Cooling Flavors for Electronic Cigarette Use

Overseen By WEI Li, PhD

Age: 18+

Sex: Any

Trial Phase: Academic

Sponsor: Yale University

Disqualifiers: Hypersensitivity, Pregnant, Asthma, Allergy, others

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

Compensation: Varies

Number of Visits: 1

Duration: 1 day

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to find the optimal concentration of cooling agents in e-cigarette liquids by comparing menthol with WS-3/WS-23. Researchers seek to determine which levels deliver the desired cooling effect without excess. Individuals who have recently used e-cigarettes and are comfortable with menthol may be suitable participants. As an unphased study, this trial offers a unique opportunity to contribute to understanding e-cigarette formulations.

Do I need to stop taking my current medications to join the trial?

The trial information does not specify whether you need to stop taking your current medications.

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

Research has shown that the synthetic cooling agents WS-23 and WS-3, often found in e-liquids, might exceed recommended safety levels. Studies have found that these coolants can alter lung cell behavior, suggesting potential health risks.

Menthol, another cooling agent, has been linked to lung problems. Research indicates that menthol can damage the lungs and impair their normal functions. Despite its common use and familiarity, menthol still poses risks when inhaled through e-cigarettes.

In summary, while these coolants are widely used, evidence suggests that high exposure could be harmful. More research is needed to fully understand their safety in humans. ^{1 2 3 4 5}

Why are researchers excited about this trial?

Researchers are excited about these e-liquid coolants because they offer a unique approach to enhancing the vaping experience without nicotine. Unlike standard e-liquids that often rely on nicotine to provide a sensory effect, these coolants use menthol and WS compounds (WS-23 and WS-3) to create a cooling sensation at various concentrations. This innovation could appeal to users seeking a non-nicotine option while still enjoying the cooling effect, potentially reducing the dependence on nicotine. Additionally, the variety of concentrations allows for personalized experiences, catering to individual preferences for cooling intensity.

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

This trial will evaluate different cooling agents in e-cigarettes, including menthol, WS-23, and WS-3, each at various concentrations. Research has shown that menthol provides a cooling sensation, which many users enjoy, and studies suggest it can make vaping more rewarding. WS-23, another widely used cooling agent, enhances the taste and feel of e-cigarettes. WS-3 is also used, but concerns exist about its safety, as it might exceed safe exposure levels. These coolants are chosen for their ability to make e-cigarettes more appealing by providing a cooling effect. Participants in this trial will be assigned to different treatment arms to assess the effects of these specific coolants. ^{1 3 6 7 8}

Who Is on the Research Team?

Suchitra Krishnan-Sarin, PhD

Principal Investigator

Yale University

Are You a Good Fit for This Trial?

Adults who have used nicotine e-cigarettes, can read and write, and have vaped in the past month. Not for those allergic to propylene glycol or nut/e-liquid flavors, pregnant or breastfeeding women, people with uncontrolled asthma, marijuana vapers, or anyone showing symptoms of lung injury from vaping.

Inclusion Criteria

Used e-cigarettes containing nicotine

Able to read and write

Use e-cigs in past 30 days

Exclusion Criteria

Known hypersensitivity to propylene glycol

My asthma is not well-managed.

Pregnant or lactating females

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

1 week

Treatment

Participants are exposed to e-liquids containing five different concentrations of two different cooling flavors without nicotine and rate 'coolness' using the generalized Labeled Magnitude Scale (gLMS)

1 day

1 visit (in-person)

Follow-up

Participants are monitored for any adverse reactions and effectiveness of the cooling sensation

1 week

What Are the Treatments Tested in This Trial?

Interventions

• E-liquid coolant (menthol, 0.05%)
• E-liquid coolant (menthol, 0.1%)
• E-liquid coolant (menthol, 0.5%)
• E-liquid coolant (menthol, 1.0%)
• E-liquid coolant (menthol, 2.0%)
• E-liquid coolant (WS-23, 0.05%)
• E-liquid coolant (WS-23, 0.1%)
• E-liquid coolant (WS-23, 0.5%)
• E-liquid coolant (WS-23, 1.0%)
• E-liquid coolant (WS-23, 2.0%)
• E-liquid coolant (WS-23, 4.0%)
• E-liquid coolant (WS-3, 0.05%)
• E-liquid coolant (WS-3, 0.1%)
• E-liquid coolant (WS-3, 0.5%)
• E-liquid coolant (WS-3, 1.0%)
• E-liquid coolant (WS-3, 2.0%)

Trial Overview The trial is testing how different concentrations of cooling agents (WS-23 and WS-3) and menthol affect the sensory experience when using e-cigarettes. It's a preliminary study to decide on concentrations for future research.

How Is the Trial Designed?

