Clove oil

Clove oil also known as Caryophylii floris aetheroleum, is the essential oil extracted by steam distillation from the dried flower buds of clove Syzygium aromaticum (L.) or Eugenia caryophyllata L. (Myrtaceae), that is used as a topical application to relieve pain and to promote healing and also finds use in the fragrance and flavoring industries ¹. Clove essential oil is known for its to its antimicrobial, antioxidant, antifungal and antiviral activity ². In addition, clove essential oil possesses antiinflammatory, cytotoxic, insect repellent and anaesthetic properties. Clove essential oil is a complex mixture of chemical substances, the main components being phenylpropanoids such as carvacrol, thymol, eugenol and cinnamaldehyde. The eugenol content noted from 63.8 to 84.8% ³ and its strong antibacterial activity make the clove oil a good candidate for the anti-biofilm agent ⁴. According to the US Food and Drug Administration (FDA) clove essential oil was approved generally recognized as safe (GRAS) to use as a food additive and in dentistry ⁵; however, it is lethal when taken via an oral dose of 3.75 g/kg body weight ⁶. The traditional use of clove oil for dental emergencies, mainly for symptomatic temporary relief of toothache due to a dental cavity and inflammation in the mouth and throat. The relief of toothache by clove essential oil is only a provisional measure. Dental attention should be sought as soon as possible. In this regard, clove oil has been reported to be used in preparation of certain toothpastes and mouth washes ⁷.

Owing to its antibacterial, antioxidant, anti-inflammatory, and analgesic properties, clove oil is one of the ideal essential oils for the healing of wounds. Clove essential oil fabricated as nanofibers with various polymers show strong antibacterial properties, especially against Staphylococcus aureus, Escherichia coli, Pseudomonas fluorescens, and Bacillus subtilis ⁸. The wound-healing effect of clove oil in nanoemulsion form was studied, and it was confirmed that the oil in nanoemulsion has a marked wound-healing capacity and reduced the incidence of inflammatory cells at the site of a wound when compared to pure clove oil and enhanced cell viability ⁹. Poly(ε-Caprolactone)/Gelatin nanofibers loaded with clove oil showed good antibacterial as well as marked healing properties ⁸. Clove oil-based nanofibrous mats showed good antifungal properties when used for candida-associated denture stomatitis prevention and treatment ¹⁰. Topical application of 1% clove oil cream demonstrated a significant beneficial effect when applied to patients suffering from chronic anal fissure ¹¹.

Clove oil becomes yellowish and is chemically unstable in air; moisture, light and temperature during storage cause highly volatile losses its activity ¹².

Clove (Caryophylli flos) is traditionally used as spice such as for gingerbread flavoring. Many spice blends, including curry contain powdered cloves, most herb liqueurs and bitter liqueurs contain clove macerates ¹³. Clove has been traditionally used in dyspeptic complaints, flatulence and diarrhea as a decoction ¹³.

Table 1. Clove oil main chemical compounds and concentrations

Compound	Concentration (%)
Eugenol	86.99 ± 0.09
α- Copaene	00.07 ± 0.01
β-Caryophyllene	08.76 ± 0.04
Cadina-1(6),4-diene	00.04 ± 0.01
α-Humulene	01.91 ± 0.03
ɣ-Muurolene	00.02 ± 0.01
β-Selinene	00.02 ± 0.01
α-Selinene	00.05 ± 0.02
β-Farnesene	00.06 ± 0.01
(Z)-Calamenene	00.11 ± 0.02
δ-Cadinene	00.27 ± 0.03
Cadina-1,4-diene	00.03 ± 0.01
Humulene epoxide	00.11 ± 0.01
Total	98.44

[Source ¹⁴ ]

