Nicotine Pouches for Nicotine Addiction

Recruiting at 1 trial location

Overseen By Adam Leventhal, PhD

Age: 18 - 65

Sex: Any

Trial Phase: Academic

Sponsor: University of Southern California

Disqualifiers: Pregnancy, Stroke, Seizures, Hypertension, others

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 3

72 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. However, if you have a history of certain health conditions like stroke, seizures, or heart problems, you may not be eligible to participate.

What data supports the effectiveness of the treatment Nicotine Pouch for nicotine addiction?

Research suggests that oral nicotine pouches, like ZYN and Zonnic, may help reduce harm compared to cigarettes and provide relief from tobacco withdrawal symptoms. They are considered a low-risk alternative to smoking and have shown potential as nicotine replacement therapies. ^{1 2 3 4 5}

Are nicotine pouches safe for human use?

Nicotine pouches, like ZYN, are considered to have a lower risk than smoking cigarettes or using traditional tobacco products, but there is limited research on their safety. They are similar to Swedish snus, which is known to have fewer health effects than smoking, but more studies are needed to fully understand their safety. ^{1 4 6 7 8}

How do nicotine pouches differ from other treatments for nicotine addiction?

Nicotine pouches are unique because they are tobacco-free and deliver nicotine orally without the harmful chemicals found in cigarettes or smokeless tobacco. They offer a potentially lower-risk alternative to traditional tobacco products and come in various flavors and nicotine strengths, making them appealing to those looking to reduce harm from smoking. ^{1 4 7 9 10}

What is the purpose of this trial?

There is a growing sector of modern tobacco-free oral nicotine pouches that are federally regulated as non-medicinal nicotine/tobacco products. While nicotine pouches employ marketing approaches that may attract current tobacco users, such as marketing themes connoting minimal harm, information on the long-term health effects of nicotine pouches is lacking. nicotine pouches may appeal to younger adults because they are available in similar product characteristics (e.g., nicotine concentration, protonated nicotine) that many younger people prefer to use in e-cigarettes. In addition, nicotine pouches may be of particular interest to younger adult e-cigarette users because these products can be used discreetly where vaping is not allowed, which may translate into an increased likelihood of becoming dual users of e-cigarettes and nicotine pouches. Indeed, approximately 15% young adults who used e-cigarettes in the past 30 days were past 30-day nicotine pouch users. Manufacturers of modern nicotine pouches use acid additives to lower pH, which changes nicotine from a free-base to a protonated nicotine, resulting in improved appeal and sensory experience and higher abuse liability. Thus, nicotine concentration and pH in modern nicotine pouches should be focal targets for regulatory policies. Evidence is also lacking on mechanisms mediating differences in product appeal and abuse liability of nicotine pouches across products varying in nicotine concentration and pH level. The scientific objective of this research is to assess the effect of variation in nicotine concentration in nicotine pouches and its interaction effect with pH level on the proximal outcomes of relevance to the U.S. Food and Drug Administration regulation: sensory attributes and product appeal among younger adults who use nicotine pouches in the past 30 days (current dual users of nicotine pouches and e-cigarettes and/or combustible cigarettes will be eligible) and are unmotivated to quit nicotine use. This innovative project proposes to conduct a double-blind within-subject randomized study in which participants (N = 72) will administer nicotine pouches varied by nicotine concentration (e.g., 3 vs 6 mg) and pH (e.g., 8.5 or greater vs. less than 8.5) to achieve the project aim: to evaluate the effects of nicotine concentration and pH on subjective product appeal and sensory attributes of nicotine pouches. The findings of this proposed research will provide the U.S. Food and Drug Administration with new evidence necessary to inform regulatory restrictions on product characteristics and constituents of nicotine pouches, which may put young adults at risk of using a novel class of oral nicotine products.

Research Team

Dae Hee Han, PhD

Principal Investigator

University of Southern California

Eligibility Criteria

This trial is for young adults who have used nicotine pouches and e-cigarettes or combustible cigarettes in the past 30 days. Participants should not be looking to quit nicotine use. The study specifically targets current dual users of these products.

Inclusion Criteria

I am between 21 and 35 years old.

I have used nicotine pouches in the last 30 days.

Positive cotinine test via saliva test strip

Exclusion Criteria

Intention to quit nicotine use in the next 30 days

I have a history of stroke, seizures, high blood pressure, heart or lung problems.

