Medically Reviewed By Vikas Londhe M.Pharm (Pharmacology)
Smoking is the leading cause of preventable death worldwide. Smoke from cigarette contains mixture of toxic chemicals, nearly 5000 chemicals produced during combustion of tobacco and its additives and many of these have harmful effect on every organ of the body. Out of these 5000 chemicals 70 chemicals are the known carcinogens like, formaldehyde, vinyl chloride etc.
But if these chemicals are all harmful and can leads to serious health condition like cancer then why people find it difficult to quit smoking? Nicotine is the chemical present in cigarette, which is highly addictive but it is non carcinogen. Nicotine makes people habitual to smoking.
Health effects of smoking
Smoking is the leading cause of many life-threatening health conditions. Smoking is the main contributor to lung cancer worldwide. Apart from this, smoking is the leading cause of heart disease, stroke, chronic obstructive pulmonary disease (COPD), and many other life-threatening conditions. Smoking can significantly increase the risk of other ailments, including type 2 diabetes, infertility, and pregnancy complications. As this is the established link in active smokers, smoking can cause serious health problems in passive non-smokers, or secondhand smokers who are exposed to smoke from primary smokers, especially children. Passive smoking can lead to health conditions like asthma, respiratory infections, or sudden infant death syndrome (SIDS). The other effects of smoking can include an economic burden on patients from healthcare costs and, at the same time, productivity loss at the workplace.
Prevalence worldwide
According to WHO report 2023, there are 1.1 billion active smokers present worldwide—smoking causes more than 8 million deaths per year globally. As per the CDC report 2023, in the USA alone, 11.5% of adults smoke; out of these, 480,000 deaths occur due to smoking annually in the USA. 41000 deaths are associated with passive smoking annually due to smoking. It all increases the economic burden up to 300 billion dollar.
Conventional smoking therapies
Conventional smoking therapies include Nicotine Replacement Therapy (NRT). It is one of the most commonly used methods and comes in several forms, like patches, gums, lozenges, inhalers, and nasal sprays. Prescription medications such as varenicline, a partial agonist at nicotinic receptors, and bupropion, an antidepressant that helps reduce cravings and withdrawal symptoms, are also widely used. Other behavioral therapies are also included in treatment regimens.
However, even if this therapies are beneficial, these therapies come with drawbacks: NRT may not fully cure psychological dependency on smoking, bupropion and varenicline can cause side effects like insomnia, mood changes, and nausea, and behavioural therapy often requires long-term commitment, access to trained professionals, and consistent follow-up, which can be barriers for many smoking quitters.
What is Cytisinicline?
Cytisinicline is a plant-based alkaloid derived from Cytisus laburnum (golden rain tree). It has been used for decades in Eastern Europe as a smoking cessation aid, particularly in Bulgaria and Poland, under the brand name Tabex. Structurally and pharmacologically, it shares similarities with varenicline, a well-known partial agonist of the nicotinic acetylcholine receptor (nAChR).
Unlike nicotine, which fully activates neuronal nicotinic acetylcholine receptors, cytisinicline acts as a partial agonist, stimulating the receptor enough to reduce withdrawal symptoms and cravings while also blocking nicotine’s ability to bind and create the rewarding “high.” This dual action is what makes cytisinicline so promising.
How Does Cytisinicline Work?
Cytisinicline targets the α4β2 subtype of nicotinic acetylcholine receptors in the brain. These receptors play a key role in the addictive properties of nicotine. By binding to them, cytisinicline helps:
Reduce nicotine withdrawal symptoms
Diminish the rewarding effects of smoking
Ease the transition away from tobacco products
Its mechanism is very similar to that of varenicline, but cytisinicline may have a better safety and tolerability profile, which is a major advantage.
Clinical Evidence and Recent Trials
While cytisinicline has a long history of use in Eastern Europe, it has only recently undergone rigorous clinical trials in the U.S. and other Western countries.
ORCA-1 Trial (2020): This Phase 2b trial showed that cytisinicline significantly improved quit rates compared to placebo. Importantly, the drug was well-tolerated, with fewer reported side effects than varenicline.
