Still Nothing New About Cyproheptadine
02/20/2026
Eleanor M. Kellon, VMD
Pituitary pars intermedia dysfunction (PPID), also known as Cushing’s disease, is caused by loss of neurons in the hypothalamus which produce dopamine. These neurons normally suppress activity of the intermediate lobe of the pituitary.
The drug pergolide works by binding to dopamine receptors and substituting for dopamine. Cyproheptadine is an antihistamine which also blocks the action of serotonin. Since serotonin antagonizes dopamine, it was felt that blocking it would increase the dopamine effect.
In 2001, The Michigan Cushing’s Project was published. This was a collaborative effort between universities to study PPID, including the effectiveness of pergolide versus cyproheptadine. A total of 77 horses were included in the study. When Adrenocorticotropic hormone (ACTH) and stimulation tests were done at start of treatment, and after 6 and 12 months, they found treatment with cyproheptadine was no better than no treatment at all.
In a 2002 publication, Donaldson, et al., reviewed the records of 14 horses and 13 ponies with PPID that were treated with either cyproheptadine or pergolide. ACTH, the hormone used to monitor treatment of PPID, was significantly higher in the cyproheptadine group.
There has been no new research to suggest cyproheptadine works or works any better when combined with pergolide. The likely reason is you cannot stimulate a dead cell. The cause of PPID is death of dopaminergic neurons in the hypothalamus. In 2020, Fortin, et al., also showed the remaining dopaminergic neurons from horses with untreated PPID are “exhausted” and depleted of dopamine.
The Equine Cushing’s and Insulin Resistance Group has been following these horses and ponies for over 25 years. We have found that many animals require more than the arbitrary upper limit of 4 ug/kg recommended by the manufacturer of Prascend. This equals 2 mg for a 500 kg horse while the recommended upper limit for the same drug in the UK is 5 mg. It is not unusual for requirements to keep ACTH normal to increase over time. There are many horses on 5 mg or more with no short term or long term side effects.
The correct dose of pergolide is the one that controls the ACTH.
Schott II HC, Coursen CL, Eberhart SW, Nachreiner RJ, Refsal KR, Ewart SL, Marteniuk JV, The Michigan Cushing’s Project, 2001 Vol 47 AAEP Proceedings. https://pmc.ncbi.nlm.nih.gov/articles/PMC7517620/
Donaldson MT, LaMonte BH, Morresey P, Smith G, Beech J, Treatment with pergolide or cyproheptadine of pituitary pars intermedia dysfunction (equine Cushing's disease). https://pubmed.ncbi.nlm.nih.gov/12465775/
Fortin JS, Benskey MJ, Lookingland KJ, Patterson JS, Howey EB, Goudreau JL, Schott II HC. Restoring pars intermedia dopamine concentrations and tyrosine hydroxylase expression levels with pergolide: evidence from horses with pituitary pars intermedia dysfunction. https://pmc.ncbi.nlm.nih.gov/articles/PMC7517620/
The Equine Cushing’s and Insulin Resistance Group www.ecirhorse.org
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About ECIR Group Inc. Celebrating 25 years, the ECIR Group is the largest field-trial database for PPID and EMS in the world and provides the latest research, diagnosis, and treatment information, in addition to dietary recommendations for horses with these conditions. Even universities do not and cannot compile and follow long term as many in-depth case histories of PPID/EMS horses as the ECIR Group.
In 2013 the Equine Cushing’s and Insulin Resistance Group Inc., an Arizona nonprofit corporation, was approved as a 501(c)3 public charity. Tax deductible contributions and grants support ongoing research, education, and awareness of Equine Cushing’s Disease/PPID and EMS. https://www.ecirhorse.org/how-to-help-ECIR.php
THE MISSION of the ECIR Group Inc. is to improve the welfare of equines with metabolic disorders via a unique interface between basic research and real-life clinical experience. Prevention of laminitis is the ultimate goal. The ECIR Group serves the scientific community, practicing clinicians, and owners by focusing on investigations most likely to quickly, immediately, and significantly benefit the welfare of the horse.
