Traditionally used for
- Teeth & mouth
- Cough & breathing
- Digestion
- Bowel health
- Pain & joints
Cautions & contraindications
- Bleeding disorders
☯ TCM Properties
Warms the Interior and Dispels Cold; Moves Qi and Alleviates Pain; Stops vomiting and checks diarrhea
Traditional Chinese Uses
Bi Ba (long pepper) is a hot, pungent herb used in Chinese medicine to warm the Stomach and Spleen, dispel cold from the interior, and relieve cold-type abdominal pain, nausea, vomiting, and diarrhea. Its intensely hot, penetrating nature makes it particularly effective when cold in the digestive system is severe and stubborn. It is also used topically for toothache from cold invasion of the dental channels. While similar in action to dried ginger, long pepper's hotter, more penetrating quality makes it useful where greater warmth is required.
Western Herbalism Properties
Relationships
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Botanical Description
Piper longum, long pepper or Bi Ba, is a slender, climbing or trailing perennial shrub in the Piperaceae, native to the foothills of the Indian subcontinent and parts of Southeast Asia. The stems are jointed and woody at the base, producing aerial roots at the nodes by which the plant climbs over rocks, trees and supports. Leaves are alternate, simple, broadly ovate to cordate, 5 to 10 cm long, with a heart-shaped base, prominent palmate venation and a glabrous, dark green upper surface. The plant is dioecious; the female inflorescence is a dense, cylindrical, sessile spike 2 to 4 cm long that matures into the commercial drug, a greyish-black, hard, catkin-like aggregate fruit composed of numerous minute, fused single-seeded berries. The mature fruits are intensely pungent and aromatic, owing to high concentrations of the alkaloid piperine and the essential oil. Bi Ba is widely cultivated in India, China, Sri Lanka and Indonesia for medicinal and culinary use.
Active Constituents
Piperine
Piperidine alkylamide alkaloidConcentration: The principal alkaloid of the fruit spike, but present at a lower level than in Piper nigrum; simultaneous quantification of five alkaloids in both species found Piper longum lower in piperine and enriched in the other four
The single most clinically important constituent of this drug, and not because of what it treats. Piperine inhibits human P-glycoprotein and CYP3A4 directly: in Caco-2 monolayers it inhibited P-gp-mediated transport of digoxin and ciclosporin A with IC50 values of 15.5 and 74.1 microM, and in human liver microsomes it inhibited CYP3A4-catalysed verapamil metabolism in a mixed fashion with Ki values of 36 to 77 microM. Because both proteins sit in enterocytes and hepatocytes and dominate first-pass extraction, a 20 mg oral dose of piperine measurably raises the systemic exposure of a wide range of co-administered drugs in humans. It also inhibits hepatic and intestinal glucuronidation.
Piperlonguminine
Isobutylamide alkaloidConcentration: One of the four alkaloids in which Piper longum is enriched relative to Piper nigrum
A characteristic alkaloid of this species rather than of black pepper, and one of the markers that chemically distinguishes the two drugs. Its own pharmacology is far less studied than piperine's.
Delta-alpha,beta-Dihydropiperlonguminine
Isobutylamide alkaloidQuantified alongside piperine, piperlonguminine, pellitorine and piperanine as one of the five characteristic constituents used to profile this drug; enriched in Piper longum relative to Piper nigrum.
Pellitorine
Alkylamide (isobutylamide)Contributes to the tingling pungency of the fruit spike and is one of the five marker alkaloids in validated quantification methods for this drug.
Piperanine
Piperidine alkylamide alkaloidA dihydro analogue of piperine; the fifth of the marker alkaloids, and again more abundant in Piper longum than in Piper nigrum.
Piperlongumine (piplartine)
Alpha,beta-unsaturated amide alkaloidThe species-defining amide of Piper longum, essentially absent from black pepper. It is an electrophilic Michael acceptor and the subject of an extensive preclinical anticancer literature based on selective induction of oxidative stress in tumour cells. None of this has been tested in humans, and its reactivity is a reason not to treat concentrated extracts of this fruit as equivalent to the culinary spice.
