Vegetable & Fruit [Discontinued] by Indiana Botanic Gardens

POSSIBLY EFFECTIVE

• Colorectal cancer. Consumption of cruciferous vegetables, including broccoli, seems to reduce the risk of developing colorectal cancer. Details: Epidemiological research suggests that the highest intakes of cruciferous vegetables, including broccoli, are associated with an 18% to 20% reduced risk of developing colorectal neoplasms when compared with the lowest intakes (14148,96187,96189).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Bladder cancer. It is unclear if consumption of broccoli reduces the risk of developing bladder cancer. Details: Epidemiological research suggests that eating about 1.75 cups daily of cruciferous vegetables, such as broccoli or cabbage, is associated with a 30% reduced risk of developing bladder cancer (14864).
• Breast cancer. It is unclear if consumption of broccoli reduces the risk of developing breast cancer. Details: Epidemiological research suggests that consumption of broccoli is associated with a modestly reduced risk of developing breast cancer in premenopausal adults. However, broccoli consumption does not seem to be associated with breast cancer risk in postmenopausal adults (14146).
• Fibromyalgia. Broccoli has only been evaluated in combination with ascorbigen; its effect when used alone is unclear. Details: A small clinical study in females with fibromyalgia shows that taking one capsule containing ascorbigen 100 mg and broccoli powder 400 mg once daily for one month improves pain by 18% and reduces physical impairment by 20% when compared to baseline (19605). It is unclear if this effect is due to broccoli, ascorbigen, or the combination. The validity of these findings is limited by the lack of a comparator group.
• Gastric cancer. It is unclear if consumption of broccoli reduces the risk of developing gastric cancer. Details: A small epidemiological study suggests that higher consumption of broccoli is associated with a reduced risk of developing gastric cancer when compared with lower consumption (14148).
• Helicobacter pylori. It is unclear if consumption of broccoli is beneficial for treating Helicobacter pylori infection. Details: A moderate-sized clinical study in adults with Helicobacter pylori infection shows that taking broccoli seed extract 200 mg, containing 16% glucosinolates, daily before bedtime for 2 months does not improve Helicobacter pylori eradication rate when compared with placebo (112445,112446).
• Hypercholesterolemia. Broccoli has only been evaluated in combination with cabbage; its effect when used alone is unclear. Details: A small clinical study in patients with mild to moderate hypercholesterolemia shows that consuming 160 grams of a beverage containing broccoli, cabbage, and fruit twice daily for 12 weeks reduces levels of low-density lipoprotein (LDL) cholesterol by 8.5% when compared to baseline. It is unclear if the improvement from baseline differed when compared with those consuming a similar beverage without broccoli and cabbage (19607). It is unclear if this effect is due to broccoli, other ingredients, or the combination.
• Hypertension. It is unclear if consumption of broccoli can prevent hypertension in healthy adults. Details: A meta-analysis of 3 prospective cohort studies in healthy adults suggests that eating 100 grams of broccoli daily is associated with a 12% reduced risk of hypertension. However, 2 other studies in the meta-analysis suggest that broccoli, consumed as part of a larger group of cruciferous vegetables, is associated with an 11% increased risk of hypertension per 100 grams eaten daily (112087).
• Prostate cancer. It is unclear if consumption of broccoli reduces the risk of developing prostate cancer; the available research is conflicting. In patients with prostate cancer, broccoli has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Some epidemiological research suggests that consumption of Brassica vegetables, such as broccoli, Brussels sprouts, cauliflower, and cabbage, is associated with a reduced risk of developing prostate cancer (14145). However, other epidemiological research has found no association (14147,15172). Clinical research in adults with prostate cancer shows that taking a whole food formulation containing broccoli powder 100 mg, turmeric powder 100 mg, pomegranate whole fruit powder 100 mg, and green tea extract 20 mg three times daily for 6 months prevents an increase in prostate specific antigen (PSA) levels. Mean PSA levels increased by 15% in the whole food formulation group, compared with 79% in the placebo group. Also, 46% of those taking the whole food formulation showed final PSA levels that were the same or lower than initial PSA levels, compared with 14% of those in the placebo group (89730). However, it is not yet known whether the whole food formulation reduces the risk of prostate cancer progression or recurrence. It is unclear if these effects are due to broccoli, other ingredients, or the combination. More evidence is needed to rate broccoli for these uses.

(Read more about BROCCOLI)

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Anxiety. It is unclear if oral celery seed extract is beneficial in patients with anxiety. Details: A small clinical study in Iranian adults with hypertension on standard antihypertensive therapy shows that taking celery seed extract 1.34 grams daily for 4 weeks reduces symptoms of anxiety and depression when compared with placebo (112409). However, it is unclear if these benefits can be extrapolated to patients in geographic locations other than Iran.
• Depression. It is unclear if oral celery seed extract is beneficial in patients with depression. Details: A small clinical study in Iranian adults with hypertension on standard antihypertensive therapy shows that taking celery seed extract 1.34 grams daily for 4 weeks reduces symptoms of anxiety and depression when compared with placebo (112409). However, it is unclear if these benefits can be extrapolated to patients in geographic locations other than Iran.
• Diabetes. It is unclear if oral celery seed extract is beneficial in patients with diabetes. Details: A small clinical study in adults with type 2 diabetes shows that taking celery seed powder 250 mg three times daily for 12 weeks does not improve fasting blood glucose, fasting insulin, insulin resistance, total cholesterol, low-density lipoprotein or high-density lipoprotein cholesterol, triglycerides, or blood pressure when compared with placebo (112411). However, the study may have been inadequately powered to detect a difference between groups.
• Dysmenorrhea. Oral celery seed has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: One clinical trial in female college students shows that taking a specific combination product containing celery seed, saffron, and anise extracts (SCA, Gol Daro Herbal Medicine Laboratory) 500 mg three times daily for 3 days, starting at the beginning of bleeding or pain, reduces severity and duration of pain symptoms associated with menstruation when compared with placebo (17214). It is not clear if these effects are due to celery, other ingredients, or the combination.
• Dyspepsia. Oral celery seed has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A moderate-sized clinical trial in adults with functional dyspepsia conducted in Iran shows that taking celery seed powder 500 mg daily with bishop's weed 500 mg daily spread over three doses after meals for 4 weeks reduces patient-reported dyspepsia symptom severity when compared with domperidone. Taking celery and bishop's weed also reduces patient-reported symptom frequency when compared to baseline (112410). However, it is unclear if these effects are due to celery, bishop's weed, or the combination, or if results can be extrapolated to patients in geographic locations other than Iran. The interpretation of these results is also limited by the lack of a placebo group.
• Gout. Oral celery has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small, open-label clinical study in patients with gout shows that taking a specific combination product (GoutFigher, Max Biocare) containing celery seed extract 600 mg, devil's claw root extract 300 mg, sour cherry extract 200 mg, and other ingredients twice daily for 45 days reduces pain, joint inflammation, and uric acid levels when compared to baseline (106488). The validity of these findings is limited by the lack of a control group. Additionally, it is unclear if these findings are due to celery, other ingredients, or the combination.
• Headache. Although there has been interest in using oral celery for headache, there is insufficient reliable information about the clinical effects of celery for this purpose.
• Hypertension. It is unclear if oral celery seed extract is beneficial in patients with hypertension. Details: A small clinical study in Iranian adults with hypertension on standard antihypertensive therapy shows that taking celery seed extract 1.34 grams daily for 4 weeks reduces daytime systolic blood pressure by about 12 mmHg compared to less than 1 mmHg with placebo. Celery seed extract also reduces night-time blood pressure, diastolic blood pressure, and mean arterial pressure, but does not impact the heart rate (110755). However, it is unclear if these benefits can be extrapolated to patients in geographic locations other than Iran.
• Impaired glucose tolerance (prediabetes). It is unclear if oral celery leaf extract is beneficial in patients with prediabetes. Details: A small clinical study in elderly patients with prediabetes shows that taking celery leaf extract 250 mg three times daily for 12 days reduces postprandial plasma glucose levels, but not insulin levels, when compared to baseline (99572). Although a control group was included in the study, statistical comparisons between treatment and control groups were not reported.
• Mosquito repellent. It is unclear if topical celery seed extract is beneficial for use as a mosquito repellant. Details: One small clinical study shows that applying gel formulations containing celery seed extract 5% to 25% can repel mosquitos in a dose-dependent manner for up to 4.5 hours. These formulations show similar repellant action when compared with DEET-containing formulations and appear to be superior to commercial repellants without DEET (40988). Celery extract has also been evaluated in combination with other ingredients. Two clinical studies show that application of a specific formulation (G10, E.A.R. Samunpri) containing celery seed extract 5%, along with vanillin, eucalyptus oil, orange oil, and citronella oil, seems to repel mosquitos for up to 4.5 hours comparably to other commercial products, including DEET 25% and Insect Block 28 (41049,41052). It is unclear if these findings are due to celery, other ingredients, or the combination.
• Osteoarthritis. Oral celery seed has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: One small, open-label clinical study in patients with mild knee osteoarthritis shows that taking a specific combination product (Tregocel, Max Biocare) providing celery seed 1000 mg, Boswellia serrata resin extract 1000 mg, devil's claw 1000 mg, ginger rhizome 330 mg, and curcumin 180 mg daily for 36 weeks reduces pain, improves functional capacity, and increases walking distance when compared to baseline (106078). The validity of these findings is limited by the lack of a control group. Additionally, it is unclear if these findings are due to celery, other ingredients, or the combination.
• Rheumatoid arthritis (RA). Although there has been interest in using oral celery juice for RA, there is insufficient reliable information about the clinical effects of celery for this purpose.
• Sexual dysfunction. It is unclear if oral celery seed powder is beneficial in females with sexual dysfunction. Details: One small clinical study in females with sexual dysfunction shows that taking celery seed powder 500 mg three times daily for 6 weeks improves sexual dysfunction symptom scores, primarily due to patient-rated improvements in sexual desire, arousal, lubrication, and pain, when compared with placebo (106486).
• Urinary tract infections (UTIs). Although there has been interest in using oral celery juice for UTIs, there is insufficient reliable information about the clinical effects of celery for this purpose. More evidence is needed to rate celery for these uses.

