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The exact molecule found in hot peppers that burns your face off, acts via adrenaline receptors and TRPV1 (like Evodia) to increase heat quickly. Can burn body fat with minimal potency, fight inflammation with decent potency, and prevent cancer with indeterminate potency.

Our evidence-based analysis on capsaicin features 108 unique references to scientific papers.

Research analysis led by and reviewed by the Examine team.
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Research Breakdown on Capsaicin

1Sources and Structure


Capsaicin ((E)-N-{(4-hydroxy-3-methoxyphenyl)methyl}-8-methyl-6-nonenamide) is one of many alkaloids that is referred to as a Capsaicinoid, which are commonly associated with chili products of the family solanaceae (subfamily capsicum).[4] It was first known to somewhat exist (due to its taste properties) well in the 1500s, first extracted in 1846,[5] the structure determined in 1919[6] and first synthesized in 1930.[7]

These vegetables (particularly the species Capsicum annuum) were initially referred to as 'chilis' due to the Aztec word tlacuilos and were later called red peppers due to having similar sensory properties to black pepper, despite not being in the same plant family (black pepper being Piper nigrum).[5] The term capsicum has unclear origins, being based on either kapto (Greek term for bite, in reference to its taste) or caspa (Latin term for box, referring to its internal plant structure).[5]

Of the capsaicinoids, there are six common ones; capsaicin, dihydrocapsaicin, nordihydrocapsaicin, homocapsaicin, homodihydrocapsaicin, and nonivamide.[8][9] When looking at the main mechanism of action for capsaicinoids (TRPV1 channel activation), nonivamide and capsaicin are the most potent analogues with dihydrocapsaicin following in potency.[10]

Similar to curcumin (of the curcuminoids) and berberine (of the protoberberine alkaloids), capsaicin is the most well known molecule in a particular collection of molecules known as capsaicinoids. It is found mostly in peppers, and due to this the molecule itself is sometimes referred to as Hot Pepper Extract

There is another subset of molecules that are somewhat similar to capsaicinoids, and are native to sweet peppers (CH-19 Sweet, a cultivar of Capsicum annuum with low pungency); these are caspiate based compounds such as caspiate, dihydrocaspiate, and nordihydrocaspiate.[11][12] Despite not having the same sensory properties, caspiate also appears to elevate body heat and suppress fat gain in rodents[13] and oral ingestion of CH-19 or isolated capsinoids in humans has also resulted in the similar increase in oxygen consumption (indicative of an increase in metabolic rate).[14][15]

Sweet pepper does not contain the classical capsaicinoids, but has similar compounds based off of caspiate; they appear to be somewhat bioequivalent

1.2Structure and Properties

Capsaicin is insoluble in cold water, but can become soluble when the temperature is increased to 52ºC.[16]

1.3Scoville and Taste

Hot peppers (or particularly, the hotness of peppers) was traditionally measured via something known as Scovilles, named after Wilbur Scoville.[17] Nowadays HPLC is almost exclusively used to quantify capsaicin content of peppers due to its accuracy although 'scoville' remains used to measure the subjective sensation of hotness.[5]

The scoville rating system is based on dilution, and the scoville rating is how diluted a molecule must be in alcohol to no longer have a percievable hotness on the tongue. In this sense, a molecule with 50,000 scovilles must be diluted to a concentration of 1:50,000 to have no percievable hotness while a scoville rating of 100,000 must be diluted to 1:100,000.[5]

The scoville rating is a measurement of how diluted the molecule must be in order to no longer have a percievable hotness, with a higher rating indicating more hotness (since it needs to be diluted to an even smaller level to lose its efficacy)

It appears that the human tongue can detect capsaicin at concentrations as low as 0.1-1µg/mL, and 10-100µg/mL of capsaicin in liquid is the range where capsaicin begins to become percieved as 'hot' and 'burning'.[18][16]



Capsaicin is metabolized extensively by the liver CYP450 enzymes and Carboxyesterase class enzymes[19] and yeild numerous byproducts via akly, aromatic, and amide metabolic pathways.[20] Due to metabolic changes to the vanilloid ring and capsaicin's hydrophobic alkyl sidechain, the metabolites possess less potential at the VR1 receptor.[21] Capsaicin also possess numerous 'electrophile' metabolites, that can bind to liver enzymes and proteins via a reactive arene oxide or quinone methide group.[10][22]

2.2Enzymatic Interactions

In vitro, capsaicin inhibits CYP3A4 with an IC50 of 21.5µM while other capsaicinoids (capsiate, dihydrocapsiate, and nordihydrocapsiate) failed to inhibit CYP3A4.[23] CYP3A4 is the most prominent enzyme of drug metabolism in the liver, consisting up to 30-40% of all P450 enzymes (those prefaced with CYP-)[24] and its inhibition should cause increases in drug exposure to the body (assessed by AUC).

