The Effects of Oral Nicotine Pouches on Cigarette Smoking Behavior and Tobacco Harm Exposure: A Randomized Pilot Trial in Adults

Abstract

Oral nicotine pouches may have potential for smoking cessation but scientific evidence on the effects of pouches and their constituents on smoking behavior is limited.

Design:

This study was a 4-week, open-label, randomized pilot trial of nicotine pouches in 3mg (low) or 6mg (high) nicotine strength.

Subjects:

US outpatient research clinic with non-treatment seeking adults who smoke cigarettes (N=30).

Interventions:

Participants selected 2 flavors and were instructed to switch to using nicotine pouches in place of cigarettes.

Main outcome measures:

We compared groups on cigarettes smoked per day, pouch use, and urinary levels of a tobacco-specific carcinogen (NNAL) over 4-weeks, biochemically-verified 7-day point prevalence smoking abstinence at week 4, and willingness to continue pouch use.

Results:

Nearly all participants completed the trial (29/30). Participants in both groups significantly reduced their cigarettes smoked per day (log-transformed) over time [F_{3, 74.4}=3.8, p=.01]. The 6mg group reported numerically greater, but non-significant, reductions in smoking than the 3mg group [least-square mean difference (LSMD) at Week 1=0.008; 95% CI:-0.42–0.44; LSMD at Week 4=0.38; 95% CI:-0.06–0.81]. The 6mg group also reported numerically higher, but non-significant, likelihood of complete smoking abstinence (13% vs. 0%) and willingness to continue pouch use (67% vs. 40%). There were no differences by group or time for NNAL.

Conclusions:

Results provide preliminary support for nicotine pouches for cigarette substitution. Compared to lower nicotine strength pouches, higher nicotine strength pouches may have greater impact on smoking behavior and adults who smoke may be more willing to use them.

INTRODUCTION

Scientific data on oral nicotine pouches, new, non-combustible tobacco products,^[1] are limited and largely from tobacco industry-sponsored studies.^[2] Industry evidence suggests that pouches might have a toxicant profile that is similar to that of nicotine replacement therapies (NRT),^[3] may mimic NRT nicotine delivery at lower strengths (≤4mg),^[4] exceed NRT nicotine delivery at higher strengths (>4mg),^[5–8] and might reduce smoking craving^{[5, 6, 9]} and behavior.^[10] The public health benefit to society could be large if nicotine pouches can help adults stop cigarette smoking.^[11]

Only two non-industry studies have examined pouches’ effects on smoking.^[12] Adults not interested in quitting smoking (N=45) were randomized to 5% nicotine e-cigarettes, 4mg pouches, or assessment only for 8 weeks. Both nicotine groups significantly reduced smoking, with greater reductions in the e-cigarette group.^[12] Another study compared 3mg and 6mg pouches to usual cigarettes in 30 adults after ≥12-hour smoking abstinence.^[13] Both pouches provided similar smoking craving relief, less than that from cigarettes. Together, these findings suggest that pouches may have appeal for smoking cessation and might have comparable effects on smoking-related behaviors at different nicotine strengths. More independent investigations of pouches and their constituents are needed.

Recent evidence from U.S. nationally representative surveys of adults with tobacco use histories estimates current pouch use at 3% and lifetime use at 5.6–16.4%.^[14] Manufacturers are marketing pouches for tobacco harm reduction^[14] and some adults are interested in using these products for smoking cessation.^[15] Therefore, it is crucial to determine if they can reduce cigarette use. The U.S. FDA is considering lower nicotine strength standards for cigarettes,^{[16, 17]} but not yet for non-combustible products. This study aimed to gather data on pouches’ effects in different nicotine strengths on smoking, to support future regulation. We hypothesized that higher nicotine pouches would promote greater smoking reductions than lower nicotine pouches.

SUBJECTS/METHODS

Design

This two-condition randomized-controlled pilot study tested pouches in adults who regularly smoked, did not want to quit, but were open to pouches for smoking substitution. Participants were randomized, open-label, for 4 weeks to: (1) 3mg pouches or (2) 6mg pouches, stratified by sex and baseline dependence. The trial (NCT04250727) was approved by Yale University’s IRB (#2000023826) (supplemental online appendix 1).

Procedures

At randomization, participants received a 1-week supply of Zyn-brand pouches (8 cans) in their assigned group. They chose up to two flavors from ten options and were asked to select one for the remaining 3 weeks. Participants could change flavors during weekly phone check-ins for safety monitoring. All participants received standardized use and storage instructions (i.e., to switch completely to pouches).^{[18, 19]} They returned unused pouches at the Week 4 and attended a follow-up visit at Week 8. They were compensated for visits.

Subjects

Participants were recruited between July 2021 and June 2022 from the local community and an outpatient tobacco treatment service if they declined care. Sample size was based on practical considerations (cost, time, adequacy to evaluate feasibility/acceptability) to identify patterns suggesting potential effects rather than statistical significance.

