What is Cytisinicline?
Cytisinicline, historically known as cytisine, is a naturally occurring plant-based alkaloid that has been utilized for smoking cessation in parts of Eastern Europe and Asia for decades. The medication works similarly to varenicline (formerly marketed as Chantix) by targeting specific receptors in the brain to reduce nicotine cravings and withdrawal symptoms. It is being developed for the U.S. market by Achieve Life Sciences, following robust clinical trial data supporting its efficacy and tolerability.
How Does the New Medication for Quitting Smoking Work?
The mechanism of action for cytisinicline is rooted in its interaction with the brain's nicotinic acetylcholine receptors (nAChRs), specifically the $\alpha4\beta2$ subtypes. Its action is two-fold:
- Partial Agonist: It selectively stimulates the receptors, though less potently than nicotine itself. This partial stimulation helps to reduce the severity of nicotine withdrawal and cravings.
- Partial Antagonist: It also partially blocks these receptors, preventing nicotine from cigarettes or other tobacco products from binding and providing a rewarding, pleasurable effect. This blunts the reinforcing properties of smoking, making it less satisfying.
This dual action is intended to both ease the discomfort of withdrawal and diminish the enjoyment of smoking, thereby supporting a successful quit attempt.
The Evidence: Clinical Trials for Cytisinicline
In recent years, cytisinicline has been evaluated in multiple U.S. clinical trials to support its New Drug Application (NDA) for FDA approval. The Phase 3 ORCA-2 and ORCA-3 trials compared cytisinicline to a placebo with supportive behavioral counseling.
- Higher Abstinence Rates: Both the 6-week and 12-week cytisinicline treatment groups achieved significantly higher biochemically confirmed continuous abstinence rates compared to the placebo group. In the ORCA-2 trial, the 12-week group showed a 21.1% continuous abstinence rate through week 24, versus 4.8% for placebo.
- Favorable Tolerability: Cytisinicline was well tolerated in the trials, with a low discontinuation rate due to adverse events. The most common side effects reported were mild to moderate, including nausea, insomnia, and abnormal dreams, but occurred in less than 10% of participants. This favorable side effect profile is a key advantage compared to other treatments.
Potential for Vaping Cessation
In addition to its use for traditional smoking, cytisinicline has also shown promise for those seeking to quit vaping. Based on successful Phase 2 clinical trial results (ORCA-V1), the FDA granted cytisinicline a Breakthrough Therapy Designation for vaping cessation. If approved, it would be the first medication authorized for this specific indication.
Comparing Cytisinicline to Existing Smoking Cessation Treatments
When considering a new therapy, it's helpful to see how it stacks up against current options. Here's a comparison of cytisinicline with other FDA-approved smoking cessation medications.
| Medication | Mechanism of Action | Efficacy (vs. Placebo) | Common Side Effects | Status |
|---|---|---|---|---|
| Cytisinicline | Partial agonist of nicotine receptors, reducing cravings and the reward of smoking. | High efficacy demonstrated in clinical trials (e.g., ORCA-2, ORCA-3). | Nausea, insomnia, abnormal dreams (generally mild and well-tolerated). | Under FDA Review (PDUFA June 20, 2026). |
| Varenicline (Chantix) | Partial agonist of nicotine receptors. | Very effective, similar efficacy to cytisinicline in some meta-analyses, but with higher risk of side effects. | Nausea, insomnia, abnormal dreams, and potential for more severe neuropsychiatric effects. | Available (temporarily recalled, now returning). |
| Bupropion (Zyban, Wellbutrin) | Antidepressant that increases dopamine and norepinephrine levels. | Effective, but generally less so than varenicline or cytisinicline. | Dry mouth, insomnia, agitation, and seizure risk. | Available (prescription). |
| Nicotine Replacement Therapy (NRT) | Provides a controlled dose of nicotine to ease withdrawal symptoms. | Effective, especially in combination therapy. | Skin irritation (patch), headache, nausea, mouth soreness (gum). | Available (OTC and prescription). |
What is the Current Regulatory Status?
As of October 2025, the U.S. FDA has accepted Achieve Life Sciences' New Drug Application for cytisinicline. This is a critical step in the approval process, and the FDA has set a Prescription Drug User Fee Act (PDUFA) target action date for June 20, 2026. If approved, cytisinicline would be made available as a new prescription medication for adults seeking to quit smoking. It is important to note that until approval is granted, cytisinicline is not yet available for prescription in the U.S.
Conclusion: A New Hope for Quitting Smoking
Cytisinicline represents a significant and long-awaited development in the field of smoking cessation. With the FDA's acceptance of the New Drug Application, hope is building for millions of individuals struggling with nicotine dependence. Its mechanism of action offers a unique dual approach to curbing withdrawal symptoms and reducing the pleasure of smoking, while its favorable tolerability profile provides a distinct advantage. Furthermore, its potential to treat vaping cessation could address a critical gap in current therapies. As the FDA review continues, cytisinicline stands poised to provide a powerful new tool in the ongoing battle against tobacco-related illness. For additional clinical information, refer to a study published in JAMA Internal Medicine discussing the clinical trial data: Cytisinicline for Smoking Cessation: A Randomized Clinical Trial.
