IngredientsCytisine, also known as baptitoxine, cytisinicline, or sophorine, is an alkaloid that occurs naturally in several plant genera, such as Laburnum and Cytisus of the family Fabaceae. Chemically, it is classified as a quinolizidine alkaloid, found in plants of the Leguminosae (Fabaceae) family, for example in Laburnum anagyroides (Golden Rain). In 1862, Husemann and MarmΓ© isolated (β)-cytisine in pure form; it is also found in several plant genera of the Leguminosae, including Laburnum and Cytisus.
Cytisine is the main alkaloid in plants of the Faboideae sub-family of the Fabaceae family, which includes the ornamental trees Laburnum anagyroides (also known as Cytisus laburnum) and Laburnum alpinum, Genista, Sophora, and a number of hybrids. Laburnum anagyroides in particular is a deciduous tree or large shrub that grows up to seven meters tall; it is widespread in Europe, as both a spontaneous and an ornamental cultivated species. In May and June, it blooms with densely packed, pendulous yellow flowers which inspired its common names "golden chain" and "golden rain." Like many plants in the pea family, it also produces legume pods containing numerous black seeds, which are toxic. These seeds contain up to 1.5% cytisine.
The highest concentrations of cytisine are found in the ripe seeds and seed pods. Beyond laburnum, cytisine also occurs in genera such as Thermopsis, Sophora, and related legumes.
The late 19th and early 20th centuries saw work to determine the structure of (β)-cytisine by chemical means. The chemical structure of cytisine was worked out by Ing (1931, 1932). The molecule is a bicyclic compound whose pyridone ring fused to a piperidine ring gives it a relatively rigid three-dimensional conformation. The molecular structure of cytisine has similarities to both nicotine and acetylcholine (ACh).
The drug is marketed in tablet and capsule form. In 1961, Bulgarian pharmacist Strashimir Ingilizov synthesized Tabex using cytisine derived from the seeds of Cytisus laburnum; it was first marketed in Bulgaria in 1964 and became widely available in the Soviet Union. In Poland, it is sold under the brand name Desmoxan, and in Canada under the brand name Cravv. Cytisine is a generic agent currently manufactured by Sopharma as Tabex and by Aflofarm Pharma as Desmoxan. Trade names include Tabex, Desmoxan, and cytisinicline; it is available as oral tablets, capsules, and oral films.
The use of plants containing cytisine dates back thousands of years. Native Americans consumed parts of cytisine-containing plants in magical rituals. Cytisine has also been used entheogenically via mescalbeans by some Native American groups, historically in the Rio Grande Valley, predating even peyote. Laburnum has been used in traditional medicine by American Indians, who consumed the seeds for their emetic effects during rites and magical practices.
In Europe, alcoholic extracts from Laburnum have been used in folk medicine for various purposes for hundreds of years. During World War II, the leaves of the Laburnum were used as a substitute for tobacco. Traditional use of Laburnum seeds for their emetic effects, and use of the leaves of L. anagyroides as a tobacco substitute, have been documented.
Cytisine was used in the USSR as a respiratory stimulant similar to lobeline and, since 1960, it has been used to treat nicotinism in Bulgaria and other eastern and central European countries. In traditional Chinese medicine, it is used to treat hepatitis and liver cancer, exploiting a small but promising effect on cell growth.
Cytisine was first used in tablet form in Bulgaria in the 1960s as a medicine to help people quit smoking. A year later, the first clinical study was published showing the anti-nicotine effectiveness of alkaloids. Cytisine has been widely used in Central and Eastern Europe and Central Asia since the 1960s. Cytisine has been marketed for many years by Sopharma in Central and Eastern Europe, and is estimated to have treated over 21 million smokers worldwide.
Cytisine itself is the sole primary active compound of clinical interest in the context of current medicinal use. It is isolated from plant material as (β)-cytisine (the levorotatory enantiomer), which is the biologically active form. Cytisine is a natural bioactive compound mainly isolated from plants of the Leguminosae family, especially the seeds of Laburnum anagyroides.
