quipazine

The effects and side effects of quipazine in humans have been described. At a dose of 25{{nbsp}}mg orally, they included nausea, flatulence, gastrointestinal discomfort, and diarrhea, with no LSD-like subjective effects.{{cite journal | vauthors = Winter JC | title = The stimulus effects of serotonergic hallucinogens in animals | journal = NIDA Res Monogr | volume = 146 | issue = | pages = 157–182 | date = 1994 | pmid = 8742798 | doi = | url = https://archives.nida.nih.gov/sites/default/files/monograph146.pdf#page=162}} Higher doses were not assessed due to serotonin 5-HT₃ receptor-mediated side effects of nausea and gastrointestinal discomfort. An anecdotal report in one or more subjects, in which the dose of quipazine was said to be 0.5{{nbsp}}mg (sic), described quipazine as producing low-dose mescaline-like effects followed by onset of dysphoria and nausea.{{cite journal | vauthors = Winter JC | title = Quipazine-induced stimulus control in the rat | journal = Psychopharmacology (Berl) | volume = 60 | issue = 3 | pages = 265–269 | date = February 1979 | pmid = 108704 | doi = 10.1007/BF00426666 | url = | quote = 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.}}

It was suggested by Jerrold C. Winter in 1994 that serotonin 5-HT₃ receptor antagonists like ondansetron could allow for use of higher doses of quipazine and assessment of whether it produces clear psychedelic effects or not. Alexander Shulgin subsequently reported in The 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".{{cite book | vauthors = Halberstadt AL, Geyer MA | title = Behavioral Neurobiology of Psychedelic Drugs | chapter = Effect of Hallucinogens on Unconditioned Behavior | series = Current Topics in Behavioral Neurosciences| year = 2016 | volume = 36 | pages = 159–199 | pmid = 28224459 | doi = 10.1007/7854_2016_466 | pmc = 5787039 | isbn = 978-3-662-55878-2 }}{{cite book | vauthors = Shulgin A, Manning T, Daley P | title=The Shulgin Index, Volume One: Psychedelic Phenethylamines and Related Compounds | publisher=Transform Press | location=Berkeley | volume=1 | year=2011 | isbn=978-0-9630096-3-0 | url=https://books.google.com/books?id=68-huAAACAAJ | access-date=2 November 2024 | page=34 | quote=Quipazine [...] (11) This experimental antidepressant is an agonist to several 5-HT2 and 5-HT3 receptors. If taken with a 5-HT3 antagonist, quipazine (blocking nausea/vomiting) it produces a full psychedelic response (Anon., 2007).}}

{{See also|Psychedelic drug#Interactions|Trip killer#Serotonergic psychedelic antidotes}}

Serotonin 5-HT₃ receptor antagonists like ondansetron have been reported to block the nausea and vomiting induced by quipazine. Serotonin 5-HT_2A receptor antagonists like ketanserin have been reported to block the psychedelic-like effects of quipazine in animals.

Quipazine is a serotonin 5-HT₃ receptor agonist and to a lesser extent a serotonin 5-HT_2A, 5-HT_2B, and 5-HT_2C receptor agonist as well as serotonin reuptake inhibitor. It also shows affinity for serotonin 5-HT₁ receptors, including the serotonin 5-HT_1B receptor and to a lesser extent the serotonin 5-HT_1A receptor.{{cite journal | vauthors = Glennon RA | title = Central serotonin receptors as targets for drug research | journal = J Med Chem | volume = 30 | issue = 1 | pages = 1–12 | date = January 1987 | pmid = 3543362 | doi = 10.1021/jm00384a001 | url = | quote = Table II. Affinities of Selected Phenalkylamines for 5-HT1 and 5-HT2 Binding Sites}} Activation of the serotonin 5-HT₃ is implicated in inducing nausea and vomiting as well as anxiety, which has limited the potential clinical usefulness of quipazine.

