DDR Prime by doTERRA

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Allergic rhinitis (hay fever). Although there has been interest in using oral bitter orange for allergic rhinitis, there is insufficient reliable information about the clinical effects of bitter orange for this purpose.
• Androgenic alopecia. Although there has been interest in using topical bitter orange for androgenic alopecia, there is insufficient reliable information about the clinical effects of bitter orange for this purpose.
• Anxiety. It is unclear if oral bitter orange or aromatherapy with bitter orange is beneficial in patients with anxiety. Details: Aromatherapy with bitter orange has been evaluated for anxiety in hospitalized or recently hospitalized patients. A clinical study in conscious patients admitted to the intensive care unit shows that inhaling bitter orange as aromatherapy for 30 minutes is associated with lower anxiety scores immediately and 3 hours after the intervention, but not at 1 hour after, when compared with placebo. It is unclear if the improvement from baseline differed between groups; baseline anxiety scores were significantly higher in the placebo group (108752). Another clinical study in adults with acute coronary syndrome shows that aromatherapy with bitter orange essential oil 30% for the 2 days immediately after hospitalization improves anxiety scores by 19%, compared with a 6% improvement in those inhaling placebo (101710). Oral bitter orange has also been evaluated in patients with anxiety. A small clinical study in postmenopausal adults with moderate anxiety shows that taking dried bitter orange flower powder 500 mg orally twice daily for 8 weeks reduces anxiety symptoms by about 4% when compared with placebo, as measured on the State-Trait Anxiety Inventory Scale (97256). However, this improvement is not likely to be considered clinically significant.
• Athletic performance. Several small, short-term clinical studies suggest that oral bitter orange does not improve athletic performance, although some conflicting findings exist. Details: One small clinical study in young males who were former athletes shows that taking 100 mg of p-synephrine from bitter orange extract (Advantra Z, Nutratech Inc.), with or without caffeine 100 mg, daily for 4 days increases the number of total repetitions and volume load by 11% during resistance squat exercise performance when compared with placebo. However, there was no difference in ratings of perceived exertion, and only the p-synephrine plus caffeine group showed an increase in mean power and velocity measures (95683). Other small studies have failed to show a benefit, with or without caffeine. One small study of physically active males with habitual caffeine use shows that taking caffeine 100 mg and bitter orange 100 mg once before exercise does not affect peak power, mean power, total work, or perceived effort or fatigue when compared with placebo (101709). Another small clinical study shows that taking p-synephrine (Synephrine HCL 99%, Nutrition Power) 3 mg/kg orally 60 minutes before exercise does not improve jump tests, 60-meter sprints, or 100-meter sprints in healthy sprint athletes (95655). A small clinical study shows that taking a specific caffeine-containing pre-workout supplement (Cellucor C4 Pre-Workout, Nutrabolt) along with bitter orange extract (Nutratech Inc.) as a single dose 30 minutes before exercise does not improve athletic performance during anaerobic cycling or leg and bench press exercises (95657). Also, taking this combination daily for 8 weeks does not improve strength or body composition when compared with placebo (95656).
• Cancer. Although there has been interest in using oral bitter orange to prevent cancer, there is insufficient reliable information about the clinical effects of bitter orange for this purpose.
• Chronic kidney disease (CKD). Although there has been interest in using oral bitter orange for CKD and other kidney and bladder conditions, there is insufficient reliable information about the clinical effects of bitter orange for these conditions.
• Conjunctivitis. Although there has been interest in using topical bitter orange for conjunctivitis, there is insufficient reliable information about the clinical effects of bitter orange for this purpose.
• Constipation. Although there has been interest in using oral bitter orange for constipation, there is insufficient reliable information about the clinical effects of bitter orange for this purpose.
• Diabetes. Oral bitter orange has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A very small clinical study in patients with type 2 diabetes shows that drinking a tea made from the leaves of Indian snakeroot and the fruit of bitter orange for 4 months decreases fasting and postprandial glucose levels and glycated hemoglobin (HbA1c) levels when compared with placebo (35751). However, it is unclear if these effects are due to bitter orange, Indian snakeroot, or the combination.
• Diarrhea. Although there has been interest in using oral bitter orange for diarrhea, there is insufficient reliable information about the clinical effects of bitter orange for this purpose.
• Dyspepsia. It is unclear if oral bitter orange is beneficial in patients with dyspepsia. Details: One small clinical trial in patients with functional dyspepsia shows that taking a specific product containing bitter orange in combination with other ingredients (Zhizhu) three times daily for 4 weeks improves symptoms of functional dyspepsia in 67% of patients, compared with 45% of patients taking a similar product containing sweet orange instead of bitter orange (35757).
• Fatigue. Although there has been interest in using oral bitter orange for fatigue, there is insufficient reliable information about the clinical effects of bitter orange for this purpose.
• Flatulence. Although there has been interest in using oral bitter orange for flatulence, there is insufficient reliable information about the clinical effects of bitter orange for this purpose.
• Frostbite. Although there has been interest in using oral bitter orange to prevent frostbite, there is insufficient reliable information about the clinical effects of bitter orange for this purpose.
• Gallbladder disease. Although there has been interest in using oral bitter orange for gallbladder disease, there is insufficient reliable information about the clinical effects of bitter orange for this purpose.
• Headache. Although there has been interest in using topical bitter orange for headache, there is insufficient reliable information about the clinical effects of bitter orange for this purpose.
• Hyperlipidemia. Although there has been interest in using oral bitter orange for hyperlipidemia, there is insufficient reliable information about the clinical effects of bitter orange for this purpose.
• Insomnia. It is unclear if using bitter orange aromatherapy for sleep disturbances is beneficial in postmenopausal or pregnant adults. Details: A small clinical study in postmenopausal adults with sleep disturbances shows that inhaling essential oil of bitter orange 10% as aromatherapy for 5 minutes twice daily for 4 consecutive days each week for 4 weeks does not improve sleep quality when compared with odorless sweet almond oil (108642). Other clinical research in pregnant adults with sleep disturbances shows that inhaling bitter orange essential oil as aromatherapy for 20 minutes twice daily for 1 month improves sleep scores, including sleep duration, latency, and efficiency, when compared with sweet almond oil (110043).
• Obesity. It is unclear if oral bitter orange, or its constituent p-synephrine, is beneficial for obesity. Details: A meta-analysis of clinical trials in adults with or without obesity shows that taking p-synephrine, a constituent of bitter orange, 6-214 mg orally daily for up to 8 weeks does not reduce body weight or fat mass, or alter blood glucose levels, when compared with placebo (109950). Bitter orange has also been studied in combination with other ingredients. One small clinical trial in overweight adults shows that taking a combination of bitter orange 975 mg, caffeine 528 mg, and St. John's wort 900 mg daily along with calorie restriction and exercise reduces body weight when compared with caloric restriction and exercise alone (11268). Another small clinical study in overweight adults shows that taking a specific combination product (Prograde Metabolism, Prograde Nutrition) containing bitter orange, raspberry ketone, caffeine, capsaicin, garlic, ginger, black pepper, cayenne pepper, and chromium along with diet and exercise for 8 weeks reduces body weight, fat mass, and hip and waist girth and increases lean body mass and energy levels when compared with placebo (91291). However, a small clinical trial in overweight and obese adults shows that taking a different combination product (Charge, Labrada), containing bitter orange 150 mg, providing 9 mg synephrine, plus caffeine and several other ingredients twice daily for 8 weeks does not reduce body weight (15381). The effects of bitter orange alone on body weight are unclear.
• Pain (acute). It is unclear if aromatherapy with bitter orange essential oil is beneficial in hospitalized patients with pain. Details: One small clinical trial in conscious patients in intensive care units shows that aromatherapy with bitter orange essential oil for 30 minutes does not reduce pain when compared with placebo (104187).
• Peptic ulcers. Although there has been interest in using oral bitter orange for peptic ulcers, there is insufficient reliable information about the clinical effects of bitter orange for this purpose.
• Premenstrual syndrome (PMS). It is unclear if aromatherapy with bitter orange essential oil is beneficial in patients with PMS. Details: One small clinical trial in healthy female students with PMS shows that inhaling bitter orange blossom 0.5% essential oil as aromatherapy for 5 minutes twice daily for 5 days, starting about one week before menstruation and repeating for two menstrual cycles, improves psychological but not physical symptoms of PMS when compared with aromatherapy with odorless sweet almond oil (98331).
• Pre-procedural anxiety. It is unclear if oral bitter orange or aromatherapy with bitter orange is beneficial for reducing anxiety before surgery. Details: One small clinical study in patients undergoing minor operations shows that taking bitter orange blossom distillate 1 mL/kg two hours prior to surgery reduces preoperative anxiety when compared to baseline. No significant improvements in anxiety were reported in patients taking placebo before surgery (35759). Another small clinical study in patients undergoing coronary angiography shows that inhaling bitter orange essential oil for 15-20 minutes about one hour prior to the procedure reduces anxiety when compared with placebo (104186).
• Pressure ulcers. Although there has been interest in using topical bitter orange for pressure ulcers, there is insufficient reliable information about the clinical effects of bitter orange for this purpose.
• Rheumatoid arthritis (RA). Although there has been interest in using topical bitter orange for RA, there is insufficient reliable information about the clinical effects of bitter orange for this condition.
• Rhinosinusitis. Although there has been interest in using oral bitter orange for rhinosinusitis, there is insufficient reliable information about the clinical effects of bitter orange for this purpose.
• Sexual dysfunction. It is unclear if topical bitter orange oil is beneficial in postmenopausal adults with sexual dysfunction. Details: Preliminary clinical research in postmenopausal adults with sexual dysfunction shows that inhaling bitter orange essential oil 10% as aromatherapy for 5 minutes twice daily, 4 days per week for 4 weeks, improves sexual dysfunction scores by 58% when compared with almond oil. Patients reported improvements in the domains of desire, arousal, lubrication, orgasm, pain, and satisfaction (110042).
• Tinea corporis. It is unclear if topical bitter orange oil is beneficial in patients with tinea corporis. Details: In one small clinical study of patients with either tinea corporis, tina cruris, or tinea pedis, 80% of patients applying a bitter orange oil 25% emulsion three times daily experienced a cure within 1-2 weeks, and 20% experienced a cure within 2-3 weeks. For those applying a solution of bitter orange oil 20% in alcohol, 50% experienced a cure in 1-2 weeks, 30% in 2-3 weeks, and 20% in 3-4 weeks (6972). The validity of these findings is limited by the lack of a comparator group.
• Tinea cruris. It is unclear if topical bitter orange oil is beneficial in patients with tinea cruris. Details: In one small clinical study of patients with either tinea corporis, tina cruris, or tinea pedis, 80% of patients applying a bitter orange oil 25% emulsion three times daily experienced cure within 1-2 weeks, and 20% experienced a cure within 2-3 weeks. For those applying a solution of bitter orange oil 20% in alcohol, 50% experienced a cure in 1-2 weeks, 30% in 2-3 weeks, and 20% in 3-4 weeks (6972). The validity of these findings is limited by the lack of a comparator group.
• Tinea pedis. It is unclear if topical bitter orange oil is beneficial in patients with tinea pedis. Details: In one small clinical study of patients with either tinea corporis, tina cruris, or tinea pedis, 80% of patients applying a bitter orange oil 25% emulsion three times daily experienced cure within 1-2 weeks, and 20% experienced a cure within 2-3 weeks. For those applying a solution of bitter orange oil 20% in alcohol, 50% experienced a cure in 1-2 weeks, 30% in 2-3 weeks, and 20% in 3-4 weeks (6972). The validity of these findings is limited by the lack of a comparator group. More evidence is needed to rate bitter orange for these uses.

