Capsaicin (8-methyl-N-vanillyl-6-nonenamide) (/kæpˈseɪ.ə.sɪn/, rarely/kæpˈseɪsɪn/)[6][7][8] is an active component ofchili peppers, which are plants belonging to the genusCapsicum. It is a potentirritant formammals, including humans, and produces a sensation of burning in anytissue with which it comes into contact. Capsaicin and several relatedamides (capsaicinoids) are produced assecondary metabolites by chili peppers, likely as deterrents against certain mammals and fungi.[9] Pure capsaicin is ahydrophobic, colorless, highlypungent (i.e., spicy)crystalline solid.[2]
Capsaicin is present in large quantities in theplacental tissue (which holds the seeds), the internal membranes and, to a lesser extent, the other fleshy parts of the fruits of plants in the genusCapsicum. The seeds themselves do not produce any capsaicin, although the highest concentration of capsaicin can be found in the whitepith of the inner wall, where the seeds are attached.[10]
The seeds ofCapsicum plants are dispersed predominantly by birds. In birds, theTRPV1 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 havemolar 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.[11] There is also evidence that capsaicin may have evolved as ananti-fungal agent.[12] The fungal pathogenFusarium, 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.
Thevanillotoxin-containing venom of a certaintarantula species (Psalmopoeus cambridgei) activates the same pathway of pain as is activated by capsaicin, an example of a shared pathway in both plant and animal anti-mammalian defense.[13]
Because of the burning sensation caused by capsaicin when it comes in contact withmucous membranes, it is commonly used in food products to provide added spiciness or "heat" (piquancy), usually in the form ofspices such aschili powder andpaprika.[14] In high concentrations, capsaicin will also cause a burning effect on other sensitive areas, such as skin or eyes.[15] The degree of heat found within a food is often measured on theScoville scale.[14]
There has long been a demand for capsaicin-spiced products likechili pepper, andhot sauces such asTabasco sauce and Mexicansalsa.[14] It is common for people to experience pleasurable and eveneuphoric effects from ingesting capsaicin.[14] Folklore among self-described "chiliheads" attribute this to pain-stimulated release ofendorphins, a different mechanism from the local receptor overload that makes capsaicin effective as a topicalanalgesic.[15]
Capsaicin is used as ananalgesic intopical ointments anddermal patches to relieve pain, typically in concentrations between 0.025% and 0.1%.[16] It may be applied in cream form for the temporary relief of minor aches and pains ofmuscles and joints associated witharthritis, backache, strains andsprains, often in compounds with otherrubefacients.[16]
It is also used to reduce the symptoms of peripheralneuropathy, such aspost-herpeticneuralgia caused byshingles.[16] A capsaicintransdermal patch (Qutenza) for the management of this particular therapeutic indication (pain due to post-herpetic neuralgia) was approved in 2009, as atherapeutic by both the U.S.Food and Drug Administration (FDA)[17][18] and the European Union.[19] A subsequent application to the FDA for Qutenza to be used as an analgesic inHIV neuralgia was refused.[20] One 2017 review of clinical studies having limited quality found that high-dose topical capsaicin (8%) compared with control (0.4% capsaicin) provided moderate to substantial pain relief from post-herpetic neuralgia,HIV-neuropathy, anddiabetic neuropathy.[21]
Although capsaicin creams have been used to treatpsoriasis for reduction of itching,[16][22][23] a review of sixclinical trials involving topical capsaicin for treatment ofpruritus concluded there was insufficient evidence of effect.[24] Oral capsaicin decreasesLDL cholesterol levels moderately.[25]
There is insufficient clinical evidence to determine the role of ingested capsaicin on several human disorders, including obesity,diabetes,cancer andcardiovascular diseases.[16]
Capsaicinoids are also an active ingredient in riot control and personal defensepepper spray agents.[2] When the spray comes in contact with skin, especially eyes ormucous 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.[26] Ground or crushed dried chili pods may be used in birdseed to deter rodents,[27] 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.[28]
An article published in theJournal 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."[29]
The first pesticide product using solely capsaicin as the active ingredient was registered with the U.S. Department of Agriculture in 1962.[26]
Capsaicin is a banned substance inequestrian sports because of its hypersensitizing and pain-relieving properties.[30] At the show jumping events of the2008 Summer Olympics, four horses tested positive for capsaicin, which resulted in disqualification.[30]
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). TheLD50 in mice is 47.2 mg/kg.[31][32]
