Cyclic vomiting syndrome

In brief

A disease of intervals: what it is and how it is defined

Most vomiting illnesses are defined by what causes them. Cyclic vomiting syndrome, abbreviated CVS in the literature quoted throughout this page, is defined by its shape in time. A person who is otherwise well is overtaken, often in the small hours of the morning, by nausea and then by vomiting that recurs several times an hour, sometimes for a day and sometimes for a week, with pallor, lethargy, abdominal pain and photophobia, a painful sensitivity to light, along with an aversion to sound, and then it stops, appetite returns within hours, and the person is well until the next time ^7,31,32,34. The attacks are stereotyped, meaning each resembles the last in its hour of onset, its length and its symptoms, so that families and patients learn to recognize the opening minutes ³⁴. Between attacks there is nothing to find. That emptiness is why the illness went unexplained for so long and why, as later sections describe, it was for decades attributed to the mind.

The Rome Foundation, the international body that writes symptom-based criteria for what it now calls disorders of gut-brain interaction, formerly functional gastrointestinal disorders, placed cyclic vomiting syndrome among the gastroduodenal disorders in Rome IV in 2016, as one of three nausea and vomiting disorders beside chronic nausea and vomiting syndrome and, for the first time, cannabinoid hyperemesis syndrome ¹. The adult criteria require stereotyped episodes of acute onset lasting less than a week, at least three in the previous year and two in the past six months at least a week apart, and the absence of vomiting between episodes, although the criteria allow milder symptoms to persist in the intervals ¹. The Rome V revision published in February 2026 keeps the same three nausea and vomiting disorders inside a gastroduodenal chapter that now has five categories, adding an inability-to-belch syndrome, and a companion pediatric chapter keeps cyclic vomiting alongside chronic nausea syndrome and functional dyspepsia ^2,29. A 2026 editorial describes the deliberate move in Rome V away from the word 'functional', which had implied that symptoms were less real or merely psychological; the word is minimized rather than abolished, and functional dyspepsia keeps its name in both the adult and the pediatric chapter ^2,29,40. Prospective data have begun to strain the adult criteria. A 6-month electronic daily-diary study of 88 adults found a median episode length of 3.0 days, but 17.8% of the 191 episodes lasted longer than 10 days, beyond the Rome IV ceiling of a week, and 14.8% of the patients vomited or retched between episodes ⁴¹. That study and a companion interview study were run by employees of the drug company Takeda with the consultancy Evidera, and the first author of the 2025 review of outcome measures lists an AstraZeneca affiliation, so industry is building the measuring instruments that a drug trial would need ^41,42,43.

Children have their own criteria and a separate guideline tradition. The North American Society for Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN) issued a consensus statement in 2008 that defined the attacks, set out four red flags that should prompt targeted testing (abdominal signs such as bilious, that is green and bile-stained, vomiting or tenderness, triggering events such as fasting or a high-protein meal, an abnormal neurological examination, and a changing or worsening pattern), and recommended cyproheptadine, an antihistamine that also blocks serotonin, for children of five and under and amitriptyline, a tricyclic antidepressant used at low doses for migraine, for older children ³². In 2025 NASPGHAN replaced that consensus with two evidence-based guidelines, one on diagnosis and one on management, built with the GRADE framework, a formal system for grading how certain the evidence behind each recommendation is ^15,26. The diagnostic guideline recommends screening blood and urine tests and an upper gastrointestinal radiographic series, a barium swallow followed through the small bowel, for every child with suggestive symptoms, finds other screening tests low in yield, and provides, for the first time, a consensus clinical approach to cannabinoid hyperemesis in children as 'a related but separate entity' ²⁶. China issued its own national pediatric treatment guideline in the same year, published in Chinese without an English abstract, so it is cited here for its existence and date only ⁴⁴.

The criteria are a convention, not a measurement, and a 2024 prospective study at Children's Wisconsin showed how loosely they fit. Of 108 children referred with unexplained vomiting episodes, 46 ended with a clinical diagnosis of cyclic vomiting and 54 did not; the cyclic group more often had four or more episodes in the preceding year (81% against 55%) and longer episodes, and receiver operating characteristic analysis, a method for finding the cutoff that best separates two groups, found that 4 to 10 episodes a year and a duration over 2 hours discriminated best ⁴⁵. Photophobia, sweating, several separate vomits in an hour, which the paper counts as emeses, stereotyped episodes and continued retching after the stomach is empty were the features that set the condition apart, and fewer than half of the children with the final diagnosis met the Rome IV or NASPGHAN criteria ⁴⁵. The Rome V pediatric chapter of 2026 adopted those thresholds. It now requires stereotyped episodes of acute onset with vomiting several times an hour, at least four discrete episodes in the prior 12 months lasting from 2 hours to 7 days, episodes at least a week apart, a return to baseline health between them, and no better explanation after evaluation; migraine in the child or the family, listlessness, sweating, photophobia, abdominal pain and retching after the stomach is empty are listed as supportive features, and milder nausea or pain between episodes is now explicitly allowed ²⁹. A separate retrospective audit of 71 children at the Sanjay Gandhi Postgraduate Institute in Lucknow, India, published in 2026 with a correction a month later, found that all of them met Rome IV but only 66.2% met the NASPGHAN criteria and 62% the International Classification of Headache Disorders, third edition (ICHD-3), the headache classification of the International Headache Society ^46,47,48.

The adult form was described before 1999, but rarely and under other names: a single adult treated with lithium in 1977 ⁴⁹, and in 1988 eight Mayo Clinic adults with 'idiopathic cyclic nausea and vomiting', whose episodes came a mean of every 3.2 months and lasted a mean of 3.5 days and who all had abnormal gastric or small-bowel motility between episodes ⁵⁰. The series that opened the modern adult literature came in 1999, when Prakash and Clouse described 17 adults seen over ten years at Washington University, with onset at a mean age of 35 (range 14 to 73), episodes averaging 6 days and symptom-free intervals averaging 3.1 months, and noted that fewer than a third reported a prodrome or trigger ²⁷. Fleisher's 2005 series of 41 adults, seen between 1994 and 2003, found onset from age 2 to 49, recognizable prodromes in 93%, and a cluster in half the patients of vomiting episodes, migraine, nausea between episodes and panic attacks; he described a pattern of deterioration in which episodes coalesce in time until the well intervals disappear ³⁴. A 2012 systematic review of 1,093 cases in 25 papers found adults had longer and more frequent attacks than children, 5.9 against 3.4 days and 14.4 against 9.6 episodes a year ⁵¹. A 2012 comparison of 101 patients at the Medical College of Wisconsin found that those with pediatric onset were more often female (86% against 57%), more often had neurocognitive disorders (14% against 3%), waited longer for a diagnosis (10 years against 5) and never used opiates chronically (0% against 23%), but were otherwise clinically alike and responded alike to treatment, which argued against treating the two as different diseases ⁵².

Gee in 1882, a century of near silence, and the whole history including its reversals

Samuel Gee, a physician at St Bartholomew's Hospital in London who is better remembered for describing celiac disease, published a short paper in the hospital's reports for 1882 under the title 'On fitful or recurrent vomiting', describing children whose vomiting came in fits separated by intervals of health ³. The paper is a primary document that PubMed does not hold and this page relies on its title and on the way later authors have characterized it rather than on a quotation ^3,67. Li's 2025 history of the field dates the bedside investigation of the syndrome to more than a century ago and the modern era to the founding of the Cyclic Vomiting Syndrome Association in 1993 ⁶⁷.

Between those two dates the literature is thin and scattered across languages. The PubMed record shows mid-century papers from Romania, Japan, Germany and Poland on 'periodic vomiting with acetonemia, meaning ketones in the blood, the product of burning fat during fasting', 'so-called autointoxication', central nervous system lesions and 'diencephalosis', which treated the ketones in the urine or a presumed deep-brain disturbance as the disease, and a 1963 Japanese paper locating it in the diencephalon, the deep brain region that includes the hypothalamus ^{68,69,70,71,72}. The same decades used the term 'periodic syndrome': Cullen and MacDonald surveyed its nature and prevalence in Australia in 1963, and a 1968 Czech paper paired it with childhood migraine in its title, so the suspicion of a link to migraine is older than the evidence of the 1990s that established it; neither record carries an abstract, and both are cited by title only ^73,74. In 1960 Hoyt and Stickler at the Mayo Clinic published a study of 44 children with 'the syndrome of recurrent (cyclic) vomiting' in Pediatrics, the first substantial American series; the record carries no abstract ⁴. Treatments were tried one at a time on a few patients: lithium in a single adult in 1977 ⁴⁹, reserpine in Czechoslovakia in 1970 ⁷⁵, pizotifen, a migraine preventive, in children in a 1985 Lancet letter, and erythromycin, used as a stomach-emptying drug, in 20 children in 1993, with 13 reporting complete resolution in a trial its authors admitted was uncontrolled and open to a placebo effect ^76,77.

The modern era has a date. In November 1993 the Journal of Pediatric Gastroenterology and Nutrition published Fleisher and Matar's review of 71 patients seen between 1968 and 1988, which set down that the length and symptoms of episodes were stereotyped for each patient, that the disorder could last from months to decades, and that it coincided with migraine and irritable bowel syndrome ⁷⁸. In the same issue Li wrote an editorial calling the syndrome 'a pediatric Rorschach test', a condition onto which each specialty projected its own explanation ⁷⁹. The patient organization was founded that year and helped launch the field's scientific symposia, and in 1995 Abu-Arafeh and Russell published the first population-based study, from the schools of Aberdeen ^7,67. From there the literature grows steadily: the first adult clinical series under the name in 1999, after an eight-patient Mayo Clinic motility study in 1988, the mitochondrial hypothesis in 1999 and 2003, the first description of cannabinoid hyperemesis in 2004, the NASPGHAN consensus in 2008, Rome IV in 2016, the first adult guideline in 2019, the first evidence-based pediatric guidelines in 2025 and Rome V in 2026 ^{1,13,15,27,32,50,65,66,80}.

The 'cyclic vomiting is psychogenic' era, and how it ended

By the 1970s, after the mid-century metabolic and deep-brain theories described above had faded, a child who vomited in stereotyped fits with every test normal was left with an explanation of last resort: the child's mind and the child's mother. The PubMed record is explicit. A 1972 paper in the Journal of the American Academy of Child Psychiatry, indexed under psychophysiologic disorders and personality development, treated cyclic vomiting as a disturbance of the child's development ⁸¹. In 1977 Reinhart and colleagues at the Children's Hospital of Pittsburgh reported 16 children seen since 1956, of whom four had undergone exploratory abdominal surgery that found nothing and five had been referred to psychiatry, and concluded that the psychological conflicts were parental anxiety, 'a prolonged symbiotic relationship with the mother, and the failure of the child to separate and individuate' ⁸². The pattern of surgery that found nothing before the right diagnosis was made recurs in the record as late as 2008, when a Beijing series of 41 children found that 11 had first been treated for epilepsy and 13 had been operated on, 9 for a presumed hiatal hernia and 4 for compression of the duodenum by the superior mesenteric artery, before cyclic vomiting was recognized; that series reports no psychiatric referrals ⁸⁷.

The era did not end with a single discovery. It ended because three kinds of evidence accumulated that a psychological account could not carry. The first was physiological: in 1991 a quantitative electroencephalogram, a recording of the brain's electrical rhythms, showed abnormal slow delta activity during two episodes in an adolescent that resolved when she was well, which the authors wrote 'counter the hypothesis that vomiting in these patients is psychosomatic' and supported a migraine equivalent ⁸³. The second was epidemiological: Abu-Arafeh and Russell's 1995 schools survey found the condition in 1.9% of ordinary Aberdeen children, with a sex ratio of 1:1, motion sickness in 29% and migraine in 21%, and triggers, accompanying symptoms and relieving factors that overlapped migraine so far that the authors suggested a common pathogenesis; the study did not assess psychiatric disorders ⁷. The third was therapeutic: Li's 1999 cohort of 214 children showed that the 82% with a migraine link responded to anti-migraine drugs 79% of the time, and Dignan's 2001 follow-up found 46% of former patients had developed migraine against 12% of matched controls ^9,10.

Fleisher's 1993 paper stands at the hinge. It describes the stereotyped episodes and the coincidence with migraine, and it still lists, among the elements of management, 'sensitivity to stresses caused by the illness and to feelings and attitudes that may predispose to attacks' ⁷⁸. That sentence is not a return to the mother-blaming of 1977; it is an early form of what the 2019 and 2025 guidelines call a biopsychosocial approach, in which anxiety and depression are treated as comorbid conditions that lower the threshold for attacks and worsen their course, not as the cause of the vomiting ^13,15. The global Rome survey found depression and anxiety independently associated with the syndrome, with an odds ratio of 3.14 for depression, meaning the odds of depression were about three times those of people without the syndrome, and 1.79 for anxiety, and a 2026 systematic review of 1,375 children found psychological stress named as the trigger in 26.2% of episodes, with infection (22%), motion sickness (19.3%) and migraine (12.9%) accounting for most of the rest ^6,88. A trigger is not a cause, and the same review found mitochondrial disease in 0.4% and surgical causes in 4.8% ⁸⁸.

The old habit has consequences that outlast it. Tarbell and van Tilburg argued in 2024 that psychological therapies for cyclic vomiting, despite reported clinical success, have no evidence base and are offered in few gastroenterology practices, which has produced an 'all guts no brain' approach, and they called for the evidence to be built ⁸⁹. A 2026 qualitative study of adults with the syndrome and their caregivers described a recurring 'epistemic rupture' in which clinicians fail to recognize or validate the illness, which the authors frame as epistemic injustice, the harm done when a person's testimony about their own body is not believed ⁹⁰. And the thread of psychological treatment persists in a modern form: a 2026 case report from Addis Ababa describes a 10-year-old whose stereotyped attacks, consistently triggered by anger and interpersonal conflict, ceased after nine months of structured psychiatric care including anger management and family psychoeducation. The child was given a psychiatric diagnosis, somatic symptom disorder, unspecified, in the terms of the fifth edition of the Diagnostic and Statistical Manual, text revision, and the authors present the case within a biopsychosocial, gut-brain framework consistent with the 2025 guideline's emphasis on stress reduction rather than as a revival of the psychogenic model ^15,91. One child's remission after a treatment is not evidence that the treatment caused it, in either direction.

The correct reading of the era is not that psychology was irrelevant but that it was placed at the wrong end of the causal arrow. The modern synthesis, as Li summarized it in 2025, is of a disorder 'inscribed on an autonomic polyvagal design', a reference to the theory that different branches of the vagus nerve govern calm and threat responses, with multiple interacting pathways, in which the stress response, the endocannabinoid system, the migraine machinery and the hypothalamic-pituitary-adrenal axis, the hormonal chain from brain to adrenal glands that produces cortisol under stress, all appear, and in which anxiety is both a consequence and an amplifier of attacks ⁶⁷. What the psychogenic era got right is that stress precipitates episodes; what it got wrong is everything it inferred from that fact.

How common it is: from the Aberdeen schools to the Rome Foundation global survey

The first number came from a questionnaire. Abu-Arafeh and Russell screened 10% of all children aged 5 to 15 attending school in Aberdeen, 2,165 of them, invited the 69 (3.9%) with a history of unexplained vomiting for interview, and found that 34 met the criteria, a prevalence of 1.9% ⁷. The children had a mean age at onset of 5.3 years, attacks about eight times a year lasting about 20 hours, equal numbers of boys and girls, motion sickness in 29% and migraine in 21%, and the authors observed that the triggers, the accompanying symptoms and the things that relieved an attack overlapped so far with migraine that a common pathogenesis seemed likely ⁷. Incidence, the rate of new cases, came from Ireland: every pediatrician on the island was surveyed monthly through 2005 and reported 41 valid new cases, 3.15 per 100,000 children per year (95% confidence interval 2.19 to 4.11), with a median age at onset of 4 years, a median of eight episodes a year, 85% of school-age children missing school and 44% admitted to the hospital ⁸. The authors compared that incidence with Crohn's disease in childhood ⁸.

Adults were first counted in the general population with the Rome IV criteria, although Rome III had already defined adult cyclic vomiting and was the basis of the Wisconsin studies of 2010 and 2012 ^52,58. In 2015 an internet survey of 5,931 adults in the general populations of the United States, Canada and the United Kingdom, sampled by quota to be representative, found 2.2% met criteria for a Rome IV functional nausea and vomiting disorder; the prevalence of cyclic vomiting syndrome specifically was 2% in the United States, 0.7% in Canada and 1% in the United Kingdom, a difference that reached statistical significance (P = 0.03, meaning a 3% probability of a difference this large arising by chance if there were none) ⁵. Across all the functional nausea and vomiting disorders, health impairment and health-care use were greater than in controls, and the independent correlates were younger age, more severe somatic symptoms, lower quality of life, irritable bowel syndrome and functional dyspepsia, meaning chronic upper-abdominal pain, burning or fullness without a structural cause; on subgroup analysis, somatic symptom severity was associated with cyclic vomiting specifically, while poor quality of life was associated with chronic nausea and vomiting syndrome and not with cyclic vomiting ⁵. The Rome Foundation Global Epidemiology Study then surveyed 54,127 adults in 26 countries with the Rome IV questionnaire and found a pooled prevalence of 0.3% (95% confidence interval 0.3 to 0.4; 187 people), highest in Brazil at 1% and with no one meeting criteria in Japan or Germany; those affected had a mean age of 36.7 years, were 56.7% women, and had independently higher odds of depression (3.14) and anxiety (1.79) and lower physical and mental quality of life ⁶. Why a United States sample gave 2% and a global one 0.3% is not settled; sampling, questionnaire translation and genuine variation are all candidates, and a 2024 review of the world's data concluded that prevalence and incidence vary widely and are hindered by inconsistent methods and poor disease recognition ⁹².

Hospital data count the severe end. In the United States National Inpatient Sample, admissions for cyclic vomiting fell from 11,055 in 2016 to 8,625 in 2019, the 2019 admissions costing over 300 million dollars; the mean age was 34.7 years, 62.5% were women, 37.2% were aged 18 to 30, anxiety or depression was recorded in 38.6% and cannabis use in 35.0%, and 90.4% went home routinely ¹¹. African Americans were disproportionately represented and Hispanic patients incurred the highest costs ^11,92. In the Epic Cosmos database of 248 million emergency department encounters from 2016 to 2024, 204,636 (0.08%) carried a code for cyclic vomiting, more than gastroparesis (165,857), which is abnormally slow stomach emptying without a blockage, or cannabinoid hyperemesis (134,059); the admission rate for cyclic vomiting fell from 20.3% in 2016 to 11.5% in 2024, mean length of stay was 4.7 days, and ondansetron was given in 63% of visits ²⁸. A separate analysis of the Nationwide Emergency Department Sample found visits coded as cyclic vomiting without cannabis fell from 300 to 186 per 100,000 between 2016 and 2022 while visits coded as both cannabis-related and cyclic vomiting, a proxy for cannabinoid hyperemesis, rose from 4.4 to a peak of 33.1 in the second quarter of 2020 and stayed at 22.3 in 2022 ⁹³. Whether that is a change in disease or in coding is unknown.

The natural history differs sharply by age. Most children stop vomiting: in the Aberdeen follow-up, half of 26 traced patients were asymptomatic, and the ones still affected often had migraine instead ¹⁰. In the 2026 Lucknow series of 71 children followed for a median of eight years, all of whom had severe disease and received prophylaxis, 50.7% had complete and 35.3% significant response, and prophylaxis was stopped successfully in 13 of 36 complete responders, three of whom relapsed ^46,47. Adults do worse. In 455 adults at a specialist clinic in Wisconsin, followed for a mean of 47 months, episodes per year fell from 18 to 6.8, emergency visits from 6.1 to 2 and hospitalizations from 2.3 to 0.7, yet only 88 (19%) resolved completely, and 19 patients (4%) died during follow-up; non-white race, a higher count of comorbid conditions, cannabis use and aprepitant use, a marker of refractory disease, each reduced the odds of resolution ¹². The study does not report causes of death, and the 4% should be read as a mortality in a referral population with heavy comorbidity, not as a death rate from vomiting.