(Read more about BITTER ORANGE)

POSSIBLY EFFECTIVE

• Ventilator-associated pneumonia (VAP). Clove mouthwash might reduce the risk of acquiring pneumonia in patients on mechanical ventilation. Details: A large clinical trial in adults in the intensive care unit on mechanical ventilation shows that administration of a clove extract 6.66% mouthwash, 15 mL twice daily for 5 days, results in a 2-fold lower incidence of ventilator-associated pneumonia when compared with chlorhexidine mouthwash (112151).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Alveolar osteitis. Although there has been interest in using topical clove for alveolar osteitis, there is insufficient reliable information about the clinical effects of clove for this purpose.
• Anal fissures. It is unclear if topical clove oil is beneficial in patients with anal fissures. Details: Preliminary clinical research in patients with chronic anal fissures shows that applying clove oil 1% cream for 6 weeks heals fissures in 60% of patients by the 3-month follow-up, compared with only 12% of patients who used topical lidocaine 5% cream and stool softeners (43487).
• Cough. Although there has been interest in using oral clove for cough, there is insufficient reliable information about the clinical effects of clove for this purpose.
• Dental plaque. Topical clove has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research shows that using a specific toothpaste (Sudantha, Link Natural Products Ltd.) containing a combination of clove, Acacia chundra Willd., malabar nut, bullet wood tree, black pepper, Indian beech, gall oak, Terminalia, and ginger twice daily for 12 weeks can reduce dental plaque, bleeding, and bacteria counts in the mouth when compared with placebo (43570). Other clinical research shows that administration of a mouth rinse containing clove, tea tree oil, and basil 10 mL twice daily for 21 days is as effective as a commercially available mouth rinse containing thymol, eucalyptol, menthol, and methyl salicylate in reducing dental plaque and gum inflammation (92160). It is unclear whether clove, another ingredient, or a combination of these ingredients is responsible for these effects.
• Diarrhea. Although there has been interest in using oral clove for diarrhea, there is insufficient reliable information about the clinical effects of clove for this purpose.
• Dyspepsia. Although there has been interest in using oral clove for dyspepsia, there is insufficient reliable information about the clinical effects of clove for this purpose.
• Flatulence. Although there has been interest in using oral clove for flatulence, there is insufficient reliable information about the clinical effects of clove for this purpose.
• Gingivitis. Although there has been interest in using topical clove for gingivitis, there is insufficient reliable information about the clinical effects of clove for this purpose.
• Halitosis. Although there has been interest in using oral clove for halitosis, there is insufficient reliable information about the clinical effects of clove for this purpose.
• Hangover. It is unclear if oral clove flower extract is beneficial for reducing hangover severity. Details: Preliminary clinical research in a very small number of healthy males with a history of hangovers shows that taking a clove flower bud polyphenol extract 250 mg prior to drinking brandy (42.8% alcohol) decreases hangover severity scores by around 55% when compared with placebo (100597).
• Hyperhidrosis. It is unclear if topical clove oil is beneficial in patients with hyperhidrosis. Details: Preliminary clinical research in patients with hyperhidrosis of the palms shows that topical application of clove oil 45% in liposome base twice daily for 2 weeks improves hyperhidrosis severity and decreases the rate of sweating by around 34% when compared with a saline control (100596). The validity of these findings is limited by a lack of subject randomization.
• Impaired glucose tolerance (prediabetes). It is unclear if oral clove flower extract is beneficial in patients with prediabetes. Details: Preliminary clinical research in a very small number of patients with prediabetes shows that taking a polyphenolic extract from clove flower buds 250 mg daily for 30 days decreases pre-prandial plasma glucose by 14 mg/dL and postprandial plasma glucose by 40 mg/dL when compared to baseline (100595). The validity of these findings is limited by the very small size of the study and the lack of a control group.
• Mosquito repellent. Small clinical studies suggest that topical clove oil may repel mosquitos for up to 4-5 hours. Details: Preliminary clinical research shows that topical application of undiluted clove oil can repel 100% of mosquitoes for up to 4 hours (43427). Other preliminary research shows that topical application of gel containing clove oil 20% can repel 86% to 97% of mosquitoes for 5 hours (43411).
• Nausea and vomiting. Although there has been interest in using oral clove for nausea and vomiting, there is insufficient reliable information about the clinical effects of clove for this purpose.
• Oral mucositis. Although there has been interest in using topical clove for oral mucositis, there is insufficient reliable information about the clinical effects of clove for this purpose.
• Pain (acute). It is unclear if topical clove is beneficial in patients with acute pain. Details: Preliminary clinical research shows that topical application of a gel containing ground cloves, applied as 4 grams of gel for 5 minutes prior to dental anesthesia injection, can reduce needle stick pain when compared with placebo. The effect of the clove gel on pain seems to be comparable to benzocaine 20% gel (43448).
• Premature ejaculation. Topical clove has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research shows that administration of a multi-ingredient cream preparation (SS Cream) containing clove flower, Panax ginseng root, Angelica root, Cistanches deserticola, Zanthoxyl species, Torlidis seed, Asiasari root, cinnamon bark, and toad venom to the glans penis, one hour prior to intercourse and washed off immediately before intercourse, increases ejaculatory latency time by over 4-fold when compared with placebo in adults with premature ejaculation (2537). It is unclear whether clove, another ingredient, or a combination of these ingredients is responsible for these effects.
• Pruritus. There is limited evidence on the topical use of clove oil in patients with chronic pruritus. Details: Preliminary clinical research in patients with chronic pruritus shows that applying clove oil 10% in petroleum jelly to the skin twice daily for 2 weeks reduces the daily duration of itching by 48 minutes and improves symptom severity and disability scores when compared with placebo (96950). More evidence is needed to rate clove for these uses.

