Much research has attempted to characterize the potential health benefits attributed to thyme and its constituents, particularly thymol and carvacrol. They include anti-inflammatory, respiratory, and neurological effects. This article provides an overview of some of thyme’s biological actions and the variety of scientific research on thyme and its essential oil and major constituents. Particular attention is devoted to the benefits of thyme associated with dietary or culinary uses. For reasons of brevity, the appendix to this article, which is available online to readers (see Appendix, Supplementary Digital Content 1, https://links.lww.com/NT/A5), provides details on the methods used in conducting the review and details of studies with isolated constituents and in vitro and animal studies. There are limitations in the literature. The composition of thyme samples was often not reported and the bioavailability of major thyme constituents after intake of thyme has not been well characterized in humans. Large amounts of undefined samples with diverse dosing protocols were tested in animals. The biological actions of thyme at intake levels involved in culinary use in foods are largely unstudied. Lastly, larger, well-controlled human studies evaluating specific actions of thyme often were not available.
HISTORY AND APPLICATIONS
Thyme is a perennial shrub with greenish-gray aromatic leaves. It originates from Southern Europe and countries bordering the Mediterranean but now is found in many areas of the world with temperate climates. The many varieties of the plant differ in their flavor profiles. Common thyme (Thymus vulgaris L; family Lamiaceae) is closely related to wild thyme (Thymus serpyllum), and there are additional cultivars such as orange thyme, lemon thyme, and caraway thyme. Common thyme typically contains 0.4% to 3.4% volatile oil and is commercially prepared by distillation of its leaves. This results in 2 commercial varieties of oil. Red thyme oil is the initial crude distillate that subsequently can be redistilled to produce colorless or white thyme oil.1
The Greek word for thyme is derived from a descriptor meaning “to fumigate,” which may refer to the aroma generated in the burning of thyme as incense in ancient temples of Greece. Traditional remedies associated with thyme include alleviation of pulmonary diseases. Roman soldiers would bathe in thyme to become courageous.1,2 Thyme was also used in embalming in ancient times.3 In the 19th century, constituents of thyme oils were used by dentists to treat oral abscesses and inflammation and as an antiseptic for endodontics.4 Thyme essential oil is used commercially in the manufacture of soaps, cosmetics, mouthwash and toothpaste, chewing gum, candy, and ice cream. Thymol and carvacrol, principal constituents of this oil, are used in perfumes, food flavorings, mouthwashes, cosmetics, pharmaceutical products, and in feed additives and pesticides.5 Thyme’s culinary uses are many. Because of its distinct aroma, this spice is often added to baked goods, stews, meats, garden salads, poultry stuffings, seafood, egg dishes, and in marinades of chicken and fish. Thyme also contributes flavor to a variety of vegetable preparations, such as beans, onions, potatoes, and carrots. The amounts of thyme essential oil reported6 to be present in foods include (ppm) baked products (28), meat products (23), condiments (20), and soups (3).
COMPOSITION AND BIOAVAILABILITY
Major volatile constituents of thyme are (Figure 1) thymol (2-isopropyl-5 methylphenol), its isomer carvacrol, p-cymene, and α-terpineol.7,8 Thymol and carvacrol are present at 8.6 and 0.7 mg/g in thyme leaves in 1 study.7 Other constituents in T vulgaris leaves were 11 mg/g fresh weight caffeic acid, 92 mg/g rosmarinic acid, and 40 mg/g luteolin.9 Thymol and carvacrol also can be found in marjoram, oregano, and rosemary. The composition of essential oils and other extracts obtained from thyme differs depending on the species of Thymus (Figure 2), the specific chemotype of T vulgaris, cultivation conditions, and method of extraction. In general, thyme oil contains a high concentration of the phenolic compounds thymol and carvacrol, although the relative amounts can vary considerably.6–18 There is little in the scientific literature on the composition of specific extracts used to evaluate the biological actions of thyme. The Table provides an example of analyses that have been reported for different extracts. The variability underscores the need for more research on the composition of extracts to permit study of their biological activities, such as comparisons of biological responses and the safety of different thyme samples.
;)
FIGURE 1: Major volatile constituents of thyme.
FIGURE 2: Sketch of thyme.
TABLE: Examples of Composition of Thyme Extracts
The bioavailability of thymol and carvacrol, important contributors to thyme’s numerous biological actions, is not well established. After oral intake, the absorption, metabolism in host tissues and gut microbiota, and systemic distribution are important determinants of the final concentrations of parent compound and metabolites reaching the target organs.22,23 Thymol, carvacrol, and other thyme constituents are absorbed and metabolized in humans and some animals.22–29 Rats given an oral dose of an ethanol extract of thyme (5 g/kg body wt) exhibited a plasma concentration of thymol sulfate of 8464 μM 1 hour after intake, indicating that thymol is rapidly absorbed in the upper gut.30 In this study rosmarinic acid was the most abundant phenolic acid (237 μmol/1.5 g extract), whereas thymol was the most abundant monoterpene (44 μmol/1.5 g extract) and luteolin-7-O-glucoside was the major flavonoid (22 μmol/1.5 g extract). It was also noted that rosmarinic acid was rapidly degraded and conjugated, with no free rosmarinic acid subsequently being detected in the plasma. In a clinical trial using 12 healthy volunteers, each given orally a Bronchipret TP tablet (Bionorica AG, Neumarkt, Germany) containing 1.08 mg thymol, the peak plasma concentration of thymol sulfate (93 ng/mL) occurred after 2 hours and thereafter was slowly eliminated. The bioavailability of thymol was estimated to be at least 16%.22,31
