overview of presentation research assessing neuroendocrine & subjective stress system changes in...
DESCRIPTION
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-pointTRANSCRIPT
Stress system adaptations in cocaine & alcohol dependent individuals: possible
implications for novel psychoactive drugs2nd International Conference on Novel Psychoactive
Substances
Helen Fox, PhDDept. of Psychiatry
Yale University School of Medicine
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
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
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
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)
Time to Relapse (Days)0 20 40 60 80 100
% P
ropo
rtio
n su
rviv
ing
0.0
0.2
0.4
0.6
0.8
1.0
0.00.20.6 MEAN1.01.41.8
(х² =7.38; P = .007; hazard ratio = 2.12; 95% CI, 1.23-3.63)
10%
50%
Time to Relapse (Days)
0 20 40 60 80 100
% P
ropo
rtio
n su
rviv
ing
0.0
0.2
0.4
0.6
0.8
1.0
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)
0.00.10.5 MEAN1.01.52.0
(х² = 5.37; P = .02; hazard ratio = 1.62)
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 agentsii) To assess whether co-abuse of these drugs potentiate
stress system changes in cocaine and alcohol dependent individuals
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).
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
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
Bas
elin
e C
ortis
ol/A
CTH
ratio
0.0
0.2
0.4
0.6
0.8
1.0Cocaine DependentCocaine Dependent + Cathinones
Day 1
Day 1
Day 2
Day 3
Day 2
Day 3
Plasma Cortisol to ACTH ratios
Cocaine sample from Fox et al., 2008
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
baselineImagery R1 R2 R3 R4 R5 R6
Anx
iety
0
2
4
6
8
baselineImagery R1 R2 R3 R4 R5 R6
Anx
iety
0
1
2
3
4
5
6
7
8
baselineImagery R1 R2 R3 R4 R5 R6
Anx
iety
0
2
4
6
8
baselineImagery R1 R2 R3 R4 R5 R6
Anx
iety
0
2
4
6
8
NEGATIVE EMOTION RESPONSE TO STRESS
In social drinkers
In alcohol dependents
In alcohol & marijuana dependents
In alcohol & K2 dependents
baselineImagery R1 R2 R3 R4 R5 R6
Neg
ativ
e em
otio
n
20
30
40
50
60
70
baselineImagery R1 R2 R3 R4 R5 R6
Neg
ativ
e em
otio
n
10
20
30
40
50
60
70
baselineImagery R1 R2 R3 R4 R5 R6
Nea
gtiv
e em
otio
n
20
30
40
50
60
70
baselineImagery R1 R2 R3 R4 R5 R6
Neg
ativ
e em
otio
n
20
30
40
50
60
70
baselineImagery R1 R2 R3 R4 R5 R6
Alc
ohol
Cra
ving
0
2
4
6
8
10
12
baselineImagery R1 R2 R3 R4 R5 R6
Alc
ohol
Cra
ving
0
2
4
6
8
10
12
baselineImagery R1 R2 R3 R4 R5 R6
Alc
ohol
Cra
ving
0
2
4
6
8
10
12
baselineImagery R1 R2 R3 R4 R5 R6
Alc
ohol
cra
ving
0
2
4
6
8
10
12
ALCOHOL CRAVING RESPONSE TO STRESS
In social drinkers
In alcohol dependents
In alcohol & marijuana dependents
In alcohol & K2 dependents
NICOTINE CRAVING RESPONSE TO STRESS
In social drinkers
In alcohol dependents
In alcohol & marijuana dependents
In alcohol & K2 dependents
baselineImagery R1 R2 R3 R4 R5 R6
nico
tine
crav
ing
0
2
4
6
8
10
baselineImagery R1 R2 R3 R4 R5 R6
Nic
otin
e C
ravi
ng
0
2
4
6
8
10
baselineImagery R1 R2 R3 R4 R5 R6
Nic
otin
e C
ravi
ng
0
2
4
6
8
10
baselineImagery R1 R2 R3 R4 R5 R6
Nic
otin
e C
ravi
ng
0
2
4
6
8
10
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