Eligibility criteria: (1) ≥21 years old, (2) smoking ≥1 cigarette per day for ≥6 months, (3) no current or planned smoking cessation treatment, and (4) English literacy. Exclusion criteria: (1) plans to quit smoking, (2) unstable medical/psychiatric conditions, (3) recent serious cardiac conditions, and (4) currently pregnant, nursing, or unwilling to use effective birth control. Females of childbearing age had pregnancy tests at intake. We did not exclude for other tobacco use.

Measures

At intake, participants completed self-reports of sociodemographics, smoking and quitting history, and use of other tobacco products. To stratify randomization by dependence, participants reported time to first cigarette, scored as ≤30 or =>30 minutes of waking), from the Fagerström Test for Nicotine Dependence.^[20]

Baseline and Week 4 Outcome Measures:

The Timeline Follow-Back Interview (TLFB)^[21–24] assessed past 28-day daily cigarettes, pouches, and other tobacco products. Primary outcome: weekly mean cigarettes/day over 4-weeks. Secondary outcomes: past 7-day smoking abstinence (Week 4), verified by expired breath carbon monoxide (CO), and weekly pouch use/day over 4 weeks.

Biochemical measures included CO (<5ppm verifying no smoking)^{[25, 26]} and urine levels of a tobacco-specific nitrosamine (TSNA), NNAL,^[27] a major metabolite of nicotine-derived nitrosamine ketone and the most potent TSNA pulmonary carcinogen linked to lung cancer.^[27] NNAL, a reliable biomarker of tobacco-related harm exposure, has a relatively long half-life of 10–45 days.^{[28, 29]}

Adverse Events: Research staff assessed possible nicotine toxicity symptoms, reviewed by the study physician if necessary.

Willingness to Continue Pouch Use: At Week 4, participants reported their likelihood of continuing pouch use from 0 (very unlikely) to 4 (very likely). Responses ≥3 were coded as willing to continue. Three non-responses were coded as 0.

Data Analysis

Outcome variables were assessed for normality, with necessary transformations following residual plot inspections. Statistical testing used a 0.05 significance level. Descriptive statistics compared groups on baseline characteristics, retention, adverse events, and willingness to continue pouches.

The primary outcome, cigarettes/day, was log-transformed. A linear mixed model evaluated this outcome over 4 weeks, with group and sex as between-subject factors and week as a within-subject factor, controlling for baseline cigarettes/day and dependence. Missing data were accommodated using maximum likelihood; a first-order autoregressive covariance structure had the smallest the Bayesian Information Criterion. Results include tests of effect slices and least square means comparisons. The same modeling strategy applied to secondary outcomes of pouch use/day and NNAL levels, using log and square-root transformations respectively. Exact logistic regression evaluated secondary outcomes of smoking abstinence at 4 weeks, with group and sex as factors, controlling for dependence.

RESULTS

Subjects

30 participants (mostly women (60%; 18/30), White (60%; 18/30) or Black (37%; 11/30) were randomized between July 2021 and June 2022. Groups were similar at baseline. They had a mean age of 56.83±11.58 years and mean daily cigarette intake of 14.67±9.10 (supplemental online appendix 2).

Feasibility and Acceptability

Nearly all participants completed the 4-week use period (97%; 29/30) and Week 8 visit (90%; 27/30) (supplemental online appendix 3). There were no severe adverse events. Two 6mg group participants reported nicotine toxicity symptoms, both involving dual use of cigarettes and pouches. One temporarily reduced smoking and pouch use, then resumed pouch use after symptoms resolved. The other stopped pouch use and withdrew.

Nicotine Pouch Use

There was a significant effect of group on daily pouch use (log-transformed) over 4-weeks but no effects of time or group x time interaction (Table 1). The 6mg group used significantly fewer pouches/day than the 3mg group across all weeks [Least Square Means Difference (LSD) =0.71(Standard Error (SE) = (0.20); 95%CI: 0.31–1.12]. However, more 6mg group participants [n=4] discontinued pouch use before Week 4 than the 3mg group [n=1], mostly due to disliking the pouches; 1 6mg participant discontinued for adverse effects.

Table 1.

Estimates of pouch use per day, cigarettes per day, and tobacco harm exposure (NNAL) over time by group (N=30)

Outcomes, LSMa (SE)	3mg Nicotine Group (n = 15)	6mg Nicotine Group (n=15)	Model	P value
Pouch use per day (log-transformed)
Week 1	1.82 (0.16)	1.37 (0.16)	Group: F1, 29.2=12.78	0.001
Week 2	1.91 (0.16)	1.22 (0.16)	Time: F3, 81.3=0.09	0.96
Week 3	2.02 (0.16)	1.14 (0.17)	Group x Time: F3, 81.3=1.47	0.23
Week 4	1.98 (0.16)	1.14 (0.17)
Cigarettes/day (baseline-adjusted, log-transformed)
Week 1	2.09 (0.23)	2.05 (0.19)	Group: F1, 26.2=1.29	0.27
Week 2	1.66 (0.23)	1.86 (0.19)	Time: F3, 74.4=3.77	0.01
Week 3	1.52 (0.24)	1.78 (0.19)	Group x Time: F3, 74.4=1.78	0.16
Week 4	1.30 (0.25)	1.83 (0.19)
NNAL (square-root transformed) ng/ml
Baseline	17.26 (1.89)	15.98 (1.89)	Group: F1, 26.3=0.57	0.46
Week 4	18.55 (1.94)	16.04 (1.91)	Time: F1, 24.6=0.95	0.34
			Group x Time: F1, 24.7=0.80	0.38

^aLSM = least squares mean

Mint flavors were most frequently selected. After Week 1, 8 participants (26.67%; evenly split between groups) asked to continue using both flavors instead of selecting one and 4 participants (13.33%) switched to new flavors (6mg=3, 3mg=1). Willingness to continue pouch use did not differ by group [Fisher’s Exact Test, p=0.27] though it was numerically greater in the 6mg group [10/15; 67%] than in the 3mg group [6/15, 40%].

