Cytisine for Smoking Cessation a Literature Review and a Meta-Analysis

REVIEW ARTICLE Cytisine for Smoking Cessation A Literature Review and a Meta-analysis

Jean-Franc¸ois Etter, PhD, MPH

Background: Cytisine is an agonist of nicotinic recep- sine. All studies were published between 1967 and 2005 ␣ ␤ tors; in particular, it binds strongly with 4 2 nicotinic in Bulgaria, Germany, Poland, and Russia. There were receptors. Cytisine has been used to treat tobacco de- 4404 smokers treated with cytisine and 3518 in control pendence for 40 years in Eastern Europe. The objective conditions. The pooled odds ratio after 3 to 8 weeks in of this study was to review the literature on the effect of the 3 placebo-controlled trials (2 were double blind and cytisine on smoking cessation. 1 was randomized) was 1.93 (95% confidence interval, 1.21-3.06). For the 2 placebo-controlled double-blind Methods: Review of PubMed, EMBASE, Psychological Ab- trials with a longer follow-up, the pooled odds ratio af- stracts, BIOSIS, Google.com, and Scholar.google.com, us- ter 3 to 6 months was 1.83 (95% confidence interval, 1.12- ing the keywords cytisine, cytisin, zytisin, cytisinum, Ta- 2.99). One placebo-controlled double-blind trial had fol- bex, and smoking cessation. Experts and the manufacturer low-up after 2 years (odds ratio, 1.77; 95% confidence of Tabex were contacted. Placebo-controlled trials were interval, 1.29-2.43). Some adverse effects were re- included in a meta-analysis. ported. Most trials were, however, of poor quality. Results: Ten studies reported the effects of cytisine on smoking cessation, including 4 controlled studies (3 pla- Conclusions: Cytisine may be effective for smoking ces- cebo controlled). Nine studies used the Bulgarian drug sation. This fact remained largely unnoticed in the English- Tabex, containing 1.5 mg of cytisine per tablet, and one language literature. Russian study used buccal films containing either 1.5 mg of cytisine or 0.75 mg of cytisine plus 0.75 mg of anaba- Arch Intern Med. 2006;166:1553-1559

OBACCO SMOKING IS THE receptors; in particular, cytisine has a high ␣ ␤ 8-10 first avoidable cause of affinity for 4 2 nicotinic receptors. In deaths and morbidity in 1978, the tobacco industry identified cyti- developed countries,1 yet sine as the substance with the pharmaco- available treatments for logical action closest to that of nico- tobacco dependence are not very effec- tine.11,12 Because of its affinity to nicotinic T2 tive. Thus, new treatments are war- receptors and its pharmacological similari- ranted. During World War II, the leaves ties to nicotine, cytisine is being used as a of Cytisus laburnum (golden rain tree) starting material for the development of new were used by smokers as a tobacco sub- drugs,7 and it is covered by several patents stitute.3 A 1955 publication4 advised for its medical use.13 smoking C laburnum or Ulex europaeus, which both contain cytisine, as a treat- See also pages 1547, ment for tobacco dependence. Cytisine (not to be confused with cytosine) is an 1561, and 1571 alkaloid found in all parts of C laburnum, Despite the known affinity of cytisine particularly in its seeds. Like nicotine, for nicotinic receptors and despite the cytisine is a natural insecticide.5 It has fact that cytisine has been used for been used for decades as a smoking cessation drug in Eastern European coun- decades as a smoking cessation drug, the tries.3,6 It is marketed for this purpose by clinical studies of cytisine are almost a Bulgarian firm under the name of never cited in the English-language lit- Tabex (information available at: http://www erature. In particular, cytisine is absent .tabex.net). Varenicline, a new and effec- from recent reviews2,14,15 of smoking ces- Author Affiliation: Institute of tive smoking cessation drug, was derived sation drugs. This study reviews the lit- 7 Social and Preventive Medicine, from cytisine. Cytisine has a molecular erature on the efficacy of cytisine for University of Geneva, Geneva, structure similar to that of nicotine and ace- smoking cessation and conducts a meta- Switzerland. tylcholine and it is an agonist of nicotinic analysis of placebo-controlled trials.

