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INSUFFICIENT RELIABLE EVIDENCE to RATE

• Atopic dermatitis (eczema). It is unclear if topical fig fruit extract is beneficial in children with eczema. Details: Preliminary clinical research in children 4 months to 14 years of age with mild to moderate atopic dermatitis shows that topical application of a cream containing fig fruit extract 8% twice daily for 14 days reduces the severity of symptoms by 56% and itchiness by 64% when compared with baseline. Fig cream is as effective as a cream containing 1% hydrocortisone and more effective than placebo (99958).
• Constipation. It is unclear if oral fig fruit is beneficial for constipation. Details: A small clinical study in adults with constipation shows that taking fig fruit paste 300 grams daily for 8 weeks improves stool consistency by 58%, compared to a 27% improvement with placebo. Fig paste also modestly improves abdominal discomfort; however, it does not affect stool frequency, abdominal pain, effort, or relief (99956).
• Diabetes. It is unclear if oral fig leaf is beneficial for glycemic control in patients with type 1 diabetes. Details: A very small clinical crossover study in adults with type 1 diabetes shows that consuming a tea made from fig leaves modestly reduces postprandial, but not pre-prandial, glucose levels and also reduces insulin requirements when compared with consuming a non-fig tea (12578).
• Vitiligo. Although there has been interest in using oral fig for vitiligo, there is insufficient reliable information about the clinical effects of fig for this condition.
• Warts. It is unclear if topical fig latex is beneficial for warts in adults and children. Details: Preliminary clinical research in adults and children 5 years of age and older shows that applying fig latex directly to a common wart three times daily for at least 4 days is slightly less effective than cryotherapy for producing complete resolution of the wart after 2 weeks (99962).
• Wound healing. Although there has been interest in using topical fig for wound healing, there is insufficient reliable information about the clinical effects of fig for this purpose. More evidence is needed to rate fig for these uses.

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INSUFFICIENT RELIABLE EVIDENCE to RATE

