Cyproheptadine Stats - Substance Search

Pharmacology

DrugBank

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.

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.

Measured Affinities

Guide to PHARMACOLOGY

Measured binding and functional data for cyproheptadine, curated by the IUPHAR/BPS Guide to PHARMACOLOGY. Each row cites the paper it came from. Lower concentrations mean tighter binding — a value in the sub-nanomolar range indicates a very potent interaction.

Target	Action	Measure	Value	Concentration	Species	Source
H1 receptor HRH1	Antagonist	pKi	10.2	0.063 nM	Human	PMID 7925364
α1B-adrenoceptor ADRA1B	Antagonist	pKi	7.6	25.12 nM	Human	PMID 11459121
α1A-adrenoceptor ADRA1A	Antagonist	pKi	7.4	39.81 nM	Human	PMID 11459121
5-HT6 receptor Htr6	Antagonist	pKi	6.9	125.89 nM	Rat	PMID 7680751
5-HT7 receptor HTR7	Antagonist	pKi	6.9	125.89 nM	Human	PMID 8226867
α1D-adrenoceptor ADRA1D	Antagonist	pKi	6.9	125.89 nM	Human	PMID 11459121
5-HT6 receptor HTR6	Antagonist	pKi	6.8	158.49 nM	Human	PMID 8522988
5-HT7 receptor Htr7	Antagonist	pKi	—	—	Rat	—

Reading this. pKi, pEC50 and pIC50 are negative log molar values, so a higher number means a tighter interaction; the concentration column converts them for you. Values from non-human species are laboratory measurements and do not translate directly to human effect. Receptor affinity is not a dose — it describes what a molecule binds, not how much of it is safe to take.

Receptor data from the IUPHAR/BPS Guide to PHARMACOLOGY (v2026.2), licensed CC BY-SA 4.0. Matched to this substance by InChIKey.

Toxicity

PubChem DrugBank

Cyproheptadine competes with free histamine for binding at HA-receptor sites. This antagonizes the effects of histamine on HA-receptors, leading to a reduction of the negative symptoms brought on by histamine HA-receptor binding.

Carcinogenicity

No indication of carcinogenicity to humans (not listed by IARC).

Toxicity (DrugBank)

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.

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.

Tolerance Decay

Half tolerance 3d Baseline ~14d

Users commonly report tolerance to the sedative effect developing over several days of continuous use and partial reversal over weeks after cessation; robust quantitative data are lacking.

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.

Cyproheptadine Stats & Data