, Volume 205, Issue 1, pp 53–62 | Cite as

The effects of acamprosate on alcohol-cue reactivity and alcohol priming in dependent patients: a randomized controlled trial

  • Anders Hammarberg
  • Nitya Jayaram-Lindström
  • Olof Beck
  • Johan Franck
  • Malcolm S. Reid
Original Investigation



Acamprosate is a widely utilized, efficacious treatment for relapse prevention in alcohol-dependent patients; yet, little is known regarding its therapeutic mechanism of action.


The aim of the present study was to examine the effect of acamprosate on cue reactivity and alcohol priming in alcohol-dependent patients.


In a double-blind design, 56 treatment seeking patients were randomized to 21 days of either acamprosate or placebo treatment and then participated in a series of cue- and alcohol-priming sessions. Alcohol cues consisted of a mixture of alcohol related visual, tactile, olfactory, and auditory stimuli. Non-alcohol-related cues were contextually similar but had no connection to alcohol. In the alcohol-priming procedure, patients were provided with an alcohol drink of their own choice at a dose corresponding to 0.20 gr. EtOH/kg bodyweight. Subjective, physiological, and biological measurements were recorded before and after each test session. Following study completion, all patients were referred to formal treatment.


The results showed that acamprosate attenuated the subjective craving induced by alcohol priming in comparison to placebo-treated patients. Furthermore, acamprosate reduced alcohol-induced elevation in blood-cortisol levels. Lastly, there was a negative correlation between acamprosate plasma levels and alcohol craving following a priming drink. No effects of acamprosate on cue reactivity, or on the acute rewarding and sedating effects of the priming drink, were observed.


These results suggest a potential mechanism by which acamprosate mediates its therapeutic effect in the treatment of alcoholism, by attenuating the urge to drink following an alcohol slip.


Alcohol dependence Treatment Acamprosate Priming Craving 



We are grateful to Margareta Gard-Hedander, RN and Else-Britt Hillner, RN for handling the study medication and Ms. Ingrid Dahlin for handling and management of blood samples. This study was supported by AFA Insurance, the Swedish Science Council (14645-04-3), the Research Council of the Swedish Alcohol Retail Monopoly (grants no 06-24:1 and 07-19:1), Milan Valverius stiftelse, and Psykiatrifonden. Study medication was generously donated by Merck-Lipha s.a.

Financial disclosures

None of the authors reported any biomedical financial interests or potential conflicts of interest.


