Less Nicotine, Less Impact: Evaluating the magnitude of autonomic and cardiovascular effects and dose–response patterns produced by smoking cigarettes with varying nicotine content

Background: The U.S Food and Drug Administration (FDA) has proposed reducing the nicotine content in cigarettes to make them minimally addictive. However, data are limited on whether lowering nicotine content affects the impact of smoking on autonomic and cardiovascular function. Studying such responses can provide insight into the potential harm-reduction implications of FDA’s reduced nicotine policy. Objective: To evaluate the magnitude of autonomic and cardiovascular effects and dose–response patterns produced by smoking cigarettes with varying nicotine contents. Methodology: 24 current smokers (50% male; mean age = 38.0 ± 7.4) completed a within-subject dose-escalation study. After abstaining from nicotine for ≥12 hours, participants completed a lab protocol involving taking eight puffs, 30 seconds apart from three cigarettes. Administered in a fixed order with 30-min washout periods, the cigarettes contained 0.4 mg nicotine per gram of tobacco, 2.5 mg/g (both reduced nicotine contents), and 14.6 mg/g (nicotine content comparable to regular cigarettes). Heart rate, heart rate variability [HRV; metrics: RMSSD (ms), SDNN (ms) LF/HF (nu)], arterial stiffness (pulse wave velocity; PWV), and skin conductance level (SCL) were assessed after smoking each cigarette. Data were log-transformed when necessary. Repeated measures ANOVAs with post-hoc adjustments for pairwise comparisons and polynomial trend analyses were conducted to evaluate dose-response patterns. Cohen's d values were calculated to quantify the magnitude of effects. Results: ANOVAs showed cigarette nicotine content significantly affected most outcomes, including: Heart rate (F = 19.65, p < 0.001, partial η 2 = 0.46), lnRMSSD (F= 17.74, p < 0.001, partial η 2 = .43), lnSDNN (F= 6.59, p = 0.003, partial η 2 = 0.22), lnLF/HF (F= 3.63, p = 0.042, partial η 2 = 0.14) and SCL (F= 4.14, p = .023, partial η 2 = 0.17), and a marginally affected PWV (F = 3.54, p = 0.056, partial η 2 = 0.14). Pairwise comparisons showed that all outcomes differed significantly between the 0.4 mg and 14.6 mg cigarettes (all p < 0.05). Between the 2.5 mg and 14.6 mg cigarettes, heart rate (p < .001), lnRMSSD (p < .001), and lnSDNN (p = .003) differed significantly. Between 0.4 mg and 2.5 mg cigarettes, no outcomes differed significantly. Trend tests exhibited linear dose-response patterns for all measures (all p < 0.05). Only heart rate yielded a significant quadratic trend. Cohen’s d for the three comparisons (0.4 vs 2.5 mg, 0.4 vs 14.6 mg and 2.5 vs 14.6 mg) were: heart rate = 0.42, 0.92, and 1.00; lnRMSSD = 0.21, 1.17, and 0.92; lnSDNN = 0.22, 0.56, 0.78; lnLF/HF = 0.20, 0.41, 0.52; PWV = 0.07, 0.67, 0.35; and SCL 0.09, 0.52, 0.49, respectively. Result Summary: Cigarettes with reduced nicotine contents, compared to regular nicotine cigarette, exhibited smaller increases in heart rate, PWV, and SCL, and attenuated the reduction in HRV. The largest differences occurred between 0.4 mg/g and 14.6 mg/g cigarettes. Most outcomes exhibited clear linear dose-response pattern. Conclusions: Reducing nicotine content attenuated autonomic and cardiovascular responses. Notably, smaller effects on HRV and PWV observed with 0.4 mg/g cigarettes, both clinically meaningful metrics, suggest that 0.4 mg/g cigarettes may confer lower risk compared to regular cigarettes. Together, these findings provide insight into the potential harm-reduction implications of the FDA’s proposed nicotine-reduction policy, suggesting benefits beyond addiction minimization. Nevertheless, 0.4mg/g cigarettes still produce measurable effects, indicating that reduced risk does not equate to no risk. Funding: Institutional Funds of Wake Forest University School of Medicine. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.