• Angina. It is unclear if oral hawthorn is beneficial in patients with angina. Details: Preliminary clinical research in patients with angina taking chronic beta-adrenergic receptor blockers or ACE inhibitor therapy shows that taking a hawthorn (Crataegus pinnatifada) extract 100 mg orally three times daily for four weeks improves angina and electrocardiogram (ECG) findings and reduces nitroglycerin intake when compared with placebo (19242). Other preliminary clinical research in patients with unstable angina shows that taking hawthorn 10 grams and hu zang 15 grams orally daily for 4 weeks does not reduce the frequency of angina pectoris attacks when compared with control. However, taking hawthorn and hu zang improved some subjective symptom scores and quality of life scores (109610).
• Anxiety. Oral hawthorn has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A clinical study in adults with mild to moderate generalized anxiety shows that taking a specific product (Sympathyl, not available in the US) containing hawthorn, magnesium, and California poppy for 90 days modestly improves anxiety scores when compared with placebo (12583). Also, a clinical study in adults with adjustment disorder and anxious mood shows that hawthorn, in combination with black horehound, passion flower, valerian, kola nut, and guarana, modestly improves anxiety scores when compared with placebo (6250). It is unclear if these effects are due to hawthorn, other ingredients, or the combination. Another small clinical study in healthy adults shows that taking a combination of herbal extracts containing hawthorn, passionflower, ballota, and valerian root daily for 14 days reduces subjective anxiety and objective sympathetic and autonomic nervous system activation in response to a psychosocial stressor when compared with placebo (111222). It is unclear if these effects are due to hawthorn, other ingredients, or the combination.
• Arrhythmia. Although there has been interest in using oral hawthorn for arrhythmia, there is insufficient reliable information about the clinical effects of arrhythmia for this condition.
• Atherosclerosis. Although there has been interest in using oral hawthorn for atherosclerosis, there is insufficient reliable information about the clinical effects of arrhythmia for this condition.
• Cardiovascular disease (CVD). Although there has been interest in using oral hawthorn for CVD, there is insufficient reliable information about the clinical effects of arrhythmia for this condition.
• Cognitive function. Oral hawthorn has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: In a preliminary clinical trial, a single dose of 25 drops of a combination product of D-camphor and hawthorn berry extract (Korodin) was superior to placebo for increasing cognitive performance in elderly female patients as measured by visuomotor speed and information processing capacity. The active treatment group showed an improvement in attentional and mental performance (19240,91504).
• Congestive heart failure (CHF). The evidence on the effects of oral hawthorn in patients with CHF is conflicting. Although some older research suggests it may be beneficial, more recent, larger studies suggest it may actually increase the risk for complications. Details: There is contradictory evidence about the effects of hawthorn extract in heart failure patients. Several clinical studies show that taking specific hawthorn leaf and flower extracts (LI 132, Faros 300, Lichtwer Pharma; WS 1442, Crataegutt forte, Dr. Willmar Schwabe Pharmaceuticals; or HeartCare, Nature's Way) 240-600 mg daily improves ejection fraction and exercise tolerance, reduces subjective symptoms, and decreases the risk of death in patients with New York Heart Association (NYHA) stage II heart failure. In these studies, the maximum effect was usually seen after 6-12 weeks of treatment (8279,8280,11449,19221,19223,19225,19226,19227,19228). Another clinical trial shows that hawthorn extract (WS 1442, Crataegutt forte, Dr. Willmar Schwabe Pharmaceuticals or HeartCare, Nature's Way) 1800 mg daily, combined with diuretic therapy, improves exercise tolerance and reduces subjective symptoms in NYHA stage III heart failure. In this study, maximum effect was usually seen after 16 weeks of treatment (8281). In another trial, patients with NYHA II heart failure taking either hawthorn (LI 132, Faros) 300 mg three times daily or captopril 12.5 mg three times daily experienced similar improvements in cardiac performance and symptoms (19230). However, other clinical research suggests no benefit and possible harm with hawthorn. A large-scale clinical trial (SPICE) in patients with NYHA stage II or III heart failure shows that taking specific hawthorn extracts (WS 1442, Crataegutt forte, Dr. Willmar Schwabe Pharmaceuticals; HeartCare, Nature's Way) 900 mg daily for 24 months, in combination with conventional treatment, does not decrease hospitalization due to progressive heart failure, non-fatal myocardial infarction, or cardiac death (17203). Another clinical trial in patients with NYHA stage II or III heart failure shows that taking these same specific hawthorn extracts at the same dose for up to 6 months does not slow the progression of heart failure when compared with placebo (19222). In a retrospective analysis of this study, it was shown that heart failure progression was significantly increased in patients taking hawthorn when compared with placebo. The rate of death was also increased by 1.7% over placebo, and heart failure-related hospitalizations increased by 8% over placebo in patients treated with hawthorn (16824).
• Hyperlipidemia. Although there has been interest in using oral hawthorn for hyperlipidemia, there is insufficient reliable information about the clinical effects of arrhythmia for this condition.
• Hypertension. It is unclear if oral hawthorn is beneficial for lowering blood pressure. Details: One preliminary clinical trial showed that taking hawthorn standardized extract 1,000-2,500 mg daily for three days does not significantly reduce blood pressure in hypertensive or prehypertensive patients when compared with placebo (19244). However, another study in patients with diabetes and hypertension shows that taking a specific hawthorn extract (LI 132) 1,200mg daily for 16 weeks significantly decreased diastolic, but not systolic, blood pressure when compared with placebo (19245).
• Obesity. Although there has been interest in using oral hawthorn for obesity, there is insufficient reliable information about the clinical effects of hawthorn for this condition.
• Orthostatic hypotension. Oral hawthorn has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in older adults with orthostatic hypotension shows that taking a specific combination product containing hawthorn and camphor (Korodin Herz-Kreislauf-Tropfen) 25 drops orally three times daily for 7 days attenuates the blood pressure reduction upon standing when compared with placebo. Signs and symptoms of orthostatic hypotension such as dizziness, blurry vision, and falls also seem to be reduced when compared with baseline (39614,39617). A meta-analysis of 4 studies shows that giving single doses of 20-25 drops of the same combination product increases systolic and diastolic blood pressure when compared with placebo (103620). However, the studies have methodologic problems and, while 2 were conducted in females with orthostatic hypotension, the others involved health young adults or normotensive elderly subjects. The effect of hawthorn alone for treatment of orthostatic hypotension has not been determined. The combination product used in these studies is not available in the US. More evidence is needed to rate hawthorn for these uses.

