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Cytisine

Common Name(s): Baptitoxine, Sophorine

Medically reviewed by Drugs.com. Last updated on Mar 1, 2018.

Clinical Overview

Use

Limited clinical data support a place in therapy for cytisine use in smoking cessation.

Dosing

Limited clinical studies are available to guide dosage. In studies of smoking cessation, the suggested dosing regimen was one cytisine dose (tablet or capsule: 1.5 mg; oral strip: 1 mg) every 2 hours initially (6 doses per day), then titrated downward over 25 days to 2 doses per day.

Contraindications

Contraindications for use include pregnancy and breastfeeding, advanced atherosclerosis, and uncontrolled hypertension.

Pregnancy/Lactation

Avoid use. Information regarding use in pregnancy and lactation is lacking.

Interactions

Information is limited. Data are lacking regarding use with other smoking cessation agents; concurrent use should be avoided.

Adverse Reactions

GI disorders (dyspepsia and nausea), headache, increased appetite, dry mouth, nightmares, and irritability have been reported.

Toxicology

Cytisine toxicity is considered to be dose dependent, and reports of fatalities due to respiratory failure following consumption of L. anagyroides plant material exist.

Scientific Family

  • Fabaceae (pea)
  • Leguminosae

Source

Cytisine is an alkaloid that exists naturally in the seeds of plants belonging to the Leguminosae/Fabaceae family, particularly L. anagyroides.Rouden 2014, Stead 2007 L. anagyroides, a small decorative garden tree (also called the Golden Rain Acacia due to its golden yellow flowers), is common in Central and Southern Europe. A synonym for L. anagyroides is Cytisus laburnum.USDA 2018, Rouden 2014

The plant species Ulex europaeus L., Baptisia tinctoria, and Sophora secundiflora contain chemicals previously identified as unique compounds (ulexine, sophorine, baptitoxine) but later determined to be identical to cytisine.Rouden 2014

Cytisine-type alkaloids have also been identified in other plant species, including Maackia amurensis, Sophora tonkinensis, and Ormosia hosiei.Pouny 2014, Rouden 2014

History

Traditional use of Laburnum seeds for their emetic effects, and use of the leaves of L. anagyroides as a tobacco substitute have been documented. By the late 19th century, the chemical structure and synthesis of cytisine was developed. Cytisine has been marketed for use in treatment of tobacco dependence in Central and Eastern Europe since the 1960s. Since the 1990s, a resurgence in interest in cytisine chemistry and potential therapeutic applications has resulted in a rise in the number of published studies evaluating its use; however, clinical trial data are lacking. Products containing cytisine are available in Russia and Poland, in other former Soviet countries, in Canada, and via the internet.Aveyard 2013, Gross 2015, Hajek 2013, Prochaska 2016, Rouden 2014

Chemistry

The chemical structure of cytisine has been described, and methods for identification of the compound have been published.Perez 2012, Rouden 2014

Methods of cytisine extraction from the seeds of L. anagyroides have been elucidated. Cytisine is a partial nicotinic agonist, similar to the FDA-approved drug varenicline.Astroug 2010, Aveyard 2013, Jeong 2015, Jeong 2017, Rouden 2014

Uses and Pharmacology

Appetite suppressant effects

Animal data

A study in rats reported that cytisine-treated animals ate less and gained less weight than the control arm.Grebenstein 2013

Clinical data

Clinical trials evaluating the effect of cytisine on appetite are lacking; however, subjects in an open-label pharmacokinetic study in healthy adults conversely reported increased appetite.Jeong 2017

Cancer

In vitro data

Cytisine induced apoptosis in HepG2 cells via a mitochondrial pathway, suggesting potential chemotherapeutic applications.Yu 2018

CNS effects

Animal and in vitro data

In vitro studies suggest neuronal protective effects of cytisine through mechanisms that involve downregulation of N-methyl-D-aspartate (NMDA) receptors.Li 2013 Limited studies in rodents have reported efficacy in treating induced depression. Treatment with cytisine for 2 weeks relieved symptoms related to unpredictable chronic mild stress.Han 2016 In another study of a mouse model, fluoxetine and cytisine were shown to have synergistic effects on depression, whereas serotonin depletion blocked the antidepressant effects of cytisine.Mineur 2015 A study in rats suggested cytisine attenuated the mental discomfort associated with nicotine withdrawal.Igari 2014 A study in rodents showed cytisine modulates chronic voluntary ethanol consumption, suggesting a possible role in alcohol addiction.Sajja 2013, Sotomajor 2013

Diabetes

Animal data

A study in mice reported efficacy in treatment of type 2 diabetes with a combination preparation containing cytisine with a water-soluble analog of vitamin E (Trolox C).Jin 2014

