IngredientsDihydrocapsaicin is a capsaicinoid and analog and congener of capsaicin in chili peppers (Capsicum). Its systematic chemical name is 8-methyl-N-vanillylnonanamide, also rendered as N-[(4-hydroxy-3-methoxyphenyl)methyl]-8-methylnonanamide. It is also identified as N-[4-hydroxy-3-methoxybenzyl]-8-methylnonanamide. It is abbreviated in the scientific literature as DHC. Dihydrocapsaicin is classified as a terpene alkaloid found in Capsicum and possesses diverse biological activities. Its molecular formula is C18H29NO3, and its CAS registry number is 19408-84-5. Dihydrocapsaicin is a VR1 vanilloid receptor agonist and is classified by ChEBI as a capsaicinoid.
Dihydrocapsaicin is the saturated structural analog of capsaicin. Whereas capsaicin contains a trans double bond in its acyl side chain (hence the "trans-6-nonenamide" portion of its name), dihydrocapsaicin lacks this double bond. The chemical structure of capsaicinoids is composed of a vanillylamide moiety and an acyl chain of 8–13 carbon atoms; the two major capsaicinoids present in most varieties of hot chilli are capsaicin (trans-8-methyl-N-vanillyl-6-nonenamide) and dihydrocapsaicin (8-methyl-N-vanillylnonanamide).
Pure dihydrocapsaicin is a lipophilic colorless odorless crystalline to waxy compound. It is soluble in dimethyl sulfoxide and 100% ethanol. Its lipophilicity is a key determinant of its membrane permeability and pharmacokinetic behavior.
Dihydrocapsaicin is isolated from Capsicum fruit. The pungency of "hot" chilli pepper results from the accumulation of capsaicin and related compounds known as capsaicinoids — organic compounds only found in the Capsicum genus, which are bioactive molecules currently relevant in medical and food science. Besides being the most potent capsaicinoids, capsaicin together with dihydrocapsaicin are estimated to represent almost 90% of all capsaicinoids in chili pepper fruit.
Dihydrocapsaicin accounts for about 22% of the total capsaicinoid mixture and has the same pungency as capsaicin. The second most common capsaicinoid is dihydrocapsaicin. Capsaicin and dihydrocapsaicin together make up 80–90% of the capsaicinoids found in the fruit. In C. annuum the total capsaicinoid content ranges from 0.1 to 1.0%, and the capsaicin:dihydrocapsaicin ratio is about 1:1. In C. frutescens (Tabasco peppers) the total content ranges from 0.4–1.0% with the ratio around 2:1.
Other compounds in chili pepper include homologous branched- and straight-chain alkyl vanillylamides (i.e., capsaicinoid compounds) such as dihydrocapsaicin, nordihydrocapsaicin, homocapsaicin, and homodihydrocapsaicin, all of which also possess pungent properties. The major components of capsaicinoids are capsaicin and dihydrocapsaicin (DHC), which together typically represent 85–90% of the total capsaicinoid content in pepper extract, with minor components including nordihydrocapsaicin, homocapsaicin, and homodihydrocapsaicin.
Dihydrocapsaicin occurs naturally as a constituent of crude chili pepper extracts, standardized capsaicinoid extracts, and oleoresin of capsicum. Dihydrocapsaicin has been used as a reference standard for the identification of dihydrocapsaicin in blood and tissue samples by high-performance liquid chromatography (HPLC) combined with tandem mass spectrometry (MS) and in tomato-based salsas by enzyme immunoassay (EIA) and LC with fluorescent detection. In research and analytical contexts, it is available as a purified isolate. As a dietary supplement or nutraceutical ingredient, it is typically present as part of capsicum oleoresin, capsaicin/capsaicinoid extracts, or standardized pepper extract preparations rather than as an isolated single compound.
