Substance P

In brief

What substance P is: a peptide, a gene, and a receptor

Substance P is a peptide, a short protein, eleven amino acids long, with the sequence arginine-proline-lysine-proline-glutamine-glutamine-phenylalanine-phenylalanine-glycine-leucine-methionine and a chemical cap, an amide, on its tail that the active molecule requires ¹. It is the best-studied member of the tachykinins, a family of signaling peptides that all share the last five residues, phenylalanine-X-glycine-leucine-methionine-amide, and all act as fast messengers in the nervous system and the gut ².

In mammals the peptide is cut from a larger precursor encoded by a single gene, TAC1, whose older names are preprotachykinin-1 and PPT-A. The Nakanishi laboratory showed in the early 1980s that this one gene is read out in more than one way by alternative splicing, the cell's trick of stitching a gene's message together in more than one arrangement, so that the same stretch of DNA, the molecule that carries the genetic code, yields either substance P alone or substance P together with a related peptide, neurokinin A, and that the proportion differs between tissues ^3,4.

Substance P acts mainly on one of three tachykinin receptors, called neurokinin-1, or NK1, which the same laboratory cloned from rat in 1989 and found to be a G-protein-coupled receptor, a protein that crosses the cell membrane seven times and passes its signal inward through an attached G protein, built from 407 amino acids ⁵. Neurokinin A prefers the NK2 receptor and a third family member, neurokinin B, prefers NK3; substance P can act at all three but binds NK1 most tightly ². How the peptide sits in that receptor was resolved only recently: nuclear magnetic resonance measurements on the human receptor in detergent in 2025 showed the tail half of substance P anchored rigidly in the binding pocket while its first five amino acids stayed flexible and exposed to solvent ³⁰.

The name is older than any of this. In 1931 Ulf von Euler and John Gaddum, working in London, found in extracts of horse brain and intestine a substance that lowered a rabbit's blood pressure and made its gut contract, and that was neither acetylcholine, the messenger nerves use to drive muscle, nor histamine, the chemical mast cells release in allergy ⁶. Gaddum and Schild returned to these depressor substances of intestine three years later ³¹; where the letter P came from is not recorded in either paper's indexed entry ^6,31. It took four decades to say what the substance was: in 1970 Chang and Leeman purified from the hypothalamus of the cow, the hormone-control region at the base of the brain, a peptide that made rats salivate and identified it as substance P, and in 1971, with Niall, they published its amino-acid sequence ^1,32.

Where the peptide is made matters for everything that follows. Antibody staining placed substance P in a specific population of small-diameter primary sensory neurons, the thin nerve cells that carry pain and temperature, and in their endings in the dorsal horn, the outermost layers of the spinal cord where those nerves arrive; in the cat, cutting the dorsal roots made the staining in those layers fade over ten days, which tied the peptide to the sensory nerve rather than to the cord itself ^7,33. Otsuka and Konishi then showed, in isolated spinal cord from newborn rats, that stimulation releases substance P in a calcium-dependent way, as a transmitter should ⁸. But it is not a pain-only molecule even in its anatomy: the tachykinins and their receptors are distributed through the brain, the wall of the gut, the airway, the bladder and immune tissue, which is why blocking the receptor has effects far from the spinal cord ².

The whole history, including the reversals

The arc of substance P is three reversals stacked on one success. First it was localized to pain-sensing nerves and crowned the pain transmitter; then the drugs that should have proved it a painkiller did not work in people ¹⁰. Next it was made the target of a new kind of antidepressant; then that program died in phase 3, the large final trials run before approval ¹¹. Alongside both failures, the same receptor blocker turned out to stop vomiting, which remains the class's main use ¹². The one exception is recent and partial: elinzanetant, which blocks both NK1 and the related NK3 receptor, was approved in 2025 for menopausal hot flashes, an effect attributed mainly to its NK3 action ^38,39.

The groundwork was laid long before the drugs. Lembeck measured substance P in the dorsal roots of the spinal cord in 1953 and proposed it as the transmitter of sensory nerve impulses, the hypothesis the next half-century tested ¹⁶. Hökfelt and colleagues used antibodies in 1975 to show that substance P sits in a specific population of small sensory neurons and their endings in the dorsal horn of the spinal cord, the first anatomical home of the idea ^7,33. Otsuka and Konishi showed the peptide is released from spinal-cord tissue when nerves are stimulated, in a calcium-dependent way that befits a transmitter ⁸. The rat receptor was cloned in 1989, defining the drugs' molecular target ⁵, and in 1991 Pfizer chemists reported CP-96,345, the first potent and selective nonpeptide blocker, which made oral drugs possible ⁴⁰.

The clinical history divides fairly neatly by decade. The 1990s belonged to the chemists and to the ferret: the first nonpeptide blocker in 1991 ⁴⁰, proof in 1994 that the antiemetic effect runs through NK1 ⁴¹, proof in 1996 that the drug has to enter the brain ³⁷, and the first human antiemetic trial in 1999 ¹⁷. The 2000s were the decade of the failures: the review explaining why the pain trials had not worked appeared in 2000 ¹⁰, and the five-trial depression program read out negative in 2006 ¹¹. The 2010s widened the antiemetic class and then pruned it, with two new drugs approved in 2014-2015 ⁴² and the intravenous form of one of them withdrawn in 2018 ^43,44. The 2020s have been spent testing the class outside vomiting, in itch, cough, gastroparesis, motion sickness and menopausal hot flashes, with one approval for motion-induced vomiting and one, for a dual NK1-NK3 blocker, for hot flashes ^15,38.

Two things are worth noticing about the shape of this history. The first is that the reversals were not quiet, and were mostly published by the people with the most to lose: a Merck pharmacologist named the analgesic failure in 2000 ¹⁰, Merck's own trialists reported the five negative depression trials in 2006 ¹¹, and the National Institutes of Health group that had reported the alcohol-craving signal in 2008 reported its collapse in 2014 ^45,46. The second is that the useful discovery was not a consolation prize found after the failures. The ferret antiemetic work ran from 1994 to 2000 and the first human antiemetic trial was published in 1999, in parallel with the depression program and years before it read out ^11,17,41,47.

Neurogenic inflammation, and a receptor that is not NK1

Nerves usually carry signals inward, from the body to the spinal cord. But a sensory nerve can also fire outward, back toward the tissue it came from. In rats in 1967, Jancsó and colleagues showed that this outward firing makes the small vessels widen and leak plasma into the tissue, an inflammation made by the nerve itself rather than by an injury or an infection, and that cutting the nerve or pretreating with capsaicin abolishes it ²³. The mediator was named later: Lembeck and Holzer proposed substance P in 1979 ³⁴, and in 1998 mice lacking the TAC1 gene, and therefore both substance P and neurokinin A, were found to have almost no neurogenic inflammation ¹⁹. That is neurogenic inflammation: the redness and swelling a nerve can create on its own ^19,23.

For decades this was told as a clean substance P story: the peptide leaves the nerve ending, binds NK1 receptors on vessels and mast cells, and inflammation follows ². In 2019 Green and colleagues complicated it. Working in mice and in human mast cells, they showed that substance P triggers mast-cell degranulation, the release of histamine and other stored chemicals, and much inflammatory hyperalgesia through a different receptor altogether, the Mas-related G-protein-coupled receptor B2 (MrgprB2) in mice and its human counterpart MRGPRX2, and that these effects did not need the NK1 receptor at all ²⁴.

That finding matters for this page twice over. Part of what substance P does in the skin bypasses the receptor that every drug on this page targets, and the same mast-cell receptor is needed to bring immune cells to the site of an injury ²⁴. It may also be one reason the NK1 blockers disappointed against inflammatory pain, but that is an inference rather than a result: the 2019 study did not test it, and the pain trials were run and reported long before this receptor was known ^10,24.

What the peptide does in the skin also explains why capsaicin became entangled with substance P. Capsaicin was the tool that abolished neurogenic inflammation in 1967, before anyone knew which mediator it was depleting ²³, and the same drug was found ten years later to empty substance P from sensory neurons ²¹. For decades the two findings were read as one mechanism. The modern reading separates them and leaves the nerve fiber, not the peptide, as the thing capsaicin acts on ²².

The reversal at the center: not the pain transmitter after all

The pain hypothesis was not foolish; it was well supported in animals. Lembeck had found substance P in the dorsal roots of the spinal cord as early as 1953 and proposed it as the sensory transmitter ¹⁶, and Hökfelt's anatomy put it in exactly the small nerves that carry noxious, that is tissue-threatening, signals ⁷. Mantyh and colleagues, in 1997, used a toxin tethered to substance P to destroy the spinal neurons that carry its receptor in rats; the animals still felt mild pain, but their hyperalgesia, an exaggerated response to painful stimuli, and their responses to intense pain fell sharply ⁴⁸. Mice lacking the TAC1 gene, and so lacking both substance P and neurokinin A, had significantly reduced responses to moderate and intense pain, and mice bred without the receptor lost spinal wind-up, the spinal cord's amplification of repeated signals, while still developing hyperalgesia ^19,20. Read carefully, even these results said substance P scales the intensity of pain and drives wind-up, not the baseline message, which glutamate is thought to carry ^19,20.

Then the drugs met people. Dionne and colleagues at the US National Institutes of Health gave CP-99,994, a laboratory code name for an early NK1 antagonist, to 78 people having wisdom teeth removed. In the first group of 60 it reduced pain significantly only at 90 minutes, while ibuprofen worked from 90 to 240 minutes; in a second group of 18, dosed closer to surgery, it reduced pain at 60, 90 and 120 minutes, still less than ibuprofen ⁹. A small but replicated analgesic, that is pain-relieving, effect in one kind of acute pain was the best the class ever showed. Across other pain conditions the antagonists failed, and in 2000 Raymond Hill, a Merck pharmacologist, set the problem out in a review whose title asked why NK1 antagonists are not analgesic in humans; his answer was that they block sensitized responses enough to register in animal tests but not enough to relieve clinical pain in people ¹⁰. Eli Lilly's antagonist lanepitant failed in migraine as well, at three doses as an acute treatment and as a daily preventive ^63,64.

Part of the species gap is concrete. In radioligand binding, two human-type NK1 antagonists bound ferret and cloned human receptors at concentrations well below one nanomolar but rodent receptors only at 17 to 64 nanomolar, that is at concentrations tens of times higher, so rodent experiments with these drugs were testing a receptor unlike ours ³⁷. That is a measured difference in pharmacology, not a demonstrated explanation; whether it contributed to the analgesic failure is not established by these sources ³⁷.

A newer explanation comes from inside the cell. When substance P activates NK1, the receptor is pulled into small internal compartments called endosomes and goes on signaling there; in rats and mice, antagonists anchored to a lipid so that they reach those compartments relieved pain for longer than ordinary antagonists acting at the cell surface ⁵². In 2023 the same group showed, in mice carrying the human receptor, that aprepitant interrupts the internal signal only briefly, while redesigned compounds that linger in acidic endosomes gave more potent and longer-lasting relief ⁵³. This is animal and cell evidence; no endosome-targeted NK1 drug has been tested in people ^52,53.

The honest reading is that substance P is a modulator of how intensely pain and sensitization are felt, not the required carrier of the pain message ^10,19.

