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Capsaicin
Capsaicin
Capsaicin
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Capsaicin
Names
Pronunciation /kæpˈseɪsɪn/ or /kæpˈseɪəsɪn/
Preferred IUPAC name
(6E)-N-[(4-Hydroxy-3-methoxyphenyl)methyl]-8-methylnon-6-enamide
Other names
(E)-N-(4-Hydroxy-3-methoxybenzyl)-8-methylnon-6-enamide
8-Methyl-N-vanillyl-trans-6-nonenamide
trans-8-Methyl-N-vanillylnon-6-enamide
(E)-Capsaicin
Capsicine
Capsicin
CPS
Identifiers
3D model (JSmol)
2816484
ChEBI
ChEMBL
ChemSpider
DrugBank
ECHA InfoCard 100.006.337 Edit this at Wikidata
EC Number
  • 206-969-8
KEGG
UNII
  • InChI=1S/C18H27NO3/c1-14(2)8-6-4-5-7-9-18(21)19-13-15-10-11-16(20)17(12-15)22-3/h6,8,10-12,14,20H,4-5,7,9,13H2,1-3H3,(H,19,21)/b8-6+ checkY
    Key: YKPUWZUDDOIDPM-SOFGYWHQSA-N checkY
  • InChI=1/C18H27NO3/c1-14(2)8-6-4-5-7-9-18(21)19-13-15-10-11-16(20)17(12-15)22-3/h6,8,10-12,14,20H,4-5,7,9,13H2,1-3H3,(H,19,21)/b8-6+
    Key: YKPUWZUDDOIDPM-SOFGYWHQBQ
  • O=C(NCc1cc(OC)c(O)cc1)CCCC/C=C/C(C)C
Properties
C18H27NO3
Molar mass 305.418 g·mol−1
Appearance Crystalline white powder[1]
Odor Highly pungent
Melting point 62 to 65 °C (144 to 149 °F; 335 to 338 K)
Boiling point 210 to 220 °C (410 to 428 °F; 483 to 493 K) 0.01 Torr
0.0013 g/100 mL
Solubility
Vapor pressure 1.32×10−8 mm Hg at 25 °C[2]
UV-vis (λmax) 280 nm
Structure
Monoclinic
Pharmacology
M02AB01 (WHO) N01BX04 (WHO)
License data
Legal status
Hazards
GHS labelling:
GHS05: CorrosiveGHS06: ToxicGHS07: Exclamation markGHS08: Health hazard
Danger
H301, H302, H315, H318
P264, P270, P280, P301+P310, P301+P312, P302+P352, P305+P351+P338, P310, P321, P330, P332+P313, P362, P405, P501
NFPA 704 (fire diamond)
NFPA 704 four-colored diamondHealth 2: Intense or continued but not chronic exposure could cause temporary incapacitation or possible residual injury. E.g. chloroformFlammability 1: Must be pre-heated before ignition can occur. Flash point over 93 °C (200 °F). E.g. canola oilInstability 0: Normally stable, even under fire exposure conditions, and is not reactive with water. E.g. liquid nitrogenSpecial hazards (white): no code
2
1
0
Safety data sheet (SDS) [2]
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
checkY verify (what is checkY☒N ?)
Capsaicin
HeatAbove peak[2]
Scoville scale16,000,000[5] SHU

Capsaicin (8-methyl-N-vanillyl-6-nonenamide) (/kæpˈseɪ.ə.sɪn/, rarely /kæpˈseɪsɪn/)[6][7][8] is an active component of chili peppers, which are plants belonging to the genus Capsicum. It is a potent irritant for mammals, including humans, for which it produces a sensation of burning in any tissue with which it comes into contact. Capsaicin and several related amides (capsaicinoids) are produced as secondary metabolites by chili peppers, likely as deterrents against eating by mammals and against the growth of fungi.[9] Pure capsaicin is a hydrophobic, colorless, highly pungent (i.e., spicy) crystalline solid.[2][10][11]

Natural function

[edit]

Capsaicin is present in large quantities in the placental tissue (which holds the seeds), the internal membranes and, to a lesser extent, the other fleshy parts of the fruits of plants in the genus Capsicum. The seeds themselves do not produce any capsaicin, although the highest concentration of capsaicin can be found in the white pith of the inner wall, where the seeds are attached.[12]

The seeds of Capsicum plants are dispersed predominantly by birds. In birds, the TRPV1 channel does not respond to capsaicin or related chemicals, but mammalian TRPV1 is very sensitive to it. This is advantageous to the plant, as chili pepper seeds consumed by birds pass through the digestive tract and can germinate later, whereas mammals have molar teeth that destroy such seeds and prevent them from germinating. Thus, natural selection may have led to increasing capsaicin production because it makes the plant less likely to be eaten by animals that do not help it disperse.[13] There is also evidence that capsaicin may have evolved as an anti-fungal agent.[14] The fungal pathogen Fusarium, which is known to infect wild chilies and thereby reduce seed viability, is deterred by capsaicin, which thus limits this form of predispersal seed mortality.

The vanillotoxin-containing venom of a certain tarantula species (Psalmopoeus cambridgei) activates the same pathway of pain as is activated by capsaicin. It is an example of a shared pathway in both plant and animal anti-mammalian defense.[15]

Uses

[edit]

Food

[edit]
Main article: Pungency
Curry dishes

Because of the burning sensation caused by capsaicin when it comes in contact with mucous membranes, it is commonly used in food products to provide added spiciness or "heat" (piquancy), usually in the form of spices such as chili powder and paprika.[16] In high concentrations, capsaicin will also cause a burning effect on other sensitive areas, such as skin or eyes.[17] The degree of heat found within a food is often measured on the Scoville scale.[16]

There has long been a demand for capsaicin-spiced products like chili pepper, and hot sauces such as Tabasco sauce and Mexican salsa.[16] It is common for people to experience pleasurable and even euphoric effects from ingesting capsaicin.[16] Folklore among self-described "chiliheads" attribute this to pain-stimulated release of endorphins, a different mechanism from the local receptor overload that makes capsaicin effective as a topical analgesic.[17]

Research and pharmaceutical use

[edit]

Capsaicin is used as an analgesic in topical ointments and dermal patches to relieve pain, typically in concentrations between 0.025% and 0.1%.[18] It may be applied in cream form for the temporary relief of minor aches and pains of muscles and joints associated with arthritis, backache, strains and sprains, often in compounds with other rubefacients.[18]

It is also used to reduce the symptoms of peripheral neuropathy, such as post-herpetic neuralgia caused by shingles.[18] A capsaicin transdermal patch (Qutenza) for the management of this particular therapeutic indication (pain due to post-herpetic neuralgia) was approved in 2009, as a therapeutic by both the U.S. Food and Drug Administration (FDA)[19][20] and the European Union.[21] A subsequent application to the FDA for Qutenza to be used as an analgesic in HIV neuralgia was refused.[22] One 2017 review of clinical studies found, with limited quality, that high-dose topical capsaicin (8%) compared with control (0.4% capsaicin) provided moderate to substantial pain relief from post-herpetic neuralgia, HIV-neuropathy, and diabetic neuropathy.[23]