(REPRINTED) ARCH INTERN MED/ VOL 166, AUG 14/28, 2006 WWW.ARCHINTERNMED.COM 1553

Downloaded From: https://jamanetwork.com/ on 09/25/2021 Table 1. Effect of Cytisine on Smoking Cessation, From Studies Without a Control Group*

No. of Patients

Study Type of Behavior Duration of At At Who Were Quit No. Source Country Patients Support Drug Follow-up Treatment Baseline Follow-up Abstinent Rate, % 1 Granatowicz,30 Poland Smoking 573 (29%) Tabex 6 mo 27 d 1968 NA 1378 70.0 1976 cessation received (based clinic other drugs on 70%) 2 Kempe,21 1967 Bulgaria Addicted, men NA Tabex 1 mo 17 d 30 NA 19 63.3 6 mo 12 40.0 3 Maliszewski and Poland 12 Men and 2 NA Tabex 40 d 25 d 14 NA 7 50.0 Straczynski,31 women 1972 4 Metelitsa,18 Russia Inpatients NA Films 15 d 15 d 41 NA 23 56.1 1987 (sample A) Russia Outpatients, NA Films 15 d 15 d 21 NA 6 28.6 (sample B) healthy Russia Hospital patients NA Films 6-14 mo 6-14 mo 18 NA 5 27.8 (sample C) Russia Healthy plus NA Films 6 mo 15 d 201 NA 100 49.8 (sample D) psychiatric Ostrovskaia,19,20 Russia Inpatients plus NA Films 6-14 mo 15 d 62 NA 23 37.1 1994 (samples A outpatients and B) 5 Paun and East Germany Group therapy Weekly group Tabex 8 wk 17 d 130 NA 83 63.8 Franze,22 (group F) patients sessions 1968 East Germany Patients with Group Tabex 8 wk 17 d 100 NA 36 36.0 (group P1) severe sessions dependence for weeks East Germany Group therapy Group Tabex 8 wk 17 d 100 NA 68 68.0 (group P2) patients sessions East Germany Group therapy Group Tabex 26 wk 17 d 130 108 51 39.2 (group F) patients sessions East Germany Group therapy Group Tabex 26 wk 17 d 100 NA 21 21.0 (group P1) patients sessions East Germany Group therapy Group Tabex 26 wk 17 d 100 81 35 35.0 (group P2) patients sessions 6 Stoyanov and Bulgaria Healthy plus NA Tabex NA 20 d 70 NA 39 55.7 Yanachkova,32 (sample A) psychiatric 1972 Bulgaria Psychiatric NA Tabex “A short 20 d 17 NA 5 29.4 (sample B) patients period of time” 7 Zatonski et al,16 Poland Patients from Visits to clinic Tabex 3 mo 25 d 436 342 120 27.5 2005 the smoking 12 mo 110 60 13.8 cessation clinic

Abbreviation: NA, data not available. *Available at: http://www.stop-tabac.ch/cytisine.

METHODS reference lists of the retrieved articles were ing as the denominator the total number consulted. Professional translators pro- of participants included at the start of vided English-language translations of all the trial, and participants absent at fol- SEARCH AND SELECTION relevant articles in Bulgarian, German, Pol- low-up were counted as smokers (in- OF STUDIES ish, and Russian. The original articles and tention-to-treat analysis), when these their translations are available at http: data were available. The smoking absti- All studies of the effect of cytisine on smok- //www.stop-tabac.ch/cytisine. Placebo- nence rates reported by the original au- ing cessation were searched, in any lan- controlled trials were included in a meta- thors were used, even though most of guage. PubMed, EMBASE, Psychological analysis. the time, no precise definition of smok- Abstracts, BIOSIS, Google.com, and ing abstinence was provided. Only 1 Scholar.google.com were reviewed, us- trial16 reported that biochemical verifi- ing the keywords cytisine, cytisin, zyti- DATA ABSTRACTION cation of smoking abstinence took place. sin, cytisinum, Tabex, and smoking cessation. The manufacturer of Tabex Because, to my knowledge, this is the (Sopharma, Sofia, Bulgaria) was con- first review on this topic, results of all META-ANALYSIS tacted and provided scientific articles and the retrieved studies are reported, con- reports on Tabex in several languages. To- trolled and uncontrolled, even though Results of the placebo-controlled trials bacco dependence specialists in Bul- uncontrolled studies have less scien- were included in a meta-analysis. The I2 garia, the Czech Republic, Germany, Po- tific value. No study was rejected. Smok- statistic was used to assess heterogene- land, and Russia were contacted, and the ing abstinence rates were calculated us- ity; this statistic describes the percent-

