Cyproheptadine

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Cyproheptadine
Cyproheptadine.svg
Cyproheptadine-Spartan-PM3-3D-balls.png
Clinical data
Pronunciation /ˌsaɪproʊˈhɛptədiːn/ [1]
Trade names Periactin, others
AHFS/Drugs.com Monograph
MedlinePlus a682541
License data
Pregnancy
category
  • AU:A
Routes of
administration 		Oral [2]
ATC code
Legal status
Legal status
Pharmacokinetic data
Protein binding 96 to 99%
Metabolism Liver, including glucuronidation [3] [4]
Onset of action 1–4 hours (peak) [5] [6]
Elimination half-life 8.6 hours [6]
Excretion Faecal (2–20%; of which, 34% as unchanged drug) and renal (40%; none as unchanged drug) [3] [4]
Identifiers
  • 4-(5H-Dibenzo[a,d]cyclohepten-5-ylidene)-1-methylpiperidine
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.004.482 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C21H21N
Molar mass 287.406 g·mol−1
3D model (JSmol)
  • c43\C(=C1/CCN(C)CC1)c2ccccc2\C=C/c3cccc4
  • InChI=1S/C21H21N/c1-22-14-12-18(13-15-22)21-19-8-4-2-6-16(19)10-11-17-7-3-5-9-20(17)21/h2-11H,12-15H2,1H3 Yes check.svgY
  • Key:JJCFRYNCJDLXIK-UHFFFAOYSA-N Yes check.svgY
   (verify)

Cyproheptadine, sold under the brand name Periactin among others, is a first-generation antihistamine which is used to treat allergies. [2] In addition, it has a number of off-label uses, such as treatment of serotonin syndrome and insomnia. [7] [8] The drug is taken orally. [2]

Contents

It is an antihistamine and hence acts as a histamine H1 receptor antagonist. [2] In addition to its antihistamine activity, cyproheptadine has anticholinergic, antiserotonergic, antidopaminergic, and local anesthetic properties. [2] [7] [9] [10] These activities make cyproheptadine useful for various additional uses besides antihistamine indications. [7] As a first-generation antihistamine, cyproheptadine crosses the blood–brain barrier and can produce sedation. [9] The drug can also produce significant central anticholinergic effects at clinically used doses. [11] [9]

Cyproheptadine was patented in 1959 and came into medical use in 1961. [12] In 2023, it was the 234th most commonly prescribed medication in the United States, with more than 1 million prescriptions. [13] [14]

Medical uses

Periactin (cyproheptadine) 4 mg tablets Periactin.jpg
Periactin (cyproheptadine) 4 mg tablets

Cyproheptadine is used to treat allergic reactions (specifically hay fever). [2] [15] There is evidence supporting its use for allergies, but second generation antihistamines such as ketotifen and loratadine have shown equal results with fewer side effects. [16]

It is also used as a preventive treatment against migraine. 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 of cyclical vomiting syndrome in infants; the only evidence for this use comes from retrospective studies. [18]

Cyproheptadine is sometimes used off-label to improve akathisia in people on antipsychotic medications. [19]

It is used off-label to treat various dermatological conditions, including psychogenic itch, [20] drug-induced hyperhidrosis (excessive sweating), [21] and prevention of blister formation for some people with epidermolysis bullosa simplex. [22]

One of the effects of the drug is increased appetite 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 with cystic fibrosis. [23] [24] [25] [26]

It is also used off-label in the management of moderate to severe cases of serotonin syndrome, a complex of symptoms associated with the use of serotonergic drugs, such as selective serotonin reuptake inhibitors (and monoamine oxidase inhibitors), and in cases of high levels of serotonin in the blood resulting from a serotonin-producing carcinoid tumor. [8] [27] [28] There is uncertainty about the proper dose of cyproheptadine for treatment of serotonin syndrome, with doses of 4 to 16 mg having been employed but doses of 20 to 30 mg possibly actually being necessary based on positron emission tomography (PET) imaging research. [8] [29] [30]

