Epilepsy is one of the most common chronic neurological disorders, affecting approximately 70 million persons all around the world and posing significant challenges and burden to public health and quality of life (1). According to the global burden of epilepsy in 2016, epilepsy accounted for 13.5 million disability-adjusted life-years (DALYs) and was responsible for 0.56% of total DALYs globally (2, 3). The prevalence of epilepsy is higher in low-income countries than in high-income countries and males demonstrating a marginally elevated risk relative to females (1, 4). The incidence has a bimodal distribution, with two distinct peaks: in infants under 1 year of age and in people aged 50 years and older (1). Within the older adult population (>50 years), the incidence rate increases with increasing age, and the incidence rate of people over 70 years old is the highest (1). Epilepsy is complex and multifactorial, with both genetic and environmental factors playing crucial roles. The risk factors vary among different age groups. Brain developmental abnormalities typically occur in those with onset before adulthood, while epilepsy related to head trauma, infection, and tumors can occur at any age and cerebrovascular disease usually occur in older people (1).

The smoke generated during smoking consists of a complex mixture of compounds, with different effects on human health, such as nicotine, tar, carbon monoxide, and polycyclic aromatic hydrocarbons. Tobacco exposure has negative effect to some diseases such as stroke, coronary heart disease, and lung cancer, while in others such as inflammatory bowel diseases, it has positive effect (5–8).

Tobacco smoke exposure is complex in epilepsy because some studies considered proconvulsant effects while others suggested anticonvulsant effects (9, 10). A prospective study, using data from the Nurses’ Health Study II, included 116,363 women aged 25–42 years. They found that after adjusting for stroke and other factors, current cigarette smoking was associated with increased risk of seizure (RR 2.60, 95% CI 1.53–4.42) and past smoking was associated with increased risk of epilepsy (RR 1.46, 95% CI 1.01–2.12) compared with never smoking (10). A meta-analysis of Mendelian randomization (MR) studies assessing the causal association of smoking in a variety of diseases and a two-sample MR study of risk factors for epilepsy identified that genetic liability to smoking was associated with increased risk of epilepsy (11, 12). For individuals in older age, the Framingham Heart Study showed that smoking was not associated with an increasing risk of epilepsy, but the Atherosclerosis Risk in Communities (ARIC) study indicated that smoking increased the risk of late-onset epilepsy (13, 14). A small sample study found that smokers with epilepsy were four times more likely to experience seizures than non-smokers with epilepsy, and the risk of refractory epilepsy did not increase (15). Furthermore, smoking and nicotine have been known to decrease the serum levels and anticonvulsive effect of lamotrigine (16–18). However, a retrospective study on Chinese males with epilepsy found a beneficial effect of smoking on seizure control (9).

In recent years, the prevalence of both active and passive smoking has been steadily increasing, particularly among individuals with poorer overall health (19–21). This trend highlights the need to pay closer attention to the impact of tobacco exposure on these vulnerable populations. The prevalence of smoking among people with epilepsy ranges from 20 to 48%, with most studies indicating that this rate is higher compared to those without epilepsy (22–29). However, the impact of tobacco exposure on epilepsy remains controversial. This study aimed to investigate the relationship between tobacco smoke exposure and epilepsy.

In this nationally representative study, 17,728 survey participants were included and the prevalence of epilepsy was 7‰, which is consistent with previous studies (4). We found no statistical association between tobacco exposure and epilepsy and the results persisted after adjusting for age, sex, race/ethnicity, body mass index category, poverty-income ratio category, insurance status, and survey year. In different subgroups of age, sex, and race/ethnicity, we only found a statistically significant association in the age-group of 40–50 years. The results were similar when using different definitions of tobacco exposure and in the group of active tobacco exposure or passive tobacco exposure.

In current literature, data on the relationship between tobacco smoke exposures and epilepsy are limited, and the association remains inconclusive. While it is widely accepted that tobacco exposure is a detrimental factor for individuals with epilepsy, our findings suggest that both active and passive tobacco smoke exposure may act as a protective factor for epilepsy in individuals aged 40–50 years. This result is similar to the research reported by Gao et al., but contrasts with other studies that identify tobacco exposure as a risk factor (9–14). These discrepancies may be attributed to differences in study populations, definitions of tobacco smoke exposure, and criteria for diagnosing epilepsy. First, many studies have been limited by small sample sizes, and none have utilized the NHANES database to explore the relationship between tobacco exposure and epilepsy. In contrast, our study employed data from the NHANES database (2013–2018) with weighted statistical analysis, providing national representativeness and a large sample size. Second, while previous studies typically relied on self-reported tobacco use, we assessed tobacco exposure through both self-reports and biomarkers. Additionally, we included participants exposed to both active and passive tobacco smoke. Finally, compared to earlier studies, we defined epilepsy based on the use of antiepileptic medications and the occurrence of recurrent seizures in the past 30 days.

