This study represents the first cohort of Mexican patients with CVS/CHS to be reported in the scientific literature, providing a unique insight into the characteristics of these conditions within this population. While CVS and CHS have been extensively studied in other regions, this analysis specifically examines these syndromes in a Mexican context, offering valuable data on sociodemographic factors, clinical features, and substance use patterns, including cannabis use in this demographic. The findings reveal distinct differences in age, gender distribution, and substance use compared to cohorts from North America and Europe, underscoring the importance of regional studies in understanding the global variability of these disorders.

The younger age and female predominance observed in the CVS group are consistent with previous studies conducted in predominantly Caucasian populations, where similar demographic trends have been reported.^12,13 The male predominance in CHS patients in this Mexican cohort also seems consistent with studies from Western countries. The average BMI was also within normal limits in Mexico compared to the US where most patients are overweight and this might be a reflection of better eating patterns in Mexico compared to the US which is flooded with calorie dense and processed foods.

Similarly, it has been observed that patients with CVS and CHS tend to use other substances such as tobacco.^14,15 However, there appears to be no association with alcohol or other types of substances.¹² This is consistent with Western data that did not show any excessive alcohol in CVS. However excessive alcohol use was seen in patients with CHS in our study in contrast to other studies from the US. The higher prevalence of risky alcohol consumption patterns among CHS patients in this study suggests that, in addition to cannabis, patients may be potentially resorting to alcohol as an anxiolytic and these findings warrant further investigation. This might indicate that patients with CHS are more prone to engaging in poly-substance use, and again mental health issues might be contributing to this pattern of substance use. These findings underscore the importance of considering the full spectrum of substance use when diagnosing and managing CHS, as well as the need for tailored interventions that address multiple substance use behaviors.

Cannabis use and stereotypical vomiting episodes are not the only clinical features shared by CVS and CHS. Hot-water bathing, which was initially thought to be a characteristic exclusive to CHS, also tends to be present in CVS.^7,16,17 Rosen et al,¹⁶ reported that 73% of CVS patients use hot-water bathing as a therapeutic measure during emetic crises, a lower percentage compared to CHS, where the prevalence ranges from 58-100%, with most studies reporting rates of > 80-100%.^13,16 In this study, the results contrast with global findings, as hot-water bathing was almost exclusive to CHS.

The longer time prior to establishing a diagnosis, 35.4 months for CVS compared to 26.5 months for CHS, underscores the diagnostic challenges associated with these conditions. This prolonged diagnostic delay for CVS is consistent with previous studies, which often highlight the lack of recognition of the pattern of vomiting and the notion that CVS is a pediatric disorder contributing to delayed recognition and diagnosis. In contrast, CHS may be diagnosed more rapidly due to its more distinct association with chronic cannabis use, which serves as a diagnostic clue for clinicians. However, the finding that CHS patients still experience a considerable delay in diagnosis emphasizes the need for increased awareness and clinical suspicion among healthcare providers, especially in regions where cannabis use is prevalent.

Regarding hospital admissions, the study found no significant differences between CVS and CHS patients in terms of the number of hospital admissions overall or in the last year. This finding aligns with earlier reports that both conditions can lead to recurrent hospitalizations due to their episodic nature and the need for acute management during severe episodes.^18,19 However, the greater number of hospital days observed in CVS patients compared to CHS (3.5 days vs 1.5 days, P = 0.090) is particularly interesting. This could suggest that CVS episodes may be more difficult to manage or that patients with CVS may require longer periods of stabilization and symptom control, a finding that has not been consistently reported in previous studies. Alternatively, it might reflect differences in the severity of episodes, response to treatment, or hospital admission practices between these 2 patient groups. These findings support the need for developing national guidelines for the management of CVS in Mexico. While under recognition has been a challenge globally, the American Neurogastroenterology and Motility and the cyclic vomiting syndrome association guidelines have significantly helped increase awareness among the medical community in the US.

The high prevalence of functional dyspepsia as the most common diagnosis prior to the final diagnosis in both CVS and CHS (41.2% in CVS and 41.7% in CHS) also aligns with earlier research. Functional dyspepsia is frequently diagnosed in patients with unexplained gastrointestinal symptoms, and it often precedes the diagnosis of more specific conditions like CVS and CHS. The other diagnoses considered in CVS patients, such as gastroparesis and pancreaticobiliary disease in 3.0%, and eating disorders in 5.9%, further illustrate the diagnostic complexity of CVS. These conditions share overlapping symptoms with CVS, though the periodic pattern of vomiting is a hall mark of CVS and CHS and should alert the clinician to making a diagnosis.