In rats, capsaicin (3-25mg/kg oral ingestion) for seven days prior to the statin known as simvastatin (metabolized primarily by CYP3A4[25] with a bit from CYP2C8[26]) is able to decrease the AUC of a dose of simvastatin in a dose-dependent manner by 67.06-77.49%.[27] The authors suggested enzymatic induction as a response to its inhibition.

Although capsaicin may interfere with CYP3A4 function initially (via inhibition), the enzyme appears to adapt and then proliferate after a week of capsaicin ingestion; the result is increased CYP3A4 activity and increased drug clearance from the body

3Molecular Targets


TRPVs (Transient Receptor Potential cation channel subfamily V; or simply Vanilloid receptor) are molecular targets which are highly permeable to cations.[28][29] They were initially called vanilloid receptors due to being responsive to vanilloid compounds (of which there are four classes; capsaicinoids, resiniferanoids, unsaturated dialdehydes, and triprenyl phenols[5]) although since there have been ligands discovered that are not vanilloid compounds[30][31] this name has fallen out of favor instead for TRPV. Capsaicin is known to be a specific TRPV1 receptor agonist.[5]

TRPV1 is also a channel that is sensitive to heat itself (greater than 48°C),[32] causing a molecular explanation for how heat treatment. Capsaicin seems to lower the threshold required for this channel to be activated, and in the presence of capsaicin TRPV1 can be activated at room temperature.[33] Other things that may sensitize TRPV1 receptors include acidity (a low pH) and inflammation (which are negative issues for inflammatory hyperalgesia)[34] as well as the endogenous ligands of LTB4 and 15(S)-HETE (arachidonic acid eicosanoids).[35][36]

Capsaicin sensitizes TRPV1, the calcium channel that is activated in response to heat. When TRPV1 is also in the presence of capsaicin, the amount of heat required to activate it is significantly reduced from 48°C or above down to room temperature

TRPV1 activation causes calcium influx, and since calcium influx into a cell is itself a relatively potent signalling process TRPV1 has a wide variety of mechanism. This calcium influx from TRPV1 is known to mediate capsaicin related improvements in exercise endurance (via mitochondrial biosynthesis and type I oxidative fiber formation),[37] type I oxidative muscle fiber formation (via PGC-1α activation),[37] mitochondrial biogenesis (via PGC-1α activation),[37] muscle protein synthesis (via mTOR activation),[38][39] adrenaline secretion from the adrenal glands[40][41] (and secondary to adrenaline, β-adrenergic stimulation[42] and the increase in metabolic rate[1]),

The activation of TRPV1, which causes intracellular calcium influx, underlies the majority of the beneficial effects of capsaicin

TRPV1 has been noted to, in muscle cells, actually be upregulated by around 50% in response to chronic (0.01% capsaicin for four months) dietary treatment with capsaicin and other proteins under the influence of TRPV1 (including PGC-1α) are simultaneously upregulated.[37] Higher doses of capsaicin (50mg/kg injections) appear to still upregulate the receptor by 40% and may act within 24 hours.[43]

TRPV1 is known to be downregulated during fat cell proliferation and adipogenesis, and with less TRPV1 expression capsaicin is less effective in releasing intracellular calcium.[44] In fact, obese men have been confirmed to have less TRPV1 in their visceral and subcutanoues adipose tissue (body fat, to 14% and 72% of lean control respectively)[44] and mechanisms of capsaicin (SNS stimulation) have been noted to be less effective in obese persons.[45] That being said, chronic ingestion of capsaicin in the mouse diet prevents a downregulation of TRPV1, and in normal control chronic ingestion of capsaicin further increases TRPV1 receptor content.[44]

TRPV1 receptor activation in the pancreas is also able to release proinflammatory cytokines which then act upon TRPV1 itself to enhance further signalling;[46] this has been described as a feed forward effect (opposite of feedback).[47]

Unlike most drug-receptor interactions, which are associated with desensitization and negative feedback to assure some degree of regulation, capsaicin on the TRPV1 receptor is associated with feed forward (amplifying) and receptor proliferating activities; in essence, the opposite of receptor desensitization


