Capsaicin

Capsaicin (8-methyl-N-vanillyl-6-nonenamide, (CH3)2CHCH=CH(CH2)4CONHCH2C6H3-4-(OH)-3-(OCH3) ) is the active component of chili peppers, which are plants belonging to the genus Capsicum. It is an irritant for mammals, including humans, and produces a sensation of burning in any tissue with which it comes into contact. Capsaicin and several related compounds are called capsaicinoids and are produced as a secondary metabolite by chili peppers, probably as deterrents against certain herbivores and fungi. Pure capsaicin is a hydrophobic, colorless, odorless, crystalline to waxy compound.

History
The compound was first extracted (albeit in impure form) in 1816 by Christian Friedrich Bucholz (1770–1818). In 1817, French chemist Henri Braconnot (1780-1855) also extracted the active component of peppers. See: Henri Braconnot (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 family Ranunculus), Annales de Chemie et de Physique, vol. 6, pages 122- 131. Other early investigators who tried to isolate the active compound in chili peppers include: (1) Benjamin Maurach (see:  Benjamin Maurach (1816) "Pharmaceutisch-chemische Untersuchung des spanischen Pfeffers" (Pharmaceutical-chemical investigation of Spanish peppers), Berlinisches Jahrbuch für die Pharmacie, vol. 17, pages 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 (Feb. 1821); (iii) "Spanischer oder indischer Pfeffer," System der Materia medica ..., vol. 6, pages 381-386 (1821). (Also contains abstract of Bucholz's analysis of peppers.)); (2) Danish geologist Johann Georg Forchhammer (see: Hans C. Oersted (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, vol. 90, pages 173-174.; and (3) German apothecary Ernst Witting (see: Ernst Witting (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, vol. 3, pages  43ff.)  He called it "capsicin," after the genus Capsicum from which it was extracted. John Clough Thresh (1850–1932), who had isolated capsaicin in almost pure form, gave it the name "capsaicin" in 1876. But it was Karl Micko who first isolated capsaicin in pure form in 1898. Capsaicin's empirical formula (chemical composition) was first determined by E. K. Nelson in 1919; he also partially elucidated capsaicin's chemical structure. Capsaicin was first synthesized in 1930 by E. Spath and S. F. Darling. In 1961, similar substances were isolated from chili peppers by the Japanese chemists S. Kosuge and Y. Inagaki, who named them capsaicinoids.

In 1873 German pharmacologist Rudolf Buchheim (1820–1879) and in 1878 the Hungarian doctor Endre Hőgyes stated that "capsicol" (partially purified capsaicin ) caused the burning feeling when in contact with mucous membranes and increased secretion of gastric juice.

Capsaicinoids
Capsaicin is the main capsaicinoid in chili peppers, followed by dihydrocapsaicin. These two compounds are also about twice as potent to the taste and nerves as the minor capsaicinoids nordihydrocapsaicin, homodihydrocapsaicin, and homocapsaicin. Dilute solutions of pure capsaicinoids produced different types of pungency; however, these differences were not noted using more concentrated solutions.

Capsaicin is believed to be synthesized in the interlocular septa of chili peppers by addition of a branched-chain fatty acid to vanillylamine; specifically, capsaicin is made from vanillylamine and 8-methyl-6-nonenoyl CoA (where CoA = Coenzyme A). Biosynthesis depends on the gene AT3, which resides at the pun1 locus, and which encodes a putative acyltransferase.

Besides the six natural capsaicinoids, one synthetic member of the capsaicinoid family exists. Vanillylamide of n-nonanoic acid (VNA, also PAVA) is used as a reference substance for determining the relative pungency of capsaicinoids.

Natural function
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.

The seeds of Capsicum plants are predominantly dispersed by birds. Birds do not have the receptor to which capsaicin binds, so it does not function as an irritant for them. Chili pepper seeds consumed by birds pass through the digestive tract and can germinate later, but mammals have molars, which destroy 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 reproduce. There is also evidence that capsaicin evolved as an anti-fungal agent, and capsaicinoids are broadly anti-microbial.

In 2006, it was discovered that tarantula venom activates the same pathway of pain as is activated by capsaicin, the first demonstrated case of such a shared pathway in both plant and animal anti-mammal defense.