Painful exposures to capsaicin-containing peppers are among the most common plant-related exposures presented to poison centers.[33] 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, andblepharospasm.[34]
The primary treatment is removal of the offending substance. Plain water is ineffective at removing capsaicin.[31] Capsaicin is soluble in alcohol, which can be used to clean contaminated items.[31]
When capsaicin is ingested, cold milk may be an effective way to relieve the burning sensation due tocaseins in milk, and the water of milk acts as asurfactant, allowing the capsaicin to form anemulsion with it.[35]
As of 2007, there was no evidence showing that weight loss is directly correlated with ingesting capsaicin. Well-designedclinical research had not been performed because thepungency of capsaicin in prescribed doses under research prevented subjects from complying in the study.[36] A 2014meta-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 towardcarbohydrates.[37]
Ingestion of high quantities of capsaicin can be deadly,[39] particularly in people with heart problems.[40] Even healthy young people can suffer adverse health effects likemyocardial infarction after ingestion of capsaicin capsules.[41]
The burning and painful sensations associated with capsaicin result from "defunctionalization" ofnociceptor nerve fibers by causing a topicalhypersensitivity reaction in the skin.[2][42] As a member of thevanilloid family, capsaicin binds to areceptor on nociceptor fibers called thevanilloid receptor subtype 1 (TRPV1).[42][43][44] TRPV1, which can also be stimulated with heat, protons and physical abrasion, permitscations to pass through thecell membrane when activated.[42] The resultingdepolarization of the neuron stimulates it to sendimpulses to the brain.[42] 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.[42]
Clarifying the mechanisms of capsaicin effects on skin nociceptors was part of awarding the 2021Nobel Prize in Physiology or Medicine, as it led to the discovery of skin sensors for temperature and touch, and identification of the singlegene causing sensitivity to capsaicin.[45][46]
The most commonly occurring capsaicinoids are capsaicin (69%), dihydrocapsaicin (22%), nordihydrocapsaicin (7%), homocapsaicin (1%), and homodihydrocapsaicin (1%).[63]
Capsaicin and dihydrocapsaicin (both 16.0 millionSHU) are the mostpungent 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). Althoughvanillylamide of n-nonanoic acid (Nonivamide, VNA, also PAVA) is produced synthetically for most applications, it does occur naturally inCapsicum species.[64]
Chili peppersVanillamine 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.
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.[65][66] Enzymes of thephenylpropanoid pathway, phenylalanine ammonia lyase (PAL), cinnamate 4-hydroxylase (C4H), caffeic acidO-methyltransferase (COMT) and their function in capsaicinoid biosynthesis were identified later by Fujiwake et al.,[67][68] and Sukrasno and Yeoman.[69] Suzuki et al. are responsible for identifying leucine as another precursor to the branched-chainfatty acid pathway.[70] 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 acidO-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.[71]
Plants exclusively of the genusCapsicum produce capsaicinoids, which arealkaloids.[72] Capsaicin is believed to be synthesized in theinterlocularseptum of chili peppers and depends on the geneAT3, which resides at thepun1locus, and which encodes a putativeacyltransferase.[73]
Capsaicin is the most abundant capsaicinoid found in the genusCapsicum, but at least ten other capsaicinoid variants exist.[77] Phenylalanine supplies the precursor to thephenylpropanoid pathway while leucine or valine provide the precursor for the branched-chain fatty acid pathway.[66][74] 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.[78] 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.[66][74]
TheCapsicum genus split fromSolanaceae 19.6 million years ago, 5.4 million years after the appearance ofSolanaceae, and is native only to the Americas.[79] 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 togenetic drift andnatural selection, across the genusCapsicum. Despite the fact that chilies within theCapsicum 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 thefitness of peppers against fungi infections, insects, andgranivorous mammals.[80]
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.[81] 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.[82] Capsaicin also inhibits fungalhyphae formation, which impacts the amount of nutrients that the rest of the fungal body can receive.[83] Thirdly, capsaicin disrupts the structure[84] 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, theergosterol 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.[85]
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.[86] Capsaicin can cause intestinaldysplasia upon ingestion, disrupting insect metabolism and causing damage to cell membranes within the insect.[87][88] This in turn disrupts the standard feeding response of insects.
