, Volume 226, Issue 4, pp 739–746 | Cite as

A randomized, placebo-controlled laboratory study of the effects of d-cycloserine on craving in cocaine-dependent individuals

  • Kimber L. Price
  • Nathaniel L. Baker
  • Aimee L. McRae-Clark
  • Michael E. Saladin
  • Stacia M. DeSantis
  • Elizabeth J. Santa Ana
  • Kathleen T. Brady
Original Investigation



d-Cycloserine (DCS), a partial glutamate N-methyl-d-aspartate (NMDA) receptor agonist, enhances extinction of conditioned fear responding; preliminary data suggest that it may facilitate extinction of drug cue reactivity.


This study investigates DCS effects on cocaine cue craving and drug use in cocaine-dependent subjects.


Thirty-two subjects were randomly assigned to receive (1) DCS only, (2) DCS before sessions 1 and 3, placebo (PBO) before session 2, or (3) PBO only 15-min before each of 3 1-h cocaine cue exposure sessions conducted 1 day apart. Craving ratings were obtained before, during, and after sessions. Drug use and cue-induced craving were assessed 1 week after the last cue session.


Repeated presentation of cocaine cues resulted in decreased craving both within and between sessions. DCS did not facilitate extinction learning and may have enhanced craving. The group that received three doses of DCS had significantly higher craving than the PBO group at the baseline ratings taken before sessions 2 and 3, as well as significantly higher cue-induced craving at follow-up. The group that received two doses of DCS did not differ from the PBO group. There were no group differences in postextinction cocaine use.


The reduction of cocaine cue reactivity in the PBO group suggests that the study procedures were sufficient to produce extinction. Under these conditions, DCS did not facilitate extinction and may have enhanced craving. Further studies of glutamatergic agents and extinction in cocaine dependence should include consideration of procedural variables that could have a major impact on study outcomes.


Cocaine Craving Cue reactivity Extinction Reconsolidation d-Cycloserine 



This study was supported by the National Institutes of Health (Grant Nos. 1R01DA023188-01A1 and 3R01DA023188-02S1). The authors thank Lisa Jenkins, Katherine Shugart, Colleen Reed, and Cullen McWhite at MUSC and Elizabeth Chapman and Margaret Garret at BHSPC for their assistance with study participants. Preliminary analyses of these data were presented in poster format at the 2010 College on Problems of Drug Dependence annual meeting in Scottsdale, AZ.