(REPRINTED) ARCH INTERN MED/ VOL 166, AUG 14/28, 2006 WWW.ARCHINTERNMED.COM 1554

Downloaded From: https://jamanetwork.com/ on 09/25/2021 age of variability due to true heterogene- treatment of depression, and posi- days, and 28.6% quit smoking at the ity rather than error or chance.17 Because tive results have been reported.33 end of treatment. Third, 18 healthy there was heterogeneity, a random- smokers were treated for 6 to 14 effects model was used to estimate the CONTROL GROUPS months, and 5 (27.8%) remained ab- pooled weighted average of odds ratios stinent at the end of the study (re- (ORs) using computer software (Re- There were 7 uncontrolled stud- sults by group were not given). view Manager, version 4.2; The Nordic 16,18-22,30-32 22-29 Cochrane Centre, The Cochrane Col- ies and4controlledstudies Fourth, a sample of 201 smokers, in- laboration, Copenhagen, Denmark). of cytisine for smoking cessation (1 cluding some psychiatric patients, study22 includedcontrolledanduncon- were treated with these films and fol- trolled samples). One Russian study lowed up after 6 months. An “abso- RESULTS compared films containing cytisine lute effect” (ie, smoking absti- with films containing anabasine, but nence) was obtained in 50.0% of STUDY CHARACTERISTICS did not report results separately for patients.18 Two more articles19,20 re- these 2 drugs.18-20 Three controlled ported on the same first 2 samples Tenstudieswerefound,reportedin16 studies22-28 comparedTabexwithapla- of 62 smokers, providing more de- articles,16,18-32 that tested the effect of cebo, and 1 controlled study29 com- tails and a longer follow-up. These cytisineonsmokingcessationin17dif- pared Tabex plus autogenic training 2 articles indicated the number of ferentsamplesofsmokers.TheBulgar- with autogenic training alone. Only 2 subjects receiving each type of film: ian drug Tabex was used in 9 of these of the 3 placebo-controlled studies24,28 1.5 mg of cytisine (n=23), 0.75 mg studies. Each tablet of Tabex contains reportedthatthetrialwasdoubleblind, of cytisine plus 0.75 mg of anaba- 1.5 mg of cytisine. These tablets are and only 1 included a clear indication sine (n=16), or 1.5 mg of anaba- swallowed, and the manufacturer rec- that randomization took place.28 sine (n=23). In these 2 articles, these ommendsusing6tabletsperday(total, Authors of the other double-blind trial 62 people were followed up for 6 to 9 mg of cytisine) during the first 3 days reportedthat“subjectsreceivedanum- 14 months, when 6 (21%) of the 29 after smoking cessation, then decreas- bered pouch with 100 Tabex or pla- short-term quitters had relapsed, ingthedosagegraduallydownto2tab- cebotablets,”24(p2093) fromwhichwecan leaving a 37.1% abstinence rate (23/ lets per day until the 25th day, when presume,butnotdefinitivelyconclude, 62) at 6 to 14 months. None of these the treatment is stopped. All studies thatsubjectswererandomized.The lat- articles indicated whether smokers ofTabexmoreorlessfollowedthisregi- ter study was reported in 4 different were randomly assigned to receiv- men, although some used a shorter articles.24-27 In one double-blind ran- ing these 3 films, nor did they indi- course of treatment. Tabex also con- domized trial conducted in West Ger- cate the numbers and proportions of tains calcium dihydrogenophosphate, many, Tabex was compared with pla- quitters per group. In all 3 articles, lactose,wheatstarch,microcrystalline cebo and with 12 other substances the authors nevertheless stated that cellulose, talc, and magnesium stea- (Atabakko [a compound of caffeine films containing cytisine or cyti- rate (data available at: http://www and theobromine], Citotal, Nicobre- sine in combination with anabasine .tabex.net/41814_packageinsert vin, Nicocortyl, Ni-Perlen, Pempidil, were more effective than films con- .phtml). One Russian study used potassium, Radix levistici, Raucher- taining anabasine. Two articles19,20 films of 0.4 cm2 placed between the stop 5 HT, Targophagin, Unilobin, reported data on the pharmacody- gum and lip, containing either 1.5 mg and Viotil).28 Finally, slow-release cy- namics of these films in 78 patients. of cytisine or 0.75 mg of cytisine plus tisine tablets are under development 0.75 mg of anabasine.18-20 Patients in Bulgaria, but, to my knowledge, no EFFECT OF TABEX took 4 to 6 of these films per day for trial of the efficacy of these new tab- 5 days after quitting smoking, and a lets has been published.34,35 Nine studies reported on the effect decreasing dose thereafter until the of the Bulgarian preparation Ta- 15th day. These films dissolve en- EFFECT OF FILMS bex, including 6 uncontrolled stud- tirely in the mouth over 1½ hours and CONTAINING CYTISINE ies16,21,22,30-32 and 4 controlled stud- were developed to obtain buccal ab- ies.22,27-29 A German study22 reported sorption of cytisine, with the aim of One Russian study18-20 tested 0.4- data from several sites, but only 1 site eliminating the digestive adverse ef- cm2 films containing cytisine, anaba- (Potsdam Rehbru¨ cke, group R) in- fects produced by cytisine pills when sine, or cytisine and anabasine. The cluded a control group that re- they are swallowed.18 effect of these 3 types of films was ceived placebo; the other groups All studies of the efficacy of cyti- studied in 281 smokers across 4 dif- were uncontrolled (groups F, P1, sine for smoking cessation were con- ferent samples.18 First, a clinical and P2). In these 9 studies, a total ducted in Bulgaria, East and West sample of 41 smokers (inpatients of 4146 smokers were treated with Germany, Poland, and Russia. Tabex with cardiovascular diseases) re- Tabex and 3518 were included in was tested for the first time for smok- ceived these films for 15 days, and control conditions. Smoking absti- ingcessationinBulgariaandEastGer- 56.0% of them quit smoking after an nence rates at the end of treatment many in 1965,21,22 and the most re- unspecified time, apparently at the (usually 4 weeks) in smokers using cent study16 was presented in 2005. end of treatment. Quit rates by group Tabex ranged from 29.0% to 76.0%, One randomized controlled trial of were not reported. Second, a sample and abstinence rates after 3 to 12 Tabex is under way in Poland.16 Cy- of 21 healthy smokers (outpa- months ranged from 13.8% to 70.0% tisine has also been tested for the tients) tested the same films for 15 (Table 1).

