Karen Drexler, M.D.
July 30, 2003
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)
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
(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:
c) physical and psychological components
3. Examples include:
(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)
(1) The Minnesota Cocaine Craving Scale (2)
(2) Tiffany Cocaine Craving Questionnaire. (18)
(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)
(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.
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.
1. Hyman, S.E., A 28-year-old man addicted to cocaine. JAMA, 2001. 286(20): p. 2586-2593.
2. Halikas, J.A., K.L. Kuhn, R. Crosby, G. Carlson, and F. Crea, The measurement of craving in cocaine patients using the Minnesota Cocaine Craving Scale. Compr Psychiatry, 1991. 32(1): p. 22-7.
3. Modell, J.G., F.B. Glaser, L. Cyr, and J.M. Mountz, Obsessive and compulsive characteristics of craving for alcohol in alcohol abuse and dependence. Alcohol Clin Exp Res, 1992. 16(2): p. 272-4.
4. Regier, D.A., M.E. Farmer, D.S. Rae, et al., One-month prevalence of mental disorders in the United States and sociodemographic characteristics: the Epidemiologic Catchment Area study. Acta Psychiatr Scand, 1993. 88(1): p. 35-47.
5. APA, Diagnostic and Statistical Manual of Mental Disorders. 4th ed. 1994, Washington, DC: American Psychiatric Association.
6. Kranzler, H.R. and D.J. Wallington, Serum prolactin level, craving, and early discharge from treatment in cocaine-dependent patients. Am J Drug Alcohol Abuse, 1992. 18(2): p. 187-95.
7. Robbins, S.J. and R.N. Ehrman, Cocaine use is associated with increased craving in outpatient cocaine abusers. Exp Clin Psychopharmacol, 1998. 6(2): p. 217-24.
8. Moak, D.H., R.F. Anton and P.K. Latham, Further validation of the Obsessive-Compulsive Drinking Scale (OCDS). Relationship to alcoholism severity. Am J Addict, 1998. 7(1): p. 14-23.
9. Weddington, W.W., B.S. Brown, C.A. Haertzen, et al., Changes in mood, craving, and sleep during short-term abstinence reported by male cocaine addicts. A controlled, residential study. Arch Gen Psychiatry, 1990. 47(9): p. 861-8.
10. Schneider, F., U. Habel, M. Wagner, et al., Subcortical correlates of craving in recently abstinent alcoholic patients. Am J Psychiatry, 2001. 158(7): p. 1075-83.
11. Volpicelli, J.R., A.I. Alterman, M. Hayashida, and C.P. O'Brien, Naltrexone in the treatment of alcohol dependence. Arch Gen Psychiatry, 1992. 49(11): p. 876-80.
12. Margolin, A., S.K. Avants and T.R. Kosten, Cue-elicited cocaine craving and autogenic relaxation. Association with treatment outcome. J Subst Abuse Treat, 1994. 11(6): p. 549-52.
13. Flannery, B.A., J.R. Volpicelli and H.M. Pettinati, Psychometric properties of the Penn Alcohol Craving Scale. Alcohol Clin Exp Res, 1999. 23(8): p. 1289-95.
14. Cooney, N.L., M.D. Litt, P.A. Morse, L.O. Bauer, and L. Gaupp, Alcohol cue reactivity, negative-mood reactivity, and relapse in treated alcoholic men. J Abnorm Psychol, 1997. 106(2): p. 243-250.
15. Sinha, R. and S. O'Malley, Craving for alcohol: finding from the clinic and the laboratory. Alcohol & Alcoholism, 1999. 34(2): p. 223-230.
16. Modell, J.G., F.B. Glaser, J.M. Mountz, S. Schmaltz, and L. Cyr, Obsessive and compulsive characteristics of alcohol abuse and dependence: quantification by a newly developed questionnaire. Alcohol Clin Exp Res, 1992. 16(2): p. 266-71.
17. Anton, R.F., D.H. Moak and P.K. Latham, The obsessive compulsive drinking scale: A new method of assessing outcome in alcoholism treatment studies. Arch Gen Psychiatry, 1996. 53(3): p. 225-31.
