1. Stress and Drinking: What is the Link? RSA Education Lecture Series June 2006 Lecturer: Rajita Sinha, Ph.D. Section Editor: Suzanne Thomas, Ph.D.

2. What Motivates People to Drink and Use Drugs? Social: to celebrate; social demand Coping: To relax; forget worries/ reduce stress; cope with bad mood/ anxiety Enhancement: Like the feeling; feel good/high; Exciting/fun risk of addiction drinking or drug use Cooper, Russell et al., Psychological Ass. 1992

3. Laboratory Studies on Stress and Drinking in College Students Exposure to Stress Increased Alcohol Drinking Stress of interpersonal evaluation Parental conflict situations Difficult or insoluble tasks Public Speaking Marlatt & Higgins, 1975; Marlatt et al., 1975; Tucker et al.,1981; Lang et al., 1989

4. ALL RIGHTS RESERVED: http://www.cartoonbank.com Environmental Cues Promote Drinking

5. What is Stress? Any event or stimulus that is a challenge, a threat or seen as harmful will produce a stress response. It may be a physical, mental/cognitive or emotional stimulus (negative mood or emotional distress). Stress results in changes in multiple response systems. –Verbal and non-verbal/behavioral expression of distress –Physiological/ cardiovascular –Hormonal and immune system responses –Behavioral/Cognitive Coping Responses Sinha R, Psychopharmacology, 2001

6. Types of Stress Acute Stress: an unexpected or novel stimuli lasting a short time: Examples include a car accident, a verbal altercation, a math problem. Important for adaptation and can be considered “good” stress Chronic Stress: –Early trauma experiences (prior to the age of 18) – physical, sexual or emotional abuse; –Chronic adult stressors – e.g., taking care of a sick parent/relative; domestic violence, unemployment Increased risk of stress related illnesses Compulsive drug use as a chronic stress state

7. How does stress promote drinking? Stress and drug itself activate the same neurobiological systems (e.g., stress hormones and reward chemicals-dopamine) By activating these systems, stress may increase the reinforcing effects of drugs. Chronic use of alcohol acts as a stressor that alters brain stress and reward pathways which in turn may increase sensitivity to stress and alcohol seeking or “craving”.

8. Stress and Alcoholism: Bidirectional Relationship Increased Drinking in Vulnerable Individuals Increased Distress (and craving) Changes in Brain Stress and Pleasure Pathways Adapted from Sinha, 2001, Breese et al., 2005 Chronic alcohol Repeated Withdrawal

9. Criteria for Substance Dependence (DSM-IV) Koob GF and Le Moal M, Science, 1997

10. Stress and Alcohol Abuse: Clinical Observations Alcohol dependence is a chronic relapsing disorder. Research has shown that more than two thirds of individuals relapse within months of initiating treatment. Although drug itself is a potent stimulus for relapse, environmental stimuli such as stressors and alcohol/drug cues are known to increase the risk of alcohol relapse.

11. Alterations Associated with Drug Withdrawal (Acute – up to 72 hours) Behavioral/Mood Changes Irritability/restlessness Depressed/anxious mood Eating and sleep changes High drug craving Loss of interest in natural rewards Attention/concentration problems Altered Neurobiology Overactive systems: –CRF –NE Under-active systems: –Dopamine –GABA –Some evidence for NPY and 5HT Adapted from Sinha, 2001; 2005

12. Alterations Associated with Protracted Alcohol Abstinence – weeks to months Behavioral/Mood Changes Alcohol Craving – reactivity to alcohol related stimuli Altered stress responses Sleep problems Negative mood symptoms Cognitive Problems Altered Neurobiology Alterations in HPA axis response Noradrenergic dysregulation Decreased activity of Dopamine receptors Decreased responsiveness of the frontal cortex Lower functioning of GABA system Adapted from Sinha, 2001; 2005

13. Stressors Leading to Increased Craving and Drug Use: Patient AG Video presentation

14. Stress and Cue-Induced Alcohol Craving in Abstinent Alcoholics STRESSALCOHOL CUE NEUTRAL Group Difference: F{1,55}= 81.13, p HC in S and Cue Response, p<.0001) Group X Condition: F{2,110}=12.07, p<.0001 Group X Timepoints: F{7,385}=3.95, p<.0004 Sinha et al., 2005

15. Stress and Cue-Induced Anxiety in Abstinent Alcoholics STRESSALCOHOL CUE NEUTRAL Group Difference: F{1,55}= 82.5, p HC in S and Cue Response, p HC (p<.007) Group X Condition: F{2,110}= 5.01, p<.008 (no increase in anxiety in cue condition for controls but greater increases in anxiety in AD subjects in all three conditions) Sinha et al., 2005

