Capsicum

Capsicum (Capsicum spp.): A Comprehensive Encyclopedic Reference

1. Identity: Botanical Classification, Chemical Names, and Natural Source

1.1 Botanical Identity

Chili belongs to the genus Capsicum and is part of the Solanaceae family. The species Capsicum annuum L., which belongs to the family Solanaceae in the class Magnoliopsida, is an annual or limited perennial herb widely used globally as a medicinal and edible plant. The genus is large and botanically diverse: the genus contains a huge biodiversity within its nearly 40 species and they have many more applications than just cooking spicy foods.

The Capsicum genus split from Solanaceae 19.6 million years ago, 5.4 million years after the appearance of Solanaceae, and is native only to the Americas. Chilies only started to quickly evolve in the past 2 million years into markedly different species.

The most commercially and medicinally important species include Capsicum annuum (bell pepper, cayenne, paprika), Capsicum frutescens (tabasco, cayenne), Capsicum chinense (habanero, scotch bonnet), Capsicum baccatum, and Capsicum pubescens. From the pungent chilli to the colorful paprika and the bell pepper, with its remarkable aroma, the genus is of great interest for its chemistry, sensory attributes, and physiological action.

1.2 Key Chemical Name

The principal bioactive compound is capsaicin. Capsaicin (trans-8-methyl-N-vanillyl-6-nonenamide) is a crystalline, lipophilic, colorless, and odorless alkaloid that is soluble in fat, alcohol, and oil. Capsaicin was first isolated in 1876, its structure was determined in 1919, and it was chemically synthesized in 1930.

1.3 Common Preparations and Forms

Traditionally, chili is usually consumed fresh and processed in different forms, such as spice, powder, paste, etc. In medicinal and supplement contexts, capsicum preparations include: dried fruit powder; oleoresin (a concentrated extract of the fruit); standardized capsaicin or capsaicinoid extracts; topical creams, gels, lotions, and patches; and oral dietary supplement capsules.

Combination homeopathic and natural preparations contain capsicum extracts, and capsicum is used in traditional Korean medicine. Capsicum contains approximately 1.5% of the irritant oleoresin. The major component of the oil is capsaicin (0.02%), a very pungent phenolic chemical.

Capsaicin is commercially available as creams and patches for treatment of pain in neuralgias and neuropathies. Lower-strength capsaicin patches, creams, and lotions are available over the counter.

2. Traditional and Historical Use

2.1 Origins and Pre-Columbian Use

It is estimated that Capsicum made an appearance in human history around 7500 BC and started to be cultivated between 5200 and 3400 BC. Records dating back to the sixth century report the use of Capsicum fruits in medicinal preparations.

Medicinal use of capsicums has a long history, dating back to the Mayas who used them to treat asthma, coughs, and sore throats. The Aztecs used chile pungency to relieve toothaches. Mexico is the center of origin and diversification of domesticated chile (Capsicum annuum L.). Traditional knowledge, uses and management of chile as food and medicine form a continuum (i.e., are not separated into distinct categories). The intermingled uses of Capsicum are diversified, deeply rooted and far-reaching into the past.

Native American cultures have traditionally used chili peppers for a variety of purposes, including pain relief, wound healing, and as a ceremonial medicine. Chilli peppers are used to treat wounds, relieve pain (e.g. stomach aches, headaches and indigestion), reduce fever, as an anti-infective agent and to treat hypertension when chewed.

2.2 Spread to Asia, Africa, and Europe

In Europe, Capsicum arrived by the Spice Route, but not as a spice. The first samples that arrived in Europe were considered rare and expensive items and were taken by botanists and aristocrats. European nobles in the sixteenth century primarily used Capsicum spp. as ornamental plants in their gardens. As it started being cultivated in the countryside of Europe by farmers who could not afford Asian black pepper, it was no longer considered interesting as an ornamental plant and instead was known as "the poor people's peppers." Only in the eighteenth century were Capsicum peppers fully consolidated in Europe as a spice in several traditional recipes.

