Piper nigrum

Black pepper/Drug Interactions:

  • GeneralGeneral: In animal study, piperine increased intestinal brush border membrane fluidity and leucine amino peptidase and glycyl-glycine dipeptidase activity (202). Using an in vitro everted intestinal sac model, piperine was found to be absorbed rapidly and potentially form apolar complexes with drugs and solutes increasing permeability across barriers (203).
  • AnalgesicsAnalgesics: In animal study, piperine had analgesic effects (tale flicking and acetic acid-induced writhing models) (20). In an in vitro study using whole-cell patch-clamp electrophysiology, piperine, a pungent alkaloid found in black pepper, had similar agonist effects on the human vanilloid receptor TRPV1 as capsaicin (4). However, piperine could induce greater receptor desensitization and exhibit a greater efficacy than capsaicin. Theoretically, concurrent use of black pepper and analgesics may have additive effects.
  • AntibioticsAntibiotics: Based on an in vitro study using 12 different genera of bacterial populations isolated from the oral cavity of 200 individuals, black pepper (Piper nigrum L.) may have antibiotic activity (21). In animal study, piperine increased Cmax, Tmax, and area under the curve of beta-lactam antibiotics, amoxycillin trihydrate, and cefotaxime sodium (204). In vitro, piperine had additive effects with ciprofloxacin, potentially due to inhibition of bacterial efflux pumps (205). In animal study, trikatu (an Ayurvedic prescription containing dried fruits of Piper nigrum and other spices) increased the area under the curve and volume of distribution of pefloxacin (93).
  • Anticoagulants and antiplateletsAnticoagulants and antiplatelets: In vitro, piperine inhibited platelet aggregation (70). Theoretically, concurrent use of black pepper and anticoagulants or antiplatelets may increase the risk of bleeding.
  • Antidepressant agentsAntidepressant agents: In animal study, piperine had antidepressant effects, with reduced duration of immobility in the forced swimming test and the tail suspension test (37; 38). In animal study, piperine protected against chronic unpredictable mild stress (39; 40). Suppression of monoamine oxidase activity has also been implicated in the antidepressant effects of piperine (41; 42). Theoretically, concurrent use black pepper and antidepressants may have additive effects.
  • Antidiabetic agentsAntidiabetic agents: In animal study, black pepper lowered blood glucose (44; 106). Theoretically, concurrent use of black pepper with antidiabetic agents may have additive glucose-lowering effects and increase the risk of hypoglycemia.
  • Antifungal agentsAntifungal agents: Based on secondary sources and in vitro study, constituents and oils of Piper nigrum may have antifungal effects (206). Theoretically, concurrent use of black pepper and antifungal agents may have additive effects.
  • AntihistaminesAntihistamines: In vitro, a polyherbal formulation (Aller-7/NR-A2) containing extracts from seven medicinal plants, including Piper nigrum, inhibited rat mesenteric mast cell degranulation, activity of lipoxygenase and hyaluronidase, and histaminic activity, and had an antispasmodic effect on contractions of guinea pig tracheal chain (19). The effects of black pepper with antihistamines are not well understood.
  • AntihypertensivesAntihypertensives: In animal study, intravenous piperine had hypotensive effects (105). Theoretically, concurrent use of black pepper with antihypertensive agents may have additive blood pressure-lowering effects and increase the risk of hypotension.
  • Anti-inflammatory agentsAnti-inflammatory agents: Based on animal study, the benzene, chloroform, and ethanol extracts of leaf galls of Piper nigrum resulted in anti-inflammatory activity for carrageenan-induced acute inflammation in albino rats (207). Based on animal study, oral administration of a methanolic extract of Piper nigrum leaf resulted in inhibition in an immediate-phase and late-phase cutaneous swelling, potentially due to inhibition of histamine release (28). Based on animal study, piperine had anti-inflammatory effects in various inflammatory models (29; 30; 31). Based on animal study, a polyherbal formulation (Aller-7/NR-A2) containing extracts from seven medicinal plants including Piper nigrum demonstrated 31.3% inhibition against carrageenan-induced acute inflammation in Wistar albino rats, while ibuprofen (50mg/kg orally) exerted 68.1% inhibition (18). Based on animal study, the ED50 was lower in piperine-treated animals vs. animal treated with nimesulide alone, with superior anti-inflammatory effects (208). In animal study, trikatu (an Ayurvedic prescription containing dried fruits of Piper nigrum and other spices) reduced the bioavailability of diclofenac sodium (74).
