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In overdose, cyproheptadine may cause central nervous system depression and sedation, as well as anticholinergic syndrome.

Apetamin is a syrup consisting of L-lysine, cyproheptadine, and B vitamins (thiamine, pyridoxine, nicotinamide, and dexpanthenol) that is produced by Indian pharmaceutical company TIL Healthcare Pvt Ltd.1 Cyproheptadine is available by prescription only in the United States,2 but Apetamin syrup is being sold illegally on social media platforms and other online sources as an unregulated weight-gain supplement.3 It has gained media attention in recent years, with social media influencers promoting it as a supplement for body enhancement, promising an hourglass figure that UK National Health Service (NHS) officials have described as unobtainable and biologically unsafe.3

The misuse of cyproheptadine as a figure enhancer is occurring on an international scale. A 2019 case report from India describes a man who gained 15 kg of weight during a 1-year period while taking a gym-tonic pill composed of cyproheptadine and dexamethasone that was illicitly prescribed by his gym instructor for weight-gain purposes.4 Another recent study, this one from the Democratic Republic of Congo, describes the C4 Phenomenon: In Kinshasa, cyproheptadine is sold as an appetite stimulant under the name C4 and promoted as a way to obtain a rounded physical appearance.5 More than two-thirds of the population surveyed reported using C4 over the past 6 months, with use found to be more common among women and those with lower educational levels.5 Almost half of users reported that it had been recommended to them by their friends, and more than 90% reported self-prescribing.5

NHS leaders in the United Kingdom have urged social media platforms such as Instagram to shut down accounts promoting or selling Apetamin, given significant concerns about its potential physical and mental health effects, particularly on young women and girls, to whom such content is predominantly targeted.3

Cyproheptadine: A Review

Cyproheptadine is a first-generation antihistamine with antiserotonergic, anticholinergic, and sedative properties.2 It has been in medical use since the 1960s and is approved by the FDA for the treatment of various allergic conditions.2,6 In the 2000s, it was studied for its orexigenic effects in undernourished children, with variable results.6 It has been used as an off-label treatment for a wide range of psychiatric conditions, including serotonin syndrome, akathisia, and selective serotonin reuptake inhibitorinduced sexual dysfunction. It has also been investigated for possible use in the treatment of nightmares in posttraumatic stress disorder, insomnia secondary to stimulant use, behavioral control in autism spectrum disorders, and neuropsychiatric sequelae of efavirenz.7

Safety Concerns

A retrospective review of the French Pharmacovigilance Database by Bertrand et al examined all reported adverse effects of cyproheptadine since its first distribution in France in 1985 and concluded that it can be considered a safe drug.6 During this 35-year period, a total of 93 adverse effects (AEs) were reported, which were primarily neurological and hepatic in nature, with drowsiness representing the most common AE; hepatotoxicity was found to be uncommon.6

The suggested initial dosing for the treatment of FDA-indicated conditions compared with the manufacturers suggested daily dose of Apetamin is outlined in Table 1.1,2

Keep in mind, however, that individuals using illicitly obtained Apetamin as a weight-gain supplement may not adhere to these dosing recommendations. One case report from 2020 describes a woman who reported drinking Apetamin syrup directly from the bottleto maximize its reported figure-enhancing effects; after 6 weeks of daily use, she developed autoimmune hepatitis.8

Additionally, given that the illicit sale of Apetamin on social media is inherently unregulated, buyers cannot be certain that the product they are receiving is consistent with the formula reported by the manufacturer or that the product has not been adulterated with other substances. Consumption of unknown quantities of Apetamin presents the risk of unintentional cyproheptadine overdose. The maximum daily dose of cyproheptadine by age is outlined in Table 2.2

In overdose, cyproheptadine may cause central nervous system depression and sedation, as well as anticholinergic syndrome, with symptoms such as dry mouth, dilated pupils, and flushing.2 A 2011 review of the characteristics of intentional cyproheptadine overdoses indicated that approximately 40% of cases were asymptomatic, whereas 17% developed anticholinergic delirium presenting as acute psychosis.9 The average dose ingested was lower for asymptomatic patients than for patients who developed delirium, at 49.8 mg and 188 mg, respectively.9

In addition, the weight gain associated with Apetamin use also presents a risk of developing obesity, which is in itself a risk factor for a range of health conditions including hypertension, type 2 diabetes mellitus, chronic kidney disease, and osteoarthritis.5

Clinical Considerations for Psychiatric Providers

Given that Apetamin misuse is occurring on a global scale, it is important for psychiatric providers worldwide to be aware of the risks this agent presents so that they are prepared to appropriately counsel patients. As influencers on social media platforms appear to be predominantly targeting young women and girls in their promotion of Apetamin, awareness is particularly important for providers treating children and adolescents.

Although the study from Kinshasa suggests that potential risk factors for use include female gender and lower educational levels,5 further research is needed into what other factors may place someone at greater risk for use. Providers may wish to consider screening patients with a known history of eating disorders, body dysmorphic disorder, or other body imagerelated concernsparticularly patients who are known to use social media platforms. Providers may also simply consider including Apetamin in their routine questioning of young women about medication and herbal supplement use.

In addition to the risks described, psychiatric providers should also keep in mind that for patients who are prescribed monoamine oxidase inhibitors, cyproheptadine has the potential to prolong anticholinergic effects.2

Dr Betterly is a resident physician in the Department of Psychiatry at Temple University Hospital in Philadelphia, Pennsylvania. Dr Barghini is an assistant professor of clinical psychiatry and behavioral science and director of the Psychiatry Residency Program in the Lewis Katz School of Medicine at Temple University in Philadelphia.

References

1. Appetite stimulants. TIL Healthcare. Accessed January 27, 2022. https://tilhealthcare.com/appetite-stimulant/

2. Cyproheptadine. Package insert. Teva Pharmaceuticals USA; 2009.

3. Murdoch C, Powis S, Wallace K. Letter to Instagram from Claire Murdoch regarding the drug Apetamin. UK National Health Service. May 3, 2021. Accessed January 27, 2022. https://www.england.nhs.uk/publication/letter-to-instagram-from-claire-murdoch-regard-the-drug-apetamin/

4. Bawaskar HS, Bawaskar PH, Bawaskar PH. Gym tonic and quadriparesis. J Assoc Physicians India. 2019;67(10):85-86.

5. Lulebo AM, Bavuidibo CD, Mafuta EM, 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.

6. Bertrand V, Massy N, Vegas N, et al. Safety of cyproheptadine, an orexigenic drug. analysis of the French National Pharmacovigilance Data-Base and systematic review.Front Pediatr. 2021;9:712413.

7. Badr B, Naguy A. Cyproheptadine: a psychopharmacological treasure trove? CNS Spectr. Published online February 26,2021.

8. Garland V, Kumar A, Theisen B, Borum ML. Apetamin hepatotoxicity: potential consequences of purchasing a body enhancement drug off the internet. ACG Case Rep J. 2020;7(6):e00398.

9. Chu FK. Review of the epidemiology and characteristics of intentional cyproheptadine overdose in Hong Kong. Clin Toxicol (Phila). 2011;49(7):681-683.

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Under the Influence: Misuse of Apetamin, the Illicit Social Media Weight-Gain Drug - Psychiatric Times