(REPRINTED) ARCH INTERN MED/ VOL 166, AUG 14/28, 2006 WWW.ARCHINTERNMED.COM 1555

Downloaded From: https://jamanetwork.com/ on 09/25/2021 same rate as placebo.28 One uncontrolled study19 reported a decrease 10 Potentially Relevant Trials Identified and Screened for Retrieval in blood pressure after 15 minutes; another31 reported, on the con- 5 Trials Excluded trary, an increase of 10 mm Hg in Reason: No Control Group blood pressure; and 2 others22,30 reported no effect on blood pressure. 5 Trials Retrieved for More Detailed 29 Evaluation One study reported tachycardia in 62 (16%) of 388 patients, 2 re- 1 Trial Excluded∗ Reason: Results by Group ported light tachycardia in 3 (4%) Not Reported of 70 patients32 and an “insignifi- cant” effect on heart rate,31 and 1 re- 4 Potentially Appropriate Trials to Be Included in the Meta-analysis ported no effect on the electrocar- diogram and blood pressure.18-20 1 Trial Excluded† Reason: No Placebo in Control Group TOXICITY

3 Trials With Usable Information, Included in the Meta-analysis There are numerous reports of people getting poisoned with seeds of C laburnum, which contain cytisine.36 One Figure. Flow diagram for the meta-analysis according to the Quality of Reporting Meta-analyses fatal case was reported in a psychiat- Conference. The literature review includes all 10 trials of cytisine for smoking cessation, but the ric patient who also used the antipsy- meta-analysis includes only 3 of these trials. The asterisk indicates the trial by Metelitsa18 and Ostrovskaia19,20; and the dagger, the trial by Marakulin et al.29 chotic drug chlorpromazine hydro- chloride (Largactil). This patient absorbed 23 pods of C laburnum, cor- META-ANALYSIS (I2 =75.1%, heterogeneity P=.04), responding to 35 to 50 mg of cyti- and the pooled effect for these 2 sine.37 The lethal dose in humans is, The 3 placebo-controlled stud- studies after 3 to 6 months was as however, unknown. Poisoning in ies22,27,28 of Tabex were included in follows: OR, 1.83 (95% confidence children who eat laburnum seeds is a meta-analysis. (The flow diagram interval, 1.12-2.99) (random- frequent. It was reported that “in an for the meta-analysis is given in the effects model). Only 1 placebo- average summer, over three thou- Figure.) No behavioral support was controlled study27 reported long- sand children are admitted to hospi- provided to participants in any of term results after 2 years (OR, 1.77; tals in England and Wales because of these 3 studies. In one study, smok- 95% confidence interval, 1.29- laburnum poisoning” but that “la- ing abstinence was assessed in 2.43) (Table 2). burnum is not as dangerous as has mailed surveys, based on replies to been thought and that many of these the following: “I have completely ADVERSE EFFECTS admissions are unnecessary.”36(p1073) stopped smoking”26 and “Are you a Poisoning symptoms with cytisine re- smoker or a non-smoker?”27 In the Smokers need a medical prescrip- semble poisoning symptoms with article by Schmidt,28 abstinence was tion to obtain Tabex. The manufac- nicotine and include nausea, abdomi- determined from answers in a mail turer of Tabex specifies that “the fol- nal pain, vomiting, muscular weak- survey to an unspecified question on lowing adverse effects are rather ness, and respiratory stimulation, “complete abstinence.” In the study often observed at the beginning of soon followed by respiratory depres- by Paun and Franze,22 abstinence Tabex treatment: changes in both sion.37 One report32 described 2 non- was determined by physicians us- taste and appetite, dryness in the lethal suicide attempts by the same pa- ing an unspecified criterion. A first mouth, headache, irritability, nau- tient, a pharmacist who swallowed 40 meta-analysis was conducted on data sea, constipation, tachycardia, light to 50 Tabex tablets (containing 60 to collected after 4 weeks,27 after 8 elevation of the arterial pressure” and 75 mg of cytisine) on her first sui- weeks,22 and at the end of treat- that Tabex is contraindicated for cide attempt and 90 tablets (contain- ment (apparently a few weeks) for people with arterial hypertension ing 135 mg of cytisine) on her sec- the placebo-controlled group only in and advanced atherosclerosis (data ond attempt. Poisoning with the article by Schmidt. In these 3 pla- available at: http://www.tabex.net laburnum is probably due to the cebo-controlled trials, there was sig- /41814_packageinsert.phtml). short-term nicotinelike effect of cy- nificant heterogeneity for short- In published studies, the ad- tisine on the central nervous system. term outcomes (I2=76.1%, P=.02), verse effects that were slightly more In the rat, the lethal dose of cytisine and the pooled effect from a random- frequent in subjects using cytisine (median lethal dose, the dose at which effects model was as follows: OR, than in those using placebo were half the animals die) is 1.7 mg/kg in- 1.93 (95% confidence interval, 1.21- weight gain,24,25 headache,28 and travenously and 101 mg/kg per os.38 3.06). In a second meta-analysis of heartburn.28 Nausea, vertigo, diar- In the animal, there are reports39 of the 2 placebo-controlled trials with rhea, and digestive problems were fatal accidental poisoning with seeds 3 and 6 months of follow-up,27,28 reported in some studies, with no of C laburnum. Incidentally, there are there was significant heterogeneity comparison with placebo or at the more reports40,41 of fatal poisoning in