  • AntilipemicsAntilipemics: In animals, piperine reduced plasma lipids and lipoproteins levels, increased levels of HDL-cholesterol, and improved levels of apo A-1 and apo B (43; 44) and inhibited acyl-CoA:cholesterol acyltransferase (ACAT) activity (209; 210). Theoretically, concurrent use of black pepper and antilipemic agents may have additive effects.
  • AntineoplasticsAntineoplastics: Based on reviews and case-controlled study, there may be a link between ingestion of black pepper and nasopharyngeal or esophageal cancer (15; 16; 17). In vitro, piperine protected cells from cisplatin-induced apoptosis (211). In animal study, piperine increased tumor growth inhibition and reduced leukemia in 5-fluorouracil-treated animals (212). In animal study, black pepper or its extract reduced the incidence of tumors and metastasis in carcinogen-stimulated animals (213; 214; 215). The effects of black pepper and antineoplastic agents are not well understood.
  • AntiprotozoalsAntiprotozoals: In vitro, essential oil of black pepper had antiparasitic effects against Dermanyssus gallinae (red mite) (59). In vitro, piperine had antiparasitic effects against Trypanosoma cruzi, which involved ultrastructural alterations (60; 61). In animal study, piperine had antiparasitic effects against Leishmania species (62; 63; 64). In vitro, Piper nigrum exhibited strong antinematodal activity against Bursaphelenchus xylophilus (216). In animal study, black pepper extract and piperine demonstrated antiamebic activity for cecal amoebiasis (58). The effects of black pepper and antiprotozoal agents are not well understood.
  • CNS depressantsCNS depressants: Based on animal study, piperine potentiated pentobarbitone sleeping time and blood and brain levels of the drug (94). There was no effect on barbital sodium. Theoretically, concurrent use of black pepper and CNS depressants may have additive effects.
  • BenzodiazepinesBenzodiazepines: In vitro, piperine showed affinity for the benzodiazepine site on the GABA(A) (gamma-amino butyric acid) receptor (217). Theoretically, concurrent use of black pepper and benzodiazepines may have additive effects.
  • CarbamazapineCarbamazapine: In epilepsy patients, piperine significantly increased the mean plasma concentrations of carbamazepine, as well as area under the curve, Cmax, and Tmax (92).
  • Cardiac glycosidesCardiac glycosides: Based on in vitro study, piperine may inhibit digoxin transport in intestinal cells (72).
  • Cholinergic agonistsCholinergic agonists: Based on in vitro study, extracts of Piper nigrum L. seeds may inhibit acetylcholinesterase (5). Theoretically, black pepper may interfere with the effects of cholinergic agonists.
  • CyclosporineCyclosporine: Based on in vitro study, piperine may inhibit cyclosporine transport in intestinal cells (72).
  • Cytochrome P450-metabolized agentsCytochrome P450-metabolized agents: In in vitro and animal study, extracts of and constituents isolated from Piper nigrum, including piperine and dipiperamides D and E, potently inhibited some CYP450 metabolic pathways, including CYP2D6 (71; 80; 81), CYP3A4 (72; 73; 81; 82), CYP2B1 (83; 84), CYP1A1 (85), CYP2E1 (86), arylhydrocarbon hydroxylase, and 7-ethoxycourmarin deethylase (87; 88). P4502B and 1A expression were enhanced in rats (86). This has been also discussed in a review (218). Theoretically, black pepper may increase the levels of drugs metabolized by cytochrome P450.
  • Diclofenac sodiumDiclofenac sodium: In animal study, trikatu (an Ayurvedic prescription containing dried fruits of Piper nigrum and other spices) reduced the bioavailability of diclofenac sodium (74).
  • Fertility agentsFertility agents: In animal study, piperine has had various negative effects on fertility in males, including alterations in enzyme levels, changes in lipid peroxidation, decreases in weight of testes and other sex organs, and damage to developing sperm (95; 96; 97). In females, negative effects of piperine included decreased mating performance and fertility (98). In superovulated female hamsters intragastrically treated with piperine, the percent fertilization following artificial insemination was increased (219). The effects of black pepper and fertility agents are not well understood.
  • Hepatotoxic agentsHepatotoxic agents: In animal study, piperine potentiated carbon tetrachloride-induced hepatotoxicity, potentially by increasing the activity of NADPH-cytochrome c reductase (108). Theoretically, concurrent use of black pepper and hepatotoxic agents may increase the risk of liver damage.
