Marco Valussi's Report on White Verbena Essential Oil

Fact Sheet Box (POWO 2023)

• Scientific name: Lippia alba (Mill.) N.E.Br. ex Britton & P.Wilson. Bot. Porto Rico 6: 141 (1925)
• Synonyms: Lantana alba Mill.; Lippia asperifolia Poepp. Ex Cham; L. citrata Willd. ex Cham.; L. geminata Kunth, ecc.  There exist an incredible number of synonyms, belonging to the genera Lippia, Lantana, Phyla, Verbena and Zapania, possibly because of the variability of the species and more generally of the complexities inherent in the Verbenaceae family.
• Phylum: Magnoliophyta Cronquist, Takht. & W.Zimm.,
• Order: Lamiales Bromhead
• Family: Verbenaceae J.St.-Hil. Native in tropical and subtropical areas.
• Genus: Lippia L.  Its a genus comprising about 254 species, varieties, and named forms, widely distributed in subtropical and tropical America, a few also in tropical portions of the Old World (Anon. 2013a)
• Species: Lippia alba. Seven infraspecific taxa were recognized, but have now been regrouped in Lippia alba: Lippia alba f. alba, L. alba var. carterae Moldenke, L. alba var. globiflora (L’Her.) Moldenke, L. alba f. intermedia Moldenke, L. alba var. lanceolata (Griseb.) Mulgura, L. alba f. macrophylla Moldenke, L. alba f. scabra Moldenke
• Popular names: White Verbena, Bushy Lippia (Engl.); mélisse de calme (creole, modification of “Mélisse des Carmes”); falsa melissa, erva cidreira, alecrim do campo, salvia limao, salsa brava, salvia da gripe (Brasil); yerba buena, romerillo, salvia del campo (Uruguay); juanilama (Costa Rica, Nicaragua, Honduras); oroazul (Panamá); salvia santa, salvia sija (Guatemala); quita dolor, menta americana, anís de España, salvia americana, contrainfluenza, palau, poleo, yerba buena americana (Cuba); mastrante, salvia betonica, sonora, té del país, té de pan, té de maceta (Mexico); pronto alivio (Colombia); orégano de burro (Perú); cariaquito blanco, toronjil, toronjil mulato (Venezuela); salvia morada, salvia trepadora, cidroma, toronjil morado, salvia de jardín, salvia maestra (Argentina), ajkukuli mop (idioma vilela), kaguetá iché itará (idioma toba)

Introduction

Lippia alba is a fragrant, perennial shrub that branches out and is native to the dry forests of tropical and subtropical regions in the Americas. It belongs to the Verbenaceae family, which includes other noteworthy plants like Aloysia triphylla (L’Hérit.) Britt. and Verbena officinalis L., known for their medicinal properties (Hennebelle et al. 2008). Despite its unassuming size, Lippia alba boasts a global distribution, underscoring its significance in traditional medicine, ethnopharmacology, its role as an ornamental plant prized for its aromatic leaves and beautiful flowers, as well as its use as a flavoring agent in foods. The plant's height varies by location but rarely exceeds 1.5 meters. It possesses slightly hairy leaves that grow opposite each other and emit a strong fragrance. These leaves are 5-10 cm long, either oval or elongated, serrated at the edges, with a stalk, and rough on the upper side but covered in fine hairs on the grayish underside. The plant produces small purplish or pinkish flowers arranged in clusters (inflorescences) (Dimitri, 1980).
Lippia alba has a broad natural range; it grows spontaneously across almost all of South America, stretching from northern Argentina through the West Indies and Central America to Mexico and the southern United States (Florida) (Hennebelle et al. 2008; Anon. 2013b). This distribution extends beyond the Americas, as it has been introduced and often escapes cultivation in other parts of the world as well (Anon. 2013b).. The plant finds application in diverse regions such as India (Singh et al., 2000), Australia (Day, Mc Andrew, 2003) and Africa (Terblanché and Kornelius, 1996).  Evolved to thrive in arid conditions, it favors high light-intensity environments and can endure dry spells lasting up to 4-6 months. In the humid Caribbean, it flourishes, generating an abundance of leafy branches. However, it faces challenges in higher altitudes and colder climates. The decline of forest cover in the tropical and subtropical dry regions has led to the decline of its natural populations, prompting several American countries to initiate projects aimed at domesticating and cultivating the species (POWO 2023). Its reputation in regional traditional medicine is largely due to its essential oil content, which holds significant cultural value.

