic symptoms rated on a
Likert scale measured at baseline, at week two, and at week four
were reported as statistically significant compared to baseline at p <
0.001. Although the results from this study are promising, it is lim-
ited due to the fact that the preparation studied was a combination
product and the contribution of the lemon balm component to the
effects is not discernable without direct comparisons of each indi-
vidual component.
Madisch et al. conducted a multicenter, randomized, placebo con-
trolled, double-blind trial to assess the efficacy and safety of an
herbal combination product STW 5-II, which contains extracts
from bitter candy tuft, matricaria flower, peppermint leaves, cara-
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way, licorice root, and lemon balm, for the treatment of patients
with functional dyspepsia.107 One hundred twenty patients with
functional dyspepsia were randomly assigned to one of four treat-
ment groups. The primary outcome measure was the improvement
of a standardized gastrointestinal symptom (GIS) score. During
the first four weeks, the GIS score was reported to significantly de-
crease in subjects on active treatment compared to those on pla-
cebo. After eight weeks 43.3% on active treatment and 3.3% on
placebo reported complete relief of symptoms. Although the re-
sults from this study are promising, it is limited due to the fact that
the preparation studied was a combination product, and the contri-
bution of the lemon balm component to the effects is not discern-
able without direct comparisons of each individual component.
In a multicenter, open case series, the efficacy of Gastrol S (a com-
bination product containing lemon balm) in the treatment of ner-
vous irritable stomach and dyspepsia was tested in 152 patients.108
A majority (58.5%) of the patients participated in the study for
more than eight weeks. In 65.5% a dosage of 20-25 drops three
times per day was recommended. Tolerance was reported as “good”
by 93.4% of the patients, and the therapy was assessed as “very
good” by 75.5%. In 82.2% of all documented cases, a distinct im-
provement of symptoms was reported. This study is limited due to
the fact that the preparation studied was a combination product and
the contribution of the lemon balm component to the effects is not
discernable without direct comparisons of each individual compo-
nent.
Sleep Quality
Summary: High-quality clinical evidence supporting the use of
lemon balm as a sedative/hypnotic is lacking.70 The available evi-
dence is conflicting, of low quality, or derived from early-phase
trials in humans. A systematic review published in 1998 concluded
that the paucity of evidence made the sedative effect of lemon
balm difficult to assess given that studies usually employed com-
bination products, most often with Valeriana officinalis, which it-
self possesses sedative properties.27 Rigorous clinical studies are
required to better support use of lemon balm as a sedative/hyp-
notic. See Table 3.
Evidence: Cerny et al. conducted a multicenter, randomized, pla-
cebo controlled, double-blind study to assess tolerance and effi-
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cacy of a Valeriana officinalis/lemon balm combination product in
the treatment of minor sleep disorders in 98 healthy volunteers.34
Subjects were randomly assigned to receive placebo or three tab-
lets of a combination product (120 mg Valeriana officinalis, 80 mg
lemon balm) one half-hour before bedtime for 30 days. Outcome
measures included rating scales for tolerability, sleep quality, and
well-being, as well as laboratory and physical parameters. Results
reported a rating of good overall tolerability by 93% of subjects in
the Valeriana officinalis/lemon balm group vs. 91% of subjects in
the placebo group. Incidence of mild adverse effects reported was
28.8% in the Valeriana officinalis/lemon balm group vs. 28.1% in
the placebo group. Among those taking Valeriana officinalis/
lemon balm, 33.3% of patients reported an improvement in sleep
quality vs. 9.4% in the placebo group (p = 0.04). No significant
changes were reported in regard to laboratory tests, physical exam-
ination, or rating of well-being, even though the Valeriana officinalis/
lemon balm group reported a higher quality of sleep compared to
the placebo group. From these results, the authors reported safety
of the Valeriana officinalis/lemon balm combination product and
possible efficacy in improving sleep quality. Though results may
appear to be promising, it is important to note that results reflect
efficacy and safety of a combination product. Further randomized,
controlled trials assessing monotherapy of lemon balm in improv-
ing sleep quality are warranted.