  • Hormonal agentsHormonal agents: In animals fed a high-fat diet resulting in negative effects on plasma lipids and hormone levels, piperine beneficially improved the plasma levels of testosterone (43). In vitro, the aqueous ethanolic Piper nigrum leaf extract resulted in inhibition of testosterone 5-alpha-reductase, and in animal study this extract had antiandrogenic activity, as observed using a hair growth assay in testosterone-sensitive male mice (220).
  • ImmunosuppressantsImmunosuppressants: In animal and in vitro study, piperine, a constituent of black pepper, improved or returned to normal various immunological endpoints, such as cell viability, oxidative stress, apoptotic markers, cell proliferative response, T and B cell phenotype changes, and cytokine release, following treatment with the immunotoxicant cadmium (99; 100; 101; 102). In vitro piperine inhibited adhesion of neutrophils to endothelial monolayer; this is potentially due to its ability to block tumor necrosis factor-alpha (TNF-alpha)-induced expression of cell adhesion molecules such as ICAM-1 (intercellular adhesion molecule-1), VCAM-1 (vascular cell adhesion molecule-1), and E-selectin (103). Theoretically, black pepper may interfere with the effects of immunosuppressants.
  • IndomethacinIndomethacin: In animal study, piperine and other constituents of black pepper decreased gastric lesions associated with indomethacin (221).
  • InotropesInotropes: In animal study, piperine exerted positive chronotropic and inotropic effects in the isolated spontaneously beating right atria and electrically driven left atria; the calcitonin gener-related peptide was involved (222; 223). Theoretically, concurrent use of black pepper and inotropes may have additive effects.
  • NevirapineNevirapine: In human study, piperine increased the area under the curve of nevirapine (75).
  • NicotineNicotine: In clinical study, inhalation of black pepper essential oil vapor reduced the craving for cigarettes (6).
  • OpioidsOpioids: Based on animal study, piperine, a constituent of black pepper, may affect the intensity of morphine dependency (224).
  • P-glycoprotein-regulated drugsP-glycoprotein-regulated drugs: In animal study, piperine may alter p-glycoprotein levels (225) and activity (226). In vitro, piperine has p-glycoprotein inhibitory (227; 225; 72) or biphasic activity (stimulation at low and inhibitory at high concentrations) (228). Theoretically, black pepper may increase levels of p-glycoprotein substrates.
  • PhenytoinPhenytoin: Based on animal and clinical trials, piperine from black pepper (Piper nigrum L.) may enhance the bioavailability of phenytoin significantly, possibly by increasing its absorption (89; 90; 91; 229).
  • PropranololPropranolol: Based on a study in healthy volunteers, piperine may increase the bioavailability of propranolol (90; 230).
  • Rifamipicin (rifampin)Rifamipicin (rifampin): Based on a study in patients with pulmonary tuberculosis, piperine may increase plasma concentrations of rifamipicin (rifampin) (90; 231). In animal study, trikatu (an Ayurvedic prescription containing dried fruits of Piper nigrum and other spices) reduced the Cmax and plasma levels of rifampin (232).
  • TheophyllineTheophylline: Based on a study in healthy volunteers, piperine may increase the bioavailability of theophylline (90; 230).
  • Thyroid hormonesThyroid hormones: In animals fed a high-fat diet, piperine modulated levels of T3, T4, and TSH (43; 106). Theoretically, black pepper may interfere with thyroid hormones.
  • UDP substratesUDP substrates: In vitro, piperine slightly down-regulated gene expression of UDP glucose dehydrogenase (76) and inhibited UDP-glucose dehydrogenase and glucuronidation activities in liver and intestine (77; 78), suggesting a role in the elimination of various drugs.

    • Black pepper/Herb/Supplement Interactions:

  • GeneralGeneral: In animal study, piperine increased intestinal brush border membrane fluidity and leucine amino peptidase and glycyl-glycine dipeptidase activity (202). Using an in vitro everted intestinal sac model, piperine was found to be absorbed rapidly and potentially form apolar complexes with drugs and solutes, increasing permeability across barriers (203).
