The recent column by Leon Gussow, MD, asserted there is no evidence for cyproheptadine for serotonin syndrome. (EMN. 2020;42(10):18; https://bit.ly/3l6GWye.) He then cited two case series supporting cyproheptadine: J Emerg Med. 1998;16(4):615 and J Clin Psychopharmacol. 2020;40(1):95.
Various case reports have also illustrated a similar benefit of cyproheptadine in serotonin syndrome. (N Engl J Med. 1994;331:1021; Ann Pharmacother. 2001;35[7-8]:870; Clin Pediatr Emerg Med. 2005;6:103.)
Admittedly, a few such case reports are mine. (Ann Emerg Med. 1999;34806; Pediatr Emerg Care. 1999;15325; Am J Emerg Med. 2000;18:638; Am J Psychiatry. 1997;154:884.)
A recent review of ToxIC data found that toxicologists use cyproheptadine in about 15 percent of cases of serotonin syndrome, although benzodiazepine use was much more common. (J Clin Psychopharmacol. 2019;39628.) These data do not compare outcomes between these two treatments, but I know that I am not alone.
A positron emission tomography (PET) study of two human volunteers found that 4 mg TID and 6 mg TID of cyproheptadine blocked 85 percent and 95 percent, respectively, of serotonin receptors in the prefrontal cortex. (Am J Psychiatry. 1997;154884.)
A recent systematic review concluded that evidence for cyproheptadine mainly comprises case reports and case series. (Curr Emerg Hosp Med Rep. Oct. 10, 2020.) In toxicology, we often have only low-quality studies supporting our care because of course we cannot deliberately poison patients to conduct a randomized, placebo-controlled trial. Low-quality but consistent observations are evidence, even if Dr. Gussow wishes otherwise.
Michael E. Mullins, MD
St. Louis, MO
Dr. Gussow responds: Thank you for your comments. I think we actually substantially concur on the issues. I stated in the column that no evidence suggests that cyproheptadine is beneficial in severe serotonin toxicity. Dr. Mullins and his co-author Zane Horowitz, MD, seem to agree in a case report: “We have occasionally seen more severe cases [of serotonin syndrome] in which cyproheptadine is of no apparent value.” (Ann Emerg Med. 1999;34:806.)
I did point out that cyproheptadine may provide some marginal benefit in reducing symptoms in mild cases when the patient can take oral medication. (The drug is not available for parenteral administration.) I would have no problem if a clinician wanted to try a reasonable dose (say, 4 mg initially) in those situations for symptomatic relief. I am somewhat concerned with the large doses recommended by some authors, such as 8-16 mg every hour. We just don't have enough experience to know how problematic anticholinergic adverse effects including urinary retention could be using that regimen.