E-Cigarette Flavors for Tobacco Addiction

(TEN Trial)

Overseen By Kenneth Houser, MS

Age: 18 - 65

Sex: Any

Trial Phase: Academic

Sponsor: Milton S. Hershey Medical Center

Must not be taking: Smoking cessation

Disqualifiers: Neurological conditions, Substance use, COPD, others

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

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 2

Duration: 10 days

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests whether certain e-cigarette flavors increase addiction by affecting brain function and behavior. Researchers focus on two specific flavors to determine their impact on nicotine use. The trial seeks regular users of inhaled tobacco products who do not plan to quit soon. Participants must read and write in English and use the provided e-cigarette device for at least three hours daily. As an unphased trial, this study allows participants to contribute to groundbreaking research on the impact of e-cigarette flavors.

Will I have to stop taking my current medications?

If you are currently using smoking cessation medications like varenicline or nicotine patches, you will need to stop taking them to participate in this trial. The protocol does not specify other medications, so it's best to discuss your specific situation with the trial coordinators.

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

Research has shown that flavoring agents in e-cigarette liquids, such as hexyl acetate, can cause health issues, including inflammation, cell damage, and DNA stress. These reactions suggest the body might respond negatively to these chemicals. However, specific information on serious side effects or their frequency remains unavailable.

The treatments tested in this study are not new drugs but different e-cigarette flavors. This trial examines how these flavors affect brain function and behavior. As an exploratory trial, it focuses on understanding the impact of these flavors rather than their safety.

When considering participation, note that hexyl acetate and ethyl acetate are already present in some e-cigarette products. This suggests the risk of serious side effects might be low, but the evidence is not definitive. Always weigh the potential risks and benefits before deciding. ^{1 2 3 4 5}

Why are researchers excited about this trial?

Researchers are excited about these treatments for tobacco addiction because they explore the impact of e-cigarette flavors, like hexyl acetate and ethyl acetate, on quitting smoking. Unlike traditional nicotine replacement therapies or medications that focus solely on delivering nicotine, these treatments investigate how specific flavors might influence smoking behavior and reduce cravings. The potential to make quitting smoking more appealing and accessible by leveraging enjoyable flavors could offer a new dimension to smoking cessation strategies, making it a promising area of study.

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

This trial will compare the effects of different e-cigarette flavors on tobacco addiction. Research has shown that flavors in e-cigarettes, such as hexyl acetate, can increase their appeal and assist people in quitting smoking. In this trial, one group will receive e-cigarettes with hexyl acetate, while another group will receive e-cigarettes with ethyl acetate. Studies indicate that flavors can alter brain function and influence behavior, potentially making e-cigarettes more attractive than regular cigarettes. Hexyl acetate is popular among users, which could encourage continued use and support smoking cessation. Additionally, flavors in e-liquids can affect brain function, possibly influencing addiction habits. Overall, these findings suggest that flavored e-cigarettes may help people reduce or quit smoking. ^{1 6 7 8 9}

Are You a Good Fit for This Trial?

This trial is for adults over 21 who regularly use tobacco products like vapes, cigarettes, or cigars and have done so for the last three months. Participants should not be planning to quit tobacco within the next month and must be able to read and write in English.

Inclusion Criteria

I am 21 years old or older.

Not planning to quit tobacco use within next month

Able to read and write in English

Exclusion Criteria

Uncontrolled serious mental illness, suicidality, or inpatient psychiatric hospitalization in the past 6 months

I do not have any severe or uncontrolled health conditions.

Current substance use impairing participation

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

1-2 weeks

Treatment

Participants use ENDS with either a neuroactive flavor (hexyl acetate) or an inactive flavor (ethyl acetate) for ten days

10 days

2 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

2-4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Flavor

Trial Overview The study is looking at how different flavors added to electronic nicotine delivery systems (ENDS) might change brain function and behavior, potentially affecting addiction levels.

How Is the Trial Designed?

Group I: Hexyl Acetate Experimental Treatment 1 Intervention

E-cigarette liquid containing hexyl acetate, ethyl maltol, propylene glycol, vegetable glycerin and methylbutyl acetate with nicotine salt.

Group II: Ethyl Acetate Active Control 1 Intervention

E-cigarette liquid containing ethyl acetate, ethyl maltol, propylene glycol, vegetable glycerin and methylbutyl acetate with nicotine salt.

Who Is Running the Clinical Trial?

Milton S. Hershey Medical Center

Lead Sponsor

Trials

515

Recruited

2,873,000+

National Institute on Drug Abuse (NIDA)

Collaborator

Trials

2,658

Recruited

3,409,000+

Published Research Related to This Trial

In a study of 383 long-term e-cigarette users, there was a significant shift in flavor preferences over time, with a notable increase in the preference for sweet flavors, particularly among younger adults and exclusive e-cigarette users.