The fruit is used in the traditional medicines of China and other countries for warming the body, 'dispelling cold' and promoting digestion. Capsicum is used in traditional Korean medicine. Capsicum frutescens (cayenne pepper) is often used as remedies for diabetes mellitus in African traditional medicine.

2.3 Documented Traditional Therapeutic Uses

In addition to the use of capsicum fruits as a food additive, in traditional medicine, it has been used for the treatment of cough, toothache, sore throat, parasitic infections, rheumatism, wound healing and also utilized as an antiseptic, counterirritant, appetite stimulator, antioxidant and immunomodulator. The fruits of C. annuum have been used as a tonic, antiseptic, and stimulating agent, to treat dyspepsia, appetites, and flatulence, and to improve digestion and circulation.

Hot cultivars also have medicinal properties and can be used to heal wounds, treat intestinal disorders, relieve muscle pain and toothache, and control arthritic pain.

3. Key Constituents and Active Compounds

3.1 Capsaicinoids

The fruit contains various active components, including capsaicin, which is the most abundant pungent compound; capsaicinoids and carotenoids. Capsaicin, dihydrocapsaicin, nordihydrocapsaicin, homocapsaicin, and homodihydrocapsaicin constitute the capsaicinoids. Capsaicin and dihydrocapsaicin constitute approximately 90% of the capsaicinoids found in any fruit belonging to the Capsicum genus, with capsaicin constituting 70–80%.

Capsaicin exists as a family of compounds including capsaicin, dihydrocapsaicin, homocapsaicin, homodihydrocapsaicin, nordihydrocapsaicin, capsaicin esters, dihydrocapsaicin esters, nordihydrocapsaicin esters, capsanthin-β-d-glucoside and dihydrocapsanthin-β-d-glucoside.

Plants exclusively of the genus Capsicum produce capsaicinoids, which are alkaloids. Capsaicin is believed to be synthesized in the interlocular septum of chili peppers and depends on the gene AT3, which resides at the pun1 locus, and which encodes a putative acyltransferase. The general biosynthetic pathway of capsaicin and other capsaicinoids was elucidated in the 1960s by Bennett, Kirby, Leete, and Louden. Radiolabeling studies identified phenylalanine and valine as the precursors to capsaicin.

3.2 Capsinoids (Non-Pungent Analogs)

Capsinoids are non-pungent capsaicin-related compounds derived from the CH-19 sweet pepper of all varieties of the Capsicum genus. The emergence of capsiate, a recently identified nonpungent capsaicin analog, presents a promising alternative for those who abstain from capsaicin-containing foods due to pungency.

3.3 Polyphenols and Flavonoids

The fruits of the genus Capsicum contain nutritionally relevant metabolites such as carotenoids (provitamin A), ascorbic acid (vitamin C), tocopherols (vitamin E), phenolic compounds, and capsaicinoids. The main bioactivities attributed to polyphenols are antioxidant, antimicrobial, antihyperglycemic, anti-inflammatory, and antihypertensive.

Many bioactive compounds were isolated from C. frutescens, including essential oils, alkaloids, glycosides, phenolic compounds, flavonoids, esters, terpenoids, noncarotenoids, lipoxygenase derivatives, carbonyls, alcohols, hydrocarbons, hydroxybenzoic acid, hydroxycinnamic acid, ascorbic acid, tannins, steroids, capsaicin, dihydrocapsaicin, capsiconinoids, capsinoids, ortho-hydroxy-N-benzyl-16-methyl-11,14-diene-octadecamide, and 9 and 12-diene-octadecanoic acid.

Researchers have evaluated the composition of two flavonoids (quercetin and luteolin) after the acid hydrolysis of a phenolic portion of a C. annuum extract. Mainly, this botanical contains a good source of vitamin C, vitamin A, vitamin E, vitamin B5, potassium, magnesium, iron, calcium, phosphorus, and carotenoids.

3.4 Variability in Composition

The composition and concentration of these metabolites are affected by the ripeness stage, cultivation systems, and fruit processing.

