by Yicen Yue

Adding a lemon verbena leaf to a cocktail will give it a lovely, refreshing tisane, and enjoying this wonderful lemon aroma is nigh on indispensable in the summer. It has been found that lemon verbena has been mentioned more and more in recipes in recent years, as it adds the flavour of lemon to fish, meat, beverages, salads, puddings, jams and yoghurt. Actually, lemon verbena has been used for a long time in cooking, garden art and ethnopharmacology, as well as being a significant element in various teas and essential oils (EOs). The main component of its EO is citral (neral and geranial) and verbascoside is the most important component in its extract. Several biological activities of lemon verbena, such as anticancer, antioxidant, anaesthesia, neuroprotection, sedative, and antibacterial, have been confirmed in cell cultures and animal studies. How does this gorgeous deciduous shrub with a wonderful lemon aroma enter the garden and kitchen from the forest? And how is it used as herbal medicine for gastrointestinal disorders in modern pharmaceutical studies? This monograph will discuss the history of lemon verbena’s use and its phytochemistry and pharmacology.

Introduction

Lemon verbena’s botanical name is Aloysia citrodora Paláu (A. citrodora). Its alternative names are: Aloysia triphylla (L’Hérit.) Britt; Verbena triphylla (L’Hérit.); Lippia citriodora (Ort.) H.B.; Lippia triphylla (L’Hérit.) Kuntze (Gattuso et al., 2008). A. citrodora is a perennial erect shrub with a strong lemon flavour (citrodora means lemon flavour in Latin). It is between one and three metres high and has light green leaves (Gruenwald et al., 2007). The leaves are between five and ten centimetres long and they are lanceolate, slightly rough to the touch and have slight teeth (ibid). Tiny flowers bloom at the end of spring or in early summer, which are white, light blue or purple (ibid). The inflorescence of A. citrodora shown in Fig.1. It is worth mentioning that A. citrodora is evergreen in the tropics and can be used to harvest two kinds of crops every year in temperate zones, which shows its value in horticulture and commercialisation (Luchian et al., 2018). This species is sensitive to the cold as it cannot withstand temperatures below ten degrees Celsius. Sometimes it can live throughout the winter in a temperate zone, depending on the overall conditions, but it loses leaves when the temperature falls below zero degrees Celsius (ibid). A. citrodora can be found in the Mecklenburg Square Garden, but it is mainly native to America, including Argentina, Chile and Uruguay (Bahramsoltani et al., 2018). It was not planted in Europe and North Africa (Morocco) until the 17th century, when it became an important horticultural plant that was used as medicine for several conditions, such as diarrhoea, insomnia and flatulence (ibid).

History and traditional usage

In America, A. citrodora is widely used in food, cosmetics and other products due to its pleasant lemon flavour, as well as being used as a natural medicine for some health problems (Elechosa et al., 2017). According to the literature, the first reported traditional use of this plant might date back to the 17th century. The importance of its ethnopharmacology has been demonstrated, as it was widely used as an Incan medicinal plant (Elechosa et al., 2017; Siedo, 2006). The ‘kallawayas’, which refers to the traditional medical experts in Inca culture, named the medicinal plant ‘quechua’ or ‘wari pankara’ and used it to treat muscle spasms, problems with the digestive tract, bronchitis and heart disease (Girault, 1987). It may be for this reason that Spanish scientists brought A. citrodora to Europe to be grown as a natural medicine and garden plant.

Many countries have a long history of using lemon verbena, such as Portugal, Peru and Brazil. A. citrodora is cultivated in several countries because citral, which is the main compound of lemon verbena, has a high commercial value (Parodi et al., 2013). In Portugal and Peru, there is a traditional refreshment drink that is very popular and is made from lemon verbena extract. It can also be used as a condiment in soft drinks and wine (Jiménez-Ferrer et al., 2017; Santos-Gomes et al., 2005). Lemon verbena is often found growing in the gardens and kitchens of Brazilian families as a seasoning for cooking, as well as an insecticide and natural medicine for tropical diseases (Alves et al., 2000). Furthermore, its tea is common in Brazil, as it contains aromatic and polyphenolic compounds, which not only relieve the symptoms of colds and fevers, but can also be used for nerve and acne problems (Carnat et al., 1999; Merétika et al., 2010). According to several studies, the preparation of infusions is the most common use of lemon verbena and the biological activities of its components have been confirmed (Gil et al., 2007). This plant can also be used as a tincture to treat skin diseases (Duarte et al., 2005).

