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Cytisine
Cytisine
Cytisine
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Cytisine
Clinical data
Trade namesTBX-Free
Other namesCytisine; baptitoxine; sophorine
License data
Routes of
administration		By mouth
ATC code
Identifiers
  • (1R,5S)-1,2,3,4,5,6-hexahydro-8H-1,5-methanopyrido[1,2-a] [1,3]diazocin-8-one
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.006.924 Edit this at Wikidata
Chemical and physical data
FormulaC11H14N2O
Molar mass190.246 g·mol−1
3D model (JSmol)
Melting point152 °C (306 °F)
Boiling point218 °C (424 °F)
  • O=C1/C=C\C=C2/N1C[C@@H]3CNC[C@H]2C3
  • InChI=1S/C11H14N2O/c14-11-3-1-2-10-9-4-8(5-12-6-9)7-13(10)11/h1-3,8-9,12H,4-7H2/t8-,9+/m0/s1
  • Key:ANJTVLIZGCUXLD-DTWKUNHWSA-N

Cytisine, 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. It has been used medically to help with smoking cessation.[1] It has been found effective in several randomized clinical trials, including in the United States and New Zealand,[1] and is being investigated in additional trials in the United States and a non-inferiority trial in Australia in which it is being compared head-to-head with the smoking cessation aid varenicline (sold in the United States as Chantix).[2] It has also been used entheogenically via mescalbeans by some Native American groups, historically in the Rio Grande Valley predating even peyote.[3]

Cytisine is on the World Health Organization's List of Essential Medicines.[4]

Uses

[edit]

Smoking cessation

[edit]

Cytisine has been available in post-Soviet states as an aid to smoking cessation under the brand name Tabex from the Bulgarian pharmaceutical company Sopharma AD.[5] In 1961, Bulgarian pharmacist Strashimir Ingilizov synthesized Tabex using the alkaloid Cytisine which was derived from the seeds of the yellow acacia (Cytisus laburnum), a European decorative shrub prevalent in Bulgaria and commonly referred to as "golden rain".[6] It was first marketed in Bulgaria in 1964 and then became widely available in the Soviet Union.[7] In Poland, it is sold under the brand name Desmoxan, and it is also available in Canada under the brand name Cravv.[8][9]

Its molecular structure has some similarity to that of nicotine, and it has similar pharmacological effects. Like the smoking cessation aid varenicline, cytisine is a partial agonist of nicotinic acetylcholine receptors (nAChRs).[10] Cytisine has a short half-life of 4.8 hours.[11] As a result, the extract 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.[12]

In 2011, a randomized controlled trial with 740 patients found cytisine improved 12-month abstinence from nicotine from 2.4% with placebo to 8.4% with cytisine.[13] A 2013 meta-analysis of eight studies demonstrated that cytisine has similar effectiveness to varenicline but with substantially lower side effects.[14] A 2014 systematic review and economic evaluation concluded that cytisine was more likely to be cost-effective for smoking cessation than varenicline.[15]

It is on the World Health Organization's List of Essential Medicines.[4]

Recreational

[edit]

Plants containing cytisine, including the scotch broom and mescalbean, have also been used recreationally. Positive effects are reported to include a nicotine-like intoxication.[13]

Reagent for organic chemistry

[edit]

(−)-Cytisine extracted from Laburnum anagyroides seeds was used as a starting material for the preparation of "(+)- sparteine surrogate", for the preparation of enantiomerically enriched lithium anions of opposite stereochemistry to those anions obtained from sparteine.[16]

Sources

[edit]

Cytisine is extracted from the seeds of Cytisus laburnum L. (golden rain acacia), and is found in several genera of the subfamily Faboideae of the family Fabaceae, including Laburnum, Anagyris, Thermopsis, Cytisus, Genista, Retama and Sophora. Cytisine is also present in Gymnocladus of the subfamily Caesalpinioideae.[citation needed]

Toxicity

[edit]

Cytisine has been found to interfere with breathing and cause death in test mice; LD50 i.v. in mice is about 2 mg/kg.[17] Cytisine is also teratogenic.[18]

Māmane (Sophora chrysophylla) can contain amounts of cytisine that are lethal to most animals. The palila (Loxioides bailleui, a bird), Uresiphita polygonalis virescens and Cydia species (moths), and possibly sheep and goats are not affected by the toxin for various reasons, and consume māmane, or parts of it, as food. U. p. virescens caterpillars are possibly able to sequester the cytisine to give themselves protection from predation; they have aposematic coloration which would warn off potential predators.[19]