As a distinct isolated molecule, dihydrocapsaicin itself has no separate pre-modern history of use; it was not identified until the modern chemical era. Its history is inseparable from the broader traditional use of chili peppers (Capsicum spp.) across human civilizations, within which dihydrocapsaicin is a naturally co-occurring constituent alongside capsaicin.
Chillies have been used for thousands of years by the Aztecs and Mayans as medicinal herbs. Studies of the pharmacopeia of the Mayans in Mesoamerica have found that they had over 32 medicinal uses for chillies, including stomach aches, skin rashes, rheumatism, and arthritis. The use of chili pepper, particularly in therapeutic applications, has been extensively recorded in numerous books and manuscripts dating back to pre-Hispanic times in Aztec and Mayan civilizations. An exemplary work in this regard is Libellus de Medicinabilus Indorum Herbtis, authored by Martin de la Cruz in 1522.
In old civilizations, chili was used by the Mayas for treating asthma, coughs, and sore throat, and by the Aztecs to relieve toothaches. Ancient Mayan codices and Aztec records describe the use of wild chili fruits for pain relief and wound dressing.
Although chili peppers originated in the Americas, Portuguese traders introduced them to India in the 16th century. Early Ayurvedic texts like the Cāraka Saṃhitā (circa 4th century CE) mention pepper but did not distinguish New World chilies. By the 17th century, local scholars in Kerala and Goa wrote about chili varieties that matched Capsicum frutescens. In India, the evidence was present in the Sushruta Samhita, an ancient Sanskrit text on Ayurveda. Chilli with pepper, liquid amber, and garlic were made into a dermal patch for decreasing pain symptoms from gout, rheumatism, and chronic lumbago. It was used for reduction of inflammation of the tonsils by preparing into a paste. Along with sugar and tragacanth, it served as a lozenge used for hoarseness. Chilli has also been applied for enhancing appetite, minimizing flatulence, and as a remedy for cholera.
Capsicum annuum, commonly known as chili pepper, is used as an important spice globally and as a crude drug in many traditional medicine systems. The fruits of C. annuum have been used as a tonic, antiseptic, and stimulating agent, to treat dyspepsia, poor appetite, and flatulence, and to improve digestion and circulation. As chili peppers diffused globally following the Columbian Exchange of the late 15th and 16th centuries, preparations containing the full capsaicinoid mixture — including dihydrocapsaicin — entered European herbal traditions. Topical applications for musculoskeletal pain, particularly as plasters and ointments, became prominent. By the 19th century, capsicum tinctures and preparations were documented in Western pharmacopeias.
The various members of the capsaicin family differ from capsaicin mainly in the substitutions on the aromatic ring and hydrophobic side chain. Dihydrocapsaicin differs from capsaicin solely by the absence of the C6–C7 trans double bond in the acyl chain, making it the fully saturated homolog. This saturated structure confers similar receptor binding but subtly distinct metabolic and enzymatic properties compared with capsaicin.
The primary and best-established mechanism shared by dihydrocapsaicin and all capsaicinoids is agonism of the transient receptor potential vanilloid 1 (TRPV1) channel. Dihydrocapsaicin is an agonist of transient receptor potential vanilloid 1 (TRPV1). The vanilloid ring of capsaicinoids binds intracellularly to TRPV1 channels on cell membranes, causing an influx of extracellular calcium into the cell and triggering numerous physiological pathways. TRPV1 is a nonselective calcium-permeable cation channel, involved in thermogenesis and pain-sensing, and is expressed in high metabolic rate tissues.
DHC has been shown to pharmacologically induce hypothermia via TRPV1 channel agonism, thus providing neuroprotection in ischemia/reperfusion models. This paradoxical thermogenic/hypothermic duality depends on the context of TRPV1 activation: peripheral activation in adipose and skeletal muscle stimulates thermogenesis, while systemic or central high-dose activation can produce pharmacological hypothermia.
