IngredientsDihydrocapsiate ((4-hydroxy-3-methoxybenzyl) 8-methylnonanoate) belongs to a group of capsinoids first identified in the fruits of a non-pungent cultivar of pepper (Capsicum annuum L.) and also occurs naturally in chilli and sweet peppers. Its CAS number is 205687-03-2. The compound is a member of the capsinoid class, and capsinoids are hydrolyzed before absorption and break down to fatty acids and to vanillyl alcohol.
Capsinoids represent a novel group of nonpungent capsaicinoid-like substances originally found in a nonpungent cultivar, Capsicum annuum "CH-19 Sweet." Subsequent studies have shown that many pungent Capsicum species contain capsinoids as well. Capsinoids are defined by a branched-chain fatty acid ester of vanillyl alcohol (VOH); the major naturally occurring capsinoids are capsiate (CST), dihydrocapsiate (DCT), and nordihydrocapsiate (NDCT). The chemical structures of the capsinoids are similar to those of the major capsaicinoids (capsaicin, dihydrocapsaicin, nordihydrocapsaicin), with the exception of the center linkage: capsinoids have an ester bond whereas capsaicinoids have an amide bond.
The content ratio of capsiate, dihydrocapsiate, and nordihydrocapsiate in "CH-19 Sweet" is approximately 5:3:1, respectively. Measured concentrations of both capsinoids in whole-pepper material vary widely across cultivars: capsinoids have been found in the range of 1.21–544.59 μg/g dry weight (DW) for capsiate and 0.61–81.95 μg/g DW for dihydrocapsiate across the pepper fruits examined. Capsiate is the major capsinoid in all pepper fruits examined.
The structural difference (ester versus amide bond) is responsible for the lower stability of capsinoids and, therefore, for their lower pungency, assessed to be about 1,000 times lower than that of capsaicinoids.
Capsiate, dihydrocapsiate, and nordihydrocapsiate are three capsinoids structurally similar to the pungent capsaicins dihydrocapsaicin and nordihydrocapsaicin—the bioactive constituents of Capsicum—except for the fact that their two moieties are connected by an ester bond instead of an amide bond.
Capsinoids were first reported in pepper fruits from the low-pungent cultivar 'CH-19 Sweet' (C. annuum) by Kobata, Todo, Yazawa, Iwai, and Watanabe in 1998. The cultivar itself has a specific origin: Yazawa et al. developed and reported a non-pungent cultivar of Capsicum annuum L., CH-19 Sweet, by fixing a non-pungent fruit over the years; it was selected from the fruits of a highly pungent cultivar CH-19, a native of Thailand.
The cultivar CH-19 Sweet is a non-pungent pepper mutant derived from a pungent pepper strain, Capsicum annuum CH-19. CH-19 Sweet biosynthesizes capsaicinoid analogs called capsinoids. The molecular reason for this non-pungency was later established: enzyme assays revealed that pAMT (putative aminotransferase) activity catalyzing vanillylamine formation was completely lost in CH-19 Sweet placenta tissue. Because vanillylamine cannot be produced, the biosynthetic pathway diverts to form vanillyl alcohol, which esterifies with fatty acyl chains to produce capsinoids rather than capsaicinoids.
In the 'Tabasco' accession, capsiate and dihydrocapsiate were quantified for the first time, ranging from 3.09 to 58.76 and 1.80 to 6.94 ÎĽg/g DW, respectively. Additionally, ESI-MS/MS(QTOF) analysis has allowed the tentative identification of two other minor capsinoids in the 'Bhut Jolokia' accession.
Dihydrocapsiate as an isolated compound has no pre-modern or traditional pharmacological history distinct from that of pepper use in general. Peppers of the genus Capsicum have a centuries-long history of use as food, spice, and medicine in Mesoamerica, South America, South Asia, and East Asia, but the specific capsinoid subclass—including dihydrocapsiate—was chemically unknown until 1998. The capsinoids of CH-19 Sweet have the same physiological activities as capsaicin and are free of a pungent taste; accordingly, they were proposed as usable food additives or pharmaceutical products following their scientific characterization.