The depression program that died in phase 3

Because substance P sits in brain regions that coordinate stress responses, Merck reasoned that blocking it might treat depression. In 1998 Kramer and colleagues published in Science that substance P antagonists suppressed isolation-induced distress calls in guinea pigs, as clinically used antidepressant and anti-anxiety drugs do, and that the NK1 antagonist MK-869, later named aprepitant, produced antidepressant effects that looked robust in a placebo-controlled trial in patients with moderate to severe major depression; in preclinical studies, they reported, these drugs did not act on the monoamine systems, the serotonin and noradrenaline signaling that older antidepressants work through ⁴⁹.

The target engagement was real. Bergström and colleagues used positron emission tomography (PET), a scan that tracks a radioactive tracer binding to receptors in the living brain, in healthy volunteers to show that aprepitant at 100 mg a day or more occupied 90 percent or more of brain NK1 receptors, with occupancy closely tracking the drug's concentration in blood ⁶⁵. A PET study run alongside the later phase 3 program confirmed continuously high receptor blockade at the doses those trials used, so a negative result could not be waved away as the drug failing to reach its target ^11,65.

It was negative anyway. Keller and colleagues reported in 2006 five eight-week phase 3 trials, around 150 patients per treatment group, in which neither dose of aprepitant beat placebo on the standard depression rating scale, while the comparator paroxetine, a standard antidepressant of the selective serotonin reuptake inhibitor class, beat placebo in every trial that included it; the authors concluded plainly that NK1 antagonism as an antidepressant mechanism was not supported ¹¹.

A cousin of that stress-system idea lived on for a while. In 2008 George and colleagues reported that an NK1 antagonist blunted alcohol craving, cortisol responses and brain-imaging responses in detoxified inpatients, a signal on surrogate markers rather than a licensed treatment ⁴⁵. It did not hold up. In 2014 the same National Institutes of Health group randomized 53 inpatients with both alcohol dependence and post-traumatic stress disorder to aprepitant, at a dose reported to occupy more than 90 percent of brain NK1 receptors, or to placebo for four weeks; the drug had no effect on symptoms, craving, or responses to stress and alcohol cues, and only one brain-imaging response changed ⁴⁶.

Where it succeeded: chemotherapy-induced vomiting

The success was built in the ferret, an animal that, unlike the rat or the mouse, can vomit. Tattersall and colleagues at Merck showed in 1994 that the NK1 antagonist CP-99,994 blocked retching and vomiting induced by apomorphine, a drug that triggers vomiting by stimulating dopamine receptors, and did so stereoselectively: the mirror-image molecule, with a thousand-fold lower affinity for the receptor, did nothing, proving the effect ran through NK1 ⁴¹. In 1996 they showed the antiemetic action required the brain: of two equally potent antagonists, only the brain-penetrant one stopped vomiting caused by cisplatin, a platinum chemotherapy drug, when given into the blood, while the one that cannot cross into the brain worked only when injected near the nucleus of the solitary tract or into the fluid space at the base of the brain ³⁷. In 2000 they showed that MK-0869, the laboratory code for what became aprepitant, blocked both the acute and the delayed vomiting that cisplatin causes, and stopped further vomiting in three of four ferrets even when dosing began 24 hours after cisplatin, once the acute phase was established; its water-soluble prodrug, an inactive form the body converts into the drug, was tested against the four-hour acute response ⁴⁷. The chemistry of that prodrug, the basis of intravenous fosaprepitant, was published the same year ⁶⁶.

Then came the people. Navari and colleagues reported in the New England Journal of Medicine in 1999 that, in 159 patients receiving cisplatin for the first time, adding the NK1 antagonist to granisetron, a serotonin blocker, and dexamethasone, a steroid, raised freedom from vomiting in the delayed phase, days 2 to 5, from 33 percent to 78 to 82 percent ¹⁷. The confirmatory phase 3 trial in 2003 showed complete response, meaning no vomiting and no rescue medicine, over days 1 to 5 in 72.7 percent of patients given aprepitant against 52.3 percent on standard therapy, and the US Food and Drug Administration approved aprepitant on 26 March 2003 as the first NK1 antiemetic ^12,14.

A class followed. Fosaprepitant, an intravenous prodrug of aprepitant, matched a three-day course of the oral drug in a single 150 mg dose among 2,322 randomized patients ^66,67. Rolapitant, long-acting, raised delayed-phase complete response from 60 to 71 percent in two pooled phase 3 trials ⁵⁰. Netupitant, combined with the serotonin blocker palonosetron as a single pill, raised overall complete response to 89.6 percent against 76.5 percent for palonosetron alone in a 694-patient dose-ranging study its authors called pivotal ⁵¹; the netupitant-palonosetron combination and rolapitant were both approved in the United States in 2014-2015 ⁴². Antiemetic guidelines now place an NK1 antagonist in the standard regimen for the chemotherapy most likely to cause vomiting, such as cisplatin ^57,58. The class also prevents postoperative vomiting: in two trials after open abdominal surgery aprepitant beat ondansetron, a serotonin (5-HT3) receptor blocker, for freedom from vomiting in the first 24 hours (90 to 95 against 74 percent, and 84 to 86 against 71 percent), but in the first trial it did no better for nausea, for rescue medicine or for complete response ¹³, and in the second its nausea advantage was modest, a lower distribution of peak nausea scores ⁶⁸.

Not every addition lasted. After postmarketing reports of anaphylaxis, a severe allergic reaction, the US Food and Drug Administration wrote to prescribers in January 2018 and the intravenous form of rolapitant was removed from US distribution; at one academic center infusion reactions had occurred in 8.7 percent of patients against 2.8 percent in the registration study ^43,44. Intravenous fosaprepitant causes infusion-site reactions attributed to an ingredient of its solution, and the class carries drug interactions that have to be managed ⁴⁴. The NK1 antagonist now shares its place with olanzapine, an antipsychotic that also prevents vomiting: a 2025 phase 3 trial describes the standard three-drug regimen as containing either an NK1 antagonist or olanzapine ⁶⁹. The indication is still widening at the edges. In the MyRisk trial, reported in 2025 and part-sponsored by the maker of netupitant-palonosetron, 401 patients at high personal risk who were receiving less emetogenic chemotherapy did better on an NK1-containing regimen than on the usual two drugs (complete response odds ratio 1.67, 95 percent confidence interval 1.12 to 2.49) ⁷⁰.

The class is still being tested where it is already standard, and the newest trials repeat the page's central pattern. In children and adolescents receiving the most emetogenic chemotherapy, a 2026 trial of 310 patients found that olanzapine could replace the steroid in a three-drug regimen built around fosaprepitant without losing control of vomiting, at the cost of much more drowsiness ⁷¹; a separate trial in 279 children could not show that a single intravenous dose of fosaprepitant was no worse than three days of oral aprepitant, the difference in acute-phase complete response being -6.1 percent with a confidence bound beyond the prespecified margin ⁷². After surgery the picture is the same: in 233 adults at raised risk after video-assisted lung resection, fosaprepitant did not significantly reduce nausea and vomiting together at 24 hours, but it did reduce vomiting at 24 hours, 8.6 against 21.4 percent, and nausea or vomiting at 48 hours, 10.3 against 20.5 percent, compared with ondansetron ⁷³. Vomiting yields to these drugs; nausea yields much less.

The area postrema, the solitary nucleus, and why NK1 blockade stops delayed vomiting

The place where this works is the back of the brainstem. The area postrema, a small patch of tissue deliberately left outside the blood-brain barrier, samples the blood for substances that provoke vomiting; in anesthetized dogs, about half of the area postrema neurons tested were excited by substance P, which was one of thirteen excitatory substances in that study, nearly all of them emetic ³⁵. The area postrema hands its signals to the neighboring nucleus of the solitary tract, the brainstem's visceral sensory relay, which also receives the vagus nerve from the gut and feeds a loose network of medullary neurons, a central pattern generator, that coordinates the act of vomiting ³⁶. In ferrets, an NK1 antagonist that cannot enter the brain was inactive given into the blood but still stopped cisplatin vomiting when injected near the nucleus of the solitary tract or into the fluid space at the base of the brain, which placed the antiemetic site in the brainstem ³⁷. Reviews put the drugs' main action there and in that ventral brainstem circuit, while the serotonin blockers act mainly on the gut endings of the vagus nerve ^36,74. Because the NK1 blockers act downstream of the inputs, they reduce vomiting whatever sets it off, including motion ⁷⁴.

Chemotherapy vomiting comes in two waves with two chemistries, and that is the key to the drugs. Cubeddu and colleagues showed in 1990, in 28 patients, that the urinary breakdown product of serotonin rises two to six hours after cisplatin in step with the episodes of vomiting, proposed that this serotonin comes from the gut lining's enterochromaffin cells, the hormone-releasing cells that store most of the body's serotonin, and found that the serotonin (5-HT3) receptor blocker ondansetron controls the acute phase, the first day ⁷⁵. Hesketh and colleagues then compared the time course of the two drug classes in pooled phase 2 data and found that serotonin drives the first 8 to 12 hours, after which substance P acting at NK1 receptors becomes the dominant mediator ²⁵. That is why an NK1 antagonist, and not a serotonin blocker, controls the delayed phase, and why the two are given together ^12,25. Where each drug acts explains the split: the serotonin blockers work on the vagal endings in the gut that drive the first day, while the NK1 blockers act in the brainstem itself ^36,74.

The same anatomy explains a limitation that runs through the rest of this page. Vomiting is a brainstem reflex, and the NK1 blockers sit in its final common pathway. Nausea, the conscious feeling, requires the brainstem to pass its information up to the cerebral hemispheres, and a 2023 review argues that these drugs reach those higher pathways poorly even at receptor occupancies approaching 100 percent, and that their anti-vomiting action depends on the vomiting pathway already being switched on ⁷⁴. That is why a drug in this class can nearly abolish vomiting and leave nausea much less changed ^74,76.

This same patch of brainstem is where a different sickness hormone acts, which is one reason substance P lost its claim on pregnancy sickness. GDF15, made by the fetus and the placenta, acts on the brainstem to produce the nausea and vomiting of pregnancy ⁵⁶, and the area postrema's business is exactly to sample the blood for such signals and pass them inward to the nucleus of the solitary tract ^35,36. Several unrelated chemical messengers converge on the same few millimeters of tissue, and a drug that blocks one of them does not block the others, which is both why NK1 antagonists work against so many triggers of vomiting and why they are not a universal antiemetic ^36,74.

Capsaicin, the depletion of substance P, and the correction

Capsaicin, the heat of chili peppers, was woven into the substance P story early. In 1978 Jessell, Iversen and Cuello reported capsaicin-induced depletion of substance P from sensory neurons, and the natural reading was that capsaicin relieves pain by emptying the nerve of its pain peptide ²¹. In 1999 Nolano and colleagues strengthened the picture in people: repeated topical capsaicin caused a loss of epidermal nerve fibers that tracked the loss of pain sensation, with both returning over weeks after the drug was stopped ⁷⁷.

The mechanism turned out to be about the nerve fiber, not the peptide. In 1997 Caterina, Julius and colleagues cloned the capsaicin receptor, then called VR1 and now TRPV1 (transient receptor potential vanilloid 1), and showed it is a channel in the nerve membrane opened by both capsaicin and noxious heat ⁷⁸. By 2011 Anand and Bley could state the correction cleanly: depletion of substance P is only a correlate of capsaicin treatment, with little or no causative role in the pain relief, which comes instead from defunctionalization of the nerve fibers, a temporary loss of the electrical charge the nerve ending needs in order to fire, an inability to carry nerve-growth factors, and a reversible retraction of the terminals, all driven through TRPV1 ²². The relief was never the emptying of substance P; it was the quieting of the whole fiber ²².

