Family

Solanaceae.

Related Species

Capsicum annuum L. var frutescens, Capsicum annuum L. var longum , Capsicum annuum L. var glabriusculum, (Dunal) Heiser and Pickersgill Capsicum minimum (Roxb). Typically, pungent varieties are classed as C. annuum and its varieties, whereas the nonpungent peppers are classed as C. frutescens .

Habitat and Cultivation

Native to Central America; naturalized to tropical and subtropical zones globally; now cultivated worldwide.

Parts Used

Dried ripe fruit.

Common Forms

• Dried:   Powdered fruit.

• Oleoresin:   Crude extract.

• Tincture:   Typically, 1:10 to 1:20, 60% to 90% ethanol.

• Topical:   Cream and ointments containing 0.02% to 0.05% capsaicinoids.

Overview

The widespread use of cayenne as a dietary ingredient contrasts with a relative lack of information about the clinical pharmacology of the whole herb. The crude herb extract, capsicum “oleoresin,” contains more than 100 different volatile components (many of which are not yet fully characterized) and must be distinguished from isolated capsaicin, which unlike the oleoresin, has been subject to considerable pharmacological research.

Activity of capsaicin and its congeners is responsible for several of the traditional therapeutic effects of cayenne, especially the topical treatment of painful peripheral disorders. Capsaicin has been used extensively in neuropharmacological research, and its vanillyl moiety lent its name to the vanilloid receptor (VR). The VR is a chemically and thermally gated cation channel that is opened by heat and closed by capsaicin. Capsaicin activation causes the release of various neuropeptides at the VR, including substance P, which mediates pain sensation in afferent peripheral nocioceptive pathways, with recent evidence suggesting additional mechanisms of central noradrenergic activation through the locus coeruleus. ¹ The VR is distributed widely in sensory afferent innervation of joints, muscles, and the integumentary, respiratory, digestive, and urogenital systems, as well as in the mucous membranes of the oral cavity and the cornea. ²

Apart from its irritant effects (well known to police departments), internal use of capsaicin isolate has also been limited by some controversy over the potential mutagenic and tumorigenic toxicities of the compound. ³ Another naturally occurring vanillyl compound, resinferatoxin (RTX), derived from Euphorbia resinefera, has been used as a more potent capsaicin analog, therapeutically investigated as an intravesical treatment for incontinence, and is preferred to capsaicin because of a better adverse effects and toxicity profile. ⁴ Capsaicin itself has been synthesized, and synthetic analogs such as nonivamide (pellargonic acid vanillamide) are also available, sometimes employed as adulterants in capsicum samples.

Therapeutic use of isolated capsaicin and the oleoresin for external use is approved in the United States and several European Union (EU) countries as an ingredient in topical over-the-counter (OTC) preparations for analgesia in various neuralgic and myalgic conditions, with strengths typically 0.02% to 0.05% for creams and ointments. The German Commission E approved capsicum (“Paprika” monograph) for external use only and suggested limits to duration of administration (2 days), which appear to be conservative. ⁵ Literature reviews of the herb are sparse, except for a recent survey by McKenna et al. ⁶

Historical/Ethnomedicine Precedent

Cayenne has been used for thousands of years by Native American and Meso-American peoples ( chili is the Mayan term for cayenne) and was introduced to Europe following Spanish exploration of the Americas in the fifteenth centuryCE. Besides its near-universal use as a pungent spice additive to the human diet, cayenne is used in the major systems of traditional medicine, including Ayurveda, Chinese, Kampo, Korean, and African.

Generally, cayenne has been used topically as a rubefacient and counterirritant for arthritis and myalgias and as an analgesic for neuralgias and rheumatic pain. Internally, it has been used as a heating and stimulating remedy for colds and respiratory conditions, colic, and dyspepsia and as a digestive and circulatory stimulant. In Western botanical medicine, cayenne was associated with the popular folk medicine doctrines of Samuel Thomson in the United States in the mid-nineteenth century. “Thomsonian medicine” was based on a primitive energetic system that used cayenne in life-threatening illness “to raise vital heat.” Thomsonian medicine later became refined and incorporated into the “Physiomedicalist school” of botanical medicine, which placed less emphasis on “heroic” therapeutic strategies of high doses of cayenne and other stimulants. In traditional Western botanical medicine, cayenne is primarily used internally as a stimulating cardiovascular and digestive tonic and topically as an analgesic.