Group I: WS-3 (5), no nicotine Experimental Treatment 1 Intervention

WS-3 block: 2.0%

Group II: WS-3 (4), no nicotine Experimental Treatment 1 Intervention

WS-3 block: 1.0%

Group III: WS-3 (3), no nicotine Experimental Treatment 1 Intervention

WS-3 block: 0.5%

Group IV: WS-3 (2), no nicotine Experimental Treatment 1 Intervention

WS-3 block: 0.1%

Group V: WS-3 (1), no nicotine Experimental Treatment 2 Interventions

WS-3 block: 0.05%

Group VI: WS-23 (6), no nicotine Experimental Treatment 1 Intervention

WS-23 block: 4.0%

Group VII: WS-23 (5), no nicotine Experimental Treatment 1 Intervention

WS-23 block: 2.0%

Group VIII: WS-23 (4), no nicotine Experimental Treatment 1 Intervention

WS-23 block: 1.0%

Group IX: WS-23 (3), no nicotine Experimental Treatment 1 Intervention

WS-23 block: 0.5%

Group X: WS-23 (2), no nicotine Experimental Treatment 1 Intervention

WS-23 block: 0.1%

Group XI: WS-23 (1), no nicotine Experimental Treatment 1 Intervention

WS-23 block: 0.05%

Group XII: Menthol (5), no nicotine Experimental Treatment 1 Intervention

Menthol block: 2.0%

Group XIII: Menthol (4), no nicotine Experimental Treatment 1 Intervention

Menthol block: 1.0%

Group XIV: Menthol (3), no nicotine Experimental Treatment 1 Intervention

Menthol block: 0.5%

Group XV: Menthol (2), no nicotine Experimental Treatment 1 Intervention

Menthol block: 0.1%

Group XVI: Menthol (1), no nicotine Experimental Treatment 2 Interventions

Menthol block: 0.05%

E-liquid coolant (menthol, 0.05%) is already approved in European Union, United States for the following indications:

Approved in European Union as Menthol for:

• General use as a flavoring agent in food and tobacco products

Approved in United States as Menthol for:

• General use as a flavoring agent in food and tobacco products

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

The synthetic coolant menthone 1,2-glycerol ketal (MGK) was found in a menthol-flavored e-liquid at a concentration of approximately 170 μg/mL, raising concerns about its potential toxicological risks when inhaled through electronic nicotine delivery systems (ENDS).

The study highlights the need for further research on the inhalation toxicity of MGK in e-liquids, as well as demonstrates a reliable method for quantifying synthetic coolants in these products using liquid chromatography-tandem mass spectrometry.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Detection of the Synthetic Coolant Menthone 1,2-Glycerol Ketal in an e-Liquid and in Electronic Waterpipe Aerosols Therefrom. Klupinski, TP., Strozier, ED., Koebel, DD., et al.[2023]

In a study involving 50 healthy volunteers, the use of 70% isopropyl alcohol significantly reduced bacterial growth on the skin from 98% to 54%.

Following alcohol preparation, the application of a vapocoolant spray further reduced bacterial growth to 46%, indicating that the vapocoolant does not compromise skin sterility after alcohol prep.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Skin Sterility After Application of a Vapocoolant Spray Part 2. Mlynek, K., Lyahn, H., Richards, B., et al.[2015]

In a study involving 50 patients, the use of alkane vapocoolant spray after standard skin disinfection did not significantly increase bacterial counts, indicating it does not recontaminate the skin before intravenous cannulation.

The vapocoolant spray demonstrated a significant bactericidal effect on unprepared skin, reducing bacterial colony counts, but it should not replace standard disinfection methods as it is not sufficient as a sole disinfectant.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of vapocoolant spray on skin sterility prior to intravenous cannulation. Evans, JG., Taylor, DM., Hurren, F., et al.[2015]

The study identified 12 flavor chemicals in commercial e-cigarette refill fluids, with over 50% containing high concentrations that can transfer efficiently into aerosols, potentially leading to cytotoxic effects.

Aerosols produced at a higher voltage (5V) were found to be generally more toxic to human lung cells compared to those produced at a lower voltage (3V), highlighting a significant health concern regarding the use of flavored e-cigarettes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Analytical and toxicological evaluation of flavor chemicals in electronic cigarette refill fluids. Behar, RZ., Luo, W., McWhirter, KJ., et al.[2022]

A study of 277 electronic cigarette refill fluids revealed that 85% contained flavor concentrations greater than 1 mg/ml, with some flavors like menthol and ethyl maltol present at levels significantly exceeding their cytotoxic concentrations, raising safety concerns.

The presence of high concentrations of certain flavor chemicals, such as cinnamaldehyde at over 100,000 times its cytotoxic level in one sample, suggests that the lack of regulation on flavor chemicals in e-cigarettes could pose serious health risks to users.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

High concentrations of flavor chemicals are present in electronic cigarette refill fluids. Omaiye, EE., McWhirter, KJ., Luo, W., et al.[2023]

This study identified and quantified 14 different carbonyl compounds produced during vaping, with the highest levels of harmful substances like formaldehyde and acetaldehyde emitted from propylene glycol and vegetable glycerin e-liquids.