Sesamin
Furofuran lignanA lignan reported from the fruit; of interest mainly because lignans of this class are themselves weak CYP modulators and add to the drug's overall interaction potential.
⚠ Drug Interactions
Phenytoin
Two independent human crossover studies show it. Piperine 20 mg daily for seven days followed by a single 300 mg phenytoin dose altered phenytoin pharmacokinetics in healthy volunteers. In a separate crossover in six healthy volunteers, a single 300 mg phenytoin tablet given 30 minutes after a soup made with black pepper significantly increased the absorption rate constant, AUC to 48 h and AUC to infinity, and delayed phenytoin elimination; intravenous phenytoin in piperine-pretreated rats showed altered elimination, indicating metabolic blockade rather than an absorption artefact alone. Phenytoin has zero-order kinetics near the therapeutic range, so a modest rise in exposure can produce a disproportionate rise in level.
Clinical note: Treat as a genuine contraindication in practice. Do not add Bi Ba, Trikatu, or any piperine-standardised bioavailability enhancer to a phenytoin regimen. If a patient has been taking it, check a phenytoin level before and after stopping, and warn them that stopping the herb can drop the level as sharply as starting it raised it.
Carbamazepine
Demonstrated in patients, not just volunteers. In twenty poorly controlled epilepsy patients on carbamazepine monotherapy at 300 mg or 500 mg twice daily, a single 20 mg oral dose of piperine significantly raised mean plasma carbamazepine at most time points, with significant increases in AUC over 12 h and average steady-state concentration, a longer elimination half-life and a lower elimination rate constant in both dose groups. In healthy volunteers given piperine 20 mg daily for ten days, a single 200 mg carbamazepine dose showed Cmax up 68.7 percent, AUC up 47.9 percent and half-life up 43.2 percent, with apparent oral clearance down 38.9 percent and a fall in the carbamazepine-epoxide to carbamazepine ratio, pointing to CYP3A4 inhibition.
Clinical note: Avoid the combination. Carbamazepine has a narrow window and the observed effect size is large enough to move a controlled patient into toxicity. If unavoidable, carbamazepine levels must be monitored and the dose reduced with specialist input.
P-glycoprotein substrates (digoxin, fexofenadine, ciclosporin, dabigatran, apixaban)
Piperine inhibits human P-glycoprotein, shown directly in Caco-2 monolayers against digoxin (IC50 15.5 microM) and ciclosporin A (IC50 74.1 microM), and confirmed clinically. In twelve healthy volunteers, piperine 20 mg once daily for ten days raised the Cmax of a single 120 mg dose of the P-gp probe fexofenadine from 406.9 to 767 ng/mL and its AUC from 3403.7 to 5724.7 ng.h/mL, while apparent oral clearance fell from 35.4 to 20.7 L/h, with no change in half-life or renal clearance, exactly the signature of reduced intestinal efflux. Digoxin and the direct oral anticoagulants dabigatran and apixaban are P-gp substrates with clinically consequential exposure-response relationships.
Clinical note: Avoid in patients on digoxin, ciclosporin, tacrolimus, dabigatran or apixaban. This applies not only to the crude drug but to any Trikatu or piperine-standardised supplement the patient may be taking on top of your prescription; ask about them explicitly.
CYP3A4 substrates generally (verapamil, midazolam, statins, calcium channel blockers, many oncology agents)
In human liver microsomes piperine inhibited CYP3A4-catalysed formation of the verapamil metabolites D-617 and norverapamil in a mixed fashion, with Ki values of 36 and 49 microM in one liver and 44 and 77 microM in another. CYP3A4 handles a large share of marketed drugs, and the enzyme's intestinal expression means first-pass extraction is the step most vulnerable to a luminal inhibitor arriving with food. The carbamazepine volunteer study provides the in vivo confirmation, with a fall in the epoxide-to-parent ratio.