Quipazine produces a head-twitch response and other psychedelic-consistent effects in animal studies including in mice, rats, and monkeys.{{cite book | vauthors = Glennon RA | title=Pharmacological Aspects of Drug Dependence | chapter=Classical Hallucinogens | series=Handbook of Experimental Pharmacology | publisher=Springer Berlin Heidelberg | publication-place=Berlin, Heidelberg | volume=118 | date=1996 | isbn=978-3-642-64631-7 | doi=10.1007/978-3-642-60963-3_10 | pages=343–371}}{{cite journal | vauthors = Nakagawasai O, Arai Y, Satoh SE, Satoh N, Neda M, Hozumi M, Oka R, Hiraga H, Tadano T | title = Monoamine oxidase and head-twitch response in mice. Mechanisms of alpha-methylated substrate derivatives | journal = Neurotoxicology | volume = 25 | issue = 1–2 | pages = 223–232 | date = January 2004 | pmid = 14697897 | doi = 10.1016/S0161-813X(03)00101-3 | bibcode = 2004NeuTx..25..223N | url = }} These effects appear to be mediated by activation of the serotonin 5-HT_2A receptor, as they are blocked by serotonin 5-HT_2A receptor antagonists like ketanserin. The head twitches induced by quipazine are potentiated by the monoamine oxidase inhibitor (MAOI) pargyline.{{cite journal | vauthors = Malick JB, Doren E, Barnett A | title = Quipazine-induced head-twitch in mice | journal = Pharmacol Biochem Behav | volume = 6 | issue = 3 | pages = 325–329 | date = March 1977 | pmid = 140381 | doi = 10.1016/0091-3057(77)90032-6 | url = }} Based on this, it has been suggested that quipazine may act as a serotonin releasing agent and that it may induce the head twitch response by a dual action of serotonin 5-HT_2A receptor agonism and induction of serotonin release.

Besides the head-twitch response, quipazine fully substitutes for LSD and partially substitutes for mescaline in rodent drug discrimination tests. In addition, quipazine substitutes for DOM in rodents and monkeys and this is blocked by serotonin 5-HT_2A receptor antagonists like pizotyline and ketanserin. When quipazine is used as the training drug, LSD, mescaline, and psilocybin all fully substitute for quipazine. In monkeys, quipazine additionally produced LSD-like behavioral changes along with projectile vomiting. In contrast to primates, rodents generally lack an emetic response, and hence the nausea and vomiting that quipazine can induce may not be a limiting factor in this order of animals. Similarly to DOI, quipazine alters time perception in rodents.{{cite journal | vauthors = Akhmirov R, Mitiureva D, Zaichenko M, Smirnov K, Sysoeva O | title = The Role of the Serotonergic System in Time Perception: A Systematic Review | journal = Int J Mol Sci | volume = 25 | issue = 24 | date = December 2024 | page = 13305 | pmid = 39769070 | pmc = 11679555 | doi = 10.3390/ijms252413305 | doi-access = free | url = }}

Quipazine can produce tachycardia, including positive chronotropic and positive inotropic effects, through activation of the serotonin 5-HT₃ receptor.

Although quipazine does not generalize to dextroamphetamine in drug discrimination tests of dextroamphetamine-trained rodents, dextroamphetamine and cathinone have been found to partially generalize to quipazine in assays of quipazine-trained rodents.{{cite journal | vauthors = Young R, Glennon RA | title = Discriminative stimulus properties of amphetamine and structurally related phenalkylamines | journal = Med Res Rev | volume = 6 | issue = 1 | pages = 99–130 | date = 1986 | pmid = 3512936 | doi = 10.1002/med.2610060105 | url = }}{{cite journal | vauthors = Glennon RA, Rosecrans JA | title = Speculations on the mechanism of action of hallucinogenic indolealkylamines | journal = Neurosci Biobehav Rev | volume = 5 | issue = 2 | pages = 197–207 | date = 1981 | pmid = 7022271 | doi = 10.1016/0149-7634(81)90002-6 | url = }} In relation to this, it has been suggested that quipazine might possess some dopaminergic activity, as the discriminative stimulus properties of amphetamine appear to be mediated by dopamine signaling. Relatedly, quipazine has been said to act as a dopamine receptor agonist in addition to serotonin receptor agonist. Conversely however, the generalization may be due to serotonergic activities of amphetamine and cathinone.{{cite journal | vauthors = Goudie AJ | title = Comparative effects of cathinone and amphetamine on fixed-interval operant responding: a rate-dependency analysis | journal = Pharmacol Biochem Behav | volume = 23 | issue = 3 | pages = 355–365 | date = September 1985 | pmid = 4048231 | doi = 10.1016/0091-3057(85)90006-1 | url = }} Fenfluramine has been found to fully generalize to quipazine, but levofenfluramine, in contrast to quipazine, did not generalize to dextroamphetamine.{{cite book | vauthors = Glennon RA | title=Transduction Mechanisms of Drug Stimuli | chapter=Site-Selective Serotonin Agonists as Discriminative Stimuli | series = Psychopharmacology Series | publisher=Springer Berlin Heidelberg | publication-place=Berlin, Heidelberg | date=1988 | volume=4 | isbn=978-3-642-73225-6 | doi=10.1007/978-3-642-73223-2_2 | pages=15–31| pmid=3293039 }}