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INSUFFICIENT RELIABLE EVIDENCE to RATE

• Acne. Although there has been interest in using topical grapefruit oil for acne, there is insufficient reliable information about the clinical effects of grapefruit for this purpose.
• Asthma. It is unclear if oral grapefruit is beneficial in patients with asthma. Details: There is some evidence that consumption of vitamin C-rich citrus fruits, including grapefruit and others, might improve lung function in people with asthma. Intake of citrus fruits 1-2 times weekly has produced this benefit in some studies (6049,6055,6056). However, other studies have shown no benefit (6057,6058).
• Atherosclerosis. Although there has been interest in using oral grapefruit to treat or prevent atherosclerosis, there is insufficient reliable information about the clinical effects of grapefruit for this purpose.
• Atopic dermatitis (eczema). It is unclear if oral grapefruit seed extract is beneficial in patients with atopic dermatitis. Details: One small, uncontrolled clinical study in patients with atopic dermatitis shows that taking a specific grapefruit seed extract product (ParaMicrocidin, Allergy Research Group) 150 mg three times daily for one month can decrease complaints of constipation, flatulence, and abdominal discomfort, possibly due to changes in intestinal microflora (5866). The validity of these findings is limited by a lack of control group.
• Depression. Although there has been interest in using inhaled grapefruit oil as aromatherapy for depression, there is insufficient reliable information about the clinical effects of grapefruit oil for this purpose.
• Gingivitis. Although there has been interest in using topical grapefruit oil as a rinse for gingivitis, there is insufficient reliable information about the clinical effects of grapefruit oil for this purpose.
• Headache. Although there has been interest in using inhaled grapefruit oil as aromatherapy for headache, there is insufficient reliable information about the clinical effects of grapefruit oil for this purpose.
• Hypercholesterolemia. It is unclear if oral grapefruit is beneficial in patients with hypercholesterolemia. Details: One small clinical study in patients with hypercholesterolemia shows that taking capsules containing grapefruit pectin 5 grams three times daily for 16 weeks decreases total cholesterol by 8% and the ratio of low-density lipoprotein (LDL) to high-density lipoprotein (HDL) cholesterol by 10% when compared to baseline (2216). The validity of these findings is limited by the lack of a comparator group.
• Hypertriglyceridemia. It is unclear if oral grapefruit is beneficial in patients with hypertriglyceridemia. Details: One small clinical study in patients with hypertriglyceridemia that is not well controlled on statin therapy shows that consuming one red or white grapefruit daily for 30 days reduces total cholesterol by 8% to 15.5% and low-density lipoprotein (LDL) cholesterol by 11% to 20% when compared with placebo. In addition, consuming one red, but not one white, grapefruit daily reduces triglyceride levels by 17% when compared with placebo in these patients (53352).
• Intestinal parasite infection. Although there has been interest in using oral grapefruit seed extract for intestinal parasite infections, there is insufficient reliable information about the clinical effects of grapefruit for this purpose.
• Lice. It is unclear if topical grapefruit extract is beneficial in children with head lice. Details: One small clinical study in children aged 2-9 years with head lice shows that applying 50 mL of a specific shampoo containing grapefruit extract (Licatack shampoo) to the hair for 10-20 minutes and then rinsing with water and combing can eliminate adult lice. Applying a second application after 10 days seems to help remove any remaining nits (91417). The validity of these findings is limited by a lack of control group.
• Obesity. While some small studies suggest that oral grapefruit extract, taken in combination with other citrus extracts, may modestly improve weight loss, the effect of oral grapefruit alone is unclear. Details: One small clinical study in obese adults shows that consuming one and a half fresh grapefruits daily for 12 weeks reduces body weight by 1.3 kg when compared with placebo. Also, although drinking 8 ounces of grapefruit juice or taking grapefruit capsules three times daily for 12 weeks did not improve body weight when compared with placebo in the overall study population, a sub-group analysis of obese adults with metabolic syndrome shows that taking grapefruit capsules or drinking grapefruit juice increases weight loss and improves insulin resistance when compared with placebo (53353). Grapefruit has also been evaluated in combination with other citrus ingredients. Two clinical studies shows that taking a specific combination product (Sinetrol, Fytexia) containing sweet orange, blood orange, and grapefruit extracts for 12 weeks can decrease body weight, body fat percentage, and body mass index (BMI) in otherwise healthy overweight adults (95517,95518). In one study, taking this supplement as 450 mg twice daily for 12 weeks reduced body weight by 1 kg and body fat percentage by 6.5% when compared with placebo. Hip circumference, waist circumference, and blood glucose were also reduced when compared with placebo (95518). In another study, taking this same supplement as 700 mg twice daily for 12 weeks reduced body weight by 5.6 kg, body fat percentage by 5%, and BMI by 2% when compared to baseline. Patients taking placebo experienced no significant improvements from baseline (95517). It is not clear if these effects are due to grapefruit extract, other ingredients, or the combination.
• Pharyngitis. Although there has been interest in using topical grapefruit oil as a gargle for pharyngitis, there is insufficient reliable information about the clinical effects of grapefruit oil for this purpose.
• Psoriasis. Although there has been interest in using oral grapefruit for psoriasis, there is insufficient reliable information about the clinical effects of grapefruit for this purpose.
• Stress. Although there has been interest in using inhaled grapefruit oil as aromatherapy for stress, there is insufficient reliable information about the clinical effects of grapefruit oil for this purpose.
• Upper respiratory tract infection (URTI). Although there has been interest in using grapefruit oil as aromatherapy for various upper respiratory tract infections, including influenza and the common cold, there is insufficient reliable information about the clinical effects of grapefruit oil for these conditions.
• Vaginal candidiasis. Although there has been interest in using oral and topical grapefruit seed extract for vaginal candidiasis, there is insufficient reliable information about the clinical effects of grapefruit seed extract for this purpose. More evidence is needed to rate grapefruit for these uses.