An extract from CH-19 Sweet chilli pepper containing capsinoids is marketed as a food supplement in America and Japan as Capsiate Natura™. Sourcing of large quantities of natural dihydrocapsiate is not sustainable because of the relatively small amounts contained in, and able to be extracted from, chilli peppers.
Dihydrocapsiate belongs to a group of capsinoids first identified in the fruits of a non-pungent cultivar of pepper (Capsicum annuum L.) and also occurs naturally in chilli and sweet peppers. Synthetic dihydrocapsiate is produced via a method involving lipase-catalysed esterification of vanillyl alcohol and 8-methylnonanoic acid.
The amount of capsinoids in the fruit of "CH-19 Sweet" is very low; therefore, they are precious ingredients that are expensive to extract from natural "CH-19 Sweet." Large-scale production by chemical synthesis has been pursued as a less expensive approach than extraction from cultivated "CH-19 Sweet," with the intention of filing with the FDA as a new dietary ingredient.
As dihydrocapsiate is present in the capsinoids contained in most peppers, it can also be found in food products made from these plants both fresh or dried, e.g., when used whole or as spices, flavorings, colorings, powders, extracts, hot sauces, barbecue sauces, ketchup, cheese, snack foods, dips, and meals such as chilli con carne, salads, and sausages.
In clinical research, dihydrocapsiate has been administered primarily in encapsulated oral forms. Studies have used DCT capsules taken three times per day, at doses of 3 mg or 9 mg total daily. The capsinoid-containing CH-19 Sweet extract has also been used in capsule form at 6 mg total capsinoids per day in human trials.
Dihydrocapsiate itself is the primary active constituent when supplementing with this ingredient. Capsinoids are esters of vanillyl alcohol with fatty acids and include capsiate, dihydrocapsiate, and nordihydrocapsiate. Dihydrocapsiate's pharmacological activity is largely understood through its structural analogy to capsaicin and its interactions with the same receptor targets.
The traits of capsaicin—and by structural analogy, capsinoids—are associated with activation of TRPV1 receptors (transient receptor potential cation channel, subfamily V, member 1), neuropeptides like substance P, calcitonin gene-related peptide (CGRP), and other neurokinins released from sensory nerve terminals.
It is known that the stimulatory effects of cold on BAT are mediated through the activation of the sympathetic nervous system, initiated by peripheral stimulation of transient receptor potential (TRP) channels in sensory neurons. This pathway is also activated by some food ingredients, such as capsaicin and capsinoids, nonpungent capsaicin analogs. Stimulation of TRP channels by capsinoids is effective for enhancement of BAT thermogenesis and upregulation of uncoupling protein 1 (UCP1), a key molecule of BAT thermogenesis, in mice.
The sympathetic nervous system (SNS) is the primary regulator of BAT activity, releasing norepinephrine through terminal neurons. The surfaces of BAT adipocytes are rich in β-adrenergic receptors, which bind to norepinephrine. These β-adrenergic receptors are coupled to a Gs protein system that activates the enzyme adenylyl cyclase and leads to the formation of cAMP as a secondary messenger.
BAT mitochondria are equipped with a specialized protein known as uncoupling protein 1 (UCP1). UCP1 short-circuits the electron transport chain, allowing mitochondrial membrane potential to be transduced to heat, making BAT a tissue capable of altering energy expenditure and fuel metabolism in mammals without increasing physical activity.
Capsinoids have been reported to enhance thermogenesis, fat oxidation, and sympathetic nerve activity and in turn promote weight reduction in both rodents and humans.
Capsinoids are hydrolyzed before absorption and break down to fatty acids and to vanillyl alcohol. According to human studies conducted to date, intact capsinoids are not present in the bloodstream following oral administration, suggesting minimal concern about untoward activation of TRPV1 receptors in other parts of the body.
Pharmacokinetics of a single gavage dose of 14C-labeled dihydrocapsiate (10 mg/kg) were investigated in male rats. Maximal plasma concentration was achieved in 40 minutes and exhibited an apparent half-life of 2.4 hours. Excretion of radioactivity in the urine, feces, and expired air was 78.2%, 19.4%, and 0.5% of the dose, respectively.
