1. The Pathophysiology and Clinical Course of Nicotine Addiction Joseph R DiFranza MD University of Massachusetts Medical School

2. Nicotine Addiction- Case histories We asked smokers what does it feel like to need a cigarette?

3. Wanting “Wanting” is the first symptom of nicotine withdrawal. Wanting is a mild transient desire to smoke that is easily ignored.

4. Craving Craving is more intense than wanting and intrudes upon the person’s thoughts. It is more persistent and difficult to ignore. “I feel like someone inside of me is really telling me to smoke.”

5. Craving Craving a cigarette “just, like, pops in your head, like someone is sending you a message.” Craving is like “being hungry, but instead of your stomach saying it, it’s your brain…it’s just hungry, except for a cigarette.”

6. Needing Needing is an intense and urgent desire to smoke that is impossible to ignore. The individual must smoke to restore a normal mental or physical state. “You really want one. You know you need it. You know you’ll feel normal after smoking, and you have to smoke to feel normal again.” “Pretty urgent… you need it and you can’t get your mind off it.”

7. Withdrawal recurs after each cigarette Wanting then Craving then Needing

8. Addiction develops in the same sequence in all smokers No withdrawal symptoms Wanting Wanting and Craving Wanting, Craving and Needing

9. Clinical Staging of Nicotine Addiction Stage 1. Can remain abstinent indefinitely without withdrawal symptoms Stage 2. Wanting “If I go too long without smoking, the first thing I will notice is a mild desire to smoke that I can ignore.” Stage 3. Craving “If I go too long without smoking, the desire for a cigarette becomes so strong that it is hard to ignore and it interrupts my thinking.” Stage 4. Needing “If I go too long without smoking, I just can’t function right, and I know I will have to smoke just to feel normal again.”

13. The Latency to Withdrawal “A little light bulb goes off and it’s like, alright, time [to smoke].” The latency is the interval between smoking one cigarette and wanting, craving, or needing another. Latency-to-wanting Latency-to-craving Latency-to-needing

14. The Latency to Withdrawal At the onset of addiction the latency-to-wanting may be longer than a month. Repeated tobacco use causes the latencies to shrink. The shortening of the latency drives the escalation in smoking.

15. The Latency to Withdrawal After smoking for 6 weeks, a 16-year-old girl noticed a latency-to-craving of 2 days which shortened to 4 hours by age 16 1/2, …to 2 hours by age 17, …to 1.5 hours by age 18, …to 1 hour by age 19, …and to 30-45 minutes by age 21.

16. The Latency to Withdrawal-Factors of 2 1) 1 week (1 cig/wk) 2) 3.5 days (2 cig/wk) 3) 42 hours 4) 21 hours 5) 11.5 hours 6) 5.6 hours 7) 2.8 hours 8) 1.4 hours 9) 42 minutes (1 ppd) 10) 21 minutes (2 ppd) In adolescents, smoking 2 cigs/wk increases the risk for heavy adult smoking 174 fold.

17. Smokers have Latencies of days or weeks With a half life of 2 hours, how can nicotine have such a prolonged impact?

18. The neuroscience shows… One dose of nicotine increases noradrenaline synthesis in the hippocampus for at least a month. One dose lowers neural activation thresholds for a month. One dose affects tyrosine hydroxylase activity for a month. One dose in adolescent rats affects behavior during adulthood.

19. The neuroscience shows… Nicotine changes the transcription of hundreds of genes in the brain. Nicotine triggers a series of events that cannot be stopped by removing it.

20. What could change in the brain that would cause addiction after one dose?

21. Homeostasis The brain seeks balance.

22. Homeostasis Nicotine disturbs the balance.

23. Homeostasis The brain compensates to regain balance.

24. Homeostasis Without nicotine the brain is disturbed.

25. Insular cortex activity during withdrawal – “A little light bulb goes off, time to smoke.” Nonsmokers Smokers

26. Homeostasis Nicotine is needed to restore balance.

27. Homeostasis Craving occurs whenever the effect of nicotine wears off.

28. Homeostasis Now you have to smoke just to feel normal.

29. Homeostasis The Latency to Withdrawal determines how long it is before the effect of each dose of nicotine wears off.