Regarding medical management, although the most used medications for crisis management in patients with CVS and CHS were antiemetics such as metoclopramide and ondansetron, a considerable number of patients also receive prokinetics. In Mexico, the wide availability of prokinetics, such as domperidone, levosulpiride, and itopride, may explain the heterogeneity observed in medical management. This diversity in prescription practices reflects both the preferences of physicians and the variations in access to different treatments, suggesting the need for more specific and uniform guidelines for managing these syndromes in the Mexican context.

For pharmacological preventive management during the interepisodic phase, the most frequently used drug class in both CVS and CHS were neuromodulators, amitriptyline in CVS and mirtazapine in CHS. Neuromodulators, particularly tricyclic antidepressants like amitriptyline, are known to have multiple effects beyond mood regulation, including pain modulation, reduction of nausea, and normalization of gastrointestinal motility, which may explain their widespread use in CVS.²⁰ Amitriptyline’s effectiveness in CVS could be due to its ability to stabilize the nervous system and reduces the frequency and severity of episodes, which is why it is the predominant choice for these patients.

In contrast, mirtazapine’s use in CHS might be linked to its dual action as an antidepressant and antiemetic. Mirtazapine^’s unique pharmacological profile, which includes the enhancement of serotonin and norepinephrine neurotransmission along with its antiemetic properties, makes it suitable for CHS patients, who may benefit from its ability to reduce nausea and vomiting associated with cannabis use.^21,22 Additionally, the choice of mirtazapine over amitriptyline in CHS could be related to its more favorable side effect profile, particularly in patients who may already be experiencing significant gastrointestinal distress.^18,23,24

Like what has been reported in the US population, migraine is prevalent in patients with CVS and CHS.^12,14 Anxiety and depression were noted in a third of patients with CVS and CHS and align with global studies, though rates have been higher in Western studies. These lower rates may be due to social and cultural differences including reporting patterns and greater social support in the Mexican population. However, the prevalence of depression is notably lower in CVS. It has been described that cannabis use is also associated with CVS and is not exclusive to CHS. Bhandari and Venkatesan¹⁴ refer to cannabis use in 14.0% of CVS patients who required hospitalization due to emetic crises. This finding is consistent with our study, where 13.3% of CVS patients reported cannabis use. However, it is noteworthy that only in CHS patients was cannabis use identified as a precipitating factor.

Due to the study design, it is not possible to determine the prevalence of CVS or CHS in the Mexican population. However, it is estimated to be low, as only 46 cases were collected from 5 centers in different regions of Mexico over a 5-year period: 30 patients diagnosed with CVS and 16 with CHS, this aligns with the findings described by Kumar et al, and Bhandari and Venkatesan,^14,15 where the Hispanic race is one of the least affected racial groups by these disorders.^11,12 This proportion is like the global prevalence reported by Sperber et al,¹ where CVS and CHS prevalence was 0.3% (0.3-0.4) and 0.01% (0.00-0.02), respectively. Nevertheless, with the legalization of cannabis in Mexico, it will be necessary to conduct epidemiological studies in the years following the legalization of cannabis consumption.

In conclusion, CVS and CHS are infrequent NVDs in the Mexican population; however, given the variability in prevalence by race, it is essential to conduct studies across different Latin American countries to understand the epidemiological profile of these NVDs. The clinical profile of CVS was less severe than what is reported globally, with a lower proportion of prodromic symptoms and a reduced need for hot-water bathing. In contrast, patients with CHS present a more severe phenotype with shorter interepisodic periods and a higher frequency of sedation requirements. Unlike other countries, Mexico has unrestricted availability of many prokinetics, antidepressants, and antipsychotics, leading to considerable variability in the management of these patients. This variability could be either beneficial or detrimental, potentially resulting in high costs, adverse effects, and therapeutic failure. Therefore, it is crucial to consider the need for implementing guidelines and consensus protocols for the management of CVS and CHS in the Latin American population.

As limitations of this study, a small sample size is highlighted due to the low prevalence of these disorders, as well as a cross-sectional design that does not provide information on disease progression, treatment responses, or long-term outcomes. For this reason, this study should encourage further larger cross-sectional, cohort, or prospective studies in Latin America. Since a convenience sampling method was used in tertiary care centers and gastroenterology-specialized medical centers, the results cannot be generalized to the broader population of CVS and CHS, which is why prevalence data is not presented. Cannabis, alcohol, and tobacco use were self-reported, introducing recall and reporting biases, which is why future studies should incorporate objective biomarkers or toxicology testing to improve data accuracy. Although a case-control analysis was performed, the comparison was made between CVS and CHS, meaning we cannot determine factors specifically associated with each of these disorders. Therefore, future studies with healthy controls should be conducted to reinforce the findings reported in this study.