Although capsaicin creams have been used to treat psoriasis for reduction of itching,[18][24][25] a review of six clinical trials involving topical capsaicin for treatment of pruritus concluded there was insufficient evidence of effect.[26] Oral capsaicin decreases LDL cholesterol levels moderately.[27]

There is insufficient clinical evidence to determine the role of ingested capsaicin on several human disorders, including obesity, diabetes, cancer and cardiovascular diseases.[18]

Pepper spray and pests

[edit]

Capsaicinoids are also an active ingredient in riot control and personal defense pepper spray agents.[2] When the spray comes in contact with skin, especially eyes or mucous membranes, it produces pain and breathing difficulty in the affected individual.[2]

Capsaicin is also used to deter pests, specifically mammalian pests. Targets of capsaicin repellants include voles, deer, rabbits, squirrels, bears, insects, and attacking dogs.[28] Ground or crushed dried chili pods may be used in birdseed to deter rodents,[29] taking advantage of the insensitivity of birds to capsaicin. The Elephant Pepper Development Trust claims that using chili peppers as a barrier crop can be a sustainable means for rural African farmers to deter elephants from eating their crops.[30]

An article published in the Journal of Environmental Science and Health, Part B in 2006 states that "Although hot chili pepper extract is commonly used as a component of household and garden insect-repellent formulas, it is not clear that the capsaicinoid elements of the extract are responsible for its repellency."[31]

The first pesticide product using solely capsaicin as the active ingredient was registered with the U.S. Department of Agriculture in 1962.[28]

Equestrian sports

[edit]

Capsaicin is a banned substance in equestrian sports because of its hypersensitizing and pain-relieving properties.[32] At the show jumping events of the 2008 Summer Olympics, four horses tested positive for capsaicin, which resulted in disqualification.[32]

Irritant effects

[edit]

Acute health effects

[edit]

Capsaicin is a strong irritant requiring proper protective goggles, respirators, and proper hazardous material-handling procedures. Capsaicin takes effect upon skin contact (irritant, sensitizer), eye contact (irritant), ingestion, and inhalation (lung irritant, lung sensitizer). The LD50 in mice is 47.2 mg/kg.[33][34]

Painful exposures to capsaicin-containing peppers are among the most common plant-related exposures presented to poison centers.[35] They cause burning or stinging pain to the skin and, if ingested in large amounts by adults or small amounts by children, can produce nausea, vomiting, abdominal pain, and burning diarrhea. Eye exposure produces intense tearing, pain, conjunctivitis, and blepharospasm.[36]

Treatment after exposure

[edit]

The primary treatment is removal of the offending substance. Plain water is ineffective at removing capsaicin.[33] Capsaicin is soluble in alcohol, which can be used to clean contaminated items.[33]

When capsaicin is ingested, cold milk may be an effective way to relieve the burning sensation due to caseins in milk, and the water of milk acts as a surfactant, allowing the capsaicin to form an emulsion with it.[37]

Weight loss and regain

[edit]

As of 2007, there was no evidence showing that weight loss is directly correlated with ingesting capsaicin. Well-designed clinical research had not been performed because the pungency of capsaicin in prescribed doses under research prevented subjects from complying in the study.[38] A 2014 meta-analysis of further trials found weak evidence that consuming capsaicin before a meal might slightly reduce the amount of food consumed, and might drive food preference toward carbohydrates.[39]

Peptic ulcer

[edit]

One 2006 review concluded that capsaicin may relieve symptoms of a peptic ulcer rather than being a cause of it.[40]

Death

[edit]

Ingestion of high quantities of capsaicin can be deadly,[41] particularly in people with heart problems.[42] Even healthy young people can suffer adverse health effects like myocardial infarction after ingestion of capsaicin capsules.[43]

Mechanism of action

[edit]

The burning and painful sensations associated with capsaicin result from "defunctionalization" of nociceptor nerve fibers by causing a topical hypersensitivity reaction in the skin.[2][44] As a member of the vanilloid family, capsaicin binds to a receptor on nociceptor fibers called the vanilloid receptor subtype 1 (TRPV1).[44][45][46] TRPV1, which can also be stimulated with heat, protons, and physical abrasion, permits cations to pass through the cell membrane when activated.[44] The resulting depolarization of the neuron stimulates it to send impulses to the brain.[44] By binding to TRPV1 receptors, capsaicin produces similar sensations to those of excessive heat or abrasive damage, such as warming, tingling, itching, or stinging, explaining why capsaicin is described as an irritant on the skin and eyes or by ingestion.[44]

Clarifying the mechanisms of capsaicin effects on skin nociceptors was part of awarding the 2021 Nobel Prize in Physiology or Medicine, as it led to the discovery of skin sensors for temperature and touch, and identification of the single gene causing sensitivity to capsaicin.[47][48]

History

[edit]

The compound was first extracted in impure form in 1816 by Christian Friedrich Bucholz (1770–1818).[49][a] In 1873 German pharmacologist Rudolf Buchheim[59][60][61] (1820–1879) and in 1878 the Hungarian doctor Endre Hőgyes[62][63] stated that "capsicol" (partially purified capsaicin[64]) caused the burning feeling when in contact with mucous membranes and increased secretion of gastric acid.

Capsaicinoids

[edit]

The most commonly occurring capsaicinoids are capsaicin (69%), dihydrocapsaicin (22%), nordihydrocapsaicin (7%), homocapsaicin (1%), and homodihydrocapsaicin (1%).[65]

Capsaicin and dihydrocapsaicin (both 16.0 million SHU) are the most pungent capsaicinoids. Nordihydrocapsaicin (9.1 million SHU), homocapsaicin and homodihydrocapsaicin (both 8.6 million SHU) are about half as hot.[5]

There are six natural capsaicinoids (table below). Although vanillylamide of n-nonanoic acid (Nonivamide, VNA, also PAVA) is produced synthetically for most applications, it does occur naturally in Capsicum species.[66]

Capsaicinoid name Abbrev. Typical
relative
amount 		Scoville
heat units 		Chemical structure
Capsaicin CPS 69% 16,000,000 Chemical structure of capsaicin
Dihydrocapsaicin DHC 22% 16,000,000 Chemical structure of dihydrocapsaicin
Nordihydrocapsaicin NDHC 7% 9,100,000 Chemical structure of nordihydrocapsaicin
Homocapsaicin HC 1% 8,600,000 Chemical structure of homocapsaicin
Homodihydrocapsaicin HDHC 1% 8,600,000 Chemical structure of homodihydrocapsaicin
Nonivamide PAVA 9,200,000 Chemical structure of nonivamide

Biosynthesis

[edit]
Chili peppers
Vanillamine is a product of the phenylpropanoid pathway.
Valine enters the branched fatty acid pathway to produce 8-methyl-6-nonenoyl-CoA.
Capsaicin synthase condenses vanillamine and 8-methyl-6-nonenoyl-CoA to produce capsaicin.

