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INSUFFICIENT RELIABLE EVIDENCE to RATE

• Alzheimer disease. It is unclear if apple juice consumption is beneficial in patients with Alzheimer disease. Details: A small clinical study in adults with moderate to severe Alzheimer disease shows that drinking 4 ounces of apple juice twice daily for one month does not improve cognitive function when compared with baseline. However, according to caregiver assessment, it seems to improve aspects of mood and behavior, such as anxiety, depression, apathy, delusion, and agitation, when compared with baseline (94422). The validity of this finding is limited by the lack of a comparator group.
• Cancer. It is unclear if apple consumption is beneficial for preventing cancer. Details: Some population research has found that eating one or more apples daily may be associated with a decreased risk of esophageal, colorectal, larynx, or breast cancer when compared with eating less than 1 apple daily (31688). Also, a case-control study in adults with lung cancer has found that increased apple consumption may be associated with a reduced risk of lung cancer (3470).
• Dental plaque. It is unclear if apple consumption is beneficial for reducing dental plaque. Details: A small clinical study in healthy patients shows that eating an apple is less effective for reducing plaque than brushing teeth. Eating an apple actually increases plaque when compared with baseline, although it decreases the measure of bacterial vitality (99447).
• Diabetes. It is unclear if consumption of powdered, dehydrated apple is beneficial in patients with type 2 diabetes. Details: A small clinical study in patients with type 2 diabetes shows that substituting 26-52 grams of white wheat flour in bread with powdered, dehydrated apple and consuming the bread daily for up to 4 weeks does not improve fasting blood glucose or postprandial glucose levels when compared with a low-fiber white bread control (13141).
• Diarrhea. It is unclear if apple juice consumption is beneficial in infants with severe diarrhea. Details: A clinical study in infants with severe diarrhea shows that drinking apple juice 15 mL/kg twice daily during episodes of diarrhea results in more fecal loss when compared with drinking water (31687).
• Metabolic syndrome. Although there has been interest in using apple for metabolic syndrome, there is insufficient reliable information about the clinical effects of apple for this purpose.
• Muscle strength. Oral apple extract has only been evaluated in combination with other ingredients; its effects when used alone is unclear. Details: Small clinical studies in resistance trained males show that taking a specific blend of ancient peat and apple extract (elevATP, VDF FutureCeuticals Inc.) 150 mg daily as a liquid with liposomes (QuSomes, BioZone Laboratories Inc.) for 12 weeks modestly increases lower body and total strength, improves lower body power output, and increases cross-sectional area of muscle when compared with placebo (94418,94419).
• Obesity. It is unclear if apple consumption is beneficial in patients with overweight or obesity. Details: A small clinical study in females with hypercholesterolemia and overweight or obesity shows that eating apples three times daily for 12 weeks is associated with weight loss of 1.2 kg, compared with weight loss of 0.9 kg in those consuming oat cookies (17997). More evidence is needed to rate apple for these uses.

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INSUFFICIENT RELIABLE EVIDENCE to RATE