Food
Because of the burning sensation caused by capsaicin when it comes in contact with mucous membranes, it is commonly used in food products to give them added spice or "heat" (pungency). In high concentrations capsaicin will also cause a burning effect on other sensitive areas of skin. The degree of heat found within a food is often measured on the Scoville scale.

Bathing the mucous membrane surfaces that have contacted capsaicin with oil is the most effective way to attenuate the associated discomfort. Since oil and capsaicin are both hydrophobic hydrocarbons the capsaicin which has not already been absorbed into tissues will be picked up into solution and easily removed. Water is almost completely ineffective. Cold milk is the second most effective solution against the burning sensation (due to caseins having a detergent effect on capsaicin ) and cold sugar solution (10%) at 20 °C is almost as effective. The burning sensation will slowly fade away over several hours if no actions are taken. In some cases people enjoy the pain; there is a growing demand for capsaicin spiced food and beverages. There have been several food products featuring capsaicin such as hot sauce, salsa, and beverages.

Beverage
Recently beverage products are emerging with capsaicin as an active ingredient. The first two capsaicin beverages to hit the market are Prometheus Springs Elixirs launched in 2007 and Sweet16 launched in 2011. It is common for people to experience pleasurable and even euphoriant effects from ingesting capsaicin. Folklore among self-described "chiliheads" attributes this to pain-stimulated release of endorphins, a different mechanism from the local receptor overload that makes capsaicin effective as a topical analgesic. In support of this theory, there is some evidence that the effect can be blocked by naloxone and other compounds that compete for receptor sites with endorphins and opiates.

Medical
Capsaicin is currently used in topical ointments, as well as a high-dose dermal patch (trade name Qutenza), to relieve the pain of peripheral neuropathy such as post-herpetic neuralgia caused by shingles. It may be used in concentrations of between 0.025% and 0.075%. It may be used as a cream for the temporary relief of minor aches and pains of muscles and joints associated with arthritis, simple backache, strains and sprains, often in compounds with other rubefacients. The treatment typically involves the application of a topical anesthetic until the area is numb. Then the capsaicin is applied by a therapist wearing rubber gloves and a face mask. The capsaicin remains on the skin until the patient starts to feel the "heat", at which point it is promptly removed. Capsaicin is also available in large bandages that can be applied to the back.

Capsaicin creams are used to treat psoriasis as an effective way to reduce itching and inflammation.

According to animal and human studies, the oral intake of capsaicin may increase the production of heat by the body for a short time. Due to the effect on the carbohydrates breakdown after a meal, cayenne may also be used to regulate blood sugar levels. Further research is required to see if capsaicin would be useful to treat obesity. Substance P, a neuropeptide released by capsaicin, has been shown to reverse diabetes in mice, but the effects to insulin secretion seems to be species dependent. In humans, substance P seems to decrease insulin release and cause fluctuations in blood sugar levels.

In 1997, a research team led by David Julius of UCSF showed that capsaicin selectively binds to a protein known as TRPV1 that resides on the membranes of pain and heat sensing neurons. TRPV1 is a heat activated calcium channel, which opens between 37 and 45 °C (98.6 and 113 °F, respectively). When capsaicin binds to TRPV1, it causes the channel to open below 37 °C (normal human body temperature), which is why capsaicin is linked to the sensation of heat. Prolonged activation of these neurons by capsaicin depletes presynaptic substance P, one of the body's neurotransmitters for pain and heat. Neurons that do not contain TRPV1 are unaffected.

The result appears to be that the chemical mimics a burning sensation, the nerves are overwhelmed by the influx, and are unable to report pain for an extended period of time. With chronic exposure to capsaicin, neurons are depleted of neurotransmitters, leading to reduction in sensation of pain and blockade of neurogenic inflammation. If capsaicin is removed, the neurons recover.

Capsaicin is being explored as a possible prophylaxis for Type 1 diabetes by researchers in Toronto, Canada. Capsaicin was injected subcutaneously in neonatal diabetes-prone NOD mice to permanently remove a prominent subset of pancreatic sensory neurons, which express the transient receptor potential vanilloid-1 (TRPV1) protein. Insulin resistance and beta cell stress of prediabetic NOD mice are prevented when TRPV1+ neurons are eliminated. In other words, mice who were genetically predisposed to Type 1 diabetes were prevented from developing Type 1 via removal of these neurons, which are thought to attract pathogenic T-cells to attacking pancreatic beta cells (i.e., the cause of Type 1 diabetes).

