Cyproheptadine Stats & Data

Depressant

Reactin Apeplus Biohept Periatin Periactin

Psychoactive Class Depressant

Half-Life Approximately 8–9 h reported; Tmax ~4 h; clinical sedation can outlast plasma half‑life, especially after larger doses.

Pharmacology

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State Solid

Description

Cyproheptadine is a potent competitive antagonist of both serotonin and histamine receptors. It is used primarily to treat allergic symptoms, though it is perhaps more notable for its use in appetite stimulation and its off-label use in the treatment of serotonin syndrome.

Mechanism of Action

Cyproheptadine appears to exert its antihistamine and antiserotonin effects by competing with free histamine and serotonin for binding at their respective receptors. Antagonism of serotonin on the appetite center of the hypothalamus may account for cyproheptadine's ability to stimulate the appetite.

Pharmacodynamics

Cyproheptadine has been observed to antagonize several pharmacodynamic effects of serotonin in laboratory animals, including bronchoconstriction and vasodepression, and has demonstrated similar efficacy in antagonizing histamine-mediated effects. The reason for its efficacy in preventing anaphylactic shock has not been elucidated, but appears to be related to its anti-serotonergic effects.

Metabolism

The principal metabolite found in human urine has been identified as a quaternary ammonium glucuronide conjugate of cyproheptadine.

Absorption

A single study examining the difference in absorption of orally administered versus sublingually administered cyproheptadine in five healthy males demonstrated a mean C_max of 30.0 mcg/L and 4.0 mcg/L, respectively, and a mean AUC of 209 mcg.h/L and 25 mcg.h/L, respectively. The T_max of orally and sublingually administered cyproheptadine was 4 hours and 9.6 hours, respectively.

Toxicity

Overdosage with cyproheptadine is likely to result in significant sedation - although paradoxical stimulation has been noted in pediatric patients - and anticholinergic adverse effects such as dry mouth and flushing. Most patients appear to recover without incident, as a review of cyproheptadine overdose cases in Hong Kong found the majority of patients had no or mild symptoms following intentional overdose. In the event of overdosage with cyproheptadine, prescribing information recommends the induction of vomiting (if it has not occurred spontaneously) using syrup of ipecac. Gastric lavage and activated charcoal may also be considered. Vasopressors may be used to treat hypotension and intravenous physostigmine salicylate may be considered for the treatment of significant CNS symptoms depending on the clinical picture.

Indication

In the US, prescription cyproheptadine is indicated for the treatment of various allergic symptomatologies - including dermatographia, rhinitis, conjunctivitis, and urticaria - as well as adjunctive therapy in the management of anaphylaxis following treatment with epinephrine. In Canada, cyproheptadine is available over-the-counter and is indicated for the treatment of pruritus and for appetite stimulation. In Australia, cyproheptadine is additionally indicated for the treatment vascular headaches. Cyproheptadine is also used off-label for the treatment of serotonin syndrome.

Elimination

Approximately 2-20% of the radioactivity from an orally administered radio-labeled dose of cyproheptadine is excreted in the feces, of which approximately 34% is unchanged parent drug (less than 5.7% of the total dose). At least 40% of radioactivity is recovered in the urine.

Tolerance & Pharmacokinetics

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Half-Life

Approximately 8–9 h reported; Tmax ~4 h; clinical sedation can outlast plasma half‑life, especially after larger doses.

Addiction Potential

Low. Primarily produces sedation and anticholinergic effects without evidence of compulsive use; tolerance to sedation can develop with repeated daily use. Dependence or withdrawal syndromes are not described in medical literature; classify reinforcement as minimal to low.

Harm Reduction

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Reasoning for updates and harm‑reduction guidance:

- Role in serotonin toxicity is adjunctive and evidence remains low‑quality. A 2025 systematic review of deliberate self‑poisoning cases found only case reports/series with heterogeneous regimens and no established efficacy; supportive care and benzodiazepines remain first-line. Do not self‑treat suspected serotonin syndrome—seek emergency care.

- If a clinician elects to use cyproheptadine for serotonin toxicity, commonly referenced toxicology regimens use an oral loading dose (e.g., 12 mg) followed by small repeat doses (e.g., 2 mg every 2 h) to clinical response, with typical daily maxima around 32 mg; however, this is based on low‑quality evidence and expert opinion. Only oral forms exist; tablets can be crushed for NG administration in hospital. This should not be improvised outside medical settings.

- Sedation and psychomotor impairment are prominent; Tmax after oral dosing is ~4 h, so peak impairment can lag the dose. Avoid driving, cycling, operating machinery, climbing, or swimming for the rest of the day and potentially into the following morning after ≥8 mg.

- Anticholinergic adverse effects (dry mouth, blurred vision, constipation, urinary retention, confusion) are common; risks are higher in older adults, in heat, with dehydration, and when combined with other anticholinergics. Angle‑closure glaucoma and symptomatic BPH are classical cautions.

- Rare but documented idiosyncratic cholestatic/mixed hepatotoxicity has occurred within 1–6 weeks of initiation (LiverTox likelihood score C). For multi‑week courses, consider baseline and symptom‑triggered LFT checks; discontinue if jaundice, pruritus, dark urine, or RUQ pain emerge.

- Paradoxical CNS stimulation can occur in pediatrics; outside clinician‑directed use (e.g., appetite stimulation), avoid non‑medical pediatric exposure.

- Using cyproheptadine to pre‑ or co‑load with MDMA/psychedelics will attenuate desired effects via 5‑HT2A antagonism; this can prompt risk‑enhancing redosing or polydrug use to “break through.” Safer practice is to avoid mixing and reserve cyproheptadine for clinician‑directed indications.

- If serotonin toxicity is suspected (e.g., after combining SSRIs/SNRIs/tramadol/DXM/MAOIs with MDMA or other serotonergics), the correct action is immediate cessation, cooling, and emergency evaluation; cyproheptadine at home may mask features while the causative drug remains active.

References

Drugs.wiki References

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