Seed dispersion and deterrents against granivorous mammals
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.[89][11] 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.[10] Birds are able to eat chilies, then disperse the seeds in their excrement, enabling propagation.[11]
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.[90] Capsaicin synthesis in chilies places a strain on their water resources.[91] This directly affects their fitness, as it has been observed that standard concentration of capsaicin of peppers in high moisture environments in the seeds andpericarps of the peppers reduced the seeds production by 50%.[92]
Allicin, the activepiquant flavor chemical in uncookedgarlic, and to a lesser extentonions (see those articles for discussion of other chemicals in them relating to pungency, and eye irritation)
^abGovindarajan VS, Sathyanarayana MN (1991). "Capsicum--production, technology, chemistry, and quality. Part V. Impact on physiology, pharmacology, nutrition, and metabolism; structure, pungency, pain, and desensitization sequences".Critical Reviews in Food Science and Nutrition.29 (6):435–474.doi:10.1080/10408399109527536.PMID2039598.
^Ellis CN, Berberian B, Sulica VI, Dodd WA, Jarratt MT, Katz HI, et al. (September 1993). "A double-blind evaluation of topical capsaicin in pruritic psoriasis".Journal of the American Academy of Dermatology.29 (3):438–442.doi:10.1016/0190-9622(93)70208-B.PMID7688774.
^Gooding SM, Canter PH, Coelho HF, Boddy K, Ernst E (August 2010). "Systematic review of topical capsaicin in the treatment of pruritus".International Journal of Dermatology.49 (8):858–865.doi:10.1111/j.1365-4632.2010.04537.x.PMID21128913.S2CID24484878.
^Jensen PG, Curtis PD, Dunn JA, Austic RE, Richmond ME (September 2003). "Field evaluation of capsaicin as a rodent aversion agent for poultry feed".Pest Management Science.59 (9):1007–1015.doi:10.1002/ps.705.PMID12974352.
^Antonious GF, Meyer JE, Snyder JC (2006). "Toxicity and repellency of hot pepper extracts to spider mite, Tetranychus urticae Koch".Journal of Environmental Science and Health. Part. B, Pesticides, Food Contaminants, and Agricultural Wastes.41 (8):1383–1391.Bibcode:2006JESHB..41.1383A.doi:10.1080/0360123060096419.PMID17090499.S2CID19121573.
^Krenzelok EP, Jacobsen TD (August 1997). "Plant exposures ... a national profile of the most common plant genera".Veterinary and Human Toxicology.39 (4):248–249.PMID9251180.
^Goldfrank LR, ed. (23 March 2007).Goldfrank's Toxicologic Emergencies. New York, New York: McGraw-Hill. p. 1167.ISBN978-0-07-144310-4.
^Senese F (23 February 2018)."Fire and Spice".General Chemistry Online. Department of Chemistry, Frostburg State University.
^Whiting S, Derbyshire EJ, Tiwari B (February 2014). "Could capsaicinoids help to support weight management? A systematic review and meta-analysis of energy intake data".Appetite.73:183–188.doi:10.1016/j.appet.2013.11.005.PMID24246368.S2CID30252935.
^Bucholz CF (1816). "Chemische Untersuchung der trockenen reifen spanischen Pfeffers" [Chemical investigation of dry, ripe Spanish peppers].Almanach oder Taschenbuch für Scheidekünstler und Apotheker [Almanac or Pocketbook for Analysts and Apothecaries]. Vol. 37. Weimar. pp. 1–30. [Note: Christian Friedrich Bucholz's surname has been variously spelled as "Bucholz", "Bucholtz", or "Buchholz".]
^In a series of articles, J. C. Thresh obtained capsaicin in almost pure form:
Thresh JC (1876). "Isolation of capsaicin".The Pharmaceutical Journal and Transactions. 3rd Series.6:941–947.
^Buchheim R (1873). "Über die 'scharfen' Stoffe" [On the "hot" substance].Archiv der Heilkunde [Archive of Medicine].14.
^Buchheim R (1872). "Fructus Capsici".Vierteljahresschrift für praktische Pharmazie [Quarterly Journal for Practical Pharmacy] (in German).4: 507ff.
^Buchheim R (1873). "Fructus Capsici".Proceedings of the American Pharmaceutical Association.22: 106.
^Hőgyes E (1877). "Adatok a Capsicum annuum (paprika) alkatrészeinek élettani hatásához" [Data on the physiological effects of the pepper (Capsicum annuum)].Orvos-természettudumányi társulatot Értesítője [ulletin of the Medical Science Association] (in Hungarian).
^Fujiwake H, Suzuki T, Iwai K (November 1982). "Intracellular distributions of enzymes and intermediates involved in biosynthesis of capsaicin and its analogues in Capsicum fruits".Agricultural and Biological Chemistry.46 (11):2685–2689.doi:10.1080/00021369.1982.10865495.
^Fujiwake H, Suzuki T, Iwai K (October 1982). "Capsaicinoid formation in the protoplast from the placenta of Capsicum fruits".Agricultural and Biological Chemistry.46 (10):2591–2592.doi:10.1080/00021369.1982.10865477.
