SRNT is the only international scientific society dedicated to fostering and disseminating research on tobacco and nicotine treatobacco.net logo Society for the Study of Addiction
Search treatobacco.net
* see translation disclaimer below
Some key links


What is cytisine?
¿Qué es la Citisina?
Qu'est-ce que la cytisine?


¿Qué es la Citisina? : ver la versión en español aquí

(versión actualizada estará disponible en breve)

Pour voir la version française choisissez le français dans l'onglet "please select your language" en haut de la page.



Cytisine for smoking cessation



By Natalie Walker, Robert West, Martin Raw, and Jean-Francois Etter


Cytisine is a plant-derived alkaloid that naturally occurs in the Golden Rain (Laburnum anagyroides) and other members of the Leguminosae family. Like varenicline, cytisine is structurally similar to nicotine and acts as a partial agonist at nicotinic acetylcholine receptors (nAChR) (Coe et al. 2005, Webb 1980, Godley 2006), with a high affinity for the alpha-4 beta-2 nAChR subtype (the main receptor that mediates the central reinforcing effects of nicotine via dopamine release in the brain). Like varenicline, cytisine is thought to aid smoking cessation by reducing the severity of withdrawal symptoms (via its agonist actions on nAChRs) and by reducing the reward and satisfaction associated with smoking (via its antagonistic properties) (Tutka & Zatonski 2006). Studies in rats show that the amount of dopamine released following cytisine administration is approximately 40% of that when nicotine is administered (Coe et al. 2005), compared with 40-60% for varenicline (Rollema et al. 2007). 

Availability of cytisine
Since the 1960s cytisine has been available over-the-counter and on prescription as a treatment for smoking dependence in Central and Eastern Europe. More recently cytisine has been sold over the internet. Cytisine is currently manufactured according to European Union Good Manufacturing Practice (GMP) requirements by two companies: Sopharma Ltd, Bulgaria (Trade name: Tabex®) and by Aflofarm Pharma, Poland (Trade name: Desmoxan®). Cytisine is only authorised for use by regulatory authorities in four European Union (EU) countries (Bulgaria, Poland, Latvia, and Lithuania) and 13 non-EU countries (Azerbaijan, Armenia, Belarus, Georgia, Kazakhstan, Kyrgyzstan, Moldova, Russia, Serbia, Tajikistan, Turkmenistan, Uzbekistan, and Ukraine). Increasingly academics and healthcare professionals from around the world have raised concerns about why, given its proven safety and efficacy (see below), there has been a failure to make cytisine available worldwide (Aveyard & West 2013, Prochaska et al. 2013, Stapleton 2013).

Dosing regimen
Cytisine is taken orally in tablet form (1.5 mg cytisine per tablet) as a tapering dose over 25 days: starting with one tablet every two hours in days 1-3 (9 mg/day), tapering to one tablet every six hours in days 21-25 (3 mg/day). Users are advised to reduce the number of cigarettes they smoke over the first five days of treatment, with a recommended quit date on day five. There are no published data to justify this, rather than another, dosing regimen.

Pharmacokinetic (PK) and pharmacodynamic (PD) findings
PK/PD data for cytisine are sparse. The half-life of cytisine is 4.8 hours (Jeong et al. 2015), compared with 17 hours for varenicline (Obach et al. 2006). Cytisine is not metabolised, it is readily absorbed in the gastrointestinal tract, and is excreted by the kidneys (Tutka & Zatonski 2006, Jeong et al. 2015). Published data on the interaction of cytisine with other medications is also limited. In a sample of 17 adults, “no unfavourable interaction with insulin and antidepressants” or neuroleptics was observed (Stoyanov & Yanachkova 1972). Animal studies report an antagonistic effect of cytisine on the anticonvulsive activity of certain antiepileptic drugs (Tutka et al. 2013). The product label for Tabex® indicates that cytisine should not be used with anti-tuberculosis medications, although no reason is provided and no published data are available to support this statement (Tutka & Zatonski 2006). There is evidence from non-human animal studies that cytisine has low penetration into the central nervous system (CNS) (Reavill et al. 1990, Romano et al. 1981), but it’s penetration into the CNS of humans has not been studied. Two PK studies are currently underway in New Zealand to investigate the influence of dose, dosing frequency and dosing duration on the pharmacokinetics and tolerability of cytisine (NCT02585024).