Smoking cessation

Cytisine as an option in smoking cessation has been the topic of a number of supportive journal articles and editorials.Mulhall 2015, Prochaska 2016, Rigotti 2014, Stapleton 2015, Walker 2016, Zatonski 2015

Animal data

Studies in rodents suggest cytisine is a nicotinic receptor agonist, behaving as both a competitive partial agonist and full agonist, depending on the subunit of attachment. Cytisine appears to have weaker peripheral effects on the cardiovascular system than nicotine.Radchenko 2015, Rouden 2014

Clinical data

Meta-analyses of available clinical trial data have been conducted, with 2 quality clinical studies identifiedVinnikov 2008, West 2011 and up to 9 other clinical studies evaluated.Cahil 2013, Hajek 2013, Leaviss 2014, Samet 2014 No head-to-head trials comparing varenicline with cytisine had been conducted as of January 2013; however, further trials evaluating cytisine have been registered or are in progress.Leaviss 2014, NIH 2018

One quality clinical trial evaluating cytisine versus placebo in middle-age smokers reported no difference in abstinence at 8 weeks, but a significant difference in abstinence at 26 weeks (10.6% for the cytisine group compared to 1.2% with placebo [P=0.01]).Vinnikov 2008 A second quality clinical trial enrolled 740 participants in a single-center, randomized, double-blind, placebo-controlled trial and reported a sustained 12-month abstinence rate of 8.4% in the cytisine group compared with 2.4% in the placebo group (95% confidence interval [CI], 2.7% to 9.2%; P=0.001).West 2011 Pooled results from these 2 clinical trials show a risk ratio for successful cessation of 3.29 (95% CI, 1.84 to 5.9) with cytisine intervention.Hajek 2013, Samet 2014

Another open-label, noninferiority trial randomly assigned 1,310 adult daily smokers to oral cytisine for 25 days or nicotine replacement therapy for 8 weeks. Cytisine was superior to nicotine replacement therapy, with higher continuous abstinence rates at 1 week, 2 months, and 6 months.Walker 2014 This study was noted to have certain methodological limitations.Mulhall 2015

Dosing

Cytisine is available as tablets and capsules (both containing cytisine 1.5 mg), and as oral strips (cytisine 1 mg).Jeong 2017 All 3 doseforms are associated with the same recommended dosing regimen for smoking cessation: One dose every 2 hours (6 doses per day) for days 1 through 3, with the dosing interval increased to every 2.5 hours (5 doses per day) days 4 through 12, to every 4 hours (4 doses per day) days 13 through 16, to every 5 hours (3 doses per day) days 17 through 20, and to every 6 hours (2 doses per day) days 21 through 25. The recommended target "quit day" is day 5.Jeong 2017, West 2011

Pharmacokinetic studies conducted in rabbitsAstroug 2010 and healthy human volunteersJeong 2017 reported rapid but incomplete absorption following oral administration. The half-life is estimated to be about 5 hours.Jeong 2017 A pharmacokinetic study reported cytisine is renally excreted, with no metabolites detected in plasma or urine.Jeong 2015

Pregnancy / Lactation

Information regarding use in pregnancy or lactation is lacking. At 4 to 5 weeks' gestation, nicotinic receptor proteins and gene transcripts for nicotinic receptor subunits exist in the human prenatal brain, making the consequences of cytisine use during pregnancy potentially similar to that of smoking.Hellstrom 2001

Interactions

Theoretically, an interaction with varenicline, also used in smoking cessation, is possible, given that both act at the nicotinic receptor.

Studies in mice demonstrated inhibition of phenytoin and lamotrigine anticonvulsant activity by cytisine,Tutka 2013 as well as that of lacosamide, levetiracetam, and pregabalin.Tutka 2017

Adverse Reactions

Evidence supports the safety of cytisine; long periods of postmarketing surveillance exist in the European Medicines Authority database.Aveyard 2013, Hajek 2013 However, dose-dependent reports of toxicity exist (see Toxicology).

