Product Standards for Reducing Nicotine in Cigarettes

Product Standards for Reducing Nicotine in Cigarettes

Eric C. Donny, Ph.D.

Professor, Department of Psychology, University of Pittsburgh

Director, Center for the Evaluation of Nicotine in Cigarettes

FundingResearch reported in this publication was supported by the National Institute on Drug Abuse and Food and

Drug Administration Center for Tobacco Products (U54 DA031659). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or the

Food and Drug Administration.

Why do people smoke?

People smoke for the nicotine…

-M.A. Russell, 1976

http://rpiwww.mdacc.tmc.edu/se/anatomy/brain/gross_brain_left.jpg

http://rpiwww.mdacc.tmc.edu/se/anatomy/brain/gross_brain_left.jpg

http://en.wikipedia.org/wiki/Image:Nicotine-3D-vdW.png



…but they die from the tar-M.A. Russell, 1976




Nic

otin

e Co

nten

t



• Enables FDA to set product standards for nicotine• Cannot be reduced to zero• Must consider the risks and benefits to the population as a

whole including users and nonusers

Family Smoking Prevention and Tobacco Control Act

Would a product standard requiring very low nicotine levels reduce cigarette use and improve

public health?

Two sources of data for today

Large clinical trial Rat self-administration

Donny et al., 2015

• Purpose: To determine how use of cigarettes varying in nicotine content impacts a wide range of outcomes in a large study of smokers not currently interested in quitting

• Double-blind, parallel, randomized trial• 840 daily smokers

• 18+ years old• 5+ CPD• Not planning to quit in next 30 days

Design

Week 3 Week 4 Week 5 Week 6Week 2Week 1Baseline AA

Usual brand

Design


Study cigarettes provided free of charge

Design

All subjects menthol matched

Nicotine Nicotine Tar Content Yield (ISO) Yield (ISO)

GROUPS (7 total) (mg/g) (mg/cig) (mg/cig)1. Usual brand variable variable variable2. Normal Nicotine 15.8 ~0.73 ~10

3. Reduced Nicotine 5.2 ~0.24 ~9

4. Very Low Nicotine 2.4 ~0.11 ~95. Very Low Nicotine 1.3 ~0.06 ~86/7. Very Low Nicotine 0.4 ~0.03 ~9 (or 13)

Data provided by NIDA

33%

15%

8%3%

Design


Abstinence Session

Design


30 dayFollow-up

Design

Week 3 Week 4 Week 5 Week 6Week 2Week 1Baseline AAScreen

In person visits (10)

Outcome measuresSmoking behavior

BiomarkersNicotine dependence

Withdrawal and cravingSafety

Design

• Compensation up to $835• Product use

• No incentive for compliance (or penalty for non-compliance) with study product

• Emphasis on honest reporting

Design

Study sites

Sample characteristics

• Age: 42• Female: 42.3%• African American: 39.7%• High school or less: 44.2%• Menthol preferred: 57%• CPD: 15.5• CO: 15.1• FTND: 5.1

Does nicotine reduction lead to reduced smoking?

Dose-dependent reduction in total CPD

Cigarettes per day

Dose-dependent reduction in total CPD

Donny E.C. et al., 2015, NEJM, 373, 1340-9

Cigarettes per day


Cigarettes per day

***

5.2 and above ↑2.4 and below ↓

*indicates significant (p<.0125) difference compared to 15.8 mg/g (controlling for BL)

*


Hypothetical CPD at $6/pack


***

*

*


Demand curve

*

0.4 mg/g15.8 mg/g

Cost 0

Take home point #1

Low nicotine content cigarettes reduce smoking relative to normal

nicotine cigarettes

CPD Elasticity of demand (hypothetical)

0.4 vs. 15.8 mg/g Reduced Reduced

Does nicotine reduction lead to compensatory smoking?

Light cigarettes have reduced nicotine yield. The content of the tobacco is the same.

With light cigarettes, smokers can and do compensate.

Machine yield Content and user exposure

These cigarettes actually contain less nicotine. It would be very difficult for smokers to adjust their

behavior to maintain nicotine levels.

Compensatory smoking

No significant differences





*

*



• Other studies also fail to find compensation that lasts beyond the first few cigarettes (Benowitz et al. 2012; Hatsukami et al., 2010, 2013, 2015; Donny et al., 2007; Donny and Jones, 2009; MacQueen et al., 2012)• CPD – similar or less than controls• Carbon monoxide – similar or less than controls• Puff Volume – similar or less than controls

• It is possible some subgroups will compensate (e.g., high dependence; Bandiera et al., 2015)

Take home point #2

Minimal evidence of compensatory smoking

CPD CO Puff volume Filter analysis

0.4 vs. 15.8 mg/g Reduced Similar Reduced Underway

Does nicotine reduction lead to decreases in nicotine exposure?

***

Biomarkers of exposure

*


*


Content vs. Exposure

Nicotine exposureNicotine content


15.8

0.4↓97%

↓57%

The “Hotel Study”• 24 participants smoked only

0.4 mg/g SPECTRUM while residing at a hotel for 4 nights.