• Rome IV and Rome V symptom criteriaThere is no blood test or scan; the diagnosis is a pattern. Rome IV (2016) required stereotyped episodes of acute onset lasting less than a week, three in the prior year and two in the past six months at least a week apart, with no vomiting between episodes; Rome V (2026) keeps cyclic vomiting as one of three nausea and vomiting disorders beside chronic nausea vomiting syndrome and cannabinoid hyperemesis syndrome, and its pediatric chapter rewrote the child criteria to require vomiting several times an hour and at least four discrete episodes in 12 months, each lasting 2 hours to 7 days and at least a week apart ^1,2,29.Every adult diagnosis and every clinical trial entryNot formally validated against an external standard, because none existsIn a prospective pediatric cohort fewer than half the children with a final clinical diagnosis met the Rome IV criteria or those of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition (see the next row) ⁴⁵
• North American Society for Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN) criteria (2008, revised 2025)The 2008 consensus criteria and the 2025 revision define attacks by frequency, duration and associated symptoms; the 2025 panel recommends screening blood and urine tests and an upper gastrointestinal radiographic series for every child, and judged other screening tests low-yield ^26,32.Children and adolescents; the upper gastrointestinal series, a barium swallow followed through the small bowel, exists to catch malrotation, a birth defect in which the intestine sits wrongly and can twist and blockA 2024 prospective study found a frequency of 4 to 10 episodes a year and a duration over 2 hours gave the best sensitivity, with photophobia, sweating, several emeses an hour and continued retching after the stomach is empty as discriminating features ⁴⁵Malrotation, acute hydronephrosis, brain tumors, Addison's disease and a fatty-acid oxidation disorder have all presented as cyclic vomiting; in 225 children with the pattern, 12% had a serious surgical, renal or central nervous system cause and 2% an endocrine or metabolic one ¹⁶⁵
• Upper endoscopy and abdominal imagingThe adult guideline's minimum work-up is an upper endoscopy and imaging of the abdomen, to exclude structural causes rather than to confirm the syndrome ^13,134.Adults at diagnosis; children selectively by red flagsFindings are usually those of the vomiting itself: in 63 Chinese children scoped during the illness, 60% had reflux esophagitis, bile reflux gastritis, erosions or ulcers, and 35% chronic gastritis alone ¹⁵³Nothing it sees proves the syndrome; a normal study is the expected result
• Cannabis history, with a trial of sustained abstinenceRome IV makes cannabinoid hyperemesis syndrome a diagnosis that requires sustained relief after stopping cannabis without setting a duration; the Rome V pediatric chapter sets at least 6 months and Bonnet argues for 6 to 12 months. Without that observation, a heavy user with cyclic vomiting cannot be assigned to either ^1,29,30,166.Every adult, since 41% of patients in one specialist clinic used cannabis and 21% used it four or more times a week ⁸⁴Hot-water bathing does not discriminate: it was reported by 44% of people with cyclic vomiting in a population survey, independent of cannabis use though augmented by it, and by 73% of a clinic cohort that included regular users ^5,22Of 57 cannabis users in one specialist cohort, 50 had abstained for more than a month and only one reported that the episodes stopped ⁸⁴

The migraine connection: the family history, the triptans, the same prophylactics, and the dorsal raphe

The strongest clue to what cyclic vomiting is comes from what it keeps company with. Li and colleagues studied all 214 children who met consensus criteria at their service in Columbus, Ohio, between 1986 and 1998 and classified 82% as having migraine-associated cyclic vomiting on one of two grounds, a family history of migraine or the later development of migraine headaches ⁹. Compared with the rest, that subgroup had milder episodes (a mean of 20.7 against 39.5 emeses per episode), more abdominal pain, headache, social withdrawal and photophobia, more identifiable triggers including psychological stress, physical exhaustion and motion sickness, and a response to anti-migraine therapy of 79% against 36% ⁹. Dignan's follow-up of the Aberdeen children found past or present migraine in 46% against 12% of matched controls ¹⁰. On the strength of the 82% figure and a 60% response to anti-migraine drugs, Olson and Li built a decision analysis in 2002 showing that an empiric trial of migraine therapy plus an upper gastrointestinal barium series, to exclude malrotation of the bowel, was cheaper than extensive testing and avoided 65% of endoscopies ⁹⁴.

The drugs confirm the kinship. Sumatriptan, which activates the serotonin receptor subtypes 5-HT1B and 5-HT1D (5-HT is the chemical name for serotonin, 5-hydroxytryptamine, and 1B and 1D name receptor subtypes) and so is called an agonist, a drug that switches a receptor on, was designed for migraine and was tested by Hikita in an uncontrolled, open trial in 12 young patients: subcutaneous injection was effective in 19 of 35 attacks in 11 patients, nasal spray completely effective in two of six attacks, and efficacy was higher in attacks in children with a family history of migraine (P = 0.048) ⁹⁵. Calhoun and Pruitt reported adults whose attacks stopped with injectable sumatriptan 'even in the absence of headache' and argued that adult cyclic vomiting lies on the migraine spectrum ⁹⁶. The 2019 adult evidence review found moderate certainty for triptans as abortive therapy, the only treatment in the syndrome to reach that grade, and the 2025 pediatric guideline made its one strong recommendation for anti-migraine agents to abort attacks in children with a personal or family history of migraine, drawing explicitly on indirect evidence from pediatric migraine trials to shore up the sparse cyclic vomiting data ^14,15. The formal classifications agree. The International Headache Society's classification, the third edition of the International Classification of Headache Disorders, lists cyclic vomiting syndrome among the 'episodic syndromes that may be associated with migraine', beside abdominal migraine, benign paroxysmal vertigo and benign paroxysmal torticollis ^48,97. The preventives are the same list: amitriptyline, cyproheptadine, propranolol, topiramate and, by extension from migraine, onabotulinumtoxinA, the botulinum toxin injections approved to prevent chronic migraine, in a single case. Greene and colleagues note in 2025 that the drugs against calcitonin gene-related peptide (CGRP, a pain-signaling peptide released by the trigeminal nerve during migraine), a 5-HT1F receptor agonist and the migraine neuromodulation devices have not yet been studied in cyclic vomiting ^15,97,98,99.

Where in the brain the two disorders meet is less certain. Positron emission tomography of spontaneous human migraine attacks in 1995 showed increased blood flow in the cingulate cortex, a midline region involved in pain and emotion, in auditory and visual cortex and in the brainstem, and only the brainstem activation persisted after sumatriptan had abolished the headache, which the authors read as an imbalance between brainstem nuclei regulating pain and vascular control ⁵³. That finding was widely taken to implicate the dorsal raphe nucleus and the locus coeruleus, the brainstem's main sources of serotonin and norepinephrine, as a 'migraine generator'; a 2001 study in conscious rats, which stimulated the trigeminal nerve, the nerve that carries sensation from the face and head, by injecting capsaicin, the burning compound of chili peppers, into the fluid around the brainstem, found that the dorsal raphe, locus coeruleus and hypothalamus all activated in response to trigeminal pain, and its authors argued that this opposed a primary pathogenic role for those nuclei, since they responded to pain rather than initiating it ¹⁰⁰. The dorsal raphe is a nausea structure in animals: in the least shrew, an animal that vomits, emesis induced by serotonin, dopamine and neurokinin-1 receptor agonists and by cisplatin, a chemotherapy drug that reliably causes vomiting, produced Fos expression, a marker of neuronal activity, not only in the dorsal vagal complex, the brainstem vomiting center made up of the area postrema, the nucleus of the solitary tract and the dorsal motor nucleus of the vagus, but in the dorsal raphe and paraventricular thalamus, nuclei 'not usually discussed regarding emesis' ⁵⁴. And cannabidiol's suppression of vomiting in shrews was blocked by a 5-HT1A antagonist given systemically, while its suppression of nausea-like gaping in rats was reversed by a 5-HT1A antagonist injected into the dorsal raphe itself, which places the anti-nausea effect of the non-intoxicating part of cannabis at serotonin autoreceptors there, receptors through which a neuron damps its own firing ⁵⁵. No study has imaged or recorded the dorsal raphe during a cyclic vomiting attack in a person; its role is an inference from migraine and from animal emesis.

Neurophysiology may yet close that gap. Levinthal and Kuo observed in 2024 that cyclic vomiting is episodic like migraine and epilepsy and responds to the drugs that prevent and abort both, which 'strongly suggest' a neural basis, and proposed that tests of cortical excitability and central neuromodulation, such as transcranial magnetic stimulation, in which magnetic pulses applied through the scalp excite or quiet the cortex, could become the next generation of diagnostics and treatments ¹⁰¹. A 2018 review noted that functional magnetic resonance imaging, a scan that tracks brain activity through changes in blood oxygen, shows in both cyclic vomiting and migraine diminished connectivity between the insula, the cortical region that represents the state of the body, and the sensorimotor network ¹⁰². These are shared signatures, not a shared lesion, and the honest summary in 2026 is that cyclic vomiting behaves like migraine in its inheritance, its triggers, its drugs and its course, and that the brainstem circuitry linking the two is assumed from migraine rather than demonstrated in cyclic vomiting.

The reversal: the mitochondrial DNA haplogroup claim and how weakly it replicated

Mitochondria are the structures inside cells that make most of their energy, and they carry their own small genome, inherited only from the mother. In 1999 Boles and Williams described six unrelated children with cyclic vomiting and a strong maternal family history, each with migraine-like features and several with developmental delay, seizures or poor growth; five had raised lactate, the acid that accumulates when energy metabolism fails, and one had a confirmed large rearrangement of mitochondrial DNA ⁶⁵. They proposed that mitochondrial DNA mutations can cause cyclic vomiting and should be considered when the picture is severe or maternally inherited ⁶⁵. In 2003, interviewing a parent of 62 children at the severe end of the spectrum, Boles found migraine, myopathy (muscle disease), seizures and symptoms resembling dysautonomia, which is disordered automatic control of heart rate, blood pressure and sweating, in 75% of mothers against 11% of fathers, maternal inheritance suggested in 86% of families, and body-fluid metabolites and muscle biopsies 'consistent with mitochondrial dysfunction in most cases tested', and concluded that mitochondrial DNA variants were at least risk factors in this 'CVS plus' group ⁶⁶.

The claim became specific in 2009. Zaki, Boles and colleagues sequenced the entire mitochondrial genome in 20 children with cyclic vomiting who belonged to haplogroup H, a common European lineage chosen for homogeneity, compared the sequences with haplogroup-H controls, and then tested the variants of interest in 10 more children and 112 adults with migraine without aura ²⁰. The polymorphism 16519C to T was found in 21 of 30 cyclic vomiting subjects (70%, odds ratio 6.2) and 58 of 112 migraineurs (52%, odds ratio 3.6) against 63 of 231 controls (27%); a second variant, 3010G to A, was present in 6 of 21 cyclic vomiting subjects carrying 16519T (29%, odds ratio 17) against 1 of 63 controls (1.6%) ²⁰. The authors wrote that the two polymorphisms 'constitute a substantial proportion of the genetic factor in migraine pathogenesis' ²⁰. Camilleri's group at the Mayo Clinic tested the same variants that year in 699 people, patients with functional gastrointestinal disorders and healthy controls, and found a modest association of 3010A with nonspecific abdominal pain (odds ratio 3.3), slower gastric emptying with 3010G and lower satiation with the haplogroup-H marker 7028C, but no association with most of the motor and sensory measures tested ¹⁰³. 16519T is a common polymorphism, present in 27% of healthy haplogroup-H controls, and 3010A was found in 1.6% of them; neither is a pathogenic mutation ²⁰.

Then it failed to replicate where it mattered most. In 2014 Venkatesan, with Zaki and Boles as co-authors, performed a quantitative pedigree analysis in 195 of 216 adults with cyclic vomiting and genotyped all 216 for 16519T and 3010A ²¹. Adults with the syndrome did have more probable maternal inheritance of functional disorders than controls (12% against 1%), but 'the prevalence of mitochondrial SNP's 16519 T, 3010A and the AT genotype were similar in Haplogroup H CVS patients compared to historical controls', and there was no correlation with age of onset, so the childhood finding did not carry into adults ²¹. A year later Boles published a study in Mitochondrion titled 'Are we describing different parts of an energy-depleted elephant?', in which the same two polymorphisms were reported as associated with chronic fatigue syndrome, complex regional pain syndrome, sudden infant death syndrome and major depressive disorder among haplogroup-H individuals ¹⁰⁴. An association that extends to a growing list of conditions in small samples is, in genetics, more often a sign of a confounded marker than of a shared cause. Two later pediatric studies outside Europe found no significant association: 16519T was present in 40% of 30 Thai children against 27.7% of Thai controls (P = 0.18) and 3010A in 6.7% against 0.7% (P = 0.07), and in 13 sequenced Shanghai children the two variants appeared in 4 and in 2 without significant association, although neither study repeats the haplogroup-H design ^105,106. The idea has not been abandoned, however: a 2015 review still proposed that cyclic vomiting 'may represent a mitochondriopathy', and the 2026 Rome V pediatric chapter still cites mitochondrial polymorphisms, maternal inheritance and metabolic abnormalities during attacks in support of mitochondrial dysfunction ^29,33. The reversal is specific: it is the two variants, and the adult population, that did not hold up, while the broader idea survives in children's guidance on weaker evidence than its standing implies. It should be noted that the corresponding author's listed email address on the 2015 paper was at Courtagen, a commercial genetic-testing company, while his listed affiliation was Children's Hospital Los Angeles ¹⁰⁴.

What survives is a treatment without a confirmed mechanism. Boles reported in 2011 a retrospective series of 30 children and adults treated on a loose protocol of fasting avoidance, coenzyme Q10 and L-carnitine, the two cofactors most often given for mitochondrial disease, with amitriptyline added in refractory cases and blood-level monitoring; episodes resolved in 23 and improved by more than 75% in three more ¹⁰⁷. The 2012 Wisconsin series treated adults with tricyclics, topiramate, coenzyme Q10 and L-carnitine and reported response in 86%, with compliance the only factor predicting it ⁵². The 2019 adult evidence review graded the mitochondrial supplements as very-low-certainty evidence and the guideline conditionally recommended coenzyme Q10, L-carnitine and riboflavin as alternate or concurrent prophylaxis; the 2025 pediatric guideline likewise conditionally recommends supplements, listing coenzyme Q10, riboflavin and magnesium ^13,14,15,16. A 2013 review of mitochondrial dysfunction in migraine put the general position plainly: the classic mitochondrial disease mutations had demonstrated no association with migraine, while 16519T and 3010A had been associated with pediatric cyclic vomiting and migraine, specific migraine-susceptibility mutations had been identified and POLG mutations, which impair the copying of mitochondrial DNA, could cause disease including migraine; testing the two polymorphisms would need very large samples ¹⁰⁸.

Genetics has moved on to other candidates, none yet confirmed. Variants in the gene for the cannabinoid receptor CB1 (CNR1 rs806380) raised the odds of cyclic vomiting and a mu-opioid receptor variant (OPRM1 rs1799971) lowered them in 65 patients compared with 1,092 controls from the 1000 Genomes Project in 2017 ⁶²; serotonin receptor variants in HTR1B, HTR1D, HTR3B and HTR3C were associated with the syndrome in 70 patients against 2,504 public controls in 2025, with one HTR1D genotype carrying a seven-fold higher risk of depression among patients ⁶³; single-nucleotide polymorphisms, the one-letter DNA variants these studies count, are common in healthy people. Both are small case-control studies using public-database controls, a design prone to false positives from population stratification, and no replication of either had been published in PubMed by October 2026. Two rare syndromes provide something firmer: in Jansen-de Vries syndrome, caused by variants in the gene PPM1D, an international survey of 21 patients found 61% met Rome IV criteria for cyclic vomiting, most undiagnosed, and in 15 people with loss of one copy of the chromatin-remodeling gene BPTF, three had a diagnosis of cyclic vomiting and four more met most of the criteria of the International Classification of Headache Disorders ^109,110. Those are single-gene disorders in which cyclic vomiting is a feature, which shows a genetic path to the phenotype exists, not that common cyclic vomiting travels it.

The Sato variant, the adrenergic hypothesis and the autonomic nervous system

In 1982 Sato and colleagues in Japan, whose forename the PubMed record does not give, described an 8-year-old girl who, for 16 months after a head injury, had periodic attacks of vomiting, psychotic depression, drowsiness and hypertension of 160/110 mm Hg ³⁷. At the start of each attack her serum ACTH, the pituitary hormone that drives cortisol, rose to 610 pg/ml and vasopressin, the hormone that retains water, to 41 microunits/ml, followed by high cortisol, low sodium and dilute plasma; urinary epinephrine and norepinephrine rose while dopamine fell, and the dopamine metabolite homovanillic acid in her spinal fluid dropped from 70 to 23 ng/ml during attacks; methyldopa and reserpine, two drugs that deplete or oppose catecholamines, suppressed the episodes ³⁷. In 1988 the same group reported two more patients, aged 17 and 3, with attacks of vomiting, hypertension and psychotic depression recurring at fixed intervals for years, in whom ACTH, vasopressin, norepinephrine and prostaglandin E2 were markedly raised at the start of each attack while dopamine was undetectable, and in whom indomethacin, a prostaglandin blocker, suppressed attacks for a year ³⁸. Their hypothesis was a periodic failure of dopaminergic restraint over norepinephrine release, with ACTH and vasopressin discharged alongside ³⁸.

These are three patients, and the syndrome named for Sato has stayed rare. Hypertension during attacks is nevertheless real and measurable: 10% of 32 Singaporean children had systemic hypertension, 2 of 110 children in Guangzhou had raised blood pressure during attacks, and a 2026 case report describes a 16-year-old with long-standing cyclic vomiting and recurrent hypertension who twice developed posterior reversible encephalopathy syndrome, a swelling of the back of the brain caused by acute hypertension, with the second episode following sustained postoperative hypertension ^39,111,112. Li's 2025 history lists 'Sato' as one of three endophenotypes of the syndrome beside migraine and cannabinoid hyperemesis, and the 2019 adult guideline recommends screening for autonomic dysfunction as a comorbid condition ^13,67.

Taché generalized the adrenergic observations in 1999 into the corticotropin-releasing factor hypothesis. Corticotropin-releasing factor (CRF) is the hypothalamic peptide that starts the stress cascade; injected into the brain or the periphery of rats and other species it inhibits gastric emptying, acts on the paraventricular nucleus of the hypothalamus and the dorsal vagal complex, and mediates the delayed gastric emptying caused by psychological, physical and immunological stress ⁵⁶. Taché noted that cyclic vomiting is precipitated by the stimuli that release CRF, that the endocrine and autonomic changes during attacks are those of central CRF activation, and that the drugs found empirically to help are known experimentally to block CRF release or action, and he wrote that the relevance of central CRF activation 'deserves further consideration' ⁵⁶. It has been considered for 27 years without a direct test in patients: no trial of a CRF antagonist in cyclic vomiting appears in the literature cited here, and the guideline committee's 2019 research agenda lists none, so the hypothesis survives because nothing has displaced it ^56,113. A 2026 mouse model of the childhood acetonemic form found that 8 hours of restraint stress depleted liver glycogen in both young and adult mice, but only young mice failed to restore it by 16 hours, because stress cut their food intake, and only young mice developed marked ketosis, which the authors offer as a step toward explaining why the ketotic form resolves around age 10 ⁵⁷. Mice cannot vomit, so the model addresses the metabolic accompaniment, not the vomiting.

The autonomic nervous system, the involuntary system that sets heart rate, blood pressure, sweating and gut movement through a sympathetic branch, the fight-or-flight side, and a parasympathetic branch, the rest-and-digest side carried largely by the vagus nerve, is measurably abnormal between attacks. Venkatesan tested 20 adults meeting the Rome III criteria, the 2006 edition, and 20 controls: 17 patients (85%) and 2 controls (10%) had abnormal thermoregulatory sweat tests (P < 0.001), 7 patients (35%) and one control had a heart-rate rise over 30 beats a minute on standing, the definition of postural tachycardia, and 18 (90%) had one or both, while the heart-rate response to deep breathing, a test of the parasympathetic branch, was normal in 95% of both groups ⁵⁸. The conclusion was sympathetic impairment with an intact parasympathetic system, in a sample of 20 ⁵⁸. A 2024 functional MRI study at Massachusetts General Hospital, applying sustained cuff pressure to the leg, found that patients lost high-frequency heart-rate variability, a marker of parasympathetic outflow, more than controls, showed weaker coupling between that variability and signal in the anterior insula and the pregenual anterior cingulate, cortical regions that register the body's internal state and pain, and in the prefrontal cortex, and reported rising pain over the stimulus where controls did not, which the authors read as altered central coding of both pain and autonomic responsiveness ⁵⁹. The two studies disagree on the parasympathetic branch, one finding it intact at rest and the other finding it abnormal under pain, and both are small.

The stomach between attacks reversed the field's first mechanistic theory. Abell's eight adults in 1988 all had abnormal motility measured between episodes, with gastric hypomotility in five, small-bowel dysmotility in six and delayed gastric emptying in two, and the authors proposed a disorder of gastrointestinal motility ⁵⁰. Scintigraphy, a scan that times how fast a radioactively labeled meal leaves the stomach, found the opposite pattern in larger series: emptying was rapid in 23 of 30 Kansas adults tested between attacks (77%), normal in 4 and delayed in 3 ¹¹⁴, and in a retrospective review of 92 adults it was rapid in 54 (59%), normal in 25 (27%) and slow in 13 (14%), the slow group largely explained by narcotics, diabetes or marijuana use ¹¹⁵. Delayed emptying, the finding that defines gastroparesis, is therefore the exception in adult cyclic vomiting rather than the rule, which matters because the two diagnoses are frequently confused. These are retrospective single-center data from referral clinics.