History

[edit]

The general biosynthetic pathway of capsaicin and other capsaicinoids was elucidated in the 1960s by Bennett and Kirby, and Leete and Louden. Radiolabeling studies identified phenylalanine and valine as the precursors to capsaicin.[67][68] Enzymes of the phenylpropanoid pathway, phenylalanine ammonia lyase (PAL), cinnamate 4-hydroxylase (C4H), caffeic acid O-methyltransferase (COMT) and their function in capsaicinoid biosynthesis were identified later by Fujiwake et al.,[69][70] and Sukrasno and Yeoman.[71] Suzuki et al. are responsible for identifying leucine as another precursor to the branched-chain fatty acid pathway.[72] It was discovered in 1999 that pungency of chili peppers is related to higher transcription levels of key enzymes of the phenylpropanoid pathway, phenylalanine ammonia lyase, cinnamate 4-hydroxylase, caffeic acid O-methyltransferase. Similar studies showed high transcription levels in the placenta of chili peppers with high pungency of genes responsible for branched-chain fatty acid pathway.[73]

Biosynthetic pathway

[edit]

Plants exclusively of the genus Capsicum produce capsaicinoids, which are alkaloids.[74] Capsaicin is believed to be synthesized in the interlocular septum of chili peppers and depends on the gene AT3, which resides at the pun1 locus, and which encodes a putative acyltransferase.[75]

Biosynthesis of the capsaicinoids occurs in the glands of the pepper fruit where capsaicin synthase condenses vanillylamine from the phenylpropanoid pathway with an acyl-CoA moiety produced by the branched-chain fatty acid pathway.[68][76][77][78]

Capsaicin is the most abundant capsaicinoid found in the genus Capsicum, but at least ten other capsaicinoid variants exist.[79] Phenylalanine supplies the precursor to the phenylpropanoid pathway while leucine or valine provide the precursor for the branched-chain fatty acid pathway.[68][76] To produce capsaicin, 8-methyl-6-nonenoyl-CoA is produced by the branched-chain fatty acid pathway and condensed with vanillylamine. Other capsaicinoids are produced by the condensation of vanillylamine with various acyl-CoA products from the branched-chain fatty acid pathway, which is capable of producing a variety of acyl-CoA moieties of different chain length and degrees of unsaturation.[80] All condensation reactions between the products of the phenylpropanoid and branched-chain fatty acid pathway are mediated by capsaicin synthase to produce the final capsaicinoid product.[68][76]

Evolution

[edit]

The Capsicum genus split from Solanaceae 19.6 million years ago, 5.4 million years after the appearance of Solanaceae, and is native only to the Americas.[81] Chilies only started to quickly evolve in the past 2 million years into markedly different species. This evolution can be partially attributed to a key compound found in peppers, 8-methyl-N-vanillyl-6-nonenamide, otherwise known as capsaicin. Capsaicin evolved similarly across species of chilies that produce capsaicin. Its evolution over the course of centuries is due to genetic drift and natural selection, across the genus Capsicum. Despite the fact that chilies within the Capsicum genus are found in diverse environments, the capsaicin found within them all exhibit similar properties that serve as defensive and adaptive features. Capsaicin evolved to preserve the fitness of peppers against fungi infections, insects, and granivorous mammals.[82]

Antifungal properties

[edit]

Capsaicin acts as an antifungal agent in four primary ways. First, capsaicin inhibits the metabolic rate of the cells that make up the fungal biofilm.[83] This inhibits the area and growth rate of the fungus, since the biofilm creates an area where a fungus can grow and adhere to the chili in which capsaicin is present.[84] Capsaicin also inhibits fungal hyphae formation, which impacts the amount of nutrients that the rest of the fungal body can receive.[85] Thirdly, capsaicin disrupts the structure[86] of fungal cells and the fungal cell membranes. This has consequential negative impacts on the integrity of fungal cells and their ability to survive and proliferate. Additionally, the ergosterol synthesis of growing fungi decreases in relation to the amount of capsaicin present in the growth area. This impacts the fungal cell membrane, and how it is able to reproduce and adapt to stressors in its environment.[87]

Insecticidal properties

[edit]

Capsaicin deters insects in multiple ways. The first is by deterring insects from laying their eggs on the pepper due to the effects capsaicin has on these insects.[88] Capsaicin can cause intestinal dysplasia upon ingestion, disrupting insect metabolism and causing damage to cell membranes within the insect.[89][90] This in turn disrupts the standard feeding response of insects.

Seed dispersion and deterrents against granivorous mammals

[edit]

Granivorous mammals pose a risk to the propagation of chilies because their molars grind the seeds of chilies, rendering them unable to grow into new chili plants.[91][13] As a result, modern chilies evolved defense mechanisms to mitigate the risk of granivorous mammals. While capsaicin is present at some level in every part of the pepper, the chemical has its highest concentration in the tissue near the seeds within chilies.[12] Birds are able to eat chilies, then disperse the seeds in their excrement, enabling propagation.[13]

Adaptation to varying moisture levels

[edit]

Capsaicin is a potent defense mechanism for chilies, but it does come at a cost. Varying levels of capsaicin in chilies currently appear to be caused by an evolutionary split between surviving in dry environments, and having defense mechanisms against fungal growth, insects, and granivorous mammals.[92] Capsaicin synthesis in chilies places a strain on their water resources.[93] This directly affects their fitness, as it has been observed that standard concentration of capsaicin of peppers in high moisture environments in the seeds and pericarps of the peppers reduced the seeds production by 50%.[94]

See also

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References

[edit]

Further reading

[edit]
[edit]
Revisions and contributorsEdit on WikipediaRead on Wikipedia

Capsaicin

View on Grokipedia
from Grokipedia
Capsaicin is an active compound primarily found in chili peppers of the genus , responsible for the burning sensation associated with their consumption, and it serves as the principal capsaicinoid that imparts to these plants. Chemically, it is classified as (E)-N-[(4-hydroxy-3-methoxyphenyl)methyl]-8-methylnon-6-enamide, with a molecular formula of C₁₈H₂₇NO₃ and a molecular weight of 305.41 g/mol, featuring an aromatic ring, a vanillyl group, and a hydrophobic acyl chain that contribute to its lipophilic properties. It appears as a white to pale yellow crystalline solid, insoluble in but soluble in alcohol, , and oils, with a of 65°C and a of approximately 210–220°C at reduced pressure. First isolated from chili peppers in 1816 by Christian Friedrich Bucholz, capsaicin's chemical structure was fully elucidated in 1919, and its biosynthetic pathway was characterized in the 1960s through enzymatic studies in Capsicum species. Historically, indigenous cultures in the Americas, such as the Aztecs and Mayans, utilized chili peppers containing capsaicin for both culinary and medicinal purposes, including as a topical remedy for pain and inflammation, long before its isolation. In modern contexts, capsaicin's discovery has significantly advanced neuroscience, notably contributing to the identification of the TRPV1 receptor in 1997 by David Julius, which earned a Nobel Prize in Physiology or Medicine in 2021 for elucidating mechanisms of pain and temperature sensation. Biologically, capsaicin acts as a potent of the transient receptor potential vanilloid 1 () , primarily expressed in sensory neurons, triggering an influx of calcium and sodium ions that produces the characteristic heat and sensation at concentrations as low as 10 ppm. This activation leads to the release and subsequent depletion of , a involved in signaling, resulting in desensitization of nociceptors over time and providing effects. In culinary applications, capsaicin is the key determinant of spiciness in foods, measured on the , where pure capsaicin rates at 16 million Scoville heat units (SHU), and it enhances flavor profiles while potentially promoting satiety and inducing thermogenesis by activating TRPV1 receptors, modestly increasing energy expenditure (typically ~50-100 kcal/day) and fat oxidation, which can partially offset a calorie surplus and attenuate fat accumulation or weight gain, though the effect is small, human evidence is limited, and high doses can cause gastrointestinal irritation. Medically, capsaicin is widely employed as a topical for conditions such as , , , and pruritus, available in formulations like creams (0.025–0.075%, e.g., Capciderm 0.075% capsaicin topical cream), high-concentration patches (e.g., 8% Qutenza approved by the FDA in 2009 for and expanded in 2020 for associated with diabetic peripheral neuropathy). Emerging research highlights its , , and potential anticancer properties through modulation of pathways like and scavenging, with ongoing studies exploring oral uses for cardiovascular health and obesity management, where evidence suggests modest increases in energy expenditure with limited benefits for weight management. Despite its efficacy, side effects include transient local burning, , and rare systemic issues like , underscoring the need for controlled administration. Overall, capsaicin exemplifies a natural compound bridging traditional , gastronomy, and contemporary .

