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Cyproheptadine (C21H21N, a tricyclic benzocycloheptene) was patented in 1959 and was introduced into medical practice shortly after. It is a first-generation antihistamine with anti-cholinergic, anti-serotonergic, and local anesthesia properties. While widely used by pediatric gastroenterologists for off-label indications, its precise mechanism of action is poorly understood, and its pharmacology and potential drug-drug interactions are not widely appreciated. We now present a focused review of cyproheptadine in pediatric gastroenterology practice, noting that the indications discussed are outside of FDA-approved labeling. An example of a common clinical scenario is an adolescent male with a 9-month history of nausea and abdominal discomfort upon awakening, which improves throughout the day. He skips breakfast on weekdays, but wakes up later on weekends or holidays, and generally feels fine. He has not gained weight for the past year. Laboratory studies, including complete blood count, serum chemistries, and celiac serologies, are negative. A presumptive diagnosis of functional dyspepsia is made, and cyproheptadine is started. Within a week, his early morning nausea and discomfort abate, and his appetite improves. When he is seen back 3 months later, he has gained weight and he and his family are very pleased. Cyproheptadine acts as a potent histamine (H1) and serotonin (5-HT) receptor antagonist, with additional calcium channel-blocking activity and anti-muscarinic properties, which contribute to its broad therapeutic utility.1, 2 While the specific serotonin receptors targeted by cyproheptadine are partially defined, its therapeutic effects suggest antagonism of serotonergic pathways in both the brain and gut. One of the most common uses of cyproheptadine in pediatric gastroenterology is promoting weight gain in children.3 Cyproheptadine achieves this effect through central serotonin type 2 (5-HT2) receptor and muscarinic receptor antagonism (Figure 1), which has been hypothesized to stimulate appetite, increase gastric accommodation, and reduce gastric hypersensitivity following distension. There is ample literature to support success in varying populations, including mild to moderately undernourished toddler-aged children and children with cystic fibrosis.4-6 Cyproheptadine is commonly recommended as a prophylactic therapeutic option to prevent episodes of cyclic vomiting syndrome in children and adolescents.7 Cyproheptadine's antimuscarinic activity is thought to partially contribute to its antiemetic effects, though a detailed characterization of this cellular pathway remains unknown.1 Its central antagonistic effects on serotonin receptors, specifically serotonin type 1 (5-HT1) and 5-HT2 (Figure 1) reduce the brain's recognition of nausea and vomiting signals and, therefore, make it an effective treatment for cyclic vomiting syndrome. Antagonism of 5-HT2 receptors significantly affects both the gastrointestinal and central nervous systems (CNSs), as serotonin regulates motility, secretion, and visceral sensitivity. In the gut, 5-HT2 blockade reduces serotonergic stimulation of longitudinal smooth muscle of the small intestine, potentially decreasing visceral pain.1 This mechanism is supported by animal studies that show initial fundic contractions followed by relaxation after 5-HT2 antagonism, with additional reduction in lower esophageal sphincter contractions.8 Additionally, cyproheptadine exerts direct antisecretory effects on gut epithelium, demonstrated by inhibition of electrogenic ion secretion in the proximal rat colon1, 9 (Figure 1). These central and visceral anti-serotonergic and anti-muscarinic effects of cyproheptadine are thought to contribute to its therapeutic benefits in the treatment of functional abdominal pain and dyspeptic symptoms.1, 8 This includes difficult-to-treat populations such as young children and those with post-operative retching after fundoplication.8 Clinicians need to remember that multiple mechanisms might be involved in the generation of symptoms post-fundoplication, including gas-bloat and dumping syndrome. Unlike other first-generation antihistamines that have been replaced due to adverse effect profiles, cyproheptadine is still being utilized due to its low cost, oral bioavailability, and clinical leveraging of some of its “adverse” effects.2, 10 Enteral tablet and syrup formulations appear to be well absorbed with peak serum levels 6–9 h after dosing in adults.2 However, anecdotally in pediatrics, the side effect of somnolence is often felt much more quickly. Cyproheptadine undergoes hepatic metabolism, with primary renal and minor biliary excretion of metabolites, which have a half-life of 16 h in adults.2 Effective histamine and serotonin receptor antagonism is achieved at relatively low doses, though sedation and anticholinergic effects remain dose-limiting.11 Dosing of cyproheptadine varies depending on the clinical indication and is often guided by the clinician's experience. For cyclic vomiting syndrome prophylaxis, the recommended dose is 0.25–0.5 mg/kg/day divided every 8–24 h with a maximum dose of 12 mg a day.7 Similarly, for appetite