Cyproheptadine has sedative effects and can be used to treat insomnia similarly to other centrally-acting antihistamines. [7] [31] [32] [33] The recommended dose for this use is 4 to 8 mg. [31]

Contraindications

Contraindications of cyproheptadine include newborns and premature infants, nursing mothers, hypersensitivity to cyproheptadine and its ingredients, monoamine oxidase inhibitors (MAOIs), angle-closure glaucoma, stenosing peptic ulcer symptomatic prostatic hypertrophy, bladder neck obstruction, pyloroduodenal obstruction, and elderly, debilitated patients. [2]

Adverse effects

Adverse effects include: [3] [4]

Overdose

Gastric decontamination measures such as activated charcoal are sometimes recommended in cases of overdose. [2] The symptoms are usually indicative of CNS depression (or conversely CNS stimulation in some) and excess anticholinergic side effects. [2] The LD50 in mice is 123 mg/kg and 295 mg/kg in rats. [2] [3] [4]

Interactions

Sedating antihistamines like cyproheptadine may have additive effects with other CNS depressants like such as alcohol, hypnotics, sedatives, tranquilizers, and anxiolytics. [2] Monoamine oxidase inhibitors (MAOIs) may prolong and intensify the anticholinergic effects of antihistamines like cyproheptadine. [2] However, cyproheptadine is safe to use in the treatment of serotonin syndrome occurring with MAOIs. [7] [9]

Cyproheptadine, due to its serotonin 5-HT2A receptor antagonism, may be useful as a hallucinogen antidote against serotonergic psychedelics or as a so-called "trip killer". [35] The drug has been clinically studied in combination with the serotonergic psychedelic dimethyltryptamine (DMT). [36] [37] [38] In an early study, cyproheptadine partially blocked the hallucinogenic effects of DMT in 2 of 3 subjects. [39] [40] [38] [41] In a follow-up study, pretreatment with cyproheptadine in 5 subjects failed to reduce the psychoactive effects of DMT and instead was found to actually intensify its effects in some cases, although the duration of DMT seemed to be shortened. [36] [37] [38] Subsequently, Rick Strassman and colleagues studied cyproheptadine in combination with DMT in 8 subjects and found that the hallucinogenic effects of DMT were not magnified but were reduced. [42] However, owing to the pronounced sedative 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 adequate serotonin 5-HT2A receptor occupancy at the assessed doses. [36] [37] Further complicating the picture, high doses of cyproheptadine have been reported to produce partial LSD-like discriminative stimulus effects in animals. [36] [37] [44]

Pharmacology

Pharmacodynamics

Activities of cyproheptadine
SiteKi (nM)Action
5-HT1A 50–59↓
5-HT1B 1,600?
5-HT1D 670?
5-HT1E 1,500?
5-HT2A 0.46–3.0↓
5-HT2B 1.5–2.6↓
5-HT2C 2.2–18↓
5-HT3 235?
5-HT4 ND?
5-HT5A 57?
5-HT6 96–150?
5-HT7 30–126?
D1 10–117?
D2 74–112↓
D3 8?
D4 120?
D5 60?
α1A 45?
α1B >10,000?
α2A 330?
α2B 220?
α2C 160?
β1 >10,000?
β2 >10,000?
H1 0.06–2.3↓
H2 4.8?
H3 >10,000?
H4 202–>10,000?
M1 12↓
M2 7↓
M3 12↓
M4 8↓
M5 11.8↓
I1 204?
σ1 >10,000 (gp)?
σ2 750 (rat)?
SERT Tooltip Serotonin transporter>10,000–
NET Tooltip Norepinephrine transporter2,550–
DAT Tooltip Dopamine transporter4,100–
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]

