KNOWLEDGE SUMMARY

Keywords: AIRWAY HYPERSENSITIVITY; BRONCHOCONSTRICTION; CYPROHEPTADINE; EOSINOPHILIC AIRWAY DISEASE; FELINE AIRWAY DISEASE; SEROTONIN

The effectiveness of cyproheptadine as a treatment option for cats with eosinophilic airway inflammation

Jillian Seeman, M.S^1*
Rachael Kreisler, VMD MSCE DACVPM¹
Jeffrey Norris, DVM PhD¹

---

¹ College of Veterinary Medicine, Midwestern University
* Corresponding author email: jillian.seeman@midwestern.edu

Vol 11, Issue 3 (2026)
Submitted 09 Sep 2024; Published: 17 Sep 2026
DOI: https://doi.org/10.18849/ve.v11i3.747

PICO question

In cats with eosinophilic airway inflammation does cyproheptadine compared with no treatment result in a reduction in severity of clinical signs?

Clinical bottom line

Category of research

Treatment.

Number and type of study designs reviewed

Four studies were evaluated: the first was a randomised, blinded, placebo-controlled, crossover study, the second was a randomised crossover study, the third was a non-randomised, controlled study, and the fourth a non-randomised, controlled study.

Strength of evidence

Moderate.

Outcomes reported

In two of the four studies it was found that cyproheptadine was not useful in resolving the symptoms of feline airway inflammation. The third study showed that the concentration of cyproheptadine that completely blocked contractile effects of serotonin did not successfully cause a significant effect on contraction caused by muscarinic stimulation. The fourth study provided evidence that cyproheptadine could reduce serotonin-induced bronchoconstriction.

Conclusion

There is no current evidence to support that cyproheptadine monotherapy has any immediate benefit over no treatment for feline eosinophilic airway inflammation, and its use is not supported for this indication.

How to apply this evidence in practice

The application of evidence into practice should take into account multiple factors, not limited to: individual clinical expertise, patient’s circumstances and owners’ values, country, location or clinic where you work, the individual case in front of you, the availability of therapies and resources.

Knowledge Summaries are a resource to help reinforce or inform decision making. They do not override the responsibility or judgement of the practitioner to do what is best for the animal in their care.

Clinical scenario

A cat presents to the clinic for the onset of bronchoconstrictive airway disease, but glucocorticoids and beta-2 agonists are contraindicated due to comorbidities or lack of access to medications.

The evidence

The findings from four relevant studies, Schooley et al. (2007), Reinero et al. (2005), Padrid et al. (1995), and Reiche & Frey (1983), were evaluated to answer this PICO question.

Two of the studies (Reiche & Frey, 1983, Padrid et. al., 1995) investigated the effects of cyproheptadine on pulmonary resistance. Reiche & Frey (1983) determined that a dose of 16.4 μg/kg administered IV reduced serotonin-induced bronchoconstriction by 50%, the study endpoint. Cyproheptadine did not reduce pulmonary resistance induced by BGA in the study by Reinero et al. (2005). In the in vitro model used by Padrid et al. (1995), pretreatment with cyproheptadine reduced the contraction of tracheal and bronchial smooth muscles harvested from cats sensitised to A. suum antigen.

Two of the studies also investigated (Schooley et. al., 2007, Reinero et al., 2005) the effects of cyproheptadine on inflammatory parameters, including pulmonary infiltrates and allergen-specific immunoglobulin levels. In Schooley et al. (2007), no differences between control and cyproheptadine-treated cats were found regarding [IgA, IgE, and IgG] [eosinophils] [histamine] [serotonin]. Reneiro et al. (2005) similarly found no differences for [IgA and IgG] and [eosinophils], as well as [CD4+, CD5+, CD8+, CD21+] lymphocytes were identical between cyproheptadine-treated cats and controls. Both studies found no difference between the numbers of eosinophils in BALF collected from cyproheptadine-treated and control cats. Schooley et al. (2007) also reported no differences between histamine and serotonin levels in BALF collected from control and cyproheptadine-treated cats.

The conclusions from these studies regarding the efficacy of cyproheptadine in physiology related to clinical signs vary considerably. Reiche & Frey (1983) provided evidence that cyproheptadine reduced serotonin-induced bronchoconstriction, which was consistent with the in vitro results provided by Padrid et al. (1995), and might be expected to reduce clinical signs associated with bronchoconstriction. However, Schooley et al. (2007) and Reinero et al. (2005) provided contradictory evidence that the use of cyproheptadine in cats with airway disease would not be expected to reduce clinical signs as it was ineffective at reducing inflammation and did not reduce pulmonary resistance resulting from the bronchoconstriction induced with BGA at the doses administered.

