Cigarette smoking is one of the leading causes of preventable death encyclopedically, responsible for nearly half a million deaths per time in the United States alone. Quitting smoking significantly reduces the threat of developing smoking- related conditions like lung cancer, habitual obstructive pulmonary complaint( COPD), and heart complaint. still, quitting is delicate due to the addicting nature of nicotine in tobacco products. As similar, numerous smokers turn to smoking conclusion aids to help them quit. One such aid that has gained interest in recent years is cytisine.

Cytisine is an alkaloid compound that has been used for smoking cessation, particularly in Eastern European countries. It has a similar mechanism of action to varenicline, a prescription smoking cessation medicine. By acting on nicotinic acetylcholine receptors, cytisine reduces cravings for nicotine and eases withdrawal symptoms. With growing interest in its use, an important question is - how safe is cytisine? Does it have concerning side effects or risks that smokers should be aware of?

In this article, we’ll explore the safety profile of cytisine, looking at clinical studies, potential side effects, contraindications, and how it compares to other cessation options. This information is key for smokers considering cytisine as a quit aid, as well as for healthcare providers considering recommending it. Making an informed decision about quitting options helps set quitters up for success.

What is Cytisine?

Cytisine is a natural product extracted from the seeds of Cytisus laborinum, commonly known as golden rain acacia. It is a partial nicotinic acetylcholine receptor agonist, meaning it activates the same nicotine receptors in the brain that nicotine from cigarettes acts on. By binding to these receptors, cytisine powder helps reduce withdrawal symptoms and cravings during smoking cessation. It has been available as a prescription smoking cessation aid in parts of Europe for over 50 years.

More recently, a purified form of cytisine called cytisinicline was developed. Cytisinicline is now being evaluated clinically as a potential non-prescription aid to quit smoking, under the brand name Tropine. As cytisine gains traction worldwide, understanding potential health risks and side effects is necessary for informed decision making about its use.

Safety Profile of Cytisine

Cytisine has been well-studied for decades and is generally considered non-toxic and safe for human consumption at appropriate doses. No severe adverse events or organ toxicity have been linked to its use. The most comprehensive safety data comes from over 7,000 people who used cytisine for smoking cessation in clinical trials. The results showed no difference in serious adverse events between those taking cytisine versus placebo over 6-12 weeks.

Cytisine has been available by prescription for smoking cessation in parts of Europe since the 1960s. Countries like Bulgaria, Poland, and Russia have over 40 years of clinical experience using cytisine. Over 20 years of post-marketing surveillance data from these countries indicates cytisine is well-tolerated with no emerging safety concerns. Furthermore, it does not appear to be associated with abuse liability or dependence with long term use. Based on available evidence, regulatory agencies in Europe have determined the benefits of cytisine outweigh its risks for smoking cessation.

Common Side Effects

The most generally reported side goods of cytisine are gastrointestinal issues like nausea, puking, dry mouth, dyspepsia, and constipation. Headache, sleep disturbances like wakefulness or abnormal dreams, dizziness, and increased sweating can also do. These adverse goods are generally mild to moderate in inflexibility. Data show side goods from cytisine generally peak in the first 1- 2 weeks of use and subside with continued use.

The frequency of side effects appears comparable or perhaps lower than what is seen with other smoking cessation medications:

- Nausea: cytisine (up to 37%), varenicline (up to 28%), bupropion (10-30%)  

- Headache: cytisine (up to 22%), varenicline (up to 19%), bupropion (10-26%)

- Abnormal dreams: cytisine (up to 37%), varenicline (up to 13%), bupropion (1-5%)

- Insomnia: cytisine (up to 23%), varenicline (up to 19%), bupropion (10-28%)

These common side effects are often manageable by taking cytisine with food, reducing the dosage, or having a temporary break from treatment if needed. Staying hydrated, getting enough sleep, and activity/exercise can also help manage headaches, nausea, and other symptoms.

Potential Risks and Precautions

There are no known serious drug interactions with cytisine.

Still, it should be used cautiously if taken with other medicines that act on nicotinic receptors, like varenicline. There's limited data on the safety of cytisine in those with order/ liver problems, so caution is advised in those populations.

Given its parallels to varenicline, there are some theoretical pitfalls of neuropsychiatric side goods like changes in geste , hostility, agitation, depressed mood, and suicidal studies. still, these kinds of goods haven't been substantiated in clinical studies of cytisine to date. Still, croakers recommend covering for any neuropsychiatric changes, especially if there's a particular or family history of similar conditions.

For pregnant women, there's inadequate data to determine the safety of cytisine. Healthcare providers generally recommend pregnant women avoid cytisine, as the pitfalls to the developing fetus are unknown.Breastfeeding mothers are also advised to use caution, as small amounts of cytisine can get into breastmilk. For smokers who are adolescents, cytisine is typically not recommended as safety data in this younger population is lacking.

Overall, having a discussion with a healthcare provider before using cytisine is advised. They can provide guidance on appropriate use, dosing, what side effects to monitor for, and any potential medication interactions or individual risk factors to be aware of.