The components of tobacco smoke are complex, and current studies have shown that some of these constituents, including nicotine, have anticonvulsant effects. Nicotine, a major alkaloid in tobacco, is rapidly absorbed into the bloodstream through the lungs and transported to the brain when tobacco products are smoked or used. In animal studies, low-dose nicotine has been shown to exert protective effects on seizure activity, suggesting a potential therapeutic role (32). The mechanisms through which nicotine influences epilepsy are multifaceted, and understanding these pathways is crucial for elucidating its clinical implications (33, 34). First, nicotine acts primarily through neuronal nicotinic acetylcholine receptors (nAChRs), which are ligand-gated ion channels widely distributed in both pre-and post-synaptic regions of the brain (33, 34). nAChRs modulate ion flux across cell membranes, influencing neuronal excitability and the release of various neurotransmitters (33, 34). This action impacts synaptic plasticity and other physiological and behavioral processes (33, 34). Dysregulation of nAChRs has been implicated in the pathophysiology of epilepsy, and nAChRs are considered potential therapeutic targets (33, 34). For instance, autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is a rare form of epilepsy caused by mutations in genes encoding nAChRs (35). Given that nicotine is an agonist of nAChRs, its chronic exposure may alter receptor sensitivity, potentially offering therapeutic benefits for epilepsy linked to nAChR mutations (34, 36–38). Additionally, studies have demonstrated that nicotine and its metabolite, cotinine, can rapidly cross the blood–brain barrier and bind directly to MD2 proteins on microglial membranes (39, 40). This binding induces conformational changes in MD2, which may influence its function and reduce neuroinflammation caused by microglial activation (39, 40). Neuroinflammation is a key contributor to the onset and progression of epilepsy, and by modulating this pathway, nicotine may reduce seizure susceptibility and protect against long-term neurological damage (41). This anti-inflammatory effect presents a novel avenue for epilepsy treatment, although the dual effects of nicotine (i.e., both potential benefits and risks) must be carefully balanced in clinical practice. Furthermore, other tobacco smoke constituents, such as selenium, zinc, carbon dioxide, toluene, acetone, and nickel chloride, have also been shown to possess anticonvulsant properties, suggesting that nicotine may not be the only active component in tobacco with potential therapeutic effects (42–47). However, the complex nature of tobacco smoke and its varying effects on the brain necessitate further investigation to better understand its overall impact on epilepsy management. While nicotine has demonstrated potential anticonvulsant effects in certain studies, these findings should be interpreted with caution, given the potential limitations of sample size, study design, and other confounding factors. It is important to note that our results may be influenced by random variation or residual confounding, and additional studies with larger sample sizes and longitudinal designs are required to validate these findings. Further research is required to fully understand the biological mechanisms underlying these effects and their clinical implications for epilepsy treatment. This finding could lead to the development of novel therapies for drug-resistant epilepsy, although the risks associated with nicotine exposure, including addiction and adverse health effects, must be considered in clinical decision-making.

Our study has several limitations that should be noted. First, our definition of epilepsy was based on medication intake, which may not have captured all individuals with epilepsy, as some patients might have refused medication or discontinued it due to good control of their condition. However, multiple previous studies had used this definition, and there was evidence that the existence of ASM can greatly improve the detection of epilepsy in research datasets (30, 31, 48, 49). Second, the NHANES database does not provide detailed information on key characteristics of epilepsy, such as seizure frequency, duration, or classification. This limits our ability to fully assess the relationship between tobacco exposure and different subtypes of epilepsy. Third, there is a risk of residual confounding due to the lack of certain covariates, such as family history of epilepsy, history of head trauma, and past encephalitis or meningitis, which could influence the risk of epilepsy. These factors were not available in the NHANES dataset and could have affected the results. Fourth, due to the lack of detailed information in NHANES, factors such as smoking frequency, duration, and intensity were not included in the analysis. Finally, it is important to emphasize that this study is cross-sectional in nature and therefore cannot establish causality. The dataset does not provide information on the temporal relationship between tobacco exposure and the onset of epilepsy. Given the potential for random variation and the limitations in sample size, further studies are needed to validate our findings. There should be some better design, more confounders considered and longitudinal studies to be performed to investigate how tobacco smoke exposure affects the epilepsy network. In the future, extract from cigarette as adjunctive medication or nicotine therapy may help obtain better seizure control in patients.

In summary, tobacco exposure was not associated with epilepsy in the US population and this result remained after adjusting for confounding factors, and the sensitivity analysis was robust. However, in stratified analysis, tobacco exposure was a protective factor for epilepsy patients aged 40–50. More studies are need to investigate how smoking affects the epilepsy network in the brain, as well as a prospective study that considers more confounding factors to increase evidence of the association between tobacco exposure and epilepsy.