Nicotine pouch pharmacokinetics compared to smoked tobacco: A systematic review and meta-analysis

Abstract

Nicotine pouches (NP) are novel agents that deliver nicotine through buccal absorption as opposed to combustion. They are proposed as a harm reduction tool compared to smoking tobacco. However, there is limited evidence on their efficacy and safety. This review article summarizes the current evidence regarding NP pharmacokinetics compared to conventional tobacco products. We searched Medline, Embase, CENTRAL and Scopus for studies that assessed pharmacokinetic parameters of nicotine pouches. We identified studies involving tobacco-dependent adults and examined pharmacokinetic parameters such as total exposure, peak concentration, and time to peak. A meta-analysis was conducted using random-effects models to calculate pooled effect sizes. The Cochrane ROB 2.0 tool was used to evaluate the risk of bias in the included studies. A total of seven RCTs and crossover trials were included. Five compared NP pharmacokinetics with smoked tobacco, while two used moist snuff as comparators. Total nicotine exposure was significantly lower with 1.5 mg and 2 mg pouches, similar with 3.5 mg and 4 mg pouches, and significantly higher with pouches containing 8 mg or more when compared to cigarettes. A meta-analysis of three trials showed that 4 mg pouches delivered 91.73 % (95 % CI 85.03 %–98.42 %) of cigarette total nicotine exposure. Peak concentration was significantly lower with 1.5 mg, 2 mg, and 3.5 mg pouches while higher concentration pouches had greater peak when compared to cigarettes. A meta-analysis of three trials showed that 4 mg pouches showed a peak nicotine concentration of 69.15 % (95 % CI 58.55 %–79.76 %) compared with cigarettes. Peak nicotine concentration was consistently achieved earlier with cigarettes (5–8 min) than with pouches (20–65 min). Despite their buccal absorption, 4 mg pouches (most commonly used), deliver similar total nicotine exposure to cigarettes, though with lower peak concentrations and slower absorption. When combined with their flavours and aggressive marketing to youth, this raises concerns about the potential of nicotine pouches to cause nicotine dependence, especially among those using the product recreationally.

Highlights

• •First systematic review & meta-analysis of nicotine pouch pharmacokinetics.
• •Nicotine uptake from NPs can meet or exceed that from conventional cigarettes.
• •Higher doses & flavoured NPs have greater total & peak nicotine exposure.
• •NP use may lead to nicotine dependence.
• •More research is needed to assess their suitability as a smoking cessation aid.
• •These findings have direct implications on health policy and regulation.

1. Introduction

The health hazards associated with tobacco and nicotine products are widely acknowledged and are predominantly attributed to the toxic ingredients present in combusted tobacco(Li and Hecht, 2022; Soleimani et al., 2022). Nicotine, a naturally occurring chemical in tobacco, gives rise to the highly addictive nature of tobacco use(Cheetham et al., 2022; Le (Foll et al., 2022). There is a spectrum of risks related to tobacco and nicotine products; combustible cigarettes having the highest threat to health while non-combustible alternatives such as e-cigarettes and smokeless tobacco are associated with lower risk (Chan et al., 2022, Cho, 2020, Goniewicz et al., 2018). Given the risk of tobacco use and benefits of cessation, tobacco harm reduction (THR) is a primary aim for patients, providers, and researchers(Munafò, 2019; Palmer et al., 2021; Patwardhan and Fagerström, 2022). First introduced in 2001, these strategies advocate for the development and investigation of tobacco and nicotine products with reduced relative risks compared to smoking cigarettes (Rajkumar et al., 2020, Shiffman et al., 2002). THR offers a practical and safer alternatives for adult individuals who smoke cigarettes who find it difficult to reduce or quit (Hatsukami and Carroll, 2020, O'Leary and Polosa, 2020). It works by shifting current individuals who smoke cigarettes to non-combustible nicotine products to satisfy cravings and address nicotine dependence (Lucherini et al., 2020). This promotes public health by reducing smoking-related sickness and death (Grandolfo et al., 2024, Peitsch et al., 2018).