In spite of their lower pungency, capsinoids exhibit similar health-promoting properties to capsaicinoids, such as being analgesic, antioxidant, anticancer and anti-inflammatory, but without such side effects as irritation or a burning sensation. Besides, capsinoids protect the gastric mucosa from injuries, improve glucose metabolism, and increase thermogenesis and body energy expenditure.
The non-pungent capsinoids capsiate and dihydrocapsiate inhibited VEGF-induced angiogenesis in both cell culture and mouse models.
In cell-based and UV-irradiation experimental models: the effect of capsiate and dihydrocapsiate on the inhibition of UV-induced COX-2 expression, UV-induced expression of pro-inflammatory cytokines IL-6, IL-8, and tumor necrosis factor-α (TNF-α), and UV-induced expression of angiogenesis factors VEGF, MMP-2, and MMP-9 was investigated. As a result, capsiate or dihydrocapsiate inhibited UV-induced COX-2 expression, UV-induced expression of pro-inflammatory cytokines IL-6, IL-8, and TNF-α, and UV-induced expression of angiogenesis factors VEGF, MMP-2 and MMP-9. It was thus confirmed that capsiate or dihydrocapsiate provides the effect of inhibiting UV-induced inflammatory response and angiogenesis. These findings are from preclinical/in vitro models and have not been confirmed in human clinical trials.
Human/Clinical Evidence
A key randomized controlled trial (RCT) published in the American Journal of Clinical Nutrition examined the effect of dihydrocapsiate on resting metabolic rate (RMR): after 1 month of supplementation, dihydrocapsiate had a small thermogenic effect of approximately 50 kcal/day, which is in the range of day-to-day RMR variability. This trial used 3 mg and 9 mg/day dosing groups and was registered at ClinicalTrials.gov (NCT00999297).
A separate 4-week RCT by Lee, Li, Zerlin, and Heber (University of California, Los Angeles) examined both adaptive and diet-induced thermogenesis under conditions of a high-protein very-low-calorie diet (VLCD): the study was designed to examine the effects of DCT on both adaptive thermogenesis resulting from caloric restriction and to determine whether DCT would increase post-prandial energy expenditure (PPEE) in response to a 400 kcal/60 g protein liquid test meal. Thirty-three subjects completed an outpatient very low calorie diet (800 kcal/day providing 120 g/day protein) over 4 weeks and were randomly assigned to receive either DCT capsules three times per day (3 mg or 9 mg) or placebo. At baseline and 4 weeks, fasting basal metabolic rate and PPEE were measured in a metabolic hood and fat-free mass (FFM) was determined using displacement plethysmography (BOD POD).
PPEE normalized to FFM was increased significantly in subjects receiving 9 mg/day DCT by comparison to placebo (p < 0.05), but decreases in resting metabolic rate were not affected. Respiratory quotient (RQ) increased by 0.04 in the placebo group (p < 0.05) at end of the 4 weeks, but did not change in groups receiving DCT. These data provide evidence for postprandial increases in thermogenesis and fat oxidation secondary to administration of dihydrocapsiate.
A study by Inoue et al. (2007) reported: enhanced energy expenditure and fat oxidation in humans with high BMI scores by the ingestion of novel and non-pungent capsaicin analogues (capsinoids).
Evidence Strength: The thermogenic effect of dihydrocapsiate in humans is small but replicated across several RCTs. The approximately 50 kcal/day increase in RMR reported by Galgani and Ravussin is noted to be within the range of day-to-day variability, indicating a marginal effect. The postprandial thermogenesis effect at 9 mg/day is statistically significant in one trial but these studies are limited by small sample sizes and short duration.
Human/Clinical Evidence
Prior evidence suggests that capsinoids ingestion may increase resting energy expenditure (EE) and fat oxidation (FATox), yet whether they can modulate those parameters during exercise conditions remains poorly understood. A hypothesis was advanced that dihydrocapsiate (DHC) ingestion would increase EE and specifically FATox during an acute bout of aerobic exercise at FATmax intensity in men with overweight/obesity. FATmax and maximal fat oxidation (MFO) during aerobic exercise appear to be indicators of metabolic flexibility.
