Capsaicin

In brief

What capsaicin is, and why a plant makes it

Capsaicin is one molecule with two ends. One end is a vanillyl group: a benzene ring carrying a hydroxyl and a methoxy group, the same arrangement that makes vanillin smell of vanilla. The other end is a nine-carbon chain, branched at the far end and carrying a single double bond. An amide bond, the same kind of bond that links amino acids in a protein, joins them ¹. The ring end is what the receptor recognizes; the greasy tail is what makes the molecule stick to membranes and refuse to dissolve in water, which is why it dissolves in fat, oil and alcohol rather than in water ¹.

It is not alone. A chili makes more than twenty closely related compounds, collectively capsaicinoids, all built the same way from vanillylamine and a fatty acid of some length, and differing in how long that acid is and whether it carries a double bond ¹. Capsaicin and dihydrocapsaicin, which is simply capsaicin without the double bond, make up about 90 percent of the total; nordihydrocapsaicin, homocapsaicin and homodihydrocapsaicin make up most of the rest ¹. Their proportions are a fingerprint of species: across 47 cultivars grown side by side, two Capsicum species averaged a 64:30:6 split between capsaicin, dihydrocapsaicin and nordihydrocapsaicin, two others a capsaicin-dominant 73:25:2, and one a dihydrocapsaicin-dominant 34:60:6 ²⁹. The absolute quantities vary just as widely: across eight Mexican cultivars grown side by side and measured by chromatography, total capsaicinoids ran from undetectable in bell pepper to 31.84 milligrams per gram of dry weight in chiltepin, and in those fruits dihydrocapsaicin exceeded capsaicin ³⁰. Heat used to be measured with the tongue: Wilbur Scoville's 1912 test dilutes an alcoholic extract step by step until a panel can no longer taste the burn ⁶. Laboratories now use high-performance liquid chromatography, which separates the capsaicinoids on a column and weighs each one ⁷. Over a year of side-by-side testing across 50,000 to 2,000,000 Scoville units, the instrumental and taste-panel results correlated at 0.95 ¹.

The plant builds it in one tissue only. Capsaicinoids are made in the epidermal cells of the placenta, the pale partition inside the fruit that the seeds hang from, by condensing vanillylamine, which comes from the phenylpropanoid pathway that also makes lignin, with 8-methyl-6-nonenoyl-CoA, which comes from the breakdown of the amino acids valine or leucine. A coenzyme A-dependent acyltransferase, an enzyme that joins a fatty acid to another molecule, puts the two together ². The common belief that the heat lives in the seeds is a misreading of the anatomy: the seeds are simply next to the tissue that makes it.

The point of making it appears to be targeted deterrence. Capsaicin keeps mammals, whose molars destroy seeds, away from the fruit, while leaving birds, which swallow seeds whole and deposit them elsewhere, entirely unbothered ³. Feeding and field experiments in 2001 made that the explicit hypothesis, and named it directed deterrence ¹³. In 2002 Sven-Eric Jordt and David Julius showed how: the chicken version of the receptor is activated by heat and by acid like the mammalian one, but not by capsaicin, and transferring one region of the rat receptor into the chicken protein makes the chicken protein capsaicin-sensitive ¹². The authors concluded that sensitivity to capsaicin-like compounds is a recent acquisition of mammalian receptors, and that the pepper's chemistry is aimed at that acquisition. Deterrence may not be the whole explanation. In a wild Bolivian chili whose plants vary in pungency, capsaicinoids protected the seeds from Fusarium, the fungus that killed most of them before they could be dispersed, and the proportion of pungent plants in a population rose with the insect damage that lets the fungus in ¹⁴.

The whole history, including the reversals

The chemistry came first, by half a century, and the physiology that explains the chemistry came last. Five of the entries below are reversals: a bladder treatment that failed its largest trial, a drug class stopped by the body's thermostat, a mechanism everyone taught that turned out to be a side effect rather than the cause, a cream whose evidence dissolved when it was examined properly, and a knee injection that failed phase 3.

What it does to a nerve ending

The channel capsaicin opens is permeable to calcium, and increasingly so: the ratio of calcium to sodium passing through starts at about 8 to 1 and rises toward 25 to 1 during a prolonged exposure ⁵. A brief opening is a pain signal. A sustained one is a flood. Calcium also comes out of internal stores, because the channel is present on organelles inside the cell as well as on its surface, and the combined load overwhelms the machinery that normally pumps calcium back out ⁵.

What follows is mechanical and metabolic rather than electrical. Calcium-dependent proteases are switched on, microtubules depolymerize, and the terminal swells because chloride follows the positive charge in and water follows the salt. Separately, and at concentrations well above those needed to open the channel, capsaicin competes with ubiquinone, the molecule that shuttles electrons inside the mitochondria, the cell's power plants, and inhibits mitochondrial electron transport directly, dissipating the mitochondrial membrane potential with a half-maximal effect at 6.9 micromolar, or millionths of a mole per liter, in sensory neurons ⁵. A nerve ending that cannot make energy cannot maintain its membrane, and it withdraws to the depth at which the capsaicin concentration was too low to do this.

The agreed name for the result is defunctionalization, and the word was chosen against the older term desensitization, which in pharmacology means something narrower: a receptor becoming less responsive during continued exposure to its agonist. Desensitization of the channel itself is too brief to explain pain relief lasting twelve weeks ⁵. Defunctionalization has several parts with different time courses: loss of excitability, failure of fast axonal transport, and physical retraction of the terminal. The 2026 human experiment separates them in the clearest way yet. Heat pain and the flare response disappeared entirely; pain to mechanical impact fell only slightly and briefly; heat pain and the response to single electrical pulses recovered within a few weeks; the flare and the pain from a minute of tonic 4 Hz stimulation were still suppressed months later ²⁵.

Which brings us to the reversal at the center of this molecule. In the late 1970s capsaicin was found to deplete substance P from sensory neurons ³³, and in the mid-1980s the same was shown in human skin after topical treatment ⁵. Substance P was then believed to be the pain transmitter, so the depletion was assumed to be the reason for the pain relief, and that assumption went into the textbooks and was used to describe how the 1980s creams worked ⁵. Two lines of evidence dismantled it. Drugs that block the substance P receptor failed repeatedly as analgesics in people, and calcitonin gene-related peptide, another neuropeptide released by the same fibers, is now thought the likelier contributor to pain. And substance P is simply one of many proteins a retracting fiber takes with it, no more causal than the loss of any other marker ⁵. That review was co-written by an employee of the patch's developer, but its argument rests on independent human biopsy work ^31,32 and on the failure of the substance P blockers. The 2011 review that made the argument noted that the old story was still being repeated in recent reviews and textbooks ⁵, and one published earlier that year, in Molecules, illustrates the point, describing the analgesia as 'due to desensitizing of the sensory neurons caused by substance P depletion' ¹.

Where it goes in the body, and how little of it gets in

Capsaicin's greasiness, which makes it hard to wash off, also keeps it out of the bloodstream. After a single 60- or 90-minute application of the 8 percent patch in 173 patients, capsaicin was measurable in plasma at any time point in only 31 percent of postherpetic neuralgia patients, 7 percent of those with nerve damage from HIV infection or its older treatments and 3 percent of those with diabetic neuropathy; the highest concentration seen in anyone was 17.8 nanograms per milliliter, the modeled mean peak after a 60-minute application was 1.86 nanograms per milliliter, and the elimination half-life, the time for the blood level to halve, was 1.64 hours ¹⁰. Treatment on the feet produced far lower exposure than treatment on the trunk, and a 90-minute application gave roughly twice the exposure of a 60-minute one ¹⁰.

Swallowed, it behaves differently. After ingestion of 26.6 mg of capsaicin the peak plasma concentration was 2.5 nanograms per milliliter at 47 minutes, with a half-life of 25 minutes ⁵. Animal work puts oral absorption near 94 percent, with the peak in blood at one hour and no detectable drug after four days ¹. Capsaicin is hydroxylated by liver cytochrome enzymes to 16-hydroxycapsaicin, 17-hydroxycapsaicin and related metabolites, and is cleared mainly by the kidneys; in skin, by contrast, metabolism is slow, which is the point of a topical drug: the molecule stays where it is working ¹.

The practical consequence is that the patch is a local procedure with a systemic footprint close to zero. The practical cost is the pain of applying it. Across the development program of 1,696 patients, the mean maximum rise in a 'pain now' score during and after application was 2.6 points on an 11-point scale, and it resolved once the patch came off; the separate score for average pain over the past 24 hours returned to baseline by the evening of the treatment day for postherpetic neuralgia and by the evening of day two for the foot neuropathies; 98 percent or more completed at least 90 percent of the intended application time ⁶⁰. Application-site redness, or erythema, was reported in 63 percent and application-site pain in 42 percent, and transient blood pressure rises accompany the pain ⁴⁹. Local anesthetic cream is used first; a Saudi retrospective series of 17 patients with thoracic postherpetic neuralgia reported that adding a thoracic paravertebral nerve block, an injection of local anesthetic beside the spine that numbs one band of the chest, to topical anesthetic removed the need for intravenous rescue opioid entirely, in a comparison of nine patients against eight ⁶¹. A larger retrospective comparison by the same author, 90 patients with painful diabetic neuropathy of the feet in three groups of 30, found that none of those given an ultrasound-guided ankle nerve block needed intravenous rescue tramadol, against 60 percent of those given numbing cream and all of those given no pretreatment, and that all of them completed the application, against 83.3 and 73.3 percent. The author notes that this is a statement about tolerating the procedure, not about how well the patch then works ⁶². A randomized trial in 69 cancer patients found that playing a standardized hypnotic recording during application did not change pain scores but did significantly lower anxiety ⁶³.

The creams, and the blinding problem

Capsaicin creams at 0.025 to 0.075 percent have been sold for forty years, usually without a prescription and often without any formal regulatory review of their efficacy ⁵. The 2004 systematic review that set the terms of the debate pooled six double-blind placebo-controlled trials in neuropathic pain, 656 patients, and found a number needed to treat of 5.7 for about half pain relief, meaning that roughly six people had to use the cream for one more of them to get that relief than would have on a placebo cream; in three musculoskeletal trials with 368 patients the number needed to treat was 8.1, with a confidence interval, the range within which the true value plausibly lies, reaching 34. About a third of patients had local adverse events. The authors called the efficacy moderate to poor and suggested the creams might be useful as an adjunct or sole therapy for a small number of people who cannot take anything else ⁶⁴.

In 2012 the same Oxford group split its broader Cochrane review of topical capsaicin in two and looked again at low concentration alone. The update found no additional eligible trials; every study it included had been published before 1996. The six studies were heterogeneous, only two reported the preferred outcome of at least 50 percent pain relief, and there were too few data to pool. The conclusion was blunt: the information available suggests low-concentration topical capsaicin is without meaningful effect beyond that of placebo creams, and given the potential for bias from small studies, a clinically useful effect is unlikely. Local skin irritation was common; the number needed to harm, which is the same arithmetic as the number needed to treat applied to a harm instead of a benefit, was 2.5 ²³. The Cochrane overview of all topical analgesics put the harms more plainly. Local adverse events occurred in 63 percent of people using low-concentration capsaicin, a number needed to harm of 2.6 across five studies and 557 participants, on high-quality evidence. Withdrawals because of adverse events were 15 percent against 3 percent on placebo, but that comparison rests on four studies and 477 participants and is graded very low quality ²⁴.

The reason the question is hard is that capsaicin announces itself. A cream that burns cannot be blinded against a cream that does not, and patients work out which arm they are in within a minute of the first application. Trialists have tried two fixes. In most high-concentration trials the control was a patch containing 0.04 percent capsaicin, enough to cause pain and redness in a substantial number of subjects ⁵. That keeps patients guessing, but the comparator is itself a weak dose of the drug, so the measured difference may understate the effect against a truly inert patch, by an amount nobody can quantify. Two of the eight trials in the Cochrane review used an inert placebo instead ¹⁶, including STEP, the trial behind the 2020 diabetic foot approval, whose patients may therefore have been able to tell which patch they had ⁵⁴. In osteoarthritis the controls were often non-pungent, and reviewers have warned that the apparent benefit may be limited by inadequate blinding in some studies because the vehicle does not burn ⁵.

With that caveat attached, the osteoarthritis evidence is this: a 2024 meta-analysis of eight double-blind randomized trials with 498 patients, using concentrations from 0.0125 to 5 percent, found a standardized mean difference in pain of -0.84 favoring capsaicin, with a confidence interval from -1.48 to -0.19. A standardized mean difference expresses the gap between groups in units of the spread of the data, so that trials using different pain scales can be pooled; 0.8 is conventionally called large. The risk ratio for a burning sensation at the application site, meaning the chance of it on capsaicin divided by the chance on placebo, was 5.56, with a number needed to harm of 3. The certainty of the evidence was low to very low, follow-up was no longer than three months, and the authors recommended topical capsaicin only for short-term management in people who cannot tolerate oral anti-inflammatories ⁶⁵. The American College of Rheumatology and the Arthritis Foundation make a conditional recommendation for topical capsaicin in knee osteoarthritis, because the effect sizes in the literature are small and the confidence intervals wide. They make a conditional recommendation against it in hand osteoarthritis, citing a lack of direct evidence and a potentially increased risk of getting it in an eye, and they did not examine the hip, which lies too deep beneath the skin for a topical drug to reach ⁶⁶. The 2025 neuropathic pain guideline gives capsaicin cream a number needed to treat of 6.1 with a confidence interval running to infinity, very low certainty, and a weak second-line recommendation ¹⁸.

The 8 percent patch: what it is approved for and how well it works

The high-concentration patch was built to solve the compliance problem, not the efficacy problem. One application of about 100 times the concentration of a drugstore cream, under supervision, for 30 or 60 minutes, delivers the whole treatment at once: no daily self-application, no contaminated bedding, no choice for the patient to stop because it hurts ⁵. Rapid delivery may also be what makes it bearable: by driving the nociceptors to a defunctionalized state quickly, the burning phase is short, and fewer than 2 percent of patients in clinical studies asked for the patch to come off early ⁵.

The pivotal postherpetic neuralgia trials were run by the patch's developer, NeurogesX, and compared it against a 0.04 percent capsaicin control patch ^47,67. In the first of them, 402 patients, pain fell 29.6 percent over weeks 2 to 8 with the 8 percent patch and 19.9 percent with the control, a difference of 9.7 percentage points; 42 percent versus 32 percent reached a 30 percent reduction, and the separation persisted through week 12 ⁴⁷. The second was the larger, at 418 patients, and found 32.0 percent against 24.4 percent, with 46 percent against 34 percent reaching a 30 percent reduction ^49,67. The Cochrane review of eight trials and 2,488 patients put the result in its least flattering frame: at both 8 and 12 weeks, about 10 percent more patients rated themselves much or very much improved with the high-concentration patch than with the 'active' placebo, giving numbers needed to treat of 8.8 at 8 weeks and 7.0 at 12 weeks against that active placebo, on moderate-quality evidence from two studies and 571 patients. The rest of the outcomes were rated very low quality because of sparse data, imputation, which means filling in missing values by assumption, and susceptibility to publication bias, the tendency of negative trials to go unpublished ¹⁶.

In painful diabetic peripheral neuropathy, the STEP trial randomized 369 patients to a single 30-minute application to the feet or a placebo patch: average daily pain fell 27.4 percent against 20.9 percent over weeks 2 to 8, the median time to response was 19 days against 72, and sleep interference improved modestly. There was no deterioration in the perception of sharp, cold, warm or vibration stimuli ⁵⁴. The 52-week open-label PACE study, meaning that everyone knew which treatment they were getting, randomized 468 patients to repeat patch treatment plus standard of care or standard of care alone; it was designed as a safety study and found no neurological deterioration, with application-site pain in 28 to 29 percent ⁸. Both STEP and PACE were sponsored by Astellas, which then marketed the patch in Europe, and Astellas employees are among the authors of each; PACE was registered only after it had begun ^8,54. A 2026 post hoc analysis of PACE, meaning a question asked of the data after the trial rather than planned in advance, went further and reported that among patients whose sensation was below normal at baseline, repeat treatment was associated with shifts back into the normal range in 21 to 26 percent of heat, cold and sharp tests at twelve months, and with better scores than standard of care alone on heat, sharp and vibration testing. Three of the analysis's five authors are employees of Averitas Pharma, which markets the patch in the United States; the question was not the trial's prespecified one, and the authors say the finding would need a dedicated trial to confirm ⁶⁸.

