#F010 Misuse of an H1-antihistamine

What is the subject ?

Misuse of cyproheptadine as an orexigen for cosmetic weight gain.

Why are we addressing this subject ?

The history of pharmacovigilance shows that drugs acting on weight (anorectics or orexigenics) have been systematically associated with isuues related to their risk profile (fenfluramine, dexfenfluramine, benfluorex, rimonabant, more recently semaglutide, see previous pharmacofact #F001 Misuse of GLP-1 receptor agonists as weight-loss product, in French).

The misuse of cyproheptadine as an appetite stimulant has a long history, but in recent years it has reappeared in several African countries before arriving in France. The practice is currently being publicized on social networks, with videos promoting the drug for aesthetic purposes, to resemble certain models or influencers.

Cyproheptadine is an H1 antihistamine indicated for the symptomatic treatment of allergies, here misused for its orexigenic side effects for weight gain purposes. The misuse of this old antihistamine for weight gain purposes exposes to numerous adverse effects due to its sedative, atropinic, adrenolytic and antiserotoninergic properties, effects which are often unrecognized by patients. In 2022, the ANSM (the French competent authority for medicines) issued a safety alert on the use of cyproheptadine as an orexigenic for aesthetic purposes. Cases of misuse of cyproheptadine nevertheless persist, and were reported to the French Regional Pharmacovigilance Centers (CRPV) in 2023.

(UPDATED 07/2024) Following these reports, cyproheptadine-based medicines can only be dispensed in pharmacies with a doctor's prescription from July 10, 2024.

The opinion of the SFPT (French Society of Pharmacology and Therapeutics)

Cyproheptadine, which no longer has a place in therapeutic strategy as an antihistamine and whose use is being diverted, exposes to numerous adverse effects (neurological, psychiatric, cardiac, hematological or digestive). The SFPT considers that the benefit-risk ratio of cyproheptadine should be reassessed with a view to withdrawing its marketing authorization or, at the very least, including it on a compulsory prescription list.

For more information

Cyproheptadine is an antihistamine which, until 2024, was not subject to compulsory medical prescription. It was launched on the market in 1974, and is indicated for the symptomatic treatment of allergic symptoms.

Why does cyproheptadine have an orexigenic effect?

Cyproheptadine is a H1, 5-HT_2A and 5-HT_2C receptor antagonist. Unlike withdrawn anorectics such as benfluorex, dexfenfluramine and fenfluramine, which present 5-HT_2C agonist properties, cyproheptadine has orexigenic effects linked to 5-HT_2C receptor antagonism. Weight gain with second-generation antipsychotic neuroleptics is also mediated by this mechanism of action. The 5-HT_2C receptors in the hypothalamus induces negative feedback on the ghrelin receptor GHSR1 (Growth hormone secretagogue receptor 1). As a result, antagonism of the 5-HT_2C receptor induces up-regulation of the ghrelin-mediated orexigenic signaling pathway by lifting the negative feedback. These pharmacological properties make cyproheptadine a drug with orexigenic properties that induce the weight gain sought in cases of misuse.

How did its misuse develop?

Cyproheptadine has been authorized for orexigenic use since it was first marketed in France in the 1970s, but this indication was withdrawn in 1994. Off-label use has continued, and in recent years misuse has reappeared, mainly in certain African countries, before arriving in France. Cyproheptadine is diverted from its intended use for aesthetic purposes, to resemble certain beauty models widely disseminated in advertisements and videos on social networks.

In an observational study of the population of Kinshasa (Democratic Republic of Congo), the authors found a rate of misuse of cyproheptadine as an orexigenic of over 70%. Most of the users were young women who used it for long periods (over 1 year).

Today, this practice is widely reported on social networks, with videos of impressive physical transformations promoting the use of cyproheptadine, with tens or even hundreds of thousands of views. Also via social networks, a pharmacist is promoting the misuse of cyproheptadine without mentioning the risks associated with taking the drug, which can create a feeling of confidence in this misuse among patients. Some social networks also offer direct resale of cyproheptadine tablets and syrups for cosmetic purposes. Since July 2024, restricting cyproheptadine dispensing in pharmacies exclusively after medical prescription (in France) should help reduce this misuse. However, it is still possible to buy products over the internet, generally falsified and advertised as containing cyproheptadine.

What is the risk profile?

Cyproheptadine presents a mechanism of action which is not selective of H1 histamine receptors, and is prone to numerous adverse effects due to its marked sedative, atropinic, adrenolytic and antiserotoninergic properties. Misuse may lead to adverse effects not necessarily known to the user, such as drowsiness, reduced vigilance, dizziness, hallucinations, anxiety, mydriasis, liver damage (cholestasis in particular), urinary retention and heart rhythm disorders. Anemia and agranulocytosis have also been reported.

References :

1.  Information de sécurité - Periactine 4 mg (cyproheptadine) - ANSM [Internet]. Available in French on : https://ansm.sante.fr/informations-de-securite/periactine-4-mg-cyproheptadine-risques-lies-a-lutilisation-non-conforme-comme-orexigene-a-des-fins-esthetiques
2. Vickers SP, Dourish CT, Kennett GA. Evidence that hypophagia induced by d-fenfluramine and d-norfenfluramine in the rat is mediated by 5-HT2C receptors. Neuropharmacology. 2001;41(2):200‑9.
3. Huang XF, Weston-Green K, Yu Y. Decreased 5-HT2cR and GHSR1a interaction in antipsychotic drug-induced obesity. Obes Rev. 2018;19(3):396‑405.
4. Lulebo AM, Bavuidibo CD, Mafuta EM, Ndelo JD, Mputu LCM, Kabundji DM, et al. The misuse of Cyproheptadine: a non-communicable disease risk behaviour in Kinshasa population, Democratic Republic of Congo. Subst Abuse Treat Prev Policy. 2016;11:7.