Known or Potential Therapeutic Uses

• External:   Arthritis, chilblains, cluster headaches, myalgias, fibromyalgia and rheumatic pains, neuralgias and neuropathies (including diabetic neuropathy, postherpetic neuropathy, shingles, postsurgical neuropathic pain), osteoarthritis, pruritus, psoriasis, rhinopathy.

• Internal:   Atony of gastrointestinal (GI) tract, chemoprevention, diaphoretic and antipyretic in feverish conditions, noninflammatory flatulent dyspepsia, peripheral circulatory insufficiency, peptic ulcer prophylaxis.

Key Constituents

Pungent “capsaicinoid” principles, 0.5% to 1.5%, consisting principally of capsaicin (8-methyl-6-noneoyl-vanillylamide) and related vanillyl derivatives, dihydrocapsaicin, nordihydrocapsaicin, homohydrocapsaicin, and homocapsaicin.

Cayenne also contains several carotenoids, including carotene, lutein, and zeaxanthin; high levels of vitamins C and A; flavonoids; and steroidal alkaloid glycosides.

Therapeutic Dosing Range

• Powdered Dried Herb (cayenne pepper):   30 to 250 mg, two or three times daily.

• Tincture:   0.25 to 1.0 mL three times daily; 1:1 equivalent.

• Topical:   0.025% capsaicinoid cream applied up to four times daily.

Strategic Considerations

The German Commission E monograph for cayenne lists no known interactions, and interactions reports for cayenne are rare. ⁵ The reason in part may be the rather narrow mainstream patterns of use as a topical analgesic. Synergistic interactions with coadministered analgesic and anti-inflammatory drugs are theoretically possible in this context, and some supportive data on this are available. However, topical herb-drug combinations are not widely employed in current clinical practice (see later discussion of antiarthritic medications). The dose of capsaicinoids in OTC topical preparations varies from 0.02% to 0.05%, applied up to four times daily to the affected area. Therapeutic context is itself apparently a determinant of capsaicin activity; animal experiments suggest that the analgesic effects of the compound are heightened in inflammatory states compared with noninflammatory controls. ⁷

Internal prescription of cayenne by practitioners of botanical medicine usually follows traditional prescribing principles; thus cayenne is often incorporated in rather small quantities as an adjunctive ingredient of polypharmacy prescriptions to confer qualities of stimulation, warmth, and dispersion to the principal formula ingredients. The British Herbal Pharmacopoeia recommended dose for internal consumption is 30 to 120 mg, thrice daily. Assuming a “high” capsaicin content of approximately 1% capsaicinoids, this would deliver a daily amount of less than 5.0 mg capsaicinoids daily. ⁸ This is somewhat less than the typical human chronic dietary consumption levels in cultures where cayenne is a principal dietary spice, estimated at approximately 0.5 to 1.0 mg/kg. ² In this context, interactions that have been extrapolated on the basis of experimental and animal data, involving relatively high levels of isolated capsaicin administered parenterally, are not directly applicable to clinical practice. (See Theoretical, Speculative, and Preliminary Interactions Research.)

Effects on Drug Metabolism and Bioavailability

The effects of dietary levels of cayenne intake on GI motility and secretion theoretically may lead to pharmacokinetic effects on drug absorption through direct actions on gut permeability, gastric acid levels, and intestinal transit times. Early reports suggested that cayenne increases gastric acid secretion, but recent studies do not confirm this. ⁹ An experimental study with a human ileocarcinoma cell line demonstrated increased cell permeability (tight junction gap increase) on administration of cayenne, although the opposite effect was observed with other spices (e.g., black pepper). ¹⁰ Animal evidence is inconclusive, although an ulceroprotective effect has been demonstrated in several studies, possibly related to increased mucous secretion and anti-inflammatory effects. ^11-14