18. Tiffany, S.T., E. Singleton, C.A. Haertzen, and J.E. Henningfield, The development of a cocaine craving questionnaire. Drug Alcohol Depend, 1993. 34(1): p. 19-28.
19. Fagerstrom, K.O. and N.G. Schneider, Measuring nicotine dependence: a review of the Fagerstrom Tolerance Questionnaire. J Behav Med, 1989. 12(2): p. 159-82.
20. Heatherton, T.F., L.T. Kozlowski, R.C. Frecker, and K.O. Fagerstrom, The Fagerstrom Test for Nicotine Dependence: a revision of the Fagerstrom Tolerance Questionnaire. Br J Addict, 1991. 86(9): p. 1119-27.
21. Jentsch, J.D. and J.R. Taylor, Impulsivity resulting from frontostriatal dysfunction in drug abuse: implications for the control of behavior by reward-related stimuli. Psychopharmacology (Berl), 1999. 146(4): p. 373-90.
22. Robinson, T.E. and K.C. Berridge, The neural basis of drug craving: an incentive-sensitization theory of addiction. Brain Research Reviews, 1993. 18: p. 247-291.
23. Roberts, A.C. and J.D. Wallis, Inhibitory control and affective processing in the prefrontal cortex: neuropsychological studies in the common marmoset. Cereb Cortex, 2000. 10(3): p. 252-62.
24. Jentsch, J.D., P. Olausson, R. De La Garza, 2nd, and J.R. Taylor, Impairments of reversal learning and response perseveration after repeated, intermittent cocaine administrations to monkeys. Neuropsychopharmacology, 2002. 26(2): p. 183-90.
25. Spanagel, R. and F. Weiss, The dopamine hypothesis of reward: past and current status. Trends Neurosci, 1999. 22(11): p. 521-527.
26. Campeau, S. and M. Davis, Involvement of the central nucleus and basolateral complex of the amygdala in fear conditioning measured with fear-potentiated startle in rats trained concurrently with auditory and visual conditioned stimuli. J Neurosci, 1995. 15(3 Pt 2): p. 2301-11.
27. Davis, M. and P.J. Whalen, The amygdala: vigilance and emotion. Mol Psychiatry, 2001. 6(1): p. 13-34.
28. Harmer, C.J., P.K. Hitchcott, S.L. Morutto, and G.D. Phillips, Repeated d-amphetamine enhances stimulated mesoamygdaloid dopamine transmission. Psychopharmacology (Berl), 1997. 132(3): p. 247-54.
29. Breiter, H.C., R.L. Gollub, R.M. Weisskoff, et al., Acute effects of cocaine on human brain activity and emotion. Neuron, 1997. 19(3): p. 591-611.
30. Breiter, H.C. and B.R. Rosen, Functional magnetic resonance imaging of brain reward circuitry in the human. Ann N Y Acad Sci, 1999. 877: p. 523-47.
31. Volkow, N.D., G.J. Wang, J.S. Fowler, et al., Association of methylphenidate-induced craving with changes in right striato-orbitofrontal metabolism in cocaine abusers: implications in addiction. Am J Psychiatry, 1999. 156(1): p. 19-26.
32. Volkow, N.D., G.J. Wang, J.S. Fowler, et al., Decreased striatal dopaminergic responsiveness in detoxified cocaine-dependent subjects. Nature, 1997. 386: p. 830-833.
33. Fink, G.R., H.J. Markowitsch, M. Reinkemeier, et al., Cerebral representation of one's own past: neural networks involved in autobiographical memory. J Neurosci, 1996. 16(13): p. 4275-82.
34. Rauch, S.L., M.A. Jenike, N.M. Alpert, et al., Regional cerebral blood flow measured during symptom provocation in obsessive-compulsive disorder using oxygen 15-labeled carbon dioxide and positron emission tomography. Arch Gen Psychiatry, 1994. 51(1): p. 62-70.
35. Modell, J.G., J.M. Mountz, G.C. Curtis, and J.F. Greden, Neurophysiologic dysfunction in basal ganglia/limbic striatal and thalamocortical circuits as a pathogenetic mechanism of obsessive- compulsive disorder. J Neuropsychiatry Clin Neurosci, 1989. 1(1): p. 27-36.
