Herb-Drug Interactions: Capsicum

Capsicum species (Solanaceae)

Synonym(s) and related species

Caspic, Cayenne, Cayenne pepper, Chili pepper, Chilli pepper, Hot pepper, Paprika, Red pepper, Tabasco pepper.

Capsicum annuum L., Capsicum baccatum L., Capsicum chinense Jacq., Capsicum frutescens L., Capsicum minimum Roxb., Capsicum pubescens Ruiz & Pavon.

Pharmacopoeias

Capsicum (British Ph 2009, European Ph 2008, US Ph 32); Capsicum Oleoresin (US Ph 32); Refined and Quantified Capsicum Oleoresin (British Ph 2009, European Ph 2008); Standardised Capsicum Tincture (British Ph 2009, European Ph, 6th ed., 2008 and Supplements 6.1, 6.2, 6.3 and 6.4).

Constituents

The pungent principles of capsicum are the capsaicinoids (to which it may be standardised), present in concentrations up to 1.5%, but more usually around 0.1%. The major components are capsaicin, 6,7-dihydrocapsaicin, nordihydrocapsaicin, homodihydrocapsaicin and homocapsaicin. Other constituents include the carotenoid pigments (capsanthin, capsorubin, carotene, lutein), vitamins including A and C, and a small amount of volatile oil.

Use and indications

Capsicum possesses stimulant, antispasmodic, carminative and counterirritant effects, which has led to its use in conditions such as colic and flatulent dyspepsia, and to increase peripheral circulation. Topical preparations are used for neuralgia including rheumatic pains and unbroken chilblains.

Capsicum is frequently eaten as part of the diet and, in particular, diets that contain spicy foods. It has been estimated that the average consumption of dietary spice from capsicum fruit is 2.5 g/person per day in India and 5 g/ person per day in Thailand. As the capsaicin content in capsicum fruit is approximately 1%, the daily dietary intake of capsaicin may range from 0.5 to 1 mg/kg per day for a 50 kg person.

Pharmacokinetics

In vitro study suggests that many of the cytochrome P450 enzymes are involved in the metabolism of capsaicinoids, by dehydrogenation, oxygenation, hydroxylation and O-demethylation. Principal isoenzymes thought to be involved are CYP2C9, CYP2E1 and to some extent CYP3A4.

Some metabolites of the capsaicinoids are thought to inhibit CYP2E1, and a study with phenazone, a probe drug for hepatic enzyme activity, suggests that capsaicin may inhibit hepatic enzymes, although the lack of interaction seen with theophylline, a substrate for CYP1A2, suggests that this isoenzyme is not significantly affected. A further in vitro study has shown that the acute use of capsaicin inhibits P-glycoprotein whereas long-term exposure induces P-glycoprotein, see digoxin.

Interactions overview

Capsicum has the potential to decrease the absorption of aspirin, increase the absorption of ciprofloxacin and theophylline, and alter the absorption of cefalexin and digoxin. However, the clinical effects of these changes are unknown, not established or not clinically significant. Capsicum may also decrease the metabolism of pentobarbital and phenazone, but it does not alter the metabolism of theophylline or quinine, which suggests that it has selective effects on hepatic enzymes.

Capsicum + Aspirin

The interaction between capsicum and aspirin is based on experimental evidence only.

Clinical evidence

No interactions found.

Experimental evidence

A study in rats given oral aspirin 20mg/kg found that the acute administration of a standardised extract of Capsicum annuum 100 mg/kg (equivalent to 10 mg/kg capsaicin) reduced the AUC and maximum serum levels of salicylic acid by 44% and 26%, respectively. The effect was dose related, with a 300-mg/kg dose of Capsicum annuum reducing the AUC and maximum serum levels of salicylic acid by 59% and 51%, respectively. Similar, but greater, results were found when aspirin was given to rats that had been treated with Capsicum annuum extract for 4 weeks.

Mechanism

It seems likely that capsaicin alters gastric motility, which reduces aspirin absorption and results in decreased salicylic acid levels.