These findings have shaped treatment more than theory. Propranolol, a beta-blocker that opposes the adrenergic signal, was more effective than amitriptyline in a randomized comparison of 181 Iranian children, with results reported for 164 of them (effective in 74 of 83 against 46 of 81), and the 2025 pediatric guideline conditionally recommends beta-blockers for prevention ^15,31. Auricular percutaneous electrical nerve field stimulation, a device that stimulates branches of the vagus and other nerves at the ear, reduced abdominal pain and state anxiety in an open-label study of 30 children with drug-refractory disease, with benefits for anxiety persisting at four to six months ¹¹⁶. Li's reading of the field in 2025 is that behavioral treatment and vagal neuromodulation appear to work 'perhaps by reestablishing autonomic (parasympathetic) balance', which is a hypothesis consistent with the data rather than a mechanism shown by them ⁶⁷.

Cannabis: one spectrum or two conditions, with the 2023 to 2026 evidence on both sides

In 2004 Allen and colleagues in South Australia reported 19 patients with chronic cannabis use and a cyclical vomiting illness; of the nine followed, cessation of cannabis ended the vomiting in seven, three who resumed relapsed, and nine of ten, including a previously published case labeled psychogenic vomiting, showed an abnormal washing behavior during episodes of active illness ⁸⁰. The authors concluded that cannabis was the cause in all cases ⁸⁰. The Mayo Clinic assembled 98 patients by 2012, all under 50; of the 37 whose duration of use was recorded, 68% (25) had used cannabis for more than two years before symptoms began, and of the 57 in whom the effect of hot-water bathing was documented, 52 (91%) reported relief with hot showers or baths, though follow-up was available in only 10, of whom 7 stopped cannabis and 6 of those improved ¹¹⁷. On that foundation Rome IV in 2016 created cannabinoid hyperemesis syndrome as a diagnosis requiring stereotyped episodes resembling cyclic vomiting, prolonged excessive cannabis use, and relief after sustained cessation ¹. Within three years the same literature had been read two ways.

The case for one spectrum rests on the overlap. Patients with cyclic vomiting use cannabis at high rates, 41% of 140 in one specialist clinic with 21% using it four or more times a week, and most of them say it helps ⁸⁴. Of the 57 current users in that cohort, 50 (88%) said they had at some point stopped for more than a month, yet only one reported that the episodes stopped while abstinent, so only that one patient met the Rome IV criteria for cannabinoid hyperemesis; that patient later resumed cannabis and stayed well ⁸⁴. Hot-water bathing, the behavior Allen made a hallmark, is reported by 44% of people with cyclic vomiting in the general population independent of cannabis, augmented but not created by it, and by 73% of a clinic cohort of 111, where more than 80% said it relieved nausea, vomiting, pain and panic, with regular cannabis users more likely to use very hot water and slower to get relief ^5,22. A 2025 Indian case report, a letter without an abstract, describes compulsive bathing in a patient with cyclical vomiting syndrome ¹¹⁸. The 2019 adult guideline committee, reviewing every published series, found most data heterogeneous with limited follow-up and wrote that it was difficult to tell whether cannabis is causal, a clinical association, or 'unmasks or triggers symptoms in patients inherently predisposed to develop CVS' ¹¹⁹. Alshaarawy, Balasubramanian and Venkatesan reiterated in 2023 that 'it is unclear if cannabinoid hyperemesis syndrome is truly a distinct entity or a subtype of cyclic vomiting that is unmasked by heavy cannabis use and the associated dysregulation of the endocannabinoid system' ¹²⁰, and Hasler, Alshaarawy and Venkatesan wrote in 2025 that hot bathing is 'not specific' for cannabinoid hyperemesis because about half of cyclic vomiting patients report it ²³. The mechanism offered is that the endocannabinoid system, which regulates stress, nausea and vomiting, is dysregulated in both conditions and that chronic high-dose cannabis pushes it the same way that chronic stress does ⁶⁴.

The case for two conditions rests on cause and course. Russo and Whiteley argued in 2024 that cannabinoid hyperemesis has 'genetic susceptibility to toxic exposure', citing five variants significantly more frequent in patients than in heavy users without symptoms, affecting the TRPV1 receptor, two dopamine genes, the enzyme CYP2C9 that metabolizes tetrahydrocannabinol and an ABC drug transporter, and wrote that 'nosological confusion', confusion about how the diseases should be classified, had arisen with cyclic vomiting even though their presentation and pathophysiology 'are clearly distinct' ²⁴. The genetic study they cite genotyped 28 patients and 12 cannabis-using controls from an online survey, reported odds ratios of 5.8 to 12 for variants that were also present in 10% to 30% of the controls rather than absent from them, and has not been replicated; its first and last authors are affiliated with CReDO Science and two co-authors with Endocanna Health, both commercial companies, a conflict of interest to note ¹²¹. Bonnet's 2026 case report and hypothesis paper holds that the only criterion that separates the two is persistent disappearance of symptoms during cannabis abstinence, that observation periods of 12 months are needed for reliability, that most published cases are therefore only suspected cannabinoid hyperemesis, and that in his patient each episode was worse than the last, suggesting a sensitization that persisted through relapse ³⁰. The 2025 NASPGHAN diagnostic guideline, after its own systematic review, provides a consensus approach to pediatric cannabinoid hyperemesis 'as a related but separate entity', and the Rome V gastroduodenal chapter of 2026 keeps the two as distinct diagnoses within one category ^2,26. The Rome V pediatric chapter goes the other way: it lists cannabinoid hyperemesis as a subcategory under cyclic vomiting and calls it 'a subtype of CVS', to be diagnosed only after prolonged, for example one to two years, near-daily cannabis use and only if the vomiting resolves with at least six months of cessation, with hot bathing and a positive urine test for tetrahydrocannabinol counted as supportive remarks rather than criteria ²⁹. In 2026, then, three bodies classify the same relationship three ways: NASPGHAN as a related but separate entity, the adult Rome committee as a sibling diagnosis, and the pediatric Rome committee as a subtype. Yacob's 2025 review puts the practical distinction as a difference of cause, epidemiology and management rather than of symptoms ¹²².

The population data of 2025 and 2026 sharpen both sides without settling the question. United States emergency visits carrying both a cannabis-related code and a cyclic vomiting code, the study's proxy for cannabinoid hyperemesis because no code for the syndrome exists, rose from 4.4 per 100,000 visits in 2016 to a peak of 33.1 in the second quarter of 2020 and 22.3 in 2022, while visits coded as cyclic vomiting without cannabis fell from 300 to 186, with risk highest at ages 18 to 25 ⁹³. A 2025 nationally representative survey of 7,034 adults found 2.7% of all respondents and 17.8% of daily cannabis users reported symptoms resembling cannabinoid hyperemesis, more often among the younger, female, non-white and poorer respondents and those with cannabis-related problems, and a companion analysis found those with symptoms had higher rates of other drug use, depression, anxiety, chronic pain and antisocial behavior than daily users without symptoms ^123,124. In a propensity-matched comparison of 18,588 adults with cyclic vomiting who used cannabis and 18,588 who did not, users were younger, more anxious and depressed, more often had gastroparesis, and accrued emergency visits 35% faster (hazard ratio 1.35, 95% confidence interval 1.31 to 1.39; a hazard ratio compares the rate at which events accumulate in two groups, not a count of visits) and hospitalizations 11% faster (1.11, 1.06 to 1.16); the users also received more abortive and less preventive treatment, which could account for part of the difference ¹²⁵. The two recent data sets disagree about sex: in the emergency-department analysis women had a slightly lower risk of the cannabinoid hyperemesis proxy (relative risk ratio 0.92, 95% confidence interval 0.88 to 0.95, that is about 8% lower than in men), while in the 2025 national survey women were more likely than other daily users to report the symptoms ^93,123. Cannabis use among admitted cyclic vomiting patients rose ten-fold from 2.2% in 2005 to 21.2% in 2014 nationally and admissions rose 46% in Colorado between 2010 and 2014 around recreational legalization, and in the Wisconsin natural-history cohort cannabis use was associated with about a third of the odds of complete resolution (odds ratio 0.36) ^12,126,127. Every one of these is an association; none can say whether cannabis caused the vomiting, worsened an existing disorder or was taken for it.

Two findings complicate the clean division. In five Mexican centers, 30 patients met criteria for cyclic vomiting and 16 for cannabinoid hyperemesis; the hyperemesis patients were older, used more tobacco and alcohol, and only 13.3% of the cyclic vomiting patients used cannabis at all, and the two groups did not differ in admissions or length of stay ¹²⁸. And a 2025 report describes two adolescent cannabis users whose cyclical vomiting followed their menstrual cycles and resolved with hormonal contraception despite continued cannabis, a 'catamenial' cyclic vomiting that would have been misread as cannabinoid hyperemesis had no one asked about periods ¹²⁹. The honest position in October 2026 is that cannabinoid hyperemesis is a clinical pattern with a defining test, sustained abstinence, that is rarely applied for long enough; that most of its features, including hot bathing, are shared with cyclic vomiting; that a susceptibility factor may exist but is unproven; and that the two names describe, at minimum, overlapping populations whose boundary no study has yet drawn. The British amitriptyline cohort found that 61% of 75 patients advised to stop opioids and cannabis and started on a low-dose tricyclic responded, with opioid cessation associated with response, in a retrospective series with no control group ¹³⁰; the guidelines likewise pair cannabis cessation with treatment of the cyclic vomiting itself ^23,131.

Preventing episodes: amitriptyline, topiramate, zonisamide, levetiracetam, aprepitant and the supplements, with their evidence

No drug is approved by the United States Food and Drug Administration for cyclic vomiting syndrome, and the 2025 review of adult treatment principles states that existing therapies rely on retrospective and open-label trials ⁴²; the 2019 evidence review graded every prophylactic as very-low-certainty, with only triptans for aborting attacks reaching moderate certainty ¹⁴. The first-line preventive is amitriptyline, a tricyclic antidepressant used at doses that also prevent migraine ¹³. Prakash and Clouse's 17 adults in 1999, treated open-label, had complete remission in 17.6% and partial response in 58.8%, a weaker result than in persistent functional nausea ²⁷. Hejazi and McCallum followed 41 adults on a tricyclic for a year and 23 for two years and found the frequency and duration of episodes and emergency visits all fell (P < 0.05), 88% reported improvement, and 34% had mild side effects ¹³². A 2012 systematic review pooled non-placebo-controlled cohorts and found tricyclic response in 75.5% of adults and 67.6% of children ⁵¹. The 2019 guideline strongly recommends a tricyclic for moderate-to-severe adult disease while its own evidence review grades that evidence very low certainty, a mismatch the reader should register ^13,14. Side effects limit it: in a 2023 pilot of 46 adults, 46% had adverse reactions and 28% stopped the drug, and genotyping of the liver enzymes CYP2C19 and CYP2D6, which metabolize amitriptyline, found 43% were ultrarapid CYP2C19 metabolizers but no significant relation between genotype and response, side effects or blood level ¹³³. A 2025 British clinic reported that 61% of 75 newly diagnosed adults responded to a three-tier algorithm starting with a low-dose tricyclic (mean 26.5 mg), with 42 of 46 responders needing the tricyclic alone, and that stopping opioids was associated with response ¹³⁰. The 2019 adult guideline came from the American Neurogastroenterology and Motility Society and the Cyclic Vomiting Syndrome Association, not from the American College of Gastroenterology, which has issued no cyclic vomiting guideline, though its journal published a critical review in 2023 ^13,134. The only adult update since is an expert commentary rather than a graded guideline: the American Gastroenterological Association Clinical Practice Update of 2024, whose PubMed abstract states its purpose and method only, so its specific advice is not quoted here ⁸⁵.

Children have the only randomized drug trials, all small and none placebo-controlled. In Shiraz, 181 children were randomized to amitriptyline or propranolol, with results reported for 164 of them: amitriptyline was effective in 46 of 81 (56%) and propranolol in 74 of 83 (92%), and the report does not state whether the assessors were blinded ³¹. In Isfahan, 64 children aged 3 to 15 were randomized to amitriptyline or cyproheptadine, an antihistamine with anti-serotonin effects, and followed six months: mean monthly attacks in the last two months were 0.38 against 0.59 (P = 0.197) and full remission 65.6% against 50% (P = 0.206), so neither was superior ¹³⁵. A second Isfahan trial randomized 72 children to amitriptyline or topiramate for three months; attack frequency did not differ, but duration was shorter on amitriptyline (3.43 against 4.90 hours, P = 0.017) and 68% stopped having attacks against 39% (P = 0.016) ¹³⁶. The 2008 consensus had recommended cyproheptadine below age five and amitriptyline above; the 2025 guideline conditionally recommends beta-blockers, neurokinin-1 and 5-HT2A antagonists, meaning drugs that block the receptor for substance P and one subtype of serotonin receptor respectively (aprepitant and cyproheptadine), and tricyclics, cautions about side effects, and reserves anticonvulsants for refractory disease ^15,32. A 2025 Turkish retrospective study of 119 children found anxiety in 78.2%, that lifestyle adherence predicted success, that all 34 children given a selective serotonin reuptake inhibitor, the common antidepressant class that includes sertraline and fluoxetine, for moderate to severe anxiety met the success definition, and that cyproheptadine added nothing over effective lifestyle change; it is retrospective and the groups were not comparable ¹³⁷.

Topiramate, an anticonvulsant that also prevents migraine, is the usual second line in adults. In 136 adults at the Medical College of Wisconsin, 92% of whom had failed a tricyclic, 65% responded by intention to treat, annual episodes fell from 18.1 to 6.2 and emergency visits from 4.3 to 1.6, higher doses, use beyond 12 months and monotherapy predicted response, anxiety predicted non-response, 55% had side effects, most often cognitive slowing, fatigue and tingling, and 32% stopped because of them ¹³⁸. A Turkish retrospective review of 38 children, 16 given topiramate and 22 propranolol for 12 months, found freedom from attacks in 81% and 59% and responder rates of 94% and 81% ¹³⁹. Zonisamide and levetiracetam, two newer anticonvulsants, were reported by Clouse in 2007 in 20 adults for whom tricyclics were unsatisfactory: 75% described at least moderate response, 20% remission, episodes fell from 1.3 to 0.5 a month, tricyclics could be stopped in 11 of 18, but 45% reported moderate or severe side effects ¹⁴⁰. That case series is the entire evidence base for the 2019 guideline's conditional recommendation of zonisamide or levetiracetam as alternate prophylaxis ^13,14. The 2025 pediatric guideline, by contrast, recommends against topiramate and valproate except in children with frequent, severe attacks who have failed the other preventives ^15,16.

Aprepitant, a neurokinin-1 receptor antagonist developed to prevent chemotherapy-induced vomiting, blocks the action of substance P, the brainstem signaling peptide that triggers vomiting through the neurokinin-1 receptor. The pediatric data began with Cristofori and colleagues at Great Ormond Street in 2014, who retrospectively reviewed 41 children, in a paper PubMed indexes as a clinical trial although it is a chart review, median age 8, refractory to conventional therapy, 16 treated prophylactically and 25 acutely; at 12 months, 13 of 16 (81%) on prophylaxis had complete (3) or partial (10) response and 19 of 25 (76%) on acute treatment responded, with fewer episodes, admissions and vomits an hour and more school attendance in both groups, and side effects, including hiccups and one severe migraine, only in the prophylactic group ¹⁷. In adults, 96 patients were prescribed aprepitant at the Wisconsin clinic; 26 (27%) could not start because of cost or insurance, and among the 70 who did, 93% refractory to other preventives and 73% taking it three times a week, 71.4% had a global response, episodes fell from 14.5 to 6.2 a year and emergency visits from 4.2 to 1.8, and 10% stopped for minor side effects ¹⁴¹. Against that, a 2024 analysis of 1,775 children admitted with cyclic vomiting across United States children's hospitals found that the 96 given aprepitant during admission had longer stays (5 against 3 days) and higher costs ($11,790 against $6,380) and the same 7-day readmission rate (17% against 16%), before and after propensity matching, so aprepitant used as an inpatient abortive did not change readmission ¹⁸. No randomized trial of aprepitant in cyclic vomiting exists, and no prospective pediatric trial of it either; the rest of the pediatric record is case reports, including a 13-year-old whose episodes stopped on oral aprepitant taken at home at the first prodromal signs, and two adolescents with cannabinoid hyperemesis whose vomiting stopped within an hour of aprepitant after 36 to 45 hours of failed conventional treatment ^142,143. The adult guideline recommends it as an alternate preventive, the pediatric guideline conditionally for both prevention and abortion, and in 2026 Hikita's review still lists it, with fosaprepitant, its intravenous form, among recommended acute agents on the same uncontrolled evidence ^13,15,16.

The mitochondrial supplements and the rest are the lowest tier. Boles's protocol of coenzyme Q10, L-carnitine and amitriptyline with blood-level monitoring resolved episodes in 23 of 30 patients in his own retrospective series ¹⁰⁷. The 2019 review graded coenzyme Q10, L-carnitine and riboflavin very-low-certainty and the guideline conditionally recommends them alone or alongside other prophylaxis; the 2025 pediatric guideline conditionally recommends coenzyme Q10, riboflavin and magnesium and other non-drug measures including trigger avoidance and biobehavioral interventions ^13,14,15,16. In the 2012 Wisconsin series the combination of tricyclics, topiramate, coenzyme Q10 and L-carnitine produced response in 86%, and compliance was the only predictor, with an odds ratio of 9.6 ⁵². Older candidates have not been revisited: pizotifen, reported in children in a 1985 Lancet letter, and erythromycin, which resolved symptoms in 13 of 20 children in a 1993 open trial whose authors could not exclude placebo, belong to the history ^76,77. The field's own 2024 assessment is that the absence of approved medications and the reliance on retrospective and open-label trials is 'a critical concern', and that cyclic vomiting lacks even a validated outcome measure with which to run the trials that would fix it ⁴².

Stopping an attack: sumatriptan, the abortive cocktails, and the emergency department protocols

An attack is easiest to stop in its prodrome, the half hour to few hours of nausea, pallor and dread before vomiting begins, which 93% of Fleisher's adults could recognize ³⁴. Anything swallowed after that is usually vomited, so abortive drugs are given early and, where possible, by routes that bypass the stomach: nasal spray, injection, suppository or vein ^15,29. Sumatriptan has the best evidence in the syndrome, which is still thin: Hikita's uncontrolled open trial in 12 young patients found subcutaneous injection responsive in 19 of 35 attacks and nasal spray fully effective in 2 of 6, with no adverse effects and better results in children with a family history of migraine, and case reports describe adults whose attacks ended with injectable or intranasal sumatriptan after a negative work-up ^95,96,144. A 2009 case in the Journal of General Internal Medicine, a 47-year-old man with a year of week-long episodes, is typical of how the adult diagnosis has usually been reached: an extensive negative work-up, then a triptan that works ¹⁴⁴. The 2019 adult review graded triptans moderate certainty for aborting attacks, drawing on indirect migraine evidence, and the 2025 pediatric guideline made anti-migraine agents its one strong recommendation, for children with a personal or family history of migraine, with conditional recommendations for oral and intravenous 5-HT3 antagonists such as ondansetron and for neurokinin-1 antagonists ^14,15. The 2026 pediatric review lists nonsteroidal anti-inflammatory drugs, triptans, ondansetron, aprepitant and fosaprepitant as the recommended acute agents and notes that 'no randomized control study on abortive therapy ... for CVS has yet been conducted' ¹⁶.

The abortive cocktail is a clinical custom rather than a studied regimen. The 2019 adult guideline conditionally recommends ondansetron and/or a triptan or aprepitant to abort symptoms, and sedation is part of the standard abortive repertoire described in the reviews ^13,134; the 2008 pediatric consensus recommended triptans, and for children needing intravenous fluids, 10% dextrose with ondansetron, the dextrose on the theory that fasting and ketosis perpetuate the attack ^13,32. A 2019 systematic review of pediatric acute management found 54 eligible studies, only six case series with quantitative data covering sumatriptan, ondansetron, phenothiazines, prokinetics, which are drugs that speed stomach emptying, carbohydrate, isometheptene, an older vessel-constricting headache drug, and aprepitant, and concluded that ondansetron had the most evidence for inclusion in emergency protocols as rescue therapy, with sumatriptan and aprepitant as candidates, while most of the literature was expert opinion ¹⁹. Levinthal's 2024 review of acute care lists what is actually used at home and in the emergency department: triptans, antiemetics, anxiolytics, neurokinin-1 antagonists, antipsychotics, sedatives, analgesics and anti-inflammatories, plus a quiet dark room, hot bathing, and topical capsaicin cream, and it concedes that 'more research is needed to develop evidence-based, individualized abortive treatment plans' and to learn whether cannabinoid hyperemesis needs a different approach ¹⁴⁵. The emergency departments themselves give ondansetron in 63% of cyclic vomiting visits and metoclopramide, a dopamine-blocking antiemetic, in 27% ²⁸. In Guangzhou, 46 children treated with intramuscular chlorpromazine and promethazine, two sedating dopamine- and histamine-blocking drugs, had a median vomiting duration of 1 day against 3 days in 20 children given intravenous ondansetron or omeprazole, an acid suppressant, a retrospective comparison in which the groups were not randomized ¹¹².

