Nicotine Dosing for Nicotine Addiction

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

Age: 18 - 65

Sex: Any

Trial Phase: Phase < 1

Sponsor: Yale University

Must not be taking: Antidepressants, Antipsychotics, Anxiolytics

Disqualifiers: Lung diseases, Substance use disorder, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

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

Compensation: Varies

Number of Visits: 5

Duration: 5 sessions

70 Participants Needed

Trial Summary

What is the purpose of this trial?

This project will examine the impact of the nicotine dose and delivery rate on nicotine's abuse potential, versus its potentially beneficial effects on smoking urges and withdrawal. Will use pulsed IV nicotine administration which closely matches nicotine delivery by inhaled tobacco use.

Will I have to stop taking my current medications?

The trial excludes people who regularly use psychotropic medications (like antidepressants or antipsychotics), so if you're taking these, you might not be eligible. The protocol doesn't specify about other medications, so it's best to ask the trial team for details.

What data supports the effectiveness of this treatment for nicotine addiction?

Research suggests that oral nicotine pouches like ZYN can help reduce withdrawal symptoms and may serve as a low-risk alternative to cigarettes for current tobacco users. They deliver nicotine effectively, similar to other nicotine replacement therapies, and are generally well-accepted by users. ^{1 2 3 4 5}

Is it safe to use nicotine pouches for nicotine addiction?

Research suggests that nicotine pouches, like ZYN and Velo, expose users to fewer harmful chemicals compared to traditional smoking. They may be a safer alternative for those looking to reduce tobacco-related harm, but more research is needed to fully understand their long-term safety. ^{1 2 6 7 8}

How does the drug nicotine pouches differ from other treatments for nicotine addiction?

Nicotine pouches are unique because they are tobacco-free and provide a smokeless way to deliver nicotine, offering a potentially lower-risk alternative to cigarettes and traditional tobacco products like snus. They are designed to be more satisfying than some nicotine replacement therapies (NRTs) like gum or lozenges, with similar or better nicotine absorption and fewer minor side effects. ^{1 2 3 6 9}

Research Team

Mehmet Sofuoglu, M.D.,Ph.D

Principal Investigator

Yale University

Eligibility Criteria

This trial is for adults aged 21 to 55 who smoke cigarettes daily, as confirmed by urine tests. Participants must be in good health and not seeking treatment for tobacco dependence. Women should use birth control methods. People with major medical or psychiatric issues, substance abuse other than nicotine, or risks for vaping-related lung injury cannot join.

Inclusion Criteria

Past year daily cigarette use, verified by urine cotinine levels above 100 ng/ml

Lifetime history of e-cigarette use

In good health as verified by medical history, screening examination, and screening laboratory tests

Exclusion Criteria

I regularly take medication for mental health issues.

I am not pregnant or breastfeeding.

Reported aversion to e-cigarettes, or tobacco flavored e-liquid

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants are randomized to nicotine doses and receive pulsed IV nicotine or saline infusions across 5 test sessions

5 sessions

5 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Long-term follow-up

Participants are monitored for long-term effects and outcomes

up to five years

Treatment Details

Interventions

• Nicotine

Trial Overview The study investigates how different doses and delivery rates of IV pulsed-nicotine affect its potential for abuse versus its benefits on reducing smoking urges and withdrawal symptoms. It mimics the nicotine hit from smoking tobacco.

Participant Groups

Group I: delivery rate for nicotine dose 1mg/70kg Active Control 1 Intervention

delivery rate 50,35, 16.6 and 12.5 ug per second

Group II: Delivery rate for nicotine dose 0.2mg/70kg Active Control 1 Intervention

delivery rate 10,5, 3.3 and 2.5

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

Approved in United States as Nicotine pouches for:

• Smoking cessation aid
• Nicotine replacement therapy

Approved in European Union as Nicotine pouches for:

• Smoking cessation aid
• Nicotine replacement therapy

Who Is Running the Clinical Trial?

Yale University

Lead Sponsor

Trials

1,963

Recruited

3,046,000+

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]

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]

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]

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]

The study found that Zyn Chill, marketed as 'Flavour-Ban Approved', activates the TRPM8 receptor, providing a cooling sensation, despite being advertised as unflavoured, indicating misleading marketing practices.

Chemical analysis revealed that Zyn Chill contains WS-3, a synthetic cooling agent, while mint-flavoured ONPs contain both WS-3 and mint flavourants, suggesting that these products still have flavoring agents that could appeal to consumers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Synthetic cooling agent in oral nicotine pouch products marketed as 'Flavour-Ban Approved'. Jabba, SV., Erythropel, HC., Woodrow, JG., 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]

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

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

3. 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]

4. 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]

5. 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]

6. 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]

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

Synthetic cooling agent in oral nicotine pouch products marketed as 'Flavour-Ban Approved'. [2023]

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

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

9. 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]