30. The Latency to Withdrawal

33. Do the Stages of Nicotine Addiction coincide with actual physical changes in the brain?

34. Fractional Anisotropy is an MRI measure of structural complexity. Low FA High FA

35. Our data show smokers have higher FA than nonsmokers in the dorsal anterior cingulate bundle (p=0.05).

36. Smoking during adolescence increases FA. Smokers generally have higher FA than nonsmokers. Yet FA decreases as addiction increases. FA correlates inversely with the FTND score: r = -.52, r = -.58, and r = -.64.

39. FA decreases with advancing Stage of Addiction: r= -.85 FA decreases with advancing addiction as measured by the Hooked on Nicotine Checklist : r = -.96

40. The dorsal anterior cingulate gyrus- the location of maximal correlation between FA and Stage of Addiction (top), and FA and FTND (bottom)

41. The dorsal anterior cingulate gyrus- The location of maximum correlation between FA and HONC

42. Interpretation Increasing FA in new smokers represents the adaptations that cause wanting, craving and needing. Decreasing FA in adult smokers represents the adaptations that cause the Latency to Withdrawal to grow shorter.

43. Smokers have more structural connection between the dorsal anterior cingulate and the prefrontal cortex than nonsmokers.

44. Structural connectivity increases between the dorsal anterior cingulate and prefrontal cortex with advancing Stage of Addiction.

45. During withdrawal the anterior cingulate shows greater functional connectivity with… Superior medial frontal cortex Inferior parietal Precuneus Middle Cingulate Middle temporal

46. Correlations between Functional Connectivity and Withdrawal Craving Correlated Circuitry Peak Correlation Coefficient ACC - Superior Frontal0.74 ACC - R Precuneus0.76 ACC - L Precuneus0.75 ACC - L Putamen0.77 ACC - Inf. Parietal0.77

47. Summary Advancing stages of addiction are associated with decreased organizational complexity in the anterior cingulate white matter and increased structural connectivity between it and the frontal cortex. These structural changes appear to be involved with craving as withdrawal craving correlates well with activity in this circuit.

48. How quickly does addiction develop?

49. Endorsement of HONC symptoms of addiction by 10th Year NZ Youth

50. The clinical data indicate that… One cigarette must rapidly change the brain.

51. The neuroscience shows… The nicotine from one cigarette occupies 88% of the brain’s nicotinic receptors. One dose stimulates an increase in the number of brain nicotine receptors over night. One dose initiates drug sensitization.

53. 5% 4% 3% 2% 1% 0 -1% -2% -3% -4% -5% B C 1 PFC 2 Acg 3 Acc 4 VP 5 HP 6 VTA 7 VC 3 3 4 1 6 A 4 6 5 5 5 77 7 2 2 2

54. Conclusion Nicotine hard-wires addiction into the brain. This process begins with the first cigarette. Addiction develops through 4 stages. The shortening of the latency to withdrawal drives the progression to daily smoking.

55. Is addiction reversible? If the brain erases all trace of the addiction, after a long abstinence, people should again have the very long latencies of novice smokers.

56. How much do people need to smoke after a relapse? The latency doubles in length over three months. After that it barely changes.

57. The neuroscience shows… New adaptations develop in the brains of rats weeks after nicotine is stopped. In humans, smoking cessation triggers an increase in nerve growth factor.

58. Recommended reading A sensitization-homeostasis model of nicotine craving, withdrawal, and tolerance: Integrating the clinical and basic science literature. DiFranza and Wellman. Nicotine & Tobacco Research. 2005; vol 7: 9-26. The natural history and diagnosis of nicotine addiction. DiFranza et al. Current Pediatric Reviews, 2011; vol 7: 88-96.