Chemistry

Molecular Structure

Capsaicin has the molecular formula C18_{18}H27_{27}NO3_{3}. Its IUPAC name is (E)-N-[(4-hydroxy-3-methoxyphenyl)methyl]-8-methylnon-6-enamide, also commonly referred to as trans-8-methyl-N-vanillyl-6-nonenamide. The molecular structure of capsaicin consists of three main components: a vanillyl group (4-hydroxy-3-methoxybenzyl), an amide linkage, and a hydrophobic alkyl chain. The vanillyl group provides a polar, phenolic head with hydroxyl and methoxy substituents on a benzene ring, connected via a methylene bridge to the amide nitrogen. The amide bond links this head to the tail, which is an 8-methylnon-6-enamide chain featuring a branched, unsaturated hydrocarbon tail with a trans double bond between carbons 6 and 7, enhancing its lipophilicity. Capsaicin is an achiral with no stereocenters, resulting in no optical isomers. The molecule exhibits geometric isomerism at the in the alkyl chain, predominantly in the E (trans) configuration in natural sources. As the primary capsaicinoid, capsaicin shares a core structure with its homologs, such as and , which differ primarily in the length, saturation, or branching of the hydrophobic alkyl tail while retaining the vanillyl moiety. This conserved framework underlies the family's pungency and .

Physical and Chemical Properties

Capsaicin is typically observed as a colorless to white crystalline solid, forming needle-like or prismatic crystals. It melts at 65 °C and boils at 210–220 °C under reduced pressure of approximately 0.01 mm Hg. Capsaicin exhibits low in , approximately 0.0013 g/100 mL at , reflecting its lipophilic character derived from the molecular structure; however, it is highly soluble in organic solvents including (over 100 g/L), acetone, and vegetable oils. The compound is sensitive to light, which can induce , and to oxidation, particularly under exposure to oxygen and elevated temperatures, necessitating storage in dark, airtight conditions to maintain . Capsaicin demonstrates pH-dependent stability, with greater retention of content at neutral compared to acidic or strongly alkaline conditions, though it remains relatively stable across neutral to mildly alkaline ranges. Purity of isolated capsaicin is commonly determined through (HPLC), which separates and quantifies it against standards with detection limits in the microgram per milliliter range. Capsaicinoids constitute a family of vanillyl that are primarily responsible for the characteristic of fruits from the Capsicum, with capsaicin serving as the predominant compound, accounting for up to 90% of the total capsaicinoid content in most varieties. These compounds share a common structure featuring a vanillyl group linked to an , but vary in the length and saturation of the fatty acid-derived . The primary capsaicinoids identified in chili peppers include , which is the second most potent after capsaicin in eliciting ; ; homocapsaicin; and homodihydrocapsaicin, among others that occur in minor amounts. typically comprises about 22-30% of the total, contributing significantly to the overall heat sensation due to its structural similarity to capsaicin. Structural variations among capsaicinoids primarily involve differences in the alkyl chain length, which ranges from 8 to 11 carbons, and the degree of saturation in that chain, influencing their relative levels. For instance, capsaicin features an unsaturated chain with a , while its dihydro analog has a fully saturated chain of the same length, resulting in comparable but slightly lower ; homologs like homocapsaicin and homodihydrocapsaicin possess longer chains, which generally reduce irritancy while maintaining some bioactivity. These modifications affect binding affinity to the receptor, with shorter, more unsaturated chains typically enhancing perceived heat. The total capsaicinoid content in chili peppers varies widely by and environmental factors, typically ranging from 0.1% to 2.5% on a dry weight basis, with quantification commonly performed using (HPLC) for accurate separation and measurement of individual components. This range reflects the diversity from mild varieties to intensely pungent ones like habaneros, where capsaicin and dominate the profile.

Occurrence and Biosynthesis

Natural Sources

Capsaicin is primarily produced in the fruits of plants from the genus Capsicum, known as chili peppers, which belong to the Solanaceae family. These peppers are the main natural source of capsaicin and related compounds, with production concentrated in the mature fruits where the compound contributes to the characteristic pungency. Within the pepper fruit, capsaicin accumulates predominantly in the placental tissue—the spongy, white internal structure that attaches the seeds—rather than the seeds or outer pericarp. Concentrations vary significantly by and environmental factors; sweet bell peppers ( var. grossum) contain no capsaicin, resulting in zero , whereas hot varieties like habaneros () can reach up to 1.3% capsaicinoids by dry weight in their placental regions. This variation underscores the of species for heat levels, with capsaicin content often measured in milligrams per gram of dried tissue. Global production of chili peppers, the key reservoir for natural capsaicin, is led by major cultivators including , , and , which together account for a substantial share of output. As of data, the worldwide annual harvest of green chilies and peppers approximates 40 million tons, supporting both culinary and industrial demands. For commercial purposes, capsaicin is isolated from these sources via solvent extraction methods applied to dried pepper material, using organic solvents like or acetone to yield purified oleoresins.

Biosynthetic Pathway

The biosynthetic pathway of capsaicin in commences with the convergence of two primary metabolic routes: the phenylpropanoid pathway, which generates the vanillylamine moiety from the , and the branched-chain pathway, which produces the 8-methyl-6-nonenoyl-CoA acyl donor from . In the phenylpropanoid branch, is first deaminated by (PAL) to form , followed by successive hydroxylations, methylations, and reductions to yield ; this aldehyde is then transaminated to vanillylamine by putative aminotransferases (pAMT), utilizing nitrogen donors such as glutamate or . Concurrently, is transaminated and decarboxylated to form 8-methyl-6-nonenoic acid, which is activated to its CoA through involving enzymes like branched-chain aminotransferase (BCAT) and synthetase. These precursors are condensed in the placental tissue of developing fruits, where capsaicin accumulation peaks around 40–50 days post-anthesis, serving as a for defense. The final and rate-limiting step is catalyzed by (CS), a specialized acyltransferase encoded by the Pun1 (also known as AT3), which facilitates the bond formation between vanillylamine and 8-methyl-6-nonenoyl-CoA, with kinetic parameters indicating high substrate affinity (Kₘ ≈ 6–8 μM for both). Key supporting s include pAMT for vanillylamine production, with the Pun1 serving as the key for the amidation and contributing to acyl chain processing for capsaicin storage. The Pun1 locus, responsible for , was mapped in the and cloned in , with its role as the capsaicin confirmed through functional studies including demonstrating capsaicin production. Regulation of the pathway is tightly linked to environmental stresses, including and attack, which upregulate phenylpropanoid genes like PAL and C4H ( 4-hydroxylase), enhancing flux toward capsaicin as a deterrent against herbivores and microbes; deficit, for instance, can increase capsaicin levels by 20–50% through elevated activities. Integration with the broader phenylpropanoid network allows crosstalk with and , prioritizing capsaicin under stress via transcription factors and modifications in placental cells. The pathway's elucidation progressed through genetic mapping in the , purification in the early , and comprehensive genomic studies by 2008, which integrated transcriptomic data from C. annuum to outline all major steps and regulatory elements.