(REPRINTED) ARCH INTERN MED/ VOL 166, AUG 14/28, 2006 WWW.ARCHINTERNMED.COM 1556

Downloaded From: https://jamanetwork.com/ on 09/25/2021 Table 2. Effect of Cytisine on Smoking Cessation, From Controlled Trials*

No. of Patients Duration Total No. of Patients Abstinent Quit Rate, % Odds Ratio Control Duration of (95% Study Group, Behavioral of Tabex Follow- Cytisine Control Present at Cytisine Control Cytisine Control Confidence P No. Source Country Blinding Support Therapy up Group Group Follow-up Group Group Group Group Interval) Value 8 Benndorf East Placebo, None, “we 20 d 4-6 wk 157 157 NA 120 48 76.4 30.6 7.36 (4.33-12.57) Ͻ.001 et al,24 Germany double avoided 1968 (first 314 blind suggestive subjects influence” only) Benndorf East Placebo, None 20 d 4-6 wk 607 607 NA 395 246 65.1 40.5 2.73 (2.15-3.47) Ͻ.001 et al,25 Germany double 1969 blind Benndorf East No controls None 20 d 5-12 mo 607 NA 204 143 NA 23.6 NA NA NA et al,26 Germany 1970 (only 395 Tabex- treated subjects abstinent at 4-6 wk) Scharfenberg East Placebo, None 20 d 4 wk 607 607 1214 395 246 65.1 40.5 2.73 (2.15-3.47) Ͻ.001 et al,27 Germany double 1971 (4 wk) blind East Placebo None 20 d 6 mo 607 607 801 185 97 30.5 16.0 2.30 (1.73-3.07) Ͻ.001 Germany (6 mo) East Placebo None 20 d 2 y 607 607 801 127 79 20.9 13.0 1.77 (1.29-2.43) Ͻ.001 Germany (2 y) 9 Marakulin Russia Autogenic Autogenic 3 wk 3 wk 388 232 NA 272 123 70.1 53.0 2.08 (1.46-2.95) Ͻ.001 et al,29 training training, 1984 12-14 sessions 5Paunand East Placebo Individual and 17 d 8 wk 36 239 NA 15 80 41.7 33.5 1.42 (0.65-3.06) .34 Franze,22 Germany, group 1968 (groups R sessions plus placebo) 10 Schmidt,28 West Placebo, None (by 3 wk 3-4 wk 250 270 Cytisine 103 84 41.2 31.1 1.55 (1.06-2.26) .02 1974 Germany double mail) group, (3-4 wk) blind 181; placebo group, 239 West Placebo, None 3 wk 3 mo 250 270 Cytisine 68 57 27.2 21.1 1.40 (0.91-2.13) .10 Germany double group, (3 mo) blind 181; placebo group, 239 West 12 Other None 3 wk 3-4 wk 250 2170 1994 103 740 41.2 34.1 1.35 (1.03-1.78) .03 Germany drugs (3-4 wk, all plus 12 other placebo drugs in trial, including placebo, excluding lime tea) West 12 Other None 3 wk 3 mo 250 2170 1994 68 521 27.2 24.0 1.18 (0.87-1.60) .27 Germany drugs (3 mo, all plus 12 other placebo drugs in trial, including placebo, excluding lime tea)

Abbreviation: NA, data not available. *Available at: http://www.stop-tabac.ch/cytisine.