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INSUFFICIENT RELIABLE EVIDENCE to RATE

• Iron deficiency anemia. Preliminary clinical research shows that consuming diluted lime juice 500 mL standardized to contain ascorbic acid 25 mg twice daily, 6 days weekly, for 8 months does not improve iron status in iron-deficient women who consume diets high in phytate and non-heme iron (59927).
• Malaria. Preliminary clinical research in children aged 5 months to 13 years with malaria shows that taking lime juice 10-15 mL three times daily in addition to artemisinin combination therapy reduces the time to achieve a reduction in parasite load of at least 75% by approximately 8 hours when compared with using artemisinin combination therapy alone. Also, by 72 hours, more than twice as many children taking lime had achieved complete clearance (100120).
• Sickle cell disease. Preliminary clinical research in infants, children, and adolescents with sickle cell disease shows that taking lime juice 5-15 mL twice daily depending on weight for 6 months, in addition to folic acid, vitamin B complex, and proguanil, reduces the rate of a painful bone crisis by approximately 55% compared with not taking lime. Rates of painful episodes, febrile illness, and hospital admission were reduced by 46%, 47%, and 10%, respectively. There was no benefit on rates of blood transfusion, hepatomegaly, splenomegaly, or jaundice (100121).
• Smoking cessation. Preliminary clinical research in people quitting smoking shows that taking fresh lime as needed for 12 weeks is as effective as nicotine gum for reducing cravings. It also seems to improve continuous abstinence over the last 3 weeks of treatment and after an additional 12 weeks. Abstinence was measured using exhaled carbon monoxide (100131). More evidence is needed to rate lime for these uses.

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LIKELY SAFE ...when the fresh or dried fruit is used orally in amounts commonly found in foods.

POSSIBLY SAFE ...when fig fruit paste is consumed orally in amounts of up to 300 grams daily for up to 8 weeks (99956).

POSSIBLY UNSAFE ...when fig leaf decoctions are used topically. Fig leaf contains psoralens (12579,12581). There have been reports of photodermatitis with burn-like lesions and rashes after fig decoctions were applied prior to sun exposure (49962,49968,49973,49975,49981). There is insufficient reliable information available about the safety of fig leaf when used orally.

PREGNANCY AND LACTATION: LIKELY SAFE
when the fresh or dried fruit is used orally in amounts commonly found in foods. There is insufficient reliable information available about the safety of fig leaf or fruit used in medicinal amounts during pregnancy and lactation; avoid use.

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POSSIBLY SAFE ...when used orally and appropriately, short-term. Hawthorn preparations in doses of up to 1800 mg daily seem to be safe when used for up to 16 weeks. Although hawthorn might be safe for long-term use, current studies have not evaluated safety past 16 weeks (8279,8280,8281,10144,17203,104689). There is insufficient reliable information available about the safety of hawthorn when used topically.

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

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LIKELY SAFE ...when used orally in amounts commonly found in foods. Lime has Generally Recognized As Safe status (GRAS) for use in foods in the US (4912).

POSSIBLY UNSAFE ...when used topically. Lime oil and lime juice contain photosensitizing constituents (12,11019,40894,59925,59928,100125,100126,100129). ...when used intravaginally. Lime juice has caused mild to moderate adverse effects in women using lime juice-soaked tampons or as a douche, especially in concentrations of 20% or more (100127,100128). There is insufficient reliable information available about the safety of lime when used orally in medicinal amounts.

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

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ANTIDIABETES DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Theoretically, fig leaf might enhance the blood glucose lowering effects of hypoglycemic drugs.  Details A small clinical study in patients with type 1 diabetes shows that consuming a tea made from fig leaves modestly reduces postprandial glucose levels and insulin requirements (12578).

INSULIN Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Fig leaf may enhance the blood glucose lowering effects of insulin.  Details A small clinical study in patients with type 1 diabetes shows that consuming a tea made from fig leaves modestly reduces postprandial glucose levels and insulin requirements (12578).

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ANTICOAGULANT/ANTIPLATELET DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, hawthorn may increase the risk of bleeding if used with anticoagulant or antiplatelet drugs.  Details In vitro and animal research shows that hawthorn can inhibit platelet aggregation (95528,95529,95530,95531). However, its effect in humans is unclear. One observational study shows that patients taking hawthorn shortly before undergoing coronary artery bypass graft (CABG) surgery or valve replacement surgery have a 10% incidence of postoperative bleeding, compared with 1% in those who never consumed hawthorn extract (95527). However, clinical research shows that taking a specific preparation of dried hawthorn leaves and flowers (Crataesor, Soria Natural Lab) 800 mg three times daily for 15 days does not affect platelet aggregation or levels of thromboxane B2, the metabolite of thromboxane A2, in healthy humans (54664).

