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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores how different nicotine doses affect smokers with varying dependence levels. Researchers aim to determine the dose at which smokers perceive nicotine, how rewarding they find it, and whether they prefer it over a non-nicotine option. Participants will experience various nicotine doses, including nicotine pouches, and compare them to a placebo (a substance with no active drug). Smokers who have been smoking at least once a week for a year or more and are otherwise healthy might be suitable for this study. As an Early Phase 1 trial, this research focuses on understanding how the treatment works in people, offering participants a chance to contribute to groundbreaking nicotine research.

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.

Is there any evidence suggesting that this treatment is likely to be safe for humans?

Research has shown that nicotine, the main focus of this study, has been widely examined for its effects on the body. Many people use nicotine in products like patches or gum to help quit smoking, and these are usually well-tolerated. However, nicotine can cause side effects like dizziness, an upset stomach, or a faster heartbeat, especially at higher doses.

This study will test lower doses of nicotine. Lower doses are less likely to cause strong side effects. The study aims to find the smallest amount of nicotine that people can notice and that makes them feel good. By using these smaller doses, the researchers expect the safety risks to be lower.

This is an early stage of research, focusing on safety and how people feel when using these low doses. While nicotine has known risks, the doses in this study are carefully controlled to reduce any potential harm. ^{1 2 3 4 5}

Why are researchers excited about this trial?

Researchers are excited about this trial because it aims to pinpoint the precise nicotine levels that lead to smoking addiction. Unlike traditional treatments that focus on cessation, such as nicotine patches or gums that deliver a steady dose to curb cravings, this study explores how varying small doses of nicotine influence addiction. By understanding these thresholds, there’s potential to develop more effective strategies for prevention and treatment of smoking addiction, tailored to how individuals respond to different nicotine levels.

What evidence suggests that nicotine pouches might be an effective treatment for smoking addiction?

This trial will compare different doses of nicotine to saline to study nicotine's addictive properties and its potential to help reduce smoking. Research has shown that nicotine is highly addictive, which is why it's often found in smoking products. Studies have found that using nicotine in products like pouches or e-cigarettes can help people smoke less. Nicotine pouches, in particular, may help reduce smoking and might be less harmful than smoking cigarettes. These products provide nicotine without the dangerous chemicals in tobacco smoke. Although nicotine is addictive, using it in controlled amounts can help people manage their smoking habits. ^{1 6 7 8 9}

Are You a Good Fit for This Trial?

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.

I am currently taking medication for bipolar disorder, psychosis, or anxiety.

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

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]

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 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 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]

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 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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12377922/

The Effects of Oral Nicotine Pouches on Cigarette Smoking ... Both nicotine groups significantly reduced smoking, with greater reductions in the e-cigarette group. Another study compared 3mg and 6mg pouches ...

2. truthinitiative.org truthinitiative.org/research-resources/emerging-tobacco-products/what-zyn-and-what-are-oral-nicotine-pouches

What is Zyn and what are oral nicotine pouches? Nicotine pouches share multiple characteristics with e-cigarettes that have been shown to lead to significant youth usage, including high ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12037535/

Oral Nicotine Pouches: Rising Popularity and State of the ... This review highlights how nicotine pouches, including ZYN, are rising in appeal and prevalence of use, particularly among adolescents and young adults.

4. yalemedicine.org yalemedicine.org/news/nicotine-pouches

What Parents Should Know About Nicotine Pouches Nicotine may not contain the chemicals and toxins found in cigarette smoke, but it is highly addictive. It can also negatively affect the ...

5. nature.com nature.com/articles/s41415-025-8446-4

Nicotine pouches: a harm reduction breakthrough or ... The pouches eliminate tobacco-related carcinogens by containing only nicotine and flavouring, presenting significantly lower health risks compared to smoking.

6. cdc.gov cdc.gov/tobacco/nicotine-pouches/index.html

Nicotine Pouches | Smoking and Tobacco Use Get the facts about nicotine pouches and their health effects. The bottom line. There are no safe tobacco products, including nicotine pouches.

7. mdanderson.org mdanderson.org/cancerwise/what-to-know-about-nicotine-pouches.h00-159773289.html

What to know about nicotine pouches Nicotine pouches are a smokeless, spitless product. While nicotine pouches are considered a tobacco product, they don't actually contain tobacco.

8. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8887571/

The New Nicotine Pouch Category: A Tobacco Harm ... Examples of new product categories are electronic cigarettes, heat-not-burn products, and nicotine pouches (NP). This commentary discusses the oral NP category.

9. sciencedirect.com sciencedirect.com/science/article/pii/S2214750024001628

Beyond smoking: Risk assessment of nicotine in pouches This study aims to assess nicotine in pouches and potential risks for health damage. 31 samples of nicotine pouches were collected and analyzed.