Nordihydrocapsaicin

Other Names

7-Methyl N-vanillyloctanamide7-Methyl nordihydrocapsaicin7-Methyl-N-vanillyl-octamidecapsaicin, nordihydro-N-(4-hydroxy-3-methoxy-benzyl)-7-methyl-caprylamideN-(4-Hydroxy-3-methoxybenzyl)-7-methyloctanamideN-vanillyloctanamideN-[(4-hydroxy-3-methoxy-phenyl)methyl]-7-methyl-octanamideN-[(4-Hydroxy-3-methoxyphenyl)methyl]-7-methyl-octanamideN-[(4-Hydroxy-3-methoxyphenyl)methyl]-7-methyloctanamideN-[(4-Hydroxy-3-methoxyphenyl)methyl]-7-methyloctanamide, 9CINDHCNordihydro CapsaicinNorhydrocapsaicinOctanamide, 7-methyl-N-vanillyl-Octanamide, N-[(4-hydroxy-3-methoxyphenyl)methyl]-7-methyl-

Synopsis

Nordihydrocapsaicin: A Comprehensive Reference

1. Identity and Chemical Characterization

Names and Identifiers

Nordihydrocapsaicin is a capsaicinoid and analog and congener of capsaicin found in chili peppers (Capsicum). Its systematic chemical name is N-[(4-Hydroxy-3-methoxyphenyl)methyl]-7-methyloctanamide, with additional synonyms including Norhydrocapsaicin and Nordihydrocapsaic. Its molecular formula is C₁₇H₂₇NO₃ and its molecular weight is 293.4 g/mol. The compound carries the UNII identifier RF657P8DA8, is classified as a chemical substance, and is stereochemically achiral with a molecular formula of C₁₇H₂₇NO₃ and molecular weight of 293.4. Its CAS registry number is 28789-35-7.

Nordihydrocapsaicin is a capsaicinoid and congener of capsaicin in chili peppers; in chemical classification, it is a member of methoxybenzenes and a member of phenols. Like capsaicin, it possesses a vanilloid group — an aromatic ring bearing a hydroxyl and a methoxy substituent — connected via an amide linkage to a hydrocarbon chain; this vanilloid group is shared among natural compounds of the vanilloid family such as vanillin, eugenol, and zingerone, and is considered the primary determinant of biological activity. The key structural distinction between nordihydrocapsaicin and capsaicin is that nordihydrocapsaicin bears a saturated alkyl chain (7-methyloctanoyl), whereas capsaicin's chain contains a trans-double bond. This saturated side chain is also what differentiates nordihydrocapsaicin from the structurally related dihydrocapsaicin (which shares the saturated chain but differs in overall chain length).

Physical Properties

Pure nordihydrocapsaicin is a lipophilic colorless, odorless crystalline to waxy solid. It appears as a white to off-white crystalline solid with low water solubility, good solubility in organic solvents such as DMSO and chloroform, and a melting point of 60–61 °C. On the Scoville scale it registers 9,100,000 SHU (Scoville heat units), which is significantly higher than that of commercial pepper spray.

Relative Pungency and Abundance

The most commonly occurring capsaicinoids in chili peppers are capsaicin (approximately 69%), dihydrocapsaicin (approximately 22%), and nordihydrocapsaicin (approximately 7%); capsaicin and dihydrocapsaicin (both approximately 16.0 million SHU) are the most pungent, while nordihydrocapsaicin (9.1 million SHU) is roughly about half as pungent.

2. Botanical Source and Natural Occurrence

Plant Genus and Species

Nordihydrocapsaicin is primarily found in the fruits of plants belonging to the genus Capsicum within the Solanaceae family, particularly in pungent varieties of chili peppers; it occurs alongside other capsaicinoids such as capsaicin and dihydrocapsaicin. Key species include Capsicum annuum, which encompasses cultivars like jalapeño and cayenne, as well as Capsicum pubescens, notably in rocoto peppers native to regions such as Peru. Chili pepper (Capsicum spp.) is among the most widely consumed vegetables and spices, belonging to the Capsicum genus within the Solanaceae family.

Localization Within the Fruit

The primary capsaicinoids — capsaicin, dihydrocapsaicin, and nordihydrocapsaicin — are produced exclusively in the epidermal cells of the chili placenta. Within the fruit, nordihydrocapsaicin is predominantly accumulated in the placental tissue, where capsaicinoids are synthesized and stored in specialized oil droplets known as vesicles.