Traditional uses.

Plants belonging to the Verbenaceae family have long been utilized in traditional medicine to alleviate gastrointestinal and respiratory ailments (Morton, 1981). Among these, Lippia alba has a storied history of use in French overseas territories such as French Guiana, Guadeloupe, and Martinique. Notably, it was one of the pioneering plants, along with Senna alata, to receive approval from the French Drug Agency (AFSSaPS) for inclusion in the French Pharmacopeia, marking its recognition as a valuable botanical remedy (Robard, 2003).
Across Latin America, Lippia alba has garnered a multitude of local and traditional names, reflecting its widespread integration into indigenous practices due to its aromatic essence and medicinal attributes. The aerial parts of the plant are harnessed to formulate antispasmodic, calming, and relaxing treatments. Additionally, its antiviral and antiherpes properties have been noted (Andrighetti-Fröhner et al., 2005), and it's employed to address stomach issues owing to its antiulcerogenic properties (Pascual et al., 2001). The leaves are steeped to create infusions or syrups that effectively combat respiratory conditions, including flu and cough. Furthermore, they serve as digestive aids, antispasmodics, sedatives, and even anticonvulsants (Zétola et al., 2002).
A multitude of scholarly works have documented ethnopharmacological investigations that have been organized based on geographical regions, providing insight into the rich traditional knowledge surrounding this plant (Hennebelle et al., 2008): 

• in Brazil the infusion of the leaves is used against digestive troubles in general, nausea and vomiting, stomach pain, and flatulence; respiratory problems, bronchitis, sore throat, flu, cough and colds; as a sedative, in case of hypertension, and for pain and wounds.  In the state of Sao Paulo the plant is very often mentioned by plant users and traditional healers (in the 29.5% of interviews). Leaves are used as an infusion, states of excitement, hypertension, digestive troubles, nausea and cold, to heal wounds locally and as a syrup against cough and bronchitis. An infusion of the roots is used against bad colds and coughs. In Esperantina, an infusion of the leaves is used, albeit not very often, against sore throat and flu. In the state of Pernambuco, local specialists use it at times against anaemia and digestive troubles. In Bahia it was one of the two most frequently cited species, and it is used as a sedative (like in Porto Alegre) and also against hypertension, flatulence and pain, while in Itacare it is used against stomach ache and digestive troubles (Holetz et al. 2002; Oliveira et al. 2006; Matos 1996)
• In a Mixe community, in Mexico, the leaves were frequently cited by traditional healers as active against gastrointestinal troubles, stomach pain, as an antispasmodic and stomachic, but it is also used as an emenagogogue and a sudorific in colds (Heinrich et al., 1992).
• In Colombia the infusion of the leaves is used against digestive troubles in general, stomach pain, diarrhea; flu  and cough, and for pain. It is one of the ten species with the highest level of significative use, according to TRAMIL: it was cited by 20% of interviewed people (Toscano-Gonzalez, 2006).
• In the Afro-Caribbean community of Guatemala the leaves are used against cough, skin diseases, flatulence, nausea and vomiting, headache (Caceres et al., 1993).
• In Argentina the leaves and aerial parts are used in infusion as emmenagogue and abortive, antispasmodic, digestive, stimulant, nerve, expectorant, diaphoretic and antihemorrhoidal (Elder et al. 1997)
• in Venezuela they are used as sudorific, diaphoretic, emmenagogue, antispasmodic, stomachic, antidiabetic, sedative (Elder et al. 1997)
• in Perù they are used for headache and diarrhea (Elder et al. 1997)
• in Cuba the leaves are used for bronchitis, colic and diarrhea, headache or stomach pain, and for cough. (Elder et al. 1997)