  • AnalgesicsAnalgesics: In animal study, piperine had analgesic effects (tale flicking and acetic acid-induced writhing models) (20). In an in vitro study using whole-cell patch-clamp electrophysiology, piperine, a pungent alkaloid found in black pepper, had similar agonist effects on the human vanilloid receptor TRPV1 as capsaicin (4). However, piperine could induce greater receptor desensitization and exhibit a greater efficacy than capsaicin. Theoretically, concurrent use of black pepper and analgesics may have additive effects.
  • AntibacterialsAntibacterials: Based on an in vitro study using 12 different genera of bacterial populations isolated from the oral cavity of 200 individuals, black pepper (Piper nigrum L.) may have antibiotic activity (21). In animal study, piperine increased Cmax, Tmax, and area under the curve of beta-lactam antibiotics, amoxycillin trihydrate, and cefotaxime sodium (204). In vitro, piperine had additive effects with ciprofloxacin, potentially due to inhibition of bacterial efflux pumps (205). In animal study, trikatu (an Ayurvedic prescription containing dried fruits of Piper nigrum and other spices) increased the area under the curve and volume of distribution of pefloxacin (93).
  • Anticoagulants and antiplateletsAnticoagulants and antiplatelets: In vitro, piperine inhibited platelet aggregation (70). Theoretically, concurrent use of black pepper and anticoagulants or antiplatelets may increase the risk of bleeding.
  • AntidepressantsAntidepressants: In animal study, piperine had antidepressant effects, with reduced duration of immobility in the forced swimming test and the tail suspension test (37; 38). In animal study, piperine protected against chronic unpredictable mild stress (39; 40). Suppression of monoamine oxidase activity has also been implicated in the antidepressant effects of piperine (41; 42). Theoretically, concurrent use black pepper and antidepressants may have additive effects.
  • AntifungalsAntifungals: Based on secondary sources and in vitro study, constituents and oils of Piper nigrum had antifungal effects (206). Theoretically, concurrent use of black pepper and antifungal agents may have additive effects.
  • AntihistaminesAntihistamines: In vitro, a polyherbal formulation (Aller-7/NR-A2) containing extracts from seven medicinal plants, including Piper nigrum, inhibited rat mesenteric mast cell degranulation, activity of lipoxygenase and hyaluronidase, and histaminic activity, and had an antispasmodic effect on contractions of guinea pig tracheal chain (19). The effects of black pepper with antihistamines are not well understood.
  • Anti-inflammatory herbsAnti-inflammatory herbs: Based on animal study, the benzene, chloroform, and ethanol extracts of leaf galls of Piper nigrum resulted in anti-inflammatory activity for carrageenan-induced acute inflammation in albino rats (207). Based on animal study, oral administration of a methanolic extract of Piper nigrum leaf resulted in inhibition in an immediate-phase and late-phase cutaneous swelling, potentially due to inhibition of histamine release (28). Based on animal study, piperine had anti-inflammatory effects in various inflammatory models (29; 30; 31). Based on animal study, a polyherbal formulation (Aller-7/NR-A2) containing extracts from seven medicinal plants, including Piper nigrum, demonstrated 31.3% inhibition against carrageenan-induced acute inflammation in Wistar albino rats, while ibuprofen (50 mg/kg orally) exerted 68.1% inhibition (18). Based on animal study, the ED50 was lower in piperine-treated animals vs. animal treated with nimesulide alone, with superior anti-inflammatory effects (208). In animal study, trikatu (an Ayurvedic prescription containing dried fruits of Piper nigrum and other spices) reduced the bioavailability of diclofenac sodium (74).
  • AntilipemicsAntilipemics: In animals, piperine reduced plasma lipids and lipoproteins levels, increased levels of HDL-cholesterol, and improved levels of apo A-1 and apo B (43; 44) and inhibited acyl-CoA:cholesterol acyltransferase (ACAT) activity (209; 210). Theoretically, concurrent use of black pepper and antilipemic agents may have additive effects.
  • AntineoplasticsAntineoplastics: Based on reviews and case-controlled study, there may be a link between ingestion of black pepper and nasopharyngeal or esophageal cancer (15; 16; 17). In vitro, piperine protected cells from cisplatin-induced apoptosis (211). In animal study, piperine increased tumor growth inhibition and reduced leukemia in 5-fluorouracil treated animals (212). In animal study, black pepper or its extract reduced the incidence of tumors and metastasis in carcinogen-stimulated animals (213; 214; 215). The effects of black pepper and antineoplastic agents are not well understood.
