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Wilson M. Compton, MD, MPE Deputy Director, National Institute on Drug Abuse

Tobacco Research at NIDA:

Neuroscience, Treatment and

Regulatory-related studies

• Basic Research Genetics (understanding impact of genetics on vulnerability

to smoking-related morbidity/mortality) Biomarkers of vulnerability

• Prevention Research (ABCD) • Medications Development • Behavioral and Integrated Treatments • Vulnerable Populations (e.g., pregnant women, mental illness) • Integrated Tobacco Epidemiology (MTF, PATH)

Themes for NIDA Research

All Drugs Abused by Humans Raise Brain Dopamine Levels in the Nucleus Accumbens

Nestler, Nature Neurosci, 2005

`

Time After Methamphetamine

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METHAMPHETAMINE 2000

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1 2.5

Dose (mg/kg IV)

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Time After Nicotine

% o

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NICOTINE

Di Chiara et al.

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Kimura et al., Nature Neuroscience 2007.

Habenula neurons increased firing for NO REWARD and decreased firing for REWARD Dopamine neurons increased firing for REWARD and decreased firing for NO REWARD.

HABENULA

Habenula inhibits dopamine neurons Habenula communicates negative reward signals to dopamine neurons

Habenula and Negative Reward

Biological Psychiatry

Convergent Results Support CHRNA5/A3/B4 Gene Cluster Association with Nicotine Dependence

Medial habenula

a5, a3, 4, have a high concentration in habenula and interpeduncular nucleus

Genes Affect Risk for Smoking Progression, Odds of Quitting and Whether Medications

May Help

*Chen LS et al., Am J Psychiatry 169: 735-42, 2012 *Belsky DW, et al., JAMA Psychiatry 70: 534-42, 2013 *Chen LS et al., Addiction 109: 128-37, 2013

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Mental Disorder

Addictive Disorder

Comorbid Disorders

COMORBIDITY

Normal Population: 23%* Alcoholism: 56.1% (past mo.); 43.5% (lifetime)** Drug Addictions: 67.9% (past mo.); 49% (lifetime)** Schizophrenia: 70-85%*** Depression: 44.7% (past mo.); 36.6% (lifetime)** Anxiety: 54.6% (past mo.); 46% (lifetime)** PTSD: 44.6% (past mo.); 45.3% (lifetime)** ADHD: 41-42% (adults)**** 19-46% (adolescents)****

Smoking Rates

*2010 National Survey on Drug Use and Health, SAMHSA 2011. **Lasser et al.,JAMA 2000; 284(20): 2606-2610. ***Ziedonis et al., Nic and Tob Res 2008;10(12):1691-1715. ****McLernon et al., Ann NY AcadSci 2008;1141: 131-147.

In the USA 44% Cigarettes Consumed by

the Mentally Ill Lasser et al., JAMA 2011

People with Severe Mental Illness Much More Likely to Use Tobacco and Other Drugs

• Individuals with SMI were 4X more likely to be heavy alcohol users and almost 4X more likely to be regular marijuana users

• Protective factors usually

associated with lower rates of substance use did not carry over to this population

*Hartz SM, et al., JAMA Psychiatry, 7: 248-54, 2014

>4 Drinks Alcohol/Day Daily Smoking > 1 mo

Marijuana > 21x/year Other Drugs > 10x

Past Month Cigarette Use and Nicotine Dependence among Persons Aged 12 or Older, by Past Year Substance Use Treatment: 2005 to 2009

The NSDUH Report: Nicotine Dependence among Persons Who Received Substance Use Treatment, SAMHSA 2011.

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Use of Mentholated Cigarette May Play Role in Cocaine Dependence and Abstinence

*Winhusen TM et al., Drug and Alcohol Dependence 133: 845-51, 2013

• Smoking cessation treatment can improve quit rates in individuals also undergoing concurrent treatment for stimulant addiction,

• However, use of menthol cigarettes may complicate cocaine treatment outcomes for cocaine-dependent individuals

*Winhusen TM et al., J Clin Psychiatry 75: 336-43, 2014

Stimulant Abstinence as a function of stimulant-dependent diagnosis and cigarette type

Maintenance pharmacotherapy+ CBT can help individuals with SMI stay smoke-free

Maintenance pharmacotherapy with varenicline and cognitive behavioral therapy improved prolonged tobacco abstinence rates for individuals with serious mental illness after 1 year of treatment and at 6 months after treatment discontinuation

*Evins et al., Maintenance Treatment with Varenicline for Smoking Cessation in Patients with SCZ and Bipolar Disorder, JAMA 311: 143-54, 2014

Smoking Cessation Treatment During Psychiatric Hospitalization Reduces Smoking Rates & Improves Mental Health

*Prochaska, Hall, et al., Efficacy of Initiating Tobacco Dependence Treatment in

Inpatient Psychiatry: A Randomized Controlled Trial, American Journal of Public

Health, 104: 1557-65, 2014

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Electronic Nicotine Delivery Systems: Promise or Peril?