Current pregnancy or breastfeeding (urine pregnancy test will be conducted during the orientation session)

Timeline

Screening

Participants are screened for eligibility to participate in the trial

1-2 weeks

1 visit (in-person)

Orientation

Participants confirm age, provide informed consent, and complete verification of nicotine use status by cotinine test strip

1 day

1 visit (in-person)

Experimental Session

Participants self-administer 4 different nicotine pouches varied by nicotine concentration and pH, and rate appeal and sensory attributes

1 day

1 visit (in-person)

Follow-up

Participants are monitored for any immediate effects post-experimental session

1 week

Treatment Details

Interventions

• Nicotine Pouch

Trial Overview The study is testing how different levels of nicotine concentration (3 mg vs 6 mg) and pH values (8.5 or higher vs lower than 8.5) in nicotine pouches affect their appeal and sensory experience among users, using a double-blind randomized design.

Participant Groups

Group I: Nicotine pouch with low pH (less than 8.5) Experimental Treatment 1 Intervention

Participants will self-administer a nicotine pouch with low pH (less than 8.5).

Group II: Nicotine pouch containing high nicotine (6-8mg) Experimental Treatment 1 Intervention

Participants will self-administer a nicotine pouch containing 6-8mg nicotine.

Group III: Nicotine pouch with high pH (8.5 or greater) Placebo Group 1 Intervention

Participants will self-administer a nicotine pouch with high pH (8.5 or greater).

Group IV: Nicotine pouch containing low nicotine (3-4mg) Placebo Group 1 Intervention

Participants will self-administer a nicotine pouch containing 3-4mg nicotine.

Nicotine Pouch is already approved in United States, European Union for the following indications:

Approved in United States as Nicotine Pouch for:

• Smoking cessation aid

Approved in European Union as Nicotine Pouch for:

• Smoking cessation aid

Who Is Running the Clinical Trial?

University of Southern California

Lead Sponsor

Trials

956

Recruited

1,609,000+

National Institute on Drug Abuse (NIDA)

Collaborator

Trials

2,658

Recruited

3,409,000+

Findings from Research

In a study involving 30 adult smokers, 6-mg oral nicotine pouches (ONPs) delivered more nicotine to the bloodstream at 30 minutes compared to both 3-mg ONPs and cigarettes, suggesting they can be effective for nicotine delivery.

However, neither concentration of ONPs provided as much relief from cravings at 5 minutes as cigarettes did, indicating that while ONPs may be less harmful, they might not satisfy cravings as effectively, which could influence their potential for misuse.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evaluating the effects of nicotine concentration on the appeal and nicotine delivery of oral nicotine pouches among rural and Appalachian adults who smoke cigarettes: A randomized cross-over study. Keller-Hamilton, B., Alalwan, MA., Curran, H., et al.[2023]

In a study of 30 adult smokers, the 4-mg nicotine pouch significantly reduced withdrawal cravings by 23 points within the first hour, outperforming nicotine gum and placebo, which showed reductions of 15 and 8 points, respectively.

Participants rated the nicotine pouch as more helpful and pleasant to use compared to gum, indicating a preference that could enhance its effectiveness as a smoking cessation aid.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A single-blind, randomized, crossover trial of the effects of a nicotine pouch on the relief of tobacco withdrawal symptoms and user satisfaction. Thornley, S., McRobbie, H., Lin, RB., et al.[2015]

In a study of 314 daily smokers, starting nicotine polacrilex gum treatment 4 weeks before the quit date did not significantly improve smoking abstinence rates compared to starting on the quit date.

Both groups showed similar self-reported and biochemically verified abstinence rates after 12 months, indicating that the timing of nicotine gum initiation may not impact long-term quitting success.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nicotine gum treatment before smoking cessation: a randomized trial. Etter, JF., Huguelet, P., Perneger, TV., et al.[2018]

ZYN nicotine pouches contain no nitrosamines or polycyclic aromatic hydrocarbons (PAHs), indicating a potentially lower risk profile compared to traditional tobacco products, which often contain harmful constituents.

The levels of harmful and potentially harmful constituents (HPHCs) in ZYN were found to be similar to those in nicotine replacement therapy (NRT) products, suggesting that ZYN may be a safer alternative for nicotine delivery compared to moist snuff, which had significantly higher levels of harmful compounds.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Harmful and potentially harmful constituents (HPHCs) in two novel nicotine pouch products in comparison with regular smokeless tobacco products and pharmaceutical nicotine replacement therapy products (NRTs). Back, S., Masser, AE., Rutqvist, LE., et al.[2023]

In a study involving 63 smokers, both snus and Zonnic were preferred over nicotine gum, showing greater effectiveness in reducing smoking urges and causing fewer side effects.

Participants experienced significant reductions in smoking (33% for gum, 37% for snus, and 42% for Zonnic), indicating that snus and Zonnic could be promising alternatives for nicotine replacement therapy, warranting further research on their long-term effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Randomized crossover trial of the acceptability of snus, nicotine gum, and Zonnic therapy for smoking reduction in heavy smokers. Caldwell, B., Burgess, C., Crane, J.[2022]

Nicotine pouches, a new product category, are being marketed with minimal research and regulatory oversight, highlighting significant gaps in understanding their potential harms and benefits.