• Allergic rhinitis (hay fever). Although there has been interest in using oral black pepper for allergic rhinitis, there is insufficient reliable information about the clinical effects of black pepper for this purpose.
• Asthma. Although there has been interest in using oral black pepper for asthma, there is insufficient reliable information about the clinical effects of black pepper for this purpose.
• Athletic performance. Oral black pepper has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: One small clinical trial in untrained males shows that taking a supplement containing black pepper extract 10 mg, caffeine 400 mg, capsicum extract 66.7 mg, and niacin 40 mg as a single dose prior to exercise does not improve strength, time to exhaustion, or maximal oxygen consumption when compared with placebo (37873).
• Depression. Although there has been interest in using oral black pepper for depression, there is insufficient reliable information about the clinical effects of black pepper for this purpose.
• Diarrhea. Although there has been interest in using oral black pepper for diarrhea, there is insufficient reliable information about the clinical effects of black pepper for this purpose.
• Dysmenorrhea. Although there has been interest in using oral black pepper for dysmenorrhea, there is insufficient reliable information about the clinical effects of black pepper for this purpose.
• Dyspepsia. Although there has been interest in using oral black pepper for dyspepsia, there is insufficient reliable information about the clinical effects of black pepper for this purpose.
• Fall prevention. It is unclear if inhaling black pepper oil as aromatherapy is beneficial for fall prevention in older adults. Details: One small clinical study in older adults shows that applying black pepper oil near the right side of the nose as an olfactory stimulant improves stability while the eyes are closed during a one-minute trial when compared with the application of water. The improvement with black pepper oil is comparable to the improvement seen with the application of lavender oil (29160). It is unclear if any benefit persists after inhalation of black pepper oil.
• Fatigue. It is unclear if oral black pepper is beneficial in patients with fatigue. Details: One small clinical trial in adults with below-average energy levels shows that taking black pepper 2 grams as a single dose does not improve sustained attention, motivation to perform cognitive tasks, or feelings of mental energy and mental fatigue when compared with placebo (91731).
• Flatulence. Although there has been interest in using oral black pepper for flatulence, there is insufficient reliable information about the clinical effects of black pepper for this purpose.
• Headache. Although there has been interest in using oral black pepper for headache, there is insufficient reliable information about the clinical effects of black pepper for this purpose.
• Insect bite. Topical black pepper has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: One small clinical trial shows that applying a specific product (Trikatu) containing black pepper, long pepper, and ginger, as well as camphor, eucalyptus oil, and menthol, directly to mosquito bites does not reduce papule size, erythema, edema, or pruritis when compared with a control compound containing the same base ingredients but without the pepper and ginger components (89893).
• Obesity. Although there has been interest in using oral black pepper for obesity, there is insufficient reliable information about the clinical effects of black pepper for this purpose.
• Pain (chronic). Although there has been interest in using topical black pepper for chronic pain related to various etiologies, including osteoarthritis, postherpetic neuralgia, and peripheral neuropathy, there is insufficient reliable information about the clinical effects of black pepper for these conditions.
• Rhinosinusitis. Although there has been interest in using oral black pepper for rhinosinusitis, there is insufficient reliable information about the clinical effects of black pepper for this purpose.
• Sexual desire. Although there has been interest in using oral black pepper for increasing sexual desire, there is insufficient reliable information about the clinical effects of black pepper for this purpose.
• Smoking cessation. It is unclear if inhaling black pepper essential oil as aromatherapy is effective for smoking cessation. Details: One small clinical trial in adult male smokers who were deprived from smoking overnight shows that inhaling a vapor from the essential oil of black pepper, as needed over a 3-hour period, reduces cigarette cravings, negative feelings, and anxiety when compared with a placebo vapor (29159). Another small clinical study in patients addicted to dipping, chewing, or smoking tobacco shows that placing a drop of black pepper essential oil on tissue paper and inhaling for 2 minutes at least three times a day for 3 days reduces nicotine cravings when compared to baseline (90502).
• Swallowing dysfunction. It is unclear if inhaling black pepper oil as aromatherapy is beneficial in patients with swallowing dysfunction. Details: One small clinical study in post-stroke residents of nursing homes shows that one minute of olfactory stimulation with black pepper oil before each meal for 30 days decreases swallowing reflex latency by 11 seconds and increases the number of swallowing movements by 3.3 when compared to baseline (29161). A small clinical trial in children with neurological disorders who were on long-term enteral nutrition shows that applying black pepper oil to the nostrils or nasal cavity for one minute improves the amount of oral intake and swallowing movement in 63% of patients. Although oral intake increased, the need for enteral nutrition was not eliminated (29162).
• Vitiligo. It is unclear if topical piperine oil, a constituent of black pepper, is beneficial in patients with vitiligo. Details: A small clinical study in patients with vitiligo shows that applying piperine oil 1% daily in addition to receiving narrowband ultraviolet B (NB-UVB) light therapy every other day for 3 months improves repigmentation more rapidly when compared with using NB-UVB alone (103820). More evidence is needed to rate black pepper for these uses.