4. Mechanisms of Action

4.1 The TRPV1 Receptor: Primary Mechanism

The molecular site of action for capsaicin is the capsaicin receptor, first proposed by Szolcsányi in 1975, or the transient receptor potential cation channel vanilloid subfamily member 1 (TRPV1), which is expressed by polymodal capsaicin-sensitive nociceptive neurons in their central branches and peripheral terminals and also in trigeminal ganglion neurons, vagal afferents in jugular and nodose ganglion neurons.

Capsaicin acts through Transient Receptor Potential Channel Vanilloid type-1 (TRPV1), a transmembrane cation channel that prefers Ca²⁺ over Na⁺, with six putative transmembrane domains and a calcium-permeable pore region. The channel can be activated by many mechanisms, including temperature, low pH, osmotic sensing, taste, pressure, stretch, vibration, and endogenous and exogenous molecules.

In neurons, cation (Ca²⁺) influx through TRPV1 causes membrane depolarization, leading to the activation of voltage-gated sodium channels and the generation of an action potential. Activation of sensory nerves by capsaicin evokes the local release of the neuropeptides calcitonin gene-related peptide (CGRP), the tachykinins, substance P (SP) and neurokinin A (NKA) and somatostatin not only into the spinal cord but also in the periphery. These neuropeptides result in local tissue vascular responses, increased microvascular permeability, plasma extravasation and neurogenic inflammation.

4.2 Desensitization: The Basis of Analgesic Action

Unique among natural irritants, capsaicin initially excites neurons but then 'calms' them into long-lasting non-responsiveness. When TRPV1 is continuously activated through prolonged exposure to an agonist (e.g., capsaicin), excessive calcium enters the nerve fiber, initiating processes that result in long-term yet reversible impairment of nociceptor function. This is believed to be the mechanism by which application of capsaicin provides relief from pain.

Capsaicin is a ligand for transient receptor potential channel vanilloid receptors, which are found in nociceptive nerve terminals in the skin. Initial exposure to topical capsaicin leads to excitation of these receptors, release of vasoactive mediators, erythema, intense burning, pain, and thereafter desensitization of sensory neurons resulting in inhibition of pain transmission.

4.3 TRPV1 in Thermosensation, GI Function, and Cardiovascular Physiology

Broadly speaking, TRPV1 has been linked to thermo-sensation (heat), autonomic thermoregulation, nociception, food intake regulation and multiple functions in the gastrointestinal (GI) tract. This channel, which is involved in a wide range of neuronal processes, is expressed in peripheral and central branches of capsaicin-sensitive nociceptive neurons, sensory ganglia, the spinal cord, and different brain regions in neuronal cell bodies, dendrites, astrocytes, and pericytes.

TRPV1 is expressed in the sensory nerves in cardiovascular structures, near the epicardium and in vascular endothelial cells. When blood flow to myocardium is reduced, such as during myocardial infarction, free oxygen radicals are produced, which activate TRPV1. Myocardial injury also upregulates 12-hydroperoxyeicosatetraenoic acid, a metabolite of 12-lipooxygenase arachidonic acid that may bind to TRPV1.

4.4 Antioxidant and Anti-Inflammatory Mechanisms

Several mechanisms have been proposed to explain the therapeutic effects of capsaicin, including antioxidation, analgesia and promotion of apoptosis. Some of the mechanisms are proposed to be mediated by the capsaicin receptor (TRPV1), but some are proposed to be independent of that receptor.

Capsaicin acts as an anti-inflammatory agent, counter-irritant, antipruritic, anti-psoriatic and anti-itch agent.

4.5 Thermogenic Mechanisms

Weight management effects are purportedly derived from the increase in sympathetic nervous system (SNS) activity, as generally it stimulates thermogenesis and fat oxidation while decreasing energy intake in both humans and rodents.

4.6 Anticancer Mechanisms (Preclinical)

Capsaicin alters the expression of several genes that arrest the cell cycle in tumor cells and promotes apoptosis. These effects have been demonstrated in colon adenocarcinoma, pancreatic cancer, hepatocellular carcinoma, prostate cancer, breast cancer and numerous other types of cancer, without damage to normal cells. 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. These mechanisms are largely established in cell culture and animal models; human clinical evidence remains limited.