Cytisine is a more effective smoking cessation treatment than placebo
To date, six placebo-controlled trials of cytisine have been published (Paun & Franze 1968, Benndorf et al. 1968 & 1969, Scharfenberg et al. 1971, Schmidt 1974, Dobreva & Danchev 2005, Vinnikov et al. 2008, West et al. 2011). Three of these trials were published in non-English language journals, and were conducted over 40 years ago in East and West Germany prior to the advent of good clinical practice guidelines, therefore raising concerns about the overall quality of the trials. One trial clearly stated that randomisation occurred (Schmidt 1974), two used double-blinding (Benndorf et al. 1968, Schmidt 1974), the trials had different treatment durations (17 to 21 days) and different follow-up periods (from 8 to 24 weeks), the outcome measures were poorly defined, information on loss to follow-up was not consistently presented and biochemical validation of self-reported quitting was not undertaken. Behavioural support was provided in one of the three trials (Paun & Franze 1968). A review article combined the data from the three trials in a meta-analysis and reported a pooled odds ratio (OR) for cessation at 3-8 weeks of 1.93 (95% Confidence Intervals [CI] 1.21 – 3.06) (Etter 2006). The pooled OR for cessation at 3-6 months was 1.83 (95% CI 1.21 – 2.99), based on data from two of the three trials, using a random effects model due to significant heterogeneity. One of the trials had long term follow-up, with an OR of 1.77 (95% CI = 1.29 – 2.43) for cessation at two years (Scharfenberg et al. 1971). 
English translations of these papers can be found at www.stoptabac.ch/cytisine.

The remaining three trials were better designed than the earlier trials. The first trial (n=150) remains unpublished (but is referenced in a review undertaken by SoPharma), and it is unclear whether it was double-blinded or whether quitting was verified (Dobreva & Danchev 2005). After 26 days of treatment, those who received cytisine were more likely to have quit compared with those receiving a placebo (37% versus 3% respectively, p<0.05).  The second trial randomised 171 people, participants were predominately male (97%), and all received two weeks of smoking cessation counselling in the form of written information (Vinnikov et al. 2008). Carbon monoxide (CO)-verified abstinence rates at eight weeks were 10.6% in the cytisine group compared with 5.8% in the control group (p=0.36) and at 26 weeks were 10.6% in the cytisine group compared with 1.2% in the placebo group (p=0.01). A larger (n=740) placebo-controlled trial undertaken in Poland included low level behavioural support, and reported CO-verified abstinence rates at six months of 10% in the cytisine group compared with 3.5% in the placebo group (p<0.001). CO-verified abstinence rates at 12 months were 8.4% in the cytisine group compared with 2.3% in the placebo group (p<0.001). Four systematic reviews have been undertaken incorporating these more recent trials, and all have found cytisine to be superior to placebo for both short- and long-term abstinence (Etter 2006, Hajek et al. 2013, Cahill et al. 2012, McRobbie et al. 2006), with a pooled relative risk [RR] ≥ six months of 3.29 (95% CI 1.84-5.90) based on the two highest quality and most recent (i.e. <30 years old) trials (Hajek et al. 2013).

A randomised trial (n=2,388) is currently underway looking at the effectiveness of cytisine and behavioural support compared to behavioural support alone for smoking cessation in tuberculosis patients. The trial is being undertaken in Bangladesh, Nepal, and Pakistan (clinical trial registration number: ISRCTN43811467).