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LIKELY SAFE ...when used orally in food amounts (14145). There is insufficient reliable information available about the safety of broccoli when used in medicinal amounts.

PREGNANCY AND LACTATION: LIKELY SAFE
when used orally in food amounts (14145). There is insufficient reliable information available about the safety of broccoli when used in medicinal amounts during pregnancy and lactation; avoid using.

(Read more about BROCCOLI)

LIKELY SAFE ...when celery stems are consumed as food. ...when celery oil or seeds are consumed in amounts commonly found in foods. Celery seed has Generally Recognized as Safe (GRAS) status in the US (4912).

POSSIBLY SAFE ...when celery seed is used orally and appropriately in medicinal amounts, short-term (12). Celery seed powder has been safely used at doses up to 1500 mg daily for up to 6 weeks and 750 mg daily for up to 12 weeks. Celery seed extract has been safely used at doses up to 1340 mg daily for up to 4 weeks (106486,110755,112409,112411). ...when celery seed extract is used topically and appropriately, short-term (40988,41049,41052).

PREGNANCY: LIKELY UNSAFE
when celery oil or seeds are used orally in larger amounts; celery might have uterine stimulant or abortifacient effects (4,19,19104).

LACTATION:
There is insufficient reliable information available about the safety of medicinal amounts of celery during lactation; avoid using.

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

POSSIBLY SAFE ...when used orally and appropriately for medicinal purposes. A grapefruit seed extract has been safely used in clinical research (5866). In addition, capsules containing grapefruit pectin 15 grams daily have been used in clinical research for up to 16 weeks (2216).

POSSIBLY UNSAFE ...when used orally in excessive amounts. Preliminary population research shows that consuming a quarter or more of a whole grapefruit daily is associated with a 25% to 30% increased risk of postmenopausal breast cancer (14858). Grapefruit juice is thought to reduce estrogen metabolism resulting in increased endogenous estrogen levels. More evidence is needed to validate this finding.

PREGNANCY AND LACTATION:
There is insufficient reliable information available about the safety of using medicinal amounts of grapefruit during pregnancy and lactation; avoid using.

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CYTOCHROME P450 1A2 (CYP1A2) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Theoretically, broccoli might reduce the levels and effects of drugs metabolized by CYP1A2.  Details Pharmacokinetic research in humans shows that eating 500 grams of fresh broccoli daily for 6-12 days can increase CYP1A2 activity by 10% to 200% (19608,95722). Induction of CYP1A2 activity by broccoli is attributed to its glucosinolate constituents (19608).

CYTOCHROME P450 2A6 (CYP2A6) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Theoretically, broccoli might reduce the levels and effects of drugs metabolized by CYP2A6.  Details Pharmacokinetic research in humans shows that eating 500 grams of broccoli daily for 6 days increases CYP2A6 activity by 135% to 550%. Induction of CYP2A6 activity is attributed to its glucosinolate constituents (19608).

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ACETAMINOPHEN (Tylenol, others) Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = D Theoretically, celery juice might increase the effects and side effects of acetaminophen.  Details Animal research suggests that concomitant use of celery juice plus acetaminophen prolongs the effects of acetaminophen. This effect has been attributed to a decrease in hepatic cytochrome P450 activity (25362). However, other animal research shows that pretreatment with celery root extract protects against acetaminophen-induced acute liver failure (106487). These effects have not been reported in humans.

AMINOPYRINE Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = D Theoretically, celery juice might increase the effects and side effects of aminopyrine.  Details Animal research suggests that concomitant use of celery juice plus aminopyrine prolongs the effects of aminopyrine. This effect has been attributed to a decrease in hepatic cytochrome P450 activity (25362). This effect has not been reported in humans.

ANTICOAGULANT/ANTIPLATELET DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, celery root might increase the risk of bleeding when taken with anticoagulant/antiplatelet drugs.  Details Celery root contains the constituents falcarinol and falcarindiol. Laboratory research suggests that these constituents can inhibit platelet aggregation (6048,40991). This effect has not been reported in humans.

ANTIHYPERTENSIVE DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Theoretically, celery seed extract might have additive effects with antihypertensive drugs.  Details Clinical research suggests that taking celery seed extract may reduce daytime systolic blood pressure by about 12 mmHg compared to less than 1 mmHg with placebo (110755).

CYTOCHROME P450 1A2 (CYP1A2) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, celery might increase levels of drugs metabolized by CYP1A2.  Details In vitro and animal research suggests that constituents of celery can inhibit CYP1A2 (68176). This effect has not been reported in humans.

LEVOTHYROXINE (Synthroid, others) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, celery seed might decrease the effects of levothyroxine.  Details Several cases of hypothyroidism with low T4 levels have been reported in people who were previously stabilized on levothyroxine and then started taking celery seed tablets. They presented with symptoms such as lethargy, bloating, and dry skin, and recovered when celery seed was stopped (10646). However, celery stem and leaf has been associated with case reports of hyperthyroidism in patients with no pre-existing thyroid disorders (102912,102914).

LITHIUM Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = D Theoretically, celery might reduce excretion and increase levels of lithium due to potential diuretic effects.  Details Celery is thought to have diuretic properties (4,6). However, this effect has not been confirmed in humans.

PHOTOSENSITIZING DRUGS Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = D Theoretically, celery might increase the risk of photosensitivity reactions when taken with photosensitizing drugs.  Details Laboratory research shows that celery contains photosensitizing agents such as phenols and psoralens (6178,40894,40917,41073,41121).

VENLAFAXINE (Effexor) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, celery root extract might increase blood levels of venlafaxine.  Details There is one case report of a patient who experienced medication-induced bipolar disorder after beginning to take celery root extract 1000 mg daily along with venlafaxine 75 mg and St. John's wort 600 mg daily. Symptoms included confusion, speech abnormalities, manic affect, and visual hallucinations. The plasma level of venlafaxine was 476.8 ng/mL (normal range 195-400 ng/mL). It is theorized that celery root increased venlafaxine levels by inhibiting cytochrome P450 2D6 (92854).

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ACEBUTOLOL (Sectral) Interaction Rating = Minor Be watchful with this combination. Severity = Insignificant •  Occurrence = Possible •  Level of Evidence = B Grapefruit juice can decrease blood levels of acebutolol, potentially decreasing the clinical effects of acebutolol.  Details Clinical research shows that grapefruit juice can modestly decrease acebutolol levels by 7% and reduce peak plasma concentration by 19% by inhibiting organic anion transporting polypeptide (OATP) (17603,18101). The acebutolol half-life is also extended by 1.1 hours when grapefruit juice is consumed concomitantly (18101). Grapefruit juice is thought to affect OATP for only a short time. Therefore, separating drug administration and consumption of grapefruit by at least 4 hours is likely to prevent this interaction (17603,17604).

ALISKIREN (Tekturna, Rasilez) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Grapefruit juice can decrease blood levels of aliskiren, potentially decreasing the clinical effects of aliskiren.  Details Clinical research shows that grapefruit juice can decrease aliskiren levels by approximately 60% by inhibiting organic anion transporting polypeptide (OATP) (91428). Grapefruit juice is thought to affect OATP for only a short time. Therefore, separating drug administration and consumption of grapefruit by at least 4 hours is likely to prevent this interaction (17603,17604).