Despite reporting some adverse reactions, such as respiratory irritations, nearly half of the participants indicated they would seek ways to access their preferred flavors even if regulations were imposed, highlighting a potential dependence on flavored e-cigarettes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Changes in Flavor Preference in a Cohort of Long-Term Electronic Cigarette Users. Du, P., Bascom, R., Fan, T., et al.[2021]

Flavours in e-liquids are a significant factor in attracting young people to start and continue vaping, as indicated by findings from 58 studies involving over 512,000 participants.

However, there is insufficient evidence to link e-liquid flavours to the initiation of tobacco smoking or to cessation of vaping, and the overall quality of the evidence is considered very low.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Youth use of e-liquid flavours-a systematic review exploring patterns of use of e-liquid flavours and associations with continued vaping, tobacco smoking uptake or cessation. Notley, C., Gentry, S., Cox, S., et al.[2023]

About 52.2% of dual users of menthol cigarettes and e-cigarettes prefer menthol/mint-flavored e-cigarettes, indicating a strong preference for similar flavors among menthol smokers.

A significant majority (around 60%) of both dual users and those who recently switched from smoking to e-cigarettes favored fruit or other flavors, suggesting that flavor preferences may extend beyond traditional tobacco flavors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

ENDS Flavor Preference by Menthol Cigarette Smoking Status among US Adults, 2018-2019. Rostron, BL., Chang, JT., Chang, CM., et al.[2021]

In a study of 89 regular e-cigarette users, nicotine significantly enhanced psychological reward and craving relief, while flavor increased satisfaction and taste without interacting with nicotine's effects.

The results indicate that e-liquid flavor and nicotine content have independent effects on vaping experiences, suggesting that both factors play distinct roles in influencing e-cigarette use and dependence.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of nicotine content and preferred flavor on subjective responses to e-cigarettes: A randomized, placebo-controlled laboratory study. Bremmer, MP., Campbell, AM., Xia, K., et al.[2023]

In a study of 2037 young e-cigarette users, it was found that fruit, mint, and menthol flavors were associated with increased nicotine dependence, as users were more likely to vape within 30 minutes of waking when using higher nicotine concentrations.

Conversely, users of tobacco-flavored e-cigarettes showed a decrease in the likelihood of vaping within 30 minutes as nicotine concentration increased, suggesting that flavor choice significantly impacts nicotine dependence and highlighting the need for regulation of e-cigarette flavors and nicotine levels to protect young users.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Influence of Flavors and Nicotine Concentration on Nicotine Dependence in Adolescent and Young Adult E-Cigarette Users. Do, EK., O'Connor, K., Kreslake, JM., et al.[2023]

Flavored e-cigarettes are more popular among adolescents than traditional cigarettes, raising concerns about increased nicotine dependence in this vulnerable group.

The review suggests that characterizing flavors may enhance the appeal and addictive potential of nicotine, highlighting the need for further research to understand how flavors influence nicotine reward and reinforcement.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

History repeats itself: Role of characterizing flavors on nicotine use and abuse. Patten, T., De Biasi, M.[2021]

A study analyzing calls to U.S. poison centers from September 2010 to February 2014 revealed increasing reports of adverse health effects associated with e-cigarette use, highlighting concerns about acute nicotine toxicity.

E-cigarette exposure calls were compared to conventional tobacco cigarette exposure calls to assess their relative safety, but the overall impact of e-cigarettes on public health remains uncertain, especially given the lack of regulation and potential access for minors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Notes from the field: calls to poison centers for exposures to electronic cigarettes--United States, September 2010-February 2014. Chatham-Stephens, K., Law, R., Taylor, E., et al.[2022]

In a study involving 39 men aged 18-45, it was found that flavored e-liquids significantly influenced how much participants liked vaping, with sweetness enhancing liking and harshness reducing it.

Despite the variations in flavor preference, participants adjusted their nicotine intake consistently, indicating that flavor does not affect the total nicotine consumed, but may make higher nicotine levels more enjoyable.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Harsh and Sweet Sensations Predict Acute Liking of Electronic Cigarettes, but Flavor Does Not Affect Acute Nicotine Intake: A Pilot Laboratory Study in Men. Baker, AN., Bakke, AJ., Branstetter, SA., et al.[2021]

A study of 1549 youth aged 13-18 revealed that fruit flavors are the most popular among e-cigarette users, significantly influencing their choice to try e-cigarettes as their first tobacco product.

Youth who preferred fruit flavors were twice as likely to have tried e-cigarettes first, while those who preferred menthol/mint flavors were less likely, highlighting the strong association between flavor preferences and e-cigarette experimentation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Correlates of youth vaping flavor preferences. Groom, AL., Vu, TT., Kesh, A., et al.[2020]

A study involving 119 current nicotine users evaluated the appeal and sensory attributes of 10 common e-cigarette flavors, revealing that flavors like vanilla and peppermint were rated as the sweetest and smoothest, respectively, indicating that sensory attributes align with marketed flavor descriptors.

