Emotional distress conditions, such as depression, stress, anxiety, and insomnia (sleep disorder), are the most prevalent mental health conditions affecting a considerable amount of people worldwide (the prevalence of sleep problems ranges from 5.0% to 50.0% (Morin and Jarrin, 2022), while depressive and anxiety disorders affect more than 280 million and 300 million people, respectively (World Health Organization, 2022), causing significant disruption to everyday life, affecting performance in occupational and educational settings, and placing considerable burden (trillions of dollars) on healthcare systems (Hafner et al., 2017; Hillman et al., 2018). It is also important to note that the COVID-19 pandemic has been found to trigger a 25% increase in the prevalence of anxiety and depression worldwide (Kupcova et al., 2023). Conventional drug treatment for depressive conditions involves the use of tricyclic antidepressants (TCAs), monoamine oxidase inhibitors (MAOIs), selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), norepinephrine–dopamine reuptake inhibitors (NDRIs), and serotonin antagonists and reuptake inhibitors (SARIs) (Arroll et al., 2016), while for anxiety disorders, the drug therapies include SSRIs, SNRIs, pregabalin, TCAs, buspirone, benzodiazepines (BZDs), and MAOIs (Bandelow et al., 2022). However, published data suggest that 30%–60% of people do not comply with these synthetic antidepressant or anxiolytic medications due to adverse events or a signatory delay in effectiveness (Demyttenaere, 2001). According to various studies, most of the conventional drugs used for emotional distress are associated with multiple side effects, such as cognitive dysfunction, excessive sedation, sexual dysfunction, respiratory depression, withdrawal syndrome, seizures, and suicide, caused by prolonged drug use or high drug resistance (de Niet et al., 2009; Seldenrijk et al., 2015; Seldenrijk et al., 2017). Conversely, these were reduced in 45% of the reported studies where dietary supplements were used as adjuvant for the same indications (Yeung et al., 2018). Over the past decades, exploration in botanical psychopharmacology has received considerable attention due to its efficacy, excellent safety, and tolerability. With growing scientific evidence, physicians and patients have developed an interest in the use of botanical-based pharmacological therapies (the use of some of them is supported by the European Medicines Agency herbal monograph (European Medicines Agency, 2023)) for the management of emotional distress and poor sleep conditions (Head and Kelly, 2009; Kavan et al., 2009; Liu et al., 2015; Kenda et al., 2022).

Of note, amongst the several reported botanicals for psychopharmacology, the leaf extract of Melissa officinalis L. (MO), commonly known as lemon balm mint, has emerged as a promising natural “calming agent” (Sharifi-Rad et al., 2021) for emotional distress and related conditions. The main chemical constituents responsible for the MO pharmacological effects are reportedly diverse antioxidant polyphenols (with rosmarinic acid (RA) as the major compound (>5%) and flavonoids, e.g., luteolin-3′-O-glucuronide) and terpenes (with citronellal, neral, and geranial as the most abundant constituents), among others (Uritu et al., 2018). Melissa officinalis L. extract is one of the most popular and widely used dietary supplements in central and southern Europe, the Mediterranean region, the United States, and South and West Asia. Historically, the therapeutic use of MO dates back over 2000 years through the Greeks and the Romans and is mentioned in the Historia Plantarum (approximately 300 B.C.) as “honey leaf”. For centuries, MO has been used in traditional Chinese medicine (TCM), traditional Persian medicine (TPM), Ayurvedic medicine, Arabic medicine, and medieval European medicine for treating diverse health conditions, such as insomnia, migraines, neuroses, and hysteria, among others (Shakeri et al., 2016). In the modern pharmacological studies, various human clinical trials (Kennedy et al., 2002; Akhondzadeh et al., 2003; Kennedy et al., 2003; Kennedy et al., 2004; Kennedy et al., 2006; Cases et al., 2011; Alijaniha et al., 2015; Ranjbar et al., 2018a; Ranjbar et al., 2018b; Haybar et al., 2018; Heydari et al., 2018; Soltanpour et al., 2019; Araj-Khodaei et al., 2020; Noguchi-Shinohara et al., 2020; Shirazi et al., 2021), animal models (Coleta et al., 2001; Guginski et al., 2009; Ibarra et al., 2010; Yoo et al., 2011; Taiwo et al., 2012; Feliú-Hemmelmann et al., 2013; Lin et al., 2015; Ghazizadeh et al., 2020; Talebi et al., 2022), and in vitro studies (Kennedy et al., 2003; Awad et al., 2007; Awad et al., 2009; López et al., 2009; Sahin et al., 2016) have investigated the neurotherapeutic effects of MO extract, with most studies reporting its antidepressant, anti-stress, anxiolytic, anti-insomnia, and anti-oxidative stress (neuroprotective) properties. According to reported evidence, the neuropharmacological effects of MO extract are due to its various biological properties, i.e., its GABAergic properties (upregulation of γ-amino butyric acid (GABA) through GABA-transaminase (GABA-T) inhibition (Awad et al., 2007; Awad et al., 2009; Yoo et al., 2011), GABA_A receptor affinity (Salah and Jäger, 2005; Abuhamdah et al., 2008; Sahin et al., 2016)), modulation of the serotonergic pathway (Dimpfel and Suter, 2008; Lin et al., 2015), and inhibition of acetylcholine esterase (AChE) (Perry et al., 1996; Ferreira et al., 2006; Dastmalchi et al., 2009) and monoamine oxidase (MAO) enzymes (Ulbricht et al., 2005; López et al., 2009; Taiwo et al., 2012; Shakeri et al., 2016). Some other studies have suggested that the neuropharmacological mechanism of MO extract may be due to its direct nicotinic and muscarinic cholinergic receptor binding properties (Perry et al., 1996; Wake et al., 2000; Kennedy et al., 2003) and its ability to decrease corticosterone levels (Yoo et al., 2011; Feliú-Hemmelmann et al., 2013). Melissa officinalis L extract also possesses strong antioxidant properties and helps in the protection of neuronal cells against oxidative stress damage (López et al., 2009; Miraj et al., 2017).