Physico-chemical properties

• Water solubility:  84.71 mg/L @ 25 °C
• Relative density at 20 °C: 0.888-0.910
• ηd at 20°C: 1.4853-1.4909

Essential oil (CAS n. 8024-12-2)

The essentials oil is obtained by steam distillation of the dried leaves, harvested preferably when the plant is in flower.  The average yield-range is 0,1-1,4%. It is generally described as very pale yellow oil, with a liquorice-like and cineolic odor, with a terpenic, cymene-like presence, and a hint of wood.  The dry-down is described as strong, smoky, woody, with some guaiacwood aspect (Burfield 2017).  The EO distilled in Angola is a mobile liquid with a pale yellow color.  It has a very sweet, lemon candy top note, and after a few seconds a terpenic aspect slowly emerges as an undernote, which takes in a strange character. This terpenic aspect lasts for a long time with very little changes, becoming slightly less sweet, and more terpenic.  After 30 minutes the lemon candy note is stil there, sweet but less fresh than before, but still strong. The end note is strong, of lemon candy/Lemon verbena

Composition

The genus Lippia is marked by a particularly remarkable trait—variations in the essential oil composition found within the same species when collected from different geographical locations. This phenomenon is strikingly exemplified by Lippia alba. Notably, a range of chemotypes (CTs) has been identified, with Hennebelle et al. (2008) delineating seven distinct CTs. These different chemotypes are defined based on variations in oil composition and the potential shared pathways underlying the biosynthesis of oils across different instances.:

• Chemotype I: characterized by the presence of geranial/neral, linalool, β-caryophyllene as the main constituents (according to the dominant one we see four subtypes: CT Ia to CT Id) (Hennebelle et al. 2008). One EO from Brazil had linalool at 78%, 1,8-cineole at 6.5% and β-caryophyllene at 2.7% (CT Ib) (Dellacassa et al., 1990), while an EO from Uruguay had linalool at up to 55% (CT Ib) (Lorenzo y col., 2001). Another Brazilian EO had geranial at 27–30% and neral at 36–41% as the major compounds, with a low amount of linalool (<5%) (CT Ia) (Fischer et al., 2004; Hennebelle et al. 2008), and one Argentinian EO (type norte santafecino) had geranial/neral at 36%, and germacrene D at 25% (CT Ia). Similar materials were detected in Indian crops and in specially irradiated materials (Bahl et al., 2000, 2002), with a yield greater than 80% linalol; and in Brazil (Frighetto et al., 1998).  The Angolan oil appears to belong to CT Ia.
• Chemotype II: characterized by the presence of tagetenone (Hennebelle et al. 2008)
• Chemotype III: characterized by the presence of limonene with variable amounts of carvone, or biosynthetically related monoterpenic ketones, such as dihydrocarvone, piperitone, and piperitenone, instead of carvone (two subtypes, IIa and IIb) (Hennebelle et al. 2008). CT IIa: an EO from the Peruvian Amazon contained carvone (63%), germacrene-D (5.6%) and limonene (5%) as the major constituents; EOs from Cuba contain carvone (33%), limonene (31%) and  α-guaiene (13%); some Brazilian EOs were rich in carvone (42–55%) and limonene (23–30%), being chemically similar to the Cuban type. Similar materials were also found in Costa Rica (Hennebelle et al. 2008), Cuba (Pino et al., 1997) and Peru (Leclercq et al., 1999).  CT IIb: an Argentinian EO  (type tucumano) contained piperitone (24-37%), limonene (34-47%) and 1,8-cineole (10-13%). A similar EO was found in Guatemala (Senatore and Rigano, 2001).
• Chemotype IV: characterized by the presence of myrcene (Hennebelle et al. 2008)
• Chemotype V: characterized by the presence of γ-terpinene (47%) and p-cymene (9%) (Gomes et al. 1993)
• Chemotype VI: characterized by the presence of camphor, 1,8-cineole and limonene (Frighetto et al., 1998)
• Chemotype VII: characterized by the presence of  estragole. (Hennebelle et al., 2006a).
• Other authors have also recognized different CTs: one from Guatemala characterized by myrcenone (Fischer et al., 2004), and one Argentinian ones characterized by α-pinene, l-dihidrocarvone, camphor, geranial/neral and linalool (tipo santafecina)
  The several CTs show as the main components camphor, 1.8-cineole (low in Angolan oil), limonene, linalool, myrcenone, piperitone (not present in Angolan oil), and geranial/neral (main components on Angolan oil), although α-pinene and dihydrocarvone (not present in Angolan oil) can occur.

