Cyproheptadine waspatented in 1959 and came into medical use in 1961.[12] In 2023, it was the 234th most commonly prescribed medication in theUnited States, with more than 1 million prescriptions.[13][14]
Cyproheptadine is used to treat allergic reactions (specificallyhay fever).[2][15] There is evidence supporting its use for allergies, but second generation antihistamines such asketotifen andloratadine have shown equal results with fewer side effects.[16]
It is also used as a preventive treatment againstmigraine. In a 2013 study the frequency of migraine was dramatically reduced in patients within 7 to 10 days after starting treatment. The average frequency of migraine attacks in these patients before administration was 8.7 times per month, this was decreased to 3.1 times per month at 3 months after the start of treatment.[16][17] This use is on the label in the UK and some other countries.
It is also used off-label in the treatment ofcyclical vomiting syndrome in infants; the only evidence for this use comes from retrospective studies.[18]
Cyproheptadine is sometimes used off-label to improveakathisia in people on antipsychotic medications.[19]
One of the effects of the drug is increasedappetite and weight gain, which has led to its use (off-label in the USA) for this purpose in children who are wasting as well as people withcystic fibrosis.[23][24][25][26]
Cyproheptadine hassedative effects and can be used to treatinsomnia similarly to other centrally-acting antihistamines.[7][31][32][33] The recommended dose for this use is 4 to 8 mg.[31]
Gastric decontamination measures such asactivated charcoal are sometimes recommended in cases ofoverdose.[2] The symptoms are usually indicative ofCNS depression (or conversely CNS stimulation in some) and excess anticholinergic side effects.[2] TheLD50 in mice is 123 mg/kg and 295 mg/kg in rats.[2][5][6]
Cyproheptadine, due to itsserotonin5-HT2A receptorantagonism, may be useful as ahallucinogen antidote againstserotonergic psychedelics or as a so-called "trip killer".[35] The drug has been clinically studied in combination with theserotonergic psychedelicdimethyltryptamine (DMT).[36][37][38] In an early study, cyproheptadine partially blocked thehallucinogenic effects of DMT in 2 of 3subjects.[39][40][38][41] In a follow-up study, pretreatment with cyproheptadine in 5subjects failed to reduce thepsychoactive effects of DMT and instead was found to actually intensify its effects in some cases, although theduration of DMT seemed to be shortened.[36][37][38] Subsequently,Rick Strassman and colleagues studied cyproheptadine in combination with DMT in 8subjects and found that the hallucinogenic effects of DMT were not magnified but were reduced.[42] However, owing to the pronouncedsedative effects of cyproheptadine, it was difficult to tell how much of cyproheptadine's effect was due to antagonism of DMT versus simple general tranquilization.[42] Overall, the findings have been described as inconclusive and higher doses of cyproheptadine being precluded by the drug's sedative effects.[43] It is unclear that cyproheptadine achieves adequateserotonin5-HT2A receptoroccupancy at the assessed doses.[36][37] Further complicating the picture, high doses of cyproheptadine have been reported to produce partialLSD-likediscriminative stimulus effects in animals.[36][37][44]
Notes: The smaller the value, the more avidly the drug binds to the site. All proteins are human unless otherwise noted. ↑ = Agonist. ↓ = Antagonist.Refs:[45][46][10]