Laboratory Synthesis

The first laboratory synthesis of capsaicin was achieved in 1930 by Ernst Späth and Stephen F. Darling, who employed an amide coupling reaction between vanillylamine and 8-methylnon-6-enoyl chloride to form the compound. This method established the foundational chemical route for producing capsaicin artificially, confirming its structure as (E)-N-[(4-hydroxy-3-methoxyphenyl)methyl]-8-methylnon-6-enamide and distinguishing it from natural biosynthetic processes that occur in chili peppers. Modern laboratory syntheses have optimized efficiency through variations of the Schotten-Baumann reaction, where vanillylamine reacts with acyl chlorides in a biphasic aqueous-organic solvent system (such as water/) under mild conditions with a base like to neutralize HCl. This approach yields capsaicin and its analogues at 93–96%, significantly higher than earlier methods, by facilitating the reaction at the phase interface and minimizing side products. Enzymatic mimicry of the natural pathway, using lipases to catalyze amidation between vanillylamine and fatty acids, provides a greener alternative with yields of 40–59%, though it requires immobilization techniques for . Commercial production of pure capsaicin relies on total chemical synthesis via acyl chloride routes for pharmaceutical-grade material, achieving yields up to 70% under industrial conditions like 140–170°C with catalysts such as cerium(III) chloride. Semi-synthetic processes, starting from pepper extracts to isolate precursors like vanillylamine before coupling, are used for lower-purity applications in food and agriculture. Key challenges include process scaling for high-volume pharmaceutical needs, where purification to >99% purity is essential, but the molecule's achirality eliminates stereoselectivity concerns.

Biological Functions

Role in Plants

In chili peppers of the genus Capsicum, capsaicin serves as a key secondary metabolite in the plant's chemical defense system, primarily deterring mammalian herbivores and fungal pathogens from consuming or infecting the fruits and seeds. Produced in the placental tissue that surrounds the developing seeds, capsaicin creates a pungent coating that induces aversion in sensitive animals, thereby reducing damage to reproductive structures without broadly toxifying the fruit. This localized production helps safeguard the plant's reproductive success by targeting threats that could destroy seeds during mastication or decomposition. Capsaicin levels accumulate progressively during fruit ripening, peaking as the seeds mature to provide heightened protection at the most vulnerable stage. This temporal increase aligns with the plant's need to defend against heightened exposure and activity post-flowering, ensuring seeds remain viable for dispersal. Studies on show that capsaicin synthesis is coordinated with fruit development, enhancing barrier effects against microbes like species that could otherwise compromise seed integrity. The deterrence provided by capsaicin is notably non-lethal, eliciting discomfort through activation of sensory receptors in mammals—such as and —that grind seeds, while sparing birds, which swallow fruits whole and excrete intact seeds. This selective mechanism promotes efficient by avian vectors insensitive to the compound, optimizing the plant's propagation strategy. In wild species, this targeted aversion has been observed to reduce mammalian predation rates significantly compared to non-pungent varieties. Capsaicin functions in synergy with other plant metabolites, such as and , to bolster overall defense efficacy. These interactions create a multifaceted chemical profile in the , where phenolics contribute properties and antioxidants that complement capsaicin's irritant effects against herbivores and pathogens. In domesticated and chilies, this combined arsenal has been linked to improved resistance profiles, with capsaicin enhancing the stability and impact of phenolic defenses during .

Evolutionary Adaptations

Capsaicin biosynthesis in species originated approximately 19 million years ago in , following the divergence from related genera such as . This evolution occurred through a series of duplications in the acyltransferase family, leading to the emergence of capsaicin synthase (CS) enzymes responsible for capsaicinoid production. Specifically, seven CS copies in pungent peppers arose from five tandem duplication events, with the final duplication enabling the novel branch-point in the capsaicin biosynthetic pathway. These genetic innovations conferred as a specialized defense mechanism unique to . The properties of capsaicin played a pivotal role in its evolutionary retention, protecting seeds and fruits from pathogens in wild populations. Capsaicinoids inhibit fungal growth, such as that of Fusarium semitectum, by disrupting ATP production through binding to and potentially compromising cell membranes, reducing seed infection rates by 45–55% at natural concentrations. Similar tolerance mechanisms in fungi like and highlight an ongoing coevolutionary arms race, where capsaicin's antimicrobial action enhances seed viability in pathogen-rich environments. This defense likely contributed to the selective advantage of pungent varieties in ancestral habitats. Insecticidal adaptations further underscore capsaicin's evolutionary utility, repelling herbivores like (Aphis cytisorum) with up to 97% mortality from extracted capsaicin and proving toxic to larvae of generalist moths such as latifascia. High capsaicin levels extend larval development, prevent pupation, and inhibit adult emergence by sequestering compounds in insect , potentially targeting TRPV1-like channels in . These effects deter feeding and oviposition, safeguarding reproductive tissues in wild chilies. Seed dispersal strategies evolved with capsaicin's pungency to favor avian vectors while deterring mammalian granivores. Mammals detect capsaicin via the receptor, experiencing aversion that reduces seed damage and predation, whereas birds lack this sensitivity due to amino acid differences in their vanilloid receptor (e.g., in transmembrane segment 3), allowing intact seed passage through their digestive tract. This directed deterrence promotes efficient long-distance dispersal by birds, enhancing in fragmented South American landscapes. Environmental pressures, particularly in arid regions, drove higher capsaicin accumulation as an adaptive response to stress-induced pathogens. Wild populations in semi-arid exhibit elevated capsaicinoid levels (up to 23.5 mg/g dry weight) compared to southern counterparts, correlating with defenses against deficit and that exacerbate fungal risks. Although can temporarily reduce synthesis during fruiting, baseline in arid-adapted genotypes bolsters resilience to opportunistic infections.