Several innovative nicotine delivery products have been proposed for adult individuals who smoke cigarettes, offering reduced harm potential compared to traditional cigarettes(Benowitz, 2014). These include nicotine replacement therapy (NRT), heated tobacco, Scandinavian snus, modern chewing tobacco, pouched snus, and e-cigarettes(O'Connor et al., 2022). By avoiding tobacco combustion, these products reduce exposure to toxicants, leading to decreased toxicity and potentially fewer adverse health effects (Cobb et al., 2021). Nicotine pouches (NPs), a recent addition to the market, present a novel class of nicotine delivery, consisting of a small paper pouch containing nicotine extract and flavorings (Hrywna et al., 2023). These pouches are similar to traditional snus, in that they are designed to be administered between the lip and gum for buccal nicotine absorption. However, NPs do not contain tobacco, and may offer a potentially safer form of NRT (Majmundar et al., 2022). A wide variety of flavors (e.g., mint, fruit, coffee, and candy-like options) are available, which may enhance product appeal, particularly among young individuals and those who do not smoke cigarettes(Vogel et al., 2025). Manufactured and marketed by major tobacco companies such as Swedish Match and Altria, popular brands worldwide include Zyn, Zonnic, On!, Velo, Rouge, and Dryft(Ling et al., 2023).

NPs have witnessed a significant surge in sales, particularly among youth and young adults(Kramer et al., 2023; Krusell, 2023). However, there is limited evidence of efficacy or safety of these products for smoking cessation. Nonetheless, given the evolving landscape of nicotine consumption and risk of promoting nicotine dependence among individuals who do not smoke cigarettes, it is necessary to thoroughly understand how these products work, especially when compared to combustible tobacco products. This review article aims to summarize the currently available evidence of NP pharmacokinetics and how it relates to conventional cigarettes.

2. Methods

This systematic review and meta-analysis was reported according to PRISMA guidelines(Rethlefsen et al., 2021) and was pre-registered (PROSPERO ascension CRD42024519247).

2.1. Literature Search

To identify studies on the pharmacokinetic effects of NPs, an expert librarian conducted a comprehensive, peer reviewed search across several databases March 13, 2024 (updated September 8, 2025): Scopus, Medline, Cochrane Central Register of Controlled Trials, EMBASE(McGowan et al., 2016). Grey literature was also searched April 2, 2024 (updated September 8, 2025), including clinical trial registries (ClinicalTrials.gov, WHO ICTRP) and pre-print servers (EuropePMC and Dimensions.ai). The main search concept comprised of terms related to nicotine pouches. No limits to language or publication data were applied, however where possible results were limited to human-only studies. Additionally, the bibliographies of the retrieved articles were reviewed to find any further relevant studies. Detailed search strategies can be found in Supplementary File 1 of the online supplement.

2.2. Study Selection

For our systematic review, we included studies that met specific criteria: they had to be original articles assessing the pharmacokinetic parameters and the study design needed to be either a randomized controlled trial (RCT) or a prospective uncontrolled study. Eligible studies focused on pharmacokinetic parameters such as total nicotine exposure, peak nicotine concentration, and the time to peak after using NP or other tobacco products. We excluded nonoriginal reports, conference abstracts, project records, letters, commentaries, and case reports. Titles and abstracts were screened independently by two reviewers using Covidence, and full texts of potentially eligible studies were reviewed in duplicate, with disagreements resolved through discussion and consensus.

2.3. Data extraction and quality assessment

For this systematic review and meta-analysis, data were extracted into a specially designed form, capturing details such as first author’s name, study setting, participant demographics, baseline characteristics, intervention specifics, study design, follow-up, and outcome measures. The Cochrane risk-of-bias tool for randomized trials version 2.0 was employed to evaluate the risk of bias in the included studies(Higgins et al., 2011). To address any missing data, we reached out to the authors of original studies, conference abstracts, and ongoing or unpublished studies. Data extraction was independently conducted by two reviewers (S. S. and E. B.), with discrepancies resolved through discussion and consensus. A pre-formed spreadsheet, pre-piloted for consistency, was used for data extraction, and any unreported symptoms were marked as missing. The risk of bias was assessed by two independent reviewers (J. H. and H. M.). Any disagreements were resolved through discussion until consensus was achieved. The certainty of evidence in the included studies was also evaluated using the GRADE approach(Hultcrantz et al., 2017).

2.4. Statistical analysis

This study aimed to evaluate the efficacy of NPs on pharmacokinetic outcomes, specifically focusing on the area under the curve (AUC) concentration and maximum concentration of nicotine (Cmax). Random-effects meta-analyses were employed to compare these variables(Riley et al., 2011). To assess heterogeneity among the included studies, the Q test and I² index were used, with a significance level set at α less than 10 %(Borenstein et al., 2017). Point estimates and 95 % confidence intervals (CIs) were calculated. The maximum concentration of nicotine after traditional smoking was considered as 100, and concentration variables such as AUC and Cmax were compared to that value. Only trials directly comparing non-flavoured 4 mg nicotine pouches with combustible cigarettes were included in the quantitative synthesis, while studies testing flavoured or high-dose formulations, or using alternative comparators such as moist snuff, were reported qualitatively. Statistical analyses were conducted using Stata version 17.0 (Stata Corp, College Station, TX, (Orsini, 2019).