(Read more about CLOVE)

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Acne. Although there is interest in using topical frankincense for acne, there is insufficient reliable information about the clinical effects of frankincense for this purpose.
• Aging skin. Small clinical studies suggest that topical cream containing frankincense extracts may improve symptoms of aging skin. Details: Small studies in females with photodamaged skin suggests that applying a cream containing boswellic acids 0.5%, from Boswellia serrata, to the face reduces fine surface lines, tactile roughness, and photo-aging scores when compared to baseline. However, no differences were found for other outcomes, such as skin pigmentation and course wrinkling (21156,21157). The validity of these findings is limited by the lack of a comparator group.
• Back pain. Topical frankincense has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in adults with chronic low back pain shows that two 15-minute sessions of lumbar massage weekly with 5 mL of frankincense 2% and myrrh 2% essential oils for 3 weeks reduces measures of pain and disability when compared with placebo (111504). It is unclear if these effects are due to frankincense oil, myrrh oil, or the combination.
• Cancer-related fatigue. It is unclear if topical frankincense oil improves fatigue in patients with cancer. Details: A small clinical study in outpatient adults with cancer-related fatigue shows that applying frankincense 5% in jojoba oil to the soles of both feet for 2 days before, during, and 2 days after chemotherapy does not improve patient-reported fatigue scores when compared with jojoba oil alone (110144).
• Coronavirus disease 2019 (COVID-19). Inhaled frankincense has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study of females aged 14-49 with ongoing fatigue for more than 5 months after COVID-19 infection shows that inhaling a specific essential oil product containing essential oils of frankincense, clove, orange, and thyme (Longevity, Young Living Essential Oils) for 15 minutes twice daily for 14 days improves self-reported fatigue and quality of life scores when compared with placebo (110143). However, the validity of these findings is limited by lack of adequate blinding.
• Osteoarthritis. It is unclear if topical frankincense is beneficial in patients with osteoarthritis. Details: A small clinical study in adults with knee osteoarthritis shows that applying an oil-based frankincense extract to the affected knee 3 times daily for 4 weeks reduces pain and improves measures of flexibility, stiffness, and function when compared with placebo (111505).
• Rheumatoid arthritis (RA). Topical frankincense has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in Chinese patients with RA shows that applying a cream containing frankincense, thunder god vine, natrii sulfas, chuanxiong root, and myrrh twice daily to affected joints for 4 weeks reduces pain and swollen, tender joints when compared with a control cream (105436).
• Radiation dermatitis. It is unclear if topical frankincense cream reduces the severity of radiation dermatitis. Details: Preliminary clinical research in patients with breast cancer shows that topical application of cream containing frankincense as Boswellia serrata extract 2% (Bosexil, Indena SpA) twice daily for approximately 5 weeks throughout radiation therapy reduces the number of patients who experience intense erythema and reduces the need for cortisone cream when compared with applying a placebo cream (91380). The validity of these findings is limited by reporting bias. This study was also funded by the cream manufacturer, which may further limit the reliability of these findings.
• Vaginal candidiasis. It is unclear if intravaginal frankincense is beneficial in patients with vaginal candidiasis. Details: A small clinical study in adults with vulvovaginal candidiasis shows that intravaginal administration of frankincense 1 gram tablets daily for 21 days reduces dyspareunia, dysuria, vaginal discharge, vulvar pruritis and swelling, curdy discharge, and erythema when compared to baseline. Compared to miconazole vaginal suppositories administered for 7 days, vaginal frankincense is similarly effective in all outcomes mentioned previously but shows greater improvement in vulval pruritis and vaginal discharge (111506). The validity of these findings is limited by the small sample size, differing dosage forms, and variance in treatment length.
• Wound healing. Although there is interest in using topical frankincense for wound healing, there is insufficient reliable information about the clinical effects of frankincense for this purpose. More evidence is needed to rate frankincense for these uses.

(Read more about FRANKINCENSE)