References

[edit]
[edit]
Revisions and contributorsEdit on WikipediaRead on Wikipedia

Cytisine

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from Grokipedia
Cytisine is a naturally occurring alkaloid primarily isolated from plants in the Fabaceae family, such as Laburnum anagyroides and Cytisus species, where it serves as a toxic principle in seeds. It features a tricyclic structure with a molecular formula of C₁₁H₁₄N₂O and a molecular weight of 190.24 g/mol, characterized by fused pyridine and piperidine rings with a ketone group. Chemically, cytisine is a white crystalline solid with a melting point of 152–153 °C and solubility in water (approximately 4.39 × 10⁵ mg/L at 16 °C), methanol, and acetone. As a at the α₄β₂ subtype of nicotinic receptors (nAChRs), cytisine mimics 's effects but with lower intrinsic activity, thereby reducing release induced by nicotine and alleviating withdrawal symptoms during . Its include a plasma of about 4.8 hours (in humans), a of approximately 115 L (in humans), and renal clearance of 43 mL/min, supporting its rapid onset and short duration of action. Beyond its primary role, cytisine exhibits diverse pharmacological activities, including neuroprotective effects, cardiovascular protection, anti-tumor properties, , and potential benefits in reducing alcohol consumption and treating . Cytisine has been utilized as a aid since 1964, particularly in under the trade name Tabex, and is noted for its efficacy comparable to with a more favorable cost profile. Phase III clinical trials, including the ORCA-2 trial in 2025, have demonstrated its ability to increase quit rates, with ongoing research exploring its broader therapeutic applications through computer-simulated target analyses. While historically limited outside , recent developments—including addition to the WHO Model List of in September 2025, recognition by UK's NICE, and a planned FDA approval application in 2025—signal growing global adoption as a natural, low-cost therapeutic agent.

Chemistry

Molecular structure

Cytisine is a quinolizidine characterized by the molecular formula C₁₁H₁₄N₂O. Its molecular weight is 190.24 g/mol. The IUPAC name for cytisine is (1R,5S)-1,2,3,4,5,6-hexahydro-1,5-methano-8H-pyrido[1,2-a][1,5]diazocin-8-one, reflecting its specific at the positions. This compound possesses a tetracyclic structure characterized by fused and rings bridged by a , with two atoms: one tertiary nitrogen and another secondary nitrogen. The structure includes a , specifically a 2-pyridone moiety, which contributes to the cyclic characteristic of the molecule. The (1R,5S) ensures a defined spatial arrangement, with the bridge oriented in an α configuration relative to the rings. Structurally, cytisine shares a partial similarity with , both featuring a ring connected to a nitrogen-containing heterocyclic ring, though cytisine's bridged bicyclic framework imparts greater rigidity compared to 's flexible ring. This core scaffold can be represented in simplified textual form as a fused piperidine-pyridone system with a -CH₂- bridge between positions 1 and 5, emphasizing the diaza-bridged nature.

Physical and chemical properties

Cytisine appears as a to off-white crystalline powder. It melts at 152–153 °C and sublimes at this temperature. The compound exhibits good in polar solvents, dissolving readily in (approximately 439 g/L at 16 °C), (approximately 286 g/L), (approximately 500 g/L), and acetone (approximately 77 g/L), while being sparingly soluble in ether and practically insoluble in . This profile arises from its polar functional groups, including the and moieties. Cytisine is a with a pKa of approximately 7.92 for the conjugate acid of its pyridine-like , reflecting the basicity of the tertiary in its quinolizidine . It demonstrates optical activity as the naturally occurring , with a of [α]_D^{20} = -108° (c = 1, ). Under normal storage conditions, cytisine remains stable, but it decomposes upon heating, releasing toxic oxides, and shows sensitivity to extreme environments that can affect its formulation stability.