Tabella 2

Activities

Lippia alba is probably one of the most studied species in the Lippia genus from a pharmacological point of view, and the antiseptic activity of the EO has been the most studied one
Fungi. The EO inhibits fungal proliferation and aflatoxin B1 production (Pandey, et al. 2016) and it potently inhibits various Candida species (Oliveira et al. 2014; Pino Alea et al., 1996)
Bacteria. The EO showed anti-QS (quorum sensing) activity on Pseudomonas putida and E. coli strains. The highest activity inhibition for Pseudomonas putida was reached by the CT Ia (Angola). Only geranial and neral were active in P. putida, inhibiting long-chain-AHL (N-acyl-homoserine lactones)-dependent QS (AHL is a class of signaling molecules involved in bacterial quorum sensing). All the CTs were active QS inhibitors on E. coli (the most active being the CT IIa. QS inhibition is independent from the effect on cell growth. (Olivero-Verbel et al. 2014; Jaramillo-Colorado, et al. 2012).  An EO with a 40% carvone content showed MIC values of 250–500 g/ml against Staphylococcus aureus (Pino Alea et al., 1996), while less significant activities  (MIC = 600–630g/ml) were observed against Staphylococcus epidermidis, Enterococcus faecalis, Serratia marcescens (Pino Alea et al., 1996). The growth inhibition zone of EOs off the CT Ia (5L/disc) was superior to that of vancomycin (10 g/disc) in methicillin-resistant Staphylococcus aureus (Oliveira et al., 2006).
Viruses. Meneses et al. (2009) have shown that the EO significantly reduces plaque-forming units of the yellow  fever virus, by means of direct inactivation of the virions, possibly by the destruction of the viral envelope by lipophilic compounds. It has a similar action on the dengue virus, with a MIC of 3.7 μg/ml. (Ocazionez et al. 2010).
It is an effective tick repellent (Benelli, Pavela 2017)
Anticonvulsant activity. EOs from three chemotypes of Lippia alba (myrcene, limonene, citral) have shown anticonvulsive effects, in that they increase the latency period and survival of mice with PTZ-induced seizures (Table 1) (Viana et al. 2000)