Capsaicin and its potent relatives also stop vomiting, and that connects back to the brainstem. In ferrets, dogs and musk shrews the TRPV1 agonist, that is a chemical that switches the receptor on, resiniferatoxin is a broad-spectrum antiemetic, and one proposed mechanism is an acute depletion of substance P at the nucleus of the solitary tract. The non-pungent TRPV1 agonist olvanil keeps a smaller antiemetic effect and still lowers body temperature, but without resiniferatoxin's marked rise in blood pressure ⁷⁹. This is the bridge to a modern clinical puzzle.

Capsaicin's clinical use now rests on the corrected mechanism rather than on substance P. The high-concentration 8 percent patch, applied once for 60 minutes, relieved neuropathic pain for up to 12 weeks in the trials that led to its approval in Europe and the United States, and the explanation offered is defunctionalization of nociceptor fibers through TRPV1 ²². In volunteers, repeated low-concentration cream cut the number of nerve fibers in the epidermis by about 80 percent, with both the fibers and normal sensation returning over about six weeks after the drug was stopped ⁷⁷. The depletion of substance P is still real and still measurable; it is simply a passenger ^21,22.

Cannabinoid hyperemesis and hyperemesis gravidarum: the true evidence strength

Cannabinoid hyperemesis syndrome is a pattern of cyclic, severe vomiting in heavy long-term cannabis users, and it has two threads that touch substance P. The first is capsaicin. Dezieck and colleagues reported a series of thirteen patients whose vomiting eased with topical capsaicin cream, and proposed, explicitly as a hypothesis in a retrospective series, that it works by impairing substance P signaling in the area postrema and the nucleus of the solitary tract through over-stimulation of TRPV1 ⁸⁰. The evidence has since improved a little. In a double-blind randomized pilot trial of 30 emergency patients, 0.1 percent capsaicin cream on the abdomen did not significantly reduce nausea at its 30-minute primary time point but did at 60 minutes (3.2 against 6.4 centimeters on a 10-centimeter scale), and 29.4 percent of the capsaicin group had complete relief against none on placebo ⁸¹. A 2024 systematic review of seven studies and 492 patients, two of them randomized, still judged the capsaicin evidence mixed and at high risk of bias ⁸².

The other treatments are better tested than substance P is. A randomized trial in 30 treated patients found that haloperidol, an antipsychotic that blocks dopamine receptors, beat ondansetron on a combined pain-and-nausea score at two hours, at the cost of two return visits for acute dystonia, a painful muscle spasm, both on the higher dose ⁸³. A systematic review of 17 studies found cannabis cessation the most reliable measure, with hot-water bathing, capsaicin, haloperidol, droperidol, benzodiazepines, propranolol and aprepitant among the reported treatments ⁸⁴. For the NK1 antagonist itself the evidence is case reports: aprepitant brought relief within an hour in two adolescents whose vomiting had resisted conventional drugs for 36 to 45 hours ⁸⁵. The syndrome is regarded as a subset of cyclic vomiting syndrome, repeated attacks of severe vomiting separated by well intervals, in which aprepitant is used to prevent attacks when other drugs have failed ⁸⁶. None of this tests whether substance P is the link; that remains a hypothesis ⁸⁰.

Hyperemesis gravidarum, the severe vomiting of pregnancy, is the harder test, and here the honest answer is that substance P has not been tested rather than that it has failed. The best-supported mechanism of nausea and vomiting of pregnancy, and of its severe form, is the hormone GDF15 (growth differentiation factor 15), made mostly by the fetus and placenta and sensed in the brainstem; Fejzo and colleagues showed in 2023 that both fetal GDF15 production and the mother's prior sensitivity to it contribute substantially to the risk, and their study did not examine substance P ⁵⁶. The indexed literature holds no trial, case series or blood measurement of substance P or of an NK1 antagonist in hyperemesis gravidarum; the only tachykinin proposal is a hypothesis review about two placental relatives, neurokinin B and endokinin, which reports no test ⁸⁷. Two things argue against expecting much from NK1 blockade here: the condition is dominated by nausea, which this class blunts far less than vomiting ^74,76, and the strongest causal evidence points to GDF15 ⁵⁶. Substance P's role in hyperemesis gravidarum is therefore untested, not disproven.

What would settle the substance P question in either condition is the experiment that settled it for chemotherapy: a randomized trial of an NK1 antagonist against placebo, with nausea and vomiting measured separately. For cannabinoid hyperemesis that trial does not exist, and the drug is used on the strength of two case reports and the class's record elsewhere ^85,86. For hyperemesis gravidarum it does not exist either, and the comparison that matters, against the GDF15 mechanism, has never been attempted ^56,87. Until then the capsaicin hypothesis and the substance P hypothesis in these syndromes are ideas with a plausible anatomy behind them, not findings ^56,80.

2018 to 2026: itch, cough, gastroparesis, motion sickness, hot flashes

Itch, or pruritus, has drawn the most new trials and produced the most mixed results. Serlopitant, an oral NK1 antagonist, reduced severe chronic itch at 1 and 5 mg daily in a phase 2 trial, and reduced the itch of prurigo nodularis, a skin disease of intensely itchy hard nodules, at weeks 4 and 8 in a second phase 2 trial of 128 patients ^88,89. Aprepitant relieved the itch caused by cancer drugs that block the epidermal growth factor receptor (EGFR) better than the antihistamine desloratadine, with a response in 53 against 24 percent of 130 patients at one week ⁹⁰. Against that, aprepitant did no better than placebo in 58 patients with antihistamine-refractory chronic nodular prurigo ⁵⁵, nor in Sézary syndrome, a lymphoma of the skin and blood ⁹¹, and tradipitant had what its sponsor's own report called mixed effects on itch in atopic dermatitis, or eczema ⁹². A 2025 meta-analysis of fifteen trials and 2,876 patients found the class does reduce chronic itch, but modestly: a four-point improvement in 33.9 percent of patients on drug against 24.7 percent on placebo ⁹³. No NK1 drug is approved for itch, and 2026 Swiss practice recommendations for chronic prurigo found the evidence too thin to make any recommendation about the class ⁹⁴.

Cough is a second frontier with an instructive ceiling. Substance P excites the vagus nerve, which carries sensation from the airway and the gut to the brainstem. Orvepitant reduced daytime cough frequency by 26 percent at four weeks in an open-label study of 13 patients with no placebo group, co-written by the drug's developers at NeRRe and Artemida ⁹⁵. In a randomized three-day crossover trial in 20 patients with lung cancer, aprepitant cut awake cough by 22 percent over placebo, and in the same paper, in isolated sections of human vagus nerve in the laboratory, aprepitant blocked 94 percent of substance P's electrical activation of the nerve, a rare direct human mechanism ⁹⁶. But a 2026 meta-analysis of five trials and 719 participants found that NK1 antagonists improve subjective, patient-reported cough while not significantly reducing objectively counted cough frequency, with more mild adverse events than placebo ⁶⁰.

In the stomach the record is a near miss preceded by an independent negative. A trial funded by the US National Institutes of Health had already tested aprepitant in 126 people with gastroparesis, a stomach that empties too slowly without any blockage; it missed its main goal, a reduction in nausea (46 against 40 percent improvement; relative risk 1.2, 95 percent confidence interval 0.8 to 1.7), although several secondary symptom scores improved ⁵⁴. Tradipitant, from Vanda Pharmaceuticals, improved nausea in a 152-patient phase 2 trial in gastroparesis ⁹⁷ but missed its primary endpoint in the phase 3 intention-to-treat population, the analysis of everyone as randomized whether or not they took the drug, turning positive only in post hoc analyses, chosen after the results were seen, that conditioned on drug blood levels ⁹⁸; and in 24 healthy volunteers it did not change how fast the stomach empties, which implies that any benefit is central rather than an effect on gastric movement ⁹⁹.

In motion sickness the drug worked. NK1 blockade against motion was not new in animals: in a 2007 field trial run by the drug's maker, 15 of 106 dogs given maropitant vomited on a car journey against 69 of 105 on placebo ¹⁰⁰. In people, two phase 3 trials, the large final trials before approval, were run on boat trips. In Motion Syros, 365 adults with a history of motion sickness on 34 trips in US coastal waters between November 2021 and April 2023 vomited 18.3 percent of the time on 170 mg of tradipitant, 19.5 percent on 85 mg and 44.3 percent on placebo ¹⁰¹; in Motion Serifos, with 316 adults, the figures were 10.4, 18.3 and 37.7 percent ¹⁰². Both trials were run and written by Vanda employees ¹⁰¹. Tradipitant received its first approval in the United States in December 2025, under the brand name Nereus, for preventing vomiting induced by motion in adults ^15,59. Two independent 2026 meta-analyses of the same three trials, 808 participants, agree that it cuts vomiting, by risk ratio 0.42 in one and 0.38 in the other, and disagree about nausea: one found no difference in nausea severity, rated low certainty by the GRADE system, a standard scale for how much confidence a body of evidence deserves, with more treatment-emergent adverse events on drug ⁶¹, while the other found an improvement in a combined nausea-or-vomiting measure and more fatigue ⁶². The approval covers vomiting only, which is why the drug is best described as a vomiting prophylactic, a drug given to prevent rather than to treat ¹⁵. It is also in development for gastroparesis and for the vomiting caused by GLP-1 drugs, the glucagon-like peptide-1 medicines such as semaglutide ¹⁵.

One frontier has already produced an approval, and it is not an antiemetic one. Elinzanetant blocks both NK1 and the related NK3 receptor, and in the OASIS 1 and 2 phase 3 trials, with about 400 postmenopausal women each, it reduced the frequency of moderate-to-severe hot flashes by about three more a day than placebo at weeks 4 and 12 and improved sleep and menopause-related quality of life ¹⁰³. It was first approved in the United Kingdom in July 2025 for moderate-to-severe vasomotor symptoms of menopause ³⁸, and is now also approved by the European Medicines Agency and the US Food and Drug Administration ³⁹. The hot-flash effect is attributed mainly to the NK3 half of the molecule, acting on the hypothalamic neurons that lose their estrogen restraint at menopause; what the NK1 half adds, perhaps to sleep and mood, is proposed rather than proven ^38,39.

Measuring it, the cancer claims, and the conflicts of interest

Substance P is hard to pin down in a patient. Plasma immunoassays have been used as research markers: in an observational study of 23 surgical patients in Japan, plasma substance P fell by the end of anesthesia and recovered by 24 hours in the 14 who had no postoperative nausea or vomiting, but did not fall, and was higher at 24 hours, in the 9 who did ¹⁰⁴. That is a single small observational study, which its authors read as a possible objective marker, and no blood level of substance P has a validated clinical cutoff. In the laboratory the peptide is mapped by antibody staining of tissue ⁷, its receptor occupancy is read by PET imaging in drug trials ⁶⁵, and capsaicin's effect on nerves is tracked by counting epidermal nerve fibers on skin biopsy ⁷⁷. None of these is a routine clinical test.