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Abdominal pain. Although there has been interest in using oral or topical lemongrass for abdominal pain, there is insufficient reliable information about the clinical effects of lemongrass for this purpose.
• Common cold. Although there has been interest in using oral lemongrass or lemongrass essential oil inhalation for the common cold, there is insufficient reliable information about the clinical effects of lemongrass for this purpose.
• Cough. Although there has been interest in using oral lemongrass for cough, there is insufficient reliable information about the clinical effects of lemongrass for this purpose.
• Dandruff. It is unclear if topical lemongrass is beneficial in patients with dandruff. Details: Preliminary clinical research in adults with dandruff shows that twice daily topical application of a hair tonic containing 5% to 15% lemongrass essential oil reduces dandruff when compared with placebo. Applying a 10% lemongrass formulation twice daily for 14 days reduced dandruff by around 81% compared with baseline. However, the level of benefit of lemongrass essential oil is difficult to assess from this evidence, as the base formulation also decreased dandruff by up to 58% (93950).
• Diabetes. Although there has been interest in using oral lemongrass for diabetes, there is insufficient reliable information about the clinical effects of lemongrass for this purpose.
• Epilepsy. Although there has been interest in using oral lemongrass for epilepsy, there is insufficient reliable information about the clinical effects of lemongrass for this purpose.
• Fatigue. Although there has been interest in using oral lemongrass for fatigue, there is insufficient reliable information about the clinical effects of lemongrass for this purpose.
• Gingivitis. It is unclear if lemongrass mouthwash is beneficial in patients with gingivitis. Details: Preliminary clinical research in children aged 9-12 years with mild gingivitis shows that using lemongrass oil 0.25% mouthwash, 10 mL twice daily, for 3 weeks moderately improves plaque and gingivitis scores when compared with no mouthwash (110622). Similarly, a small clinical trial in orthodontic patients aged 13 years and older with mild to moderate gingivitis shows that using a lemongrass 0.25% mouthwash for 1 minute daily for 3 weeks improves plaque and gingivitis scores when compared with no mouthwash (112153). Additionally, the lemongrass mouthwash was slightly better than chlorhexidine on some, but not all, tooth surfaces.
• Headache. Although there has been interest in using topical lemongrass for headache, there is insufficient reliable information about the clinical effects of lemongrass for this purpose.
• Hypercholesterolemia. It is unclear if oral lemongrass is beneficial in patients with hypercholesterolemia. Details: Preliminary clinical research shows that taking lemongrass essential oil 140 mg daily orally for 90 days does not reduce cholesterol levels when compared with baseline in patients with hypercholesterolemia (59670).
• Hypertension. Although there has been interest in using oral lemongrass for hypertension, there is insufficient reliable information about the clinical effects of lemongrass for this purpose.
• Influenza. Although there has been interest in using lemongrass essential oil inhalation for influenza, there is insufficient reliable information about the clinical effects of lemongrass for this purpose.
• Nausea and vomiting. Although there has been interest in using oral lemongrass for nausea and vomiting, there is insufficient reliable information about the clinical effects of lemongrass for this purpose.
• Neuropathic pain. Although there has been interest in using oral lemongrass for neuropathic pain, there is insufficient reliable information about the clinical effects of lemongrass for this purpose.
• Pain (acute). Although there has been interest in using oral or topical lemongrass, or lemongrass essential oil inhalation for acute pain, there is insufficient reliable information about the clinical effects of lemongrass for this purpose.
• Rheumatoid arthritis (RA). It is unclear if topical lemongrass is beneficial in patients with RA. Details: Preliminary clinical research shows that applying pure lemongrass essential oil to the skin daily for 30 days can lead to a modest, gradual reduction in pain scores when compared with baseline in adults with mild, moderate, or severe RA (97052). The validity of these results is limited by the lack of a control group.
• Thrush. It is unclear if oral lemongrass is beneficial in patients with thrush. Details: Preliminary clinical research shows that consuming a lemongrass infusion 250 mL twice daily for 10 days decreases thrush symptoms in patients with HIV/AIDS more effectively than applying a topical solution of gentian violet 0.5%. The lemongrass infusion used in this study was prepared by adding dried lemongrass 12.5 mL to 500 mL of boiling water and boiling for 10 minutes (59630). More evidence is needed to rate lemongrass for these uses.

(Read more about LEMONGRASS)

There is insufficient reliable information available about the effectiveness of summer savory.

(Read more about SUMMER SAVORY)

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Aging skin. It is unclear if a topical thyme flower and leaf extract reduces wrinkles. Details: A small clinical trial in healthy females aged 40-60 years with wrinkles shows that applying a specific gel preparation (ThymLec 2%, PhytoPharmaTech) containing thyme flower and leaf 1-3% extract in lecithin on the face twice daily for 60 days reduces facial wrinkles when compared with inactive control gel, but not when compared with an active comparator gel containing propanediol, ornithine, phospholipids, and glycolipids (105909).
• Alopecia areata. Topical thyme oil has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: One small clinical study shows that applying a combination of the essential oils from thyme, rosemary, lavender, and cedarwood improves hair growth in up to 44% of patients after 7 months of treatment when compared with baseline (5177). The validity of this finding is limited by the lack of a comparator group. Additionally, it is unclear if this effect is due to thyme, other ingredients, or the combination.
• Bronchitis. Oral thyme has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Some research has evaluated thyme in combination with cowslip. One observational study in adults and children has found that taking a specific product (Bronchipret) containing thyme and cowslip relieves symptoms of bronchitis and increases production of sputum (13557). A clinical study in patients with acute bronchitis shows that taking a similar combination extract (Bronchicum Tropfen) containing thyme and cowslip root 1 mL five times daily for 7-9 days seems to reduce severity and duration of coughing when compared with placebo (49219). Other thyme and cowslip preparations such as Bronchicum Elixir S and Bronchcium Tropfen seem to be similarly beneficial for bronchitis (49223). Thyme has also been studied in combination with other ingredients. A large clinical study in patients with acute bronchitis shows that taking a specific syrup (Bronchipret Saft, Bionorica AG) containing thyme and English ivy leaf 5.4 mL three times daily for 11 days reduces the frequency and duration of cough when compared with placebo (78152). Additionally, an observational study in children with acute bronchitis has found that taking this combination product in an age-specific dosing schema is associated with reduced bronchitis severity and coughing fits when compared to baseline (78181). However, due to the lack of a comparator group, it is unclear if these changes are due to the product or to the natural resolution of the condition.
• Colic. Although there is interest in using oral thyme for colic, there is insufficient reliable information about the clinical effects of thyme for this condition.
• Cough. Oral thyme has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A large open-label, uncontrolled study in adults with acute cough due to an upper respiratory tract infection who purchased a specific syrup (Bronchipret drops, Bionorica AG) containing thyme and English ivy leaf extracts suggests that taking this product as 2.6 mL three times daily for at least 4 days may improve patient-reported bronchitis symptom severity, cough severity, and quality of life, with over 90% of patients reporting overall satisfaction and product tolerability (110401). However, due to the lack of a comparator group, it is unclear if these changes are due to the product or the natural resolution of the condition. Additionally, the validity of these findings is limited by poor study methodology.
• Common cold. Although there is interest in using oral thyme for the common cold, there is insufficient reliable information about the clinical effects of thyme for this condition.
• Dementia. It is unclear if aromatherapy with thyme oil is beneficial in patients with dementia. Details: One very small clinical study in patients with advanced dementia shows that attaching a pad containing thyme oil to the collar area of the shirt does not reduce agitation when compared with lavender oil or unscented grapeseed oil (12213).
• Developmental coordination disorder (DCD). Oral thyme oil has only been evaluated in combination with other oils; its effect when used alone is unclear. Details: One very small clinical study in children with DCD shows that taking thyme oil, in combination with evening primrose oil, fish oil, and vitamin E (Efalex, Efamol Ltd.), seems to modestly improve movement disorders when compared with baseline (5708). The validity of this finding is limited by the lack of a comparator group. Additionally, it is unclear if this effect is due to thyme, other ingredients, or the combination.
• Dyspepsia. Although there is interest in using oral thyme for dyspepsia, there is insufficient reliable information about the clinical effects of thyme for this condition.
• Dysmenorrhea. It is unclear if drinking thyme tea is beneficial for the prevention of dysmenorrhea. Details: One small observational study in adolescents living in Ethiopia has found that drinking thyme tea is associated with a lower occurrence of primary dysmenorrhea when compared with those who did not drink thyme tea (105910).
• Halitosis. It is unclear whether oral thyme is beneficial for halitosis. Details: One small retrospective study in adults with gingival halitosis who received periodontal treatment and oral hygiene instructions suggests that drinking thyme tea twice daily for 1 week is associated with a reduction in volatile sulfur compounds, which is a marker for halitosis, when compared with chlorhexidine or oral hygiene alone (111716). However, the interpretation of this finding is limited by the lack of thyme dosing information and the narrow focus on intraoral halitosis, excluding most extraoral halitosis-associated conditions.
• Laryngitis. Although there is interest in using oral and topical thyme for laryngitis, there is insufficient reliable information about the clinical effects of thyme for this condition.
• Oral mucositis. Although there is interest in using oral and topical thyme for oral mucositis, there is insufficient reliable information about the clinical effects of thyme for this condition.
• Tonsillitis. Although there is interest in using oral and topical thyme for tonsillitis, there is insufficient reliable information about the clinical effects of thyme for this condition. More evidence is needed to rate thyme for these uses.