The emergency department is where the illness is most often mishandled, and the guidelines' answer is a written protocol. The 2019 adult guideline states that emergency treatment 'is best achieved with the use of an individualized treatment protocol' shared with the care team and provides an example; Rosen and Reeves describe the Cyclic Vomiting Syndrome Action Plan, a written plan for home and emergency management modeled on the action plans used in other complex chronic conditions, which has anecdotal and indirect support and no efficacy trial of its own ^13,146. Levinthal argues that every patient should receive 'nonjudgmental, informed, and compassionate care' in the emergency department, a sentence that exists because the opposite is common; the 2026 qualitative study of patients and caregivers describes repeated clinical dismissal, and the Wisconsin natural-history data show that at presentation the average adult patient had 6.1 emergency visits a year ^12,90,145. The only randomized emergency trials in this territory enrolled cannabis users. In the HaVOC trial, 30 cannabis users with active vomiting were given triple-blind intravenous haloperidol, an antipsychotic that blocks dopamine receptors, or ondansetron; at 2 hours haloperidol reduced pain and nausea by 2.3 cm more on a 10-cm scale (95% confidence interval 0.6 to 4.0), with less rescue medication and earlier discharge (3.1 against 5.6 hours), and two patients returned with acute dystonia, a drug-induced muscle spasm, both on the higher dose ¹⁴⁷. A double-blind placebo-controlled pilot in 30 patients found that 0.1% topical capsaicin cream reduced nausea at 60 minutes but not at 30 ¹⁴⁸. On that evidence the Society for Academic Emergency Medicine GRACE-4 guideline suggests haloperidol or droperidol, and topical capsaicin, added to usual care for adults with cannabinoid hyperemesis, each on very-low-certainty evidence ¹⁴⁹, and the American Gastroenterological Association issued an expert update on the syndrome the same year ⁸⁶. None of these trials enrolled people with cyclic vomiting who do not use cannabis, which is where the two literatures have diverged ^131,145. The 2025 pediatric guideline conditionally recommends presenting early when intravenous treatment is needed, and the Rome V pediatric chapter states that early emergency treatment reduces admissions ^15,29. In the Epic Cosmos data the admission rate for cyclic vomiting visits fell from 20.3% to 11.5% over nine years, which may reflect better protocols or simply a change in who is coded ²⁸.

Two non-drug approaches have trial evidence, both from the Wisconsin and Ohio State groups. In a randomized trial, 49 adults were allocated to conventional care or an integrative model with a care coordinator and heartfulness meditation taught by a certified instructor; by intention to treat, the meditation group improved in coping (positive reframing, planning, less self-blame) and physical quality of life at six months, with reduced psychological distress and better sleep among those who complied ¹⁵⁰. One of that trial's authors was affiliated with the Heartfulness Institute, the organization whose method and instructors were being tested, a conflict of interest to note ¹⁵⁰. A 2024 single-arm study of app-delivered meditation in 30 completers found improved anxiety, mood, distress, sleep and quality of life over six weeks and a rise in anandamide and the related lipids oleoylethanolamine and palmitoylethanolamide after meditation at week six, which the authors proposed as the mechanism; a correction to that paper was published in October 2026 and should be consulted alongside it ^61,151. Neither study measured vomiting episodes as its primary outcome. Auricular nerve-field stimulation in 30 children reduced pain and anxiety with no serious side effects, again without a control group ¹¹⁶. These are additions to prophylaxis, not substitutes for an abortive plan.

Where it leads: dehydration, Mallory-Weiss tears, esophagitis, the teeth, malnutrition, and death

The immediate danger of an attack is fluid. A child vomiting several times an hour for a day loses water, sodium, potassium and acid, and in the Irish incidence study 44% of children were admitted for supportive treatment or investigation, while in the Lucknow series 77.5% required hospitalization ^8,46,47. Kaul's review lists dehydration and hematemesis, vomiting of blood, from a Mallory-Weiss tear, a split in the lining at the junction of esophagus and stomach caused by the force of retching, as the complications of severe cases, and adds that 'no mortality has been reported as a direct result of CVS' in children ³³. Fleisher's 1995 management review had set out the same list more fully: esophagitis, hematemesis, depletion of intracellular electrolytes, hypertension, and inappropriate secretion of antidiuretic hormone, the water-retaining hormone whose excess lowers the blood sodium ¹⁵². No cohort study has counted how often Mallory-Weiss tears occur in cyclic vomiting; that complication rests on reviews and clinical experience ^33,152. The esophagus and stomach show the wear: among 63 Chinese children who underwent gastroscopy during the illness, only 3 were normal, 35% had chronic gastritis alone, and 60% had further changes including reflux esophagitis, meaning acid inflammation of the esophagus, in 16, bile reflux gastritis, stomach inflammation from bile washing back, in 12, duodenitis, inflammation of the first part of the small intestine, in 13, erosive gastritis, shallow breaks in the stomach lining, in 10, and a gastric or duodenal ulcer in 5, and of 15 children monitored for acid reflux between attacks, 9 had pathological reflux ¹⁵³. Whether those changes are consequences of vomiting or part of the disorder cannot be told from a cross-section; the 2001 finding that gastric mucosa from children with the syndrome released more nitric oxide in culture than control mucosa, between attacks, is a single in vitro study of 10 children that has not been followed up ¹⁵⁴.

Repeated vomiting bathes the teeth in stomach acid, and erosion would be expected by analogy with bulimia and reflux, but the cyclic vomiting literature on teeth consists only of case reports. A 2006 report in General Dentistry describes an adult with the syndrome who developed complications after dental extractions, with the authors reviewing the disease for dentists; a 2016 pediatric dental case report describes symptomatic oral management of an affected child; and a 2024 Japanese case describes planning general anesthesia for dental surgery in a woman with the syndrome during a remission, with stress hormones monitored to avoid provoking an attack ^155,156,157. The historical literature adds Charles Darwin, whose decades of episodic vomiting have been retrospectively attributed to cyclic vomiting syndrome from a mitochondrial disorder and who developed the dental problems common to patients with repeated vomiting, a diagnosis that cannot be tested and is offered here only as the origin of the association in print ^158,159. No study has measured dental erosion in a cyclic vomiting cohort; the claim that the teeth are damaged is a reasonable extrapolation from bulimia and reflux, not a finding in this disease.

The slower harm is nutritional, and it hides behind a normal weight. In a 2026 prospective study of 80 adults meeting Rome IV criteria, 85% with moderate-to-severe disease, 70% were at risk of malnutrition on a validated patient-completed screen (42.5% severe), 62.5% of those assessed by a dietitian were malnourished, and yet 27% were obese and 20% overweight, with no difference in body mass index between the well-nourished and the malnourished; the authors conclude that body mass index should not be used to screen for malnutrition in this disorder ³⁵. The same cohort found that 37.5% screened positive for avoidant/restrictive food intake disorder, a pattern of eating too little or too narrowly from fear of symptoms rather than from concern about shape or weight, and those patients were younger, more anxious and depressed, more often used cannabis, were more often malnourished (73% against 30%) and more often food insecure (30% against 0%) ³⁶. In children the deficit is plainer: 40% of 32 Singaporean children (12 of them) were underweight at diagnosis, with a median body mass index z-score of -3.2 among those 12, and among the 16 given prophylaxis the median z-score improved from -2.9 to -0.9 ¹¹¹. The 2026 editorial accompanying the avoidant-eating study argues that nutritional vulnerability has been an invisible part of the illness ¹⁶⁰.

The rarer sequelae follow from the physiology of the attack. Hypertension can be dangerous. A 16-year-old with long-standing cyclic vomiting and chronic recurrent hypertension developed posterior reversible encephalopathy syndrome twice, the second time during sustained postoperative hypertension; the authors name the hypertension as the immediate driver and raise the autonomic dysregulation of cyclic vomiting only as a possible contributor, and they do not describe the case as the Sato variant ³⁹. Cannabinoid hyperemesis has produced pneumomediastinum, air in the space between the lungs, in a 17-year-old daily cannabis user; she was watched closely for an esophageal perforation, none was detected, and she recovered without surgery ¹⁶¹. Pregnancy can worsen the syndrome, and one report describes attacks ceasing on amitriptyline at 12 weeks with a healthy term birth, in a condition that must be separated from hyperemesis gravidarum ¹⁶². Growth failure, school absence in 85% of affected Irish schoolchildren, repeated unnecessary surgery in the years before diagnosis, and the diagnostic delay itself, a median of 1.2 years in the Lucknow series and 10 years for pediatric-onset patients reaching an adult clinic in Wisconsin, are the complications of not recognizing it ^{8,46,47,52,87}.

Death is recorded but unexplained. Of 455 adults in the Wisconsin natural-history cohort, 19 (4%) died over a mean follow-up of about four years; the paper reports the number and not the causes, in a referral population with a mean age of 33 in which comorbidity count and cannabis use predicted non-resolution ¹². Kaul's statement that no child has died as a direct result of the syndrome and the Wisconsin figure are not necessarily in conflict, since the Wisconsin paper reports neither the causes of death nor which patients died, and the absence of any cause-of-death study in cyclic vomiting is itself a finding. The disorder's course in adults, with only 19% resolving and about 30% remaining symptomatic between episodes ^12,36, means that its complications are those of a chronic illness: in Fleisher's words, 'delayed or mis-diagnosis and ineffectual, sometimes inappropriately invasive management' ³⁴.

What was believed and is not, what changed, and what is still unknown

Three beliefs about cyclic vomiting have been reversed. The first is that it is psychogenic, the product of an anxious mother and a child who would not separate; that explanation, written into the pediatric literature of 1972 and 1977, was abandoned as physiological, epidemiological and therapeutic evidence tied the disorder to migraine, and the Rome V criteria of 2026 have now moved deliberately away from the word 'functional' because of the same implication, though some names, functional dyspepsia among them, keep it ^{2,9,40,81,82,83}. The second is that it is a disease of children; adult cases were reported in 1977 and 1988 and the first adult clinical series under the name came in 1999, adults now account for more than 8,000 United States hospital admissions a year, and in a population survey adults in the United States met criteria at 2% ^{5,11,27,49,50}. The third is that a mitochondrial DNA signature marks it; the variant 16519T, found in 70% of haplogroup-H children in 2009, and the rarer 3010A were no more common than in historical controls when 216 adults were genotyped in 2014, and the supplements built on the hypothesis survive only as conditional, very-low-certainty recommendations ^14,20,21.

A fourth belief is under revision rather than reversed. Hot-water bathing was taken in 2004 to be the stamp of cannabis on cyclic vomiting, and compulsive bathing remains a criterion in the Mayo proposal; it is now known to occur in roughly half of people with cyclic vomiting, independent of cannabis use though augmented by it, so it marks the vomiting more than the drug ^{5,22,23,80,117}. Whether cannabinoid hyperemesis is a separate disease or the same one with a trigger remains the field's open argument, with one side pointing to unmasking in predisposed people and the other to a toxic exposure with genetic susceptibility, and the three current documents classifying the relationship three ways: NASPGHAN 2025 calls it 'related but separate', the Rome V adult chapter lists it beside cyclic vomiting, and the Rome V pediatric chapter calls it a subtype of cyclic vomiting ^{2,23,24,26,29,30,120}.

What is not known is most of the mechanism. No study has imaged or recorded the brainstem during a human attack, so the dorsal raphe and the rest of the migraine circuitry are inferred from migraine imaging and from animals that vomit ^53,54,55. The corticotropin-releasing factor hypothesis has never been tested with an antagonist in patients ⁵⁶. The autonomic findings come from two small studies that disagree about the parasympathetic branch ^58,59. The genetic associations with cannabinoid, opioid and serotonin receptor genes are unreplicated case-control findings against public-database controls ^62,63. There is no biomarker, no validated patient-reported outcome measure, and no approved drug, and the 2019 and 2025 guidelines are built almost entirely on retrospective series, which is why the two professional societies have called for a multicenter registry and for trials with standardized end points ^13,15,42,113. A 2026 review of antiemetic drug development names cyclic vomiting syndrome among the conditions where the treatment gap remains widest, and notes that nausea itself is still poorly quantified in trials ¹⁶³. The 2026 Rome V chapter does not change this; it reorganizes the criteria, it does not add a test ².

New signals arrived in 2026 that the next revision will have to weigh. A disproportionality analysis, which compares how often an event is reported for one drug class against all other drugs, of 288,408 reports to the United States Food and Drug Administration's adverse event system found that cyclic vomiting syndrome was among the strongest safety signals for the glucagon-like peptide-1 (GLP-1) receptor agonists, the semaglutide class of diabetes and obesity drugs, that held up when only reports naming the drug as the primary suspect were counted; its reporting odds ratio, which compares how often an event is reported with these drugs against all others, was 64.8, mostly from semaglutide, second among the headline signals to gallbladder injury at 84.2; this is a hypothesis-generating signal from spontaneous reports that cannot establish incidence or causation, but these drugs act on the area postrema and delay gastric emptying, and whether they unmask cyclic vomiting in susceptible people is a question that did not exist before ¹⁶⁴. A real-world comparison of 18,588 matched pairs of adults, which the paper's title counts as 34,988 individuals, found that cannabis users with the syndrome accrued emergency visits 35% faster (hazard ratio 1.35), and a national survey found 17.8% of daily cannabis users reporting hyperemesis-like symptoms, numbers that will shape how cannabis is counseled whether or not the two-disease question is resolved ^123,125. A mouse model has reproduced the stress-induced ketosis of the acetonemic childhood form in young but not adult mice ⁵⁷.

And the oldest unknown is the simplest. Why does the vomiting stop? Why does a child who has vomited every six weeks for five years wake one morning and not vomit again, often to develop migraine instead, while only about a fifth of adults at a specialist clinic stop entirely? The follow-up studies record the fact without explaining it, the 2026 Lucknow cohort found that prophylaxis could be withdrawn in a third of complete responders with a few relapses, and no study has measured anything, in the brain or the blood, across that transition ^10,12,46,47. Gee's title in 1882 called the vomiting 'fitful', and 144 years later the fitfulness, the interval of health between attacks, is still the part of the disease with no explanation at all ³.

Where it connects

Sources

166 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
   Stanghellini V, Chan FKL, Hasler WL, et al. Gastroduodenal Disorders.Gastroenterology · 2016 · 150(6):1380-92doi:10.1053/j.gastro.2016.02.011 · PMID 27147122

   The Rome IV chapter that placed cyclic vomiting syndrome among three nausea and vomiting disorders and created cannabinoid hyperemesis syndrome as a diagnosis. The adult criteria quoted on this page come from it.

2. 2
   Törnblom H, Carbone F, Hasler WL, et al. Gastroduodenal Disorders.Gastroenterology · 2026 · 170(6):1240-1260doi:10.1053/j.gastro.2026.01.038 · PMID 41713705

   The Rome V gastroduodenal chapter, published February 2026: five categories including nausea and vomiting disorders with the same three subcategories as Rome IV (chronic nausea vomiting syndrome, cyclic vomiting syndrome, cannabinoid hyperemesis syndrome) and a new inability-to-belch syndrome. The current criteria.

3. 3
   Gee S. On fitful or recurrent vomiting.St Bartholomew's Hospital Reports · 1882 · 18:1-6

   The first description of the syndrome in children, by the physician who also described celiac disease. Primary document, not indexed in PubMed; this page relies on its title and on later authors' characterization rather than on quotation.

4. 4
   Hoyt CS, Stickler GB. A study of 44 children with the syndrome of recurrent (cyclic) vomiting.Pediatrics · 1960 · 25:775-80PMID 14403528

   The first substantial twentieth-century American series, from the Mayo Clinic. The PubMed record carries no abstract, so it is cited here for its existence and date only.

5. 5
   Aziz I, Palsson OS, Whitehead WE, Sperber AD, Simrén M, Törnblom H. Epidemiology, Clinical Characteristics, and Associations for Rome IV Functional Nausea and Vomiting Disorders in Adults.Clinical Gastroenterology and Hepatology · 2019 · 17(5):878-886doi:10.1016/j.cgh.2018.05.020 · PMID 29857155

   Internet survey of 5,931 adults in the United States, Canada and the United Kingdom in 2015: cyclic vomiting prevalence 2%, 0.7% and 1%; compulsive hot-water bathing in 44% of cyclic vomiting against 19% of chronic nausea and vomiting, independent of cannabis but augmented by it. The central evidence that hot bathing is not specific to cannabis.

6. 6
   Izagirre A, Sarasqueta C, Flores-Arriaga J, et al. Worldwide Prevalence and Description of Cyclic Vomiting Syndrome According to the Results of the Rome Foundation Global Epidemiology Study.American Journal of Gastroenterology · 2025 · 120(5):1108-1115doi:10.14309/ajg.0000000000003105 · PMID 39319824

   Rome IV questionnaire in 54,127 adults across 26 countries: pooled prevalence 0.3% (95% CI 0.3 to 0.4), highest in Brazil at 1%, none in Japan or Germany; 56.7% women, mean age 36.7; depression (OR 3.14) and anxiety (OR 1.79) independently associated; impaired quality of life. Cross-sectional, so associations only.

7. 7
   Abu-Arafeh I, Russell G. Cyclical vomiting syndrome in children: a population-based study.Journal of Pediatric Gastroenterology and Nutrition · 1995 · 21(4):454-8doi:10.1097/00005176-199511000-00014 · PMID 8583299

   Questionnaire screening of 2,165 Aberdeen schoolchildren aged 5 to 15 with clinical interview of symptomatic children: 34 met criteria, prevalence 1.9%; attacks about eight a year lasting about 20 hours; features overlapping migraine. The first population prevalence.

8. 8
   Fitzpatrick E, Bourke B, Drumm B, Rowland M. The incidence of cyclic vomiting syndrome in children: population-based study.American Journal of Gastroenterology · 2008 · 103(4):991-5doi:10.1111/j.1572-0241.2007.01668.x · PMID 18070235

   Monthly surveillance of every pediatrician in Ireland through 2005: 41 new cases, incidence 3.15 per 100,000 children per year, median onset 4 years, 85% missing school, 44% admitted. The only population incidence figure.

9. 9
   Li BU, Murray RD, Heitlinger LA, Robbins JL, Hayes JR. Is cyclic vomiting syndrome related to migraine?Journal of Pediatrics · 1999 · 134(5):567-72doi:10.1016/s0022-3476(99)70242-8 · PMID 10228291

   Of 214 children, 82% had migraine-associated cyclic vomiting by family history or later migraine; that subgroup had milder episodes, more migraine features and 79% response to anti-migraine therapy against 36%. The key association study, from a single referral service.

10. 10
    Dignan F, Symon DN, AbuArafeh I, Russell G. The prognosis of cyclical vomiting syndrome.Archives of Disease in Childhood · 2001 · 84(1):55-57doi:10.1136/adc.84.1.55 · PMID 11124785

    Of 26 traced Aberdeen patients, half were asymptomatic and 46% had past or present migraine against 12% of matched controls. Medium-term prognosis in a small cohort.

11. 11
    Shweikeh F, Jabir AR, Simons M, et al. Cyclic Vomiting Syndrome in Adults at the National Level: Impact of Demographics, Burden of Comorbidities, Effect of Hospital Factors, and Determinants of Mortality.Journal of Clinical Gastroenterology · 2026 · 60(10):885-892doi:10.1097/MCG.0000000000002180 · PMID 40372977

    National Inpatient Sample 2016 to 2019: admissions fell from 11,055 to 8,625, the 2019 admissions costing over 300 million dollars; mean age 34.7, 62.5% women, anxiety or depression in 38.6%, cannabis use in 35.0%, 90.4% discharged home; longer stays with age, female sex, depression and teaching hospitals; African Americans disproportionately affected. Administrative data.

12. 12
    Partovi O, Patel M, Kovacic K, Petrova A, Garacchi Z, Venkatesan T. Clinical characteristics and long-term outcomes in patients with cyclic vomiting syndrome: A 15-year experience at a tertiary referral center.Neurogastroenterology and Motility · 2023 · 35(7):e14571doi:10.1111/nmo.14571 · PMID 36989184

    455 adults followed a mean 47.4 months: episodes fell from 18 to 6.8 a year, emergency visits 6.1 to 2, hospitalizations 2.3 to 0.7, but only 88 (19%) resolved completely and 19 (4%) died; non-white race, comorbidity count, cannabis use and aprepitant use reduced the odds of resolution. The main adult natural-history data; causes of death not reported.

13. 13
    Venkatesan T, Levinthal DJ, Tarbell SE, et al. Guidelines on management of cyclic vomiting syndrome in adults by the American Neurogastroenterology and Motility Society and the Cyclic Vomiting Syndrome Association.Neurogastroenterology and Motility · 2019 · 31 Suppl 2:e13604doi:10.1111/nmo.13604 · PMID 31241819

    The first adult guideline, GRADE-based with a patient representative: tricyclic antidepressant strongly recommended first line; topiramate or aprepitant alternates; zonisamide, levetiracetam and mitochondrial supplements conditional; ondansetron and triptans or aprepitant to abort; an individualized emergency protocol; screening for comorbid anxiety, depression, migraine, autonomic dysfunction, sleep disorders and substance use.