Two newer appraisals set the size of the effect in context. A Bayesian network meta-analysis, a method that ranks many drugs at once by combining direct and indirect comparisons, of 38 randomized trials and 8,621 patients with postherpetic neuralgia found the 8 percent patch produced a statistically significant reduction in pain intensity, a mean difference of -9.2 with a confidence interval from -12.0 to -6.6 on a pain-intensity measure the abstract does not name, while amitriptyline plus pregabalin ranked highest overall for clinical superiority. Some of the figures in that abstract are internally inconsistent, which is a reason to hold it loosely ⁶⁹. The 2025 Neuropathic Pain Special Interest Group meta-analysis, 313 trials and 48,789 participants, calculated a number needed to treat of 13.2 for the 8 percent patch, with a confidence interval from 7.6 to 50.8 and moderate certainty, against 4.6 for tricyclic antidepressants, the older antidepressants such as amitriptyline used in low doses for nerve pain, and 8.9 for the gabapentinoids, meaning gabapentin and pregabalin. The number needed to harm for the patch, counted as people stopping treatment because of side effects, was about 1,129, the most favorable in the entire analysis, but its confidence interval runs from about 136 to infinity. The group's recommendation is weak and second line ¹⁸.

That combination, a small chance of benefit with almost no chance of systemic harm, is what the use case rests on, and it is why the drug keeps being tried in new indications. A systematic review of long-term studies, written by employees of the manufacturer, found the patch had been studied in more long-term studies than any other recommended treatment for peripheral neuropathic pain, thirteen of them, a count helped by an extra literature search the authors ran for the patch alone, and that it had the lowest rates of discontinuation for adverse events ⁷⁰. An observational study of 73 women with chemotherapy-induced peripheral neuropathy, the burning and tingling in the hands and feet left behind by some cancer drugs, after breast cancer treatment, also with industry co-authors and with no control group, reported scores on painDETECT, a questionnaire that rates how neuropathic symptoms are rather than how severe the pain is, falling from 19.7 to 15.8 after the first treatment, with 40 percent achieving at least 30 percent pain relief by week 36 ⁷¹. A 2026 meta-analysis of seven studies of the patch in nerve pain from HIV reported a large improvement, an effect size of about 1, but it pooled pain scores before and after treatment with no control group, which cannot separate the patch from time and expectation; the randomized HIV trials found about 10 percent more responders than control ^16,72. Against that, the only randomized trial in chronic postoperative neuropathic pain, 46 participants, found no significant improvement over an inactive placebo patch, at very low certainty ⁷³. And in Scotland the patch has been judged cost-effective as an add-on at an incremental cost-effectiveness ratio of 13,516 pounds per quality-adjusted life year, which is the extra cost of gaining one additional year of life in full health, in a model built and published by the manufacturer ⁷⁴.

Cannabinoid hyperemesis: the hot shower, and the cream

In 2004 John Allen and colleagues in South Australia described a cyclical vomiting illness in chronic cannabis users. Nineteen patients were identified; nine were reported in detail with one previously published case. Vomiting stopped when cannabis stopped in seven, returned on rechallenge in three, and nine of the ten displayed a strange behavior the authors had not expected: compulsive hot bathing during attacks ⁷⁵. Compulsive hot bathing is now listed as a supportive, secondary feature rather than a required criterion in the Rome IV definition, which classes the syndrome among the nausea and vomiting disorders ^76,77. It is also the clue that pointed to capsaicin, because heat is one of the stimuli that opens TRPV1 ³⁴.

The reasoning is specific. TRPV1 sits on the vagal sensory endings in the gut whose central terminals converge on the brainstem nuclei that produce nausea and vomiting; a hot shower and a capsaicin cream both activate the same channel in the skin or the gut, and the proposal is that this interferes with the signal ^34,35. There is a second, older link between this channel and cannabis: the body's own cannabinoid, anandamide, activates the same receptor capsaicin does, which was shown in 1999 when the vasodilation anandamide causes in isolated arteries turned out to be capsaicin-sensitive, blocked by a vanilloid antagonist rather than by a cannabinoid one ⁷⁸. So the channel the cream acts on is already inside the system cannabis acts on. That is a plausible mechanism. It is not the same thing as a treatment that works.

The clinical record, in order of strength. Thirteen cases from two academic emergency departments, all of whom improved after other treatments had failed ³⁵. A retrospective cohort of 43 patients in Colorado: length of stay fell by a statistically insignificant 22 minutes, patients given capsaicin received fewer additional medications (a median of three doses against four) and much less opioid, and 67 percent of visits where capsaicin was used needed nothing else ⁷⁹. A retrospective cohort of 201 patients, 25 of them under 21: 55 percent of the capsaicin group met the authors' definition of an efficacious result against 21 percent of the comparison group, and time to discharge after the reference medication was 3.7 hours against 6.1; total medications and overall length of stay did not differ ⁸⁰. That paper carries a published corrigendum ⁸¹, and the odds ratio printed in its abstract, 1.44 with an interval of 0.59 to 0.82, cannot be right as printed, so only the percentages are repeated here. A San Francisco retrospective cohort of 55 patients, 35 given capsaicin and 20 not, found no difference in time to discharge (4.46 against 3.52 hours), rounds of medication, return within 24 hours or admission; only when capsaicin was given within the first two rounds of treatment was the stay shorter, 4.83 against 7.09 hours, which is a subgroup finding ⁸². A meta-analysis of seven studies and 106 patients reported, from the only two of those studies that measured them, a mean time to symptom resolution of 325 minutes and a mean emergency department stay of 379 minutes, which tells you about the course of the illness more than about the drug ⁸³.

There is one randomized trial. Thirty patients at a Detroit emergency department were randomized to 0.1 percent capsaicin cream or placebo cream on the abdomen. Nausea at 30 minutes was 4.1 against 6.1 centimeters on a visual analog scale, a 10-centimeter line the patient marks, a difference whose confidence interval included no difference; at 60 minutes it was 3.2 against 6.4, and that interval did not. Complete resolution of nausea occurred in 29.4 percent of the capsaicin arm and none of the placebo arm. One patient could not tolerate the cream because of skin irritation. The authors called it a pilot trial ⁸⁴.

Two systematic reviews have graded this body of evidence and reached the same place from different directions. The Society for Academic Emergency Medicine's review of direct evidence found seven studies and 492 patients, five of them on capsaicin cream with 386 patients, and described the evidence for capsaicin as mixed and the evidence for dopamine antagonists such as haloperidol as more consistent ²¹. The GRACE-4 guideline, published in the same 2024 issue of the journal after the review had appeared online in 2023, suggested offering topical capsaicin in addition to usual care, and suggested haloperidol or droperidol, grading both at very low certainty ⁵⁶. The Royal College of Emergency Medicine's guidance names both ⁵⁷. A systematic review for consultation-liaison psychiatrists, the psychiatrists who advise on patients in general hospital wards, published in 2025 but searching the literature only to July 2021 and built from 34 articles and 63 individual cases, concluded that capsaicin cream, antipsychotics and benzodiazepines were reported to work more often than ondansetron, promethazine or metoclopramide, and acknowledged that an algorithm built on case reports is a weak foundation ⁸⁵. A German review puts the practical point most usefully: rubbing the abdomen with 0.075 to 0.1 percent capsaicin cream does help, but less quickly than a hot shower or intramuscular haloperidol ⁷⁷.

What the cream cannot do is treat the disease. Full remission comes only with sustained abstinence from cannabis, and telling cannabinoid hyperemesis apart from cyclic vomiting syndrome, which is recurrent bouts of vomiting with well intervals and no known cause, and in which about 30 percent of patients also use cannabis chronically, requires remission established over at least six months of abstinence ⁷⁷, or six to twelve months in the same author's companion review ⁸⁶. Nor does adding capsaicin to a protocol necessarily change what happens to the patient: when a pediatric emergency department introduced a management algorithm, capsaicin use rose from 2.7 percent to 22.2 percent of encounters and metoclopramide from 6.8 to 42.6 percent, with no significant change in admissions or length of stay across 128 encounters ⁸⁷.

Chili and the stomach: the ulcer belief, and what reversed it

For most of the twentieth century patients with ulcers and with reflux were told to avoid spicy food, on the reasoning that something which burns the mouth must burn the stomach. The reasoning was tested in healthy stomachs in 1988, and it found no support. David Graham and colleagues in Houston ran a randomized crossover trial, in which every volunteer received every test meal in random order, in twelve healthy adults. Each of the four studies gave the same test meal at noon and again in the evening, with endoscopy, a camera passed into the stomach, before and about twelve hours after the last meal: a bland steak meal, the same meal with 1,950 mg of aspirin, a Mexican meal containing 30 grams of jalapeno peppers, and a pepperoni pizza. Eleven of twelve developed multiple gastric erosions, which are shallow breaks in the stomach lining, after the aspirin meal, scoring as severe injury. The median endoscopic score after each of the other three meals was zero, with a single erosion in one person after the Mexican meal and one after the pizza. In a second experiment, 30 grams of jalapeno peppers were ground and placed directly into the stomach: endoscopy 24 hours later showed no visible mucosal damage at all ²⁶.

The correction went further than neutrality. In Singapore in 1995, eighteen healthy volunteers took 20 grams of chili with water, then 600 mg of aspirin half an hour later, on one occasion, and water then aspirin on another. The median gastric injury score was 1.5 after chili against 4 after water: the chili protected against the aspirin ⁸⁸. A case-control study from the same group, meaning that people with the disease were compared with people without it and both were asked about past habits, set 103 Chinese patients with peptic ulcer against 87 controls, excluding anyone who avoided chili deliberately. Ulcer patients used chili a median of eight times a month, controls 24 times, and the odds ratio for ulcer disease among those with higher chili intake, adjusted for age, sex, analgesic use and smoking, was 0.47 ⁸⁹. An odds ratio says how much more or less common an exposure is among cases than among controls, so 0.47 means roughly half as common. This is an association from one city with modest numbers; it does not establish that chili prevents ulcers. But combined with the endoscopic experiments, it points away from the old advice, though nobody has tested whether eating chili changes outcomes in people who already have an ulcer.

The mechanism proposed is the one the rest of this page keeps returning to. Capsaicin-sensitive sensory nerves in the stomach wall, when stimulated, release neuropeptides that increase mucosal blood flow, and increased blood flow is protective against the injuries that aspirin and alcohol produce ¹. Rodent work shows the relationship is dose-dependent and can reverse: low concentrations protect the gastric mucosa against ethanol injury, high concentrations worsen it ¹.

Practical advice today is narrower than either the old prohibition or the new enthusiasm. There is no good evidence that spicy food causes ulcers ^26,88,89. The established causes are infection with Helicobacter pylori, the spiral bacterium found in the stomach lining of most patients with gastritis and ulcer by Barry Marshall and Robin Warren in 1984 ⁹⁰, and anti-inflammatory drugs such as aspirin ⁹¹. People with reflux or an irritable bowel may still find chili uncomfortable, and that is a reason for them to avoid it. And very high-pungency products are a different proposition from food: a 9-year-old in the Netherlands vomited blood and had a significant fall in hemoglobin after eating potato chips flavored with a very high-pungency chili, and endoscopy showed diffuse bleeding from the lining of the body of the stomach, treated with a powder sprayed through the endoscope to stop bleeding. The authors could find no other explanation, and noted that no previous report described such a case, although the news media had carried reports of illness and death after high-pungency food challenges ²⁷.

Eating it: mortality, stomach cancer, and the weight-loss numbers

The largest study of chili and death is the China Kadoorie Biobank. Between 2004 and 2008, 199,293 men and 288,082 women aged 30 to 79 reported how often they ate spicy food, once, at enrollment. Over 3.5 million person-years, which is the number of people followed multiplied by the years each was followed, and a median of 7.2 years, 20,224 died. Absolute mortality rates were 6.1, 4.4, 4.3 and 5.8 deaths per thousand person-years across the categories of less than weekly, one or two days a week, three to five days, and six or seven days. Adjusted hazard ratios against the lowest category, meaning the rate of death in one group divided by the rate in the comparison group, were 0.90, 0.86 and 0.86: a 14 percent relative reduction for the most frequent eaters, stronger in people who did not drink alcohol, with similar inverse associations for cancer, ischemic heart disease and respiratory deaths ¹⁹.

Three things about that study are worth holding onto. The exposure was self-reported spicy food, not measured capsaicin, and once. People who eat spicy food every day differ from people who never do in ways no model fully captures. And the shape of the curve is not a straight line: the mortality rate in the most frequent category was higher than in the middle ones, which an adjusted hazard ratio hides.

The finding has replicated in other populations. The Moli-sani study in Italy followed 22,811 adults for a median of 8.2 years, with 1,236 deaths: eating chili pepper more than four times a week carried a hazard ratio of 0.77 for all-cause death and 0.66 for cardiovascular death, independent of adherence to a Mediterranean diet ⁹². Meta-analyses that pool the same handful of cohorts from the United States, China, Italy and Iran reach consistent numbers: 0.87 for all-cause mortality across four cohorts and 564,748 people with no heterogeneity ⁹³; 0.88 in another pooling of the same four, with 0.82 for cardiac death and a non-significant 0.79 for cerebrovascular death ⁹⁴; 0.87, 0.83 and 0.92 for all-cause, cardiovascular and cancer death in a third ⁹⁵. These are the same four studies rearranged, which is why the numbers agree. They are associations. One of the meta-analyses states that chili intake 'could significantly reduce the risk' of death, which is a causal claim the design cannot support ⁹³. And when the same Chinese cohort was followed for a median 12.1 years with new vascular disease rather than death as the outcome, the association nearly vanished: hazard ratios of 0.95, 0.96 and 0.97 for eating spicy food one or two, three to five, and six or seven days a week, a relative difference of 3 to 5 percent ⁹⁶.

The gastric cancer literature runs the other way, and does so most clearly in the populations that eat the most chili. A Mexico City case-control study of 220 incident cases and 752 population controls in 1989 and 1990 found an age- and sex-adjusted odds ratio of 5.49 for chili consumers against non-consumers, rising to 17.11 for self-rated high consumers, with a highly significant trend across self-rated levels, but no significant trend when consumption was measured as frequency per day, which the authors flagged themselves ⁹⁷. A meta-analysis of 16 studies and 8,337 cases found a pooled odds ratio of 1.51 for the highest against the lowest intake, with striking regional differences: 2.05 in Mexico, 1.92 in Asia, 2.03 in Colombia with an interval crossing one, and 0.48 in the remaining countries, where chili eating was associated with less gastric cancer ⁹⁸. A second meta-analysis of 13 studies, 3,095 cases and 4,761 controls, found an odds ratio of 1.96 for moderate-to-high intake, 2.28 for high intake, and 0.72 for moderate intake alone, with the interval crossing one, and a non-linear dose relationship with capsaicin ⁹⁹. For the esophagus, a meta-analysis of 25 studies and 7,810 cases found an odds ratio of 1.70 for the highest against the lowest spicy food intake, driven by the Chinese studies, with no significant association in India or elsewhere and one prospective study pointing the other way ¹⁰⁰; a 14-year follow-up of 11,397 adults in a high-risk rural area of China, with 189 incident cases, found very spicy diets among the exposures associated with more esophageal squamous cell carcinoma ¹⁰¹. An umbrella review of eleven systematic reviews lists direct associations with esophageal, gastric and gallbladder cancer alongside inverse associations with mortality, metabolic measures and cardiovascular disease, and concludes that the health effect of chili is unclear and depends on the region and population ²⁰.

Reconciling the two bodies of evidence is the honest difficulty. Case-control studies of gastric cancer recall diet after the disease has begun, in populations where Helicobacter pylori, salt and preservation methods vary with chili intake; prospective cohorts measure a habit once in healthy people and follow them. The protective signal is strongest in prospective data and the harmful signal is strongest in retrospective data from high-intake, high-gastric-cancer regions. That pattern is compatible with confounding in either direction, and no trial will settle it.