Synthesis

The first total synthesis of racemic cytisine was achieved by Bohlmann and colleagues in 1955, employing a multi-step sequence starting from derivatives to construct the quinolizidine core through sequential alkylations and cyclizations, though overall yields were low due to the complexity of the bridged ring system. In the same year, van Tamelen and Baran independently reported a route utilizing a pyridine-derived A-ring, involving followed by reduction and cyclization, achieving cytisine in approximately 4% overall yield over multiple steps. Modern synthetic approaches have focused on stereoselective methods to access enantiopure cytisine, leveraging advanced catalytic techniques for efficiency and selectivity. For instance, a 2004 enantioselective synthesis by Lesma et al. employed ring-closing metathesis (RCM) with a catalyst to form the central pyridone ring, followed by an intramolecular aza-Michael addition to establish the piperidine C-ring , yielding (-)-cytisine in 12 steps from commercially available materials with high enantiomeric excess (>98% ee). Similarly, O'Brien's 2005 route used RCM to close the B-ring in a bispidine intermediate, followed by lithiation and installation, delivering racemic cytisine in 6 steps with an overall yield of 19%. More recent work, such as the 2018 synthesis by Chavdarian et al., highlighted a stereodivergent 6-endo aza-Michael addition to forge the C-ring from a chiral enone precursor, enabling access to (-)-cytisine in 10 steps with 25% overall yield and complete diastereocontrol. Semisynthetic methods typically begin with extraction of natural (-)-cytisine from plant sources like anagyroides seeds, followed by selective modifications to generate analogs. Common techniques include N-acylation or sulfonylation at the piperidine nitrogen using acid chlorides or sulfonyl chlorides under basic conditions, as demonstrated in the preparation of N-benzoyl cytisine derivatives with yields exceeding 80%. Halogenation at C-3 or C-5 positions via , such as bromination with N-bromosuccinimide, provides functionalized intermediates in 70-90% yields for further elaboration. Cytisine serves as a versatile in , particularly for constructing related and pharmaceuticals. It acts as a structural lead and synthetic scaffold for , a cytisine-inspired for ; while varenicline is not directly derived from cytisine, semisynthetic modifications of cytisine analogs informed its optimization, with key steps involving partial degradation of the quinolizidine to a 9-aminobenzazepine core. Additionally, cytisine is employed in the synthesis of lupin congeners, such as anagyrine, through regioselective C-alkylation followed by oxidative dimerization, achieving 50-60% yields in modular sequences. Efficiency comparisons across methods reveal trade-offs between step economy and stereocontrol: early routes like van Tamelen's offer foundational strategies but suffer low yields (∼4%), while modern RCM-based syntheses (e.g., O'Brien, 19% over 6 steps) and aza-Michael approaches (e.g., Chavdarian, 25% over 10 steps) provide higher efficiencies and enantioselectivity, making them preferable for analog preparation; semisynthetic modifications remain the most efficient for derivative libraries, often exceeding 70% yield from isolated cytisine.

Natural occurrence

Plant sources

Cytisine is primarily obtained from plants in the family, particularly the seeds of Laburnum anagyroides (commonly known as the golden chain tree) and various species. These shrubs or small trees are the richest natural sources, with cytisine serving as the predominant . Other genera, such as (including Sophora secundiflora) and , also contain cytisine, though typically in lower amounts. In Laburnum anagyroides, cytisine concentrations can reach up to 3% of the dry weight in ripe seeds, making them the preferred extraction material, while levels in leaves, pods, and bark are substantially lower (often below 1%). In Cytisus species and Sophora, cytisine is present at 0.1–2% in seeds and other parts, varying by species and environmental factors. Laburnum anagyroides is native to central and southeastern Europe, ranging from to , where it grows in temperate woodlands and scrublands. Cytisus species are also predominantly European, while Sophora genera like S. secundiflora are native to . These plants are widely cultivated ornamentally in temperate regions worldwide for their pendulous yellow flowers. Extraction of cytisine typically involves solvent-based methods from ground seeds, starting with alkaline treatment to form a paste, followed by extraction using organic solvents such as , , or in a Soxhlet apparatus. The crude extract is then purified through acid-base partitioning to isolate the base, with final refinement via recrystallization from acetone or , or for higher purity. Historically, source plants like Laburnum anagyroides and Cytisus laburnum have been used in European as emetics and purgatives due to their toxicity, with seeds inducing vomiting and gastrointestinal effects in small doses. Similarly, Sophora secundiflora seeds were employed by Native American groups for emetic purposes in rituals, leveraging the plant's poisonous properties. These uses highlight the plants' recognition as potent toxins long before cytisine's isolation.