Quipazine is said to differ in its pharmacology and effects from other serotonergic arylpiperazines like TFMPP and mCPP. Relatedly, unlike quipazine, neither TFMPP nor mCPP substitute for DOM in drug discrimination tests. In addition, DOM and TFMPP mutually antagonize each others' stimulus effects. In contrast to quipazine, TFMPP and mCPP show prominent bias or preference for the serotonin 5-HT_2C receptor over the serotonin 5-HT_2A receptor.

Quipazine is a very weak agonist of the human trace amine-associated receptor 1 (TAAR1).{{cite journal | vauthors = Zilberg G, Parpounas AK, Warren AL, Yang S, Wacker D | title = Molecular basis of human trace amine-associated receptor 1 activation | journal = Nat Commun | volume = 15 | issue = 1 | pages = 108 | date = January 2024 | pmid = 38168118 | pmc = 10762035 | doi = 10.1038/s41467-023-44601-4 | bibcode = 2024NatCo..15..108Z | url = }}

Quipazine is a substituted piperazine and quinoline. It is structurally related to 6-nitroquipazine, isoquipazine, 1-(2-naphthyl)piperazine (2-NP), and 1-(1-naphthyl)piperazine (1-NP).

Novel analogues of quipazine with retained serotonin 5-HT_2A receptor agonism and reduced undesirable off-target activity such as serotonin 5-HT₃ receptor agonism and associated adverse effects have been developed and characterized.{{cite web | author=Psychedelic Alpha | title=Notes from the International Society for Research on Psychedelics' 2024 Conference in New Orleans (Guest Contribution) | website=Psychedelic Alpha | date=20 March 2024 | url=https://psychedelicalpha.com/news/notes-from-the-international-society-for-research-on-psychedelics-2024-conference-in-new-orleans-guest-contribution | access-date=10 May 2025 | quote = 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]}}{{cite conference | author = Jason Younkin | title = Pharmacological characterization of quipazine analogs as a new structural class of psychedelic 5-HT2A receptor agonists | conference = International Society for Research on Psychedelics | date = 16 February 2024 | url = }}

File:Quipazine synthesis.svg

Quipazine is synthesized by reacting 2-chloroquinoline with piperazine.

Quipazine was first described in the scientific literature by 1966.{{cite journal | vauthors = Salas M, Cervantes M, Guzman-Flores C | title = Mechanism of action of quipazine maleate on the central nervous system | journal = Bol Inst Estud Med Biol Univ Nac Auton Mex | volume = 24 | issue = 1 | pages = 191–205 | date = 1966 | pmid = 5299393 | doi = | url = }} It was described as an antidepressant-like agent by 1971.{{cite journal | vauthors = Rodríguez R, Pardo EG | title = Quipazine, a new type of antidepressant agent | journal = Psychopharmacologia | volume = 21 | issue = 1 | pages = 89–100 | date = 1971 | pmid = 5567294 | doi = 10.1007/BF00404000 | url = }} The psychedelic-like effects of quipazine in animals were first described by 1977.{{cite journal | vauthors = Malick JB, Doren E, Barnett A | title = Quipazine-induced head-twitch in mice | journal = Pharmacol Biochem Behav | volume = 6 | issue = 3 | pages = 325–329 | date = March 1977 | pmid = 140381 | doi = 10.1016/0091-3057(77)90032-6 | url = }}

• 2C-B-PP
• FPPQ
• ORG-37684

{{Reflist}}

• [https://psychedelicreview.com/quipazine-a-long-standing-enigma-in-psychedelic-research/ Quipazine: A Long-Standing Enigma in Psychedelic Research - Mario de la Fuente Revenga - Psychedelic Science Review (PSR)]
• [https://psychedelicreview.com/the-serotonin-5-ht2a-receptor-from-mice-to-humans/ The Serotonin 5-HT2A Receptor: From Mice to Humans - Ian Liddle - Psychedelic Science Review (PSR)]

{{Psychedelics}}

{{Serotonin receptor modulators}}

{{Monoamine reuptake inhibitors}}

{{Arylpiperazines}}

{{Chemical classes of psychoactive drugs}}

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Category:Psychedelic arylpiperazines

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