AMIODARONE (Cordarone) Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Probable •  Level of Evidence = B Grapefruit juice can increase blood levels of amiodarone, potentially increasing the effects and adverse effects of amiodarone.  Details Clinical research shows that grapefruit juice inhibits metabolism and increases absorption of amiodarone. Grapefruit juice increases amiodarone plasma levels by 50% and peak concentration by 84% (17601,17672,22120).

AMPRENAVIR (Agenerase) Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = B Grapefruit juice might decrease blood levels of amprenavir, although this is not likely to be clinically significant.  Details Some clinical research shows that grapefruit juice can slightly decrease amprenavir levels (17673); however, this is probably not clinically significant.

ARTEMETHER (Artenam, Paluther) Interaction Rating = Major Do not take this combination. Severity = Moderate •  Occurrence = Likely •  Level of Evidence = B Grapefruit juice can increase blood levels of oral artemether, potentially increasing the effects and adverse effects of artemether.  Details Clinical research shows that grapefruit juice increases the levels of oral artemether by 90% to 250% in healthy males (5065,5066).

BENZODIAZEPINES Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Likely •  Level of Evidence = B Grapefruit juice might increase blood levels of some oral benzodiazepines, potentially increasing the effects and adverse effects of these drugs.  Details Clinical research shows that grapefruit juice can increase plasma triazolam concentrations. Repeated consumption of grapefruit juice greatly increases triazolam concentrations and prolongs the half-life, probably due to inhibition of cytochrome P450 3A4 (CYP3A4) (7776,22118,22131,22133). Some studies show that grapefruit juice, particularly when taken in large quantities, reduces the clearance and increases the maximum blood levels, area under the plasma concentration curve (AUC), and duration of effect of midazolam. However, there is no effect on intravenous midazolam (4300,10159,11275,17601,22117,22119,16711,91427,95978). Grapefruit juice has also been shown to increase the maximum blood levels and duration of effect of diazepam, but the clinical significance of this is not known (3228). This interaction does not appear to occur with alprazolam (17674).

BLONANSERIN (Lonasen) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Grapefruit juice can increase blood levels of blonanserin, potentially increasing the effects and adverse effects of blonanserin.  Details Blonanserin is metabolized primarily by cytochrome P450 3A4 (CYP3A4). A small clinical study shows that taking grapefruit juice along with oral blonanserin increases exposure to blonanserin almost 6-fold due to inhibition of intestinal CYP3A4 by grapefruit juice and prolongs the elimination half-life of blonanserin by 2.2-fold due to inhibition of hepatic CYP3A4 by grapefruit juice (96943).

BUDESONIDE (Entocort, UCERIS) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Grapefruit juice can increase blood levels of budesonide, potentially increasing the effects and adverse effects of budesonide.  Details Budesonide is metabolized by cytochrome P450 3A4 (CYP3A4). A small clinical study shows that taking grapefruit juice along with oral budesonide increases the plasma concentration of budesonide. This effect is attributed to grapefruit-induced inhibition of CYP3A4 in both the colon and small intestine (91425).

BUSPIRONE (BuSpar) Interaction Rating = Major Do not take this combination. Severity = Moderate •  Occurrence = Likely •  Level of Evidence = B Grapefruit juice can increase blood levels of buspirone, potentially increasing the effects and adverse effects of buspirone.  Details Clinical research shows that grapefruit juice increases absorption and plasma concentrations of buspirone (3771).

CAFFEINE Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = D Grapefruit juice can decrease the clearance of caffeine, potentially increasing the effects and adverse effects of caffeine.  Details Clinical research shows that grapefruit juice decreases caffeine clearance (4300).

CALCIUM CHANNEL BLOCKERS Interaction Rating = Major Do not take this combination. Severity = Moderate •  Occurrence = Likely •  Level of Evidence = B Grapefruit juice can increase blood levels of oral calcium channel blockers, potentially increasing the effects and adverse effects of these drugs.  Details Clinical research shows that grapefruit juice increases absorption and plasma concentrations of amlodipine (523), nifedipine (528,22114), nisoldipine (529), verapamil (7779,8285), felodipine, nimodipine, nicardipine, diltiazem, pranidipine, nitrendipine, and manidipine (524,528,1388,4300,7780,11276,22136,53338,22138,22139) (22140,22141,22142,22143,22147,22148,22149,53367,22158), This interaction is likely the result of the inhibition of intestinal metabolism of these drugs by CYP3A4 (7779,7780), although some research suggests grapefruit may alter plasma drug levels by reducing the rate of gastric emptying (22167). Consuming grapefruit juice 1 liter daily increases steady state concentrations of verapamil by as much as 50% (8285). However, some references dispute the clinical relevance of the interactions with amlodipine, diltiazem, and verapamil (3230,4300,22159). Other research in healthy individuals suggests plasma levels of felodipine and nifedipine are not affected when given intravenously (22144,22146). There is considerable interindividual variability in the effect of grapefruit juice on drug metabolism, which might account for inconsistent study results (7777,7779,8285). In healthy older adults, the hemodynamic response to felodipine plus grapefruit juice might be influenced by altered autonomic regulation. In older healthy adults, a single dose of grapefruit juice and felodipine enhanced the blood pressure-lowering effects of felodipine. However, after a week of grapefruit juice and felodipine (steady state), the hypotensive activity was reduced, possibly due to compensatory tachycardia (1392). Research indicates it is necessary to withhold grapefruit juice for as long as 3 days to avoid interactions with felodipine and nisoldipine (5068,5069,6453,22145).

CARBAMAZEPINE (Tegretol) Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Likely •  Level of Evidence = B Grapefruit juice can increase blood levels of carbamazepine, potentially increasing the effects and adverse effects of carbamazepine.  Details Clinical research shows that grapefruit juice increases absorption and plasma concentrations of carbamazepine (524).

CARVEDILOL (Coreg) Interaction Rating = Major Do not take this combination. Severity = Moderate •  Occurrence = Likely •  Level of Evidence = B Grapefruit juice can increase blood levels of carvedilol, potentially increasing the effects and adverse effects of carvedilol.  Details Clinical research shows that grapefruit juice increases the bioavailability of a single dose of carvedilol by 16% (5071).

CELIPROLOL (Celicard) Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Probable •  Level of Evidence = B Grapefruit juice can decrease blood levels of celiprolol, potentially decreasing the clinical effects of celiprolol.  Details In human research, taking grapefruit juice within two hours of celiprolol appears to decrease absorption and blood levels of celiprolol by approximately 85% (91421). This interaction is due to grapefruit-induced inhibition of organic anion transporting polypeptide (OATP) (17603,17604,22161). Grapefruit juice is thought to affect OATP for only a short time. Therefore, separating drug administration and consumption of grapefruit by at least 4 hours is likely to prevent this interaction (17603,17604).

CISAPRIDE (Propulsid) Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Likely •  Level of Evidence = B Grapefruit juice can increase blood levels of cisapride, potentially increasing the effects and adverse effects of cisapride.  Details Clinical research shows that grapefruit juice increases the absorption and plasma concentrations of cisapride. According to the cisapride prescribing information, grapefruit juice is contraindicated in patients taking cisapride (1383,3226,17601,22164,22165).

CLOMIPRAMINE (Anafranil) Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Probable •  Level of Evidence = D Theoretically, grapefruit juice might increase blood levels of clomipramine, potentially increasing the effects and adverse effects of clomipramine.  Details Case reports have shown that clomipramine trough levels increase significantly after the addition of grapefruit juice to the therapeutic regimen (5064).

CLOPIDOGREL (Plavix) Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Probable •  Level of Evidence = B Grapefruit juice can decrease blood levels of the active metabolite of clopidogrel, thereby decreasing the antiplatelet effect of clopidogrel.  Details Clopidogrel is an antiplatelet prodrug that is metabolized primarily by cytochrome P450 2C19 (CYP2C19) to form the active metabolite. A small clinical study shows that taking grapefruit juice with clopidogrel decreases plasma levels of the active metabolite by more than 80% and impairs the antiplatelet effect of clopidogrel. This effect is possibly due to grapefruit-induced inhibition of CYP2C19 (91419).

