How Does Ketamine Work?

Signaling mechanisms for ketamine and rapid acting antidepressants.Duman et al, Nature Medicine, 2016.
Signals between brain cells are transmitted by chemicals and electrical currents that cause many complicated negative and positive feedback loops. The human brain is very complicated, our knowledge of what goes on is somewhat superficial and just beginning to become sophisticated. At this point, we can only scratch the surface of the complexities of the effects of any particular substance on the brain’s activity, much less begin to formulate theories on the interactions between brain and consciousness.
However, it appears that ketamine affects communication and signaling between brain cells. Ketamine acts upon many different receptors in the brain, but its main effect is as an NMDA-receptor antagonist. This means that it blocks a particular type of receptor, the N-methyl-D-aspartate (NMDA) receptor, on certain brain cells. One way ketamine seems to work is that it stops a type of brain cell whose job is to stop the activity of a different type of brain cell. Basically it takes the foot off the brakes, and allows some specific brain cells to be more active.
mPFC Layer V Pyramidal Neurons

Figure adapted from Duman RS, Aghajanian GK. Synaptic dysfunction in depression: potential therapeutic
targets. Science. 2012 Oct 5:338(6103):68-72
This increased activity can bring about new connections and interactions between different areas of the brain. For example, it seems that ketamine turns down activity in what has been called the default mode network while at the same time promoting new connections in other regions of the brain. These effects likely explain some of the changes in consciousness in the minutes, hours, and days after administration of ketamine. There is evidence that ketamine actually stimulates the growth of brain cells and strengthens and creates new connections between brain cells. In this way, it seems that ketamine can enhance neuroplasticity, or the ability for the brain to change its connections and even structure.

Group (healthy control (HC), major depressive disorder (MDD)) differences in connectivity with the posterior cingulate cortex (PCC) seed of the default mode network (DMN) across scans at each scan day. The mean Z-score maps are shown at a threshold of p< 0.05, familywise error (FWE) corrected. The red circles highlight regions of significant difference (second row: bilateral insula (salience network (SAL)) and anterior cingulate cortex (ACC, central executive network (CEN)); third row: right BA22 and left BA46 (SAL); fifth row:
BA18).