POTENTIAL HEALTH BENEFITS
Antioxidant Actions
Thyme is 1 of 8 dried herbs from a group of over 60 analyzed that contained high total concentrations of antioxidants, greater than 75 mmol/100 g.32 For example, garden thyme contained 87 to 103 mmol/100 g and oregano 113 to 165 mmol/100 g. Levels of antioxidants in commercial samples of thyme were 2.8-fold greater than in ginger and 30-fold greater than in garlic. The authors suggested that the intake of herbs in a normal diet may be an even better contributor of dietary antioxidants than other plant foods. Essential oils are prepared by diverse methods, including hydrodistillation, supercritical fluid extraction, and liquid-liquid continuous extraction. The essential oil of T vulgaris has substantial antioxidant activity in assays that measured such endpoints as the scavenging of nitric oxide (NO) and 2,2-diphenyl-1-picrylhydrazyl radicals, the inhibition of superoxide radical formation and β-carotene bleaching, and the suppression of lipoxygenase and peroxidation activities. Additional assays used in antioxidant analyses of essential oils include the conjugated diene assay, aldehyde/carboxylic acid assay, and malondialdehyde/gas chromatography assay. In some cases, thyme essential oil was the most potent antioxidant among several oils evaluated.33–37 For example, thyme oil was compared with the oils of basil, rosemary, lavender, chamomile, sage, eucalyptus, cinnamon, and clove. Clove leaf and thyme oils demonstrated considerable inhibitory action in both antioxidant and lipoxygenase assays,33 and thyme oil antioxidant activity in lipophilic systems was considered as potent as that of butylated hydroxytoluene and α-tocopherol.34 Hydrophilic extracts of thyme have substantial antioxidant activity in vitro that apparently is due in large part to rosmarinic acid and some flavonoids.9,13,20,21,36–39 With respect to effects on cells, an ethanol extract of thyme used to pretreat HepG2 cells (0.5–1.0 mg/mL) protected DNA from H2O2-induced oxidative damage and stimulated cellular activity of glutathione peroxidase (GPx).40 Analysis of this extract indicated that rosmarinic acid (14.7 mg/g dry extract), salvanolic acid (3.1 mg/g), luteolin-hexoside (2.0 mg/g), and apigenin glycosides (4 mg/g) were major constituents. Other notable individual antioxidant constituents of thyme identified by in vitro assays include thymol, carvacrol, p-cymene, γ-terpinone, terpinolene, and some flavonoids.13,17,20,36–38 In lymphocyte cell cultures, thymol and carvacrol inhibited H2O2-induced oxidative damage at doses below 200 and 100 μM, respectively.41 At doses greater than 750 μM, thymol stimulated superoxide formation in human leukocyte cultures.42 Based on levels of thymol measured in humans22,31 after intake of thymol (<100 ng/mL in plasma), the concentrations used in these lymphocyte and leukocyte cells are probably not physiologically relevant. In contrast, it is of interest that when added to cultures of lipopolysaccharide-stimulated murine macrophages, thymol and carvacrol (10–100 ng/mL) significantly reduced NO and H2O2 production as well as NO synthase and reduced nicotinamide adenine dinucleotide oxidase activities.43 This finding suggests that cellular pathways regulated by NO synthesis may be relevant to thymol’s actions in humans and be worth additional focus.
Collectively, experimental animal studies showed orally administered thymol, carvacrol, and thyme oil to improve antioxidant status biomarkers in a variety of tissues (see Appendix, Supplemental Digital Content 1, https://links.lww.com/NT/A5). Similar effects were also evident with injections. These studies showed that thyme had the potential to protect against the oxidative damage that may contribute to chronic diseases of aging. However, they are difficult to interpret because of the different samples, animal models, and experimental designs evaluated, although they nonetheless indicate that thyme has general oxidation suppressing actions. Also unknown is whether individual effects are caused by individual constituents acting alone or if effects are caused by a combination of constituents acting together. Mechanisms of action are unknown but include free-radical scavenging and regulation of signaling pathways controlling the production of endogenous antioxidant molecules or enzymes. It is also unclear whether the parent molecules or specific metabolites are the active agents. Further research is needed to characterize the effects of acute and chronic dietary intakes of culinary-relevant levels of thyme on recognized biomarkers of oxidative stress in both animals and humans. Unfortunately, no data are available on human dietary intakes of thyme. However, a study of 146 healthy Norwegians found that their intake of most individual herbs and spices likely was not greater than 10 mg per person per day, with total herb and spice consumption ranging from 0.19 to 4.5 g per person per day.44 Median intake was 2.7 g per person per day. An estimate of carvacrol intake of 3 to 7 mg/d also has been reported.45,46 Based on these amounts, human intakes of 10 mg per person per day of thyme might be considered an initial reference dose in the design of future studies.