Proportion of Total Capsaicinoids

Capsicum contains a mixture of at least seven closely related vanillyl acids, with approximate composition being: capsaicin (69%), dihydrocapsaicin (22%), nordihydrocapsaicin (7%), homocapsaicin (1%), homodihydrocapsaicin (1%), and norcapsaicin (<1%). Approximately 80–90% of the total capsaicinoid content of chili pepper is represented by capsaicin and dihydrocapsaicin, which are the most potent substances among capsaicinoids; the remaining part is represented by nordihydrocapsaicin, homodihydrocapsaicin, and homocapsaicin. In one standardized commercial capsaicinoid concentrate (Capsimax®), nordihydrocapsaicin constitutes 0.1–0.2% of the total concentrate, which is itself standardized to 2% total capsaicinoids.

Biosynthesis

The capsaicinoids in pepper are biosynthesized from branched-chain amino acids and phenylalanine in pepper fruit. The general biosynthetic pathway of capsaicin and other capsaicinoids was elucidated in the 1960s by Bennett, Kirby, Leete, and Louden. In nordihydrocapsaicin specifically, the acyl side chain is derived from valine (yielding the branched 7-methyloctanoyl moiety), while the vanillylamine (aromatic) portion is derived from phenylalanine via the phenylpropanoid pathway.

Common Preparations and Forms

Nordihydrocapsaicin is not typically isolated as a standalone supplement; rather, it naturally occurs within whole dried chili pepper powder, oleoresin capsicum (a lipid-soluble extract), and standardized capsaicinoid concentrates. Over 200 active components known as capsaicinoids have been identified in chili peppers, the most abundant being capsaicin, dihydrocapsaicin, and nordihydrocapsaicin. In pharmaceutical and research contexts, nordihydrocapsaicin is available as a high-purity isolated reference standard. Nordihydrocapsaicin can be used as a reference standard, with possible traceability to pharmacopeial standards such as USP or EP. When present in commercial dietary supplement products, it appears as a minor constituent within full-spectrum capsaicinoid extracts or proprietary blends, administered orally in enteric-coated or microencapsulated forms to reduce gastrointestinal irritation.

3. Historical and Traditional Use

Pre-Columbian Mesoamerica and South America

Archaeological evidence suggests that chili peppers have been cultivated and consumed for thousands of years; the earliest known evidence of chili pepper consumption dates back to around 7,000 BC, based on the presence of chili pepper remnants found in ancient kitchen remains in Mexico. In South America, researchers have identified starch grains of Capsicum on milling stones and cooking pots recovered from house floors in southwestern Ecuador, dating them to around 6,000 years ago. Multiregional models of domestication suggest that domesticated chili peppers may have arisen in more than one area, with two key archaeological loci for the earliest use of chili being Romero's Cave near Ocampo, Tamaulipas, and Coxcatlán Cave in the Tehuacán Valley, Puebla.

Native American cultures have traditionally used chili peppers for a variety of purposes, including pain relief, wound healing, and as a ceremonial medicine. Traditional uses of capsicum also include treatment of respiratory ailments, such as coughs and congestion, as well as digestive disorders and skin conditions.

Traditional Chinese Medicine

The fruit of chili pepper is used in the traditional medicines of China and other countries for warming the body, 'dispelling cold,' and promoting digestion. Practitioners of traditional Chinese medicine use cayenne pepper in several ways, including to help treat circulatory problems. In Chinese traditional classification, hot pepper (là jiāo) is viewed as acrid and hot in nature, acting on the heart, spleen, and stomach channels, and is used to warm the middle burner, dispel cold, and relieve pain.

Ayurvedic and South Asian Use

Classical Ayurvedic texts like the Charaka Samhita and Sushruta Samhita do not list chili peppers — because peppers arrived post-Columbus — but later compendia such as Bhojana Kutuhalam (15th century) popularized its use for digestive dysfunctions and weak appetite. In Ayurveda and Eastern medicine, Capsicum annuum is used to stimulate digestive secretions, promote intestinal motility, and relieve bloating and indigestion. By the 18th century, chili oils and ointments spiced with chili began circulating in colonial Indian pharmacies, used topically for muscular aches and internally as a digestive stimulant.