COLCHICINE Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = B Theoretically, grapefruit juice might increase blood levels of colchicine, potentially increasing the effects and adverse effects of colchicine.  Details Colchicine is an alkaloid that undergoes P-glycoprotein (P-gp) mediated drug efflux in the intestines, followed by metabolism by cytochrome P450 3A4 (CYP3A4). There is concern that grapefruit juice will increase the effects and adverse effects of colchicine due to grapefruit-induced inhibition of P-gp and/or CYP3A4. In vitro evidence shows that grapefruit juice increases absorption of colchicine by inhibiting P-gp (94158). A case of acute colchicine toxicity has been reported for an 8-year-old female who drank grapefruit juice while taking high-dose colchicine, long-term (94157). However, one small clinical study in healthy adults shows that drinking grapefruit juice 240 mL twice daily for 4 days does not affect the bioavailability or adverse effects of a single dose of colchicine 0.6 mg taken on the fourth day (35762).

CYCLOSPORINE (Neoral, Sandimmune) Interaction Rating = Major Do not take this combination. Severity = Moderate •  Occurrence = Likely •  Level of Evidence = B Grapefruit juice can increase blood levels of oral cyclosporine, potentially increasing the effects and adverse effects of cyclosporine.  Details Clinical research shows that grapefruit juice increases the absorption and plasma concentrations of cyclosporine (522,11270,22113,22150,22152,22153,22154,22155). The mechanism of action is unclear. However, there is no effect on intravenous cyclosporine (22151).

CYTOCHROME P450 1A2 (CYP1A2) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, grapefruit juice might increase levels of drugs metabolized by CYP1A2.  Details In vitro research suggests that grapefruit juice might inhibit CYP1A2 enzymes (12479). So far, this interaction has not been reported in humans.

CYTOCHROME P450 2C19 (CYP2C19) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Theoretically, grapefruit juice might increase levels of drugs metabolized by CYP2C19.  Details In vitro research suggests that grapefruit juice might inhibit CYP2C19 enzymes (12479). Also, a small clinical study shows that taking grapefruit juice with clopidogrel, an antiplatelet prodrug that is metabolized primarily by CYP2C19, decreases plasma levels of the active metabolite and impairs the antiplatelet effect of clopidogrel. This effect is likely due to grapefruit-induced inhibition of CYP2C19 (91419).

CYTOCHROME P450 2C9 (CYP2C9) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, grapefruit juice might increase levels of drugs metabolized by CYP2C9.  Details In vitro research suggests that grapefruit juice might inhibit CYP2C9 enzymes (12479). So far, this interaction has not been reported in humans.

CYTOCHROME P450 3A4 (CYP3A4) SUBSTRATES Interaction Rating = Major Do not take this combination. Severity = Moderate •  Occurrence = Likely •  Level of Evidence = B Grapefruit juice can increase levels of drugs metabolized by CYP3A4.  Details Clinical research shows that grapefruit juice can inhibit CYP3A4 metabolism of drugs, causing increased drug levels and potentially increasing the risk of adverse effects (3227,3774,8283,8285,8286,22129,91427,104190). When taken orally, effects of grapefruit juice on CYP3A4 levels appear to last at least 48 hours (91427). Grapefruit's ability to inhibit CYP3A4 has even been harnessed to intentionally increase levels of venetoclax, which is metabolized by CYP3A4, in an elderly patient with acute myeloid leukemia who could not afford full dose venetoclax. The lower dose of venetoclax in combination with grapefruit juice resulted in serum levels of venetoclax in the therapeutic reference range of full dose venetoclax and positive treatment outcomes for the patient (112287). Professional consensus recommends the consideration of patient age, existing medical conditions, additional medications, and the potential for additive adverse effects when evaluating the risks of concomitant use of grapefruit juice with any medication metabolized by CYP3A4. While all patients are at risk for interactions with grapefruit juice consumption, patients older than 70 years of age and those taking multiple medications are at the greatest risk for a serious or fatal interaction with grapefruit juice (95970,95972).

DAPOXETINE (Priligy) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Grapefruit juice can increase blood levels of dapoxetine, potentially increasing the effects and adverse effects of dapoxetine.  Details Pharmacokinetic research shows that drinking grapefruit juice 250 mL prior to taking dapoxetine 60 mg can increase the maximum plasma concentration of dapoxetine by 80% and prolong the elimination half-life by 43%. This effect is attributed to the inhibition of both intestinal and hepatic cytochrome P450 3A4 (CYP3A4) by grapefruit (95975).

DEXTROMETHORPHAN (Robitussin DM, others) Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Probable •  Level of Evidence = B Grapefruit juice can increase blood levels of dextromethorphan, potentially increasing the effects and adverse effects of dextromethorphan.  Details Clinical research shows that grapefruit juice can inhibit cytochrome P450 3A4 (CYP3A4) metabolism, causing increased dextromethorphan levels (11362).

ERYTHROMYCIN Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Grapefruit juice can increase blood levels of erythromycin, potentially increasing the effects and adverse effects of erythromycin.  Details Clinical research shows that concomitant use of erythromycin with grapefruit can inhibit cytochrome P450 3A4 (CYP3A4) metabolism of erythromycin, increasing plasma concentrations of erythromycin by 35% (8286).

ESTROGENS Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Probable •  Level of Evidence = B Grapefruit juice can increase blood levels of estrogens, potentially increasing the effects and adverse effects of estrogens.  Details Clinical research shows that grapefruit increases the levels of endogenous and exogenous estrogens by inhibiting cytochrome P450 3A4 (CYP3A4) enzymes (525,526,14858). Grapefruit juice increases exogenously administered 17-beta-estradiol by about 20% in females without ovaries and ethinyl-estradiol in healthy females (525,526,22160).

ETOPOSIDE (VePesid) Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Probable •  Level of Evidence = B Grapefruit juice can decrease blood levels of etoposide, potentially decreasing the clinical effects of etoposide.  Details Clinical research shows that grapefruit juice decreases the absorption and plasma concentrations of etoposide. There is some evidence that grapefruit juice co-administered with oral etoposide can reduce levels of etoposide by about 26% (8744). Grapefruit juice seems to inhibit organic anion transporting polypeptide (OATP), which is a drug transporter in the gut, liver, and kidney (7046,17603,17604). Grapefruit juice is thought to affect OATP for only a short time. Therefore, separating drug administration and consumption of grapefruit by at least 4 hours is likely to prevent this interaction (17603,17604).

FEXOFENADINE (Allegra) Interaction Rating = Moderate Be cautious with this combination. Severity = Mild •  Occurrence = Likely •  Level of Evidence = B Grapefruit juice can decrease blood levels of fexofenadine, thereby decreasing the clinical effects of fexofenadine.  Details Clinical research shows that grapefruit juice can significantly decrease oral absorption and blood levels of fexofenadine. In one study, consuming a drink containing grapefruit juice 25% decreased bioavailability of fexofenadine by about 24%. Consuming a full-strength grapefruit juice drink reduced bioavailability by 67% (7046). In another study, consuming grapefruit juice 300 mL decreased fexofenadine levels by 42%. Consuming 1200 mL of grapefruit juice reduced levels by 64% (17602). Similarly, drinking grapefruit juice 240 mL decreased the oral bioavailability of fexofenadine by 25% in another pharmacokinetic study (112288). Fexofenadine manufacturer data indicates that concomitant administration of grapefruit juice and fexofenadine results in larger wheal and flare sizes in research models. This suggests that grapefruit also reduces the clinical response to fexofenadine (17603). Grapefruit juice seems to inhibit organic anion transporting polypeptide (OATP), which is a drug transporter in the gut, liver, and kidney (7046,17603,17604,22161). Grapefruit juice is thought to affect OATP for only a short time. Therefore, separating drug administration and consumption of grapefruit by at least 4 hours is likely to prevent this interaction (17603,17604).