(Read more about THYME)

LIKELY SAFE ...when used orally in amounts commonly found in foods. Bitter orange has Generally Recognized as Safe (GRAS) status in the US (4912,35751).

POSSIBLY SAFE ...when bitter orange essential oil is used topically or by inhalation as aromatherapy (6972,7107,98331,104186,104187,108642).

POSSIBLY UNSAFE ...when used orally for medicinal purposes. Although single doses of synephrine, or low daily doses used short-term, may be safe in healthy adults (2040,11269,15381,35757,35759,91681,97256,98332), laboratory analyses raise concerns that many marketed bitter orange products contain higher amounts of synephrine and other natural and synthetic amines than on the label, increasing the risk for serious stimulant-related adverse effects (104185). Additionally, there is a lack of agreement regarding a safe daily dose of synephrine. Health Canada has approved 50 mg of p-synephrine daily when used alone, or 40 mg of p-synephrine in combination with up to 320 mg of caffeine daily in healthy adults (91684). The Federal Institute for Risk Assessment in Germany recommends that supplements should provide no more than 6.7 mg of synephrine daily. This recommendation is meant to ensure that patients who frequently consume synephrine in conventional foods will receive no more than 25.7 mg daily (91290). These limits are intended to reduce the risk for serious adverse effects. There have been several case reports of ischemic stroke and cardiotoxicity including tachyarrhythmia, cardiac arrest, syncope, angina, myocardial infarction, ventricular arrhythmia, and death in otherwise healthy patients who have taken bitter orange extract alone or in combination with other stimulants such as caffeine (2040,6979,12030,13039,13067,14326,14342,91680).

PREGNANCY AND LACTATION: LIKELY SAFE
when used orally in the amounts found in foods. Bitter orange has Generally Recognized as Safe (GRAS) status in the US (4912).

PREGNANCY AND LACTATION: POSSIBLY UNSAFE
when used orally for medicinal purposes. There are case reports of cardiotoxicity including tachyarrhythmia, syncope, and myocardial infarction in otherwise healthy adults who have taken bitter orange extract alone or in combination with other stimulants such as caffeine (2040,6979,12030,13039,13067,14326,14342,91680). The effects of bitter orange during lactation are unknown; avoid use.

(Read more about BITTER ORANGE)

LIKELY SAFE ...when used orally in amounts commonly found in foods. Clove, clove oil, and eugenol have Generally Recognized As Safe (GRAS) status for use in foods in the US (4912).

POSSIBLY SAFE ...when clove oil is applied topically (272). A clove oil 1% cream has been applied to the anus with apparent safety for up to 6 weeks (43487). A liposome-based product containing clove oil 45% has been applied to the palms with apparent safety for up to 2 weeks (100596).

LIKELY UNSAFE ...when clove smoke is inhaled. Smoking clove cigarettes can cause respiratory injury (17,43599). ...when clove oil is injected intravenously. This can cause pulmonary edema, hypoxemia, and acute dyspnea (16384). There is insufficient reliable information available about the safety of using clove orally in medicinal amounts.

CHILDREN: LIKELY UNSAFE
when clove oil is taken orally. Ingesting 5-10 mL of undiluted clove oil has been linked to reports of coagulopathy, liver damage, and other serious side effects in infants and children up to 3 years of age (6,17,43385,43395,43419,43457,43652).

PREGNANCY AND LACTATION: LIKELY SAFE
when used orally in amounts found in foods (4912). Clove, clove oil, and eugenol have Generally Recognized As Safe (GRAS) status for use in foods in the US (4912). There is insufficient reliable information available about the safety of using clove in medicinal amounts during pregnancy and lactation; avoid using.

(Read more about CLOVE)

POSSIBLY SAFE ...when frankincense essential oil is used topically or by inhalation as aromatherapy (7107). ...when frankincense gum extracts of Boswellia are used topically. Cream containing Boswellia 0.5% to 2% has been used with apparent safely for up to 30 days (21156,21157,91380).

PREGNANCY AND LACTATION:
Insufficient reliable information available; avoid using.

(Read more about FRANKINCENSE)

LIKELY SAFE ...when used orally in amounts commonly found in foods. Lemongrass has Generally Recognized as Safe (GRAS) status in the US (4912).

POSSIBLY SAFE ...when used orally or topically, short-term for medicinal purposes. Dried leaves of lemongrass or lemongrass essential oil have been safely used in studies lasting up to 2 weeks (6,12,2612,93950). ...when the essential oil of lemongrass is used by inhalation as a component of aromatherapy (2612).

PREGNANCY: LIKELY UNSAFE
when used orally. Lemongrass seems to have uterine and menstrual flow stimulating effects (12); avoid using.

LACTATION:
Insufficient reliable information available; avoid using.

(Read more about LEMONGRASS)

LIKELY SAFE ...when used orally in amounts commonly found in foods. Summer savory has Generally Recognized as Safe (GRAS) status in the US (4912).

POSSIBLY SAFE ...when used orally and appropriately in medicinal amounts (5,6,18). ...when the diluted oil is used topically. The diluted oil of summer savory is nonirritating and nonsensitizing (6,11).

POSSIBLY UNSAFE ...when the undiluted oil is applied topically. The undiluted oil of summer savory is a severe topical irritant (6).

PREGNANCY AND LACTATION:
Insufficient reliable information available; avoid using amounts greater than those found in foods.

(Read more about SUMMER SAVORY)

LIKELY SAFE ...when used in amounts commonly found in foods. Thyme has Generally Recognized as Safe (GRAS) status in the US (4912).

POSSIBLY SAFE ...when thyme is used orally and appropriately in supplemental amounts. Orally, thyme, in combination with other herbs, has been used safely for up to 23 days (13557,49219,49223,78133). ...when diluted thyme oil is used topically, short-term. Diluted thyme oil has been used with apparent safety for up to 7 months (5177). There is insufficient reliable information available about the safety of thyme oil when used orally or when inhaled.

CHILDREN: LIKELY SAFE
when used in amounts commonly found in foods. Thyme has Generally Recognized as Safe (GRAS) status in the US (4912).

CHILDREN: POSSIBLY SAFE
when thyme is used orally in medicinal amounts in combination with English ivy. Thyme has been used with apparent safety in combination with English ivy for up to 10 days (78181). There is insufficient reliable information available about the safety of thyme oil when used orally or topically in children.

PREGNANCY AND LACTATION: LIKELY SAFE
when used in amounts commonly found in foods. Thyme has Generally Recognized as Safe (GRAS) status in the US (4912). There is insufficient reliable information available about the safety of thyme when used in medicinal amounts during pregnancy and breast-feeding; avoid using.

(Read more about THYME)

ANTIDIABETES DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Theoretically, bitter orange might increase the risk of hypoglycemia when taken with antidiabetes drugs.  Details Some clinical research shows that drinking a tea containing bitter orange and Indian snakeroot reduces fasting and postprandial glucose levels in patients with type 2 diabetes who are using antidiabetes drugs (35751). However, it is unclear if these effects are due to bitter orange, Indian snakeroot, or the combination. An animal study also shows that p-synephrine in combination with gliclazide , a sulfonylurea, causes an additional 20% to 44% decrease in glucose levels when compared with gliclazide alone (95658).

CAFFEINE Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = B Bitter orange might increase blood pressure and heart rate when taken with caffeine.  Details Small clinical studies show that taking bitter orange in combination with caffeine can increase blood pressure and heart rate in otherwise healthy normotensive adults (13657,95659). Theoretically, this might increase the risk of serious cardiovascular adverse effects.