Clinical note: Review the whole medication list before prescribing this herb, not just the obvious candidates. Where a CYP3A4-dependent drug with a steep dose-response is involved, choose a different warming interior herb such as Gan Jiang or Rou Gui.
Diclofenac and other CYP2C9 substrates (warfarin, phenytoin, glipizide, losartan)
In twelve healthy volunteers, piperine 20 mg once daily for ten days raised the Cmax of a single 100 mg diclofenac dose from 2.24 to 3.68 microg/mL and AUC from 7.09 to 11.81 microg.h/mL, with half-life up from 1.23 to 1.65 h and apparent oral clearance down from 7.57 to 4.52 L/h, all significant. The authors attributed it to inhibition of CYP2C9. Warfarin's more potent S-enantiomer is a CYP2C9 substrate, so the same mechanism predicts a rise in INR, although no piperine-warfarin study has been done.
Clinical note: Use caution with NSAIDs, sulfonylureas and especially warfarin. If a warfarinised patient takes this herb, check INR within a week of starting and again after stopping.
Propranolol and theophylline
In a crossover study, six subjects per group took a single oral dose of propranolol 40 mg or theophylline 150 mg alone or with piperine 20 mg daily for seven days. Piperine gave an earlier tmax and higher Cmax and AUC for propranolol, and a higher Cmax, longer elimination half-life and higher AUC for theophylline. The original authors framed this as an opportunity to reduce doses; for a practitioner adding a herb to an existing stable regimen it is a hazard, because theophylline toxicity is arrhythmogenic and convulsant.
Clinical note: Avoid in patients on theophylline. With propranolol, watch for bradycardia and hypotension if the herb is started or stopped.
Curcumin and other poorly bioavailable co-prescribed herbs
The magnitude here is the point. After 2 g of curcumin alone, human serum levels were undetectable or very low; with 20 mg of piperine given concomitantly, concentrations were far higher from 0.25 to 1 h and bioavailability rose by 2000 percent, with no adverse effects reported at these doses. The mechanism is inhibition of hepatic and intestinal glucuronidation. Whenever this drug appears in a formula, it is changing the exposure of everything else in it, herb and drug alike.
Clinical note: Do not assume a formula containing Bi Ba behaves like the sum of its parts. When adding or removing it from an established prescription, expect the effective strength of the rest of the formula to change, and re-titrate rather than holding doses fixed.
Piper nigrum (Hu Jiao) and Piper sarmentosum fruit spikes
Two separate identity problems. First, Bi Ba is routinely conflated with black pepper in interaction discussions, but validated simultaneous quantification of five alkaloids in both species found Piper longum lower in piperine and enriched in piperlonguminine, dihydropiperlonguminine, pellitorine and piperanine, and Piper longum alone carries piperlongumine. Interaction data generated with purified piperine or with black pepper therefore transfers directionally but not quantitatively. Second, the fruit spike of Piper sarmentosum is described in Chinese herb-identification practice as a substitute encountered in trade: it is shorter (0.8 to 2 cm against 1.5 to 3.5 cm), lacks the stalk at the base, has irregularly arranged berries without the neat oblique rows of bracts, and is only faintly aromatic without the numbing pungency of genuine Bi Ba.
Clinical note: Check that spikes are 1.5 to 3.5 cm, stalked, with regularly arranged surface protrusions, and that they are strongly aromatic and numbing on tasting. Do not reason about interactions from black pepper data as though the two drugs were the same.
Dosage
| Form | Amount | Frequency | Duration | Population | Notes |
|---|---|---|---|---|---|
| decoction, or powder/pills | 1–3 g | Daily | — | — | 中国药典 2020 【用法与用量】1～3g。外用适量，研末塞龋齿孔中。 【性味与归经】辛，热。归胃、大肠经。 — Chinese Pharmacopoeia 2020, quoted verbatim; route and cautions preserved. Replaces a cleared category-filler value. |
Evidence Tier
Moderate evidence · 9 studiesRecorded studies by study design, strongest design at the top. This is a study-design tier only, not a GRADE rating: it does not weigh risk of bias, consistency or precision.
