cytisine for smoking cessation

 The NY Times had a recent article on cytisine as an effective treatment for smoking cessation: https://www.nytimes.com/2024/10/02/well/quit-smoking-cytisine.html?smid=nytcore-ios-share&referringSource=articleShare&sgrp=c-cb

 

they make a few well-substantiated points:

-- it is pretty easy to stop smoking, the issue is maintaing abstinence (and 47%  of those who try to quit are smoking 1 year later: https://pmc.ncbi.nlm.nih.gov/articles/PMC3723776/ )

-- cytisine was developed as a pill in Bulgaria in 1964 and has been used in Eastern Europe for 50 years for smoking cessation

-- cytisine was approved in Canada in 2017 and Britain last year for smoking cessation

-- there have been many scientific articles showing a great effect of cytisine in smoking cessation (several noted below), with a 2014 editorial by Nancy Rigotti referring to cytisine as “a tobacco treatment hiding in plain sight”: https://www.nejm.org/doi/full/10.1056/NEJMe1412313 

 

Commentary:

-- cigarette smoking, per the FDA, is the leading preventable cause of disease and death in the US, with >480,000 deaths/year: https://www.fda.gov/tobacco-products/public-health-education/health-effects-tobacco-use

    -- cigarettes expose smokers to “a toxic mix of over 7,000 chemicals”, along with the highly addictive nicotine, and is perhaps the most important single modifiable cardiovascular risk factor

-- the FDA has not approved cytisine (and it is not available in the US), but is considering it pending more info on safety data, though mathematical analysis suggests that utilizing cytisine could lead to “71,000 more people would quit smoking over 1 year and maintain long-term abstinence, producing more than 500,000 additional life-years”, and “each year of delay in the availability of cytisine might reduce population-level like expectancy by 10,000 years” (https://jamanetwork.com/journals/jama-health-forum/fullarticle/2822687 )

 

Cytisine review with history:

 

A 2021 review of cytisine and its derivatives (https://www.sciencedirect.com/science/article/pii/S104366182100284X ) made the following comments:

-- cytisine is a natural bioactive alkaloid compound mainly isolated from plants of the Leguminosae family (especially the seeds of Laburnum anagyroides). Cytisine is the main alkaloid in this small tree (or shrub), with the seeds having up to 3% cytisine. These plants are now known as golden chain trees or golden rain acacias, and are quite common in Europe.

     -- cytisine is also in some foods, especially those with high RNA content, such as organ meats, brewer’s yest, beer

-- cytisine is the oxidized dimer of cysteine, binding through a disulfide bond

-- cytisine has been used in Europe to help with smoking cessation for more than 50 years

    -- cytisine has been well-known from antiquity and cultivated in Greece for its beauty and pharmaco-toxicological properties. It has been used in traditional Chinese medicine to treat hepatitis and liver cancer

    -- the pharmacologic effects of cytisine were first described in 1912

-- the target of cytisine is the nicotinic acetylcholine receptors

   -- preclinical trials have found that the interactions with various of these receptor subtypes found in different areas the central and peripheral nervous system are neuroprotective, have a wide range of biological effects on nicotine and alcohol addiction, regulate mood, food intake, and motor activity, and they influence the autonomic and cardiovascular systems

    -- during World War II, soldiers used laburnum leaves as a substitute for tobacco, since cytisine has both antagonist and weak agonist effects on the receptor. At the highest doses of cytisine, there is increasing antagonism to nicotine’s receptor stimulation: https://pubmed.ncbi.nlm.nih.gov/25839895/

    -- the adverse effects are particularly profound by ingestion of the seeds, and they are associated with vomiting, pupil dilation, tachycardia, fatigue, excitement, delirium, hallucinations, muscle twitches, diarrhea, sweating, and even death due to respiratory paralysis

-- there is currently significant scientific activity associated with developing cytisine variants with increased cerebral pharmacokinetics, since oral cytisine has pretty low brain penetration, much less than that of nicotine or varenicline

-- this article has huge amounts of detailed data to document the above, including more information about the effect of cytisine on the overall dopamine reward system in the brain, reducing alcohol consumption and potentially reducing marijuana and cocaine use. There is some suggestion, for unclear reasons, that cytisine may have antidepressant effects, and it may have synergistic antidepressant activity with SSRIs. Cytisine also seems to reduce food intake leading to weight loss, similar to the effects of nicotine itself. Some neuroprotective effects of cytisine, largely based on animal studies, is potentially for Parkinson’s disease, Alzheimer’s disease, as well as stimulation of respiration but also blood pressure, blood glucose levels, and heart rate. As noted above, the Chinese have used cytisine as an herbal medicine to treat liver cancer, and studies have suggested that it may have anti-proliferative of as well as pro-apoptotic cellular effects. There is also some information that cytisine may decrease bone loss, perhaps by suppressing osteoclastogenesis