The thermogenesis claim has been measured directly, and the effect is small and inconsistent. A meta-analysis of 13 placebo-controlled trials in healthy adults found that capsaicinoids or their non-pungent cousins the capsinoids raised resting metabolic rate by 34 kilocalories a day, with a confidence interval from 16 to 52, and lowered the respiratory quotient by 0.01, indicating a shift toward burning fat ¹⁰². An earlier meta-analysis of nine trials put the increase at 59 kilocalories a day overall, with no detectable effect in people whose average body mass index was below 25 and 70 kilocalories a day in those above it ¹⁰³. Fifteen randomized trials in 762 overweight or obese people found supplementation reduced body mass index by 0.25 units, weight by 0.51 kilograms and waist circumference by 1.12 centimeters: the authors called these effects 'rather modest', which is accurate ¹⁰⁴. The most recent pooling is less generous still. A 2026 update covering 24 randomized studies published through 2024 found that the effect on energy expenditure did not reach statistical significance in single-meal studies, in longer studies, or overall during dieting. What held up was a consistently lower respiratory quotient, meaning slightly more fat burned, and less loss of the feeling of fullness while dieting; the authors concluded that culinary doses 'do not fully prevent' the metabolic slowing that comes with weight loss ¹⁰⁵. Thirty-four kilocalories is about a third of an apple.

Into the bladder, and into the knee

If defunctionalizing nerve endings in skin relieves pain, the same should work on any surface where overactive sensory fibers cause trouble. The bladder was the first target. In 1992 Clare Fowler and colleagues instilled capsaicin into the bladder of patients with neurogenic bladder dysfunction, aiming at the C fibers that drive reflex bladder contractions ⁴¹; capsaicin had been put into the human bladder once before, in six patients in Florence in 1989 ⁴². A Florentine group's ten-year experience is the honest account of what followed: of 54 patients with detrusor hyperreflexia, an overactive bladder muscle that contracts on its own, after spinal cord injury, given 10 millimolar capsaicin between 1992 and 2001, 29 (53.7 percent) improved in symptoms and bladder capacity at three months, but only 7 of those 29 were still receiving it by June 2001. Resiniferatoxin, the ultrapotent relative, performed better in the same clinic: 73 percent improved and more than half continued ¹⁰⁶.

Resiniferatoxin's clinical story is itself a reversal. In a 36-patient dose-escalation trial in refractory detrusor hyperreflexia, discomfort on instillation was mild and bladder capacity rose 53 and 48 percent at three weeks in the 0.5 and 1.0 micromolar groups, but with four patients per group nothing reached statistical significance ¹⁰⁷. Then the large trial arrived. In 163 patients with interstitial cystitis, a single instillation at three doses did not improve the global response assessment, a single seven-point rating of overall change in symptoms, nor pain, urgency, frequency, nocturia or average voided volume over twelve weeks, and it produced dose-dependent pain on instillation. It was, when published, the largest prospective randomized trial of intravesical vanilloid therapy, and it was negative ⁴⁴. In the one head-to-head trial against the treatment that displaced it, 25 spinal-cord-injured patients randomized to intravesical resiniferatoxin or botulinum A toxin injected into the detrusor, both helped, and botulinum toxin was significantly better on incontinence episodes, the volume at which the bladder first contracted on its own, bladder capacity and contraction pressure at 6, 12 and 18 months ¹⁰⁸. In that trial botulinum toxin was the better treatment, and it, rather than any intravesical vanilloid, became the standard option ¹⁰⁸.

The knee was, until recently, the most advanced target. CNTX-4975, the developer's code name for the compound, is high-purity synthetic trans-capsaicin injected once into the joint, with the aim of defunctionalizing the nerve endings inside the knee rather than those in the skin above it. In the phase 2 trial, 172 patients with moderate-to-severe knee osteoarthritis pain were randomized 2:1:2 to placebo, 0.5 mg or 1.0 mg. The 1.0 mg dose reduced the area under the curve for pain with walking through week 12, meaning pain averaged across every measurement over those weeks, by a least-squares mean difference, which is the gap between groups after statistical adjustment, of 1.6 points on a 0 to 10 scale against placebo, and the benefit was still significant at week 24 at 1.4 points; 0.5 mg gave 0.79 points at week 12, which did not reach significance, and nothing measurable at 24 weeks. Treatment-emergent adverse events were similar to placebo. All eight authors were employees of the developing company or of its contract research organizations ⁵⁵. The drug received a fast-track designation from the United States Food and Drug Administration ¹⁰⁹. Then the program reversed. The developer ran two phase 3 trials of the 1.0 mg dose against placebo, and each missed its primary endpoint of pain on walking; only an analysis pooling the two reached statistical significance at 12 weeks, and a 2026 review judges the trials likely to have been underpowered ⁵⁸. A separate 2026 critical appraisal concludes that intra-articular TRPV1 agonists failed their phase 3 primary endpoints despite expedited regulatory designations, and that TRPV1-targeted therapy for osteoarthritis has, in its words, 'completed a full translational cycle without yielding regulatory approval' ⁵⁹. Neither phase 3 trial has been published in full in the indexed literature; what is known of them comes through these reviews.

The same idea is being pursued with resiniferatoxin injected into joints. The 2025 review of that program, written by investigators at the National Institutes of Health with a co-author from the developing company, states plainly that the results of several phase 1 clinical trials have so far been reported only in abstract form, and describes the human evidence as preliminary ¹¹⁰. A global phase 3 trial of intra-articular resiniferatoxin for knee osteoarthritis has been completed, and its results had not been published by early 2026 ⁵⁸. A 2024 review of the whole approach notes why agonists are ahead of antagonists in this field: capsaicin and resiniferatoxin have provided proof of concept for modulating the pathway in knee osteoarthritis, while antagonists have been held back by hyperthermia and by blunting of heat sensation ¹¹¹. The 2026 survey of the field lists the promising agonists as low- and high-dose capsaicin, resiniferatoxin, CNTX-4975 and vocacapsaicin, and the potentially applicable antagonists as NEO6860, mavatrep, ACD-440, AJH-2947, DWP05195 and XEN-D0501 ⁵⁸. Resiniferatoxin has also been injected into the spinal fluid to silence pain fibers for good. In a first-in-human, open-label phase 1 study of 19 people with intractable cancer pain in the abdomen or legs, a single intrathecal dose was followed by a 38 percent fall in worst pain, from 8.4 to 5.2 on a 0 to 10 scale, and 57 percent less opioid at day 15. Every patient had at least one adverse event: urinary retention lasting more than a day in seven, loss of heat sensation in three, and transient changes on the electrocardiogram in five. Nine patients died, an average of 70 days later, deaths the authors judged consistent with advanced cancer. This was an uncontrolled interim analysis ¹¹².

The most convincing recent human result for an injected capsaicin comes from surgery rather than arthritis. Vocacapsaicin is a prodrug: a modified molecule that is not itself pungent and releases capsaicin slowly at the site where it is instilled. In a triple-blinded, randomized, placebo-controlled trial, meaning that patients, surgeons and analysts were all kept from knowing the assignment, 147 patients undergoing bunionectomy, the surgical removal of a bunion, had 14 milliliters of placebo or one of three vocacapsaicin concentrations placed in the surgical site. At the highest concentration, pain at rest over the first 96 hours fell 33 percent against placebo, 26 percent of patients needed no opioid at all against 5 percent, and opioid consumption fell by half, with a concentration-response relationship across all endpoints and no safety signal. The trial was designed and reported by the developing company with academic collaborators ¹¹³.

The antagonist problem: why blocking the receptor raises body temperature

If activating TRPV1 relieves pain by exhausting the nerve, blocking it should relieve pain without the burning. Several companies built selective antagonists on that logic in the 2000s. The program ran into the fact that the channel does something else for a living.

In phase 1 trials of AMG 517, a highly selective antagonist, blockade produced marked, reversible, generally concentration-dependent hyperthermia. The same had been seen in rats, dogs and monkeys. It attenuated with repeated dosing at the highest dose tested, but when AMG 517 was given after molar extraction, a surgical cause of acute pain, the hyperthermia was long-lasting and the maximum body temperature passed 40 degrees Celsius. The authors, at the company developing the drug, concluded that TRPV1-selective antagonists like AMG 517 cannot be developed for systemic use as stand-alone agents, that individual susceptibility determines the size of the effect, and that TRPV1 plays a pivotal role in human body temperature regulation ⁴⁵. The same paper then set out the mechanism in rats: the antagonist produced hyperthermia by constricting the tail skin vessels and increasing heat production, which is what an animal does when it thinks it is cold ⁴⁵.

Capsaicin itself does the opposite, as it must: agonists cause pain and a fall in body temperature ⁴⁶. That symmetry is the clearest evidence that the channel sits in the thermoregulatory loop rather than merely near it.

The field's response has been to look for antagonists that separate the two jobs. A 2024 study in mice compared four antagonists across three genotypes and found that the hyperthermia tracked with binding at a particular region of the channel, the linker between the fourth and fifth of the six segments that cross the membrane, which faces the pocket where capsaicin binds. A compound that did not bind there, PSFL2874, was effective against inflammatory pain without changing core body temperature. The authors argue that nociception and temperature regulation are coupled to the channel through different conformations, meaning different shapes the protein can take, and that the two can be pulled apart ⁵³. This is mouse work. Whether a human antagonist can be built on it is unsettled; the 2026 survey still lists several antagonists only as potential candidates ⁵⁸.

Pepper spray: the same molecule as a weapon

Oleoresin capsicum, the oily extract of chili used in self-defense sprays and crowd-control munitions, has capsaicin as its principal active constituent ¹¹. The medical literature on it is thinner than its use would suggest, and much of it is forensic.

The most careful experimental study is a randomized crossover trial in 35 healthy subjects exposed to oleoresin capsicum spray or placebo and then placed either sitting or in a prone maximal restraint position, lying face down with the wrists and ankles bound together behind, for ten minutes. In the sitting position the spray produced no significant change in forced vital capacity or forced expiratory volume, which measure how much air can be blown out and how fast, nor in oxygen saturation or end-tidal carbon dioxide, the carbon dioxide in exhaled breath and so a measure of ventilation. In the restraint position both groups showed falls in lung volumes of 14 to 19 percent, but these did not differ by whether the subject had been sprayed, and there was no evidence of low blood oxygen or impaired ventilation in either group ¹¹⁴. The study was done in healthy volunteers under controlled conditions, which is both its strength and the limit of what it can say about a struggling, intoxicated or asthmatic person held face down.

In-custody deaths following pepper spray have been reported since the 1990s. A 1995 forensic paper described two such deaths, temporally associated with spray use, and argued that only a full autopsy, toxicology and reconstruction of the premortem sequence can establish whether the spray was unrelated, contributory or causative ¹¹⁵. A separate chemical analysis found that two licensed formulations sold in the same American state differed considerably in composition, which the authors said could lead to substantial inconsistency in how strongly any given canister works ¹¹⁶: a product used as a measured force option is not standardized the way a drug is.

The best estimate of population harm comes from a systematic review of injuries from chemical crowd-control agents worldwide between 1990 and 2015, covering tear gas and pepper spray together. Thirty-one studies from eleven countries reported on 5,131 injured people, of whom two died and 58 suffered permanent disability. Of 9,261 injuries, 8.7 percent were severe enough to require professional medical management, 17 percent were moderate and 74.3 percent minor, with skin and eyes most often affected. Two hundred and thirty-one injuries came from the projectiles that deliver the agents, and 27 percent of those were severe, including major head injuries and loss of vision. Severity rose with enclosed spaces, longer exposure and higher quantities ²⁸.

Children are exposed too, usually by accident or at school. A retrospective series from a tertiary, meaning specialist referral, pediatric emergency department in southern Israel between 2016 and 2024 described 84 children exposed to civilian-grade chemical irritants. These included both pepper spray and tear gas, which the study did not separate, so nothing in it can be attributed to capsaicin alone. The median age was 12.5 years and most exposures happened at home or at school. Among the children examined by an ophthalmologist with fluorescein, an orange dye that reveals scratches on the surface of the eye, 54.5 percent had superficial punctate keratitis, meaning tiny scattered spots of damage on the cornea, which is 21.5 percent of the whole group; respiratory and skin symptoms were mild and self-limited, and 96.4 percent went home ¹¹⁷. The eye is where capsaicin's own toxicology is best characterized, including neurogenic inflammation and corneal changes ¹¹, though this series cannot say which agent caused which injury.

Capsaicin and cancer cells, at their true strength

Search for capsaicin and cancer and you will find a large literature reporting that it kills tumor cells, most of it in cell culture, with some work in animals ^2,118. The concentrations tell the story. Capsaicin reduced the proliferation of prostate cancer cell lines that no longer depend on male hormones at 10 micromolar, or millionths of a mole per liter, and above ²; in cells from a human kidney cancer, 400 micromolar left 36 percent of the cells after 24 hours ¹¹⁹. The highest plasma concentration recorded among the 173 patients in the patch's pharmacokinetic study was 17.8 nanograms per milliliter ¹⁰, which is about 0.06 micromolar: more than a hundredfold below the weakest concentration used in those dishes, and thousands of times below the strongest. Nothing a person can eat or wear reaches these numbers in blood.

The animal and epidemiological evidence does not point in one direction either. Ann Bode and Zigang Dong titled their 2011 review 'The two faces of capsaicin' and set out the problem directly: conflicting epidemiological data and conflicting basic research, with capsaicin appearing as a carcinogen in some settings and a cancer preventive in others. Their own finding was that chronic long-term topical capsaicin increased skin carcinogenesis in mice treated with a tumor promoter, and they suggested caution about capsaicin-containing topical products used in the presence of a promoter such as sunlight ¹²⁰. That is a mouse result with a specific design, and it has not been shown in people; it is also the opposite of the claim usually made for the molecule. More recently, a high-capsaicin diet accelerated the spread of transplanted human gastric cancer cells in mice and in zebrafish, an effect the authors linked partly to TRPV1 and partly to shifts in gut bacteria ¹²¹. That too is animal work.

The literature also has an integrity problem. Searching PubMed for capsaicin and cancer and restricting the results to retracted publications returns four papers: one reporting that capsaicin and cold exposure promoted colorectal cancer metastasis in rats ¹²², one reporting that capsaicin induced apoptosis, meaning programmed cell death, in pancreatic cancer cells and extended survival in mice carrying transplanted human tumors ¹²³, one on esophageal squamous cell carcinoma cells ¹²⁴, and one reporting that capsaicin-loaded nanoparticles shrank chemically induced lung tumors in rats ¹²⁵. All four have been retracted. They pointed in different directions, which means the retractions do not conveniently clean up the picture; they remove four data points from a thin literature.

Current reviews, read carefully, say less than their titles. A 2026 review of natural compounds as epigenetic modulators in gynecological cancers lists capsaicin among the phytochemicals reported to affect DNA methyltransferases and histone deacetylases, enzymes that switch genes on and off without changing their sequence, and microRNA networks, and then states the position: these agents are mechanistically plausible but clinically under-validated, limited by poor bioavailability, meaning how little of a swallowed dose reaches the bloodstream intact, by pharmacokinetic variability, by absent data on whether the drug ever engages its target in tumor tissue, and by weak potency compared with approved epigenetic drugs ²². A 2026 review of capsaicin and tumor immunity describes effects on T cells, natural killer cells, macrophages and dendritic cells and proposes combination strategies, all of it preclinical ¹¹⁸.

There is one place where capsaicin genuinely helps people with cancer, and it is not the tumor. The 8 percent patch is used for chemotherapy-induced peripheral neuropathy, the burning and tingling in the hands and feet left behind by certain chemotherapy drugs. The largest reported experience is a 2025 analysis of 169 patients in a German pain registry, retrospective and written largely by employees of the patch's European marketer, in which at least 30 percent pain relief rose from 20 percent of the patients who had one treatment to 98 percent of those who had four. People who benefit are the ones who come back for more, so that gradient partly measures selection ¹²⁶. Before it, the largest was an observational study, not a trial, in 73 women with painful neuropathy after breast cancer treatment, with industry co-authors and no control arm, reporting a fall in questionnaire scores and progressive improvement over 36 weeks with repeated treatments ⁷¹. That is a symptomatic treatment for nerve damage, and it should not be confused with an anticancer effect.

