Cyproheptadine

Limits on what this shows

• Null and negative findings: Retrospective cohort of 50 treated and 738 untreated prepubertal Taiwanese children: median age-adjusted weight did not differ significantly between groups (no P-value, weights or CI in the abstract); within the treated group at 0.3 mg/kg/day for a mean of 97.2 days (range 14 to 532), age-adjusted weight and BMI were positively associated with treatment duration (P = 0.026 and P = 0.04) and inversely with age (both P < 0.001); abstract read through an OpenAlex record [6]. RCT of 40 children on methylphenidate: no significant difference in weight, growth rate or sleep quality [28]. Minimal to no benefit in malignant or progressive disease [3].
• At-risk subgroups: Children under 2, newborns, nursing mothers, elderly or debilitated patients, and anyone on MAOIs or other CNS depressants (label) [1].

Regulatory status

The label read lists allergic conditions as indications, not appetite stimulation. "Increased appetite/weight gain" appears among the miscellaneous adverse reactions, with sedation, dry mouth, urinary retention, constipation, nausea and diarrhea [1].

Population evidence

Systematic review (PRISMA-guided, all ages): 46 articles, 21 treatment populations, 32 RCTs, 4 prospective and 4 retrospective cohorts, 4 case reports, 2 case series; 39 of 46 found significant weight gain; sedation the most common side effect, typically transient and mild to moderate; few studies used objective appetite measures [3] (abstract via summarizing fetch). Adults: RCT of 375 adults (189 cyproheptadine, 186 placebo) for 8 weeks reported an appetite score difference of 0.38 (P = 0.0307) with weight and BMI rising significantly; mean appetite score change was -2.42 (cyproheptadine) vs -2.03 (placebo), a difference of 0.38 with 95% CI -0.73 to -0.04 (P = 0.0307); the arithmetic difference between the two group changes is -0.39, so the CI is consistent with a difference reported in absolute value, and the numbers were read from a secondary news summary [38] of the abstract. A kilogram weight effect size was still not retrieved ("substantial increases in weight and body mass index" only) [9]. Cystic fibrosis: RCT, 16 completers, 12 weeks, 3.45 vs 1.1 kg [11]; RCT, 25 completers (11 cyproheptadine, 14 placebo), 4 mg three times daily for 12 weeks, 1.61 vs 0.67 kg (P = 0.036), BMI z-score +0.20 vs -0.19 (P = 0.003), energy intake change +300 vs -72 kcal (P = 0.546), with no hemoglobin, albumin, zinc, vitamin or ferritin values reported (full text read) [12]; Cochrane update pooled cyproheptadine and megestrol trials (4 trials, 70 participants), weight at 3 months MD 1.25 kg (95% CI 0.45 to 2.05; 2 trials, 42 participants), low certainty, drug-specific stratification not visible in the retrieved summary [10]. Children: RCT of 77 evaluable undernourished children aged 24 to 64 months, cyproheptadine plus multivitamin vs multivitamin alone for 4 weeks, weight gain 0.60 vs 0.11 kg at 8 weeks, BMI higher on cyproheptadine (P < 0.041), no weight or height velocity difference, anthropometry only (abstract) [36]; retrospective review of 14 children with cancer: 11 responded, mean gain 1.44 kg, weight-for-age z-score -2.22 to -1.56, no laboratory values in the abstract [37]; non-randomized controlled study of 44 children aged 1 to 3 years with failure to thrive and food allergy, 0.15 mg/kg twice daily for 12 weeks: weight 10.32 vs 9.05 kg (P = 0.002), WAZ -1.15 vs -2.05 (P < 0.001), BMI 15.40 vs 14.07 (P = 0.001), no height or length-for-age difference, no confidence intervals reported, SD vs SEM unclear [7]. Retrospective chart review: 127 treated, 82 analyzed, weight-for-age z-scores improved more than a comparison group [4]. Silver-Russell syndrome, 23 children analyzed: mean +1.1 SD weight and +0.5 SD height at 1 year, 91% gained at least +0.5 SDS weight [5]. Pediatric cancer cachexia: 66 evaluable, 50 responders, mean gain 2.6 kg [13].