Anti-inflammatory Actions
Many processes involved in inflammation and its suppression are affected by thyme. For example, 1 group affected are the cytokines, chemical messengers that are produced by a variety of cell types, which can have proinflammatory actions (interleukin [IL]-1β, IL-6, and tumor necrosis factor-α) or anti-inflammatory effects (IL-10 and IL-4). The balance between these proinflammatory and anti-inflammatory cytokines regulates the magnitude of inflammatory response.47 Both the nuclear factor kappa-light-chain-enhancer of activated B cells and mitogen-activated protein kinase signaling pathways, when activated, can influence cytokine synthesis. However, the overall biological response can depend on complex interactions among the mitogen-activated protein kinase subgroups, p38, extracellular signal-regulated kinases, and c-Jun N-terminal kinases. Nitric oxide and H2O2 productions also are involved in managing cellular responses after inflammatory stimuli. Prostaglandins are lipid compounds derived from arachidonic acid that can contribute to the regulation of numerous body processes, including inflammation. The cyclooxygenase (COX) enzymes catalyze the first step of prostaglandin synthesis. Cyclooxygenase-2 enzyme activity in particular leads to increases in prostaglandin production during induction of inflammation. Agonists of peroxisome proliferator-activated receptors (PPARs) have been associated with anti-inflammatory activity, in part through suppression of COX-2 activity.48–51
There is much preclinical evidence that thyme, and particularly its constituent carvacrol stimulate antiinflammatory processes and extracts of T vulgaris have anti-inflammatory properties in vitro. For example, thyme oil suppressed COX-2 promoter activity and activated PPARα and PPARγ when added (0.002%–0.008%) to cultures of endothelial cells.48 Thyme oil added to cultures of oxidized low density lipoprotein-stimulated THP-1 macrophages (5-25 μg/mL) significantly reduced production and gene expression of the proinflammatory mediators tumor necrosis factor-α, IL-1β, and IL-6 and, conversely, increased production and gene expression for IL-10.49 This oil’s composition was reported to contain 71% thymol, 6% p-cymene, and 4% carvacrol. An undefined water extract of thyme activated dendritic cells in culture, decreased proliferation of mitogen-stimulated lymphocytes, and inhibited the release of IL-8 from cultures of stimulated human peripheral blood lymphocytes.52,53 An ethanol extract of thyme added to macrophage cultures (0.1%–0.4%) inhibited NO production as well as decreased inducible nitric oxide synthase mRNA expression, compared with controls,54 without altering cell viability. However, a methanol extract of thyme was ranked least potent among 8 spices in inhibiting NO release from lipopolysaccharide-activated macrophages.50 Individual constituents of thyme also have been evaluated in vitro for anti-inflammatory activity and the effects are mixed (see Appendix, Supplemental Digital Content 1, https://links.lww.com/NT/A5). Information about the effects of p-cymene and α-terpineol is not as substantial as that for carvacrol and thymol. Thyme and especially carvacrol also suppressed multiple markers of inflammation in a variety of tissues in experimental animals (see Appendix, Supplemental Digital Content 1, https://links.lww.com/NT/A5). However, the studies used different animal models, different dosing schedules, and doses much higher than in human diets, so their relevance to human health is uncertain. Future studies should examine the safety of chronic intakes of lower, culinary-relevant dietary doses of thyme on markers of inflammation in both healthy and ill animals, including arthritis, to assess thyme’s ability to alter the balance of proinflammatory and anti-inflammatory cytokines and other signaling pathways in tissues.
Possible Respiratory Benefits and Effects on Cough
In traditional medicines, thyme is claimed to possess antispasmodic, broncholytic, and secretomotor properties, and it is used in Central and South Europe for alleviation of bronchitis, whooping cough, and mucosal inflammation of the respiratory tract.45,46 The German Commission E report on herbal medicines mentions thyme bath oil to treat airway diseases.46 Possibly, the carvacrol and thymol in these medicinals have mild irritant effects on the lung that stimulate mucosal secretions and enhance ciliary movement in the bronchial epithelia leading to a decongestive response.
Most human studies have evaluated thyme in combination with other plant extracts. For example, in a controlled, multicentered, postmarketing surveillance study (not randomized or placebo controlled), Bronchipret tablets containing ethanol extracts of thyme (160 mg) and Primulae radix (60 mg) were compared with other herbal medications as well as the synthetic drugs N-acetyl cysteine and Ambroxol for efficacy among adults and children in treating cough.55 Patients (n = 7783) were assessed after 10 days of dosing with either Bronchipret or the other secrolytic drugs. Several clinical endpoints were assessed, including body temperature, auscultation, coughing pain, and quantity and viscosity of sputum. Treatment success or therapeutic benefit was determined by comparing pretreatment and posttreatment ratings as either symptom free, symptoms improved, symptoms unchanged, or symptoms deteriorated. It was determined that Bronchipret provided greater therapeutic benefit compared with the reference medications, although this benefit was less pronounced in children compared with adults. Adverse drug reactions were detected by participating physicians who asked patients about side effects and subsequently assessed whether these were causally related to the medication. For Bronchipret, gastrointestinal (GI) system (<0.7%), nervous system (<0.1%), and respiratory system (<0.1%) prevalence was less than that in other treatment groups. However, these findings were considered preliminary and were not prospective, controlled trials that included a placebo arm and comparison with a recognized efficacious drug.1 In another open trial to assess safety and efficacy toward cough, a mixture of thyme extract and extracts of ivy leaf, aniseed, and marshmallow root56 was administered at a 10 mL dose for 2 weeks to a heterogeneous group of 62 adults with either common colds and irritating coughs, or acute or chronic bronchitis, or respiratory tract diseases with substantial amounts of viscous mucus. They were evaluated at baseline and at the end for changes in symptom scores for strength of cough stimulus and in ease, amount, consistency, and color of expectoration. The group taking the herbal cough syrup had a greater improvement in cough symptoms than did controls, and patients reported no adverse reactions. However, this was not a randomized controlled trial either. Another study did use a double-blind, randomized, placebo-controlled design to determine the efficacy and tolerability of an extract of thyme and primrose root57 in adult outpatients with acute bronchitis. A total of 150 patients were randomized to treatment with either Bronchicum (MCM Klosterfrau, Koln, Germany) as drops (5 × 1 mL/d) or placebo for 7 to 9 days. Medication efficacy was assessed by severity of bronchitis compared with controls at the end of the study using a bronchitis severity score that measured cough, sputum, coughing pain, and dyspnea on a 5-point rating scale. More patients were symptom free in the treatment group (59%) compared with the placebo group (5%), and the therapeutic benefit was stronger for those presenting with a greater severity of acute bronchitis. The frequency, nature, and severity of adverse events were recorded by the participating physician during scheduled examinations. Only 7 adverse events were observed, 2 in the treatment group and 5 in the placebo group. In the thyme-ivy treatment group, only 1 event, slight and limited nausea, was medication related. There were no changes in blood pressure, heart rate, or body temperature. A double-blind, placebo-controlled study was conducted to evaluate the efficacy of a combination of thyme and ivy extracts in adult outpatients with productive cough.58 For this study, 351 adult outpatients were randomly assigned to receive a placebo or Bronchipret treatment (3 × 5.4 mL/d) for 11 days. Its efficacy was determined by physician assessment of bronchitis symptoms of strength of cough and expectoration and by patient self-assessment of daily coughing fits and symptoms of bronchitis. The thyme-ivy extract group had a significant reduction of coughing fits and faster bronchitis response rates than the placebo controls. Adverse drug reactions were determined by investigators at scheduled examinations, and additional safety parameters (blood pressure, heart rate, body temperature) were evaluated. Only 7 mild adverse events were reported for the thyme-ivy group and no clinically relevant changes in the safety parameters occurred. Similar findings were subsequently reported in another study for a combination of thyme herb and primrose root in adults with acute bronchitis with productive cough.59 As in previous studies, the herbal combination was well tolerated and no serious adverse events were reported. However, because undisclosed proprietary formulations of combinations of herbs were used, the individual contribution of thyme cannot be determined. Only 1 study55 provided a gas chromatographic analysis of the main bioactives in the formulation provided. Other deficiencies in these studies include inadequate validation of bronchitis severity scores and of the response criteria taken from patient diaries. There also was a lack of clear definition of some conditions such as acute bronchitis. Thus, the data from these trials were viewed as insufficient to justify the use of these treatments for cough.45,46
In a related study, nasal brushings were obtained from the inferior nasal turbinate of 10 healthy subjects and incubated with several essential oils including thyme.60 Exposure to thyme oil (0.2%–2.0%) did not enhance ciliary beat frequency, suggesting that nasal administration of thyme would be unlikely to improve mucociliary clearance for those seeking relief from sinusitis. In a more recent human study, 18 healthy volunteers with normal lung function were tested for cough before and after nasal administration of thymol (0.025 mL of 1 mM suspension). Quantitation of coughs was estimated during a capsaicin cough challenge.61 Although the cough threshold was not influenced, the total count of coughs after nasal thymol challenge was significantly decreased, compared with saline or vehicle controls. Moreover, the urge to cough was improved. Thus, intranasal administration of thymol-containing drops weakened the cough response to aerosolized capsaicin in these healthy volunteers. The authors suggested that thymol may have elicited its antitussive actions mainly through olfactory signaling.
