For Thomas Varley, who researches how different consciousness-altering drugs affect the complexity of dynamic brain activity, the mystery lies in how the complex science of ketamine translates into its physical (and mental) effects.
“We know a lot about what is happening at the level of individual neurons and receptors,” Varley tells Inverse, “and we know what kind of mind-altering effects these drugs induce in humans, but how do you get from Point A to Point B?
“How do you get from Point A to Point B?”
“How is it that a small bundle of carbon interacting with the NMDA receptor results in out-of-body experiences, hallucinations, and other exotic states of consciousness?”
Understanding what ketamine does in the brain could be vital in not only treating depression but furthering our understanding of other mood disorders. When an estimated 792 million people globally have mental health disorders, understanding how they work — and the mechanism by which certain drugs can alleviate them — is vital for public health.
Here are four critical questions (and answers) to help you get a better sense of what ketamine does to your brain, and how that could lead to new treatments for the stubborn condition that is depression.
4. How does ketamine work 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.
But for our purposes, we’re going to focus on glutamate, so you can forget about that other one.
There are many kinds of glutamate receptors. One type is the NMDA (N-methyl-D-aspartate) receptor, which functions as a tiny gate on the neuron’s surface that can open and close. When glutamate binds to it, the gate opens and ions rush in, increasing the probability it will fire.
Ketamine functionally blocks the gate, which prevents the signal from passing through it. This results in bursts of increases in glutamate levels in the brain, and these bursts are correlated with the dissociative states ketamine produces.
If that’s too confusing, here’s a helpful metaphor. Picture a bunch of people trying to get into your house for a party. If you block all the doors, they’re not going to come in, but they will party in the street. In this metaphor, glutamate is the people and ketamine is the bouncer blocking the door to your house. Because they can’t get into your house, the glutamate is increased in the street, in this case, your brain.
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.
3. Ketamine vs. propofol: What’s the difference?
Before ketamine was a club drug, it was an anesthesia. Created in the 1960s, it was used for over a decade before physicians realized the duration of its anesthetic properties was shorter and less potent than other options. One of those options was propofol, which is still used in surgeries today.
In hopes of better understanding ketamine’s Point A to Point B journey, Varley and his colleagues analyzed differences in the brains of macaques when they were on propofol compared to ketamine.
By comparing the brains of macaques when they were on the two drugs, researchers hoped to understand why ketamine has anesthetic properties similar to propofol, while still producing markedly different effects.
The researchers used data taken from electrical recording devices placed on the brains of macaques while anesthetized with the two drugs. The results were published in June in Royal Society Open Science.
What they found– Varley and his colleagues determined 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.”
2: How does ketamine work in the brain on the macro-scale?
Varley and his colleagues’ findings make sense with what we know about what’s happening in the brain during “k-holes” or disassociative states induced by the drug. A June 2020 study published in Nature found that when sheep were on high doses of ketamine, activity in the cerebral cortex stopped.
Following the publication of the study, Jenny Morton, the lead study author and a professor of neurobiology at The University of Cambridge, tells Inverse that while there must have been some brain activity happening in the deep brain, the cerebral cortex, which is “usually very active, had just gone very quiet.”
“The activity in the cortex in some of the sheep stops completely for a short time,” she says, “but the brain is NOT dead or damaged.”
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.
Despite all we know about ketamine, there’s much that remains a mystery. Varley plans to continue working on ketamine and other hallucinogenic drugs.
Ultimately, Varley hopes 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.”
1. How can ketamine be used to treat depression?
Varley’s study builds on what we know about ketamine and brings the mechanisms by which ketamine treats depression into clearer focus. 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 being completely knocked out by anesthesia. We know from previous studies that despite having some awareness during these states, the activity in the cerebral cortex is greatly reduced. The cerebral cortex is where much of our executive functioning and sense of self is processed. This reduced activity is likely responsible for the “ego-death” that occurs on high doses of ketamine.
Ultimately, there are still some mysteries about why ketamine is so effective in treating depression, perhaps because there’s still so much we don’t understand about depression. But every new study builds on what we know, bringing us closer to a holistic picture of the neurobiology of depression and how to treat it.