Cytisine is a more effective smoking cessation treatment than nicotine replacement therapy
One trial has been undertaken comparing cytisine with another form of smoking cessation pharmacotherapy. This pragmatic trial undertaken in New Zealand amongst 1,310 adult daily smokers motivated to quit, used a non-inferiority design to compare cytisine to nicotine replacement therapy (NRT) (Walker et al. 2014). The trial recruited via the national Quitline service and provided all participants with standard Quitline behavioural support, with the NRT provided consisting of a combination of nicotine patches (7, 14 or 21 mg) and/or nicotine gum (2 or 4 mg) or lozenge (1 or 2 mg). At one month post-quit date the self-reported continuous abstinence rate from smoking was 40% in those that received cytisine, compared with 31% in those that received NRT (risk difference 9.32, 95% CI 4.16-14.48). Cytisine was also superior to NRT at one week (continuous abstinence 60% vs 46%, p<0.001), two months (continuous abstinence 31% vs 22%, p<0.001) and six months (continuous abstinence 22% vs 15%, p=0.002). In those who relapsed, time to relapse back to smoking was significantly delayed in the cytisine group compared to NRT, especially in those who were treatment compliant (127 vs 20 days respectively).

It remains unclear how effective cytisine is compared with other smoking cessation treatments
No published trials have compared cytisine with other commonly used smoking cessation medications, such as varenicline, nortriptyline, bupropion, or mono-NRT. However, four trials are currently underway:
  • A non-inferiority trial (n=1,242) of cytisine versus varenicline for smoking cessation is underway in Australia (clinical trial registration number pending).
  • A non-inferiority trial (N=2,140) of cytisine versus varenicline for smoking cessation is underway in New Zealand among indigenous Māori (clinical trial registration number pending).
  • A placebo-controlled, double-blind trial (n=567) of nortriptyline compared with cytisine is underway in Thailand (clinical trial registration number pending).
  • A 4-arm placebo-controlled double-blind trial (n=400) looking at the effectiveness of cytisine, varenicline and NRT on alcohol consumption and smoking cessation in HIV infected, heavy drinking smokers in Russia (NCT02797587).
A systematic review identified a trial (n=620) from 1983 published in a non-English language journal, which compared autogenic training (a relaxation method) with autogenic training plus cytisine (Marakulin et al. 1984). After three weeks of treatment 53% of the 232 receiving the autogenic training alone had quit smoking compared with 70% of the 388 that received the autogenic training plus cytisine (p<0.05).
An English translation of this paper can be found at www.stoptabac.ch/cytisine.

Cytisine is well-tolerated at its therapeutic dose
The toxicity of cytisine depends on dosage. Like nicotine, cytisine is toxic in animals when ingested in large amounts. Preclinical studies have shown an increase in liver transaminases in animals administered 1.35 mg/kg for a period of 90 days (Tutka & Zatonski 2006). There is a single published case report of a 48-year old pharmaceutical specialist who made two unsuccessful suicide attempts by ingesting up to 90 Tabex® tablets (estimated at 135 mg cytisine in total) (Stoyanov & Yanachkova 1972). Symptoms analogous to nicotine intoxication are observed in cytisine overdose and include nausea, vomiting, pupil dilation, tachycardia, general weakness, clonic convulsions, and paralysis of respiration (Musshoff & Madea 2009). 

Trial data indicate that cytisine is well tolerated at its therapeutic dose (1.5–9 mg per day for 25 days), with few adverse events noted compared to a placebo (pooled RR=1.09, 95% CI 0.94-1.26). Reported events are mostly gastrointestinal in nature (pooled RR=1.76, 95% CI 1.28-2.42) (Hajek et al. 2013). In the non-inferiority trial comparing cytisine with NRT, self-reported adverse events were almost twice as common in the cytisine group (288 events in 204 participants) than in the NRT group (174 events in 134 participant; incidence rate ratio 1.67, 95% CI 1.38-2.01, p<0.001).  However, these events were generally non-serious and self-limiting, and were predominantly related to nausea, vomiting and sleep disturbance. The observed adverse events in the cytisine group were similar to those seen in previous placebo-controlled cytisine trials (Etter 2006, Hajek et al. 2013, Cahill et al. 2012, McRobbie et al. 2006), a clinical audit of 436 smokers attending a cessation clinic in Poland (Zatonski et al. 2006), as well as those reported in a periodic safety update report provided to European authorities based on more than seven million exposed persons (West et al. 2001).

