Here’s How Ketamine Affects The Brain

Here’s How Ketamine Affects The Brain

To understand how ketamine works, you need to know how it affects the brain. The therapeutic effects of ketamine come down to these brain changes, which are diverse and multi leveled.

This post takes a look at how ketamine causes changes in the brain at the level of neurotransmitters, as well as brain regions. We will also describe the psychological effects associated with these changes, such as psychedelic experiences and improvements in depression.

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Ketamine and Glutamate

At the level of neurotransmitters, we find that ketamine changes the levels of glutamate. Glutamate is an excitatory neurotransmitter. It is in a balanced state, or “homeostasis,” with GABA (gamma-Aminobutyric acid,) which is an inhibitory neurotransmitter. Think of Glutamate as the “gas pedal” and GABA as the “brakes” of central nervous system. Many factors can alter the balance in the glutamate and GABA systems, including states of high anxiety, mood changes, and physical dependence on heavy CNS depressants (e.g., benzodiazepines, alcohol, opioids). Ketamine can help restore this balance. 

Glutamate is a chemical that has links to major depressive disorder (MDD). Ketamine is an antagonist of the NMDA receptor, a type of receptor for glutamate. The drug actually blocks these receptors, which then produces an increase in levels of glutamate. The burst of glutamate is brief, correlating with how long the dissociative effects of ketamine last.

According to the glutamate hypothesis of depression, clinical depression results from a malfunction in the brain mechanisms that regulate glutamate levels. The way that ketamine changes the brain seems to support this hypothesis. As the authors of a study published in Biological Psychiatry state, “The increase in glutamate release produced by ketamine seems to be essential for its antidepressant effects”.

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Ketamine and Synapses

Synapses are the small pockets of space between two cells (and also can mean between nerve cell and a gland or muscle cell.) This allows cells to pass electrical or chemical signals to each other. This is how cells communicate messages. Synapses also allow neurons to form circuits within the brain. Neuroscientist Ronald S. Duman has said the following:

“We and others in the field reasoned that ketamine, via this glutamate burst, could increase synaptic connections in brain regions known to undergo atrophy and loss of synapses in animals exposed to chronic stress and in depressed patients.”

In animal studies, Duman and other Yale researchers tested the effects of ketamine on synapses in the prefrontal cortex, an area of the brain that shrinks in patients with depression. “The results were astounding: a single dose of ketamine rapidly increased the number and function of these synapses,” says Duman. Also, the increase in the number of synapses occurred as early as two hours after a single dose of ketamine. This is consistent with the rapid antidepressant effects of the drug.

A single dose of ketamine can reverse the shortage of synapses from chronic stress. This helps behavioral issues such as anhedonia (the inability to experience pleasure, a common symptom of depression).

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How Ketamine Changes Brain Regions

Ketamine leads to changes in various brain regions. Illuminating results from studies show the following:

  • Ketamine enhances neural responses to positive emotion in the right caudate in patients with depression. After ketamine, there is greater connectivity to positive emotions.
  • Major depression decreases connectivity between the pre-frontal cortex/subcortex and the rest of the brain. However, this connectivity normalized after ketamine.
  • Decreased amygdala activation predicted the antidepressant effects of ketamine. The amygdala is a brain region from fear responses, and its activity often has ties linked to depression. However, the amygdala is more famously linked with anxiety disorders such as PTSD.
  • Decreased suicidality post-ketamine is correlated with decreased metabolism of glucose in the infralimbic cortex.
  • Improvements in depression are significantly correlated with increased glucose metabolism in the superior temporal gyrus, middle temporal gyrus, and cerebellum, and with decreased metabolism in the parahippocampal gyrus and inferior parietal cortex.
  • Decreased anhedonia following ketamine is related to increased glucose metabolism in the dorsal anterior cingulate cortex and putamen. The biggest improvements in depressive symptoms after ketamine are correlated with the largest metabolic increases in the right ventral striatum.

Furthermore, ketamine enhances structural plasticity in certain brain regions. Structural plasticity refers to the brain’s ability to change its physical structure. This is important in the context of depression. One study concludes the following.

“These results suggest that the prolonged antidepressant effects observed after a single infusion of ketamine in TRD [treatment-resistant depression] patients can be related to a transient enhancement of structural plasticity induced by a glutamate “burst” occurring not only in frontal and hippocampal neurons but also in mesencephalic DA neurons…Since MDD/TRD has been associated to defective neural plasticity, the structural plasticity induced by these treatments could be interpreted as a potential remediation of an underlying neurobiological mechanism that sustains depressive symptoms.”

Ketamine Switches Off The Brain

Researchers from the University of Cambridge have discovered that high doses of ketamine can temporarily switch off the brain. The researchers measured the brain waves of sheep sedated by the drug. Changes to these brain waves may explain the out-of-body experiences and state of complete oblivion (known as the ‘k-hole’) that ketamine can cause. Professor Jenny Morton, from the University of Cambridge’s Department of Physiology, Development and Neuroscience, said that “after the high dose of ketamine the brains of these sheep completely stopped. We’ve never seen that before. A few minutes later, their brains were functioning normally again — as if they had just been switched off and on.”

The researchers believe that this pause in brain activity may correspond to the experience of the k-hole, which is comparable to a near-death experience and associated with a feeling of peace and serenity. The purpose of this research was not to better understand the effects of ketamine, but to use the drug to “probe the brain activity in sheep with and without the Huntington’s disease gene,” said Morton. She also added the following.

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“But our surprising findings could help explain how ketamine works. If it disrupts the networks between different regions of the brain, this could make it a useful tool to study how brain networks function – both in the healthy brain and in neurological diseases like Huntington’s disease and schizophrenia.”

There’s Still Plenty of Positive Information To Learn

Indeed, studies have shown that ketamine can induce psychosis-like symptoms in both healthy volunteers and patients with schizophrenia. Other researchers share Morton’s belief that ketamine could help us better understand schizophrenia. Knowing how ketamine affects the brain is essential with respect to this objective.

Ketamine is a drug that affects the brain on many different levels. But we still don’t fully understand all the brain changes that occur after its administration, including all the alterations responsible for the compound’s psychedelic and therapeutic effects. Research continues to offer us surprising results on how exactly this drug works.

Sam Woolfe

Sam Woolfe

View all posts by Sam Woolfe

Sam Woolfe is a freelance writer based in London. His main areas of interest include mental health, mystical experiences, the history of psychedelics, and the philosophy of psychedelics. He first became fascinated by psychedelics after reading Aldous Huxley's description of the mescaline experience in The Doors of Perception. Since then, he has researched and written about psychedelics for various publications, covering the legality of psychedelics, drug policy reform, and psychedelic science.

Abid Nazeer

This post was medically approved by Abid Nazeer

Dr. Nazeer is the Founder and President of APS Ketamine/Advanced Psychiatric Solutions, which he established in 2016 as the first psychiatric outpatient ketamine clinic in Illinois. He is board certified in Psychiatry as well as Addiction Medicine. He completed his psychiatry residency at Louisiana State University Health Sciences in Shreveport where he held the role of Chief Resident. Dr. Nazeer is providing medical oversight to the growth plan of Wesana Clinics, with the model of comprehensive psychiatry clinics specialized ketamine and psychedelic therapies, integrated brain health and wellness centers, and technology utilization of Wesana Solutions remote patient monitoring product.

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