Literature Review on Nicotine’s Role in Human Health
Authors: Scherer Gerhard , Pluym Nikola , Scherer Max 
Published: April 2024

Summary

Background
Next generation of nicotine/tobacco products (NGPs) include electronic cigarettes (ECs), heated tobacco products (HTPs), oral nicotine pouches (NPs) and smokeless tobacco (SLT) products (in particular snus). These products commonly contain nicotine and are intended to replace combustible cigarettes (CCs) and thus can be regarded as tobacco harm reduction products. To fulfill this role, it is essential that nicotine, which has well established addictive properties, is not causally related to health risks upon chronic use.

Objectives
The purpose of this review is to evaluate the scientific literature to answer the question, whether nicotine is involved in the development of any diseases or disorders associated with the acute, short, mid- and long-term use of NGPs. Appropriate results from studies with nicotine replacement therapy (NRT) products (gum, patches, inhalers, lozenges) are included as reference basis for inferring the health effects of NGPs. Furthermore, suggestions for filling identified gaps and for avoiding or minimizing limitations and weaknesses in study design are provided.

Methods
Literature databases such as MEDLINE, Google Scholar and an in-house ABF library (containing about 180,000 articles) were searched for relevant articles. Furthermore, pertinent monographs (such as the US Surgeon General Reports) and recent reviews were screened for further publications. Inclusion criteria were: all human studies investigating the association between use (preferably chronic use) of the nicotine/tobacco products mentioned above and health effects, including diseases, disorders, changes in biomarkers of biological effect (BOBEs). In vivo (animal) and in vitro studies were also considered, provided effects of NGPs in the presence and absence of nicotine or in relation to the nicotine exposure dose were reported. Also, reference lists of recent suitable articles were screened. In total, about 500 articles were retrieved by this approach. The role of nicotine was evaluated by considering the article authors’ statements and their cited references as well as by own judgement of reported results. Human studies are presented in a standardized table format.

Results
In total, 183 human studies were evaluated, with cardiovascular diseases (CVD) ranking highest (N = 75 studies), followed by respiratory diseases (43), oral health disorders (23), cancer (10), metabolic syndrome (7), reproduction disorders (5) and several other diseases (< 5). The majority of studies do not provide evidence for a participation of nicotine in the pathogenesis. Some (weak) evidence was found that nicotine might be involved in some CVD-related effects and metabolic syndrome. This would be also supported by results from animal and in vitro studies.

Discussion
Human studies showed some severe limitations and weaknesses with respect to the study design and time of availability of NGPs on the market. A severe flaw is the insufficient consideration of dual use (NGP + CC), particularly in studies on chronic use, which could have led to erroneously increased risks for NGPs with direct consequences also for the role of nicotine. Additionally, prior effects from using CC have an impact. Both circumstances could have led to inaccurate conclusions in terms of elevated risk levels, which require changes in method designs. Suggestions for methodological improvements are provided for future studies.

Conclusions
A final evaluation of the role of nicotine in disease development in NGP users is currently not possible because use durations are too short. Chronic studies often suffer from insufficient separation between NGP only and dual use together with CCs, which may falsely increase the observed health risk. There is some limited evidence that nicotine may be involved in CVD-related effects, which, however, has to be verified in well controlled long-term studies. The potential involvement of nicotine in other patho-mechanisms also requires further research.