Of theserotonin receptors, it is an especially potent antagonist of the5-HT2 receptors. This is thought to underlie its effectiveness in the treatment ofserotonin syndrome.[29] However, it is possible that blockade of5-HT1 receptors may also contribute to its effectiveness in serotonin syndrome.[47] Cyproheptadine has been reported to block 85% of 5-HT2 receptors in the human brain at a dose of 4mg three times per day (12mg/day total) and to block 95% of 5-HT2 receptors in the human brain at a dose of 6mg three times per day (18mg/day total) as measured withpositron emission tomography (PET).[30] The most widely used dose of cyproheptadine for serotonin syndrome has been said to be 4mg, though doses of up to 16mg have been used.[8][48][49][29] However, according to Ken Gillman, the dose of cyproheptadine recommended to ensure blockade of the 5-HT2 receptors for serotonin syndrome is 20 to 30mg based on the PET findings.[29]
Blockade of the serotonin 5-HT2B receptor may be specifically involved in theantimigraine effects of cyproheptadine.[50] The drug has been found to preventpergolide-inducedcardiac valvulopathy, which can be assumed to be due to its serotonin 5-HT2B receptor antagonism.[51][52]
Cyproheptadine is well-absorbed followingoral ingestion, with peak levels occurring after 1 to 4hours.[3][4] Itselimination half-life when taken orally is approximately 8.6hours.[4]
Cyproheptadine is thegeneric name of the drug and itsINNTooltip International Nonproprietary Name,BANTooltip British Approved Name, andDCFTooltip Dénomination Commune Française.[62][63] The drug'sDCITTooltip Denominazione Comune Italiana isciproeptadina, while itsBANMTooltip British Approved Name iscyproheptadine hydrochloride (as thehydrochloridesalt) and itsJANTooltip Japanese Accepted Name iscyproheptadine hydrochloride hydrate (as the hydrochloride hydrate form).[62][63] Synonyms of cyproheptadine includeFl-5967,HSp-1229,Glutodina,Axoprol, andDihexazin.[62][63] The drug is sold under many brand names, but its major brand names arePeriactin and to a lesser extentPeritol.[62][63]
Cyproheptadine was studied in one small trial as an adjunct in people withschizophrenia whose condition was stable and were on other medication; while attention and verbal fluency appeared to be improved, the study was too small to draw generalizations from.[64] It has also been studied as an adjuvant in two other trials in people with schizophrenia, around fifty people overall, and did not appear to have an effect.[65]
^abcdGunja N, Collins M, Graudins A (2004). "A comparison of the pharmacokinetics of oral and sublingual cyproheptadine".Journal of Toxicology. Clinical Toxicology.42 (1):79–83.doi:10.1081/clt-120028749.PMID15083941.S2CID20196551.
^"Cyproheptadine".MedlinePlus Drug Information. U.S. National Library of Medicine.
^abDe Bruyne P, Christiaens T, Boussery K, Mehuys E, Van Winckel M (January 2017). "Are antihistamines effective in children? A review of the evidence".Archives of Disease in Childhood.102 (1):56–60.doi:10.1136/archdischild-2015-310416.PMID27335428.S2CID21185048.
^Saito Y, Yamanaka G, Shimomura H, Shiraishi K, Nakazawa T, Kato F, et al. (May 2017). "Reconsideration of the diagnosis and treatment of childhood migraine: A practical review of clinical experiences".Brain & Development.39 (5):386–394.doi:10.1016/j.braindev.2016.11.011.PMID27993427.S2CID34703034.
^Ashton AK, Weinstein WL (May 2002). "Cyproheptadine for drug-induced sweating".The American Journal of Psychiatry.159 (5):874–875.doi:10.1176/appi.ajp.159.5.874-a.PMID11986151.
^So JY, Teng J (1993)."Epidermolysis Bullosa Simplex". In Adam MP, Everman DB, Mirzaa GM, Pagon RA, Wallace SE, Bean LJ, Gripp KW, Amemiya A (eds.).GeneReviews. University of Washington, Seattle.PMID20301543.
^Harrison ME, Norris ML, Robinson A, Spettigue W, Morrissey M, Isserlin L (June 2019). "Use of cyproheptadine to stimulate appetite and body weight gain: A systematic review".Appetite.137:62–72.doi:10.1016/j.appet.2019.02.012.PMID30825493.S2CID72333631.
^Rossi S, ed. (2013).Australian Medicines Handbook (2013 ed.). Adelaide: The Australian Medicines Handbook Unit Trust.ISBN978-0-9805790-9-3.