Research findings have demonstrated that dihydrocapsaicin could successfully reduce the reactivation of NF-κB and its molecular targets in endothelial cells mediated by TNF-α, and that dihydrocapsaicin pretreatment could substantially decrease monocyte adhesion. Capsaicin and dihydrocapsaicin increased nitric oxide and scavenged free radicals; dihydrocapsaicin inhibited NF-κB and protected the endothelium against inflammation.
DHC activated nuclear-related factor-2 (Nrf2), which involves antioxidant enzymes like superoxide dismutase (SOD) and glutathione peroxidase (GPx), and significantly decreased oxidative stress and inflammation via down-regulated reactive oxygen species (ROS), NADPH oxidase (NOX2, NOX4), nuclear factor kappa-beta (NF-κB), and matrix metalloproteinases-9 (MMP-9) levels.
A distinct nuclear receptor-mediated mechanism has been identified in the context of atherosclerosis research. Studies demonstrated that cellular cholesterol content was significantly decreased while apoA1-mediated cholesterol efflux was significantly increased following treatment with DHC in THP-1 macrophage-derived foam cells. Plasma levels of TG, LDL-C, VLDL-C, IL-1β, IL-6, TNF-α, and CRP were markedly decreased while plasma levels of apoA1 and HDL-C were significantly increased, and atherosclerotic lesion development was significantly inhibited by DHC treatment.
Dihydrocapsaicin (DHC), an analog of capsaicin, is a potential inducer of autophagy. DHC was more cytotoxic than capsaicin in HCT116, MCF-7, and WI38 cell lines. Capsaicin and DHC induced G(0)/G(1) arrest in HCT116 and MCF-7 cells. DHC caused the autophagosome marker GFP-LC3 to redistribute and upregulated expression of autophagy-related proteins.
Among tested chili pepper compounds, dihydrocapsaicin displayed the strongest inhibitory activity against epidermal growth factor (EGF)-induced neoplastic transformation. Dihydrocapsaicin specifically suppressed EGF-induced phosphorylations of the p70S6K1-S6 pathway and the expression of c-Fos. A reduction in c-Fos levels led to a concomitant downregulation of AP-1 activation.
The capsaicinoid spice principles capsaicin and dihydrocapsaicin were shown to be thermogenic in the isolated rat hindlimb perfused with constant flow. Both principles elicited similar maximal increases in oxygen consumption (VO2) and perfusion pressure. These findings suggest that capsaicin and dihydrocapsaicin can be thermogenic in the rat and that the mechanism of action directly involves vasoconstriction in some manner.
Results demonstrate that both capsaicin and dihydrocapsaicin significantly inhibit the activity of clotting factors VIII:C and IX, as well as ADP-induced platelet aggregation. Capsaicin (25–100 µmol/l) or dihydrocapsaicin (6.25–100 µmol/l) inhibited platelet aggregation in venous whole blood and the activity of coagulation factors VIII:C and IX in plasma from healthy subjects.
Dihydrocapsaicin is active against E. faecalis, B. subtilis, S. aureus, P. aeruginosa, K. pneumoniae, E. coli, and C. albicans (MICs = 0.6–10 µg/ml). This activity has been characterized in in vitro assays only; no human clinical data exist on this application.
Dihydrocapsaicin scavenges DPPH and ABTS radicals in cell-free assays. This antioxidant capacity underlies several of its reported downstream effects on inflammation and cellular integrity in experimental models.
Dihydrocapsaicin inhibits NETosis induced by phorbol 12-myristate 13-acetate (PMA) in isolated human neutrophils. NETosis (neutrophil extracellular trap formation) is an innate immune process linked to thromboinflammation; this finding, reported in an in vitro human cell model, is preliminary.
The most extensive body of DHC-specific preclinical evidence concerns neuroprotection in cerebral ischemia/reperfusion (I/R) models.