In an open-label pharmacokinetic study in healthy adults, no effects on blood pressure or respiratory rate were observed, and reported adverse effects included increased appetite, dry mouth, dream/nightmares, and irritability.Jeong 2017 Similar findings have been reported in a systematic review of the literature.Leaviss 2014

A Cochrane meta-analysis of 3 clinical trials using cytisine report a lack of significant adverse effects, with GI disorders (dyspepsia and nausea) and headache most commonly reported.Cahill 2013 Similarly, a review that included 8 clinical trials reported more adverse GI effects with cytisine than placebo (relative risk, 1.76; 95% CI, 1.28 to 2.42) but no significant safety concerns.Hajek 2013

Contraindications for use include pregnancy and breastfeeding, severe atherosclerosis, and uncontrolled hypertension.Prochaska 2013

Toxicology

Animal studies have shown that the leaves and seeds of L. anagyroides and related plants are toxic. A lethal dose in horses has been estimated to be 0.5 g/kg of L. anagyroides seedpods.Jeong 2017, Rouden 2014, Simeonova 2010

Cytisine toxicity is considered to be dose dependent, and reports of fatalities due to respiratory failure following consumption of L. anagyroides plant material exist.Jeong 2017, Musshoff 2009

No antidote to cytisine toxicity has been identified, and management is supportive.Rouden 2014

Index Terms

  • Laburnum anagyroides
  • Golden chain acacia
  • Golden rain acacia
  • Kowhai (New Zealand)