Cyproheptadine is a potent antihistamine or inverse agonist of the histamine H1 receptor. [7] [10] It also has anticholinergic, antiserotonergic, antidopaminergic, and local anesthetic activities. [7] [10] In one study, cyproheptadine had about the same affinity for the serotonin 5-HT2A and 5-HT2B receptors as for the histamine H1 receptor, about 8-fold selectivity for the histamine H1 receptor over the serotonin 5-HT2C receptor, about 2- to 8-fold selectivity for the H1 receptor over the muscarinic acetylcholine receptors, and about 4- to 52-fold selectivity for the histamine H1 receptor over the dopamine receptors. [10] The drug shows lower affinity for α-adrenergic receptors and little to no affinity for the monoamine transporters. [10]

Of the serotonin receptors, it is an especially potent antagonist of the 5-HT2 receptors. This is thought to underlie its effectiveness in the treatment of serotonin syndrome. [29] However, it is possible that blockade of 5-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 4 mg three times per day (12 mg/day total) and to block 95% of 5-HT2 receptors in the human brain at a dose of 6 mg three times per day (18 mg/day total) as measured with positron emission tomography (PET). [30] The most widely used dose of cyproheptadine for serotonin syndrome has been said to be 4 mg, though doses of up to 16 mg 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 30 mg based on the PET findings. [29]

Blockade of the serotonin 5-HT2B receptor may be specifically involved in the antimigraine effects of cyproheptadine. [50] The drug has been found to prevent pergolide-induced cardiac valvulopathy, which can be assumed to be due to its serotonin 5-HT2B receptor antagonism. [51] [52]

Cyproheptadine has been found to partially block the discriminative stimulus properties of the psychedelic drug LSD in rodent drug discrimination tests. [53] [54] [55] It also antagonizes the discriminative stimulus properties of various other serotonergic agents, like 5-MeO-DMT, quipazine, fenfluramine, and 5-hydroxytryptophan (5-HTP). [56] In addition, cyproheptadine blocks the head-twitch response induced by LSD, 5-MeO-DMT, quipazine, and 5-HTP in rodents. [57] [58] However, high doses of cyproheptadine have been reported to produce partial LSD-like discriminative stimulus effects in rodents. [53] [36] [37] [44] [59] [60] [61] Possibly in relation to this, cyproheptadine has been said to sometimes be associated with hallucinations in humans. [36] [37] As an alternative possibility however, the partial generalization may instead be related to the highly non-selective nature of cyproheptadine and interactions at other neurotransmitter sites. [59]

Pharmacokinetics

Cyproheptadine is well-absorbed following oral ingestion, with peak levels occurring after 1 to 4 hours. [5] [6] Its elimination half-life when taken orally is approximately 8.6 hours. [6]

Chemistry

Cyproheptadine is a tricyclic benzocycloheptene and is closely related to pizotifen and ketotifen as well as to tricyclic antidepressants.

History

Cyproheptadine was patented in 1959 and was introduced for medical use in 1961. [12]

Society and culture

Names

Cyproheptadine is the generic name of the drug and its INN Tooltip International Nonproprietary Name, BAN Tooltip British Approved Name, and DCF Tooltip Dénomination Commune Française. [62] [63] The drug's DCIT Tooltip Denominazione Comune Italiana is ciproeptadina, while its BANM Tooltip British Approved Name is cyproheptadine hydrochloride (as the hydrochloride salt) and its JAN Tooltip Japanese Accepted Name is cyproheptadine hydrochloride hydrate (as the hydrochloride hydrate form). [62] [63] Synonyms of cyproheptadine include Fl-5967, HSp-1229, Glutodina, Axoprol, and Dihexazin. [62] [63] The drug is sold under many brand names, but its major brand names are Periactin and to a lesser extent Peritol. [62] [63]

Availability

Cyproheptadine is available widely throughout the world. [62] [63] This includes in Australia, Canada, Europe, Hong Kong, India, Japan, Mexico, Turkey, the United Kingdom, and the United States, among others. [62] [63]