Cytisine acts as a partial agonist at nicotinic acetylcholine receptors, particularly the alpha-4 beta-2 (Ξ±4Ξ²2) subtype, and is used as a smoking cessation medication. Recent pharmacological research has elucidated that the drug is a low-efficacy partial agonist of alpha4beta2 nicotinic acetylcholine receptors, which are believed to be central to the effect of nicotine on the reward pathway.
The proposed mechanism of action of cytisinicline is two-fold: (1) acting as a selective partial agonist, stimulating subtypes of nicotinic acetylcholine receptors in the brain, much as nicotine does, to reduce nicotine withdrawal and craving, and (2) acting as a temporary partial antagonist at these same receptors, blocking the effects of nicotine, and so reducing the reinforcing effects of a lapse cigarette.
Cytisine can affect nicotinic transmission by acting both at the cell surface as a high-affinity, partial agonist of the Ξ±4Ξ²2 subtype, a nearly full agonist of Ξ±6Ξ²2*-containing receptors, and a full agonist of the Ξ±3Ξ²4 and Ξ±7 subtypes, as well as acting as an intracellular chaperone that modulates nAChR assembly and trafficking, leading to an upregulation of cell-surface receptors.
Both nicotine and cytisine bind strongly and preferentially to pre-synaptic Ξ±4Ξ²2 receptors that mediate the release of dopamine in the shell of the nucleus accumbens. This receptor subtype has been implicated in the development and maintenance of nicotine dependence and was the primary target for varenicline.
As a result of this partial agonism, cytisine provides smokers with satisfaction similar to smoking a cigarette, alleviating the urge to smoke and reducing the severity of nicotine withdrawal symptoms, while also reducing the reward experience of any cigarettes smoked.
Its main targets are neuronal nicotinic acetylcholine receptors (nAChRs), and pre-clinical studies have shown that its interactions with various nAChR subtypes located in different areas of the central and peripheral nervous systems are neuroprotective, have a wide range of biological effects on nicotine and alcohol addiction, regulate mood, food intake and motor activity, and influence the autonomic and cardiovascular systems.
Oral cytisine reaches peak concentration two hours post-dose and is excreted unchanged renally without hepatic metabolism, lowering the risk of drug interactions. The mean half-life for cytisine was 4.09 h Β± 0.82. Cumulative amounts of cytisine were excreted in the urine within 24 h, indicating that cytisine is most likely readily absorbed from the gastrointestinal tract after oral administration and may not undergo significant metabolic processes, since approximately 64% of the administered dose was excreted as unchanged cytisine within 24 hours. The apparent volume of distribution for cytisine in one study (115 L) was more than three times that of the blood compartment (35 L), suggesting that cytisine may distribute to other compartments very rapidly. Plasma cytisine concentrations declined with an average elimination half-life of 4.8 h.
Blood levels peak 1 to 2 hours after each oral administration and then decline with a half-life of 4.8 hours. The logarithmic plot of mean cytisine concentration versus time after the peak showed a single elimination phase, indicating that single-dose pharmacokinetics of cytisine may be described using a single-compartment model.
Smoking cessation constitutes the overwhelmingly dominant body of human clinical evidence for cytisine. The evidence base includes multiple randomized controlled trials (RCTs), systematic reviews, and meta-analyses.
TASC Trial (2011): A large, well-conducted placebo-controlled trial (n = 740) of cytisine for smoking cessation confirmed the findings of earlier studies, with 12-month continuous abstinence rates of 8.4% in the cytisine group compared to 2.4% in the placebo group (relative risk = 3.4; 95% confidence intervals 1.7β7.1). This TASC trial was sponsored by the UK Centre for Tobacco Control Studies and evaluated cytisine versus placebo in 740 primarily moderate-to-heavy smokers treated for 25 days in a single center in Warsaw, Poland.