  • AntioxidantsAntioxidants: In animal study, Piper nigrum had antioxidant potential against the free radical 2,2'-azinobis-(3-ethylbenzothiazoline-6-sulphonic acid) (ABTS); in combination with other spices (in Amrita Bindu) it also offered antioxidant potential (233). In animal study, black pepper and piperine protected erythrocytes from oxidative stress and reduced oxidative stress associated with a high-fat diet (reduced TBARS, conjugated dienes, and maintained superoxide dismutase, catalase, glutathione peroxidase, and glutathione S transferase, and reduced glutathione) (33; 34). Theoretically, concurrent use of black pepper and antioxidants may have additive effects.
  • AntiparasiticsAntiparasitics: In vitro, essential oil of black pepper had antiparasitic effects against Dermanyssus gallinae (red mite) (59). In vitro, piperine had antiparasitic effects against Trypanosoma cruzi, which involved ultrastructural alterations (60; 61). In animal study, piperine had antiparasitic effects against Leishmania species (62; 63; 64). In animal study, black pepper extract and piperine demonstrated anti-amebic activity for cecal amoebiasis (58). In vitro, Piper nigrum exhibited strong antinematodal activity against Bursaphelenchus xylophilus (216). The effects of black pepper and antiprotozoal agents are not well understood.
  • Beta-caroteneBeta-carotene: In human study, black pepper extract (98% piperine) increased plasma levels of beta-carotene over beta-carotene alone (234).
  • CapsaicinCapsaicin: In human study, piperine applied to the tongue induced stimulus recovery under conditions of cross-sensitization with capsaicin (235; 236).
  • Cardiac glycosidesCardiac glycosides: Based on in vitro study, piperine may inhibit digoxin transport in intestinal cells (72).
  • Centella asiatica (gotu kola)Centella asiatica (gotu kola): In animal study, the combination of methanolic extracts of Piper nigrum and Centella asiatica increased activity of Centella asiatica, suggesting improved bioactivity in the presence of Piper nigrum (237).
  • Cholinergic herbsCholinergic herbs: Based on in vitro study, extracts of Piper nigrum L. seeds may inhibit acetylcholinesterase (5). Theoretically, black pepper may interfere with the effects of cholinergic agonists.
  • Coenzyme Q10Coenzyme Q10: In human study, black pepper extract (98% piperine) increased plasma levels of coenzyme Q10 over coenzyme Q10 alone (238).
  • CurcuminCurcumin: In human study, a combination of piperine and curcumin resulted in a reduction in erythrocyte malondialdehyde levels in patients with tropical pancreatitis (239). Piperine acts as a bioavailability enhancer for curcumin, but bioavailability is not as good as that seen with curcumin encapsulated in nanoparticles (240). Addition of piperine to curcumin for efficacy study in animal models suggests piperine increases its absorption and efficacy in some (241; 242; 243), but not all (244) studies. According to a review, piperine might increase curcumin bioavailability by interfering with glucuronidation (245).
  • Cytochrome P450 metabolized herbs and supplementsCytochrome P450 metabolized herbs and supplements: In in vitro and animal study, extracts of and constituents isolated from Piper nigrum, including piperine and dipiperamides D and E, potently inhibited some CYP450 metabolic pathways, including CYP2D6 (71; 80; 81), CYP3A4 (72; 73; 81; 82; 97), CYP2B1 (83; 84), CYP1A1 (85), CYP2E1 (86), arylhydrocarbon hydroxylase, and 7-ethoxycourmarin deethylase (87; 88). P4502B and 1A expression were enhanced in rats (86). This has been also discussed in a review (218). Theoretically, black pepper may increase the levels of drugs metabolized by cytochrome P450.
  • Echinacea angustifoliaEchinacea angustifolia: Black pepper was added to a nutritional dental supplement, containing folic acid, vitamin B12, vitamin C, Echinacea angustifolia, grape seed, and coenzyme Q10, in order to increase bioavailability of these ingredients (246), based on earlier study suggesting increased nutrient bioavailability in the presence of Bioperine? (234).
  • Eclipta alba (false daisy)Eclipta alba (false daisy): In animal study, the combination of methanolic extracts of Piper nigrum and Eclipta alba increased activity of Eclipta alba, suggesting improved bioactivity in the presence of Piper nigrum (237).