The commentary suggests a comprehensive assessment approach to inform regulatory policies, aiming to enhance public health outcomes while reducing unintended negative effects associated with nicotine pouch use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The New Nicotine Pouch Category: A Tobacco Harm Reduction Tool? Patwardhan, S., Fagerström, K.[2023]

The novel tobacco-free nicotine pouch, ZYN, delivers nicotine effectively, with the 6 mg and 8 mg doses providing similar or faster nicotine absorption compared to traditional smokeless products like General snus and Longhorn moist snuff.

ZYN products showed a higher extraction fraction of nicotine (50-59%) compared to General snus (32%) and Longhorn moist snuff (19%), indicating a more efficient delivery of nicotine without significant adverse effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetic Comparison of a Novel Non-tobacco-Based Nicotine Pouch (ZYN) With Conventional, Tobacco-Based Swedish Snus and American Moist Snuff. Lunell, E., Fagerström, K., Hughes, J., et al.[2021]

Introducing the nicotine pouch ZYN in the US in 2000 could potentially lead to 249 fewer deaths among a simulated cohort of 100,000 smokers by 2050, translating to approximately 700,000 fewer deaths nationwide.

The model suggests that even with conservative estimates of ZYN's reduced risk compared to smoking, switching to ZYN could significantly lower product-related mortality, highlighting its potential as a safer alternative for smokers not intending to quit.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Estimating the public health impact had tobacco-free nicotine pouches been introduced into the US in 2000. Lee, PN., Fry, JS., Ljung, T.[2022]

Participants in focus groups perceived oral nicotine pouches (ONPs) as having similar or lower risks compared to traditional cigarettes and smokeless tobacco, although they acknowledged potential gastrointestinal and cardiovascular risks.

ONPs were viewed as situational substitutes rather than complete replacements for cigarettes and smokeless tobacco, which could lead to increased overall nicotine use in certain populations, particularly in Appalachia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Perceptions of oral nicotine pouches & their marketing among Ohio Appalachia smokers and smokeless tobacco users. Long, L., Alalwan, MA., Keller-Hamilton, B., et al.[2023]

In a study involving adult smokers, nicotine pouches (NPs) showed lower peak nicotine levels (Cmax) and longer time to peak (tmax) compared to traditional cigarettes, indicating a slower nicotine delivery.

Participants reported lower cravings for cigarettes when using NPs, suggesting that these products may have a lower abuse potential and could serve as a safer alternative for smokers looking to switch from cigarettes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nicotine pharmacokinetics and subjective response among adult smokers using different flavors of on!® nicotine pouches compared to combustible cigarettes. Rensch, J., Liu, J., Wang, J., et al.[2021]

References

1. England pubmed.ncbi.nlm.nih.gov

Evaluating the effects of nicotine concentration on the appeal and nicotine delivery of oral nicotine pouches among rural and Appalachian adults who smoke cigarettes: A randomized cross-over study. [2023]

2. England pubmed.ncbi.nlm.nih.gov

A single-blind, randomized, crossover trial of the effects of a nicotine pouch on the relief of tobacco withdrawal symptoms and user satisfaction. [2015]

3. United States pubmed.ncbi.nlm.nih.gov

Nicotine gum treatment before smoking cessation: a randomized trial. [2018]

4. Switzerland pubmed.ncbi.nlm.nih.gov

Harmful and potentially harmful constituents (HPHCs) in two novel nicotine pouch products in comparison with regular smokeless tobacco products and pharmaceutical nicotine replacement therapy products (NRTs). [2023]

5. England pubmed.ncbi.nlm.nih.gov

Randomized crossover trial of the acceptability of snus, nicotine gum, and Zonnic therapy for smoking reduction in heavy smokers. [2022]

6. England pubmed.ncbi.nlm.nih.gov

The New Nicotine Pouch Category: A Tobacco Harm Reduction Tool? [2023]

7. England pubmed.ncbi.nlm.nih.gov

Pharmacokinetic Comparison of a Novel Non-tobacco-Based Nicotine Pouch (ZYN) With Conventional, Tobacco-Based Swedish Snus and American Moist Snuff. [2021]

8. England pubmed.ncbi.nlm.nih.gov

Estimating the public health impact had tobacco-free nicotine pouches been introduced into the US in 2000. [2022]

9. United States pubmed.ncbi.nlm.nih.gov

Perceptions of oral nicotine pouches & their marketing among Ohio Appalachia smokers and smokeless tobacco users. [2023]

10. Germany pubmed.ncbi.nlm.nih.gov

Nicotine pharmacokinetics and subjective response among adult smokers using different flavors of on!® nicotine pouches compared to combustible cigarettes. [2021]