A large literature reports the substance P-NK1 system over-expressed in tumors and proposes repurposing aprepitant as an anticancer drug, including in pediatric cancers ²⁶. Two cautions belong on it. First, almost all of it is preclinical, cell and animal work, and no clinical treatment rests on it ²⁶. Second, the field carries a visible cluster of retractions concentrated in one laboratory group: a PubMed search on 19 October 2026 for retracted publications on substance P, NK1 antagonists and cancer returned nine records, of which five make claims about the substance P-NK1 system in cancer, and all five, including the three cited here on esophageal and ovarian cancer cell lines, come from the same laboratory in Mashhad, Iran ^27,28,29. Individual results in this literature should not be taken at face value.

Commercial sponsorship runs through the whole subject. Merck designed and funded the depression and chemotherapy-vomiting programs that built the class ^11,12,49; Eli Lilly ran the lanepitant migraine trials ^63,64; TESARO funded the rolapitant phase 3 trials ⁵⁰; Helsinn staff co-wrote the netupitant trials and the MyRisk trial ^51,70; NeRRe and Artemida staff co-wrote the orvepitant cough study ⁹⁵; Vanda employees ran and wrote the tradipitant trials in gastroparesis, itch and motion sickness ^92,98,101; and Bayer ran the elinzanetant trials ¹⁰³. The pain trial that came closest to a positive result was run at the US National Institutes of Health rather than by a company ⁹, and so was the clearest negative trial in gastroparesis ⁵⁴. That does not make the industry results false, but it is a reason to read every efficacy claim with the funder in view.

Why the peptide resists measurement is itself informative. Substance P acts where it is released, over short distances and for seconds, and the receptors that matter sit in the brainstem or the skin rather than in the bloodstream, so a plasma level reports very little about what is happening at a receptor; that is why the measurement that actually guided drug development was receptor occupancy by PET imaging rather than any blood test ^65,104. It is also why the tissue work is done with antibodies in animal and surgical specimens ^7,33, and why the most direct human mechanistic measurement on this page was made on strips of vagus nerve in a laboratory rather than in a patient ⁹⁶.

• Plasma or serum substance P immunoassayRadioimmunoassay or ELISA (enzyme-linked immunosorbent assay), two antibody-based blood tests, have been used as research markers. In 23 surgical patients, plasma substance P fell during anesthesia and recovered by the next day in the 14 who had no postoperative nausea or vomiting, but stayed level and then rose in the 9 who did ¹⁰⁴.Research studies of pain, itch, nausea and stress; not a routine clinical test.One small observational study of 23 patients; no blood level of substance P has a validated diagnostic cutoff for any disease ¹⁰⁴.Cannot diagnose any disease; a blood level does not report what is happening at a receptor in the brainstem or skin.
• NK1-receptor PET imagingPositron emission tomography with [18F]SPA-RQ, a radioactive tracer that sticks to NK1 receptors, measured how fully aprepitant occupies brain NK1 receptors in healthy volunteers, showing 90 percent or more occupancy at 100 mg a day or more ⁶⁵.Drug development, to prove a candidate reaches and blocks its brain target before a trial.Occupancy tracked plasma drug concentration closely in healthy volunteers.A research and industry tool, costly and not clinical; it shows target engagement, not whether the drug helps.
• Immunohistochemistry of substance P in tissueAntibody staining localized substance P to small sensory neurons and their spinal endings, the anatomy behind the pain hypothesis ⁷.Laboratory mapping of where the peptide is made and stored.Depends on antibody specificity and is qualitative to semi-quantitative.Shows presence, not release or activity, and cannot be done in a living person.
• Epidermal nerve-fiber density on skin biopsyCounting nerve fibers in a skin biopsy showed topical capsaicin causes a loss of epidermal fibers that parallels its loss of pain sensation, with regrowth on stopping ⁷⁷.Pharmacodynamic readout of capsaicin's effect on sensory nerves.Quantitative and reproducible for fiber counts.Not specific to substance P; it measures nerve fibers, not the peptide.

What changed, and what is still unknown

What changed is the job description. Substance P began as the pain transmitter and ended as an antiemetic peptide; the modern, defensible view is that it modulates the intensity of sensation, inflammation and sickness rather than carrying any one message on its own ¹⁰. The drugs that failed to kill pain and failed to lift depression are, as antiemetics, among the most useful supportive medicines in oncology ^12,57. The one approval the class has won outside vomiting, elinzanetant for menopausal hot flashes, is credited mainly to its action at the NK3 receptor rather than at NK1 ^38,39.

What is unknown is still substantial. No one fully understands why NK1 antagonists prevent vomiting well but blunt nausea poorly, a gap that limits them in gastroparesis, cyclic vomiting and pregnancy sickness alike ^13,76; one review suggests their effect depends on the vomiting pathway already being switched on, and that nausea, which needs the higher brain, is reached poorly even at receptor occupancies near 100 percent ⁷⁴. The weight of the MRGPRX2 pathway, through which substance P acts without the NK1 receptor, is not yet settled in human disease ²⁴. Whether blocking the receptor inside endosomes, which gives longer-lasting pain relief in animals, can be turned into a drug for people is untested ^52,53. And whether tradipitant's remaining indications, gastroparesis and the vomiting caused by GLP-1 drugs, hold up in independent trials remains to be seen ^15,98.

Some of what remains unknown is basic. It is not settled how much of substance P's work in people runs through MRGPRX2 rather than NK1, because that finding is recent and was made in mice and in isolated human mast cells ²⁴. The structural picture of how the peptide engages its receptor was filled in only in 2025, and the flexible front half of the peptide, which the earlier structures could not see, affects how strongly it signals ³⁰. And the alternative splicing of TAC1, which decides whether a cell releases substance P alone or together with neurokinin A, has never been mapped onto a human disease ⁴.

What this page cannot tell you is whether the class has another real indication in it. The honest summary of the last decade is one approval for motion-induced vomiting ¹⁵, one approval for hot flashes that is credited mainly to a different receptor ^38,39, a modest and inconsistent effect on itch ⁹³, a clear ceiling in cough ⁶⁰, and a failure in gastroparesis that no post hoc analysis repairs ^54,98. A molecule can be real, abundant, precisely localized and thoroughly drugged, and still turn out to be useful for less than its biology seemed to promise ^10,74.

Where it connects

Sources

104 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
   Chang MM, Leeman SE, Niall HD. Amino-acid sequence of substance P.Nat New Biol · 1971 · 232(29):86-7doi:10.1038/newbio232086a0 · PMID 5285346

   The primary source for the eleven-amino-acid sequence. No abstract in PubMed; cited for the sequence itself.

2. 2
   Steinhoff MS, von Mentzer B, Geppetti P, Pothoulakis C, Bunnett NW. Tachykinins and their receptors: contributions to physiological control and the mechanisms of disease.Physiol Rev · 2014 · 94(1):265-301doi:10.1152/physrev.00031.2013 · PMID 24382888

   Comprehensive review of tachykinin biology and receptors; states that the singular clinical success of NK1 antagonists is against nausea and vomiting. Secondary source for family and receptor facts.

3. 3
   Nawa H, Hirose T, Takashima H, Inayama S, Nakanishi S. Nucleotide sequences of cloned cDNAs for two types of bovine brain substance P precursor.Nature · 1983 · 306(5938):32-6doi:10.1038/306032a0 · PMID 6195531

   Cloned the precursor cDNAs and found a second tachykinin (neurokinin A) bounded by basic residues within the same precursor. Molecular biology, bovine brain.

4. 4
   Nawa H, Kotani H, Nakanishi S. Tissue-specific generation of two preprotachykinin mRNAs from one gene by alternative RNA splicing.Nature · 1984 · 312(5996):729-34doi:10.1038/312729a0 · PMID 6083453

   Showed the single preprotachykinin (TAC1) gene yields substance P alone or with neurokinin A by alternative splicing, in tissue-specific proportions. Establishes the gene behavior.

5. 5
   Yokota Y, Sasai Y, Tanaka K, et al. Molecular characterization of a functional cDNA for rat substance P receptor.J Biol Chem · 1989 · 264(30):17649-52PMID 2478537

   Cloned the rat NK1 receptor: 407 amino acids, seven transmembrane domains, a G-protein-coupled receptor binding substance P. No DOI in record.

6. 6
   v Euler US, Gaddum JH. An unidentified depressor substance in certain tissue extracts.J Physiol · 1931 · 72(1):74-87doi:10.1113/jphysiol.1931.sp002763 · PMID 16994201

   The founding observation: a substance in horse brain and intestine extracts that lowered blood pressure and contracted gut, distinct from acetylcholine and histamine. No abstract in PubMed; cited for the discovery and date, not for molecular detail.

7. 7
   Hökfelt T, Kellerth JO, Nilsson G, Pernow B. Substance P: localization in the central nervous system and in some primary sensory neurons.Science · 1975 · 190(4217):889-90doi:10.1126/science.242075 · PMID 242075

   Immunohistochemical evidence placing substance P in small primary sensory neurons and CNS terminals, the anatomical basis for the pain hypothesis. Animal tissue (rat, cat).

8. 8
   Otsuka M, Konishi S. Release of substance P-like immunoreactivity from isolated spinal cord of newborn rat.Nature · 1976 · 264(5581):83-4doi:10.1038/264083a0 · PMID 12474

   Showed calcium-dependent, stimulation-evoked release of substance P from spinal cord, consistent with a transmitter role. No abstract; newborn rat tissue.

9. 9
   Dionne RA, Max MB, Gordon SM, et al. The substance P receptor antagonist CP-99,994 reduces acute postoperative pain.Clin Pharmacol Ther · 1998 · 64(5):562-8doi:10.1016/S0009-9236(98)90140-0 · PMID 9834049

   In wisdom-tooth surgery (78 subjects in two cohorts), CP-99,994 gave a small analgesic effect, weaker than ibuprofen: significant only at 90 minutes in the first cohort of 60, and at 60 to 120 minutes in a second cohort of 18 dosed closer to surgery. The authors read it as a replicate demonstration of clinical analgesia; later pain trials did not bear it out [22].

10. 10
    Hill R. NK1 (substance P) receptor antagonists--why are they not analgesic in humans?Trends Pharmacol Sci · 2000 · 21(7):244-6doi:10.1016/s0165-6147(00)01502-9 · PMID 10871891

    The review that names the reversal: NK1 antagonists block sensitized responses in animal tests but fail to relieve clinical pain in people. Author was at Merck; a candid industry assessment.

11. 11
    Keller M, Montgomery S, Ball W, et al. Lack of efficacy of the substance p (neurokinin1 receptor) antagonist aprepitant in the treatment of major depressive disorder.Biol Psychiatry · 2006 · 59(3):216-23doi:10.1016/j.biopsych.2005.07.013 · PMID 16248986

    Five phase 3 trials: aprepitant did not beat placebo while paroxetine did; concludes NK1 antagonism as an antidepressant mechanism is not supported. The definitive negative; industry-run.

12. 12
    Hesketh PJ, Grunberg SM, Gralla RJ, et al. The oral neurokinin-1 antagonist aprepitant for the prevention of chemotherapy-induced nausea and vomiting: a multinational, randomized, double-blind, placebo-controlled trial in patients receiving high-dose cisplatin.J Clin Oncol · 2003 · 21(22):4112-9doi:10.1200/JCO.2003.01.095 · PMID 14559886

    Phase 3: complete response days 1-5 of 72.7 vs 52.3 percent with aprepitant added. The registration trial for the first NK1 antiemetic; industry-sponsored.