In humans, hot pepper sauce (e.g., Tabasco) appears to slow gastric emptying, but overall orocecal time is unchanged, indicating increased intestinal transit. ¹⁵ This corresponds with the empirical observation that diarrhea can result from hot spicy food ingested by individuals who do not consume it regularly. Other evidence suggests a general metabolic stimulation; resting metabolic rate increases after cayenne spice ingestion in a meal, and the simultaneous increases in oxygen uptake, lipolysis, and carbohydrate metabolism may be associated with a degree of beta-adrenergic stimulation. ^16,17Gender differences in these effects have also been recorded. ^18,19Currently, dietary cayenne studies suggest that absorption of drugs ingested with cayenne-spiced food may be enhanced, regardless of the drug's characteristics. The degree to which this effect may be clinically significant is variable and unpredictable. Furthermore, some experimental data appear to conflict with this general conclusion; in rats, for example, cayenne coadministration appears to reduce the oral bioavailability of aspirin. ²⁰

Pharmacokinetic effects of capsaicin on drug-metabolizing enzymes have been an area of research interest, partly because of apparently conflicting data on carcinogenicity of the compound from epidemiological and experimental studies. Capsaicin itself is a substrate of hepatic CYP450 2E1, a cytochrome that shares with 1A1 and 1A2 the role of metabolism of potentially carcinogenic aromatic hydrocarbons. ²¹ Other pathways for capsaicin metabolism have been investigated, including aliphatic hydroxylation. ²² Capsaicin has been reported to be a tumor promoter, carcinogen, and potential mutagen. ²³ At the same time, it has also been found to have antigenotoxic, antimutagenic, and anticancer effects. ^24,25More recently, capsaicin has also been found to inhibit nuclear factor kappa B (NF-κB) and to have proapoptotic effects, which support a multimechanism basis for its chemopreventive properties. ^26-28

Capsaicin and dihydrocapsaicin directly inhibit CYP2E1, which has been suggested as a mechanism of its anticarcinogenic effects. ^25,29-33The primary drug substrates of 2E1 include the halogenated aliphatic anesthetics (enflurane, halothane, isoflurane, methoxyflurane, sevoflurane), as well as acetaminophen and ethanol. Ethanol, smoking, obesity, and diabetes all induce 2E1, which is unusual among the CYP450 enzymes in being subject to so many environmental influences. However, capsaicin can also undergo bioactivation. ^23,24The formation of reactive intermediates from capsaicin may also be a result of pan-P450 metabolism of capsaicin, according to a recent study by Reilly et al., ³⁴ who report that this is an essential part of detoxification of capsaicin rather than bioactivation because the intermediates can be “trapped” by addition of glutathione (GSH), suggesting that they are normally conjugated harmlessly. Overall, current data seem to indicate that capsaicin either can be metabolized as a straightforward detoxification or can be bioactivated, generating intermediates that may have direct or indirect toxicity through pan-P450 enzyme inhibition or covalent adduct formation with hepatic microsomal deoxyribonucleic acid (DNA), depending on the circumstances. Animal experiments suggesting prolongation of pentobarbital- and phenobarbital-induced sleeping times may support the pan-P450 inhibition by reactive intermediates (these agents are multi-P450 substrates, and pharmacokinetic-increased levels would require pan-P450 inhibition). ³⁵

Preliminary experimental evidence also suggests that capsaicin inhibits P-glycoprotein (P-gp). Drug resistance to vinblastine in a P-gp–overexpressing, multidrug-resistant carcinoma cell line (KB-C2) was significantly inhibited in vitro by capsaicin at 50 µmol. ³⁶ Further data on the effects of capsaicin on drug resistance are needed before clinical extrapolations can be made.

Knowledge of the impact of chronic capsaicin or cayenne ingestion combined with pharmaceuticals on this complex system is clearly incomplete. However, obvious pharmacokinetic interactions resulting from CYP2E1 inhibition have not been reported, with the possibly relevant exception of theophylline (see later).

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