• Promise: “If governments, parliaments, regulation agencies, and experts are able to restrain their yearning to restrict access to e-cigarettes, these products are likely to represent a revolution in public health.” Etter, 2013.

• Peril: “Urged on by myopic health professionals who seem to have lost any population health focus they might have had, this may become one of the biggest blunders of modern public health.” Chapman, 2013.

• Middle ground: “… [our responses to ECIGs] will provide the greatest public health benefit when they are proportional, based on evidence, and incorporate a rational appraisal of likely risks and benefits.” Hajek et al., in press.

Slide Courtesy of Thomas Eissenberg, Virginia Commenwealth University, USA

More Youth in USA Using E-Cigarettes Than Tobacco Cigs

Monitoring the Future Study, University of Michigan

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8th Grade 10th Grade 12th Grade

Tobacco Cigarettes

E-Cigarettes

Past Month Use of E-Cigs vs. Traditional Cigarettes in the 2014 Monitoring the Future Study of 8th, 10th and 12th Grade Students in USA

8.1%

16.2% 17.1%

4.0%

7.2%

13.6%

Large Numbers of Youth in USA Using E-Cigarettes Without Prior Use of Tobacco

Monitoring the Future Study, University of Michigan

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E-Cigs Only

E-Cigs and Any LifetimeTobacco

Past Month Use of E-Cigarettes Among Youth with/without Any Lifetime Use of Tobacco Cigarettes or Smokeless Tobacco in the 2014 Monitoring the Future Study

of 8th, 10th and 12th Grade Students in USA

36%

30%

21%

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Adolescent Brain Cognitive Development National Longitudinal Study

NIDA, NIAAA, NCI, NICHD, NIMHD, ORWH, NIMH, NINDS, OBSSR

Ten year longitudinal study of 10,000 children from age 10 to 20 years to assess effects of drugs on

individual brain development trajectories

Population Assessment of Tobacco and Health (PATH) Study

• National, longitudinal cohort study of 45,000+ users of tobacco products and those at risk for tobacco use ages 12 and older in the U.S.

• Funded by the Center for Tobacco Products, FDA.

• Results from this study will inform the impact of FDA regulatory authority over tobacco products, and help to inform future activities.

2011 2012 2013 2014 2015 2016

Contract Award 1

Baseline Field Test

Wave 2 Wave 3

Today

PATH Study Domains (examples)

• Baseline Sample 45,971 total (32,320 age 18+, 13,651 age 12-17)

• Outcomes – Tobacco Product Use including Dual Use, Switching, New

Products – Tobacco Use Behaviors including Initiation, Cessation/Quitting,

Relapse – Health Outcomes

• Mediators/Moderators – Demographics – Knowledge, Attitudes, Beliefs, and Risk Perceptions – Tobacco Addiction – Peer, Environmental, Contextual influences – Mental Health/Substance Abuse Co-morbidities

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0%

20%

40%

60%

80%

100%

Population Any TobaccoUse

Cigarettes E-cigarettes Cigarillos Hookah Smokeless,excl snus

Traditionalcigars

Filteredcigars

Pipe Snus

Alcohol Use Past 12 Months (n=1023)

Blunt Use Past 12 Months (n=337)

Any Marijuana Use Past 12 Months (n=596)

Suppre

ssed

Suppre

ssed

Suppre

ssed

Suppre

ssed

The PATH Study Baseline (interim analysis)

Youth Past 12 Month Alcohol, Blunt, and Marijuana Use Prevalence* By Past 30 Day Tobacco Use

* Current use for each tobacco product is use in the past 30 days. Past year alcohol use is defined as using any alcohol in the past 12 months. Blunt use is report of having smoked all or part of a cigar with marijuana in it in the past 12 months. ‘Any Marijuana’ use is blunt use or report of having used marijuana, hash, THC, grass, pot or weed in the past 12 months.

WARNING: Interim preliminary results from a portion of the baseline wave. Results from entire

baseline wave will differ. Inferences from these data should be made with caution.