However, therapeutic evidence for MO’s neuropharmacological effects is still limited, and the determination of its optimal clinical dosage and duration remains unknown (Świąder et al., 2019). Further studies are needed to validate the efficacy of MO extract supplementation in conditions of depression, mood, anxiety, stress, and related conditions and to demonstrate its mechanism of action, safety, and tolerability. Moreover, many phytochemicals have limited bioavailability and bioactivity after ingestion due to their limited solubility, stability, and absorption characteristics. Hence, efforts should also be focused on developing efficient carrier systems to achieve improved MO bioavailability for physiological functions. In the present prospective, randomised, double-blinded, placebo-controlled clinical trial, for the first time, we investigated the possible neuropharmacological effects of an innovative phospholipid carrier-based (Phytosome™) MO aqueous extract (Relissa™) in individuals with a moderate degree of emotional distress and/or poor sleep conditions. It is anticipated that the phospholipid carrier will aid in achieving the maximum bioavailability of the extract chemical constituents for pharmacological MO effects.

In the present study, we investigated the impact of a 3-week-long supplementation of an innovative phospholipid carrier-based formulation of a standardised MO extract (daily 400 mg dosage) on emotional distress and related conditions. Findings revealed that the consumption of MO extract improved depression, anxiety, and stress scores and sleep quality in individuals with a moderate degree of depression, stress, anxiety, or sleep complaints. Additionally, we found that the extract improved overall mental wellbeing, affective state, and quality of life.

One of the notable outcomes of this study is the significant reduction in depression, anxiety, and stress levels in participants who received MO phospholipid extract supplementation. It is noteworthy that these improvements were observed only after 3 weeks of supplementation, suggesting a relatively rapid onset of therapeutic effects of the extract. These findings are broadly in line with the previous research showing the contemporary role of MO extract as a “calming agent” and a mild sedative following acute and chronic supplementation (Kennedy et al., 2002; Kennedy et al., 2003; Kennedy et al., 2004; Cases et al., 2011; Alijaniha et al., 2015; Soltanpour et al., 2019). It is important to note that, unlike our study utilising well-known and clinically validated scales to measure depression, stress, and anxiety in healthy individuals, previous research has measured calmness/anxiety by utilising visual analogue scales in unhealthy individuals (e.g., individuals undergoing coronary artery bypass surgery); hence, our results, in fact, extend the previous findings and show a potential therapeutic impact of the MO extract on subclinical conditions (such as elevated depression, anxiety, and stress levels) in healthy individuals.

Additionally, participants who consumed MO extract experienced a significant increase in overall mental wellbeing and positive affective state and a significant decrease in negative affective state, as evidenced by improvements in the WEMWBS and PANAS scores, respectively. This outcome suggests that in addition to its calming effect, MO phospholipid extract also fosters positive psychological wellbeing and affective state, as well as mitigates negative emotional states. Given that the supplement and placebo groups differed in baseline negative affect scores, the effect of MO supplementation on alleviating negative emotional feelings should be interpreted with caution. Nevertheless, this improvement in emotional states aligns with the observed reductions in the symptoms of depression, anxiety, and stress and underscores the comprehensive impact of MO supplementation on mental health.

