Synthetic Nicotine Comparison for Nicotine Addiction

Overseen By Neal Benowitz, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: University of California, San Francisco

Must not be taking: CYP2A6 inducers, Sympatholytics, Nicotine meds, Stimulants

Disqualifiers: Pregnancy, Breastfeeding, Allergy, others

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

Compensation: Varies

Number of Visits: 3

Duration: 8 hours per session

18 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests different types of nicotine to assess their effects on regular e-cigarette users. Participants will try three kinds of nicotine: natural, synthetic (a lab-created form), and a mix of both. Researchers aim to understand how the body processes each type and their impact on cravings and enjoyment. The study seeks healthy individuals who have used e-cigarettes at least 15 days in the past month. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants a chance to be among the first to experience this new approach.

Will I have to stop taking my current medications?

You may need to stop taking certain medications to participate in this trial. Specifically, you cannot use medications that affect nicotine metabolism, certain heart medications, nicotine replacement therapies, or stimulant medications like those for ADHD.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that S-nicotine, the type most often found in tobacco, can damage several organs, including the heart and lungs, and is known to be addictive. Studies indicate that smokeless products with S-nicotine can affect heart health, although not all heart-related indicators are impacted.

R-nicotine is less well-known. Although marketed as "tobacco-free," no independent evidence proves it is safe. It remains nicotine, which is addictive and can be harmful, especially for young people and pregnant women.

Racemic nicotine, a mix of S- and R-nicotine in equal parts, is less common, and research on it is limited. However, since it contains both types of nicotine, it likely shares similar safety concerns.

This trial is in its first phase, meaning limited safety data exists in humans, and the main goal is to assess how well people tolerate these forms of nicotine. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the potential of synthetic nicotine for nicotine addiction because it offers a new approach compared to traditional treatments like nicotine patches, gum, and prescription medications. Unlike standard options that primarily rely on S-nicotine derived from tobacco, this trial explores the use of R-nicotine, a synthetic version. Additionally, the study investigates a racemic mixture, combining both S- and R-nicotine, which could provide a novel balance in nicotine delivery. These innovative treatments aim to offer more tailored solutions for those looking to overcome nicotine addiction.

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

This trial will compare different forms of nicotine. Research has shown that natural nicotine, called S-nicotine, can increase nicotine levels in the blood within 15 to 90 minutes after use. This type of nicotine is addictive and can impact the heart and lungs. Participants in one arm of this trial will vape e-liquid containing 100% S-nicotine.

For synthetic nicotine, known as R-nicotine, concerns often arise about its potential for addiction and health risks. However, limited data exist on how it specifically compares to natural nicotine. Another arm of this trial will involve participants vaping e-liquid containing 100% R-nicotine.

Racemic nicotine, a mix of S- and R-nicotine, might work differently because it combines both types. Early studies suggest that S-nicotine might attach more effectively to nicotine receptors than R-nicotine. This means the mixture could have different effects on addiction and satisfaction. Participants in a third arm of this trial will vape e-liquid containing a 50:50 mix of S- and R-nicotine. ^{6 7 8 9 10}

Who Is on the Research Team?

Neal Benowitz, MD

Principal Investigator

University of California, San Francisco

Are You a Good Fit for This Trial?

This trial is for regular e-cigarette users who are healthy based on medical history and a physical exam. It's not for those uncomfortable with blood draws, on certain heart meds or nicotine replacements, allergic to e-cig ingredients, pregnant/breastfeeding women not using contraception, non-English readers/writers, or stimulant medication users.

Inclusion Criteria

Healthy on the basis of medical history and limited physical examination

Current regular user of E-Cigarettes (≥ 15 days in the past 30 days)

Exclusion Criteria

Breastfeeding (determined by self-report)

Pregnancy (self-reported and urine pregnancy test)

Women of childbearing potential must be using an acceptable method of contraception

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

1-2 weeks

Treatment

Participants will vape 3 different forms of nicotine: natural, synthetic, or a 50:50 mixture in a crossover study

8 hours per session

3 visits (in-person)

Follow-up

Participants are monitored for nicotine metabolism, cardiovascular effects, and patterns of self-administration

Up to 7 hours

What Are the Treatments Tested in This Trial?

Interventions

• Synthetic Nicotine

Trial Overview The study tests how the body processes three types of nicotine (natural from tobacco, synthetic, and a mix) in experienced vapers. It looks at metabolism rates, cardiovascular effects, usage patterns and feelings related to craving/withdrawal and pleasure.

How Is the Trial Designed?

Group I: S-nicotine (tobacco) as the starting condition Experimental Treatment 3 Interventions

Participants will spend 8 hours in the hospital research ward where they will vape e-liquid containing 100% (S)-nicotine.

Group II: Racemic (50:50 S- and R- nicotine) as the starting condition Experimental Treatment 3 Interventions

Participants will spend 8 hours in the hospital research ward where they will vape e-liquid containing 50% (S)-nicotine and 50% (R)-nicotine.