COLCHICINE Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Bitter orange might affect colchicine levels.  Details Colchicine is a substrate of P-glycoprotein and cytochrome P450 3A4 (CYP3A4). Bitter orange has been reported to inhibit CYP3A4 and increase levels of CYP3A4 substrates (7029,11362,93470). However, one small clinical study in healthy adults shows that drinking bitter orange juice 240 mL twice daily for 4 days and taking a single dose of colchicine 0.6 mg on the 4th day decreases colchicine peak serum levels by 24%, time to peak serum level by 1 hour, and overall exposure to colchicine by 20% (35762). The clinical significance of this finding is unclear.

CYTOCHROME P450 2D6 (CYP2D6) SUBSTRATES Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = D Theoretically, bitter orange might increase levels of drug metabolized by CYP2D6.  Details In vitro research shows that octopamine, a constituent of bitter orange, weakly inhibits CYP2D6 enzymes (91878). This effect has not been reported in humans.

CYTOCHROME P450 3A4 (CYP3A4) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Bitter orange might increase levels of drugs metabolized by CYP3A4.  Details Small clinical studies suggest that single or multiple doses of freshly squeezed bitter orange juice 200-240 mL can inhibit CYP3A4 metabolism of drugs (7029,11362,93470), causing increased drug levels and potentially increasing the risk of adverse effects. However, the extent of the effect of bitter orange on CYP3A4-mediated drug interactions is unknown. Some evidence suggests that bitter orange selectively inhibits intestinal CYP3A4, but not hepatic CYP3A4. Its effect on P-glycoprotein, which strongly overlaps with CYP3A4 interactions, is unclear (7029,11269,11270,11362). One small clinical study shows that drinking 8 ounces of freshly squeezed bitter orange juice has no effect on cyclosporine, which seems to be more dependent on hepatic CYP3A4 and P-glycoprotein than intestinal CYP3A4 (11270).

DEXTROMETHORPHAN (Robitussin DM, others) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Bitter orange might increase blood levels of dextromethorphan.  Details One small clinical study shows that bitter orange juice increases dextromethorphan levels, likely through cytochrome P450 3A4 (CYP3A4) inhibition (11362). Theoretically, bitter orange might increase the risk for dextromethorphan-related adverse effects.

FELODIPINE (Plendil) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Bitter orange might increase blood levels of felodipine.  Details One small clinical study shows that bitter orange juice increases felodipine levels, likely through cytochrome P450 3A4 (CYP3A4) inhibition (7029). Theoretically, bitter orange might increase the risk for felodipine-related adverse effects.

INDINAVIR (Crixivan) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Bitter orange might increase blood levels of indinavir.  Details One small clinical study shows that bitter orange juice slightly increases indinavir levels, but this effect is likely to be clinically insignificant. Bitter orange selectively inhibits intestinal cytochrome P450 3A4 (CYP3A4); however, the metabolism of indinavir seems to be more dependent on hepatic CYP3A4 (11269). The effect of bitter orange on other protease inhibitors has not been studied.

MIDAZOLAM (Versed) Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Probable •  Level of Evidence = B Bitter orange might increase blood levels of midazolam.  Details One small clinical study shows that bitter orange juice can increase midazolam levels, likely through inhibition of cytochrome P450 3A4 (CYP3A4) (7029). Theoretically, bitter orange might increase the risk of midazolam-related adverse effects.

MONOAMINE OXIDASE INHIBITORS (MAOIs) Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Probable •  Level of Evidence = D Theoretically, taking MAOIs with synephrine-containing bitter orange preparations might increase the hypertensive effects of synephrine, potentially leading to hypertensive crisis.  Details Bitter orange contains tyramine, octopamine, and synephrine, which are MAO substrates (11267,11995,12378).

QT INTERVAL-PROLONGING DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, bitter orange might have an additive effect when combined with drugs that prolong the QT interval, potentially increasing the risk of ventricular arrhythmias.  Details One case report suggests that taking bitter orange in combination with other stimulants such as caffeine might prolong the QT interval in some patients (13039).

SILDENAFIL (Viagra) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Bitter orange juice might increase blood levels of sildenafil.  Details A small clinical study in healthy adult males shows that drinking freshly squeezed bitter orange juice 250 mL daily for 3 days and taking a single dose of sildenafil 50 mg on the 3rd day increases the peak plasma concentration of sildenafil by 18% and the overall exposure to sildenafil by 44%. Theoretically, this may be due to inhibition of cytochrome P450 3A4 by bitter orange (93470).

STIMULANT DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Theoretically, bitter orange might increase the risk of hypertension and adverse cardiovascular effects when taken with stimulant drugs.  Details Bitter orange appears to have stimulant effects (2040,6979).

(Read more about BITTER ORANGE)

ANTICOAGULANT/ANTIPLATELET DRUGS Interaction Rating = Minor Be watchful with this combination. Severity = Moderate •  Occurrence = Unlikely •  Level of Evidence = D Theoretically, clove oil may increase the risk of bleeding if used with anticoagulant or antiplatelet drugs.  Details Laboratory research suggests that eugenol, a constituent of clove, has antiplatelet activity (12889,43558,43650,43654). This interaction has not been reported in humans.

ANTIDIABETES DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, concomitant use of clove extracts with antidiabetes drugs might increase the risk of hypoglycemia.  Details Clinical and laboratory research suggest that polyphenol extracts from clove flower buds might lower blood glucose levels (100595). Dosing adjustments for insulin or oral hypoglycemic agents may be necessary when taken with clove. Monitor blood glucose levels closely.

IBUPROFEN (Advil, others) Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = D Theoretically, topical application of clove oil with ibuprofen might increase the absorption and side effects of topical ibuprofen.  Details Laboratory research shows that topical application of clove oil increases the absorption of topical ibuprofen (98854). This interaction has not been reported in humans.

(Read more about CLOVE)

(Read more about FRANKINCENSE)

CYTOCHROME P450 1A1 (CYP1A1) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, lemongrass might decrease the metabolism of CYP1A1 substrates.  Details Animal research shows that lemongrass and its constituent citral inhibit CYP1A1 (97051).

CYTOCHROME P450 3A4 (CYP3A4) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, lemongrass might decrease the metabolism of CYP3A4 substrates.  Details Animal research shows that lemongrass and its constituent citral inhibit CYP3A4 (97051).

GLUCURONIDATED DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, lemongrass might increase the clearance and decrease the levels of glucuronidated drugs.  Details Animal research shows that lemongrass and its constituent citral induce uridine diphosphoglucuronosyl transferase (UGT), the major phase 2 enzyme that is responsible for glucuronidation (97051).

PENTOBARBITAL (Nembutal) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, lemongrass might increase the effects and adverse effects of pentobarbital.  Details Animal research shows that high doses of lemongrass essential oil increases sleep time and decreases time to fall asleep in animals administered pentobarbital.

(Read more about LEMONGRASS)

(Read more about SUMMER SAVORY)

ANTICHOLINERGIC DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, concurrent use of anticholinergic drugs and thyme essential oil might reduce the effects of anticholinergic drugs.  Details In vitro evidence suggests that thyme essential oil and specific essential oil constituents like thymohydroquinone and carvacrol can inhibit acetylcholinesterase (AChE) (78155). However, this effect has not been observed in humans.

ANTICOAGULANT/ANTIPLATELET DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, thyme leaf extract might have additive effects with anticoagulant or antiplatelet drugs.  Details In vitro and animal research suggests that thyme leaf extract has antiplatelet effects (13457,18335,49445). However, this effect has not been observed in humans.

CHOLINERGIC DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, concurrent use of cholinergic drugs and thyme essential oil might cause additive cholinergic effects.  Details In vitro evidence suggests that thyme essential oil and specific essential oil constituents like thymohydroquinone and carvacrol can inhibit acetylcholinesterase (AChE) (78155). However, this effect has not been observed in humans.

ESTROGENS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, thyme might competitively inhibit the effects of estrogen replacement therapy.  Details In vitro research shows that thyme has estrogen receptor-binding activity and phytoestrogen content (3701). However, this effect has not been observed in humans.