Collectively, the preclinical and clinical data are suggestive but not well established that thyme is contributing to alleviation of respiratory irritations. Findings of combination human trials are difficult to interpret because thyme’s individual action cannot be assessed. The phytochemicals in thyme responsible for any respiratory benefits also have not been well defined. In vitro and in vivo data suggest that it is carvacrol more than thymol that is linked to bronchodilatory actions. Variability in thymol’s efficacy could be better explored by evaluating multiple routes of administration, including inhalation, in light of the human evidence that nasal application of thymol may have antitussive actions.61 The preclinical demonstrations that oral administration of carvacrol and thymol can lead to improved tracheal function underscore the need to evaluate thyme alone as a dietary constituent in similar studies. Finally, dose-response studies of the effect of chronic dietary intakes of culinary-relevant levels of thyme on respiratory endpoints in humans and in animal models of cough and congestion would be worthwhile.62,63 It is possible that specific varieties of thyme can be identified that contain a mix of biologically active phytochemicals capable of best improving these respiratory endpoints. Much more work is needed.
Neurological Actions
- 1. Antinociceptive activity
The antinociceptive and anesthetic activities of thyme extracts and individual thyme constituents are present in in vitro systems and animal experiments (see Appendix, Supplemental Digital Content 1, https://links.lww.com/NT/A5).
In humans, a randomized, single-blind clinical trial was conducted among 120 women suffering from primary dysmenorrhea.64 Participants were randomly assigned to 2 groups, orally receiving either the herbal treatment Broncho T.D. (commercial information not available but consists of the essential oil of Zataria multiflora Boiss. [Shirazi or Iranian thyme]) orally (4 × 5 mL/d) or ibuprofen (3 × 400 mg/d). Broncho T.D. contains 1.0 to 1.5 mg thymol per 120 mL.65 Additional active constituents were not reported. The primary outcome was patient-reported severity of menstrual pain as measured by use of a visual analog scale. Those receiving ibuprofen (400 mg, 3 times a day) experienced a reduction in pain severity that was not significantly different from the pain reduction reported by those orally administered the herbal oil. The pain reduction was suggested to be the result of antiprostaglandin and antispasmodic actions of the herbal agent.66
- 2. Neurobehavioral and neuroprotective properties
Both in vitro and in vivo studies discussed in the appendix (see Appendix, Supplemental Digital Content 1, https://links.lww.com/NT/A5) point to an ability of thyme phytochemicals to influence processes associated with cognition and mood. There is some evidence that carvacrol exhibits multiple neuromodulatory actions, and therefore, because it is widely used as a food additive, it has potential to be incorporated into strategies for alleviating various neurological conditions.67–69 In vitro experiments show that carvacrol, thymol, α-terpineol, and thyme essential oil inhibited acetylcholinesterase (AChE) properties.70–72 This is of relevance in light of the fact that AChE inhibitors have been developed for treatment of degenerative neurological disorders. Moreover, carvacrol exerted an AChE inhibitory effect 10-fold greater than that of thymol, despite thymol’s similarity in structure to carvacrol. However, variable doses and dosing protocols were used in the animal studies, making their applicability to dietary exposure unclear. It would be helpful for animal models to be studied using carvacrol-containing thyme preparations at levels encountered in the human diet to see if at these levels, they modulate cognitive and neurological endpoints and prevent brain deterioration. It also would be helpful to evaluate thyme in combination with other plant-based materials commercially available for mood-improving actions in humans for any interactions or enhancement of benefits.
GI Actions
Thyme and carvacrol-rich water have been used in traditional medicines to relieve digestive tract ailments.1 In vitro and in vivo studies evaluating cellular and biochemical effects of thyme on GI tissues are limited, and the results are mixed. However, these are summarized in the supplementary materials in the appendix (see Appendix, Supplemental Digital Content 1, https://links.lww.com/NT/A5).
The preclinical data provide only preliminary evidence of thyme’s GI benefits and often varied in experimental design, used different samples of thyme and thyme oil, and chose doses of thymol and carvacrol that differed substantially among studies. Further in vivo studies are needed before any beneficial impacts of thyme on the GI tract can be assessed. Such assessments must include evaluating the impact of chronic intake of dietary thyme at levels encountered in culinary use on established markers of GI health and on processes associated with GI distress in aging human populations, such as gastroesophageal reflux.
