RESEARCH MONOGRAPH · KDC-MN-353
Cyproheptadine
Cyproheptadine, sold as Periactin, is a first-generation antihistamine that also potently blocks 5-HT2A and 5-HT2C serotonin receptors. The combination gives it three fairly distinct clinical roles: appetite stimulation (5-HT2C blockade) used in pediatric failure-to-thrive and in cachexia; treatment of serotonin syndrome (5-HT2A blockade rapidly reverses the toxidrome); and migraine prophylaxis. The H1 and anticholinergic activity produces sedation and dry mouth as expected for a first-generation antihistamine. The serotonin syndrome reversal use is the most clinically important and is not interchangeable with other antihistamines. Not stocked by Kodiac. This monograph is provided for research and educational reference.
Intrigue 0–100 blends mechanism novelty, evidence strength, and translational potential. Kodiac editorial, not peer-reviewed.
First-generation antihistamine + 5-HT2 antagonist
A piperidine first-generation antihistamine with 5-HT2A and 5-HT2C antagonist activity; used for appetite stimulation, serotonin syndrome reversal, and migraine prophylaxis.
Abstract
Cyproheptadine (4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-methylpiperidine; CAS 129-03-3; molecular formula C21H21N; molecular weight 287.40) is a piperidine first-generation antihistamine with potent 5-HT2A and 5-HT2C antagonist activity, approved by the FDA in 1961 (Periactin). The compound combines H1 antihistamine activity (Ki approximately 1 nM, comparable to diphenhydramine) with strong 5-HT2 antagonism (Ki approximately 1 nM at 5-HT2A); the combined activity drives appetite stimulation (5-HT2C antagonism, the same mechanism as the appetite gain seen with olanzapine and clozapine), serotonin syndrome reversal, and migraine prophylaxis. Plasma half-life is approximately 8 hours. Approved for allergic conditions; off-label use in failure-to-thrive (pediatric appetite stimulation), serotonin syndrome (the only specific antidote besides supportive care), and post-SSRI sexual dysfunction (5-HT2A antagonism). Used as the canonical 5-HT2 antagonist antihistamine in research.
Mechanism of action
First-generation H1 antihistamine combined with potent 5-HT2A and 5-HT2C antagonism. 5-HT2C blockade drives appetite stimulation; 5-HT2A blockade reverses serotonin syndrome.
Reported research dose ranges
Clinical 4 to 16 mg in the published literature.
References
- Goldman MJ. Cyproheptadine: a brief review of its multiple therapeutic uses. J Tenn Med Assoc 1976.
- Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med 2005.
- Couch JR. Cyproheptadine in the prophylaxis of migraine in adults. Headache 2011.
Read the full monograph
The full reference document is available as a research-use-only PDF download. Note: PDFs for newly added compounds may take a few hours to propagate after this article was published.
The full reference document is provided strictly for research use only. It reports research dose ranges from the published literature, not instructions for use in humans or animals.
FOR RESEARCH USE ONLY. Not for medical, diagnostic, or therapeutic purposes. Not for human consumption. All information is provided for research and educational purposes only.