We thank Professor Bonnet for his comments regarding our review on ketamine's potential for the management of pain and treatment-resistant depression. In his letter, Professor Bonnet focuses on ketamine's liability for misuse if it is broadly accepted in the clinic. He purports the idea that ketamine may have a similar liability for misuse as ethanol and backs his idea with preclinical and clinical studies showing functional changes in spine synapse remodelling and glutamatergic systems. He argues that ketamine might share some pharmacological effects with ethanol, and that such effects may eventually lead to addiction by triggering similar brain circuitry.

It is indeed true that ketamine and ethanol both relieve pain at moderate concentrations, and that both may lead to loss of consciousness at high concentrations. However, we believe that here the parallel ends, for the following reasons. First, pharmacologically, ketamine and ethanol are quite different substances; whereas ketamine isomers and their metabolites specifically bind to NMDA and aminomethylphosphonic acid (AMPA) receptors, this is very unlikely for simple molecules such as ethanol and its metabolites. Second, ethanol is a lipophilic molecule, and at higher doses it will influence GABA neurotransmission through its direct action on the chlorine channel. It might even influence cell membrane integrity at very high doses, thus indirectly influencing central neurotransmission. Third, benzodiazepines also indirectly increase GABA neurotransmission and are effective anxiolytics, but they are devoid of antidepressant effects. It can also be argued that current animal models of depression have limited value and are more likely to be measuring anxiety than depression. Fourth, in a recent Nature article, ^{Reference Zanos, Moaddel, Morris, Georgiou, Fischell and Elmer1} compelling evidence was presented that it is not ketamine itself but its OH-norketamine metabolite that is responsible for the antidepressant effect through its action on AMPA receptors. This is also in line with earlier studies showing that ketamine has antagonistic properties at both NMDA and AMPA receptors. It was also noted that the metabolite displayed very few side-effects, which is consistent with a very specific action. ^{Reference Zanos, Moaddel, Morris, Georgiou, Fischell and Elmer1}

Thus, however intriguing the suggestion of our esteemed colleague might be, we believe that any pharmacological resemblance between ketamine and ethanol is merely superficial. Still, ketamine may be responsible for addiction through its action on the reward system through dopamine D₂ and serotonin 5-HT_2C receptors in the ventral tegmental area. ^{Reference Kapur and Seeman2,Reference Pietersen, Bosker, Doorduin, Jongsma, Postema and Haas3} We also agree that finding the optimal route of administration and dosing of ketamine to produce a preferably long-term antidepressant response without burgeoning tolerance remains a big challenge. Hopefully, the OH-norketamine metabolite will open the door to a new generation of rapidly acting antidepressants with minimal adverse effects and less liability for misuse and addiction.