Mechanism of Action

Molecular Interactions

Capsaicin primarily targets the , a non-selective cation channel expressed predominantly in sensory neurons, where it functions as a potent by binding to an intracellular located within the . This is accessible via permeation through the , as capsaicin, being lipophilic, crosses the plasma membrane to reach the intracellular formed by residues in the S3 and S4 helices. Structural studies using cryo-electron microscopy (cryo-EM) have elucidated that capsaicin adopts a "tail-up, head-down" orientation in this pocket, with its vanillyl moiety forming hydrogen bonds with residues such as Thr550, Ser513, and Glu571, while the aliphatic tail engages in van der Waals interactions that contribute to binding stability. These interactions, visualized in high-resolution structures of rat (e.g., at 3.4 Å resolution), demonstrate how capsaicin stabilizes the channel's open state by inducing outward movement of the S4-S5 linker, which in turn propagates to dilate the intracellular gate. Recent cryo-EM studies from the have further detailed capsaicin's membrane-mediated entry pathway to the . Upon binding, capsaicin activates by opening its pore, permitting influx of monovalent cations (primarily Na⁺) and divalent Ca²⁺ ions, which generates a depolarizing current under physiological conditions. This activation threshold aligns with 's polymodal sensitivity, as the channel can also be gated by noxious (temperatures exceeding 43°C) or extracellular protons (low < 6.0), with capsaicin lowering the for these stimuli through allosteric modulation. Prolonged or repeated activation leads to channel desensitization, a process involving calcium-dependent mechanisms such as binding and activity, alongside depletion of neuropeptides like from presynaptic terminals in nociceptive neurons, which reduces subsequent excitability. Cryo-EM structures from the 2010s onward, including those of capsaicin-bound in lipid nanodiscs, have confirmed these dynamics by capturing intermediate conformations that reveal pore dilation and subsequent constriction during desensitization. The binding affinity of capsaicin to is relatively high, with a dissociation constant () of approximately 0.4 μM for the wild-type channel, as measured via single-channel patch-clamp on concatemeric constructs fitted to a Monod-Wyman-Changeux model. Beyond , capsaicin interacts with other transient receptor potential (TRP) channels, including and TRPV3, though with lower potency and often through indirect mechanisms such as heterotetramer formation in co-expressing cells, which can alter channel gating properties and sensitivity to stimuli. For instance, co-assembly of with subunits has been observed to modulate responses in heterologous systems, potentially enhancing overall nociceptive signaling. Additionally, capsaicin modulates voltage-gated sodium channels (e.g., Na_V1.7 and Na_V1.8 in sensory neurons) by inhibiting their activation and slowing recovery from inactivation, an effect attributed to capsaicin's amphipathic nature altering elasticity and mechanically coupling to channel function, as demonstrated in patch-clamp studies on neurons. These interactions, while secondary to TRPV1 agonism, contribute to capsaicin's broader effects on neuronal excitability.

Sensory and Physiological Responses

Capsaicin activates nociceptors in the skin, mucosa, and other sensory tissues, primarily through binding to the transient vanilloid 1 (TRPV1) channel, resulting in a characteristic burning sensation that is perceived as intense heat despite no actual change in tissue temperature. This sensory response mimics thermal but originates from chemical , leading to sharp, stinging, or fiery discomfort that varies in intensity based on concentration and exposure site. The burning is mediated by the depolarization of primary afferent C-fibers and A-delta fibers, which transmit signals to the , evoking both localized and perceptions. Physiologically, capsaicin exposure triggers , causing redness and warmth in the affected area due to the release of neuropeptides like and (CGRP) from sensory nerve endings. This is often accompanied by increased sweating, particularly when applied topically, as it enhances the onset and rate of eccrine gland activity to facilitate heat dissipation. Cardiovascular responses include an elevation in , reflecting sympathetic activation in response to the nociceptive input, though these effects are typically transient and dose-dependent. Additionally, the intense pain sensation can stimulate the release of , endogenous opioids that bind to mu-opioid receptors, producing a subsequent feeling of euphoria or pleasure akin to a "runner's high" after the initial discomfort subsides. The human sensory response to capsaicin follows a dose-response curve, with a detection threshold in the oral cavity around 5.9 nanomoles (approximately 0.0018 mg) in a 10 mL volume, below which is not perceived. Higher doses amplify the burning intensity, but repeated or prolonged exposure leads to desensitization, where sensory neurons become temporarily , reducing the perceived and pain over time. This desensitization is reversible and depends on the frequency and duration of applications, often resulting in diminished responses after multiple low-dose exposures. In non-human species, responses differ markedly; birds exhibit insensitivity to capsaicin due to variations in their receptors, which lack the binding affinity for the compound seen in mammals. Avian , for instance, is structurally divergent, preventing activation and allowing birds to consume capsaicin-rich peppers without aversion.

Applications

Culinary Uses

Capsaicin is the primary compound responsible for the pungent heat sensation in chili peppers, often accompanied by a subtle bitterness that enhances the overall flavor profile of dishes. This heat is quantified using the Scoville Heat Units (SHU) scale, where pure capsaicin registers at 16 million SHU, serving as the benchmark for measuring spiciness in foods. The sensation arises from capsaicin's interaction with sensory receptors, creating a burning effect without altering the fundamental tastes like sweet or sour, though it can amplify perceived bitterness in certain preparations. In culinary applications, capsaicin is widely incorporated into sauces, blends, and even chocolates to add intensity and depth to flavors. It features prominently in global cuisines, such as dishes like salsas and mole sauces, Indian curries with chili powders, and Thai stir-fries using fresh or dried peppers for balanced heat. These uses highlight capsaicin's versatility in elevating both savory and sweet profiles while allowing cooks to adjust intensity based on regional preferences. The stems mainly from capsaicin and related capsaicinoids found in peppers. Consumption trends show increasing global demand for spicy foods, driven by adventurous palates and fusion cuisines, with the hot sauce market alone valued at approximately $5.5 billion in 2024. For standardized heat in processed foods, capsaicin is often extracted as , a concentrated form that mixes easily into liquids, oils, and dry blends for products like snacks, marinades, and condiments. This preparation ensures consistent without the variability of whole peppers, supporting industrial-scale production.

Medical and Pharmaceutical Applications

Capsaicin is widely utilized in medical and pharmaceutical contexts primarily for its properties, targeting through topical applications that modulate transient receptor potential vanilloid 1 () channels. The high-concentration 8% capsaicin patch, known as Qutenza, is approved by the FDA for managing associated with (PHN), a common of . Clinical trials and meta-analyses demonstrate its efficacy, with single applications yielding ≥30% pain reduction in 37–47% of PHN patients and ≥50% reduction in 23–36%, often sustained for up to three months. A 2025 narrative review of randomized controlled trials confirms consistent pain relief and quality-of-life improvements across peripheral conditions, including PHN and painful diabetic . Beyond PHN, capsaicin features in treatments for other pain syndromes, such as , where low-concentration creams (0.025–0.075%) provide relief for symptoms in the hands and knees, as well as chronic muscle pain and sprains, postherpetic neuralgia, painful diabetic neuropathy, and muscle-joint pains. For example, Capciderm (0.075% capsaicin topical cream) is indicated for the symptomatic relief of postherpetic neuralgia following herpes zoster (after skin lesions have healed), painful diabetic peripheral polyneuropathy, arthritis, osteoarthritis, and muscle and joint pains. These creams work by producing an initial burning sensation through TRPV1 activation, which depletes substance P stores in sensory nerves, leading to desensitization that blocks pain signals to the brain; the burning sensation typically subsides with regular use. Application is typically thin and performed 3-4 times daily. A 2024 meta-analysis of randomized controlled trials involving various patients showed that topical capsaicin (0.0125–5%) significantly reduced pain severity compared to , with effects noticeable after at least four weeks of use. Emerging research also highlights capsaicin's anticancer potential through modulation, which induces and disrupts tumor metabolism in various cancer types. A 2025 editorial review underscores its role in targeting for pharmacological interventions against cancer progression. Recent studies have expanded capsaicin's therapeutic scope to cardioprotective applications, demonstrating antihypertensive effects in preclinical models. A investigation found that capsaicin pretreatment in the hypothalamic paraventricular nucleus attenuated salt-sensitive by alleviating via the AMPK/Akt/Nrf2 pathway. Similarly, clinical data from hypertensive patients indicated that capsaicin supplementation lowered , supporting its role in cardiovascular health. In inflammation-related conditions like , capsaicin reduces inflammatory responses independently of by inhibiting the PKM2-LDHA-mediated effect, as shown in a study using proteomic and metabolic analyses. Capsaicin is delivered in diverse pharmaceutical forms to suit clinical needs, including patches, gels, and oral supplements. The Qutenza 8% patch, first FDA-approved in 2009 for PHN-associated , remains a standard option with ongoing clinical reaffirmation through post-marketing studies up to 2025. Lower-concentration topical gels (0.025–0.075%) are commonly prescribed for , while oral capsaicin supplements are explored for systemic effects like cardioprotection, though they require further validation for broader indications.