3. Results

3.1. Study identification

Our search strategy initially retrieved 5589 citations. After removing 2896 duplicates, we were left with 2876 unique citations. Following a thorough title and abstract screening, 96 trials were selected for full-text review. However, after further scrutiny, 89 studies were excluded based on criteria detailed in the PRISMA flow diagram (Fig. 1). Ultimately, seven studies(Rensch et al., 2021[Chapman et al., 2022; Liu et al., 2022; McEwan et al., 2022; Mallock-Ohnesorg et al., 2024; Kanobe et al., 2025; Keller-Hamilton et al., 2025) were eligible for inclusion, resulting in seven studies focusing on pharmacokinetic trials of various NPs included in the systematic review. Three studies(Rensch et al., 2021; Liu et al., 2022; Kanobe et al., 2025) were eligible for quantitative synthesis of AUC and Cmax outcomes, while the others(Chapman et al., 2022; McEwan et al., 2022; Mallock-Ohnesorg et al., 2024; Keller-Hamilton et al., 2025) were reported qualitatively.

Fig. 1.

PRISMA flow diagram of study selection.

3.2. Study characteristics

The main characteristics of included studies are presented in Table 1. The included RCTs were published between 2021 and 2025. The studies were conducted in the UK(Chapman et al., 2022), Sweden(McEwan et al., 2022; Kanobe et al., 2025), the USA(Rensch et al., 2021; Liu et al., 2022; Keller-Hamilton et al., 2025) and Germany (Mallock-Ohnesorg et al., 2024). The number of participants ranged from 15 to 62. Three studies included individuals who use both cigarettes and smokeless tobacco, while four studies focused exclusively on individuals who smoke cigarettes or use smokeless tobacco. The mean age of participants ranged from 27.9 to 41.5 years, with one small trial reporting a mean of 29.3 years. The mean Body Mass Index (BMI) varied from 23.3 to 28.5.

Table 1.

Main characteristics of included studies.

