, Volume 172, Issue 1, pp 16–24 | Cite as

Acute effects of memantine in combination with alcohol in moderate drinkers

Original Investigation



Alcohol effects in humans involve N-methyl-d-aspartate (NMDA) receptor-mediated glutamatergic neurotransmission. It has been proposed that NMDA receptor antagonists may be effective in the treatment of alcohol dependence.


This study evaluated the acute effects of memantine, an NMDA receptor antagonist, on the subjective, physiological, and performance effects of alcohol in moderate (10–30 drinks per week) alcohol drinkers.


Eighteen volunteers without alcohol dependence were tested using a double-blind design with three 3-day long inpatient phases separated by at least a 2-week wash-out period. Memantine (0, 15, and 30 mg) was administered 4 h before alcohol (1.5 g/l body water), which was given in four divided doses every 20 min.


Pretreatment with memantine attenuated the craving for alcohol before alcohol administration, but not after alcohol was given. Memantine increased the dissociative effects of alcohol, without altering its sedative, stimulant, and overall intoxicating effects. Memantine also did not affect alcohol-induced impairment in performance, physiological changes, or pharmacokinetics. Memantine increased subjective reports of dissociation, confusion, and stimulation, and impaired motor coordination on the balance task.


Memantine was well tolerated in combination with alcohol. The findings suggest that NMDA receptor neurotransmission may be involved in alcohol craving and alcohol-induced subjective dissociative effects.


Memantine NMDA Alcohol response Alcohol craving Moderate drinkers 



This work was supported by research grants from the National Institute of Alcohol Abuse and Alcoholism (AA12599) to Dr. Evans, the National Institute of Drug Abuse to Dr. Bisaga (K23 DA00429), and the National Institute of Mental Health to Dr. Papp (MH 61274). Portions of the data contained in this manuscript were presented at the 24th Annual Meeting of the Research Society on Alcoholism, Montreal, Canada, 2001. The authors thank Dr. Richard Foltin for help in analyzing data, Drs. Meg Haney and Wojciech Danysz for reviewing the manuscript, Dr. Laszlo Papp for the use of the research unit, and Beth Fishbein, Jordyn Conrad and Charise Freundlich for their help in conducting this research.