The signal transducer and activator of transcription (STAT), in particular STAT3, is a molecular target of cancer therapy due to being involved in cell survival, proliferation, chemoresistance, and angiogenesis.[48] It is activated by factors such as IL-6[49] and then activates janus-activated kinases (JAKs) and Srcs to dimerize and then influence genetic signalling.[50]

Capsaicin can inhibit both constituative and inducible STAT3 activation (via IL-6) without influencing STAT5,[51][52] and due to this it suppressed activation of STAT3 dependent gene products such as cyclin D1, Bcl-2, Bcl-xL, survivin, and VEGF.[52] This inhibition occurs fully at 50μM capsaicin without affecting the protein content of STAT3[52] and appears to be associated with a depletion intracellular GP130 pools in a cell (capsaicin at 100μM stresses the endoplasmic reticulum and causes a reduction of GP130; levels of GP130 are correlated with STAT3 activity).[53]

Capsaicin appears to be a STAT3 inhibitor, although the lowest active dose seen (50μM) is significantly higher than the concentration required to stimulate TRPV1 (1μM); practical significance of STAT3 is not ascertained at this moment in time

At least one study has found the opposite reaction, and that capsaicin (100µM in SW480 cancer cells) caused activation of STAT3 and, subsequent to that, enhanced migratory and invasive potential of cells.[54]

There is potential that capsaicin may also activate STAT3, and not enough is known to understand under what circumstances STAT3 is activated or inhibited

3.3Neurokinin Receptors

Capsaicin is known to phosphorylate ERK in sensory neurons, and this is effectively prevented by blocking the NK1 (neurokinin) receptor[55] although the NK2 receptor appears to mediate the effects of capsaicin in the dorsal root ganglia.[56] Capsaicin is also known to release Substance P which is able to act upon NK1 receptors to phosphorylate ERK,[57] and this stimulation of ERK1/2 is thought to underlie the ability of capsaicin to induce NGF (known to occur secondary to ERK phosphorylation).[58]

Capsaicin appears to stimulate neurokinin receptors, possible secondary to increasing secretion of Substane P (which is a ligand of NK1 and NK2); this appears to be independent of the TRPV channels



Capsaicin is known to interact with neuropathic pain in an algesic manner (pain causing) due to enhancing signalling through TRPV1.[59] TRPV1 is known to be a positive modulator of neuropathic pain, and either enhancing signalling (inflammation, acidity, capsaicin) or proliferating TRPV1 receptors[60][61] may exacerbate neuropathic pain.


Capsaicin has been noted to reduce food intake in mice that are on a high fat diet as well as the normal control (dose not specified), although it lost efficacy after ten days of oral supplementation.[44]

In rodents, capsaicin appears to reduce food intake but loses its efficacy within a week or so

Suppression of food intake and self-reported appetite has been noted in humans with red pepper vegetable consumption (6-10g)[62] which is associated with β-adrenergic stimulation,[1] and supplementation of 750mg capsaicin in otherwise healthy men (even after controlling for the spicy sensation) appears to reduce food intake in the range of 8.1-8.5% primarily through a reduced fat intake (13.3-15.5%).[16] A reduction in relative fat consumption has also been reported elsewhere with pepper consumption.[63]

Appetite reductions have been confirmed with capsaicin and hot pepper ingestion (attributed to capsaicin), but all studies have been quite short in duration

5Cardiovascular Health

5.1Heart Rate

Supplementation of 150mg capsaicin an hour prior to low intensity activity (as well as at rest) does not alter heart rate in otherwise healthy men.[64]

6Fat Mass and Obesity

6.1Metabolic Rate

Capsaicin is known to stimulate the metabolic rate secondary to β-adrenergic activity,[42] which is thought to be secondary to catecholamine (adrenaline) release from the adrenal glands.[41] The release of catecholamines from the adrenal glands is eventually traced back to TRPV1 activation by capsaicin.[40]

Consumption of 10g of red pepper appears to enhance metabolic rate for 30 minutes after a meal (with no significant influence over the next 120 minutes), which was due to β-adrenergic stimulation since it was abolished with propanolol.[1]

Capsaicin acts on TRPV1 receptors in the adrenal glands to release adrenaline, and the increased adrenaline per se increases the metabolic rate by acting on β-adrenergic receptors on fat cells



6.2Fat Oxidation

Fat oxidation (the percentage of calories used which come from fatty acids rather than other substrate such as glucose) appears to be increased following ingestion of capsaicin in rats, with maximal efficacy at 10mg/kg oral intake and secondary to adrenaline secretion.[66]