Where else it has been tried, and what came of it

Cluster headache was an early target, for a reason that was explicit at the time: capsaicin applied to the nasal mucosa releases neuropeptides from trigeminal sensory endings and then exhausts them, which was thought to be the pathway the attacks ran along ³⁸. The experiments are striking to read. Intranasal capsaicin reproduced much of the attack immediately, burning in the nose, eye and temple with tearing and a running nose, and these faded over days of daily application; in patients the number and intensity of attacks fell as the capsaicin response faded ³⁸. A small double-blind placebo-controlled trial found headaches significantly less severe in the capsaicin group on days 8 to 15, with episodic patients benefiting more than chronic ones ³⁹, and a two-year follow-up found the benefit returned on re-treatment in 65 percent of responders, though in chronic cluster headache it never lasted more than a month ⁴⁰.

A commercial version followed and did less. Civamide is the cis isomer of capsaicin: the same atoms, with the chain bent the other way at its double bond. In a multicenter double-blind trial at fourteen American centers, 28 patients with episodic cluster headache received 50 micrograms intranasally daily for seven days or vehicle, the same spray without the drug. The percentage decrease in headaches during the first week after treatment was 55.5 percent against 25.9 percent, significant at P = 0.03, but the differences in the second and third weeks after treatment only approached significance, and there was no difference in pain intensity, number of severe headaches or associated symptoms. Nasal burning occurred in 14 of 18 treated patients and in 1 of 10 controls. The authors concluded that it may be modestly effective ¹²⁷. Patients' own verdict, collected in an international survey of 1,604 people with cluster headache, is harsher: 5 percent rated intranasal capsaicin completely or very effective, against 54 percent for oxygen and 54 percent for the triptans, the standard acute migraine and cluster drugs, although it was among the best tolerated options, with no or minimal physical complications in 91 percent ¹²⁸.

Two newer uses are worth naming because they illustrate how a defunctionalizing drug can do more than mask pain. In non-freezing cold injury, a condition in military personnel whose skin biopsies show reduced nerve fiber density, sixteen service members in an open-label study received a 30-minute 8 percent patch to the feet and calves: spontaneous and cold-evoked pain fell modestly, and skin biopsies three months later showed significantly more nerve fibers, including fibers carrying growth-associated protein 43, a marker made by regrowing nerve fibers, with the increase in fiber density correlating with the fall in pain ¹²⁹. The study was uncontrolled and small, and it reports regrowth rather than loss, which is the opposite of what the drug is usually described as doing.

The second is as a research tool rather than a treatment. Topical capsaicin reliably produces a zone of mechanical hypersensitivity in the surrounding skin, which is a model of central sensitization: the state in which the spinal cord amplifies ordinary input. That model is now standard in early-phase drug trials. In a four-way crossover study in 25 healthy volunteers, a selective sphingosine-1-phosphate receptor agonist, a drug acting on a lipid-signaling receptor carried by nerve and immune cells, significantly shrank the capsaicin-induced area of secondary pain at the two higher doses, by about 300 square millimeters, providing the first human evidence for that target in neuropathic pain even though it failed the study's primary endpoint on ultraviolet-inflamed skin ¹³⁰. The limits of the model matter too: in 26 healthy adults, capsaicin produced the expected mechanical hypersensitivity but no group-level increase in the summation of tonic heat pain, meaning the way pain builds during a long steady heat stimulus: a modality-specific pattern under that protocol, which the authors caution does not exclude a moderate effect on heat pain ¹³¹.

Capsaicin is also the standard provocation for cough. Inhaled in doubling concentrations until the subject coughs five times, it gives a reproducible measure of cough reflex sensitivity, stable to within two doubling concentrations in 90 to 100 percent of repeat challenges over intervals from two weeks to just over five years ¹³²; it is sensitive enough to detect sex differences in cough threshold and to track an urge-to-cough threshold separately from the cough itself ¹³³. Its use as a measuring instrument, for cough and for sensitized skin, is in quiet terms one of its most widespread contributions to clinical research.

What changed, and what is still unknown

What changed: the mechanism. Substance P depletion was the explanation in every textbook for twenty-five years and is now described by the people who study the drug as a correlate with little if any causal role ⁵. Defunctionalization replaced it, and the 2026 human time-course study has started to break even that into parts, showing that heat pain, flare and mechanical pain are lost and recovered on different schedules ²⁵.

What changed: the dose. The creams that made capsaicin a household remedy do not have evidence behind them; the review that looked hardest found six pre-1996 trials and concluded a clinically useful effect was unlikely ²³. The patch that does have evidence is not a stronger cream but a different treatment, applied once by a clinician, with a number needed to treat around 13 and a number needed to harm, counted as stopping treatment because of side effects, estimated at about 1,100 but uncertain enough that it could be as low as about 136 ¹⁸.

What changed: the ulcer. Spicy food was prohibited for people with ulcers on reasoning that a 1988 endoscopic trial found no support for, finding no visible mucosal damage from heavily spiced meals in twelve healthy volunteers, and a small randomized experiment then showed chili protecting healthy stomachs against aspirin injury rather than adding to it ^26,88.

What is still unknown: whether eating chili does anything to how long a person lives. Every number comes from observational cohorts, the same four of which are repeatedly pooled, and the exposure is a habit reported once ^19,94. No trial exists and none is likely.

What is still unknown: why gastric cancer associations point one way in Mexico and Asia and the other way elsewhere, and whether the explanation is Helicobacter pylori, salt, preservation, recall bias, or a real dose threshold above which the irritation matters ^20,98.

What is still unknown: whether an injected TRPV1 agonist can change knee osteoarthritis pain enough to win approval. The phase 2 result for CNTX-4975 did not hold up: both phase 3 trials missed their primary endpoints and only a pooled analysis was positive ^58,59. A phase 3 trial of intra-articular resiniferatoxin has been completed with results pending, and the earlier resiniferatoxin data remain largely in abstract form ^58,110.

What is still unknown: whether a TRPV1 antagonist can be built that relieves pain without moving body temperature. The mouse work separating the two through different channel conformations is the most promising lead, and it is mouse work ^53,58.

What is still unknown: whether capsaicin cream helps cannabinoid hyperemesis more than time and a hot shower. One randomized trial of thirty people, a handful of retrospective cohorts, and guideline recommendations graded very low certainty is the entire basis for a treatment now used in emergency departments worldwide ^21,56,84.

And one thing worth stating plainly because it is so often blurred: there is no evidence that eating chili or wearing a capsaicin patch treats cancer. The cell experiments use concentrations more than a hundred times what a human plasma level can reach ^10,119, the animal data include a finding that chronic topical capsaicin promoted skin tumors in mice exposed to a promoter ¹²⁰, and at least four supporting papers have been retracted ^{122,123,124,125}.

The tests, one by one

• High-performance liquid chromatography (HPLC) of capsaicinoidsThe capsaicinoids are separated on a column and measured one by one, so capsaicin, dihydrocapsaicin and the minor relatives are reported as separate numbers in micrograms per gram ⁷.Food and spice testing, pepper breeding, forensic analysis of sprays, quality control of patches and creamsDetection limits around 0.09 to 0.10 micrograms per gram in one validated method, which reported 4,249 micrograms per gram of capsaicin in hot chilies and effectively none in sweet peppers ⁷; it resolves capsaicin from dihydrocapsaicin and from added synthetic nonivamide ¹.It measures the molecule, not the sensation: pungency also depends on which capsaicinoid dominates, and the capsaicin-to-dihydrocapsaicin ratio differs by species, from 73:25 in some to 34:60 in others ²⁹.
• The Scoville organoleptic testA pepper extract in alcohol is diluted step by step and tasted by a panel until the burn disappears; the dilution at which it vanishes is the Scoville heat unit value ⁶.The scale on every hot sauce bottle, and still the common currency for comparing cultivarsIt is a panel's palate, not a measurement: the unit is arbitrary and depends on the taster ². Chromatography run alongside sensory testing over a year across 50,000 to 2,000,000 Scoville units correlated at 0.95 ¹.Tasters adapt and disagree, and the ranking of the hottest cultivars has shifted as the scale was pushed upward; one comparative study found Bhut Jolokia at 1,001,304 units and the Red Savina habanero, long advertised as hotter, below the ordinary orange habanero ².
• Skin punch biopsy with PGP 9.5 stainingA 3 mm core of skin is stained for protein gene product 9.5, a marker present in nerve fibers, and the fibers crossing into the epidermis are counted ³¹.The standard way to show that capsaicin has defunctionalized the nerve endings, and the standard way small-fiber neuropathy is diagnosedSensitive to the effect and quantitative: 82 percent fewer fibers in biopsies after three weeks of cream, 74 percent fewer in blister specimens by day three, about 80 percent fewer one week after a single 8 percent patch, and 93 percent recovery by 24 weeks ^31,32.Fiber counts fall with age and with distance down the leg in healthy people, and a single core samples one small patch of skin in a condition that is patchy ⁵.
• Quantitative sensory testing after a capsaicin challengeCalibrated heat, cold, pinprick and brush stimuli are applied to treated and untreated skin, often after a deliberate capsaicin application used as a model of nerve pain ^25,131.Drug trials in healthy volunteers, and safety monitoring for loss of protective sensation after the patchIt separates what is lost from what is not: after the 8 percent patch, heat pain and the flare were abolished while pain to mechanical impact was barely reduced ²⁵. In the 52-week diabetic neuropathy safety study, repeat treatment produced no worsening of sharp, warm, cold or vibration sensation ⁸.The model is not the disease. In 26 healthy adults topical capsaicin produced mechanical hypersensitivity in the skin around the application, but as a main effect only, with no individual time point surviving adjustment for multiple comparisons, and it did not raise the summation of tonic heat pain as a group ¹³¹.
• Inhaled capsaicin cough challengeDoubling concentrations of nebulized capsaicin are inhaled until the subject coughs five times; that concentration, C5, is the measure of cough reflex sensitivity ¹³².Testing cough medicines and comparing cough sensitivity between groupsReproducible: in 40 healthy adults retested at 14 days and 40 retested 6 to 62 months later, 90 to 100 percent of repeat challenges fell within two doubling concentrations, and over the short interval C5 was the more stable endpoint than the two-cough threshold ¹³².It measures a provoked reflex, not the cough a patient actually has, and sensitivity differs systematically between men and women ¹³³.

Where it connects

Sources

133 sources, numbered as they are cited. Every one was checked against PubMed or its publisher before it was cited here; the note under each says what it shows and what it does not.

1. 1
   Reyes-Escogido Mde L, Gonzalez-Mondragon EG, Vazquez-Tzompantzi E. Chemical and pharmacological aspects of capsaicin.Molecules · 2011 · 16(2):1253-70doi:10.3390/molecules16021253 · PMID 21278678

   Source for the 1876 crystallization and naming, the 1919 structure, the capsaicinoid family, metabolism and the sensory-versus-chromatography correlation. Also an example of the substance P depletion explanation still being printed in 2011.

2. 2
   Chapa-Oliver AM, Mejia-Teniente L. Capsaicin: from plants to a cancer-suppressing agent.Molecules · 2016 · 21(8):931doi:10.3390/molecules21080931 · PMID 27472308

   Used for the biosynthetic route, the Scoville values including 16,000,000 for pure capsaicin and 1,001,304 for Bhut Jolokia, and the in vitro prostate concentrations. Its anticancer framing rests on cell-line data.

3. 3
   Fattori V, Hohmann MSN, Rossaneis AC, Pinho-Ribeiro FA, Verri WA. Capsaicin: current understanding of its mechanisms and therapy of pain and other pre-clinical and clinical uses.Molecules · 2016 · 21(7):844doi:10.3390/molecules21070844 · PMID 27367653

   Broad review; used for the 1876 purification and 1919 structure, the placental localization, the indifference of birds and the proportion of capsaicin among capsaicinoids.

4. 4
   Caterina MJ, Schumacher MA, Tominaga M, Rosen TA, Levine JD, Julius D. The capsaicin receptor: a heat-activated ion channel in the pain pathway.Nature · 1997 · 389(6653):816-24doi:10.1038/39807 · PMID 9349813

   The cloning of TRPV1 by calcium-influx expression screening of sensory neuron cDNA, and the finding that the same channel opens to noxious heat. Shows what capsaicin binds to; says nothing about clinical effect.

5. 5
   Anand P, Bley K. Topical capsaicin for pain management: therapeutic potential and mechanisms of action of the new high-concentration capsaicin 8% patch.Br J Anaesth · 2011 · 107(4):490-502doi:10.1093/bja/aer260 · PMID 21852280

   The review that replaced substance P depletion with defunctionalization, and the source for the 2009 approvals, the 1850 report, the calcium permeability ratio and the concentration giving half the maximal mitochondrial effect. One author was an employee of NeurogesX, which developed Qutenza, and the company paid the open access charge.

6. 6
   Crapnell RD, Banks CE. Electroanalytical overview: the pungency of chile and chilli products determined via the sensing of capsaicinoids.Analyst · 2021 · 146(9):2769-2783doi:10.1039/d1an00086a · PMID 33949422

   Describes Scoville's 1912 organoleptic test, the dilution-to-no-burn method, and the capsaicin to dihydrocapsaicin ratio of about 6:4. An analytical chemistry review.

7. 7
   Al Othman ZA, Ahmed YBH, Habila MA, Ghafar AA. Determination of capsaicin and dihydrocapsaicin in Capsicum fruit samples using high performance liquid chromatography.Molecules · 2011 · 16(10):8919-29doi:10.3390/molecules16108919 · PMID 22024959

   Method limits of detection, 4,249 micrograms per gram in hot chilies, 67,984.60 Scoville units, and an estimated 7.584 mg daily capsaicin intake in Riyadh. A market survey with modeled intake, not a dietary study.

8. 8
   Vinik AI, Perrot S, Vinik EJ, Pazdera L, Jacobs H, Stoker M, Long SK, Snijder RJ, van der Stoep M, Ortega E, Katz N. Capsaicin 8% patch repeat treatment plus standard of care (SOC) versus SOC alone in painful diabetic peripheral neuropathy: a randomised, 52-week, open-label, safety study.BMC Neurol · 2016 · 16(1):251doi:10.1186/s12883-016-0752-7 · PMID 27919222

   The PACE study, 468 patients over 52 weeks, designed as a safety study: no neurological deterioration, application-site pain in 28-29 percent. Open label, industry-sponsored, registered retrospectively.

9. 9
   Mallick-Searle T, Adler JA. Update on treating painful diabetic peripheral neuropathy: a review of current US guidelines with a focus on the most recently approved management options.J Pain Res · 2024 · 17:1005-1028doi:10.2147/JPR.S442595 · PMID 38505500

   Source for the 2020 Food and Drug Administration approval of the capsaicin 8 percent topical system for painful diabetic peripheral neuropathy and for its status as the only approved non-oral drug for that indication.

10. 10
    Babbar S, Marier JF, Mouksassi MS, Beliveau M, Vanhove GF, Chanda S, Bley K. Pharmacokinetic analysis of capsaicin after topical administration of a high-concentration capsaicin patch to patients with peripheral neuropathic pain.Ther Drug Monit · 2009 · 31(4):502-10doi:10.1097/FTD.0b013e3181a8b200 · PMID 19494795

    173 patients: capsaicin measurable in 31 percent with postherpetic neuralgia and 3 percent with diabetic neuropathy, maximum 17.8 ng/mL, half-life 1.64 hours. Authors include employees of the developer; the finding of minimal systemic exposure is consistent with the molecule's physical chemistry.

11. 11
    Krishnatreyya H, Hazarika H, Saha A, Chattopadhyay P. Capsaicin, the primary constituent of pepper sprays and its pharmacological effects on mammalian ocular tissues.Eur J Pharmacol · 2018 · 819:114-121doi:10.1016/j.ejphar.2017.11.042 · PMID 29191767

    Review of the ocular pharmacology of capsaicin as the principal constituent of oleoresin capsicum sprays. Written from a defense research laboratory; a pharmacological review, not an injury series.

