Lemon Balm Improves Sleep Quality In Placebo-Controlled RCT

Melissa officinalis, known colloqually as Lemon Balm, has a venerable history of use as a relaxant, anxiolytic, and sleep aid. A new study shows nightly supplementation with a phytosomal extract of this plant improved sleep quality in a cohort of people with insomnia (Photo: Cristina Ionescu/Shutterstock)

These days, a lot of people could use some help in the sleep department. For many of them, phytosomal extract of Lemon Balm (Melissa officinalis) could be just the ticket.

Data from a recent double-blind crossover study of 30 people with chronic insomnia show that nightly supplementation with 400 mg of Melissa officinalis Phytosome® (Indena), taken 30 minutes prior to bedtime, markedly reduced composite Insomnia Severity Index (ISI) scores and increased the amount of time spent in restorative slow-wave sleep.

The findings were strong enough to prompt lead investigator Francesco Di Pierro, PhD, of the University of Insubria, Varese, Italy, to consider this form of M. officinalis a “viable alternative to pharmaceutical treatments for insomnia, offering a natural and potentially safer option for individuals seeking relief from sleep disorders.”

Dr. Di Pierro, who specializes in the study of probiotics, botanicals, the microbiome, and the human immune system, worked with researchers at the University of Urbino, to test the viability of M. officinalis as a first line sleep remedy.

The herb, which is native to the Mediterranean and to East Asia, has a venerable history of medical use. It is documented in ancient Persian, Mediterranean, Middle Eastern, and early European herbal medicine texts, and is widely used as an anxiolytic, anti-spasmodic, mood enhancing, and soporific remedy.

Plausible Mechanisms

M. officinalis contains many volatile compounds, triterpenoids, phenolic acids, and flavonoids. It is rich in hydroxycinnamic acids, a phytochemical category that includes cinnamic acid, coumarin acids, ferulic acids, chlorogenic acid, and, most importantly, rosmarinic acid. This latter compound has GABA-ergic effects. Extracts of M. officinalis have been shown, in vitro, to interact with acetylcholinesterase and gamma amino butyric acid (GABA) transaminase, as well as with matrix metallo-proteinase 2 (MMP2), all of which suggest plausible mechanisms for the herb’s long-documented anxiolytic and relaxant effects.

There are animal studies indicating that intake of M. officinalis can reduce sleep latency while increasing total sleep time (Kim TH, et al. Biomed. Pharmacother. 2022; Kwon YO, et al. Biomol Ther. 2016; Rodrigues Coelho V, et al. Naunyn Schmiedebergs Arch Pharmacol. 2016). But previous human trials have given mixed and inconclusive results (Falcone PH, et al. Nutr Res. 2019; Tubbs AS, et al. Int J Envir Res Public Health. 2021).

Rosmarinic acid, a polyphenol found in M. officinalis, has GABA-ergic effects

Di Pierro and colleagues believe the lack of clear-cut sleep benefits in previous human studies is likely due to the fact that many key phytochemicals in most M. officinalis products have low oral bioavailability. The phytosomal form used in this study, produced by Indena–one of Europe’s leading manufacturers of botanical ingredients and marketed as Relissa–was developed specifically to rectify this problem.

Crossover Study Design

For the present study, the investigators used a prospective, double-blind, placebo-controlled, cross-over study design. They recruited 30 patients (13 males and 17 females) from two different clinical centers, one in central Italy (Pesaro) and the other in the north (Milan). The subjects ranged in age from 18 to 65 years, and all regularly experienced difficulty sleeping, fatigue upon waking, and unrefreshing sleep.

They were all free from anxiolytic drugs, antidepressants, or hypnotics for at least 15 days prior to the start of the study. The exclusion criteria included: diabetes; asthma; thyroid dysfunctions (hypo- or hyperthyroidism); alcoholism; smoking; and current or recent past use of prescription drugs or other herbal remedies for sleep disorders.

At the outset, each patient was given a Garmin VenuSq smartwatch which served as a monitor for quantifying total sleep duration, and time spent in the light, slow-wave, and REM phases of sleep. The investigators also collected data on heart rate and blood oxygen saturation levels. They gathered subjective self-reported data using the seven-item Insomnia Severity Index (ISI) questionnaire. The higher the ISI score, the more severe and burdensome the insomnia.

In addition to the smartwatch, each participant also received a kit containing two boxes: one containing the Melissa Phytosometablets; the other containing placebo tablets identical in appearance, size, shape, and color. The patients were blind to the contents of each box.

Following randomization, the subjects were divided into two groups, and the boxes in each person’s kit were numbered with “1” or “2”, which corresponded to the order of intake. Group 1 took the active M. officinalis first, for 15 days, followed by the placebo. For Group 2, the order was reversed. For both groups, there was a 5-day washout period between rounds.