stimulation, the recommended dose is 0.25 mg/kg/day divided twice daily, with a maximum dose ranging from 12 to 32 mg depending on patient age.2 An effective dosing range for use in disorders of the gut–brain interaction (DGBIs) in pediatric patients (median age 9 years) of 0.13–0.2 mg/kg/day has been reported when used on average for 9 months, with a mean initial dose of 4.85 mg/day and final dose of 5.34 mg/day.1 A retrospective open-label study for refractory dyspepsia in children (mean age 10 years) found an effective dosing range of 0.04–0.62 mg/kg/day when used for an average of 5 months, with a median daily dose of 6 mg. Positive predictors of response to therapy included being under 12 years of age, female sex, and lower body weight.8 Interestingly, this contrasts findings from a different study in which lower body weight was found to be a negative predictor of response in their cohort.1 A large, systematic review from France identified the median dose for all pediatric clinical indications to be 0.25 mg/kg/day (range 0.1–0.8 mg/kg/day), or 7.5 mg/day (range 1–16 mg).10 However, despite all these studies, the frequency of dosing cyproheptadine is not standardized. Many clinicians use once-daily dosing to improve adherence. Additionally, although there is no current literature on the topic, there are anecdotal reports of tachyphylaxis with prolonged, daily administration of cyproheptadine. To overcome tachyphylaxis, clinicians may consider cycling the medication to regain maximum efficacy; however, this remains an area requiring further investigation. Cyproheptadine is contraindicated in newborns and premature infants due to the potential for CNS depression and a lack of evidence in its safety and efficacy.2, 11 Additional contraindications include hypersensitivity to cyproheptadine, angle-closure glaucoma, stenosing peptic ulcer, symptomatic prostatic hypertrophy, bladder neck obstruction, and pyloroduodenal obstruction.11 Caution is warranted in renal impairment due to reduced clearance.11 Dose adjustment may be warranted despite the absence of manufacturer dosing recommendations. There are no hepatic dose adjustments. Due to its diverse pharmacological actions, cyproheptadine has potential for multiple drug-drug interactions, and dose adjustments may be required with concomitant therapies. Concomitant use with CNS depressants (e.g., benzodiazepines, barbiturates, and opioids) can produce additive sedative effects leading to excessive drowsiness and increased risk of respiratory depression. Concomitant anticholinergics, including tricyclic antidepressants and antipsychotics, may further intensify the anticholinergic burden, causing blurred vision, dry mouth, constipation, and urinary retention. In addition, cyproheptadine's anti-serotonin antagonism may diminish the efficacy of serotonergic medications, such as serotonin reuptake inhibitors. Importantly, concomitant cyproheptadine and monoamine oxidase inhibitors use is contraindicated due to the risk of anticholinergic effects and reduction in serotonergic effects. Cyproheptadine is widely considered to be a safe medication for pediatric use. However, several common side effects should be discussed with patients and their families. Recent publications suggest that up to 30% of patients will experience mild and self-limited side effects while taking cyproheptadine.8 The most common side effects are somnolence, increased appetite, weight gain, and behavior changes.1, 8 Caution should be exercised in the use of cyproheptadine in children who are already considerably overweight. Given that serotonin significantly impacts behavior, its blockade may increase the risk of transient, self-limited aggression and/or irritability in some individuals.8 When patients continued cyproheptadine despite mild side effects, the majority had resolution of the symptoms over time.8 A rare side effect of adrenal insufficiency due to decreased adrenocorticotropic hormone and cortisol synthesis suppression has been documented in pediatric patients.8 An overdose of cyproheptadine can lead to anticholinergic syndrome, peripheral and CNS manifestations, and death.10 A retrospective study reported that 83% of patients with intentional cyproheptadine overdose reported mild to no sedative effects at a mean dose of 49 mg, while 17% experienced delirium at very high doses of 188 mg. Most symptoms occurred within 6 h of ingestion.12 A large, systematic review from France identified potential hepatic complications from cyproheptadine in both children and adults. However, only 15 cases were recorded in their database between 1986 and 2016, and five cases in the literature spanning 1960–2020. Of these patients, only two were children.10 Cyproheptadine is a first-generation antihistamine that also has anti-muscarinic, anti-serotonergic, and calcium channel blocking properties. These characteristics support its use in a wide array of clinical situations. Successful use is often accompanied by dramatic results in a short period of time. Clinicians should be familiar with its clinical pharmacology as well as drug–drug interactions to mitigate untoward complications associated with its use. The authors declare no conflicts of interest.