Important contextual note: Virtually all traditional uses documented in the historical record pertain to whole chili pepper or crude capsicum preparations containing the full complement of capsaicinoids. Nordihydrocapsaicin as an isolated compound was not known or used historically; any traditional activity attributed to chili pepper capsaicinoids reflects the collective action of the capsaicinoid mixture, of which nordihydrocapsaicin is one minor constituent.

4. Key Constituents and Mechanisms of Action

Nordihydrocapsaicin Within the Capsaicinoid Family

Chili peppers are the major natural source of capsaicinoids, which consist of capsaicin, dihydrocapsaicin, nordihydrocapsaicin, homodihydrocapsaicin, and homocapsaicin; capsaicinoids are found to exert multiple pharmacological and physiological effects, including analgesia, anticancer, anti-inflammation, antioxidant, and anti-obesity activities. The most abundant forms are capsaicin, dihydrocapsaicin, and nordihydrocapsaicin, and available information indicates that the capsaicinoids as a group possess a wide variety of biological and physiological properties, including anti-inflammatory, antioxidant, and anticancer activities.

TRPV1 Receptor Interaction

Some of the pharmacological effects of capsaicinoids are mediated by the receptor called 'transient receptor potential cation channel subfamily V member 1' (TRPV1), to which capsaicin binds specifically. TRPV1 is activated in response to capsaicin, protons, temperature, and reactive oxygen species (ROS) released from inflammatory molecules after exposure to harmful stimuli. After TRPV1 has been activated by a capsaicinoid, the receptor enters a long-lasting refractory state in which it does not respond to mechanical pressure, pain, or inflammatory agents; this so-called 'defunctionalization' results from the closing of the channel pore due to conformational changes that depend on extracellular Ca²⁺, though the extent to which this transient defunctionalization explains the observed analgesic effects remains unclear.

Critically, there is no direct evidence on the modulation of responses through activation of the TRPV1 channel for the capsaicinoids nordihydrocapsaicin, homodihydrocapsaicin, and homocapsaicin specifically. Most mechanistic evidence at TRPV1 pertains to capsaicin and, to a lesser extent, dihydrocapsaicin. Nordihydrocapsaicin's TRPV1 agonism has been inferred by structural analogy and preliminary binding data, but specific high-quality mechanistic studies dedicated to this minor capsaicinoid are limited.

Antioxidant Pathways: Nrf2 and NADPH Oxidase

A proprietary capsaicinoid preparation containing nordihydrocapsaicin (0.1–0.2% of a 10 mg/kg BW oral dose, daily for 8 weeks) was reported to prevent low-fat–high-carbohydrate diet and high-fat diet-induced obesity by regulating the NADPH oxidase and Nrf2 pathways in rats. In the aortic tissue of these rats, capsaicinoid treatment depressed levels of NFκB p65, gp91phox, and p22phox — essential components of NADPH oxidase — while levels of Nrf2, Sirt1, and endothelial nitric oxide synthase were significantly increased. These effects were attributable to the capsaicinoid mixture as a whole; the specific contribution of nordihydrocapsaicin cannot be isolated from these results.

Thermogenic Mechanisms

It is commonly acknowledged that thermogenesis induced by capsaicinoid administration is mediated via the TRPV1 receptor, which regulates the body's internal temperature in animals via autonomic thermo-effector mechanisms. The potential anti-obesity mechanism involves TRPV1 activation and brown fat's thermogenic effect, which aids in boosting energy consumption and metabolic action.

Substance P Depletion and Nociceptive Modulation

Capsaicin appears to act selectively on primary afferent neurons, depleting these processes of the peptide substance P; as a result, chronic administration causes an insensitivity to some types of nociceptive stimuli. When activated by capsaicin-type agonists, TRPV1 mediates Ca²⁺ influx and glutamate release, which may damage cutaneous autonomic nerve fibers and sensory nerve endings, thereby decreasing pain sensation. These mechanisms are inferred to apply to nordihydrocapsaicin by structural similarity, but direct evidence for nordihydrocapsaicin specifically at this mechanistic level is not robustly established in the published literature.