^Suzuki T, Kawada T, Iwai K (1981). "Formation and metabolism of pungent principle ofCapsicum fruits. 9. Biosynthesis of acyl moieties of capsaicin and its analogs from valine and leucine inCapsicum fruits".Plant & Cell Physiology.22:23–32.doi:10.1093/oxfordjournals.pcp.a076142.
^Curry J, Aluru M, Mendoza M, Nevarez J, Melendrez M, O'Connell MA (1999). "Transcripts for possible capsaicinoid biosynthetic genes are differentially accumulated in pungent and non-pungentCapsicum spp".Plant Sci.148 (1):47–57.Bibcode:1999PlnSc.148...47C.doi:10.1016/s0168-9452(99)00118-1.S2CID86735106.
^Kozukue N, Han JS, Kozukue E, Lee SJ, Kim JA, Lee KR, et al. (November 2005). "Analysis of eight capsaicinoids in peppers and pepper-containing foods by high-performance liquid chromatography and liquid chromatography-mass spectrometry".Journal of Agricultural and Food Chemistry.53 (23):9172–9181.doi:10.1021/jf050469j.PMID16277419.
^Thiele R, Mueller-Seitz E, Petz M (June 2008). "Chili pepper fruits: presumed precursors of fatty acids characteristic for capsaicinoids".Journal of Agricultural and Food Chemistry.56 (11):4219–4224.Bibcode:2008JAFC...56.4219T.doi:10.1021/jf073420h.PMID18489121.
The results of Bucholz's and Braconnot's analyses ofCapsicum annuum appear in:Pereira J (1854).The Elements of Materia Medica and Therapeutics. Vol. 2 (3rd US ed.). Philadelphia, Pennsylvania: Blanchard and Lea. p. 506.
Biographical information about Christian Friedrich Bucholz is available in:Rose HJ (1857). Rose HJ, Wright T (eds.).A New General Biographical Dictionary. Vol. 5. London, England: T. Fellowes. p. 186.
Some other early investigators who also extracted the active component of peppers:
Maurach B (1816). "Pharmaceutisch-chemische Untersuchung des spanischen Pfeffers" [Pharmaceutical-chemical investigation of Spanish peppers].Berlinisches Jahrbuch für die Pharmacie (in German).17:63–73. Abstracts of Maurach's paper appear in: (i)Repertorium für die Pharmacie, vol. 6,page 117-119 (1819); (ii)Allgemeine Literatur-Zeitung, vol. 4, no. 18,page 146 (February 1821); (iii) "Spanischer oder indischer Pfeffer",System der Materia medica ..., vol. 6,pages 381–386 (1821) (this reference also contains an abstract of Bucholz's analysis of peppers).
Henri Braconnot, French chemistBraconnot H (1817). "Examen chemique du Piment, de son principe âcre, et de celui des plantes de la famille des renonculacées" [Chemical investigation of the chili pepper, of its pungent principle [constituent, component], and of that of plants of the familyRanunculus].Annales de Chimie et de Physique (in French).6:122- 131.
Johann Georg Forchhammer, Danish geologistOersted HC (1820). "Sur la découverte de deux nouveaux alcalis végétaux" [On the discovery of two new plant alkalis].Journal de physique, de chemie, d'histoire naturelle et des arts [Journal of Physics, Chemistry, Natural History and the Arts] (in French).90:173–174.
Ernst Witting, German apothecaryWitting E (1822). "Considerations sur les bases vegetales en general, sous le point de vue pharmaceutique et descriptif de deux substances, la capsicine et la nicotianine" [Thoughts on the plant bases in general from a pharmaceutical viewpoint, and description of two substances, capsicin and nicotine].Beiträge für die Pharmaceutische und Analytische Chemie [Contributions to Pharmaceutical and Analytical Chemistry] (in French).3: 43. He called it "capsicin", after the genusCapsicum from which it was extracted. John Clough Thresh (1850–1932), who had isolated capsaicin in almost pure form,[48][49] gave it the name "capsaicin" in 1876.[50] Karl Micko isolated capsaicin in its pure form in 1898.[51][52] Capsaicin's chemical composition was first determined in 1919 by E. K. Nelson, who also partially elucidated capsaicin's chemical structure.[53] Capsaicin was first synthesized in 1930 by Ernst Spath and Stephen F. Darling.[54] In 1961, similar substances were isolated fromchili peppers by the Japanese chemists S. Kosuge and Y. Inagaki, who named them capsaicinoids.[55][56]