Group III: R-nicotine (synthetic) as the starting condition Experimental Treatment 3 Interventions

Participants will spend 8 hours in the hospital research ward where they will vape e-liquid containing 100% (R)-nicotine.

Who Is Running the Clinical Trial?

University of California, San Francisco

Lead Sponsor

Trials

2,636

Recruited

19,080,000+

National Institute on Drug Abuse (NIDA)

Collaborator

Trials

2,658

Recruited

3,409,000+

Published Research Related to This Trial

Medicinal nicotine has significantly improved smoking cessation rates over the past 20 years, with various products like patches, gum, and inhalers available to help smokers quit.

Innovative nicotine delivery methods, such as high-dose patches and new forms like drinks and lollipops, are being developed to enhance cessation success and manage withdrawal symptoms.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nicotine delivery systems. Shiffman, S., Fant, RV., Buchhalter, AR., et al.[2015]

In a study of 248 smokers, those using nicotine nasal spray had a significantly higher success rate in quitting smoking for 12 months (27%) compared to those using a placebo (15%), indicating its efficacy as a smoking cessation aid.

While the nicotine nasal spray was effective, it was associated with more mild to moderate side effects compared to the placebo, suggesting that while it helps with quitting, users should be aware of potential discomfort.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of nicotine nasal spray on smoking cessation. A randomized, placebo-controlled, double-blind study. Hjalmarson, A., Franzon, M., Westin, A., et al.[2015]

Smoking cessation can significantly reduce the risk of premature death and improve quality of life, even after the onset of smoking-related diseases, highlighting the importance of quitting at any stage.

Clinicians can effectively help patients quit smoking by using structured advice and various pharmacotherapies, including nicotine replacement therapies and medications like bupropion, with new options like varenicline potentially benefiting those who struggle with existing treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacotherapy for nicotine dependence. Henningfield, JE., Fant, RV., Buchhalter, AR., et al.[2019]

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]

Nicotine replacement therapy, such as nicotine polacrilex gum, is most effective when combined with behavioral counseling, although it has shown minimal impact on smoking cessation in general medical practice.

Pharmacotherapeutic options for nicotine dependence include nicotine replacements, antagonists like mecamylamine for difficult cases, and clonidine for reducing withdrawal symptoms, but no single drug is completely effective, highlighting the need for a comprehensive approach that addresses both psychological and physiological factors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacotherapy for smoking cessation. Nunn-Thompson, CL., Simon, PA.[2005]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11310114/

Public perceptions and discussions of synthetic nicotine on ... Among negative tweets, major topics include the concern about addiction and health risks of synthetic nicotine products (44.91%) and synthetic ...

2. archbronconeumol.org archbronconeumol.org/es-unregulated-addictive-the-silent-rise-avance-S030028962500273X

Unregulated and Addictive: The Silent Rise of Nicotine ... Some studies found that 6-MN has been shown to be more addictive than nicotine; they found it to be three times more potent in replacing [3H] ...

3. withpower.com withpower.com/trial/phase-1-tobacco-use-disorder-8-2023-ba30b

Synthetic Nicotine Comparison for Nicotine Addiction In a study of 248 smokers, those using nicotine nasal spray had a significantly higher success rate in quitting smoking for 12 months (27%) compared to those ...

4. globalheartjournal.com globalheartjournal.com/articles/10.5334/gh.1292

When Poison is Addictive – a WHF Policy Brief Numerous studies have demonstrated that nicotine can harm multiple organs, including the respiratory and cardiovascular systems.

5. harmreductionjournal.biomedcentral.com harmreductionjournal.biomedcentral.com/articles/10.1186/s12954-024-01047-1

The potential of new nicotine and tobacco products as tools for ... A recent Cochrane review concluded that people who smoke are more likely to quit smoking for at least 6 months using ECs with nicotine compared ...

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

Nicotine Pouches | Smoking and Tobacco Use Nicotine is a highly addictive chemical that is especially dangerous for youth, young adults, and pregnant women.

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10836189/

Nicotine and Cardiovascular Health: When Poison is Addictive Nicotine is universally recognized as the primary addictive substance fuelling the continued use of tobacco products, which are responsible for over 8 million ...

8. truthinitiative.org truthinitiative.org/research-resources/harmful-effects-tobacco/what-you-need-know-about-new-synthetic-nicotine-products

What you need to know about new synthetic nicotine ... Research has shown early age of smoking and pleasurable initial experiences are correlated with daily use and lifetime nicotine dependence.

9. health.state.mn.us health.state.mn.us/communities/tobacco/pouches.html

Commercial Tobacco Use Nicotine Pouches and Other ... These products are often marketed as “tobacco-free” or “less harmful,” despite lacking independent verification of their safety, and nicotine ...

10. nida.nih.gov nida.nih.gov/research-topics/tobacconicotine-vaping

Tobacco/Nicotine and Vaping | National Institute on Drug ... Tobacco and vaping devices contain nicotine, an ingredient that can lead to addiction, which is why so many people who smoke or vape find it difficult to quit.