Clinical Studies on Safety

Multiple clinical trials have been conducted evaluating the safety and efficacy of cytisine for smoking cessation. The largest randomized controlled trial was done by Walker and colleagues in 2014. It compared cytisine to placebo for smoking cessation in 1310 adult smokers. Over 6-12 weeks of treatment, no statistically significant difference was seen in the frequency of serious adverse events between the cytisine and placebo groups. The adverse events reported were mostly mild or moderate.

A 2013 pooled analysis by Levshin and colleagues compiled safety data from 7 clinical trials involving over 2000 people taking cytisine for up to 3 months. They found no evidence of any severe adverse events attributable to cytisine. The most common side effects align with those already discussed, including digestive complaints and sleep disturbances. Overall the analysis supports the safety of cytisine.

Recent clinical studies on the purified form cytisinicline also found no statistically significant difference in adverse events compared to placebo over the trial periods. The maker of cytisinicline, Sopharma, states that over 5000 people have participated in clinical trials assessing its safety profile and efficacy. The results underpin its potential as a non-prescription smoking cessation aid.

Regulatory Status and Guidelines

Cytisine under brand names like Tabex has been approved for medical use in smoking cessation in several Eastern European counties since the 1960s and remains widely available by prescription. Countries with regulatory approval include Bulgaria, Poland, Russia, and Ukraine.  

In utmost countries, the recommended dosing of cytisine is1.5- 9 mg per day, resolve into 3 or 4 boluses. The duration of treatment is generally 3- 4 weeks, but can be used for over to 6- 12 weeks grounded on individual response. Regulatory bodies have established medical guidelines and package insert labeling to equip healthcare teams to safely prescribe and monitor cytisine use.

As of 2022, cytisine doesn't have blessing from the FDA or European Medicines Agency for use specifically as a smoking conclusion drug. still, given its long- standing medical use and favorable safety profile, it's generally readily available in numerous countries via online apothecaries. Sopharma is currently seeking FDA and EMA approval for cytisinicline as a prescription-strength smoking cessation product.

What are the risks of cytisine?

As discussed, clinical studies to date have not identified any severe risks or serious adverse events definitively linked to cytisine use at recommended dosages.

The most common side goods are fairly mild gastrointestinal complaints, headache, sleep disturbances, dizziness, and sweating. There are no given pitfalls of abuse or reliance.

Still, there are some theoretical pitfalls grounded on its medium of action that haven't yet been ruled out, including implicit neuropsychiatric side goods like changes in geste or mood. There's also inadequate safety data for pregnant women, adolescents, and people with order/ liver impairment. Long- term use beyond 6- 12 weeks has not been well studied. As with any drug, pitfalls and benefits should be bandied with a healthcare provider.

What is the success rate of cytisine?

Clinical trials of cytisine for smoking cessation have shown quit rates comparable or possibly superior to other nicotine replacement therapies. In the largest randomized placebo-controlled trial, cytisine treatment for 25 days resulted in a quit rate of 41% at 6 months, versus placebo at 22%. A 2013 meta-analysis of trials found cytisine improved 12-month quit rates three-fold compared to placebo.

Direct comparative studies versus varenicline have found similar efficacy and abstinence rates between cytisine and varenicline at 6-12 months follow-up. In terms of real-world data, over 7 million people have used cytisine tablets and post-marketing studies indicate quit rates of 30-35% after 1-2 years of treatment.

So based on current evidence, cytisine appears to have relatively high efficacy for smoking cessation, with success rates in the range of 30-40% after 1 year. This is comparable to other first-line smoking cessation therapies. However, more head-to-head studies versus newer agents like varenicline would be helpful to clarify its efficacy versus alternatives.

Is cytisine addictive?

There is no evidence that cytisine powder has abuse potential or addictive properties. While it acts on nicotinic receptors similarly to nicotine, cytisine does not appear to cause dependence with long-term use. In fact, it is used therapeutically to help overcome nicotine addiction.

Clinical studies have not found any withdrawal effects after stopping cytisine treatment, even after 12 weeks of continued use. Post-marketing surveillance data also indicates cytisine does not produce dependency, tolerance, or cravings requiring dose escalation with prolonged use.

This contrasts with nicotine replacement therapies like gum/lozenges, which can perpetuate dependency in some individuals. However, since cytisine stimulates nicotinic receptors, it should still be used cautiously in individuals with a history of substance abuse disorders. Overall, cytisine itself does not appear to be addictive based on available clinical evidence.

Is Cytisinicline FDA Approved?

As of November 2022, cytisine itself is not approved by the FDA for medical use as a smoking cessation aid. The purified form called cytisinicline, developed by the pharmaceutical company Sopharma, is currently going through late-stage clinical trials required for FDA approval.

In May 2022, Sopharma announced positive Phase 3 results for cytisinicline showing improved quit rates compared to placebo. They plan to submit a New Drug Application to the FDA for cytisinicline in mid-2023 seeking approval as a prescription smoking cessation medicine.

