Cytisine for smoking cessation: as good as nicotine replacement -- and cheap

The smoking cessation drug varenicline (Chantix) works by weakly activating and also blocking nicotine receptors in the brain, simultaneously. This neat trick has the dual effects of reducing tobacco cravings while also blunting the "high" from smoking.

That combination has made Chantix the most successful smoking-cessation therapy on the market, but it costs about $500 for 12 weeks. Chantix sticker shock puts off many smokers who want to quit (even though most are already spending $150/month on cigarettes), if they weren't already scared off by varenicline's black box warning about psychiatric effects.

Like many prescription drugs, varenicline was inspired by a template already existing in nature: cytisine, an alkaloid in the seeds of the golden rain tree, native to central and southern Europe. Like varenicline, cytisine is a partial agonist of nicotinic acetylcholine receptors in the brain. Cytisine has been used as a smoking-cessation aid in the formerly communist states of Eastern Europe for decades, where it costs less than $30 for a 25-day course.

Golden rain tree, Laburnum anagyroides (courtesy: Wikipedia)

Multiple randomized trials and systematic reviews have shown that cytisine significantly improves the chances of quitting smoking compared to placebo. A new randomized trial in the New England Journal of Medicine is the first to test cytisine against nicotine replacement therapy.

1,310 smokers in New Zealand who had called the national quit hotline were randomized to receive either cytisine for 25 days or nicotine replacement therapy for 8 weeks. The therapies were provided free or at very low cost.

The phase III trial was funded by Extab, a company licensed to promote and sell cytisine (brand name Tabex) globally outside Central and Eastern Europe. Extab also funded a previous phase III trial, published in 2011, showing cytisine's superiority over placebo.

After a month, 40% of cytisine-takers reported continuous abstinence, compared to 31% of those getting nicotine replacement. The benefits held at 6 months, when 22% of those taking cytisine reported smoking abstinence compared to 15% of those using nicotine replacement.

Varenicline worked better than nicotine patches in one randomized trial, and meta-analyses suggest Chantix is better than nicotine replacement overall for smoking cessation. Cytisine's numerical advantage over nicotine replacement did not reach statistical significance in this trial.

Does cytisine have weird effects on the brain, like the well-known vivid dreams of Chantix? It may be too soon to say: about 5% of patients taking cytisine reported "sleep disorders" (due to dreams?) or nausea; strange dreams and nausea are among the most common reported side effects of varenicline. Extab's website interprets the trial results as a "strong safety and side-effect profile with no neuropsychiatric issues" from cytisine.

With this second phase III trial, Extab's goal of bringing cytisine profitably to the masses appears closer to realization. The European Medicines Agency is reviewing safety data from 8 million Central and Eastern European patients treated with cytisine. There is relatively little toxicity data available on cytisine, but it is known to cause respiratory suppression at high doses. Toxicologists have pointed out it is probably hard for humans to overdose on cytisine successfully, since large ingestions should produce severe vomiting.

The FDA turned down a 2006 request by supplement manufacturers to market cytisine as a supplement in the U.S., citing absence of safety data.

Extab hopes additional well-conducted clinical trials will overcome those concerns and establish cytisine's place as a safe and effective smoking cessation aid. Rick Stewart, Extab's CEO told Reuters recently, “Extab expects to commence additional Phase 3 clinical trials in 2015 with a goal of filing a New Drug Application with the U.S. Food and Drug Administration and a Marketing Authorization Application with the European Medicines Agency in late 2016.”

With its low cost and apparent effectiveness, cytisine seems to have great promise as a smoking cessation tool. But don't expect to see it for 2 years or longer in the E.U. or the U.S. The adventuresome smoker willing to accept the risk of safety, counterfeit medication, and violation of any applicable laws can buy cytisine online, where it is being sold eagerly as Tabex (or at least in boxes that say so) by Internet entrepreneurs.

Natalie Walker et al. Cytisine versus Nicotine for Smoking Cessation. N Engl J Med 2014; 371:2353-2362.