  1. Anton RF, Moak DH, Latham P (1995) The Obsessive-Compulsive Drinking Scale; a self-rated instrument for the quantification of thoughts about alcohol and drinking behavior. Alc Clin Exp Res 19:92–99CrossRefGoogle Scholar
  2. Bachteler D, Economidou D, Danysz W, Ciccocioppo R, Spanagel R (2005) The effects of acamprosate and neramexane on cue-induced reinstatement of ethanol-seeking behavior in rat. Neuropsychopharmacology 30(6):1104–1110PubMedCrossRefGoogle Scholar
  3. Besson J, Aeby F, Kasas A, Lehert P, Potgieter A (1998) Combined efficacy of acamprosate and disulfiram in the treatment of alcoholism: a controlled study. Alc Clin and Exp Res 22:573–579CrossRefGoogle Scholar
  4. Burattini C, McGeehan AJ, Griffin WC 3rd, Gass JT, Kinder JR, Janak PH, Olive MF (2008) A microdialysis study of extracellular levels of acamprosate and naltrexone in the rat brain following acute and repeated administration. Addict Biol 13(1):70–79PubMedCrossRefGoogle Scholar
  5. Chick J, Howlett H, Morgan MY, Ritson B (2000) United Kingdom Multicentre Acamprosate Study (UKMAS): a 6-month prospective study of acamprosate versus placebo in preventing relapse after withdrawal from alcohol. Alc & Alc 35(2):176–187Google Scholar
  6. Cole JC, Littleton JM, Little HJ (2000) Acamprosate, but not naltrexone, inhibits conditioned abstinence behaviour associated with repeated ethanol administration and exposure to a plus-maze. Psychopharmacology (Berl) 147(4):403–411CrossRefGoogle Scholar
  7. Cowen MS, Adams C, Kraehenbuehl T, Vengeliene V, Lawrence AJ (2005) The acute anti-craving effect of acamprosate in alcohol-preferring rats is associated with modulation of the mesolimbic dopamine system. Addict Biol 10(3):233–242PubMedCrossRefGoogle Scholar
  8. Dahchour A, De Witte P, Bolo N, Nédélec JF, Muzet M, Durbin P, Macher JP (1998) Central effects of acamprosate: part 1. Acamprosate blocks the glutamate increase in the nucleus accumbens microdialysate in ethanol withdrawn rats. Psychiatry Res 82(2):107–14Google Scholar
  9. Davidson D, Palfai T, Bird C, Swift R (1999) Effects of naltrexone on alcohol self-administration in heavy drinkers. Alcohol Clin Exp Res 23(2):195–203PubMedGoogle Scholar
  10. De Witte P, Littleton J, Parot P, Koob G (2005) Neuroprotective and abstinence-promoting effects of acamprosate: elucidating the mechanism of action. CNS Drugs 19(6):517–537 ReviewPubMedCrossRefGoogle Scholar
  11. DiClemente CC, Bellino LE, Neavins TM (1999) Motivation for change and alcoholism treatment. Alcohol Res Health 23(2):86–92PubMedGoogle Scholar
  12. Drummond DC (2001) Theories of drug craving, ancient and modern. Addiction 96(1):33–46PubMedCrossRefGoogle Scholar
  13. Flannery BA, Volpicelli JR, Pettinati HM (1999) Psychometric properties of the penn alcohol craving scale. Alcohol Clin Exp Res 23(8):1289–1295Google Scholar
  14. Griffiths RR, Troisi JR, Silverman K, Mumford GK (1993) Multiple-choice procedure: an efficient approach for investigating drug reinforcement in humans. Behav Pharmacol 4(1):3–13PubMedCrossRefGoogle Scholar
  15. Hölter SM, Landgraf R, Zieglgänsberger W, Spanagel R (1997) Time course of acamprosate action on operant ethanol self-administration after ethanol deprivation. Alcohol Clin Exp Res 21(5):862–868PubMedCrossRefGoogle Scholar
  16. Johnson BA, Rosenthal MD, Capece JA, Wiegand F, Mao L, Beyers K, McKay A et al (2007) Topiramate for treating alcohol dependence. JAMA 298:1641–1651PubMedCrossRefGoogle Scholar
  17. Kalivas PW (2007) Cocaine and amphetamine-like psychostimulants: neurocircuitry and glutamate neuroplasticity. Dialogues Clin Neurosci 9(4):389–397PubMedGoogle Scholar
  18. Kiefer F, Jahn H, Tarnaske T, Helwig H, Briken P, Holzbach P, Kampf P, Stracke R, Baehr M, Naber D, Wiedemann W (2003) Comparing and combining naltrexone and acamprosate in relapse prevention of alcoholism: a double-blind, placebo-controlled study. Arch Gen Psych 60:92–99CrossRefGoogle Scholar
  19. Kiefer F, Jahn H, Otte C, Naber D, Wiedemann K (2006) Hypothalamic-pituitary-adrenocortical axis activity: a target of pharmacological anticraving treatment? Biol Psych 60(1):74–6CrossRefGoogle Scholar
  20. Love A, James D, Willner P (1998) A comparison of two alcohol craving questionnaires. Addiction 93(7):1091–1102PubMedCrossRefGoogle Scholar
  21. Martin CS, Earleywine M, Musty RE, Perrine MW, Swift RM (1993) Development and validation of the Biphasic Alcohol Effects Scale. Alc Clin Exp Res 17(1):140–146CrossRefGoogle Scholar
  22. Mason BJ, Crean R (2007) Acamprosate in the treatment of alcohol dependence: clinical and economic considerations. Expert Rev Neurother 7(11):1465–1477PubMedCrossRefGoogle Scholar
  23. Mason BJ, Goodman AM, Chabac S, Lehert P (2006) Effect of oral acamprosate on abstinence in patients with alcohol dependence in a double-blind, placebo-controlled trial: the role of patient motivation. J Psychiatr Res 40(5):383–393 Epub 2006 Mar 20PubMedCrossRefGoogle Scholar
  24. McCaul ME, Turkkan JS, Stitzer ML (1989) Psychophysiological effects of alcohol-related stimuli. I. The role of stimulus intensity. Alcoholism: Clin. Exp. Res. 13:386–398CrossRefGoogle Scholar