Phytochemistry

The widespread traditional use of lemon verbena attracted the attention of chemists and pharmacists. In order to study its biological activity, a variety of flavonoids were isolated from the lemon verbena plant, including flavonols, flavones, isoflavones, flavanols and flavanones (Pandey and Rizvi, 2009). In 1988, a series of flavonoids were isolated from its leaves using column chromatography, and all its flavonoid structures were identified (Skaltsa and Shammas, 1988). According to recent studies, Zhang, et al. (2015) isolated new flavonoids, including nepetin and jaceosidin. In addition to the aforementioned phytochemicals, other phytochemicals that have been isolated from the plants and their EOs include terpenes, fatty alcohols, ketones, lignans and triterpenoids (Bahramsoltani et al., 2018).

As is commonly known, plants indisputably contain many phytochemicals. Although several phytochemicals have been isolated and certified, their content and activity still require further study. Argyropoulou et al. (2007) pointed out that monoterpenes can be extracted from the EO of the aboveground part of A. citrodora. In Greece and Portugal, limonene (5.8–17.7%), neral (21.8–24.5%) and geranial (26.8–38.7%) are the major compounds in the EOs of A. citrodora (Argyropoulou et al., 2007). Samples of A. citrodora were collected from other EOs in Jordan, Argentina, Chile and Paraguay, and they were detected to have similar components, but there was a slight difference in their content (Hudaib et al., 2013). In the study, although there was a slight difference in the plant’s source and chemical content, the major compounds in the EOs were once again confirmed. Furthermore, sesquiterpenoids were also detected in the EOs, although they made up only 14.1–15.1% of the EO, whereas monoterpenoids accounted for 79.5–83.3% (Argyropoulou et al., 2007). It is worth mentioning that monoterpenes seem to be relevant to the antibacterial activity of A. citrodora; however, due to the low content of the compounds, this bactericidal effect is not particularly obvious (Parodi et al., 2014).

Pharmacological activities

The pharmacological activities of lemon verbena mainly include antibacterial, antioxidant, gastrointestinal, neuropsychological, estrogenic, cardiovascular, anticancer and anti-inflammatory effects (Bahramsoltani et al., 2018). Its pharmacological activities are associated with its phytochemical characteristics. For example, its antibacterial activity is related to its terpenes, and verbascoside has an antioxidant activity (Gressler et al., 2014; Hashemi et al., 2018). Several major pharmacological activities will be discussed in the following sections.

Antibacterial activity
Although monoterpenes are the main chemical components in the EOs of lemon verbena and studies have shown that monoterpenes are related to antibacterial mechanisms, it is still not clear whether or not lemon verbena has an adequate antibacterial activity. Hammer et al. (1999) found that the lipophilic properties of terpenes are related to antibacterial mechanisms. Hashemi et al. (2018) pointed out that lipophilic EOs can destroy the membrane of microorganisms. In addition, Hashemi et al. (2018) believed that the cytotoxic activity related to ethylene oxide could destroy the structure of the cell polysaccharide, the fatty acids and the phospholipid layer. Hashemi used an agar diffusion assay to determine antimicrobial activity, which showed that the EOs of lemon verbena have an antibacterial effect on Escherichia coli, Staphylococcus aureus, Bacillus cereus, Pseudomonas aeruginosa and Salmonella Typhimurium, and the different extraction technologies show the different extents of their antibacterial activities (Hashemi et al., 2018). Among them, Staphylococcus aureus strains are highly sensitive to EOs extracted by hydrodistillation — both continuous and pulsed ultrasonic-assisted hydrodistillation. The most susceptible microorganism is Bacillus cereus and the most resistant microorganism is Pseudomonas aeruginosa (Hashemi et al., 2018). However, Parodi et al. (2014) have proven that, although lemon verbena has antibacterial activities, its bactericidal effect is not particularly obvious because of the low content of its compounds.