Biosynthesis

Cytisine, a quinolizidine , is biosynthesized in plants of the family through a pathway originating from L-lysine. The process initiates with the of L-lysine to , catalyzed by lysine decarboxylase (LDC), an enzyme specific to quinolizidine alkaloid (QA) production. Cadaverine is subsequently oxidized by copper amine oxidases (CuAO) to yield the intermediate Δ¹-piperideine. This key then dimerizes with another Δ¹-piperideine to form tetrahydroanabasine, the bicyclic quinolizidine core structure. Further enzymatic modifications, including dehydrogenation and N-methylation, convert this scaffold into cytisine, particularly in species like Laburnum anagyroides. The genetic basis of this pathway involves several genes clustered or co-expressed in QA-producing . The LDC gene, first cloned from , encodes the rate-limiting enzyme and has coevolved with biosynthesis across the Leguminosae, correlating with the presence of QAs in over 400 . Transcriptomic studies in lupins and related genera have identified candidate genes for CuAO and downstream enzymes, such as those for ring closure and oxidation, revealing conserved motifs but species-specific expression patterns that direct flux toward particular alkaloids. For instance, an S-adenosyl-L-methionine-dependent N-methyltransferase specifically methylates cytisine precursors in , enhancing its accumulation. Evolutionarily, the cytisine biosynthetic pathway has adapted as a defense mechanism in against s, where QAs act as feeding deterrents and toxins, reducing palatability and digestibility for insects and mammals. This protective role is evident in the inducible accumulation of cytisine in response to herbivory and its correlation with reduced herbivore damage in alkaloid-rich genotypes. The pathway's antiquity in Leguminosae suggests it contributed to the family's diversification by enabling colonization of herbivore-pressured environments. Across species, variations in the QA pathway arise from differential activities and substrate specificities, leading to distinct profiles. In species, the pathway predominantly yields lupanine and through alternative cyclizations and reductions, whereas cytisine production in genera like and involves unique dehydrogenases that introduce the characteristic pyridone ring via oxidation of the quinolizidine nitrogen. These divergences reflect ecological adaptations, with cytisine-dominant species often inhabiting Mediterranean regions where specific pressures favor its toxicity profile over other QAs.

Pharmacology

Mechanism of action

Cytisine acts primarily as a at the α₄β₂ subtype of nicotinic receptors (nAChRs), which are pentameric ligand-gated ion channels predominantly expressed in the and involved in . By binding to these receptors, cytisine elicits a submaximal response compared to full agonists like , thereby attenuating the reinforcing effects of nicotine while partially activating the receptor to alleviate withdrawal symptoms. This partial leads to rapid desensitization of the α₄β₂ nAChRs, reducing their responsiveness to subsequent nicotine exposure and thereby diminishing nicotine-induced release in reward pathways. The binding affinity of cytisine for α₄β₂ nAChRs is high, with a Ki value of approximately 0.2 nM, enabling effective competition with at these sites. In contrast, cytisine exhibits lower affinity for other nAChR subtypes, such as α₃β₄ (Ki ≈ 100–300 nM) and α₇ (Ki ≈ 200–600 nM), resulting in weak off-target activity at these receptors. At higher doses, cytisine can function as an by further promoting receptor desensitization and blocking full effects. Structurally, cytisine's nicotine-like binding is facilitated by its lupinane scaffold, which mimics the ring of , allowing it to occupy the orthosteric site at the α₄β₂ nAChR interface between subunits. This interaction involves key hydrophobic contacts and hydrogen bonding with aromatic residues in the receptor's binding pocket, stabilizing the in a conformation that supports partial activation and subsequent desensitization.

Pharmacokinetics

Cytisine exhibits rapid absorption following , with peak plasma concentrations typically reached within 1 hour. Studies in healthy volunteers have reported a mean time to maximum concentration (T_max) of approximately 0.92 hours after a 1.5 mg dose, and 1-2 hours across doses ranging from 1.5 to 4.5 mg. is estimated at around 42%, based on animal data extrapolated to s, though direct human measurements indicate efficient gastrointestinal uptake without significant food effects. The drug distributes widely throughout the body, with a of approximately 6.2 L/kg observed in preclinical models, suggesting extensive tissue penetration. Cytisine crosses the blood-brain barrier to exert central effects, though it does so less readily than , contributing to its profile at nicotinic receptors. Metabolism of cytisine is minimal, with no detectable metabolites identified in plasma or following oral dosing. The compound undergoes slight , primarily in the liver, but the majority remains unchanged. occurs predominantly via the renal route, with approximately 64% of an administered dose recovered unchanged in within 24 hours. Biliary and fecal elimination is minor, accounting for less than 3-11% in preclinical studies. The elimination ranges from 4 to 6 hours, which supports dosing schedules involving multiple daily administrations over extended regimens, such as 25 days for therapeutic use. Due to its limited hepatic metabolism and primary renal clearance, cytisine has a low overall potential for pharmacokinetic interactions, though caution may be warranted with agents affecting renal function.