14. 14
    Sharaf RN, Venkatesan T, Shah R, et al. Management of cyclic vomiting syndrome in adults: Evidence review.Neurogastroenterology and Motility · 2019 · 31 Suppl 2:e13605doi:10.1111/nmo.13605 · PMID 31241818

    The evidence review behind the guideline: very-low-quality evidence for amitriptyline, topiramate, aprepitant, zonisamide/levetiracetam and mitochondrial supplements; moderate certainty for triptans as abortive therapy; limited evidence for ondansetron. The grading that every treatment claim on this page defers to.

15. 15
    Karrento K, Rosen JM, Tarbell SE, et al. North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition 2025 guidelines for management of cyclic vomiting syndrome in children.Journal of Pediatric Gastroenterology and Nutrition · 2025 · 80(6):1028-1061doi:10.1002/jpn3.70020 · PMID 40223700

    Sixteen GRADE recommendations replacing the 2008 consensus: a strong recommendation for anti-migraine agents to abort episodes in children with a personal or family history of migraine; conditional recommendations for 5-HT3 and NK-1 antagonists, trigger avoidance, supplements, biobehavioral and neuromodulation interventions, beta-blockers, NK-1 and 5-HT2A antagonists and tricyclics; anticonvulsants only in refractory disease; indirect evidence from pediatric migraine used where cyclic vomiting data are absent.

16. 16
    Hikita T. Cyclic vomiting syndrome.Brain and Development · 2026 · 48(2):104515doi:10.1016/j.braindev.2026.104515 · PMID 41719916

    Pediatric review: mean onset 5.7 and diagnosis 8.0 years with 2.3 years' delay, prevalence 0.3% to 2%, no randomized trial of abortive therapy, and a summary of the 2025 NASPGHAN recommendations (NSAIDs, triptans, ondansetron, aprepitant and fosaprepitant acutely; coenzyme Q10, riboflavin, magnesium, propranolol, cyproheptadine, aprepitant and amitriptyline preventively; topiramate and valproate not recommended except in refractory cases).

17. 17
    Cristofori F, Thapar N, Saliakellis E, et al. Efficacy of the neurokinin-1 receptor antagonist aprepitant in children with cyclical vomiting syndrome.Alimentary Pharmacology and Therapeutics · 2014 · 40(3):309-17doi:10.1111/apt.12822 · PMID 24898244

    Retrospective review at Great Ormond Street of 41 refractory children, 16 on prophylactic and 25 on acute aprepitant: at 12 months 81% and 76% had complete or partial response, with fewer episodes, admissions and vomits per hour and more school attendance; side effects only in the prophylactic group. The first pediatric aprepitant series, uncontrolled.

18. 18
    Thavamani A, Malay S, Khatana J, Velayuthan S, Sankararaman S. Utility of Aprepitant in the Management of Pediatric Patients with Cyclical Vomiting Syndrome.Medicines (Basel) · 2024 · 11(8):21doi:10.3390/medicines11080021 · PMID 39728392

    Pediatric Health Information System: of 1,775 children admitted with cyclic vomiting, 96 received inpatient aprepitant, with longer stays (5 against 3 days), higher costs and the same 7-day readmission (17% against 16%) before and after propensity matching. Inpatient aprepitant did not change readmission; confounding by severity is likely.

19. 19
    Gui S, Patel N, Issenman R, Kam AJ. Acute Management of Pediatric Cyclic Vomiting Syndrome: A Systematic Review.Journal of Pediatrics · 2019 · 214:158-164.e4doi:10.1016/j.jpeds.2019.06.057 · PMID 31540764

    Of 799 studies to 2018, 54 included, only six case series with quantitative data on sumatriptan, ondansetron, phenothiazines, prokinetics, carbohydrate, isometheptene and aprepitant; ondansetron had the most support for emergency protocols, sumatriptan and aprepitant were candidates, the rest expert opinion. Shows how thin the acute-care evidence is.

20. 20
    Zaki EA, Freilinger T, Klopstock T, et al. Two common mitochondrial DNA polymorphisms are highly associated with migraine headache and cyclic vomiting syndrome.Cephalalgia · 2009 · 29(7):719-28doi:10.1111/j.1468-2982.2008.01793.x · PMID 19220304

    Whole mitochondrial genome sequencing in 20 haplogroup-H children, then testing in 10 more and 112 migraineurs: 16519T in 70% of cyclic vomiting subjects (OR 6.2) and 52% of migraineurs against 27% of controls; 3010A in 29% of 16519T carriers against 1.6%. The claim that was later not replicated in adults.

21. 21
    Venkatesan T, Zaki EA, Kumar N, et al. Quantitative pedigree analysis and mitochondrial DNA sequence variants in adults with cyclic vomiting syndrome.BMC Gastroenterology · 2014 · 14:181doi:10.1186/1471-230X-14-181 · PMID 25332060

    Pedigree analysis in 195 of 216 adults and genotyping of all 216: more probable maternal inheritance of functional disorders than controls (12% against 1%), but the prevalence of 16519T, 3010A and the combined genotype was similar to historical controls, with no relation to age of onset. The reversal, with Boles as senior author.

22. 22
    Rosen S, Diaz R, Garacci Z, et al. Hot-Water Bathing Improves Symptoms in Patients with Cyclic Vomiting Syndrome and Is Modulated by Chronic Cannabis Use.Digestive Diseases and Sciences · 2021 · 66(4):1153-1161doi:10.1007/s10620-020-06343-x · PMID 32472256

    Cross-sectional study of 111 clinic patients: 73% reported hot-water bathing during episodes, over 80% with marked relief of nausea, vomiting, pain and panic; regular cannabis users more often used very hot water and took longer to get relief. Hot bathing common in a mixed cohort of users and non-users.

23. 23
    Hasler WL, Alshaarawy O, Venkatesan T. Cannabis use patterns and association with hyperemesis: A comprehensive review.Neurogastroenterology and Motility · 2025 · 37(3):e14895doi:10.1111/nmo.14895 · PMID 39164887

    Review: 40% to 80% of cyclic vomiting patients use cannabis; most cannabinoid hyperemesis patients have used daily for over two years; compulsive hot bathing is reported by most hyperemesis patients but 'not specific' because about half of cyclic vomiting patients report it; abstinence is the cornerstone of management and hard to achieve. A balanced statement of the overlap from the adult guideline authors.

24. 24
    Russo EB, Whiteley VL. Cannabinoid hyperemesis syndrome: genetic susceptibility to toxic exposure.Frontiers in Toxicology · 2024 · 6:1465728doi:10.3389/ftox.2024.1465728 · PMID 39507417

    Review arguing for a distinct disease: five variants reported as significantly more frequent in patients than in asymptomatic heavy users (TRPV1, two dopamine genes, CYP2C9, an ABC transporter), escalating high-potency intake, and a claim that confusion with cyclic vomiting is nosological error because the two are 'clearly distinct'. The two-conditions case; the genetic study it rests on genotyped 28 patients and 12 controls and is unreplicated [143], and both authors list a private company, CReDO Science, as their affiliation.

25. 25
    Hyams JS, Di Lorenzo C, Saps M, Shulman RJ, Staiano A, van Tilburg M. Functional Disorders: Children and Adolescents.Gastroenterology · 2016 · published online 15 February 2016doi:10.1053/j.gastro.2016.02.015 · PMID 27144632

    The Rome IV pediatric chapter, which replaced 'no evidence for organic disease' with 'after appropriate medical evaluation the symptoms cannot be attributed to another medical condition' and so allowed a positive diagnosis with selective testing.

26. 26
    Karrento K, Rosen JM, Gelfand AA, et al. North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition 2025 guidelines on the diagnosis of cyclic vomiting syndrome in children.Journal of Pediatric Gastroenterology and Nutrition · 2025 · 81(5):1346-1359doi:10.1002/jpn3.70193 · PMID 40836301

    Recommends screening serum and urine tests and an upper gastrointestinal radiographic series for every child with suggestive symptoms, finds other screening tests low-yield, revises the diagnostic criteria and algorithm, and provides a consensus approach to pediatric cannabinoid hyperemesis 'as a related but separate entity'.

27. 27
    Prakash C, Clouse RE. Cyclic vomiting syndrome in adults: clinical features and response to tricyclic antidepressants.American Journal of Gastroenterology · 1999 · 94(10):2855-60doi:10.1111/j.1572-0241.1999.01428.x · PMID 10520833

    Seventeen adults over ten years: onset at a mean of 35 years, episodes averaging 6 days, intervals 3.1 months, fewer than a third with a prodrome; open-label tricyclics gave complete remission in 17.6% and partial response in 58.8%, less than in functional nausea. The first adult series and the first tricyclic data.

28. 28
    Shalaby M, Moyer E, Buell KG, Bernard K, Gottlieb M. Presentations to United States emergency departments for gastroparesis, cyclic vomiting, and cannabinoid hyperemesis syndrome from 2016 to 2024.American Journal of Emergency Medicine · 2025 · 96:201-207doi:10.1016/j.ajem.2025.06.067 · PMID 40602005

    Epic Cosmos, 248 million adult emergency encounters: 204,636 (0.08%) coded cyclic vomiting, 134,059 cannabinoid hyperemesis, 165,857 gastroparesis; cyclic vomiting admission rate fell from 20.3% to 11.5%, mean stay 4.7 days, ondansetron given in 63% and metoclopramide in 27%. Coding-based national picture of acute care.

29. 29
    Rosen R, Borrelli O, Faure C, et al. Rome V Pediatric Upper Gastrointestinal Disorders of Gut-Brain Interaction.Gastroenterology · 2026 · 170(6):1347-1366doi:10.1053/j.gastro.2026.01.039 · PMID 41713704

    The Rome V pediatric chapter, expanded to esophageal, air-transit and feeding disorders alongside rumination, cyclic vomiting, chronic nausea syndrome and functional dyspepsia, with testing playing a larger role than in past iterations.

30. 30
    Bonnet U. Cannabis hyperemesis syndrome: the rare case of a valid diagnosis plus hypersensitization hypothesis for development and chronification of this severe somatic cannabis use disorder.Fortschritte der Neurologie-Psychiatrie · 2026 · published online 28 January 2026doi:10.1055/a-2731-3369 · PMID 41605419

    Case report and hypothesis: the only criterion distinguishing cannabinoid hyperemesis from cyclic vomiting is persistent remission during abstinence, 12-month observation is needed, most published cases are only suspected, and each episode in this patient was worse than the last, suggesting sensitization. A single case; its methodological point about abstinence periods is the useful part.

31. 31
    Haghighat M, Rafie SM, Dehghani SM, Fallahi GH, Nejabat M. Cyclic vomiting syndrome in children: experience with 181 cases from southern Iran.World Journal of Gastroenterology · 2007 · 13(12):1833-6doi:10.3748/wjg.v13.i12.1833 · PMID 17465476

    181 consecutive children over 11 years in Shiraz randomized to amitriptyline or propranolol: effective in 46 of 81 (56%) against 74 of 83 (92%); mean diagnostic delay 2 years; 70% of attacks began between midnight and early morning. Results reported for 164 of the 181. The basis for the pediatric beta-blocker recommendation; blinding not reported.

32. 32
    Li BUK, Lefevre F, Chelimsky GG, et al. North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition consensus statement on the diagnosis and management of cyclic vomiting syndrome.Journal of Pediatric Gastroenterology and Nutrition · 2008 · 47(3):379-93doi:10.1097/MPG.0b013e318173ed39 · PMID 18728540

    The 2008 consensus: diagnostic criteria, four red flags for targeted testing, cyproheptadine under five and amitriptyline over five, triptans and 10% dextrose with ondansetron for attacks. Expert opinion, replaced by the 2025 guidelines.

33. 33
    Kaul A, Kaul KK. Cyclic Vomiting Syndrome: A Functional Disorder.Pediatric Gastroenterology, Hepatology and Nutrition · 2015 · 18(4):224-9doi:10.5223/pghn.2015.18.4.224 · PMID 26770896

    Review: the four phases, triggers, complications of dehydration and hematemesis from Mallory-Weiss tears in severe cases, abortive and prophylactic therapy, and the statement that no mortality has been reported as a direct result in children. Narrative review, cited for the complications list.

34. 34
    Fleisher DR, Gornowicz B, Adams K, Burch R, Feldman EJ. Cyclic Vomiting Syndrome in 41 adults: the illness, the patients, and problems of management.BMC Medicine · 2005 · 3:20doi:10.1186/1741-7015-3-20 · PMID 16368014

    Retrospective series of 41 adults seen 1994 to 2003: onset from 2 to 49 years, recognizable prodromes in 93%, a cluster of episodes, migraine, inter-episodic nausea and panic attacks in half, deterioration marked by coalescence of episodes, and delayed, sometimes invasive mismanagement. The descriptive foundation of adult cyclic vomiting.

35. 35
    Venkatesan T, Goday PS, Arumugam S, et al. Malnutrition Is Common in Cyclic Vomiting Syndrome: A Prospective Study Using Validated Nutritional Assessment Tools.Digestive Diseases and Sciences · 2026 · 71(11):5465-5472doi:10.1007/s10620-026-10088-4 · PMID 42423933

    Prospective study of 80 Rome IV adults: 70% at risk of malnutrition on the PG-SGA short form (42.5% severe), 62.5% malnourished on dietitian assessment, yet 27% obese and 20% overweight with no difference in body mass index between nourished and malnourished. Body mass index is useless as a screen in this disorder.

36. 36
    Venkatesan T, Goday PS, Arumugam S, et al. Avoidant-Restrictive Food Intake Disorder Is Common in Adults With Cyclic Vomiting Syndrome and Is Associated With Malnutrition.Neurogastroenterology and Motility · 2026 · 38(4):e70294doi:10.1111/nmo.70294 · PMID 41923288

    Same 80 adults: 37.5% screened positive for ARFID risk; those were younger, had more severe disease, more anxiety and depression, more inter-episodic symptoms, more cannabis use, more malnutrition (73% against 30%) and more food insecurity (30% against 0%), with lower calorie and micronutrient intake. Screening study, cross-sectional.

37. 37
    Sato T, Uchigata Y, Uwadana N, Kita K, Suzuki Y, Hayashi S. A syndrome of periodic adrenocorticotropin and vasopressin discharge.Journal of Clinical Endocrinology and Metabolism · 1982 · 54(3):517-22doi:10.1210/jcem-54-3-517 · PMID 6276429

    An 8-year-old with periodic vomiting, psychotic depression, drowsiness and hypertension of 160/110 after head injury: ACTH 610 pg/ml and vasopressin 41 microunits/ml at attack onset, raised urinary epinephrine and norepinephrine with reduced dopamine, and suppression by methyldopa and reserpine. The first Sato case.

38. 38
    Sato T, Igarashi N, Minami S, et al. Recurrent attacks of vomiting, hypertension and psychotic depression: a syndrome of periodic catecholamine and prostaglandin discharge.Acta Endocrinologica · 1988 · 117(2):189-97doi:10.1530/acta.0.1170189 · PMID 2837885

    Two patients aged 17 and 3 with fixed-periodicity attacks: ACTH, vasopressin, norepinephrine and prostaglandin E2 markedly raised at onset, dopamine undetectable; clonidine partially effective and indomethacin suppressed attacks for a year. The adrenergic hypothesis in its original form, built on three patients in all.

39. 39
    Mahmood A, Mao A, Tuna IS. Recurrent PRES in a Patient With Cyclic Vomiting Syndrome.Case Reports in Radiology · 2026 · 2026:3914162doi:10.1155/crra/3914162 · PMID 42369578

    A 16-year-old with criteria-based cyclic vomiting and chronic recurrent hypertension who developed MRI-confirmed posterior reversible encephalopathy syndrome twice, with secondary causes of hypertension excluded; the authors call hypertension the immediate driver and CVS-related autonomic dysregulation a possible contributor. A single case of hypertensive PRES in cyclic vomiting; Sato-type hormone surges are not reported.

40. 40
    Remes-Troche JM. Rome V: minimizing "functional", maximizing precision in gut-brain disorders.Revista Española de Enfermedades Digestivas · 2026 · 118(8):438-441doi:10.17235/reed.2026.12073/2026 · PMID 42439384

    Editorial on Rome V's deliberate move away from the word 'functional', which had implied symptoms were less real or merely psychological, and on the clearer separation of chronic nausea and vomiting, gastroparesis, cyclic vomiting and cannabinoid hyperemesis. Commentary, not criteria.

41. 41
    Chen YJ, Rodriguez D, Richmond CA, et al. Symptom Patterns in Adults With Cyclic Vomiting Syndrome: A 6-Month Prospective Observational Study.Neurogastroenterology and Motility · 2025 · 37(2):e14974doi:10.1111/nmo.14974 · PMID 39737520

    Electronic daily diaries in 88 adults: 191 episodes, median 3.0 days, 17.8% longer than 10 days, and 14.8% of patients with vomiting or retching between episodes, under a study definition that ends an episode only after 7 days without vomiting or retching. Run by employees of Takeda and the consultancy Evidera, a commercial interest to note.

42. 42
    Chen YJ, Patel M, Venkatesan T. Treatment principles in adults and development of patient-reported outcomes in cyclic vomiting syndrome.Neurogastroenterology and Motility · 2025 · 37(3):e14910doi:10.1111/nmo.14910 · PMID 39552561

    Review of adult treatment principles underscoring the absence of FDA-approved medications and the reliance on retrospective and open-label trials, and a roadmap for disease-specific patient-reported outcome measures. First author listed as an AstraZeneca outcomes researcher, a commercial affiliation to note.

43. 43
    Karrento K, Wu M, Rodriguez D, et al. Understanding the adult and adolescent patient experience with cyclic vomiting syndrome: a concept elicitation study.BMC Gastroenterology · 2025 · 25(1):85doi:10.1186/s12876-025-03595-7 · PMID 39962369

    Qualitative interviews with 13 adults and 15 adolescents, the groundwork for a patient-reported outcome measure; most authors are Takeda or Evidera employees, a commercial interest to note.

44. 44
    [Guidelines for the treatment of cyclic vomiting syndrome in children (2025)].Zhonghua Er Ke Za Zhi (Chinese Journal of Pediatrics) · 2025 · 63(2):107-116doi:10.3760/cma.j.cn112140-20241120-00850 · PMID 39844485

    China's national pediatric treatment guideline, in Chinese with no abstract in the PubMed record; cited for its existence and date only.

45. 45
    Bujarska M, Bora G, Li BUK, et al. Diagnostic characteristics of pediatric cyclic vomiting syndrome.Journal of Pediatric Gastroenterology and Nutrition · 2025 · 80(3):417-425doi:10.1002/jpn3.12448 · PMID 39737559

    Prospective study of 108 children with unexplained vomiting episodes at Children's Wisconsin, 46 with a final diagnosis of cyclic vomiting: 4 to 10 episodes a year and duration over 2 hours discriminated best; photophobia, sweating, several emeses an hour, stereotypy and continued retching set the condition apart; fewer than half met Rome IV or NASPGHAN criteria. Shows the criteria's insensitivity.

46. 46
    Ananthashayana R, Srivastava A, Aravind A, Samanta A, Sarma MS, Poddar U. Clinical features, response to therapy and outcome in pediatric cyclical vomiting syndrome: Experience from the developing world.Indian Journal of Gastroenterology · 2026 · published online 23 April 2026doi:10.1007/s12664-026-01998-2 · PMID 42026408

    Seventy-one children in Lucknow 2008 to 2024: median diagnostic delay 1.2 years, 43.6% misdiagnosed elsewhere, 77.5% hospitalized, family history of migraine in 52.1%, all met Rome IV but only 66.2% NASPGHAN and 62% ICHD-3; at a median eight years, 50.7% complete and 35.3% significant response, prophylaxis stopped in 13 of 36 complete responders with 3 relapses. Retrospective; a correction was published on 13 May 2026 [144] and should be read with it.

47. 47
    Ananthashayana R, Srivastava A, Aravind A, Samanta A, Sarma MS, Poddar U. Correction: Clinical features, response to therapy and outcome in pediatric cyclical vomiting syndrome: Experience from the developing world.Indian Journal of Gastroenterology · 2026 · published 13 May 2026doi:10.1007/s12664-026-02020-5 · PMID 42126724

    Published erratum to the 2026 Lucknow series; the PubMed record gives no detail of what was corrected.

48. 48
    Headache Classification Committee of the International Headache Society (IHS). The International Classification of Headache Disorders, 3rd edition.Cephalalgia · 2018 · 38(1):1-211doi:10.1177/0333102417738202 · PMID 29368949

    The headache classification (ICHD-3). The PubMed record has no abstract; its placement of cyclic vomiting among episodic syndromes that may be associated with migraine is stated here as reported by the 2025 review [154].

49. 49
    Reid AH, Leonard A. Lithium treatment of cyclical vomiting in a mentally defective patient.British Journal of Psychiatry · 1977 · 130:316doi:10.1192/bjp.130.3.316 · PMID 843782

    A letter reporting lithium in a single adult with cyclical vomiting and intellectual disability. No abstract; cited as an example of the one-patient treatment reports of the era.

