molecules Review Thymol and Thyme Essential Oil—New Insights into Selected Therapeutic Applications Adam Kowalczyk 1 , Martyna Przychodna 2, Sylwia Sopata 2, Agnieszka Bodalska 1,* and Izabela Fecka 1 1 Department of Pharmacognosy and Herbal Medicines, Faculty of Pharmacy, Wroclaw Medical University, Borowska 211, 50-556 Wroclaw, Poland; [email protected] (A.K.); [email protected] (I.F.) 2 Student’s Scientific Group of Department of Pharmacognosy and Herbal Medicines, Faculty of Pharmacy, Wroclaw Medical University, Borowska 211, 50-556 Wroclaw, Poland; [email protected] (M.P.); [email protected] (S.S.) * Correspondence: [email protected] Received: 16 July 2020; Accepted: 8 September 2020; Published: 9 September 2020 Abstract: Thymol (2-isopropyl-5-methylphenol) belongs to the phenolic monoterpenes and mostly occurs in thyme species. It is one of the main compounds of thyme essential oil. Both thymol and thyme essential oil have long been used in traditional medicine as expectorant, anti-inflammatory, antiviral, antibacterial, and antiseptic agents, mainly in the treatment of the upper respiratory system. The current search for new directions of biological or therapeutic activities of natural plant substances with known structures includes thyme essential oil and thymol. Novel studies have demonstrated their antibiofilm, antifungal, antileishmanial, antiviral, and anticancer properties. Also, their new therapeutic formulations, such as nanocapsules containing these constituents, can be beneficial in medicinal practice and create opportunities for their extensive use. Extensive application of thymol and thyme essential oil in the healthcare sector is very promising but requires further research and analysis. Keywords: thymol; thyme essential oil; new therapeutic applications 1. Introduction The genus Thymus from the Lamiaceae family contains many representatives. These plants, originating from the Mediterranean area, are commonly used for food, cosmetic, and medicinal purposes [1]. A thyme herb obtained from Thymus vulgaris L. and Thymus zygis L. is the most well-known herbal substance in the pharmaceutical industry. Nowadays, only standardized preparations of thyme herb and essential oil that meet the requirements of national pharmacopeias or European Pharmacopoeia X (Ph. Eur. X) are used for the production of medicines. According to the Ph. Eur. X definition, thyme herb is described as whole leaves and flowers separated from the dried stems of T. vulgaris or T. zygis or their mixture with 12 mL/kg of minimum essential oil (EO) and minimum thymol and carvacrol contents of 40% [2]. Thyme EO is defined as a product of the steam distillation of fresh flowering aerial parts of one or a mixture of both species with 37–55% thymol and 0.5–5.5% carvacrol concentrations [2,3]. The thyme herb, EO, and their main volatile components—thymol and carvacrol—have found wide application for therapeutic objectives. The scope of medical usage, preclinical, and clinical data, as well as the chemical composition of thyme herb and EO, have been summarized and published by the Committee on Herbal Medicinal Products (HMPC) of the European Medicines Agency (EMA) as the corresponding assessment reports and monographs [3,4]. When discussing the chemical composition Molecules 2020, 25, 4125; doi:10.3390/molecules25184125 www.mdpi.com/journal/molecules Molecules 2020, 25, x FOR PEER REVIEW 2 of 18 Molecules 2020, 25, 4125 2 of 17 composition and activity of thyme herb and its hydroalcoholic extracts, except for the volatile andfraction, activity non of- thymevolatile herb components and its hydroalcoholic such as flavonoid extracts, glycosides, except for thecaffeic volatile acid fraction, oligomers, non-volatile simple componentsphenolic acids, such hydroquinone as flavonoid glycosides,derivatives, ca andffeic terpenoids acid oligomers, should simple also be phenolic taken into acids, account. hydroquinone Detailed derivatives,information andabout terpenoids these components should also can bebe takenfound intoin the account. literature Detailed [5–7]. information about these componentsThyme canEO be compounds found in the literaturebelong to [5 –7various]. chemical groups including monoterpenes, monoterpeneThyme EO alcohols, compounds phenol belong derivatives, to various ketones, chemical aldehydes, groups including ethers monoterpenes,, and esters. There monoterpene are also alcohols,numerous phenol chemotypes derivatives, within the ketones, T. vulgaris aldehydes, species, ethers,differing and in the esters. main Therecomponent are also of EO numerous, but only chemotypes“thymol type” within with the thymolT. vulgaris as thespecies, main constituent differing in is the listed main in component the European