Figure 1. Eugenol chemical structure

Clove oil benefits

Clove oil expresses a strong antimicrobial activity ¹⁴. Clove oil’s minimum inhibitory concentrations (MICs) against bacteria Staphylococcus aureus, Staphylococcus epidermidis, Escherichia coli, and Pseudomonas aeruginosa were noted in the range of 0.2–0.625 mg/mL ¹⁵. Minimum inhibitory concentrations (MICs) are defined as the lowest concentration of an antimicrobial that will inhibit the visible growth of a microorganism after overnight incubation, and minimum bactericidal concentrations (MBCs) as the lowest concentration of antimicrobial that will prevent the growth of an organism after subculture on to antibiotic-free media, usually reported as mg/L or mcg/mL ¹⁶. Clove oil antibacterial effect is assigned to its main compound eugenol interactions with bacterial cell membranes and disruption of DNA synthesis ¹⁵. The antifungal activity of the clove oil was proved against a variety of yeast and molds: Candida albicans, Candida parapsilosis, Candida krusei, Alternaria sp., Aspergillus niger, Aspergillus fumigatus, Penicillum sp., Microsporum canis, Microsporum gypseum, Trichophyton rubrum, Trichophyton mentagrophytes, and Epidermophyton floccosum ¹⁷. The antifungal activity of clove oil is attributed to a decrease of ergosterol synthesis, the component of the fungal cell wall ¹⁸. Clove oil at the concentrations in the range of 2.5–10.0% was also effective against food contaminants Bacillus cereus, Bacillus subtilis, Staphylococcus sp., E. coli, Aspergillus sp., Penicillium sp., and Rhizopus sp. ¹⁷. Clove oil action against food borne pathogens Listeria monocytogenes, S. aureus, E. coli O157:H7, and Salmonella sp. was also confirmed ¹⁹. The vivid antibiofilm effect of clove oil was observed against E. coli O157:H7 ²⁰, Pseudomonas aeruginosa, and Aeromonas hydrophila ²¹. The clove oil even in its sub-minimum inhibitory concentrations substantially inhibited the bacterial biofilm formation and reduced virulence factors of the pathogens. Interestingly, solid liposomes of clove oil applied on raw vegetables exhibited anti-biofilm activity against E. coli O157:H7 without any adverse effects on sensory quality of food ²².

In the recent past, studies have demonstrated that clove is antimutagenic ²³, antioxidant, antithrombotic, antiparasitic and anti-inflammatory ²⁴. Studies in the arthritic rat model have shown that eugenol exhibits anti-inflammatory and anti-arthritic activities ²⁵. Feng and Lipton ²⁶ have demonstrated that eugenol significantly reduced fever when given to rabbits made febrile by the injection of interleukin 1 (IL-1). These findings provide support for some of the traditionally accepted medicinal uses of clove oil.

Antibacterial effects

The majority of publications on pharmacological effects of clove, clove essential oil and eugenol deal with the antimicrobial effects. Only some selected references are cited below.

Eugenol (1 mg/ml) showed pronounced antibacterial properties against Gram-positive as well as against Gram-negative microorganisms comparable with 500 μg/ml neomycin ²⁷. Growth inhibition was even more pronounced for Candida species in comparison with nystatin (5000 U/ml).

0.4% clove oil in 63% sugar syrup inactivated after 2–7 minutes Candida albicans, Clostridium perfringens, Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa and Staphylococcus aureus ²⁸. The effect was not affected by addition of serum. Added sugar is not needed for an effect; however, it stabilizes the dispersion of the essential oil ²⁸.

The effect of 0–300 ppm clove oil on the growth and synthesis of aflatoxins from Aspergillus parasiticus was studied in submerged culture ²⁹. 0–250 ppm led to a slower growth, but had no influence on the weight of the mycelium after 21 days. 300 ppm completely inhibited the growth. The production of aflatoxins was dose-dependently delayed ²⁹.

Clove oil was superior to rosemary oil when tested against several Gram-positive and Gram-negative bacteria as well as against two fungi. A synergistic effect was observed against Candida albicans, an antagonism for Aspergillus niger ³⁰.