A multi-center, placebo controlled, double-blind trial studied the
therapeutic effect of a high dose standardized Valeriana officinalis-
lemon balm combination (Euvegal forte) on mild insomnia in 68
patients.109 Patients with mild insomnia as defined by the DSM-
3-R and the ICD10 were included in the study. Outcome measures
included quality of sleep, general health, and overall clinical im-
pression. Patients received two tablets twice per day of Euvegal
and were examined after two weeks of treatment. All criteria were
reported as significantly improved vs. placebo. No hangover or re-
bound phenomena were reported.
Lindahl et al. conducted a randomized, double-blind, crossover
trial with 27 subjects with sleep difficulties to assess the effects of
a combination product containing Valeriana officinalis,Flores
humuli, and lemon balm on sleep quality.110 Subjects received the
combination product (400 mg of Valeriana officinalis, 375 mg of
Flores humuli, and 160 mg of lemon balm) or placebo for the first
night and then received the opposite treatment the following night.
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Outcome measures including sleep quality were recorded on a pa-
tient questionnaire that was completed on the second morning.
From the results, the authors reported that 21 out of 27 patients
rated the combination product better than placebo. The difference
between ratings of the two preparations was reported as statisti-
cally significant (p < 0.001). In terms of sleep quality, 24 out of 27
subjects reported an improvement, and 12 reported “perfect” sleep.
No side effects were noted. Short study duration limits the clinical
utility of these results. Long-term trials may be more helpful in
evaluating efficacy of a product in sleep disturbances. Longer,
well-designed, randomized, controlled trials assessing the mono-
therapy of lemon balm are warranted.
In a randomized, placebo controlled trial, the sedative effects of
aValeriana officinalis-Humulus lupulus-lemon balm-Leonurus
cardiaca combination product were examined in 50 male alcohol
abusers with sleep disturbances and other withdrawal symptoms.111
From their evaluation of the results, the authors reported signifi-
cant improvement in sleep quality and significant decrease in sleep
interruption and bad dreams. Morning sleepiness was observed as
a side effect.
Dressing et al. conducted a controlled, double-blind study to as-
sess effects of a Valeriana officinalis/lemon balm preparation on
sleep in 20 healthy volunteers.36 Subjects were divided into
good and poor sleepers. Subjects received either a Valeriana
officinalis/lemon balm preparation (Euvegal Forte®: 160 mg Valeriana
officinalis, 80 mg lemon balm), triazolam (125 mg), or placebo at
bedtime. Outcome measures included sleep efficiency, length,
time in sleep stages, and delta sleep. From the results, the authors
suggested that the use of the Valeriana officinalis/lemon balm
combination product on the poor sleepers induced a significant in-
crease in sleep efficiency and in sleep stages three and four. A sig-
nificant increase in delta sleep in the group of poor sleepers was
also reported. Rebound effects were not reported for groups taking
the Valeriana officinalis/lemon balm preparation or the triazolam.
Limitations to this study include lack of randomization and the use
of a combination product.
In an open, multicenter study of sleep quality, the efficacy and toler-
ance of Novo-Baldriparan, containing Valeriana officinalis,Humulus
lupulus, and lemon balm, was investigated in 225 patients.112 The
study included patients that reported difficulties falling asleep and
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sleeping through the night and/or states of nervous agitation. The
two-week therapy with this product was reported to yield a signifi-
cant improvement in the severity and frequency of the principal
symptoms. According to the reported results, both the nervous agi-
tation, which was identified as the underlying cause of the sleep
disorders, as well as the sleep disorders themselves were signifi-
cantly reduced. Specifically, the authors reported that the difficul-
ties falling asleep improved in 89% of the patients, the difficulties
sleeping through the night improved in 80%, and the states of ner-
vous agitation improved in 82% of the patients. The quantity of
sleep was reported to increase markedly, while external stressors
were reported as being less distressing. A similar improvement in
the somatic symptoms, like headache, dizziness, cardiovascular,
or gastrointestinal discomfort, was reported. The reduction in
heart rate and blood pressure under therapy was reported to be ac-
companied as a whole by a noticeable improvement in the pa-
tients’ well being. The tolerability of Novo-Baldriparan was rated
positively by both physicians and patients: 96.9% of the physi-
cians and 96.4% of the patients gave the rating “very good” or
“good.” The primary limitation of this study includes the use of a
combination product.
