Melissa officinalis: Review of Published Evidence in Humans by Rebecca R Word, ND
Abstract
Melissa officinalis (MO) is broadly distributed across the globe, and as a member of the mint family can grow in seemingly inhospitable conditions. In addition to a rich history as a revered medicinal plant, a large and growing body of human level evidence has emerged evaluating MO for a very broad range of applications. Human evidence has emerged for a role of MO in neurodegeneration, mental health, and cardiovascular health. There is also evidence supporting a role of MO for use in children, dysmenorrhea, and a selection of other indications with limited yet existing human level evidence. The herb is administered in a variety of forms (crude herb, tea, aqueous or ethanolic extracts) as well as in a variety of methods (topical, aromatherapy, oral ingestion). This review will assimilate existing human level evidence of MO in hopes of reacquainting healthcare providers with this important medicine.
Introduction
Melissa officinalis (MO), also known as lemon balm, bee balm, garden balm, Melissa, melissengeist (Rasmussen 2011), has been used for ages across many cultures and with a wide variety of applications. This plant was first seen in print in the famous first century work “De Materia Medica” by the Greek physician Dioscorides. MO is a pleasant, aromatic member of the mint family (Lamiaceae) that will literally take over anywhere it finds itself with soil and a bit of sun. Melissa reveals a wide variety of constituents: volatile aromatic compounds, triterpenoids, phenolic acids and flavonoids to name just a few considered to have therapeutic benefit. It is used as infusion, tincture, essential oil, freeze-dried, and as a cooking herb that enhances digestion (Valussi 2012). More recently isolated constituent compounds have received attention for a wide variety of clinical applications. Regarding the literature in humans, crude preparations and specific extractions from MO exhibit numerous pharmacological effects. Anxiolytic, antiviral, antispasmodic, and anti-arrhythmic activities as well as benefit on mood, cognition, and memory have been shown in clinical trials (Shakeri et al 2016). There is a plethora of studies on MO evaluating in vitro and animal models, yet the focus of this review will be to examine what the literature has to offer for us humans in detail.
Neurological/Cognitive/Mood
Monoterpenes and sesquiterpenes are proposed to provide the main neurological enhancement on memory and mood. Relevant effects including antioxidant activity, activation of the cholinergic system (including cholinesterase inhibition) leading to increased acetylcholine, up regulation of GABA, as well as inhibition of matrix metalloproteinase-2 are the main mechanisms proposed for the widely discussed neurological effects of this incredibly useful and accessible plant (Shakeri et al 2016, Wightman 2017). This is very promising, especially given the startling rise in degenerative neurological diagnoses in recent years and the lack of well-tolerated and effective pharmaceutical intervention. MO and other non-toxic botanicals have long historical use for cognitive longevity. MO extracts have most notably been shown to bind directly to both nicotinic and muscarinic receptors in human brain tissue and exhibit acetylcholinesterase inhibition supporting memory functions. “Given the side effect profile of prescribed cholinesterase inhibitors, and a current lack of a well-tolerated nicotinic receptor agonist, these herbal treatments may well provide effective and well-tolerated treatments for dementia, either alone, in combination, or as an adjunct to conventional treatments” (Kennedy and Scholey 2006). What do the studies reveal?
Twenty healthy, young participants received single doses of 300, 600 and 900mg of MO or a matching placebo at seven-day intervals with assessment at one, 2.5, four and six-hour intervals. Benefits were seen in memory and calmness scores at 600mg. “Alertness” was shown to be reduced at highest dosing (Kennedy et al 2002). Another trial led by the same author again tested 20 healthy, young participants with single doses of 600, 1000, and 1600mg of encapsulated dried leaf, or a matching placebo, at seven-day intervals. Cognitive performance and mood were assessed pre-dose and at one, three, and six-hours post-administration. Again, calmness and improved memory performance were observed, especially at the highest dose. Results “suggest that doses of MO at or above the maximum employed can improve cognitive performance and mood and may therefore be a valuable adjunct in the treatment of Alzheimer’s disease” (Kennedy et al 2003).