BETA-BLOCKERS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, concomitant use might cause additive effects on blood pressure and heart rate.  Details Some evidence shows that hawthorn might lower blood pressure and heart rate (12595,19245,113112,113113).

CALCIUM CHANNEL BLOCKERS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, concomitant use might cause additive coronary vasodilation and hypotensive effects.  Details Some evidence shows that hawthorn might lower blood pressure due to vasodilatory effects (12595,19245).

DIGOXIN (Lanoxin) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, hawthorn might potentiate the effects and adverse effects of digoxin.  Details Hawthorn appears to improve cardiac output (12595); however, hawthorn does not appear to affect digoxin pharmacokinetics (19249). Case reports suggest that at least one species of hawthorn root extract (Crataegus mexicana) may produce adverse effects similar to digoxin and can cross-react with digoxin assays, leading to falsely elevated plasma digoxin levels (113112,113113).

NITRATES Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Probable •  Level of Evidence = D Theoretically, concomitant use might cause additive coronary vasodilatory effects.  Details Some evidence shows that hawthorn might lower blood pressure due to vasodilatory effects (12595,19245).

PHOSPHODIESTERASE-5 INHIBITORS Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Probable •  Level of Evidence = D Theoretically, concomitant use might result in additive vasodilation and hypotension.  Details Hawthorn might inhibit PDE-5 and cause vasodilation (12595).

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General ...Orally, the fresh or dried fig fruit is well tolerated in amounts commonly found in foods. A thorough evaluation of safety outcomes has not been conducted when fig fruit is used orally as medicine.
Topically, fig leaf may cause photodermatitis. There is limited reliable information available about the safety of fig fruit or latex when applied topically.
Serious Adverse Effects (Rare):
Orally: Allergy and, in rare cases, anaphylaxis.
Topically: The fig leaf may cause photodermatitis.

Dermatologic ...Topically, fig leaf might cause photodermatitis. The leaf contains psoralens (12579,12581). Many cases of photodermatitis from fig leaf have been reported (49962,49968,49973,49975,49981). In at least two cases, the burns were serious enough to require hospitalization. Severe anemia and sepsis developed in one patient (49962). Avoid excessive sunlight or ultraviolet light exposure while using products containing fig leaf.

Orally, fig fruit is unlikely to cause photodermatitis (12581).

Immunologic ...Orally, fig fruit can cause allergy and, in rare cases, anaphylaxis (8815,12580). Topically, exposure to fig fruit and leaves can cause contact dermatitis. In some cases, sun exposure can make contact dermatitis worse (12689,99961).

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General ...Orally, hawthorn seems to be well tolerated when used appropriately. Topically, no adverse effects have been reported, although a thorough evaluation of safety outcomes has not been conducted.
Serious Adverse Effects (Rare):
Orally: Multiorgan hypersensitivity reactions resulting in acute renal failure have been reported rarely.

Cardiovascular ...Orally, tachycardia (with facial pains) of uncertain relationship to hawthorn was reported in a multicenter clinical trial (54640). Palpitations (19244) were reported in three patients in a large surveillance trial of 3,664 patients with cardiac failure (54692) and in 11 patients with congestive heart failure (CHF) in a literature review of 5,577 patients (19247). Circulation failure has been reported in two patients with CHF in a literature review of 5,577 patients (19247). Incidences of hospitalization, hospitalization due to CHF, worsening of CHF, angina, and atrial fibrillation have also been reported with the use of hawthorn extract WS 1442 (Crataegutt forte), although it is unclear if these events are related to hawthorn supplementation or existing CHF (19222). In clinical trials, chest pain (8281), short-term increases in blood pressure (19240), and other non-specific heart problems (17203) have also been reported following the use of various hawthorn preparations (e.g. WS 1442, Korodin).
Orally, severe bradycardia, bradypnea, and Mobitz type 1 second degree heart block have been reported in a 16-year-old female who consumed Hawthorn root extract. Blood tests indicated plasma digoxin levels in the therapeutic range, despite no history of digoxin use. Medical treatment for digoxin cardiotoxicity did not improve symptoms. Symptoms gradually normalized over 3 days after discontinuation of the product (113112). Similarly, a 40-year-old female presented with bradycardia and elevated plasma digoxin levels after taking hawthorn root extract 196 mg daily for 2 days with no history of digoxin use. Symptoms resolved within 24 hours (113113).