50. 50
    Abell TL, Kim CH, Malagelada JR. Idiopathic cyclic nausea and vomiting--a disorder of gastrointestinal motility?Mayo Clinic Proceedings · 1988 · 63(12):1169-75doi:10.1016/s0025-6196(12)65401-9 · PMID 3199884

    Eight adults with unexplained cyclic nausea and vomiting, episodes a mean of every 3.2 months lasting a mean of 3.5 days; motility abnormal in all eight between episodes (gastric hypomotility in five, small-bowel dysmotility in six, delayed gastric emptying in two). An early adult series and the origin of a motility theory later reversed.

51. 51
    Lee LYW, Abbott L, Mahlangu B, Moodie SJ, Anderson S. The management of cyclic vomiting syndrome: a systematic review.European Journal of Gastroenterology and Hepatology · 2012 · 24(9):1001-6doi:10.1097/MEG.0b013e328355638f · PMID 22634989

    1,093 cases in 25 papers to 2011, all but one retrospective: over 40% with headache or migraine, family history of migraine in 38.9%, adults with longer and more frequent attacks (5.9 against 3.4 days; 14.4 against 9.6 a year), tricyclic response 75.5% in adults and 67.6% in children in uncontrolled cohorts, sumatriptan effective in adults. A pooling of uncontrolled data.

52. 52
    Kumar N, Bashar Q, Reddy N, et al. Cyclic Vomiting Syndrome (CVS): is there a difference based on onset of symptoms--pediatric versus adult?BMC Gastroenterology · 2012 · 12:52doi:10.1186/1471-230X-12-52 · PMID 22639867

    Retrospective review of 101 Rome III patients at the Medical College of Wisconsin, 29 with pediatric and 72 with adult onset: pediatric-onset patients were more often female with a 10-year diagnostic delay against 5, but clinical features and treatment response were otherwise alike; 86% responded to tricyclics, topiramate, coenzyme Q10 and L-carnitine, with compliance the only predictor (OR 9.6). Argues against separate pediatric and adult diseases.

53. 53
    Weiller C, May A, Limmroth V, et al. Brain stem activation in spontaneous human migraine attacks.Nature Medicine · 1995 · 1(7):658-60doi:10.1038/nm0795-658 · PMID 7585147

    PET during spontaneous migraine: increased blood flow in cingulate, auditory and visual cortex and brainstem, with only the brainstem activation persisting after sumatriptan relieved the headache. The origin of the 'migraine generator' idea applied to the dorsal raphe; a study of migraine, not cyclic vomiting.

54. 54
    Ray AP, Chebolu S, Darmani NA. Receptor-selective agonists induce emesis and Fos expression in the brain and enteric nervous system of the least shrew (Cryptotis parva).Pharmacology, Biochemistry, and Behavior · 2009 · 94(1):211-8doi:10.1016/j.pbb.2009.08.010 · PMID 19699757

    Vomiting induced by 5-HT3, dopamine D2/D3 and NK1 agonists and cisplatin in a vomiting mammal activated the dorsal vagal complex and also the dorsal raphe and paraventricular thalamus, nuclei 'not usually discussed regarding emesis'. Animal evidence that the dorsal raphe participates in vomiting.

55. 55
    Rock EM, Bolognini D, Limebeer CL, et al. Cannabidiol, a non-psychotropic component of cannabis, attenuates vomiting and nausea-like behaviour via indirect agonism of 5-HT(1A) somatodendritic autoreceptors in the dorsal raphe nucleus.British Journal of Pharmacology · 2012 · 165(8):2620-34doi:10.1111/j.1476-5381.2011.01621.x · PMID 21827451

    Cannabidiol suppressed vomiting in shrews and conditioned gaping in rats, effects blocked by 5-HT1A antagonists given systemically or into the dorsal raphe. Animal pharmacology placing cannabis's anti-nausea action in the dorsal raphe.

56. 56
    Taché Y. Cyclic vomiting syndrome: the corticotropin-releasing-factor hypothesis.Digestive Diseases and Sciences · 1999 · 44(8 Suppl):79S-86SPMID 10490044

    Review proposing central CRF activation as the common path: CRF inhibits gastric emptying in animals via the hypothalamic paraventricular nucleus and dorsal vagal complex, the triggers of cyclic vomiting release CRF, the attack physiology matches CRF activation, and the empirical drugs block CRF. A hypothesis from animal physiology, untested in patients with an antagonist.

57. 57
    Taniguchi H, Kunimaru R, Kasai A, Seiriki K, Hashimoto H, Ao T. Glucose metabolic responses to psychological stress vary across developmental stages in mice.Journal of Pharmacological Sciences · 2026 · 162(3):206-212doi:10.1016/j.jphs.2026.08.005 · PMID 42810777

    Mouse model of the stress-induced glycogen depletion and ketosis of childhood cyclic vomiting with acetonemia: 8 hours of restraint depleted liver glycogen in young and adult mice, only young mice failed to recover it by 16 hours because of stress-induced hypophagia, and only young mice developed marked ketosis. Animal metabolism; mice do not vomit.

58. 58
    Venkatesan T, Prieto T, Barboi A, et al. Autonomic nerve function in adults with cyclic vomiting syndrome: a prospective study.Neurogastroenterology and Motility · 2010 · 22(12):1303-7doi:10.1111/j.1365-2982.2010.01577.x · PMID 20667005

    Twenty adults and 20 controls: abnormal thermoregulatory sweat test in 85% against 10%, postural tachycardia in 35% against one control, 90% with one or both, parasympathetic deep-breathing response normal in 95% of both. Sympathetic impairment with intact parasympathetic function, in a small sample.

59. 59
    Bolender A, Staley R, Garcia RG, et al. Altered parasympathetic outflow and central sensitization response to continuous pain in cyclic vomiting syndrome: a functional magnetic resonance imaging study.American Journal of Physiology. Gastrointestinal and Liver Physiology · 2025 · 328(2):G125-G135doi:10.1152/ajpgi.00011.2024 · PMID 39545877

    During sustained cuff pain, patients lost high-frequency heart-rate variability more than controls, showed reduced coupling between it and signal in insula, anterior cingulate and prefrontal cortex, and reported rising pain where controls did not. Case-control imaging; disagrees with the 2010 study on the parasympathetic branch.

60. 60
    Bashashati M, Bradshaw HB, Johnson CT, et al. Plasma endocannabinoids and cannabimimetic fatty acid derivatives are altered in cyclic vomiting syndrome: The effects of sham feeding.Journal of Investigative Medicine · 2023 · 71(8):821-829doi:10.1177/10815589231196591 · PMID 37572030

    Ten adults with cyclic vomiting and 8 controls: lower parasympathetic tone, higher baseline 2-arachidonoylglycerol and 2-oleoylglycerol, no difference in anandamide, and disease-dependent lipid responses to sham feeding. Very small human study of endocannabinoid levels.

61. 61
    Venkatesan T, Hillard CJ, Ayer L, et al. Acute and Long-Term Effects of App-Delivered Heartfulness Meditation on Psychological Outcomes and the Endocannabinoid Signaling System in Cyclic Vomiting Syndrome.Clinical and Translational Gastroenterology · 2024 · 15(7):e00711doi:10.14309/ctg.0000000000000711 · PMID 38713142

    Six-week single-arm pilot in 30 completers: improved state and trait anxiety, mood, distress, sleep, coping and quality of life, and post-meditation rises in anandamide, oleoylethanolamine and palmitoylethanolamide at week six. Uncontrolled; a correction was published in 2026.

62. 62
    Wasilewski A, Lewandowska U, Mosinska P, et al. Cannabinoid Receptor Type 1 and mu-Opioid Receptor Polymorphisms Are Associated With Cyclic Vomiting Syndrome.American Journal of Gastroenterology · 2017 · 112(6):933-939doi:10.1038/ajg.2017.73 · PMID 28349993

    Case-control study of 65 patients against 1,092 controls from the 1000 Genomes Project: CNR1 rs806380 AG/GG genotypes raised risk, CNR1 rs806368 CC and OPRM1 rs1799971 AG/GG lowered it, with correlations to migraine and treatment response. Small, with public-database controls, unreplicated.

63. 63
    Binienda A, Salaga M, Patel M, Włodarczyk J, Fichna J, Venkatesan T. Serotonin Receptors Polymorphisms Are Associated With Cyclic Vomiting Syndrome.Neurogastroenterology and Motility · 2025 · 37(5):e15012doi:10.1111/nmo.15012 · PMID 39888244

    Seventy patients against 2,504 public controls: HTR1B/1D and HTR3B genotypes associated with increased risk, HTR3B and HTR3C alleles with decreased risk, and an HTR1D genotype with a seven-fold risk of depression among patients. The same design and the same limitations as the 2017 study.

64. 64
    DeVuono MV, Venkatesan T, Hillard CJ. Endocannabinoid signaling in stress, nausea, and vomiting.Neurogastroenterology and Motility · 2025 · 37(3):e14911doi:10.1111/nmo.14911 · PMID 39223918

    Review of the endocannabinoid system in stress, nausea and vomiting: cannabinoids relieve nausea at some doses and provoke it at others, and prolonged cannabis use or heightened stress may dysregulate the system in ways that contribute to both cyclic vomiting and cannabinoid hyperemesis. Mechanistic synthesis, largely from animal data.

65. 65
    Boles RG, Williams JC. Mitochondrial disease and cyclic vomiting syndrome.Digestive Diseases and Sciences · 1999 · 44(8 Suppl):103S-107SPMID 10490048

    Six unrelated children with cyclic vomiting and a maternal family history, with migraine features, developmental delay, seizures or poor growth; raised lactate in five and a confirmed mitochondrial DNA rearrangement in one. The origin of the mitochondrial hypothesis, from the severe end of the spectrum.

66. 66
    Boles RG, Adams K, Ito M, Li BUK. Maternal inheritance in cyclic vomiting syndrome with neuromuscular disease.American Journal of Medical Genetics Part A · 2003 · 120A(4):474-82doi:10.1002/ajmg.a.20126 · PMID 12884425

    Questionnaire interviews for 62 children with 'CVS plus': migraine, myopathy, seizures and dysautonomia-like symptoms in 75% of mothers against 11% of fathers, maternal inheritance suggested in 86% of families. Pedigree inference, not sequencing, in a selected severe subgroup.

67. 67
    Li BUK. Landscape of Cyclic Vomiting Syndrome: From Bedside to Bench, Past to Present.Neurogastroenterology and Motility · 2025 · 37(3):e14990doi:10.1111/nmo.14990 · PMID 39789960

    Historical and mechanistic overview by the field's senior pediatric investigator: the modern era from the 1993 founding of the patient association, endophenotypes (migraine, Sato, cannabinoid hyperemesis), confirmed pathways (NK1, CB1, HPA axis, PPM1D, biological calendar, estrogen) and possible ones (TRPV1, CGRP, GDF-15, mitochondrial dysfunction), and a polyvagal autonomic design. A synthesis, not primary data.

68. 68
    Iwanami F. [The diencephalon and cyclic vomiting].Sogo Igaku · 1963 · 20:493-8PMID 13957102

    A Japanese-language paper locating cyclic vomiting in the diencephalon. No abstract; cited only as evidence of mid-century neurological theorizing in the gap between Gee and the modern era.

69. 69
    Rusnac C, Metz O, Kandler E. [Periodic vomiting with acetonemia in children. (Clinical and laboratory study of 49 personal cases)].Pediatria (Bucharest) · 1970 · 19(4):355-64PMID 5485448

    A Romanian-language series of 49 children framed around acetonemia, the ketosis of the attack, as the disease. No abstract; cited as an example of the mid-century acetonemic framing.

70. 70
    Furusho K, Muraishi K, Sato K, Noda C. [Hyperactivity of the beta-receptor in children--with special reference to periodic vomiting (so-called autointoxication) and orthostatic dysregulation].Nihon Rinsho · 1974 · 32(9):2907-18PMID 4475181

    A Japanese-language paper treating periodic vomiting, there called autointoxication, as a disorder of beta-adrenergic hyperactivity alongside orthostatic dysregulation. No abstract; an early adrenergic framing that anticipated Sato.

71. 71
    Lang K. [On the significance of central nervous system lesions for periodic vomiting in childhood].Monatsschrift für Kinderheilkunde · 1963 · 111:161-7PMID 13928549

    A German-language paper relating periodic vomiting in childhood to central nervous system lesions and birth injury. No abstract; cited for the mid-century neurological framing.

72. 72
    Lenartowska I, Koslacz Folga A, Raszek J. [Periodic vomiting in children as a form of diencephalosis].Pediatria Polska · 1963 · 38:133-43PMID 14053649

    A Polish-language paper proposing periodic vomiting as a form of 'diencephalosis', a disturbance of the deep brain. No abstract; cited for the mid-century framing.

73. 73
    Cullen KJ, MacDonald WB. The periodic syndrome: its nature and prevalence.Medical Journal of Australia · 1963 · 50(2):167-73PMID 14024194

    No abstract in the PubMed record, which indexes it under 'periodic disease'; cited by title only, as evidence that the 'periodic syndrome' was being counted in the 1960s.

74. 74
    Svatý J. [Periodic syndrome and migraine in children].Ceskoslovenska Pediatrie · 1968 · 23(10):943-4PMID 5701267

    A Czech-language paper pairing the periodic syndrome with childhood migraine in its title, indexed under vomiting and migraine. No abstract; cited by title only.

75. 75
    Solc J, Sauerová Z. [Reserpine therapy of periodic vomiting and abdominal pain in children].Ceskoslovenska Pediatrie · 1970 · 25(4):199-200PMID 5444510

    A Czech-language report of reserpine, a catecholamine-depleting drug, for periodic vomiting in children. No abstract; cited as an early empirical treatment that anticipated the adrenergic hypothesis.

76. 76
    Salmon MA, Walters DD. Pizotifen in the prophylaxis of cyclical vomiting.Lancet · 1985 · 1(8436):1036-7doi:10.1016/s0140-6736(85)91630-7 · PMID 2859478

    A letter reporting the migraine preventive pizotifen in children with cyclical vomiting. No abstract; cited as an early anti-migraine treatment attempt.

77. 77
    Vanderhoof JA, Young R, Kaufman SS, Ernst L. Treatment of cyclic vomiting in childhood with erythromycin.Journal of Pediatric Gastroenterology and Nutrition · 1993 · 17(4):387-91doi:10.1097/00005176-199311000-00009 · PMID 8145093

    Twenty children given oral erythromycin as a prokinetic for 7 days: 13 reported total resolution at 2 and 6 months, all boys responded, and the authors state the trial was uncontrolled and a placebo effect could not be excluded. An honest early open trial.

78. 78
    Fleisher DR, Matar M. The cyclic vomiting syndrome: a report of 71 cases and literature review.Journal of Pediatric Gastroenterology and Nutrition · 1993 · 17(4):361-9PMID 8145089

    Seventy-one patients seen 1968 to 1988: episodes stereotyped for each patient, a course of months to decades, coincidence with migraine and irritable bowel; management still includes attention to feelings and attitudes that may predispose to attacks. The hinge between eras.

79. 79
    Li BU. Cyclic vomiting syndrome: a pediatric Rorschach test.Journal of Pediatric Gastroenterology and Nutrition · 1993 · 17(4):351-3doi:10.1097/00005176-199311000-00001 · PMID 8145085

    Editorial accompanying Fleisher's series, naming the syndrome a condition onto which each specialty projected its own explanation. No abstract; cited for the phrase and the moment.

80. 80
    Allen JH, de Moore GM, Heddle R, Twartz JC. Cannabinoid hyperemesis: cyclical hyperemesis in association with chronic cannabis abuse.Gut · 2004 · 53(11):1566-70doi:10.1136/gut.2003.036350 · PMID 15479672

    Nineteen South Australian cannabis users with cyclical vomiting, nine followed: cessation ended vomiting in seven, three who rechallenged relapsed, and nine of ten showed an abnormal washing behavior. The first description of cannabinoid hyperemesis and of compulsive bathing; the authors conclude cannabis was the cause in all cases.

81. 81
    Davenport CW, Zrull JP, Kuhn CC, Harrison SI. Cyclic vomiting.Journal of the American Academy of Child Psychiatry · 1972 · 11(1):66-87doi:10.1016/s0002-7138(09)61805-7 · PMID 5011231

    A child psychiatry paper indexed under psychophysiologic disorders and personality development: the psychogenic era in print. No abstract is available; cited for its framing and date.

82. 82
    Reinhart JB, Evans SL, McFadden DL. Cyclic vomit in children: seen through the psychiatrist's eye.Pediatrics · 1977 · 59(3):371-7PMID 840555

    Sixteen Pittsburgh children seen since 1956, four of whom had exploratory surgery that found nothing; the authors attribute the illness to parental anxiety and a prolonged symbiotic relationship with the mother. The clearest statement of the belief later reversed.

83. 83
    Jernigan SA, Ware LM. Reversible quantitative EEG changes in a case of cyclic vomiting: evidence for migraine equivalent.Developmental Medicine and Child Neurology · 1991 · 33(1):80-5doi:10.1111/j.1469-8749.1991.tb14787.x · PMID 1995411

    Abnormal delta activity during two episodes that resolved when the patient was well; the authors state the changes counter the psychosomatic hypothesis. A single case, but a physiological argument against a psychological cause.

84. 84
    Venkatesan T, Hillard CJ, Rein L, Banerjee A, Lisdahl K. Patterns of Cannabis Use in Patients With Cyclic Vomiting Syndrome.Clinical Gastroenterology and Hepatology · 2020 · 18(5):1082-1090.e2doi:10.1016/j.cgh.2019.07.039 · PMID 31352091

    Cross-sectional study of 140 clinic patients: 41% current users, 21% regular (four or more times a week); of 57 users, 50 had abstained for over a month and only one reported resolution, so one patient met Rome IV criteria for cannabinoid hyperemesis. Evidence that abstinence rarely cures cyclic vomiting patients who use cannabis; single specialist clinic.

85. 85
    Levinthal DJ, Staller K, Venkatesan T. AGA Clinical Practice Update on Diagnosis and Management of Cyclic Vomiting Syndrome: Commentary.Gastroenterology · 2024 · 167(4):804-811.e1doi:10.1053/j.gastro.2024.05.031 · PMID 39023502

    American Gastroenterological Association expert commentary, peer reviewed but not a GRADE guideline; the abstract states its purpose and method only, so its specific advice is not quoted here.

86. 86
    Rubio-Tapia A, McCallum R, Camilleri M. AGA Clinical Practice Update on Diagnosis and Management of Cannabinoid Hyperemesis Syndrome: Commentary.Gastroenterology · 2024 · 166(5):930-934.e1doi:10.1053/j.gastro.2024.01.040 · PMID 38456869

    The companion American Gastroenterological Association expert commentary on cannabinoid hyperemesis; abstract states purpose and method only.

87. 87
    Dong M, Li ZH, Li G. [Clinical characteristics of 41 children with cyclic vomiting syndrome].Zhonghua Er Ke Za Zhi (Chinese Journal of Pediatrics) · 2008 · 46(6):450-3PMID 19099785

    Forty-one children at Peking Union Medical College 1994 to 2007: mean diagnostic delay 4 years, 11 first treated as epilepsy, 9 operated on for presumed hiatal hernia and 4 for superior mesenteric artery syndrome before diagnosis, hypertension and salivation during attacks, most recovering over years. Chinese-language with English abstract; documents misdiagnosis and unnecessary surgery.

88. 88
    Waisfeld A, Randazzo I, Aronoff S, Feinstein L, Del Vecchio M. Etiologies of Cyclic Vomiting Syndrome in Children: A Systematic Review of 1,373 Patients.Pediatric Gastroenterology, Hepatology and Nutrition · 2026 · 29(1):62-70doi:10.5223/pghn.2026.29.1.62 · PMID 41567250

    Seventeen studies, 1,375 patients, Bayesian rate estimates: psychological stress 26.2%, infection 22%, motion sickness 19.3%, migraine 12.9% as triggers or associated diagnoses; surgical causes 4.8% and mitochondrial disease 0.4%. Mixes triggers with causes, which limits it, but gives the proportions.

89. 89
    Tarbell SE, van Tilburg MAL. Psychogastroenterology of cyclic vomiting syndrome: A crucial need to build evidence.Neurogastroenterology and Motility · 2026 · 38(1):e14888doi:10.1111/nmo.14888 · PMID 39099154

    Call to action: despite clinical use of psychological therapies, the evidence base is absent and few practices offer them, producing an 'all guts no brain' approach. Opinion piece from the guideline's psychologists.

90. 90
    Hibbert K, Williams A, Seabrook L. When the Doctor Doesn't Know: Exploring the Liminal Space Occupied by Patients and Caregivers Living with Cyclic Vomiting Syndrome.Narrative Inquiry in Bioethics · 2026 · 16(2):139-155doi:10.1353/nib.2026.a1002105 · PMID 42803041

    Qualitative analysis of illness narratives from adults and caregivers: a pattern of 'epistemic rupture' in which clinicians fail to recognize or validate the illness, framed as epistemic injustice. Narrative data; documents the legacy of the psychogenic era in patients' experience.