FLUVOXAMINE (Luvox) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Grapefruit juice can increase blood levels of fluvoxamine, potentially increasing the effects and adverse effects of fluvoxamine.  Details Clinical research shows that grapefruit juice inhibits metabolism and increases fluvoxamine levels and peak concentration (17675).

HALOFANTRINE Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Probable •  Level of Evidence = B Grapefruit juice can increase blood levels of halofantrine, potentially increasing the effects and adverse effects of halofantrine.  Details Clinical research shows that grapefruit juice inhibits cytochrome P450 3A4 (CYP3A4) metabolism, which increases halofantrine levels and peak concentration, as well as a marker of ventricular tachyarrhythmia potential (22129).

HMG-CoA REDUCTASE INHIBITORS ("Statins") Interaction Rating = Major Do not take this combination. Severity = Moderate •  Occurrence = Likely •  Level of Evidence = B Grapefruit juice can increase blood levels of statins that are metabolized by cytochrome P450 3A4 (CYP3A4), potentially increasing the effects and adverse effects of these statins. Additionally, grapefruit juice might interfere with the bioavailability of statins that are substrates of organic anion transporting polypeptides (OATP).  Details Clinical research shows that grapefruit juice inhibits metabolism and increases absorption and plasma concentrations of statins that are metabolized by CYP3A4. These include lovastatin (527,11274), simvastatin (3774,7782,22127), and atorvastatin (3227,12179,22126). Keep in mind that there is considerable variability in the effect of grapefruit juice on drug metabolism, so individual patient response is difficult to predict (7777,7781). Some statins, including pravastatin, fluvastatin, pitavastatin, and rosuvastatin, are not metabolized by CYP3A4. However, grapefruit juice might still affect the bioavailability of these statins. These statins are substrates of OATP. Grapefruit juice can inhibit OATP. Therefore, grapefruit juice may reduce the bioavailability or increase drug levels of these statins depending on the type of OATP. However, grapefruit juice affects OATP for only a short time. Therefore, separating drug administration by at least 4 hours is likely to avoid this interaction (3227,12179,17601,22126,91420).

ITRACONAZOLE (Sporanox) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Grapefruit juice can interfere with itraconazole absorption, although the clinical significance of this interaction is unclear.  Details Clinical research shows that grapefruit juice can affect itraconazole absorption and might increase or decrease itraconazole levels (310,17601,22123).

LEVOTHYROXINE (Synthroid, others) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Grapefruit juice can decrease blood levels of levothyroxine, potentially decreasing the effectiveness of levothyroxine.  Details Clinical research shows that grapefruit juice modestly decreases levothyroxine levels by 11% by inhibiting organic anion transporting polypeptide (OATP) (17604,22163). Grapefruit juice is thought to affect OATP for only a short time. Therefore, separating drug administration and consumption of grapefruit by at least 4 hours is likely to prevent this interaction (17603,17604).

LOSARTAN (Cozaar) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Grapefruit juice can decrease blood levels of the active metabolite of losartan, potentially decreasing the clinical effects of losartan.  Details Losartan is an inactive prodrug which must be metabolized to its active form, E-3174, to be effective. In one human study, grapefruit juice reduced losartan metabolism, increased losartan AUC, and reduced the AUC of the major active losartan metabolite, E-3174 (1391).

METHADONE (Dolophine) Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Probable •  Level of Evidence = B Grapefruit juice can increase blood levels of methadone, potentially increasing the effects and adverse effects of methadone.  Details Clinical research shows that grapefruit juice inhibits the metabolism of methadone, increasing methadone levels and peak concentrations (17676). In one case, a 51-year-old male taking methadone 90 mg daily and no other medications was found unresponsive. The patient reported drinking grapefruit juice 500 mL daily for 3 days prior to the event. Methadone is a substrate of cytochrome P450 3A4 (CYP3A4), and grapefruit juice-induced inhibition of CYP3A4 is the likely cause of this interaction (102056).

METHYLPREDNISOLONE Interaction Rating = Major Do not take this combination. Severity = Moderate •  Occurrence = Likely •  Level of Evidence = B Grapefruit juice can increase blood levels of methylprednisolone, potentially increasing the effects and adverse effects of methylprednisolone.  Details Clinical research shows that grapefruit juice can increase the plasma concentration of orally administered methylprednisolone. Grapefruit juice 200 mL three times daily given with methylprednisolone 16 mg increased methylprednisolone half-life by 35%, peak plasma concentration by 27%, and total area under the curve by 75% (3123).

NADOLOL (Corgard) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Grapefruit juice might decrease blood levels of nadolol, potentially decreasing the clinical effects of nadolol.  Details Nadolol is a substrate of organic anion transporting polypeptide 1A2 (OATP1A2) (17603,17604,22161). Some research shows that grapefruit juice and its constituent naringin can inhibit organic anion transporting polypeptides (OATP), which can reduce the bioavailability of OATP substrates (17603,17604,22161,91427). However, preliminary clinical research shows that grapefruit juice containing a low amount of naringin does not significantly affect levels of nadolol (91422). It is not known if grapefruit juice containing higher amounts of naringin reduces the bioavailability of nadolol.

NILOTINIB (Tasigna) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Grapefruit juice can increase blood levels of nilotinib, potentially increasing the effects and adverse effects of nilotinib.  Details Clinical research shows that grapefruit juice inhibits metabolism and increases absorption of nilotinib. Grapefruit juice increases nilotinib levels by 29% and peak concentration by 60% (17677).

ORGANIC ANION-TRANSPORTING POLYPEPTIDE SUBSTRATES (OATP) Interaction Rating = Major Do not take this combination. Severity = Moderate •  Occurrence = Likely •  Level of Evidence = B Grapefruit juice can decrease levels of drugs that are substrates of OATP.  Details In vitro and clinical research show that consuming grapefruit juice inhibits OATP, which reduces the bioavailability of oral drugs that are substrates of OATP. Various clinical studies have shown reduced absorption of OATP substrates when taken with grapefruit, including fexofenadine, acebutolol, aliskiren, celiprolol, levothyroxine, nadolol, and pitavastatin (17603,17604,18101,22126,22134,22161,22163,91420,91427,91428,112288). Grapefruit juice is thought to affect OATP for only a short time. Therefore, separating drug administration and consumption of grapefruit by at least 4 hours is likely to prevent this interaction (17603,17604).

OXYCODONE (Oxycontin) Interaction Rating = Moderate Be cautious with this combination. Severity = Mild •  Occurrence = Probable •  Level of Evidence = B Grapefruit juice can increase blood levels of oxycodone, potentially increasing the effects and adverse effects of oxycodone.  Details Oxycodone is metabolized by both cytochrome P450 3A4 (CYP3A4) and cytochrome P450 2D6 (CYP2D6). A small clinical study shows that grapefruit juice can increase plasma levels of oral oxycodone about 1.7-fold by inhibiting CYP3A4. While the analgesic effects of oxycodone do not seem to be affected, taking grapefruit juice along with oxycodone may theoretically increase the adverse effects of oxycodone (91423).

P-GLYCOPROTEIN SUBSTRATES Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = B Grapefruit juice does not seem to affect renal P-glycoprotein (P-gp). Theoretically, it might inhibit intestinal P-gp, but evidence is conflicting.  Details While most in vitro research shows that grapefruit products inhibit P-gp, (1390,11270,11278,11362,95976), research in humans is less clear. Two small clinical studies in healthy adults using digoxin as a probe substrate show that grapefruit juice does not inhibit P-gp in the kidneys (11277,11282). It is unclear whether this applies to intestinal P-gp, for which digoxin is not considered to be a sensitive probe (105568). Grapefruit juice has been shown to reduce levels of fexofenadine (7046,17602,112288), and increase levels of quinidine (5067,22121). However, as both of these drugs are also substrates of other enzymes and transporters, it is unclear what role, if any, intestinal P-gp has in these findings.