150mg of capsaicin an hour prior to low intensity exercise is able to increase fat oxidation rates in otherwise healthy adult men (otherwise untrained).[64]

Fat oxidation appears to be increased following oral ingestion of capsaicin, and this has been demonstrated in humans following supplementation of standard dosages


Capsaicin can also induce heat production via neuronal stimulation[67], possibly by neurons expressing the VR1 receptors.[68] These increases in heat seem to be vicariously through beta-adrenergic stimulation.[42][69]

These effects have also been noted with Capsiate, a non-pungent capsaicinoid compound.[13][14]


Fat cells (adipocytes) are known to express TRPV1, including 3T3-L1 adipocytes.[44]

In isolated 3T3-L1 adipocytes, capsaicin is active at 10nM with maximal activity at 1,000nM (1µM)[44] and maximal activity of capsaicin over 8 days is able reduce fat cell accumulation to 62% of control during adipogenesis while reducing fatty acid synthase activity (91% reduction).[44] When not in the state of adipogenesis, capsaicin is without effect.[44]

When given a high fat diet, mice also given capsaicin (undisclosed dose) effectively prevented obesity over 120 days; this was without significant alterations in food intake.[44] This anti-obesity effect was not present when the mice lacked the TRPV1 receptor.[44]

Capsaicin appears to confer an anti-obese effect secondary to preventing accumulation of triglycerides into fat cells, and this occurs at a low enough concentration that it likely applies to nutritional supplementation

7Skeletal Muscle and Physical Performance


It is known that neuronal nitric oxide synthase (nNOS, found in the sarcolemma of muscles[70]) is activated in response to mechanical stress causing activation of TRPV1 (also found in the sarcolemma[71][37][72]), which is activated by peroxynitrate (product of nitric oxide and superoxide, mediated by the Nox4 enzyme[73]) and subsequently causes calcium influx; said calcium influx then induces muscle protein synthesis via activating mTOR.[38] Blocking nNOS attenuates (but does not abolish) muscle growth despite not interfering with inflammation, fiber type composition, nor satellite cell recruitment.[38]

When investigating the cGMP pathway (activating via nitric oxide acting upon the cGMP receptor and producing cGMP), there was no evidence that this pathway was responsble for muscle protein synthesis.[38] Although nitric oxide itself has been implicated in acting on TRPV channels,[74] sequestering peroxynitrate abolishes the benefits observed (suggesting nitric oxide acts solely via peroxynitrate) and abolishing Nox4 also prevents exercise induced hypertrophy;[38] nNOS inhibition, peroxynitrate sequestering, and Nox4 inhibition can all be circumvented with direction stimulation of TRPV1 with capsaicin (injections of 10μM to mice)[38] which activates mTOR without activating AMPK, Akt, or GSK3β.[39]

Muscle contraction induces muscle protein synthesis, and it seems that one of these pathways that promote muscle protein synthesis in response to exercise involves nitric oxide signalling through TRPV1. Capsaicin is a direct activator of TRPV1 and can stimulate muscle protein synthesis despite antioxidant presence in a cell


The mitochondrial factor PGC-1α, when activated, is known to cause changes in skeletal muscle associated with increased energy consumption and a shift from type II muscles towards type I;[75] this is usually downstream of intracellular calcium signalling from exercise[76][77] and due to the ability of capsaicin to cause calcium influx via TRPV1[38] it has been investigated for its interactions with PGC-1α. In accordance with the above theory, application of 100nM capsaicin to a muscle cell culture increases PGC-1α activation in a manner that is dependent on calcium influx.[37]

Mechanistically, the TRPV1 receptor activation from capsaicin also activates PGC-1α which regulates mitochondrial biosynthesis and profliferation

Administration during deloading or acute administration of capsaicin (10μM injections to mice) does not modify muscle fiber composition[38] although dietary intake of 0.01% capsaicin for four months without concurrent resistance training in mice appears to cause an increase in oxidative type I fibers relative to type II.[37]

Chronic ingestion appears to be able to promote type I muscle (oxidative), although acute ingestion does not appear to have such an effect.