  • (-)-Epigallocatechin-3-gallate (EGCG)(-)-Epigallocatechin-3-gallate (EGCG): Based on study in mice, piperine from black pepper may enhance the bioavailability of EGCG, a polyphenol constituent from green tea (Camellia sinensis) (247).
  • Fertility agentsFertility agents: In animal study, piperine has had various negative effects on fertility in males, including alterations in enzyme levels, changes in lipid peroxidation, decreases in weight of testes and other sex organs, and damage to developing sperm (95; 96; 97). In females, negative effects of piperine included decreased mating performance and fertility (98). In superovulated female hamsters intragastrically treated with piperine, the percent fertilized following artificial insemination was increased (219). The effects of black pepper and fertility agents are not well understood.
  • Ferulic acidFerulic acid: A combination of Piper nigrum and Angelica sinensis increased the relative bioavailability of ferulic acid (248).
  • Folic acidFolic acid: Black pepper was added to a nutritional dental supplement containing folic acid, vitamin B12, vitamin C, Echinacea angustifolia, grape seed, and coenzyme Q10, in order to increase the bioavailability of these ingredients (246), based on earlier study suggesting increased nutrient bioavailability in the presence of Bioperine? (234).
  • Gallic acidGallic acid: In animal study, a combination of piperine and gallic acid had additive protective effects on beryllium-induced biochemical alterations and oxidative stress involved in hepatotoxicity (249).
  • Grape seedGrape seed: Black pepper was added to a nutritional dental supplement containing folic acid, vitamin B12, vitamin C, Echinacea angustifolia, grape seed, and coenzyme Q10, in order to increase the bioavailability of these ingredients (246), based on earlier study suggesting increased nutrient bioavailability in the presence of Bioperine? (234).
  • Green tea (Camellia sinensis)Green tea (Camellia sinensis): Based on study in mice, piperine from black pepper may enhance the bioavailability of EGCG, a polyphenol constituent from green tea (Camellia sinensis) (247).
  • Hepatotoxic herbsHepatotoxic herbs: In animal study, piperine potentiated carbon tetrachloride-induced hepatotoxicity, potentially by increasing the activity of NADPH-cytochrome c reductase (108). Theoretically, concurrent use of black pepper and hepatotoxic agents may increase the risk of liver damage.
  • HypoglycemicsHypoglycemics: In animal study, black pepper lowered blood glucose (44; 106). Theoretically, concurrent use of black pepper with antidiabetic agents may have additive glucose-lowering effects and increase the risk of hypoglycemia.
  • HypotensivesHypotensives: In animal study, intravenous piperine had hypotensive effects (105). Theoretically, concurrent use of black pepper with antihypertensive agents may have additive blood pressure-lowering effects and increase the risk of hypotension.
  • ImmunosuppressantsImmunosuppressants: In animal and in vitro study, piperine, a constituent of black pepper, improved or returned to normal various immunological endpoints such as cell viability, oxidative stress, apoptotic markers, cell proliferative response, T and B cell phenotype changes, and cytokine release, following treatment with the immunotoxicant cadmium (99; 100; 101; 102). In vitro piperine inhibits adhesion of neutrophils to endothelial monolayer; this is potentially due to its ability to block tumor necrosis factor-alpha (TNF-alpha)-induced expression of cell adhesion molecules such as ICAM-1 (intercellular adhesion molecule-1), VCAM-1 (vascular cell adhesion molecule-1), and E-selectin (103). Theoretically, black pepper may interfere with the effects of immunosuppressants.
  • InotropesInotropes: In animal study, piperine exerted positive chronotropic and inotropic effects in the isolated spontaneously beating right atria and electrically driven left atria; the calcitonin gener-related peptide was involved (222; 223). Theoretically, concurrent use of black pepper and inotropes may have additive effects.
  • P-glycoprotein modulatorsP-glycoprotein modulators: In animal study, piperine may alter p-glycoprotein levels (225) and activity (226). In vitro, piperine had p-glycoprotein inhibitory (227; 225; 72) or biphasic activity (stimulation at low and inhibitory at high concentrations) (228). Theoretically, black pepper may increase levels of p-glycoprotein substrates.
  • ProbioticsProbiotics: In vitro, aqueous extracts of black peppercorns increased the growth of the probiotic bacteria L. reuteri (250).
  • SedativesSedatives: Based on animal study, piperine potentiated pentobarbitone sleeping time and blood and brain levels of the drug (94). There was no effect on barbital sodium. Theoretically, concurrent use of black pepper and sedatives may have additive effects.