Importance and management

Evidence is limited, but capsaicin appears to decrease aspirin bioavailability. However, the clinical significance of this effect is unclear, especially as the capsaicin dose used in the study is 10-fold greater than the expected dietary intake in countries where a spicy diet is typically eaten, and many times higher than the expected exposure if capsaicin is given as a cream, or ingested as a medicinal product. More study is needed before any clinical recommendations can be made.

Capsicum + Cefalexin

The interaction between capsicum and cefalexin is based on experimental evidence only.

Clinical evidence

No interactions found.

Experimental evidence

An in vitro study using animal tissue found that high concentrations of capsaicin instilled into rat intestines resulted in a lower rate of absorption of cefalexin.

Mechanism

It was suggested that the capsaicin affected the transport channels in the intestine through which cefalexin is absorbed.

Importance and management

Evidence appears to be limited to this study. Although the rate of cefalexin absorption was decreased the total amount of cefalexin absorbed was not studied, and therefore no conclusions can be drawn on the possible clinical relevance of the findings.

Capsicum + Ciprofloxacin

The interaction between capsicum and ciprofloxacin is based on experimental evidence only.

Clinical evidence

No interactions found.

Experimental evidence

A study in which rats were given oral ciprofloxacin 20 mg/kg with placebo, or capsaicin in concentrations of 0.01%, 0.1%, 0.5% or 1%, found that the maximum levels and AUC of ciprofloxacin increased with increasing concentrations of capsaicin up to 0.5%. The increase in AUC was 49%, 51%, 68% and 15% for capsaicin 0.01%, 0.1%, 0.5% or 1%, respectively.

Mechanism

It is possible that the irritant nature of the capsaicin increased blood flow to the gastrointestinal absorption site or, alternatively, the rate of gastric emptying was increased, so ciprofloxacin reached the duodenum more quickly, where the pH enhances its absorption.

Importance and management

Evidence appears to be limited to this study. The doses of the antibacterial and capsaicin were chosen to reflect those likely to be encountered clinically, and those encountered within dietary levels, respectively. Therefore if these findings are replicated in humans it seems possible that a clinically relevant rise in ciprofloxacin levels could occur; however, given the magnitude of the rise, the effect seems most likely to be beneficial rather than adverse, although more study is needed to establish this.

Capsicum + Digoxin

The interaction between capsicum and digoxin is based on experimental evidence only.

Clinical evidence

No interactions found.

Experimental evidence

In an in vitro study, P-glycoprotein function was assessed by looking at the transport of digoxin, a known substrate of this transporter protein. In the presence of capsaicin the transport of digoxin across cells was enhanced, suggesting that capsaicin induces P-glycoprotein.

Mechanism

Capsaicin may induce P-glycoprotein.

Importance and management

Evidence is limited and difficult to extrapolate to a clinical situation. The study found that the acute use of capsaicin inhibited P-glycoprotein, whereas long-term exposure induced P-glycoprotein. Clinically, P-glycoprotein induction has resulted in reduced digoxin absorption from the intestine and increased biliary excretion, the end result being a reduction in digoxin levels. Whether capsaicin would initially raise then subsequently lower digoxin levels remains to be established, but it may be prudent to consider the possibility of this effect if large doses of capsaicin are given systemically.

Capsicum + Food

No interactions found. Capsicum is widely used as a spice in food.

Capsicum + Herbal medicines

No interactions found.

Capsicum + Iron compounds

Capsicum modestly reduces the absorption of dietary iron.

Clinical evidence

In a randomised, crossover study, 30 healthy women were given a standard Thai meal (fortified with about 4 mg of isotopically labelled ferrous sulfate), with soup, to which 4.2 g of ground Capsicum annuum had been added. Capsicum annuum reduced iron absorption by about 38%.

Experimental evidence

No relevant data found.

Mechanism

Uncertain. It was thought that polyphenols in Capsicum annuum may inhibit iron absorption.