13. 13
    Gan TJ, Apfel CC, Kovac A, et al. A randomized, double-blind comparison of the NK1 antagonist, aprepitant, versus ondansetron for the prevention of postoperative nausea and vomiting.Anesth Analg · 2007 · 104(5):1082-9doi:10.1213/01.ane.0000263277.35140.a3 · PMID 17456656

    Aprepitant beat ondansetron for no-vomiting (90-95 vs 74 percent) but not for complete response or nausea control. Shows the class is stronger against vomiting than nausea.

14. 14
    Flemm LA. Aprepitant for chemotherapy-induced nausea and vomiting.Clin J Oncol Nurs · 2004 · 8(3):303-6doi:10.1188/04.CJON.303-306 · PMID 15208824

    States that the US Food and Drug Administration approved aprepitant (Emend, Merck) on 26 March 2003 for use with standard antiemetics against acute and delayed vomiting from highly emetogenic chemotherapy. Cited for the approval date.

15. 15
    Lee A. Tradipitant: First Approval.Drugs · 2026 · 86(6):957-61doi:10.1007/s40265-026-02313-1 · PMID 41945307

    Records the first approval, United States, December 2025, for prevention of vomiting induced by motion in adults (Vanda), and lists gastroparesis and GLP-1 agonist vomiting as in development. The verified regulatory status.

16. 16
    Lembeck F. [Central transmission of afferent impulses. III. Incidence and significance of the substance P in the dorsal roots of the spinal cord].Naunyn Schmiedebergs Arch Exp Pathol Pharmakol · 1953 · 219(3):197-213PMID 13099355

    German, with no abstract or DOI in PubMed; cited for its title and date. The origin of the idea that substance P transmits sensory impulses in the dorsal roots.

17. 17
    Navari RM, Reinhardt RR, Gralla RJ, et al. Reduction of cisplatin-induced emesis by a selective neurokinin-1-receptor antagonist.N Engl J Med · 1999 · 340(3):190-5doi:10.1056/NEJM199901213400304 · PMID 9917226

    The pivotal human trial: adding L-754,030 (aprepitant) raised freedom from delayed vomiting from 33 to about 80 percent. Multicenter randomized; the breakthrough result.

18. 18
    Hargreaves R, Ferreira JCA, Hughes D, et al. Development of aprepitant, the first neurokinin-1 receptor antagonist for the prevention of chemotherapy-induced nausea and vomiting.Ann N Y Acad Sci · 2011 · 1222:40-8doi:10.1111/j.1749-6632.2011.05961.x · PMID 21434941

    Merck account of aprepitant's development and its role as the first marketed NK1 antagonist. Review by the developers; cited for the approval milestone and history.

19. 19
    Cao YQ, Mantyh PW, Carlson EJ, Gillespie AM, Epstein CJ, Basbaum AI. Primary afferent tachykinins are required to experience moderate to intense pain.Nature · 1998 · 392(6674):390-4doi:10.1038/32897 · PMID 9537322

    TAC1-knockout mice felt mild pain normally but had reduced moderate-to-intense pain and almost absent neurogenic inflammation. Shows substance P scales pain intensity; mouse genetics.

20. 20
    De Felipe C, Herrero JF, O'Brien JA, et al. Altered nociception, analgesia and aggression in mice lacking the receptor for substance P.Nature · 1998 · 392(6674):394-7doi:10.1038/32904 · PMID 9537323

    NK1-receptor-knockout mice lost spinal wind-up but kept acute pain and hyperalgesia, and showed altered stress analgesia and aggression. Mouse genetics; limits the pain claim.

21. 21
    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

    Origin of the depletion-of-substance-P account of capsaicin analgesia. No abstract; rat; later shown to be a correlate rather than the cause of relief.

22. 22
    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

    States the correction plainly: substance P depletion is only a correlate of capsaicin treatment with little or no causative role; relief is by defunctionalization through TRPV1. Review.

23. 23
    Jancsó N, Jancsó-Gábor A, Szolcsányi 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

    Classic demonstration of nerve-driven inflammation, abolished by denervation or capsaicin. No abstract; rat experiments; the foundation of the neurogenic-inflammation concept.

24. 24
    Green DP, Limjunyawong N, Gour N, Pundir P, Dong X. A Mast-Cell-Specific Receptor Mediates Neurogenic Inflammation and Pain.Neuron · 2019 · 101(3):412-420.e3doi:10.1016/j.neuron.2019.01.012 · PMID 30686732

    Shows substance P drives mast-cell degranulation and inflammatory pain via MrgprB2 (mouse) and MRGPRX2 (human), independent of NK1. Mouse genetics plus human mast cells; a key mechanistic qualifier.

25. 25
    Hesketh PJ, Van Belle S, Aapro M, et al. Differential involvement of neurotransmitters through the time course of cisplatin-induced emesis as revealed by therapy with specific receptor antagonists.Eur J Cancer · 2003 · 39(8):1074-80doi:10.1016/s0959-8049(02)00674-3 · PMID 12736106

    Serotonin mediates the first 8-12 hours, after which substance P at NK1 dominates; explains why NK1, not 5-HT3, blockade controls delayed emesis. Pooled phase 2 data; Merck authors.

26. 26
    Rosso M, Alcaide C, Munoz M. Aprepitant, a Neurokinin-1 Receptor Antagonist, as a Disruptive Drug for the Treatment of Pediatric Cancer.J Clin Med · 2026 · 15(18):7004doi:10.3390/jcm15187004 · PMID 42795776

    Review arguing the substance P-NK1 system is over-expressed in pediatric cancers and that aprepitant could be repurposed. Advocacy review; preclinical evidence, no clinical treatment established.

27. 27
    Javid H, Asadi J, Zahedi Avval F, Afshari AR, Hashemy SI. The role of substance P/neurokinin 1 receptor in the pathogenesis of esophageal squamous cell carcinoma through constitutively active PI3K/Akt/NF-kB signal transduction pathways.Mol Biol Rep · 2020 · 47(3):2253-63doi:10.1007/s11033-020-05330-9 · PMID 32072401

    Claimed, in esophageal cancer cell lines, that aprepitant inhibits growth through NK1; PubMed lists it as a Retracted Publication, so its figures should not be relied on. From the same laboratory in Mashhad, Iran as [68] and [97]; cited as an example of the retraction cluster in the substance P cancer literature.

28. 28
    Momen Razmgah M, Ghahremanloo A, Javid H, AlAlikhan A, Afshari AR, Hashemy SI. The effect of substance P and its specific antagonist (aprepitant) on the expression of MMP-2, MMP-9, VEGF, and VEGFR in ovarian cancer cells.Mol Biol Rep · 2022 · 49(10):9307-14doi:10.1007/s11033-022-07771-w · PMID 35960409

    Claimed, in ovarian cancer cells, that aprepitant blocks migration and angiogenesis; PubMed lists it as a Retracted Publication. From the same Mashhad laboratory as [67] and [97]; a second example of why this literature must be read with caution.

29. 29
    Mohammadi F, Javid H, Afshari AR, Mashkani B, Hashemy SI. Substance P accelerates the progression of human esophageal squamous cell carcinoma via MMP-2, MMP-9, VEGF-A, and VEGFR1 overexpression.Mol Biol Rep · 2020 · 47(6):4263-72doi:10.1007/s11033-020-05532-1 · PMID 32436041

    PubMed lists this cell-line paper as a Retracted Publication. Cited only as a third member of the retraction cluster from the same laboratory in Mashhad, Iran; its results should not be relied on.

30. 30
    Ge H, Yang L, Chen C, Xu Y, Liu D, Wüthrich K. Human Substance P Interactions with G Protein-Coupled Receptor NK1R Observed by NMR in Solution.J Am Chem Soc · 2025 · 147(48):44114-22doi:10.1021/jacs.5c12553 · PMID 41264783

    Fluorine nuclear magnetic resonance on labeled substance P bound to detergent-solubilized human NK1 receptor: the tail half of the peptide is anchored rigidly in the binding pocket while the first five amino acids stay flexible and solvent-exposed, which earlier cryo-electron-microscopy structures could not see. Biophysics in micelles, not cells.

31. 31
    Gaddum JH, Schild H. Depressor substances in extracts of intestine.J Physiol · 1934 · 83(1):1-14doi:10.1113/jphysiol.1934.sp003206 · PMID 16994608

    No abstract in PubMed; full text in PubMed Central (PMC1394298). Cited for its title and date, the return to the depressor activity of intestinal extracts three years after the first report.

32. 32
    Chang MM, Leeman SE. Isolation of a sialogogic peptide from bovine hypothalamic tissue and its characterization as substance P.J Biol Chem · 1970 · 245(18):4784-90PMID 5456150

    Purified the peptide from cow hypothalamus using a rat-salivation bioassay and identified it as substance P. No DOI or abstract in the record; establishes the isolation, not the sequence.

33. 33
    Hökfelt T, Kellerth JO, Nilsson G, Pernow B. Experimental immunohistochemical studies on the localization and distribution of substance P in cat primary sensory neurons.Brain Res · 1975 · 100(2):235-52doi:10.1016/0006-8993(75)90481-3 · PMID 1104079

    Companion detailed study in cat showing substance P in small sensory cell bodies and dorsal-horn fibers, with loss after dorsal-root section. Anatomy, not function.

34. 34
    Lembeck F, Holzer P. Substance P as neurogenic mediator of antidromic vasodilation and neurogenic plasma extravasation.Naunyn Schmiedebergs Arch Pharmacol · 1979 · 310(2):175-83doi:10.1007/BF00500282 · PMID 93706

    No abstract in PubMed; rat experiments. Cited for the proposal its title states, that substance P mediates nerve-driven vasodilation and plasma leakage.

35. 35
    Carpenter DO, Briggs DB, Strominger N. Responses of neurons of canine area postrema to neurotransmitters and peptides.Cell Mol Neurobiol · 1983 · 3(2):113-26doi:10.1007/BF00735276 · PMID 6140078

    122 neurons recorded in anesthetized dogs; substance P was one of 13 substances that excited about half the cells tested, and nearly all the excitatory substances were emetic. Animal electrophysiology.

36. 36
    Hornby PJ. Central neurocircuitry associated with emesis.Am J Med · 2001 · 111 Suppl 8A:106S-112Sdoi:10.1016/s0002-9343(01)00849-x · PMID 11749934

    Review of the brainstem vomiting circuitry: the area postrema relays blood-borne emetic signals to the nucleus tractus solitarius, which also receives abdominal vagal afferents and projects to a central pattern generator; serotonin blockers act mainly on vagal afferents and NK1 antagonists in the dorsal vagal complex.

37. 37
    Tattersall FD, Rycroft W, Francis B, et al. Tachykinin NK1 receptor antagonists act centrally to inhibit emesis induced by the chemotherapeutic agent cisplatin in ferrets.Neuropharmacology · 1996 · 35(8):1121-9doi:10.1016/s0028-3908(96)00020-2 · PMID 9121615

    A brain-penetrant NK1 antagonist stopped cisplatin emesis systemically; a non-penetrant one worked only injected near the nucleus of the solitary tract. Localizes the antiemetic site to the brainstem; ferret; also notes ferret NK1 resembles human.