PRODUCTS STUDIED
Brands Used in Clinical Trials
Euvegal Forte®(Spitzner, Germany)36,105,109
Iberogast®(Phyto Pharmica, Germany)63
Klosterfrau Melissengeist®(Klosterfrau, Germany)37
Songha Night®(Pharmaton Natural Health Products, Bioggio/
Lugano, Switzerland)34
Lomaherpan®cream23,24,103
STW 5-II107
STW-5-S63
Baldriparan Stark N Beruhigungs-Dragees68
Seda-Plantina104
Gastrol S108
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United States Patents
6,881,776 Gel compositions
6,831,103 Composition comprising theanine
6,827,944 Percutaneous administration preparations
6,797,284 Phytopharmaceutical food products or integrators
6,780,825 Cleansing compositions with milk protein and aroma-
therapy
6,703,022 Composition and method useful for treating colic
6,664,225 Single-dose quick-dissolving cleansing agent with me-
dicinal properties
6,641,801 Gargle method to reduce the duration of common cold
symptoms
6,629,835 Combinations of diterpene triepoxide lactones and ditepene
lactones or triterpenes for synergistic inhibition of cyclooxygenase-2
6,589,566 Composition comprising theanine
6,509,042 Antiviral composition
6,444,253 Flavor delivery system
6,423,336 Chewing gums and method of manufacturing the same
6,416,769 Cosmetic compositions comprising exfoliating enzymes
and uses thereof
6,405,948 Liberating intracellular matter from biological material
6,346,250 Composition and method useful for treating colic
6,342,208 Oil-in-water emulsion containing C10-C24 fatty acid
derivatives for treating skin of mammals
6,210,738 Freeze-dried ginseng berry tea
6,165,964 Aqueous solution of essential oil, and antimicrobial
agents, microbicides and antimicrobial finishes for washing
6,060,061 Method for preventing or treating disorders involving
an inflammatory process
6,024,998 Process for the removal of undesired lipophilic contam-
inations and/or residues, which are contained in beverages or in
vegetable preparations
5,958,499 Fluidized fat
5,906,848 Process for the removal of undesired contaminations
and/or residues contained in beverages or in vegetable preparation
5,869,340 Plant clones containing elevated secondary metabolite
levels
5,720,962 Analgesic lotion for hemorrhoids and method of mak-
ing such lotion
Natural Standard Review 105
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5,472,699 Composition and method for visibly reducing the size
of skin pores
5,415,861 Composition and method for visibly reducing the size
of skin pores
5,399,353 Preparations for covering undamaged and/or damaged
areas of human or animal skin
5,318,503 Method and apparatus for auditory and olfactory relax-
ation
5,176,913 Process for preparing a partial extract containing the
volatile in steam components and further lipophilic components of
medical plants and/or spice plants
5,064,675 Herbal extract composition
4,933,177 Cosmetic compositions for the treatment of the hair
and skin contain in the form of powder particles resulting from
the pulverization of at least one plant substance and a cohesion
agent
4,767,618 Cosmetic compositions for the treatment of the hair and
skin in the form of powder particles resulting from the pulveriza-
tion of at least one plant substance and a cohesion agent
4,569,839 Cosmetic compositions for the treatment of the hair and
skin in the form of powder particles resulting from the pulveriza-
tion of at least one plant substance and a cohesion agent
4,358,442 Rosmarinic acid-phospholipide-complex
4,354,035 Process for isolating rosmarinic acid from plants
4,329,361 Use of rosmarinic acid in the treatment of inflamma-
tions and pharmaceutical products used therein
AUTHOR/UPDATE INFORMATION
Last Updated: August 2005.
Authors/Editors: Thomas Brendler, BA (PlantaPhile, Berlin);
Joerg Gruenwald, PhD (Phytopharm Consulting); Benjamin
Kligler, MD, MPH (Continuum Center for Health and Heal-
ing); David Keifer, MD (University of Arizona); Tracee Rae
Abrams, PharmD (University of Rhode Island); Jen Woods,
BS (Northeastern University); Heather Boon, BScPhm, PhD
(University of Toronto); Catherine DeFranco Kirkwood, MPH,
CCCJS-MAC (MD Anderson Cancer Center); Ethan Basch,
MD (Memorial Sloan-Kettering Cancer Center); Hope J. Lafferty,
106 JOURNAL OF HERBAL PHARMACOTHERAPY
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AM (Memorial Sloan-Kettering Cancer Center); Catherine
Ulbricht, PharmD (Massachusetts General Hospital), Dana A.