Oral ingestion of up to 10mg/kg capsaicin in mice causes dose-dependent increases in swimming performance in rats associated with increased adrenaline secretion, which only occurred 2 hours after acute ingestion (60 and 180 minutes ineffective) and 15mg/kg was ineffective in mice[66] yet is an active dose in rats.[78] This increased performance is associated with elevated plasma fatty acids and catecholamines,[78][66] and there is no effect in mice who do not have adrenal glands.[66]

Secondary to increasing adrenaline secretion from the adrenals, capsaicin may increase endurance performance in rodents

Capsaicin (0.01% of the diet for four months) in mice not routinely trained is able to increase endurance performance as assessed by running; this is due to increased mitochondrial content and type I muscle content, and did not occur in mice that lacked TRPV1.[37]

Appears to promote endurance performance in mice secondary to TRPV1 activation, which causes proliferation of mitochondria in muscle tissue (see the Bioenergetics section). These benefits may take a prolonged period of time to manifest rather than being after a single dose

8Intearctions with Organ Systems


In newborn rats, administration of capsaicin appears to be able to enhance ulcerogenesis (formation of ulcer) thought to be associated with neurodegeneration in the stomach[79] since these neurons are known to be gastroprotective.[80]

Visceral hypersensitivity is a phenomena where the respones to various stimuli (be they chemical, mechanical, or thermal) are enhanced to higher than normal levels, and is thought to be the main issue to address with dyspepsia not associated with stomach ulceration.[81][82] It is thought that application of capsaicin can be used to identify this hypersensitivity, since while direct application causes sensations in normal subjects[83] those with dyspepsia are hypersensitive[84] and it has been used in some studies suggesting that it is greater than placebo at identifying hypersensitivity.[85]

Due to a hypersensitivity to capsaicin in the stomach of persons with dyspepsia not related to ulcers (but related to visceral hypersensitivity), it can be used as a diagnostic tool to identify said hypersensitivity

8.2Adrenal Glands

An infusion of 200µg/kg capsaicin to anaestheized rats appears to be able to induce adrenaline secretion from the adrenal glands without a significant release of noradrenaline.[86] Stimulation of TRPV1 is known to cause adrenaline secretion in a biphasic manner[66] which has been shown in vivo with capsaicin[40] as well as other vanniloids such as 10-shogaol from ginger.[87] TRPA1 channel activation is also known to induce adrenaline secretion in a similar manner.[88]

At times, capsaicin appears to be able to stimulate adrenaline secretion from the adrenal glands secondary to stimulation of TRPV1

Capsaicin appears to be capable of suppressing a neurogenic response to adrenaline secretion but not a non-neurogenic, and the increases in adrenaline from insulin stress (via hypoglycemia) and cold stress is attenuated or abolished with capsaicin[89][90] by reducing the sensitivity of adrenal neurons to such stimuli.[91] This inhibition of catecholamine secretion from stimulators is suppressed at an IC50 value of 9.5µM (carbachol), 11.8µM (veratridine), and 62µM (high potassium) and basal synthesis of catecholamines are reduced at 10.6µM somewhere upstream of L-DOPA decarboxylase; these mechanisms are independent of TRPV1 and calcium channels in general.[92]

There appears to also be an inhibitory effect of capsaicin on adrenal gland secretion of adrenaline, which is due to desensitizing the neurons in this organ so they respond less to other things that would normally secrete adrenaline. The mechanism is not known, but it is not associated with TRPV1

9Interactions with Cancer Metabolism


One of the mechanisms by which capsaicin can promote cancer and tumor growth is via inhibition of the CYP450-2E1 enzyme, which typically prevents select carcinogencs (vinyl carbamate, dimethyl nitrosamine) from being metabolized to their toxic metabolites.[93][94] Although this same mechanism may be protective against some carcinogens which are bio-activated by P450 enzymes.[95][96]

It seems to have more pro-carcinogenic effects when paired with certain carcinogens, and in doses found in supplementation.[97][98]


Capsaicins have been shown to be protective against lung cancers that are promoted by polycyclic aromatic hydrocarbons, such as Naphthalene and NNK (the major nitrosamine in cigarette smoke[99]).[100][101] This may be due to the reduction in P450 activity, and that these carcinogens are actually bioactivated by these compounds rather than properly detoxified.[102]

10Nutrient-Nutrient Interactions

10.1Cold Exposure

It seems that the increase in plasma adrenaline from the adrenal glands of cold-stressed rats is abolished in capsaicin pretreated rats.[89]

11Safety and Toxicology


Capsaicin holds a Generally Recognized as Safe (GRAS) title for usage in foods.[103]

Oral LD50 values as low as 161.2 mg/kg (rats) and 118.8 mg/kg (mice) have been reported for Capsaicin in acute oral toxicity studies[103] although lower levels (0.58mg/kg and 1.6mg/kg) are needed with injections.[104]

11.2Case Studies

At least one report exists linking capsaicin to death[105] although there have been multiple deaths linked to pepper spray usage.[106][107]


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