Women & Addiction: Why is it more difficult for women to quit smoking? Nora D. Volkow, M.D. Director National Institute on Drug Abuse National Institutes of Health

Natural & Drug Reinforcers Increase Dopamine in NAc Time (min) % of Basal Release Empty Box Feeding Di Chiara et al. FOOD VTA/SN nucleus accumbens nucleus accumbens frontal cortex frontal cortex Drugs of abuse increase DA in the Nucleus Accumbens, which is believed to trigger the neuroadaptions that result in addiction hr Time After Nicotine % of Basal Release Accumbens NICOTINE Accumbens

Long term effects of nicotine differs in males and females and this is influenced by age Menarche Menopause Prevalence Rate Smokers: Men % Women % 2010 National Survey on Drug Use & Health (NSDUH), SAMHSA, 2011.

Tobacco Addiction is a Developmental Disease that Starts in Adolescence and Earlier in Girls than Boys NIAAA National Epidemiologic Survey on Alcohol and Related Conditions, Age at tobaccouse dependence as per DSM IV Age 0.0% 0.2% 0.4% 0.6% 0.8% 1.0% 1.2% 1.4% 1.6% 1.8% % in each age group who develop first time dependence White et al. (2002) Time from onset to dependence: Girls: 3 weeks Boys: 6 months DiFranza et al. (2002)

Rates of Cotinine Clearance (ml/min/kg) Benowitz et al., 2006, Clin Pharm Ther * * * OC: oral contraceptives Rates of Nicotine Clearance (ml/min/kg) * * *

Nicotine: More than Dopamine Aromatase* (Estrogen synthase, CYP19A1) HO CH 3 CH 3 CH 3 O aromatase OH OH testosterone 17  -estradiol Mediates sexual differentiation of the brain during development (Wu et al., Cell 2009) Baseline mg/kg 0.03 mg/kg Acute nicotine inhibits aromatase in the Brain (Biegon et al., Biological Psychiatry, 2010)

Smoking has Adverse Effects on Womens’ Endocrinology and Reproductive Health Female smokers show hypo-estrogenic effects including early menopause, dysmenorrhea, menstrual irregularity Lower bone mineral density (osteoporosis) Conception delay, primary/secondary infertility Pregnancy & delivery complications Stillborn, neonatal death Surgeon General’s Report 2001, Women & Smoking

Smoking During Pregnancy… Affects prenatal and postnatal growth Increases the risk of developmental and behavioral deficits

Nicotine Gets into the Fetus’ Brain Fetal brain Placenta Fetal Liver Maternal Brain Fetal brain Nicotine gets into the fetal brain Source: Benveniste et al. Unpublished data [11C]Nicotine and metabolites Use of Drugs During Pregnancy Not Only Affects the Physiology of the Mother But Also that of the Fetus

Secondhand smoke (SHS) exposure decreased 2-FA binding in brain demonstrating α 4 β 2 * nicotinic acetylcholine receptor occupancy Control Second Hand Smoke Secondhand smoke (SHS) leads to significant α 4 β 2 * nicotinic acetylcholine receptor occupancy (18-22%) Effect of Secondhand Smoke on Occupancy of Nicotinic Acetylcholine Receptors in Brain Brody et al. Arch General Psych 2011.

Second Hand Smoke (SHS) Exposure Increases risk of pregnancy complications and affects fetal health Worldwide, 50% of men smoke and particularly in developing countries, there are few proscriptions against smoking in the home Children exposed to SHS have increased risk of: -- Sudden Infant Death Syndrome -- Lower respiratory tract infections -- Ear infections -- Asthma -- Becoming smokers

Women have a harder time quitting… Factors control smoking -- Women are less sensitive to nicotine as a pharmacologic agent -- Women are more sensitive to non-nicotine factors Greater role in women -- stress & negative affect -- depression --weight concerns

The Smoker’s Body Smokers have a 35-45% reduction in MAO B in heart, lungs, kidneys and spleen

Lung cancer risk is 2 x greater in women than in men; women develop lung cancer with less time than men Heart attacks relative risk for smokers vs non-smokers Men: Women: 2.24 As Women Age, the Medical Consequences from Smoking are Greater than for Males Breast cancer risk dose-dependently increases with exposure risk of breast cancer spreading to lungs is 2x than in nonsmokers Breast cancer risk dose-dependently increases with exposure risk of breast cancer spreading to lungs is 2x than in nonsmokers

Throat Lung Kidney Bladder Stomach Leukemia (blood) Mouth Esophagus Larynx (voice box) Pancreas Cervix Smoking Causes Cancer in Organs Throughout the Body

Clinical Implications Less attention to NRTs (except the inhaler) More attention to CBT to deal with the non-nicotine aspects of smoking -- environmental cues, mood Cognitive restructuring regarding risks -- weight gain Non-NRT pharmacotherapies -- bupropion: M=F; F only with CYP2BG polymorphism -- varenicline: M=F -- naltrexone: effective only in F Menstrual cycle