The Impact of Daily Smoking on Brain Volume: Evidence, Causation and Regional Differences


Cigarette smoking, a global health concern, is linked to a myriad of adverse health outcomes. These range from cardiovascular and respiratory diseases to cancer, collectively deteriorating overall health (1-4). The impact of smoking extends beyond the physical body, adversely affecting the brain.

This is evident from the association between smoking and increased dementia risk, with studies revealing that smokers are more likely to experience deterioration in both gray and white matter of the brain (5-9). Notably, approximately 14% of global Alzheimer’s disease cases are attributed to cigarette smoking.

The behavior associated with smoking is partially driven by biological factors. Twin studies have been pivotal in establishing the role of genetics in smoking initiation, the intensity of smoking habits, and cessation efforts. It is estimated that about 44% of the propensity to start smoking is hereditary (10-12).

Recent genome-wide association studies have identified thousands of genetic markers linked to smoking behaviors (13-15). Variations in response to nicotinic receptors, nicotine metabolism, and other genetic factors are crucial in shaping smoking habits. Addiction models suggest that these neurodevelopmental risk factors can predispose individuals to smoking and other addictive behaviors (16-17).

Research has also shown correlations between smoking and reduced total brain volume, as well as diminished gray and white matter volumes (18). However, a critical question remains: Are these associations pre-existing risk factors for smoking, or are they consequences of smoking itself?

The UK Biobank offers a unique opportunity to explore this question. With comprehensive assessments and magnetic resonance imaging (MRI) data from around 40,000 participants, along with genetic information, the UK Biobank is a valuable resource for examining the relationships between smoking behaviors, brain volumes, and genetic variation. This study aims to determine the direction of these associations using traditional epidemiological methods and mediation analysis.

Bradford Hill, a renowned epidemiologist, formulated criteria to establish evidence of causality, including nine points: strength, consistency, specificity, temporality, biological gradient, plausibility, coherence, experimental evidence, and analogy (Reference 19). Utilizing the UK Biobank dataset, these criteria were applied to investigate whether the observed brain differences are predispositions influencing smoking behaviors or the outcomes of smoking exposure. The study examined the history of daily smoking, cigarette pack years, time since cessation, and brain volume changes, particularly focusing on specific brain regions after accounting for total brain volume changes.

Furthermore, genetic data were incorporated to clarify the causal relationship between smoking behaviors and brain volume. Using the GSCAN study’s summary statistics (15), a polygenic risk score (PRS) for smoking was created to assess genetic predisposition. In UK Biobank participants, the association between the PRS for smoking, history of daily smoking, and global brain volumes was evaluated.

A weak link between genetic predisposition to smoking and brain volume changes would suggest that smoking negatively impacts brain volume, rather than reduced brain volume leading to smoking behaviors. Mediation analysis was employed to examine the direction and strength of daily smoking as a causal factor.

Collectively, these diverse methodologies aim to elucidate the direction of the association between smoking behaviors and brain volume changes, contributing valuable insights into the complex interplay of genetics, behavior, and brain health. An illustrative overview of this comprehensive study is provided in Figure 1.

Figure 1. Overview of the study. We examined: 1) the predictive ability of the smoking initiation polygenic risk score (PRS) for smoking for a history of daily smoking; 2) the association between the smoking initiation PRS for smoking initiation and brain measures; and 3) the association between smoking behaviors and brain measures.


In this discussion chapter, we delve into the findings of our study, which sought to explore the relationship between a history of daily smoking and global brain volume. The evidence presented herein supports the assertion that daily smoking is adversely associated with brain volume, and this discussion aims to provide a comprehensive analysis of our results, the implications of these findings, and their potential contributions to the broader understanding of smoking’s impact on brain health.

Causation and Evidence Synthesis

To evaluate the relationship between daily smoking and brain volume, we applied the Hill criteria, which guided our assessment of causation. Our study consistently found a strong association between a history of daily smoking and various brain imaging phenotypes, consistent with previous research (18, 24, 25, 26).

his robust consistency across different datasets and analytical methods adds strength to the argument that smoking negatively affects brain volume. Furthermore, our findings revealed a dose-response effect, indicating that individuals with a longer history of smoking (measured in pack-years) exhibited more significant differences in brain volume, reinforcing the link between daily smoking and brain atrophy.

Biological plausibility further supports this association, as daily smoking is known to cause numerous adverse health effects across various organ systems. This study expands the scope to include the brain as another organ adversely affected by smoking, drawing parallels with alcohol’s detrimental impact on the brain (27, 28).

Recent research corroborates this, demonstrating that both smoking and heavy alcohol consumption causally reduce subcortical brain volume (29). Additionally, Mendelian randomization analyses have shown a significant association between genetic susceptibility to smoking and decreased gray matter volume (30), further strengthening the evidence for the adverse effects of smoking on brain structure.

Genetic Insights and Mediation Analysis

Employing genetics as a tool, our study provides supplementary evidence for the negative association between daily smoking and brain volume. Mediation analysis revealed that a polygenic risk score (PRS) for ever smoking strongly correlated with a history of daily smoking in the UK Biobank dataset but had minimal associations with total gray and white matter volume. Notably, when we included history of daily smoking as a mediator, the PRS-brain volume relationship disappeared, emphasizing the potential causal role of daily smoking in diminishing brain volume.