 

Some articles on cytisine and smoking cessation:

 

-- cytisine vs placebo: a 2023 study of 810 patients (mean age 53, 55% women, averaging 1 pack of cigarettes/d) found that a 6-week course of cytisine vs placebo yielded an odds ratio of 8.0 (25.3% on cytisine vs 4.4% on placebo) for continuous abstinence during weeks 3-6 and an OR of 3.7 during weeks 3-24. For a 12-week course of cytisine, the continuous abstention rate OR was 6.3 for weeks 9-12 (32.6% vs 7.0%) and 5.3 for weeks 9-24 (21.2% vs 4.8%). Adverse events of nausea, abnormal dreams, and insomnia occurred in  <10%, with 2.9% discontinuing the cytisine from an adverse event: https://pubmed.ncbi.nlm.nih.gov/37432430/

    -- And a systematic review and meta-analysis of 8 RCTs found that cytisine was more than twice as effective as placebo: https://onlinelibrary.wiley.com/doi/10.1111/add.16399

 

-- cytisine vs nicotine replacement therapy (NRT): 1310 New Zealand adult smokers were randomized to cytisine for 25 days or nicotine-replacement therapy  (NRT) for 8 weeks (patches along with gum or lozenges) found that continuous abstinence from smoking was reported in 40% of those on cytisine vs 31% on NRT at one month, and the effectiveness of cytisine was superior to NRT at 1 week, 2 months and 6 months. There were more adverse events reported with cytisine, mostly nausea/vomiting and sleep disturbances.  Those on cytisine found that they had fewer symptoms of nicotine withdrawal, found smoking less rewarding, and reduced the number of cigarettes smoked per day.  other similar trials have noted higher success rates in men, though this current study did not find that. See smoking cessation cytisine nejm 2014 or N Engl J Med 2014;371:2353-62

 

-- cytisine vs varenicline:

— a non-inferiority trial of cytisine vs varenicline (the single most effective medication treatment we now have, though some insurers do not cover it. probably because of cost?). In 1452 Australian adult smokers willing to make a quit attempt found that 1.5mg cytisine capsules 6 times daily with titration down over 25 days vs varenicline for 84 days assessing continuous abstinence verified by carbon monoxide breath test at followup found that cytisine for 25 days was non-inferior to varenicline for 84 days and had fewer adverse events: see smoking cessation cytisine vs varenicline jama2021 in dropbox, or doi:10.1001/jama.2021.7621

    -- though both cytisine and varenicline actually have a similar mechanism of action by targeting the same receptor, cytisine has milder nicotine withdrawal symptoms than varenicline. [both varenicline and cytisine have mild agonist effects on the receptor as well as strong antagonist effects; my guess from the medical literature is that varenicline has more CNS penetration than cytisine and more CNS receptor antagonism, leading to more adverse central nervous system effects]

 

-- cytisine for decreasing e-cigarette use: a trial comparing cytisine to people who were regularly using e-cigarettes but not cigarettes found twice as many on cytisine discontinued their continuous vaping for up to 4 months, vs placebo (https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2818194 )

 

-- another medication that seems to do well with smoking cessation is the GLP-1 receptor agonists: https://gmodestmedblogs.blogspot.com/2024/09/semaglutide-assoc-with-tobacco-cessation.html . though neither glp1s  nor cytisine are FDA-approved for smoking cessation

 

so, a pretty remarkable effect of cytisine in smoking cessation, with a few comments:

-- it works, pretty consistently in the many studies done

-- quite unusually, the effects of short-term interventions (eg 25 days) have profound long-lasting effects (several studies have found that with our current meds, there is a pretty high risk of reinstating smoking around 2 months after quitting, and as per above, 47% are back smoking by 1 year), with patients noting a longer-term decreased smoking desire (and, in my experience, many patients who do quit by taking our current meds, do have persistent feelings of wanting to smoke)

-- cytisine really does not seem to have a lot more short-term or long-term adverse effects than those mentioned above, since it has been used for >50 years in some countries

-- smoking is such a huge scourge on our country (and globally) with huge numbers of people having smoking-related profound disabilities (strokes, PAD, Mis, cancers) or deaths annually

-- and cystine should be very cheap (one would hope…), unlike varenicline or the GLP-1 receptor agonists, and should be more easily covered by insurance companies

-- so, why is the FDA dragging its feet???

 

geoff

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