Antioxidant and anti-inflammatory effects
The administration of lemon verbena in rats demonstrated an increase in antioxidant enzyme activity, including catalase and glutathione reductase (Gred) and glutathione peroxidase (Gpx), as well as a decrease in myeloperoxidase (MPO) activity and the protection of blood cells (Quirantes-Piné et al., 2013). Furthermore, a clinical study tested the antioxidant characteristics of lemon verbena as a sports beverage. The drink created from lemon verbena extract presented antioxidant activities, significantly increasing Gpx and Gred (Mestre-Alfaro et al., 2011). Similarly, a randomised, double-blind clinical trial monitored 15 subjects for three weeks to evaluate the antioxidant effect of lemon verbena extract (Carrera-Quintanar et al., 2012). The results showed that red blood cells and lymphocytes (P < 0.05) were significantly improved (ibid), which illustrates that lemon verbena extract is likely to improve antioxidant enzyme activity and oxidative stress.

The extract of lemon verbena has demonstrated strong antioxidant activity (Caturla et al., 2011). As joint diseases (osteoarthritis and rheumatoid arthritis) are closely associated with oxidative stress and inflammation, oxidants have an important role in the pathogenesis of inflammatory-related disorders (Rosenbaum et al., 2010). After ingesting Omega-3 fatty acids in fish oil with standardised lemon verbena extract (14% verbascoside, w/w), 45 subjects with symptoms of pain and stiffness reported that their symptoms had been significantly reduced. Their physical functions also improved after nine weeks, as shown in their Lequesne score (78% decrease) and Western Ontario MacMaster (53% decrease) (Caturla et al., 2011).

Gastrointestinal effects
The aqueous extracts of lemon verbena can inhibit acetylcholine (ACh) and relax the intestinal smooth muscle (Ragone et al., 2007). Another test used charcoal gum acacia to induce the hyperactivity of peristalsis in rats, showing that the methanolic extract of lemon verbena can moderately inhibit movement in the small intestine, with 32% inhibition, which is almost equivalent to loperamide (Calzada et al., 2010). These results support the aforementioned statement that lemon verbena can be used as a traditional antidiarrheal. Furthermore, the leaf of lemon verbena (Latin name: Aloysiae folium) is used as a herbal medicine for gastrointestinal disorders, having been registered in the European Pharmacopoeia (2007).

Safety and toxicity

In recent studies, the safety and toxicology of lemon verbena has rarely been assessed. Studies show that 1mg/kg/day of verbascoside had a teratogenic effect on rats (Etemad et al., 2015), whereas 0.5mg/kg of extract had no adverse effect on embryo development in pregnant animals without teratogenic characteristics (Shirvan et al., 2016). Moreover, in the acute toxicity evaluation, the LD50 of verbascoside was higher than 5g/kg. In the subacute toxicity evaluation, no obvious pathological, haematological or biochemical toxic effects were observed three weeks after administration (Etemad et al., 2015). It has also been reported that gastric irritation is likely to be caused by high doses of lemon verbena, and the EOs of lemon verbena that contain high neral and geranial content might cause photosensitivity (Bahramsoltani et al., 2018).

Conclusion

Lemon verbena is an important natural medicinal plant in traditional American medicine. It is now not only a forest plant, as it can also be found in gardens and as potted plants in kitchens. In addition, lemon verbena has been used as a natural medicine in different countries for various diseases, such as problems with one’s digestive tract, muscle spasms and heart disease. Both nonclinical and clinical studies have proven its activities in antibacterial, antioxidant and gastrointestinal effects, as well as many other activities. However, it is essential that these therapeutic effects should be confirmed in well-designed clinical tests. Furthermore, the safety of the plant has not been fully evaluated in clinical studies. Therefore, safety and toxicological studies associated with the plant’s use should be developed.

DISCLAIMER

In this essay, we do not intend to advise or recommend herbs for health benefits or medicinal use. This information is for educational purposes only and should not be considered as a recommendation or an endorsement of any particular medical or health treatment. The use of any such product should be based on the appropriate advice of a healthcare professional or the information available in the patient information leaflets (i.e. for THR products). The information provided should not be used during any medical emergencies or for the diagnosis or treatment of any medical conditions.

© Yicen Yue 2020. All rights reserved.

Yicen Yue, MSc. Student in Medicinal Natural Products and Phytochemistry at the UCL School of Pharmacy (2019-2020).
UCL School of Pharmacy, Univ. London
29-39 Brunswick Sq., London WC1N 1AX

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Images
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