38. 38
    Lee A. Elinzanetant: First Approval.Drugs · 2026 · 86(1):121-5 (online 12 Nov 2025)doi:10.1007/s40265-025-02244-3 · PMID 41222830

    Elinzanetant, a combined neurokinin-1 and neurokinin-3 receptor antagonist from Bayer, received its first approval in the United Kingdom in July 2025 for moderate-to-severe vasomotor symptoms of menopause. The verified regulatory record for the one non-antiemetic approval in the class.

39. 39
    Pogoda K, Arecco L, Lambertini M. Neurokinin pathway antagonists for vasomotor symptoms in women with breast cancer: focus on elinzanetant and fezolinetant.Breast · 2026 · 88:104812doi:10.1016/j.breast.2026.104812 · PMID 42160911

    Narrative review stating that elinzanetant is approved by the European Medicines Agency and the US Food and Drug Administration, and summarizing the OASIS program including OASIS-4 in women on endocrine therapy for breast cancer.

40. 40
    Snider RM, Constantine JW, Lowe JA, et al. A potent nonpeptide antagonist of the substance P (NK1) receptor.Science · 1991 · 251(4992):435-7doi:10.1126/science.1703323 · PMID 1703323

    CP-96,345, the first potent selective nonpeptide NK1 antagonist: competitive at the receptor, inactive at NK2 and NK3. Pfizer authors; the chemistry that made oral NK1 drugs possible.

41. 41
    Tattersall FD, Rycroft W, Hill RG, Hargreaves RJ. Enantioselective inhibition of apomorphine-induced emesis in the ferret by the neurokinin1 receptor antagonist CP-99,994.Neuropharmacology · 1994 · 33(2):259-60doi:10.1016/0028-3908(94)90018-3 · PMID 8035913

    CP-99,994 blocked emesis stereoselectively; the low-affinity enantiomer did nothing, proving the effect runs through NK1. Ferret; Merck. Foundational antiemetic finding.

42. 42
    Herrstedt J, Roila F, Warr D, et al. 2016 Updated MASCC/ESMO Consensus Recommendations: Prevention of Nausea and Vomiting Following High Emetic Risk Chemotherapy.Support Care Cancer · 2017 · 25(1):277-88doi:10.1007/s00520-016-3313-0 · PMID 27443154

    Guideline update recording that netupitant (given with palonosetron as NEPA) and rolapitant completed phase 2 and 3 programs and were approved by the Food and Drug Administration in 2014-2015, and that adding either to a serotonin blocker and dexamethasone raised complete response by 8 to 20 percent. Cited for the approval years.

43. 43
    Cass AS, Odinet JS, Valgus JM, Crona DJ. Infusion reactions following administration of intravenous rolapitant at an academic medical center.J Oncol Pharm Pract · 2019 · 25(7):1776-83doi:10.1177/1078155218808084 · PMID 30348072

    Records the January 2018 US Food and Drug Administration letter on anaphylaxis and other serious hypersensitivity reactions with intravenous rolapitant, and six cases at one center where reactions occurred in 8.7 percent of patients against 2.8 percent in the registration study. Case series.

44. 44
    Navari RM, Schwartzberg LS. Evolving role of neurokinin 1-receptor antagonists for chemotherapy-induced nausea and vomiting.Onco Targets Ther · 2018 · 11:6459-78doi:10.2147/OTT.S158570 · PMID 30323622

    Review of the whole NK1 antiemetic class: intravenous rolapitant was removed from US distribution after hypersensitivity and anaphylaxis, intravenous fosaprepitant causes infusion-site reactions attributed to its polysorbate 80 excipient, and the class carries drug-drug interactions.

45. 45
    George DT, Gilman J, Hersh J, et al. Neurokinin 1 receptor antagonism as a possible therapy for alcoholism.Science · 2008 · 319(5869):1536-9doi:10.1126/science.1153813 · PMID 18276852

    NK1 antagonism suppressed alcohol craving and cortisol responses and altered fMRI in detoxified inpatients. Surrogate markers in a small trial; not a licensed treatment.

46. 46
    Kwako LE, George DT, Schwandt ML, et al. The neurokinin-1 receptor antagonist aprepitant in co-morbid alcohol dependence and posttraumatic stress disorder: a human experimental study.Psychopharmacology (Berl) · 2015 · 232(1):295-304 (online 18 Jul 2014)doi:10.1007/s00213-014-3665-4 · PMID 25030801

    53 inpatients randomized to aprepitant 125 mg a day or placebo for 4 weeks at the National Institutes of Health Clinical Center, a dose reported to occupy more than 90 percent of central receptors: no effect on symptoms, craving, or responses to stress or alcohol cues; only a brain-imaging response changed. The reversal of the 2008 alcohol signal.

47. 47
    Tattersall FD, Rycroft W, Cumberbatch M, et al. The novel NK1 receptor antagonist MK-0869 (L-754,030) and its water soluble phosphoryl prodrug, L-758,298, inhibit acute and delayed cisplatin-induced emesis in ferrets.Neuropharmacology · 2000 · 39(4):652-63doi:10.1016/s0028-3908(99)00172-0 · PMID 10728886

    MK-0869 (aprepitant) and its prodrug blocked acute and delayed cisplatin emesis, even started after the acute phase. Ferret; the preclinical basis for the clinical trials.

48. 48
    Mantyh PW, Rogers SD, Honore P, et al. Inhibition of hyperalgesia by ablation of lamina I spinal neurons expressing the substance P receptor.Science · 1997 · 278(5336):275-9doi:10.1126/science.278.5336.275 · PMID 9323204

    Targeted destruction of NK1-bearing lamina I neurons in rats left mild pain intact but reduced intense pain and hyperalgesia. Strong animal support for the pain role; rat only.

49. 49
    Kramer MS, Cutler N, Feighner J, et al. Distinct mechanism for antidepressant activity by blockade of central substance P receptors.Science · 1998 · 281(5383):1640-5doi:10.1126/science.281.5383.1640 · PMID 9733503

    Phase 2 report that MK-869 (aprepitant) had antidepressant effects without acting on monoamines. Merck authors; the launch of the depression program later overturned.

50. 50
    Rapoport BL, Chasen MR, Gridelli C, et al. Safety and efficacy of rolapitant for prevention of chemotherapy-induced nausea and vomiting after cisplatin-based highly emetogenic chemotherapy: two randomised, active-controlled, double-blind, phase 3 trials.Lancet Oncol · 2015 · 16(9):1079-89doi:10.1016/S1470-2045(15)00035-2 · PMID 26272769

    Rolapitant raised delayed-phase complete response (pooled 71 vs 60 percent). Phase 3; funded by TESARO; widened the class.

51. 51
    Hesketh PJ, Rossi G, Rizzi G, et al. Efficacy and safety of NEPA, an oral combination of netupitant and palonosetron, for prevention of chemotherapy-induced nausea and vomiting following highly emetogenic chemotherapy: a randomized dose-ranging pivotal study.Ann Oncol · 2014 · 25(7):1340-6doi:10.1093/annonc/mdu110 · PMID 24608196

    The netupitant-palonosetron combination (300 mg netupitant) gave overall complete response 89.6 versus 76.5 percent for palonosetron alone. Phase 2 dose-ranging study of 694 patients, described by its authors as pivotal; Helsinn authors; the basis for the single-pill combination.

52. 52
    Jensen DD, Lieu T, Halls ML, et al. Neurokinin 1 receptor signaling in endosomes mediates sustained nociception and is a viable therapeutic target for prolonged pain relief.Sci Transl Med · 2017 · 9(392):eaal3447doi:10.1126/scitranslmed.aal3447 · PMID 28566424

    Rat and mouse tissue and cells: the NK1 receptor keeps signaling after being drawn into endosomes, and antagonists anchored to lipids to reach those compartments gave longer-lasting relief than surface-acting ones. Animal and cell evidence only.

53. 53
    Hegron A, Peach CJ, Tonello R, et al. Therapeutic antagonism of the neurokinin 1 receptor in endosomes provides sustained pain relief.Proc Natl Acad Sci U S A · 2023 · 120(22):e2220979120doi:10.1073/pnas.2220979120 · PMID 37216510

    In mice carrying the human NK1 receptor, aprepitant disrupted endosomal signaling only transiently while redesigned netupitant analogs that persist in acidic endosomes gave more potent and longer antinociception. Animal evidence; no such drug has been tested in people.

54. 54
    Pasricha PJ, Yates KP, Sarosiek I, et al. Aprepitant Has Mixed Effects on Nausea and Reduces Other Symptoms in Patients With Gastroparesis and Related Disorders.Gastroenterology · 2018 · 154(1):65-76.e11doi:10.1053/j.gastro.2017.08.033 · PMID 29111115

    126 patients, 4 weeks, National Institutes of Health-funded: aprepitant missed its primary nausea endpoint (46 versus 40 percent improvement; relative risk 1.2, 95 percent CI 0.8-1.7) while several secondary symptom scores improved. The independent negative trial in gastroparesis.

55. 55
    Tsianakas A, Zeidler C, Riepe C, et al. Aprepitant in Anti-histamine-refractory Chronic Nodular Prurigo: A Multicentre, Randomized, Double-blind, Placebo-controlled, Cross-over, Phase-II trial (APREPRU).Acta Derm Venereol · 2019 · 99(4):379-85doi:10.2340/00015555-3120 · PMID 30653242

    58 patients, aprepitant 80 mg a day for 4 weeks in a crossover design: no significant difference from placebo on any parameter investigated. The negative itch trial that balances the serlopitant results.

56. 56
    Fejzo M, Rocha N, Cimino I, et al. GDF15 linked to maternal risk of nausea and vomiting during pregnancy.Nature · 2024 · 625(7996):760-7 (online 13 Dec 2023)doi:10.1038/s41586-023-06921-9 · PMID 38092039

    Reports that fetal and placental GDF15 production and the mother's prior sensitivity to the hormone both contribute substantially to the risk of hyperemesis gravidarum, supporting a putative causal role for this brainstem-acting hormone. The study did not examine substance P; the strongest mechanism for the condition points away from it.

57. 57
    Hesketh PJ, Kris MG, Basch E, et al. Antiemetics: ASCO Guideline Update.J Clin Oncol · 2020 · 38(24):2782-97doi:10.1200/JCO.20.01296 · PMID 32658626

    ASCO guideline keeping NK1 antagonists in the standard regimen for high-emetic-risk chemotherapy, with intravenous aprepitant and netupitant-palonosetron options. Guideline.

58. 58
    Herrstedt J, Clark-Snow R, Ruhlmann CH, et al. 2023 MASCC and ESMO guideline update for the prevention of chemotherapy- and radiotherapy-induced nausea and vomiting.ESMO Open · 2024 · 9(2):102195doi:10.1016/j.esmoop.2023.102195 · PMID 38458657

    International guideline update confirming the NK1 antagonist's place in prophylaxis. Guideline; current standard of care.

59. 59
    Tradipitant (Nereus) for motion sickness.Med Lett Drugs Ther · 2026 · 68(1757):97-98doi:10.58347/tml.2026.1757a · PMID 42295170

    No abstract in PubMed; an independent drug bulletin confirming the brand name Nereus and United States marketing for motion sickness. Cited for the brand name and marketing status only.