Chemical analysis showed a wide variety of flavoring constituents without clear distinctions among flavor categories, suggesting that subjective sensory ratings may be more effective for characterizing e-cigarette flavors than chemical composition alone.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Characterizing different-flavored e-cigarette solutions from user-reported sensory attributes and appeal. Anderson, MK., Whitted, L., Mason, TB., et al.[2023]

In a study involving 14 participants over 3 days, e-liquid flavors significantly influenced nicotine exposure, with strawberry-flavored e-liquid leading to higher systemic nicotine levels compared to tobacco flavor, despite similar amounts inhaled.

Participants reported that usual flavors were more satisfying than strawberry and tobacco, suggesting that flavor preference may affect how users adjust their nicotine intake and experience with e-cigarettes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Impact of e-liquid flavors on nicotine intake and pharmacology of e-cigarettes. St Helen, G., Dempsey, DA., Havel, CM., et al.[2018]

A systematic review of 104 studies indicates that higher nicotine concentrations and a variety of flavors in e-cigarettes are linked to increased abuse potential and appeal among adult smokers and former smokers.

These characteristics may help facilitate complete switching from traditional cigarettes to e-cigarettes, suggesting that future regulations should carefully consider their impact on smoking cessation and harm reduction efforts.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Role of Nicotine and Flavor in the Abuse Potential and Appeal of Electronic Cigarettes for Adult Current and Former Cigarette and Electronic Cigarette Users: A Systematic Review. Gades, MS., Alcheva, A., Riegelman, AL., et al.[2023]

A study analyzed 320 e-liquids using gas chromatography-mass spectrometry (GC-MS) and found that the average e-liquid contained about 6 different flavorings, with vanillin, ethyl butyrate, and cis-3-hexenol being the most prevalent.

The research identified four clusters of flavor categories, with fruit and dessert flavors having a higher number of flavorings compared to tobacco and spice flavors, suggesting that flavor variety may influence e-cigarette use and potential toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

GC-MS analysis of e-cigarette refill solutions: A comparison of flavoring composition between flavor categories. Krüsemann, EJZ., Pennings, JLA., Cremers, JWJM., et al.[2021]

Citations

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Flavoured Vaping Products in Tobacco Harm Reduction Examining associations of e-cigarette flavour restrictions with e-cigarette use and success quitting smoking among US adults. Bold KW ...

2. withpower.com withpower.com/trial/phase-tobacco-use-disorder-5-2023-27f67

E-Cigarette Flavors for Tobacco Addiction (TEN Trial) Flavors like fruit are popular among users and may play a role in the appeal and continued use of e-cigarettes, potentially aiding in smoking cessation.

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9987575/

Chemical Flavorants in Vaping Products Alter ... Chemical flavorants in vaping products alter neurobiology in a sex-dependent manner to promote vaping-related behaviors.

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E-liquid flavors and nicotine concentration choices over 6 ... We tracked flavor choice and nicotine concentration at 1, 2, 4, and 8 weeks, and at 6 months, after the target quit date, comparing participants ...

5. tobaccoinduceddiseases.org tobaccoinduceddiseases.org/An-ingredient-co-occurrence-network-gives-insight-into-ne-liquid-flavor-complexity,175955,0,2.html

An ingredient co-occurrence network gives insight into e ... In e-liquids, we found 214 ingredient pairs with a co-occurrence odds ratio greater than 10. Together, these consisted of 62 unique ingredients.

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10726647/

Flavoring Agents in E-cigarette Liquids Research has demonstrated that flavoring agents can induce inflammation, endothelial dysfunction, epithelial barrier disruption, oxidative stress, DNA damage.

7. health.ec.europa.eu health.ec.europa.eu/system/files/2022-08/scheer_o_017.pdf

Opinion on electronic cigarettes There is strong evidence that nicotine in e-liquids is implicated in the development of addiction and that flavours have a relevant contribution ...

8. clinicaltrials.gov clinicaltrials.gov/study/NCT05836051

Testing the Effect of ENDS Flavors on Neurotransmission For this randomized double-blind controlled trial, tobacco users will be randomized to use ENDS with an e-liquid containing a neuroactive flavor (hexyl acetate) ...

9. cureus.com cureus.com/articles/382895-flavoured-vaping-products-in-tobacco-harm-reduction-a-regulatory-perspective

Flavoured Vaping Products in Tobacco Harm Reduction The main factors used to determine the abuse liability of tobacco and nicotine products are nicotine pharmacokinetics, principally the rate and ...