Enhancement of Sleep Quality and Mood Following Supplementation With Lemon Balm in an Adult Population (Lemslp)

Overview

This study aims to investigate the effect of a 4-week dietary intervention of 300mg encapsulated aqueous lemon balm extract on measures of sleep quality, mood and well-being, alongside relevant biomarkers of circadian rhythms in healthy adults aged 18-40 years with mild sleep problems (PSQI entry of 5 and above). Three visits to the university alongside completing some home tests involving self-test stool, saliva and mood tests and wearing an wrist-secured actiwatch over 4-weeks whilst recording a daily sleep diary will be monitored to estimate sleep changes. Mood ratings, stool and saliva biomarkers will serve as a proxy to sleep improvement.

Full Title of Study: “A Randomised Double-blind Placebo-controlled Trial on Encapsulated Lemon Balm Efficacy and Tolerance on Sleep Quality Changes, and Mood and Wellbeing Effects Using Objective and Subjective Measures”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Randomized
    • Intervention Model: Parallel Assignment
    • Primary Purpose: Prevention
    • Masking: Triple (Participant, Investigator, Outcomes Assessor)
  • Study Primary Completion Date: May 23, 2023

Detailed Description

A randomised, double-blind, placebo-controlled, parallel-design study assessing the effect of a 4-week intervention of lemon balm extract (or matched placebo) in young to middle-age adults with mild sleep problems. A total of 108 participants will be randomly assigned to either 300 mg lemon balm extract or a matched placebo capsule consumed nightly before retiring to bed. The severity of sleep problems, depression, anxiety, perceived stress, quality of life and well-being will be measured at baseline and after 4 weeks of daily consumption. In addition, we will assess changes in microbiota and saliva neurohormone profiles at baseline and after 4 weeks of treatment. Entry to the study to determine eligibility involves a sleep quality questionnaire (PSQI) score of 5 and above. The study comprises of a familiarisation visit and then two test days at the Nutritional Psychology Unit based at the University of Reading where primary sleep (PSQI), and exploratory measures of sleep (ISI, LSEQ) and mood (PANAS, Vivascentz(TM), FFS, PSS, DASS-21) tests will be completed. The screening visit will further assess habitual diet (Epic-Norfolk FFQ), and general health and lifestyle patterns to confirm eligibility. Participants will then continuously wear an wrist-secured actiwatch whilst recording a daily sleep diary to estimate sleep changes over the 4-week period. In addition, some further exploratory tests will be completed by participants from home 24h before baseline and 24h before post-intervention (saliva, stool, PANAS-X).

Interventions

  • Dietary Supplement: Lemon balm
    • 300mg Lemon balm and Maltoxdextrin capsules Other Name: Melissa Officinalis L.
  • Dietary Supplement: Placebo
    • 300mg Maltodextrin capsules

Arms, Groups and Cohorts

  • Experimental: Lemon balm
    • 300mg Lemon balm and Maltodextrin
  • Placebo Comparator: Placebo
    • Placebo

Clinical Trial Outcome Measures

Primary Measures

  • Pittsburgh Sleep Quality Index (PSQI)
    • Time Frame: 4 weeks
    • A validated measure of sleep assessing qualities and patterns within the last month of sleep habits in adults. Seven components of sleep (quality, latency, duration, efficiency, disturbance, use of sleep medication, daytime dysfunction) will be summed to achieve a global PSQI score ranging from 0 to 21 points, where scores above 5 indicates sleep problems.