Safety
When used in amounts found in foods, thyme and thyme oil are regarded by the US Food and Drug Administration as natural flavoring or seasoning agents that are generally recognized as safe for their intended uses.73,74 However, when taken orally in undiluted form, thyme oil can be unsafe.1 Carvacrol is 1 of the most widespread constituents of plant essential oils and is approved by the Food and Drug Administration for food use as a synthetic flavoring substance and adjuvant to be used in the minimum quantity required to produce its intended effect.75 It was included by the Council of Europe in the list of flavorings called category B, meaning that it may be added to foods at the level of 2 ppm in beverages, 5 ppm in food, and 25 ppm in candy.6
Data from animal studies presented in this overview often have little relevance to doses for culinary use because they use very high doses and often are not administered orally. Some limited toxicological information is available on thyme, thymol, and carvacrol. Diets containing 2% or 10% T vulgaris leaves were not toxic to rats; the LD50 of thyme essential oil in mice was reported to be 4000 mg/kg.19,76 The European Chemicals Agency reports that in rats, thymol does not elicit chronic adverse effects (at doses of 8–200 mg/kg), nor is it teratogenic at doses of 67 to 667 mg/kg. Thymol has an oral LD50 of 980 mg/kg in rats.65 The oral LD50 for carvacrol in rats is 810 mg/kg. Mild allergic reactions in humans to external use of thyme-containing products are possible.77–79 No serious adverse events from human intakes of thyme-herbal combinations used in bronchitis studies have been reported. The European Medicines Agency names the maximum permissible dose of thymol and carvacrol in herbal products to be 4.7 and 0.34 mg/kg bw, respectively.46 Preclinical data for the thyme phytochemicals carvacrol and thymol suggest that they likely have low toxicity for humans when consumed as ingredients in spices for culinary use, but the side effects associated with chronic intake of dietary thyme need to be more thoroughly examined in animals, especially if dietary thyme essential oil or thyme extracts are contemplated for use at concentrations greater than those currently allowed for food use.79,80 Thyme’s gabaergically active constituents may potentiate the effects of general anesthetics,81 and other thyme constituents seem to interact with drug-metabolizing enzymes and could hypothetically interact with some medications if taken at the same time in high amounts, although practically, this is unlikely at dietary levels of consumption.82–85 The doses necessary to do this have not been characterized. Another possible concern related to plants in the Lamiaceae family is the presence of thujone a bicyclic monoterpene ketone that is found in plants commonly used in food, beverages, and herbal medicines. It can be toxic and can cause seizures in humans.86 Food products derived particularly from the Lamiaceae plant sage (Salvia officinalis), such as for example sage herbal tea, are the major contributors to its intake.87,88 However, thyme, another member of the Lamiaceae family, has not been identified as a likely source of this compound,86,89 and it has not been routinely detected in thyme essential oil.17
CONCLUSION
Thyme, its essential oil, and some of its phytochemical components seem to have some effects on inflammation, oxidative stress, respiratory and GI distress, and neurological impairments in experiments in animals. However, the impact of culinary uses of thyme on human health are unclear, and more research is necessary to assess these findings in humans. To do so, the bioavailability and target tissue distribution of major thyme constituents following oral dosing of thyme must be better characterized in animals and humans. Extracts of thyme and thyme samples used in in vivo studies need to be analyzed for their composition of major bioactive constituents to better compare studies using different extracts. Dose-response effects of culinary-relevant intakes and measures of accepted biological markers of health in relevant animal models and thorough study of any potential side effects are needed. It is also of interest to examine the effects of short- and long-term intake of culinary doses of thyme on a variety of health-associated endpoints in humans. The possible associations between thyme and improved health in humans should be investigated with additional and more consistent reports from larger, well-controlled human studies.
REFERENCES
1. Basch E, Ulbricht C, Hammerness P, Bevins A, Sollars D. Thyme (
Thymus vulgaris L.) Thymol.
J Herbal Pharmacother. 2004; 4: 49–67.
2. Haas LF.
Thymus serpyllum (wild thyme).
J Neurol Neurosurg Psychiatry. 1996; 60: 224.
3. Halmai J. Common thyme (
Thymus vulgaris) as employed for the ancient methods for embalming.
Ther Hung. 1972; 20: 162–165.
4. Meeker HG, Linke HA. The antibacterial action of eugenol, thyme oil, and related essential oils used in dentistry.
Compendium. 1988; 9: 32, 34–35, 38 passim.
5. US Environmental Protection Agency. R.E.D. Facts: thymol. 1993. EPA-738-F-93-010.
6. De Vincenzi M, Stammati A, De Vincenzi A, Silano M. Constituents of aromatic plants: carvacrol.
Fitoterapia. 2004; 75: 801–804.
7. Lee S, Umano K, Shibamoto T, Lee K. Identification of volatile components in basil (
Ocimum basilicum L.) and thyme leaves (
Thymus vulgaris L.) and their antioxidant properties.
Food Chem. 2006; 91: 131–137.
8. Goodner K, Mahattanatawee K, Plotto A, Sotomayor J, Jordan M. Aromatic profiles of
Thymus hyemalis and Spanish
T. vulgaris essential oils by GC-MS/GC-O.
Indust Crops Prod. 2006; 24: 264–268.
9. Zheng W, Wang SY. Antioxidant activity and phenolic compounds in selected herbs.
J Agric Food Chem. 2001; 49: 5165–5170.
10. Schmidt E, Wanner J, Hiiferl M, et al. Chemical composition, olfactory analysis and antibacterial activity of
Thymus vulgaris chemotypes geraniol, 4-thujanol/terpinen-4-ol, thymol and linalool cultivated in southern France.
Nat Prod Commun. 2012; 7: 1095–1098.
11. Díaz-Maroto MC, Díaz-Maroto Hidalgo IJ, Sánchez-Palomo E, Pérez-Coello M. Volatile components and key odorants of fennel (
Foeniculum vulgare Mill.) and thyme (
Thymus vulgaris L.) oil extracts obtained by simultaneous distillation-extraction and supercritical fluid extraction.
J Agric Food Chem. 2005; 53: 5385–5389.