of EO, Pharmacopoeia. but only “thymol The type”main withcomponents thymol of as thyme the main EO constituent are the isomeric is listed phenolic in the Europeanmonoterpenes Pharmacopoeia. thymol (2-isopropyl The main-5- componentsmethylphenol) of thyme and EOcarvacrol are the isomeric(2-methyl phenolic-5-(propan monoterpenes-2-yl)phenol). thymol Both (2-isopropyl-5-methylphenol) these monoterpenes are andbiosynthesized carvacrol (2-methyl-5-(propan-2-yl)phenol). by the hydroxylation of p-cymene Both after these the aromatization monoterpenes of are γ-terpinene biosynthesized to p-cymene. by the hydroxylationThe scheme of ofthe p-cymene biosynthesis after pathway the aromatization is shown in of Figureγ-terpinene 1 [6]. toThymolp-cymene. is a colorless, The scheme crystalline of the biosynthesiscompound with pathway characteristic is showns inincluding Figure1 [strong6]. Thymol odor and is asolub colorless,ility in crystalline alcohol and compound other organic with characteristicssolvents, but it includingis only slightly strong soluble odor andin water solubility [8]. Carvacrol, in alcohol on and the otherother organichand, is solvents,a colorless but to itpale is onlyyellow slightly liquid, soluble insoluble in water in water [8]. but Carvacrol, highly soluble on the in other ethanol, hand, acetone, is a colorless and diethyl to pale ether yellow and liquid,with a insolublethymol odor in water [9]. Structures but highly solubleof thymol, in ethanol, carvacrol acetone,, and other and diethyl thyme ether EO components and with a thymol—p-cymene, odor [ 9γ].- Structuresterpinene, oflinalool, thymol, carvacrol,β-myrcene, and terpinen other thyme-4-ol— EOare components— shown in pFigure-cymene, 2. γThymol-terpinene, after linalool, oral βadministration-myrcene, terpinen-4-ol—are is rapidly absorbed shown and in Figure slowly2. eliminated Thymol after approximately oral administration within is 24 rapidly h. It is absorbed found in andthe slowlyform of eliminated thymol sulfate approximately in plasma within, and 24two h. Itphase is found II conjugates in the form— ofthymol thymol sul sulfatefate and in plasma,thymol andglucuronide two phase—can II conjugates—thymol be found in the urine. sulfate The formation and thymol of glucuronide—canglucuronide was observed be found only in the at higher urine. Thedoses. formation Thymol of metabolites glucuronide are was presented observed in Figure only at 3. higher Oral bioavailability doses. Thymol referred metabolites to as thymol are presented sulfate inis Figureapproximately3. Oral bioavailability 16% and the referredplasma half to as-life thymol is approximately sulfate is approximately 1.5 h [10,11]. 16% The and bioactivity the plasma and half-lifetoxicological is approximately actions of carvacrol 1.5 h [10 were,11]. described The bioactivity by Sharifi and and toxicological co-workers actions [9]. of carvacrol were described by Sharifi and co-workers [9]. Figure 1. Scheme of the key steps of thymol and carvacrol biosynthesis. Figure 1. Scheme of the key steps of thymol and carvacrol biosynthesis. MoleculesMolecules2020 2020, 25, 2,5 4125, x FOR PEER REVIEW 33 of of 17 18 Figure 2. The structure of the main components of thyme essential oil. Figure 2. The structure of the main components of thyme essential oil. Thyme herb and its volatile oil have long been used for the treatment of upper respiratory tract infections, symptoms of bronchitis, parasitic infections, pruritus associated with dermatitis, bruises, and sprains. Nowadays, it is generally used as an expectorant in cough associated with cold and also in dentistry as a disinfectant [12]. It exerts an antibacterial effect on Gram-positive and Gram-negative bacteria and has antiviral (herpes simplex virus type I, human rhinoviruses and influenza viruses), antifungal, antioxidant, anti-inflammatory, and spasmolytic activity. Although thyme volatile oil has cytotoxic properties in high concentrations and may cause intestinal cell damage when administered orally, no toxicity has been reported at commonly used doses, and it can be considered as a safe drug. Skin administration in high concentrations may cause irritation. In rare cases, an allergic reaction can occur, manifesting as skin rash, bronchospasm, asthma attack, and anaphylaxis. Therefore, this EO is contraindicated in persons allergic to thyme or other plants from the Lamiaceae family due to a possible cross-reactivity [3,13,14]. Molecules 2020, 25, 4125 4 of 17 Molecules 2020, 25, x FOR PEER REVIEW 4 of 18 Figure 3. Thymol metabolites. Figure 3. Thymol metabolites. Thymol, as the main active ingredient responsible for the activity of thyme EO, has been shownThyme to possessherb and antiseptic, its volatile oil antibacterial,