5. Scientific Evidence by Area of Use

5.1 Pain Management (Topical Application)

Topical capsaicin for pain is the most thoroughly studied and clinically validated use of capsicum-derived compounds. Evidence spans from systematic reviews of randomized controlled trials to regulatory approval.

5.1.1 Neuropathic Pain and Postherpetic Neuralgia

A 2013 Cochrane database systematic review of six randomized trials compared single application of high-dose (8%) capsaicin patch to low-dose (0.04%) patch in 2,073 adult patients with chronic neuropathic pain. Four of these trials involved 1,272 patients with postherpetic neuralgia (PHN). At 8 and 12 weeks, capsaicin 8% patch therapy was associated with an increase in patients' reports of feeling much or very much better, with numbers needed to treat of 8.8 and 7, respectively. Serious adverse effects were not more frequent with high-dose treatment than control. There was no difference in adverse event withdrawals, but "lack of efficacy withdrawals" were more common with control than active treatment.

A patch containing 8% capsaicin (marketed under the trade name Qutenza®) provides a localized therapy with effects lasting up to 12 weeks after a single 60-minute application.

In a meta-analysis examining 2,057 persons with PHN and HIV-associated neuropathy, the proportion of responders with relief (>30% improvement in pain lasting from 2–12 weeks) over a 12-week treatment period was 43% in the capsaicin 8% patch group and 34% in the control group, a statistically significant difference.

The incidence of side effects from using topical capsaicin is consistently higher in all included studies, but topical capsaicin is a promising treatment option for specific patient groups or certain neuropathic pain conditions such as postherpetic neuralgia.

5.1.2 Chronic Musculoskeletal and Mixed Neuropathic Pain (Low-Concentration Topical)

Based on 313 patients in 4 studies, capsaicin resulted in a statistically significant improvement in neuropathic pain at 4 weeks (RR 1.4, 95% CI: 1.1, 1.7); the corresponding number needed to treat was 6.4 (95% CI: 3.8, 21).

The relative benefit from topical capsaicin 0.075% compared with placebo was 1.4 (95% confidence interval 1.2 to 1.7) and the number needed to treat was 5.7 (4.0 to 10.0). Three double-blind placebo-controlled trials (368 patients) were pooled for analysis of musculoskeletal conditions. The relative benefit from topical capsaicin 0.025% or plaster compared with placebo was 1.5 (1.1 to 2.0) and the number needed to treat was 8.1 (4.6 to 34).

Although topically applied capsaicin has moderate to poor efficacy in the treatment of chronic musculoskeletal or neuropathic pain, it may be useful as an adjunct or sole therapy for a small number of patients who are unresponsive to, or intolerant of, other treatments.

5.1.3 Diabetic Peripheral Neuropathy

Analysis at final visit for 252 patients showed statistical significance favoring capsaicin compared with vehicle for the following: 69.5% vs 53.4% pain improvement by the physician's global evaluation scale, 38.1% vs 27.4% decrease in pain intensity, and 58.4% vs 45.3% improvement in pain relief. With the exception of transient burning, sneezing, and coughing, capsaicin was well tolerated. Study results suggest that topical capsaicin cream is safe and effective in treating painful diabetic neuropathy.

The high-concentration (8%) patch was subsequently approved by the FDA for the treatment of neuropathic pain associated with diabetic peripheral neuropathy (DPN) of the feet in adults.

5.1.4 Osteoarthritis

Results suggested modest beneficial effects on different kinds of pain such as diabetic neuropathy, postherpetic neuralgia, chronic musculoskeletal pain, and arthritis-related pains. Several randomized controlled trials (RCTs) that assessed the efficacy of capsaicin for the treatment of pain in osteoarthritis (OA) patients have been published in recent decades. These studies often arrive at contradictory conclusions creating confusion and adding to the existing uncertainties. These conclusions are based on very low to low certainty of the evidence.

