Nicotine Thresholds for Smoking Addiction

Overseen By Mehmet S Sofuoglu, M.D.,Ph.D.

Age: 18 - 65

Sex: Any

Trial Phase: Phase < 1

Sponsor: Yale University

Must not be taking: Mood stabilizers, Antipsychotics, Anxiolytics

Disqualifiers: Major medical, Psychiatric disorders, others

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 5

36 Participants Needed

Trial Summary

What is the purpose of this trial?

To determine the nicotine threshold dose(s) for discrimination, subjective-rewarding effects, -and reinforcement in smokers with different levels of dependence.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but it excludes people who regularly use certain psychotropic medications (like those for mood disorders or anxiety). It's best to discuss your specific medications with the trial team.

What data supports the effectiveness of the treatment Nicotine, Nicotine pouches, Oral nicotine pouches, Tobacco-free oral nicotine pouches, ZYN, On!, VELO, LOOP for smoking addiction?

Research suggests that oral nicotine pouches, like ZYN, may help reduce harm compared to cigarettes and provide relief from tobacco withdrawal symptoms, similar to nicotine gum. They are considered a low-risk alternative for current tobacco users and may be acceptable for smoking reduction. ^{1 2 3 4 5}

Are nicotine pouches safe for human use?

Research suggests that nicotine pouches, like ZYN and Velo, expose users to fewer harmful chemicals compared to traditional smoking and tobacco products. They may serve as a lower-risk alternative for smokers, but more research is needed to fully understand their long-term safety. ^{1 6 7 8 9}

How does the nicotine pouch treatment differ from other smoking addiction treatments?

Nicotine pouches are a novel, tobacco-free option that deliver nicotine orally, offering a potentially lower-risk alternative to cigarettes and traditional smokeless tobacco products. They provide similar nicotine satisfaction to lozenges but with greater user satisfaction and fewer minor side effects, making them a unique choice for those seeking to reduce smoking-related harm. ^{1 6 7 10 11}

Eligibility Criteria

This trial is for adults aged 21 to 59 who have been smoking at least once a week for over a year. Participants must be in good health, not seeking treatment for tobacco dependence, and women should use birth control. Smokers will be categorized by their level of addiction using the FTND scores.

Inclusion Criteria

It is prudent to reach out to your primary care physician when appropriate.

I am between 21 and 59 years old.

I am 21 years old or older.

Exclusion Criteria

You currently have a problem with using alcohol or other drugs, except for nicotine.

I am not pregnant or breastfeeding.

History of major medical or psychiatric disorders that the physician investigator deems as contraindicated for the participant to be in the study

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Adaptation

Participants undergo an Adaptation Session to familiarize with study procedures

1 day

1 visit (in-person)

Test Days

Participants undergo 4 Test Days with different nicotine doses compared to saline for discrimination, subjective effects, and reinforcement

4 days

4 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after the test days

4 weeks

Treatment Details

Interventions

• Nicotine

Trial Overview The study aims to find out the lowest amount of nicotine that can still produce noticeable effects, feelings of reward, and desire to continue use in smokers with varying levels of addiction.

Participant Groups

Group I: Nicotine Active Control 2 Interventions

Adaptation Session followed by 4 Test Days. The Adaptation Session will familiarize the participants with study procedures. In each Test Day, a different nicotine dose (0.1, 0.05, 0.025, and 0.0125 mg nicotine/pulse) will be compared to saline for nicotine discrimination, subjective effects, and reinforcement. Participants will first sample the assigned nicotine dose and saline, followed by 4 trials to test their ability to discriminate it from saline. This will be followed by 4 Choice trials where participants will be able to choose between nicotine (at the session-assigned dose) or saline (A or B).

Group II: saline Placebo Group 2 Interventions

Subjects will have sample A and B, one being nicotine and one being saline. The doses will be blinded from PI, subject and staff. The subject must choose A or B for the next ten choices.

Who Is Running the Clinical Trial?

Yale University

Lead Sponsor

Trials

1,963

Recruited

3,046,000+

National Institute on Drug Abuse (NIDA)

Collaborator

Trials

2,658

Recruited

3,409,000+

Findings from Research

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 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 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]

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 7,832 U.S. youth and young adults aged 15-24, 12% reported currently using oral nicotine pouches, with a notable overlap in use among current cigarette smokers, indicating a potential trend of dual use among tobacco products.

The research highlights a stable rate of oral nicotine pouch use among adolescents and young adults from September 2020 to May 2022, suggesting a need for regulation to prevent nicotine-naïve individuals from starting and to address concurrent use with cigarettes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Patterns of oral nicotine pouch use among U.S. adolescents and young adults. Patel, M., Kierstead, EC., Kreslake, J., et al.[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]

Exclusive users of Velo nicotine pouches showed significantly lower levels of harmful biomarkers compared to smokers, including a 91% reduction in total NNAL and a 46% reduction in carbon monoxide levels, indicating a lower risk of smoking-related diseases.

Velo users had higher total nicotine equivalents than smokers, but overall exposure to tobacco toxicants was much lower, suggesting that Velo pouches may be a safer alternative for nicotine delivery.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Assessment of biomarkers of exposure and potential harm, and physiological and subjective health measures in exclusive users of nicotine pouches and current, former and never smokers. Azzopardi, D., Haswell, LE., Frosina, J., et al.[2023]

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]

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]

Smokeless tobacco is an addictive substance that delivers nicotine at levels comparable to other drugs of abuse, leading to tolerance and dependence among users.

Low-dose smokeless tobacco products are often marketed to young, inexperienced users, who may develop dependence and eventually switch to higher-dose products, increasing their risk of addiction.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Smokeless tobacco: an addicting drug. Henningfield, JE., Fant, RV., Tomar, SL.[2022]

In a study involving 34 healthy adult smokers, tobacco-free oral nicotine pouches (NPs) showed similar nicotine absorption to lozenges and significantly better absorption than gum, indicating they may be an effective alternative for nicotine delivery.

Participants reported higher satisfaction with NPs compared to lozenges, and NPs had a lower incidence of minor adverse events, suggesting they are a well-tolerated option for smokers seeking nicotine replacement.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A randomised study to assess the nicotine pharmacokinetics of an oral nicotine pouch and two nicotine replacement therapy products. Azzopardi, D., Ebajemito, J., McEwan, M., et al.[2022]

References

1. 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]

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. 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]

4. 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]

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

Patterns of oral nicotine pouch use among U.S. adolescents and young adults. [2023]

6. 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]

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

Assessment of biomarkers of exposure and potential harm, and physiological and subjective health measures in exclusive users of nicotine pouches and current, former and never smokers. [2023]

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. England pubmed.ncbi.nlm.nih.gov

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

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

Smokeless tobacco: an addicting drug. [2022]

11. England pubmed.ncbi.nlm.nih.gov

A randomised study to assess the nicotine pharmacokinetics of an oral nicotine pouch and two nicotine replacement therapy products. [2022]