12. 12
    Jordt SE, Julius D. Molecular basis for species-specific sensitivity to "hot" chili peppers.Cell · 2002 · 108(3):421-30doi:10.1016/s0092-8674(02)00637-2 · PMID 11853675

    The chicken receptor answers to heat and protons but not capsaicin; a region of the rat receptor transferred into it confers sensitivity. The molecular basis of directed deterrence; a molecular and animal study.

13. 13
    Tewksbury JJ, Nabhan GP. Seed dispersal. Directed deterrence by capsaicin in chilies.Nature · 2001 · 412(6845):403-4doi:10.1038/35086653 · PMID 11473305

    The field and feeding work behind directed deterrence: capsaicin discourages the vertebrates that destroy seeds without deterring the birds that disperse them. An ecological study, and a hypothesis about function rather than a demonstration of it.

14. 14
    Tewksbury JJ, Reagan KM, Machnicki NJ, Carlo TA, Haak DC, Peñaloza ALC, Levey DJ. Evolutionary ecology of pungency in wild chilies.Proc Natl Acad Sci U S A · 2008 · 105(33):11808-11doi:10.1073/pnas.0802691105 · PMID 18695236

    In a wild Bolivian chili that varies in pungency, Fusarium fungus was the main cause of seed death before dispersal, capsaicinoids protected seeds from it in experiments, and the share of pungent plants tracked the insect damage that lets the fungus in. It complicates deterrence as the single explanation.

15. 15
    Logan DW. Hot to touch: the story of the 2021 Nobel Prize in Physiology or Medicine.Dis Model Mech · 2021 · 14(10)doi:10.1242/dmm.049352 · PMID 34704598

    Editorial account of the 2021 prize to David Julius and Ardem Patapoutian. Used only for the prize and its subject matter.

16. 16
    Derry S, Rice ASC, Cole P, Tan T, Moore RA. Topical capsaicin (high concentration) for chronic neuropathic pain in adults.Cochrane Database Syst Rev · 2017 · 1(1):CD007393doi:10.1002/14651858.CD007393.pub4 · PMID 28085183

    Eight trials, 2,488 participants; about 10 percent more much-or-very-much improved than active placebo; numbers needed to treat 8.8 at 8 weeks and 7.0 at 12 weeks, both against the 0.04 percent control patch and both from two studies and 571 participants (moderate quality); most other outcomes very low quality. Also the source for the 'defunctionalized' framing of why the patch was developed, and for the fact that two of the eight trials used an inert placebo instead.

17. 17
    Wallace M, Pappagallo M. Qutenza: a capsaicin 8% patch for the management of postherpetic neuralgia.Expert Rev Neurother · 2011 · 11(1):15-27doi:10.1586/ern.10.182 · PMID 21158551

    Review of the approval in both the European Union and the United States and of the up-to-12-week duration after a single 60-minute application.

18. 18
    Soliman N, Moisset X, Ferraro MC, de Andrade DC, Baron R, Belton J, et al. Pharmacotherapy and non-invasive neuromodulation for neuropathic pain: a systematic review and meta-analysis.Lancet Neurol · 2025 · 24(5):413-428doi:10.1016/S1474-4422(25)00068-7 · PMID 40252663

    The NeuPSIG update: 313 trials, 48,789 participants. Capsaicin 8 percent patch number needed to treat 13.2 and number needed to harm 1,129 (interval 135.7 to infinity) at moderate certainty; capsaicin cream number needed to treat 6.1 at very low certainty; both weak second-line recommendations.

19. 19
    Lv J, Qi L, Yu C, Yang L, Guo Y, Chen Y, et al. Consumption of spicy foods and total and cause specific mortality: population based cohort study.BMJ · 2015 · 351:h3942doi:10.1136/bmj.h3942 · PMID 26242395

    China Kadoorie Biobank, 487,375 adults, 3.5 million person-years, 20,224 deaths; hazard ratios 0.90, 0.86 and 0.86 across increasing frequency. Exposure was self-reported spicy food once at baseline; an association, not a causal finding.

20. 20
    Ao Z, Huang Z, Liu H. Spicy food and chili peppers and multiple health outcomes: umbrella review.Mol Nutr Food Res · 2022 · 66(23):e2200167doi:10.1002/mnfr.202200167 · PMID 36111960

    Eleven systematic reviews, 27 findings: direct associations with esophageal, gastric and gallbladder cancer, inverse associations with mortality, metabolism and cardiovascular disease, and a non-linear dose-response for gastric cancer risk with capsaicin intake.

21. 21
    Sabbineni M, Scott W, Punia K, Manuja K, Singh A, Campbell K, MacKillop J, Balodis I. SAEM GRACE: dopamine antagonists and topical capsaicin for cannabis hyperemesis syndrome in the emergency department: a systematic review of direct evidence.Acad Emerg Med · 2024 · 31(5):493-503doi:10.1111/acem.14770 · PMID 37391387

    Seven studies and 492 patients: evidence for capsaicin mixed across five studies and 386 patients, evidence for dopamine antagonists more consistent. The review names small samples, unstandardized administration and risk of bias as the limits.

22. 22
    Lingasamy P, Kiruba B, Rajakumar S, Surisetti SM, Patel N, Lulu S S, Salumets A, Modhukur V. Natural compounds as epigenetic modulators in gynaecological cancers: from chemoresistance to precision oncology.Biomed Pharmacother · 2026 · 202:119777doi:10.1016/j.biopha.2026.119777 · PMID 42468209

    Lists capsaicin among phytochemicals with preclinical epigenetic effects and states the limits plainly: poor bioavailability, pharmacokinetic variability, no tumor-tissue target engagement data, weak potency, and no biomarker-driven trials.

23. 23
    Derry S, Moore RA. Topical capsaicin (low concentration) for chronic neuropathic pain in adults.Cochrane Database Syst Rev · 2012 · 2012(9):CD010111doi:10.1002/14651858.CD010111 · PMID 22972149

    Six trials, 389 participants, all published before 1996; heterogeneous, with too few data to pool; conclusion that low-concentration capsaicin is probably without meaningful effect beyond placebo cream. The strongest statement available, and it is a statement about absent evidence as much as absent effect.

24. 24
    Derry S, Wiffen PJ, Kalso EA, Bell RF, Aldington D, Phillips T, Gaskell H, Moore RA. Topical analgesics for acute and chronic pain in adults - an overview of Cochrane Reviews.Cochrane Database Syst Rev · 2017 · 5(5):CD008609doi:10.1002/14651858.CD008609.pub2 · PMID 28497473

    Thirteen reviews, 206 studies, around 30,700 participants. Source for local adverse events in 63 percent with low-concentration capsaicin (number needed to harm 2.6, five studies, 557 participants, high quality) and withdrawals of 15 percent against 3 percent, that last from four studies and 477 participants at very low quality.

25. 25
    Litewczuk D, Truini A, Schmelz M, Rukwied R. Topical capsaicin 8% differentially blocks activation of nociceptors by mechanical, heat, and electrical stimuli in human skin.Pain · 2026 · 167(8):e358-e368doi:10.1097/j.pain.0000000000004011 · PMID 42152692

    Twenty healthy volunteers followed for 12 weeks: heat pain and axon reflex flare abolished, mechanical impact pain barely changed, flare and tonic electrical pain suppressed for months. The clearest dissection of what defunctionalization removes; healthy skin, not patients.

26. 26
    Graham DY, Smith JL, Opekun AR. Spicy food and the stomach. Evaluation by videoendoscopy.JAMA · 1988 · 260(23):3473-5PMID 3210286

    Randomized crossover endoscopy study in twelve volunteers: 11 of 12 had multiple gastric erosions after aspirin, median score zero after the jalapeno meal, the pizza and the bland meal, and no visible damage when 30 g of ground jalapeno was placed directly in the stomach. No DOI is indexed for this 1988 item.

27. 27
    van der Pol RJ, van den Berg A, van der Woerd WL. Gastric hemorrhage due to high pungency food?JPGN Rep · 2026 · 7(2):278-280doi:10.1002/jpr3.70152 · PMID 42110134

    A 9-year-old who vomited blood, with a significant fall in hemoglobin and diffuse bleeding from the stomach lining, after eating potato chips flavored with a very high-pungency chili, treated with a powder sprayed through the endoscope. One case, with no other cause identified; the authors note it is the first such report.

28. 28
    Haar RJ, Iacopino V, Ranadive N, Weiser SD, Dandu M. Health impacts of chemical irritants used for crowd control: a systematic review of the injuries and deaths caused by tear gas and pepper spray.BMC Public Health · 2017 · 17(1):831doi:10.1186/s12889-017-4814-6 · PMID 29052530

    Thirty-one studies from eleven countries, 1990 to 2015: 5,131 people injured, two deaths, 58 permanent disabilities; of 9,261 injuries, 8.7 percent severe. Tear gas and pepper spray are pooled, so the pepper spray share cannot be separated.

29. 29
    Alghamdi M, Rathinasabapathy T, Komarnytsky S. Capsaicinoid profiles, phenolic content, and antioxidant properties of chili peppers grown in urban settings.Int J Mol Sci · 2025 · 26(10):4916doi:10.3390/ijms26104916 · PMID 40430052

    Forty-seven cultivars: species-specific capsaicin to dihydrocapsaicin to nordihydrocapsaicin ratios of 64:30:6, 73:25:2 and 34:60:6. Cited only for those ratios; its cell experiments are in a macrophage line.

30. 30
    Gonzalez-Zamora A, Sierra-Campos E, Luna-Ortega JG, Perez-Morales R, Rodriguez Ortiz JC, Garcia-Hernandez JL. Characterization of different Capsicum varieties by evaluation of their capsaicinoids content by high performance liquid chromatography, determination of pungency and effect of high temperature.Molecules · 2013 · 18(11):13471-86doi:10.3390/molecules181113471 · PMID 24184818

    HPLC across eight Mexican cultivars: total capsaicinoids from undetectable in bell pepper to 31.84 mg/g dry weight in chiltepin, with dihydrocapsaicin exceeding capsaicin in these fruits. Agricultural sampling, one region.

31. 31
    Nolano M, Simone DA, Wendelschafer-Crabb G, Johnson T, Hazen E, Kennedy WR. Topical capsaicin in humans: parallel loss of epidermal nerve fibers and pain sensation.Pain · 1999 · 81(1-2):135-45doi:10.1016/s0304-3959(99)00007-x · PMID 10353501

    0.075 percent cream four times daily for three weeks in volunteers: 74 percent fiber loss by day three, 79-82 percent at three weeks, full reinnervation over six weeks except cold sensation. Small healthy-volunteer study, not a pain trial.

32. 32
    Kennedy WR, Vanhove GF, Lu SP, Tobias J, Bley KR, Walk D, Wendelschafer-Crabb G, Simone DA, Selim MM. A randomized, controlled, open-label study of the long-term effects of NGX-4010, a high-concentration capsaicin patch, on epidermal nerve fiber density and sensory function in healthy volunteers.J Pain · 2010 · 11(6):579-87doi:10.1016/j.jpain.2009.09.019 · PMID 20400377

    Single 60-minute 8 percent patch on volunteers' thighs: about 80 percent fiber loss at one week, incomplete regeneration at 12 weeks, 93 percent recovery at 24 weeks. Several authors were employees of the developer.

33. 33
    Jessell TM, Iversen LL, Cuello AC. Capsaicin-induced depletion of substance P from primary sensory neurones.Brain Res · 1978 · 152(1):183-8doi:10.1016/0006-8993(78)90146-4 · PMID 209869

    The rat observation that launched the substance P depletion hypothesis. No abstract is indexed; cited for the observation itself, not for the causal interpretation later placed on it.

34. 34
    Louis-Gray K, Tupal S, Premkumar LS. TRPV1: a common denominator mediating antinociceptive and antiemetic effects of cannabinoids.Int J Mol Sci · 2022 · 23(17):10016doi:10.3390/ijms231710016 · PMID 36077412

    Review setting out the proposed vagal, solitary nucleus and area postrema pathway by which hot water and topical capsaicin might both relieve cannabinoid hyperemesis. A mechanistic hypothesis, explicitly described as unproven.

35. 35
    Dezieck L, Hafez Z, Conicella A, Blohm E, O'Connor MJ, Schwarz ES, Mullins ME. Resolution of cannabis hyperemesis syndrome with topical capsaicin in the emergency department: a case series.Clin Toxicol (Phila) · 2017 · 55(8):908-13doi:10.1080/15563650.2017.1324166 · PMID 28494183

    Thirteen patients identified retrospectively at two academic centers, all of whom improved after other treatments failed. The TRPV1 and area postrema mechanism is proposed here; a case series cannot test it.

36. 36
    Jancso N, Jancso-Gabor A, Szolcsanyi J. Direct evidence for neurogenic inflammation and its prevention by denervation and by pretreatment with capsaicin.Br J Pharmacol Chemother · 1967 · 31(1):138-51doi:10.1111/j.1476-5381.1967.tb01984.x · PMID 6055248

    The founding rat experiments on neurogenic inflammation and its prevention by capsaicin pretreatment. No abstract is indexed; cited for the finding and the date.

37. 37
    Szolcsanyi J. Forty years in capsaicin research for sensory pharmacology and physiology.Neuropeptides · 2004 · 38(6):377-84doi:10.1016/j.npep.2004.07.005 · PMID 15567473

    First-hand review of the Hungarian work from capsaicin desensitization to the postulated capsaicin receptor. A participant's history, not an independent assessment.

38. 38
    Sicuteri F, Fanciullacci M, Nicolodi M, Geppetti P, Fusco BM, Marabini S, Alessandri M, Campagnolo V. Substance P theory: a unique focus on the painful and painless phenomena of cluster headache.Headache · 1990 · 30(2):69-79doi:10.1111/j.1526-4610.1990.hed3002069.x · PMID 1689282

    Describes the immediate burning, tearing and rhinorrhea after intranasal capsaicin, the tachyphylaxis over days of application, and the fall in attacks in treated patients. Uncontrolled clinical observation within a mechanistic paper.

39. 39
    Marks DR, Rapoport A, Padla D, Weeks R, Rosum R, Sheftell F, Arrowsmith F. A double-blind placebo-controlled trial of intranasal capsaicin for cluster headache.Cephalalgia · 1993 · 13(2):114-6doi:10.1046/j.1468-2982.1993.1302114.x · PMID 8495452

    Randomized intranasal capsaicin for seven days; headaches on days 8-15 significantly less severe than placebo, with episodic patients benefiting more. The abstract does not report the number randomized; the rationale given was substance P depletion.

40. 40
    Fusco BM, Fiore G, Gallo F, Martelletti P, Giacovazzo M. "Capsaicin-sensitive" sensory neurons in cluster headache: pathophysiological aspects and therapeutic indication.Headache · 1994 · 34(3):132-7doi:10.1111/j.1526-4610.1994.hed3403132.x · PMID 7515383

    Two-year follow-up of 25 responders (17 episodic, 8 chronic): benefit returned on re-treatment in 65 percent, and in chronic cluster headache lasted a month at most. Also shows depletion of substance P and calcitonin gene-related peptide fibers in rat nasal mucosa.

41. 41
    Fowler CJ, Jewkes D, McDonald WI, Lynn B, de Groat WC. Intravesical capsaicin for neurogenic bladder dysfunction.Lancet · 1992 · 339(8803):1239doi:10.1016/0140-6736(92)91186-c · PMID 1349978

    The letter that opened the intravesical program. No abstract is indexed; cited for the report and its date, not for priority, which belongs to the 1989 Florentine study.

42. 42
    Maggi CA, Barbanti G, Santicioli P, Beneforti P, Misuri D, Meli A, Turini D. Cystometric evidence that capsaicin-sensitive nerves modulate the afferent branch of micturition reflex in humans.J Urol · 1989 · 142(1):150-4doi:10.1016/s0022-5347(17)38701-3 · PMID 2733095

    Capsaicin instilled into the bladder of six patients in Florence, five of them with hypersensitive lower urinary tract disorders: concentration-related falls in bladder capacity and in the pressure threshold for urinating, and symptoms attenuated for a few days. The authors call it the first indication that capsaicin-sensitive structures exist in the human bladder, which is why it comes before the 1992 report.