Hackman, BS (c) (Northeastern University).
Blinded Peer-Review: Natural Standard Editorial Board.
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... Moreover, the cropping system (conventional vs. organic farming) may also affect the composition of essential oils [15], although there are studies in which the major compound content remained unaffected [19,30]. Finally, although lemon balm oil is generally regarded as safe (included in the GRAS list) [31], according to Stojanović et al. [32] the essential oil of the lemon balm, as well as the individual major compounds (citronella, geranial and neral) may exhibit moderate oral toxicity. ...
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The ongoing climate crisis necessitates the sustainable use of natural resources and the adoption of environmentally friendly agronomic practices. Deficit irrigation is an ecofriendly technique that allows for the improvement in the water use efficiency of crops. On the other hand, medicinal and aromatic crops, which usually have an innate tolerance to harsh conditions, are suitable candidates for cultivation under low-input cropping systems. In the present study, Melissa officinalis plants were cultivated under conventional and organic cropping systems, while in each system two irrigation regimes (full irrigation or deficit irrigation) were tested. The aerial parts of the plants were evaluated in terms of growth and physiological parameters, chemical composition, antioxidant activity, essential oil yield and essential oil composition. Our results indicate that prolonged water stress after two deficit irrigation cycles had detrimental effects on the plant growth and biomass production, whereas it significantly increased the essential oil yield, regardless of the cropping system (organic or conventional cultivation). The recorded physiological parameters are in agreement with morphological features, especially the stomatal conductance, which was significantly reduced under deficit irrigation for both cultivation systems, revealing that the growth inhibition was the result of stomatal closure and carbon dioxide deprivation. Deficit irrigation and organic cultivation also increased total phenol and total flavonoid content, especially in the second harvest, thus resulting in higher antioxidant activity assayed by the FRAP method. In contrast, DPPH and ABTS methods did not show any differences among the tested treatments in the second harvest, which suggests that other bioactive compounds are also involved in the overall antioxidant mechanism of lemon balm plants, as indicated by the increased ascorbic acid content. Regarding the essential oil composition, the major detected compounds were geranial and neral and, although they were both increased under the organic cropping in the first harvest, the same trend was not observed in the second harvest. Finally, a variable effect of cropping system and irrigation regime on minerals content was recorded. In conclusion, deficit irrigation is an ecofriendly practice that could be applied in conventional and organic cropping systems of lemon balm crops, aiming to reduce irrigation water consumption and compensate for reduced herb yields with increased essential oil yield and polyphenol content.
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The development of drugs from medicinal herbs may be good to find novel therapeutic agents in the treatment of anxiety. Melissa officinalis L. (lemon balm) belongs to the Lamiaceae family and grows widely in the Mediterranean region, western Asia, southwestern Siberia, and northern Africa. Melissa officinalis L. has been used in traditional medicine to treat headaches, indigestion, colic, nervousness, cardiac failure and depression. In addition, it has been reported in several researches that lemon balm had many beneficial effects such as anti-inflammatory and ant nociceptive, Antioxidant. leaves contain several classes of constituents including polyphenolic compounds (rosmarinic acid, caffeic acid and protocatechuic acid), essential oils (geranial, neral, citronellal, geraniol, beta-pinene, alpha-pinene, beta-caryophyllene, germacrene D, and ocimene), monotherpenoid aldehydes, sesquiterpenes, flavonoids (luteolin) and tannins. The aims of this study were to evaluate the phytochemical screening of ethanolic extract of Melissa officinalis L. One study examined a chemically-validated essential oil derived from Melissa and found that Melissa inhibited binding of GABAA to receptor channel in the rat forebrain, but had no effect on or nicotinic acetylcholine receptors (Abuhamdah et al., 2008). They also found that Melissa elicited a significant dose-dependent reduction in both inhibitory and excitatory transmission.. The aromatic balm leaves are often used in beverages and as a seasoning in salads, dressings and sauces, as well as in cooked foods, e.g., in soups and stews. Some vernacular names are balm, common balm, blue balm, dropsy plant, honey plant, Herzkraut, citronelle, cytria, cedronella.