A study investigated the effect of dihydrocapsaicin (DHC) on cerebral and blood–brain barrier (BBB) damage in cerebral ischemia/reperfusion (I/R) models induced by middle cerebral artery occlusion (MCAO) for 2 hours followed by reperfusion. Rats were divided into five groups: sham/control; vehicle; and 2.5 mg/kg, 5 mg/kg, and 10 mg/kg BW DHC-treated I/R groups. After 24 hours of reperfusion, DHC significantly reduced the area of infarction, morphological changes in neuronal cells including apoptotic cell death, and decreased BBB damage via reducing Evan Blue leakage, water content, and ultrastructure changes, as well as increasing tight junction (TJ) protein expression.
DHC protected the cerebral tissue and the BBB from I/R injury via attenuation of oxidative stress and inflammation. This study was conducted in an animal (rat) model. Evidence level: preclinical (animal) only. No human clinical trials of DHC in stroke or cerebral ischemia have been published.
Other referenced preclinical work has examined DHC-induced angiogenesis and improved functional recovery after cerebral I/R in rat models, as well as neuroprotection after cardiopulmonary resuscitation through induction of mild hypothermia via TRPV1. Studies suggesting a neuroprotective potential for dihydrocapsaicin or a benefit of hot peppers in diet for human neuroprotection have been discussed in review literature, but these remain extrapolations from animal and in vitro models.
The effect of DHC in atherosclerotic plaque progression was explored in apoE−/− mice fed a high-fat/high-cholesterol diet; mice were randomly divided into two groups and fed the diet with or without DHC for 12 weeks. DHC treatment demonstrated that cellular cholesterol content was significantly decreased while apoA1-mediated cholesterol efflux was significantly increased in THP-1 macrophage-derived foam cells. Plasma levels of TG, LDL-C, VLDL-C, IL-1β, IL-6, TNF-α, and CRP were markedly decreased while plasma levels of apoA1 and HDL-C were significantly increased, and atherosclerotic lesion development was significantly inhibited.
In a separate in vitro study of endothelial biology, capsaicin and dihydrocapsaicin increased nitric oxide and scavenged free radicals; dihydrocapsaicin inhibited NF-κB and protected the endothelium against inflammation, and reduced monocyte adhesion to the endothelial surface. Cytotoxicity was observed at higher concentrations: DHC at concentrations up to 50 µM did not affect cell viability, while concentrations of 100 and 500 µM of DHC led to endothelial cytotoxicity.
Evidence level: preclinical (animal and in vitro cell culture) only. There are no published human clinical trials specifically examining isolated DHC for cardiovascular outcomes.
An in vitro study using human blood samples found that capsaicin and dihydrocapsaicin reduced the activity of factors VIII:C and IX of normal reference plasma in a concentration-dependent manner. Platelet aggregation was inhibited in a concentration-dependent manner by both compounds.
A follow-up study examined synergistic effects: capsaicinoids including capsaicin and dihydrocapsaicin individually inhibit in-vitro platelet aggregation. The effects of 12.5 and 6.25 µmol/l CAP and DHC individually, and in combination (CAP:DHC, 60:40, reflecting their natural ratio in chillies), on arachidonic acid-induced, ADP-induced, and collagen-induced aggregation were investigated. The combination of CAP and DHC produced a significantly greater inhibitory effect on arachidonic acid-induced platelet aggregation and subsequent TXB2 formation compared to the individual capsaicinoids.
Research further showed that the inhibitory effect of vanilloids on platelet aggregation appeared to be independent of TRPV1, CB1, and CB2 receptors. Evidence level: in vitro human blood samples. No human clinical trials of antiplatelet effects of isolated DHC have been conducted.
Capsaicin and dihydrocapsaicin have been shown to be thermogenic in the isolated rat hindlimb; both principles elicited similar maximal increases in oxygen consumption and perfusion pressure. Evidence from human clinical studies of thermogenesis exists primarily for capsaicin (the dominant capsaicinoid), with DHC studied indirectly as part of capsaicinoid mixtures. Capsaicin from chili pepper is known to stimulate thermogenesis through a central nervous mechanism, but at doses required to observe this metabolic effect, intolerable gastrointestinal side effects occur.