60. 60
    Yang Y, Wang J, Hu Z, Wang G, Li J. Efficacy and safety of neurokinin-1 receptor antagonist on cough suppression: a systematic review and meta-analysis.Front Pharmacol · 2026 · 17:1915023doi:10.3389/fphar.2026.1915023 · PMID 42889769

    Five trials, 719 participants: NK1 antagonists improved subjective cough scores but did not significantly reduce objective cough frequency, with more mild adverse events. The sobering ceiling on the cough indication.

61. 61
    Elsaadouni MR, Aldekhail NH, Alhawamdeh ATA, et al. Efficacy and safety of tradipitant in motion sickness: a systematic review and meta-analysis.Acta Neurol Belg · 2026 (online 12 Aug 2026)doi:10.1007/s13760-026-03161-2 · PMID 42584554

    Three randomized trials, 808 participants: vomiting risk ratio 0.42 (0.33-0.53); nausea severity standardized mean difference -0.05 (-0.24 to 0.13), not significant, GRADE low; any treatment-emergent adverse event risk ratio 1.94. Concludes tradipitant is a selective vomiting prophylactic. Independent authors (Saudi Arabia, Pakistan).

62. 62
    Ibrahim T, Burhan M, Shahid ZUA, et al. Efficacy and Safety of Tradipitant for Motion Sickness-A GRADE Assessed Systematic Review and Meta-Analysis.Ann Pharmacother · 2026 (online 15 Oct 2026)doi:10.1177/10600280261474866 · PMID 42877980

    Three randomized trials, 808 participants: vomiting risk ratio 0.38 (0.30-0.48); the combined nausea-or-vomiting outcome also improved, risk ratio 0.48 (0.35-0.65); fatigue was more frequent, risk ratio 2.66 (1.02-6.93). Independent authors (Pakistan, Sudan). It does not by itself support a no-effect-on-nausea statement; for nausea severity see Elsaadouni 2026 [72].

63. 63
    Goldstein DJ, Wang O, Saper JR, Stoltz R, Silberstein SD, Mathew NT. Ineffectiveness of neurokinin-1 antagonist in acute migraine: a crossover study.Cephalalgia · 1997 · 17(7):785-90doi:10.1046/j.1468-2982.1997.1707785.x · PMID 9399010

    Lanepitant failed to relieve acute migraine at three doses. Industry-sponsored (Lilly); negative.

64. 64
    Goldstein DJ, Offen WW, Klein EG, et al. Lanepitant, an NK-1 antagonist, in migraine prevention.Cephalalgia · 2001 · 21(2):102-6doi:10.1046/j.1468-2982.2001.00161.x · PMID 11422091

    Lanepitant did not significantly prevent migraine (response 41 vs 22 percent, p=0.065). Industry-sponsored; negative, extending the pain-indication failures.

65. 65
    Bergström M, Hargreaves RJ, Burns HD, et al. Human positron emission tomography studies of brain neurokinin 1 receptor occupancy by aprepitant.Biol Psychiatry · 2004 · 55(10):1007-12doi:10.1016/j.biopsych.2004.02.007 · PMID 15121485

    PET showed aprepitant occupies 90 percent or more of brain NK1 receptors at the doses used, so later depression failure was not due to poor target engagement. Healthy volunteers.

66. 66
    Hale JJ, Mills SG, MacCoss M, et al. Phosphorylated morpholine acetal human neurokinin-1 receptor antagonists as water-soluble prodrugs.J Med Chem · 2000 · 43(6):1234-41doi:10.1021/jm990617v · PMID 10737756

    Chemistry of fosaprepitant, the water-soluble prodrug that converts rapidly to aprepitant in vivo. Medicinal chemistry; underlies the intravenous formulation.

67. 67
    Grunberg S, Chua D, Maru A, et al. Single-dose fosaprepitant for the prevention of chemotherapy-induced nausea and vomiting associated with cisplatin therapy: randomized, double-blind study protocol--EASE.J Clin Oncol · 2011 · 29(11):1495-501doi:10.1200/JCO.2010.31.7859 · PMID 21383291

    A single intravenous 150 mg dose of fosaprepitant was noninferior to three days of oral aprepitant. 2,322 randomized; establishes the single-dose intravenous option.

68. 68
    Diemunsch P, Gan TJ, Philip BK, et al. Single-dose aprepitant vs ondansetron for the prevention of postoperative nausea and vomiting: a randomized, double-blind phase III trial in patients undergoing open abdominal surgery.Br J Anaesth · 2007 · 99(2):202-11doi:10.1093/bja/aem133 · PMID 17540667

    Confirmatory postoperative trial: aprepitant was noninferior to ondansetron for complete response at 24 hours and superior for no vomiting at 24 and 48 hours (84-86 versus 71 percent, and 82-85 versus 66 percent), with a lower distribution of peak nausea scores. Supports the postoperative indication; the nausea advantage was modest.

69. 69
    Chen S, Pei YY, Zhang HW, et al. Randomized, double-blind phase III trial of a dexamethasone-free regimen for managing highly emetogenic chemotherapy-induced nausea and vomiting.Int J Cancer · 2026 · 158(1):131-9 (online 30 Jul 2025)doi:10.1002/ijc.70069 · PMID 40735921

    254 adults on highly emetogenic chemotherapy; cited for its statement that the standard three-drug regimen includes either an NK1 receptor antagonist or olanzapine, and for the finding that olanzapine plus a serotonin blocker was noninferior to the steroid-containing triplet.

70. 70
    Molassiotis A, Jordan K, Karthaus M, et al. Personalised antiemetic prophylaxis with NEPA for patients at high risk of chemotherapy-induced nausea and vomiting receiving moderately emetogenic chemotherapy: results from the randomised, multinational MyRisk trial.Ann Oncol · 2026 · 37(2):260-70 (online 17 Oct 2025)doi:10.1016/j.annonc.2025.10.017 · PMID 41110696

    Phase 4 open-label trial, 401 randomized and 388 analyzed: adding the netupitant-palonosetron combination for patients at high personal risk on moderately emetogenic chemotherapy raised complete response across three cycles (odds ratio 1.67, 95 percent CI 1.12-2.49). Helsinn Medical Affairs co-authors.

71. 71
    Radhakrishnan V, Srinivasan P, Das G, et al. Dexamethasone-Free Antiemetic Prophylaxis for Children and Adolescents Receiving Highly Emetogenic Chemotherapy: A Multicenter, Phase III, Noninferiority Trial (CIVIC POD).J Clin Oncol · 2026 · 44(25):2379-89 (online 30 Jul 2026)doi:10.1200/JCO-26-00677 · PMID 42535876

    310 patients aged 4-18 randomized to dexamethasone or olanzapine, each with palonosetron and the NK1 antagonist fosaprepitant: complete response to vomiting 56.9 versus 63.5 percent, meeting noninferiority, with drowsiness of any grade in 50.7 versus 17.2 percent. Investigator-initiated.

72. 72
    Rasheed AA, Ganguly S, Sra MS, et al. Intravenous Fosaprepitant Versus Oral Aprepitant for Children Receiving Highly Emetogenic Chemotherapy: An Investigator-Initiated Randomized, Open-Label, Non-Inferiority Trial.Pediatr Blood Cancer · 2026 · 73(5):e70171 (online 13 Mar 2026)doi:10.1002/1545-5017.70171 · PMID 41823195

    279 children: complete response to vomiting in the acute phase 54.3 percent with a single intravenous dose of fosaprepitant versus 60.4 percent with three days of oral aprepitant, a difference of -6.1 percent whose 90 percent confidence interval (-15.7 to +3.6) crossed the prespecified margin, so noninferiority was not established. Investigator-initiated.

73. 73
    Qi X, Zhang J, Sun J, et al. Fosaprepitant versus Ondansetron for Preventing Postoperative Nausea and Vomiting After Video-Assisted Thoracoscopic Lung Resection: A Randomized Controlled Clinical Trial.Drug Des Devel Ther · 2026 · 20:584402 (online 10 Mar 2026)doi:10.2147/DDDT.S584402 · PMID 41836527

    233 adults at raised risk: nausea and vomiting together at 24 hours 31.0 versus 41.0 percent, not significant; vomiting at 24 hours 8.6 versus 21.4 percent and nausea or vomiting at 48 hours 10.3 versus 20.5 percent, both significant. The vomiting-versus-nausea pattern again.

74. 74
    Andrews PLR, Golding JF, Sanger GJ. An assessment of the effects of neurokinin1 receptor antagonism against nausea and vomiting: Relative efficacy, sites of action and lessons for future drug development.Br J Clin Pharmacol · 2023 · 89(12):3468-90doi:10.1111/bcp.15852 · PMID 37452618

    Review: nausea is less affected, or possibly unaffected, by NK1 receptor blockade than vomiting is; the anti-vomiting action is placed in the nucleus tractus solitarius and the ventral brainstem central pattern generator, and depends on the vomiting pathway already being activated. Expert synthesis, not new data.

75. 75
    Cubeddu LX, Hoffmann IS, Fuenmayor NT, Finn AL. Efficacy of ondansetron (GR 38032F) and the role of serotonin in cisplatin-induced nausea and vomiting.N Engl J Med · 1990 · 322(12):810-6doi:10.1056/NEJM199003223221204 · PMID 1689807

    Showed cisplatin releases serotonin and that the 5-HT3 blocker ondansetron controls acute emesis, with urinary serotonin metabolite tracking vomiting. Establishes the serotonin arm of the two-phase model.

76. 76
    Sanger GJ, Golding JF, Andrews PLR. New therapies to treat nausea and vomiting: clinical need, progress towards novelty and research challenges.Expert Rev Clin Pharmacol · 2026 · 19(6):535-58doi:10.1080/17512433.2026.2682294 · PMID 42212356

    Review noting that NK1 antagonists have the widest antiemetic spectrum but that treatment gaps remain, for example gastroparesis and cyclic vomiting syndrome, and that efficacy is lower against nausea than against vomiting. Current expert synthesis.

77. 77
    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

    In humans, topical capsaicin caused loss of epidermal nerve fibers paralleling loss of pain, reversible over weeks. Shows fiber defunctionalization, the pharmacodynamic basis for a skin-biopsy readout.

78. 78
    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

    Cloned TRPV1, the capsaicin and noxious-heat receptor; identifies the true target of capsaicin, not substance P depletion. Expression cloning.

79. 79
    Rudd JA, Nalivaiko E, Matsuki N, Wan C, Andrews PL. The involvement of TRPV1 in emesis and anti-emesis.Temperature (Austin) · 2015 · 2(2):258-76doi:10.1080/23328940.2015.1043042 · PMID 27227028

    Review proposing that TRPV1 agonists are broad-spectrum antiemetics, possibly via acute substance P depletion at the nucleus of the solitary tract; notes olvanil shares the effect. Animal evidence (ferret, musk shrew); mechanism is hypothesis.

80. 80
    Dezieck L, Hafez Z, Conicella A, et al. 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 improved with topical capsaicin; proposes, explicitly as a hypothesis, that it impairs substance P signaling in the area postrema and solitary nucleus via TRPV1. Retrospective case series; mechanism unproven.

81. 81
    Dean DJ, Sabagha N, Rose K, et al. A Pilot Trial of Topical Capsaicin Cream for Treatment of Cannabinoid Hyperemesis Syndrome.Acad Emerg Med · 2020 · 27(11):1166-72doi:10.1111/acem.14062 · PMID 32569429

    Double-blind randomized placebo-controlled pilot trial, 30 emergency patients (17 capsaicin, 13 placebo). Nausea at 60 minutes 3.2 versus 6.4 cm on a 10-cm scale; the 30-minute primary endpoint was not significant; complete relief in 29.4 versus 0 percent. Small pilot.