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INSUFFICIENT RELIABLE EVIDENCE to RATE

• Diabetes. It is unclear if oral Irvingia gabonensis is beneficial in patients with diabetes. Details: Preliminary clinical research shows that taking 4 grams of ground Irvingia gabonensis seed fiber orally, dissolved in 100 mL water, daily for one month can reduce fasting blood glucose, total cholesterol, and triglycerides, and can increase high-density lipoprotein (HDL) cholesterol, when compared with baseline in patients with type 2 diabetes (61589). The validity of these findings is limited by the lack of a comparator group.
• Hypercholesterolemia. It is unclear if oral Irvingia gabonensis is beneficial in patients with hypercholesterolemia. Details: Preliminary clinical research shows that taking Irvingia gabonensis crude seed extract 150 mg to 3.15 grams orally daily for 4-10 weeks lowers total and low-density lipoprotein (LDL) cholesterol and raises high-density lipoprotein (HDL) cholesterol in overweight adults who have normal or mildly elevated cholesterol levels when compared with placebo (17069,17070,104524). A meta-analysis of 5 small clinical studies in obese or overweight adults shows that taking Irvingia gabonensis 0.3-3.15 grams orally daily for 4-10 weeks reduces LDL by an average of 24% and increases HDL by an average of 10% when compared with placebo. The average change in triglycerides was inconclusive. However, the small size, poor quality, and heterogeneity of the included studies limits the validity of these findings (104524).
• Metabolic syndrome. It is unclear if oral Irvingia gabonensis is beneficial in patients with metabolic syndrome. Details: A preliminary clinical study in adults with metabolic syndrome shows that taking Irvingia gabonensis seed extract 150 mg orally twice daily for 90 days reduces triglycerides by 25%, waist circumference by 3%, and blood glucose upon oral glucose tolerance testing by 14%, but does not significantly affect low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, body weight, or body mass index, when compared with baseline. The validity of this study is limited by a very small sample size and the lack of a comparator group (104525).
• Obesity. Small clinical studies suggest that Irvingia gabonensis may modestly improves weight loss in overweight adults. Details: One preliminary clinical study shows that taking a crude seed extract 1.05 grams orally three times daily, combined with a low-fat, low-calorie diet, reduces weight by about 4 kg after 4 weeks, compared to no weight reduction in those taking placebo (17069). Another preliminary clinical study shows that taking a standardized seed extract (IGOB131) 150 mg twice daily orally for 10 weeks reduces weight by 12.8 kg, compared with 0.7 kg in those taking placebo. However, in this study, overweight patients taking Irvingia gabonensis consumed an average of 2767 kcal/day, compared to 3156 kcal/day in the placebo group (17070). Similar results also occurred in a study using a combination of standardized Irvingia gabonensis seed extract (IGOB131) and Cissus quadrangularis, for 10 weeks (16457). A meta-analysis of these and 2 additional trials in obese or overweight adults shows that taking Irvingia gabonensis 0.3-3.15 grams orally daily for 4-10 weeks reduces body weight by an average of 9%, body fat by 4%, and waist circumference by 7% when compared with placebo. However, the small size, poor quality, and heterogeneity of the included studies limits the validity of these findings (104524). In addition, some research shows conflicting results. Preliminary clinical research in overweight and obese individuals shows that taking a standardized seed extract (IGOB131) 300 mg orally daily for 12 weeks does not reduce body weight, body mass index, or fat mass when compared with placebo (112220). However, the study may have been inadequately powered to detect a difference between groups. The reasons for these discrepant findings are unclear but may be explained by differences in doses and patient populations studied or by changes in overall caloric intake, rather than the study drug. More evidence is needed to rate Irvingia gabonensis for these uses.

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LIKELY SAFE ...when used orally in food amounts. Eating apples and consuming apple juice is safe for most people. Apples are a common food source (3470,3472). However, eating apple seeds should be avoided because they can be toxic (6).

CHILDREN: LIKELY SAFE
when used orally in food amounts. Eating apples and consuming apple juice is safe for most people. Apples are a common food source (3470,3472).

CHILDREN: POSSIBLY SAFE
when apple pectin is used orally and appropriately, short-term. Preliminary clinical research suggests that combination products containing apple pectin and German chamomile (Diarrhoesan) are safe when used in infants for up to one week (19705,19706).