A randomized, double-blinded, crossover, placebo-controlled clinical trial in healthy subjects measured the impact of TRP channel agonists on energetic metabolism and autonomic nervous system function, primarily examining capsaicin and cinnamaldehyde as TRPV1 and TRPA1 agonists. The trial was designed to be double-blinded, randomized, cross-over, and placebo-controlled with healthy subjects, and the impact on energetic metabolism and the autonomic nervous system of cinnamaldehyde, capsaicin, and a cooling flavor was measured during the 90 minutes after ingestion. Energy expenditure and substrate oxidation were measured by indirect calorimetry. Dihydrocapsaicin was not studied as an isolated compound in this trial. Evidence level for DHC-specific thermogenesis in humans: extrapolated from capsaicin studies and animal data; no human clinical trial isolating DHC has been published.
While ample studies have examined the effect of capsaicin in carcinogenesis, the chemopreventive effect of other major components in chili pepper, including dihydrocapsaicin, is relatively unclear. Investigation of the inhibitory effect of chili pepper components on malignant cell transformation found that among tested compounds, dihydrocapsaicin displayed the strongest inhibitory activity against EGF-induced neoplastic transformation.
Capsaicin, dihydrocapsaicin, and some carotenoids are reported as the major active compounds with several pharmacological potentials especially as anticancer and cardioprotectant. The anticancer effect of capsaicinoids is mainly mediated through mechanisms involving the interaction of Ca2+-dependent activation of the MAPK pathway, suppression of NOX-dependent reactive oxygen species generation, and p53-mediated activation of mitochondrial apoptosis in cancer cells.
Dihydrocapsaicin (DHC), an analog of capsaicin, was identified as a potential inducer of autophagy, and was more cytotoxic than capsaicin in HCT116, MCF-7, and WI38 cell lines. DHC increases LC3-II, a marker of autophagy, and catalase levels, and reduces reactive oxygen species (ROS) production in normal WI38 lung fibroblasts and H1299, but not A549 or H460, lung cancer cells when used at a concentration of 200 µM.
Research into DHC and human cervical cancer cells has also been reported: dihydrocapsaicin (DHC), a prominent capsaicinoid derived from red chili peppers, has shown cytotoxic effects against various cancer cell types. A study investigated the effects of DHC on tumor necrosis factor-α (TNF-α)-induced cell cycle arrest and apoptosis in HeLa human cervical cancer cells.
Evidence level: in vitro cell culture studies and one chemopreventive cell transformation assay. No human clinical trials have examined DHC alone as an anticancer agent. Extrapolation to clinical benefit is not currently warranted by the available evidence.
Multiple in vitro studies have examined DHC's anti-inflammatory mechanisms. The current body of work has aimed to investigate the direct effects of DHC on endothelial inflammation, NO release, and free radical scavenging properties; DHC at concentrations up to 50 µM did not affect cell viability. The downstream anti-inflammatory effects attributed to DHC include inhibition of NF-κB, reduction of adhesion molecules (VCAM-1 and ICAM-1), and suppression of pro-inflammatory cytokines. Evidence level: in vitro and animal studies; no dedicated human clinical trials for isolated DHC.
It was long established that capsaicin (85–95% of the administered dose via oral gavage) and its analogs are readily transported to the portal vein through the gastrointestinal tract by a nonactive process and partly digested during absorption in rats. Capsaicin and dihydrocapsaicin are absorbed to a greater extent by the jejunum and ileum than by the stomach.
Several aspects such as dose and the route of administration play a major role in determining concentration in target tissues and the pharmacological activity of capsaicin-like compounds. Even though mainly found in the liver, dihydrocapsaicin-hydrolyzing enzyme activity has been identified in various organs of rats. Hepatic metabolism is therefore a primary route of DHC clearance, consistent with it being a lipophilic amide susceptible to hydrolysis and oxidation.
The following dosages are reported solely as they appeared in the referenced scientific literature and do not represent recommended human doses.