(REPRINTED) ARCH INTERN MED/ VOL 166, AUG 14/28, 2006 WWW.ARCHINTERNMED.COM 1557

Downloaded From: https://jamanetwork.com/ on 09/25/2021 humans with nicotine than with cy- ological standards were not widely hensive. The available data suggest tisine, and both situations are quite adopted at that time, even in the that cytisine may be effective for rare. Studies of the toxicity of cytisine West.42 Probably because of their smoking cessation. This result is all in humans were conducted by So- poor quality, several studies re- the more interesting considering that pharma, the company that produces ported unrealistically high quit rates no behavioral support was pro- Tabex, but these reports (in Bulgar- (60%-70%) and should be inter- vided to participants in any of the 3 ian) (cited on: http://www.tabex preted with caution. However, quit placebo-controlled trials. It is nec- .net) were not published in scien- rates and ORs in the 3 placebo- essary to conduct state-of-the-art tific journals and were not sent to the controlled trials are well in the range clinical trials to confirm these re- author when requested. of short-term outcomes in studies of sults. However, given the uncertain- other smoking cessation drugs (nico- ties about the toxicity of cytisine, it tine replacement therapy and bu- may not be ethical to conduct phase COMMENT propion).2 These 3 studies seem, 3 clinical trials before more is known therefore, to be credible, if consid- about the toxicity and tolerability of Research conducted during the past ering in addition that cytisine binds cytisine in humans, at the dosage 40 years suggests that cytisine is ef- strongly with nicotinic receptors and recommended by the manufac- fective for smoking cessation. Thus, that varenicline is effective for smok- turer. An apparently effective treat- an apparently effective smoking ces- ing cessation. ment for the first avoidable cause of sation drug that has been used for de- Few adverse effects of cytisine death in developed countries re- cades in Germany and Eastern Euro- were reported in the studies remained largely unnoticed, despite re- pean countries remained unnoticed viewed herein, which does not mean search published during the past 40 in other countries. Most of the articles that cytisine is innocuous. Cytisine years. How many other effective reviewed herein were never cited in causes poisoning, and toxicity tests drugs are there for which efficacy re- the English-language literature. De- of cytisine in humans were con- mained unnoticed because existing spite the existence of 3 placebo- ducted and results published as in- trials were not published in En- controlled trials, recent reviews of the ternal industry reports in Bulgar- glish in Western countries? efficacy of smoking cessation drugs ian; however, despite repeated 2,14,15 omitted cytisine and little re- attempts, I was unable to obtain Accepted for Publication: April 21, searchoncytisinehasbeenconducted these reports. Thus, it is apparently 2006. in recent years. not known whether cytisine has any Correspondence: Jean-Franc¸ois Etter, This omission is probably ex- effect on organ damage or whether PhD, MPH, Institute of Social and plained because studies of the effi- it is carcinogenic, teratogenic, or Preventive Medicine, University cacy of cytisine were not published genotoxic in humans. Apart from the of Geneva, 1, rue Michel-Servet, in English and because the avail- relatively short-term adverse ef- CH-1211 Geneva 4, Switzerland able evidence is based on studies that fects reported in smoking cessation ([email protected]). do not conform to current stan- trials, it is unknown whether the rec- Financial Disclosure: None re- dards in conducting and reporting ommended dose of Tabex and cyti- ported. drug trials. In particular, only 1 re- sine films (9 mg/d) carries any risk cent study16 used biochemical veri- and what would be the conse- fication of smoking status, and most quences if children swallowed these REFERENCES studies did not indicate which cri- tablets.3 There is some discrepancy 1. Mokdad AH, Marks JS, Stroup DF, Gerberding JL. terion was used to define smoking between the adverse effects re- Actual causes of death in the United States, 2000. abstinence. Only 1 of the 3 placebo- ported in published studies and the JAMA. 2004;291:1238-1245. controlled studies clearly indicated list of adverse effects in the manu- 2. Lancaster T, Stead L, Silagy C, Sowden A. Effec- that randomization took place, and facturer’s leaflet. In particular, more tiveness of interventions to help people stop smok- only 2 were double blind. Most stud- weight gain using cytisine than using: findings from the Cochrane Library. BMJ. 2000;321:355-358. ies were short term, and the num- ing placebo was reported in 1 3. Seeger R. Cytisine as an aid for smoking cessa- 25 ber of participants present at fol- study, and vertigo was mentioned tion [in German]. Med Monatsschr Pharm. 1992; low-up was not always reported. in some studies but not in the manu- 15:20-21. This research probably also re- facturer’s leaflet. On the other hand, 4. Lickint F. Medikamento¨se Unterstu¨tzung der Tabakentwo¨hnung. Therapiewoche. 1955-1956; mained unnoticed because all stud- increases in blood pressure and heart 6:444-448. 16,28 ies except 2 were conducted in rate are listed in the manufacturer’s 5. Wanchun L, Yunshou L, Liyi M, Shin-Foon C. Eastern European countries before list of adverse effects, but were not Toxicity of cytisine against the mustard aphid Li- democratization. However, the only consistently reported in published paphis erysimi Kaltenbach (homoptera: aphidi- randomized, double-blind, placebo- studies. dae) and its effect on esterases. Pestic Biochem 28 Physiol. 1999;65:1-5. controlled study was conducted in One limitation of this review is 6. Larson PS, Silvette H. Tobacco, Experimental and West Germany, and it showed sta- that it was conducted by only 1 per- Clinical Studies: Supplement III. Baltimore, Md: tistically significant effects of cyti- son. A duplication of the data search Williams & Wilkins; 1975:364. sine. Research conducted in the and extraction processes by a sec- 7. Coe JW, Brooks PR, Vetelino MG, et al. Vareni- cline: an ␣4␤2 nicotinic receptor partial agonist West during the same period (1960s ond person would have been pref- for smoking cessation. J Med Chem. 2005;48: and 1970s) was also often of poor erable, but the search process was, 3474-3477. quality, because current method- nevertheless, extensive and compre- 8. Coe JW, Vetelino MG, Bashore CG, et al. In pur-