CASCAID Trial (2014, NEJM): This trial investigated whether cytisine was at least as effective as nicotine-replacement therapy in helping smokers to quit. It was a pragmatic, open-label, noninferiority trial in New Zealand in which 1,310 adult daily smokers who were motivated to quit were randomly assigned in a 1:1 ratio to receive cytisine for 25 days or nicotine-replacement therapy for 8 weeks; cytisine was provided by mail, free of charge, and nicotine-replacement therapy was provided through vouchers for low-cost patches along with gum or lozenges, with low-intensity telephone-delivered behavioral support provided to both groups. The relative risk for continuous one-month abstinence was 1.3 for cytisine (40% cytisine arm compared to 31% in the NRT arm; P<0.001). A secondary outcome included a relative risk of 1.4 for continuous six-month abstinence (22% cytisine arm compared to 15% in the NRT arm; P=0.002). When combined with brief behavioral support, cytisine was found to be superior to nicotine-replacement therapy in helping smokers quit smoking, but it was associated with a higher frequency of self-reported adverse events.
ORCA-2 and ORCA-3 Trials (US Phase 3): ORCA-3 was a three-group double-blind, placebo-controlled, replication randomized trial conducted at 20 clinical trial sites in the US from January 2022 to March 2023. It compared a novel cytisinicline regimen at 6 and 12 weeks to placebo among 792 adults who smoked 10 or more cigarettes daily and sought to quit; participants were randomized 1:1:1 to 3-mg cytisinicline 3 times daily for 12 weeks, or 3-mg cytisinicline 3 times daily for 6 weeks followed by placebo for 6 weeks, or placebo 3 times daily for 12 weeks, with follow-up and behavioral support continuing for 24 weeks. In ORCA-3, of participants receiving 6-week cytisinicline administration, 14.8% were abstinent from smoking for weeks 3 to 6 compared to 6% in placebo; in the 12-week treatment group, 30.3% were abstinent for weeks 9 to 12 versus 9.4% of placebo. ORCA-3 was the second randomized, placebo-controlled Phase 3 clinical trial evaluating cytisinicline for smoking cessation in 792 U.S. adults, and the authors concluded that ORCA-3 reaffirms cytisinicline's efficacy and tolerability for smoking cessation in adult smokers.
A 2023 systematic review and meta-analysis (published in a peer-reviewed journal) included 14 RCTs involving 9,953 adults. Cytisine was superior to placebo (risk ratio [RR] 2.25, 95% confidence interval [CI] 1.13β4.47; 5 RCTs, 4,325 participants), but not statistically distinguishable from varenicline (RR 1.13). Cytisine shows greater efficacy than placebo and NRT, but more adverse events. It is comparable to varenicline, with fewer adverse events.
Placebo-controlled trials indicate that cytisine, a partial agonist that binds the nicotinic acetylcholine receptor and is used for smoking cessation, almost doubles the chances of quitting at 6 months.
A more recent (2025) systematic review and meta-analysis confirms cytisine's efficacy for smoking cessation and provides exploratory evidence suggesting that treatment optimization β particularly extending duration to 12 weeks and using fixed-dose regimens β may substantially improve outcomes. While the lack of statistical significance in subgroup comparisons precludes definitive clinical recommendations, the magnitude and consistency of observed trends, combined with favorable safety profiles and low treatment costs, strongly support investment in confirmatory trials.
Cytisinicline's NDA acceptance by the FDA marks a potential breakthrough in smoking cessation treatment, with a PDUFA date set for June 20, 2026. The ORCA-2 and ORCA-3 trials showed cytisinicline significantly increased smoking abstinence rates compared to placebo, with over 2,000 participants involved. Cytisinicline acts on nicotinic acetylcholine receptors, reducing nicotine cravings and withdrawal symptoms, and may become the first new smoking cessation drug in 20 years.
Cytisine has been in use since 1964 and is now being registered in an increasing number of countries worldwide; currently, cytisine is registered as a drug in 34 countries (mainly in Europe and Asia).
The evidence for cytisine in smoking cessation is strong by the standards of clinical pharmacology. Multiple Phase 3 RCTs, a systematic review encompassing 14 RCTs and nearly 10,000 participants, and decades of post-marketing surveillance collectively constitute a robust and consistent body of support. The primary limitation in Western contexts has been the historical absence of trials conducted to the standard required for regulatory approval in those markets, a gap being addressed by the ORCA program.
