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Antidote / Antihistamine Pregnancy: B - avoid in third trimester (neonatal withdrawal possible); use if serotonin toxicity is life-threatening

Cyproheptadine

Brand names: Periactin

Adult dose

Dose: Serotonin syndrome: 12 mg PO loading dose, then 2 mg every 2 h while symptoms persist (max 32 mg/24 h). Maintenance once controlled: 8 mg every 6 h
Route: PO
Frequency: 2-hourly (titrated to response); max 32 mg/24 h
ONLY oral formulation available - ensure patient can swallow or crush tablets. For intubated patients, administer via NGT. Cyproheptadine is a serotonin (5-HT1/5-HT2) antagonist and H1 antihistamine. Not available IV - supportive care and benzodiazepines remain first-line.

Paediatric dose

Route: PO
Frequency: 2-hourly
Max: 0.25 mg/kg/day
Children 2-6 y: 2 mg every 8-12 h (max 12 mg/day). Children 7-14 y: 4 mg every 8-12 h (max 16 mg/day). Not routinely used in serotonin syndrome in children - consult NPIS.

Dose adjustments

Renal

No dose adjustment required.

Clinical pearls

  • Serotonin syndrome triad: mental status changes + autonomic instability + neuromuscular hyperactivity (clonus, hyperreflexia, tremor) - distinguished from NMS by rapid onset and presence of clonus.
  • Cyproheptadine is adjunctive therapy - benzodiazepines (diazepam IV) and stopping the offending agent are the primary interventions.
  • Sedation from cyproheptadine may be clinically beneficial in agitated serotonin syndrome (reduces sympathetic activation).
  • Only PO/NGT route available - if patient is intubated and sedated, cyproheptadine adds little over benzo sedation.
  • Hunter Criteria for serotonin syndrome: spontaneous clonus OR agitation + diaphoresis + (tremor or hyperreflexia) OR ocular clonus + (agitation or diaphoresis) OR hypertonia + temperature >38C + ocular/inducible clonus.
  • Common precipitants: SSRI + tramadol, SSRI + triptans, fentanyl + methylene blue, linezolid + SSRIs.

Contraindications

  • Narrow-angle glaucoma
  • Urinary retention / BPH
  • MAO inhibitor use (within 14 days)
  • Premature neonates (benzyl alcohol in some formulations)
  • Severe hepatic impairment

Side effects

  • Sedation, drowsiness (may be useful in agitated serotonin syndrome)
  • Dry mouth, urinary retention (anticholinergic effects)
  • Weight gain (appetite stimulation - relevant only in chronic use)
  • Tachycardia
  • Confusion in elderly

Interactions

  • SSRIs / SNRIs / MAOIs: used specifically to antagonise their serotonergic excess in toxicity
  • Tramadol, linezolid, lithium, triptans, fentanyl: all serotonergic - cyproheptadine used to counter combined serotonin excess
  • CNS depressants: additive sedation

Monitoring

  • Temperature (hyperthermia = poor prognosis)
  • HR and BP
  • Neuromuscular exam (clonus, hyperreflexia)
  • Agitation / sedation score
  • Urine output (urinary retention)

Reference: BNFc; TOXBASE; NPIS UK; BNF 84; Hunter Criteria (Duncum et al.); UpToDate Serotonin Syndrome 2024. Verify against your local formulary and the latest BNF before prescribing.

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Curated clinical cross-links plus same-class fallbacks.

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