Assessment 4 – Does nicotine provoke seizures?
Background
My previous blog discussed the effect of caffeine consumption on the possible induction of seizures (Assessment 3). Another widely used substance is nicotine which reportedly has the potential to induce seizures under some conditions. The main route of nicotine use is by inhalation in smoking tobacco. Alternative routes include absorption in the oral cavity with chewing tobacco, snuff, nicotine gum and lozenges, and as anti-smoking aids, vaping with E-cigarettes, and transdermal absorption with a nicotine patch. How does nicotine use relate to seizures?
Seizures and Nicotine – Confounding Issues
The scientific literature on seizures and nicotine, comprehensively reviewed up to 2014 by Rong et al., emphasizes the following confounding issues:
1. Impossible to separate nicotine from toxins in smoke
It is incredibly difficult to determine whether nicotine in smoking tobacco can provoke seizures because in the act of smoking tobacco, the smoker not only absorbs nicotine, the addictive component of tobacco, but also absorbs over 7000 other compounds (Rong et al., 2014). Among these, some cause seizures e.g. carbon monoxide; arsenic; cresol, some prevent seizures e.g. acetone and the remainder are unstudied. So it is not only nicotine that might provoke a seizure but anyone of a number of inhaled compounds of smoke. Hence, it is impossible at present to sort this out.
2. Indirect effects of smoking on health may induce seizures
A second consideration is that long term smoking produces harmful changes in the heart, blood vessels and lungs, causes inflammation and blood clots and initiates cancers. These changes secondarily may induce seizures, and are highly probable with a stroke. Therefore, smoking (not necessarily nicotine alone) may indirectly elevate the risk of seizures.
3. No convincing studies on seizures and just nicotine alone
Nicotine use, other than smoking, should provide insights into the direct effects of nicotine on seizures. However, sadly, there are no large scale interventional studies that have investigated this.
Scientific literature (nicotine and seizures) – up to 2014
There have been two prospective studies with the objective of defining the risk of smoking to seizures (see review Rong et al., 2014). The first of these by Dworetzky et al.,( 2010) using data from the Nurses’ Health Study II, assessed the effect of chronic cigarette smoking by women 25-42 (over 110,000 participants at start in 1989) on the risk of seizures or epilepsy. Participants answered a questionnaire every two years and self-reported seizures over a 15 year period. Only responses with seizure verification by medical records were included. The researchers reported a “doubling in the risk of seizures and a modest non-significant increase in epilepsy in current smokers compared with never smokers that appeared to be independent of stroke”. Whether this was strictly due to nicotine was not determined.
The second study (de Carvalho et al., 2012) reported the relation of smoking to seizures in a specific systemic autoimmune disease, primary antiphospholipid syndrome. Of the 88 individuals with primary antiphospholipid syndrome, approximately 10% experienced epileptic seizures. Chronic smoking was the only factor statistically associated with their seizures.
In contrast, several case histories of individuals diagnosed with autosomal dominant nocturnal frontal lobe epilepsy are benefitted by use of nicotine patches (Rong et al., 2014). In these few cases, nicotine patches were comparable to antiepileptic drugs and diminished seizure frequency.
Results of animal studies tell a different story. By different routes, (into the brain ventricles of cats), (subcutaneously, intraperitoneally into rats and mice), nicotine induced seizures, reduced the efficacy of antiepileptic drugs or potentiated known proconvulsant compounds or electric shock. Doses were considered high (generally 3mg/kg or higher).
Interestingly, studies that chronically exposed rats to cigarette smoke or administered low doses of nicotine (0.8 -2 mg), observed a protective effect against chemically-induced seizures (kainic acid or high dose nicotine). In other words, in animal experiments, low doses of nicotine prevent seizures while high doses (greater than obtained with routine smoking) induce seizures.
Relation of nicotine use and seizures – up to present
A small pilot retrospective study of Chinese males (278) with various types of diagnosed epilepsy analyzed the effect of smoking on seizure frequency ( Gao et al., 2017) . While the data show a trend that smoking reduces the frequency of seizures, the type of study design and small size limit reliability of this report.
In contrast, in a comparison of nonsmoking epileptic patients with smoking epileptic patients, Johnson et al.,(2019) showed that smokers had a higher risk of a seizure than non smokers in the past year. Although the study validated smoking with a biochemical test, the cross-section study design, small number of participants and weak validation of seizures in the preceding year, limit reliability of this study. Thus to date, there are no convincing data regarding the effect of smoking on seizures in man.
In animals, injection of cigarette smoke condensate (CSC) into the cerebral ventricle of the rat induced seizures comparable to those produced by intraventricular injection of kainic acid, a known proconvulsant. Interestingly, the effect of the CSC could be block by pretreatment with atropine, a classic inhibitor of the nicotinic acetylcholine receptor. This is the receptor that nicotine activates to produce its stress reducing effects (Xiao et al., 2020). These findings strongly supporting a mechanistic role of nicotine in the induction of seizures (Laadraoui et al., 2018). Iha et al.(2017) identified the seizure-sensitive brain regions affected by intraperitoneal injection of a high dose of nicotine (4mg/kg nicotine) in mice and rats. Selectively removing these areas negated the seizure-inducing effects of nicotine. These results strongly suggest that the nicotine in animal models is a potential cause of seizures. Unfortunately, there is no corroborative data in man.
Vaping and Seizures
Electronic nicotine delivery systems (ENDS) e.g. e-cigarettes are marketed as a means to quit smoking. Seizures are associated with use of ENDS as summarized in 122 voluntary reports (Faulcon et al., 2020). Sixty-two percent indicated seizures occurred within 30 minutes after last use; 85% indicated seizures occurred within 24 hours of last use. According to Benowitz (2020) these reports lack biological plausibility for the following reasons: a) timing of seizures (30 minutes-24 hours) does not relate to the presence of nicotine (minutes), b) description of nicotine poisoning differs from voluntary reports, c) impossibility of relating recurrent seizures to last use. It is possible that other components, added drugs or e-cigarette components may be responsible for reported seizures.
Summary
Does nicotine consumption by any route induces seizures?
Animal studies show low doses of nicotine protect against seizures while high doses induce them. However, contradictory results also exist. Generally, except with toxic overdosing, the high doses used in animals are never achieved in man with smoking or other routes.
Thus, the bottom line is that in man there is no reliable data to indicate either way whether smoking presents a risk to seizure induction or is, in fact, protective. Furthermore, these is no data at all on the effect of chewing tobacco, snuff, patches, lozenges or gum on seizure induction.
Unfortunately and regrettably, the available science is incomplete and inadequate to convincingly state whether nicotine use a) induces seizures, b) suppresses seizures or c) is without effect in man.