It was suggested by Jerrold C. Winter in 1994 that serotonin 5-HT3 receptor antagonists likeondansetron could allow for use of higher doses of quipazine and assessment of whether it produces clear psychedelic effects or not.[1]Alexander Shulgin subsequently reported inThe Shulgin Index (2011), based on an anonymous report dated to 2007, that quipazine in combination with a serotonin 5-HT3 receptor antagonist, presumably ondansetron, produced a "full psychedelic response".[4][11][2][12]
Notes: The smaller the value, the more avidly the drug binds to the site. All proteins are human unless otherwise specified.Refs:[14][15][13][16][17][18][19][20][21]
Quipazine produces ahead-twitch response and otherpsychedelic-consistent effects in animal studies including in mice, rats, and monkeys.[2][4][23][24][25] These effects appear to be mediated by activation of the serotonin 5-HT2A receptor, as they are blocked by serotonin 5-HT2A receptor antagonists likeketanserin.[2][4][25] The head twitches induced by quipazine are potentiated by themonoamine oxidase inhibitor (MAOI)pargyline.[25][26] Based on this, it has been suggested that quipazine may act as aserotonin releasing agent and that it may induce the head twitch response by a dual action of serotonin 5-HT2A receptor agonism and induction of serotonin release.[25][26]
Besides the head-twitch response, quipazine fully substitutes forLSD and partially substitutes formescaline in rodentdrug discrimination tests.[1] In addition, quipazine substitutes forDOM in rodents and monkeys and this is blocked by serotonin 5-HT2A receptor antagonists likepizotyline andketanserin.[2] When quipazine is used as the training drug, LSD, mescaline, andpsilocybin all fully substitute for quipazine.[2] In monkeys, quipazine additionally produced LSD-like behavioral changes along withprojectile vomiting.[1] In contrast to primates, rodents generally lack anemetic response, and hence the nausea and vomiting that quipazine can induce may not be a limiting factor in this order of animals.[2] Similarly toDOI, quipazine alterstime perception in rodents.[27]
Although quipazine does not generalize todextroamphetamine indrug discrimination tests of dextroamphetamine-trained rodents, dextroamphetamine andcathinone have been found to partially generalize to quipazine in assays of quipazine-trained rodents.[28][29] In relation to this, it has been suggested that quipazine might possess somedopaminergic activity, as thediscriminative stimulus properties ofamphetamine appear to be mediated by dopamine signaling.[28][29] Relatedly, quipazine has been said to act as adopamine receptor agonist in addition to serotonin receptor agonist.[25] Conversely however, the generalization may be due to serotonergic activities of amphetamine and cathinone.[30]Fenfluramine has been found to fully generalize to quipazine, butlevofenfluramine, in contrast to quipazine, did not generalize to dextroamphetamine.[28][24]
Quipazine is said to differ in its pharmacology and effects from other serotonergicarylpiperazines likeTFMPP andmCPP.[2][4] Relatedly, unlike quipazine, neither TFMPP nor mCPP substitute for DOM in drug discrimination tests.[2][4] In addition, DOM and TFMPP mutually antagonize each others' stimulus effects.[2] In contrast to quipazine, TFMPP and mCPP show prominent bias or preference for the serotonin 5-HT2C receptor over the serotonin 5-HT2A receptor.[4]
^abcdCappelli A, Butini S, Brizzi A, Gemma S, Valenti S, Giuliani G, et al. (2010). "The interactions of the 5-HT3 receptor with quipazine-like arylpiperazine ligands: the journey track at the end of the first decade of the third millennium".Curr Top Med Chem.10 (5):504–526.doi:10.2174/156802610791111560.PMID20166948.
^abRodríguez R, Pardo EG (1971). "Quipazine, a new type of antidepressant agent".Psychopharmacologia.21 (1):89–100.doi:10.1007/BF00404000.PMID5567294.
^abPsychedelic Alpha (20 March 2024)."Notes from the International Society for Research on Psychedelics' 2024 Conference in New Orleans (Guest Contribution)".Psychedelic Alpha. Retrieved10 May 2025.Dr. Jason Younkin, a postdoctoral researcher at Virginia Commonwealth University and adjunct professor at Virginia State University, gave a talk and displayed interesting findings with quipazine analogs during the poster session. Quipazine is a unique psychedelic as its chemical structure includes a piperazine group. While it produces psychedelic effects, it is not used as frequently as other serotonergic psychedelics due to its effects on the gastrointestinal tract via 5-HT3 receptor activation. The goal of this study was to find analogs of quipazine that do not produce these negative side effects or the hallucination-like effects of all classical psychedelics using a battery of molecular and pharmacological techniques. [Photograph]
^abJason Younkin (16 February 2024).Pharmacological characterization of quipazine analogs as a new structural class of psychedelic 5-HT2A receptor agonists. International Society for Research on Psychedelics.
