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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to understand how varying doses and delivery rates of nicotine affect its addiction potential and its impact on cravings and withdrawal. Researchers will deliver nicotine intravenously to mimic smoking. The trial includes two groups, each receiving different doses and delivery speeds of nicotine. Participants must have smoked cigarettes daily in the past year and have a history of using e-cigarettes. As an Early Phase 1 trial, this research focuses on understanding nicotine delivery in people, offering participants a unique opportunity to contribute to groundbreaking insights.

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.

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

Research has extensively studied nicotine in various forms, such as smoking and other products. Although nicotine is addictive, the primary health risks stem from the harmful chemicals in tobacco smoke.

This study tests nicotine in a way that mimics smoking but is controlled through an IV (intravenous) method. This approach allows researchers to regulate the amount and speed of nicotine delivery. Past studies with nicotine in forms like patches or pouches have shown it can be safe when used correctly. However, nicotine can still increase heart rate and blood pressure, and high doses might cause dizziness or nausea.

This trial is in the early stages, focusing on how the body reacts to different nicotine doses and identifying any immediate side effects. Participants should know that since this is early research, the full safety of this IV method is still under investigation. Participants should discuss any concerns with the trial team to understand the possible risks and benefits. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatment?

Unlike the standard nicotine replacement therapies like patches or gums, this new approach to nicotine addiction involves precise control over the delivery rate of nicotine. Researchers are excited about this because it allows for better customization of dosing to match individual needs, potentially reducing withdrawal symptoms more effectively. By fine-tuning the delivery rate, it might help smokers transition away from cigarettes more smoothly, offering a more tailored and potentially more successful path to quitting smoking.

What evidence suggests that this trial's treatments could be effective for nicotine addiction?

Research shows that nicotine can reduce the urge to smoke and ease withdrawal symptoms. Previous studies found that even small amounts of nicotine can lead to reduced smoking compared to those who don't use it. This trial will test different delivery rates of nicotine, as studied in the trial's arms, to assess their impact on smoking addiction. Although nicotine is addictive, using it in a controlled study might help manage cravings and ease the quitting process. Overall, nicotine's ability to lessen smoking urges makes it a promising area for research on treatments for smoking addiction. ^{3 6 7 8 9}

Who Is on the Research Team?

Mehmet Sofuoglu, M.D.,Ph.D

Principal Investigator

Yale University

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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 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]

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 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]

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]

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 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]

Citations

1. 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? Current oral nicotine pouch use among 10th and 12th graders doubled from 1.3% in 2023 to 2.6% in 2024. · According to JAMA Network Open research, ...

2. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/41001885/

Nicotine pouches and clinical outcomes related to smoking ... Conclusions: Tobacco-free nicotine pouches appear to be well tolerated and may reduce cigarette consumption compared with control, with effects ...

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. keck.usc.edu keck.usc.edu/news/use-of-nicotine-pouches-increases-significantly-among-u-s-teens/

Use of nicotine pouches increases significantly among U.S. ... Like the USC-led survey, the NYTS also found significant increases in lifetime use of nicotine pouches between 2023 and 2024 among U.S. high ...

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. fda.gov fda.gov/news-events/press-announcements/fda-authorizes-marketing-20-zyn-nicotine-pouch-products-after-extensive-scientific-review

FDA Authorizes Marketing of 20 ZYN Nicotine Pouch ... As part of its evaluation, the FDA reviewed data regarding youth risk and found that youth use of nicotine pouches remains low despite growing ...

7. 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.

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

What to know about nicotine pouches While nicotine pouches may have fewer ingredients than cigarettes and other smokeless tobacco products, studies have found hazardous substances ...

9. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12417499/

Nicotine pouches: a narrative review of the existing literature The FDA determined that these tobacco-free products pose a lower risk of cancer and other serious health conditions than combustible tobacco, ...