In an investigation of various aromatic waters, clove oil–water had no sustainable growth-inhibiting effect on Pseudomonas. Clove oil-water exhibited in the serial dilution test and agar diffusion test only a weak antimicrobial effect. The minimum inhibitory concentration (MIC) in the serial dilution test was in the case of Bacillus subtilis, Escherichia coli and Pseudomonas aeruginosa for each 1:20, for Mycobacterium phlei 1:640 and for Staphylococcus aureus 1:160 or 1:320 ³¹. The minimal fungicidal dilution was 1:320 in case of Aspergillus niger, for Penicillium chrysogenum 1:40 and for Mucor, Rhizopus and Candida albicans for each 1:20. The results in the agar diffusion test differ in part from that in the serial dilution test ³¹.

Ali et al ³² found that eugenol inhibits the growth of 30 Helicobacter pylori strains tested, at a concentration of 2μ/ml after 9 and 12 hour of incubation. A lower pH-value increased the activity. The bacteria did not develop any resistance even after 10 passages grown at sub-inhibitory concentrations. The authors conclude that eugenol may prevent the growth of Helicobacter pylori ³².

Dorman and Deans ³³ tested the antibacterial activity of clove essential oil in 25 bacteria. The results suggest that the essential oil is equally effective against both Gram-positive and Gram-negative microorganisms. A different sensitivity of the bacteria tested was observed.

Saini et al ³⁴ investigated the effect of orally administered clove essential oil on respiratory tract infections with Klebsiella pneumoniae in rats. The daily oral supplementation was 0.5 ml of a 1% w/v solution. The comparison of short term (15 days) and long term (30 days) treatment resulted in a significantly lower bacterial load in the lungs of mice fed clove oil for 30 days. The authors stated also a significant decrease of bacterial colonization already after 15 days ³⁴.

Khan et al ³⁵ studied the influence of clove oil and of eugenol on quorum sensing (QS = mechanism by which bacterial populations coordinate the expression according to the density of the local population) regulated functions in bacteria. The production of violacein by Chromobacterium violaceum is QS-controlled. Clove oil reduces at sub-MICs this production up to 78% compared to control. The swarming motility in Pseudomonas aeruginosa which is also QS-controlled was reduced up to 78%. Eugenol was not responsible for these effects ³⁵.

The antibacterial activity of eugenol may be due to an interaction of eugenol with the bacterial cell membrane ³⁶. The membrane is disrupted and macromolecules of the membrane are deformed.

Antifungal effect

The antifungal activity of clove essential oil against Aspergillus section Flavi was evaluated in sterile maize grain ³⁷. The effect of clove essential oil added to maize grains on growth rate, lag phase and aflatoxin B1 (AFB1) accumulation of Aspergillus section Flavi were evaluated at different water activity conditions (a measure for water content; 0.982; 0.955; and 0.90). The essential oil had an inhibitory effect on Aspergillus section Flavi growth rate; the efficacy depended mainly on the water activity and concentration. Clove essential oil showed a considerable inhibitory effect on the AFB1 accumulation. When the water activity was 0.982, the AFB1 inhibition percentage for all aflatoxigenic strains exceeded 98% at all clove essential oil concentrations ³⁷.

The antifungal effect of clove oil was tested against several dermatophytes using the agar diffusion method ³⁸. Hyphal growth was completely inhibited in Trichophyton mentagrophytes, T. rubrum and Microsporum gypseum in concentrations of 0.2 mg clove oil per ml. Eugenol was found to be the most effective compound against Trichophyton mentagrophytes and Microsporum canis ³⁸.