Contraindications for cytisine, as listed by the manufacturers, include arterial hypertension, advanced atherosclerosis, and pregnancy/breastfeeding. Caution is also recommended by the manufacturers for smokers who have ischemic heart disease, heart failure, cerebrovascular lesions, obliterating arterial diseases, hyperthyroidism, diabetes, renal/hepatic failure, and peptic ulcers. These cautions appear theoretical and are likely stated due to insufficient clinical experience with cytisine in smokers with these conditions. Some NRT product licences have similar cautions, despite their proven safety over 30 years. 

Cytisine is more affordable than other smoking cessation treatments
A major advantage of cytisine over other pharmacological cessation products on the market is its much lower cost. In Eastern Europe cytisine costs about US$20-$30 for a complete course of 25 days. In comparison, NRT costs about US$112-$685 for a complete course of 8-10 weeks, and varenicline costs about US$474-$501 for a complete course of 12 weeks (Prochaska et al. 2013). Because of cytisine’s potential low cost it is affordable even in low income countries according to the “Effectiveness and Affordability Review and Affordability Calculator” recently developed and published by Robert West and colleagues (West et al. 2015 - also available via treatobacco.net). Other research has shown cytisine to have the lowest cost per quality-adjusted-life-year (QALY) of all smoking cessation medications (estimated for smokers aged 35-54 years at US$162, 95% CI US$106-$363 where US$1=£0.62, or 0.74€) (Stapleton 2013), and modelling suggests cytisine may be more cost-effective than varenicline (Leaviss et al. 2014). Two confirmatory non-inferiority trials looking at the effectiveness and cost-effectiveness of cytisine versus varenicline for smoking cessation are currently underway in Australia (N=1,242) and New Zealand (N=2,140) -  clinical trial registration numbers pending.



References


Aveyard P, West R. Cytisine and the failure to market and regulate for human health.  Thorax. 2013;68:989.

Benndorf S, Kempe G, Scharfenberg G, Wendekamm R, Winkelvoss E. [Results of the smoking-habit breaking using cytisine (Tabex). I]. Dtsch Gesundheitsw. 1968;23:2092-6.

Benndorf S, Scharfenberg G, Kempe G, Wendekamm R, Winkelvoss E. [Smoking withdrawal treatment with Cytisin (Tabex). Results of a semi-annual survey of former smokers after 4 weeks of therapy]. Dtsch Gesundheitsw. 1970;24:774-6.

Benndorf S, Scharfenberg G, Kempe G, Winkelvoss E, Wendekamm R. [Further reports on a double blind trial of the Bulgarian cytisine compound Tabex® on 1214 smokers wishing to quit and practical experience in conducting clinics for such smokers]. Dtsch Gesundheitsw. 1969;24:1135-40.

Cahill K, Stead LF, Lancaster T. Nicotine receptor partial agonists for smoking cessation. Cochrane Database of Systematic Reviews, The Cochrane Library 2012; (2): Art. No.: CD006103.

Coe JW, Brooks PR, Vetelino MG, et al. Varenicline: an alpha4beta2 nicotinic receptor partial agonist for smoking cessation. J Med Chem. 2005;48:3474-7.

Dobreva D, Danchev N. Tabex - Sopharma - natural alternative for smoking cessation and treatment of nicotine dependence. Pharmacia. 2005;52:30-5.

Etter JF. Cytisine for smoking cessation: a literature review and a meta-analysis. Arch Intern Med. 2006;166:1553-9.

Godley E. Introducing Kowhai. Styx report. Christchurch: Landcare Research, 2006.

Hajek P, McRobbie H, Myers K. Efficacy of cytisine in helping smokers to quit: systematic review and meta analysis. Thorax. 2013;68:1037-42.

Jeong SH, Newcombe D, Sheridan J, Tingle M. Pharmacokinetics of cytisine, an α4β2 nicotinic receptor partial agonist, in healthy smokers following a single dose. Drug Test Anal. 2015;7:475-82.

