Karen Drexler, M.D.

July 30, 2003


[Slide #1]

I.       Overview (Slide #2)

A.    What is craving?

B.    Why is it so compelling?

C.    How do we measure it?

D.    What are the neural mechanisms that drive craving?

E.     How can we treat it?

II.      What is craving? (Slide #3)

A.    First hand description:

One man with cocaine dependence describes it: “An intense craving for me is when my heart starts beating fast- actually, I get a little sweaty- and all I think about doing is just going to smoke.  That’s it.  Nothing else- everything that’s on my mind just kind of disappears.  First you start thinking about it, then your body almost reproduces the feeling that you get from a high.” (1)

B.    Key features of craving

1.     An intense desire that compels drug-seeking behavior in dependent individuals. 

a)    Halikas- “Craving is to desire what panic is to anxiety” (2)

b)    Not just a thought, physiological symptoms (heart racing, palms sweaty, etc)

2.     Compels drug seeking in dependent individuals- common in dependent individuals, but not in occasional users. (3,4)

(Slide #4)

a)    What do we mean by “dependence”?

b)    DSM-IV defines psychoactive substance dependence as “ a cluster of cognitive, behavioral and physiological symptoms indicating that the individual continues substance use despite significant substance-related problems”. (5)

c)    DSM-IV criteria for diagnosis- 3 or more of the following occurring within the same 12 month period of time

(1)  Tolerance

(2)  Withdrawal

(3)  Substance taken in larger amounts that intended

(4)  Persistent unsuccessful efforts to cut down or control substance use

(5)  A great deal of time spent getting the substance, using it, being intoxicated and/or recovering from its effects

(6)  Important activities given up or reduced in order to continue using the substance

(7)  Continued use despite knowledge of a psychological or physical problem exacerbated by use of the substance

d)    Understanding craving may help us to understand some of the more baffling features of this illness.

(1)  Why do dependent individuals end up using more than they intend?

(2)  Why is it difficult to cut down or control use?

(3)  Why do individuals who have suffered multiple severe problems as a result of substance use relapse after a period of abstinence?

III.     Why is craving so compelling? (Slide #6)

A.    Triggers drug use in dependent individuals.

B.    Craving correlates with drug use in dependent individuals.

1.     Cocaine craving correlates with cocaine use in previous 30 days (6)

2.     Cocaine craving is associated with cocaine use during aftercare- craving doubled during periods of cocaine use and cocaine use was 4 times higher in periods of craving (7) (Slide #7)

3.     Alcohol craving correlates with other measures of alcohol dependence. (8)

C.    Craving decreases with treatment

1.     Cocaine and alcohol craving decrease over 28-days of inpatient rehabilitation (9,10)

2.     Alcoholic patients taking naltrexone have less craving and fewer relapses. (11)

D.    Craving can predict treatment outcome. In general, more recent, outpatient studies using multidimensional craving measures have found a significant relationship.

1.     Persistence of cue-induced cocaine craving predicts relapse (12)

2.     Alcohol craving at week 2 correlates with relapse in weeks 3 – 12. (13) 

3.     Alcohol craving during negative mood states predicts time to relapse (14)

IV.   How do we measure craving? (Slide #8)

A.    Multidimensional scales (Slide #9)

1.     Correlate with treatment outcome. (15)

2.     Measure multiple aspects:

a)    intensity,

b)    frequency,

c)    physical and psychological components

3.     Examples include:

a)    Alcohol-

(1)  The Yale-Brown Obsessive Compulsive Scale modified for heavy drinkers. (3) (16)

(2)  The Obsessive Compulsive Drinking Scale for alcohol dependence. (17) (8)

(3)  The Penn Alcohol Craving Scale (13)

b)    Cocaine-

(1)  The Minnesota Cocaine Craving Scale (2)

(2)  Tiffany Cocaine Craving Questionnaire. (18)

c)    Nicotine-

(1)  Fagerstrom Tolerance Questionnaire (19)

(2)  Fagerstrom Nicotine Dependence Questionnaire (20)

B.    Single variable intensity scales (Slide #10)

1.     Correlate with physiologic measures.

2.     Examples include visual analogue or Likert scales:

V.    What are the neural mechanisms that drive craving? (Slide #11)

A.    Three mechanisms help explain why craving develops in psychoactive substance dependence.  (21) (Slide #12)

1.     Sensitization of motivation for drugs through the mesocorticolimbic dopamine pathway causes urges to use  to become more intense even as tolerance develops to the pleasurable effects of drugs and alcohol. (22) (Slide #13)

a)    Ventral tegmental area (VTA) →

b)    Medial forebrain bundle (MFB) →

c)    Nucleus accumbens (NAcc)

d)    Prefrontal cortex (PFC).