In the realm of sleep quality, consistent with the previous research, participants who consumed the MO phospholipid extract demonstrated a significant improvement in the total PSQI score (Cases et al., 2011; Haybar et al., 2018; Heydari et al., 2018; Soltanpour et al., 2019), highlighting its potential as a holistic approach to sleep management. Given that the MO extract positively affected mental health and wellbeing, it could also indirectly affect the quality of sleep by reducing mental health symptomatology. However, similar to negative affect, participants in the supplement and placebo groups differed in sleep quality at the baseline, hence, the results should be interpreted with caution.

Another important aspect of this study is that the MO supplement elicited a positive impact on various domains of QoL, e.g., physical and social aspects. Although there were differences between the supplement and placebo groups in terms of baseline scores of the total QoL, psychological, and environmental subscales, which may have driven the observed effects, the treatment group exhibited improvements in all quality-of-life measures at 3 weeks follow-up. These improvements suggest that MO supplementation has the potential to enhance overall life satisfaction and functioning and further add to the evidence base.

It is important to highlight that none of the participants who received the supplement (daily dosage 400 mg) reported any serious side effects, such as those associated with conventional antidepressants and anxiolytic drugs, at least during the 3-week study period, demonstrating the excellent safety and tolerability of the phospholipid carrier-based formulation of MO extract supplementation. These results are consistent with the previously reported studies with other MO formulations (Ballard et al., 2002; Akhondzadeh et al., 2003; Burns et al., 2011; Cases et al., 2011; Alijaniha et al., 2015; Noguchi-Shinohara et al., 2015; Soltanpour et al., 2019; Araj-Khodaei et al., 2020). In general, MO extract supplementation is considered a safe alternative therapy for the management of emotional distress and related conditions. Noguchi-Shinohara et al. (2020) analysed that in patients with mild dementia due to Alzheimer’s disease (AD), a daily dose of 500 mg of MO extract supplementation for 24 weeks failed to produce any adverse events. Asadi et al. (2019) observed that in patients with type 2 diabetes, a daily dose of 700 mg of MO extract supplementation for 3 months was safe and tolerable. However, it has been repeatedly pointed out that MO should be used with caution in patients with thyroid dysfunction as it mediates thyroid hormone inhibition (Ulbricht et al., 2005). Overall, no common serious side effects have so far been reported for MO extract supplementation (Rafieian-Kopaei et al., 2013) in otherwise healthy adults or when used in nutritional amounts. As a matter of fact, in 2013, the European Medicines Agency approved MO leaf extract prepared as a herbal infusion, dry extract, or fluid extract as a non-prescription medicine for alleviating mild symptoms of mental stress and fostering sleep, and for relieving mild digestive disorders, which included bloating and flatulence (HMPC Community herbal monograph on Melissa officinalis L. folium, 2007). The European Scientific Cooperative on Phytotherapy (ESCOP) also recommends the use of the MO extract for tenseness, restlessness, and irritability (Escop European Scientific Cooperative on Phytotherapy, 2003). In the US, the MO extract has received FDA GRAS (Generally Recognised as Safe) status for use as a food ingredient (US Food and Drug Administration, 2016).

Due to the demonstrated neuropharmacological therapeutic effects of the oral MO extract, as observed in the present study, it is currently one of the most popular over-the-counter supplements for the management of low mood conditions, particularly in individuals who are refractory to conventional antidepressant/anxiolytic drugs. Among the reported clinical trials, the MO extract supplement dosage of 300 to 1,600 mg has shown benefits in the management of depression, anxiety, stress, and poor sleep. In terms of duration, studies have shown that a period between 10 days and 8 weeks is required to improve depressive symptoms. Some clinical trials have shown that the shortest duration of MO oral supplementation that led to improvement in anxiety disorders was 5–7 days (Soltanpour et al., 2019; Saeidi et al., 2020). In the presence of available evidence on scientific rationale, clinical efficacy, and safety, we propose that phospholipid carrier-based MO extract supplementation may serve as a promising short-term natural intervention for individuals seeking relief from symptoms of depression, anxiety, and stress while simultaneously enhancing their overall mental wellbeing.