^Iqbal MM, Basil MJ, Kaplan J, Iqbal MT (November 2012). "Overview of serotonin syndrome".Annals of Clinical Psychiatry.24 (4):310–318.doi:10.1177/104012371202400410.PMID23145389.
^abcdGillman PK (1999)."The serotonin syndrome and its treatment"(PDF).Journal of Psychopharmacology.13 (1):100–109.doi:10.1177/026988119901300111.PMID10221364.S2CID17640246.The evidence for cyproheptadine is less substantial, perhaps because the dose of cyproheptadine necessary to ensure blockade of brain 5-HT2 receptors is 20–30 mg, which is higher than that used in the cases reported to date (4–16 mg). [...] In only one case was the response rated as good. The improvement, within 30 min of only 4 mg of cyproheptadine, is rapid for oral onset of action and may represent spontaneous resolution. [...] Cyproheptadine is only available in tablet form. It can be crushed and given via a naso-gastric tube. Doses of 4–16 mg, used in reported cases, may be too low for optimum benefit; Kapur's recent data using positron emission tomography indicate that about 30 mg is needed (as a single oral dose) to achieve 85±95% blockade of brain 5-HT2A receptors (Kapur et al., 1997). This is supported by one of this author's cases where 16 mg of cyproheptadine failed to provide any amelioration of symptoms in a moderately severe case, whereas chlorpromazine 50 mg IM was followed by resolution of symptoms in 2 h (Gillman, 1997b). The evidence for the clinical effectiveness of chlorpromazine and cyproheptadine in human cases of SS is somewhat unsatisfactory because it is based on post hoc analysis of case reports. However, it is supported by extensive data from animal work that clari®es the role of 5-HT. More work is needed, especially to elucidate the extent to which various combinations of drugs raise intra-synaptic 5-HT, which is probably the most important factor determining severity.
^abKapur S, Zipursky RB, Jones C, Wilson AA, DaSilva JD, Houle S (June 1997). "Cyproheptadine: a potent in vivo serotonin antagonist".The American Journal of Psychiatry.154 (6): 884a–884.doi:10.1176/ajp.154.6.884a.PMID9167527.
^Wanderer AA, St Pierre JP, Ellis EF (October 1977). "Primary acquired cold urticaria. Double-blind comparative study of treatment with cyproheptadine, chlorpheniramine, and placebo".Archives of Dermatology.113 (10):1375–1377.doi:10.1001/archderm.113.10.1375.PMID334082.
^Aghajanian GK (1994)."Serotonin and the Action of LSD in the Brain".Psychiatric Annals.24 (3):137–141.doi:10.3928/0048-5713-19940301-09.As yet there are no FDA-approved selective 5-HT2 antagonists available for use clinically. There are a few classical 5-HT antagonists (eg, cyproheptadine), approved for other indications that may have effectiveness against the hallucinogens since they have antagonist activity at 5-HT2 receptors. However, side effects produced by actions at other receptors may limit their clinical utility.
^abcdefHalberstadt AL, Nichols DE (1 January 2010)."CHAPTER 4.7 - Serotonin and Serotonin Receptors in Hallucinogen Action".Handbook of Behavioral Neuroscience. Vol. 21. Elsevier. pp. 621–636.doi:10.1016/s1569-7339(10)70103-x.ISBN978-0-12-374634-4. Retrieved9 July 2025.Meltzer and colleagues (Tueting et al., 1992) examined whether the moderately selective 5-HT 2A/2C antagonist cyproheptadine and the D2 antagonist haloperidol could block the psychological effects induced by DMT in normal human volunteers. Neither drug effectively blocked the effects of DMT, and in some subjects the effects of DMT were actually intensified by pretreatment with cyproheptadine. The finding that cyproheptadine intensified the effects of DMT is intriguing in light of reports that high doses of cyproheptadine produce LSD-like behavioral effects in rats (Colpaert et al., 1982). Nonetheless, it is not clear that the dose of cyproheptadine used in the study (4 mg, p.o.) produces significant occupation of 5-HT2 sites.
