Where Can I Buy Cytisine
The finding was a major disappointment in that cytisine -- a plant alkaloid that, like varenicline, stimulates nicotinic acetylcholine receptors -- had previously been shown to be superior to placebo and to standard nicotine replacement therapy (NRT) in separate trials. Moreover, a trial involving some of the same researchers and reported earlier this year, conducted among native Maori and family members in New Zealand, found that cytisine was more effective than varenicline.
where can i buy cytisine
But Courtney's group was clear that the new trial doesn't spell doom for cytisine. Extended dosing would be worth testing in a future study, they indicated. And the contrary results in the Maori trial might suggest that populations more accepting of "natural" products would respond better to cytisine than to varenicline.
Some of these questions could be answered in an ongoing, placebo-controlled, phase III trial with a proprietary cytisine formulation called cytisinicline, in which the agent is given for up to 12 weeks.
In its native form, cytisine has been in common use outside the West for some 50 years. As a partial agonist for nicotinic acetylcholine receptors, it reportedly suppresses nicotine cravings and withdrawal symptoms when people stop smoking cigarettes. The standard treatment interval has been 25 to 30 days, although Courtney and colleagues noted that this isn't necessarily optimal -- as a cheap plant derivative, it hasn't had the financial backing to test multiple dosing regimens as Big Pharma would do for a product that needs FDA approval. (Cytisine appears not to be carried by U.S.-based herbal supplement vendors, but it can be ordered online from overseas.)
Nevertheless, varenicline has been the leading non-NRT drug for smoking cessation in the the Western world. For cytisine to stake a claim as an effective agent -- particularly in countries other than the U.S. that would want evidence of at least noninferiority for it to be included in national formularies -- a head-to-head trial in a Western-type population could help its case.
Hence, the Australian government sponsored the new trial, dubbed CESSATE, which had no involvement from Pfizer or cytisine suppliers. Participants were daily smokers, recruited from ads in print, radio, and online media, as well as from a telephone quit line, who said they wanted to quit and weren't currently using other smoking-cessation pharmacotherapies. Some 5% were Aboriginal or Torres Strait Islanders. Half were men, and mean participant age was 43. Mean smoking intensity was 18 cigarettes per day; total smoking history in pack-years wasn't reported, but the mean starting age for smoking was 16. They were randomized 1:1 to the two study agents, unblinded for pragmatic reasons.
Not surprisingly, given that most cessation attempts fail, the primary endpoint was met by 11.7% of the cytisine group and 13.3% of the varenicline group. To be considered noninferior, the lower bound of the risk difference's one-sided 97.5% confidence interval had to be no more than -5%. In the end, the risk difference was -1.62% with a confidence interval of -5.02% to infinity. A secondary Bayesian analysis found only a 15% probability of noninferiority, with other statistical tests also pointing toward lower efficacy with cytisine.
Two findings did fall in cytisine's favor. First, when participants were contacted by phone at the end of 1 month -- at which point those in the cytisine group had finished dosing -- self-reported abstinence in the previous week stood at 42.5% with cytisine versus 32.3% for varenicline. That was one reason why Courtney and colleagues suggested a longer cytisine dosing period could be beneficial.
Serious events, almost all requiring hospitalization, also appeared more common with varenicline (32 people vs 17 with cytisine), but the difference was not statistically significant. These events made somewhat of a puzzle, showing no clear pattern. Twelve were orthopedic, whereas only five could be considered neuropsychiatric. However, one of the latter was a suicide attempt by a varenicline recipient with a mental illness history. (On the other hand, the previous trial comparing cytisine to standard NRT found more adverse events with the former.)
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.
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
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
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
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
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
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
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
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
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).
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 041b061a72