Secondary Measures

  • Combined Sleep Diary and Research-Grade Actiwatch Sleep-Wake Patterns
    • Time Frame: Continuous over 4 weeks
    • Passive motion tracking of sleep-wake patterns (heart rate variability) will be recorded via a wrist-worn research-grade actiwatch. The actiwatches will be secured on the participant’s wrist throughout the study period. To cross-examine the actiwatch data, an in-house standardised daily sleep diary will measure sleep quality, sleep duration and sleep latency (how many times awoken during sleep time) (Carney et al., 2012; Orchard et al., 2020) where meaningful sleep outcomes will be manually inputted into actiwatch software at the end of sleep monitoring, as per standard practice in sleep research.
  • Diurnal Salivary Cortisol and Melatonin Patterns
    • Time Frame: 4 weeks
    • Determination of changes in circadian sleep-wake patterns after 4-weeks daily 300mg lemon balm treatment by assessing diurnal sleep neurohormones, melatonin and cortisol. Changes in melatonin and cortisol will be assessed using 12 salivary self-test sampling kits taken in two windows (6 samples per window), within 24h before baseline day and within 24h before post-intervention day. For each test day, two samples will be taken first thing in the morning, 11am, 5pm and a final two samples in the evening. Sleep neurohormones will then be assessed against subjective sleep scores.
  • Gut Microbiota Changes
    • Time Frame: 4 weeks
    • Examination of gut responses to mood and sleep physiology changes after 4-weeks daily 300mg lemon balm treatment by assessing changes in faecal microbiota levels. Two samples will be collected over the entire study. Microbiome diversity will be determined using self-test stool sampling kits taken in two windows, within 24h before baseline day and within 24h before post-intervention day. Faecal microbiota will then be compared to subjective sleep and mood scores.
  • Insomnia Severity Index (ISI)
    • Time Frame: 4 weeks
    • A validated 7-item instrument designed to assess the nature, severity and impact of both nighttime and daytime components of insomnia within the last month. The scale ranges from 0 to 28 where higher scores indicate more severe insomnia.
  • Leeds Sleep Evaluation Questionnaire (LSEQ)
    • Time Frame: 4 weeks
    • A 10-item self-report slider scale to evaluate ease of getting to sleep, sleep quality, ease of waking and behaviour following wakefulness. Higher scores indicate better sleep quality.
  • Perceived Stress Scale (PSS)
    • Time Frame: 4 weeks
    • A validated 10-item questionnaire to measure levels of perceived stress. The scale ranges from 0 to 40 points with higher scores indicating greater stress levels.
  • Positive affect as measured by PANAS-X
    • Time Frame: 4 weeks
    • General positive affect for assessing trait mood over the past month will be calculated by adding the values of 10 positive items in correspondence with the original PANAS, ranging from 0-50 where higher scores indicate positive affect. In addition, the expanded Positive and Negative Affect Schedule-X will assess higher order scales Surprise, Joviality,Self-Assurance, Attentiveness, and Serenity and these collective scores combined with general positive affect range from 0 to 170 points, where higher scores indicate better mood.
  • Positive affect as measured by PANAS-NOW
    • Time Frame: 4 weeks
    • General positive affect for assessing transient mood as the respondent feels in the present moment will be calculated by adding the values of 10 positive items. Scores range from 0-50 points where higher scores indicate positive affect.
  • Negative affect as measured by PANAS-X
    • Time Frame: 4 weeks
    • General positive affect for assessing trait mood over the past month will be calculated by adding the values of 10 negative items in correspondence with the original PANAS, ranging from 0-50 where higher scores indicate negative affect. In addition, the expanded Positive and Negative Affect Schedule-X will assess higher order scales Fear, Sadness, Guilt, Hostility, Shyness, Fatigue and these collective scores combined with general negative affect range from 0 to 170 points, where higher scores indicate worse mood.
  • Negative affect as measured by PANAS-NOW
    • Time Frame: 4 weeks
    • General negative affect for assessing transient mood as the respondent feels in the present moment will be calculated by adding the values of 10 negative items, ranging from 0-50 where higher scores indicate negative affect.
  • Depression, Anxiety and Stress Scale – 21 items (DASS-21)
    • Time Frame: 4 weeks
    • A validated 21-item measure to assess the severity of depression, anxiety and stress components, with 7 items per component. Each item is scored from 0-3 where higher scores indicate higher levels of distress in anxiety (scores range from 0 to >20), depression (0 to >28) and/or stress (0 to >34).
  • Flinders Fatigue Scale (FFS)
    • Time Frame: 4 weeks
    • A self-report 7-item questionnaire to assess perception of frequency and severity of fatigue over the past 2 weeks. Global fatigue scores range from 0 to 31, where higher scores indicate greater fatigue.
  • Vivascentz(TM) Metric
    • Time Frame: 4 weeks
    • An in-house Givaudan wellbeing metric, and patent approved (WO2020165463). This 18-item scale measures transient feelings in the present moment assessing 9 positive and 9 negative attributes (reverse scored) to contribute to overall wellbeing scores. Scores range from 0 to 180, where higher scores indicate higher wellbeing.

Participating in This Clinical Trial

Inclusion Criteria

  • Healthy, between18-40 years old – Mild Sleep problems (PSQI less than or equal to 5) – Willingness to provide stool and saliva samples, wear an actiwatch and complete a nightly sleep diary. Exclusion Criteria:

  • Use medications that may affect the outcome – Any long-term psychological or physiological health conditions – Have any allergic reactions to ingredients in the capsules – Have a BMI greater than or equal to 30 – Are vegetarian – Taking any dietary supplements which they are unwilling to stop for the duration of the study

Gender Eligibility: All

Minimum Age: 18 Years

Maximum Age: 40 Years

Are Healthy Volunteers Accepted: Accepts Healthy Volunteers

Investigator Details

  • Lead Sponsor
    • University of Reading
  • Collaborator
    • Naturex
  • Provider of Information About this Clinical Study
    • Principal Investigator: Prof Claire Williams, Chair of Neuroscience – University of Reading
  • Overall Official(s)
    • Claire M Williams, Professor, Principal Investigator, University of Reading

References

Scholey A, Gibbs A, Neale C, Perry N, Ossoukhova A, Bilog V, Kras M, Scholz C, Sass M, Buchwald-Werner S. Anti-stress effects of lemon balm-containing foods. Nutrients. 2014 Oct 30;6(11):4805-21. doi: 10.3390/nu6114805.