^abcdefHalberstadt AL, Nichols DE (1 January 2020)."Chapter 43 - Serotonin and serotonin receptors in hallucinogen action".Handbook of Behavioral Neuroscience. Vol. 31. Elsevier. pp. 843–863.doi:10.1016/b978-0-444-64125-0.00043-8.ISBN978-0-444-64125-0. Retrieved9 July 2025.DMT. Meltzer and colleagues (Tueting, Metz, Rhoades, & Boutros, 1992) examined whether the moderately selective 5-HT2A/2C antagonist cyproheptadine and the D2 antagonist haloperidol could block the psychological effects induced by DMT in normal human volunteers. Neither drug effectively blocked the effects of DMT, and in some subjects the effects of DMT were actually intensified by pretreatment with cyproheptadine. The finding that cyproheptadine intensified the effects of DMT is intriguing in light of reports that high doses of cyproheptadine produce LSD-like behavioral effects in rats (Colpaert et al., 1982). Nonetheless, it is not clear that the dose of cyproheptadine used in the study (4 mg, p.o.) produces significant occupation of 5-HT2 sites.
^Nichols DE (February 2004). "Hallucinogens".Pharmacol Ther.101 (2):131–181.doi:10.1016/j.pharmthera.2003.11.002.PMID14761703.The most compelling evidence that hallucinogens have agonist activity at 5-HT2A receptors was obtained from two clinical studies. The first study was not definitive, however, where the mixed 5-HT2A/2C antagonist cyproheptadine antagonized the subjective effects of DMT in some subjects (Meltzer et al., 1982). [...]
^abStrassman R (1 December 2000).DMT: The Spirit Molecule: A Doctor's Revolutionary Research into the Biology of Near-Death and Mystical Experiences. Simon and Schuster.ISBN978-1-59477-973-2. Retrieved9 July 2025.The next serotonin receptor blockade study used cyproheptadine, an antihistamine drug with additional anti-serotonin properties. In this case, cyproheptadine prevents drugs from attaching to the serotonin "2" site, the receptor researchers believe is the most important in controlling how psychedelics work. This protocol was identical in design to that of the pindolol study in that volunteers received cyproheptadine several hours before DMT. Eight volunteers completed this study. Most were new recruits. There appeared to be some suppression of effects, so we gave the high dose, 0.4 mg/kg, with and without the serotonin blocker. Because cyproheptadine clearly did not magnify DMT's effects, we hoped that using this large dose would give us the best chance of establishing a significant level of DMT suppression. However, the sedating properties of the drug were so pronounced that they complicated interpretation of the data. It was difficult to tell how much was specific DMT blockade, and how much was general tranquilization.
^abWinter JC (1994). "The stimulus effects of serotonergic hallucinogens in animals".NIDA Res Monogr.146:157–182.PMID8742798.Figures 5 through 7 show the agonistic effects (upper panels) and the antagonistic effects (lower panels) of a series of serotonergic antagonists in rats trained with LSD as a discriminative stimulus. It is obvious that a full spectrum of activity is represented. Methysergide, cyproheptadine, and mianserin are significantly LSD-like (figure 5, upper panel) and are, as would be expected from their agonistic effects, only marginally effective as antagonists (lower panel). [...] Agonist and antagonist effects of methysergide, cyproheptadine, and minaserin in rats trained with LSD [0.16 mg/kg] and saline. [...] Of the three purported antagonists showing the highest degree of LSD-like stimulus effects in the rat, two—methysergide and cyproheptadine—are claimed to be sometimes associated with hallucinations in humans.
^Roth BL, Driscol J."PDSP Ki Database".Psychoactive Drug Screening Program (PDSP). University of North Carolina at Chapel Hill and the United States National Institute of Mental Health. Retrieved14 August 2017.
