Ketamine-assisted psychotherapy has been gaining incredible momentum in the past few years as a highly effective treatment option for treatment-resistant depression. While ketamine is classified as a psychedelic, its functions in the brain are distinct from other substances in this class and not fully understood yet.
A recent article published in Inverse offers a thorough explanation of what science has discovered so far about the mechanisms through which ketamine impacts the brain.
The author explores four key questions to better understand how the substance functions in the brain:
How ketamine works in the brain on the micro-scale
Ketamine affects two primary neurotransmitters in the brain: GABA and glutamate.
"GABA is inhibitory: when a GABA receptor is activated, it decreases the likelihood that its host neuron will fire. Glutamate is excitatory: when a glutamate receptor is activated, it increases the probability that the host neuron will fire."
Ketamine seems to inhibit the functions of one form of glutamate receptors called NMDA (N-methyl-D-aspartate) causing a sharp increase in glutamate levels in the brain which seems to be responsible for the dissociative states ketamine produces.
"But something else is happening when those glutamate bursts occur, something that researchers believe is one of the elements at the core of ketamine’s antidepressant effects: it facilitates neuronal growth.
Ketamine re-establishes and strengthens neural connections via dendrites — microscopic spine-like structures that send and receive information. When a person is chronically stressed or depressed, these spine-like structures die, but studies have shown that ketamine facilitates the growth of dendrites in mice."
The differences between ketamine and propofol
Ketamine has a long history of being used as an anesthetic. To better understand the mechanisms by which ketamine functions, researchers conducted testing comparing ketamine to another commonly used anesthetic; propofol.
They found that "... ketamine combined both aspects of normal consciousness and aspects of anesthetic “sleep.” This created a kind of liminal space where some of the aspects of the brain dynamics of macaques on ketamine looked a lot like propofol, while others looked a lot like wakefulness.
When they plotted the brain activity on a graph, the researchers found that ketamine-induced brain activity was just that — right between wakefulness and anesthesia-induced sleep.
“We hypothesized that this might explain why the state of consciousness produced by ketamine is as strange as it is,” Varley says. “You have the anesthesia-like components, like lack of responsiveness and diminished sensation, but also some vivid consciousness-like components like complex visual experiences and continued awareness.”
How ketamine works in the brain on the macro-scale
A June 2020 study published in Nature found that high doses of ketamine stopped activity in the cerebral cortex, in sheep.
"The researchers in that study observed the sheep’s brain waves oscillated between lower frequency theta waves and higher frequency gamma waves. These oscillations might represent that in-between state of not being totally awake or totally asleep Varley and his colleagues were able to chart on that scatter plot."
Researchers hope to “bring together the consciousness-science aspect of the analysis with the mental health aspect to try and understand if we can get new insights into how drugs like psilocybin and LSD can have such remarkable effects when used to treat disorders like depression.”
How ketamine can be used to treat depression
This study supports us in better understanding how ketamine treats depression. "At the micro-level, we know that by blocking certain receptors, ketamine increases levels of glutamate in the brain. These increased levels are associated with the unique dissociative state ketamine produces. It may also help repair dendrites and facilitate neuron growth, addressing one likely cause of depression."
Those dissociative states exist in a grey area that is somewhere between being awake and under anesthesia. As past studies have demonstrated, the activity in the cerebral cortex is greatly reduced in these states. This could explain the "ego-death" experience since much of our executive functioning and sense of self are processed in the cerebral cortex.
More studies are warranted for us to better understand the mechanism responsible for the efficacy of ketamine as a viable treatment option for depression.