12. Vergara-Salinas JR, Pérez-Jiménez J, Torres JL, Agosin E, Pérez-Correa JR. Effects of temperature and time on polyphenolic content and antioxidant activity in the pressurized hot water extraction of deodorized thyme (
Thymus vulgaris).
J Agric Food Chem. 2012; 60: 10920–10929.
13. Grosso C, Figueiredo A, Burillo J, et al. Composition and antioxidant activity of
Thymus vulgaris volatiles: comparison between supercritical fluid extraction and hydrodistillation.
J Sep Sci. 2010; 33: 2211–2218.
14. Baranauskiene R, Venskutonis P, Viskelis P, Dambrauskiene E. Influence of nitrogen fertilizers on the yield and composition of thyme.
J Agric Food Chem. 2003; 51: 7751–7758.
15. Hashmi LS, Hassain MA, Weli AM, Riyami Q, Al-Sabahi JN. Gas chromatography-mass spectrometry analysis of different organic crude extracts from the local medicinal plant
Thymus vulgaris L.
Asian Pac J Trop Biomed. 2013; 3: 69–73.
16. Roby M, Sarhan M, Selim K, Khalel K. Evaluation of antioxidant activity, total phenols and phenolic compounds in thyme (
Thymus vulgaris L.), sage (
Salvia officinalis L.), and marjoram (
Origanum majorana L.) extracts.
Ind Crops Prod. 2013; 43: 827–831.
17. Amiri H. Essential oils composition and antioxidant properties of three
Thymus species.
Evid Based Complement Altern Med. 2012; 728065. doi:10.1155/2012/728065.
18. Cerda A, Martínez ME, Soto C, et al. The enhancement of antioxidant compounds extracted from
Thymus vulgaris using enzymes and the effect of extracting solvent.
Food Chem. 2013; 139: 138–143.
19. Fachini-Queiroz FC, Kummer R, Estevão-Silva C, et al. Effects of thymol and carvacrol, constituents of
Thymus vulgaris L. essential oil on the inflammatory response.
Evid Based Complement Alternat Med. 2012; 2012: 657026.
20. Anthony KP, Deolu-Sobogun SA, Saleh MA. Comprehensive assessment of antioxidant activity of essential oils.
J Food Sci. 2012; 77: C839–C843.
21. Chizzola R, Michitsch H, Franz C. Antioxidative properties of
Thymus vulgaris leaves: comparison of different extracts and essential oil chemotypes.
J Agric Food Chem. 2008; 56: 6897–6904.
22. Kohlert C, Schindler G, März R, et al. Systematic availability and pharmacokinetics of thymol in humans.
J Clin Pharmacol. 2002; 42: 731–737.
23. Baser KH. Biological and pharmacological activities of carvacrol and carvacrol bearing essential oils.
Curr Pharm Des. 2008; 14: 3106–3119.
24. Satou T, Takahashi M, Kasuya H, et al. Organ accumulation in mice after inhalation of single or mixed essential oil compounds.
Phytother Res. 2013; 27: 306–311.
25. Austgulen LT, Solheim E, Scheline RR. Metabolism in rats of
p-cymene derivatives: carvacrol and thymol.
Pharmacol Toxicol. 1987; 61: 98–102.
26. Thalhamer B, Buchberger W, Waser M. Identification of thymol phase I metabolites in human urine by headspace sorptive extraction combined with thermal desorption and gas chromatography mass spectrometry.
J Pharm Biomed Anal. 2011; 56: 64–69.
27. Wepeirre J, Cohen Y, Valette G. Percutaneous absorption and removal by the body fluids of
14C ethyl alcohol,
3H perhydrosqualene and
14C
p-cymene.
Eur J Pharmacol. 1968; 3: 47–50.
28. Pass GJ, McLean S, Stupans I, Davies N. Microsomal metabolism and enzyme kinetics of the terpene
p-cymene in the common brushtail possum (
Trichosurus vulpecula), koala (
Phascolarctos cinereus) and rat.
Xenobiotica. 2002; 32: 383–397.
29. Takada M, Agata I, Sakamoto M, Yagi N, Hayashi N. On the metabolic detoxication of thymol in rabbit and man.
J Toxicol Sci. 1979; 4: 341–350.
30. Rubió L, Serra A, Macià A, Borràs X, Romero MP, Motilva MJ. Validation of determination of plasma metabolites derived from thyme bioactive compounds by improved liquid chromatography coupled to tandem mass spectrometry.
J Chromatogr B Analyt Technol Biomed Life Sci. 2012; 905: 75–84.
31. Bhattaram VA, Graefe U, Kohlert C, Veit M, Derendorf H. Pharmacokinetics and bioavailability of herbal medicinal products.
Phytomedicine. 2002; 9(suppl 3): 1–33.
32. Dragland S, Senoo H, Wake K, Holte K, Blomhoff R. Several culinary and medicinal herbs are important sources of dietary antioxidants.
J Nutr. 2003; 133: 1286–1290.
33. Wei A, Shibamoto T. Antioxidant/lipoxygenase inhibitory activities and chemical compositions of selected essential oils.
J Agric Food Chem. 2010; 58: 7218–7225.
34. Lee KG, Shibamoto T. Determination of antioxidant potential of volatile extracts isolated from various herbs and spices.
J Agric Food Chem. 2002; 50: 4947–4952.
35. Haraguchi H, Saito T, Ishikawa H, et al. Antiperoxidative components in
Thymus vulgaris.
Plant Med. 1996; 62: 217–221.
36. Dapkevicius A, van Beek TA, Lelyveld GP, et al. Isolation and structure elucidation of radical scavengers from
Thymus vulgaris leaves.
J Nat Prod. 2002; 65: 892–896.
37. Asbaghian S, Shafaghat A, Zarea K, Kasimov F, Salimi F. Comparison of volatile constituents, and antioxidant and antibacterial activities of the essential oils of
Thymus caucasicus,
T. kotschyanus, and
T. vulgaris.
Nat Prod Commun. 2011; 6: 137–140.