(REPRINTED) ARCH INTERN MED/ VOL 166, AUG 14/28, 2006 WWW.ARCHINTERNMED.COM 1558

Downloaded From: https://jamanetwork.com/ on 09/25/2021 suit of ␣4␤2 nicotinic receptor partial agonists for ling smoking [in Russian]. Biull Vsesoiuznogo 5000 Rauchern im Doppelblindversuch. MMW smoking cessation: carbon analogs of (-)-cytisine. Kardiol Nauchn Tsentra AMN SSSR. 1987;10: Munch Med Wochenschr. 1974;116:557-564. Bioorg Med Chem Lett. 2005;15:2974-2979. 109-112. 29. Marakulin VS, Komarov VM, Chuprin VV. Treat- 9. Papke RL, Heinemann SF. Partial agonist prop- 19. Ostrovskaia TP. Results of clinical investigation ment of nicotinism [in Russian]. Voen Med Zh. erties of cytisine on neuronal nicotinic receptors of anti-nicotine drug patches [in Russian]. Med 1984;1:55-58. containing the ␤2 subunit. Mol Pharmacol. 1994; Tekh. 1994;3:42-43. 30. Granatowicz J. Smoking cessation through the use 45:142-149. 20. Ostrovskaia TP. Clinical trial of antinicotine drug- of cytisine and other therapy. World Smoking 10. Imming P, Klaperski P, Stubbs MT, Seitz G, Gun- containing films. Biomed Eng. 1994;28:168-171. Health. 1976;1:8-11. disch D. Syntheses and evaluation of haloge- 21. Kempe G. Observation about the Bulgarian medi- 31. Maliszewski L, Straczynski A. Therapeutic use of nated cytisine derivatives and of bioisosteric thio- cine for smoking withdrawal Tabex produced by Tabex [in Polish]. Wiad Lek. 1972;25:2207-2210. cytisine as potent and selective nAChR ligands. Pharmachim-Sofia. Savr Med. 1967;18:355-356. 32. Stoyanov S, Yanachkova M. Tabex: therapeutic Eur J Med Chem. 2001;36:375-388. 22. Paun D, Franze J. Raucherentwo¨hnung mit cytis- efficacy and tolerance. Savr Med XX111. 11. Glass LE. Alkaloids that have a pharmacology like inhaltigen “Tabex” Tabletten. Dtsch Gesundheitsw. 1972;6:30-33. nicotine. http://legacy.library.uscf.edu. Ac- 1968;23:2088-2091. 33. Vlaev S. Possibilities and Limits of Application of cessed November 24, 2005. 23. Paun D, Franze J. Tabex, registering and treat- the Preparation Tabex in Cases of Depressive 12. Vagg R, Chapman S. Nicotine analogues: a re- ment of smokers with chronic bronchitis in the Patients. Sofia, Bulgaria: Sopharma. view of tobacco industry research interests. consultation against tobacco smoking. Medicobio- 34. Dimitrov M, Dotcheva D, Lambov N. Preparation Addiction. 2005;100:701-712. logic Information. 1970;3:14-19. and characterization of polyethilene oxide hydro- 13. Tilotta MC. Novel nicotinic acetylcholine recep- 24. Benndorf S, Kempe G, Scharfenberg G, Wendekamm gels with cytisine. Acta Pharmaceutica Turcica. tor ligands based on cytisine, ferruginine, ana- R, Winkelvoss E. Ergebnisse der medikamento¨sen 2004;46:49-54. toxin-a and choline: in vitro evaluation and struc- Raucherentwo¨hnung mit Cytisin (Tabex). Dtsch 35. Dimitrov M, Shenkov S, Lambov N. Comparative ture-activity relationships [PhD dissertation]. http: Gesundheitsw. 