The composition and antifungal activity of clove essential oil were tested by Pinto et al ³⁹. MICs, determined according to Clinical and Laboratory Standards Institute protocols, and minimum fungicidal concentration were used to evaluate the antifungal activity of the clove oil and its main component eugenol, against Candida, Aspergillus clinical isolates (e.g. American Type Culture Collection strains). The essential oil and eugenol showed inhibitory activity against all the tested strains. Propidium iodide rapidly penetrated the majority of the yeast cells when the cells were treated with concentrations just over the MICs. Therefore the fungicidal effect may result from extensive lesions of the cell membrane. Clove oil and eugenol also caused a considerable reduction in the quantity of ergosterol, a specific fungal cell membrane component. Germ tube formation by Candida albicans was completely or almost completely inhibited by the essential oil and eugenol concentrations below the MIC values. The authors conclude that the results indicate that clove oil and eugenol have considerable antifungal activity against clinically relevant fungi, including fluconazole-resistant strains ³⁹.

Eugenol significantly reduced the number of colony forming units (CFUs) sampled from the oral cavity of immunosuppressed rats treated for 8 days ⁴⁰. Eugenol was used in a concentration of 24 mM (= double MIC) in agar solution. Nystatin was used as a poisitive control in a concentration of 58 μM (= tenfold MIC). Eugenol and nystatin gave similar results. Only few zones were occupied by hyphae with eugenol, while under nystatin hyphae were found in the folds of the tongue mucosa ⁴⁰.

There was a significant reduction of colony counts in a prophylactic approach and a treatment approach in cases of vaginal candidiasis in an immunosuppressed rat model. The rats received 10 mg/kg/day eugenol via an intravaginal route ⁴¹. Lee et al ⁴² evaluated the antifungal effect of eugenol against skin lesions in guinea pigs infected with Microsporum gypseum. Eugenol was adjusted to 10% concentration with a base of vaseline petroleum jelly and was applied topically to the skin lesions daily for 3 weeks. Eugenol was clinically active.

Antiviral effect

For eugenol no significant antiviral activity against herpes simplex virus type 1 was found in vitro using the plaque reduction assay ⁴³.

Antiprotozoal effects

Clove oil inactivated in vitro Trichomonas vaginalis in a dose- and time-depending manner ¹³. After addition of 4, 2, 1, 0.5 and 0.25 mg/ml to the culture medium no surviving Trichomonads were detectable after an incubation period of 5 min to 8 hours. Concentrations of 0.01 and 0.05 mg/ml were not effective. With eugenol comparable effects were achieved. With 4–0.05 mg/ml of the reference substance metronidazol the effect was achieved after 30 min to 2 hours ¹³.

The IC₅₀ is the concentration of drug required for 50% inhibition.Treatment of epimastigotes of Trypanosoma cruzi with different concentrations of clove essential oil resulted in a dose-dependent growth inhibition with IC₅₀/24 hours of about 99.5 μg/ml; IC₅₀/24 hours values obtained after treatment of bloodstream trypomastigotes were about 57.5 μg/ml ⁴⁴. The values obtained for epimastigotes treated with eugenol were 246 μg/ml, while treatment of bloodstream trypomastigotes resulted in IC₅₀/24 hours values of 76 μg/ml for eugenol ⁴⁴.

Antiparasitic effects

In a study by Eamsobhana et al ⁴⁵ commercially produced essential oils of 13 plant species and ethanol (control) were tested for repellent activity against host-seeking larvae of chigger mite (Leptotrombidium imphalum). Dilutions of each essential oil were prepared in absolute ethanol. Clove essential oil exhibited 100% repellent activity at 5% concentration.

Analgesic effects

Patch-clamp experiments showed that eugenol reversibly activates calcium ion channels and chloride ion channels in dorsal root ganglion cells from rats ⁴⁶. The applied eugenol concentrations ranged from 0.125 to 1 mmol/l. These effects may be responsible for the analgesic activity ⁴⁶. Sodium and calcium channels act as targets for eugenol for its analgesic effect. Eugenol inhibits ATP-induced P2X currents in trigeminal ganglion neurons, which contributes to the analgesic effect ⁴⁷.

Intrathecal treatment of mice with eugenol (12.5 to 50 μg) for 24 hours, dose-dependently inhibited the formalin-induced nociceptive response ⁴⁸. Capsazepine shifted the dose-response curves in parallel to the right. Eugenol may exert its antinociceptive effect via the capsaicin receptor located on sensory terminals in the spinal cord. These results indicate that eugenol acts as a capsaicin-like substance ⁴⁸.