Therapeutic uses

Cytisine serves as a primary for , acting as a at the α4β2 nicotinic receptors (nAChRs) to mimic 's effects while reducing cravings and withdrawal symptoms by limiting release in response to subsequent exposure. This mechanism helps attenuate the rewarding properties of , facilitating without fully replicating 's addictive potential. The standard treatment regimen involves a 25-day course, typically using 1.5 mg tablets such as those in the commercial product Tabex. Patients begin with 1 tablet every 2 hours (6 tablets daily) for the first 3 days, alongside instructions to reduce consumption gradually; this is followed by tapering to 1 tablet every 2-3 hours (4-5 daily) through day 12, then 1-2 tablets daily until day 25, with complete cessation targeted by day 5. Minimal behavioral support, such as counseling, is often integrated to enhance outcomes. Meta-analyses of randomized controlled trials demonstrate cytisine's , with biochemically verified continuous rates at 6 months approximately 1.5 to 2 times higher than ( 2.00-2.99) and superior to ( 1.76). Its effectiveness is comparable to , though with fewer severe adverse events. Key clinical s, including the phase 3 ORCA-2 (published 2023) and its replication ORCA-3 (published 2025), of cytisinicline—a synthetic analog of cytisine—have reported 6-week and 12-week regimens yielding 25-32% rates at 12 weeks versus 4-12% for in ORCA-2, confirming tolerability and high compliance (over 75%). Cytisine is available over-the-counter in Central and Eastern European countries, including Bulgaria, Poland, and Russia, where it has been used since the 1960s as a low-cost generic option. In Western countries, it remains investigational; as of November 2025, the U.S. FDA has accepted a new drug application for cytisinicline for smoking cessation under standard review, with a PDUFA target action date of June 20, 2026, supported by completed phase 3 trials.

Other applications

In the mid-20th century, cytisine was investigated and used as a respiratory in the former and during the 1950s and 1960s, primarily to treat conditions involving respiratory depression, with effects qualitatively similar to those of lobeline, another plant-derived . This historical application leveraged cytisine's ability to stimulate nicotinic acetylcholine receptors (nAChRs) to enhance respiratory drive, though it was largely supplanted by more modern therapies due to variability in efficacy and safety concerns. Emerging preclinical research has explored cytisine's potential in neurodegenerative and inflammatory disorders through its modulation of nAChRs. In models, cytisine and its derivatives, such as 3-bromocytisine and 5-bromocytisine, have demonstrated neuroprotective effects by enhancing release in nigrostriatal pathways and protecting neurons from , suggesting a role in mitigating motor symptoms via α4β2 nAChR partial . For , cytisine derivatives like N-methylcytisine exhibit anti-inflammatory properties in dextran sulfate sodium-induced colitis models, reducing pro-inflammatory cytokines such as TNF-α and IL-6 via suppression of the pathway, highlighting potential gut-protective effects. Derivatives of cytisine are under investigation for broader therapeutic applications. Cytisinicline, a stabilized formulation of cytisine, is in clinical trials (e.g., the program) not only for but also for vaping cessation, showing promising efficacy in reducing nicotine cravings across addiction subtypes with a favorable tolerability profile compared to . In October 2025, the FDA awarded a Commissioner's National Priority Voucher for its use in vaping cessation. Analogs of cytisine, including cytisine itself in studies, have displayed antinociceptive effects in models of and tonic pain, attributed to partial at α4β2 nAChRs, which attenuates without the full addictive potential of . Limited veterinary applications have been explored, primarily in preclinical animal models for de-addiction. Cytisine reduces consumption and nicotine-induced alcohol intake in rodents like mice by decreasing mesolimbic activity, offering a potential tool for managing substance use disorders in animals, though no widespread clinical veterinary use has been established. Despite these prospects, most alternative applications of cytisine remain preclinical or historical, constrained by its dose-dependent toxicity profile, which includes gastrointestinal upset, dizziness, and, at high doses, respiratory failure or convulsions leading to rare fatalities, limiting broader adoption beyond controlled settings.

History

Discovery and isolation

Cytisine was first identified as a toxic present in the seeds of anagyroides (now classified as laburnum) in 1818 by the French chemist , who detected its presence during analyses of plant extracts but did not isolate it. This early recognition stemmed from observations of the plant's poisonous properties, with reports of human and animal poisonings causing symptoms such as , , convulsions, and respiratory distress, attributed to the alkaloid's presence. Throughout the , toxicity studies focused on seed ingestions, confirming the alkaloid's role in fatal cases involving respiratory failure, though quantitative assessments were limited by the lack of pure compound. The pure isolation of cytisine was achieved in 1865 by German chemists Alfred Husemann and Wilhelm Marmé, who extracted it from the seeds of Cytisus laburnum and named it after the plant's genus, reflecting its botanical origin. Their work, published in the Zeitschrift für Chemie, involved precipitation as a crystalline nitrate salt, marking the first characterization of cytisine as a distinct with emetic and purgative effects in preliminary animal tests. This isolation enabled further 19th-century investigations into its toxicity, including dose-response studies in that highlighted its nicotine-mimicking paralytic actions at high doses. Initial biological assays in the early revealed cytisine's pharmacological similarity to . In 1912, British pharmacologists and Patrick Playfair Laidlaw conducted systematic experiments on cats and frogs, demonstrating that cytisine produced qualitatively identical effects to , including stimulation of autonomic ganglia, increased , and contractions, albeit at higher doses. These findings established cytisine as a prototypical in animal models. The complete structural elucidation of cytisine occurred in the 1930s through combined degradation and synthetic approaches. In 1932, British chemist Harold R. Ing reported the first , proposing a lupinane-based framework that aligned with partial degradation products. Subsequently, Austrian chemists Späth and Friedrich Galinovsky confirmed the quinolizidine in 1936 via oxidative degradation and spectroscopic analysis, resolving earlier ambiguities and enabling precise biosynthetic correlations.