The American Association for Cancer Research reports studies suggesting capsaicin is able to kill prostate cancer cells by causing them to undergo apoptosis. The studies were performed on tumors formed by human prostate cancer cell cultures grown in mouse models, and showed tumors treated with capsaicin were about one-fifth the size of the untreated tumors. There have been several clinical studies conducted in Japan and China that showed natural capsaicin directly inhibits the growth of leukemic cells.

Another study carried out at the University of Nottingham suggests capsaicin is able to trigger apoptosis in human lung cancer cells as well.

Capsaicin is also the key ingredient in the experimental drug Adlea, which is in Phase 2 trials as a long-acting analgesic to treat post-surgical and osteoarthritis pain for weeks to months after a single injection to the site of pain. More over, it reduces pain resulted rheumatoid arthritis as well as joint or muscle pain from fibromyalgia or other causes.

Proposed drug abuse deterrent
Clifford Woolf, the Richard J. Kitz Professor of Anesthesia Research at Harvard Medical School, has suggested using capsaicin to deter abuse of certain extended-release drugs such as OxyContin and Ritalin. When taken as prescribed, opioid prescription drugs such as OxyContin or stimulant drugs such as Adderall XR release their active chemical over time, but when crushed and insufflated, taken as a suppository, chewed, or injected, the larger than normal dosage is absorbed all at once and a much stronger effect is produced that can be highly habit forming and potentially fatal due to the higher risk of overdose. Woolf has argued that adding capsaicin into the capsules would be a safe way to deter abuse. A person taking the capsule in the prescribed way (i.e., swallowing it whole) would suffer no ill effects from the additive. However, a person crushing it would expose the irritant. Anyone then chewing it, snorting it, or injecting it would be exposed to the full power of the chemical. "Imagine snorting an extract of 50 jalapeño peppers and you get the idea," Woolf said in an interview with the Harvard University Gazette. As of 2006, Woolf's proposal is still in the preliminary stages of development and the additive has not yet entered the production stage. A major downside of the idea is that drug users would likely turn to polluted street drugs rather than abusing pure pills. Also, should a user choose to crush a number of pills and swallow them inside a medium, such as rolling paper or tissue, the danger of ill effects or overdose may exist not only from the drug itself, but also as a result of the large dose of capsaicin the individual would be exposed to over a short period of time.

Less-than-lethal force
Capsaicin is also the active ingredient in riot control and personal defense pepper spray chemical agents. When the spray comes in contact with skin, especially eyes or mucous membranes, it is very painful, and breathing small particles of it as it disperses can cause breathing difficulty, which serves to discourage assailants. Refer to the Scoville scale for a comparison of pepper spray to other sources of capsaicin.

In large quantities, capsaicin can cause death. Symptoms of overdose include difficulty breathing, blue skin, and convulsions. The large amount needed to kill an adult human and the low concentration of capsaicin in chilies make the risk of accidental poisoning by chili consumption negligible.

Pest deterrent
Capsaicin is also used to deter mammalian pests. A common example is the use of ground-up or crushed dried chili pods in birdseed to deter squirrels, since birds are unaffected by capsaicin. Another example is the use of chili peppers by the Elephant Pepper Development Trust to improve crop security for rural communities in Africa.

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.

There are manufacturers that do sell a capsaicin-based gel product that is reported to be a feral-pigeon (Columba livia) deterrent from specific roosting and loafing areas. Some of these products do have an EPA label and NSF approval.

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

Mechanism of action
The burning and painful sensations associated with capsaicin result from its chemical interaction with sensory neurons. Capsaicin, as a member of the vanilloid family, binds to a receptor called the vanilloid receptor subtype 1 (VR1). First cloned in 1997, VR1 is an ion channel-type receptor. VR1, which can also be stimulated with heat and physical abrasion, permits cations to pass through the cell membrane and into the cell when activated. The resulting depolarization of the neuron stimulates it to signal the brain. By binding to the VR1 receptor, the capsaicin molecule produces the same sensation that excessive heat or abrasive damage would cause, explaining why the spiciness of capsaicin is described as a burning sensation.