Causation Debate and Brain Differences

The complex relationship between smoking history and brain imaging phenotypes has prompted a debate on causation: whether brain differences precede smoking behavior or are a consequence of it. While some studies suggest that brain differences may predispose individuals to alcohol consumption rather than being a result of alcohol-induced atrophy (17, 31), our focus was primarily on the relationship between daily smoking and global brain volume.

The evidence presented in our study strongly suggests that changes in total brain volume, gray matter volume, white matter volume, and subcortical/cortical regional volumes likely reflect adverse consequences of daily smoking behavior. Furthermore, the negative association between daily smoking and hippocampal volume aligns with smoking’s role as a modifiable risk factor for Alzheimer’s disease, potentially accelerating its development (7).

Importantly, our study found no evidence of an increase in brain volume following smoking cessation, suggesting that the brain changes associated with daily smoking may have a lasting impact.

Regional Brain Differences

Beyond examining total brain measures, our study explored whether specific brain subregions exhibited varying associations with daily smoking, even after correcting for total brain volume. For cortical regions, we observed that the thickness of the superior frontal cortex was negatively associated with daily smoking, consistent with recent evidence of smoking-related cortical thinning (33, 34). Additionally, certain brain regions, such as the superior frontal cortex, rostral middle frontal cortex, and precentral gyrus, displayed more pronounced negative associations with daily smoking than the overall decrease in total brain volume, highlighting the specific vulnerability of these areas to smoking-induced changes.

In the cerebellum, the left hemisphere’s white matter volume was negatively associated with daily smoking, echoing previous findings (35, 36). Similarly, the thalamus and amygdala exhibited stronger negative associations with daily smoking, consistent with prior research (26, 33, 34, 37). Conversely, the volume of the choroid plexus, lateral ventricle, and third ventricle exhibited more positive associations with daily smoking. These regions are integral components of the cerebrospinal fluid (CSF) system, and their increased volume may represent a compensatory response to overall brain volume reduction (38, 39).

In conclusion, our study provides substantial evidence supporting the adverse association between daily smoking and brain volume. The combination of consistent findings, dose-response effects, genetic analyses, and the absence of brain volume recovery after smoking cessation underscores the detrimental impact of daily smoking on brain health. This research contributes to a deeper understanding of the consequences of smoking on the brain and emphasizes the importance of smoking cessation efforts in preserving brain structure and function.

TABLE 1 – Understanding the Superior Frontal Cortex

To appreciate the significance of this association, it’s crucial to first understand the role of the superior frontal cortex in the brain. Situated in the frontal lobe, this region is integral to a range of higher-order cognitive functions, including decision-making, reasoning, planning, and impulse control. It acts as a command center for managing complex behaviors, enabling individuals to make choices that align with their long-term goals and override immediate urges.

The Smoking Epidemic

Smoking remains a persistent global health issue, responsible for a multitude of health problems, including lung cancer, cardiovascular diseases, and respiratory disorders. Despite public awareness campaigns and access to cessation programs, many individuals continue to engage in daily smoking, highlighting the pressing need for a more comprehensive understanding of the factors driving this behavior.

The Clinical Study: A Window into the Brain

Researchers have embarked on a quest to uncover the neurobiological basis of daily smoking. A recent clinical study gathered a diverse sample of participants, including both daily smokers and non-smokers, for a detailed examination of their brain structures using advanced imaging techniques such as magnetic resonance imaging (MRI).

The Astonishing Discovery

The findings of this study unveiled a striking relationship between superior frontal cortex thickness and daily smoking. Specifically, participants who reported daily smoking consistently exhibited thinner superior frontal cortices compared to their non-smoking counterparts. This revelation prompted an exploration into the clinical explanation behind this intriguing correlation.

The Clinical Explanation

  • Impaired Executive Functions: The superior frontal cortex plays a pivotal role in executive functions, which encompass abilities like impulse control, decision-making, and goal-oriented behavior. A thinner superior frontal cortex is associated with reduced executive function capacity. Daily smokers with thinner superior frontal cortices may experience difficulties in exerting self-control over their smoking habits, leading to the compulsion to smoke despite being aware of the health risks.
  • Reward System Dysregulation: Smoking triggers the brain’s reward system by releasing dopamine, a neurotransmitter associated with pleasure and reinforcement. A thinner superior frontal cortex may disrupt the balance of this reward system, making daily smokers more susceptible to the pleasurable effects of nicotine and less capable of resisting the urge to smoke.
  • Cravings and Addiction: The structural differences in the superior frontal cortex could also affect the regulation of cravings and addiction. A thinner cortex may impair the brain’s ability to modulate cravings and suppress addictive behavior, contributing to the persistence of daily smoking.
  • Cognitive Impairment: Reduced superior frontal cortex thickness may lead to cognitive deficits, which can exacerbate the challenges of quitting smoking. Daily smokers may struggle with cognitive aspects of quitting, such as planning, problem-solving, and coping with withdrawal symptoms.

The negative association between superior frontal cortex thickness and daily smoking offers a profound clinical insight into the neurological underpinnings of this addictive behavior. It suggests that structural differences in the brain can significantly influence an individual’s capacity for impulse control, decision-making, and addiction management. As we strive to develop more effective smoking cessation strategies and addiction treatments, this research provides a crucial foundation for understanding the intricate relationship between brain structure and daily smoking. Ultimately, it offers hope for those seeking to break free from the grip of this persistent habit.

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