Anti-inflammatory effects

Eugenol inhibited the nitric oxide (NO) production in a dose-dependent manner in RAW264.7 cells treated with 1 μg/ml lipopolysaccharide for 24 hours ⁴⁹. Isoeugenol was more effective. LPS-dependent expression of COX-2 was also inhibited by isoeugenol and less effectively by eugenol ⁴⁹.

Sedative effect

Wagner and Sprinkmeyer ¹³ investigated the sedative effect of clove essential oil. Mice received 1 to 100 mg/kg orally. The motility in the photocell cage was compared with the results of the day before (without treatment). The authors observed a non dose-dependent reduction of motility ¹³.

Spasmolytic effect

A saturated aqueous solution of clove oil was active in vitro on isolated organs against various spasmogens: rat/duodenum/acetylcholine: 20 to 40% inhibition; rat/duodenum/barium chloride: 40 to 60% inhibition; guinea-pig/ileum/histamine: >60% inhibition; rabbit/jejunum/nicotine: >60% inhibition ¹³. No further details on the methodology are available ¹³. Clove oil antagonized in vitro the carbachol-induced spasm of guinea pig trachea muscles and the electrically stimulated contraction of longitudinal muscles of guinea pig ileum. Half maximal effective concentration (EC50) refers to the concentration of the drug at a stable state inducing half of the maximum effect. The EC50 was 3.8 mg/ml (trachea; isoprenaline EC50 = 3.9 nmol/l) or 6.8 mg/ml (ileum; papaverine EC50 = 3.7 μmol/l) ⁵⁰. Eugenol relaxes the rabbit thoracic aorta while suppressing the Ca2+ sensitivity and both the uptake and extrusion mechanisms for Ca2+ ⁵¹.

Anticancer effects

Mice received 20 mg of isolated sesquiterpenes once every 2 days. The sesquiterpenes ß-caryophyllene, ß-caryophyllene oxide, alpha-humulene, alpha-humulene epoxide and eugenol induced the detoxifying enzyme glutathione S-transferase in the mouse liver and intestine ⁵². Eugenol showed chemopreventive effects. Eugenol, but not its isomer isoeugenol, was found to be a potent inhibitor of melanoma cell proliferation. It inhibits the growth of melanoma cells in culture (50% inhibition by 0.5 μM). Eugenol causes significant tumour growth delay, decrease of tumor size and prevents tumor metastasis in mice (125 mg/kg) ⁵³.

Effect on coagulation

Clove oil inhibited in vitro the platelet aggregation which was induced by arachidonic acid, epinephrine and collagen ⁵⁴. The formation of thromboxane B2 induced by arachidonic acid was inhibited in intact and in lysed platelet preparations. The effect, which exceeds the in vitro effect of acetylsalicylic acid, might be attributed to eugenol and eugenyl acetate. The combination of these compounds inhibits the platelet aggregation in a superadditive manner ⁵⁴.

The IC₅₀ is the concentration of drug required for 50% inhibition. The IC₅₀ of eugenol (3.0 x 10^-7 M) and isoeugenol (7.2 x 10^-7 M) were comparable with indomethacin (2.2 x 10^-7 M) on platelet aggregation ²⁷.

Eugenol and isoeugenol inhibit the arachidonic acid (1 x 10^-4 g/ml) induced platelet aggregation, the IC₅₀ values were 4.5 x 10^-8 g/ml and 1 x 10^-7 g/ml respectively ⁵⁵.

Effect on prostaglandin synthesis

The addition of 37 μM clove oil to in vitro preparations from sheep seminal vesicles inhibits (based on average molecular weight of 200) the prostaglandin synthesis from [1-14C] arachidonic acid by 84.1% compared to a control without the essential oil ⁵⁶. The IC₅₀ of eugenol was 11 μM; the IC50 of indomethacin was 1.2 μM ⁵⁶. Eugenol and its derivatives are inhibitors of LOX-5 and COX-2 ⁵⁷.