Pharmaceutical development

Cytisine's pharmaceutical development began with its exploration as a therapeutic agent in during the mid-20th century. In the , clinical trials in the USSR and investigated cytisine as a respiratory , similar to lobeline, for treating conditions involving respiratory depression. These early studies laid the groundwork for its later applications, demonstrating its ability to stimulate nicotinic receptors. By the , Bulgarian pharmacologists at Sopharma developed cytisine into a structured treatment, launching it as Tabex in 1964—the first commercial product containing cytisine (1.5 mg tablets) specifically for . Key milestones in cytisine's development include renewed Western interest after 2000, spurred by its activity at α4β2 nicotinic receptors, which inspired the synthesis of by in 1997. , a cytisine with improved , received FDA approval in 2006 for , highlighting cytisine's role as a foundational compound in modern . This period marked a shift toward rigorous clinical validation, with a 2011 placebo-controlled trial in confirming cytisine's efficacy (8.4% at 12 months versus 2.4% for ) and a 2013 showing a 3.29-fold increase in six-month rates compared to . By 2025, cytisine held regulatory approval in over 30 countries, primarily in , , the , and , often under brand names like Tabex, Desmoxan, and Cravv, with availability as both prescription and over-the-counter (OTC) in select markets such as and . In the US and , Achieve Life Sciences advanced cytisinicline—a cytisine formulation—for approval through Phase 3 trials; the ORCA-2 trial (2023) demonstrated superior six- and 12-week treatment continuous abstinence rates of 6.8% (6-week treatment) and 18.7% (12-week treatment) versus 4.8% for at six months, while ORCA-3 (published 2025) replicated these findings in 792 participants, with 6-month rates of 6.8% (6-week) and 20.5% (12-week) versus 4.2% and 1.1% for , confirming sustained efficacy and tolerability with reduced cravings. The FDA accepted the for cytisinicline in September 2025, with a of June 2026; as of November 2025, Achieve submitted a 120-day safety update on November 3, the ORCA-OL long-term safety trial completed treatment in October, and the FDA granted designation on October 17 for e-cigarette or vaping cessation. The continues evaluation amid ongoing trials. Despite these advances, cytisine's global adoption has been limited by its status as a low-cost generic lacking strong protection, which deterred large-scale investment in Western markets until recent formulations like cytisinicline addressed issues. Competition from patented alternatives, notably (off-patent in 2020 but with established branding), further constrained expansion, as varenicline's superior absorption and marketing overshadowed cytisine's affordability. A noninferiority found cytisine comparable to in efficacy but with fewer gastrointestinal side effects, yet regulatory hurdles persisted. Recent progress from 2023 to has bolstered cytisine's profile, with a Cochrane review (2023) analyzing eight trials (3,833 participants) reporting a of 1.30 (95% CI 1.15-1.47) for versus , and a 2024 meta-analysis (six trials) yielding a of 2.65 (95% CI 1.50-4.67). These confirm cytisine's , particularly in low- and middle-income settings, supporting its addition to the WHO Model List of in 2025. Potential OTC expansion is underway, with approvals in additional markets and Achieve's trials paving the way for broader accessibility in the and post-2026.