Systematic review / meta-analysis
0
Randomized controlled trial
0
Other clinical trial
3
3 verified · 0 unverified
Show 3 studies
Observational / case report
4
0 verified · 4 unverified
Show 4 studies
- The influence of piperine on the pharmacokinetics of fexofenadine, a P-glycoprotein substrate, in healthy volunteers
- Study on influence of piperine treatment on the pharmacokinetics of diclofenac in healthy volunteers
- Piperine in food: Interference in the pharmacokinetics of phenytoin
- Effect of piperine on bioavailability and pharmacokinetics of propranolol and theophylline in healthy volunteers
In vitro / animal
2
0 verified · 2 unverified
Other / unclassified
0
Verified: design read from PubMed for a DOI that resolves to the cited paper Unverified: taken from the study's recorded description
Clinical Studies
Pharmacokinetic interaction of single dose of piperine with steady-state carbamazepine in epilepsy patients
Twenty poorly controlled epilepsy patients on carbamazepine monotherapy, ten on 300 mg twice daily and ten on 500 mg twice daily, were sampled over 12 h on carbamazepine alone and again after a single 20 mg oral dose of piperine. Piperine significantly raised mean plasma carbamazepine at most time points in both dose groups, with significant increases in AUC over 12 h, average steady-state concentration and elimination half-life and a fall in the elimination rate constant. Cmax and tmax rose significantly only in the 500 mg group. This is the interaction demonstrated in the patient population that would actually be harmed by it.
Effect of Piperine on the Metabolism and Pharmacokinetics of Carbamazepine in Healthy Volunteers
Open-label two-period sequential study in twelve healthy volunteers. Piperine 20 mg once daily for ten days raised the Cmax, AUC and half-life of a single 200 mg carbamazepine dose by 68.7, 47.9 and 43.2 percent, and lowered the elimination rate constant and apparent oral clearance by 23.8 and 38.9 percent. The carbamazepine-epoxide to carbamazepine ratio fell for both Cmax and AUC, identifying CYP3A4 inhibition as the mechanism rather than improved absorption alone.
The influence of piperine on the pharmacokinetics of fexofenadine, a P-glycoprotein substrate, in healthy volunteers
Twelve healthy volunteers took a single 120 mg dose of the P-glycoprotein probe fexofenadine before and after ten days of piperine 20 mg daily. Cmax rose from 406.9 to 767 ng/mL and AUC from 3403.7 to 5724.7 ng.h/mL, apparent oral clearance fell from 35.4 to 20.7 L/h, and half-life and renal clearance were unchanged. The pattern is diagnostic of reduced intestinal P-glycoprotein efflux and is the clinical confirmation of the Caco-2 data.
Study on influence of piperine treatment on the pharmacokinetics of diclofenac in healthy volunteers
Open-label two-period sequential study in twelve healthy volunteers. Ten days of piperine 20 mg daily raised the Cmax of a single 100 mg diclofenac dose from 2.24 to 3.68 microg/mL and AUC from 7.09 to 11.81 microg.h/mL, extended half-life from 1.23 to 1.65 h and cut apparent oral clearance from 7.57 to 4.52 L/h, all significant. The authors attributed the change to CYP2C9 inhibition and described the interaction as clinically significant.
Piperine, a Major Constituent of Black Pepper, Inhibits Human P-glycoprotein and CYP3A4
The mechanistic anchor for every clinical piperine interaction. Piperine inhibited P-glycoprotein-mediated polarised transport of digoxin and ciclosporin A in Caco-2 monolayers with IC50 values of 15.5 and 74.1 microM, and inhibited CYP3A4-catalysed formation of the verapamil metabolites D-617 and norverapamil in human liver microsomes in a mixed fashion with Ki values of 36 plus or minus 8 and 49 plus or minus 6 microM in one liver and 44 plus or minus 10 and 77 plus or minus 10 microM in another. Both proteins are expressed in enterocytes and hepatocytes, which is why oral first-pass extraction is the step affected.