Summary of the evidence

Padrid et al. (1995)

Cyproheptadine-induced attenuation of type-I immediate-hypersensitivity reactions of airway smooth muscle from immune-sensitised cats

Aim: To study the effect of serotonergic inhibition by cyproheptadine on the responsiveness of tracheal smooth muscle (tsm) strips and epithelium-intact third-generation bronchial rings from immune-sensitized (Ascaris suum) cats after exposure to antigen.

 

Reiche & Frey (1983)

Antagonism of the 5-HT-induced bronchoconstriction in the cat

Aim: To compare the bronchodilator effects of ketanserin, cyproheptadine, clenbuterol, and aminophylline.

 

Reinero et al. (2005)

Effects of drug treatment on inflammation and hyperreactivity of airways and on immune variables in cats with experimentally induced asthma

Aim: To compare the effects of an orally administered corticosteroid (prednisone), an inhaled corticosteroid (flunisolide), a leukotriene-receptor antagonist (zafirlukast), on the asthmatic phenotype in cats with experimentally induced asthma.

 

Schooley et al. (2007)

Effects of cyproheptadine and cetirizine on eosinophilic airway inflammation in cats with experimentally induced asthma

Aim: To determine whether oral administration of cyproheptadine or cetirizine blocks the action of serotonin and histamine, respectively, and results in diminished eosinophilic airway inflammation in cats with experimentally induced asthma.

 

Appraisal, application and reflection

Feline eosinophilic airway disease is common in cat populations. Clinical signs observed by veterinarians and owners typically include persistent respiratory issues such as sneezing, hacking, coughing, nasal discharge or mucus production, and abnormal lower airway sounds on physical examination, including crackles or wheezes. Additionally, affected cats may exhibit increased respiratory effort or an elevated respiratory rate. Advanced diagnostics can be performed on patients suspected of having lower airway disease such as bronchial alveolar lavage or lower airway wash using sterile saline. In cases of true eosinophilic airway disease, cytologic analysis of lower airway fluid may reveal moderate eosinophilic infiltration.

Feline eosinophilic airway disease is characterised by airway hyperresponsiveness and inflammation leading to increased pulmonary resistance and progressive fibrosis (Trzil, 2020). The potencies of physiological mediators of bronchoconstriction vary by species. Pulmonary smooth muscle constriction in cats is strongly stimulated by the bioactive amine serotonin, which is released from mast cells. Based on this effect, the serotonin receptor antagonist cyproheptadine merits consideration for use in the treatment of feline eosinophilic airway disease.

Two of the studies reported here (Reiche & Fry, 1983, Padrid et al., 1995) provided direct evidence that supports this treatment consideration. Reiche & Frey (1983) found that cyproheptadine reduced pulmonary resistance caused by direct administration of serotonin following intravenous administration. Padrid et al. (1995) determined that the drug reduced constriction of tracheal and bronchial smooth muscles harvested from cats sensitised to Ascaris suum (A. suum) antigen. However, serotonin increases in tissue perfusion buffers were not detected following stimulation of the tissues with the antigen. The clinical utility of these studies is limited by their experimental nature for two primary reasons. Firstly, Reiche & Frey (1983) only examined the inhibition cyproheptadine on serotonin-induced bronchoconstriction, where as Padrid et al. (1995) did not observe the clinical effects of the drug in living cats. Secondly, neither of the models evaluated clinical signs following treatment.

Reinero et al. (2005) investigated the effects of cyproheptadine on pulmonary resistance and reported no effect in Bermuda grass allergen (BGA)-sensitised cats. Circulating levels of the drug were not determined in this study. The adult cats used in this study were administered 2 mg/kg of cyproheptadine by mouth (PO) twice daily. Norris et al. (1998) reported the pharmacokinetics of cyproheptadine in cats and found that a PO dose of 8 mg led to maximal concentrations of 419 ± 96 ng/mL (n = 6) in circulation. Reiche & Frey (1983) demonstrated that an intravenous (IV) dose of 16.5 μg/kg cyproheptadine produced a 50% reduction in bronchoconstriction. Direct comparison between the results of these studies is difficult, because it would involve assuming a linear relationship between dose and plasma concentration, ignoring differences in bioavailability between the oral and intravenous administration, and does not account for the potential plateau effect of drug efficacy. Therefore, administration of a much larger oral dose than has previously been reported may be necessary to reduce pulmonary resistance in cats.

