2. OVERVIEW OF PRESENTATION Research assessing neuroendocrine & subjective stress system changes in substance abusers The importance of these stress system adaptations in terms of predicting outcome Why it may be important to assess similar emotional & biological adaptations in a) cocaine dependent individuals also using cathinone-derivative drugs, and b) alcoholics using spice / K2

3. Stress System Adaptations Robust stress system adaptations observed in all drugs of abuse (Fox & Sinha for review) “Shift” in hedonic / reward set-point underlies the acquisition of dependence (Koob & Le Moal, 1997, 2001) Research objectives in the last decade have been to elucidate some of the endocrine, biophysiological & emotional mechanisms characterizing this “shift” in set-point

4.  EMOTIONAL: Sensitized anxiety & negative affect response to stress in both alcohol &cocaine dependent individuals (Fox et al., 2007; 2008)  HPA / AUTONOMIC: BASAL elevation of cortisol, NE & blood pressure (Fox et al., 2006; Sinha et al., 2009)  PHASIC response to stress suppressed in alcoholics & up-regulated in cocaine dependent individuals (Fox et al., 2009; Sinha et al.,2009)  Stress-related cortisol associated with relapse in 50 Cocaine dependent individuals (Sinha and Fox et al., 2006)  Elevated Cortisol / ACTH ratios at resting state & following stress are predictive of shorter time to alcohol relapse in 93 alcoholics (Sinha and Fox et al., 2011) Stress system changes in early abstinent cocaine & alcohol dependent individuals ELEVATED CRAVING RELAPSE FACTORS RISK OF DEPENDENCE

5. Time to alcohol relapse: Estimated survival functions Mean value of Resting Cortisol/ACTH ratio as well as +1 +2 +3, -1, -2 SDs above & below the mean (Sinha and Fox et al., 2011) 0.0 0.2 0.6 MEAN 1.0 1.4 1.8 ( х² =7.38; P =.007; hazard ratio = 2.12; 95% CI, 1.23-3.63) 10% 50%

6. Time to alcohol relapse: Estimated survival functions Mean value of stress-induced Cortisol / ACTH ratio as well as +1 +2 +3, -1, -2 SDs above & below the mean (Sinha and Fox et al., 2011) 0.0 0.1 0.5 MEAN 1.0 1.5 2.0 ( х² = 5.37; P =.02; hazard ratio = 1.62)

7. Plans for future research  Cocaine dependent individuals - cathonine - Derivatives (bath salts; plant food; Mkat)  Alcohol dependent individuals – spice; K2  Aims:  i) To elucidate stress system changes in individuals chronically using new synthetic agents  ii) To assess whether co-abuse of these drugs potentiate stress system changes in cocaine and alcohol dependent individuals

8. Positive & Negative Reinforcing Effects Addiction Potential Targets Stress Systems  Rats administer mephedrone, methylone & synthetic marijuana over saline (Aarde et al., 2013; Shortall et al., 2013)  Mephedrone & synthetic marijuana potentiate responding for ICSS in a dose-dependent manner (Robinson et al., 2012)  Spice results in tolerance, withdrawal & dependence (Zimmerman et al., 2009)  In 100 mephedrone users 30% met criteria for dependence (Winstock et al., 2011).  Case studies of sympathomimetic toxicity, CNE hyper-stimulation & cardiovascular compromise in both K2 & cathinone-derivatives (Gunderson et al., 2012; Heath et al., 2012)  Khat & cathinones associated with changes in cortisol levels (Islam et al., 1990; Mohammed & Engidawork, 2011)  Endocannabinoid system regulates the HPA axis (Fox et al. 2013; Wade et al., 2006).

9. Future objectives…  To assess subjective and neuroendocrine changes to the stress system in: i) cocaine dependent individuals abusing synthetic cathinone derivatives, and ii) alcoholics abusing synthetic marijuana  To examine whether these adaptations are associated in increased craving for these agents as well as for other drugs of abuse  To examine whether these adaptations are associated with relapse factors

10. Paradigm…  To assess basal stress system adaptations  To assess phasic stress system adaptations following exposure to a personalized guided imagery (stress and relaxing)  Recent event (in the past year)  Has to be described as “stressful” on a VAS of 1 to 10  Inclusion of interoceptive / visceral information

11. Day 1 Day 2Day 3Day 2Day 3 Plasma Cortisol to ACTH ratios Cocaine sample from Fox et al., 2008

12. ANXIETY RESPONSE TO STRESS In social drinkers (Sinha et al.,2009) In alcohol dependents (Sinha et al.,2009) In alcohol & marijuana dependents (Fox et al., 2013) In alcohol & K2 dependents

13. NEGATIVE EMOTION RESPONSE TO STRESS In social drinkers In alcohol dependents In alcohol & marijuana dependentsIn alcohol & K2 dependents

14. ALCOHOL CRAVING RESPONSE TO STRESS In social drinkers In alcohol dependents In alcohol & marijuana dependents In alcohol & K2 dependents

15. NICOTINE CRAVING RESPONSE TO STRESS In social drinkers In alcohol dependents In alcohol & marijuana dependentsIn alcohol & K2 dependents

16. Summary…  Subjective, autonomic & biophysiological markers of stress system dysregulation predict stress-related craving and relapse  As NPS may have abuse potential and target the stress systems it may be important to assess some of these markers in dependent individuals who also chronically use these new agents compared with those who do not  May help define stress-related outcome targets in NPS as well as evidence of cross-sensitization in terms of craving and relapse