38. Miura K, Nakatan N. Antioxidative activity of flavonoids from thyme (
Thymus vulgaris L.).
Agric Biol Chem. 1989; 53: 3043–3045.
39. Kim IS, Yang MR, Lee OH, Kang SN. Antioxidant activities of hot water extracts from various spices.
Int J Mol Sci. 2011; 12: 4120–4131.
40. Kozics K, Klusová V, Srančíková A, et al. Effects of
Salvia officinalis and
Thymus vulgaris on oxidant-induced DNA damage and antioxidant status in HepG2 cells.
Food Chem. 2013; 141: 2198–2206.
41. Aydin S, Basaran AA, Basaran N. Modulating effects of thyme and its major ingredients on oxidative DNA damage in human lymphocytes.
J Agric Food Chem. 2005; 53: 1299–1305.
42. Suzuki Y, Nakamura S, Sugiyama K, Furuta H. Differences of superoxide production in blood leukocytes stimulated with thymol between human and non-human primates.
Life Sci. 1987; 41: 1659–1664.
43. Kavoosi G, Teixeira da Silva JA, Saharkhiz MJ. Inhibitory effects of
Zataria multiflora essential oil and its main components on nitric oxide and hydrogen peroxide production in lipopolysaccharide-stimulated macrophages.
J Pharm Pharmacol. 2012; 64: 1491–1500.
44. Carlsen M, Blomhoff R, Andersen L. Intakes of culinary herbs and spices from a food frequency questionnaire evaluated against 28-days estimated record.
Nutr J. 2011; 10: 50.
http://www.nutritionj.com/content/10/1/50.
45. European Medicines Agency. Assessment of
Thymus vulgaris L. and
Thymus zygis L., herba and
Primula veris L. and
Primula elatior (L.) Hill, radix. 2011. EMA/HMPC/130038/2010. London, United Kingdom: European Medicine Agency; 2010.
46. European Medicines Agency. Assessment report on
Thymus vulgaris L.,
Thymus zygis Loefl. Ex L., aetheroleum. EMA/HMPC/131903/2009. London, United Kingdom: European Medicine Agency; 2010.
47. Lima M, Quintans-Junior LJ, de Santana W, et al. Anti-inflammatory effects of carvacrol: evidence for a key role of interleukin-10.
Eur J Pharmacol. 2013; 699: 112–117.
48. Hotta M, Nakata R, Katsukawa M, et al. Carvacrol, a component of thyme oil, activates PPARalpha and gamma and suppresses COX-2 expression.
J Lipid Res. 2010; 51: 132–139.
49. Ocaña A, Reglero G. Effects of thyme extract oils (from
Thymus vulgaris,
Thymus zygis, and
Thymus hyemalis) on cytokine production and gene expression of oxLDL-stimulated THP-1-macrophages.
J Obes. 2012. doi:10:1155/2012/104706.
50. Tsai PJ, Tsai TH, Yu CH, Ho SC. Evaluation of NO-suppressing activity of several Mediterranean culinary spices.
Food Chem Toxicol. 2007; 45: 440–447.
51. Chan AS, Pang H, Yip EC, Tam YK, Wong YH. Carvacrol and eugenol differentially stimulate intracellular Ca
2+ mobilization and mitogen-activated protein kinases in Jurkat T-cells and monocytic THP-1 cells.
Planta Med. 2005; 71: 634–639.
52. Chohan M, Naughton DP, Jones L, Opara EI. An investigation of the relationship between the anti-inflammatory activity, polyphenolic content, and antioxidant activities of cooked and
in vitro digested culinary herbs.
Oxid Med Cell Longev. 2012; 2012: 627843. doi:10:1155/2012/627843.
53. Amirghofran Z, Ahmadi H, Karimi M. Immunomodulatory activity of the water extract of
Thymus vulgaris,
Thymus daenensis and
Zataria multiflora on dendritic cells and T cells responses.
J Immunoassay Immunochem. 2012; 33: 388–402.
54. Vigo E, Cepeda A, Gualillo O, Perez-Fernandez R. In-vitro anti-inflammatory effect of
Eucalyptus globulus and
Thymus vulgaris: nitric oxide inhibition in J774A.1 murine macrophages.
J Pharm Pharmacol. 2004; 56: 257–263.
55. Ernst E, März R, Sieder C. A controlled multi-centre study of herbal versus synthetic secretolytic drugs for acute bronchitis.
Phytomedicine. 1997; 4: 287–293.
56. Büechi S, Vögelin R, von Eiff MM, Ramos M, Melzer J. Open trial to assess aspects of safety and efficacy of a combined herbal cough syrup with ivy and thyme.
Forsch Komplementarmed Klass Naturheilkd. 2005; 12: 328–332.
57. Gruenwald J, Graubaum HJ, Busch R. Efficacy and tolerability of a fixed combination of thyme and primrose root in patients with acute bronchitis: a double-blind, randomized, placebo-controlled clinical trial.
Arzneimittelforschung. 2005; 55: 669–676.
58. Kemmerich B, Eberhardt R, Stammer H. Efficacy and tolerability of a fluid extract combination of thyme herb and ivy leaves and matched placebo in adults suffering from acute bronchitis with productive cough: a prospective, double-blind, placebo-controlled clinical trial.
Arzneimittelforschung. 2006; 56: 652–660.
59. Kemmerich B. Evaluation of efficacy and tolerability of a fixed combination of dry extracts of thyme herb and primrose root in adults suffering from acute bronchitis with productive cough: a prospective, double-blind, placebo-controlled multicentre clinical trial.
Arzneimittelforschung. 2007; 57: 607–615.
60. Neher A, Gstöttner M, Thaurer M, Augustijns P, Reinelt M, Schobersberger W. Influence of essential and fatty oils on ciliary beat frequency of human nasal epithelial cells.
Am J Rhinol. 2008; 22: 130–134.
61. Gavliakova S, Biringerova Z, Buday T, et al. Antitussive effects of nasal thymol challenge in healthy volunteers.
Respir Physiol Neurobiol. 2013; 187: 104–107.