PITAVASTATIN (Livalo) Interaction Rating = Moderate Be cautious with this combination. Severity = Mild •  Occurrence = Likely •  Level of Evidence = B Grapefruit juice can increase blood levels of pitavastatin, potentially increasing the effects and adverse effects of pitavastatin.  Details Pharmacokinetic research shows that taking grapefruit juice with pitavastatin 2-4 mg can increase blood levels of pitavastatin by 13% to 14%. Unlike simvastatin and atorvastatin, pitavastatin is not significantly metabolized by cytochrome P450 3A4 (CYP3A4) enzymes. Grapefruit juice appears to increase levels of pitavastatin by inhibiting its uptake by organic anion transporting polypeptide 1B1 (OATP1B1) into hepatocytes for metabolism and clearance from the body (22126,91420). Grapefruit juice seems to increase levels of pitavastatin to a greater degree in patients homozygous for a specific polymorphism (388A>G) in the OATP1B1 gene compared to those heterozygous for this polymorphism (91420).

PRASUGREL (Effient) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Grapefruit juice can decrease blood levels of the active metabolite of prasugrel, thereby decreasing the antiplatelet effect of prasugrel.  Details Prasugrel is a prodrug that is metabolized by cytochrome P450 3A4 (CYP3A4) into its active metabolite. A small pharmacokinetic study in healthy volunteers shows that drinking grapefruit juice 200 mL three times daily for 4 days and taking a single dose of prasugrel 10 mg with an additional 200 mL of grapefruit juice on day 3, results in a 49% lower peak plasma level and a 26% lower overall plasma exposure to the active metabolite when compared with drinking water. However, despite the reduced exposure, platelet aggregation seems to be reduced by an average of only 5% (105567). The clinical significance of this interaction is unclear.

PRAZIQUANTEL (Biltricide) Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Probable •  Level of Evidence = B Grapefruit juice can increase blood levels of praziquantel, potentially increasing the effects and adverse effects of praziquantel.  Details Clinical research shows that grapefruit juice can inhibit cytochrome P450 3A4 (CYP3A4) metabolism of praziquantel. Plasma concentrations of praziquantel can increase by as much as 160% when administered with 250 mL of commercially available grapefruit juice (8282).

PRIMAQUINE Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Grapefruit juice may increase blood levels of primaquine, potentially increasing the effects and adverse effects of primaquine.  Details Clinical research shows that grapefruit juice increases the bioavailability of primaquine by approximately 20% (22130). The clinical significance of this interaction is not clear.

QT INTERVAL-PROLONGING DRUGS Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Probable •  Level of Evidence = B Grapefruit or grapefruit juice, especially if consumed in large amounts, can cause additive QT interval prolongation when taken with QT interval-prolonging drugs, potentially increasing the risk of ventricular arrhythmias.  Details Clinical research in healthy volunteers shows that drinking 6 liters of grapefruit juice over 6 hours prolonged the QTc by a peak amount of 14 milliseconds (ms). This prolongation was similar to the QT prolongation caused by the drug moxifloxacin. In individuals with long QT syndrome, a smaller dose of grapefruit juice, 1.5 liters, resulted in a greater peak QTc prolongation of about 30 ms (100249). The effect of smaller quantities of grapefruit juice on the QT interval is unclear.

QUETIAPINE (Seroquel) Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Probable •  Level of Evidence = B Grapefruit juice may increase blood levels of quetiapine, increasing the effects and adverse effects of quetiapine.  Details Quetiapine is metabolized by cytochrome P450 3A4 (CYP3A4). Grapefruit can inhibit CYP3A4 (3227,3774,8283,8285,8286,22129,91427,104190). In one case report, a healthy 28-year-old female with bipolar disorder stabilized on quetiapine 800 mg daily presented with quetiapine toxicity considered to be related to consuming a gallon of grapefruit juice over the past 24 hours (108848).

QUINIDINE Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Probable •  Level of Evidence = B Grapefruit juice can alter blood levels of quinidine, potentially increasing or decreasing the clinical effects of quinidine.  Details Clinical research shows that grapefruit juice decreases quinidine absorption, clearance, and metabolism, and prolongs the half-life by about 20% (5067,22121).

SAQUINAVIR (Fortovase, Invirase) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Grapefruit juice can increase blood levels of saquinavir, potentially increasing the effects and adverse effects of saquinavir.  Details Clinical research shows that grapefruit juice increases the absorption and plasma concentrations of saquinavir (3773,22132).

SCOPOLAMINE (Transderm Scop) Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Probable •  Level of Evidence = B Grapefruit juice can increase blood levels of scopolamine, potentially increasing the effects and adverse effects of scopolamine.  Details Clinical research shows that grapefruit juice can inhibit cytochrome P450 3A4 (CYP3A4) metabolism of scopolamine, increasing its absorption and plasma concentrations. Oral bioavailability of scopolamine can increase by 30% when administered with 150 mL of grapefruit juice (8284).

SERTRALINE (Zoloft) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Grapefruit juice can increase blood levels of sertraline, potentially increasing the effects and adverse effects of sertraline.  Details Clinical research shows that grapefruit juice inhibits the cytochrome P450 3A4 (CYP3A4) metabolism of sertraline, increasing blood levels of sertraline (22122).

SILDENAFIL (Viagra) Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Probable •  Level of Evidence = B Grapefruit juice can increase blood levels of sildenafil, potentially increasing the effects and adverse effects of sildenafil.  Details Clinical research shows that grapefruit juice inhibits cytochrome P450 3A4 (CYP3A4) metabolism of sildenafil, increasing its absorption and plasma concentrations. Oral bioavailability of sildenafil can increase by 23% when administered with 500 mL of commercially available grapefruit juice (8283).

SUNITINIB (Sutent) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Unlikely •  Level of Evidence = B Grapefruit juice may slightly increase blood levels of sunitinib, potentially increasing the effects and adverse effects of sunitinib.  Details Sunitinib is metabolized by cytochrome P450 3A4 (CYP3A4). Grapefruit and grapefruit juice can inhibit CYP3A4 and increase levels of some drugs metabolized by this enzyme. One small clinical study shows that drinking 200 mL of grapefruit juice three times daily can increase the bioavailability of sunitinib by 11% (91429). While this effect is unlikely to be clinically significant, patients should use caution when using grapefruit along with sunitinib. Dose adjustments may be necessary.

TACROLIMUS (Prograf) Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Likely •  Level of Evidence = B Grapefruit juice can increase blood levels of tacrolimus, potentially increasing the effects and adverse effects of tacrolimus.  Details Clinical research shows that drinking grapefruit juice 200 mL daily while taking tacrolimus 3 mg daily increases the trough blood concentration of tacrolimus by approximately 3-fold in patients with connective tissue diseases (95974). A single case has also reported a 10-fold increase in tacrolimus trough levels after the ingestion of grapefruit juice over 3 days (22122). This effect is attributed to the inhibition of cytochrome P450 3A4 (CYP3A4) by grapefruit (95974).

TADALAFIL (Cialis) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, grapefruit juice might increase blood levels of tadalafil, potentially increasing the effects and adverse effects of tadalafil.  Details Animal research shows that grapefruit juice increases tadalafil serum concentrations and overall exposure, likely through inhibition of cytochrome P450 3A4 enzymes (104189).

TALINOLOL Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Grapefruit juice might decrease blood levels of talinolol, potentially decreasing the clinical effects of talinolol.  Details Clinical research suggests that grapefruit juice reduces talinolol bioavailability, likely by inhibiting intestinal uptake (22135). The clinical significance of this effect is unclear.