91. 91
    Tilinty HM, Kebabwe BE. Psychiatric management of pediatric cyclic vomiting syndrome using nonpharmacological interventions from a gut-brain perspective: a case report.Journal of Medical Case Reports · 2026 · 20(1)doi:10.1186/s13256-026-06287-2 · PMID 42387600

    A 10-year-old in Addis Ababa whose stereotyped attacks, triggered by anger and conflict, ceased after nine months of structured psychiatric care including anger management and family psychoeducation. The child was diagnosed with somatic symptom disorder, unspecified (DSM-5-TR), and the authors frame the case within a biopsychosocial gut-brain model. One case.

92. 92
    Frazier R, Ghoshal UC, Remes-Troche J, et al. Exploring cyclic vomiting syndrome (CVS) worldwide: Current epidemiological insights and recent developments.Neurogastroenterology and Motility · 2025 · 37(3):e14932doi:10.1111/nmo.14932 · PMID 39370604

    Review of global prevalence and incidence data, noting wide variation hindered by inconsistent methods and poor recognition, and disparities in outcomes among African Americans and Hispanics in the United States. Narrative review with patient-association co-authors.

93. 93
    Swartz JA, Franceschini D. Cannabinoid Hyperemesis Syndrome, 2016 to 2022.JAMA Network Open · 2025 · 8(11):e2545310doi:10.1001/jamanetworkopen.2025.45310 · PMID 41284293

    Nationwide Emergency Department Sample, 806 million weighted visits: a proxy for cannabinoid hyperemesis (cannabis code plus cyclic vomiting code) rose from 4.4 per 100,000 visits to a peak of 33.1 in the second quarter of 2020 and 22.3 in 2022, while cyclic vomiting without cannabis fell from 300 to 186; risk highest at ages 18 to 25. Coding-based; cannot separate changed disease from changed recognition.

94. 94
    Olson AD, Li BUK. The diagnostic evaluation of children with cyclic vomiting: a cost-effectiveness assessment.Journal of Pediatrics · 2002 · 141(5):724-8doi:10.1067/mpd.2002.129300 · PMID 12410206

    Decision analysis using the 82% migraine family history and 60% response to anti-migraine therapy: an upper GI series plus empiric migraine treatment ($1,600) was cheaper than extensive evaluation ($3,020) and avoided 65% of endoscopies, with the series kept because a missed malrotation costs more. Modeling, not a trial.

95. 95
    Hikita T, Kodama H, Kaneko S, et al. Sumatriptan as a treatment for cyclic vomiting syndrome: a clinical trial.Cephalalgia · 2011 · 31(4):504-7doi:10.1177/0333102410390398 · PMID 21147834

    Twelve children: subcutaneous sumatriptan responsive in 19 of 35 attacks in 11 patients, nasal spray completely effective in 2 of 6; efficacy higher with a family history of migraine (P = 0.048); no adverse effects. The main pediatric triptan data; open-label.

96. 96
    Calhoun AH, Pruitt AP. Injectable sumatriptan for cyclic vomiting syndrome in adults: a case series.Headache · 2014 · 54(9):1526-30doi:10.1111/head.12444 · PMID 25168483

    Case series and review arguing that adult cyclic vomiting lies on the migraine spectrum, responds to migraine preventives and in some cases to injectable sumatriptan 'even in the absence of headache'. Case-level evidence.

97. 97
    Greene KA, Gelfand AA, Charleston L. Evidence-based review and frontiers of migraine therapy.Neurogastroenterology and Motility · 2025 · 37(3):e14899doi:10.1111/nmo.14899 · PMID 39133210

    Review noting that ICHD-3 lists cyclic vomiting among the 'episodic syndromes that may be associated with migraine', and that CGRP-pathway drugs, a 5-HT1F agonist and migraine neuromodulation devices have yet to be studied in it. Proposal, not data.

98. 98
    Hayes WJ, Weisensee LA, Kappes JA, Dalton SM, Lemon MD. OnabotulinumtoxinA Injections for the Treatment of Cyclic Vomiting Syndrome.Pharmacotherapy · 2015 · 35(5):e51-5doi:10.1002/phar.1570 · PMID 25823714

    A 45-year-old woman whose cyclic vomiting improved dramatically when onabotulinumtoxinA injections were started for coexisting migraine. A single case extending a migraine preventive to the syndrome.

99. 99
    Yu ES, Priyadharsini S S Y, Venkatesan T. Migraine, Cyclic Vomiting Syndrome, and Other Gastrointestinal Disorders.Current Treatment Options in Gastroenterology · 2018 · 16(4):511-527doi:10.1007/s11938-018-0202-2 · PMID 30361855

    Review of the shared pathophysiology, presentation and drug responses of migraine and cyclic vomiting (tricyclics, triptans, antiepileptics) and of CGRP inhibitors as a potential future therapy. Proposal, not data.

100. 100
     Ter Horst GJ, Meijler WJ, Korf J, Kemper RH. Trigeminal nociception-induced cerebral Fos expression in the conscious rat.Cephalalgia · 2001 · 21(10):963-75doi:10.1046/j.1468-2982.2001.00285.x · PMID 11843868

     In conscious rats, trigeminal capsaicin activated the dorsal raphe, locus coeruleus and hypothalamus along with the area postrema and nucleus of the solitary tract; the authors argue this opposes a pathogenic (initiating) role for those nuclei in migraine. Animal evidence against reading the 1995 PET finding as a generator.

101. 101
     Levinthal DJ, Kuo B. Future Applications of Central Neuromodulation and Neurophysiological Testing in Cyclic Vomiting Syndrome.Neurogastroenterology and Motility · 2025 · 37(3):e14991doi:10.1111/nmo.14991 · PMID 39737523

     Brief review arguing from the episodic pattern and shared drugs with migraine and epilepsy that the syndrome has a neural basis, and proposing cortical excitability testing and central neuromodulation as future tools. Prospective, not evidence of mechanism.

102. 102
     Donnet A, Redon S. Cyclic Vomiting Syndrome in Children.Current Pain and Headache Reports · 2018 · 22(4):30doi:10.1007/s11916-018-0684-6 · PMID 29556858

     Review from a French headache center: clinical phases, circadian and circannual periodicity suggesting a chronobiological disease, functional MRI in both cyclic vomiting and migraine showing diminished insular connectivity with the sensorimotor network, injectable or intranasal sumatriptan often effective, and no controlled pediatric trials. Narrative review.

103. 103
     Camilleri M, Carlson P, Zinsmeister AR, et al. Mitochondrial DNA and gastrointestinal motor and sensory functions in health and functional gastrointestinal disorders.American Journal of Physiology. Gastrointestinal and Liver Physiology · 2009 · 296(3):G510-6doi:10.1152/ajpgi.90650.2008 · PMID 19147801

     In 699 patients and controls genotyped at 7028, 16519 and 3010: 3010A associated with nonspecific abdominal pain (OR 3.3), 3010G with slower gastric emptying and the haplogroup-H marker 7028C with lower satiation, but no association with most motor and sensory functions tested. A Mayo Clinic test of the same variants in functional disorders, with modest results.

104. 104
     Boles RG, Zaki EA, Kerr JR, Das K, Biswas S, Gardner A. Increased prevalence of two mitochondrial DNA polymorphisms in functional disease: Are we describing different parts of an energy-depleted elephant?Mitochondrion · 2015 · 23:1-6doi:10.1016/j.mito.2015.04.005 · PMID 25934187

     An original association study reporting the same two polymorphisms as associated with chronic fatigue syndrome, complex regional pain syndrome, sudden infant death syndrome and major depressive disorder among haplogroup-H individuals. The widening of a marker to many conditions in small samples is a warning sign; the corresponding author's listed email address is at Courtagen, a commercial genetic-testing company, while his listed affiliation is Children's Hospital Los Angeles; a potential conflict of interest to note.

105. 105
     Veenin K, Wattanasirichaigoon D, Suktitipat B, et al. Association of Mitochondrial DNA Polymorphisms With Pediatric-Onset Cyclic Vomiting Syndrome.Frontiers in Pediatrics · 2022 · 10:876436doi:10.3389/fped.2022.876436 · PMID 35685918

     Thirty Thai children sequenced against 148 Thai controls: 16519T in 40% against 27.7% (P = 0.18) and 3010A in 6.7% against 0.7% (P = 0.07), no significant association. Small, and in a non-European population, so not a direct replication of the haplogroup-H design.

106. 106
     Ye Z, Xue A, Huang Y, Wu Q. Children with cyclic vomiting syndrome: phenotypes, disease burden and mitochondrial DNA analysis.BMC Gastroenterology · 2018 · 18(1):104doi:10.1186/s12876-018-0836-5 · PMID 29969994

     Forty-two Shanghai children, 13 sequenced: 16519T in 4 and 3010A in 2, not significantly associated with the syndrome. Very small.

107. 107
     Boles RG. High degree of efficacy in the treatment of cyclic vomiting syndrome with combined co-enzyme Q10, L-carnitine and amitriptyline, a case series.BMC Neurology · 2011 · 11:102doi:10.1186/1471-2377-11-102 · PMID 21846334

     Retrospective chart review of 30 patients of one clinician treated with fasting avoidance, coenzyme Q10 and L-carnitine, adding amitriptyline or cyproheptadine with blood-level monitoring: episodes resolved in 23 and improved over 75% in three more. Single-clinician, uncontrolled, by the author of the mitochondrial hypothesis.

108. 108
     Yorns WR, Hardison HH. Mitochondrial dysfunction in migraine.Seminars in Pediatric Neurology · 2013 · 20(3):188-93doi:10.1016/j.spen.2013.09.002 · PMID 24331360

     Review of biochemical, morphological, genetic and therapeutic evidence linking mitochondria to migraine: the classic mitochondrial disease mutations show no association with migraine; 16519T and 3010A had been associated with pediatric cyclic vomiting and migraine, POLG mutations can cause disease including migraine, other specific mutations confer migraine susceptibility, and very large samples would be needed. Context for the cyclic vomiting claim.

109. 109
     Pizzol A, Adams KA, de Vries BBA, Curry CJ, Calvo PL. Cyclic Vomiting Syndrome in Patients Affected by Jansen-de Vries Syndrome: Results From an International Survey.American Journal of Medical Genetics Part A · 2025 · 197(3):e63918doi:10.1002/ajmg.a.63918 · PMID 39494522

     Online survey of 21 patients or guardians with the PPM1D-related neurodevelopmental disorder: 6 had a cyclic vomiting diagnosis and 7 more met Rome IV criteria undiagnosed, a prevalence of 61%. A single-gene syndrome in which cyclic vomiting is a core feature; survey data, small.

110. 110
     Ferretti A, Furlan M, Glinton KE, et al. Cyclical Vomiting Syndrome in Individuals With BPTF Haploinsufficiency.Pediatric Neurology · 2025 · 170:58-65doi:10.1016/j.pediatrneurol.2025.06.010 · PMID 40614698

     Fifteen individuals with pathogenic BPTF variants: 3 diagnosed with cyclic vomiting and 4 more meeting most ICHD-3 criteria, episodes from a median age of 3 triggered by poor sleep and fever, with benefit from acute and prophylactic therapy. A second monogenic route to the phenotype.

111. 111
     Goh L, Ho JMD, Chiou FK. Disease characteristics and long-term outcomes of cyclic vomiting syndrome in Singaporean children.World Journal of Gastrointestinal Pharmacology and Therapeutics · 2025 · 16(2):103971doi:10.4292/wjgpt.v16.i2.103971 · PMID 40575359

     Thirty-two children 2011 to 2021: 40% underweight at diagnosis with a median body mass index z-score of -3.2, systemic hypertension in 10%, mean four attacks a year; half received prophylaxis with 75% responding to first-line therapy and body mass index z-score improving from -2.9 to -0.9. Small retrospective cohort.

112. 112
     Xiong LY, Chen PY, Xie J, et al. [Clinical characteristics of cyclic vomiting syndrome and the therapeutic efficacy of chlorpromazine combined with promethazine].Zhonghua Er Ke Za Zhi (Chinese Journal of Pediatrics) · 2026 · 64(3):314-318doi:10.3760/cma.j.cn112140-20250601-00467 · PMID 41674423

     110 children in Guangzhou 2015 to 2025: onset 6.5 years, autonomic symptoms in 21 including raised blood pressure in 2; 46 given intramuscular chlorpromazine with promethazine had a median vomiting duration of 1 day against 3 days in 20 given intravenous ondansetron or omeprazole. Retrospective, non-randomized comparison; Chinese-language with English abstract.

113. 113
     Hasler WL, Levinthal DJ, Tarbell SE, et al. Cyclic vomiting syndrome: Pathophysiology, comorbidities, and future research directions.Neurogastroenterology and Motility · 2019 · 31 Suppl 2:e13607doi:10.1111/nmo.13607 · PMID 31241816

     The guideline committee's research agenda: no placebo-controlled randomized trials exist, and a multicenter standardized registry, disease-specific outcome measures and biomarker studies are needed. States the evidence gap plainly.

114. 114
     Namin F, Patel J, Lin Z, et al. Clinical, psychiatric and manometric profile of cyclic vomiting syndrome in adults and response to tricyclic therapy.Neurogastroenterology and Motility · 2007 · 19(3):196-202doi:10.1111/j.1365-2982.2006.00867.x · PMID 17300289

     Thirty-one Kansas adults meeting Rome II criteria: gastric emptying rapid in 23 of 30 (77%), normal in 4 and delayed in 3; anxiety disorder in 84%; 93% of 24 on amitriptyline improved. Single-center series.

115. 115
     Hejazi RA, Lavenbarg TH, McCallum RW. Spectrum of gastric emptying patterns in adult patients with cyclic vomiting syndrome.Neurogastroenterology and Motility · 2010 · 22(12):1298-302doi:10.1111/j.1365-2982.2010.01584.x · PMID 20723071

     Retrospective scintigraphy in 92 Rome III adults: rapid emptying in 54 (59%), normal in 25 (27%), slow in 13 (14%), the slow group associated with narcotics, diabetes and marijuana. Shows delayed emptying is the exception in adult cyclic vomiting.

116. 116
     Karrento K, Zhang L, Conley W, et al. Percutaneous electrical nerve field stimulation improves comorbidities in children with cyclic vomiting syndrome.Frontiers in Pain Research · 2023 · 4:1203541doi:10.3389/fpain.2023.1203541 · PMID 37389229

     Open-label study of six weeks of auricular neurostimulation in 30 children aged 8 to 18 with drug-refractory disease: abdominal pain and state anxiety fell at six weeks and at four to six months, sleep improved short-term, no serious side effects. Uncontrolled; vomiting frequency was not the primary outcome.

117. 117
     Simonetto DA, Oxentenko AS, Herman ML, Szostek JH. Cannabinoid hyperemesis: a case series of 98 patients.Mayo Clinic Proceedings · 2012 · 87(2):114-9doi:10.1016/j.mayocp.2011.10.005 · PMID 22305024

     Ninety-eight patients, all under 50; 68% of those asked had used cannabis more than two years, 86% had abdominal pain, 91% of the 57 asked found relief in hot bathing; follow-up in only 10, of whom 7 stopped and 6 improved. The largest early series and the source of proposed major and supportive criteria.

118. 118
     Chatorikar SA, Agarwal S, Purohith AN, Shenoy S, P RB, Sharma P. Compulsive Bathing Associated with Cyclical Vomiting Syndrome: A Case Report.Indian Journal of Psychological Medicine · 2025 · published online 30 May 2025doi:10.1177/02537176251339409 · PMID 40453759

     A letter describing compulsive bathing in a patient with cyclical vomiting syndrome. No abstract; cited as one further instance of the behavior in the syndrome, from psychiatry.

119. 119
     Venkatesan T, Levinthal DJ, Li BUK, et al. Role of chronic cannabis use: Cyclic vomiting syndrome vs cannabinoid hyperemesis syndrome.Neurogastroenterology and Motility · 2019 · 31 Suppl 2:e13606doi:10.1111/nmo.13606 · PMID 31241817

     Systematic collation of published cannabinoid hyperemesis case series and reports against Rome IV criteria by the adult guideline committee: data heterogeneous with limited follow-up, making it 'difficult to ascertain whether chronic cannabis use is causal, merely a clinical association with CVS, or unmasks or triggers symptoms'; proposes revised criteria. The one-spectrum case stated by the guideline authors.

120. 120
     Alshaarawy O, Balasubramanian G, Venkatesan T. Cannabis use in the United States and its impact on gastrointestinal health.Nutrition in Clinical Practice · 2024 · 39(2):281-292doi:10.1002/ncp.11111 · PMID 38142306

     Review stating that given the heterogeneity of the literature 'it is unclear if cannabinoid hyperemesis syndrome is truly a distinct entity or a subtype of cyclic vomiting that is unmasked by heavy cannabis use'. The one-spectrum position stated in 2023.

121. 121
     Russo EB, Spooner C, May L, Leslie R, Whiteley VL. Cannabinoid Hyperemesis Syndrome Survey and Genomic Investigation.Cannabis and Cannabinoid Research · 2022 · 7(3):336-344doi:10.1089/can.2021.0046 · PMID 34227878

     Online survey of 585 respondents; 28 patients and 12 cannabis-using controls completed genotyping; odds ratios 5.8 to 12 for variants in COMT, TRPV1, CYP2C9, DRD2 and ABCA1, each also present in 10% to 30% of controls. Small and unreplicated; the first and last authors are affiliated with CReDO Science and two co-authors with Endocanna Health, both commercial companies, a conflict of interest to note.

122. 122
     Yacob D. Cyclic Vomiting Syndrome and Cannabinoid Hyperemesis Syndrome: Their Intersection and Joint Existence.Gastroenterology Clinics of North America · 2025 · 54(3):557-568doi:10.1016/j.gtc.2025.05.004 · PMID 40752916

     Review holding that the two disorders share clinical features but differ in pathophysiology, epidemiology and management, cyclic vomiting being a gut-brain disorder tied to migraine and autonomic dysfunction and cannabinoid hyperemesis being directly linked to chronic heavy cannabis use. The two-conditions position from a pediatric gastroenterologist.

123. 123
     Ilgen MA, Price AM, Goldman P, Whittington BJ, Hicks BM. Prevalence and Correlates of Symptoms of Cannabinoid Hyperemesis Syndrome in the United States, 2025.American Journal of Public Health · 2026 · published online 1 October 2026, e1-e10doi:10.2105/AJPH.2026.308753 · PMID 42821817

     Nationally representative survey of 7,034 United States adults, May to September 2025: 2.7% of all respondents and 17.8% of daily cannabis users reported hyperemesis-like symptoms, more often among younger, female, non-white, lower-income respondents and those with cannabis-use problems. Self-reported symptoms, not diagnoses.

124. 124
     Hicks BM, Price AM, Whittington BJ, Goldman P, Ilgen MA. Links between cannabinoid hyperemesis syndrome symptoms and drug use, mental health problems, antisocial behavior, and personality in a national survey of adults in the United States.Drug and Alcohol Dependence · 2026 · 287:113323doi:10.1016/j.drugalcdep.2026.113323 · PMID 42617216

     Same 2025 survey of 7,034 adults: those with hyperemesis-like symptoms reported more use of other drugs, more overdoses, more depression, anxiety, sleep disturbance, chronic pain and antisocial behavior than daily cannabis users without symptoms (mean effect size d = 0.58). Cross-sectional self-report.

125. 125
     Kilani Y, Nguyen C, Mosquera DAG, et al. Cannabis Use Is Associated With Increased Healthcare Utilization and Poorer Outcomes in Cyclical Vomiting Syndrome-A Propensity Matched Analysis of 34,988 Individuals.Neurogastroenterology and Motility · 2026 · 38(4):e70263doi:10.1111/nmo.70263 · PMID 41935343

     TriNetX real-world data: 18,588 adults with cyclic vomiting who used cannabis matched 1:1 with non-users; users were younger with more mood disorders and gastroparesis, and had more emergency visits (HR 1.35, 95% CI 1.31 to 1.39) and hospitalizations (HR 1.11). Association after matching on measured variables only.

126. 126
     Siddiqui MT, Bilal M, Singh A, et al. Prevalence of cannabis use has significantly increased in patients with cyclic vomiting syndrome.Neurogastroenterology and Motility · 2020 · 32(4):e13806doi:10.1111/nmo.13806 · PMID 31990435

     National Inpatient Sample 2005 to 2014, 129,090 admissions with a primary diagnosis of cyclic vomiting: cannabis use coded in 10.4% overall, rising ten-fold from 2.2% in 2005 to 21.2% in 2014. Administrative coding; cannot distinguish cause, association or self-treatment.

127. 127
     Bhandari S, Jha P, Lisdahl KM, Hillard CJ, Venkatesan T. Recent trends in cyclic vomiting syndrome-associated hospitalisations with liberalisation of cannabis use in the state of Colorado.Internal Medicine Journal · 2019 · 49(5):649-655doi:10.1111/imj.14164 · PMID 30426628

     Colorado inpatient database 2010 to 2014: cyclic vomiting admissions rose 46% from 806 to 1,180, cannabis use far higher in cyclic vomiting admissions than others, and use rose in both after recreational legalization in 2012. An ecological association around legalization, not a causal test.