  1. Bienkowski P, Koros E, Kostowski W, Danysz W (1999) Effects of N-methyl-d-aspartate receptor antagonists on reinforced and nonreinforced responding for ethanol in rats. Alcohol 18:131–137CrossRefPubMedGoogle Scholar
  2. Bisaga A, Popik P (2000) In search of a new pharmacological treatment for drug and alcohol addiction: N-methyl-d-aspartate (NMDA) antagonists. Drug Alcohol Depend. 59:1–15Google Scholar
  3. Bisaga A, Gianelli P, Popik P (1997) Opiate withdrawal with dextromethorphan. Am J. Psychiatry 154: 584Google Scholar
  4. Bisaga A, Popik P, Bespalov AY, Danysz W (2000) Therapeutic potential of NMDA receptor antagonists in the treatment of alcohol and substance use disorders. Exp Opin Invest Drugs 9:2233–2248Google Scholar
  5. Bisaga A, Comer SD, Ward AS, Popik P, Kleber HD, Fischman MW (2001) The NMDA antagonist memantine attenuates the expression of opioid physical dependence in humans. Psychopharmacology 157:1–10CrossRefPubMedGoogle Scholar
  6. Blomqvist O, Hernandez-Avila CA, Van Kirk J, Rose JE, Kranzler HR (2002) Mecamylamine modifies the pharmacokinetics and reinforcing effects of alcohol. Alcohol Clin Exp Res 26:326–331PubMedGoogle Scholar
  7. Bremner JD, Krystal JH, Putnam FW, Southwick SM, Marmar C, Charney DS, Mazure CM (1998) Measurement of dissociative states with the Clinician-Administered Dissociative States Scale (CADSS). J Trauma Stress 11:125–136CrossRefPubMedGoogle Scholar
  8. Crews FT, Morrow AL, Criswell H, Breese G (1996) Effects of ethanol on ion channels. Int Rev Neurobiol 39:283–367Google Scholar
  9. Danysz W, Dyr W, Jankowska E, Glazewski S, Kostowski W (1992) The involvement of NMDA receptors in acute and chronic effects of ethanol. Alcohol Clin Exp Res 16:499–504PubMedGoogle Scholar
  10. de Wit H, Pierri J, Johanson CE (1989) Assessing individual differences in ethanol preference using a cumulative dosing procedure. Psychopharmacology 98:113–119PubMedGoogle Scholar
  11. de Wit H, Svenson J, York A (1999) Non-specific effect of naltrexone on ethanol consumption in social drinkers. Psychopharmacology 146:33–41CrossRefPubMedGoogle Scholar
  12. Evans SM, Funderburk FR, Griffiths RR (1990) Zolpidem and triazolam in humans: behavioral and subjective effects and abuse liability. J Pharmacol Exp Ther 255:1246–1255PubMedGoogle Scholar
  13. Evans SM, Levin FR, Fischman MW (2000) Increased sensitivity to alprazolam in females with a paternal history of alcoholism. Psychopharmacology 150:150–162CrossRefPubMedGoogle Scholar
  14. Grant KA, Colombo G (1993) Discriminative stimulus effects of ethanol: effect of training dose on the substitution of N-methyl-d-aspartate antagonists. J Pharmacol Exp Ther 264:1241–1247PubMedGoogle Scholar
  15. Herman BH, Frankenheim J, Sheridan P, Litten R, Weight F (2001) Glutamate and addiction. Humana Press, Totowa, N.J.Google Scholar
  16. Hindmarch I, Kerr JS, Sherwood N (1991) The effects of alcohol and other drugs on psychomotor performance and cognitive function. Alcohol Alcohol 26:71–79PubMedGoogle Scholar
  17. Holter SM, Danysz W, Spanagel R (1996) Evidence for alcohol anti-craving properties of memantine. Eur J Pharmacol 314:R1–2PubMedGoogle Scholar
  18. Holter SM, Danysz W, Spanagel R (2000) Novel uncompetitive N-methyl-d-aspartate (NMDA)-receptor antagonist MRZ 2/579 suppresses ethanol intake in long-term ethanol-experienced rats and generalizes to ethanol cue in drug discrimination procedure. J Pharmacol Exp Ther 292:545–552PubMedGoogle Scholar
  19. Hundt W, Danysz W, Holter SM, Spanagel R (1998) Ethanol and N-methyl-d-aspartate receptor complex interactions: a detailed drug discrimination study in the rat. Psychopharmacology 135:44–51PubMedGoogle Scholar
  20. Johnson BA, Campling GM, Griffiths P, Cowen PJ (1993) Attenuation of some alcohol-induced mood changes and the desire to drink by 5-HT3 receptor blockade: a preliminary study in healthy male volunteers. Psychopharmacology 112:142–144Google Scholar
