Most, but not all, studies have found that women smokers have lower quit rates and respond less robustly to nicotine. Hormonal differences might explain this (CNS Drugs 32:421). Most lab and clinical studies have found that progesterone decrease cigarette craving, blunts positive effects of tobacco, and improves cognitive functioning and stress during withdrawal. For example, one study found that increased progesterone levels were associated with an increase in the quit rate by 23%. Similar positive effects of progesterone have been found for those trying to stop cocaine use.
Three prior RCTs have tested progesterone as a treatment for smoking cessation. The one study with a short treatment (4 days) did not find an effect, but the two studies that examined long-term treatment (4-8 weeks) increased quit rates. However, all three studies had small sample sizes (total n = 41-64) and in one study the positive effect was small. Now comes an RCT of 4 weeks of progesterone in 103 pre-menopausal women and 113 men (Addiction , epub). At 12 week follow-up, progesterone increased quitting from 17% to 35% (OR = 2.6) in women but not in men. The mechanism for the increased quit rate was not clear. Adverse events were minimal. Chronic use of progesterone administration is associated with several significant medical problems. That this would occur with brief administration seems unlikely.
Is this sufficient evidence to start using short-term progesterone in those who have failed first line treatments for smoking cessation? Unfortunately, my search of US and European trial registries located no ongoing studies of progesterone treatment. Part of me says that the importance of quitting smoking is so large, we should be willing to use any treatment with “a reasonable chance of efficacy”. The other part of me says, lots of positive trials are not replicated. So I guess my compromise is to use progesterone as an add-on to varenicline or combined gum/patch in those who have failed these treatments in the past and to describe this as a “non-FDA approved experimental treatment.”