Importance and management

The study suggests that capsicum inhibits the absorption of dietary levels of iron. The levels of capsicum used were high, but they are not unusual in a typical Thai meal. However, the effects of capsicum on iron supplementation (e.g. ferrous sulfate in doses of 200 mg) does not appear to have been studied, so it is difficult to predict the effect of the use of capsicum as a herbal medicine on iron replacement therapy. However, consider this interaction if a patient taking capsicum supplements has a poor response to iron replacement therapy.

Capsicum + Pentobarbital

The interaction between capsicum and pentobarbital is based on experimental evidence only.

Clinical evidence

No interactions found.

Experimental evidence

In a placebo-controlled study, rats were given a single 10-mg/kg subcutaneous dose of capsaicin followed 6 hours later by pentobarbital. The sleeping time of rats in response to the pentobarbital was more than doubled by capsaicin.

Mechanism

It is thought that capsaicin may inhibit the cytochrome P450-mediated metabolism of pentobarbital.

Importance and management

Evidence is limited to this study in rats. If the findings are replicated in humans it seems likely that capsaicin could increase the response to pentobarbital. Therefore if patients taking pentobarbital are given systemic capsacicin it may be prudent to warn them that prolonged drowsiness may occur.

Capsicum + Phenazone (Antipyrine)

The interaction between capsicum and phenazone is based on experimental evidence only.

Clinical evidence

No interactions found.

Experimental evidence

In a placebo-controlled study, rats were given capsaicin 25 mg/kg daily for 7 days, followed by a single 10-mg intravenous dose of phenazone. It was found that capsaicin increased the half-life of phenazone by 28%, and increased the AUC of phenazone by 43%.

Mechanism

Capsaicin inhibits the metabolism of phenazone by hepatic enzymes.

Importance and management

Evidence is limited to this study in rats. Although rises in phenazone levels of this magnitude may be of clinical relevance, the dose of capsicum used in the study was very high, so it seems unlikely that these effects would be reproduced with clinical or dietary quantities of capsaicin.

Capsicum + Quinine

The information regarding the use of capsicum with quinine is based on experimental evidence only.

Clinical evidence

No interactions found.

Experimental evidence

In a placebo-controlled study, rats were given capsaicin 25 mg/kg daily for 7 days, followed by a single 25-mg/kg intravenous dose of quinine. It was found that capsaicin had no effect on the pharmacokinetics of quinine.

Mechanism

No mechanism expected.

Importance and management

The available evidence suggests that no pharmacokinetic interaction would be expected between capsaicin and quinine.

Capsicum + Theophylline

Although capsicum may slightly increase the absorption of theophylline, it does not appear to be clinically relevant.

Clinical evidence

A study in 6 healthy subjects found that the absorption of theophylline 400 to 500 mg was increased after they ate a spicy meal, when compared with a European standard meal: the AUC0-6 and AUC0-12 were increased by 23% and 15%, respectively.

Experimental evidence

In a study, rabbits were given a single intravenous 12-mg/kg dose of theophylline either with a single dose of ground capsicum suspension, or after 7 days of treatment with ground capsicum suspension. Capsicum did not affect the pharmacokinetics of theophylline, apart from a 40% increase in the elimination rate constant after the single dose of capsicum.

A previous study by the same authors found that a ground capsicum fruit suspension, given at the time of the theophylline dose and 11 hours later, increased the AUC of a 20-mg/kg oral dose of theophylline, and increased peak theophylline levels by 33%.

In contrast, a placebo-controlled study in rats given capsaicin 25 mg/kg daily for 7 days followed by a single 10-mg/kg intravenous dose of theophylline, given as aminophylline, found that capsaicin did not affect the pharmacokinetics of theophylline.

Mechanism

Capsaicin has been shown in animal studies to increase mesenteric blood flow, which may result in increased absorption of theophylline.

Importance and management

The evidence suggests that capsaicin has only modest effects on the pharmacokinetics of theophylline. The clinical study found an increase in the theophylline AUC of about 20%, which would not generally be expected to be clinically relevant. It would therefore appear that no specific additional precautions are necessary if patients taking theophylline also take capsaicin.