Safety and toxicity

Adverse effects

Cytisine is generally well-tolerated at therapeutic doses for , with most adverse effects being mild and transient. Common side effects primarily involve the gastrointestinal and neurological systems, often resolving without intervention. Gastrointestinal adverse effects are among the most frequently reported, including , dyspepsia, and , occurring in approximately 6-23% of users depending on the study and dosing regimen. and have been noted in up to 8.4% of patients, while dyspepsia and are also common but typically self-limiting. These effects may be influenced by cytisine's pharmacokinetic profile, such as its rapid absorption and partial at nicotinic receptors, though they rarely necessitate treatment changes. Neurological side effects, such as , , and , affect 3-23% of individuals, with reported in up to 11% and in 3-22.7%. These symptoms are often attributable to during rather than direct cytisine toxicity, and abnormal dreams occur in less than 10% of cases. and mood changes, including anxiety, are also observed but tend to diminish over time. Cardiovascular effects are uncommon and mild, manifesting as or in sensitive individuals, with tachycardia reported in 4-16% in some trials and hypertension considered very common (>10%) in product information. These are generally transient and do not lead to serious outcomes in therapeutic use. Overall, discontinuation rates due to adverse effects are low, at less than 5% across clinical trials, with 2.9% reported in a phase 3 study. This is lower than with varenicline, where adverse events occur more frequently. Management typically involves dose reduction or supportive care, as effects are self-limiting in most cases.

Acute toxicity

Cytisine exhibits significant acute toxicity primarily due to its action as a partial agonist at nicotinic acetylcholine receptors (nAChRs), with a narrow therapeutic window in overdose scenarios. The median lethal dose (LD50) is approximately 1.73 mg/kg via intravenous administration in mice and 5–50 mg/kg via oral administration in rats. Human oral LD50 estimates range from 50–100 mg/kg based on extrapolation from animal data, though the precise lethal dose remains undetermined due to sparse clinical reports. Overdose symptoms typically involve gastrointestinal distress (nausea and ), central nervous system effects (, , convulsions, and clonic spasms), cardiovascular changes ( or ), and respiratory depression, potentially progressing to and . These arise from initial nAChR overstimulation causing excitation, followed by persistent and receptor blockade, leading to neuromuscular failure. indicate no teratogenic effects. A 2024 case report documented a 64-year-old who inadvertently overdosed on cytisine tablets (totaling about 54 mg over three days, exceeding the recommended dose), presenting with transient , clonic spasms, profuse sweating, trembling, vertigo, and mild gastrointestinal upset; she recovered completely without lasting sequelae after supportive management. In a contrasting fatal incident, a 20-year-old male in 2009 succumbed to following ingestion of cytisine-rich anagyroides tea, confirmed by postmortem LC-MS/MS analysis detecting high cytisine levels in biological fluids. Management of acute overdose focuses on supportive care, including gastrointestinal decontamination with activated charcoal or if ingestion was recent, hemodynamic stabilization, and for respiratory compromise; no specific is available. Cytisine is contraindicated in due to potential fetal risks and in patients with cardiovascular conditions such as advanced or uncontrolled , where toxicity may exacerbate hemodynamic instability.