(Read more about THYME)

General ...Orally, bitter orange might be unsafe when used in medicinal amounts. Topically and when inhaled as aromatherapy, bitter orange seems to be well tolerated.
Most Common Adverse Effects:
Orally: Hypertension and tachycardia, particularly when used in combination with caffeine and/or other stimulant ingredients.
Topically: Skin irritation.
Serious Adverse Effects (Rare):
Orally: Myocardial infarction, QT prolongation, seizures, stroke, syncope, tachyarrhythmia, and ventricular fibrillation have been reported in patients taking bitter orange in combination with other ingredients. It is unclear if these effects are due to bitter orange, other ingredients, or the combination.

Cardiovascular ...Bitter orange, which contains adrenergic agonists synephrine and octopamine, may cause hypertension and cardiovascular toxicity when taken orally (2040,6969,6979). Studies evaluating the effect of bitter orange on cardiovascular parameters have been mixed. Several studies show that taking bitter orange alone or in combination with caffeine increases blood pressure and heart rate. In one clinical study, bitter orange in combination with caffeine increased systolic and diastolic blood pressure and heart rate in otherwise healthy normotensive adults (13657). In another study, a single dose of bitter orange 900 mg, standardized to 6% synephrine (54 mg), also increased systolic and diastolic blood pressure and heart rate for up to 5 hours in young, healthy adults (13774). Using half that dose of bitter orange and providing half as much synephrine, did not seem to significantly increase blood pressure or QT interval in healthy adults (14311). Increased diastolic, but not systolic, blood pressure or heart rate also occurred in a clinical trial involving a specific supplement containing synephrine 21 mg and caffeine 304 mg (Ripped Fuel Extreme Cut, Twinlab) (35743). Synephrine given intravenously to males increased systolic blood pressure, but lacked an effect on diastolic blood pressure or heart rate (12193).
In clinical research and case reports, tachycardia, tachyarrhythmia, QT prolongation, ischemic stroke, variant angina, and myocardial infarction have occurred with use of bitter orange or synephrine-containing multi-ingredient products (12030,13039,13067,13091,13657,14326,35749,91680). In one case report, a combination product containing bitter orange may have masked bradycardia and hypotension while exacerbating weight loss in a 16 year-old female with an eating disorder taking the product for weight loss (35740). From 1998 to 2004, Health Canada received 16 reports of serious adverse cardiovascular reactions such as tachycardia, cardiac arrest, ventricular fibrillation, blackout, and collapse. In two of these cases, the patient died. In almost all of these cases, bitter orange was combined with another stimulant such as caffeine, ephedrine, or both (14342).
Other research has found no significant effect of bitter orange on blood pressure or heart rate. Several clinical studies have reported that, when taken as a single dose or in divided doses ranging from 20-100 mg for one day, p-synephrine had no significant effect on blood pressure, heart rate, electrocardiogram results or adverse cardiovascular events in healthy adults (35772,91681,91681,95659,101708) Similarly, no difference in blood pressure, heart rate or electrocardiogram results were reported when p-synephrine from bitter orange (Advantra Z/Kinetic; Nutratech/Novel Ingredients Inc.) was taken for 6 weeks in healthy patients (11268). Another clinical study showed no significant effect of bitter orange (Nutratech Inc.), standardized to synephrine 20 mg, on blood pressure or heart rate when taken daily for 8 weeks in healthy males (95656). In other research, changes in blood pressure, heart rate, or QTc interval were lacking when bitter orange was given alone or in combination with caffeine and green tea (14311,35753,35755,35764,35769,35770). In one study of healthy adults, taking a single dose of p-synephrine 103 mg actually reduced mean diastolic blood pressure by 0.4-4 mmHg at 1 and 2 hours after administration when compared with placebo (95659).
A meta-analysis of clinical trials in adults with or without obesity suggests that taking p-synephrine 6-214 mg orally daily does not affect blood pressure or heart rate when used short-term, but modestly increases blood pressure and heart rate when taken for 56-60 days (109950).
The effect of bitter orange on blood pressure, heart rate, and electrocardiogram results in patients with underlying conditions, particularly cardiovascular disease, is unknown and requires further study.

Dermatologic ...Photosensitivity may occur, particularly in fair-skinned people (11909). In a clinical trial, topical application with bitter orange essential oil resulted in irritation (6972).

Endocrine ...Some clinical research shows that taking a specific supplement containing 21 mg of synephrine and 304 mg of caffeine (Ripped Fuel Extreme Cut, Twinlab) increases levels of postprandial glucose (35743). Other preliminary clinical research shows that taking a specific pre-workout supplement (Cellucor C4 Pre-Workout, Nutrabolt) along with a bitter orange extract standardized for synephrine 20 mg (Nutratech Inc.) 30 minutes once before exercise causes a significant 12% increase in glucose (95657); however, there is no difference in blood glucose when compared with placebo when this combination is taken daily for 8 weeks (95656). The effect of bitter orange itself is unclear.

Gastrointestinal ...Bitter orange has been linked to a report of ischemic colitis. In one case, a 52-year-old female developed ischemic colitis after taking a bitter orange-containing supplement (NaturalMax Skinny Fast, Nutraceutical Corporation) for a week. Symptoms resolved within 48 hours after discontinuing the supplement (15186). As this product contains various ingredients, the effect of bitter orange itself is unclear.

Musculoskeletal ...Unsteady gait has been noted in one case report of a patient taking bitter orange (13091). In another case, an otherwise healthy, Black male with sickle cell trait, developed severe rhabdomyolysis following ingestion of a specific weight loss product (Lipo 6, Nutrex Research Inc.), which contained synephrine and caffeine (16054). However, other preliminary clinical research shows that taking a specific pre-workout supplement (Cellucor C4 Pre-Workout, Nutrabolt) along with a bitter orange extract standardized for synephrine 20 mg (Nutratech Inc.), taken 30 minutes once before exercise (95657) or daily for 8 weeks, does not affect creatine kinase or serum creatinine levels when compared with placebo (95656). As these products contain various ingredients, the effect of bitter orange itself is unclear.

Neurologic/CNS ...Dizziness, difficulty in concentrating, memory loss, syncope, seizure, and stroke have been noted in case reports following bitter orange administration (13091,13039). Theoretically, bitter orange may trigger a migraine or cluster headache due to its synephrine and octopamine content (35768). When used as aromatherapy, bitter orange essential oil has also been reported to cause headache in some patients (104187). Sprint athletes taking the bitter orange constituent p-synephrine 3 mg/kg (Synephrine HCL 99%, Nutrition Power) 60 minutes before exercises and sprinting reported more nervousness (mean difference 0.9) when compared with placebo on a Likert scale. Although statistically significant, this difference is not considered clinically significant (95655).

(Read more about BITTER ORANGE)

General ...Orally, clove is well tolerated when consumed as a spice; however, clove oil in doses of only 5-10 mL can be toxic in children. Topically, clove is generally well tolerated. When inhaled or used intravenously, clove may be unsafe.
Most Common Adverse Effects:
Topically: Burning, contact dermatitis, dental decay, itching, mucous membrane irritation, tingling, ulcers.
Inhaled: Dental decay, hypertension, itching, tachycardia.
Serious Adverse Effects (Rare):
Orally: Liver failure, respiratory distress.
Inhaled: Pneumonitis, pulmonary edema, respiratory distress.

Cardiovascular ...Smoking clove cigarettes increases heart rate and systolic blood pressure (12892).

Dental ...Population research has found that the risk of dental decay is increased in clove cigarette smokers (43332). Repeated topical application of clove in the mouth can cause gingival damage and skin and mucous membrane irritation (4,272,512). Eugenol, a constituent of clove and a material commonly found in dentistry, has been associated with side effects including gum inflammation and irritation (43365,43373,43522).