5. Scientific Evidence by Health Area

5.1 Pain and Analgesia

Both capsaicin and its analogs have been used medicinally for centuries, but in recent decades they have been extensively studied for their analgesic, antioxidant, anti-inflammatory, and anti-obesity properties, and, most recently, for their anticancer activity against a variety of cancer types. The analgesic evidence base for the capsaicinoid class is relatively robust for capsaicin itself. The US Food and Drug Administration has granted approval of a capsaicin dermal analgesic patch, which is also authorized in the EU to manage peripheral neuropathic pain in adults, either as a monotherapy or in conjunction with other therapeutic agents.

For nordihydrocapsaicin specifically, there are no independent human clinical trials in the published literature isolating nordihydrocapsaicin's analgesic effects from those of the broader capsaicinoid mixture. Its analgesic potential is inferred from its structural relatedness to capsaicin and its shared pharmacophore. The analgesic component of TRPV1 receptor activation is thought to be mediated by capsaicinoid-induced desensitization of the primary sensory afferent terminal, and this long-lasting anti-nociceptive effect of capsaicin has prompted the clinical use of capsaicin analogs as analgesic agents.

Evidence strength: For nordihydrocapsaicin as an isolated agent in analgesia — preclinical/mechanistic inference only; no dedicated human clinical data.

5.2 Metabolic Effects: Obesity and Energy Expenditure

Several studies have shown that capsaicin stimulates thermogenesis by increasing energy expenditure; a decrease in the respiratory quotient and a beneficial effect of capsaicin on fat oxidation have also been reported. Capsaicin is one of the five naturally occurring capsaicinoids: capsaicin, dihydrocapsaicin, nordihydrocapsaicin, homocapsaicin, and homodihydrocapsaicin.

A key animal study examining nordihydrocapsaicin within a capsaicinoid mixture was published in PMC: The study investigated the hypothesis that capsaicinoids (CAPs) mitigate obesity in rats. Rats were divided into six groups, including control (±10 mg CAPs/kg body weight), low-fat–high-sucrose diet (±10 mg CAPs/kg BW), and high-fat diet (±10 mg CAPs/kg BW); blood samples and liver and aortic tissues were taken at end of study. CAPs supplementation significantly reduced hyperglycemia and hyperlipidemia (P<0.001) and ameliorated oxidative damage by reducing malondialdehyde concentrations in serum and liver and by increasing total antioxidant capacity in serum.

Regarding human data on capsaicinoid mixtures (including nordihydrocapsaicin): Capsaicinoids are the major pungent, naturally occurring active compounds in capsicum fruits, with the most abundant forms being capsaicin, dihydrocapsaicin, and nordihydrocapsaicin; one open-label, placebo-controlled acute study found extrapolated resting energy expenditure (REE) changes in 24 hours of 130 kcal/day for capsaicinoids versus 8 kcal/day for placebo, with no changes in heart rate and no adverse events; the authors noted that further long-term clinical studies are required to explore the use of supplements in nutritional studies for weight management.

Evidence strength: Anti-obesity and thermogenic effects are established for the capsaicinoid class in animal models and in some short-term human studies; the specific, isolated contribution of nordihydrocapsaicin to these effects has not been studied clinically. All relevant human trials use mixed capsaicinoid preparations. Evidence in humans is preliminary and based on short-duration studies.

5.3 Antioxidant Effects

A plausible mechanism for chemopreventive action of capsaicinoids involves their anti-oxidative effects; capsaicin and its analogs elicit a biphasic antioxidant action, acting directly to scavenge free radicals and upregulating the expression of several antioxidant enzymes. There is a positive correlation between the levels of capsaicin and its analogues and the antioxidant activity of peppers of the genus Capsicum. These findings imply that nordihydrocapsaicin — as one of the co-occurring capsaicinoids in pepper extracts — contributes to the antioxidant profile of such extracts, though its independent contribution has not been quantified in clinical settings.

Evidence strength: In vitro and animal evidence for capsaicinoid antioxidant activity (including contributions from nordihydrocapsaicin); no isolated human clinical data for nordihydrocapsaicin specifically.

5.4 Anti-Inflammatory Effects

Capsaicinoids are found to exert multiple pharmacological and physiological effects, including the activities of analgesia, anticancer, anti-inflammation, antioxidant, and anti-obesity, and therefore may have potential clinical value for pain relief, cancer prevention, and weight loss. The anti-inflammatory mechanism in the capsaicinoid class broadly involves modulation of NFκB signaling and reduction of pro-inflammatory cytokine expression; in rat models, capsaicinoid treatment depressed levels of NFκB p65, gp91phox, and p22phox — essential components of NADPH oxidase — in the aorta.