2.     Degradation of inhibitory control mediated by the prefrontal cortex causes urges to become more compelling and irresistable. (23) (24) (Slide #14)

3.     Enhanced stimulus-reward learning involving the amygdala and the nucleus accumbens and medial prefrontal cortex causes urges to become more frequent as more conditioned stimuli become associated with substance use. (25) (26) (27) (28)  (Slide #15)


VI.   Neural correlates of craving in humans (Slide #16)

A.    Confirm these hypotheses- raise others.

B.    Two types of provocation paradigms

1.     Substance-induced craving - cocaine dependence: (Slide #17)

a)    Craving associated with initial use of a substance is thought to drive the loss of control- in DSM-IV “often using more than intended”.

b)    From above hypotheses, one might expect that use of a stimulant might activate the mesolimbic dopamine pathway (increased desire) and deactivate the orbitofrontal cortex (decreased inhibition).

c)    Stimulants (Cocaine and methylphenidate) used to induce craving: (29) (30)  (31,32)

d)    In fact, stimulant injection is primarily associated with activation of ventral striatum and interconnected structures involved in reward processing (mesolimbic pathway), but also areas involved in sensory processing (thalamus), conditioned learning (amygdala), and cognitive control (orbitofrontal cortex (OFC). (33) (34) (35)

(a)  Ventral striatum/ Nucleus accumbens (N Acc) –Reward processing and prediction (29) (30) (31)

(b)  Subcallosal cortex (SCC)- highly connected to N Acc, activation in anticipation of injection then correlates with substance-induced craving (30)

(c)  Orbitofrontal cortex (OFC)- implicated in cognitive control of behavior and OCD- correlates with intensity of subjective craving (31)

(d)  Thalamus- involved in sensory and emotional processing and OCD- correlates with subjective craving (32)

(e)  Amygdala (-/+ correlation)- important in learned associations- fear and reward conditioning- negatively correlates with craving in one study, positive in another (29) (30)

(f)   Hippocampus, and parahippocampal gyrus- important in long-term declarative memory- correlates with craving (29) (Slide #18)

2.     Cue -induced craving (Cue reactivity)

a)    Neural correlates: (Slide #19)

(1)  Widely distributed cortical activations (frontal and prefrontal cortex)

(2)  Less often associated with mesolimbic dopaminergic pathway

b)    Structures include (in order of frequency of reported activation): (Slide #20)

(1)  DLPFC, ACC, OFC, amygdala, temporal cortex, insula, mesolimbic dopaminergic pathway.

(2)  Dorsolateral prefrontal cortex (DLPFC)- (working memory, strategic planning, and cognitive control) (Slide #21) (36)

(a)  One of the two most common activations. (37) (38) (39) (40) (41) (42)

(b)  Activity positively correlates with craving. (37) (43) (38)

(3)  Anterior cingulate cortex (reward processing, performance monitoring, decision-making) (Slide #21, #22 and #23) (44) (45)

(a)  Activated in response to cocaine- and heroin-cues. (38) (39) (46) (43) (47) (41)

(4)  Orbitofrontal cortex (reward processing, response monitoring, inhibition, OCD) (34) (48) (49)

(a)  Activated in response to cocaine- and heroin-cues (37) (50) (40) (41) (51)

(b)  One of second most common activations in response to drug cues.

(c)  Also activated by cocaine infusion.

(5)  Amygdala (learning, stimulus-reward associations) (Slide #23, #24 and #26)

(a)  Activated by cocaine- and alcohol-cues (10) (37) (46) (43) (40)

(b)  One of second most common activations in cue-reactivity.

(c)  Rarely reported in response to drug infusion.

(6)  Anterior temporal pole/ temporal cortex (anger and episodic emotional memory) (Slide #24) (33) (52) (53)

(a)  Activated in cue-induced craving to both cocaine and alcohol. (10) (39) (37)

(b)  Activity positively correlates with subjective craving in cocaine craving. (43)

(7)  Insula (physiological emotional responses, depression, episodic emotional memory) (Slide #25 and #26) (33) (54)

(a)  Activation in response to drug cues for both cocaine and heroin. (39,50) (43) (51)

(8)  Mesocorticolimbic dopaminergic pathway. (Slide #25 and #26)

(a)  Ventral striatum (43)

(b)  Midbrain

(c)  Subcallosal cortex (SCC)

VII.  Implications for Treatment (Slide #28 and #29)

A.    Cognitive Behavioral Therapy

1.     Cue-induced craving involves activation of systems mediating conditioned learning and cognitive control of behavior. 

2.     Psychotherapy techniques that facilitate extinction and cognitive control of behavior may be especially efficacious in preventing relapse in response to conditioned drug and alcohol cues.

B.    Medications

1.     Agonists- Methadone, Nicotine replacement

2.     Others- Naltrexone, Buproprion

VIII. Summary and Clinical significance (Slide #30)

A.    Craving is a key feature of psychoactive substance dependence.  It compels drug seeking behavior and correlates with drug use and treatment outcome in substance dependent individuals.

B.    The neural correlates of craving offer insights into the neural circuitry of psychoactive substance dependence and relapse.

C.    Stimulant injection and stimulant-induced craving are associated with activation of reward circuitry in the brain.

D.    Cue-induced craving is associated with widespread activation of cortical circuits involved in learning, memory, emotion, and cognitive control of behavior.

E.     Treatments that target craving have shown some efficacy in treatment of addiction. Improved understanding of the neural correlates of craving may direct more informed development of medications and psychotherapy interventions for addiction treatment.






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