Conflicts of interest



  1. Baker DA, McFarland K, Lake RW, Shen H, Tang XC, Toda S, Kalivas PW (2003) Neuroadaptations in cystine–glutamate exchange underlie cocaine relapse. Nat Neurosci 6:743–749PubMedCrossRefGoogle Scholar
  2. Botreau F, Paolone G, Stewart J (2006) d-Cycloserine facilitates extinction of a cocaine-induced conditioned place preference. Behav Brain Res 172:173–178PubMedCrossRefGoogle Scholar
  3. Bouton ME (2004) Context and behavioral processes in extinction. Learn Mem 11:485–494PubMedCrossRefGoogle Scholar
  4. Childress AR, McLellan AT, O’Brien CP (1986) Abstinent opiate abusers exhibit conditioned craving, conditioned withdrawal and reductions in both through extinction. Br J Addict 81:655–660PubMedCrossRefGoogle Scholar
  5. Eisenberg M, Kobilo T, Berman DE, Dudai Y (2003) Stability of retrieved memory: inverse correlation with trace dominance. Science 301:1102–1104PubMedCrossRefGoogle Scholar
  6. Hofmann SG, Meuret AE, Smits JA, Simon NM, Pollack MH, Eisenmenger K, Shiekh M, Otto MW (2006a) Augmentation of exposure therapy with d-cycloserine for social anxiety disorder. Arch Gen Psychiatry 63:298–304PubMedCrossRefGoogle Scholar
  7. Hofmann SG, Pollack MH, Otto MW (2006b) Augmentation treatment of psychotherapy for anxiety disorders with d-cycloserine. CNS Drug Rev 12:208–217PubMedCrossRefGoogle Scholar
  8. Kalivas PW, Volkow ND (2005) The neural basis of addiction: a pathology of motivation and choice. Am J Psychiatry 162:1403–1413PubMedCrossRefGoogle Scholar
  9. Kelamangalath L, Seymour CM, Wagner JJ (2009) d-Serine facilitates the effects of extinction to reduce cocaine-primed reinstatement of drug-seeking behavior. Neurobiol Learn Mem 92:544–551PubMedCrossRefGoogle Scholar
  10. Lee JL, Gardner RJ, Butler VJ, Everitt BJ (2009) d-Cycloserine potentiates the reconsolidation of cocaine-associated memories. Learn Mem 16:82–85PubMedCrossRefGoogle Scholar
  11. Myers KM, Carlezon WA Jr, Davis M (2011) Glutamate receptors in extinction and extinction-based therapies for psychiatric illness. Neuropsychopharmacology 36:274–293PubMedCrossRefGoogle Scholar
  12. Nic Dhonnchadha BA, Szalay JJ, Achat-Mendes C, Platt DM, Otto MW, Spealman RD, Kantak KM (2010) d-Cycloserine deters reacquisition of cocaine self-administration by augmenting extinction learning. Neuropsychopharmacology 35:357–367PubMedCrossRefGoogle Scholar
  13. Norberg MM, Krystal JH, Tolin DF (2008) A meta-analysis of d-cycloserine and the facilitation of fear extinction and exposure therapy. Biol Psychiatry 63:1118–1126PubMedCrossRefGoogle Scholar
  14. Paolone G, Botreau F, Stewart J (2009) The facilitative effects of d-cycloserine on extinction of a cocaine-induced conditioned place preference can be long lasting and resistant to reinstatement. Psychopharmacology (Berl) 202:403–409CrossRefGoogle Scholar
  15. Parnas AS, Weber M, Richardson R (2005) Effects of multiple exposures to d-cycloserine on extinction of conditioned fear in rats. Neurobiol Learn Mem 83:224–231PubMedCrossRefGoogle Scholar
  16. Peters J, Kalivas PW, Quirk GJ (2009) Extinction circuits for fear and addiction overlap in prefrontal cortex. Learn Mem 16:279–288PubMedCrossRefGoogle Scholar
  17. Price KL, McRae-Clark AL, Saladin ME, Maria MM, DeSantis SM, Back SE, Brady KT (2009) d-cycloserine and cocaine cue reactivity: preliminary findings. Am J Drug Alcohol Abuse 35:434–438PubMedCrossRefGoogle Scholar
  18. Quartermain D, Mower J, Rafferty MF, Herting RL, Lanthorn TH (1994) Acute but not chronic activation of the NMDA-coupled glycine receptor with d-cycloserine facilitates learning and retention. Eur J Pharmacol 257:7–12PubMedCrossRefGoogle Scholar
  19. Quirk GJ, Mueller D (2008) Neural mechanisms of extinction learning and retrieval. Neuropsychopharmacology 33:56–72PubMedCrossRefGoogle Scholar
  20. Reissner KJ, Kalivas PW (2010) Using glutamate homeostasis as a target for treating addictive disorders. Behav Pharmacol 21:514–522PubMedCrossRefGoogle Scholar
  21. Ressler KJ, Rothbaum BO, Tannenbaum L, Anderson P, Graap K, Zimand E, Hodges L, Davis M (2004) Cognitive enhancers as adjuncts to psychotherapy: use of d-cycloserine in phobic individuals to facilitate extinction of fear. Arch Gen Psychiatry 61:1136–1144PubMedCrossRefGoogle Scholar
  22. Santa Ana EJ, Rounsaville BJ, Frankforter TL, Nich C, Babuscio T, Poling J, Gonsai K, Hill KP, Carroll KM (2009) d-Cycloserine attenuates reactivity to smoking cues in nicotine dependent smokers: a pilot investigation. Drug Alcohol Depend 104:220–227PubMedCrossRefGoogle Scholar
  23. Sheehan D, Janavs J, Baker R, Harnett-Sheehan K, Knapp E, Sheehan M (2003) MINI: Mini International Neuropsychiatric InterviewGoogle Scholar
  24. Sinha R (2005) Imagery script development procedures, unpublished manualGoogle Scholar
  25. Sobell LC, Sobell MB (1992) Timeline follow-back: a technique for assessing self-reported ethanol consumption. In: Allen J, Litten RZ (eds) Measuring alcohol consumption: Psychological and biological methods. Humana Press, Totowa, NJ, pp 41–72CrossRefGoogle Scholar
  26. Thanos PK, Bermeo C, Wang GJ, Volkow ND (2009) d-Cycloserine accelerates the extinction of cocaine-induced conditioned place preference in C57bL/c mice. Behav Brain Res 199:345–349PubMedCrossRefGoogle Scholar
  27. Torregrossa MM, Sanchez H, Taylor JR (2010) d-Cycloserine reduces the context specificity of Pavlovian extinction of cocaine cues through actions in the nucleus accumbens. J Neurosci 30:10526–10533PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2012

Authors and Affiliations

  • Kimber L. Price
    • 1
    • 4
  • Nathaniel L. Baker
    • 2
  • Aimee L. McRae-Clark
    • 1
  • Michael E. Saladin
    • 3
  • Stacia M. DeSantis
    • 2
  • Elizabeth J. Santa Ana
    • 1
  • Kathleen T. Brady
    • 1
  1. 1.Department of Psychiatry and Behavioral Sciences, Division of Clinical NeuroscienceMedical University of South CarolinaCharlestonUSA
  2. 2.Department of Medicine, Division of Biostatistics and EpidemiologyMedical University of South CarolinaCharlestonUSA
  3. 3.Department of Health Sciences and ResearchMedical University of South CarolinaCharlestonUSA
  4. 4.CharlestonUSA

Personalised recommendations