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Medicinal plants are being used worldwide for centuries for their beneficial properties. Some of the most popular medicinal plants belong to the Melissa genus, and different health beneficial effects have already been identified for this genus. Among these species, in particular, the Melissa officinalis L. has been reported as having many biological activities, such as antioxidant, antimicrobial, antitumour, antiviral, antiallergic, anti-inflammatory, and also flatulence inhibiting effects. The beneficial properties of the Melissa officinalis, also known as “lemon balm herb”, can be related to the bioactive compounds such as terpenoids, alcohols, rosmarinic acid, and phenolic antioxidants which are present in the plant. In this updated review, the botanical, geographical, nutritional, phytochemical, and traditional medical aspects of M. officinalis have been considered as well as in vitro and in vivo and clinically proven therapeutic properties have been reviewed with a special focus on health-promoting effects and possible perspective nutraceutical applications. To evidence the relevance of this plant in the research and completely assess the context, a literature quantitative research analysis has been performed indicating the great interest towards this plant for its beneficial properties.
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Ethnopharmacological relevance Besides psyche-related symptoms, patients with anxiety disorders can have a large number of somatic symptoms as well. Although the treatment of these disorders is mainly focused on resolving their mental component, one cannot neglect the need for the treatment of accompanying somatic symptoms. Melissa officinalis L. (lemon balm), in various formulations, has been extensively used as an ethnomedicinal remedy for the treatment of different psyche-related symptoms, and its use is considered relatively safe. Aim of the study: In the present study, the activity of M. officinalis (MO) essential oil was evaluated in several in vitro and in vivo models mimicking or involving anxiety-related somatic symptoms. Materials and methods To address the effect of MO essential oil on the gastrointestinal and heart-related symptoms accompanying anxiety disorders, in vitro models were utilized that follow the function of the isolated mouse ileum and atria tissues, respectively, after exposure to MO essential oil. Effects of MO essential oil on BALB/c mice motor activity was estimated using the open field, rota-rod, and horizontal wire tests. Additionally, the essential oil was assayed for its potential in inhibiting acetylcholinesterase activity. Results The performance of mice treated with 25 mg/kg of the oil showed a statistically significant decrease in the motor impairment arising from acute anxiety (open field test), while there was a prolonged latency and a reduction of the frequency of falling from a rotating rod and/or a horizontal wire (signs of muscle weakness/spasms). Concentrations of the essential oil higher than 1 μg/mL were found to inhibit both spontaneous and induced ileum contractions. Moreover, the essential oil and citronellal were found to decrease isolated mouse atria contraction frequency, as well as contraction force. However, the oil was found to be a very weak acetylcholinesterase inhibitor. Conclusion The modulation of anxiety-related symptoms by the oil was found not to be mediated through the inhibition of the acetylcholinesterase, nonetheless, the mechanistic studies involving the ileum and cardiac tissues, revealed that the activity of MO and citronellal might be related to the modification of either voltage-gated Ca²⁺ channels or muscarinic receptors. Mice locomotion, balance, and muscle strength were not impacted by the essential oil; however, its main constituent, citronellal, was found to exert a certain degree of muscle function inhibition. All these results suggest that the activity of MO essential oil arises from synergistic and/or antagonistic interactions of its constituents, and is not completely dependent on the oil's main constituent.
