Quitting smoking better when tied to menstrual cycle

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Women who want to quit smoking may have better success by carefully timing their quit date with optimal days within their menstrual cycle, according to a new study from researchers at the Perelman School of Medicine at the University of Pennsylvania.

Cigarette smoking remains the leading cause of preventable death in the US, and women experience more severe health consequences from cigarette smoking than men, including a 25% increased risk of developing coronary heart disease and chronic obstructive pulmonary disease. Research also shows that women have greater difficulty with smoking cessation than men.

“Understanding how menstrual cycle phase affects neural processes, cognition and behaviour is a critical step in developing more effective treatments and in selecting the best, most individualised treatment options to help each cigarette smoker quit,” said the study’s lead author, Dr Reagan Wetherill, a research assistant professor of psychology.

Wetherill and senior author Dr Teresa Franklin, a research associate professor of neuroscience in psychiatry, have been studying the brains of premenopausal women who smoke cigarettes for several years in Penn’s Centre for the Studies of Addiction. Their work is based on a significant animal literature showing that the natural sex hormones – oestrogen and progesterone – which fluctuate over the course of the menstrual cycle modulate addictive behaviour. The animal data show that during the pre-ovulatory, or follicular phase of the menstrual cycle, when the progesterone-to-oestrogen ratio is low, women are more likely to be spurred toward addictive behaviours. Alternatively, during the early pre-menstrual or luteal phase of the menstrual cycle, when the progesterone-to-oestrogen ratio is high, addictive behaviours are thwarted, suggesting that progesterone might protect women from relapsing to smoking.

In the current study, 38 physically healthy, premenopausal women who smoke and who were not taking hormonal contraceptives, ranging from 21 to 51 years of age, received a functional MRI scan to examine how regions of the brain that help control behaviour are functionally connected to regions of the brain that signal reward.

The researchers theorised that the natural fluctuations in ovarian hormones that occur over the course of the monthly menstrual cycle affect how women make decisions regarding reward – smoking a cigarette – and so-called “smoking cues,” which are the people, places and things that they associate with smoking, such as the smell of a lit cigarette or going on their coffee break. These “appetitive reminders” to smoke are perceived as pleasant and wanted, and similar to cigarettes, are also rewarding.

In 2015, the researchers showed that compared to when women are in the luteal phase of their menstrual cycle, which is the period of time following ovulation and prior to menstruation, women in the follicular phase – which begins at menstruation and continues until ovulation – have enhanced responses to smoking cues in reward-related brain regions. This finding led them to further test whether groups differed in the strength of the functional connections that exists between regions exerting cognitive control and reward-related brain regions. The weaker the functional connections between cognitive control brain regions and reward signaling brain regions, the less ability women have to ‘Just Say No’ when attempting to quit.

The women in the study were separated into two groups – those in their follicular phase and those in their luteal phase. Results revealed that during the follicular phase, there was reduced functional connectivity between brain regions that helps make good decisions (cortical control regions) and the brain regions that contain the reward center (ventral striatum), which could place women in the follicular phase at greater risk for continued smoking and relapse. Orienting attention towards smoking cues (pictures of smoking reminders such as an individual smoking) was also shown to be associated weaker connections between cognitive control regions in follicular females.

“These data support existing animal data and an emerging human literature showing that progesterone may exert protective effects over addictive behavior and importantly, the findings provide new insights into sex differences in smoking behavior and relapse,” Franklin said. “Interestingly, the findings may represent a fundamental effect of menstrual cycle phase on brain connectivity and may be generalisable to other behaviors, such as responses to other rewarding substances (alcohol and foods high in fat and sugar).
“The results from this study become extremely important as we look for more ways to help the over 40 million individuals in the US alone addicted to cigarettes,” Franklin, continued. “When we learn that something as simple as timing a quit date may impact a woman’s cessation success, it helps us to provide more individualised treatment strategies for individuals who are struggling with addiction.”

Abstract 1
Introduction: Functional magnetic resonance imaging (fMRI) has been used extensively in an attempt to understand brain vulnerabilities that mediate maladaptive responses to drug cues. Using perfusion fMRI, we have consistently shown reward-related activation (medial orbitofrontal cortex/ventral striatum) to smoking cues (SCs). Because preclinical and clinical studies generally show that progesterone may reduce reward and craving, we hypothesized that females in the follicular phase of the cycle (FPs; when progesterone levels are low) would have greater reward-related neural responses to SCs compared with females in the luteal phase (LPs).
Methods: Sated cigarette-dependent premenopausal naturally cycling females underwent pseudocontinuous arterial spin-labeled perfusion fMRI during exposure to 10-min audio visual clips of appetitive SCs and non-SCs. Brain responses to SCs relative to non-SCs were examined among females grouped according to menstrual cycle (MC) phase at the time of scanning (22 FPs, 15 LPs). Craving scores were acquired pre- and post-SC exposure.
Results: FPs showed increased neural responses to SCs compared with non-SCs in the medial orbitofrontal cortex (p ≤ .05corrected), whereas LPs did not. FPs reported SC-elicited craving (p ≤ .005), whereas LPs did not. Within FPs, SC-induced craving correlated with increased neural responses in the anterior insula (r = 0.73, p < .0001).
Conclusions: FPs may be more vulnerable to relapse during appetitive SC exposure than LPs. Because the influence of MC phase on drug cue neural activity has not been examined, these results contribute to our knowledge of the neurobiological underpinnings of responses to drug cues, and they highlight the importance of monitoring menstrual cycle phase in all areas of addiction research.

Abstract 2
Sex differences in tobacco-related morbidity and mortality exist, with women experiencing more severe health consequences and greater difficulty with smoking cessation than men. One factor that likely contributes to these sex differences is menstrual cycle phase and associated neural and cognitive changes associated with ovarian hormone fluctuations across the menstrual cycle. Previously, we showed that naturally cycling, cigarette-dependent women in the follicular phase of their menstrual cycle showed greater reward-related neural activity and greater craving during smoking cue exposure. To better understand our results and the observed sex differences in smoking behavior and relapse, we explored potential menstrual cycle phase differences in resting-state functional connectivity (rsFC) in naturally cycling, cigarette-dependent women. Understanding how menstrual cycle phase affects neural processes, cognition, and behavior is a critical step in developing more efficacious treatments and in selecting the best treatment option based on a patient’s needs.
Resting-state functional connectivity analyses were used to examine connectivity strength differences between naturally cycling, premenopausal, cigarette-dependent women who were in the follicular phase (FPs; n = 22) and those in the luteal phase (LPs, n = 16) of their menstrual cycle. We also explored associations between connectivity strength and attentional bias to smoking cues.
Compared with LPs, FPs showed decreased rsFC between the dorsal anterior cingulate cortex (dACC) and the subgenual anterior cingulate cortex, medial orbitofrontal cortex (mOFC), and ventral striatum. Among FPs, rsFC strength between the dACC and the bilateral dorsolateral prefrontal cortex (DLPFC), the bilateral dorsal striatum, and the left temporal gyrus was inversely correlated with attentional bias to smoking cues.
This is the first study to explore menstrual cycle phase differences in rsFC among cigarette-dependent women, and results suggest that FPs show differences in rsFC underlying cognitive control, which could place them at greater risk for continued smoking and relapse. These findings provide new insights toward individualized treatment strategies.

Reagan R. Wetherill, Kanchana Jagannathan, Nathan Hager, Melanie Maron and Teresa R. Franklin

University of Pennsylvania material
Nicotine and Tobacco Research abstract
Biology of Sex Differences abstract

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