Leaviss J, Sullivan W, Ren S, Everson-Hock E, Stevenson M, Stevens JW, Strong M, Cantrell A. What is the clinical effectiveness and cost-effectiveness of cytisine compared with varenicline for smoking cessation? A systematic review and economic evaluation. Health Tech Assess. 2014;18:1-119.

McRobbie H, Hajek P, Bullen C, Feigen V. Rapid review of non-NHS treatments for smoking cessation. 2006.

Marakulin V, Komarov V, Chuprin V. Treatment of nicotinism. Voen Med Zh. 1984;(1) 55-8.

Musshoff F, Madea B. Fatal cytisine intoxication and analysis of biological samples with LC-MS/MS. Forensic Sci Int. 2009;186:e1-4.

Obach R, Reed-Hagen A, Krueger S, Obach BJ, O'Connell TN, Zandi KS, Miller S, Coe JW. Metabolism and disposition of varenicline, a selective alpha4beta2 acetylcholine receptor partial agonist, in vivo and in vitro. Drug Metab Dispos. 2006;34:121-30.

Paun D, Franze J. [Breaking the smoking habit using cytisine containing "Tabex" tablets]. Dtsch Gesundheitsw. 1968;23:2088-91.

Prochaska J, Das S, Benowitz N. Cytisine, the world's oldest smoking cessation aid. BMJ. 2013;347:f5198.

Reavill C, Walther B, Stolerman I, Testa B. Behavioural and pharmacokinetic studies on nicotine, cytisine and lobeline. Neuropharmacol. 1990;29:619-24.

Rollema H, Chambers L, Coe J, et al. Pharmacological profile of the alpha4beta2 nicotinic acetylcholine receptor partial agonist varenicline, an effective smoking cessation aid. Neuropharmacol. 2007;52:985-94.

Romano C, Goldstein A, Jewell N. Characterization of the receptor mediating the nicotine discriminative stimulus. Psychopharmacol. 1981;74:310-5.

Scharfenberg G, Benndorf S, Kempe G. [Cytisine (Tabex) as a pharmaceutical aid in stopping smoking]. Dtsch Gesundheitsw. 1971;26:463-5.

Schmidt F. [Medical support of nicotine withdrawal. Report on a double blind trial in over 5000 smokers]. MMW Munch Med Wochenschr. 1974;116:557-64.

Stapleton J. The case for licensing cytisine now for smoking cessation is overwelming [letter]. BMJ. 2013;347:f5736.

Stoyanov S, Yanachkova M. Tabex - therapeutic efficacy and tolerance. Savr Med XX111. 1972;6:30-3.

Tutka P, Mróz T, Bednarski J, Styk A, Ognik J, Mosiewicz J, Łuszczki J. Cytisine inhibits the anticonvulsant activity of phenytoin and lamotrigine in mice. Pharmacol Rep. 2013;85:195-200.

Tutka P, Zatonski W. Cytisine for the treatment of nicotine addiction: from a molecule to therapeutic efficacy. Pharmacol Rep. 2006;58:777-98.

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, McRobbie H, Barnes J, Nosa V, Parag V, Bassett B, Bullen C. Cytisine versus nicotine for smoking cessation. New Engl J Med. 2014;371:2353-62.

Webb C. Checklist of dicotyledons naturalised in New Zealand. NZ J Botany. 1980;18:463-72.

West R, Zatonski W, Cedzynska M, Lewandowska D, Pazik J, Aveyard P, Stapleton J. Placebo-controlled trial of cytisine for smoking cessation. New Engl J Med. 2011;365:1193-200.

West R, Raw M, McNeill A, Stead L, Aveyard P, Bitton J, Stapleton J, McRobbie H, Pokhrel S, Lester-George A, Borland R. Healthcare interventions to promote and assist tobacco cessation: a review of efficacy, effectiveness and affordability for use in national guideline development. Addiction. 2015;110:1388-403.

Zatonski W, Cedzynska M, Tutka P, West R. An uncontrolled trial of cytisine (Tabex) for smoking cessation. Tob Control. 2006;15:481-4.


treatobacco.net logo
Home | Sitemap