43. 43
    Caterina MJ, Leffler A, Malmberg AB, Martin WJ, Trafton J, Petersen-Zeitz KR, Koltzenburg M, Basbaum AI, Julius D. Impaired nociception and pain sensation in mice lacking the capsaicin receptor.Science · 2000 · 288(5464):306-13doi:10.1126/science.288.5464.306 · PMID 10764638

    Knockout mice show no vanilloid-evoked pain, impaired detection of painful heat and little inflammatory thermal hypersensitivity, with normal mechanical responses. Animal evidence for what the channel does.

44. 44
    Payne CK, Mosbaugh PG, Forrest JB, Evans RJ, Whitmore KE, Antoci JP, et al. Intravesical resiniferatoxin for the treatment of interstitial cystitis: a randomized, double-blind, placebo controlled trial.J Urol · 2005 · 173(5):1590-4doi:10.1097/01.ju.0000154631.92150.ef · PMID 15821499

    163 patients, three doses, 12 weeks: no improvement in overall symptoms, pain, urgency, frequency, nocturia or voided volume, and dose-dependent instillation pain. The largest randomized trial of intravesical vanilloid therapy, and negative.

45. 45
    Gavva NR, Treanor JJS, Garami A, Fang L, Surapaneni S, Akrami A, et al. Pharmacological blockade of the vanilloid receptor TRPV1 elicits marked hyperthermia in humans.Pain · 2008 · 136(1-2):202-10doi:10.1016/j.pain.2008.01.024 · PMID 18337008

    The phase 1 experience with AMG 517: marked reversible hyperthermia, temperature above 40 degrees Celsius after molar extraction, and the conclusion that selective antagonists cannot be used systemically as stand-alone agents. Reported by the company that developed the compound.

46. 46
    Gavva NR. Body-temperature maintenance as the predominant function of the vanilloid receptor TRPV1.Trends Pharmacol Sci · 2008 · 29(11):550-7doi:10.1016/j.tips.2008.08.003 · PMID 18805596

    Sets out the symmetry: agonists cause hypothermia, antagonists hyperthermia, across rodents to primates. A review by the same group, so not an independent appraisal.

47. 47
    Backonja M, Wallace MS, Blonsky ER, Cutler BJ, Malan P, Rauck R, Tobias J. NGX-4010, a high-concentration capsaicin patch, for the treatment of postherpetic neuralgia: a randomised, double-blind study.Lancet Neurol · 2008 · 7(12):1106-12doi:10.1016/S1474-4422(08)70228-X · PMID 18977178

    One of the two pivotal postherpetic neuralgia trials, and the smaller of them: 402 patients, 29.6 against 19.9 percent pain reduction over weeks 2-8, 42 against 32 percent reaching a 30 percent reduction. The comparator was an active 0.04 percent capsaicin patch, which is why the difference is small.

48. 48
    Capsaicin patch (Qutenza) for postherpetic neuralgia.Med Lett Drugs Ther · 2011 · 53(1365):42-3PMID 21617594

    Independent drug bulletin recording the United States Food and Drug Administration approval of the 8 percent patch for postherpetic neuralgia. No DOI is indexed for this item.

49. 49
    Jones VM, Moore KA, Peterson DM. Capsaicin 8% topical patch (Qutenza) - a review of the evidence.J Pain Palliat Care Pharmacother · 2011 · 25(1):32-41doi:10.3109/15360288.2010.547561 · PMID 21426216

    Summarizes both pivotal trials, and the source for application-site erythema in 63 percent, application-site pain in 42 percent, the transient blood pressure rises and the three-month minimum interval between applications.

50. 50
    Liao M, Cao E, Julius D, Cheng Y. Structure of the TRPV1 ion channel determined by electron cryo-microscopy.Nature · 2013 · 504(7478):107-12doi:10.1038/nature12822 · PMID 24305160

    TRPV1 resolved at 3.4 angstroms, breaking the side-chain resolution barrier for a membrane protein without crystallization. Structural biology; it says nothing about clinical effect.

51. 51
    Cao E, Liao M, Cheng Y, Julius D. TRPV1 structures in distinct conformations reveal activation mechanisms.Nature · 2013 · 504(7478):113-8doi:10.1038/nature12823 · PMID 24305161

    The companion paper: structures of the channel held open by a spider toxin and by vanilloids, showing rearrangement of the outer pore and dilation of a constriction at the lower gate.

52. 52
    Yang F, Xiao X, Cheng W, Yang W, Yu P, Song Z, Yarov-Yarovoy V, Zheng J. Structural mechanism underlying capsaicin binding and activation of the TRPV1 ion channel.Nat Chem Biol · 2015 · 11(7):518-524doi:10.1038/nchembio.1835 · PMID 26053297

    Modeling checked by site-directed mutation: capsaicin sits tail-up, head-down, anchored by its vanillyl and amide groups, and stabilizes the open channel by pulling on the linker between the fourth and fifth membrane-crossing segments.

53. 53
    Huang YZ, Ma JX, Bian YJ, Bai QR, Gao YH, Di SK, et al. TRPV1 analgesics disturb core body temperature via a biased allosteric mechanism involving conformations distinct from that for nociception.Neuron · 2024 · 112(11):1815-1831.e4doi:10.1016/j.neuron.2024.02.016 · PMID 38492574

    Mouse work identifying the S4-S5 linker as the site responsible for antagonist hyperthermia, and an antagonist (PSFL2874) effective against inflammatory pain without temperature change. Animal evidence only.

54. 54
    Simpson DM, Robinson-Papp J, Van J, Stoker M, Jacobs H, Snijder RJ, Schregardus DS, Long SK, Lambourg B, Katz N. Capsaicin 8% patch in painful diabetic peripheral neuropathy: a randomized, double-blind, placebo-controlled study.J Pain · 2017 · 18(1):42-53doi:10.1016/j.jpain.2016.09.008 · PMID 27746370

    The STEP trial: 369 patients, one 30-minute application to the feet, 27.4 against 20.9 percent pain reduction, median response at 19 against 72 days, no sensory deterioration. Several authors were employees of Astellas.

55. 55
    Stevens RM, Ervin J, Nezzer J, Nieves Y, Guedes K, Burges R, Hanson PD, Campbell JN. Randomized, double-blind, placebo-controlled trial of intraarticular trans-capsaicin for pain associated with osteoarthritis of the knee.Arthritis Rheumatol · 2019 · 71(9):1524-1533doi:10.1002/art.40894 · PMID 30888737

    Phase 2 trial of CNTX-4975 in 172 patients: 1.0 mg gave a least-squares mean difference of -1.6 at week 12 and -1.4 at week 24; 0.5 mg did not reach significance. Authors were employees of Centrexion Therapeutics or its research partners. The two phase 3 trials that followed missed their primary endpoints; they are reported in reviews [45][114] but have not been published in full.

56. 56
    Borgundvaag B, Bellolio F, Miles I, Schwarz ES, Sharif S, Su MK, et al. Guidelines for Reasonable and Appropriate Care in the Emergency Department (GRACE-4): alcohol use disorder and cannabinoid hyperemesis syndrome management in the emergency department.Acad Emerg Med · 2024 · 31(5):425-455doi:10.1111/acem.14911 · PMID 38747203

    Suggests haloperidol or droperidol, and suggests offering topical capsaicin, both in addition to usual care and both at very low certainty of evidence.

57. 57
    Humphries C, Gillings M. RCEM best practice guideline: suspected cannabinoid hyperemesis syndrome in emergency departments.Emerg Med J · 2024 · 41(5):328-331doi:10.1136/emermed-2024-213886 · PMID 38448215

    United Kingdom emergency medicine guidance naming haloperidol and capsaicin among treatment options, on the best available evidence, which it acknowledges is limited.

58. 58
    Tsai EH, Gan TJ. TRPV1 receptor modulators: emerging therapies for neuropathic, osteoarthritic, and perioperative pain.CNS Drugs · 2026 · 40(4):523-534doi:10.1007/s40263-026-01272-1 · PMID 41722000

    Current inventory of the promising agonists (capsaicin formulations, resiniferatoxin, CNTX-4975, vocacapsaicin) and the potentially applicable antagonists (NEO6860, mavatrep, ACD-440, AJH-2947, DWP05195, XEN-D0501). Also the source for the two failed phase 3 trials of CNTX-4975 and for the completed, unpublished phase 3 trial of intra-articular resiniferatoxin. A narrative review, not a trial.

59. 59
    Matta C, Takács R, Jin EJ, Helyes Z, Horváth ÁI, Juhász KZ, Tóth BI, Ellis R, Mobasheri A. The rise and fall of TRPV1-targeted analgesia in osteoarthritis: a critical appraisal.Expert Opin Pharmacother · 2026 · 27(11):1179-1196doi:10.1080/14656566.2026.2696489 · PMID 42373560

    Narrative critical appraisal: systemic antagonists were abandoned, intra-articular agonists failed their phase 3 primary endpoints despite expedited regulatory designations, and TRPV1-targeted osteoarthritis therapy has in the authors' words 'completed a full translational cycle without yielding regulatory approval'. A review of other people's trials, not a trial.

60. 60
    Peppin JF, Majors K, Webster LR, Simpson DM, Tobias JK, Vanhove GF. Tolerability of NGX-4010, a capsaicin 8% patch for peripheral neuropathic pain.J Pain Res · 2011 · 4:385-92doi:10.2147/JPR.S22954 · PMID 22247621

    Integrated tolerability analysis of 1,696 patients: mean maximum rise in 'pain now' of 2.6 points, return to baseline by the evening of day one or two, and 98 percent or more completing the application. Two authors were employees of the developer.

61. 61
    Moria HA. Cooling the burn: EMLA alone vs. paravertebral block plus EMLA for improving tolerability of 8% capsaicin patch application in thoracic postherpetic neuralgia - a retrospective cohort study.Front Aging Neurosci · 2026 · 18:1762229doi:10.3389/fnagi.2026.1762229 · PMID 41777672

    Nine patients given topical anesthetic alone, all of whom needed intravenous rescue opioid, against eight who also had a paravertebral block and needed none. Retrospective, single center, seventeen patients in total; the author calls for prospective controlled evaluation.

62. 62
    Moria H. Procedural optimization of capsaicin 8% patch therapy using ultrasound-guided bilateral ankle nerve block in painful diabetic peripheral neuropathy: a retrospective comparative cohort study.Healthcare (Basel) · 2026 · 14(16)doi:10.3390/healthcare14162563 · PMID 42651332

    Ninety patients in three groups of 30: no patient given an ultrasound-guided ankle block needed intravenous rescue tramadol, against 60 percent with numbing cream and all of those given no pretreatment, and all completed the application. The author states plainly that this concerns tolerating the procedure and should not be read as better pain relief afterward.

63. 63
    Etienne R, Laurent M, Henry A, Bioy A, Salleron J, Schohn CH, Cretineau N. Interest of a standardized hypnotic message for the reduction of pain and anxiety in cancer patients treated by capsaicin patch for neuropathic pain: a randomized controlled trial.BMC Complement Med Ther · 2021 · 21(1):154doi:10.1186/s12906-021-03329-8 · PMID 34044838

    Sixty-nine patients randomized to standard application, a recorded hypnotic message or relaxing music: no difference in pain scores between groups (p = 0.355), but significantly lower anxiety with hypnosis than standard application (p = 0.007).

64. 64
    Mason L, Moore RA, Derry S, Edwards JE, McQuay HJ. Systematic review of topical capsaicin for the treatment of chronic pain.BMJ · 2004 · 328(7446):991doi:10.1136/bmj.38042.506748.EE · PMID 15033881

    Six neuropathic trials (656 patients, number needed to treat 5.7) and three musculoskeletal trials (368 patients, number needed to treat 8.1); about a third had local adverse events; efficacy described as moderate to poor. Superseded in part by the later Cochrane reviews.

65. 65
    Tshering G, Posadzki P, Kongkaew C. Efficacy and safety of topical capsaicin in the treatment of osteoarthritis pain: a systematic review and meta-analysis.Phytother Res · 2024 · 38(7):3695-3705doi:10.1002/ptr.8223 · PMID 38761115

    Eight double-blind randomized trials, 498 patients: standardized mean difference -0.84 for pain, risk ratio 5.56 for burning with a number needed to harm of 3. Short trials, small samples, high heterogeneity, low to very low certainty.

66. 66
    Kolasinski SL, Neogi T, Hochberg MC, Oatis C, Guyatt G, Block J, et al. 2019 American College of Rheumatology/Arthritis Foundation guideline for the management of osteoarthritis of the hand, hip, and knee.Arthritis Care Res (Hoboken) · 2020 · 72(2):149-162doi:10.1002/acr.24131 · PMID 31908149

    Conditionally recommends topical capsaicin for knee osteoarthritis and conditionally recommends against it for the hand, citing absent direct evidence and the risk of getting it in an eye; the panel did not examine the hip. Cited for the recommendations and their strength only.

67. 67
    Irving GA, Backonja MM, Dunteman E, Blonsky ER, Vanhove GF, Lu SP, Tobias J. A multicenter, randomized, double-blind, controlled study of NGX-4010, a high-concentration capsaicin patch, for the treatment of postherpetic neuralgia.Pain Med · 2011 · 12(1):99-109doi:10.1111/j.1526-4637.2010.01004.x · PMID 21087403

    The second pivotal postherpetic neuralgia trial, and the larger of the two at 418 patients: pain fell 32.0 against 24.4 percent over weeks 2 to 8 (P = 0.011), and 46 against 34 percent reached a 30 percent reduction. Run by the patch's developer, NeurogesX, whose employee is the last author.

68. 68
    Katz NP, Allen S, Carnevale A, Marcondes L, Simpson DM. Effect of capsaicin (8%) topical system on sensory function in patients with diabetic peripheral neuropathy: analysis of the PACE study.Muscle Nerve · 2026 · 73(6):1109-1117doi:10.1002/mus.70237 · PMID 41932827

    Post hoc analysis reporting shifts from below-normal to normal sensation in 21-26 percent of tests at 12 months with repeat treatment. Not prespecified; three authors are employees of Averitas Pharma, which markets the patch in the United States; the authors state a dedicated trial would be needed.

69. 69
    Guo Z, Xia Y, Zhang Z. Efficacy and safety of different medications compared for the treatment of postherpetic neuralgia: a network meta-analysis.Front Pharmacol · 2025 · 16:1614587doi:10.3389/fphar.2025.1614587 · PMID 40808683

    Thirty-eight randomized trials, 8,621 participants: the 8 percent patch produced a significant reduction in pain intensity (mean difference -9.20), while amitriptyline plus pregabalin ranked highest overall. Nine of 38 trials were at high risk of bias.

70. 70
    Eerdekens MH, Both C, Freitas RL. Long-term efficacy and safety of treatments for chronic peripheral neuropathic pain: a systematic review and narrative synthesis.Pain Ther · 2026 · 15(5):1313-1343doi:10.1007/s40122-026-00884-1 · PMID 42671707

    Thirty-one studies; the patch had the most long-term studies and the lowest discontinuation rates for adverse events. All three authors are employees of Grünenthal, which markets the patch; a supplemental search specifically for the patch was added to the protocol.

71. 71
    Lux MP, Flöther L, Frömter C, Rack B, Veselinovic K, Heine M, Paepke S, Krabisch P, Quandel T, Sabatowski R. Topical treatment of chemotherapy-induced peripheral neuropathy (CIPN) with high-concentration (179 mg) capsaicin patch in breast cancer patients - results of the QUCIP study.Front Oncol · 2024 · 14:1452099doi:10.3389/fonc.2024.1452099 · PMID 39309732

    Prospective observational study in 73 women: painDETECT fell from 19.71 to 15.80 after the first treatment, with 40 percent achieving 30 percent relief by week 36. No control group; two authors are employees of Grünenthal.

72. 72
    Goodwin BJ, Jain A, Mitchell J, Khokhar D, Fagbemigun R, Brancaccio H, Sadik E, Khawer A, Chhatre A. 8% capsaicin patches for HIV-induced polyneuropathy: a systematic review and meta-analysis.Pain Manag · 2026 · 16(9):1019-1026doi:10.1080/17581869.2026.2681558 · PMID 42237588

    Seven studies pooled as before-and-after pain scores, giving an effect size of about 1 for the commonest application duration. Without control groups the design cannot separate the patch from time and expectation, which is why the randomized Cochrane estimate of about 10 percent more responders is the more informative number.