First name Author, et al., year	Country of Origin	Number of Participants	Smoking Status (individuals who smoke cigarettes, never Smoked)	Type of Nicotine Pouches	Dose of Nicotine pouches	Control group	Age of Participants Mean (SD)	Main Outcomes*	Funding Support
Rensch et al., (Rensch et al., 2021)	USA	42	Individuals who exclusively smoke cigarettes (10 +/day) for 1 year prior	on!	4 mg	Own brand cigarette	41.5 (10.7)	•Original 4 mg nicotine pouches = =>  Cmax= 9.0 ng/mL, Tmax= 30.1 min, and similar AUC compared to cigarettes. •Wintergreen 4 mg nicotine pouches = =>  Cmax= 9.5 ng/mL, Tmax= 32.5 min, and similar AUC compared to cigarettes. •Cinnamon 4 mg nicotine pouches = =>  Cmax= 10.2 ng/mL, Tmax= 34.9 min, and similar AUC compared to cigarettes. •Citrus 4 mg nicotine pouches = =>  Cmax= 11.5 ng/mL, Tmax= 33.5 min, and slightly higher AUC compared to cigarettes. •Berry 4 mg nicotine pouches = =>  Cmax= 10.8 ng/mL, Tmax= 32.8 min, and similar AUC compared to cigarettes. •Coffee 4 mg nicotine pouches = =>  Cmax= 9.3 ng/mL, Tmax= 31.2 min, and slightly lower AUC compared to cigarettes. •Control (Cigarette): Cmax= 16.3. ng/mL, Tmax= 7.5 min	Altria Client Services LLC
Chapman et al.(Chapman et al., 2022)	UK	24	Dual use of snus and cigarettes for > 1 year with a minimum weekly consumption of 2 +  snus cans and > 5 cigarettes	Zone X #2, ZoneX #3 (manufactured by Skruf Snus, Sweden)	5.8 mg, 10.1 mg	Marlboro Gold Cigarette (0.8 mg)	30.4 (10.0)	•5.8 mg nicotine pouches: Cmax= 5.2 ng/mL, Tmax= 26 min, AUC lower than cigarettes. •10.1 mg nicotine pouches: Cmax= 7.9 ng/mL, Tmax= 22 min, AUC slightly lower than cigarettes. •Control (Cigarette): Cmax= 11.6 ng/mL, Tmax= 8.6 min	Imperial Brands PLC.
McEwan et al.,(McEwan et al., 2022)	Sweden	35	Dual snus (6 months prior) and cigarette use (>5/week) for past year)	(5 different brands) Lyft, zyn, Nordic, Skruf, on!	6 mg, 8 mg, 9 mg, 10 mg,	Combustible Pall Mall Red Cigarette	27.9 (8.1)	•On! 6 mg nicotine pouches = =>  Cmax= 17.5 ng/mL, Tmax= 65 min, and significantly higher AUC compared to cigarettes. •Skruf 8 mg nicotine pouches = =>  Cmax= 13.0 ng/mL, Tmax= 60 min, and similar AUC compared to cigarettes. •Nordic Spirit 9 mg nicotine pouches = =>  Cmax= 18.4 ng/mL, Tmax= 62 min, and significantly higher AUC compared to cigarettes. •Lyft 10 mg nicotine pouches = =>  Cmax= 17.1 ng/mL, Tmax= 60 min, and significantly higher AUC compared to cigarettes. •Zyn 10 mg nicotine pouches = =>  Cmax= 11.9 ng/mL, Tmax= 65 min, and lower AUC compared to cigarettes. •Control (Cigarette): Cmax= 13.9 ng/mL, Tmax= 7 min	British American Tobacco
Liu et al., (Liu et al., 2022)	USA	30	Dual use of MST and 10 +  cigarettes/day for at least 12 months	on!	1.5 mg, 2 mg, 3.5 mg, 4 mg and 8 mg	Own brand cigarette and moist smokeless tobacco	34.9 (9.63)	•1.5 mg nicotine pouches = =>  Cmax= 3.2 ng/mL, Tmax= 32.5 min, and significantly lower AUC compared to cigarettes. •2 mg nicotine pouches = =>  Cmax= 4.6 ng/mL, Tmax= 33.9 min, and significantly lower AUC compared to cigarettes. •3.5 mg nicotine pouches = =>  Cmax= 7.1 ng/mL, Tmax= 33.9 min, and AUC not significantly different from cigarettes. •4 mg nicotine pouches = =>  Cmax= 8.4 ng/mL, Tmax= 33.9 min, and AUC not significantly different from cigarettes. •8 mg nicotine pouches = =>  Cmax= 14.5 ng/mL, Tmax= 33.9 min, and significantly higher AUC compared to cigarettes. •Control (Cigarette): Cmax= 12.2 ng/mL, Tmax= 8.5 min	Altria Client Services LLC.
(Keller-Hamilton et al., 2025)	USA	62	Current moist snuff use (≥1 year)	Rogue (low freebase), Zyn (high freebase), peppermint	6 mg	Usual brand moist snuff	34.5 (10.1)	•Rogue (low freebase, 6 mg nicotine pouches): Cmax = 7.5 ng/mL, AUC = 507 ng·min/mL •Zyn (high freebase, 6 mg nicotine pouches): Cmax = 15.1 ng/mL, AUC = 998 ng·min/mL •Control (Moist snuff): Cmax = 13.7 ng/mL, AUC = 919 ng·min/mL	Independent/academic
Mallock-Ohnesorg et al., (Mallock-Ohnesorg et al., 2024)	Germany	15	Cigarette smoking (daily, 12 CPD)	White Fox (flavoured mint)	6 mg, 20 mg, 30 mg	Own brand cigarette	29.3 (8.9)	•6 mg nicotine pouches: Cmax = 2.8 ng/mL, AUC = 4.9 ng·h/mL •20 mg nicotine pouches: Cmax = 7.1 ng/mL, AUC = 11.6 ng·h/mL •30 mg nicotine pouches: Cmax = 29.4 ng/mL, AUC = 45.7 ng·h/mL •Control (Cigarette): Cmax = 15.2 ng/mL, AUC = 22.1 ng·h/mL	Independent academic funding
Kanobe et al., (Kanobe et al., 2025)	Sweden	42	Cigarette smoking (≥10 CPD)	Velo Mini (Modern Traditions, non-flavoured)	4 mg	Own brand cigarette	32 (NR)	•4 mg nicotine pouches (non-flavoured): AUC = 714 ng·min/mL (81 % of cigarette), Cmax = 5.7 ng/mL (69 % of cigarette), Tmax = 39 min •Control (Cigarette): AUC = 881 ng·min/mL, Cmax = 8.2 ng/mL, Tmax = 7.5 min	British American Tobacco

^⁎C_max: Maximum observed plasma concentration, AUC: Area under the plasma concentration–time curve, T_max: Time to reach maximum plasma concentration

