Buspirone, sold under the nameBuspar among others, is ananxiolytic medication primarily used for the treatment ofgeneralized anxiety disorder. Unlikebenzodiazepines, buspirone does not produce significantsedation,dependence, orwithdrawal effects. Its principalmechanism of action involvespartial agonism at postsynaptic serotonin5-HT1A receptor andfull agonism at presynaptic 5-HT1Aautoreceptors, which initially reduces serotonergic neuron firing. Over time, autoreceptor desensitization occurs, leading to increased serotonin release and enhanced serotonergic tone, which may contribute to its clinical efficacy. Buspirone also has weak antagonistic effects at dopamine D2, D3, and D4 receptors and α1- and α2-adrenergic receptors.
Buspirone is approved for the management of generalized anxiety disorder. It is sometimes used off-label for other anxiety disorders, depression augmentation, and certain behavioral conditions. Buspirone is not effective as a sedative-hypnotic or muscle relaxant and does not have anticonvulsant properties.
Buspirone was developed in 1968 and approved for medical use in the United States in 1986.[13][16] It is available as ageneric medication.[14] In 2023, it was the 40th most commonly prescribed medication in the United States, with more than 15million prescriptions.[17][18]
Buspirone has no immediateanxiolytic effects, and hence has a delayedonset of action; its full clinical effectiveness may require 2–4 weeks to manifest itself.[24] The drug is effective in the treatment ofgeneralized anxiety disorder (GAD) similar to benzodiazepines includingdiazepam, alprazolam,lorazepam, andclorazepate.[6] Buspirone is not known to be effective in the treatment of anxiety disorders other than GAD.[25]
SSRI andSNRI antidepressants such asparoxetine andvenlafaxine, respectively, may cause jaw pain/jaw spasm reversible syndrome, although it is not common, and buspirone appears to be successful in treating antidepressant-inducedbruxism.[30][31]
Buspirone appears to be relatively benign in cases of single-drugoverdose, although no definitive data on this subject appear to be available.[34] In oneclinical trial, buspirone was administered to healthy male volunteers at a dosage of 375 mg/day, and produced side effects includingnausea,vomiting,dizziness,drowsiness,miosis, andgastric distress.[19][20][22] In early clinical trials, buspirone was given at dosages even as high as 2,400 mg/day, withakathisia,tremor, andmuscle rigidity observed.[35] Deliberate overdoses with 250 mg and up to 300 mg buspirone have resulted in drowsiness in about 50% of individuals.[35] One death has been reported in a co-ingestion of 450 mg buspirone withalprazolam,diltiazem,alcohol, andcocaine.[35]
Fluvoxamine: Moderately increased plasma levels of buspirone.[37]
Elevated blood pressure has been reported when buspirone has been administered to patients taking monoamine oxidase inhibitors (MAOIs).[32]
Buspirone has been found to markedly reduce thehallucinogenic effects of theserotonergic psychedelicpsilocybin in humans.[38][39][40] This parallels findings in which serotonin 5-HT1A receptor agonists like8-OH-DPAT attenuate thehead-twitch response, a behavioral proxy of psychedelic effects, induced by serotonergic psychedelics in rodents.[41] Paradoxically however, buspirone enhances the head-twitch response, a behavioral proxy of psychedelic effects, induced by5-hydroxytryptophan (5-HTP) pluspargyline in rodents.[42][43]
Values are Ki (nM). The smaller the value, the more strongly the drug binds to the site.
Buspirone acts primarily on the serotonin 5-HT1A receptor. It behaves as a full agonist at presynaptic 5-HT1A autoreceptors in the dorsal raphe, reducing the firing of serotonin-producing neurons, and as a partial agonist at postsynaptic 5-HT1A receptors in forebrain regions. This difference in activity between presynaptic and postsynaptic sites is thought to result from variations in receptor density and coupling efficiency.[55][56][57][58][59][60]
Buspirone also has lower affinity for other serotonin receptors, including 5-HT2A, 5-HT2B, 5-HT2C, 5-HT6, and 5-HT7, where it is thought to act primarily as an antagonist.[61] In addition, buspirone has weak antagonistic activity at dopamine D2, D3, and D4 receptors, with preferential blockade of presynaptic D2 autoreceptors at low doses and postsynaptic D2 receptors only at higher doses.[62]
A major metabolite of buspirone, 1-(2-pyrimidinyl)piperazine (1-PP), circulates at higher levels than buspirone itself and is a potent α_2-adrenergic receptor antagonist, which may contribute to some of buspirone's noradrenergic and dopaminergic effects.[63][64][65] Buspirone has very weak affinity for α_1-adrenergic receptors, and does not interact with the GABA_A receptor complex, unlike benzodiazepines.[66][67]
Buspirone has a loworalbioavailability of 3.9% relative tointravenous injection due to extensivefirst-pass metabolism.[6] Thetime to peak plasma levels following ingestion is 0.9 to 1.5 hours.[6] It is reported to have anelimination half-life of 2.8 hours,[6] although a review of 14 studies found that the mean terminal half-life ranged between 2 and 11 hours, and one study even reported a terminal half-life of 33 hours.[8] Buspirone ismetabolized primarily byCYP3A4, and prominentdrug interactions withinhibitors andinducers of thisenzyme have been observed.[11][12] Majormetabolites of buspirone include 5-hydroxybuspirone, 6-hydroxybuspirone, 8-hydroxybuspirone, and 1-PP.[68][8][9][10] 6-Hydroxybuspirone has been identified as the predominanthepatic metabolite of buspirone, with plasma levels that are 40-fold greater than those of buspirone after oral administration of buspirone to humans.[9] The metabolite is a high-affinity partial agonist of the 5-HT1A receptor (Ki=25 nM) similarly to buspirone, and has demonstrated occupancy of the 5-HT1A receptorin vivo.[9] As such, it is likely to play an important role in the therapeutic effects of buspirone.[9] 1-PP has also been found to circulate at higher levels than those of buspirone itself and may similarly play a significant role in the clinical effects of buspirone.[69][70]
A number of methods of synthesis have also been reported.[76][77][78] One method begins withalkylation of 1-(2-pyrimidyl)piperazine (1) with 3-chloro-1-cyanopropane (4-chlorobutyronitrile) (2) to give (3). Next, reduction of the nitrile group is performed either bycatalytic hydrogenation or withlithium aluminium hydride (LAH) giving (4). The primary amine is then reacted with 3,3-tetramethyleneglutaric anhydride (5) in order to yield buspirone (6).[79][80][81][82][83]
Buspirone was firstsynthesized by a team atMead Johnson in 1968[25] but was not patented until 1980.[84][79][85] It was initially developed as anantipsychotic acting on the D2 receptor but was found to be ineffective in the treatment ofpsychosis; it was then used as an anxiolytic.[6] In 1986,Bristol-Myers Squibb gained FDA approval for buspirone in the treatment of GAD.[25][86] Thepatent expired in 2001, and buspirone is available as ageneric drug.