A small 2018 two-week pilot study (44 subjects) found that an oral ethanol extraction of Salvia officinalis, Salvia rosmarinus (formerly Rosmarinus officinalis) and MO is more effective than a placebo in supporting verbal episodic memory in healthysubjects under 63 years of age (Perry et al 2018). Another study in healthy young adults confirmed absorption of rosmarinic acid as a marker for acute lemon balm administration and found self-reported enhancement of mood and cognitive performance (Scholey et al 2014).
Another study showed that once daily usage for two weeks of MO essential oil as aromatherapy significantly reduced agitation in elders living in residential care who had not been diagnosed with dementia. Interestingly, Lavandula essential oil once daily for two weeks was more effective for those with agitation plus diagnosis of dementia. Placebo treatment of sunflower seed oil yielded no discernible benefit for agitation. Results were quantified using Neuropsychiatric Inventory (NPI) and Cohen-Mansfield Agitation Inventory (CMAI) (Watson et al 2019).
Disappointingly, the detailed methodology of this small trial (49 elders) was not well explained. Were the oils applied topically or inhaled? This is a harmless (and pleasant) intervention that could easily be applied widely in eldercare settings, however, it is worth noting that the price difference between Melissa and Lavandula essential oils is significant (Melissa is expensive when pure and appropriately extracted) (Watson et al 2019).
A 2018 RCT from Iran looked at a combination of Melissa and Boswellia serrata (BS) for memory support in 70 elder participants. Thirty-five subjects received tablets and 35 received placebo for one month. Using a demographic questionnaire and the Wechsler Memory Scale-Revised (WMS-R), the results showed auditory immediate, immediate memory, visual immediate and working memory were increased after consumption of the BS and MO tablets (Taghizadeh et al 2018).
The following 24-week double blind RCT of 23 participants diagnosed with mild dementia examined safety and tolerability of MO extract containing rosmarinic acid (500mg/d). The intervention was well tolerated. Cognitive effects were assessed via NPI-Q and improved 0.5 in the treatment group, while decreasing 0.7 in the placebo group, showing a small but significant result (Noguchi-Shinohara et al 2020). Another small study (n=11) also investigated safety of the same dosage of MO with rosmarinic acid and found that it did not affect liver, kidney, or blood cell function parameters. No adverse effects were reported (Noguchi-Shinohara 2015).
A separate four-month study of 42 Alzheimer’s patients found that MO extract was beneficial for management of mild to moderate Alzheimer’s disease and had a positive effect on agitation (Akhondzadeh et al 2003).
Another aromatherapy RCT looked at MO essential oil for 72 patients in the UK with clinically significant agitation in the context of severe dementia. In this study either the MO oil or sunflower oil was put into a base cream and massaged into the face and arms of participants twice daily. Both groups showed benefit via Cohen-Mansfield Agitation Inventory, 35% in the MO group vs 11% in the placebo group. Quality of life scores also improved in the treatment group (Ballard et al 2002). This study suggests two important areas for further investigation: First the clinical application of MO aromatherapy, and second, the benefit of physical touch in dementia patients.
As a follow up to that thought, another trial utilizing applied MO aromatherapy, placebo or donepezil in elders with diagnosed or probable Alzheimer’s disease found no evidence that MO aromatherapy is superior to placebo or donepezil for agitation. However, there was a large, positive placebo effect, suggesting that non-specific benefits of touch and interaction in the treatment of agitation may be occurring (Burns et al 2011).
Mood
A 2020 RCT compared the use of three agents in subjects meeting DSM-5 criteria for Major Depressive Disorder. Forty-five participants were divided into three groups receiving either: 2g/day of Lavandula angustifolia, 2g/day of MO, or 20mg/d fluoxetine for eight weeks. Hamilton Rating Scale for Depression was used as the main endpoint measure. The outcome showed that both Lavandula and Melissa were comparable to fluoxetine for mild to moderate depression (Araj-Khodaei et al 2020).