One study used the ‘Zone X’ brand, while two studies used the ‘on!’ brand. McEwan et al.(McEwan et al., 2022) used a mix of different NP brands. Rensch et al. (2021) and Kanobe et al., 2025;Kanobe et al., 2025) investigated 4 mg NPs, with Kanobe focusing on a non-flavoured formulation. Keller-Hamilton et al. (Keller-Hamilton et al., 2025) evaluated nicotine delivery from low- and high-freebase peppermint NPs compared to moist snuff, while Mallock-Ohnesorg et al. (2024); Mallock-Ohnesorg et al. (2024) assessed higher-dose NPs (6–30 mg) against cigarettes. Across studies, NPs showed wide variability in mean nicotine Cmax values, ranging from 2.8 ng/mL (6 mg NP, Mallock-Ohnesorg) to 29.4 ng/mL (30 mg NP, Mallock-Ohnesorg). By comparison, cigarette Cmax values ranged from 8.2 ng/mL (Kanobe) to 16.3 ng/mL (Rensch). Oral moist smokeless tobacco (MST) produced an intermediate Cmax of 9.8 ng/mL (Liu). The time to reach Cmax (Tmax) was consistently longer for NPs and MST, ranging from 26.0 to 65.0 min, compared to cigarettes, which showed rapid nicotine delivery with Tmax between 7.0 and 8.6 min across studies.

3.3. Pharmacokinetic findings of NPs

The seven included studies in this systematic review employed a randomized crossover design as their methodology, examining the pharmacokinetics and subjective effects of NPs, though with some variation in objective. The primary objective of two of these studies was to evaluate NPs as a potential THR tool, while the other five studies sought to determine the potential for nicotine use and dependence of NPs. Additionally, varying brands, flavors, types, and strengths of NPs were utilized across these studies.

3.4. Total nicotine exposure (AUC, measured in ng·h/mL)

In Liu et al. (Liu et al., 2022), the AUC from 0 to 180 min was significantly lower for 1.5 mg (p < 0.001) and 2.0 mg (p < 0.001) NPs compared to participants’ OBC, with no significant differences for the 3.5 mg (p = 0.065) and 4.0 mg (p = 0.336) NPs. However, the 8.0 mg NP showed a significantly higher AUC than the OBC (p < 0.001). In Chapman et al. (2022), the AUCt was significantly lower for the ZoneX #2 NP (5.8 mg, p < 0.001) compared to the other products tested, but the AUC for the ZoneX #3 NP (10.1 mg, p = 0.000) was slightly lower than that for cigarettes, with no significant differences between the other study products. In McEwan et al. (2022), the geometric mean AUC from 0 to 6 h ranged from 35.8 to 53.7 ng·h/mL for NPs, compared to 25.2 ng·h/mL for the cigarette, with the 10.0 mg Lyft NP showing significantly higher AUC than both the combustible cigarette and the 10.0 mg Zyn NP (p < 0.001). There were no significant differences between the Lyft NP and other NPs except that it was higher than the Skruf 8.0 mg NP. Lastly, In Rensch et al. (2021), AUC values for four NP flavors with 4.0 mg of nicotine were within ±8 % of participants’ OBC, with the coffee-flavored NP having an AUC approximately 15 % lower and the citrus-flavored NP 10 % higher than the OBC (p = 0.050). Nicotine AUC values for the NP flavors were comparable within a 25 % range of one another. Kanobe et al. (2025) reported that non-flavoured 4 mg NPs delivered a mean AUC equivalent to ~81 % of cigarette exposure. Mallock-Ohnesorg et al. (2024) demonstrated a clear dose-response, with AUC increasing from 4.9 ng·h/mL at 6 mg to 45.7 ng·h/mL at 30 mg, exceeding cigarette exposure. Keller-Hamilton et al. (2025), although not including cigarettes as a comparator, showed that high-freebase formulations produced higher AUC than both low-freebase NPs and moist snuff. These studies suggest that the nicotine exposure, measured as AUC, varies between NPs and traditional cigarettes. Lower nicotine doses of NPs result in lower AUC than cigarettes, while higher doses, especially 8 mg and above, result in higher AUC values. Some NPs can provide a higher nicotine exposure than cigarettes, but the effect also depends on factors such as NP flavor and brand.

With seven included studies overall, only three contributed comparable 4 mg NP versus cigarette data to the meta-analysis (Fig. 2). In this meta-analysis, the nicotine concentration for cigarettes was standardized to 100, and the nicotine concentrations produced by nicotine pouches were compared to this baseline. The pooled analysis indicated that 4 mg NPs delivered 91.73 % (95 % CI 85.03–98.42 %) of cigarette nicotine exposure as measured by AUC.

Fig. 2.

Meta-analysis of geometric mean AUC for 4 mg nicotine pouches compared to cigarettes.