Clove oil uses

Clove oil has been traditionally used externally or locally for the temporary relief of toothache and the treatment of minor infections of the mouth and skin, dressing of minor wounds, sore throats and coughs associated with the common cold, muscle ache (myalgia), rheumatic complaints, insect bites, flatulent colic or nausea ⁵⁸. Clove oil can be used on adults, the elderly and children over 2 years old. The German commission E (a scientific advisory board of the Federal Institute for Drugs and Medical Devices similar to the FDA) proposes the use of the clove essential oil for treatment of inflammations of the oral and pharyngeal mucosa and in dentistry for topical anaesthesia ⁵⁹. Clove oil or eugenol alone is widely used in dentistry mixed with zinc oxide as temporary filling material ¹³. Undiluted clove essential oil or solutions in a strength of minimum 50% or gels in a strength of 20% is authorized products in the UK for the temporary relief of toothache due to dental cavity ⁶⁰. Repeat administration after 20 minutes, then every 2 hours thereafter if necessary. However, the relief of toothache by clove essential oil is only a provisional measure. Dental attention should be sought as soon as possible. Topical application of 1% clove oil cream demonstrated a significant beneficial effect when applied to patients suffering from chronic anal fissure ¹¹.

• DO NOT use Clove oil in teething.
• DO NOT use Clove oil on surrounding gums.

Clove oil mouth washes

Clove oil mouth washes corresponding to 1–5% essential oil is used for the inflammations of the oral and pharyngeal mucosa ⁵⁹.

Traditional use in children and adolescents

• Oromucosal use:
  • Children between 1 and 4 years of age: a strength of 1–2% of clove essential oil ⁶¹.
  • Children between 4 and 12 years of age and adolescents: a strength of 1–5% of clove essential oil ⁶¹.

Clove oil dosage

Clove oil for dental use

Undiluted clove essential oil or solutions in a strength of minimum 50% or gels in a strength of 20%. According to the electronic medicines compendium of UK medicinal products ⁶²: A small piece of cotton wool should be soaked in the undiluted clove oil or in a diluted solution; semisolid dosage forms should be placed on a cotton bud. Cotton bud or cotton wool should be accurately directed to the decayed part of the tooth as required. Avoid contact with gums. Repeat administration after 20 minutes, then every 2 hours if necessary. Repeated use may cause gum damage. Not to be used for more than 1 week. The relief of toothache by clove essential oil is only a temporary measure. See your dentist as soon as possible. The use in children and adolescents under 18 years of age is not recommended due to lack of adequate data.

Use of eugenol in dentistry: Eugenol can be part of temporary pulp fillings in dentistry. Eugenol is mixed with zinc oxide, giving a paste which hardens quickly when coming into contact with saliva.

Clove oil for mouthwashes

Mouthwashes corresponding to 1–5% clove essential oil. Apply several times daily. The use in children and adolescents under 18 years of age is not recommended due to lack of adequate data.

Clove oil side effects

Clove oil can have side effects, although these don’t affect everyone. Side effects are ⁶²:

• Temporary skin irritation.
• Dermatitis (skin rash, itching, flaking).
• Swelling of the lips.
• Blistering and swelling in the mouth.
• You may also become sensitive to clove oil.
• If you notice these or any other side effect notincluded above, stop use and tell your dentist or pharmacist. They will tell you what to do.

Clove essential oil acts in high concentrations as local irritant, allergic reactions may also be possible ⁶⁰. However, when applied in diluted form, no reports on severe adverse events are published. When applied correctly in the proposed routes of administration, clove essential oil can be considered as clinically safe ⁶⁰.