82. 82
    Sabbineni M, Scott W, Punia K, et al. 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, 492 patients, two of them randomized: the capsaicin evidence is mixed, dopamine antagonists potentially beneficial, and all studies small and at risk of bias. The current systematic appraisal.

83. 83
    Ruberto AJ, Sivilotti MLA, Forrester S, Hall AK, Crawford FM, Day AG. Intravenous Haloperidol Versus Ondansetron for Cannabis Hyperemesis Syndrome (HaVOC): A Randomized, Controlled Trial.Ann Emerg Med · 2021 · 77(6):613-9doi:10.1016/j.annemergmed.2020.08.021 · PMID 33160719

    Triple-blind randomized trial; 30 of 33 enrolled patients treated. Haloperidol beat ondansetron on a combined pain-and-nausea score at 2 hours (difference 2.3 cm, 95 percent CI 0.6 to 4.0); two return visits for acute dystonia, both on the higher dose.

84. 84
    Senderovich H, Patel P, Jimenez Lopez B, Waicus S. A Systematic Review on Cannabis Hyperemesis Syndrome and Its Management Options.Med Princ Pract · 2022 · 31(1):29-38doi:10.1159/000520417 · PMID 34724666

    Reviews 17 studies published between January 2009 and June 2021: cannabis cessation is the most reliable measure, with hot-water bathing, topical capsaicin, haloperidol, droperidol, benzodiazepines, propranolol and aprepitant among the reported treatments. The evidence base is mostly case reports and series.

85. 85
    Sigal A, Padilla G, Carroll T, Mautone SG. Cannabinoid Hyperemesis Syndrome in Adolescents: The Role of Aprepitant as a New Treatment Option for Rapid Symptom Relief.J Adolesc Health · 2025 · 77(6):1223-5doi:10.1016/j.jadohealth.2025.08.004 · PMID 40965394

    Two adolescents whose vomiting resisted conventional drugs for 36-45 hours improved within an hour of aprepitant. Case report; suggestive, not controlled.

86. 86
    Frazier R, Li BUK, Venkatesan T. Diagnosis and Management of Cyclic Vomiting Syndrome: A Critical Review.Am J Gastroenterol · 2023 · 118(7):1157-67doi:10.14309/ajg.0000000000002216 · PMID 36791365

    Review placing cannabinoid hyperemesis as a subset of cyclic vomiting syndrome, with aprepitant used as refractory prophylaxis. Expert review.

87. 87
    Lowry P, Woods R. The placenta controls the physiology of pregnancy by increasing the half-life in blood and receptor activity of its secreted peptide hormones.J Mol Endocrinol · 2018 · 60(1):R23-R30 (online 6 Dec 2017)doi:10.1530/JME-17-0275 · PMID 29212865

    Hypothesis review proposing roles for the placental tachykinins neurokinin B and endokinin in morning sickness and hyperemesis; reports no test and no data on substance P.

88. 88
    Yosipovitch G, Ständer S, Kerby MB, et al. Serlopitant for the treatment of chronic pruritus: results of a randomized, multicenter, placebo-controlled phase 2 clinical trial.J Am Acad Dermatol · 2018 · 78(5):882-891.e10doi:10.1016/j.jaad.2018.02.030 · PMID 29462657

    Serlopitant reduced chronic pruritus dose-dependently (1 and 5 mg significant vs placebo). Phase 2; the itch indication's early win.

89. 89
    Ständer S, Kwon P, Hirman J, et al. Serlopitant reduced pruritus in patients with prurigo nodularis in a phase 2, randomized, placebo-controlled trial.J Am Acad Dermatol · 2019 · 80(5):1395-402doi:10.1016/j.jaad.2019.01.052 · PMID 30894279

    Serlopitant improved itch in prurigo nodularis at weeks 4 and 8. Phase 2; modest effect sizes; not yet an approval.

90. 90
    Zhou T, Zhang Y, Ma Y, et al. Comparison of aprepitant versus desloratadine for EGFR-TKI-induced pruritus: A randomized phase 2 clinical trial.Cancer · 2022 · 128(22):3969-76doi:10.1002/cncr.34474 · PMID 36197287

    Aprepitant relieved itch from EGFR-inhibitor cancer drugs faster and more often than an antihistamine (response 53 vs 24 percent at 1 week). Phase 2; a positive itch result.

91. 91
    Zic JA, Straka BT, McGirt LY, et al. Aprepitant for the Treatment of Pruritus in Sézary Syndrome: A Randomized Crossover Clinical Trial.JAMA Dermatol · 2018 · 154(10):1221-2doi:10.1001/jamadermatol.2018.2510 · PMID 30140912

    Aprepitant did not reduce itch versus placebo in Sézary syndrome. A negative itch trial; balances the positive pruritus results.

92. 92
    Welsh SE, Xiao C, Kaden AR, et al. Neurokinin-1 receptor antagonist tradipitant has mixed effects on itch in atopic dermatitis: results from EPIONE, a randomized clinical trial.J Eur Acad Dermatol Venereol · 2021 · 35(5):e338-40doi:10.1111/jdv.17090 · PMID 33330999

    Research letter with no abstract in PubMed; cited for the finding stated in its title. Authors are almost all Vanda Pharmaceuticals employees.

93. 93
    Ho PY, Huang YC, Lin YT. Systemic neurokinin-1 receptor antagonists mitigate chronic pruritus: A systematic review and meta-analysis.J Eur Acad Dermatol Venereol · 2025 · 39(10):1738-49doi:10.1111/jdv.20807 · PMID 40551532

    Thirteen randomized and two non-randomized trials plus gray literature, 2,876 patients: itch scores fell modestly (standardized mean difference -0.448, 95 percent CI -0.735 to -0.161), with a 4-point improvement in 33.9 percent on drug against 24.7 percent on placebo. Independent meta-analysis; the effect is real but small.

94. 94
    Mueller SM, Beltraminelli H, Boehncke WH, et al. Swiss Practice Recommendations for Chronic Prurigo Including Prurigo Nodularis.Int J Dermatol · 2026 (online 18 Jun 2026)doi:10.1111/ijd.70533 · PMID 42316333

    Expert consensus of twelve specialists: dupilumab and nemolizumab are recommended, and no recommendation could be made for neurokinin-1 receptor antagonists. Current guidance, not new data.

95. 95
    Smith J, Allman D, Badri H, et al. The Neurokinin-1 Receptor Antagonist Orvepitant Is a Novel Antitussive Therapy for Chronic Refractory Cough: Results From a Phase 2 Pilot Study (VOLCANO-1).Chest · 2020 · 157(1):111-8doi:10.1016/j.chest.2019.08.001 · PMID 31421110

    Open-label pilot: orvepitant reduced daytime cough frequency by 26 percent at 4 weeks. Small, uncontrolled; sponsored by NeRRe/Artemida.

96. 96
    Smith JA, Harle A, Dockry R, et al. Aprepitant for Cough in Lung Cancer. A Randomized Placebo-controlled Trial and Mechanistic Insights.Am J Respir Crit Care Med · 2021 · 203(6):737-45doi:10.1164/rccm.202006-2359OC · PMID 32966755

    Crossover trial: aprepitant cut awake cough by 22 percent and blocked substance P from depolarizing human vagus nerve. Small but gives a direct human mechanism for cough.

97. 97
    Carlin JL, Lieberman VR, Dahal A, et al. Efficacy and Safety of Tradipitant in Patients With Diabetic and Idiopathic Gastroparesis in a Randomized, Placebo-Controlled Trial.Gastroenterology · 2021 · 160(1):76-87.e4doi:10.1053/j.gastro.2020.07.029 · PMID 32693185

    Phase 2: tradipitant reduced nausea versus placebo over 4 weeks (reduction 1.2 vs 0.7, p=0.0099). Vanda-sponsored; the positive early signal in gastroparesis.

98. 98
    Carlin JL, Polymeropoulos C, Camilleri M, et al. The Efficacy of Tradipitant in Patients With Diabetic and Idiopathic Gastroparesis in a Phase 3 Randomized Placebo-Controlled Clinical Trial.Clin Gastroenterol Hepatol · 2024 · 22(12):2506-16doi:10.1016/j.cgh.2024.01.005 · PMID 38237696

    Phase 3 in 201 patients: missed its primary and secondary endpoints in the intention-to-treat population; positive only in post hoc exposure-adjusted analyses. Vanda-sponsored; a negative pivotal trial rescued only after the fact.

99. 99
    Khanna L, Zheng T, Atieh J, et al. Clinical trial: a single-centre, randomised, controlled trial of tradipitant on satiation, gastric functions, and serum drug levels in healthy volunteers.Aliment Pharmacol Ther · 2022 · 56(2):224-30doi:10.1111/apt.17065 · PMID 35644931

    Tradipitant did not change gastric emptying or volumes in 24 healthy volunteers, implying its gastroparesis effect, if any, is central rather than on gastric motility. Mechanistic negative.

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     In a blinded placebo-controlled field study, 15 of 106 dogs given the NK1 antagonist maropitant vomited on a car journey against 69 of 105 on placebo. Pfizer Animal Health authors; dogs, not people.

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     Polymeropoulos VM, Kiely L, Bushman ML, et al. Motion Syros: tradipitant effective in the treatment of motion sickness; a multicenter, randomized, double-blind, placebo-controlled study.Front Neurol · 2025 · 16:1550670doi:10.3389/fneur.2025.1550670 · PMID 40103934

     Phase 3 on boat trips: vomiting 18.3 and 19.5 percent on tradipitant doses vs 44.3 percent on placebo. All authors Vanda employees; the key positive motion-sickness trial.

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     Nguyen T, Willett KC, Daly LR, et al. Tradipitant: A Novel Neurokinin-1 Receptor Antagonist for Motion Sickness.Am J Ther · 2026 · 33(4):e324-e328doi:10.1097/MJT.0000000000002147 · PMID 42150111

     Reviews the two phase 3 trials (Motion Syros and Motion Serifos) and pharmacology (half-life 34 hours). Secondary source confirming the motion-sickness trial results.

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     Pinkerton JV, Simon JA, Joffe H, et al. Elinzanetant for the Treatment of Vasomotor Symptoms Associated With Menopause: OASIS 1 and 2 Randomized Clinical Trials.JAMA · 2024 · 332(16):1343-54doi:10.1001/jama.2024.14618 · PMID 39172446

     Two phase 3 trials, about 400 postmenopausal women each: elinzanetant cut hot-flash frequency by about 3 more episodes a day than placebo at weeks 4 and 12, and improved sleep and quality of life. Bayer-funded with Bayer co-authors.

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     Kadota T, Kakuta N, Horikawa YT, et al. Plasma substance P concentrations in patients undergoing general anesthesia: an objective marker associated with postoperative nausea and vomiting.JA Clin Rep · 2016 · 2(1):9doi:10.1186/s40981-016-0034-9 · PMID 29497664

     In 23 surgical patients, plasma substance P fell by the end of anesthesia and recovered at 24 hours in the 14 without postoperative nausea and vomiting, but did not fall and was higher at 24 hours in the 9 with it. Small observational study; the authors propose it as an objective marker, and it illustrates both the research use and its limits.