PREGNANCY AND LACTATION:
There is insufficient reliable information available about the safety of apple in amounts greater than those found in foods during pregnancy and lactation; avoid using.

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

POSSIBLY SAFE ...when black pepper oil is applied topically. Black pepper oil is nonirritating to the skin and is generally well tolerated (11). ...when black pepper oil is inhaled through the nose or as a vapor through the mouth, short-term. Black pepper oil as a vapor or as an olfactory stimulant has been used with apparent safety in clinical studies for up to 3 days and 30 days, respectively (29159,29160,29161,90502). There is insufficient reliable information available about the safety of black pepper when used orally in medicinal amounts.

CHILDREN: LIKELY SAFE
when used orally in amounts commonly found in foods (11).

CHILDREN: POSSIBLY UNSAFE
when used orally in large amounts. Fatal cases of pepper aspiration have been reported in some patients (5619,5620). There is insufficient reliable information available about the safety of topical pepper oil when used in children.

PREGNANCY: LIKELY SAFE
when used orally in amounts commonly found in foods (11).

PREGNANCY: LIKELY UNSAFE
when used orally in large amounts. Black pepper might have abortifacient effects (11,19); contraindicated. There is insufficient reliable information available about the safety of topical pepper when used during pregnancy.

LACTATION: LIKELY SAFE
when used orally in amounts commonly found in foods (11). There is insufficient reliable information available about the safety of black pepper when used in medicinal amounts during breast-feeding.

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POSSIBLY SAFE ...when Irvingia gabonensis seed extract is used orally and appropriately, short-term. Irvingia gabonensis crude seed extract has been used safely in doses of up to 1.05 grams three times daily for up to 12 weeks (17069,104524,104525). A standardized seed extract (IGOB131) has been used safely in doses up to 150 mg twice daily for up to 12 weeks (17070,112220).

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

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ALISKIREN (Tekturna, Rasilez) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Concomitant consumption of apple juice can significantly decrease oral absorption and blood levels of aliskiren.  Details Pharmacokinetic research shows that coadministration of apple juice 200 mL along with aliskiren 150 mg decreases the bioavailability of aliskiren by 63% (17670). Apple juice seems to inhibit organic anion transporting polypeptide (OATP), which is involved in drug uptake in the gut, liver, and kidney (7046,94413). It is thought that apple juice might affect OATP for only a short time. Therefore, separating drug administration and consumption of apple juice by at least 4 hours might avoid this interaction (17603,17604).

ANTIDIABETES DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, consuming apple juice with antidiabetes drugs might interfere with blood glucose control.  Details Clinical research suggests that consuming apples or drinking apple juice can raise blood glucose levels, with the effects of drinking apple juice being more significant than consuming apples (31699).

ANTIHYPERTENSIVE DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Mild •  Occurrence = Probable •  Level of Evidence = B Consuming apple juice with antihypertensive drugs might interfere with blood pressure control.  Details Some clinical evidence suggests that consuming apple and cherry juice can increase blood pressure in elderly patients (31680).

ATENOLOL (Tenormin) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Concomitant consumption of apple juice can significantly decrease oral absorption and blood levels of atenolol.  Details Pharmacokinetic research shows that coadministration of apple juice 600-1200 mL decreases levels of atenolol by 58% to 82% in a dose-dependent manner (17999). Apple juice seems to inhibit organic anion transporting polypeptide (OATP), which is involved in drug uptake in the gut, liver, and kidney (7046). It is thought that apple juice might affect OATP for only a short time. Therefore, separating drug administration and consumption of apple juice by at least 4 hours might avoid this interaction (17603,17604).

FEXOFENADINE (Allegra) Interaction Rating = Moderate Be cautious with this combination. Severity = Mild •  Occurrence = Likely •  Level of Evidence = B Concomitant consumption of apple juice can significantly decrease oral absorption and blood levels of fexofenadine.  Details Pharmacokinetic research shows that coadministration of apple juice 400-1200 mL along with fexofenadine 60-120 mg decreases bioavailability of fexofenadine by up to 78% (7046,94413). Coadministration with smaller quantities of apple juice (150 mL or less) does not appear to affect the bioavailability of fexofenadine (94421). Apple juice seems to inhibit organic anion transporting polypeptide (OATP), which is involved in drug uptake in the gut, liver, and kidney (7046,94413). It is thought that apple juice might affect OATP for only a short time. Therefore, separating drug administration and consumption of apple juice by at least 4 hours might avoid this interaction (17603,17604).