Eighty individuals diagnosed with stable angina were randomized to receive 3g/day of MO versus placebo for eight weeks. The MO group was judged to have improvements in anxiety, depression and insomnia associated with their diagnosis. Measurements were taken before and after the eight-week study using the shortened 21-item version of the depression, anxiety, and stress scale (DASS-21) and Pittsburgh Sleep Quality Index (PSQI) (Haybar et al 2018).
Twenty volunteers participated in a 15-day study using a patented MO extract called Cyracos, standardized to consist of more than 7% rosmarinic acid and greater than 15% hydroxycinnamic acid derivatives. The study showed 18% improvement in anxiety manifestation, 15% improvement in anxiety-associated symptoms, and 42% improvement in insomnia (Cases et al 2011).
A very cursory study investigating MO benefit in stress found 600mg versus 300mg or placebo effectively improved mood assessed using the Defined Intensity Stressor Simulation (DISS) battery. MO at 600mg per day also increased self-ratings of calmness yet reduced self-ratings of alertness (Kennedy et al 2004).
Sleep
Multiple human studies have investigated the use of MO for sleep, either solo or in combination with a variety of other natural substances. A Polish open-label study gave 40 participants Novanuit® Triple Action (a combo of classic soporifics melatonin, vitamin B6, Eschscholzia extract, Passiflora incarnata extract, and MO extract) capsules daily for two weeks noting reported benefit in sleep onset latency, total sleep duration, and sleep-related daytime parameters (Lemoine et al 2019). Another RCT investigated a combination of MO and Valeriana officinalis (VO) in 100 peri-menopausal or menopausal women ages 50-60 with diagnosed sleep disturbance. Significant improvement was seen in the treatment group using the PSQI (Taavoni et al 2013).
One interesting preliminary study looked at homeopathic preparations of MO, Phytolacca decandra (PD), MO + PD, or placebo for the treatment of sleep bruxism (SB) in 52 children (6.62 ± 1.79 years old). Visual Analogue Scale (VAS) was used as the primary outcome measure with the additional measurements of subjective parental/guardian sleep diary and the trait of anxiety scale (TAS). MO and MO + PD both showed improvement on SB via VAS scores. Other markers were not influenced. There were no adverse effects observed in any of the four groups (Tavares-Silva et al 2019).
Stress
MO has been used historically for stress and anxiety management both as a simple and in combination (Sarris et al 2013). One RCT using men only to evaluate a multi-herb product called Ze-185 (containing VO, MO, Passiflora incarnata, and Petasites hybridus) found the product significantly reduced the subjective emotional stress response during an acute stressor. This was measured via salivary cortisol and self-report (Meier et al 2018). The same preparation, Ze-185, was assessed via a retrospective case-control study in 3,252 psychiatric in-house patients analyzed over a 3.5-year period. Findings revealed that significantly fewer benzodiazepine prescriptions were required in the treatment group over the course of the study (Keck et al 2020).
Another trial combined MO and VO in twenty-four healthy volunteers comparing three doses (600mg, 1200mg, 1800mg) of the combo, or a placebo, on separate days with seven-day interval between dosing with assessment at one, three and six-hours post on treatment days. The 600mg dose showed reduced anxiety scores via DISS battery, but at 1800mg the anxiety scores seemed to mildly increase (Kennedy et al 2006).
A lozenge comprised of MO, Lavandula essential oil, and extracts from Humulus lupulus and Aveena sativa or matching placebo was given to sixteen healthy volunteers. Those receiving the lozenge exhibited increases in alpha-1 (associated with relaxation), alpha-2 (associated with working memory) and beta-1 (associated with anxiolytic intervention) electrical activity via electrode measurement (Dimpfel et al 2004).
Cardiovascular/Metabolic
There exists historical and empirical literature for the usage of MO for a variety of cardiovascular conditions including congestive heart failure, hypertension, angina pectoris, atherosclerosis, cerebral insufficiency, venous insufficiency, and arrhythmia. There is also a decent amount of animal data regarding MO for cardio-protective benefits. One 2021 study claims that the only symptomatology confirmed for human clinical use of MO is heart palpitations (Draginic et al 2021), however, the studies detailed below suggest more possible markers for cardiovascular and metabolic application.
