The reason piperine is in supplement stacks is exactly the reason it is on this page: it inhibits CYP3A4 and P-glycoprotein, so it raises the blood level of whatever it is sold alongside. "Enhanced bioavailability" and "drug interaction" are the same sentence read from two directions.
Also known as: piperine, Piper nigrum, long pepper, BioPerine. Category: seasoning.
What it does, mechanism by mechanism
CYP3A4 inhibition — inhibits, moderate
Slows the enzyme that metabolises roughly half of all prescription drugs. A CYP3A4 substrate taken with a CYP3A4 inhibitor reaches higher blood levels than its dose implies.
Volak et al. characterise piperine as a relatively SELECTIVE CYP3A4 inhibitor among the common spice constituents. Shoba et al. measured a 20-fold increase in curcumin bioavailability in humans from 20 mg piperine.
Blocks the efflux pump that ejects drugs back into the gut lumen and out of the brain. Raises absorption of P-gp substrates like digoxin, and can raise brain exposure independently of blood level.
Endocannabinoid transport inhibition — inhibits, moderate
Slows the movement of anandamide and 2-AG out of the synapse and into the cell. A third route to the same raised tone, and one that stacks with FAAH and MAGL inhibition because the mechanisms are separate. The transport mechanism itself is not settled science.
Guineensine, a separate pepper alkaloid from piperine, inhibits endocannabinoid membrane transport in the nanomolar range (reported EC50 near 290 nM) and does NOT inhibit FAAH or MAGL — a mechanistically clean case, and the reason black pepper appears on the endocannabinoid axis and not only the CYP one.
Activates the peripheral and immune-cell cannabinoid receptor. Not psychoactive. Relevant here because several very common dietary constituents do it, so it is a real pharmacology hiding in the spice rack rather than an exotic one.
Beta-caryophyllene is 7-35% of the essential oil and is a selective CB2 agonist with GRAS status as a food additive.
This list is what is IN the table. It is not the set of substances this interacts with — that set is
larger and partly unknown, and the mechanism is the thing to carry to a substance we have not listed.
A clean result means NO DOCUMENTED INTERACTION IN THIS DATASET. It does not mean safe, and it is not a clearance. Most substances are not in this dataset at all, and for many pairs that are, nobody has ever studied the combination.
Serotonergic drugs and the serotonin-toxicity mechanism
Dietary tyramine and L-dopa loads
The major cytochrome P450 pathways: CYP3A4, CYP2D6, CYP1A2, CYP2C9, CYP2C19 — inhibition and induction
P-glycoprotein inhibition and induction
11β-HSD2 inhibition (the licorice mechanism) and the potassium consequences that follow it
QT prolongation as an additive pharmacodynamic axis
Culinary seasonings and common foods with documented pharmacological activity
A selected set of narrow-therapeutic-index drugs where those shifts matter most
The endocannabinoid enzymes and transport: FAAH, MAGL, endocannabinoid membrane transport, CB1 and CB2
Additive CNS depression and GABA-A positive modulation — the alcohol / benzodiazepine / opioid / kava axis
The phytocannabinoids delta-9-THC, cannabidiol and the converted cannabinoids, as both substrates and inhibitors
Synthetic full CB1 agonists as a class, and why they are pharmacologically unlike cannabis
CYP2E1, and phase-2 glucuronidation and sulfation where a specific entry names them
The sedative and potentiator botanicals of the kava literature, and dietary L-dopa from Mucuna
Not in this dataset
Any substance not named in this dataset — which is most substances. There are tens of thousands of marketed drugs and this table holds fewer than a hundred entries.
Phase-2 conjugation (UGT, SULT, NAT2, COMT) except where a specific entry names it. The oilahuasca corpus turns heavily on phase 2 and this engine models it only in passing.
Pharmacogenomics. CYP2D6 and CYP2C19 are strongly polymorphic; a poor metaboliser and an ultra-rapid metaboliser can have opposite outcomes from the same pair, and this engine does not know your genotype.
Dose, timing, duration, formulation and route — all of which change whether a documented interaction is clinically real for you.
Renal and hepatic impairment, age, pregnancy, and body composition.
Bleeding and antiplatelet risk, hypoglycaemia, anticholinergic load, and most other pharmacodynamic axes beyond the ones listed above. Additive CNS depression and GABA-A modulation ARE now modelled — see the covers list — but the absence of a sedation finding still only means the agents you named are not on that axis in this dataset.
Herb–herb interactions outside the named entries, and essentially the whole botanical world: most plants have no interaction literature at all.
Allergy, intolerance, and contamination or adulteration of unregulated products.
Anything published after the last-reviewed date below.
Bleeding and antiplatelet risk, which is the mechanism that matters most for garlic, ginkgo and several other common supplements. It is not modelled at all, so a clean result says nothing about it.
Whether any of the natural FAAH, MAGL or transport inhibition reported in vitro occurs at all at a dose a person would take. For most of these compounds nobody has measured it.
The actual contents of an unregulated cannabinoid product. This engine models named compounds; an unidentified isomer or side-product in a converted-cannabinoid product is outside it by construction.
Dose. Every cannabinoid interaction here scales with dose, and consumer product labelling for this category is repeatedly found inaccurate in published surveys.
Inhalation-specific hazards — thermal degradation products, diluents chosen for rheology rather than for inhalation toxicology, and carrier and adulterant contamination.
101 substances, 33 mechanisms,
101 citations. Last reviewed .
Primary literature (every DOI resolved against the Crossref API) and FDA drug labelling. There is no free, openly-licensed, comprehensive drug-interaction dataset to draw on; NLM retired its Drug Interaction API on 2024-01-02 and DrugBank's interaction set is a commercial licence.
References
Bhardwaj RK, Glaeser H, Becquemont L, Klotz U, Gupta SK, Fromm MF (2002). Piperine, a Major Constituent of Black Pepper, Inhibits Human P-glycoprotein and CYP3A4. The Journal of Pharmacology and Experimental Therapeutics. doi:10.1124/jpet.102.034728
Volak LP, Ghirmai S, Cashman JR, Court MH (2008). Curcuminoids Inhibit Multiple Human Cytochromes P450, UDP-Glucuronosyltransferase, and Sulfotransferase Enzymes, whereas Piperine is a Relatively Selective CYP3A4 Inhibitor. Drug Metabolism and Disposition. doi:10.1124/dmd.108.020552
Shoba G, Joy D, Joseph T, Majeed M, Rajendran R, Srinivas PSSR (1998). Influence of Piperine on the Pharmacokinetics of Curcumin in Animals and Human Volunteers. Planta Medica. doi:10.1055/s-2006-957450
Nicolussi S, Viveros-Paredes JM, Gachet MS, et al. (2014). Guineensine is a novel inhibitor of endocannabinoid uptake showing cannabimimetic behavioral effects in BALB/c mice. Pharmacological Research. doi:10.1016/j.phrs.2013.12.010
Nicolussi S, Gertsch J (2015). Endocannabinoid transport revisited. Vitamins and Hormones. doi:10.1016/bs.vh.2014.12.011
Gertsch J, Leonti M, Raduner S, et al. (2008). Beta-caryophyllene is a dietary cannabinoid. PNAS. doi:10.1073/pnas.0803601105
Every DOI above was resolved against the Crossref API on 2026-09-09 and the returned
title checked against the one printed here. Three DOIs in the first draft resolved to real but different
papers and were corrected before publication.