73. 73
    Niven M, Inwood M, Forget P. High-concentration (8%) capsaicin patch for chronic postoperative neuropathic pain: a systematic review of randomised controlled trials.Br J Pain · 2025 · online ahead of print, 20494637251396094doi:10.1177/20494637251396094 · PMID 41281261

    Searched to July 2025 and found one eligible randomized trial of 46 participants, which showed no significant improvement over an inactive placebo patch; certainty very low. A negative finding about the evidence base rather than about the drug.

74. 74
    Freitas R, van Keep M, Kandaswamy P, Prüfert A, Ager M, Eerdekens M. Cost-effectiveness of a high-concentration (179 mg) capsaicin patch for the treatment of patients with peripheral neuropathic pain in Scotland.Pain Ther · 2025 · 14(5):1573-1595doi:10.1007/s40122-025-00769-9 · PMID 40887562

    Markov model giving an incremental cost-effectiveness ratio of 13,516 pounds per quality-adjusted life year. Built and published by the manufacturer; a model, not an observed outcome.

75. 75
    Allen JH, de Moore GM, Heddle R, Twartz JC. Cannabinoid hyperemesis: cyclical hyperemesis in association with chronic cannabis abuse.Gut · 2004 · 53(11):1566-70doi:10.1136/gut.2003.036350 · PMID 15479672

    The original South Australian series: cessation stopped the vomiting in seven of nine followed cases, rechallenge brought it back in three, and nine of ten showed compulsive hot bathing. A case series with attrition, not a cohort.

76. 76
    Stanghellini V, Chan FKL, Hasler WL, Malagelada JR, Suzuki H, Tack J, Talley NJ. Gastroduodenal disorders.Gastroenterology · 2016 · 150(6):1380-92doi:10.1053/j.gastro.2016.02.011 · PMID 27147122

    The Rome IV classification, which places cannabinoid hyperemesis syndrome among the nausea and vomiting disorders beside cyclic vomiting syndrome. Cited for that classification only.

77. 77
    Bonnet U. [Cannabinoid hyperemesis syndrome: a scoping review].Fortschr Neurol Psychiatr · 2025 · online ahead of printdoi:10.1055/a-2704-5465 · PMID 41224199

    German-language scoping review: 0.075 to 0.1 percent capsaicin cream rubbed on the abdomen helps but more slowly than a hot shower or intramuscular haloperidol, and distinguishing the syndrome from cyclic vomiting needs remission established over at least six months of abstinence.

78. 78
    Zygmunt PM, Petersson J, Andersson DA, Chuang H, Sørgård M, Di Marzo V, Julius D, Högestätt ED. Vanilloid receptors on sensory nerves mediate the vasodilator action of anandamide.Nature · 1999 · 400(6743):452-7doi:10.1038/22761 · PMID 10440374

    The endocannabinoid anandamide activates the same receptor capsaicin does, in isolated arteries and in cells expressing the cloned channel. Shows the body makes its own agonists for this channel; animal and in vitro work.

79. 79
    Wagner S, Hoppe J, Zuckerman M, Schwarz K, McLaughlin J. Efficacy and safety of topical capsaicin for cannabinoid hyperemesis syndrome in the emergency department.Clin Toxicol (Phila) · 2020 · 58(6):471-475doi:10.1080/15563650.2019.1660783 · PMID 31482758

    Retrospective cohort of 43 patients: length of stay fell by a non-significant 22 minutes, fewer additional medications were given, opioid use was lower, and 67 percent of capsaicin visits needed nothing further. Retrospective and unblinded.

80. 80
    Kum V, Bell A, Fang W, VanWert E. Efficacy of topical capsaicin for cannabinoid hyperemesis syndrome in a pediatric and adult emergency department.Am J Emerg Med · 2021 · 49:343-351doi:10.1016/j.ajem.2021.06.049 · PMID 34242945

    Retrospective cohort of 201 patients: 55 against 21 percent met the authors' definition of efficacy, and time to discharge after the reference agent was 3.72 against 6.11 hours, with no difference in total medications or length of stay. Carries a published corrigendum.

81. 81
    Kum V, Bell A, Fang W, VanWert E. Corrigendum to "Efficacy of topical capsaicin for cannabinoid hyperemesis syndrome in a pediatric and adult emergency department".Am J Emerg Med · 2024 · 79:233doi:10.1016/j.ajem.2024.01.016 · PMID 38423935

    The correction attached to the preceding paper. Noted because corrections to the small capsaicin literature for this syndrome matter to how much weight it carries.

82. 82
    Yusuf HM, Geier C, Staidle A, Montoy JCC. Efficacy of topical capsaicin for the treatment of cannabinoid hyperemesis syndrome: a retrospective cohort study.Am J Emerg Med · 2021 · 43:142-148doi:10.1016/j.ajem.2021.01.073 · PMID 33561623

    San Francisco retrospective cohort of 55 patients, 35 given capsaicin and 20 not: no difference in time to discharge, rounds of medication, return within 24 hours or admission. Only the subgroup given capsaicin within the first two rounds of treatment had a shorter stay. The negative comparative cohort in this literature.

83. 83
    Pourmand A, Esmailian G, Mazer-Amirshahi M, Lee-Park O, Tran QK. Topical capsaicin for the treatment of cannabinoid hyperemesis syndrome, a systematic review and meta-analysis.Am J Emerg Med · 2021 · 43:35-40doi:10.1016/j.ajem.2021.01.004 · PMID 33493995

    Seven studies, 106 patients: mean time to symptom resolution 325 minutes and emergency department stay 379 minutes. With no control arms, these are descriptions of the illness course as much as of the treatment.

84. 84
    Dean DJ, Sabagha N, Rose K, Weiss A, France J, Asmar T, et al. A pilot trial of topical capsaicin cream for treatment of cannabinoid hyperemesis syndrome.Acad Emerg Med · 2020 · 27(11):1166-1172doi:10.1111/acem.14062 · PMID 32569429

    The only randomized trial: 30 patients, nausea 4.1 against 6.1 cm at 30 minutes with an interval including no difference, 3.2 against 6.4 at 60 minutes, complete resolution in 29.4 against 0 percent. A pilot, and far too small to be definitive.

85. 85
    Hsu J, Kashyap S, Hurd C, McCormack L, Herrmann Z, Schwartz AC, Jackson J, DeMoss D. Treatment of cannabinoid hyperemesis syndrome: a systematic review and treatment algorithm for consultation-liaison psychiatrists.Gen Hosp Psychiatry · 2025 · 97:185-191doi:10.1016/j.genhosppsych.2025.10.012 · PMID 41129865

    Thirty-four articles and 63 individual cases: capsaicin cream, antipsychotics and benzodiazepines were reported to help more often than ondansetron, promethazine or metoclopramide. The authors state the algorithm rests on case reports.

86. 86
    Bonnet U. [The cannabinoid hyperemesis syndrome: a narrative review].Nervenarzt · 2025 · 97(4):377-381doi:10.1007/s00115-025-01864-0 · PMID 40689972

    The same author's companion German-language review, which puts the abstinence needed to separate the syndrome from cyclic vomiting at 6 to 12 months rather than at least 6. Cited for that longer figure, and the two reviews should be read as one body of opinion rather than two independent sources.

87. 87
    Kelly CM, Attridge M, Katsogridakis YL, Mrozek L, Jackson K, Hoffmann JA. Implementation of a standardized management algorithm for cannabis hyperemesis syndrome in a pediatric emergency department.Pediatr Emerg Care · 2026 · 42(7):535-543doi:10.1097/PEC.0000000000003588 · PMID 42003265

    128 encounters by 44 adolescents before and after an algorithm: capsaicin use rose from 2.7 to 22.2 percent and metoclopramide from 6.8 to 42.6 percent, with no significant change in admission odds or length of stay.

88. 88
    Yeoh KG, Kang JY, Yap I, Guan R, Tan CC, Wee A, Teng CH. Chili protects against aspirin-induced gastroduodenal mucosal injury in humans.Dig Dis Sci · 1995 · 40(3):580-3doi:10.1007/BF02064374 · PMID 7895549

    Eighteen healthy volunteers, each their own control: median gastric injury score 1.5 after 20 g of chili before aspirin against 4 after water before aspirin. Small, single-center, short-term.

89. 89
    Kang JY, Yeoh KG, Chia HP, Lee HP, Chia YW, Guan R, Yap I. Chili - protective factor against peptic ulcer?Dig Dis Sci · 1995 · 40(3):576-9doi:10.1007/BF02064373 · PMID 7895548

    103 Chinese ulcer patients and 87 controls in Singapore: median chili use eight against 24 times a month, adjusted odds ratio 0.47 for higher intake. An association in one population, with deliberate avoiders excluded.

90. 90
    Marshall BJ, Warren JR. Unidentified curved bacilli in the stomach of patients with gastritis and peptic ulceration.Lancet · 1984 · 1(8390):1311-5doi:10.1016/s0140-6736(84)91816-6 · PMID 6145023

    Curved bacilli found in antral biopsies from 58 of 100 consecutive patients and present in almost all of those with active chronic gastritis, duodenal ulcer or gastric ulcer. Cited for the discovery and its date.

91. 91
    Lanas A, Chan FKL. Peptic ulcer disease.Lancet · 2017 · 390(10094):613-624doi:10.1016/S0140-6736(16)32404-7 · PMID 28242110

    Seminar review cited only for the established causes of peptic ulcer: Helicobacter pylori infection and anti-inflammatory drugs, with ulcers unrelated to either now a recognized and growing third group.

92. 92
    Bonaccio M, Di Castelnuovo A, Costanzo S, Ruggiero E, De Curtis A, Persichillo M, et al. Chili pepper consumption and mortality in Italian adults.J Am Coll Cardiol · 2019 · 74(25):3139-3149doi:10.1016/j.jacc.2019.09.068 · PMID 31856971

    Moli-sani cohort, 22,811 adults, 1,236 deaths over a median 8.2 years: hazard ratio 0.77 for all-cause and 0.66 for cardiovascular death with intake more than four times weekly. Observational.

93. 93
    Yang L, Sun J, Zhao M, Xi B. Chili pepper intake and all-cause and disease-specific mortality.Int J Vitam Nutr Res · 2022 (epub) · 93(4):378-384doi:10.1024/0300-9831/a000746 · PMID 35038885

    Meta-analysis of four cohorts and 564,748 people: hazard ratios 0.87 all-cause, 0.89 cardiovascular, 0.92 cancer, with no heterogeneity. The authors write that chili 'could significantly reduce the risk', which the observational design cannot support.

94. 94
    Ofori-Asenso R, Mohsenpour MA, Nouri M, Faghih S, Liew D, Mazidi M. Association of spicy chilli food consumption with cardiovascular and all-cause mortality: a meta-analysis of prospective cohort studies.Angiology · 2021 · 72(7):625-632doi:10.1177/0003319721995666 · PMID 33657876

    The same four cohorts from the United States, China, Italy and Iran, 564,748 adults, median 9.7 years: 12 percent lower all-cause mortality, lower cardiac death, no significant effect on cerebrovascular death.

95. 95
    Kaur M, Verma BR, Zhou L, Lak HM, Kaur S, Sammour YM, Kapadia SR, Grimm RA, Griffin BP, Xu B. Association of pepper intake with all-cause and specific cause mortality - a systematic review and meta-analysis.Am J Prev Cardiol · 2021 · 9:100301doi:10.1016/j.ajpc.2021.100301 · PMID 34977833

    Four studies again: all-cause 0.87, cardiovascular 0.83, cancer 0.92. The authors note that the mode and amount of consumption varied so much across studies that no intake recommendation can be derived.

96. 96
    You D, Sun D, Zhao Z, Song M, Pan L, Wu Y, et al. Spicy food consumption and risk of vascular disease: evidence from a large-scale Chinese prospective cohort of 0.5 million people.Chin Med J (Engl) · 2025 · 138(14):1696-1704 (epub 19 Jul 2024)doi:10.1097/CM9.0000000000003177 · PMID 39030074

    The same China Kadoorie Biobank cohort, 486,335 people followed a median 12.1 years, with new vascular disease rather than death as the outcome: hazard ratios 0.95, 0.96 and 0.97 across increasing frequency. The association almost disappears, which is worth knowing before the mortality figures are read as large.

97. 97
    López-Carrillo L, Hernández Avila M, Dubrow R. Chili pepper consumption and gastric cancer in Mexico: a case-control study.Am J Epidemiol · 1994 · 139(3):263-71doi:10.1093/oxfordjournals.aje.a116993 · PMID 8116601

    220 incident cases and 752 population controls in Mexico City: odds ratio 5.49 for consumers, 17.11 for high self-rated consumers, but no significant trend when intake was counted as frequency per day, which the authors reported.

98. 98
    Luo L, Yan J, Wang X, Sun Z. The correlation between chili pepper consumption and gastric cancer risk: a meta-analysis.Asia Pac J Clin Nutr · 2021 · 30(1):130-139doi:10.6133/apjcn.202103_30(1).0016 · PMID 33787049

    Sixteen studies, 8,337 cases: pooled odds ratio 1.51 overall, 2.05 in Mexico, 1.92 in Asia, 2.03 in Colombia with an interval crossing one, and 0.48 in other countries. The regional split is the main finding.

99. 99
    Du Y, Lv Y, Zha W, Hong X, Luo Q. Chili consumption and risk of gastric cancer: a meta-analysis.Nutr Cancer · 2021 · 73(1):45-54doi:10.1080/01635581.2020.1733625 · PMID 32241189

    Thirteen studies, 3,095 cases and 4,761 controls: odds ratio 1.96 for moderate-to-high intake, 2.28 for high intake, 0.72 for moderate intake alone with the interval crossing one, and a non-linear relationship with capsaicin.

100. 100
     Xie P, Xia W, Lowe S, Zhou Z, Ding P, Cheng C, et al. High spicy food intake may increase the risk of esophageal cancer: a meta-analysis and systematic review.Nutr Res · 2022 · 107:139-151doi:10.1016/j.nutres.2022.09.006 · PMID 36215887

     Twenty-five studies and 7,810 esophageal cancer cases: odds ratio 1.70 for the highest against the lowest intake, with significant heterogeneity, the association confined to Chinese studies, and one prospective study pointing the other way.

101. 101
     Pan D, Su M, Wang Y, Xu D, Han J, Wang X, et al. Esophageal squamous cell carcinoma prevention in high-risk, resource-limited rural China: dysplasia screening and modifiable risk factors in a 14-year follow-up study.Cancer Epidemiol · 2026 · 105:103248doi:10.1016/j.canep.2026.103248 · PMID 42858638

     Fourteen-year follow-up of 11,397 adults in a high-risk rural area, with 189 incident esophageal squamous cell carcinomas: very spicy diets were among the exposures significantly associated with higher risk, alongside male sex, age, lower body mass index, family history and shallow well or surface drinking water. Prospective, but one region and a self-reported diet.

102. 102
     Irandoost P, Lotfi Yagin N, Namazi N, Keshtkar A, Farsi F, Mesri Alamdari N, Vafa M. The effect of capsaicinoids or capsinoids in red pepper on thermogenesis in healthy adults: a systematic review and meta-analysis.Phytother Res · 2021 · 35(3):1358-1377doi:10.1002/ptr.6897 · PMID 33063385

     Thirteen placebo-controlled trials: resting metabolic rate rose 33.99 kilocalories a day (95 percent confidence interval 15.95 to 52.03) and respiratory quotient fell 0.01. A real but very small measured effect in healthy adults.

103. 103
     Zsiborás C, Mátics R, Hegyi P, Balaskó M, Pétervári E, Szabó I, et al. Capsaicin and capsiate could be appropriate agents for treatment of obesity: a meta-analysis of human studies.Crit Rev Food Sci Nutr · 2018 · 58(9):1419-1427doi:10.1080/10408398.2016.1262324 · PMID 28001433

     Nine trials: energy expenditure rose 58.56 kilocalories a day overall, with no effect below a mean body mass index of 25 and 69.79 kilocalories a day above it. The title overstates what a 59 kilocalorie difference can do.