  21. King AC, Volpicelli JR, Frazer A, O’Brien CP (1997) Effect of naltrexone on subjective alcohol response in subjects at high and low risk for future alcohol dependence. Psychopharmacology 129:15–22CrossRefPubMedGoogle Scholar
  22. Koob GF, Roberts AJ, Schulteis G, Parsons LH, Heyser CJ, Hyytia P, Merlo-Pich E, Weiss F (1998) Neurocircuitry targets in ethanol reward and dependence. Alcohol Clin Exp Res 22:3–9PubMedGoogle Scholar
  23. Krystal JH, Karper LP, Seibyl JP, Freeman GK, Delaney R, Bremner JD, Heninger GR, Bowers MB Jr, Charney DS (1994) Subanesthetic effects of the noncompetitive NMDA antagonist, ketamine, in humans. Psychotomimetic, perceptual, cognitive, and neuroendocrine responses. Arch Gen Psychiatry 51:199–214PubMedGoogle Scholar
  24. Krystal JH, Petrakis IL, Webb E, Cooney NL, Karper LP, Namanworth S, Stetson P, Trevisan LA, Charney DS (1998) Dose-related ethanol-like effects of the NMDA antagonist, ketamine, in recently detoxified alcoholics. Arch Gen Psychiatry 55:354–360PubMedGoogle Scholar
  25. Krystal JH, Petrakis IL, D’Souza DC, Mason G, Trevisan L (2002) Alcohol and glutamate neurotransmission in humans: implications for reward, dependence, and treatment. In: Herman BH (ed) Glutamate and addiction. Humana Press, Totowa, N.J., pp 389–398Google Scholar
  26. Krystal JH, Petrakis IL, Krupitsky EM, Schutz CG, Trevisan L, D’Souza DC (2003) NMDA receptor antagonism and the ethanol intoxication signal: from alcoholism risk to pharmacotherapy. Ann N Y Acad Sci (in press)Google Scholar
  27. Ling W, Wesson DR, Charuvastra C, Klett CJ (1996) A controlled trial comparing buprenorphine and methadone maintenance in opioid dependence. Arch Gen Psychiatry 53:401–407PubMedGoogle Scholar
  28. Lovinger DM (1997) Alcohols and neurotransmitter gated ion channels: past, present and future. Naunyn-Schmiedeberg’s Arch Pharmacol 356:267–282Google Scholar
  29. Lovinger DM, White G, Weight FF (1989) Ethanol inhibits NMDA-activated ion current in hippocampal neurons. Science 243:1721–1724PubMedGoogle Scholar
  30. Martin CS, Earleywine M, Musty RE, Perrine MW, Swift RM (1993) Development and validation of the Biphasic Alcohol Effects Scale. Alcohol Clin Exp Res 17:140–146PubMedGoogle Scholar
  31. McCaul ME, Wand GS, Eissenberg T, Rohde CA, Cheskin LJ (2000) Naltrexone alters subjective and psychomotor responses to alcohol in heavy drinking subjects. Neuropsychopharmacology 22:480–492CrossRefPubMedGoogle Scholar
  32. McLeod DR, Griffiths RR, Bigelow GE, Yingling J (1982) An automated version of the Digit Symbol Substitution Test (DSST). Behav Res Meth Instr 14:463–466Google Scholar
  33. McNair DM, Lorr M, Droppelman LF (1971) EITS manual for the Profile of Mood States. Educational and Industrial Testing ServiceGoogle Scholar
  34. Miller TP, Taylor JL, Tinklenberg JR (1988) A comparison of assessment techniques measuring the effects of methylphenidate, secobarbital, diazepam and diphenhydramine in abstinent alcoholics. Neuropsychobiology 19:90–96PubMedGoogle Scholar
  35. Nestler EJ, Aghajanian GK (1997) Molecular and cellular basis of addiction. Science 278:58–63Google Scholar
  36. O’Malley SS, Krishnan-Sarin S, Farren C, Sinha R, Kreek J (2002) Naltrexone decreases craving and alcohol self-administration in alcohol-dependent subjects and activates the hypothalamo-pituitary-adrenocortical axis. Psychopharmacology 160:19–29Google Scholar
  37. Parsons CG, Danysz W, Quack G (1999) Memantine is a clinically well tolerated N-methyl-d-aspartate (NMDA) receptor antagonist—a review of preclinical data. Neuropharmacology 38:735–767PubMedGoogle Scholar