No standardized human clinical dose for isolated dihydrocapsaicin as a dietary supplement has been established in the peer-reviewed literature as of the most recent available evidence.
A significant and well-characterized interaction concern involves cytochrome P450 (CYP450) enzymes. Capsaicin and dihydrocapsaicin, the two most abundant members of capsaicinoids in chili peppers, are widely used as food additives and for other purposes. Their inhibitory potentials against CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A were examined. The results demonstrated that capsaicin and dihydrocapsaicin moderately inhibited five isozymes (IC50 values ranging from 4.4 to 61.8 µM), with the exception of CYP2E1 (IC50 >200 µM). Both capsaicinoids exhibited competitive, mixed, and noncompetitive inhibition on these isozymes (Ki = 3.1 ± 0.5 – 78.6 ± 8.4 µM). The findings indicated that the possibility of food–drug interactions mediated by capsaicin and dihydrocapsaicin could not be excluded.
After multiple administrations of dihydrocapsaicin (1, 4, and 10 mg/kg) to rats, chlorzoxazone 6-hydroxylase activity and the expression of CYP2E1 were increased in liver microsomes, indicating potential inductive as well as inhibitory effects on specific P450 isoforms depending on dose regimen.
Results demonstrate that both capsaicin and dihydrocapsaicin significantly inhibit the activity of clotting factors VIII:C and IX, as well as ADP-induced platelet aggregation. These findings suggest potential dietary implications for capsaicinoids in the prevention and treatment of cardiovascular diseases. Because dihydrocapsaicin inhibits platelet aggregation and coagulation factors in vitro, concomitant use with anticoagulant or antiplatelet medications may theoretically enhance bleeding risk, though this has not been evaluated in clinical pharmacokinetic/pharmacodynamic studies.
DHC at concentrations up to 50 µM did not affect endothelial cell viability, while concentrations of 100 and 500 µM of DHC led to endothelial cytotoxicity. Capsaicin decreased cell viability at 500 µM. The relevant concentrations at which endothelial cytotoxicity was observed are high relative to physiological dietary exposures, but suggest a non-linear dose–response that warrants caution with high-concentration preparations.
Like capsaicin, dihydrocapsaicin is an irritant. As a pungent capsaicinoid, it shares the mucosally irritating properties of the capsaicinoid class. Capsaicin from chili pepper, at doses required to observe thermogenic metabolic effects, causes intolerable gastrointestinal side effects. This is expected to apply equivalently to dihydrocapsaicin, as it has essentially identical pungency to capsaicin.
Dihydrocapsaicin-hydrolyzing enzyme activity has been identified in various organs of rats, with main activity in the liver. The dual capacity to both inhibit certain CYP isoforms at pharmacological concentrations and induce CYP2E1 after multiple doses suggests complex hepatic pharmacology that could affect the metabolism of co-administered drugs metabolized by these enzymes.
The overwhelming majority of evidence for dihydrocapsaicin specifically (as distinct from the broader class of capsaicinoids or capsaicin) derives from in vitro cell culture assays and animal models. Several lines of evidence have demonstrated that extracts from capsaicinoids have multiple pharmacological and physiological effects, including anti-cancer, anti-inflammation, antioxidant, anti-obesity, and pain relief, but few studies have previously specifically mentioned the advantages of DHC as compared to capsaicin. Human clinical trials isolating DHC as the test compound are absent from the published literature. Safety characterization in humans — including dose ranges, tolerability, chronic exposure effects, and formal drug interaction studies — has not been established for DHC as a stand-alone supplement ingredient.
Health conditions that Dihydrocapsaicin may help support.
Dihydrocapsaicin is one of the major capsaicinoids in hot peppers alongside capsaicin, sharing the same TRPV1-activating thermogenic mechanism. It increases energy expenditure and fat oxidation and is included in the capsaicinoid class of thermogenic compounds studied in multiple human and animal trials.
Body systems that Dihydrocapsaicin may help support.
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