Table 1

Anxiolytic effects. Hatano and colleagues (2012) conducted research using animal models to uncover the impact of an EO predominantly composed of d-carvone. This particular EO displayed anxiolytic-like effects without affecting motor activity when assessed in the elevated-T maze test. This response resembled the actions of the reference drug diazepam. The administration of this EO via intraperitoneal injection (i.p.) in male rats prompted the authors to speculate that d-carvone was the key compound behind the anxiolytic effects (Hatano et al., 2012).
However, a different perspective was presented by Vale et al. (1999, 2002), who explored the anxiolytic effects of three distinct chemotypes of the EO, as well as certain major constituents (citral, myrcene, limonene), via i.p. administration. Notably, these chemotypes included: 1) 55% citral, 10% myrcene; 2) 63% citral, 23% limonene; and 3) 55% carvone, 12% limonene. Surprisingly, all three chemotypes and their constituents demonstrated comparable anxiolytic effects.
It's worth noting that these findings are difficult to align with traditional methods of use, and the reference drug diazepam (administered at 0.75 mg/kg i.p.) displayed much stronger activity. Consequently, drawing conclusive insights about the sedative attributes of Lippia alba's essential oil within a traditional context remains uncertain at this juncture (Hennebelle et al., 2007).
An additional study examined the EO's impact on animal models and identified an anesthetic effect. This suggests a potential influence on GABAergic mechanisms, which could account for the anxiolytic-like responses observed (Heldwein et al., 2012).
Analgesic and anti-inflammatory activities. Essential oils (EOs) falling into the categories of CT Ia and CT IIa demonstrated considerable inhibition of acetic acid-induced writhing in mice, with reductions reaching up to 80.5%. Notably, CT Ia stood out as the sole category that extended the latency time in the hot plate test to the same degree (51.5%) as the standard drug. Interestingly, the pain-relieving impact of CT Ia was counteracted by the opioid antagonist naloxone, indicating its engagement with morphine-related mechanisms. However, the effect produced by CT IIa remained unaffected by naloxone administration. These findings highlight the potential distinct action pathways of these two chemotypes (Viana et al., 1998).
Antioxidant activity. One EO CT II (61% carvone), had antioxidant activities (tested by the DPPH assay and TEAC), with very low activities (Puertas-Mejia et al., 2002). Another (51% carvone, 33% limonene) inhibited FeSO4-induced linoleic acid peroxydation (Stashenko et al., 2004).
Cancer: an EO distinguished by its high content of nerol/geraniol (27.1%), neral/geranial (21.9%), 6-methyl-5-heptene-2-one (12.0%), and β-caryophyllene (9.3%) has demonstrated noteworthy effects against cancer. This EO exhibited substantial anti-cancer properties when tested against both murine melanoma and human lung adenocarcinoma cell lines. Impressively, its effectiveness was such that it displayed lower IC50 values compared to well-established chemotherapy agents like cisplatin and paclitaxel (Santos et al., 2016).

Hazards

While there haven't been targeted safety assessments specifically for Lippia alba essential oils (EOs), potential risks can be inferred from their chemical composition. Notably, p-Cymene is present at approximately 3-4%, and while it might have a mild irritant or allergenic effect, this warrants attention. In higher concentrations (15-16.0%), Limonene could trigger skin reactions when oxidized. The combined presence of Geranial and Neral at around 30% concentration underscores a likelihood of skin sensitization, although their allergenic potential remains relatively low.
A substantial content of Camphor, accounting for 17.6%, poses notable concerns. This compound carries the potential for neurotoxicity, impacting the central nervous system and potentially causing adverse effects on the liver and kidneys. It also acts as a central nervous system stimulant, capable of inducing anything from mild excitement to more severe grand-mal convulsions..

Theoretical safety limits for the Angolan EO

-  Human daily oral maximum dose (calculated taking citrals content into account): 150 mg for an adult of 70 kg
-  Human daily oral maximum dose (calculated taking camphor content into account): 2 mg/kg/day = 140 mg/day camphor for a 70 kg adult = 814 mg/day EO for a 70 kg adult
-  Maximum dermal (leave-on) concentration (calculated taking citral content into account): 2%
-  Maximum dermal exposure: 3-4.6% camphor, 17.5-25% EO
-  Nebulization exposure limit (averaged over an 8-hour work shift) = 2-12 mg/m³.  For a room of medium size (4x3.5 m = 39 m³ and 20 cm³) = 80-480 mg camphor = 0.5-2.8 g OE

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