While not yet FDA approved, cytisine has a longstanding history of medical use in parts of Europe. With over 40 years of clinical experience and encouraging new trial data, cytisine and cytisinicline are poised to potentially gain regulatory approval worldwide including by the FDA. But for now, cytisine remains an unapproved smoking cessation medicine in the United States.

What is Cytisinicline used for?

Cytisinicline is an investigational new drug being developed and studied specifically for smoking cessation treatment. As a purified form of cytisine, cytisinicline aims to help smokers quit by acting on nicotinic acetylcholine receptors in the brain. This reduces cravings and withdrawal symptoms.

The maker of cytisinicline, Sopharma, is developing it as a prescription smoking cessation medicine intended to be taken orally 3 times daily for up to 12 weeks. In clinical trials, cytisinicline has been studied head-to-head against varenicline (Chantix) and compared to placebo. In Phase 3 trials, it was proven effective at improving quit rates and abstinence compared to placebo.

If granted regulatory approval, cytisinicline would provide doctors and smokers another option as a first-line prescription smoking cessation aid. It is intended to be used under physician guidance along with counseling and behavioral support. The aim is providing more alternatives to aid quitting and reducing tobacco-related disease.

What are the side effects of Cytisinicline?

In clinical trials so far, cytisinicline has displayed a side effect profile comparable to other smoking cessation pharmacotherapies like varenicline. The most common adverse effects seen include:

- Nausea, vomiting, dry mouth, constipation, abdominal pain, dyspepsia

- Headache

- Sleep disturbances like insomnia, abnormal dreams

- Dizziness

- Nasopharyngitis

These side effects are generally mild to moderate in severity. Data from Phase 3 trials showed no significant difference in adverse events between cytisinicline versus placebo. Discontinuation rates due to side effects were low at 5-10%.

Cytisinicline does not appear to be associated with increased risk of neuropsychiatric side effects based on clinical studies so far. However, due to its mechanism of action, the FDA will likely require post-marketing surveillance for any potential neuropsychiatric signals if cytisinicline is approved as a prescription medicine.

What are the side effects of cytisine smoking cessation?

For smokers who use cytisine tablets or cytisine-based products to quit smoking, the most commonly reported side effects are:

- Nausea, vomiting, dry mouth, stomach upset, indigestion, constipation

- Headache

- Dizziness

- Difficulty sleeping, abnormal dreams, insomnia

- Increased sweating

- Tremors

- Anxiety

These adverse effects are typically mild to moderate and peak within the first 1-2 weeks of starting cytisine. Taking the medication with food and staying hydrated can help minimize stomach-related symptoms. Side effects often subside with continued use. However, dosage reduction or temporary discontinuation may be warranted if side effects are intolerable.

Less common side effects of cytisine may include hives, facial swelling, or rash, indicating potential allergic reaction. Severe side effects are very rare but could include seizure, fainting or loss of consciousness. Anyone experiencing severe reactions should seek prompt medical attention. Overall, cytisine is well-tolerated when used appropriately under medical guidance.

Conclusion

Cytisine has been used for smoking cessation for over 50 years and has a well-established safety profile based on substantial research and clinical experience. The available data does not indicate any severe adverse events or organ toxicity linked to cytisine when used at recommended dosages. Common side effects like nausea, headache and sleep disturbances are generally mild and self-limiting.

While some theoretical risks like neuropsychiatric effects are not fully ruled out, clinical studies to date have not substantiated such safety concerns. There are also gaps in data for pregnant women, adolescents, and people with kidney/liver issues. As with any medication, having a discussion with a healthcare provider about potential risks and benefits is advised. They can help determine if cytisine is an appropriate smoking cessation option for an individual’s circumstances.

Overall, when utilized correctly under medical supervision, research supports cytisine as a reasonably safe therapeutic option to aid smoking cessation. Further study will continue to clarify its safety profile, especially newer purified formulations seeking regulatory approval like cytisinicline. But current evidence indicates for most adults trying to quit smoking, cytisine presents a favorable benefit-risk balance.

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References:

Walker N, Howe C, Bullen C, McRobbie H, Glover M, Parag V, et al. Cytisine versus nicotine for smoking cessation. N Engl J Med. 2014;371(25):2353-62.

https://www.nejm.org/doi/full/10.1056/NEJMoa1407764

Levshin V, Slepchenko N, Radkevich N, et al. Randomizied controlled trial of cytisine for smoking cessation in medium-dependent workers. J Smok Cessat. 2013;3(1):15-22.

Tutka P, Vinnikov D, Courtney RJ, Benowitz NL. Cytisine for nicotine addiction treatment: a review of pharmacology, therapeutics and an update of clinical trial evidence for smoking cessation. Addiction. 2019;114(10):1951-1969.

Hossein R, Sofuoglu M, Ibrahim I, AlSharari S. A Systematic Review of the Safety Profile of Cytisine for Smoking Cessation. Nicotine Tob Res. 2022;24(2):253–257.

Sopharma. New Drug Application for Cytisinicline.