3.5. Peak nicotine concentration (Cmax, measured in ng/mL)

Across multiple studies, Cmax values varied significantly between NPs and traditional combustible cigarettes. In Liu et al. (2022), Cmax for the 1.5, 2, and 3.5 mg NPs was significantly lower (p < 0.0001) compared to participants’ own brand cigarette. The 4 mg NP had a similar Cmax, while the 8 mg NP showed a significantly higher Cmax (p < 0.0001). The Cmax geometric mean values for NPs ranged from 3.2 ng/mL for the 1.5 mg NP to 14.5 ng/mL for the 8 mg NP, with the AUC showing a similar trend. McEwan et al. (2022) found that Cmax for the Lyft 10 mg NP was significantly higher than both the combustible cigarette and other NPs, such as Zyn 10 mg NP and Skruf 8 mg NP, but no significant difference was found between Lyft and other NPs. Rensch et al. (2021) indicated that Cmax for all NP flavors with 4 mg of nicotine were within 25 % of one another, but all were significantly lower compared to cigarettes, with nicotine Cmax being around 30–44 % lower than participants’ OBCs (p < 0.0001). Kanobe et al. (2025) reported that the Cmax of non-flavoured 4 mg NPs was approximately 69 % of cigarette levels. Mallock-Ohnesorg et al. (2024) demonstrated a dose-response relationship: Cmax increased from 2.8 ng/mL at 6 mg to 29.4 ng/mL at 30 mg, with the highest dose exceeding cigarette Cmax (15.2 ng/mL). Keller-Hamilton et al. (2025) found that high-freebase peppermint NPs produced Cmax values (15.1 ng/mL) similar to or greater than moist snuff (13.7 ng/mL) and substantially higher than low-freebase NPs (7.5 ng/mL). These studies suggest that the peak nicotine concentration varies based on the NPs dose and type. Lower nicotine doses of NPs result in lower peak nicotine concentration than cigarettes, while higher doses result in higher peak concentration than cigarettes.

The meta-analysis including Liu 2022, Rensch 2021, and Kanobe 2025 (non-flavoured 4 mg) showed that 4 mg NPs achieved a pooled mean Cmax of 69.15 % (95 % CI 58.55–79.76 %) relative to cigarettes (Fig. 3). This suggests that the 4 mg NPs deliver a significantly lower peak nicotine concentration compared to traditional cigarettes, even though total nicotine exposure (AUC) may be similar.

Fig. 3.

Meta-analysis of nicotine pouches geometric means of Cmax for 4 mg nicotine pouches compared to cigarettes.

3.6. Time to peak (T_max, measured in hours)

The metric Tmax (time to reach Cmax) was used by all seven studies to reflect the rate at which nicotine is absorbed. The Tmax values for NPs across all four studies were found to be longer on average, compared to the Tmax values of a traditional cigarette, suggesting a slower rate of nicotine absorption. In Chapman et al. (2022), the Tmax was 2.6–3 times faster with cigarettes when compared to NP. In McEwan et al. (2022), the Tmax was 7 min for the combustible cigarette following a 5-minute smoking session, while for NPs, Tmax occurred much later, between 60 and 65 min after a 60-minute use session. The elimination half-life (T1/2) for nicotine was consistent across all products, ranging from 2.15 ± 0.31 h for the 6 mg On! NP to 2.82 ± 3.29 h for the 10 mg Zyn NP. Notably, there was greater variability in the T1/2 for Zyn, likely due to an anomalous result from one participant. In Rensch et al. (2021), the median Tmax was also earlier for the cigarette at 7.5 min, while for NPs, it ranged from 30 to 35 min, depending on the flavor. The T1/2 for both NP flavors and cigarettes was similar, ranging from approximately 109–123 min. In Liu et al. (2022), the Tmax for NPs was consistently slower (32.5–33.9 min) compared to own-brand cigarettes (8.5 min) and was similar to moist smokeless tobacco (34.4 min). Kanobe et al. (2025) further confirmed that non-flavoured 4 mg NPs exhibited a mean Tmax of 39 min, compared with 7.5 min for cigarettes. Mallock-Ohnesorg et al. (2024) demonstrated Tmax values of NP ranging from 15 min to 20 min depending on dose, while cigarettes reached peak levels at 5 min. Keller-Hamilton et al. (2025) found no significant differences between low- and high-freebase peppermint NPs, with Tmax averaging 36–42 min, closely aligned with moist snuff comparators (median 36 min). These findings collectively suggest that nicotine from traditional cigarettes reaches its peak concentration in the blood much faster (5–8 min) compared to nicotine pouches, which generally take between 20 and 65 min to reach peak levels. However, the time it takes for the body to eliminate nicotine (T1/2) is relatively similar across product types, though more variability is observed with certain NP formulations.