Source: Society for Research on Nicotine and Tobacco Annual Meeting, February 2015

0%

20%

40%

60%

80%

Population AnyTobacco Use

Cigarettes E-cigarettes Cigarillos Hookah Smokeless,Excl snus

Traditionalcigars

Filteredcigars

Pipe Snus

Low (n=2852)

Moderate (n=1759)

High (n=1421)

Suppre

ssed

Suppre

ssed

Suppre

ssed

Suppre

ssed

*Includes significant problems during the past year with: feeling very trapped/sad/depressed; trouble sleeping; feeling nervous/anxious/tense/scared; being distressed/upset about the past. Severity indicates the report of 0-1 problems (Low), 2-3 (Moderate), or 4 (High).

The PATH Study Baseline (interim analysis)

Youth Past 12 Month Internalizing Severity* By Past 30 Day Tobacco Use

WARNING: Interim preliminary results from a portion of the baseline wave. Results from entire

baseline wave will differ. Inferences from these data should be made with caution.

Source: Society for Research on Nicotine and Tobacco Annual Meeting, February 2015

0%

20%

40%

60%

80%

Population AnyTobacco

Use

Cigarettes E-cigarettes Cigarillos Hookah Smokeless,Excl snus

Traditionalcigars

Filteredcigars

Pipe Snus

Low (n=2927)

Moderate (N=2492)

High (n=573)

Suppre

ssed

Suppre

ssed

Suppre

ssed

Suppre

ssed

*Include two or more occurrences in the past year of: hard time paying attention/following instructions; lied/ conned to get something; bullied/threatened people; started a physical fight. Severity indicates the report of 0-1 (Low), 2-3 (Moderate), 4-5 (High).

The PATH Study Baseline (interim analysis)

Youth Past 12 Month Externalizing Severity* By Past 30 Day Tobacco Use

WARNING: Interim preliminary results from a portion of the baseline wave. Results from entire

baseline wave will differ. Inferences from these data should be made with caution.

Source: Society for Research on Nicotine and Tobacco Annual Meeting, February 2015

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0%

20%

40%

60%

80%

100%Alcohol Use Past 12 Months (n=10050) Blunt Use Past 12 Months (n=1770) Any Marijuana Use Past 12 Months (n=3002)

* Current cigarette use is 100 lifetime and currently use everyday or some days; other tobacco products currently use everyday or some days. Past year alcohol = any in past 12 mos. Blunt = smoked all or part of a cigar with MJ in past 12 mos. ‘Any Marijuana’ = blunt or MJ, hash, THC, grass, pot or weed in past 12 mos.

The PATH Study Baseline (interim analysis)

Adult Past 12 Month Alcohol, Blunt, and Marijuana Use Prevalence* By Current Tobacco Use*

WARNING: Interim preliminary results from a portion of the baseline wave. Results from entire

baseline wave will differ. Inferences from these data should be made with caution.

Source: Society for Research on Nicotine and Tobacco Annual Meeting, February 2015

0%

20%

40%

60%

80% Low (n=8486) Moderate (n=3405) High (n=2452)

The PATH Study Baseline (interim analysis)

Adult Past 12 Month Internalizing Severity By Current Tobacco Use

WARNING: Interim preliminary results from a portion of the baseline wave. Results from entire

baseline wave will differ. Inferences from these data should be made with caution.

Source: Society for Research on Nicotine and Tobacco Annual Meeting, February 2015

0%

20%

40%

60%

80%

Low (n=10407) Moderate (N=3458) High (n=410)

The PATH Study Baseline (interim analysis)

Adult Past 12 Month Externalizing Severity By Current Tobacco Use

WARNING: Interim preliminary results from a portion of the baseline wave. Results from entire

baseline wave will differ. Inferences from these data should be made with caution.

Source: Society for Research on Nicotine and Tobacco Annual Meeting, February 2015

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PATH Next Steps

• Data collection ongoing

• Selected analysis ongoing

• Accelerated efforts to have the PATH Study be a resource to the scientific community while ensuring highest data quality

• More Information: PATHstudyinfo.nih.gov

• Basic Research Genetics (understanding impact of genetics on vulnerability

to smoking-related morbidity/mortality) Biomarkers of vulnerability

• Prevention Research (ABCD) • Medications Development • Behavioral and Integrated Treatments • Vulnerable Populations (e.g., pregnant women, mental illness) • Integrated Tobacco Epidemiology (MTF, PATH)

Themes for NIDA Research