References

  1. https://pubchem.ncbi.nlm.nih.gov/compound/Cytisine
  2. https://go.drugbank.com/drugs/DB09028
  3. https://analyticalsciencejournals.onlinelibrary.wiley.com/doi/abs/10.1002/dta.1707
  4. https://www.sciencedirect.com/science/article/pii/S075333222400091X
  5. https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2832701
  6. https://ash.org/new-tobacco-cessation-drug-added-to-who-eml-cytisine/
  7. https://www.goodrx.com/conditions/smoking-cessation/cytisine-smoking-cessation
  8. https://webbook.nist.gov/cgi/cbook.cgi?ID=485-35-8
  9. https://pmc.ncbi.nlm.nih.gov/articles/PMC10413377/
  10. https://www.chemicalbook.com/ProductChemicalPropertiesCB1136805_EN.htm
  11. https://pubs.acs.org/doi/10.1021/acs.jpclett.2c02021
  12. https://www.sigmaaldrich.com/US/en/product/aldrich/712264
  13. https://patents.google.com/patent/EP3834814A1/en
  14. https://www.sciencedirect.com/topics/pharmacology-toxicology-and-pharmaceutical-science/cytisine
  15. https://www.drugs.com/npp/cytisine.html
  16. https://pmc.ncbi.nlm.nih.gov/articles/PMC7551552/
  17. http://irjpms.com/wp-content/uploads/2019/02/IRJPMS-V2N2P175-19.pdf
  18. https://patents.google.com/patent/EP2292629A1/en
  19. https://powo.science.kew.org/taxon/urn:lsid:ipni.org:names:501428-1
  20. https://bibliotekanauki.pl/articles/895314.pdf
  21. https://www.sciencedirect.com/topics/biochemistry-genetics-and-molecular-biology/laburnum
  22. https://www.henriettes-herb.com/eclectic/kings/cytisus-labu.html
  23. https://www.frontiersin.org/journals/plant-science/articles/10.3389/fpls.2017.00087/full
  24. https://pubs.rsc.org/en/content/articlehtml/2022/np/d1np00069a
  25. https://academic.oup.com/plcell/article/24/3/1202/6097240
  26. https://www.frontiersin.org/journals/plant-science/articles/10.3389/fpls.2012.00239/full
  27. https://link.springer.com/article/10.1007/BF00398724
  28. https://link.springer.com/article/10.1007/BF00303957
  29. https://pubs.acs.org/doi/10.1021/acsomega.3c02179
  30. https://www.sciencedirect.com/topics/agricultural-and-biological-sciences/cytisine
  31. https://pmc.ncbi.nlm.nih.gov/articles/PMC3390607/
  32. https://www.sciencedirect.com/science/article/pii/S104366182100284X
  33. https://www.tandfonline.com/doi/pdf/10.1080/13102818.2007.10817436
  34. https://www.ncsct.co.uk/library/view/pdf/Cytisine-1-5mg-uk-spc-clean.pdf
  35. https://pubmed.ncbi.nlm.nih.gov/30526213/
  36. https://www.sciencedirect.com/topics/neuroscience/cytisine
  37. https://pmc.ncbi.nlm.nih.gov/articles/PMC2984121/
  38. https://www.sciencedirect.com/topics/[neuroscience](/page/Neuroscience)/cytisine
  39. https://pmc.ncbi.nlm.nih.gov/articles/PMC4859792/
  40. https://pmc.ncbi.nlm.nih.gov/articles/PMC2563682/
  41. https://www.tabex.net/application-of-tabex.php
  42. https://pubmed.ncbi.nlm.nih.gov/37678096/
  43. https://onlinelibrary.wiley.com/doi/10.1111/add.16592
  44. https://jamanetwork.com/journals/jama/fullarticle/2807079
  45. https://cdn.who.int/media/docs/default-source/2025-eml-expert-committee/addition-of-new-medicines/a.8_cytisine.pdf?sfvrsn=5df4226_6
  46. https://www.hcplive.com/view/smoking-cessation-aid-cytisnicline-up-for-fda-review
  47. https://ir.achievelifesciences.com/news-events/press-releases/detail/247/achieve-life-sciences-reports-third-quarter-2025-financial-results-provides-updates-on-cytisinicline-program
  48. https://achievelifesciences.com/achieve-meets-key-milestones-advancing-cytisinicline-nda-for-smoking-cessation/
  49. https://pubmed.ncbi.nlm.nih.gov/11841781/
  50. https://www.sciencedirect.com/science/article/abs/pii/S0014299908005219
  51. https://pmc.ncbi.nlm.nih.gov/articles/PMC6017650/
  52. https://psychiatryonline.org/doi/10.1176/appi.pn.2024.09.8.4
  53. https://ir.achievelifesciences.com/news-events/press-releases/detail/243/achieve-life-sciences-receives-fda-commissioners-national-priority-voucher-for-cytisinicline-for-treatment-of-nicotine-dependence-for-e-cigarette-or-vaping-cessation
  54. https://pmc.ncbi.nlm.nih.gov/articles/PMC3422531/
  55. http://if-pan.krakow.pl/pjp/pdf/2006/6_777.pdf
  56. https://pmc.ncbi.nlm.nih.gov/articles/PMC6179352/
  57. https://link.springer.com/article/10.1007/s00706-019-02415-5
  58. https://ir.achievelifesciences.com/news-events/press-releases/detail/224/achieve-life-sciences-announces-cytisinicline-phase-3-orca-3-trial-publication-on-smoking-cessation-in-jama-internal-medicine
  59. https://www.globenewswire.com/news-release/2025/11/06/3182358/0/en/Achieve-Life-Sciences-Reports-Third-Quarter-2025-Financial-Results-Provides-Updates-on-Cytisinicline-Program.html
  60. https://jamanetwork.com/journals/jama/fullarticle/2781643
  61. https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD006103.pub9/full
  62. https://pmc.ncbi.nlm.nih.gov/articles/PMC5953578/
  63. https://pmc.ncbi.nlm.nih.gov/articles/PMC11693792/
  64. https://dtb.bmj.com/content/62/5/71
  65. https://www.sanxinherbs.com/knowledge/is-cytisine-safe
  66. https://pmc.ncbi.nlm.nih.gov/articles/PMC12009246/
  67. https://turkjfampract.org/article/view/877
  68. https://pmc.ncbi.nlm.nih.gov/articles/PMC10336611/
  69. https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/410807
  70. https://medicines.bedfordshirelutonandmiltonkeynes.icb.nhs.uk/wp-content/uploads/2024/05/BLMK-ICB-Cytisinicline-Factsheet-for-Prescribers.pdf
  71. https://pubmed.ncbi.nlm.nih.gov/37432430/
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