A total of 24 sedentary men (age = 40.2 ± 9.2 years; body mass index = 31.6 ± 4.5 kg/m²; n = 11 overweight, n = 13 obese) participated in this randomized, triple-blinded, placebo-controlled, crossover trial. The title of this 2022 study states explicitly that dihydrocapsiate does not increase energy expenditure nor fat oxidation during aerobic exercise in men with overweight/obesity.
Evidence Strength: This well-designed crossover trial shows that, while dihydrocapsiate may modestly increase resting EE, it does not appear to increase energy expenditure or fat oxidation during aerobic exercise in overweight and obese men. This limits the interpretation that the compound enhances exercise metabolism.
Human/Clinical Evidence
A pivotal 6-week human study published in the Journal of Clinical Investigation (Yoneshiro et al., 2013) investigated whether repeated capsinoid ingestion could recruit BAT in humans: in nonobese subjects, the 6-week capsinoid treatment increased EE, although it caused only a slight and insignificant reduction of body fat. All these results suggest that the antiobesity effects of capsinoids are based on the thermogenic activity of recruited BAT. Thus, repeated ingestion of capsinoids can mimic the chronic effects of cold exposure on BAT and body fat in humans.
The review published in the American Journal of Clinical Nutrition (2012) by the same group noted that: a significant reduction in adiposity and an elevation of EE after a 12-week treatment with capsinoids was reported in middle-aged and slightly obese human subjects. Reports in small rodents suggest a role of BAT in the thermic effect of capsaicin and capsinoids.
The systematic review "Activation of Human Brown Adipose Tissue by Capsinoids, Catechins, Ephedrine, and Other Dietary Components" (PMC, 2019) synthesized the clinical evidence, noting that brown adipose tissue (BAT) generates heat via nonshivering thermogenesis (NST) to maintain a constant core body temperature at low ambient temperatures. NST occurs via the action of uncoupling protein 1 (UCP1), a molecular hallmark of BAT. This protein is expressed in both brown adipocytes (classical BAT) and brite adipocytes (brown-like adipocytes emerging in white adipose depots, also known as beige adipocytes).
Evidence Strength: The BAT-activation hypothesis for capsinoids is mechanistically plausible and supported by both animal and human data. The key Yoneshiro 2013 JCI study used FDG-PET/CT imaging to confirm BAT involvement. The evidence is more robust for BAT-positive individuals; the prevalence of BAT decreases with age and BAT is present in less than 30% of individuals in their forties, which may explain why the effects are heterogeneous across populations.
Human/Clinical Evidence
The 12-week RCT by Snitker, Fujishima et al. (2009, American Journal of Clinical Nutrition) was designed to explore the safety and efficacy of capsinoids taken orally (6 mg/d) for weight loss, fat loss, and change in metabolism and to examine whether candidate genes are predictors of capsinoid response. This was a 12-week, placebo-controlled, double-blind, randomized study. Eligibility criteria included a BMI of 25–35 kg/m².
In a study in overweight men, encapsulated capsinoids (6 mg/d for 12 weeks) did not modify metabolic rate, although a higher but non-significant increase in fat oxidation was detected after the 12-week treatment period when compared with the placebo group. However, the authors failed to normalise their data for the metabolically active tissue before and after intervention.
Body fat reduction and increased EE were shown after capsinoid treatment for 12 weeks in mildly obese human subjects.
Evidence Strength: Evidence for meaningful body weight and body fat reduction in humans is mixed. Some trials show modest improvements in fat oxidation or body fat at 12 weeks, while others fail to reach statistical significance. The overall effect size on body composition is small, and the evidence is not sufficient to support strong conclusions about clinically meaningful weight reduction.
Evidence
Studies have shown that capsiate, dihydrocapsiate, and their analogues possess highly significant antioxidant activity. This activity has been demonstrated primarily in vitro and in preclinical models. No large controlled human trials of dihydrocapsiate specifically as an antioxidant supplement have been identified in the published literature.