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A systematic review and a meta-analytic approach were considered to investigate the effects of lemon balm as a medicinal herb on anxiety and depression in clinical trials and its side effects. All randomized clinical trials published up to October 30, 2020 that examined lemon balm in patients with symptoms of depression or anxiety , with acute or chronic manifestations, were searched in 12 online databases. Statistical analysis was performed using RevMan software. Continuous data were analyzed using standardized mean differences. Statistical heterogeneity was assessed using Chi 2 , I 2 , and p value tests. Based on meta-analysis results, lemon balm significantly improved mean anxiety and depression scores compared with the placebo (SMD:-0.98; 95% CI: À1.63 to À0.33; p = 0.003), (SMD:-0.47; 95% CI: À0.73 to À0.21; p = 0.0005) respectively, without serious side effects. Current evidence suggests that lemon balm may be effective in improving anxiety and depressive symptoms , particularly in the acute setting. Due to the high level of heterogeneity between studies, results should be interpreted with caution. The small number of clinical trials and differences between their methods were the limitations of the present study. Further high-quality studies are needed to firmly establish the clinical efficacy of the lemon balm. K E Y W O R D S anxiety, depression, lemon balm, Melissa officinalis, systematic review
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This review aimed to provide a summary on the traditional uses, phytochemistry, and pharmacological activities in the cardiovascular system and cardiotoxicity of Melissa officinalis (MO), with the special emphasis on the protective mechanisms in different cardiovascular pathologies. MO is a perennial aromatic herb commonly known as lemon balm, honey balm, or bee balm, which belongs to Lamiaceae family. Active components are mainly located in the leaves or essential oil and include volatile compounds, terpenoid (monoterpenes, sesquiterpenes, triterpenes), and polyphenolic compounds [rosmarinic acid (RA), caffeic acid, protocatechuic acid, quercitrin, rhamnocitrin, luteolin]. For centuries, MO has been traditionally used as a remedy for memory, cognition, anxiety, depression, and heart palpitations. Up until now, several beneficial cardiovascular effects of MO, in the form of extracts (aqueous, alcoholic, and hydroalcoholic), essential oil, and isolated compounds, have been confirmed in preclinical animal studies, such as antiarrhythmogenic, negative chronotropic and dromotropic, hypotensive, vasorelaxant, and infarct size–reducing effects. Nonetheless, MO effects on heart palpitations are the only ones confirmed in human subjects. The main mechanisms proposed for the cardiovascular effects of this plant are antioxidant free radical–scavenging properties of MO polyphenols, amelioration of oxidative stress, anti-inflammatory effects, activation of M2 and antagonism of β1 receptors in the heart, blockage of voltage-dependent Ca2+ channels, stimulation of endothelial nitric oxide synthesis, prevention of fibrotic changes, etc. Additionally, the main active ingredient of MO-RA, per se, has shown substantial cardiovascular effects. Because of the vastness of encouraging data from animal studies, this plant, as well as the main ingredient RA, should be considered and investigated further as a tool for cardioprotection and adjuvant therapy in patients suffering from cardiovascular diseases.
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Background: Menopause is a critical period with frequent sexual disorders. Objectives: The current study assessed the therapeutic effect of a combination of the aerial part of Melissa officinalis, fennel fruit extract, and Nigella sativa seed powder on the sexual dysfunction of postmenopausal women. Methods: This randomized clinical trial was performed on 48 menopausal women from April 2015 to October 2017. The participants included the menopausal women referring to the clinic of Gorgan health centers aged between 41 and 54 years with natural menopause (amenorrhea for at least 12 months) and discomfort in sexual activity. They were randomized into two treatment groups. Group 1 (n = 27) received 1000 mg capsules (Melissa officinalis, fennel extract, and Nigella sativa powder), and group 2 (n = 21) received a placebo (1000 mg starch capsules (in an eight-week course of treatment (one capsule per day for each group). The variables in the female sexual function index (FSFI) questionnaire were compared in the two groups before and after the intervention. Results: The results showed that the mean scores of sexual dysfunction in the domains of arousal, lubrication, orgasm, satisfaction, and pain were not significantly different between the two groups (P > 0.05). Conclusions: Despite many studies on the effectiveness of Melissa, Foenculum, and Nigella, this study showed that a combination of Foeniculum vulgare, Melissa officinalis extract, and Nigella sativa seed powder does not improve the sexual function of postmenopausal women with sexual dysfunction, and it might be the synergism effect of this combination.