Research

Psychiatric disorders

Cyproheptadine was studied in one small trial as an adjunct in people with schizophrenia 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]

Cyproheptadine has been studied for the treatment of post-traumatic stress disorder. [65]

Sexual dysfunction

There have been some trials to see if cyproheptadine could reduce sexual dysfunction caused by selective serotonin reuptake inhibitor (SSRI) and antipsychotic medications. [66]

Veterinary use

Cyproheptadine is used in cats as an appetite stimulant [67] [68] : 1371  and as an adjunct in the treatment of asthma. [69] Possible adverse effects include excitement and aggressive behavior. [70] The elimination half-life of cyproheptadine in cats is 12 hours. [69]

Cyproheptadine is a second line treatment for pituitary pars intermedia dysfunction in horses. [71] [72]

References

  1. ↑ "Cyproheptadine". Dictionary.com Unabridged (Online). n.d.
  2. 1 2 3 4 5 6 7 8 9 10 11 12 https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/087056s045lbl.pdf
  3. 1 2 3 4 "Cyproheptadine Hydrochloride tablet [Boscogen, Inc.]" (PDF). DailyMed. U.S. National Library of Medicine. November 2010. Retrieved 26 October 2013.
  4. 1 2 3 4 "Product Information: Periactin (cyproheptadine hydrochloride)" (PDF). Aspen Pharmacare Australia. Aspen Pharmacare Australia Pty Ltd. 17 November 2011. Archived from the original (PDF) on 29 October 2013. Retrieved 26 October 2013.
  5. 1 2 Murray L, Daly F, McCoubrie DM, Cadogan M (15 January 2011). Toxicology Handbook. Elsevier Australia. p. 388. ISBN   978-0-7295-3939-5 . Retrieved 27 November 2011.
  6. 1 2 3 4 Gunja 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. PMID   15083941. S2CID   20196551.
  7. 1 2 3 4 5 6 7 Badr B, Naguy A (October 2022). "Cyproheptadine: a psychopharmacological treasure trove?". CNS Spectrums. 27 (5): 533–535. doi: 10.1017/S1092852921000250 . PMID   33632345.
  8. 1 2 3 4 Jacobs ET, Akers KG, Vohra V, King AM (2020). "Cyproheptadine for Serotonin Toxicity: an Updated Systematic Review and Grading of Evidence". Current Emergency and Hospital Medicine Reports. 8 (4): 151–159. doi:10.1007/s40138-020-00222-5. ISSN   2167-4884. "Administration of drugs with serotonin antagonist properties, such as cyproheptadine and chlorpromazine has been utilized in a few patients. Cyproheptadine 4 mg orally is the most widely used antidote for SS."
  9. 1 2 3 4 Bertrand V, Massy N, Vegas N, Gras V, Chalouhi C, Tavolacci MP, et al. (2021). "Safety of Cyproheptadine, an Orexigenic Drug. Analysis of the French National Pharmacovigilance Data-Base and Systematic Review". Front Pediatr. 9 712413. doi: 10.3389/fped.2021.712413 . PMC   8525494 . PMID   34676184.
  10. 1 2 3 4 5 6 Young R, Khorana N, Bondareva T, Glennon RA (October 2005). "Pizotyline effectively attenuates the stimulus effects of N-methyl-3,4-methylenedioxyamphetamine (MDMA)". Pharmacol Biochem Behav. 82 (2): 404–410. doi:10.1016/j.pbb.2005.09.010. PMID   16253319.
  11. ↑ Watemberg NM, Roth KS, Alehan FK, Epstein CE (January 1999). "Central anticholinergic syndrome on therapeutic doses of cyproheptadine". Pediatrics. 103 (1): 158–160. doi:10.1542/peds.103.1.158. PMID   9917456.
  12. 1 2 Fischer J, Ganellin CR (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 547. ISBN   978-3-527-60749-5.
  13. ↑ "The Top 300 of 2023". ClinCalc. Archived from the original on 12 August 2025. Retrieved 12 August 2025.
  14. ↑ "Cyproheptadine Drug Usage Statistics, United States, 2013 - 2023". ClinCalc. Retrieved 20 August 2025.
  15. ↑ "Cyproheptadine". MedlinePlus Drug Information. U.S. National Library of Medicine.