Overall assessment of topical capsaicin for pain: The clinical evidence base for topical capsaicin in neuropathic pain is the strongest among all capsicum applications, supported by multiple RCTs and systematic reviews, and has resulted in FDA regulatory approval at the high-concentration (8%) formulation. Evidence for musculoskeletal conditions is present but of lesser quality.

5.2 Thermogenesis and Weight/Metabolic Management

Evidence indicates that capsaicin and capsiate both augment energy expenditure and enhance fat oxidation, especially at high doses. Furthermore, the balance of the literature suggests that capsaicin and capsiate suppress orexigenic sensations. The magnitude of these effects is small.

A systematic review and meta-analysis published in PLOS One found that pooled effect sizes revealed that compared with placebo, capsaicinoids/capsinoids significantly increased resting metabolic rate (WMD: 33.99 Kcal/day, 95% CI: 15.95, 52.03; I² = 0%, p = .94), energy expenditure, and fat oxidation.

Treatments of either laboratory rodents or humans with capsinoids, the non-pungent analogues of capsaicin, were able to induce energy expenditure through thermogenesis, but it did not affect fat storage and weight loss.

A critical review evaluating the available experimental and clinical evidence for and against capsaicin as a weight control agent comes to the conclusion that capsaicin is not a magic "exercise in a pill," although there is emerging evidence that it may help restore a healthy gut microbiota.

Overall assessment: The thermogenic effects of capsaicinoids in humans are statistically detectable in meta-analyses but are small in absolute magnitude. There is insufficient evidence from clinical trials to conclude that capsaicin supplementation alone produces clinically meaningful weight loss. Most evidence comes from short-term studies in healthy adults, and long-term RCT data are lacking.

5.3 Gastrointestinal Effects

Red pepper as a drug is given in atonic dyspepsia and flatulence due to increasing the motility in the gastric antrum, duodenum, proximal jejunum and colon. It can also increase parietal, pepsin, and bile acid secretions.

Based on the results of past studies, capsaicin may have potential effects on the treatment of functional dyspepsia (FD). However, most studies mainly investigate functional dyspepsia-treatment effects.

However, the relationship between capsaicin and gastrointestinal symptoms is bidirectional and complex. Capsaicin enhances noxious postprandial heartburn, presumably by direct effects on sensory neurons. TRPV1 is also upregulated in several human pathological conditions including vulvodynia, GI inflammation, Crohn's disease and ulcerative colitis.

Overall assessment: The gastrointestinal evidence is mixed. Capsicum may stimulate digestive motility and secretion, and it has a traditional use in functional dyspepsia, but it can also exacerbate heartburn and irritate mucous membranes. The clinical evidence for dyspepsia benefit is preliminary, based largely on observational data and animal studies, with limited high-quality RCT data.

5.4 Cardiovascular Effects

Capsaicin is a potent agonist of the TRPV1 channel and is a common component found in the fruits of the genus Capsicum plants, which have been known to humanity and consumed in food for approximately 7,000–9,000 years. Capsaicin itself has been proposed to exhibit vasodilatory, antimicrobial, anti-cancer, and antinociceptive properties.

Large epidemiological studies imply health benefits for chili lovers, including lower risk for obesity and cardiovascular disease. Despite intensive research, the molecular mechanisms by which capsaicin may exert these health benefits are yet to be determined.

The lipid-lowering, antihypertensive, antidiabetic and anti-obesity effects of C. annuum have been demonstrated in several studies. The results showed still more research projects need to be done to confirm its advantages especially in humans.

A critical safety note: a growing body of evidence reveals a vasoconstrictory potential of capsaicin acting via the vascular TRPV1 channel and suggests that unnecessarily high consumption of capsaicin may cause severe consequences, including vasospasm and myocardial infarction in people with underlying inflammatory conditions.

Overall assessment: Epidemiological associations between regular chili consumption and improved cardiometabolic markers are promising, but causality is not established. The cardiovascular effects of capsaicin are complex and can be protective or potentially harmful depending on dose, formulation, route of administration, and the individual's cardiovascular status. Human interventional RCT evidence is limited.

5.5 Anticancer Research

Capsaicin exerts antioxidative, antitumor, antiulcer and analgesic effects and it has demonstrated potential as a treatment for cardiovascular, gastrointestinal, oncological and dermatological conditions.