• Nicotine exposure decreased by at least 92-94%

↓94%

↓92%

Non-adherence • Self-report: Each week, 30-60% of participants

assigned to reduced nicotine cigarettes reported smoking other cigarettes. • How much? 2-4 CPD (median when non-compliant)• When? Most often first thing in morning

• Biomarkers: TNE at week 6 • Only about 25% of participants in the 0.4 mg/g groups had

TNE < 6.4 nmol/ml

Take home point #3

Low nicotine content cigarettes reduce nicotine exposure, but

people seek out other sources of nicotine

Clinical trialTNE

HotelTNE

Clinical trial UB cigs

0.4 vs. 15.8 mg/g Reduced 57% Reduced >94% Increased

Does nicotine reduction reduce dependence and/or lead to

quitting?

Dependence

**


*


Dependence

*



Quit attempts

*

*indicates significant (p<.0125) difference compared to 15.8 mg/g

*


Cigarettes per day

**


*


Take home point #4

Low nicotine content cigarettes reduce nicotine dependence and may increase the likelihood that

smokers will try to quit

FTND & WIDSM

Quit attemptsat Follow-up

CPD at Follow-up

0.4 vs. 15.8 mg/g Reduced Increased Reduced

Does nicotine reduction lead to other potentially harmful

unintended consequences?

Potential unintended consequences

• Compensatory smoking• Depression/disrupted affect

• Decreased positive• Increased negative

• Weight gain• Alcohol/drug use• Impaired cognitive function• Others

• AEs• Platelet activation

Depression


CESD Maximum score: 60Commonly use clinical cutoff: 16

• No significant differences in mean CESD scores

• Approximately 23% had a score ≥ 16+ at Week 6• No significant differences

between groups• 23% of 15.8 mg.g• 22% of 0.4 mg/g

Weight gain

0.4 mg/g conditions only

(n=56)(n=164)

** *

**

Take home point #5

Low nicotine content cigarettes do not appear to increase depression,

but do lead to expected gains in weight

CESDOverall & >16

Weight

0.4 vs. 15.8 mg/g Similar Increased

Note: a significant portion of participants use other products

Sprague-Dawley rats1-hr daily self-administration sessions

Respond for intravenous (i.v.) infusions of nicotine

Rat self-administration

Smith et al., 2013 Nicotine and Tobacco Research

Smith et al., 2013 Nicotine and Tobacco ResearchNicotine and Tobacco Research


Would nicotine reduction reduce the uptake of smoking?

Adult male Sprague-Dawley ratsSmith et al., 2014 Exp & Clinical Psychopharm

Initiation of self-administration

The just BELOW threshold dose from the reduction study

The just ABOVE threshold dose from the reduction study

15

3.75

7.5

60

0.0

DOSE

Initiation of self-administration

Adolescents (male or female) fail to acquire at 10 ug/kg or lower

Schassburger et al., under review, Nicotine and Tobacco Research

Take home point #6

Reducing nicotine may decrease the uptake of

smoking

# inf. % acq. Adolescents vs. adults

low vs. high nicotine Reduced Reduced Similar or reduced sensitivity

Could other constituents maintain behavior?

Cigarette Smoke Constituents

• Nicotine: Primary reinforcing constituent

• > 8,000 other constituents

Constituent Dose (µg/kg/inf) % Nicotine

Minor alkaloids

• anabasine 0.9 3.0

• anatabine 0.09 0.3

• cotinine 0.09 0.3

• myosmine 0.09 0.3

• nornicotine 0.9 3.0

Beta-carbolines

• harman 0.1 0.3

• norharman 0.3 1.0

Acetaldehyde 16 53

+ Pre-session inj of MAO inhibitor, 1.0 mg/kg tranylcypromine (TCP)


Smith et al., Under Review


Smith et al., 2015, Drug and Alcohol Dependence


FR3

FR5

Smith et al., 2015, Drug and Alcohol Dependence

Take home point #7

Although most other constituents may have little effect, constituents

that inhibit MAO increase the reinforcing effects of low doses of

nicotine# infusions at low cost

# infusions at high cost

Cocktail Non-sign Non-sign

MAO inhibition Increased Non-sign

Take home points - summary1) Very low nicotine content (VLNC) cigarettes reduces smoking

relative to normal nicotine cigarettes.2) VLNC cigarettes lead to minimal evidence for compensatory

smoking.3) VLNC cigarettes reduce nicotine exposure, but people seek out

other sources of nicotine.4) VLNC cigarettes reduce nicotine dependence and may increase

the likelihood that smokers will try to quit.5) VLNC cigarettes do not appear to increase depression in healthy

volunteers, but do lead to weight gain similar to cessation.6) Reducing nicotine decreases the uptake of self-administration in

rats.7) Non-nicotine constituents tend to have minimal effect on rat self-

administration, although constituents that inhibit MAO may increase the reinforcing effects of low doses of nicotine.

Conclusions

• Reducing nicotine in cigarettes and other combusted tobacco products could improve public health.

• Large reductions in nicotine content may be necessary to produce the optimal health impact.

Missing in actionCore staff

Many critically important RAs, students, physicians, nurses, and other staff at all the CENIC project sites

NIDA, RTI and 22nd century

FDA & NIH

Pitt general counsel and research compliance offices

Anyone else I forgot!

Critical question for audience

What additional data do you think are necessary before FDA should consider regulating the nicotine

content of cigarettes?

Product Standards for Reducing Nicotine in Cigarettes

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