  16. 1 2 De 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. PMID   27335428. S2CID   21185048.
  17. ↑ 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. PMID   27993427. S2CID   34703034.
  18. ↑ Salvatore S, Barberi S, Borrelli O, Castellazzi A, Di Mauro D, Di Mauro G, et al. (July 2016). "Pharmacological interventions on early functional gastrointestinal disorders". Italian Journal of Pediatrics. 42 (1) 68. doi: 10.1186/s13052-016-0272-5 . PMC   4947301 . PMID   27423188.
  19. ↑ Taylor DM, Paton C, Kapur S (2015). The Maudsley Prescribing Guidelines in Psychiatry. John Wiley & Sons. p. 85. ISBN   978-1-118-75457-3.
  20. ↑ Szepietowski JC, Reszke R (2016). "Psychogenic Itch Management". Current Problems in Dermatology. 50: 124–132. doi:10.1159/000446055. ISBN   978-3-318-05888-8. PMID   27578081.
  21. ↑ 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. PMID   11986151.
  22. ↑ 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. PMID   20301543.
  23. ↑ "Ciproheptadina, estimulante del apetito" [Cyproheptadine, appetite stimulant]. vademecum.es (in Spanish).
  24. ↑ "Bioplex NF". Archived from the original on 18 April 2018. Retrieved 18 April 2018.
  25. ↑ 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. PMID   30825493. S2CID   72333631.
  26. ↑ Kim SY, Yun JM, Lee JW, Cho YG, Cho KH, Park YG, et al. (October 2021). "Efficacy and Tolerability of Cyproheptadine in Poor Appetite: A Multicenter, Randomized, Double-blind, Placebo-controlled Study". Clinical Therapeutics. 43 (10): 1757–1772. doi:10.1016/j.clinthera.2021.08.001. PMID   34509304. S2CID   237493456.
  27. ↑ Rossi S, ed. (2013). Australian Medicines Handbook (2013 ed.). Adelaide: The Australian Medicines Handbook Unit Trust. ISBN   978-0-9805790-9-3.
  28. ↑ 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. PMID   23145389.
  29. 1 2 3 4 Gillman PK (1999). "The serotonin syndrome and its treatment" (PDF). Journal of Psychopharmacology. 13 (1): 100–109. doi:10.1177/026988119901300111. PMID   10221364. S2CID   17640246. 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.
  30. 1 2 Kapur 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. PMID   9167527.
  31. 1 2 Ekambaram V, Owens J (January 2021). "Medications Used for Pediatric Insomnia". Child and Adolescent Psychiatric Clinics of North America. 30 (1): 85–99. doi:10.1016/j.chc.2020.09.001. PMID   33223070. S2CID   227131545.
  32. ↑ Rombaut NE (1995). Antihistamines and Sedation: Methods and Measures (Thesis). OCLC   59660401. ProQuest   301570569.
  33. ↑ 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. PMID   334082.
  34. ↑ Chertoff J, Alam S, Clark V (July 2014). "Cyproheptadine-Induced Acute Liver Failure". ACG Case Reports Journal. 1 (4): 212–213. doi:10.14309/crj.2014.56. PMC   4286888 . PMID   25580444.
  35. ↑ 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.
  36. 1 2 3 4 5 6 Halberstadt 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. ISBN   978-0-12-374634-4 . Retrieved 9 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.
  37. 1 2 3 4 5 6 Halberstadt 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. ISBN   978-0-444-64125-0 . Retrieved 9 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.
  38. 1 2 3 Tueting PA, Metz J, Rhoades BK, Boutros NN (July 1992). "Pharmacologic challenge in ERP research". Ann N Y Acad Sci. 658 (1): 223–255. Bibcode:1992NYASA.658..223T. doi:10.1111/j.1749-6632.1992.tb22847.x. PMID   1497260.
  39. ↑ Nichols DE (February 2004). "Hallucinogens". Pharmacol Ther. 101 (2): 131–181. doi:10.1016/j.pharmthera.2003.11.002. PMID   14761703. 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). [...]