Cigarette Smoking Outcomes

For the primary outcome of baseline-adjusted average cigarettes/day (log-transformed), there was a significant effect of time, but no significant group effect or no significant group by time interaction (Table 1). Both groups significantly reduced their smoking (supplemental online appendix 4). Compared to Week 1, cigarettes per day day was significantly lower at Week 2 [LSMD=0.17(0.07); 95%CI: 0.03–0.32], Week 3 [LSMD=0.33(0.10); 95%CI: 0.13–0.52], and Week 4 [LSMD=0.32(0.11); 95%CI: 0.09–0.54]. Cigarettes per day also significantly reduced between Weeks 2 and 3 [LSMD=0.16(0.07); 95%CI: 0.008–0.31], but not between Weeks 2 and 4 or Weeks 3 and 4.

There was no significant group effect for biochemically-confirmed 7-day point prevalence smoking abstinence at Week 4 [X²_1,3= 2.14, p=.14]. Two 6mg participants [13%] achieved abstinence, but none in the 3mg group [0%].

Tobacco Harm Exposure

For the secondary outcome of NNAL (square-root transformed) from baseline to Week 4, there were no significant effects of group, time, or group by time interaction (Table 1).

DISCUSSION

This preliminary randomized, controlled trial compared the effects of pouches, in different nicotine concentrations, on cigarette smoking behavior and tobacco harm exposure in adults open to trying pouches for cigarette substitution. It is the first study to evaluate pouches for cigarette substitution and tobacco harm reduction in adults who smoke and whether these effects vary by nicotine concentration. Both 3mg and 6mg nicotine pouches significantly reduced cigarette smoking over 4 weeks, with 6mg nicotine pouches showing numerically greater reductions in cigarette smoking, including two participants who completely switched. Our findings build upon a prior non-industry, preliminary study that showed 4mg pouches could reduce cigarette smoking, including promoting cessation in one participant.^[12]

Though pouches significantly reduced smoking, they did not decrease NNAL values (biomarker of tobacco harm exposure), likely because few quit entirely. Pouch use > 4 weeks may be needed for smoking cessation and corresponding NNAL changes, given NNAL’s long half-life. Future studies should investigate longer pouch use duration, other biomarkers, and adults motivated to quit smoking. Adults who smoke may also need more guidance on using pouches effectively for cigarette substitution,^[12] as pouches do not replicate the sensory aspects of smoking^[12] and offer moderate appeal and craving relief compared to cigarettes.^[13]

This study’s strengths include random assignment to nicotine groups, limited exclusions, and use of biomarkers for smoking and tobacco harm exposure measurement. However, limitations include a small, mostly White, non-Hispanic US sample, lack of blinding, short duration, and no pouch use topography measures. A larger trial is needed to better understand pouches’ effects on smoking behaviors and tobacco harm exposure.

The study provides preliminary evidence to inform pouch regulation and nicotine concentration levels. Findings suggest pouches show promise for helping adults transition from smoking, with higher nicotine pouches potentially more effective and preferred. Larger trials evaluating various nicotine concentrations, including higher levels, are needed to clarify the health benefits versus risks of these products.

WHAT IS ALREADY KNOWN ON THIS SUBJECT

• Oral nicotine pouches may have moderate appeal and lower smoking craving relief than cigarettes among adults who smoke.

• Preliminary evidence suggests that 4mg oral nicotine pouches may reduce cigarette smoking, but less effectively than e-cigarettes.

WHAT IMPORTANT GAPS IN KNOWLEDGE EXIST ON THIS TOPIC

• We do not know if the effect of oral nicotine pouches on smoking behaviors varies by nicotine concentration level.

• It remains to be tested whether substituting oral nicotine pouches for cigarettes reduces biomarkers of tobacco harm exposure.

WHAT THIS STUDY ADDS

• Oral nicotine pouches in 3mg and 6mg strengths significantly reduced smoking over 4 weeks among adults open to using pouches for cigarette substitution but only the 6mg promoted complete smoking cessation in some participants.

• Though oral nicotine pouches significantly reduced cigarette smoking over 4 weeks, they did not decrease tobacco-related harm exposure, likely because few participants quit smoking entirely.

Data Availability

The study protocol and all participant data collected during the study will be deidentified and made available beginning 9 months after publication upon request by researchers who provide a methodologically sound proposal for any purpose and agree to complete a signed data access agreement by contacting the corresponding author.