TERFENADINE (Seldane) Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Probable •  Level of Evidence = B Grapefruit juice can increase blood levels of terfenadine, potentially increasing the effects and adverse effects of terfenadine.  Details Clinical research shows that grapefruit juice increases the absorption and plasma concentrations of terfenadine (530,22124,22125). The mechanism of action is unclear.

THEOPHYLLINE Interaction Rating = Moderate Be cautious with this combination. Severity = Mild •  Occurrence = Probable •  Level of Evidence = B Grapefruit juice can decrease blood levels of theophylline, potentially decreasing the effectiveness of theophylline.  Details Clinical research shows that grapefruit juice seems to modestly decrease theophylline levels when given concurrently with sustained-release theophylline (11013). The mechanism of this interaction is unknown.

TICAGRELOR (Brilinta) Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Probable •  Level of Evidence = B Grapefruit juice can increase blood levels of ticagrelor, thereby increasing the effects and adverse effects of ticagrelor.  Details Ticagrelor is metabolized by cytochrome P450 3A4 (CYP3A4). Grapefruit can inhibit CYP3A4. A small clinical study shows that taking grapefruit juice with ticagrelor increases blood levels of ticagrelor more than two-fold and increases the antiplatelet activity of ticagrelor (91418).

TOLVAPTAN (Samsca) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Grapefruit juice can increase blood levels of tolvaptan, potentially increasing the effects and adverse effects of tolvaptan.  Details Tolvaptan is metabolized by cytochrome P450 3A4 (CYP3A4). Grapefruit can inhibit CYP3A4. A small clinical study shows that grapefruit juice can increase the bioavailability and blood levels of tolvaptan by approximately 1.6-fold for up to 16 hours (91426).

WARFARIN (Coumadin) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, drinking large amounts of grapefruit juice might increase the effects and adverse effects of warfarin.  Details In one case report, a patient experienced significantly increased international normalized ratio (INR) associated with consumption of 50 ounces of grapefruit juice daily (12061). However, smaller amounts of grapefruit juice might not be a problem. In a small clinical trial, consumption of 24 ounces of grapefruit juice daily for one week had no effect on INR in males treated with warfarin (12063).

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General ...Broccoli is well tolerated when consumed as food. A thorough evaluation of safety outcomes when broccoli is taken as medicine has not been conducted.

Dermatologic ...Topically, allergic reactions to broccoli have caused contact dermatitis (14158).

Gastrointestinal ...Orally, loose stools, diarrhea, abdominal pain, and abdominal cramping have been reported following intake of broccoli seed and sprout extracts, particularly at high doses (114753).

Hepatic ...In one case report, a 56-year-old adult developed elevated transaminases, with alanine aminotransferase (ALT) 5. 8 times above normal, aspartate aminotransferase (AST) 2.4 times above normal, and gamma-glutamyl transpeptidase (GGT) 5.1 times above normal. This was thought to be related to the consumption of 800 mL of broccoli juice daily over a 4-week period. Values returned to normal 15 days after cessation of juice consumption (96191).

Immunologic ...Topically, allergic reactions to broccoli have caused contact dermatitis (14158).

(Read more about BROCCOLI)

General ...Orally, celery seems to be well tolerated.
Most Common Adverse Effects:
Orally: Photosensitivity. Oral allergy syndrome in sensitive individuals.
Topically: Photosensitivity. Contact dermatitis in sensitive individuals.
Serious Adverse Effects (Rare):
Orally: Anaphylaxis in sensitive individuals.

Dermatologic ...Due to its psoralen content, contact with or ingestion of celery and exposure to ultraviolet radiation may cause photodermatitis (4,34347,40968,40969,40986,41085,41087,41143,41146,41151). Acute symptoms include skin eruption with edema and erythema; the main chronic symptom is hyperpigmentation at the eruption site (41093).
Celery can also cause contact or atopic dermatitis (19,41118,41124) and urticaria pigmentosa (40908).

Endocrine ...Celery has been associated with hyperthyroidism in otherwise healthy adults. In one case report a 36-year-old female presented with weight loss, blurred vision, nausea, palpitations, sweating, exophthalmos, elevated serum T4 levels, and low thyroid stimulating hormone (TSH) levels after taking 8 grams of a powdered celery extract for 78 days (102912). In another case report, a 48-year-old male presented with weight loss, exophthalmos, sweating, elevated serum T4 levels, and low TSH levels after taking 4 grams of dried celery leaves for 45 days (102914). In both of these cases, symptoms resolved and thyroid function tests normalized after discontinuing celery and completing a course of methimazole.
In contrast, several cases of hypothyroidism with low T4 levels have been reported in people who were previously stabilized on levothyroxine and then started taking celery seed tablets. They presented with symptoms such as lethargy, bloating, and dry skin, and recovered when celery seed was stopped (10646).

Gastrointestinal ...Symptoms of celery allergy have included oral allergy syndrome, characterized by itching and burning in the mouth and throat (41159,40977), and laryngeal edema (40953).

Immunologic ...Raw celery, cooked celery, and celery juice can all cause allergic reactions (40908,40926,41118,41131,92852,92855). Symptoms of celery allergy include laryngeal edema, skin reactions, an urticaria-edema-anaphylactic shock syndrome, celery-dependent exercise-induced anaphylaxis, and anaphylactic shock (40953,41100,41102,41107,41115,41124,41129,41135,41137,92852)(92855). Additionally, in clinical research, itchy throat has been reported in individuals taking celery seed powder (112410).
There is a case report of anaphylactic shock involving hypotension, tachycardia, and tachypnea in a patient who had ingested raw celery 15 minutes prior to symptom onset. The patient was treated with epinephrine, dexamethasone, and antazoline (92855). Another case report describes a patient with positive skin prick tests to celery, pollens including birch, chrysanthemum, mugwort, and ragweed, and to dust mites. When celery was consumed 30 minutes prior to exercise, the patient had an anaphylactic reaction that required treatment with intravenous pheniramine and corticosteroid, as well as nebulized albuterol (92852). Another patient with a history of anaphylactic reactions to undeclared celery in restaurant meals was able to undergo desensitization with gradually increasing oral doses of celery juice over several months, and then chronic daily ingestion of the juice to maintain hyposensitization (40908).

(Read more about CELERY)

General ...Orally, grapefruit and grapefruit juice are generally well tolerated.
Serious Adverse Effects (Rare):
Orally: Allergic reactions in sensitive individuals have been reported. When large quantities are consumed, arrhythmias, mineralocorticoid excess, QT prolongation, and pseudohyperaldosteronism have been reported. There is also some concern for increased breast cancer risk with grapefruit consumption.

Cardiovascular ...Orally, consumption of pink grapefruit juice 1000 mL can cause QT prolongation and cause arrhythmias in healthy patients and worsen arrhythmias in cardiomyopathy patients (13031,91424).

Endocrine ...Orally, high doses of grapefruit juice have been observed to cause pseudohyperaldosteronism and mineralocorticoid excess (53340,53346).

Gastrointestinal ...In a case report, grapefruit juice held against the teeth resulted in enamel and tooth surface loss (53368).

Immunologic ...Orally, grapefruit can cause allergic sensitization characterized by eosinophilic gastroenteritis, urticaria, and generalized pruritus (53351,53360).

Oncologic ...Preliminary population research shows that postmenopausal adults who consume a quarter or more of a whole grapefruit daily have a 25% to 30% increased risk of developing breast cancer (14858). Grapefruit is a potent inhibitor of cytochrome P450 3A4, which metabolizes estrogen. Consuming large amounts of grapefruit might significantly increase endogenous estrogen levels and therefore increase the risk of breast cancer. More evidence is needed to validate these findings. Until more is known, advise patients to consume grapefruit in moderation.

Renal ...In population research, consumption of 240 mL/day of grapefruit juice is associated with an increased risk of kidney stones (4216,53372).

(Read more about GRAPEFRUIT)