LD50 assessment

Lethal dose 50 (LD50) is the amount of an ingested substance that kills 50 percent of a test sample. It is expressed in mg/kg, or milligrams of substance per kilogram of body weight. The median intraperitoneal LD50 of clove oil was 161.9 mg/kg ⁶³. Mice treated with up to 50 mg/kg clove oil and observed for 96 hours did not show abnormal symptoms, consistent with no decrease in food intake (data not shown). Furthermore, no deaths were observed. These data indicate that the toxicity of the clove oil is limited. Injection of doses ≥90 mg/kg body weight produced various observable effects, including in motor activity and respiration, within 45 minutes. Mice showed ataxia (unsteady gait), sedation and decreased motor activity, piloerection, tremor, ptosis and 25% mortality. Also, a dose-dependent mortality was observed after increasing the doses: 292 mg/kg clove oil was 100% lethal ⁶³.

Skin and mucosal irritations

In concentrated form, clove oil may be irritating to mucosal tissues ⁴⁶. In contrast to this, Anton et al ⁶⁴ report that there is no skin irritation (undiluted clove oil) on hairless mice. Under occlusion the undiluted clove oil was moderately irritating in rabbits.

Allergic effects

In patients sensitized to Peru balsam, a hexane extract of clove, caused, in concentrations higher than 0.12% in petrolatum, local reactions. In a concentration of 1% in petrolatum, in two of four patients, a moderate reaction was observed, in the other two, an intense reaction occurred (large, infiltrated, dark spots with numerous vesicles) ⁶⁵. In a skin test with clove powder (on filter paper moistened with water), out of 78 patients with allergy against Peru balsam, 36 reacted positive. In a control group of 156 probands lacking Peru balsam allergy, nobody responded positively ⁶⁶ . A 22 years old patient with eczema on the hands reacted to a oral stress test 2 times 100 mg clove powder in gelatine capsules) with blisters on palms and fingers ⁶⁶. Clove cigarettes have been reported to cause acute respiratory problems in humans that rapidly progress to hemorrhagic pulmonary edema or pneumonia ¹³.

In a patch test study a 10% ethanol extract of clove was investigated among other herbal preparations used in the Traditional Chinese Medicine. Out of 30 patients 8 reacted positively to clove extract ⁶⁷.

Clove oil, 20% incorporated in petrolatum, produced redness in 2 of 25 healthy subjects ⁶⁸. In concentrations of 2% and 0.2% in petrolatum, no reactions were observed ⁶⁸.

When trying to administer clove essential oil onto an aching tooth, a 24 year old woman disposed accidentally the oil on the upper lip and cheek ⁶⁹. Although she tried to remove the essential oil, a sensation of burning and inflammation occurred, which disappeared within a few hours. Subsequently, local anaesthesia and reduced sweat production in the affected areas were observed. The medical examination after 11 months revealed a dry, slightly erythematous skin with reduced pressure sensitivity. During the following 9 months the situation remained unchanged ⁶⁹.

Root canal fillings with eugenol cement

When eugenol cement is applied near the pulpa (intact dentin layer) no toxicity is observed ⁶⁰. However, when applied directly to the exposed pulp, pulp necrosis and inflammation appeared ⁷⁰.

A root canal filling with eugenol cement resulted in a patient with a generalized urticaria (hives or red itchy welts) ⁷¹. In the skin test, the patient responded positively to Peru balsam and cloves. A distributed oral provocation test with 0.1 to 0.5 ml of eugenol, in water, resulted in urticaria which persisted for several weeks ⁷¹.

Pregnancy and breastfeeding

Safety during pregnancy and lactation has not been established. In the absence of sufficient data, the use during pregnancy and lactation is not recommended.

Clove oil contraindications

The medicinal use of clove essential oil should be contraindicated in cases of hypersensitivity to clove essential oil or Eugenol as well hypersensitivity to Peru balsam ¹³.