Dermatologic ...The American Dental Association has accepted clove for professional use, but not nonprescription use, due to potential damage to soft tissue that may be induced by clove application. In clinical research, small aphthous-like ulcers appeared in the area of the mouth where clove gel was applied in four participants (43448). Skin irritation and stinging have been reported with clove oil application (43338,43626). In a 24-year-old, exposure to a clove oil spill resulted in permanent local anesthesia and anhidrosis, or lack of sweating, at the affected area (43626).

Endocrine ...A case of hypoglycemia and metabolic acidosis have been reported after administration of one teaspoon of clove oil to a seven-month-old infant (43457). A case of electrolyte imbalance following accidental ingestion by a seven-month-old has also been reported (6).

Hematologic ...A case of disseminated intravascular coagulation has been reported in a 2-year-old patient after consuming between 5-10 mL of clove oil. The patient was treated with heparin, fresh frozen plasma, protein C, factor VII, and antithrombin III. On the fifth day, the patient started to improve and made a full recovery (43652).

Hepatic ...There are three cases of hepatic failure occurring in children after ingestion of 5-10 mL of clove oil (43395,43419,43652). Liver injury also occurred in a 3-year-old male (96949). These patients were successfully treated with N-acetylcysteine. The course of liver injury seems to be milder and shorter with early N-acetylcysteine treatment (43395,43419,96949). Another patient, who also presented with disseminated intravascular coagulation, was successfully treated with heparin, fresh frozen plasma, protein C, factor VII, and antithrombin III (43652).

Immunologic ...Contact dermatitis and urticaria has been reported following topical exposure to clove oil or eugenol, a constituent of clove oil (12635,43339,43606,43346).

Neurologic/CNS ...CNS depression has been reported in a 7-month-old who was given one teaspoon of clove oil accidentally in place of mineral oil for diarrhea. The patient was successfully treated with supportive care and gastric lavage (43457). A case of confusion and inability to speak has been reported secondary to oral exposure to clove oil and alcohol. The patient required intubation and was successfully treated with thiamine and normal saline (43580). Seizure and coma have been reported in a two-year-old male after ingesting 5-10 mL of clove oil (43652).

Pulmonary/Respiratory ...Clove cigarettes have been associated with throat and chest tightness (43337), pulmonary edema (43618), and fatal aspiration pneumonitis (43599). The causative factor may be clove alone or clove along with other substances found in cigarettes. Clove cigarettes contain significant amounts of nicotine, tar, and carbon monoxide and increase plasma levels of nicotine and exhaled carbon monoxide, which might cause long-term health effects similar to tobacco smoking (12892). According to the American Medical Association, inhaling clove cigarette smoke has been associated with severe lung injury in a few susceptible individuals with prodromal respiratory infection. Also, some individuals with normal respiratory tracts have apparently suffered aspiration pneumonitis as the result of a diminished gag reflex induced by a local anesthetic action of eugenol, which is volatilized into the smoke (43602).
Intravenous injection of clove oil in a 32-year-old female resulted in hypoxia, acute dyspnea, interstitial and alveolar infiltrates, and non-cardiogenic pulmonary edema. The patient was managed with supplemental oxygen and recovered over the next seven days (16384).
Occupational exposure to eugenol, a constituent of clove, has also been reported to cause asthma and rhinitis (43492).

Renal ...Proteinuria and other urinary abnormalities were observed in a seven-month-old infant given one teaspoon of clove oil accidentally in place of mineral oil for diarrhea. The patient was successfully treated with supportive care and gastric lavage (43457).

(Read more about CLOVE)

General ...Topically and by inhalation, frankincense essential oil seems to be well tolerated. For information on the safety of frankincense when used orally, see the Boswellia serrata monograph.
Most Common Adverse Effects:
Topically: Dermatitis, irritation, itching.

Dermatologic ...In one case report, a 68-year-old female presented with contact dermatitis after frequent diffusion of a specific frankincense essential oil product (Young Living Essential Oils) and application to the pillow each night. The patient also applied various other creams to the face. Patch testing identified a positive reaction to frankincense oil and multiple other substances (110145). In another case report, a 28-year-old female developed a severe eczematous rash on the thigh after applying a cream containing frankincense, rosemary, olive oil, and beeswax for 5 days. Patch testing identified a positive reaction to frankincense only (36892).

Immunologic ...Frankincense has been rarely reported to cause allergic skin reactions. In one case report, a 68-year-old female with no history of atopy presented with contact dermatitis after frequent diffusion of a specific frankincense essential oil product (Young Living Essential Oils) and application to the pillow each night. The patient also applied various other creams to the face. Patch testing identified a positive reaction to frankincense oil and multiple other substances (110145). In another case report, a 28-year-old female with a history of atopy developed a severe eczematous rash on the thigh after applying a cream containing frankincense, rosemary, olive oil, and beeswax for 5 days. Patch testing identified a positive reaction to frankincense only (36892).

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General ...Lemongrass is generally well tolerated when taken orally, applied topically, or inhaled as aromatherapy.
Most Common Adverse Effects:
Topically: Allergic reactions, irritation, rash.
Serious Adverse Effects (Rare):
Inhalation: Toxic alveolitis.

Dermatologic ...Topical use of lemongrass essential oil has caused a rash or irritation, possibly due to an allergic reaction (59513,59517,59567,59500). However, allergic reactions to topical use of lemongrass essential oil are rare (2,18).

Pulmonary/Respiratory ...There have been two cases of toxic alveolitis associated with inhalation of an unknown quantity of lemongrass essential oil (2).

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General ...There is limited reliable information available about the adverse effects of summer savory when used orally. Topically, summer savory can cause skin eruptions (12). The concentrated oil of summer savory is strongly irritating (6).

Dermatologic ...Topically, summer savory can cause skin eruptions (12). The concentrated oil of summer savory is strongly irritating (6).

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General ...Orally, thyme is well tolerated when used in food and seems to be well tolerated when used medicinally. Topically, thyme seems to be generally well tolerated.
Most Common Adverse Effects:
Orally: Allergic reactions, diarrhea, dizziness, headache, heartburn, nausea, or vomiting.
Topically: Contact dermatitis and skin irritation.

Dermatologic ...Topically, thyme, thyme oil, or the constituent thymol can cause contact dermatitis and skin irritation (13463,78252,78362,78384,77982,78154,78310,78313,78384). In one study of 100 patients with contact allergies, 5% were attributed to thyme oil as an allergen contained in wound dressings (78362). Toothpastes containing thymol have been associated with cheilitis and glossitis (13463).

Gastrointestinal ...Orally, thyme and thyme oil may cause heartburn, nausea, vomiting, stomach upset, or diarrhea (13557,94033). In a clinical study, two patients using extracts of thyme herb and ivy leaves experienced temporary stomach ache and mild nausea (78181).
Intravaginally, cream containing thyme and garlic has been associated with reports of nausea and vomiting in one clinical study (88387). It is not clear if these adverse effects were associated with thyme, garlic, or the combination.

Genitourinary ...Intravaginally, cream containing thyme and garlic has been associated with reports of vaginal dryness and vaginal irritation in one clinical study (88387). It is not clear if these adverse effects were associated with thyme, garlic, or the combination.

Immunologic ...Orally, thyme can cause allergic reactions; however, this is uncommon (13463). Allergic reactions to thyme might be more common in people who are also allergic to oregano and other Lamiaceae species (3808).

Neurologic/CNS ...Orally, thyme may case headache or dizziness (94033).

Pulmonary/Respiratory ...By inhalation, occupational exposure to thyme dust can cause acute airway obstruction (783,13463,13464,77982,78098).

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