Clinical studies have shown that cytisine is a more effective smoking cessation aid than nicotine replacement therapy and at least as effective as varenicline in treating tobacco cigarette addiction. It may also be an effective agent in treating addiction to electronic cigarettes. Achieve Life Sciences has conducted a successful end-of-Phase 2 meeting with the FDA for the vaping indication and expects to initiate its single Phase 3 clinical study in vaping in 2025. Evidence strength: Preliminary β Phase 2 data only as of this writing; Phase 3 results are pending.
Animal studies show that cytisine had antidepressant-like effects in several animal models of antidepressant efficacy. Immunohistochemical analyses indicated that cytisine could reduce c-fos immunoreactivity in the basolateral amygdala by approximately 50%, showing that cytisine acts like classical antidepressants in rodent models. It has been proposed that blockade rather than activation of Ξ²2-containing (Ξ²2*) nicotinic acetylcholine receptors may lead to antidepressant-like effects; cytisine was used as a partial agonist of Ξ±4/Ξ²2* nAChRs and a full agonist at Ξ±3/Ξ²4* nAChRs in these tests.
Despite the interesting preclinical studies that consistently have demonstrated antidepressant-like effects of cytisine and other cytisine-based partial Ξ±4Ξ²2 nAChR agonists, the clinical trials in humans were in general rather negative. Evidence strength: Preclinical (animal models only); no verified positive human clinical trial data.
Accumulating evidence has shown that cytisine has neuroprotective effects in some neurological diseases such as Parkinson's disease, depression, and cerebral injury induced by ischemia-reperfusion in animal models. Early indications that smoking may correlate with protection and a delay in the onset of Alzheimer's disease stimulated research into whether the nicotinic cholinergic pathway has a neuroprotective effect. Evidence strength: Animal model and in vitro data only; no human clinical trials have validated these effects.
Cytisine also seems to be a valid and appropriate candidate for the treatment of alcohol addiction, although more studies are required to clarify the mechanisms underlying its anti-alcohol effects. Evidence strength: Preliminary; no completed human RCTs.
In recent years, various biological activities of cytisine have been explored in preclinical research, showing certain effects in reducing drinking behavior, anti-tumor activity, cardiovascular protection, blood sugar regulation, neuroprotection, and osteoporosis prevention and treatment. These expanded applications are primarily based on nonclinical studies and in vitro experiments, and further clinical trials are needed to validate these findings.
The cytisine commercial dose is 1.5 mg per tablet, administered 6 times a day for the first 3 days, then titrated down on specific days within a 25-day treatment period to only one tablet on Day 25.
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.
When taken at the recommended dosage (1.5 to 9 mg per day for 25 days), cytisine is associated with no significant increase in adverse events as compared with placebo (20.5% vs. 19.6%), although gastrointestinal symptoms are more common.
A relatively new dosing schedule of 3 mg three times per day for 6 to 12 weeks was developed after pharmacokinetic studies demonstrated that blood levels peak 1 to 2 hours after each oral administration and then decline with a half-life of 4.8 hours.
The ORCA-3 trial compared 3-mg cytisinicline 3 times daily for 12 weeks; 3-mg cytisinicline 3 times daily for 6 weeks followed by placebo for 6 weeks; or placebo 3 times daily for 12 weeks.
In one observational study, 36 hospitalized participants from a Cardiology Department received oral cytisine 1.5 mg for 25 days, according to the West Dosing Schedule (6 capsules for the first 3 days, gradually decreased up to 2 capsules on the last 6 days), in combination with supportive care.
The pharmacokinetic properties of cytisinicline were tested after a single oral dose of the formulation containing 1.5 mg in 36 healthy volunteers. After oral administration, cytisinicline was quickly absorbed from the gastrointestinal tract, with a mean maximum plasma concentration of 15.55 ng/mL achieved after a mean of 0.92 hours. 64% of the dose was excreted unchanged in the urine within 24 hours; the mean half-life in plasma was approximately 4 hours.