36. Miller, E.K. and J.D. Cohen, An integrative theory of prefrontal cortex function. Annu Rev Neurosci, 2001. 24: p. 167-202.
37. Grant, S., E.D. London, D.B. Newlin, et al., Activation of memory circuits during cue-elicited cocaine craving. Proc Natl Acad Sci U S A, 1996. 93(21): p. 12040-5.
38. Maas, L.C., S.E. Lukas, M.J. Kaufman, et al., Functional magnetic resonance imaging of human brain activation during cue-induced cocaine craving. Am J Psychiatry, 1998. 155(1): p. 124-6.
39. Garavan, H., J. Pankiewicz, A. Bloom, et al., Cue-induced cocaine craving: Neuroanatomical specificity for drug users and drug stimuli. Am J Psychiatry, 2000. 157(11): p. 1789-1798.
40. Bonson, K.R., S.J. Grant, C.S. Contoreggi, et al., Neural systems and cue-induced cocaine craving. Neuropsychopharmacology, 2002. 26(3): p. 376-86.
41. Daglish, M.R., A. Weinstein, A.L. Malizia, et al., Changes in regional cerebral blood flow elicited by craving memories in abstinent opiate-dependent subjects. Am J Psychiatry, 2001. 158(10): p. 1680-6.
42. George, M.S., R.F. Anton, C. Bloomer, et al., Activation of prefrontal cortex and anterior thalamus in alcoholic subjects on exposure to alcohol-specific cues. Arch Gen Psychiatry, 2001. 58(4): p. 345-52.
43. Kilts, C.D., J.B. Schweitzer, C.K. Quinn, et al., Neural activity related to drug craving in cocaine addiction. Arch Gen Psychiatry, 2001. 58(4): p. 334-341.
44. Carter, C.S., A.M. Macdonald, M. Botvinick, et al., Parsing executive processes: strategic vs. evaluative functions of the anterior cingulate cortex. Proc Natl Acad Sci U S A, 2000. 97(4): p. 1944-8.
45. Elliott, R., K.J. Friston and R.J. Dolan, Dissociable neural responses in human reward systems. J Neurosci, 2000. 20(16): p. 6159-65.
46. Childress, A.R., P.D. Mozley, W. McElgin, et al., Limbic activation during cue-induced cocaine craving. Am J Psychiatry, 1999. 156(1): p. 11-18.
47. Wexler, B.E., C.H. Gottschalk, R.K. Fulbright, et al., Functional magnetic resonance imaging of cocaine craving. American Journal of Psychiatry, 2001. 158(1): p. 86-95.
48. Berns, G.S., S.M. McClure, G. Pagnoni, and P.R. Montague, Predictability modulates human brain response to reward. J Neurosci, 2001. 21(8): p. 2793-8.
49. Casey, B.J., R.J. Trainor, J.L. Orendi, et al., A developmental functional MRI study of prefrontal activation during performance of a go-no-go task. J Cognit Neurosci, 1997. 9(6): p. 835-847.
50. Sell, L.A., J.S. Morris, J. Bearn, et al., Neural responses associated with cue evoked emotional states and heroin in opiate addicts. Drug Alcohol Depend, 2000. 60: p. 207-216.
51. Wang, G.J., N.D. Volkow, J.S. Fowler, et al., Regional brain metabolic activation during craving elicited by recall of previous drug experiences. Life Sci, 1999. 64(9): p. 775-84.
52. Dougherty, D.D., L.M. Shin, N.M. Alpert, et al., Anger in healthy men: a PET study using script-driven imagery. Biol Psychiatry, 1999. 46(4): p. 466-72.
53. Kimbrell, T.A., M.S. George, P.I. Parekh, et al., Regional brain activity during transient self-induced anxiety and anger in healthy adults. Biol Psychiatry, 1999. 46(4): p. 454-65.
54. Mayberg, H.S., M. Liotti, S.K. Brannan, et al., Reciprocal limbic-cortical function and negative mood: converging PET findings in depression and normal sadness. Am J Psychiatry, 1999. 156(5): p. 675-82.