  38. Peoples RW, White G, Lovinger DM, Weight FF (1997) Ethanol inhibition of N-methyl-d-aspartate-activated current in mouse hippocampal neurones: whole-cell patch-clamp analysis. Br J Pharmacol 122:1035–1042PubMedGoogle Scholar
  39. Rammes G, Rupprecht R, Ferrari U, Zieglgansberger W, Parsons CG (2001) The N-methyl-d-aspartate receptor channel blockers memantine, MRZ 2/579 and other amino-alkyl-cyclohexanes antagonise 5-HT(3) receptor currents in cultured HEK-293 and N1E-115 cell systems in a non-competitive manner. Neurosci Lett 306:81–84CrossRefPubMedGoogle Scholar
  40. Rassnick S, Pulvirenti L, Koob GF (1992) Oral ethanol self-administration in rats is reduced by the administration of dopamine and glutamate receptor antagonists into the nucleus accumbens. Psychopharmacology 109:92–98Google Scholar
  41. Roache JD, Griffiths RR (1987) Interactions of diazepam and caffeine: behavioral and subjective dose effects in humans. Pharmacol Biochem Behav 26:801–812PubMedGoogle Scholar
  42. Rohsenow DJ, Niaura RS, Childress AR, Abrams DB, Monti PM (1990) Cue reactivity in addictive behaviors: theoretical and treatment implications. Int J Addict 25:957–993Google Scholar
  43. Shelton KL, Balster RL (1994) Ethanol drug discrimination in rats: substitution with GABA agonists and NMDA antagonists. Behav Pharmacol 5:441–451PubMedGoogle Scholar
  44. Soyka M, Bondy B, Eisenburg B, Schutz CG (2000) NMDA receptor challenge with dextromethorphan—subjective response, neuroendocrinological findings and possible clinical implications. J Neural Transm 107:701–714CrossRefPubMedGoogle Scholar
  45. Spanagel R, Zieglgansberger W (1997) Anti-craving compounds for ethanol: new pharmacological tools to study addictive processes. Trends Pharmacol Sci 18:54–59PubMedGoogle Scholar
  46. Steffensen SC, Nie Z, Criado JR, Siggins GR (2000) Ethanol inhibition of N-methyl-d-aspartate responses involves presynaptic gamma-aminobutyric acid(B) receptors. J Pharmacol Exp Ther 294:637–647PubMedGoogle Scholar
  47. Sung KW, Engel SR, Allan AM, Lovinger DM (2000) 5-HT(3) receptor function and potentiation by alcohols in frontal cortex neurons from transgenic mice overexpressing the receptor. Neuropharmacology 39:2346–2351Google Scholar
  48. Swift RM, Davidson D, Whelihan W, Kuznetsov O (1996) Ondansetron alters human alcohol intoxication. Biol Psychiatry 40:514–521PubMedGoogle Scholar
  49. Tiffany ST, Drobes DJ (1991) The development and initial validation of a questionnaire on smoking urges. Br J Addict 86:1467–1476PubMedGoogle Scholar
  50. Tsai G, Coyle JT (1998) The role of glutamatergic neurotransmission in the pathophysiology of alcoholism. Annu Rev Med 49:173–184PubMedGoogle Scholar
  51. Vivian JA, Waters CA, Szeliga KT, Jordan K, Grant KA (2002) Characterization of the discriminative stimulus effects of N-methyl-d-aspartate ligands under different ethanol training conditions in the cynomolgus monkey (Macaca fascicularis). Psychopharmacology 162:273–281CrossRefPubMedGoogle Scholar
  52. Watson PE, Watson ID, Batt RD (1980) Total body water volumes for adult males and females estimated from simple anthropometric measurements. Am J Clin Nutr 33:27–39PubMedGoogle Scholar
  53. West R, Shiffman S (2001) Effect of oral nicotine dosing forms on cigarette withdrawal symptoms and craving: a systematic review. Psychopharmacology 155:115–122Google Scholar
  54. Willetts J, Balster RL, Leander JD (1990) The behavioral pharmacology of NMDA receptor antagonists. Trends Pharmacol Sci 11:423–428PubMedGoogle Scholar
  55. Woodward JJ (1999) Ionotropic glutamate receptors as sites of action for ethanol in the brain. Neurochem Int 35:107–113PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2004

Authors and Affiliations

  1. 1.Department of PsychiatryColumbia University College of Physicians and SurgeonsNew YorkUSA
  2. 2.New York State Psychiatric InstituteNew YorkUSA

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