Flavored e-liquids not only produced a wider variety of carbonyls but also showed that certain flavoring chemicals can transform into potentially harmful compounds, indicating a complex interaction that may pose health risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Carbonyl Composition and Electrophilicity in Vaping Emissions of Flavored and Unflavored E-Liquids. Chen, JY., Canchola, A., Lin, YH.[2021]

In a study involving 99 adults undergoing needle electromyography, vapocoolant spray significantly reduced pain intensity compared to a control group, with a visual analog scale (VAS) score of 31.9 versus 52.9 for the control (P=.002).

The vapocoolant spray also resulted in higher patient satisfaction and preference for repeated use compared to EMLA cream, indicating it may be a more effective option for pain management during this procedure.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of the effects of vapocoolant spray and topical anesthetic cream on pain during needle electromyography in the medial gastrocnemius. Moon, YE., Kim, SH., Choi, WH.[2022]

In a study involving 13 healthy adults, the application of vapocoolant spray (cold spray) resulted in a temporary decrease in blood flow and oxygenation in the superficial layer of thigh muscles, observed for up to 3 minutes after application.

The findings suggest that while cold spray can provide a short-term analgesic effect by affecting superficial tissues, its limited impact on deeper muscle layers may restrict its overall therapeutic benefits, indicating a need for further clinical trials on injured muscles.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Subcutaneous and Intramuscular Hemodynamics and Oxygenation After Cold-Spray Application as Monitored by Near-Infrared Spectroscopy. Shadgan, B., Med, S., Pakravan, AH., et al.[2022]

In a study involving 127 children aged 9 to 18 undergoing intravenous cannulation, ethyl vinyl chloride vapocoolant spray did not significantly reduce pain compared to a placebo (isopropyl alcohol spray) or no treatment.

The mean pain scores reported by children receiving ethyl vinyl chloride spray (34 mm) were similar to those in the placebo (33 mm) and control (31 mm) groups, indicating that this vapocoolant spray is ineffective for pain management in this context.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ethyl vinyl chloride vapocoolant spray fails to decrease pain associated with intravenous cannulation in children. Costello, M., Ramundo, M., Christopher, NC., et al.[2013]

E-cigarettes with ice-hybrid flavors and synthetic cooling agents like WS-3 and WS-23 have been developed since 1974, but their inhalational toxicology and long-term health effects are still unknown, highlighting a need for further research and regulatory scrutiny.

These products are popular among adolescents and young adults, potentially leading to increased vaping frequency and nicotine dependence, which raises concerns about their impact on public health and the effectiveness of tobacco control measures.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ice flavours and non-menthol synthetic cooling agents in e-cigarette products: a review. Leventhal, AM., Tackett, AP., Whitted, L., et al.[2023]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9742947/

E-cigarette synthetic cooling agent WS-23 and nicotine ... Among various cooling agents analyzed, the synthetic cooling agent WS-23 was reportedly used most prominently [16]. 2-isopropyl-N,2,3-trimethylbutyramide, ...

2. pubs.acs.org pubs.acs.org/doi/10.1021/acs.chemrestox.1c00423

Disposable Puff Bar Electronic Cigarettes: Chemical ... The purpose of this study was to determine flavor chemicals, synthetic coolants, and nicotine concentrations in 16 disposable Puff devices.

3. escholarship.org escholarship.org/content/qt8pf530nq/qt8pf530nq.pdf

Disposable Puff Bar Electronic Cigarettes: Chemical ... The purpose of our study was to (1) identify and quantify nicotine, flavor chemicals, and synthetic coolants in Puff fluids, (2) determine the ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11076411/

Effects of 'Ice' flavoured e-cigarettes with synthetic cooling ... This clinical experiment tested the effects of exposure to e-cigarettes with WS-23 or menthol cooling additives on user appeal and sensory attributes.

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. drugsandalcohol.ie drugsandalcohol.ie/36742/

Disposable Puff Bar electronic cigarettes: chemical ... The purpose of this study was to determine flavor chemicals, synthetic coolants, and nicotine concentrations in 16 disposable Puff devices.

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9199944/

Synthetic Cooling Agents in US-marketed E-cigarette Refill ... Synthetic cooling agents (WS-3/WS-23) were present in US-marketed E-cigarettes, at levels that may result in consumer exposures exceeding safety thresholds.

8. chemicalbook.com chemicalbook.com/ChemicalProductProperty_EN_CB4227036.htm

2-Isopropyl-N,2,3-trimethylbutyramide | 51115-67-4 2-Isopropyl-N,2,3-trimethylbutanamide is flavored compound and comprising the recount flavored compound for electronic cigarette liquid.