LITHIUM Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D There is some concern that concomitant consumption of apple juice might decrease oral absorption and blood levels of lithium.  Details In one case report, a patient had an undetectable serum lithium level when lithium citrate was administered with apple juice. When lithium was administered with an alternative beverage, the lithium level became detectable and the patient demonstrated clinical improvement (105342).

ORGANIC ANION-TRANSPORTING POLYPEPTIDE SUBSTRATES (OATP) Interaction Rating = Major Do not take this combination. Severity = Moderate •  Occurrence = Likely •  Level of Evidence = B Concomitant consumption of apple juice can significantly decrease oral absorption and blood levels of OATP substrates.  Details Research shows that consuming apple juice inhibits OATP, which reduces bioavailability of oral drugs that are substrates of OATP (7046,17605). Fexofenadine, atenolol, and aliskiren are substrates of OATP. Clinical research shows that coadministration of apple juice decreases bioavailability of fexofenadine by up to 78% (7046,94413), aliskiren by 63% (17670), and atenolol by up to 82% (17999). These effects appear to increase with larger quantities of apple juice. It is thought that apple juice might affect OATP for only a short time. Therefore, separating drug administration and consumption of apple juice by at least 4 hours might avoid this interaction (17603,17604).

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AMOXICILLIN (Amoxil, Trimox) Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = D Theoretically, black pepper might increase the effects and side effects of amoxicillin.  Details Animal research shows that taking piperine, a constituent of black pepper, with amoxicillin increases plasma levels of amoxicillin (29269). This 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, black pepper might increase the risk of bleeding when taken with antiplatelet or anticoagulant drugs.  Details In vitro research shows that piperine, a constituent of black pepper, seems to inhibit platelet aggregation (29206). This has not been reported in humans.

ANTIDIABETES DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, black pepper might increase the risk of hypoglycemia when taken with antidiabetes drugs.  Details Animal research shows that piperine, a constituent of black pepper, can reduce blood glucose levels (29225). Monitor blood glucose levels closely. Dose adjustments might be necessary.

ATORVASTATIN (Lipitor) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, black pepper might increase blood levels of atorvastatin.  Details Animal research shows that taking piperine, a constituent of black pepper, 35 mg/kg can increase the maximum serum concentration of atorvastatin three-fold (104188). This has not been reported in humans.

CARBAMAZEPINE (Tegretol) Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = B Theoretically, black pepper might increase blood levels of carbamazepine, potentially increasing the effects and side effects of carbamazepine.  Details One clinical study in patients taking carbamazepine 300 mg or 500 mg twice daily shows that taking a single 20 mg dose of purified piperine, a constituent of black pepper, increases carbamazepine levels. Piperine may increase carbamazepine absorption by increasing blood flow to the GI tract, increasing the surface area of the small intestine, or inhibiting cytochrome P450 3A4 (CYP3A4) in the gut wall. Absorption was significantly increased by 7-10 mcg/mL/hour. The time to eliminate carbamazepine was also increased by 4-8 hours. Although carbamazepine levels were increased, this did not appear to increase side effects (16833). In vitro research also shows that piperine can increase carbamazepine levels by 11% in a time-dependent manner (103819).

CYCLOSPORINE (Neoral, Sandimmune) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, black pepper might increase the effects and side effects of cyclosporine.  Details In vitro research shows that piperine, a constituent of black pepper, increases the bioavailability of cyclosporine (29282). This has not been reported in humans.

CYTOCHROME P450 1A1 (CYP1A1) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, black pepper might increase levels of drugs metabolized by CYP1A1.  Details In vitro research suggests that piperine, a constituent of black pepper, inhibits CYP1A1 (29213). This has not been reported in humans.