Evidence strength: Anti-inflammatory effects are demonstrated in animal and in vitro models for capsaicinoid mixtures that include nordihydrocapsaicin. No human clinical evidence is available specifically for isolated nordihydrocapsaicin as an anti-inflammatory agent.

5.5 Anticancer and Antiproliferative Effects

Overall, capsaicin has shown effectiveness against various human malignancies in preclinical research; however, although there is an increasing focus on assessing the clinical effects of capsaicin, especially its analgesic activity, the anticancer efficacy is currently limited in human studies. Capsaicinoids have been studied for pharmacological and physiological effects including anticancer activity. No clinical trials specifically isolating nordihydrocapsaicin as an anticancer agent appear in the peer-reviewed literature.

Evidence strength: For nordihydrocapsaicin specifically in anticancer contexts — preliminary and indirect; the available anticancer evidence pertains predominantly to capsaicin itself, and nordihydrocapsaicin is simply co-present in the studied preparations.

5.6 Cardiovascular and Gastrointestinal Effects

Capsaicinoids display benefits on the cardiovascular and gastrointestinal system. Somatostatin released from sensory nerve terminals following activation of peripheral nociceptors elicits a systemic anti-inflammatory response by binding to G-protein coupled membrane receptors, decreasing the release of pro-inflammatory neuropeptides; TRPV1 stimulation by capsaicin has also been demonstrated to protect the gastric mucosa from noxious injury. These effects derive from class-level capsaicinoid pharmacology, and nordihydrocapsaicin's specific role therein is not independently established.

Evidence strength: Class-level evidence in animal models; no human clinical evidence specific to nordihydrocapsaicin.

6. Body Systems Associated with Nordihydrocapsaicin

Peripheral and central nervous system: Via TRPV1-mediated modulation of nociceptive signaling; relevance to pain perception and neurogenic inflammation.
Metabolic system: Potential anti-obesity mechanism involves TRPV1 activation and brown fat's thermogenic effect, which aids in boosting energy consumption and metabolic action.
Cardiovascular system: Capsaicinoid treatment significantly increased levels of Nrf2, Sirt1, and endothelial nitric oxide synthase in the aorta of rats, suggesting a role in vascular health.
Gastrointestinal system: Capsaicinoids influence gastric acid secretion, gastrointestinal motility, and mucosal protection, as demonstrated in animal and mechanistic studies.
Immune and inflammatory pathways: Modulation of NFκB and NADPH oxidase, with downstream effects on inflammatory cytokine production.
Integumentary system (topical application): As an irritant and potential topical analgesic agent within capsaicinoid preparations.

7. Dosage Forms and Reported Dosages

Nordihydrocapsaicin is not prescribed or studied as a standalone supplement at defined isolated doses. It occurs as a minor constituent in broader capsaicinoid preparations. Dosages reported in the scientific literature pertain to total capsaicinoid content or to preparations where nordihydrocapsaicin is a fraction of the whole:

A rat study used a preparation providing 0.1–0.2% nordihydrocapsaicin as part of a 10 mg/kg BW per day oral capsaicinoid dose, administered daily for 8 weeks.
In another rat study, groups received ±10 mg total CAPs/kg body weight across control, low-fat–high-sucrose, and high-fat dietary conditions.
In a further rat study using capsinoids, male Wistar rats were exposed to a high-fat diet for 27 consecutive weeks; after characterization of obesity at week 19, obese animals received capsinoids at 10 mg/kg/day by orogastric gavage.
In a standardized commercial capsaicinoid concentrate (Capsimax®), nordihydrocapsaicin constitutes 0.1–0.2% of the concentrate, which is itself standardized to 2% total capsaicinoids; the concentrate is composed of 1.2–1.35% capsaicin and 0.6–0.8% dihydrocapsaicin.

No peer-reviewed human clinical trial has established a specific therapeutic dosage for nordihydrocapsaicin as an isolated compound. Reported dosages in human capsaicinoid research reflect the total capsaicinoid mixture, not nordihydrocapsaicin individually.