ORCA-2 Trial (2022): A pivotal Phase 3 study that met its primary endpoint. The trial demonstrated that a 12-week course of cytisinicline significantly increased smoking abstinence compared to placebo. The quit rates were approximately 2.6 to 6.3 times higher than placebo, depending on the dosing regimen.
ORCA-3 Trial (2024): The most recent Phase 3 trial confirmed the results of ORCA-2, showing sustained abstinence at 6 and 12 weeks, with very few adverse events. The most common side effects were mild gastrointestinal discomfort and sleep disturbances.
Safety Profile
Across multiple studies, cytisinicline has been well tolerated. The most frequently reported side effects Nausea, Abnormal dreams, Insomnia, Headache, Fatigue and Anxiety. Cytisinicline appears to have a more favourable side effect profile compared to varenicline. Cytisinicline is associated with lower rates of nausea and sleep disturbances.
Conclusion
Cytisinicline is emerging as a serious contender in the smoking cessation space. With a strong safety profile, promising efficacy, and a natural origin, it could offer a much-needed alternative to current therapies. If FDA approved, cytisinicline may become a first-line option for smokers trying to quit and possibly the next big thing in the fight against nicotine addiction.
References
1.Varghese J, Muntode Gharde P. A Comprehensive Review on the Impacts of Smoking on the Health of an Individual. Cureus. 2023 Oct 5;15(10):e46532. doi: 10.7759/cureus.46532. PMID: 37927763; PMCID: PMC10625450.
2. Edward D. Gometz, Health Effects of Smoking and the Benefits of Quitting, AMA journal of ethics, Jan 2011, available from https://journalofethics.ama-assn.org/article/health-effects-smoking-and-benefits-quitting/2011-01
3. WHO report on the global tobacco epidemic, 2023: protect people from tobacco smoke, 31 July 2023, World Health Organization, available from https://www.who.int/publications/i/item/9789240077164
4. Notes from the Field: Tobacco Product Use Among Adults — United States, 2017–2023, Morbidity and Mortality Weekly Report, March 6, 2025 / 74(7);118–121
5. Nides M, Rigotti NA, Benowitz N, Clarke A, Jacobs C. A Multicenter, Double-Blind, Randomized, Placebo-Controlled Phase 2b Trial of Cytisinicline in Adult Smokers (The ORCA-1 Trial). Nicotine Tob Res. 2021 Aug 29;23(10):1656-1663. doi: 10.1093/ntr/ntab073. PMID: 33847362; PMCID: PMC8403245.
6. Rigotti NA, Benowitz NL, Prochaska J, et al. Cytisinicline for Smoking Cessation: A Randomized Clinical Trial. JAMA.2023; 330(2):152–160. doi:10.1001/jama.2023.10042
7. Rigotti NA, Benowitz NL, Prochaska JJ, et al. Cytisinicline for Smoking Cessation: The ORCA Phase 3 Replication Randomized Clinical Trial. JAMA Intern Med.Published online April 21, 2025. doi:10.1001/jamainternmed.2025.0628
8. Current Cigarette Smoking among Adults in the United States, 17 Sep 2024, Smoking and Tobacco Use available from https://www.cdc.gov/tobacco/php/data-statistics/adult-data-cigarettes/index.html
9. Centers for Disease Control and Prevention (US); National Center for Chronic Disease Prevention and Health Promotion (US); Office on Smoking and Health (US). How Tobacco Smoke Causes Disease: The Biology and Behavioral Basis for Smoking-Attributable Disease: A Report of the Surgeon General. Atlanta (GA): Centers for Disease Control and Prevention (US); 2010. 3, Chemistry and Toxicology of Cigarette Smoke and Biomarkers of Exposure and Harm. Available from: https://www.ncbi.nlm.nih.gov/books/NBK53014/
10. What’s in a cigarette? Cancer research UK, available from https://www.cancerresearchuk.org/about-cancer/causes-of-cancer/smoking-and-cancer/whats-in-a-cigarette-0
Add a Comment