If you were to analyze hundreds of studies examining what it takes to quit smoking, what do you think you’d find to be the most effective tool:
1) A nicotine patch?
2) A medication that is also widely prescribed for depression?
3) A natural health product sold over the counter in Canada?
4) Nicotine-free e-cigarettes?
5) A drug created to mimic a shrub that some soldiers smoked during World War II?
If you picked 3 and 5, well done. According to a study published last month in a leading medical journal, cytisine, a compound found in some seeds, and varenicline, a synthetic compound designed to work similarly, are far more effective than most other methods for quitting smoking. Alas, for the millions of smokers in the United States who try to quit each year, neither of these medications is easy to get one’s hands on. Though cytisine has long been popular in Eastern Europe and became available in Canada in 2017, it’s not sold in the U.S. Varenicline is technically available, but doctors often discourage smokers from trying it. Why would this be? The answer has to do in part with the economics of drug development.
One of the researchers is hoping that the finding will help revive interest in widening access to cytisine in particular. “We have all this evidence that it works. Shouldn’t we be throwing everything we can at this?” Jamie Hartmann-Boyce, who is now a professor in the School of Public Health and Health Sciences and the University of Massachusetts, Amherst, told me.
“Works” in the world of addiction, of course, is never anywhere near the 100 percent we all wish it were. Hartmann-Boyce’s meta-analysis found that across hundreds of studies, an average of 14 percent of cytisine users quit for more than six months. But that’s far higher than many other methods.
To figure out which smoking interventions were most effective, Hartmann-Boyce—then at Oxford—and her colleagues sifted through hundreds of randomized control trials, dating from the 1990s to 2022. This included nicotine-free medications like Bupropion (aka Wellbutrin), nicotine-filled smoking-cessation tools like patches, and e-cigarettes with and without nicotine. After whittling the studies down to 320 that met their criteria, they had a pool of 157,000 or so smokers to analyze.
The researchers plotted the odds of quitting for at least six months while using a particular intervention versus the odds of quitting for that same period without using anything. Just three interventions—a nicotine e-cigarette, cytisine, and varenicline—had more than twice the odds, meaning that around 14 of 100 people trying to quit smoking with these techniques were likely to succeed. (Fourth place went to nicotine patch combined with another nicotine-filled something-or-other, like lozenges or gum.)
As to whether quitting cigarettes to start using nicotine e-cigarettes truly counts as quitting, that’s up to the smoker. (The same is true for replacing the pack of cigarettes with a $40 bag of nicotine mints devoured while wearing a patch.) Experts in this realm are divided about whether it’s wise to present e-cigs as a gentle offramp; some warn that it encourages swapping out one unhealthy addiction for another, while others insist that it’s the most realistic way to save smokers’ lives. I’m going to stay out of this debate for now. The relevant takeaway from this study seems to be: There are two nicotine-free medications that help people stop smoking at comparable rates to e-cigarettes, and unlike e-cigarettes, you may not know anyone who’s tried them.
Why not? It’s more than the impossible-to-remember names. Let’s begin with cytisine. The plant compound found in the seeds of a variety of different trees has been used in Poland and Eastern European countries for many decades. Ultimately it mimics some of nicotine’s effects, thereby reducing withdrawal symptoms and making smoking less enjoyable. This is particularly helpful for the first four-week period after someone vows to take their last drag. Some have reported side effects, such as nausea and abnormal dreams, but overall, the drug has performed impressively in studies.
“It should be available to patients in the U.S.,” Dr. Maher Karam Hage, a professor of behavioral science at the University of Texas’ MD Anderson Cancer Center, told me. Lisa Fucito, a professor at Yale School of Medicine who is also the director of the Tobacco Treatment Service at Smilow Cancer Hospital, agrees. “The challenge in the U.S. is that you need a pharma company behind a med,” she said.
Since it’s a naturally occurring compound, cytisine cannot be patented any more easily than oregano can. That reduces the incentive for a big drug manufacturer to try to propel it through the enormously costly FDA approval process. In recent years, several companies have attempted to develop the drug as a prescription medication and an over-the-counter treatment. But no one has made it to the goal line of pharmacy placement in the United States.
In Canada it’s a different story. In 2017, the country’s version of an FDA approved the compound as a natural health product, meaning it’s available over the counter. “It was almost immediate; first day taking CRAVV I had no craving for cigarettes,” one reviewer wrote. (Cravv is the brand under which cytisine is marketed.) “I don’t understand why they don’t promote the product more,” wrote another.
The story of varenicline, a synthetic compound designed to work like cytisine, is even trickier. A major pharmaceutical company already did the tough work of getting FDA approvals and turning it into a drug with a more memorable name: Chantix. But pretty quickly it became associated with serious side effects including depression and suicidal tendencies. The experts I spoke to pointed out that later studies failed to show major risks and that the FDA eventually took the unusual step of lifting a black-box warning. Vivid dreams and nausea are not uncommon, as with cytisine, but later studies showed the drug to be safe for patients who are in a mentally sound place.
“I believe the earlier concerns about neuropsychiatric side effects were overblown,” Jonathan Foulds, a tobacco addiction researcher at the Penn State Cancer Institute, told me. (Foulds has worked as a consultant for Pfizer. But those with no affiliation made similar comments.)
Nonetheless, the damage was done—and the drugs’ reputation just got worse when early in the pandemic, the FDA caught impurities in one batch, prompting a recall. The impurities did not hurt anyone and should have been insufficient to halt the drug’s trajectory, several researchers told me. After all, it’s one of the most effective tools for ending a habit that kills hundreds of thousands of Americans a year.
“Varenicline is superior to any other medication and all research to date supports that,” Karam Hage told me. He pointed to one major study that gave it a 38 percent quit rate after 12 weeks, nearly three times that of a placebo.
But by the time Pfizer was no longer consumed with managing its COVID vaccine, the FDA had approved a generic version of the smoking treatment. Generics can be great for consumers, bringing down drug prices. But alternately, their existence can remove incentives for the original patent-holders to defend their drug.
Fucito, of Yale, has been alarmed to find that even many smart colleagues have misperceptions about varenicline, warning patients against it. “If someone is telling you not to take that, I’d want to know why and get a second opinion,” she said.
Ultimately Fucito and others noted that using medication to quit is not going to be the best approach for everyone. And even those who are open to it should combine the pills with counseling to minimize the risk of relapse. If they can find a friend or family member willing to help them out, they might also consider applying a lesson from a previous study by Hartmann-Boyce. In that analysis, her team examined the effectiveness of financial incentives on quitting smoking. Participants who received compensation quit more effectively than those who did not. It didn’t actually matter whether the person got paid $100 or $700; the important thing was that money was involved.
This fall, I’ll be regularly writing about drugs and mental health for Slate. Got a tip, frustration, idea, or question? Let me know at firstname.lastname@example.org.