1968;23:2092-2096. technological and biopharmaceutical studies on the //hss.ulb.uni-bonn.de/diss_online/math_nat_fak 25. Benndorf S, Scharfenberg G, Kempe G, Winkel- cytisine tablets. Pharmacia. 2004;51:14-20. /2004/tilotta_maria/0464.pdf. Accessed December voss E, Wendekamm R. Weitere Mitteilungen u¨ber 36. Forrester RM. Have you eaten laburnum [brief 2, 2005. einen doppelten Blindversuch mit dem cytisinhalti- report]? Lancet. 1979;1:1073. 14. Anderson JE, Jorenby DE, Scott WJ, Fiore MC. gen bulgarischen Pra¨parat Tabex: an 1214 ent- 37. Richards HG, Stephens A. A fatal case of labur- Treating tobacco use and dependence: an evi- wo¨hnungswilligen Rauchern und praktische Erfahr- num seed poisoning. Med Sci Law. 1970;10: dence-based clinical practice guideline for to- ungen bei der Durchfu¨hrung einer Sprechstunde fu¨r 260-266. bacco cessation. Chest. 2002;121:932-941. entwo¨hnungswillige Raucher. Dtsch Gesundheitsw. 38. Barlow RB, McLeod LJ. Some studies on cyti- 15. McRobbie H, Lee M, Juniper Z. Non-nicotine phar- 1969;24:1135-1140. sine and its methylated derivatives. Br J Pharmacol. macotherapies for smoking cessation. Respir Med. 26. Benndorf S, Scharfenberg G, Kempe G, Wendekamm 1969;35:161-174. 2005;99:1203-1212. R, Winkelvoss E. Medikamento¨se Raucherent- 39. Clarke ML, Clarke EG, King T. Fatal laburnum poi- 16. Zatonski W, Cedzynska M, Przewozniak E, et al. wo¨hnung mit Cytisin (Tabex): ergebnisse der Hal- soning in a dog. Vet Rec. 1971;88:199-200. An open label observational study of herbal cyti- bjahresbefragung bei den vier Wochen nach Kur- 40. Moriya F, Hashimoto Y. A fatal poisoning caused sine (Tabex) as an aid to smoking cessation. Poster beginn abstinenten ehemaligen Rauchern. Dtsch by methomyl and nicotine. Forensic Sci Int. 2005; presented at: Society for Research on Nicotine and Gesundheitsw. 1970;24:774-776. 149:167-170. Tobacco Conference; March 21, 2005; Prague, 27. Scharfenberg G, Benndorf S, Kempe G. Cytisine 41. Lavoie FW, Harris TM. Fatal nicotine ingestion. Czech Republic. (Tabex) as a pharmaceutical aid in stopping smok- J Emerg Med. 1991;9:133-136. 17. Higgins JPT, Thompson SG, Deeks JJ, Altman DG. ing [in German]. Dtsch Gesundheitsw. 1971; 42. Gehan EA, Schneiderman MA. Historical and meth- Measuring inconsistency in meta-analyses. BMJ. 26:463-465. odological developments in clinical trials at the 2003;327:557-560. 28. Schmidt F. Medikamento¨se Unterstu¨tzung der National Cancer Institute. Stat Med. 1990;9: 18. Metelitsa VI. Pharmacological agents in control- Raucherentwo¨hnung: Bericht u¨ber Versuche an u¨ber 871-880.

(REPRINTED) ARCH INTERN MED/ VOL 166, AUG 14/28, 2006 WWW.ARCHINTERNMED.COM 1559

Downloaded From: https://jamanetwork.com/ on 09/25/2021