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New findings: What is the central question of this study? Prolonged stress exposure induces detrimental changes in the brain structure, and increases the vulnerability to develop psychiatric disorders. The central question of this study is how Melissa officinalis L. ameliorates anxiety- and depressive-like behavior of mice. What is the main finding and its importance? Melissa officinalis L. possessed anxiolytic and anti-depressant effects, which could mainly mediate through its antioxidant and anti-apoptotic properties. Abstract: Objective This study evaluated the effects of hydro-alcoholic extract of Melissa officinalis (HAEMO) on anxiety- and depressive-like behaviors, oxidative stress, and apoptosis markers in the restraint-stress exposed mice. Methods In order to induce depression-like model, mice were subjected to restraint-stress (3 h day-1 for 14 days) and received normal saline or HAEMO (50, 75, and 150 mg kg-1 day-1 ) for 14 days. The administered doses of HAEMO were designated based on one the main phenolic compounds present in the extract, rosmarinic acid (RA), concentration (2.55 mg kg-1 at lowest dose), other phytochemical analysis including assays for antioxidant activity, total phenols, and flavonoids contents were also carried out. The behavioral changes in the open field task, elevated plus maze, tail suspension, and forced swimming tests were evaluated. Also, malondialdehyde (MDA) levels and enzyme activities of superoxide dismutase (SOD) and glutathione peroxidase (GPx), and total antioxidant capacity were assessed in the prefrontal cortex (PFC) and hippocampus (HIP). Moreover, levels of Bcl-2, Bax, and caspase 3, in the brain as well as serum concentration of corticosterone (CORT), were evaluated. Results HAEMO (75 and 150 mg kg-1 ) significantly reversed anxiety- and depressive-like behaviors. Also, the HAEMO reduced MDA levels, enhanced enzymatic antioxidant activities, and restored serum levels of CORT. The immunoblotting analysis also demonstrated that HAEMO decreased levels of pro-apoptotic markers and increased anti-apoptotic protein levels in the PFC and HIP of restraint-stress exposed mice. Conclusion Our findings suggested that HAEMO reduced inflammation and had anxiolytic and antidepressant effects in mice. This article is protected by copyright. All rights reserved.
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The anti-HIV-1 activity of aromatic herbs in Labiatae was evaluated in vitro. Forty five extract from among 51 samples obtained from 46 herb species showed significant inhibitory effects against HIV-1 induced cytopathogenicity in MT-4 cells. In particular, the aqueous extracts of Melissa officinalis, a family of Mentha x piperita "grapefruit mint," Mentha x piperita var. crispa, Ocinum basilicum cv "cinnamon," Perilla frutescens var. crispa. f. viridis, Prunella vulgaris subsp. asiatica and Satureja montana showed potent anti-HIV-1 activity (with an ED of 16 mu g/ml). The active components in the extract samples were found to be water-soluble polar substances, not nonpolar compounds such as essential oils. In addition, these aqueous extracts inhibited giant cell formation in co-culture of Molt-4 cells with and without HIV-1 infection and showed inhibitory activity against HIV-1 reverse transcriptase.
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Enantioselective capillary gas chromatography, as well as isotope ratio mass spectrometry (IRMS), online coupled with capillary gas chromatography are used in the origin specific analysis and authenticity control of balm oil compounds. Scope and limitations of the methods are discussed.
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Leaf verticils of a single plant of Melissa officinalis L., Lamiaceae, have been analyzed separately with regard to essential oil composition and content. Drastic changes in quantitative composition were observed between the leaf oil of the basal region and that from the top leaves. Particularly this holds true for the monoterpene aldehydes citronellal and citral, the monoterpene esters methylcitronellate and geranylacetate and the amount of sesquiterpenes. By analyzing individually mapped glands from leaf tips of a defined age it could be demonstrated that the oil composition of corresponding glands changes dramatically e.g. from 0% to 71% citronellal within two months. Related to leaf weight and area, the essential oil yield was maximal in the small leaves of the terminal verticils. The highest absolute amount of essential oil, however, was found in the largest leaves from the middle region of the stem. The results are discussed with respect to the physiology of essential oil formation and turnover. Considering quality criteria for the leaf drug growing conditions and harvest time are suggested.
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Lemon Balm (Melissa officinalis L. subsp. officinalis) is the only of three known subspecies that is in pharmaceutical use today. Our knowledge about the two other subspecies (inodora and altissima) is scarce and not very detailed. This may be amazing since both have to be regarded as possible adulteration of the drug lemon balm. The subspecies altissima has a geographical distribution that widely overlaps with lemon balm. Thus we focused our studies on Melissa officinalis subsp. altissima in this communication. We cultivated strains of the subsp. altissima from different European regions. Following the specifications for lemon balm in the German Pharmacopoeia we investigated two characteristics. Firstly, we analysed types and density of trichomes found on subsp. altissima with regard to differentiation from authentic lemon balm. Secondly the essential oil was analysed with the same intention. In addition we proofed the essential oil accumulation for a glandular trichome that only occurs in subsp. altissima in this special size. The results are discussed with respect to the identification of subsp. altissima among the dried leaves of authentic lemon balm. We point out that some quality requirements for lemon balm may help to exclude such adulterations. We propose a high relative amount of citral and a high total amount of essential oil as suitable additional criteria.