CYTOCHROME P450 2B1 (CYP2B1) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, black pepper might increase levels of drugs metabolized by CYP2B1.  Details In vitro research suggests that piperine, a constituent of black pepper, inhibits CYP2B1 (29332). This has not been reported in humans.

CYTOCHROME P450 2D6 (CYP2D6) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, black pepper might increase levels of drugs metabolized by CYP2D6.  Details In vitro research suggests that some constituents of black pepper inhibit CYP2D6 (29207,29212,38375). This has not been reported in humans.

CYTOCHROME P450 3A4 (CYP3A4) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, black pepper might increase levels of drugs metabolized by CYP3A4.  Details In vitro research shows that piperine, a constituent of black pepper, as well as the pepper fruit seem to inhibit CYP3A4 (14375,29212). This has not been reported in humans.

LITHIUM Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = D Theoretically, black pepper might increase blood levels of lithium due to its diuretic effects. The dose of lithium might need to be reduced.  Details Black pepper is thought to have diuretic properties (11).

NEVIRAPINE (Viramune) Interaction Rating = Moderate Be cautious with this combination. Severity = Mild •  Occurrence = Probable •  Level of Evidence = D Black pepper might increase blood levels of nevirapine.  Details Clinical research shows that piperine, a constituent of black pepper, increases the plasma concentration of nevirapine. However, no adverse effects were observed in this study (29209).

P-GLYCOPROTEIN SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, black pepper might increase levels of P-glycoprotein substrates.  Details In vitro research shows that piperine, a constituent of black pepper, seems to inhibit P-glycoprotein (14375,29281,29283).

PENTOBARBITAL (Nembutal) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, black pepper might increase the sedative effects of pentobarbital.  Details Animal research shows that piperine, a constituent of black pepper, increases pentobarbital-induced sleeping time (29214).

PHENYTOIN (Dilantin) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = B Black pepper might increase blood levels of phenytoin.  Details Clinical research shows that piperine, a constituent of black pepper, seems to increase absorption, slow elimination, and increase levels of phenytoin (537,14442). Taking a single dose of black pepper 1 gram along with phenytoin seems to double the serum concentration of phenytoin (14375). Consuming a soup with black pepper providing piperine 44 mg/200 mL of soup along with phenytoin also seems to increase phenytoin levels when compared with consuming the same soup without black pepper (14442).

PROPRANOLOL (Inderal) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Black pepper might increase blood levels of propranolol.  Details Clinical research shows that piperine, a constituent of black pepper, seems to increase absorption and slow elimination of propranolol (538).

RIFAMPIN (Rifadin) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = B Black pepper might increase blood levels of rifampin.  Details Clinical research shows that piperine, a constituent of black pepper, seems to increase absorption and serum levels of rifampin (14375,29284).

THEOPHYLLINE Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Black pepper might increase blood levels of theophylline.  Details Clinical research shows that piperine, a constituent of black pepper, seems to increase absorption and slow elimination of theophylline (538).

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ANTIDIABETES DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Theoretically, taking Irvingia gabonensis with antidiabetes drugs might increase the risk of hypoglycemia in some patients.  Details Human research shows that Irvingia gabonensis decreases blood sugar in diabetic patients being treated with antidiabetes agents (61589,61591). Monitor blood glucose levels closely. Dose adjustments might be necessary.

TESTOSTERONE Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, taking Irvingia gabonensis with testosterone products drugs might cause additive effects in some patients.  Details Animal research suggests that Irvingia gabonensis increases testosterone levels (61613). The mechanism of action is unclear. Until more is known, advise patients taking testosterone to avoid using or use Irvingia gabonensis cautiously.

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General ...Orally, apple fruit is well tolerated. Apple seeds, which contain cyanide, may cause serious adverse effects when consumed in large amounts.
Most Common Adverse Effects:
Orally: Bloating, flatulence.
Serious Adverse Effects (Rare):
Orally: Allergic reactions, including anaphylaxis. Ingestion of large amounts of apple seeds may cause cyanide poisoning, leading to death.

Gastrointestinal ...Orally, apple products, including whole apples, apple puree, and apple juice, may cause bloating and flatulence in some people (104184).