Reinero et al. (2005) and Schooley et al. (2007) investigated immunological effects in live cats using crossover study designs. Cyproheptadine did not reduce pulmonary inflammatory markers in either study, which both included pulmonary eosinophil numbers. The lack of effect on immunological markers is to be expected as serotonin is not generally considered to strongly modulate immune function. Consistent with the results from Padrid et al. (1995), Schooley et al. (2007) did not observe increases in serotonin in the bronchoalveolar lavage fluid (BALF) from BGA-sensitised cats compared to controls.

The PICO question this Knowledge Summary aimed to answer is if adult cats with eosinophilic airway inflammation cyproheptadine results in less severe clinical signs. However, the current understanding of cyproheptadine is insufficient to recommend its use for treatment of feline eosinophilic airway disease at the dosages investigated. Schooley et al. (2007) showed no statistical difference in plasma and BALF histamine concentrations between cyproheptadine and placebo groups suggesting that there was no improvement in inflammation with cyproheptadine as a monotherapy. Reinero et al. (2005) found that the prednisone significantly reduced serum allergen-specific IgE compared to the control, whereas cyproheptadine did not show statistically significant difference. Together, these studies provide evidence that cyproheptadine is ineffective and should not be used as a monotherapy at the dosages used. Padrid et al. (1995) demonstrated that pretreatment with cyproheptadine resulted in improvement in experimentally-induced inflammatory airway disease. However, the study did not address how these findings might translate to the treatment of naturally occurring disease in cats, and therefore, does not justify the use of cyproheptadine as a monotherapy for eosinophilic airway disease. Lastly, Reiche & Frey (1983) found that a dosage of 16.4 μg/kg of cyproheptadine reduced serotonin induced bronchoconstriction by 50% for 42 minutes. However, the degree of bronchoconstriction induced in this model was not directly compared to that observed in feline eosinophilic airway disease, making the clinical relevance of a 50% reduction following administration of cyproheptadine unclear, and this study cannot justify use of cyproheptadine as a monotherapy.

While the current understanding of cyproheptadine and its effects on feline eosinophilic airway disease remain unclear at its current dosing, further investigation is necessary to establish more accurate and evidence-based treatment recommendations. Norris et al. (1998) showed that cyproheptadine has 100% bioavailability following PO administration, and dose escalation studies may be warranted. Norris et al. (1998) was not appraised due to the study measuring blood levels of the medication rather than observing clinical signs of the drugs effect on a research level. Neither Reinero et al. (2005) or Schooley et al. (2007) noted any adverse effects associated with cyproheptadine treatment of cats at PO doses studied thus far.

Identification of serotonin receptor subtypes in the bronchial and tracheal smooth muscles of cats and their affinities for other serotonin receptor inhibitors may also be warranted to determine other possible drug candidates. In eosinophilic airway disease cats with diabetes mellitus, for whom treatment with glucocorticoids or beta-agonists may alter insulin requirements, or those with cardiac disease, for whom treatment with beta-agonists may be contraindicated, further investigation of serotonin antagonists for bronchoconstriction may be beneficial.

Limitations to the above studies include that many of the studies reviewed in this manuscript analyse data derived from experimentally-induced eosinophilic airway disease rather than naturally occurring cases. Induced disease may not fully replicate the complexity of the naturally occurring condition, which would exhibit different responses to the treatments under investigation. Further studies are warranted in cats with naturally occurring eosinophilic airway disease to draw definitive conclusions about the effects of cyproheptadine. Additionally, the studies did not provide an indication of clinical signs pre- and post-treatment, nor did they specify how these signs were measured. To enhance the quality of airway disease studies and improve patient care, it is recommended to implement standardised scoring systems (e.g., scales from 1–10 or 1–5) to assess symptom severity and quality of life indicators. This will allow standardised comparison to be made at different points in treatment and allow practitioners to make informed decisions of quality of life and ongoing management. Each of the studies discussed used various experimental methods which may also pose certain limitations on the findings. Schooley et al. (2007) and Reinero et al. (2005) utilised a crossover study design, which may produce an overrepresentation of treatment effects if carryover effects occur, when the washout period is insufficient and treatment effects persist into the placebo phase. Crossover designs may also underrepresent treatment effects due to their typically shorter treatment windows, which may not allow enough time for the therapeutic benefits to fully take effect.

However, Padrid et al. (1995) and Reiche & Frey (1983) utilised non-randomised controlled studies, which carry a higher risk of confounding. Without randomisation, differences in comorbidities or overall health between groups may lead to either over- or underestimation of treatment effects due to uncontrolled variability. Additionally, these studies did not address any subjective data regarding the clinical symptoms relevant to this PICO, including sneezing, wheezing, and respiratory distress.