Araj-Khodaei M, Noorbala AA, Yarani R, Emadi F, Emaratkar E, Faghihzadeh S, Parsian Z, Alijaniha F, Kamalinejad M, Naseri M. A double-blind, randomized pilot study for comparison of Melissa officinalis L. and Lavandula angustifolia Mill. with Fluoxetine for the treatment of depression. BMC Complement Med Ther. 2020 Jul 3;20(1):207. doi: 10.1186/s12906-020-03003-5.

Kennedy DO, Scholey AB, Tildesley NT, Perry EK, Wesnes KA. Modulation of mood and cognitive performance following acute administration of Melissa officinalis (lemon balm). Pharmacol Biochem Behav. 2002 Jul;72(4):953-64. doi: 10.1016/s0091-3057(02)00777-3.

Haybar H, Javid AZ, Haghighizadeh MH, Valizadeh E, Mohaghegh SM, Mohammadzadeh A. The effects of Melissa officinalis supplementation on depression, anxiety, stress, and sleep disorder in patients with chronic stable angina. Clin Nutr ESPEN. 2018 Aug;26:47-52. doi: 10.1016/j.clnesp.2018.04.015. Epub 2018 May 19.

Ghazizadeh J, Hamedeyazdan S, Torbati M, Farajdokht F, Fakhari A, Mahmoudi J, Araj-Khodaei M, Sadigh-Eteghad S. Melissa officinalis L. hydro-alcoholic extract inhibits anxiety and depression through prevention of central oxidative stress and apoptosis. Exp Physiol. 2020 Apr;105(4):707-720. doi: 10.1113/EP088254. Epub 2020 Feb 21.

Noguchi-Shinohara M, Ono K, Hamaguchi T, Iwasa K, Nagai T, Kobayashi S, Nakamura H, Yamada M. Pharmacokinetics, Safety and Tolerability of Melissa officinalis Extract which Contained Rosmarinic Acid in Healthy Individuals: A Randomized Controlled Trial. PLoS One. 2015 May 15;10(5):e0126422. doi: 10.1371/journal.pone.0126422. eCollection 2015.

Buysse DJ, Hall ML, Strollo PJ, Kamarck TW, Owens J, Lee L, Reis SE, Matthews KA. Relationships between the Pittsburgh Sleep Quality Index (PSQI), Epworth Sleepiness Scale (ESS), and clinical/polysomnographic measures in a community sample. J Clin Sleep Med. 2008 Dec 15;4(6):563-71. Erratum In: J Clin Sleep Med. 2010 Feb 15;6(1):table of contents.

Rivest RW, Schulz P, Lustenberger S, Sizonenko PC. Differences between circadian and ultradian organization of cortisol and melatonin rhythms during activity and rest. J Clin Endocrinol Metab. 1989 Apr;68(4):721-9. doi: 10.1210/jcem-68-4-721.

Carlson LE, Campbell TS, Garland SN, Grossman P. Associations among salivary cortisol, melatonin, catecholamines, sleep quality and stress in women with breast cancer and healthy controls. J Behav Med. 2007 Feb;30(1):45-58. doi: 10.1007/s10865-006-9082-3. Epub 2007 Jan 24.

Chang WP, Lin CC. Relationships of salivary cortisol and melatonin rhythms to sleep quality, emotion, and fatigue levels in patients with newly diagnosed lung cancer. Eur J Oncol Nurs. 2017 Aug;29:79-84. doi: 10.1016/j.ejon.2017.05.008. Epub 2017 Jun 2.

Citations Reporting on Results

Ibarra A, Feuillere N, Roller M, Lesburgere E, Beracochea D. Effects of chronic administration of Melissa officinalis L. extract on anxiety-like reactivity and on circadian and exploratory activities in mice. Phytomedicine. 2010 May;17(6):397-403. doi: 10.1016/j.phymed.2010.01.012. Epub 2010 Feb 18.

Cases J, Ibarra A, Feuillere N, Roller M, Sukkar SG. Pilot trial of Melissa officinalis L. leaf extract in the treatment of volunteers suffering from mild-to-moderate anxiety disorders and sleep disturbances. Med J Nutrition Metab. 2011 Dec;4(3):211-218. doi: 10.1007/s12349-010-0045-4. Epub 2010 Dec 17.

Carney CE, Buysse DJ, Ancoli-Israel S, Edinger JD, Krystal AD, Lichstein KL, Morin CM. The consensus sleep diary: standardizing prospective sleep self-monitoring. Sleep. 2012 Feb 1;35(2):287-302. doi: 10.5665/sleep.1642.

Orchard F, Gregory AM, Gradisar M, Reynolds S. Self-reported sleep patterns and quality amongst adolescents: cross-sectional and prospective associations with anxiety and depression. J Child Psychol Psychiatry. 2020 Oct;61(10):1126-1137. doi: 10.1111/jcpp.13288. Epub 2020 Jun 17.

Buysse DJ, Reynolds CF 3rd, Monk TH, Berman SR, Kupfer DJ. The Pittsburgh Sleep Quality Index: a new instrument for psychiatric practice and research. Psychiatry Res. 1989 May;28(2):193-213. doi: 10.1016/0165-1781(89)90047-4.

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