  • RhodiolaRhodiola: In animal study, the combination of piperine and rhodiola extract reduced the activity of the rhodiola extract (251).
  • Thyroid agentsThyroid agents: In animals fed a high-fat diet, piperine improved levels of T3, T4, and TSH (43; 106). Theoretically, black pepper may interfere with thyroid hormones.
  • Vitamin B12Vitamin B12: Black pepper was added to a nutritional dental supplement containing folic acid, vitamin B12, vitamin C, Echinacea angustifolia, grape seed, and coenzyme Q10, in order to increase the bioavailability of these ingredients (246), based on earlier study suggesting increased nutrient bioavailability in the presence of Bioperine? (234).
  • Vitamin CVitamin C: Black pepper was added to a nutritional dental supplement, containing folic acid, vitamin B12, vitamin C, Echinacea angustifolia, grape seed, and coenzyme Q10, in order to increase bioavailability of these ingredients (246), based on earlier study suggesting increased nutrient bioavailability in the presence of Bioperine? (234).
  • UDP substratesUDP substrates: In vitro, piperine slightly down-regulated gene expression of UDP glucose dehydrogenase (76) and inhibited UDP-glucose dehydrogenase and glucuronidation activities in liver and intestine (77; 78), suggesting a role in elimination of various drugs.

    • Black pepper/Food Interactions:

  • GeneralGeneral: Based on a review, consumption of black pepper may lead to greater satiety (57).
  • ProteinProtein: In animal study, protein digestibility and biological value of the protein were increased in combination with a mixture of spices including Piper nigrum (252; 253).

    • Black pepper/Lab Interactions:

  • AdrenalineAdrenaline: In human study, inhalation of pepper oil increased plasma adrenaline (254).
  • Beta-caroteneBeta-carotene: In human study, black pepper extract (98% piperine) increased plasma levels of beta-carotene over beta-carotene alone (234).
  • Blood glucoseBlood glucose: In alloxan-induced diabetic animals, an aqueous extract of black pepper seeds resulted in a lowering of blood sugar (44). In animal study, piperine lowered the serum levels of glucose (106).
  • Blood pressureBlood pressure: Based on animal study, piperine may reduce blood pressure (105).
  • Carbamazapine levelsCarbamazapine levels: In epilepsy patients, piperine significantly increased the mean plasma concentrations of carbamazepine, as well as area under the curve, Cmax, and Tmax (92).
  • Coagulation panelCoagulation panel: Based on in vitro reports, piperine inhibited platelet aggregation (70).
  • Coenzyme Q10Coenzyme Q10: In human study, black pepper extract (98% piperine) increased plasma levels of coenzyme Q10 over coenzyme Q10 alone (238).
  • CurcuminCurcumin: Addition of piperine to curcumin for efficacy study in animal model suggests piperine increased its absorption and efficacy in some (241; 242; 243), but not all (244) studies.
  • Cyclosporine levelsCyclosporine levels: Based on in vitro study, piperine may inhibit cyclosporine transport in intestinal cells (72).
  • Drug assaysDrug assays: Based on clinical study of intestinal peristalsis in 16 healthy volunteers, consumption of black pepper may increase orocecal transit time (79). Based on in vitro study, constituents isolated from Piper nigrum, including piperine and dipiperamides D and E, may potently inhibit some CYP450 metabolic pathways, including CYP2D6 (71) and CYP3A4 (72; 73). In animal study, piperine may alter p-glycoprotein levels (225) and activity (226). In vitro, piperine has p-glycoprotein inhibitory (227; 225; 72) or biphasic activity (stimulation at low and inhibitory at high concentrations) (228). Theoretically, black pepper may increase levels of p-glycoprotein substrates.
  • Diclofenac sodiumDiclofenac sodium: In animal study, trikatu (an Ayurvedic prescription containing dried fruits of Piper nigrum and other spices) reduced the bioavailability of diclofenac sodium (74).
  • DigoxinDigoxin: Based on an in vitro study, piperine from black pepper may inhibit digoxin transport in intestinal cells (72).
  • Eclipta alba (false daisy)Eclipta alba (false daisy): In animal study, the combination of methanolic extracts of Piper nigrum and Eclipta alba increased activity of Eclipta alba, suggesting improved bioactivity in the presence of Piper nigrum (237).