Each active M. officinalis tablet contained 200 mg of Melissa officinalis Phytosome (Relissa™); patients took two tablets every night, roughly 30 minutes prior to bed.  The study administrators sent a nightly reminder to each participant, to drive adherence.

The subjects filled out the ISI questionnaires prior to supplementation, and on the days immediately following each 15-day treatment period. The study ran through March and April of 2024.

Clear Benefits

The impact of M. officinalis on sleep patterns was quick, measurable, and statistically significant. Dr. Di Pierro and colleagues report an overall 2.9-point reduction in ISI scores during periods when subjects were taking the active supplement compared with periods on the placebo. Average ISI scores went from 9.7 ± 3.7 for the placebo to 6.8 ± 4.1 for the M. officinalis.

In the group that took the active herbal tablets during the first treatment period, the average ISI score increased after they switched to the placebo, indicating a worsening of insomnia severity. In contrast, the group that took the placebo first, shows the opposite pattern: average ISI scores decreased while taking the active M. officinalis, indicating improvement of sleep.  

While patients were taking the herb, the total amount of time spent in short-wave sleep (SWS) phases increased by an average of 15%, while total time in REM phases dropped by 10%. This is important because neurologists consider short-wave “deep” sleep to be the most restorative phase of sleep. Prolonged periods of SWS are beneficial for restoration of synaptic homeostasis, and consolidation of memory and learning (Keklund G, Ackerstedt T. J Sleep Res. 1997). Many researchers consider SWS to be the most important overall predictor of sleep quality.

(Image: Owl Vision Studio)

There’s also some evidence that prolonged SWS can improve daytime cognitive performance. In 2022 Stuart McCarter and his team of sleep researchers at Mayo Clinic, published a review of 65 studies looking at impact of various sleep parameters on objective measures of cognitive performance. They found a moderate correlation between SWS and indicators of motor speed, executive function, and other measures of daytime cognitive function (McCarter SJ, et al. Sleep Med Rev. 2022).

SWS, Memory, & Dementia Risk

SWS quality and duration have particular importance for people at risk of Alzheimer’s or other forms of dementia. A 2022 metanalysis of 24 polysomnographic studies showed a strong inverse association between time spent in SWS and severity of cognitive decline over time (Zhang Y, et al. Transl Psych. 2022). In one study, researchers at Washington University, St. Louis, showed that reduced or disrupted SWS correlated with increases in amyloid-β, even in pre-clinical phases of Alzheimer’s disease development (Ju YS, et al. Brain. 2017).

A 2023 study of data from 346 participants in the Framingham Heart Study looked at the impact of SWS changes on dementia risk over a 17-year follow-up period. The observations are striking: for each percentage point of annual SWS reduction, the investigators calculated a 27% increased risk of dementia (Himali JJ, et al. JAMA Network. 2023).

Dr. Di Pierro and his co-authors stress that they did not directly measure memory or daytime cognitive function in this study, and so they are unable to make any claim that nightly supplementation with M. officinalis can lead to memory improvement or prevention of dementia. But the fact that there was a consistent pattern of increased SWS is certainly suggestive and worthy of further research.

Subjective Improvements

Subjectively, 87% of the subjects in the Di Pierro study reported some degree of improvement in their sleep experience, their sense of being well-rested, and their self-assessment of daytime function during the periods when they were taking the active herbal treatment. In contrast, only 30% reported these improvements during the periods when they were on placebo.

The authors note that there were no major differences in physical activity levels between the two groups, or between the two treatment phases. This eliminates exercise/activity as a potential confounding variable in terms of impact on sleep. The patients were all similar with regard to scores on the State-Trait Anxiety Index (STAI), which dispels the possibility that the observed changes in sleep quality could be a reflection of differences in anxiety or stress levels.

The herbal treatment did not appear to have any impact on baseline anxiety levels.

The investigators did not report any adverse effects associated with the phytosomal M. officinalis. The treatment was well-tolerated and safe.

Clear & Pressing Need

There is a clear need for safe, effective, non-addictive, and easily accessible treatments for insomnia and poor sleep. Di Pierro and colleagues note that, “Insomnia is the most common sleep disorder and one of the most prevalent pathological conditions in primary care.” The add that a 2022 study of 748 Italian subjects over 50 years of age, showed an insomnia prevalence of 55%. A high percentage of these people were using hypnotic and antidepressant drugs, as and sometimes melatonin supplements, to improve their sleep (Proserpio P, et al. Neurol Sci. 2022).

Data from the Centers for Disease Control indicate that in the year 2020, 8.4% of all US adults were taking prescription sleep drugs every day or on most days. Though use of Rx sleep meds has been trending downward in recent years—presumably because patients are aware of the potential for side effects—the problem surely has not disappeared.

In summarizing their observations, Di Pierro and colleagues note that photosomal M. officinalis “proved particularly effective and safe, suggesting it as a viable alternative to traditional pharmaceutical treatments for insomnia, offering a natural and potentially safer option for individuals seeking relief from sleep disorders.”

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