3.7. Adverse events

NPs were well tolerated, with no serious adverse events reported. Reported adverse events included headaches, hiccups, dizziness, restless legs, asthenia, fatigue, extremity pain, gingival bleeding, nausea, and mouth irritation or cardiovascular effects at higher NP doses. Most effects were mild to moderate in nature.

3.8. Quality assessment and certainty of evidence

Fig. 4 presents the quality assessments of seven included studies. Overall, risk of bias ranged from low to high across trials. In domain-level appraisals, objective PK outcomes (LC-MS/MS) generally supported low risk for outcome measurement (D4), while open-label crossover designs and incomplete reporting of randomization/allocation occasionally introduced concerns in D1 and D5. Specifically, Kanobe et al. (2025) was judged low risk across domains (D1–D5), whereas Keller-Hamilton et al., 2025 and Mallock-Ohnesorg et al. (2024) had some concerns (notably D1/D5). The risk of bias in the randomized controlled trials (RCTs) was assessed using the RoB2 tool, as outlined in the Cochrane Handbook (Eldridge et al., 2016). When necessary, the authors of the studies were contacted for clarification. The quality of evidence was further evaluated using the GRADE system through the GRADE pro-GDTT tool (Brignardello-Petersen et al., 2018), which initially classifies evidence quality based on the study design. Based on risk of bias and limited number of studies, the overall certainty of evidence was rated as "moderate" for AUC findings and Cmax results (Supplementary File 2).

Fig. 4.

Risk of bias assessment of included studies.

4. Discussion

To the best of our knowledge, this is the first systematic review and meta-analysis to evaluate and compare the effects of NPs with traditional combustive cigarettes on pharmacokinetic outcomes. This analysis is topical given the increasing use and recent regulations imposed in Canada restricting the purchase and advertisement of NPs. The review focused on high quality evidence, resulting in the inclusion of seven RCTs. The studies evaluated reliable and reproducible variables such as Cmax and the AUC, allowing for the comparison of pharmacokinetics.

There were several interesting findings of this review. First, when comparing NP to cigarettes, pharmacokinetic parameters are heavily affected by the NP dose. For example, Kanobe et al., 2025 tested non-flavoured 4.0 mg pouches and found lower Cmax and AUC compared to cigarettes, whereas Liu et al. (2022) showed that 8.0 mg pouches produced significantly higher values than cigarettes. Pouches at lower doses (≤4 mg) have significantly lower total nicotine exposure and peak concentration while higher doses (>8 mg) have significantly higher total nicotine exposure and peak concentration compared to cigarettes. Mallock-Ohnesorg et al. (2024) extended this evidence by testing high-dose pouches up to 30.0 mg and demonstrated Cmax values exceeding those observed for cigarettes.

Cigarettes are inhaled leading to rapid uptake of nicotine into the blood stream via gas exchange in the alveoli; NP result in slower absorption of nicotine in the bloodstream via the buccal mucosa (Olsson Gisleskog et al., 2021; Taylor et al., 2021). Given the marketing of these products for recreational use, especially towards youth and young adults, this raises concern about the potential of NPs leading to nicotine addiction and dependence (Gaiha et al., 2023; Mallock-Ohnesorg et al., 2024). Second, while the time to peak was earlier among individuals who smoke cigarettes (~5 min) compared to individuals who use NP (~22–65 min across studies), the total time of exposure as measured by elimination half-life, was similar among both groups. Third, flavours and formulation characteristics appear to affect pharmacokinetics. Rensch et al. (Rensch et al., 2021) showed variation among 4.0 mg flavoured pouches, with citrus producing the highest Cmax and coffee the lowest. In addition, Keller-Hamilton et al. (2025) demonstrated that freebase content strongly influenced delivery, with high-freebase peppermint pouches producing significantly greater Cmax and AUC than low-freebase pouches and moist snuff. These findings will have important implications for policy makers, beyond the existing concerns that these may make the product more attractive for recreational use among youth and young adults (McEwan et al., 2023; Vogel et al., 2023). Lastly, NPs were well-tolerated in the acute setting with no serious adverse events. Only mild adverse events such as headaches and nausea were reported (Mallock-Ohnesorg et al., 2024).

