Rethinking Nicotine Harm Reduction: A Neuroscientist’s Perspective on Scientific Gaps and Future Directions — By Dr. Xin-an Liu

Key Points

In this article, Dr. Liu argues that:

• Separating nicotine from combustion is essential. The pharmacology of nicotine differs fundamentally from the toxicology of tobacco smoke, and regulatory debates must reflect that distinction.

• Animal models remain critical for causal clarity. Because human data is often confounded by prior smoking history, controlled experimental models are necessary to isolate respiratory and cardiovascular risks.

• Developmental and cross-generational effects require urgent study. Long-term cohort research is needed to assess how electronic nicotine delivery may affect brain development and metabolic health.

• Advanced modeling tools should complement traditional toxicology. Integrating computational methods and machine learning can help regulators assess the wide variability of products and formulations.

• Science must lead policy. Standardized research methods and greater international data-sharing are essential to ensure that harm reduction debates remain evidence-driven.

Disclaimer: The views expressed in this article are solely those of the author and do not necessarily reflect those of 2Firsts.

 Xin-an Liu, Ph.D.

Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences

Founding Member, Nicotine Science Exchange（NSE）

February 24, 2026

The recent risk assessment report by the French Agency for Food, Environmental and Occupational Health & Safety (ANSES) provides a balanced evaluation of electronic cigarettes. The report concludes that e-cigarettes are likely less harmful than combustible tobacco, yet significant scientific uncertainties remain. Among the most important challenges are the lack of long-term data, extreme product heterogeneity, and confounding effects from prior smoking history.

From a neuroscientist’s perspective, these uncertainties are not reasons for inaction. Instead, they define a research agenda. As electronic nicotine delivery systems become widely used across populations, science must advance at the same pace.

Nicotine Is Not Combustible Tobacco

A central scientific issue is the need to distinguish nicotine itself from the toxic mixture produced by tobacco combustion. In our recent study (Jia et al., Advanced Science, July 2025), we found that chronic oral nicotine exposure in aged mice reprogrammed aging-related metabolic pathways and was accompanied by improved motor performance. These findings do not suggest that nicotine is harmless. Rather, they emphasize that the long-term biological effects of nicotine alone are not equivalent to those of cigarette smoke, which contains thousands of combustion-derived toxicants.

Nicotine is a neuromodulator acting primarily through nicotinic acetylcholine receptors. It influences dopamine signaling, mitochondrial metabolism, inflammation, and synaptic plasticity. Tobacco smoke, by contrast, introduces carcinogens, oxidants, and particulates that drive cancer, chronic lung disease, and vascular injury. If harm-reduction science is to be rigorous, it must carefully separate nicotine pharmacology from combustion toxicology.

Biological Complexity: Dose, Route, and Developmental Stage

Nicotine is biologically complex. Its effects depend on dose, duration, delivery route, and developmental context.

At the Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, our laboratory utilizes well-established animal models to investigate the systemic and neural effects of nicotine. Our data suggest that:

• Low versus high doses can produce distinct physiological outcomes;
• Inhaled (aerosolized) nicotine differs substantially from oral or injectable delivery;
• Adolescents, adults, and aged individuals may respond differently.

Electronic cigarettes add another layer of complexity: devices vary in heating temperature, aerosol chemistry, and nicotine concentration. Human epidemiological studies often cannot precisely control for these variables. Therefore, well-designed animal models remain essential. Under controlled conditions, they allow us to dissect causal mechanisms safely before translation to human studies.

Neurodevelopment and Transgenerational Questions

One of the most urgent knowledge gaps concerns developmental exposure.

Nicotinic receptors play key roles in brain development, influencing neuronal migration, synaptic refinement, and circuit formation. Exposure during pregnancy or adolescence may alter executive function, reward processing, or addiction vulnerability. Yet long-term developmental data specific to electronic nicotine delivery remain limited. Our ongoing research, together with evidence from other laboratories' published studies, explores the cross-generational neuro-metabolic effects of nicotine exposure. Early findings suggest that nicotine may induce persistent metabolic changes. Whether such effects translate to humans requires careful longitudinal study. If electronic cigarettes are widely used among reproductive-age populations, long-term birth cohort studies should be initiated without delay.

Cardiovascular and Systems-Level Effects

The ANSES report notes short-term cardiovascular responses associated with nicotine, such as increased heart rate and blood pressure. However, definitive long-term outcomes remain uncertain.

Nicotine influences sympathetic activity, vascular tone, and mitochondrial energetics. Chronic adaptation may differ from acute responses, particularly under low-dose, intermittent inhalation patterns typical of e-cigarette use.

Addressing these questions requires:

• Rigorous long-term cardiovascular studies in validated animal models;
• Comprehensive multi-omics profiling of metabolic and inflammatory mechanisms;
• Well-designed clinical investigations of nicotine pharmacokinetics and systemic physiological effects.

Only integrated systems-level research can clarify whether nicotine-containing e-cigarettes pose sustained cardiovascular risks.

The Role of AI and International Collaboration

Electronic cigarettes present a unique scientific challenge: extreme product heterogeneity. Thousands of flavors and device configurations create enormous variability in exposure. Traditional toxicology alone cannot efficiently evaluate this landscape.

Our team is integrating machine learning approaches to model chemical formation in aerosols, predict receptor interactions, and analyze addiction-related neural responses. The long-term goal is to build structured databases linking chemical composition, toxicology, neurobehavioral outcomes, and population-level data. Such efforts require international collaboration. Regulatory agencies including the U.S. Food and Drug Administration, public health institutions, and research laboratories should work collaboratively to share data and harmonize research methodologies. Cross-population studies are particularly important, as genetic and environmental backgrounds may influence nicotine’s biological effects. Nicotine harm reduction is a global issue. The science supporting it must also be global.

Moving Forward: A Clear Research Path

Compared to combustible tobacco—studied for more than a century—electronic cigarettes are relatively new. Yet their adoption has been rapid and widespread.

From a scientific standpoint, several priorities are clear:

• Distinguish nicotine’s pharmacological effects from combustion-related toxicity.
• Standardize dose- and route-specific preclinical models.
• Launch long-term developmental and transgenerational studies.
• Integrate AI-based predictive toxicology.
• Strengthen international cooperation and shared databases.

Harm reduction must be guided by evidence rather than ideology. Electronic cigarettes may represent a reduced-risk alternative for adult smokers, but reduced risk does not mean zero risk. At the same time, uncertainty should motivate research—not polarization.

As scientists, our responsibility is to investigate carefully, communicate transparently, and collaborate globally. Only through rigorous and forward-looking research can nicotine harm reduction policy rest on solid scientific foundations.

2Firsts welcomes submissions from scientists, researchers, and subject-matter experts.For inquiries or submissions, please contact: alan@2firsts.com

(Cover Photo: Dr. Xin-an Liu speaks at the 2Firsts 2025 Next-Generation Tobacco Seminar. Source: 2Firsts.)

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