Within the last two decades, there have been several clinical reports on the use of capsaicin. However, most of the studies have mainly examined the analgesic activity of capsaicin. There have been few reports on the use of capsaicin in cancer patients; however, these studies have examined the pain relief function of capsaicin in addition to other treatment regimens.

Capsaicin 8% patch could promote the regeneration and restoration of skin nerve fibres in chemotherapy-induced peripheral neuropathy in addition to pain relief.

Overall assessment: Preclinical (in vitro and animal) evidence for anticancer activity is substantial, but human clinical evidence for anticancer efficacy of capsicum/capsaicin is essentially absent. The anticancer findings should not be extrapolated to clinical recommendations. Research in this area is active but at an early stage.

5.6 Metabolic Syndrome Components (Blood Glucose, Lipids, Hypertension)

According to various studies, red pepper as well as capsaicin has ability to control of metabolic syndrome and its related disorders such as obesity, disrupted lipid profile, diabetes and its complications.

A low dose of capsaicin stimulated glucose absorption from the gastrointestinal tract in healthy human subjects and promoted the mobilization of glycogen via the stimulation of capsaicin-sensitive afferent nerves. This result indicates that capsaicin-sensitive afferent nerves exert an important role in glucose utilization.

Capsicum frutescens increased serum insulin concentration in high-fat diet-fed streptozotocin-induced type 2 diabetes rats after four weeks of treatment. The data of this study suggest that 2% of dietary Capsicum frutescens is insulinotropic rather than hypoglycemic in the experimental methods. This is an animal finding and has not been confirmed with the same specificity in human trials.

Overall assessment: Metabolic effects are biologically plausible and supported by animal and in vitro research, and some human studies show modest effects on individual metabolic parameters. However, the quality and consistency of human clinical trial evidence for these endpoints remain insufficient to support definitive therapeutic claims.

6. Body Systems and Health Areas of Association

• Nervous system / Pain pathways: Capsaicin acts directly on nociceptive TRPV1 receptors; clinically validated in neuropathic and musculoskeletal pain.
• Integumentary system: Topical applications target skin nociceptors; indications include postherpetic neuralgia, psoriasis (proposed), and pruritus. In the market, several ointments contain capsaicin, which is administered topically for pain relief, migraines, headaches, psoriasis, and herpes simplex virus infection.
• Gastrointestinal system: Capsaicin stimulates GI motility and secretion, is used in functional dyspepsia; however, it can worsen heartburn in susceptible individuals.
• Cardiovascular system: TRPV1 receptors are present in cardiac and vascular tissue; epidemiological associations with cardiovascular benefit exist, but interventional human data are limited.
• Endocrine / Metabolic system: Modulates thermogenesis via the sympathetic nervous system; investigational for obesity and metabolic syndrome.
• Immune / Inflammatory pathways: Several mechanisms have been proposed to explain the therapeutic effects of capsaicin, including antioxidation, analgesia and promotion of apoptosis.
• Oncology (preclinical): Influences apoptotic and cell-cycle pathways in cancer cell lines; not yet established in human clinical use for cancer treatment.

7. Dosage Forms and Reported Dosages

7.1 Topical (Low-Concentration, Over-the-Counter)

Studies evaluated topical capsaicin applied 3 to 4 times daily. The included studies evaluated either 0.025% or 0.075% topical capsaicin, or 11 mg capsinoid capsicum plaster, with or without concomitant oral analgesics.

Clinical studies on the efficacy of capsaicin topical medication usually involve two to three applications per day on the site of pain for a duration ranging from 2 weeks to several weeks.

7.2 High-Concentration Capsaicin Patch (Prescription)

Qutenza is a prescription skin patch containing 8% capsaicin (179 mg). Each patch contains 179 mg of capsaicin, of which approximately 0.9% (~1.6 mg) is delivered to the skin during a 60-minute application.