Immunologic ...Patients allergic to other fruits in the Rosaceae family, including apricot, almond, plum, peach, pear, and strawberry, can also be allergic to apples (7129). Rarely, the allergy has resulted in anaphylaxis (94425).

Other ...Orally, ingestion of large amounts of apple seeds, which contain hydrogen cyanide (HCN), may cause cyanide poisoning, leading to death. One death is attributed to ingestion of a cupful of apple seeds. To release cyanide, seeds must be hydrolyzed in the stomach, and several hours may elapse before poisoning symptoms occur (6).

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General ...Orally, black pepper seems to be well tolerated when used in the amounts found in food or when taken as a medicine as a single dose. Topically and as aromatherapy, black pepper oil seems to be well tolerated.
Most Common Adverse Effects:
Orally: Burning aftertaste, dyspepsia, and reduced taste perception.
Inhalation: Cough.
Serious Adverse Effects (Rare):
Orally: Allergic reaction in sensitive individuals.

Gastrointestinal ...Orally, black pepper can cause a burning aftertaste (5619) and dyspepsia (38061). Single and repeated application of piperine, the active constituent in black pepper, to the tongue and oral cavity can decrease taste perception (29267). By intragastric route, black pepper 1.5 grams has been reported to cause gastrointestinal microbleeds (29164). It is not clear if such an effect would occur with oral administration.

Immunologic ...In one case report, a 17-month-old male developed hives, red eyes, facial swelling, and a severe cough following consumption of a sauce containing multiple ingredients. Allergen skin tests were positive to both black pepper and cayenne, which were found in the sauce (93947).

Ocular/Otic ...Topically, ground black pepper can cause redness of the eyes and swelling of the eyelids (5619).

Pulmonary/Respiratory ...When inhaled through the nose as an olfactory stimulant, black pepper oil has been reported to cause cough in one clinical trial (29162).

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General ...Orally, Irvingia gabonensis is generally well tolerated.
Most Common Adverse Effects:
Orally: Flatulence, headache, insomnia, nausea.

Gastrointestinal ...Flatulence has been reported following 10 weeks of supplementation with Irvingia gabonensis alone (17070) or in combination with Cissus quadrangularis (16457). Similar events were observed in controls. Mild nausea has also been reported following the administration of Irvingia gabonensis 0.3-4 grams daily for up to 12 weeks; however, some of these symptoms were alleviated by the addition of milk to the test preparation (61589,112220).

Hepatic ...One case of acute hepatitis secondary to Irvingia gabonensis has been reported. A 45-year old male with a ten-day history of Irvingia gabonensis supplementation, at a dose of 350 mg of seed extract twice daily for body fat reduction, was admitted with jaundice, abdominal discomfort, and new onset malaise. His complaints began four days after starting Irvingia gabonensis supplementation. Prior to supplementation, all outpatient laboratory parameters were normal. At the time of admission, liver function tests were as follows: ALT 902 U/L, AST 708 U/L, alkaline phosphatase 198 U/L, gamma-glutamyl transferase 998 U/L, total bilirubin 9.1 mg/dL, direct bilirubin 6.1 mg/dL, and serum albumin 4.2 grams/dL. Hemoglobin was 15.3 grams/dL, white blood cell count 9.2 x 10³ /mm³, platelets 240 x 10³/mm³, prothrombin time 16.1 seconds, and ferritin level 115 ng/mL. Urinalysis revealed 2+ bilirubin and urobilinogens. Tests for viral hepatitis, autoimmune hepatitis, hemochromatosis, alpha-1-antitypsin deficiency, and Wilson's disease were negative. Ultrasonography showed a bright liver parenchyma consistent with steatosis, 15 cm in vertical size with regular edges. A spleen 13 cm in vertical size was also seen. Acute hepatitis secondary to Irvingia gabonensis was the diagnosis. When the Irvingia gabonensis capsules were discontinued, an immediate improvement was seen. Liver enzymes and other laboratory tests were normal 3 weeks after the admission (92824).

Neurologic/CNS ...Headache and insomnia have been reported in patients taking Irvingia gabonensis alone or in conjunction with Cissus quadrangularis for periods of 10 weeks (16457,17070). Similar events were observed in control groups.

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