^Brown CH (17 November 2010)."Drug-Induced Serotonin Syndrome".U.S. Pharmacist – The Leading Journal in Pharmacy.Administration of drugs with serotonin antagonist properties, such as cyproheptadine and chlorpromazine, has been utilized in a few patients.4,16,18 Cyproheptadine 4 mg orally is the most widely used antidote for SS.36
^Lappin RI, Auchincloss EL (October 1994). "Treatment of the serotonin syndrome with cyproheptadine".N Engl J Med.331 (15):1021–1022.doi:10.1056/NEJM199410133311514.PMID8084345.
^Elangbam CS (October 2010). "Drug-induced valvulopathy: an update".Toxicol Pathol.38 (6):837–848.doi:10.1177/0192623310378027.PMID20716786.A subsequent study by Droogmans et al. (2009) showed that cyproheptadine (5-HT2BR antagonist) co-treatment prevented the development of pergolide-induced valvulopathy in rats with a reduced number of 5-HT2BR–positive VICs, suggesting that 5-HT2BR plays an important role in the pathogenesis of valvulopathy.
^Droogmans S, Roosens B, Cosyns B, Degaillier C, Hernot S, Weytjens C, et al. (June 2009). "Cyproheptadine prevents pergolide-induced valvulopathy in rats: an echocardiographic and histopathological study".Am J Physiol Heart Circ Physiol.296 (6):H1940–H1948.doi:10.1152/ajpheart.01177.2008.PMID19346455.
^abHeym J, Jacobs BL (1987). "Serotonergic mechanisms of hallucinogenic drug effects".Monogr Neural Sci. Frontiers of Neurology and Neuroscience.13:55–81.doi:10.1159/000414570.ISBN978-3-8055-4561-7.PMID2891030.Several studies have found classical serotonin antagonists such as cinanserin, cyproheptadine and methysergide to be effective blockers of the discriminative stimulus properties of hallucinogens, including DOM, mescaline, and LSD [20, 22, 23, 38, 58, 98, 109]. [...] In addition, many of the classical antagonists display a complex effect in the drug discrimination paradigm [23]. Low doses of methysergide, mianserin and cyproheptadine, for example, have been reported to only partially antagonize an LSD cue while higher doses of these same compounds actually show a partial generalization to the LSD stimulus [23]. This latter finding suggests that at high doses these antagonists are perceived to some extent as LSD. Perhaps this explains the clinical experience with methysergide where psychoactive effects have been noted [82].
^Appel JB, West WB, Buggy J (January 2004). "LSD, 5-HT (serotonin), and the evolution of a behavioral assay".Neurosci Biobehav Rev.27 (8):693–701.doi:10.1016/j.neubiorev.2003.11.012.PMID15019419.The structural congeners of LSD, BOL and methysergide (UML) blocked the LSD cue partially (30% of control) as did another centrally acting 5-HT antagonist, cyproheptadine; the peripherally acting 5-HT antagonist xylamidine had no effect at any dose tested.
^Marona-Lewicka D, Nichols DE (October 2007). "Further evidence that the delayed temporal dopaminergic effects of LSD are mediated by a mechanism different than the first temporal phase of action".Pharmacol Biochem Behav.87 (4):453–461.doi:10.1016/j.pbb.2007.06.001.PMID17618679.Combination tests (Tables 5 and 6) with the highly selective 5-HT2A antagonist, MDL 11,393 confirmed that a 5-HT2A antagonist effectively blocks only the LSD-30, and not the LSD-90 cue. Even the nonselective 5-HT antagonist, cyproheptadine, which significantly inhibited the LSD-30 effect (Table 6), had no effect against the LSD-90 cue (Table 5). Thus, we provide further evidence that activation of the 5-HT2A receptor is not essential for the delayed effect of LSD treatment
^Halberstadt AL, Geyer MA (2018). "Effect of Hallucinogens on Unconditioned Behavior".Behavioral Neurobiology of Psychedelic Drugs. Curr Top Behav Neurosci. Vol. 36. pp. 159–199.doi:10.1007/7854_2016_466.ISBN978-3-662-55878-2.PMC5787039.PMID28224459.The 5-HT2A receptor is believed to be responsible for the hallucinogen HTR. It was reported as early as 1967 that the nonselective 5-HT antagonists methysergide and cyproheptadine block the ability of LSD and other hallucinogens to induce the HTR (Corne and Pickering 1967); subsequent studies confirmed that many other 5-HT antagonists ameliorate the response.