The VR1 ion channel has subsequently been shown to be a member of the superfamily of TRP ion channels, and as such is now referred to as. There are a number of different TRP ion channels that have been shown to be sensitive to different ranges of temperature and probably are responsible for our range of temperature sensation. Thus, capsaicin does not actually cause a chemical burn, or indeed any direct tissue damage at all, when chili peppers are the source of exposure. The inflammation caused by the burn or physical abrasion that the body believes it has undergone can potentially cause tissue damage in cases of extreme exposure, as is the case for many substances that trick the body into inflaming itself.

Acute health effects
Capsaicin is a highly irritant material 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). Severe over-exposure to pure capsaicin can result in death; the lethal dose ( in mice) is 47.2 mg/kg.

Painful exposures to capsaicin-containing peppers are among the most common plant-related exposures presented to poison centers. 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.

Drug interactions
Capsaicin is indicated as interacting with a number of drugs, including the commonly prescribed high-blood pressure drug Lisinopril, to induce a side-effect cough.

Treatment after exposure
The primary treatment is removal from exposure. Contaminated clothing should be removed and placed in airtight bags to prevent secondary exposure. Capsaicin could be washed off the skin using soap, shampoo, or other detergents, or rubbed off with oily compounds such as vegetable oil, paraffin oil, petroleum jelly (Vaseline), creams, or polyethylene glycol. Plain water is ineffective at removing capsaicin, as are vinegar, bleach, sodium metabisulfite, topical antacid suspensions, and other home remedies.

Burning and pain symptoms can be effectively relieved by cooling, such as from ice, cold water, cold bottles, cold surfaces, or a flow of air from wind or a fan. In severe cases, eye burn might be treated symptomatically with topical ophthalmic anesthetics; mucous membrane burn with lidocaine gel. The gel from the aloe plant has also been shown to be very effective. Capsaicin-induced asthma might be treated with nebulized bronchodilators or oral antihistamines or corticosteroids.

Effects of dietary consumption
Ingestion of spicy food or ground jalapeño peppers does not cause mucosal erosions or other abnormalities. Some mucosal microbleeding has been found after eating red and black peppers, but there was no significant difference between aspirin (used as a control) and peppers. The question of whether chili ingestion increases or decreases risk of stomach cancer is unresolved: a study of Mexican patients found self-reported capsaicin intake levels associated with increased stomach cancer rates (however, this is very likely attributed to Helicobacter pylori ) while a study of Italians suggests eating hot peppers regularly was protective against stomach cancer. A preliminary study using county population and mortality data showed significantly higher rates for stomach and liver cancer in counties inhabited by groups with high consumption of capsaicin-rich foods than in matched control counties. Carcinogenic, co-carcinogenic, and anticarcinogenic effects of capsaicin have been reported in animal studies.

General references

 * Garnanez RJ, McKee LH (2001) "Temporal effectiveness of sugar solutions on mouth burn by capsaicin" IFT Annual Meeting 2001
 * Tarantula Venom, Chili Peppers Have Same "Bite," Study Finds http://news.nationalgeographic.com/news/2006/11/061108-tarantula-venom.html
 * Minna M. Hamalainen, Alberto Subieta, Christopher Arpey, Timothy J. Brennan, "Differential Effect of Capsaicin Treatment on Pain-Related Behaviors After Plantar Incision," The Journal of Pain, 10,6 (2009), 637-645.
 * Tarantula Venom, Chili Peppers Have Same "Bite," Study Finds http://news.nationalgeographic.com/news/2006/11/061108-tarantula-venom.html
 * Minna M. Hamalainen, Alberto Subieta, Christopher Arpey, Timothy J. Brennan, "Differential Effect of Capsaicin Treatment on Pain-Related Behaviors After Plantar Incision," The Journal of Pain, 10,6 (2009), 637-645.
 * Tarantula Venom, Chili Peppers Have Same "Bite," Study Finds http://news.nationalgeographic.com/news/2006/11/061108-tarantula-venom.html
 * Minna M. Hamalainen, Alberto Subieta, Christopher Arpey, Timothy J. Brennan, "Differential Effect of Capsaicin Treatment on Pain-Related Behaviors After Plantar Incision," The Journal of Pain, 10,6 (2009), 637-645.
 * Minna M. Hamalainen, Alberto Subieta, Christopher Arpey, Timothy J. Brennan, "Differential Effect of Capsaicin Treatment on Pain-Related Behaviors After Plantar Incision," The Journal of Pain, 10,6 (2009), 637-645.