Mechanism

Serotonin and histamine antagonism per the label [1]. The 2026 pediatric study reports lower serum nesfatin-1 and NUCB2 after treatment (NUCB2 10.55 vs 11.61 ng/mL between groups, P = 0.043) and calls this exploratory; whether it reflects a direct drug effect or better nutrition is unknown [7].

Sedation and anticholinergic effects

Label: additive CNS depression, atropine-like effects, caution in asthma, glaucoma, hyperthyroidism, cardiovascular disease [1]. Pediatric study: one child of 25 had mild transient drowsiness [7]. Dry mouth and constipation could in principle lower intake; no study retrieved measured this.

Counter-evidence held on record

Counter-evidence on record Most pediatric evidence is uncontrolled or non-randomized and subject to confounding by indication, regression to the mean in underweight children, and concurrent feeding programs. No cohort reports caloric or micronutrient intake with the weight outcome. Framing caution Weight gain on this drug is not evidence of improved micronutrient status. This is not a deficiency claim in either direction, and no supplementation is implied.

Regulatory status

The label read does not mention growth hormone, IGF-I or growth effects [1].

Population evidence

Adults: oral 8 to 12 mg daily for 5 days in normal men significantly reduced GH responses to insulin hypoglycemia and exercise [15]; IV 5 mg in 7 male volunteers completely inhibited sleep-related GH release in 3 of 7 [16]; 2 days of cyproheptadine in 4 volunteers reduced GH secretion by 73 ± 15.1% [17]. A 1976 study in obese and underweight patients aged 10 to 39 found no change in circadian GH pattern or hypoglycemia response [18]. Children: RCT of 21 underweight children (10 cyproheptadine, 11 placebo, 4 months): weight velocity, height velocity and IGF-I z-scores higher than placebo, with the authors concluding increased caloric intake and IGF-I enhanced growth; numeric effect sizes were not retrievable (closed access) [8]. Six children with idiopathic GH deficiency on GH therapy: height velocity 9.1 to 12.1 cm/year and weight velocity 1.3 to 7.8 kg/year after adding cyproheptadine, called preliminary [14]. Silver-Russell: +0.5 SD height at 1 year [5]. 12-week pediatric study: no height or LAZ difference [7].

Mechanism

Serotonergic modulation of GH release is the proposed mechanism for acute suppression [15][16]; the IGF-I rise in children is attributed by the authors to higher caloric intake [8].

Counter-evidence held on record

Counter-evidence on record The adult suppression studies were acute, in healthy men, with provocative stimuli; the pediatric trial is small and in a different population. They do not contradict each other because they measure different things in different settings. Framing caution A hormone effect and growth outcome, not a nutrient finding. No inference should be drawn about protein, zinc or other growth-linked nutrients.

Regulatory status

Not mentioned in the label read [1].

Population evidence

Case series of 3 patients with Cushing's disease on 24 mg/day for 3 to 6 months: sustained clinical and laboratory remission, one biochemical relapse after stopping [19]. Report of 3 patients: two hyperpulsatile patients improved, the hypopulsatile patient only had reduced spikes [20]. One patient on 24 mg/day: no clear suppression during therapy and cortisol above baseline after withdrawal [21]. Volunteers: early-morning cortisol rise suppressed in all 5 given IV infusions [16]; cortisol secretion fell 81 ± 11.4% after 2 days in 4 volunteers, with unchanged glucose recovery after insulin hypoglycemia [17].

Mechanism

Reduced ACTH release, possibly at the pituitary, via serotonin antagonism; one case report suggests a pituitary site of action.

Counter-evidence held on record

Counter-evidence on record Evidence is small case series and acute volunteer studies at 5 to 24 mg doses; no cortisol data were retrieved for children treated at appetite-stimulant doses. Framing caution Not a nutrient entry and not a deficiency claim. It is listed so the endocrine effect is not misread as a nutrient effect.