^Winter JC (February 1979). "Quipazine-induced stimulus control in the rat".Psychopharmacology (Berl).60 (3):265–269.doi:10.1007/BF00426666.PMID108704.As yet, no report of the effects of quipazine in human subjects has been published. The implications of the present findings and those of White et al. (1977) for the clinical pharmacology of quipazine are obvious. One would expect the drug to produce at least a portion of the mescaline-LSD syndrome. In a preliminary clinical investigation (H. Daumier, personal communication) normal human subjects reported 'low dose mescaline-like' effects at a dose of 0.5 mg. The study of higher doses was precluded by the onset of dysphoric effects including nausea.
^abButler JJ, Ricci D, Aman C, Beyeler A, De Deurwaerdère P (November 2024). "Classical psychedelics' action on brain monoaminergic systems".Int J Biochem Cell Biol.176 106669.doi:10.1016/j.biocel.2024.106669.PMID39332625.
^Nelson DL (December 1991). "Structure-activity relationships at 5-HT1A receptors: binding profiles and intrinsic activity".Pharmacol Biochem Behav.40 (4):1041–1051.doi:10.1016/0091-3057(91)90124-k.PMID1816558.
^abEgan C, Grinde E, Dupre A, Roth BL, Hake M, Teitler M, et al. (February 2000). "Agonist high and low affinity state ratios predict drug intrinsic activity and a revised ternary complex mechanism at serotonin 5-HT(2A) and 5-HT(2C) receptors".Synapse.35 (2):144–150.doi:10.1002/(SICI)1098-2396(200002)35:2<144::AID-SYN7>3.0.CO;2-K.PMID10611640.
^Cappelli A, Giuliani G, Gallelli A, Valenti S, Anzini M, Mennuni L, et al. (May 2005). "Structure-affinity relationship studies on arylpiperazine derivatives related to quipazine as serotonin transporter ligands. Molecular basis of the selectivity SERT/5HT3 receptor".Bioorg Med Chem.13 (10):3455–3460.doi:10.1016/j.bmc.2005.03.008.PMID15848758.
^Glennon RA (January 1987). "Central serotonin receptors as targets for drug research".J Med Chem.30 (1):1–12.doi:10.1021/jm00384a001.PMID3543362.Table II. Affinities of Selected Phenalkylamines for 5-HT1 and 5-HT2 Binding Sites
^Glennon RA (1996). "Classical Hallucinogens".Pharmacological Aspects of Drug Dependence. Handbook of Experimental Pharmacology. Vol. 118. Berlin, Heidelberg: Springer Berlin Heidelberg. pp. 343–371.doi:10.1007/978-3-642-60963-3_10.ISBN978-3-642-64631-7.
^abGlennon RA (1988). "Site-Selective Serotonin Agonists as Discriminative Stimuli".Transduction Mechanisms of Drug Stimuli. Psychopharmacology Series. Vol. 4. Berlin, Heidelberg: Springer Berlin Heidelberg. pp. 15–31.doi:10.1007/978-3-642-73223-2_2.ISBN978-3-642-73225-6.PMID3293039.
^abcdeNakagawasai O, Arai Y, Satoh SE, Satoh N, Neda M, Hozumi M, et al. (January 2004). "Monoamine oxidase and head-twitch response in mice. Mechanisms of alpha-methylated substrate derivatives".Neurotoxicology.25 (1–2):223–232.Bibcode:2004NeuTx..25..223N.doi:10.1016/S0161-813X(03)00101-3.PMID14697897.
^abcYoung R, Glennon RA (1986). "Discriminative stimulus properties of amphetamine and structurally related phenalkylamines".Med Res Rev.6 (1):99–130.doi:10.1002/med.2610060105.PMID3512936.
^abGlennon RA, Rosecrans JA (1981). "Speculations on the mechanism of action of hallucinogenic indolealkylamines".Neurosci Biobehav Rev.5 (2):197–207.doi:10.1016/0149-7634(81)90002-6.PMID7022271.
^Goudie AJ (September 1985). "Comparative effects of cathinone and amphetamine on fixed-interval operant responding: a rate-dependency analysis".Pharmacol Biochem Behav.23 (3):355–365.doi:10.1016/0091-3057(85)90006-1.PMID4048231.
^abcYang, Yilun."Design and Synthesis of Quipazine Analogs for Programmable Control of Psychedelic Effects".doi:10.7916/0K6K-YC03.To better understand how to potentially regulate these effects, we focused on the design of compounds with programmable psychedelic intensity through fine-tuning the 5-HT2A receptor signaling efficacy. We turned to the source that drives the psychedelic effects of serotonergic psychedelics, the 5-HT2A receptor. By modifying the scaffold of quipazine, we aimed to control the psychedelic intensity by tuning different levels of 5-HT2A signaling efficacy within the quipazine analog series, and thus provide design guidelines for developing desirable pharmacological agents with varying degree of psychedelic effects.{{cite journal}}:Cite journal requires|journal= (help)
^Salas M, Cervantes M, Guzman-Flores C (1966). "Mechanism of action of quipazine maleate on the central nervous system".Bol Inst Estud Med Biol Univ Nac Auton Mex.24 (1):191–205.PMID5299393.
