Yale Tobacco Center of Regulatory Yale Tobacco Center of Regulatory SciencesSciences

Suchitra Krishnan-Sarin, Ph.D.

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Stephanie O’Malley, Ph.D.

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GoalsGoals

• Overarching: Reduce Addiction to Tobacco Products

• Specific: Evaluation of the Influence of Flavors (like Menthol), Sweeteners, and Other Attributes on the Addictive Potential of Tobacco Products

Why Flavors and Sweeteners?Why Flavors and Sweeteners?

• Flavors banned in cigarettes.

• Menthol still present in most cigarettes, even in those not sold as menthol cigarettes.

• Flavors are present in most other tobacco products, especially newer products like e-cigarettes.

• Sweeteners are present in tobacco products.

Flavors are everywhere!Flavors are everywhere!

For successful regulation of flavors and For successful regulation of flavors and sweeteners empirical evidence on what sweeteners empirical evidence on what

they do is essentialthey do is essential

• Yale TCORS will examine if flavors alter reinforcement from tobacco products

• If so– how do they alter reinforcement?– Is this effect dose dependent?

ApproachApproach

• Translational

• Multiple methods and disciplines

• Four proposed studies that bridge basic, clinical and population science

– Results will be integrated to develop a more comprehensive understanding of the role of flavors and sweeteners

Core Team Includes Experts in…Core Team Includes Experts in…• Chemosensory perceptions (Barry Green)

• Menthol and irritant receptor biology (Sven Jordt)

• Dopamine and brain reward pathways (Nii Addy)

• Nicotinic receptor biology (Marina Picciotto)

• Adolescent tobacco use (Suchitra Krishnan-Sarin)

• Human behavioral pharmacology (Mehmet Sofuoglu)

• Tobacco addiction (Stephanie O’Malley/Benjamin Toll)

• Clinical pharmacokinetics of drugs of abuse (Peter Jatlow)

• Health economics and decision making science (Jody Sindelar/ Johanna Catherine Maclean)

Yale TCORS organizationYale TCORS organization

Project 1Project 1: Effect of Flavors on Nicotine Choice and Central Reward mechanisms

• In new consumers of dissolvable tobacco products, do menthol and other flavors counteract the initial aversive effects of nicotine and tobacco aromas?

• In chronic consumers, do sweeteners and menthol increase the addictive properties of tobacco products? – If so, is this mediated through enhancing central dopaminergic

mechanisms

Sven Jordt, Ph.D. Marina Picciotto, Ph.D. Nii Addy, Ph.D.

Project 1: Project 1: Effect of Flavors on Nicotine Choice and Central Reward mechanisms

• Determine whether flavor constituents in dissolvable tobacco products alter nicotine intake and nicotine reinforcement using

– Oral nicotine choice paradigms with adolescent and adult mice, and mice deficient in receptors for menthol and sweeteners (TRPM8, TRPA1, T1R2/3)

– Fast scan cyclic voltammetry to measure dopamine release during nicotine and menthol/ sweetener self-administration in rats

Project 2: Project 2: Menthol’s Effects on Nicotine Reinforcement in Smokers

• In young adults, does acute menthol administration via either e-cigarettes or sublingual tablets enhance the reinforcing effects of intravenously administered pure nicotine?

Mehmet Sofuoglu,M.D.,Ph.D. Barry Green, Ph.D. Gerald Valentine,M.D.

Project 2: Project 2: Menthol’s Effects on Nicotine Reinforcement in Smokers

• Two pilot studies to determine menthol doses – E-cigarettes and dissolvables

• Two double-blind, placebo-controlled studies with – E-cigarettes and dissolvables

• Each study – Crossover design – Reinforcement from IV nicotine doses will be examined

• High or low dose of menthol or a control flavor

Project 3: Project 3: Flavor and E-cigarette Effects in Adolescent Smokers

• In adolescent smokers

– does presence of menthol and/or other flavors in e-cigarettes influence reinforcement?

– Does preference for menthol predict the type of tobacco product used at one year follow up ?

Suchitra Krishnan-Sarin, Ph.D Barry Green, Ph.D.

Project 3Project 3: Flavor and E-cigarette Effects in Adolescent Smokers

• Two pilots– Psychophysical chemosensory studies to determine high and low doses

of menthol and other flavors for e-cigarettes

• Two double-blind, placebo-controlled studies – Crossover design – Reinforcement from one of three different doses of nicotine

High or low dose of menthol or a control flavor

Project 4: Project 4: Economics, Experiments and PATH: Creating Knowledge for Tobacco Regulation

• To examine how individuals perceive and trade-off the risks of different attributes of cigarettes– levels of nicotine– levels of toxins– flavorings

• To examine the impact of flavorings and other attributes on perceptions of risk about cigarettes and e-cigarettes

Jody Sindelar, Ph.D Johanna Catherine Maclean, Ph.D

Project 4: Project 4: Economics, Experiments and PATH: Creating Knowledge for Tobacco Regulation

• To study how sources of information affect the credibility of information about menthol in cigarettes and e-cigarettes.

• To examine peer effects on use of e-cigarettes.

• Use secondary data combined with findings from our experiments to predict the national use of MRTPs and to estimate the impact of potential FDA regulations.

CoresCores

Administrative

Career Development

Pilot Core

Laboratory Core

Marina Picciotto, Ph.D Marney White, Ph.D

Benjamin Toll, Ph.D Stephanie O’Malley Ph.D

Peter Jatlow, M.D. Tore Eid, M.D., Ph.D

Stephanie O’Malley, Ph.DSuchitra Krishnan-Sarin, Ph.D

Center Specific ResourcesCenter Specific Resources• Analytics

– Nicotine metabolites, menthol

• Molecular neuroscience

• Animal behavior– IV Nicotine self-administration, operant paradigms

• Human laboratory paradigms– IV nicotine administration and self-administration, tobacco product self-

administration, smoking topography – Human sensory measurements

• Health economics/Discrete choice experiments

Expertise and access to populationsExpertise and access to populations

• Substance abusers

• Psychiatric co-morbidities

• Medically ill patients, including cancer patients

• Adolescents and young adults

• Women’s health

• Veterans

Other ResourcesOther Resources

• Proteomics and Genomics

• Neuroimaging: PET, SPECT, fmRI, MRS

• Data Collection Platforms: Teleforms, Qualtrics, Oncore, Sample Repository

• Ethics of research in vulnerable populations