The recommended dose of Qutenza for neuropathic pain associated with postherpetic neuralgia is a single, 60-minute application of up to four topical systems. The recommended dose for neuropathic pain associated with diabetic peripheral neuropathy is a single, 30-minute application on the feet of up to four topical systems. Treatment with Qutenza may be repeated every three months or as warranted by the return of pain (not more frequently than every three months).

7.3 Thermogenesis and Metabolic Studies (Oral)

Studies on thermogenesis have used varying oral doses of capsaicinoids. In the United States, capsiate is available as "CH-19 Sweet Extract" with recommendations to consume three 1 mg capsules once daily by mouth to "naturally increase basal metabolic rate."

The outcomes of earlier trials are controversial concerning the effect of capsaicinoids/capsinoids on thermogenesis. Systematic reviews and meta-analyses have been carried out to examine the effect of capsaicinoids/capsinoids on thermogenesis indices including resting metabolic rate and respiratory quotient in healthy adults, with electronic literature searches conducted between 1990 and 2019.

8. Safety Considerations and Known Interactions

8.1 Local Adverse Effects (Topical Use)

Common adverse effects of the capsaicin 8% patch are transient mild-to-moderate self-limiting application-site burning, pain, erythema, pruritus, papules, swelling, dryness, and hypertension.

Common (over-the-counter topical) adverse effects include burning, urticaria and contact dermatitis; mild to moderate coughing; pain and pruritus at the application site. Transient (intranasal) effects include burning sensations, lacrimation, and rhinorrhea.

Around one-third of patients experienced local adverse events with capsaicin, which would not have been the case with placebo.

Capsaicin can irritate mucous membranes, the eyes, and broken skin. For all capsaicin creams, gels, and lotions, wear gloves during application and wash hands with soap and water afterwards to avoid spreading the active ingredient to these sensitive areas.

8.2 Cardiovascular Adverse Effects

Capsaicin use should be considered when encountering adverse cardiovascular effects in the absence of illicit substance use and especially in young patients. Patients with unstable or poorly controlled hypertension or a recent history of cardiovascular or cerebrovascular events may be at increased risk of adverse cardiovascular effects.

A growing body of evidence reveals a vasoconstrictory potential of capsaicin acting via the vascular TRPV1 channel and suggests that unnecessarily high consumption of capsaicin may cause severe consequences, including vasospasm and myocardial infarction in people with underlying inflammatory conditions.

8.3 Pharmacokinetics and Systemic Exposure

The clinical usefulness of capsaicin is limited by its short half-life. With the high-concentration patch, systemic absorption is deliberately minimized: trans-capsaicin solutions, formulated with PEG300 or in an aqueous formulation, minimize long-term systemic exposure.

8.4 Drug Interactions

Qutenza (the 8% capsaicin patch) has no known drug–drug interactions and the most common adverse reactions included application site reactions, such as erythema, pain, and pruritus.

For oral ingestion, no specific, well-characterized drug–drug interactions for capsicum supplements are established in the peer-reviewed literature reviewed here. However, given capsaicin's effects on gastric motility, mucosal permeability, and the sympathetic nervous system, caution is warranted in patients using medications with narrow therapeutic windows, antihypertensives, or drugs sensitive to alterations in gastrointestinal absorption.

8.5 Gastrointestinal Irritation

Chilies are known to protect against gastrointestinal ailments including dyspepsia, loss of appetite, gastroesophageal reflux disease, and gastric ulcer due to several mechanisms such as reducing the food transition time through the gastrointestinal tract and anti-Helicobacter pylori effects. However, acute or high-dose exposure can have the opposite effect: capsaicin enhances noxious postprandial heartburn, presumably by direct effects on sensory neurons.

8.6 High-Concentration Patch: Procedural Safety

Qutenza must not be dispensed to patients for self-administration or handling. Only physicians or healthcare professionals are to administer and handle Qutenza. There is no clinical experience with Qutenza overdose in humans. There is no specific antidote for overdose with capsaicin.

8.7 Inhalation Risk

Aerosolization of capsaicin can occur upon rapid removal of the Qutenza patch. Therefore, the patch should be removed gently and slowly by rolling the adhesive side inward.

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