Despite the concerns highlighted related to the effect of NP for recreational use, some of the pharmacokinetic parameters may be beneficial for smoking cessation. Moderate doses of NPs (~4 mg) can deliver similar amounts of nicotine but at a slower rate than cigarettes. This could help individuals who smoke cigarettes to reduce the intensity of nicotine cravings and withdrawal symptoms, making it easier to manage their nicotine dependency(Mallock-Ohnesorg et al., 2024). By providing a controlled and lower dose of nicotine, NPs can theoretically serve as a less harmful alternative to smoking, potentially aiding in THR(Shahab et al., 2013; Alizadehgharib et al., 2022; Yu et al., 2022). This can be particularly useful for individuals who smoke cigarettes looking to quit, as it allows them to satisfy their nicotine cravings without the harmful toxins in combustible tobacco(Brose et al., 2021 Pluym et al., 2024). While the pharmacokinetic results are interesting, this hypothesis requires thorough evaluation in clinical trials, which ideally compare NPs to conventional oral forms of NRT(Grandolfo et al., 2024). Until this point, NPs are not considered an appropriate tool for smoking cessation. The current evidence does not support the use of these agents for smoking cessation and should not be recommended by clinicians for this purpose.

There are several limitations of this study. First, NPs are newer products and there are few studies evaluating their pharmacokinetics. Second, there is heterogeneity in the pouch brand, dose, flavours, comparator group, and outcome metrics in the included studies, which affects generalizability. Although seven studies were identified, only three provided comparable data on unflavoured 4 mg pouches versus cigarettes suitable for quantitative synthesis. The lack of overlapping results limited our ability to perform meta-analyses across other doses or flavoured formulations. Given that flavoured NPs have higher peak and total nicotine exposure than unflavoured NPs, our meta-analysis likely underestimate real-world exposure where flavoured NPs are more commonly consumed than unflavoured NPs. Third, most of included studies were funded by the tobacco industry. Industry involvement may bias study design, reporting, and interpretation, as has historically been observed in tobacco research (Burki, 2021; Braun et al., 2024). Tobacco companies may manipulate research by funding biased studies, selectively publishing favorable results, influencing study design, crafting misleading messaging, and lobbying for weaker regulations, ultimately prioritizing profit over public health (Cohen et al., 2009; Abdalla and Abdalla, 2021; Hird et al., 2022). Objective measures, such as pharmacokinetics markers measured in this study, are more reliable and reproducible, which may mitigate this risk. Our updated search also identified two studies with similar findings that were independently funded (Keller-Hamilton 2025, Mallock-Ohnesorg 2024), strengthening the validity of our findings. Fourth, demographic factors such as age, sex, and genetic variability remain unexplored. Most included studies were conducted in young participants concurrently using cigarette, which may have influenced NP pharmacokinetics and limits generalizability to those who exclusively use NP. Future studies should include independent, larger-scale trials with standardized dosing, comparator groups, and outcome measures to allow for more robust meta-analyses. These should also evaluate long-term safety, cessation outcomes, and patterns of use in diverse populations. Importantly, several of the new trials (2024–2025) show that research activity has resumed after an apparent gap since 2022, but independent replication remains limited.

Despite these limitations, this study provides valuable information about NP pharmacokinetics, including dose, formulation, and flavour effects. This can inform future clinical trials aimed at comparing these novel nicotine products to conventional NRT for cessation or harm reduction.

5. Conclusion

Pharmacokinetics of nicotine pouches are affected by the dose and flavour of the pouch. Lower doses (≤4 mg) have significantly lower total nicotine exposure and peak concentration while higher doses (>8 mg) have significantly higher total nicotine exposure and peak concentration compared to cigarettes. Unflavoured 4 mg pouches have similar total exposure amount and time but at a lower peak concentration and with slower absorption. Flavoured pouches, which are most commonly consumed, have significantly higher exposure and peak concentration compared to unflavoured products. This, combined with their aggressive marketing to youth, raises serious concerns about the potential of nicotine pouches to cause nicotine dependence, especially among those using them recreationally. These findings have direct implications on health policy and regulation of nicotine pouches. While NPs may offer a safer alternative to cigarettes, additional research is required to confirm efficacy and safety, especially compared to existing smoking cessation medications, before being recommended as a smoking cessation aid.

Funding

None

CRediT authorship contribution statement

Sarah Visintini: Writing – review & editing, Writing – original draft, Software, Resources. Emma Lynn Bates: Writing – review & editing, Writing – original draft. Spencer Shahen: Writing – review & editing, Writing – original draft. Hassan Mir: Writing – review & editing, Writing – original draft, Investigation, Data curation, Conceptualization. Evyanne Quirouette: Writing – review & editing, Writing – original draft, Methodology, Investigation. Kerri-Anne Mullen: Writing – review & editing, Writing – original draft, Supervision. Javad Heshmati: Writing – review & editing, Writing – original draft, Investigation.

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Appendix A. Supplementary material

Supplementary material

Supplementary material

Data Availability

Data will be made available on request.