References

Astroug H, Simeonov R, Kassabova LV, Danchev N, Svinarov D. Pharmacokinetics of cytisine after single intravenous and oral administration in rabbits. Interdiscip Toxicol. 2010;3(1):15-20.21217866
Aveyard P, West R. Cytisine and the failure to market and regulate for human health. Thorax. 2013;68(11):989.23908130
Cahill K, Stevens S, Perera R, Lancaster T. Pharmacological interventions for smoking cessation: an overview and network meta-analysis. Cochrane Database Syst Rev. 2013;(5):CD009329.23728690
Grebenstein PE, Harp JL, Rowland NE. The effects of noncontingent and self-administered cytisine on body weight and meal patterns in male Sprague-Dawley rats. Pharmacol Biochem Behav. 2013;110:192-200.23876236
Gross N. The COPD Pipeline, XXVI. Chronic Obstr Pulm Dis. 2015;2(1):81-84.28848832
Hajek P, McRobbie H, Myers K. Efficacy of cytisine in helping smokers quit: systematic review and meta-analysis. Thorax. 2013;68(11):1037-1042.23404838
Han J, Wang DS, Liu SB, Zhao MG. Cytisine, a partial agonist of α4β2 nicotinic acetylcholine receptors, reduced unpredictable chronic mild stress-induced depression-like behaviors. Biomol Ther (Seoul). 2016;24(3):291-297.27098858
Hellström-Lindahl E, Seiger A, Kjældgaard A, Nordberg A. Nicotine-induced alterations in the expression of nicotinic receptors in primary cultures from human prenatal brain. Neuroscience. 2001;105(3):527-534.11516820
Igari M, Alexander JC, Ji Y, Qi X, Papke RL, Bruijnzeel AW. Varenicline and cytisine diminish the dysphoric-like state associated with spontaneous nicotine withdrawal in rats. Neuropsychopharmacology. 2014;39(2):455-465.23966067
Jeong SH, Newcombe D, Sheridan J, Tingle M. Pharmacokinetics of cytisine, an α4 β2 nicotinic receptor partial agonist, in healthy smokers following a single dose. Drug Test Anal. 2015;7(6):475-482.25231024
Jeong SH, Sheridan J, Newcombe D, Tingle M. Plasma concentrations of cytisine, a commercially available plant-based alkaloid, in healthy adult smokers taking recommended doses for smoking cessation. Xenobiotica. 2017:1-4.29168931
Jin L, Tu J, Jia J, et al. Drug-repurposing identified the combination of Trolox C and cytisine for the treatment of type 2 diabetes. J Transl Med. 2014;12:153.24885253
Laburnum anagyroides. USDA, NRCS. 2018. The PLANTS Database (http://plants.usda.gov, July 2016). National Plant Data Team, Greensboro, NC 27401-4901 USA. Accessed February 2018. USDA.2018
Leaviss J, Sullivan W, Ren S, et al. What is the clinical effectiveness and cost-effectiveness of cytisine compared with varenicline for smoking cessation? A systematic review and economic evaluation. Health Technol Assess. 2014;18(33):1-120.24831822
Li YJ, Yang Q, Zhang K, et al. Cytisine confers neuronal protection against excitotoxic injury by down-regulating GluN2B-containing NMDA receptors. Neurotoxicology. 2013;34:219-225.23022271
National Institute of Health. Cytisine. ClinicalTrials.gov website. https://clinicaltrials.gov/ct2/results?cond=&term=cytisine&cntry=&state=&city=&dist=. Accessed February 7, 2018.
Mineur Y S, Einstein EB, Bentham MP, et al. Expression of the 5-HT1A serotonin receptor in the hippocampus is required for social stress resilience and the antidepressant-like effects induced by the nicotinic partial agonist cytisine. Neuropsychopharmacology. 2015;40(4):938-946.25288485
Mulhall A, Cole A, Patel S. Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis, cytisine versus nicotine for smoking cessation, and FACED score for non-cystic fibrosis bronchiectasis. Am J Respir Crit Care Med. 2015;192(2):249-251.26177172
Musshoff F, Madea B. Fatal cytisine intoxication and analysis of biological samples with LC-MS/MS. Forensic Sci Int. 2009;186(1-3):e1-4.19217730
Pérez EG, Méndez-Gálvez C, Cassels BK. Cytisine: a natural product lead for the development of drugs acting at nicotinic acetylcholine receptors. Nat Prod Rep. 2012;29(5):555-567.22367109
Pouny I, Batut M, Vendier L, et al. Cytisine-like alkaloids from Ormosia hosiei Hemsl. & E.H. Wilson. Phytochemistry. 2014;107:97-101.25172516
Prochaska JJ, Benowitz NL. The past, present, and future of nicotine addiction therapy. Annu Rev Med. 2016;67:467-486.26332005
Prochaska JJ, Das S, Benowitz NL. Cytisine, the world's oldest smoking cessation aid. BMJ. 2013;347:f5198.23974638
Radchenko EV, Dravolina OA, Bespalov AY. Agonist and antagonist effects of cytisine in vivo. Neuropharmacology. 2015;95:206-214.25839895
Rigotti NA. Cytisine--a tobacco treatment hiding in plain sight. N Engl J Med. 2014;371(25):2429-2430.25517710
Rogers E, Sherman S. ACP Journal Club. Review: cytisine increases smoking abstinence. Ann Intern Med. 2013;159(4):JC11.24026275
Rouden J, Lasne MC, Blanchet J, Baudoux J. (-)-Cytisine and derivatives: synthesis, reactivity, and applications. Chem Rev. 2014;114(1):712-778.24117010
Sajja RK, Rahman S. Cytisine modulates chronic voluntary ethanol consumption and ethanol-induced striatal up-regulation of DeltaFosB in mice. Alcohol. 2013;47(4):299-307.23601929
Samet JM. Cytisine is effective for smoking cessation: should clinicians use it? Evid Based Med. 2014;19(4):134.24550234
Simeonova R, Vitcheva V, Mitcheva M. Effect of cytisine on some brain and hepatic biochemical parameters in spontaneously hypertensive rats. Interdiscip Toxicol. 2010;3(1):21-25.21217867
Sotomayor-Zárate R, Gysling K, Busto UE, Cassels BK, Tampier L, Quintanilla ME. Varenicline and cytisine: two nicotinic acetylcholine receptor ligands reduce ethanol intake in University of Chile bibulous rats. Psychopharmacology (Berl). 2013;227(2):287-298.23344555
Stapleton JA. Cytisine is more effective than nicotine replacement for smoking cessation. Evid Based Med. 2015;20(4):130.25935656
Stead D, O'Brien P. Total synthesis of the lupin alkaloid cytisine: comparison of synthetic strategies and routes. Tetrahedron. 2007;63(9):1885-1897.
Tutka P, Kondrat-Wróbel MW, Zaluska K, Żółkowska D, Florek-Łuszczki M, Łuszczki JJ. Cytisine inhibits the protective activity of various classical and novel antiepileptic drugs against 6 Hz-induced psychomotor seizures in mice. Psychopharmacology (Berl). 2017;234(2):281-291.27778062
Tutka P, Mróz T, Bednarski J, et al. Cytisine inhibits the anticonvulsant activity of phenytoin and lamotrigine in mice. Pharmacol Rep. 2013;65(1):195-200.23563038
Vinnikov D, Brimkulov N, Burjubaeva A. A double-blind, randomised, placebo-controlled trial of cytisine for smoking cessation in medium-dependent workers. J Smok Cessat. 2008;3:57-62.
Walker N, Howe C, Glover M, et al. Cytisine versus nicotine for smoking cessation. N Engl J Med. 2014;371(25):2353-2362.25517706
Walker N, Bullen C, Barnes J, et al. Getting cytisine licensed for use world-wide: a call to action. Addiction. 2016;111(11):1895-1898.27426482
West R, Zatonski W, Cedzynska M, et al. Placebo-controlled trial of cytisine for smoking cessation. N Engl J Med. 2011;365(13):1193-1200.21991893
Yu L, Jiang B, Chen Z, et al. Cytisine induces endoplasmic reticulum stress caused by calcium overload in HepG2 cells. Oncol Rep. 2018;39(3):1475-1484.29328482
Zatoński W, Zatoński M. Cytisine versus nicotine for smoking cessation. N Engl J Med. 2015;372(11):1072.25760363

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