Non-Medical Uses

Capsaicin is the primary active ingredient in oleoresin capsicum (OC) formulations used in pepper sprays for purposes, with major capsaicinoid concentrations typically ranging from 0.18% to 1.33% in civilian and products. These sprays incapacitate individuals through severe irritant effects on the eyes and , inducing involuntary eye closure, lacrimation, , and that cause coughing, , and temporary disorientation lasting 20–90 minutes. In and pest , capsaicin functions as a natural repellent against , rabbits, ground squirrels, and various , applied via sprays or coatings on crops, trees, and structures to protect against damage without harming non-target organisms. Field studies demonstrate its efficacy in reducing pest infestations, such as achieving up to 95.81% reduction in populations using 7.5% chili extract following application. By exploiting the compound's aversive sensory properties, these applications minimize pre-harvest losses from and pests while serving as an alternative to synthetic pesticides. Within equestrian care, capsaicin is incorporated into counterirritant liniments applied topically to horses' legs to alleviate swelling and promote circulation by inducing localized and heat sensation. However, due to its potential to mask pain and enhance performance, capsaicin is classified as a banned substance under the Fédération Equestre Internationale (FEI) Equine Prohibited Substances List, prohibiting its use in competition environments. Additional non-medical applications leverage capsaicin's repellent and antimicrobial properties in specialized coatings, such as marine anti-fouling paints designed to deter organisms like and on vessel hulls. These eco-friendly formulations, often combining capsaicin with acrylic or matrices, exhibit synergistic effects that inhibit bacterial by up to 99.9% and reduce overall marine growth during immersion. In veterinary contexts, topical capsaicin (0.025%) applied twice daily has been evaluated for managing pruritus associated with in dogs, showing overall tolerability despite potential initial worsening of symptoms.

Health Effects

Irritant and Acute Effects

Capsaicin acts as a potent irritant primarily due to its activation of transient receptor potential vanilloid 1 () receptors, leading to immediate inflammatory responses upon contact with sensitive tissues. Exposure to capsaicin occurs through several routes, each producing distinct acute symptoms. On the skin, it causes intense burning pain and , with peaking within approximately one hour in animal models. Contact with the eyes results in tearing, swelling, , , and temporary or . Inhalation exposure triggers coughing, , wheezing, and dyspnea, particularly in sensitive individuals. Oral ingestion leads to irritation, particularly exacerbating sore throats by inflaming sensitive throat tissues and increasing burning, coughing, or discomfort through TRPV1 activation in mucosal tissues, often manifesting as , , abdominal cramps, and , especially in smaller quantities. Acute symptoms from capsaicin exposure typically include a burning sensation that peaks in intensity between 30 and 60 minutes after contact, with severity depending on the dose; for example, as little as 1 mg can produce an intense burn on . Higher doses exacerbate these effects, potentially causing prolonged or more severe respiratory distress upon . Treatment focuses on rapid removal of capsaicin from the affected area to alleviate symptoms. For oral exposure, milk or fatty substances are recommended as they dissolve the lipophilic capsaicin more effectively than . Skin and eye exposures should be managed preferably with oil-based washes, such as petroleum jelly, or grease-cutting detergents like dish soap, as capsaicin's oil-solubility means plain water or regular soap can spread it across the skin without effectively removing it, potentially worsening the burn; cool rinses may offer temporary relief but are less effective, and hot must be avoided as it can enhance penetration and irritation. In cases of inhalation, supportive measures such as nebulized bronchodilators or corticosteroids may be necessary for severe . Certain groups are more vulnerable to capsaicin's acute effects, including children who may experience severe gastrointestinal symptoms from even small amounts, and individuals with who face heightened risk of and respiratory distress. Rare cases of have been reported in response to capsaicin-containing peppers, with an incidence estimated at less than 1%.

Therapeutic Effects

Capsaicin provides therapeutic benefits primarily through its interaction with the transient receptor potential vanilloid 1 () channel, leading to initial activation followed by desensitization that mitigates signals. This mechanism involves the temporary influx of calcium ions upon TRPV1 binding, which depletes and other neuropeptides in sensory neurons, resulting in prolonged analgesia for conditions such as and . Clinical applications demonstrate that repeated exposure reduces by diminishing responsiveness to inflammatory mediators, offering relief in peripheral neuropathies without systemic effects. In metabolic regulation, capsaicin induces thermogenesis by activating TRPV1 receptors, increasing energy expenditure and fat oxidation, typically by approximately 50-100 kcal/day in humans. This may partially offset a calorie surplus by raising calorie burn, potentially attenuating fat accumulation or weight gain, though the effect is modest and insufficient to fully prevent weight gain in the presence of a significant calorie surplus. Animal studies demonstrate stronger preventive effects on obesity in high-fat diet models, while human evidence remains limited and shows only modest benefits for weight management. Capsaicin enhances and fat oxidation by activating in and the , promoting catecholamine release and increasing energy expenditure. A 2023 meta-analysis of randomized controlled trials involving and individuals found that capsaicin supplementation led to modest reductions in body weight, , and waist circumference over 6–12 weeks. These effects stem from elevated and shifted toward greater lipid utilization, supporting its role in management. Capsaicin exerts actions by inhibiting the signaling pathway, which suppresses the transcription of pro-inflammatory cytokines in activated immune cells. In models, research highlights its potential to reduce COX-2 expression, thereby attenuating the inflammatory cascade and effect independently of activation. This modulation shifts polarization toward phenotypes, offering protective effects against . For cardiovascular health, topical capsaicin improves endothelial function by enhancing bioavailability and release, which dilates microvasculature and reduces . A 2025 study on hypertensive rat models showed that such applications lower mean arterial blood pressure by approximately 36 mmHg over two weeks through TRPV1-mediated microvascular effects. These benefits extend to cardioprotection by mitigating ischemia-reperfusion injury without altering systemic adversely. Epidemiological evidence further links regular dietary consumption of spicy foods, rich in capsaicinoids, to reduced overall mortality risk, including cardiovascular benefits; a large cohort study reported that individuals consuming spicy foods almost every day had a 14% lower risk of all-cause mortality compared to those consuming them less than once a week. As of 2025, emerging research indicates capsaicin acts as a modulator, influencing composition to potentially enhance metabolic health and reduce via the gut-brain axis. Preliminary studies suggest it may alleviate ADHD symptoms by increasing beneficial bacteria such as and , though human trials are ongoing.