A RCT examining MO for palpitation was conducted using 500mg twice a day of lyophilized aqueous extract of MO leaves for 14 days. Mean frequency of episodes and somatic symptomology were significantly decreased (Alijaniha et al 2015).
A 12-week RCT by Asadi et al (2019) (62 participants) utilized 700mg twice daily of MO extract capsules and found the intervention safe and beneficial on lipid profile, glycemic control, and reduction of inflammation. Measures used in the study were fasting blood glucose, HbA1c, hs-CRP, TG, HDL-C, and systolic blood pressure. However, total cholesterol, LDL-C, insulin, and HOMA-IR showed no significant changes between the groups.
A 2019 RCT was conducted in 37 patients with a diagnosis of type II Diabetes Mellitus (DMII) utilizing a 500mg capsule twice daily of MO for three months and showed that MO decreases TG levels in dyslipidemic diabetic patients. Beneficial results were greatest in those with TG>200mg/dl pre-trial. The same study showed significant decreases in both systolic (SBP) and diastolic blood pressure (DBP) in those with greatest measures at the beginning of the trial (SBP>130/DBP>85) (Nayebi et al 2019).
Another study used 1000mg MO or placebo in 58 hyperlipidemic patients and evaluated pre/post study with measures of fasting blood glucose, HDL, LDL, TG, Creatinine, AST and ALT. MO significantly reduced levels of LDL and AST (Jandaghi et al 2016).
A follow-up study regarding MO use in DMII recruited seventy diagnosed diabetic patients aged 20-65. Participants were randomly assigned to receive a hydro-alcoholic extract of MO at 700mg/day or placebo twice-daily for 12 weeks. Multiple markers were gathered; improvement of Apo A-I, Apo B/Apo A-I, and lipid ratios were reported (Asadi et al 2018).
Eighty patients diagnosed with coronary artery disease and chronic stable angina were randomized to receive 3g MO/day or placebo for eight weeks. Among individuals with stable angina, MO improved lipid levels, malondialdehyde, hs-CRP, and paraxonase-1 (Javid et al 2018).
A less-than-glowing 2020 systematic review and meta-analysis of RCTs utilizing MO for cardiovascular concerns found that MO was not associated with statistically significant changes in triglycerides, low-density lipoprotein, diastolic blood pressure, high sensitivity c-reactive protein levels, fasting blood sugar, HbA1c, insulin or high-density lipoprotein levels. While there were no serious adverse events reported, the study opined that bias was high in a considerable number of studies. The study did acknowledge safety and beneficial effects on TC and SBP, and concluded that higher-quality trials are needed (Heshmati et al 2020). One consideration in weighing this conclusion is that most of the RCTs reviewed are of relatively short duration; it would be interesting to see what prolonged use of a gentle intervention such as MO might provide given that cardiovascular diseases are certainly chronic in origin.
Menstruation
One double blind RCT recruited ninety students (ages 18-26) experiencing symptoms of moderate to severe dysmenorrhea (evaluated via McGill system). Participants were randomized to receive either 330mg MO or placebo capsules containing corn starch. Doses were given to both groups for three days from the beginning of menstruation, three times daily for two cycles. The group taking MO experienced reduced neurological symptoms, fatigue and lethargy. Menstrual headache was not significantly impacted in either group (Mirabi et al 2018).
Childhood Concerns
MO is a frequently used herb in childhood complaints (Gurol et al 2019), which attests to its safety profile. One 28-day infantile colic (IC) study in 176 babies found a combination of Matricaria chamomilla, MO and tyndallized L. acidophilus (HA122) and L. reuteri DSM 17938 is significantly more effective than simethicone in IC (Martinelli et al 2017). Another study of 93 breastfed infants found improvement in colic within seven days of treatment with a combination of Matricaria, Foeniculum vulgare and MO (Savino et al 2005).