16. Stress and Cue-Induced Heart Rate Response Abstinent Alcoholics STRESS ALCOHOL CUE NEUTRAL Group Difference: AD > HC, p<.001 Group X Condition: F{2,110}=6.02, p<.003 Sinha et al., 2005

17. Altered Stress-Induced ACTH and Cortisol Responses in Abstinent Alcoholics (AD) Junghanns et al., 2003; Sinha et al., unpublished AD > Controls (p<.05) AD < Controls (p<.05)

18. Summary Enhanced sensitivity to distress and alcohol craving in 4-week abstinent alcohol dependent patients marked by: –Increased alcohol craving, anxiety and negative emotions –Dysregulated cardiovascular responses and ACTH responses –Suppressed cortisol responses

19. Cue-Induced Craving Produces a Stress Response: Patient DD Video presentation

20. Is stress and alcohol/drug cue-induced craving and stress responses associated with higher likelihood of relapse?

21. Negative Mood-Induced Alcohol Craving Predicts Time to First Drink After Inpatient Treatment Cooney et al. (1997). Journal of Abnormal Psychology,106, 243-250.

22. Stress Induced Cocaine Craving and Time to Cocaine Relapse Greater the stress-induced cocaine craving, shorter the time to relapse after treatment (Cox PH Regression Model: X 2 =5.58, p<.02; HR: 1.31). Sinha et al., Archives of General Psychiatry, 2006

23. R 2 =.20, t=3.48, p<.001 Stress-Induced Alcohol Craving Predicts Frequency of Drinking Following Discharge r =.44, p<.001 Findings presented in Breese et al., 2005

24. Stress Induced ACTH Response Predicts Amount of Cocaine Used Per Occasion After Discharge F=10.34, p<.002; R 2 =.19 Group Main Effect: F{1,47}=13.03, p<.0007 r =.44, p<.002 Sinha et al., Archives of General Psychiatry, 2006

25. Relapsing Alcoholics Show Decreased Stress- Induced Cortisol Responses Junghanns et al., 2003 * p<.05

26. Brain Activation During Exposure to Alcohol-Related Cues and During Emotional Stress

27. Brain Activity in Stress and Reward Regions During Alcohol-Related Cue Exposure In Abstinent Alcoholics Heinz et al., American Journal of Psychiatry, 2004; Grusser et al., Psychopharmacology, 2004

28. y = 30.6 mm y = 4.3 mm y = -4 mm y = -12 mm Patients Controls Pts – Ctrls (p<.01) Decreased Frontal Activation But Increased Striatal- Thalamic Activity During Stress in Cocaine-Alcoholics RL Sinha et al., Psychopharmacology 2005 Increased Activity p<.001 Decreased Activity p<.001 p<.01

29. Stress-induced Drug Craving Correlates with the Caudate/Dorsal Striatum Region (p<.005) y = -4 mm y = -12 mm RL Positive Correlation p<.005 p<.01 Sinha et al., Psychopharmacology 2005

30. Summary The Stress-induced and alcohol cue induced craving state is associated with the following neural activity: –Decreased activity in prefrontal executive control/regulation related regions, suggesting a decreased ability to self-regulate/control distress states. –Increased activity in dorsal striatum (caudate, putamen) associated with stress-induced and cue- induced drug/alcohol craving, regions that drive reward-related and automatic, habit-based repetitive behaviors.

31. Treatment Strategies to Reduce Craving and Normalize Stress Regulation PHARMACOLOGICAL STRATEGIES: CRF Antagonists GABAergic Agents (Baclofen; Topiramate) Noradrenergic Agents (Alpha – 2 Adrenergic Agonists - Lofexidine, Guanfacine, Prazocin) Cannabinoid agents ? Agents targeting the NPY system ?

32. Stress Management is a Key Component of Efficacious Behavioral Treatments for Alcoholism Cognitive Behavioral Treatment Focuses on Stress Management training –Cognitive restructuring, problem solving skills 12-Step Facilitation Targets Increase social support –AA, NA or other peer support programs –Enlist family and friends –Case management services - housing, employment, medical care

33. Whether an individual will abuse alcohol in response to stress depends on: Genetic determinants Belief that using will reduce stress Intensity of the alcohol craving and stressor Sense of control over the stressor Range of coping resources Availability of social support

34. THE END…. Stress increases risk of developing alcohol abuse and also the risk of alcohol relapse. Brain stress and reward pathways are altered with chronic stress and chronic alcohol abuse, changes that appear to facilitate responses to emotional stress and alcohol related stimuli in the environment. These factors confer some unique risk in the addictive process. Alcoholism treatment outcomes could benefit from targeting stress and alcohol cue-induced craving and related responses that increase motivation to drink and risk of relapse.