8. Safety Considerations and Interactions

Irritant Properties

Like capsaicin, nordihydrocapsaicin is an irritant. Capsicum extracts are recognized skin and respiratory irritants; occupational exposure — for example in manufacturing plants — can produce cough, sneezing, wheezing, and dermatitis. Pure nordihydrocapsaicin is lipophilic, meaning that it dissolves in fats, oils, and lipids rather than in water. This lipophilicity influences its absorption characteristics and its capacity to irritate mucosal membranes on contact.

Gastrointestinal Concerns

High chili consumption has been linked to gastric tissue irritation, though causality remains inconclusive. Nordihydrocapsaicin, as a capsaicinoid, shares this potential for gastrointestinal mucosal irritation at high concentrations. Microencapsulation and enteric-coating strategies in commercial products are specifically designed to mitigate this effect.

Genotoxicity and Carcinogenicity

EFSA and EMA acknowledged potential genotoxic signals in early data for capsaicin (e.g., SCF 2002), but more recent risk assessments did not find genotoxic risk at typical exposure levels. Nordihydrocapsaicin itself has not been independently assessed for genotoxicity by EFSA or equivalent regulatory bodies in published opinions, though it is structurally similar to capsaicin.

Dermal Sensitization

Capsicum extracts are generally not systemically sensitizing; dermatological patch tests at low concentrations (0.1–1.0%) are mostly negative.

Regulatory Reference Standards

Capsicum has been officially defined in USP 23 as the dried ripe fruit of Capsicum frutescens Linné or Capsicum annuum Linné. Nordihydrocapsaicin is listed in the USP, EP, and BP as a reference standard compound, primarily for the purpose of quality control and analytical method development in capsaicinoid-containing products. It is supplied as a high-quality reference standard with comprehensive characterization data, essential for analytical method development, method validation, quality control applications, and Abbreviated New Drug Applications (ANDA).

Acute Toxicity

Like other capsaicinoids, nordihydrocapsaicin exhibits analgesic, anti-inflammatory, and potential anticancer and anti-obesity effects, though it poses risks of irritation and acute oral toxicity. Specific LD₅₀ values or detailed acute toxicology data for isolated nordihydrocapsaicin in humans are not established in the peer-reviewed literature; toxicological extrapolations are generally made from capsaicin data by analogy.

Drug Interactions

No specific drug interaction studies for isolated nordihydrocapsaicin have been identified in the peer-reviewed literature. By pharmacological class, TRPV1 agonists such as capsaicinoids may theoretically interact with anticoagulants (altered platelet aggregation has been studied for capsaicin), antihypertensives (via effects on vascular tone and nitric oxide), and pain medications (altered nociceptive threshold). These considerations derive from the capsaicinoid class profile and are not confirmed in specific nordihydrocapsaicin studies.

9. Research Limitations and Current Knowledge Gaps

The most important scientific caveat regarding nordihydrocapsaicin is that the overwhelming majority of published biological and clinical evidence pertains to capsaicin or to mixed capsaicinoid preparations, not to nordihydrocapsaicin studied as an isolated compound. There is no direct evidence on the modulation of responses through activation of the TRPV1 channel specifically for nordihydrocapsaicin, homodihydrocapsaicin, and homocapsaicin. Over 200 active components known as capsaicinoids have been identified in chili peppers, the most abundant being capsaicin, dihydrocapsaicin, and nordihydrocapsaicin — yet research investment has been heavily skewed toward capsaicin.

Key gaps include: (1) no dedicated human clinical trials for isolated nordihydrocapsaicin in any indication; (2) absence of pharmacokinetic studies specific to nordihydrocapsaicin in humans; (3) no regulatory opinion from EMA, EFSA, or FDA specifically addressing nordihydrocapsaicin in isolation; (4) uncertainty about whether nordihydrocapsaicin's saturated side chain confers meaningfully different pharmacokinetics or receptor kinetics compared to the unsaturated capsaicin. Studies using whole capsaicinoid preparations reflect synergistic or additive effects and cannot be used to assign specific activities to nordihydrocapsaicin alone.

References

Health Conditions

Health conditions that Nordihydrocapsaicin may help support.

No conditions available.

Body Systems

Body systems that Nordihydrocapsaicin may help support.

No body systems available.