62. Lewis CA, Ambrose C, Banner K, et al. Animal models of cough: literature review and presentation of a novel cigarette smoke-enhanced cough model in the guinea-pig.
Pulm Pharmacol Ther. 2007; 20: 325–333.
63. Bolser DC, Davenport PW. Codeine and cough: an ineffective gold standard.
Curr Opin Allergy Clin Immunol. 2007; 7: 32–36.
64. Direkvand-Moghadam A, Khosravi A. The impact of a novel herbal Shirazi
Thymus vulgaris on primary dysmenorrhea in comparison to the classical chemical ibuprofen.
J Res Med Sci. 2012; 17: 668–670.
65. Sajed H, Sahebkar A, Iranshahi M.
Zataria multiflor Boiss. (Shirazi thyme) – an ancient condiment with modern pharmaceutical uses.
J Ethnopharmacol. 2013; 145: 686–698.
66. Iravani M. Clinical effects of
Zataria multiflora essential oil on primary dysmenorrhea.
J Med Plants. 2009; 8: 54–60.
67. Zotti M, Colaianna M, Morgese MG, et al. Carvacrol: from ancient flavoring to neuromodulatory agent.
Molecules. 2013; 18: 6161–6172.
68. Azizi Z, Ebrahimi S, Saadatfar E, Kamalinejad M, Majlessi N. Cognitive-enhancing activity of thymol and carvacrol in two rat models of dementia.
Behav Pharmacol. 2012; 23: 241–249.
69. Yu H, Zhang ZL, Chen J, et al. Carvacrol, a food-additive, provides neuroprotection on focal cerebral ischemia/reperfusion injury in mice.
PLoS One. 2012; 7: e33584.
70. Jukic M, Politeo C, Maksimovic M, Milos M, Milos M. In vitro acetylcholinesterase inhibitory properties of thymol, carvacrol and their derivatives thymoquinone and thymohydroquinone.
Phytother Res. 2007; 21: 259–261.
71. Dohi S, Terasaki M, Makino M. Acetylcholinesterase inhibitory activity and chemical composition of commercial essential oils.
J Agric Food Chem. 2009; 57: 4313–4318.
72. Vladimir-Knežević S, Blažeković B, Kindl M, Vladić J, Lower-Nedza AD, Brantner AH. Acetylcholinesterase inhibitory, antioxidant and phytochemical properties of selected medicinal plants of the Lamiaceae family.
Molecules. 2014; 19: 767–782.
73. Code of Federal Regulations, Title 26, Vol. 6, 21CFR582.20.
74. Code of Federal Regulations, Title 21, Vol. 3, 21CFR182.10.
75. Code of Federal Regulations, Title 21, vol. 3, 21CFR172.515.
76. Haroun EM, Mahmoud OM, Adam S. Effect of feeding
Cuminum cyminum fruits,
Thymus vulgaris leaves or their mixture to rats.
Vet Hum Toxicol. 2002; 44: 67–69.
77. Benito M, Jorro G, Morales C, Peláez A, Fernández A. Labiatae allergy: systemic reactions due to ingestion of oregano and thyme.
Ann Allergy Asthma Immunol. 1996; 76: 416–418.
78. Andersen A. Final report on the safety assessment of sodium
p-chloro-
m-cresol,
p-chloro-
m-cresol, chlorothymol, mixed cresols,
m-cresol,
o-cresol,
p-cresol, isopropyl cresols, thymol,
o-cymen-5-ol, and carvacrol.
Int J Toxicol. 2006; 25(Suppl 1): 29–127.
79. European Medicines Agency. Community herbal monograph on
Thymus vulgaris L.,
Thymus zygis Loefl. Ex L., aetheroleum. EMA/HMPC/131901/2009. London, United Kingdom: European Medicine Agency; 2009.
80. Burt S. Essential oils: their antibacterial properties and potential applications in foods–a review.
Int J Food Microbiol. 2004; 94: 223–253.
81. Boudry G, Perrier C. Thyme and cinnamon extracts induce anion secretion in piglet small intestine via cholinergic pathways.
J Physiol Pharmacol. 2008; 59: 543–552.
82. Sasaki K, Wada K, Tanaka Y, Yoshimura T, Matuoka K, Anno T. Thyme (
Thymus vulgaris L.) leaves and its constituents increase the activities of xenobiotic-metabolizing enzymes in mouse liver.
J Med Food. 2005; 8: 184–189.
83. Dong RH, Fang ZZ, Zhu LL, et al. Investigation of UDP-glucuronosyltransferases (UGTs) inhibitory properties of carvacrol.
Phytother Res. 2012; 26: 86–90.
84. Dong RH, Fang ZZ, Zhu LL, et al. Identification of CYP isoforms involved in the metabolism of thymol and carvacrol in human liver microsomes (HLMs).
Pharmazie. 2012; 67: 1002–1006.
85. Foster BC, Vandenhoek S, Hana J, et al. In vitro inhibition of human cytochrome P450-mediated metabolism of marker substrates by natural products.
Phytomedicine. 2003; 10: 334–342.
86. Pelkonen O, Abass K, Wiesner J. Thujone and thujone-containing herbal medicinal and botanical products: toxicological assessment.
Regul Toxicol Pharmacol. 2013; 65(1): 100–107.
87. Arceusz A, Occhipinti A, Capuzzo A, Maffei ME. Comparison of different extraction methods for the determination of α- and β-thujone in sage (
Salvia officinalis L.) herbal tea.
J Sep Sci. 2013; 36: 3130–3134.
88. Lachenmeier DW, Uebelacker M. Risk assessment of thujone in foods and medicines containing sage and wormwood–evidence for a need of regulatory changes?
Regul Toxicol Pharmacol. 2010; 58: 437–443.
89. Waidyanatha S, Johnson JD, Hong SP, et al. Toxicokinetics of α-thujone following intravenous and gavage administration of α-thujone or α- and β-thujone mixture in male and female F344/N rats and B6C3F1 mice.
Toxicol Appl Pharmacol. 2013; 271: 216–228.
