This study investigates the nicotine delivery and acute effects of tobacco-free nicotine pouches with high nicotine contents (up to 30 mg). It is a single-center, five-arm, crossover study involving 15 regular cigarette smokers who consumed nicotine pouches from different brands (6, 20, and 30 mg nicotine) and compared them with nicotine-free pouches and tobacco cigarettes. Plasma nicotine concentrations, effects on cigarette craving, and side effects were measured at baseline and at predefined time points over a 240-minute study period. Cardiovascular parameters, including arterial stiffness, were also assessed. The study found that 30 mg nicotine pouches resulted in higher nicotine uptake compared to tobacco cigarettes, with a maximum plasma concentration (Cmax) of 29.4 ng/mL versus 15.2 ng/mL and an area under the curve (AUC) of 45.7 ng/mL·h versus 22.1 ng/mL·h. Nicotine uptake was rapid during use of the 30 mg pouch and cigarette. The extraction rate of nicotine varied between pouches. All products reduced acute cigarette craving, even the nicotine-free pouch. Heart rate increased significantly during consumption of the cigarette and the 20 and 30 mg pouches. Arterial stiffness parameters were elevated, and all pouches caused mouth irritations. The 30 mg pouches had the strongest side effects and may induce addiction. The study suggests that high nicotine contents may not be necessary for craving reduction, and a limit on nicotine content is warranted. The nicotine release rate varies across products and needs to be known to estimate nicotine delivery. The study highlights the importance of understanding the pharmacokinetic properties of nicotine pouches to assess their potential for addiction and cardiovascular effects. The findings suggest that nicotine pouches with high nicotine doses may pose a risk for addiction and cardiovascular events, and that nicotine content should be limited to reduce these risks.This study investigates the nicotine delivery and acute effects of tobacco-free nicotine pouches with high nicotine contents (up to 30 mg). It is a single-center, five-arm, crossover study involving 15 regular cigarette smokers who consumed nicotine pouches from different brands (6, 20, and 30 mg nicotine) and compared them with nicotine-free pouches and tobacco cigarettes. Plasma nicotine concentrations, effects on cigarette craving, and side effects were measured at baseline and at predefined time points over a 240-minute study period. Cardiovascular parameters, including arterial stiffness, were also assessed. The study found that 30 mg nicotine pouches resulted in higher nicotine uptake compared to tobacco cigarettes, with a maximum plasma concentration (Cmax) of 29.4 ng/mL versus 15.2 ng/mL and an area under the curve (AUC) of 45.7 ng/mL·h versus 22.1 ng/mL·h. Nicotine uptake was rapid during use of the 30 mg pouch and cigarette. The extraction rate of nicotine varied between pouches. All products reduced acute cigarette craving, even the nicotine-free pouch. Heart rate increased significantly during consumption of the cigarette and the 20 and 30 mg pouches. Arterial stiffness parameters were elevated, and all pouches caused mouth irritations. The 30 mg pouches had the strongest side effects and may induce addiction. The study suggests that high nicotine contents may not be necessary for craving reduction, and a limit on nicotine content is warranted. The nicotine release rate varies across products and needs to be known to estimate nicotine delivery. The study highlights the importance of understanding the pharmacokinetic properties of nicotine pouches to assess their potential for addiction and cardiovascular effects. The findings suggest that nicotine pouches with high nicotine doses may pose a risk for addiction and cardiovascular events, and that nicotine content should be limited to reduce these risks.