104. 104
     Zhang W, Zhang Q, Wang L, Zhou Q, Wang P, Qing Y, Sun C. The effects of capsaicin intake on weight loss among overweight and obese subjects: a systematic review and meta-analysis of randomised controlled trials.Br J Nutr · 2023 · 130(9):1645-1656doi:10.1017/S0007114523000697 · PMID 36938807

     Fifteen randomized trials, 762 participants: body mass index -0.25, weight -0.51 kg, waist -1.12 cm. The authors describe the effects as rather modest, which matches the numbers.

105. 105
     Ludy MJ, Moore GE, Mattes RD, Westerterp-Plantenga MS. Attenuation of adaptive thermogenesis by a culinary dose of red pepper during 24-hour negative energy balance.Nutr Rev · 2026 · 84(Suppl 1):3-24doi:10.1093/nutrit/nuaf300 · PMID 42186269

     Updated meta-analysis of 24 randomized studies published through 2024: the effect on energy expenditure did not reach statistical significance in single-meal studies, in long-term studies, or overall during negative energy balance, while respiratory quotient fell consistently, indicating more fat burned. Published in a journal supplement, and its own tables mark several of the pooled trials as funded by the McCormick Science Institute, a spice industry body.

106. 106
     Lazzeri M, Spinelli M, Zanollo A, Turini D. Intravesical vanilloids and neurogenic incontinence: ten years experience.Urol Int · 2004 · 72(2):145-9doi:10.1159/000075969 · PMID 14963356

     Fifty-four patients given capsaicin from 1992 to 2001: 53.7 percent improved at three months but only seven of those 29 were still on treatment by the end; resiniferatoxin fared better at 73 percent. Single-center retrospective experience.

107. 107
     Kim JH, Rivas DA, Shenot PJ, Green B, Kennelly M, Erickson JR, O'Leary M, Yoshimura N, Chancellor MB. Intravesical resiniferatoxin for refractory detrusor hyperreflexia: a multicenter, blinded, randomized, placebo-controlled trial.J Spinal Cord Med · 2003 · 26(4):358-63doi:10.1080/10790268.2003.11753706 · PMID 14992337

     Thirty-six patients in a dose-escalation design: bladder capacity rose 53 and 48 percent at three weeks in the two highest dose groups and incontinence episodes fell by about half, but with four patients per group nothing reached statistical significance.

108. 108
     Giannantoni A, Di Stasi SM, Stephen RL, Bini V, Costantini E, Porena M. Intravesical resiniferatoxin versus botulinum-A toxin injections for neurogenic detrusor overactivity: a prospective randomized study.J Urol · 2004 · 172(1):240-3doi:10.1097/01.ju.0000132152.53532.5d · PMID 15201783

     Twenty-five spinal-cord-injured patients: both treatments helped, and botulinum toxin was significantly better on incontinence, first uninhibited contraction, capacity and contraction pressure at 6, 12 and 18 months.

109. 109
     Obeidat AM, Donner A, Miller RE. An update on targets for treating osteoarthritis pain: NGF and TRPV1.Curr Treatm Opt Rheumatol · 2020 · 6(3):129-145doi:10.1007/s40674-020-00146-x · PMID 34178580

     Review noting the United States Food and Drug Administration fast-track designation for CNTX-4975 and the burning sensation as the common adverse event of TRPV1 agonists.

110. 110
     Iadarola MJ, Sapio MR, Nahama A, Mannes AJ. Intraarticular resiniferatoxin, a potent TRPV1 agonist, for treatment of osteoarthritic pain.Pain Manag · 2025 · 15(10):659-670doi:10.1080/17581869.2025.2535271 · PMID 40776673

     Review stating that the phase 1 human results for intraarticular resiniferatoxin have so far been reported only in abstract form. One author is affiliated with the company developing the drug.

111. 111
     Mobasheri A, Rannou F, Ivanavicius S, Conaghan PG. Targeting the TRPV1 pain pathway in osteoarthritis of the knee.Expert Opin Ther Targets · 2024 · 28(10):843-856doi:10.1080/14728222.2024.2416961 · PMID 39450875

     States that antagonist development has been limited by hyperthermia and thermal hypesthesia while agonist development has progressed further. One author is an employee of Grünenthal.

112. 112
     Mannes AJ, Heiss JD, Berger A, Alewine CC, Butman JA, Hughes MS, Rabbee N, Hayes C, Williams TS, Sapio MR, Iadarola MJ. Treatment of intractable cancer pain with resiniferatoxin - an interim study.NEJM Evid · 2025 · 4(6):EVIDoa2400423doi:10.1056/EVIDoa2400423 · PMID 40423401

     First-in-human, open-label phase 1 interim analysis of a single intrathecal dose in 19 patients with intractable cancer pain: worst pain fell 38 percent and opioid use 57 percent by day 15, with at least one adverse event in every patient and nine deaths an average of 70 days later, which the authors judged consistent with advanced cancer. Uncontrolled and interim; funded by the intramural program of the National Institutes of Health and others.

113. 113
     Shafer SL, Teichman SL, Gottlieb IJ, Singla N, Minkowitz HS, Leiman D, Vaughn B, Donovan JF. Safety and efficacy of vocacapsaicin for management of postsurgical pain: a randomized clinical trial.Anesthesiology · 2024 · 141(2):250-261doi:10.1097/ALN.0000000000005027 · PMID 38662910

     147 bunionectomy patients: the highest concentration of this capsaicin prodrug cut pain at rest by 33 percent through 96 hours, left 26 against 5 percent opioid-free, and halved opioid use. Designed and reported with the developing company.

114. 114
     Chan TC, Vilke GM, Clausen J, Clark RF, Schmidt P, Snowden T, Neuman T. The effect of oleoresin capsicum "pepper" spray inhalation on respiratory function.J Forensic Sci · 2002 · 47(2):299-304PMID 11908598

     Randomized crossover in 35 healthy subjects, sitting or in prone maximal restraint: no abnormal spirometry, no low oxygen and no hypoventilation attributable to the spray. Healthy volunteers under controlled conditions; no DOI is indexed.

115. 115
     Steffee CH, Lantz PE, Flannagan LM, Thompson RL, Jason DR. Oleoresin capsicum (pepper) spray and "in-custody deaths".Am J Forensic Med Pathol · 1995 · 16(3):185-92doi:10.1097/00000433-199509000-00001 · PMID 7495257

     Two deaths temporally associated with pepper spray, presented to illustrate what an investigation must establish before calling the spray unrelated, contributory or causative. Two cases; no denominator.

116. 116
     Haas JS, Whipple RE, Grant PM, Andresen BD, Volpe AM, Pelkey GE. Chemical and elemental comparison of two formulations of oleoresin capsicum.Sci Justice · 1997 · 37(1):15-24doi:10.1016/S1355-0306(97)72136-1 · PMID 9022856

     Two licensed products differed considerably in organic and inorganic composition, which the authors said could produce inconsistency in weapon effectiveness. A chemistry study of two products, not a survey of the market.

117. 117
     Kaplan O, Pasternak E, Test G, Kestenbom I, Tavor O. Pediatric tear gas poisoning in southern Israel: clinical characteristics and outcomes.Isr Med Assoc J · 2026 · 28(10):635-639PMID 42867095

     Eighty-four children exposed to civilian-grade chemical irritants, pepper spray and tear gas together and not separated by the study, 2016 to 2024: superficial punctate keratitis in 54.5 percent of those examined with fluorescein (21.5 percent of the whole group), mild self-limited respiratory and skin symptoms, 96.4 percent discharged. Retrospective, single center; no DOI is indexed.

118. 118
     Xie K, Qi Z, Chen Z, Zhang R, Liu L, Li W, Cao D, Xie D, Shen J. Immunometabolic and immune regulatory functions of capsaicin in cancer: mechanistic insights and emerging perspectives.Front Immunol · 2026 · 17:1806015doi:10.3389/fimmu.2026.1806015 · PMID 42292433

     Review of capsaicin's reported effects on T cells, natural killer cells, macrophages and dendritic cells, and proposed combinations with chemotherapy. All preclinical; no human outcome data.

119. 119
     Perla V, Nadimi M, Reddy R, Hankins GR, Nimmakayala P, Harris RT, Valluri J, Sirbu C, Reddy UK. Effect of ghost pepper on cell proliferation, apoptosis, senescence and global proteomic profile in human renal adenocarcinoma cells.PLoS One · 2018 · 13(10):e0206183doi:10.1371/journal.pone.0206183 · PMID 30379886

     In vitro only: capsaicin at 400 micromolar left 36 percent of renal adenocarcinoma cells at 24 hours. Cited to show the concentrations such experiments require, which are far above any achievable human blood level.

120. 120
     Bode AM, Dong Z. The two faces of capsaicin.Cancer Res · 2011 · 71(8):2809-14doi:10.1158/0008-5472.CAN-10-3756 · PMID 21487045

     Review of the conflicting carcinogen-versus-chemopreventive evidence, and the authors' own mouse finding that chronic topical capsaicin increased skin carcinogenesis in the presence of a tumor promoter. Mouse data; not shown in people.

121. 121
     Deng R, Yu S, Ruan X, Liu H, Zong G, Cheng P, Tao R, Chen W, Wang A, Zhao Y, Wei Z, Lu Y. Capsaicin orchestrates metastasis in gastric cancer via modulating expression of TRPV1 channels and driving gut microbiota disorder.Cell Commun Signal · 2023 · 21(1):364doi:10.1186/s12964-023-01265-3 · PMID 38129926

     A high-capsaicin diet accelerated the spread of transplanted human gastric cancer cells in mice and zebrafish, an effect the authors linked partly to TRPV1 expression and partly to a shift in gut bacteria. Animal and cell work, and it points toward harm rather than benefit.

122. 122
     Nong F, Xing S. Capsaicin and cold exposure promote EMT-mediated premetastatic niche formation to facilitate colorectal cancer metastasis. [RETRACTED]J Cancer · 2024 · 15(2):356-369doi:10.7150/jca.83985 · PMID 38169517

     Retracted. Reported that capsaicin promoted colorectal cancer metastasis in a rat model. Cited only as an example of withdrawn work in this literature; its findings should not be used.

123. 123
     Lin S, Zhang J, Chen H, Chen K, Lai F, Luo J, et al. Involvement of endoplasmic reticulum stress in capsaicin-induced apoptosis of human pancreatic cancer cells. [RETRACTED]Evid Based Complement Alternat Med · 2013 · 2013:629750doi:10.1155/2013/629750 · PMID 23781265

     Retracted. Reported capsaicin-induced apoptosis in pancreatic cancer cells and prolonged survival in xenografted mice. Cited only as a retraction in this field.

124. 124
     Guo Y, Liu N, Liu K, Gao M. Capsaicin inhibits the migration and invasion via the AMPK/NF-κB signaling pathway in esophagus sequamous cell carcinoma by decreasing matrix metalloproteinase-9 expression. [RETRACTED]Biosci Rep · 2019 · 39(8)doi:10.1042/BSR20190819 · PMID 31324733

     Retracted. Reported that capsaicin inhibited migration and invasion of an esophageal cancer cell line. Cited only as a retraction, alongside the others, to show that withdrawn papers in this field point in several directions.

125. 125
     Parashar P, Tripathi CB, Arya M, Kanoujia J, Singh M, Yadav A, Saraf SA. A facile approach for fabricating CD44-targeted delivery of hyaluronic acid-functionalized PCL nanoparticles in urethane-induced lung cancer: Bcl-2, MMP-9, caspase-9, and BAX as potential markers. [RETRACTED]Drug Deliv Transl Res · 2019 · 9(1):37-52doi:10.1007/s13346-018-0575-8 · PMID 30178279

     Retracted. Reported that capsaicin-loaded nanoparticles reduced tumor volume and improved survival in chemically induced rat lung cancer. The fourth capsaicin-and-cancer retraction, and the only one of the four that reported benefit in a whole animal.

126. 126
     Überall MA, Sabatowski R, Lux MP, Heine M, Garcia Guerra L, Eerdekens M, Quandel T. Real-world 12-month outcomes of repeated high-concentration capsaicin patch in chemotherapy-induced peripheral neuropathy: results from the CASPAR study.Front Oncol · 2025 · 15:1711597doi:10.3389/fonc.2025.1711597 · PMID 41426310

     Retrospective analysis of 169 patients in a German pain registry: at least 30 percent pain relief in 20.0, 54.3, 76.0 and 97.7 percent of those who received one, two, three and four treatments. People who benefit are the ones who come back, so the gradient partly measures selection. Four of the seven authors are employees of Grünenthal, which markets the patch in Europe.

127. 127
     Saper JR, Klapper J, Mathew NT, Rapoport A, Phillips SB, Bernstein JE. Intranasal civamide for the treatment of episodic cluster headaches.Arch Neurol · 2002 · 59(6):990-4doi:10.1001/archneur.59.6.990 · PMID 12056936

     Twenty-eight patients randomized 2:1 to civamide or vehicle: headaches fell 55.5 against 25.9 percent during the first week after treatment, with the second and third weeks only approaching significance and no change in pain intensity. Nasal burning in 14 of 18. The authors called it modestly effective.

128. 128
     Pearson SM, Burish MJ, Shapiro RE, Yan Y, Schor LI. Effectiveness of oxygen and other acute treatments for cluster headache: results from the Cluster Headache Questionnaire, an international survey.Headache · 2019 · 59(2):235-249doi:10.1111/head.13473 · PMID 30632614

     1,604 respondents with cluster headache: 5 percent rated intranasal capsaicin completely or very effective against 54 percent for oxygen, though complications were minimal in 91 percent. A self-selected internet survey using non-validated questions.

129. 129
     Anand P, Privitera R, Donatien P, Misra VP, Woods DR. Capsaicin 8% patch treatment in non-freezing cold injury: evidence for pain relief and nerve regeneration.Front Neurol · 2021 · 12:722875doi:10.3389/fneur.2021.722875 · PMID 34489857

     Open-label study in 16 military personnel: modest falls in spontaneous and cold-evoked pain, and significantly increased intra-epidermal and regenerating nerve fibers on biopsy at three months. Uncontrolled and small.

130. 130
     Bakker WA, Eijsvogel P, Klaassen ES, Kim J, Chen R, Demitrack MA, Dahan A, Niesters M, Hijma HJ, Groeneveld GJ. Effects of selective sphingosine-1-phosphate receptor 1 agonist, TRV045, on evoked pain tests: an exploratory, four-way cross-over study in healthy volunteers.Eur J Pain · 2026 · 30(6):e70314doi:10.1002/ejp.70314 · PMID 42310852

     Twenty-five healthy volunteers: the drug missed its primary endpoint on ultraviolet-inflamed skin but significantly reduced the secondary area of capsaicin-induced pain at 150 and 300 mg. Cited as an example of capsaicin being used as a measuring instrument; three authors are employees of the sponsor.

131. 131
     Potter S, Banjanovic E, Abunahla N, Shah J, Srbely J. Topical capsaicin produces secondary mechanical hyperalgesia without a group-level increase in tonic heat pain summation in healthy adults.J Neurophysiol · 2026 · 136(4):1544-1556doi:10.1152/jn.00548.2025 · PMID 42789982

     Twenty-six healthy adults in a masked crossover: 0.075 percent capsaicin produced significant secondary mechanical hyperalgesia but no group-level increase in temporal summation of tonic heat pain. Defines a limit of the capsaicin sensitization model.

132. 132
     Dicpinigaitis PV. Short- and long-term reproducibility of capsaicin cough challenge testing.Pulm Pharmacol Ther · 2003 · 16(1):61-5doi:10.1016/S1094-5539(02)00149-9 · PMID 12657501

     Two groups of 40 subjects retested at 14 days and at a mean of 16.7 months: 90 to 100 percent of repeat challenges fell within two doubling concentrations, with C5 the more stable endpoint.

133. 133
     Dicpinigaitis PV, Rhoton WA, Bhat R, Negassa A. Investigation of the urge-to-cough sensation in healthy volunteers.Respirology · 2012 · 17(2):337-41doi:10.1111/j.1440-1843.2011.02094.x · PMID 22026384

     One hundred healthy non-smokers: all coughed to capsaicin, cough reflex sensitivity was greater in women, and the urge-to-cough threshold was separately and reproducibly measurable.