Methodology

Search Strategy

 

Exclusion / Inclusion Criteria

 

Search Outcome

 

Acknowledgements

The authors would like to acknowledge Angelina R. Demartino BS, Midwestern University College of Veterinary Medicine 2027; Riley C. Hrasky BS, Midwestern University College of Veterinary Medicine 2027; Robin G. Simul BS, Midwestern University College of Veterinary Medicine 2027; Sarah Hefferan DVM, faculty at Midwestern University; and Victoria N. Moran BS, Midwestern University College of Veterinary Medicine 2027.

ORCiD

Jillian Seeman: https://orcid.org/0009-0001-5121-803X
Rachael Kreisler: https://orcid.org/0000-0002-5562-5521
Jeffrey Norris: https://orcid.org/0009-0009-6039-1529

Conflict of Interest

The authors declare no conflicts of interest.

References

1. Norris, C.R., Boothe, D.M., Esparza, T., Gray, C. & Ragsdale, M. (1998). Disposition of cyproheptadine in cats after intravenous or oral administration of a single dose. American Journal of Veterinary Research. 59(1), 79–81. DOI: https://doi.org/10.2460/ajvr.1998.59.01.79
2. Padrid, P.A., Mitchell, R.W., Ndukwu, I.M., Spaethe, S., Shiou, P., Cozzi, P. & Leff, A. (1995). Cyproheptadine-induced attenuation of type-I immediate-hypersensitivity reactions of airway smooth muscle from immune-sensitized cats. American Journal of Veterinary Research. 56(1), 109–115. DOI: https://doi.org/10.2460/ajvr.1995.56.01.109
3. Reiche, R. & Frey, H. (1983). Antagonism of the 5-HT-induced bronchoconstriction in the cat. Archives internationales de pharmacodynamie et de thérapie, 263(1), 139–145.
4. Reinero, C.R., Decile, K.C., Byerly, J.R., Berghaus, R.D., Walby, W.F., Berghaus, L.J., Hyde, D.M., Schelegle, E.S. & Gershwin, L.J. (2005). Effects of drug treatment on inflammation and hyperreactivity of airways and on immune variables in cats with experimentally induced asthma. American Journal of Veterinary Research. 66(7), 1121–1127. DOI: https://doi.org/10.2460/ajvr.2005.66.1121
5. Schooley, E.K., McGee Turner, J.B., JiJi, R.D., Spinka, C.M. & Reinero, C.R. (2007). Effects of cyproheptadine and cetirizine on eosinophilic airway inflammation in cats with experimentally induced asthma. American Journal of Veterinary Research. 68(11), 1265–1271. DOI: https://doi.org/10.2460/ajvr.68.11.1265
6. Trzil J. (2020). Feline Asthma: Diagnostic and Treatment Update. The Veterinary Clinics of North America: Small Animal Practice. 50(2), 375–391. DOI: https://doi.org/10.1016/j.cvsm.2019.10.002

 

Contribute to the evidence

There are two main ways you can contribute to the evidence base while you are enhancing your CPD:

• Tell us your information need
• Write a Knowledge Summary

Either way, you will be helping to add to the evidence base, and strengthen the decisions that veterinary professionals around the world make to give animals the best possible care. Learn more here: https://veterinaryevidence.org/index.php/ve/author-hub

Licence

Copyright (c) 2026 Jillian Seeman, Rachael Kreisler, Jeffrey Norris

This work is licensed under a Creative Commons Attribution 4.0 International License.

Veterinary Evidence uses the Creative Commons copyright Creative Commons Attribution 4.0 International License. That means users are free to copy and redistribute the material in any medium or format. Remix, transform, and build upon the material for any purpose, even commercially – with the appropriate citation.

Intellectual Property Rights

Authors of Knowledge Summaries submitted to RCVS Knowledge for publication will retain copyright in their work, and will be required to grant to RCVS Knowledge a non-exclusive licence to publish including but not limited to the right to publish, re-publish, transmit, sell, distribute and otherwise use the materials in all languages and all media throughout the world, and to licence or permit others to do so.

Disclaimer

Knowledge Summaries are a peer-reviewed article type which aims to answer a clinical question based on the best available current evidence. It does not override the responsibility of the practitioner. Informed decisions should be made by considering such factors as individual clinical expertise and judgement along with patient’s circumstances and owners’ values. Knowledge Summaries are a resource to help inform and any opinions expressed within the Knowledge Summaries are the author's own and do not necessarily reflect the view of the RCVS Knowledge. Authors are responsible for the accuracy of the content. While the Editor and Publisher believe that all content herein are in accord with current recommendations and practice at the time of publication, they accept no legal responsibility for any errors or omissions, and make no warranty, express or implied, with respect to material contained within. For further information please refer to our Terms of Use.

---