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Striking Similarities between Clinical and Biological Properties of Ketamine and Ethanol: Linking Antidepressant-After Effect and Burgeoning Addiction?

Udo Bonnet and Norbert Scherbaum

Ketamine is an old drug of abuse showing currently a new wave in its spread. Also, ketamine`s therapeutic quality is currently under strong observation, especially in terms of its value in the treatment of depression and suicidality. It`s a potential revolution in understanding the mechanisms of antidepressant treatment that single and repeated therapeutic administrations of sub-anesthetic ketamine doses are associated with a rapid and robust but transient antidepressant after-effect (ADE) in patients with treatment resistant major depression. There is increasing evidence that this ADE might result primarily from ketamine`s feature of being a non-competitive antagonist of glutamatergic N-methyl-D-aspartate (NMDA)-receptors embedded in synaptic membranes of neuronal cortico-limbic networks promoting an extracellular glutamate surge, thereby mediating changes in synaptic and cellular plasticity via local glutamate non-NMDA-receptors. Here, we focus on a couple of striking clinical and biological overlaps with ketamine and ethanol being a non-competitive antagonist of NMDA-receptors, too. Among them, a good portion is currently assumed to be specifically involved in both, the mechanisms of ADE (in the case of ketamine) and the development of addiction (in the case of ethanol). These overlaps are mainly addressed here in more detail, what may draw the reader in terms of the treatment of mood disorders to both, the possibility of a progressing transfer from ADE to addiction when repeatedly using therapeutic ketamine pulses, and on the other hand, a hypothesized therapeutic `antidepressant window´ of modest and cautious ethanol use in depressives, who are (still?) not addicted to ethanol. Of course, more frequent and intense use of ethanol or ketamine would prepare the brain to tolerance and dependence possibly using the same pathways.