Evidence Strength: Antioxidant evidence for dihydrocapsiate is largely preclinical (in vitro and animal). Human data specific to dihydrocapsiate's antioxidant effects are not currently available in the form of high-quality RCTs.
Evidence
Capsinoids exhibit similar health-promoting properties to capsaicinoids, including anti-inflammatory activity, but without such side effects as irritation or a burning sensation. At the molecular level, preclinical research in UV-irradiation cell models has shown that capsiate and dihydrocapsiate inhibit UV-induced COX-2 expression and UV-induced expression of pro-inflammatory cytokines IL-6, IL-8, and tumor necrosis factor-α (TNF-α).
Evidence Strength: Anti-inflammatory evidence for dihydrocapsiate is currently preclinical (in vitro and animal model data). Confirmation in human clinical trials is lacking. Claims of anti-inflammatory activity in humans should be regarded as preliminary.
Evidence
Capsinoids have been shown to improve glucose metabolism in animal research. An animal study examining dihydrocapsiate supplementation in high-fat diet mice investigated its effect on body weight gain, glucose tolerance, lipid accumulation in various metabolically active tissues (white adipose tissue, brown adipose tissue, liver), mRNA expression of genes regulating energy expenditure and lipid metabolism in these tissues, intestinal morphology, specific gut microbial population, and short-chain fatty acid (SCFA) production.
Evidence Strength: Evidence for effects on glucose metabolism stems primarily from animal studies. The human clinical trial evidence specific to dihydrocapsiate and glucose metabolism is limited and insufficient to establish clinical benefit.
Single-dose oral administration of up to 30 mg capsinoids did not raise blood pressure or heart rate in healthy volunteers, nor did administration of CH-19 Sweet. This is an important distinction from capsaicin, which has been associated with cardiovascular stimulation at higher doses.
The following dosages are reported directly from identified clinical studies and should not be interpreted as recommendations:
Dihydrocapsiate has been subject to a comprehensive preclinical toxicology series (published as "Studies of the Toxicological Potential of Capsinoids"), comprising multiple study types:
Sub-chronic (13-week) toxicity in rats: Sprague-Dawley rats, 10 rats/sex/group, were administered dihydrocapsiate daily by gavage at dose levels of 0 (vehicle), 100, 300, or 1000 mg/kg/day. There were no changes observed in clinical signs, body weight, food consumption, water intake, ophthalmology, urinalysis, hematology, or blood chemistry attributable to dihydrocapsiate. The only change attributable to dihydrocapsiate administration involved the liver and occurred only at the high dose (1000 mg/kg). Both sexes had an increase in organ weights, but this increase correlated with a change in histopathology (hepatocyte hypertrophy) only in the males. No dihydrocapsiate-related histopathological changes were observed in males at doses ≤300 mg/kg or in females at any of the doses tested (≤1000 mg/kg). It was concluded that the NOAEL of dihydrocapsiate was 300 mg/kg/day for male rats and 1000 mg/kg/day for female rats in this 13-week gavage study.
Sub-chronic (13-week) toxicity in rats (earlier study series): In the absence of histopathological changes attributable to the test article, the liver weight changes were considered adaptive (physiological) in nature and not of toxicological significance. It was concluded that the NOAEL of dihydrocapsiate was 1000 mg/kg/day for both male and female rats in this 13-week gavage study.
26-week gavage toxicity in rats: To further evaluate the safety of dihydrocapsiate, a 26-week gavage toxicity study was conducted in Sprague-Dawley rats (20/sex/group). Test animals received either dihydrocapsiate at 100, 300, or 1000 mg/kg/day or vehicle (medium-chain triglyceride) by gavage. After the end of the dosing period, reversibility was assessed following a 4-week recovery period. There were no adverse or toxicological changes observed in clinical signs, body weight. It was concluded that the NOAEL of dihydrocapsiate was 1000 mg/kg/day for both sexes in this 26-week gavage study.