From marketing safety reporting for cytisine, the most frequent adverse effects include: nausea, gastrointestinal symptoms (including abdominal pain, dyspepsia, and dry mouth), sleep disorder, dizziness, and headache. Most reported adverse effects appear mainly at the beginning of therapy, are short-lived, mild-to-moderate intensity, and resolve spontaneously. It is not always possible to dissociate effects due to cytisine from those related to nicotine withdrawal.
In 6 placebo-controlled clinical trials (N=2,844), 1,389 subjects received cytisine. The most commonly reported adverse events in the cytisine group were effects on the gastrointestinal system: upper abdominal pain, nausea, dyspepsia, dry mouth, vomiting, constipation, and diarrhea. Nervous system and psychiatric disorders were also common, most frequently headache and dizziness, as well as somnolence and insomnia. However, statistical analysis did not reveal any significant difference in nervous system adverse events between the cytisine and placebo groups (p=0.12).
Digestive adverse effects, including nausea and vomiting, were reported in up to 8.4% of patients treated with cytisine. Other serious psychiatric adverse effects have been reported, such as anxiety and psychosis, but the symptoms appeared to be resolved after drug discontinuation. Certain cases of allergic reactions, including urticaria, have been noted.
Throughout more than forty years of cytisine utilization as a smoking cessation aid, no serious adverse events have been documented at therapeutic levels. Evidence supports the safety of cytisine; long periods of post-marketing surveillance exist in the European Medicines Authority database.
The plant alkaloid cytisine has been shown to have a safe profile, with a minimal risk for drug interactions. However, previous studies have excluded cardiovascular disease (CVD) patients, so there are few existing data examining cytisine safety in this critical population. In an observational study among 36 hospitalized cardiology patients, 11 mild-to-moderate adverse drug reactions were reported by 9 (25%) participants; these included initial insomnia (11%), nausea (6%), sleep disorders (6%), headache (3%), gastritis (3%), and diarrhoea (3%).
It has been known for a long time that all parts of plants containing cytisine are toxic, particularly the seeds. Adverse effects of cytisine ingestion at toxic doses include nausea and vomiting, dilation of the pupils, tachycardia followed by dizziness, mental confusion, muscular incoordination and weakness, and convulsions. Symptoms of nicotine intoxication are observed in cytisinicline overdose. No antidote to cytisine toxicity has been identified, and management is supportive.
Pre-clinical toxicity data (from regulatory documentation): The LD50 values obtained after intravenous (IV), subcutaneous (SC), and oral (PO) administration were 2.3, 13, and 13 mg/kg for male mice, and 3.1, 13, and 29 mg/kg for female mice, respectively. In rats (of both sexes), the LD50s were 9, 11, and 38 mg/kg after intraperitoneal (IP), SC, and PO administration, respectively.
Contraindications for use include pregnancy and breastfeeding, advanced atherosclerosis, and uncontrolled hypertension. Per the official Summary of Product Characteristics: there are no or limited data from the use of cytisinicline in pregnant women; animal studies are insufficient with respect to reproductive toxicity; cytisinicline is contraindicated during pregnancy and during breast-feeding.
There is no clinical experience of cytisinicline in patients with renal or hepatic impairment; the drug product is not recommended for use in this patient population. Due to limited clinical experience, cytisinicline is not recommended for use in elderly patients over 65. The safety and efficacy in persons under 18 years of age have not been established; cytisinicline is not recommended for use in persons under 18.
Because cytisine is excreted unchanged renally without hepatic metabolism, the risk of drug interactions is lowered. Data are lacking regarding use with other smoking cessation agents; concurrent use should be avoided. Simultaneous administration of cytisine and smoking or use of products containing nicotine could lead to aggravated adverse reactions of nicotine. It is currently unknown whether cytisinicline may reduce the effectiveness of systemically acting hormonal contraceptives; women using hormonal contraceptives should add a second barrier method.
The proportion of patients who discontinued treatment because of adverse reactions was 6β15.5%, and in controlled studies this was comparable to the proportion in the placebo group. Mild to moderate adverse reactions have usually been observed, most frequently concerning the gastrointestinal tract. The majority of adverse reactions occurred at the beginning of therapy and resolved during treatment.
Health conditions that Cytisine may help support.
Body systems that Cytisine may help support.
Go back