Serious events

A 17-year-old male high-school student died of rapidly progressive inflammatory lung disease that developed hours after smoking a clove cigarette ⁶⁰. The student was recovering from a lower respiratory infection at the time. The California Department of Health Service and Centers for Disease Control (CDC) collected 110 cases of clove cigarette toxicity by 1984, two of which were fatal ⁴⁶. During 1984 and 1985, the Centers for Disease Control received 11 case reports of clove cigarette smoking-associated acute respiratory system injury in adolescents and young adults; two deaths were also reported. The reported respiratory adverse effects included hemoptysis, bronchospasm, hemorrhagic and nonhemorrhagic pulmonary oedema, pleural effusion, respiratory insufficiency, respiratory infection and aspiration of foreign material ⁴⁶.

Clove oil overdose

No case of clove oil overdose from oromucosal use or dental use has been reported. After oral administration of 5-10 ml of clove oil in children below 2 years of age, life threatening conditions were observed. Overdose may lead to central nervous system depression, urinary abnormalities, anion gap acidosis, deterioration of liver function, coma, seizure and low blood glucose levels. Treatment should be supportive and symptomatic; there have been reports in the literature that N-acetylcysteine has been successfully used as an antidote ⁷².

Case reports

A 7-month-old boy received 1 teaspoon of clove oil ⁷³. The dose corresponds to about 500 mg/kg eugenol. On admission to hospital, an attenuation of the central nervous system (awake, but without a direct response to environment), leukocytosis, proteinuria and ketonuria were observed ⁷³. The also observed metabolic acidosis was attributed to the already existing diarrhea. 3 hours after ingestion, gastric lavage was performed with the addition of activated carbon. An endoscopy the next morning showed no evidence of mucosal damage in the stomach or esophagus. After 48 hours acidosis and leukocytosis were no longer detectable. The patient recovered completely and was released from hospital after 4 days ⁷³.

A 2 year old boy drank 5 to 10 ml of clove oil ⁷⁴. After 1 hour only mild drowsiness was observed. Within the next 3 hours, a drastic deterioration occurred with deep coma and severe acidosis. 8.5 hours after the ingestion, generalized cramps occurred which were treated with diazepam. The patient had an unrecordable blood glucose level which was treated with intravenous dextrose. 24 hours after ingestion, the patient was unconscious ⁷⁴. A severely impaired liver function and disseminated intravascular coagulopathy (therapy with plasma, heparin, antithrombin III, protein C, factor VII) was observed. The liver function deteriorated further in the following days. During the 5th day, the patient awoke and on day 6, he was fully conscious. From this time point, the symptoms gradually disappeared, the patient fully recovered ⁷⁴.

A very similar case – ingestion of about 10 ml of clove oil by a 2 year old boy resulting in convulsions, unconsciousness and severe coagulation – is described by Brown et al ⁷⁵. The patient was treated with heparin and fresh frozen plasma, and, following specific hemostasis assays, with appropriate coagulation factor and inhibitor concentrates ⁷⁵.

A 3 month old girl developed a fulminant hepatic failure after ingestion of less than 8 ml of clove oil (exact amount not documented) ⁷⁶. She was successfully treated with N-acetylcystein infusion and recovered completely ⁷⁶.

A similar case is reported by Janes et al ⁷⁷: a 15 month old boy developed a fulminant hepatic failure after ingestion of 10 ml of clove oil. After 24 hour, the ALT level was in excess of 13,000 U/l, with blood urea and creatinine of 11.8 mmol and 134 μmol/l respectively. The hepatic impairment resolved after intravenous administration of N-acetylcysteine so that 6 h later, the ALT level was approximately 10,000 U/l. The liver function and clinical status improved over the next 4 days ⁷⁷.

Clove oil drug interactions

The antiplatelet effect of clove oil may increase the risk of bleeding if taken with these medications. Clove may result in a false increase in phenytoin levels ⁴⁶. However, the routes of administration of clove oil for oromucosal and dental use; the duration of use is limited. Therefore these mentioned theoretical drug interactions are not relevant for the traditional use of clove oil for the short term treatment of toothache or as an antiseptic mouthwash ⁶⁰.

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