Regulatory status

Not mentioned in the label read [1].

Population evidence

Human: 8 children given IV or oral glucose after one month of low-dose cyproheptadine had a blunted insulin response; the authors concluded reduced insulin reserves (abstract summary via OpenAlex; no glucose values, no comparator detail) [22]. Rat studies (Tier B): glucose intolerance and hyperglycemia at 40 mg/kg IP for 10 days with recovery after withdrawal; glucose intolerance by day 5 at 45 mg/kg/day orally; glucose-stimulated insulin secretion inhibited at 3 and 24 hours and normal by 48 hours; cell-line insulin content about 33 to 34% of control at 10 uM for 48 hours, recovering after removal [23] (listing summaries).

Mechanism

Blocked glucose-induced calcium uptake in beta cells and reduced (pro)insulin synthesis, with metabolites more potent than the parent drug in rat islets [23].

Counter-evidence held on record

Counter-evidence on record Animal doses far exceed human appetite-stimulant doses. Volunteer glucose recovery after hypoglycemia was unchanged [17]. The pediatric weight-gain trials seen reported no glycemic outcome. Framing caution A disturbance of glucose homeostasis, not a deficiency. It is not a nutrient entry and implies no dietary change.

Limits on what this shows

• Why no grade: Dual condition met: no Tier B or C evidence of a measured nutrient change, and no circulating nutrient-depletion claim for cyproheptadine located [29][30][39][40]. The 1970 pediatric paper measured hemoglobin and serum proteins, but without access to its results it cannot support a grade. Re-check it through a library copy. Not a finding of safety.

What was searched

PubMed listings: "cyproheptadine zinc" (9 results, none measuring zinc in treated subjects; two older reviews list zinc and cyproheptadine as separate anorexia nervosa options), "cyproheptadine hemoglobin", "cyproheptadine iron", "cyproheptadine anemia", "cyproheptadine micronutrient" (10 results, none pairing cyproheptadine with a measured level), and a broad vitamin/albumin phrasing (no cyproheptadine records). "cyproheptadine vitamin", "cyproheptadine vitamin deficiency" and "cyproheptadine vitamin D OR B12" returned 429 and were not read. The 2026 pediatric study reported only nesfatin-1 and NUCB2 [7]. A 1970 paper on cyproheptadine, serum proteins and hemochromes in children exists but had no abstract [27].

Repair-pass searches (2026-10-08)

The previously rate-limited vitamin phrasing was re-run: PubMed listing for cyproheptadine with vitamin, vitamin D, vitamin B12 or vitamin deficiency (45 results, first 10 read) found no record reporting a vitamin level in cyproheptadine-treated people (a migraine case report co-administered vitamin B2 with no level; a formulation assay measured vitamins in a product). The 1970 paper [27]: PubMed record re-read (title, Italian title, authors Pecorella, Cassata and Raimondo, Pediatria (Napoli) 1970;78(6):969-82, MeSH terms Blood Proteins, Hemoglobins, Hemoglobinometry, Body Weight; no abstract; indexed as Journal Article and Review); the OpenAlex record has no abstract and no DOI; a web search returned no copy. Full or abstract-level reads of other cyproheptadine trials found anthropometry only: cystic fibrosis RCT full text with no laboratory nutrient values [12], a 77-child undernutrition RCT [36] and a pediatric cancer review [37]. A search for ferritin, hemoglobin, zinc, albumin and vitamin phrasings returned no cyproheptadine-linked study.

Channel outcomes

PubMed listings: read (7 phrasings across both passes; several additional PubMed single-record and listing calls were refused with 429 and were not retried). Web search: worked, several phrasings. Crossref: two relevance queries returned unrelated papers. Clinical trial registry pages (NCT01314989, NCT07006181) did not render usable content. Genuine thin literature plus a residual tooling limit: the 1970 paper cannot be read.