  • (-)-Epigallocatechin-3-gallate (EGCG)(-)-Epigallocatechin-3-gallate (EGCG): Based on study in mice, piperine from black pepper may enhance the bioavailability of EGCG, a polyphenol constituent from green tea (Camellia sinensis) (247).
  • Ferulic acidFerulic acid: A combination of Piper nigrum and Angelica sinensis increased the relative bioavailability of ferulic acid (248).
  • HexosamineHexosamine: In animal study of metastases, piperine reduced lung hexosamine levels (215).
  • HydroxyprolineHydroxyproline: In animal study of metastases, piperine reduced lung collagen hydroxyproline (215).
  • Gamma-glutamyl transpeptidaseGamma-glutamyl transpeptidase: In animal study of metastases, piperine reduced serum activity of gamma-glutamyl transpeptidase activity (215).
  • Immune panelImmune panel: In animal and in vitro study, piperine, a constituent of black pepper, improved or returned to normal, various immunological endpoints such as cell viability, oxidative stress, apoptotic markers, cell proliferative response, T and B cell phenotype changes, and cytokine release, following treatment with the immunotoxicant cadmium (99; 100; 101; 102). Based on animal study, piperine, a constituent of black pepper, may result in a reduction of tumor necrosis factor-alpha (TNF-alpha) (104). In vitro piperine inhibits adhesion of neutrophils to endothelial monolayer; this is potentially due to its ability to block TNF-alpha-induced expression of cell adhesion molecules such as ICAM-1 (intercellular adhesion molecule-1), VCAM-1 (vascular cell adhesion molecule-1), and E-selectin (103).
  • InsulinInsulin: In animals fed a high-fat diet resulting in negative effects on insulin, piperine beneficially improved the plasma levels of insulin (43).
  • Lipid profileLipid profile: In animals, piperine reduced plasma lipids and lipoproteins levels, increased levels of HDL-cholesterol, and improved levels of apo A-1 and apo B (43; 44) and inhibited acyl-CoA:cholesterol acyltransferase (ACAT) activity (209; 210).
  • NevirapineNevirapine: In human study, piperine increased area under the curve of nevirapine (75).
  • Nitric oxideNitric oxide: Based on animal study, piperine, a constituent of black pepper, may result in a reduction of nitrite (104).
  • PefloxacinPefloxacin: In animal study, trikatu (an Ayurvedic prescription containing dried fruits of Piper nigrum and other spices) increased the area under the curve and volume of distribution of pefloxacin (93)
  • PentobarbitonePentobarbitone: Based on animal study, piperine potentiated pentobarbitone sleeping time and blood and brain levels of the drug (94). There was no effect on barbital sodium.
  • PhenytoinPhenytoin: Based on animal and clinical trials, piperine from black pepper (Piper nigrum L.) may enhance the bioavailability of phenytoin significantly, possibly by increasing its absorption (89; 90; 91).
  • PropranololPropranolol: Based on a study in healthy volunteers, piperine may increase the bioavailability of propranolol (90; 230).
  • Rifamipicin (rifampin)Rifamipicin (rifampin): Based on a study in patients with pulmonary tuberculosis, piperine may increase plasma concentrations of rifamipicin (rifampin) (90). In animal study, trikatu (an Ayurvedic prescription containing dried fruits of Piper nigrum and other spices) reduced the Cmax and plasma levels of rifampin (232).
  • SerotoninSerotonin: In animal study, piperine stimulated serotonin synthesis (255).
  • Sialic acidSialic acid: In animal study of metastases, piperine reduced serum levels of sialic acid (215).
  • Substance PSubstance P: In animal and in vitro study, piperine resulted in substance P release (256; 257).
  • TestosteroneTestosterone: In animals fed a high-fat diet resulting in negative effects on hormone levels, piperine beneficially improved the plasma levels of testosterone (43). In vitro, the aqueous ethanolic Piper nigrum leaf extract resulted in inhibition of testosterone 5-alpha-reductase, and in animal study this extract had antiandrogenic activity, as observed using a hair growth assay in testosterone sensitive male mice (220).
  • TheophyllineTheophylline: Based on a study in healthy volunteers, piperine may increase the bioavailability of theophylline (90; 230).
  • Thyroid function testsThyroid function tests: In animals fed a high-fat diet, piperine improved levels of T3, T4, and TSH (43).
  • Uronic acidUronic acid: In animal study of metastases, piperine reduced tissue levels of uronic acid (215).