  40. ↑ Strassman RJ (March 1995). "Hallucinogenic Drugs in Psychiatric Research and Treatment: Perspectives and Prospects". J Nerv Ment Dis. 183 (3): 127–138. doi:10.1097/00005053-199503000-00002. PMID   7891058. Cyproheptadine, a 5-HT2A c antagonist (Hoyer and Schoeffter, 1991), prevented the subjective effects of DMT in two of three normal volunteers (Meltzer et al., 1982).
  41. ↑ Meltzer HY, Wiita B, Tricou BJ, Simonovic M, Fang VS, Manov G (1982). "Effect of Serotonin Precursors and Serotonin Agonists on Plasma Hormone Levels". In Beng T. Ho (ed.). Serotonin in Biological Psychiatry. Books on Demand. pp. 128–133. ISBN   978-0-608-00638-3.
  42. 1 2 Strassman 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. ISBN   978-1-59477-973-2 . Retrieved 9 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.
  43. ↑ Halberstadt AL, Geyer MA (September 2011). "Multiple receptors contribute to the behavioral effects of indoleamine hallucinogens". Neuropharmacology. 61 (3): 364–381. doi:10.1016/j.neuropharm.2011.01.017. PMC   3110631 . PMID   21256140. The mechanism for the subjective effects of DMT has also been investigated clinically. Blockade studies with low doses of the nonselective 5-HT2 antagonist cyproheptadine produced inconclusive results (Tueting et al., 1992), and the sedative effects of cyproheptadine precluded testing higher doses (Strassman, 2001).
  44. 1 2 Winter JC (1994). "The stimulus effects of serotonergic hallucinogens in animals". NIDA Res Monogr. 146: 157–182. PMID   8742798. 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.
  45. ↑ 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. Retrieved 14 August 2017.
  46. ↑ Liu T. "BindingDB BDBM50017721 1-Methyl-4-(5H-dibenzo(a,d)cycloheptenylidene)piperidine::1-methyl-4-(5-dibenzo(a,e)cycloheptatrienylidene)piperidine::4-(5-dibenzo(a,d)cyclohepten-5-ylidine)-1-methylpiperidine::4-(5H-dibenzo(a,d)cyclohepten-5-ylidene)-1-methylpiperidine::4-(5H-dibenzo[a,d][7]annulen-5-ylidene)-1-methylpiperidine4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-methylpiperidine::5-(1-methylpiperidylidene-4)-5H-dibenzo(a,d)cyclopheptene::CHEMBL516::CYPROHEPTADINE". BindingDB. Retrieved 6 December 2024.
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  49. ↑ 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. PMID   8084345.
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  51. ↑ Elangbam CS (October 2010). "Drug-induced valvulopathy: an update". Toxicol Pathol. 38 (6): 837–848. doi:10.1177/0192623310378027. PMID   20716786. 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.
  52. ↑ 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. PMID   19346455.
  53. 1 2 Heym 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. ISBN   978-3-8055-4561-7. PMID   2891030. 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].
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  55. ↑ 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. PMID   17618679. 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
  56. ↑ Glennon RA (1988). "Site-Selective Serotonin Agonists as Discriminative Stimuli". Transduction Mechanisms of Drug Stimuli. Psychopharmacology Series. Vol. 4. pp. 15–31. doi:10.1007/978-3-642-73223-2_2. ISBN   978-3-642-73225-6. PMID   3293039.
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  58. ↑ 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. ISBN   978-1-59259-629-4. 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. [...]
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