Nine hundred eighteen children under the age of 12 were given a combination of MO/VO for sleep. Dyssomnia was improved in 80.9% of patients, and restlessness was improved in 70.4% of patients. The intervention was well tolerated (Muller and Klement 2006).
A combination of proprietary extracts of MO/VO was given to 169 primary school-age children assessed with concentration and hyperactivity issues. The children were given a daily dose (640mg VO root extract and 320mg MO extract) and assessed at two and seven weeks by parents and pediatricians via questionnaire. Findings revealed that strong/very strong symptoms of poor ability to focus decreased from 75% to 14%, hyperactivity from 61% to 13%, and impulsiveness from 59% to 22%. There were also improvements in parent rated social behavior, sleep and overall symptom burden. Only two of the 169 children had reported adverse effects (Gromball et al 2014, Ross 2015).
Miscellaneous
One very interesting clinical trial investigated the benefit of MO prepared as tea twice daily (1.5g/100 mL) for 30 days upon the lab measured effects of ionizing radiation in 55 radiology department staff. There were significant improvements in plasma levels of catalase, superoxide dismutase, and glutathione peroxidase and a marked reduction in plasma DNA damage, myeloperoxidase, and lipid peroxidation. These outcomes were interpreted as improvements in oxidative stress and reduced DNA damage among individuals occupationally exposed to radiation (Zeraatpishe et al 2011).
In another study 24 patients diagnosed with chronic non-specific colitis were treated with a combination of Taraxacum officinale, Hypericum perforatum, MO, Calendula officinalis and Foeniculum vulgare. Spontaneous and palpable pains along the large intestine disappeared in 95.83 percent of participants by the 15th day of treatment (Chakurski et al 1981).
Viral Considerations
Topical treatments of prepared MO cream have given relief from oral herpes simplex in two double-blinded trials (Gaby 2006, Nelson et al 2020). While there are a lot of studies that show efficacy for inhibition of herpetic viruses in vitro, in vivo findings also indicate that M. officinalis L. extract inhibits HSV-2 replication at non-toxic doses (100mg/mL) (Mahendra and Kateryna 2013) and that topical preparations including MO are beneficial for prodromal/acute HSV1 outbreak (Nelson et al 2020).
Traditional Applications with no Human Data
Though lemon balm is used traditionally as an anti-viral, only the above two studies confirmed this usage. Only one review alluded to the common usage of MO in influenza and not specifically (Sargin 2021). No literature could be found for use of MO as a febrifuge, though this too is a classic application in historical herbal medicine (alone or in combo). What about contraindication with sluggish thyroid? Many of us (NDs/herbalists) learned that MO is contraindicated for use in a person with diagnosed hypothyroidism. Are there any data to back this up? No research data could be found in PubMed regarding MO contraindication in hypothyroidism though this is well established for use in mild hyperthyroidism historically (usually in combination with Lycopus virginicus and Leonorus cardiaca).
Areas of Promise for Future Research
Of course, we would all like to see more exploration of all of the above applications. As of now, there are numerous cell-line studies of MO extract inhibition of various human cancer cell lines (colon cancer cells, glioblastoma multiforme cells, etc); this will be an area to watch. Another positive retinal cell line study shows promise for macular degeneration. Likewise, cell studies of MO (and other Lamiaciae plants) for anti-viral (HSV, HIV) and anti-bacterial application are promising for further human study (Allahverdiyev et al 2004, Mikus et al 2000, Schnitzler and Reichling 2011, Yamasaki et al 1998). Exciting things are possible, especially given MO is such an inexpensive, sustainable, and accessible medicinal plant.
MO is easy to grow, has a wide array of beneficial applications in humans (both proven and empirical), and is safe for babies, elders, and everyone in between. It tastes good. In an age when Alzheimer’s, neurodegenerative conditions, cardiovascular disease, and all chronic inflammatory conditions are on the rise this plant could easily be incorporated in a variety of ways from the home kitchen. More technical extractions of Melissa officinalis also show promise. The essential oils smell clean and bright and are soothing. We could likely all benefit from having this lovely garden herb in our lives.
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