Adverse and Toxic Effects

Capsaicin exhibits relatively low , with oral LD50 values reported as approximately 148 mg/kg in female rats and 161 mg/kg in male rats. In mice, the LD50 is lower, around 47-119 mg/kg depending on sex. For humans, the estimated probable lethal oral dose ranges from 0.5 to 5 g/kg body weight, equating to 35-350 grams for a 70 kg individual, though such extreme intakes are rare and impractical from dietary sources. No confirmed human deaths from pure capsaicin have been documented, though rare fatalities have occurred from extreme consumption of ultra-high-concentration capsaicin products, such as in spicy food challenges (e.g., the 2023 Paqui One Chip Challenge), which can trigger cardiopulmonary arrest, particularly in individuals with pre-existing cardiac conditions; normal dietary intake of spicy foods poses negligible lethal risk due to far lower capsaicin levels. primarily manifests as severe gastrointestinal distress rather than . Regarding gastrointestinal effects, early concerns suggested that high capsaicin intake could exacerbate peptic ulcers by irritating the mucosa, but subsequent research has debunked this, demonstrating protective mechanisms instead. Capsaicin inhibits secretion while stimulating alkali and production, as well as enhancing gastric mucosal blood flow, which collectively aid in prevention and healing. These gastroprotective actions are mediated through capsaicin-sensitive afferent neurons, countering oxidative damage and promoting epithelial repair. In the context of weight management, capsaicin supplementation may support initial fat oxidation and modest energy expenditure increases, but longitudinal studies indicate limited efficacy in preventing post-diet weight regain due to metabolic adaptations such as reduced resting energy expenditure. A study following modest weight loss (5-10%) found that daily capsaicin intake (135 mg) did not significantly limit subsequent regain compared to placebo, despite sustained effects on substrate oxidation. Recent analyses reinforce that while capsaicin influences thermogenesis short-term, adaptive responses in energy balance often lead to rebound, particularly without sustained dietary integration. Chronic exposure risks, including potential carcinogenicity, remain debated but unclassified by major agencies. The International Agency for Research on Cancer (IARC) has not assigned a specific group to capsaicin, indicating insufficient for carcinogenicity in humans. Comprehensive reviews highlight mixed and results, with some concerns at high doses, yet predominant anticarcinogenic effects through induction and free radical scavenging in various cancer models. For high-dose supplements, ongoing monitoring is advised, as 2020s epidemiological data show no consistent link to cancer incidence, though variability in exposure levels warrants caution. Recent data on topical applications, such as capsaicin 8% patches for , note that overuse can lead to reversible -like symptoms, including heightened sensory deficits and . These effects stem from transient defunctionalization, resolving within hours to weeks post-exposure, but repeated applications beyond recommended intervals (e.g., every 3 months) may prolong recovery. Clinical trials emphasize that while effective for diabetic management, adherence to dosing prevents such complications. A 2025 study reported that long-term intake of capsicum diets may negatively impact liver function, indicating potential from prolonged high capsaicin exposure, warranting caution in chronic supplementation.

History

Discovery and Isolation

The , including the , recognized the pungent properties of chili peppers (genus ) as early as the 16th century, incorporating them into for treating ailments such as pain, coughs, and . Archaeological evidence indicates that species were domesticated in approximately 6,000 years ago, with the using chili peppers not only as a culinary spice but also for their effects in poultices and remedies. In 1493, encountered these plants during his second voyage and introduced them to , where they spread rapidly as a novel spice and medicinal agent, marking the beginning of global dissemination. The active pungent principle in chili peppers, later identified as capsaicin, was first isolated in impure form in 1816 by German chemist Christian Friedrich Bucholz from Capsicum fruits; he named the extract "capsicin" after the . This initial extraction involved processing the from pods, yielding a substance responsible for the characteristic burning sensation, though it contained impurities and was not fully characterized. Further purification efforts advanced in the late . In 1876, British pharmacist John Clough Thresh isolated capsaicin in nearly pure form through solvent extraction and recrystallization techniques, coining the name "capsaicin" to reflect its origin from . The compound's pure crystalline form was achieved in 1898 by Karl Micko, who refined isolation methods using extraction and cooling, enabling more precise chemical analysis. Early scientific studies focused on capsaicin's physiological properties. In 1873, Rudolf Buchheim examined a partially purified extract (capsicol) and determined it to be a non-nitrogenous, lipid-soluble substance, distinguishing it from typical alkaloids. Around the same period, Hungarian pharmacologist Endre Hogyes conducted initial toxicity tests on animals, including rabbits and dogs, instilling capsaicin solutions into their eyes and observing dose-dependent irritation, lacrimation, and stimulation without systemic lethality at low doses, laying groundwork for understanding its irritant effects.

Development and Modern Research

The of capsaicin was elucidated in the through degradative methods, including of derivatives to identify key fragments such as vanillylamine and the unsaturated chain. This work built on partial determinations from and enabled precise characterization by researchers like Ernst Späth. A major milestone came in 1930 with the first of capsaicin by Späth and Stephen F. Darling, confirming its as (E)-N-[(4-hydroxy-3-methoxyphenyl)methyl]-8-methylnon-6-enamide and opening avenues for analog production. Advancements accelerated in the late with the discovery of the transient receptor potential vanilloid 1 () as capsaicin's primary target in 1997, revealing its role in sensing heat, protons, and pain signals in sensory neurons. This molecular insight shifted capsaicin from a mere irritant to a tool for studying and led to targeted pharmaceutical development. In 2009, the U.S. approved Qutenza, an 8% capsaicin patch, for , marking the first high-concentration topical formulation for management. Recent studies from 2023 to 2025 have reinforced capsaicin's efficacy in long-term treatment, with repeated applications of the 8% patch yielding sustained reductions in intensity (e.g., from 52.5 mm to 21.5 mm on visual analog scales after four treatments) and improvements in exceeding 30% in patient-reported outcomes. These findings highlight incremental benefits with ongoing use across conditions like , addressing gaps in earlier trials by demonstrating durability beyond 12 weeks. Commercially, capsaicin's evolution includes its adoption in non-lethal sprays, with the first aerosol formulation patented in 1973 by Allan Lee Litman, enabling widespread use by law enforcement from the onward. The global capsaicin market, driven by pharmaceutical and defensive applications, reached approximately USD 263.5 million in 2024, reflecting growth in high-purity extracts for medical delivery. Emerging research in 2025 has explored capsaicin's role in neuroendocrine regulation via , positioning it as a potential modulator of body weight, , and obesity-related pathways. Studies from 2023–2025 also demonstrate protective effects against , including attenuation of and through mechanisms in animal models. In cardiovascular health, capsaicin has shown promise in reducing arterial , , and , with topical applications improving cardiac function in overload models. High-potency extracts, such as those exceeding 8% concentration, continue to be investigated for enhanced and properties in therapeutic contexts.

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