With regards to possible mechanisms of action, the beneficial effects of MO supplementation on low mood and/or anxiety are believed to be largely driven by the natural GABAergic properties of the supplement. γ-Amino butyric acid is the principal inhibitory neurotransmitter in the central nervous system (Brambilla et al., 2003; Granger et al., 2005) that has been implicated in a range of behaviours, including, but not limited to, low mood, anxiety, stress regulation, memory enhancement, and circadian rhythm (Hepsomali et al., 2020). Brain cells low GABA levels and/or impaired GABA functioning are known to be associated with the aetiology and maintenance of acute and chronic stress (Jie et al., 2018), anxiety, depressive disorders (Nemeroff, 2003), and insomnia (Gottesmann, 2002). Melissa officinalis L. inhibits GABA-T (Awad et al., 2007; Awad et al., 2009; Yoo et al., 2011), resulting in an increase in brain GABA levels and a subsequent increase in GABA transmission. Amongst the bioactive chemical constituents of the MO extract, rosmarinic acid (a hydroxycinnamic acid ester polyphenol) is the major ingredient and an important biomarker used for the standardisation of MO extract (Arceusz et al., 2015; Noguchi-Shinohara et al., 2015; Shakeri et al., 2016). Rosmarinic acid has the ability to cross the blood–brain barrier (Falé et al., 2011). Therefore, the psychopharmacological effects of the MO extract are predominantly attributed to RA (Awad et al., 2007; Awad et al., 2009; Jin et al., 2013; Sahin et al., 2016; Ghazizadeh et al., 2020), possibly acting in a synergistic or additive way with other biochemical mechanisms (Savelev et al., 2003), such as GABA-T inhibition by ursolic and oleanolic acid contents present in the MO extract (Awad et al., 2009; Ibarra et al., 2010). The Melissa officinalis L. extract has also shown an affinity for GABA_A receptors (Salah and Jäger, 2005; Abuhamdah et al., 2008; Sahin et al., 2016), leading to an enhancement in GABAergic signalling. GABA receptors are targets for many pharmacological treatments for insomnia, such as benzodiazepines. GABA_A receptor modulation is one of the four key mechanisms of action of the approved pharmacological therapies for insomnia (Avidan and Neubauer, 2017).

The phospholipid carrier-based (Phytosome™) MO extract (Relissa™) used in the present study is an innovative food-grade formulation developed to achieve increased bioavailability and therapeutic effects of the extract. The Phytosome™ carrier is a solid botanical dispersion recently reported to improve the effectiveness and target reach of a wide range of natural compounds, such as quercetin (Riva et al., 2019b), berberine (Rondanelli et al., 2021), curcumin (Pivari et al., 2022), boswellic acids (Riva et al., 2019a), and other botanical extracts, without safety concerns. We can hypothesise that the possible “calming effect” observed in the present study after 3-week supplementation of the phospholipid carrier-based MO extract could also be due to this new formulation used; however, more studies are needed to better clarify the role of the Phytosome™ carrier.

However, it is essential to acknowledge some limitations of this study, such as evaluation of only one dose of MO extract, lack of compliance measurements, and the absence of evaluation of therapeutic effect in the form of objective biomarkers such as cortisol, C-reactive protein (CRP), adrenocorticotropic hormone (ACTH), dehydroepiandrosterone (DHEA), and corticosterone levels etc, which should be considered in future studies. In the current study, although the men/women ratio was somewhat balanced in the supplement group, there were more female participants in the placebo group. Given that the NIH Policy (Arnegard et al., 2020) recommends considering sex as a biological variable, future studies should consider this crucial factor in the recruitment and analysis stages. Although this study primarily focused on short-term effects (3 weeks of supplementation) on mental health and related conditions, it is essential to acknowledge the potential for sustained benefits over extended periods. Future research should explore the long-term impact of MO phospholipid extract supplementation on mental health, wellbeing, and sleep quality to ascertain its utility as a continuous intervention. While this study has demonstrated the positive effects of MO supplementation, the underlying mechanisms remain a subject for further investigation. Understanding how MO’s bioactive compounds interact with neuronal pathways and physiological processes could shed light on its therapeutic actions and guide the development of more targeted interventions. Additionally, research studies should explore optimal dosage regimens and potential interactions with other interventions or medications. The results observed in the present study underscore the potential breadth and depth of MO phospholipid extract supplementation’s effects on mental health and related conditions. They hint at the possibility of enduring benefits, gender-specific responses, and opportunities for elucidating the mechanisms that drive these improvements. As such, they emphasise the need for future research to explore these facets in greater detail and promote a more comprehensive understanding of MO’s extract therapeutic potential.

In conclusion, this rigorous, randomised, prospective, multi-centre, double-blinded, placebo-controlled clinical study has provided compelling evidence of the beneficial effects of MO phospholipid extract supplementation on mental health, wellbeing, and sleep quality. The findings of this study have several important implications and open avenues for future research and clinical applications.