Some distorted thoughts about ketamine as a psychedelic and a novel hypothesis based on NMDA receptor-mediated synaptic plasticity.

Abstract Ketamine, a channel blocking NMDA receptorantagonist, is used off-label for its psychedelic effects, which may arise from a combination of several inter-related actions. Firstly, reductions of the contribution of NMDA receptorsto afferent information from external and internal sensory inputs may distort sensations and their processing in higher brain centres. Secondly, reductions of NMDA receptor-mediated excitation of GABAergic interneurons can result in glutamatergic overactivity. Thirdly, limbic cortical disinhibitionmay indirectly enhance dopaminergic and serotonergic activity. Fourthly, inhibition of NMDA receptormediated synaptic plasticity, such as short-term potentiation (STP) and long-term potentiation(LTP), could lead to distorted memories. Here, for the first time, we compared quantitatively the effects of ketamine on STP and LTP. We report that ketamine inhibits STP in a double sigmoidal fashion with low (40 nM) and high (5.6 μM) IC 50 values. In contrast, ketamine inhibits LTP in a single sigmoidal manner (IC 50 value ∼ 15 μM). A GluN2D-subunit preferring NMDA receptorantagonist, UBP145, has a similar pharmacological profile. We propose that the psychedelic effects of ketamine may involve the inhibition of STP and, potentially, associated forms of working memory. This article is part of the Special Issue entitled ‘Psychedelics: New Doors, Altered Perceptions’.