Piperine in food: Interference in the pharmacokinetics of phenytoin
Six healthy volunteers took a 300 mg phenytoin tablet 30 minutes after a soup prepared with or without black pepper, in crossover. Piperine increased the absorption rate constant, AUC to 48 h and AUC to infinity, and delayed phenytoin elimination. Companion work showed the same direction in mice and, importantly, that intravenous phenytoin in piperine-pretreated rats had an altered elimination phase, establishing metabolic blockade rather than absorption enhancement alone. That an ordinary peppered meal did this is the reason to take the herbal dose seriously.
Influence of Piperine on the Pharmacokinetics of Curcumin in Animals and Human Volunteers
In humans given 2 g of curcumin alone, serum levels were undetectable or very low; concomitant piperine 20 mg produced much higher concentrations from 0.25 to 1 h and raised bioavailability by 2000 percent, with no adverse effects. In rats the increase was 154 percent. The mechanism proposed is inhibition of hepatic and intestinal glucuronidation. The size of the effect is the reason piperine-containing drugs cannot be treated as pharmacologically neutral additions to a formula.
Effect of piperine on bioavailability and pharmacokinetics of propranolol and theophylline in healthy volunteers
Crossover study, six subjects per group, taking a single oral dose of propranolol 40 mg or theophylline 150 mg alone or with piperine 20 mg daily for seven days. Propranolol showed an earlier tmax and higher Cmax and AUC; theophylline showed a higher Cmax, longer elimination half-life and higher AUC. Small, but consistent with every later study and with the in vitro mechanism.
Identification and simultaneous quantification of five alkaloids in Piper longum L. by HPLC-ESI-MSn and UFLC-ESI-MS/MS and their application to Piper nigrum L.
A validated UFLC-ESI-MS/MS method quantifying piperine, piperlonguminine, dihydropiperlonguminine, pellitorine and piperanine in Piper longum and applied to Piper nigrum. The finding that matters for identity: compared with Piper nigrum, Piper longum had lower piperine content but was enriched in the other four alkaloids. The two pepper drugs are chemically distinguishable and should not be treated as interchangeable sources of piperine.
Historical Texts
Kai Bao Ben Cao (Materia Medica of the Kaibao Reign)
Northern Song dynasty, 973-974 CEZhongguo Yaodian (Pharmacopoeia of the People's Republic of China)
Current official standard, 2020 editionCharaka Samhita, Chikitsa Sthana, Rasayana Adhyaya, third pada (Karaprachitiya) - Pippali Vardhamana Rasayana
Ayurvedic classical period, compiled c. 1st-2nd century CETrikatu (the three pungents: Piper longum, Piper nigrum, Zingiber officinale), Ayurvedic classical formulary
Ayurvedic classical and medieval period, in continuous useReferences
- G. Bano; V. Amla; R. Raina; U. Zutshi; C. Chopra. The Effect of Piperine on Pharmacokinetics of Phenytoin in Healthy Volunteers . Planta Medica (1987) [DOI]
- M. K. Santosh; D. Shaila; I. Rajyalakshmi; I. Sanjeeva Rao. RP-HPLC Method for Determination of Piperine from Piper longum Linn. and Piper nigrum Linn . Journal of Chemistry (2005) [DOI]
- A. Khound; P.C. Barua; B. Saud; A. Saikia; S. Kumar. Piperine content variation in different Piper longum germplasms of North East India determined through RP-HPLC method . Journal of Applied and Natural Science (2017) [DOI]
This information is for educational purposes only and is not intended to replace professional medical advice. Always consult a qualified healthcare provider before using any herbal remedy, especially if you are pregnant, nursing, or taking medications.
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