Dermatologic ...Orally, erythematous rash has been reported in patients with CHF in a literature review of 5,577 patients (19247). Non-specific rashes and itching (19222,19243) as well as toxiderma from the fruits of hawthorn (54670) have also been reported.

Gastrointestinal ...Orally, rare abdominal discomfort of uncertain relationship to hawthorn has been reported in a large clinical trial, surveillance study, case reports, and a literature review (19247,54640,54692,113112). Digestive intolerance (19241), diarrhea (19243,113112), flatulence (8281), gastroenteritis (8281), increased bowel movements (19243), obstipation (8281), mild and rare nausea (10144,19247,19244), vomiting (113112), nutritional and metabolic problems (17203), and other non-specific gastrointestinal effects (19222), have also been reported. Furthermore, gastrointestinal hemorrhage has been reported in two patients with CHF in a literature review of 5,577 patients (19247).

Musculoskeletal ...In clinical trials, arthritis (8281), back pain (8281), weakness (19243), and other non-specific musculoskeletal effects (19222) have been reported following the use of various hawthorn preparations g. WS 1442, CKBM-A01). Additionally, in a case report, myalgia has been reported following use of hawthorn root extract (113113).

Neurologic/CNS ...Orally, headache and dizziness/vertigo were reported in 2 patients in a large surveillance trial of 3,664 patients with cardiac failure (54692), in 15 patients with CHF as reported in a literature review of 5,577 patients (19247), in a varying number of clinical trial participants (8281,19222,19244), and in case reports (113112,113113). Incidences of fainting (19222), fever (17203), and infrequent, mild and transient sleepiness have also been reported (19221,54692).

Psychiatric ...Orally, agitation was reported in a large surveillance trial of 3,664 patients with cardiac failure (54692).

Pulmonary/Respiratory ...Orally, bronchitis has been reported following the use of hawthorn extract WS 1442 (8281), and bradypnea has been reported following the use of hawthorn root extract (113112).

Renal ...A case of multiorgan hypersensitivity reaction and acute renal failure following the consumption of C. orientalis has been reported (54654).

Other ...Flu-like syndrome (8281) and other non-specific infections have been reported following the use of the hawthorn extract WS 1442 (17203,19222). Hawthorn has also been reported to cause nosebleeds (8281,10144).

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General ...Orally, lime juice may cause diarrhea or tooth sensitivity and wear, but these adverse effects are rare (59927,100123,100131).
Topically, lime oil and lime juice can cause allergic contact dermatitis (12,4058,100122,100132). Phytophotodermatitis is common when topical exposure to lime is followed by exposure to the sun (40894,59925,59928,100125,100126,100129).
Intravaginally, 20% to 100% lime juice can cause burning, dryness, pain, itching, erythema, edema, or abnormal bleeding (100127).

Dental ...Orally, tooth sensitivity and erosion of teeth have been reported for a woman who had consumed 150-300 mL of lime juice each night before bed for 3 years without brushing her teeth (100123). Tooth sensitivity has also been reported in a clinical trial (100131).

Dermatologic ...Topically, lime can cause phytophotodermatitis hours to days after exposure (40894,59925,59928,100125,100126,100129). Lime phytophotodermatites related to shaking of Mexican beer and the preparation of mojitos or sangria have been reported. Symptoms include redness, swelling, bullae, and later hyperpigmentation (100125,100126,100129).

Gastrointestinal ...Orally, diarrhea has been reported as an adverse effects in a clinical trial (59927).

Genitourinary ...Intravaginally, 20% lime juice has resulted in burning, dryness, erythema, and edema (100127). Higher doses of 25%, 50%, or 100% lime juice were dose-dependently related to vaginal, cervical, or vulval symptoms, especially pain, itching, and abnormal bleeding. The abnormal bleeding was most common in women that had applied 100% lime juice with a tampon. Peeling, erythema, discharge, and tenderness also occurred (100128).

Immunologic ...Topically, lime can rarely contribute to allergic contact dermatitis (4058,100122,100132).

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