^Glennon RA (1992). "Animal Models for Assessing Hallucinogenic Agents".Animal Models of Drug Addiction. Vol. 24. Totowa, NJ: Humana Press. pp. 345–381.doi:10.1385/0-89603-217-5:345.ISBN978-1-59259-629-4.5-HTP-induced head-twitch in rodents can be antagonized by a wide variety of 5-HT antagonists, including cinanserin, cyproheptadine, metergoline, methysergide, and mianserin (Come et al., 1963; Bedard and Pycock, 1977; Ortmann et al., 1982; Colpaert and Janssen, 1983; Green, 1984; Lucki et al., 1984; Gerber et al., 1985). In the rat, cyproheptadine also antagonizes the head-twitch induced by LSD (Vetulani et al., 1980; Lucki et al., 1984), quipazine (Vetulani et al., 1980), and 5-OMe-DMT (Matthews and Smith, 1980). [...] Examining eight 5-HT antagonists (2-bromo LSD, cinanserin, cyproheptadine, methiothepin, methysergide, metergoline, mianserin, pizotifen), Colpaert and Janssen (1983) found that all blocked 5-HTP-induced head-twitch in the rat, but did so in a biphasic manner. There is an initial sharp decrease in response frequency followed by a further, but shallower, rate of decrease. [...]
^abWinter JC (April 2009). "Hallucinogens as discriminative stimuli in animals: LSD, phenethylamines, and tryptamines".Psychopharmacology (Berl).203 (2):251–263.doi:10.1007/s00213-008-1356-8.PMID18979087.Two factors complicated this simple picture; the second of these was yet to appear but the first was evident at the time. The antagonists then available, drugs such as cinanserin, methysergide, cyproheptadine, mianserin, and pizotyline (BC-105), were nonselective with respect to other neurotransmitter systems and, indeed, some had behaviorally evident partial agonist effects in LSD-trained rats (Colpaert et al. 1982).
^Stephenson JD (1 January 1990). "Neuropharmacological Studies of the Serotonergic System".International Review of Psychiatry.2 (2):157–178.doi:10.3109/09540269009028280.ISSN0954-0261.Several 5-HT antagonists had partial LSD-like agonist activity and were therefore only weakly effective as antagonists of the LSD cue (Colpaert et al., 1982). These compounds included metergoline, methysergide, cyproheptadine, metetepine and cinanserin.
^Colpaert FC, Niemegeers CJ, Janssen PA (April 1982). "A drug discrimination analysis of lysergic acid diethylamide (LSD): in vivo agonist and antagonist effects of purported 5-hydroxytryptamine antagonists and of pirenperone, a LSD-antagonist".J Pharmacol Exp Ther.221 (1):206–214.doi:10.1016/S0022-3565(25)33038-7.PMID7062283.
^abDabaghzadeh F, Khalili H, Ghaeli P, Dashti-Khavidaki S (December 2012). "Potential benefits of cyproheptadine in HIV-positive patients under treatment with antiretroviral drugs including efavirenz".Expert Opinion on Pharmacotherapy.13 (18):2613–2624.doi:10.1517/14656566.2012.742887.PMID23140169.S2CID25769557.
^Nunes LV, Moreira HC, Razzouk D, Nunes SO, Mari J (2012). "Strategies for the treatment of antipsychotic-induced sexual dysfunction and/or hyperprolactinemia among patients of the schizophrenia spectrum: a review".Journal of Sex & Marital Therapy.38 (3):281–301.doi:10.1080/0092623X.2011.606883.PMID22533871.S2CID23406005.