128. 128
     Felix-Tellez FA, Morel-Cerda EC, Jiménez-Castillo RA, et al. Clinical Characteristics and Associated Factors in Mexican Patients With Cyclic Vomiting Syndrome and Cannabinoid Hyperemesis Syndrome.Journal of Neurogastroenterology and Motility · 2025 · 31(3):330-339doi:10.5056/jnm24182 · PMID 40625249

     Cross-sectional study in five Mexican centers: 30 with cyclic vomiting and 16 with cannabinoid hyperemesis; hyperemesis patients older with more tobacco and risky alcohol use; only 13.3% of cyclic vomiting patients used cannabis; no difference in admissions or length of stay. A population with low cannabis use, small.

129. 129
     Sinan K, Beydoun S, Lulgjuraj T. The Clinical Conundrum of Cyclic Vomiting in the Cannabinoid User: Simply Cannabinoid Hyperemesis or Could It Be More?ACG Case Reports Journal · 2025 · 12(5):e01711doi:10.14309/crj.0000000000001711 · PMID 40401049

     Two adolescent cannabis users whose cyclical vomiting tracked the menstrual cycle and resolved with hormonal contraception despite continued cannabis. Two cases; shows how a catamenial pattern can be misread as cannabinoid hyperemesis.

130. 130
     Butt MF, Cefalo F, Sbarigia C, Dhali A, Corsetti M. Impact of Opioid and Cannabis Use on Low-Dose Amitriptyline Efficacy in Cyclical Vomiting Syndrome: A Real-World Study in the United Kingdom.Neurogastroenterology and Motility · 2025 · 37(6):e70007doi:10.1111/nmo.70007 · PMID 40017095

     Seventy-five newly diagnosed Rome IV adults at a Nottingham clinic, 2016 to 2024, advised to stop opioids and cannabis and started on a low-dose tricyclic (mean 26.5 mg among responders): 61% responded to a three-tier algorithm, 42 of 46 responders on the tricyclic alone; opioid cessation was associated with response. Retrospective single-center.

131. 131
     Won KJ, Celmins L. Managing cannabinoid hyperemesis syndrome in adult patients in the emergency department.American Journal of Health-System Pharmacy · 2025 · 82(24):1340-1352doi:10.1093/ajhp/zxaf125 · PMID 40458910

     Pharmacy review of emergency treatment of cannabinoid hyperemesis: haloperidol and droperidol, conventional antiemetics, topical capsaicin, and advice against opioids and benzodiazepines as first-line, with cessation as the cure. Where the cannabis form's acute pharmacology has diverged from cyclic vomiting's.

132. 132
     Hejazi RA, Reddymasu SC, Namin F, Lavenbarg T, Foran P, McCallum RW. Efficacy of tricyclic antidepressant therapy in adults with cyclic vomiting syndrome: a two-year follow-up study.Journal of Clinical Gastroenterology · 2010 · 44(1):18-21doi:10.1097/MCG.0b013e3181ac6489 · PMID 20027010

     Open-label follow-up of 41 adults for one year and 23 for two: frequency and duration of episodes, emergency visits and hospitalizations all reduced (P < 0.05), 88% improved by global assessment, mild side effects in 34%. The best adult tricyclic data, uncontrolled.

133. 133
     Patel M, Partovi O, Karrento K, Garacchi Z, Balasubramanian G, Venkatesan T. Pharmacogenomic testing for CYP2C19 and CYP2D6 in cyclic vomiting syndrome.Neurogastroenterology and Motility · 2024 · 36(1):e14705doi:10.1111/nmo.14705 · PMID 37953495

     Pilot in 46 adults on amitriptyline: 43% ultrarapid CYP2C19 metabolizers, 9% poor CYP2D6 metabolizers, adverse reactions in 46% with 28% stopping, and no significant association between genotype and response, side effects or drug level (trend P = 0.06). Too small to settle whether genotyping helps.

134. 134
     Frazier R, Li BUK, Venkatesan T. Diagnosis and Management of Cyclic Vomiting Syndrome: A Critical Review.American Journal of Gastroenterology · 2023 · 118(7):1157-1167doi:10.14309/ajg.0000000000002216 · PMID 36791365

     Critical review: prevalence about 2% in the United States, diagnosis by Rome criteria with an upper endoscopy and abdominal imaging as minimum testing, comorbid anxiety, depression and autonomic dysfunction, and the view that cannabinoid hyperemesis is a subset of cyclic vomiting with heavy cannabis use. The adult specialists' position in 2023.

135. 135
     Badihian N, Saneian H, Badihian S, Yaghini O. Prophylactic Therapy of Cyclic Vomiting Syndrome in Children: Comparison of Amitriptyline and Cyproheptadine: A Randomized Clinical Trial.American Journal of Gastroenterology · 2018 · 113(1):135-140doi:10.1038/ajg.2017.194 · PMID 28719594

     Single-blinded randomized trial of 64 children aged 3 to 15 in Isfahan, followed six months: monthly attacks 0.38 against 0.59 (P = 0.197), full remission 65.6% against 50% (P = 0.206). No superiority; no placebo arm.

136. 136
     Bagherian Z, Yaghini O, Saneian H, Badihian S. Comparison of the Efficacy of Amitriptyline and Topiramate in Prophylaxis of Cyclic Vomiting Syndrome.Iranian Journal of Child Neurology · 2019 · 13(1):37-44PMID 30613204

     Randomized trial of 72 children aged 3 to 15 for three months: attack frequency similar, duration shorter on amitriptyline (3.43 against 4.90 hours, P = 0.017), 68% against 39% free of attacks (P = 0.016). Short follow-up, no placebo. No DOI in the PubMed record.

137. 137
     Altuntaş C, Sevinçok D, Hilal Dolu M, Gültekin E. Lifestyle and SSRI Interventions in Pediatric Cyclic Vomiting Syndrome: Rethinking First-Line Management.Children (Basel) · 2025 · 12(8):964doi:10.3390/children12080964 · PMID 40868416

     Retrospective study of 119 Rome IV children in Istanbul: anxiety in 78.2%, lifestyle adherence (73.9%) predicted success, all 34 given an SSRI for moderate to severe anxiety met the success definition, cyproheptadine added nothing over lifestyle change and six stopped it for drowsiness or weight gain. Non-randomized groups chosen by clinical need.

138. 138
     Mooers H, Srivastava S, Garacci E, Venkatesan T. Retrospective review of patients treated for cyclic vomiting syndrome with topiramate.Alimentary Pharmacology and Therapeutics · 2021 · 54(2):153-159doi:10.1111/apt.16457 · PMID 34114666

     136 adults, 92% having failed tricyclics: 65% responded by intention to treat, annual episodes 18.1 to 6.2, emergency visits 4.3 to 1.6; higher dose, use over 12 months and monotherapy predicted response, anxiety predicted failure; 55% side effects and 32% discontinuation. The adult topiramate evidence, retrospective.

139. 139
     Sezer OB, Sezer T. A New Approach to the Prophylaxis of Cyclic Vomiting: Topiramate.Journal of Neurogastroenterology and Motility · 2016 · 22(4):656-660doi:10.5056/jnm16035 · PMID 27302967

     Retrospective review of 38 Turkish children on 12 months of prophylaxis: freedom from attacks in 81% on topiramate (16) and 59% on propranolol (22), responder rates 94% and 81%, similar adverse events. Retrospective and small.

140. 140
     Clouse RE, Sayuk GS, Lustman PJ, Prakash C. Zonisamide or levetiracetam for adults with cyclic vomiting syndrome: a case series.Clinical Gastroenterology and Hepatology · 2007 · 5(1):44-8doi:10.1016/j.cgh.2006.10.004 · PMID 17157078

     Twenty adults for whom tricyclics were unsatisfactory, given zonisamide (median 400 mg/day) or levetiracetam (median 1000 mg/day): 75% at least moderate response, 20% remission, episodes 1.3 to 0.5 a month, tricyclics stopped in 11 of 18, moderate or severe side effects in 45%. The entire evidence base for these two drugs.

141. 141
     Patel M, Partovi O, Mooers H, Kovacic K, Garacchi Z, Venkatesan T. Efficacy of aprepitant as a prophylactic medication in adults with cyclic vomiting syndrome.Neurogastroenterology and Motility · 2023 · 35(4):e14530doi:10.1111/nmo.14530 · PMID 36740813

     Of 96 adults prescribed aprepitant, 27% could not start for cost; of 70 treated, 93% refractory and 73% dosing three times a week, 71.4% had a global response with episodes falling from 14.5 to 6.2 a year; 10% stopped for minor side effects. Retrospective; cost as the main barrier.

142. 142
     Nivatsi M, Aslanidou I, Mantadakis E. Highly effective use of aprepitant in an adolescent girl with severe cyclic vomiting syndrome.BMJ Case Reports · 2021 · 14(3):e241132doi:10.1136/bcr-2020-241132 · PMID 33664041

     A 13-year-old who had failed oral ondansetron and had no further vomiting episodes after starting oral aprepitant at home at the first prodromal signs. One case.

143. 143
     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.Journal of Adolescent Health · 2025 · 77(6):1223-1225doi:10.1016/j.jadohealth.2025.08.004 · PMID 40965394

     Two adolescents meeting Rome IV criteria for cannabinoid hyperemesis whose vomiting resolved within an hour of aprepitant after 36 to 45 hours of failed treatment. Two cases.

144. 144
     Kowalczyk M, Parkman H, Ward L. Adult cyclic vomiting syndrome successfully treated with intranasal sumatriptan.Journal of General Internal Medicine · 2010 · 25(1):88-91doi:10.1007/s11606-009-1162-y · PMID 19911235

     A 47-year-old man with a year of 4-to-7-day episodes, an extensive negative work-up, and termination of episodes with intranasal sumatriptan. A single case typical of how adult diagnoses are reached.

145. 145
     Levinthal DJ, Killian B, Issenman RM. Acute care of cyclic vomiting syndrome and cannabinoid hyperemesis syndrome in the home and emergency department.Neurogastroenterology and Motility · 2025 · 37(3):e14901doi:10.1111/nmo.14901 · PMID 39155452

     Review of abortive treatment at home and in the emergency department: triptans, antiemetics, anxiolytics, NK-1 antagonists, antipsychotics, sedatives, analgesics, a quiet dark room, hot bathing and topical capsaicin; calls for evidence-based individualized plans, compassionate emergency care, and care plans for frequent attenders. A patient-association co-author.

146. 146
     Rosen JM, Reeves PT. A call to action [plans] for cyclic vomiting syndrome.Neurogastroenterology and Motility · 2025 · 37(3):e14896doi:10.1111/nmo.14896 · PMID 39189212

     Describes the Cyclic Vomiting Syndrome Action Plan for home and emergency management, modeled on action plans for other chronic conditions, with anecdotal and indirect support and no efficacy trial. A tool, not evidence.

147. 147
     Ruberto AJ, Sivilotti MLA, Forrester S, et al. Intravenous Haloperidol Versus Ondansetron for Cannabis Hyperemesis Syndrome (HaVOC): A Randomized, Controlled Trial.Annals of Emergency Medicine · 2021 · 77(6):613-619doi:10.1016/j.annemergmed.2020.08.021 · PMID 33160719

     Triple-blind randomized trial in 30 treated cannabis users with active vomiting: haloperidol beat ondansetron by 2.3 cm on 10-cm pain and nausea scales at 2 hours (95% CI 0.6 to 4.0), with less rescue medication and earlier departure (3.1 against 5.6 hours); two returns for acute dystonia, both on the higher dose. Small; enrolled cannabis users only.

148. 148
     Dean DJ, Sabagha N, Rose K, et al. A Pilot Trial of Topical Capsaicin Cream for Treatment of Cannabinoid Hyperemesis Syndrome.Academic Emergency Medicine · 2020 · 27(11):1166-1172doi:10.1111/acem.14062 · PMID 32569429

     Double-blind placebo-controlled pilot in 30 emergency patients with suspected cannabinoid hyperemesis: 0.1% capsaicin cream reduced nausea at 60 but not at 30 minutes. Pilot scale.

149. 149
     Borgundvaag B, Bellolio F, Miles I, et al. Guidelines for Reasonable and Appropriate Care in the Emergency Department (GRACE-4): Alcohol use disorder and cannabinoid hyperemesis syndrome management in the emergency department.Academic Emergency Medicine · 2024 · 31(5):425-455doi:10.1111/acem.14911 · PMID 38747203

     Society for Academic Emergency Medicine GRADE guideline: for adults with cannabinoid hyperemesis, suggests haloperidol or droperidol, and topical capsaicin, in addition to usual care, each on very-low-certainty evidence.

150. 150
     Venkatesan T, Porcelli A, Matapurkar A, et al. An integrative healthcare model with heartfulness meditation and care coordination improves outcomes in cyclic vomiting syndrome.Neurogastroenterology and Motility · 2021 · 33(11):e14132doi:10.1111/nmo.14132 · PMID 33774892

     Randomized trial of 49 adults, 22 to an integrative model with a care coordinator and heartfulness meditation and 27 to conventional care: by intention to treat the meditation group improved in coping and physical quality of life at six months, with more benefit in compliant patients. The only randomized trial in adults; outcomes psychological, not episode counts; a Heartfulness Institute co-author.

151. 151
     Venkatesan T, Hillard CJ, Iyer L, et al. Correction to: Acute and Long-Term Effects of App-Delivered Heartfulness Meditation on Psychological Outcomes and the Endocannabinoid Signaling System in Cyclic Vomiting Syndrome.Clinical and Translational Gastroenterology · 2026 · published 5 October 2026doi:10.14309/ctg.0000000000001106 · PMID 42831869

     Published correction to the 2024 meditation study; the PubMed record has no abstract, and its author list gives the third author as Iyer L where the original record has Ayer L, so the correction may concern authorship; consult it alongside the original.

152. 152
     Fleisher DR. Management of cyclic vomiting syndrome.Journal of Pediatric Gastroenterology and Nutrition · 1995 · 21 Suppl 1:S52-6doi:10.1097/00005176-199501001-00015 · PMID 8708870

     Management review listing the complications of episodes as esophagitis, hematemesis, depletion of intracellular electrolytes, hypertension and inappropriate secretion of antidiuretic hormone. Expert review.

153. 153
     Song L, Li YJ, Wang J, et al. [Clinical and gastroscopic features of children with cyclic vomiting syndrome: an analysis of 63 cases].Zhongguo Dang Dai Er Ke Za Zhi (Chinese Journal of Contemporary Pediatrics) · 2022 · 24(12):1340-1344doi:10.7499/j.issn.1008-8830.2206007 · PMID 36544416

     Sixty-three children in Beijing, all scoped: 3 normal, 35% chronic gastritis alone, 60% with reflux esophagitis (16), bile reflux gastritis (12), duodenitis (13), erosive gastritis (10) or ulcer (5); 9 of 15 had pathological acid reflux between attacks. Chinese-language paper with English abstract; the mucosal cost of vomiting, or part of the disorder.

154. 154
     Zicari A, Corrado G, Pacchiarotti C, et al. Cyclic vomiting syndrome: in vitro nitric oxide and interleukin-6 release by esophageal and gastric mucosa.Digestive Diseases and Sciences · 2001 · 46(4):831-5doi:10.1023/a:1010712703685 · PMID 11330420

     Mucosal cells from 10 children between attacks and 10 controls: gastric mucosa from patients released more nitric oxide, esophageal release was similar, and no interleukin-6 was detectable in patients' gastric supernatants. A single in vitro study, not followed up.

155. 155
     Stoopler ET, Almog I, Sollecito TP, Tananis R. An oral complication in a patient with cyclic vomiting syndrome: a case report and review.General Dentistry · 2006 · 54(6):389-92PMID 17134074

     A dental case report of an adult with the syndrome who developed complications after extractions, with a review of the disease for dentists. One of very few dental papers on cyclic vomiting; no DOI in the PubMed record.

156. 156
     Mettu S, Animireddy D, Kanumuri PK, Muppa R. Symptomatic management of a child with cyclic vomiting syndrome.BMJ Case Reports · 2016 · 2016:bcr2016216499doi:10.1136/bcr-2016-216499 · PMID 27530876

     A pediatric dentistry case report of oral management in an affected preschool child, indexed under oral hygiene and mouthwashes. No abstract; one of the few dental papers on the syndrome.

157. 157
     Kuroda H, Kaneko R, Katagiri N, et al. General Anesthesia for Patients With Cyclic Vomiting Syndrome and Obesity: A Case Report.Cureus · 2024 · 16(7):e65130doi:10.7759/cureus.65130 · PMID 39171030

     Dental surgery under general anesthesia in a 21-year-old with the syndrome, scheduled during remission, with ACTH, vasopressin and cortisol measured before and after and no postoperative vomiting. A single case on perioperative planning.

158. 158
     Hayman J, van Wyhe J. Charles Darwin and the Dentists.Journal of the History of Dentistry · 2018 · 66(1):25-35PMID 30184385

     Historical article: Darwin's episodic nausea, retching and vomiting, the dental problems common to patients with repeated vomiting, and his extractions under chloroform. Retrospective diagnosis of a historical figure; cited only for the origin of the dental association in print.

159. 159
     Finsterer J, Hayman J. Mitochondrial disorder caused Charles Darwin's cyclic vomiting syndrome.International Journal of General Medicine · 2014 · 7:59-70doi:10.2147/IJGM.S54846 · PMID 24453499

     A literature-based argument that Darwin's multisystem illness, with cyclic vomiting as its most disabling feature and dental problems among the gastrointestinal manifestations, was a mitochondrial disorder. Untestable retrospective diagnosis; the title asserts more than the method can show.

160. 160
     Butt MF, van Tilburg MAL. Beyond Food Avoidance: ARFID and Nutritional Vulnerability in Cyclic Vomiting Syndrome.Neurogastroenterology and Motility · 2026 · 38(7):e70391doi:10.1111/nmo.70391 · PMID 42464087

     Editorial accompanying the 2026 ARFID study, framing nutritional vulnerability as a neglected part of the illness. Commentary; no abstract.

161. 161
     Klazura G, Geraghty JR, Rojnica M, Sims T, Koo N, Lobe T. Cannabinoid Hyperemesis Syndrome Complicated by Pneumomediastinum: Implications for Pediatric Surgeons.Clinical Surgery Journal · 2022 · 5(Suppl 13):6-13PMID 36438163

     A 17-year-old daily cannabis user with repetitive vomiting and pneumomediastinum, managed without surgery while watching for esophageal perforation. A single case of a severe mechanical complication in the cannabis form; no DOI in the record.

162. 162
     Tamai H, Kinugasa M. Pregnancy complicated by cyclic vomiting syndrome successfully treated with amitriptyline.Obstetrics and Gynecology · 2015 · 125(6):1487-1489doi:10.1097/AOG.0000000000000662 · PMID 25774931

     A 27-year-old whose attacks ceased once amitriptyline, stopped at the pregnancy diagnosis, was restored at 12 weeks, with a healthy term birth. A single case noting that pregnancy can worsen the syndrome.

163. 163
     Sanger GJ, Golding JF, Andrews PLR. New therapies to treat nausea and vomiting: clinical need, progress towards novelty and research challenges.Expert Review of Clinical Pharmacology · 2026 · 19(6):535-558doi:10.1080/17512433.2026.2682294 · PMID 42212356

     Review naming cyclic vomiting syndrome among the remaining treatment gaps in antiemetic therapy, with NK1 receptor antagonists the widest-spectrum single agents and nausea poorly quantified in trials. Narrative review.

164. 164
     Xu S. Safety Signals of GLP-1 Receptor Agonists: A Multi-Method Pharmacovigilance Analysis of FAERS (2018-2025) With Sensitivity-Stratified Prioritisation, Notoriety-Bias Assessment, and Cross-Database Validation.Diabetes, Obesity and Metabolism · 2026 · 28(10):9251-9264doi:10.1111/dom.71138 · PMID 42481928

     Disproportionality analysis of 288,408 GLP-1 receptor agonist reports against 11.3 million others: cyclic vomiting syndrome among the leading primary-suspect-stable signals (reporting odds ratio 64.8, semaglutide-dominant), second to gallbladder injury (84.2); 16 of 17 priority signals (94.1%) replicated in the Japanese database. A single-author analysis. Spontaneous reports; hypothesis-generating, cannot establish incidence or causation, as the author states.

165. 165
     Li BU, Murray RD, Heitlinger LA, Robbins JL, Hayes JR. Heterogeneity of diagnoses presenting as cyclic vomiting.Pediatrics · 1998 · 102(3 Pt 1):583-7doi:10.1542/peds.102.3.583 · PMID 9738180

     Of 225 children with a cyclic pattern, 88% had idiopathic cyclic vomiting, but 12% had serious surgical, renal or central nervous system disorders and 2% endocrine or metabolic disease. The reason the criteria insist on exclusion.

166. 166
     Bonnet U. [The cannabinoid hyperemesis syndrome-A narrative review].Der Nervenarzt · 2025 · 97(4):377-381doi:10.1007/s00115-025-01864-0 · PMID 40689972

     German-language narrative review with English abstract: clear separation of cannabinoid hyperemesis from cyclic vomiting is possible only by full remission during 6 to 12 months of abstinence, and about a third of people with cyclic vomiting also use cannabis regularly. Opinion and review.