Single-dose acute toxicity: These results suggested that the lethal dose of dihydrocapsiate was >5000 mg/kg. No mortality was observed during the 14-day observation period following test article administration. During the 2 hours immediately following dosing, mice treated with dihydrocapsiate exhibited one or more of the following: staggered gait, decreased spontaneous movement, increased time in the prone position, tremors, gasping, or red-brownish urine. All mice had completely recovered by the 6-hour observation interval. No effects on body weights or necropsy findings were observed as a result of dihydrocapsiate administration.
Genotoxicity studies: The in vivo gene mutation assay with transgenic rats produced negative results, as did the in vivo mouse micronucleus assay, which failed to induce micronucleated polychromatic erythrocytes. Taken together, these results suggest that dihydrocapsiate has a low or extremely low likelihood of inducing genotoxicity. In an in vivo micronucleus test using BDF(1) male mice, commercial-grade dihydrocapsiate neither increased the incidence of micronucleated polychromatic erythrocytes (MNPCEs) nor decreased the ratio of polychromatic erythrocytes (PCEs) in any of the treatment groups. The results suggest that commercial-grade dihydrocapsiate is unlikely to be an in vivo clastogen.
Teratology (reproductive toxicity): In studies in rats and rabbits: in the rabbit study, there were no test substance-related effects on clinical signs, body weight, food consumption, or necropsy findings in any group. There were neither test substance-related abortions nor test substance-related effects on the number of corpora lutea, number of implantations, or implantation index in any group. There were no test substance-related effects on the number of dead embryos/fetuses, the number, sex ratio, or body weight of live fetuses, or gross pathological findings of placentae. There were no test substance-related external abnormalities, or incidence of visceral or skeletal abnormalities or variations, and there were no test substance-related effects on the progress of ossification in any group. Based upon these data, the NOAEL of dihydrocapsiate for general toxicity in dams, reproductive functions of dams, and embryofetal development was judged to be 1000 mg/kg/day both in rats and rabbits.
The overview from the UK Advisory Committee on Novel Foods and Processes (ACNFP) application file summarizes: an extensive package of toxicology conducted by the oral route has shown no evidence of toxicity or pathogenicity at dose levels of up to 1000 mg/kg bw/day over 26 weeks, and teratology and genotoxicity studies did not indicate adverse findings.
In human studies at the doses tested (3–9 mg/day as dihydrocapsiate; up to 30 mg/day as total capsinoids): dihydrocapsiate is described as a natural safe food ingredient which is structurally related to capsaicin from chili pepper; it has been shown to elicit the thermogenic effects of capsaicin but without its gastrointestinal side effects.
The spices Capsicum (plant source: Capsicum frutescens L. or Capsicum annuum L.) and paprika (plant source: Capsicum annuum L.) are among the spices and other natural seasonings and flavorings that are generally recognized as safe (GRAS) in the USA for their intended use. Synthetically produced dihydrocapsiate has been developed by Ajinomoto Co., Inc. for use as a dietary supplement ingredient, and has been filed with the Food and Drug Administration (FDA) as a new dietary ingredient.
A notable finding that distinguishes dihydrocapsiate from capsaicin is the absence of cardiovascular stimulation at studied doses: according to human studies conducted to date, intact capsinoids are not present in the bloodstream following oral administration, suggesting minimal concern about untoward activation of TRPV1 receptors in other parts of the body. Single-dose oral administration of up to 30 mg capsinoids did not raise blood pressure or heart rate in healthy volunteers.
Dihydrocapsiate is among the better-characterized non-pungent capsaicinoid analogs. Its thermogenic and metabolic effects have been evaluated in multiple human RCTs, consistently showing small but statistically significant increases in resting and postprandial energy expenditure at doses of 6–9 mg/day. The mechanistic basis—TRPV1 activation, sympathetic stimulation, and BAT-dependent thermogenesis—is well-established in animal studies and has been partially confirmed in humans using FDG-PET/CT imaging. However, several limitations apply to the current body of evidence:
Health conditions that Dihydrocapsiate may help support.
Body systems that Dihydrocapsiate may help support.
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