  25. Morley KC, Teesson M, Reid SC, Sannibale C, Thomson C, Phung N et al (2006) Naltrexone versus acamprosate in the treatment of alcohol dependence: A multi-centre, randomized, double-blind, placebo-controlled trial. Addiction 101(10):1451–1462PubMedCrossRefGoogle Scholar
  26. Olive MF, Nannini MA, Ou CJ, Koenig HN, Hodge CW (2002) Effects of acute acamprosate and homotaurine on ethanol intake and ethanol-stimulated mesolimbic dopamine release. Eur J Pharmacol 437(1–2):55–61PubMedCrossRefGoogle Scholar
  27. O'Malley SS, Krishnan-Sarin S, Farren C, Sinha R, Kreek MJ (2002) Naltrexone decreases craving and alcohol self-administration in alcohol-dependent subjects and activates the hypothalamo-pituitary-adrenocortical axis. Psychopharmacology (Berl) 160(1):19–29CrossRefGoogle Scholar
  28. Ooteman W, Koeter MW, Verheul R, Schippers GM, van den Brink W (2007) The effect of naltrexone and acamprosate on cue-induced craving, autonomic nervous system and neuroendocrine reactions to alcohol-related cues in alcoholics. Eur Neuropsychopharmacol 17(8):558–566PubMedCrossRefGoogle Scholar
  29. Paille FM, Guelfi JD, Perkins AC, Royer RJ, Stern L, Parot P (1995) Double-blind randomised multicentre trial of acamprosate in maintaining abstinence from alcohol. Alc & Alc 30:239–247Google Scholar
  30. Pelc I, Verbanck P, Le Bon O, Gavrilovic M, Lion K, Lehert P (1997) Efficacy and safety of acamprosate in the treatment of detoxified alcohol dependent patients: a 90 days placebo- controlled dose finding study. Brit J of Psych 171:73–77CrossRefGoogle Scholar
  31. Rammes G, Mahal B, Putzke J, Parsons C, Spielmanns P, Pestel E, Spanagel R, Zieglgänsberger W, Schadrack J (2001) The anti-craving compound acamprosate acts as a weak NMDA-receptor antagonist, but modulates NMDA-receptor subunit expression similar to memantine and MK-801. Neuropharmacology 40(6):749–746PubMedCrossRefGoogle Scholar
  32. Reid MS, Flammino F, Starosta F, Palamar FJ (2006) Physiological and subjective responding to alcohol cue exposure in alcoholics and control subjects: evidence for appetitive responding. J Neural Transm 113:1519–1535PubMedCrossRefGoogle Scholar
  33. Rivier C, Bruhn T, Vale W (1984) Effect of ethanol on the hypothalamic-pituitary-adrenal axis in the rat: role of corticotropin-releasing factor (CRF). J Pharmacol Exp Ther 229(1):127–131PubMedGoogle Scholar
  34. Rivier C, Lee S (1996) Acute alcohol administration stimulates the activity of hypothalamic neurons that express corticotropin-releasing factor and vasopressin. Brain Res 726(1–2):1–10PubMedCrossRefGoogle Scholar
  35. Sayette MA, Martin CS, Wertz JM, Perrott MA, Peters AR (2005) The effects of alcohol on cigarette craving in heavy smokers and tobacco chippers. Psychol Addict Behav 19(3):263–270PubMedCrossRefGoogle Scholar
  36. Sass H, Soyka M, Mann K, Zieglegansberger W (1996) Relapse prevention by acamprosate: Results from a placebo-controlled study on alcohol dependence. Arch Gen Psych 53:673–680Google Scholar
  37. Sobell LC, Sobell MB (1992) Timeline Follow Back. A technique for assessing self-reported alcohol consumption. In: Litten R, Allen J (eds) Measuring Alcohol Consumption. Humana Press, Totowa, pp 41–72Google Scholar
  38. Spanagel R, Hölter SM, Allingham K, Landgraf R, Zieglgänsberger W (1996) Acamprosate and alcohol: I. Effects on alcohol intake following alcohol deprivation in the rat. Eur J Pharmacol 305(1–3):39–44Google Scholar
  39. Sullivan JT, Sykora K, Schneiderman J, Naranjo CA, Sellers EM (1989) Assessment of alcohol withdrawal: the revised clinical institute withdrawal assessment for alcohol scale (CIWA-Ar). Br J Addict 84(11):1353–1357PubMedCrossRefGoogle Scholar
  40. Tempesta E, Janiri L, Bignamini A, Chabac S, Potgieter A (2000) Acamprosate and relapse prevention in the treatment of alcohol dependence: a placebo controlled study. Alc & Alc 35:202–209Google Scholar
  41. Volpicelli JR, Alterman Al, Hayashida M, O’Brien CP (1992) Naltrexone in the treatment of alcohol dependence. Arch Gen Psychiatry 49(11):876–880PubMedGoogle Scholar
  42. Watson D, Clark LA, Tellegren A (1998) Development and validation of brief measures of positive and negative affect: the PANAS scales. J Pers Soc Psychol 54(6):1063–1070Google Scholar
  43. Whitworth AB, Fischer F, Lesch OM, Limmerrichter A, Oberbauer H, Platz T, Potgieter A, Walter H, Fleischhacker WW (1996) Comparison of acamprosate and placebo in long-term treatment of alcohol dependence. The Lancet 347:1438–1442CrossRefGoogle Scholar
  44. World Health Organization (2004) WHO global status report on alcohol. WHO, Geneva, pp 30–48Google Scholar
  45. Zeise ML, Kasparov S, Capogna M, Zieglgänsberger W (1993) Acamprosate (calciumacetylhomotaurinate) decreases postsynaptic potentials in the rat neocortex: possible involvement of excitatory amino acid receptors. Eur J Pharmacol 231(1):47–52PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  • Anders Hammarberg
    • 1
  • Nitya Jayaram-Lindström
    • 1
  • Olof Beck
    • 2
  • Johan Franck
    • 1
  • Malcolm S. Reid
    • 3
  1. 1.Department of Clinical Neuroscience, Division of PsychiatryKarolinska University HospitalStockholmSweden
  2. 2.Department of Medicine, Division of Clinical PharmacologyKarolinska University HospitalStockholmSweden
  3. 3.Department of PsychiatryNew York UniversityNew YorkUSA

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