Buspirone is theINNTooltip International Nonproprietary Name,BANTooltip British Approved Name,DCFTooltip Dénomination Commune Française, andDCITTooltip Denominazione Comune Italiana of buspirone, while buspirone hydrochloride is itsUSANTooltip United States Adopted Name,BANMTooltip British Approved Name, andJANTooltip Japanese Accepted Name.[1][87][88][89]
Buspirone was primarily sold under the brand name Buspar.[87][89] Buspar is currently listed as discontinued by the U.S.Food and Drug Administration (FDA).[90] In 2010, in response to a citizen petition, the FDA determined that Buspar was not withdrawn from sale for reasons of safety or effectiveness.[91]
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^abWong H, Dockens RC, Pajor L, Yeola S, Grace JE, Stark AD, et al. (August 2007). "6-Hydroxybuspirone is a major active metabolite of buspirone: assessment of pharmacokinetics and 5-hydroxytryptamine1A receptor occupancy in rats".Drug Metabolism and Disposition.35 (8):1387–1392.doi:10.1124/dmd.107.015768.PMID17494642.S2CID25558546.
^abcdZhu M, Zhao W, Jimenez H, Zhang D, Yeola S, Dai R, et al. (April 2005). "Cytochrome P450 3A-mediated metabolism of buspirone in human liver microsomes".Drug Metabolism and Disposition.33 (4):500–507.doi:10.1124/dmd.104.000836.PMID15640381.S2CID10142905.
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^Trinchieri M, Trinchieri M, Perletti G, Magri V, Stamatiou K, Cai T, et al. (August 2021). "Erectile and Ejaculatory Dysfunction Associated with Use of Psychotropic Drugs: A Systematic Review".The Journal of Sexual Medicine.18 (8):1354–1363.doi:10.1016/j.jsxm.2021.05.016.PMID34247952.S2CID235798526.Buspirone, a non-benzodiazepine anxiolytic, have even demonstrated enhancement of sexual function in certain individuals. For this reason, they have been proposed as augmentation agents (antidotes) or substitution agents in patients with emerging sexual dysfunction after treatment with antidepressants.
^Sontheimer DL, Ables AZ (March 2001). "Is imipramine or buspirone treatment effective in patients wishing to discontinue long-term benzodiazepine use?".The Journal of Family Practice.50 (3): 203.PMID11252203.
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^Lilja JJ, Kivistö KT, Backman JT, Lamberg TS, Neuvonen PJ (December 1998). "Grapefruit juice substantially increases plasma concentrations of buspirone".Clinical Pharmacology and Therapeutics.64 (6):655–660.doi:10.1016/S0009-9236(98)90056-X.PMID9871430.S2CID22009095.
^Lamberg TS, Kivistö KT, Laitila J, Mårtensson K, Neuvonen PJ (1998). "The effect of fluvoxamine on the pharmacokinetics and pharmacodynamics of buspirone".European Journal of Clinical Pharmacology.54 (9–10):761–766.doi:10.1007/s002280050548.PMID9923581.S2CID21939719.
^Brandt SD, Kavanagh PV, Twamley B, Westphal F, Elliott SP, Wallach J, et al. (February 2018)."Return of the lysergamides. Part IV: Analytical and pharmacological characterization of lysergic acid morpholide (LSM-775)".Drug Test Anal.10 (2):310–322.doi:10.1002/dta.2222.PMC6230476.PMID28585392.Additionally, pretreatment with the 5‐HT1A agonist buspirone (20 mg p.o.) markedly attenuates the visual effects of psilocybin in human volunteers.59 Although buspirone failed to completely block the hallucinogenic effects of psilocybin, the limited inhibition is not necessarily surprising because buspirone is a low efficacy 5‐HT1A partial agonist.60 The level of 5‐HT1A activation produced by buspirone may not be sufficient to completely counteract the stimulation of 5‐HT2A receptors by psilocin (the active metabolite of psilocybin). Another consideration is that psilocin acts as a 5‐HT1A agonist.30 If 5‐HT1A activation by psilocin buffers its hallucinogenic effects similar to DMT58 then competition between psilocin and a weaker partial agonist such as buspirone would limit attenuation of the hallucinogenic response.
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