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What Neurotransmitters Does Ketamine Affect Most In The Brain?

What Neurotransmitters Does Ketamine Affect Most In The Brain?

Psychedelic compound chemicals can affect a range of neurotransmitters in the brain. However, some alter the levels of a particular neurotransmitter more so than others. The serotonergic psychedelics, for example, as their name suggests, strongly affect the neurotransmitter serotonin. These compounds include DMT, LSD, mescaline, and psilocybin.

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Ketamine is distinct from these serotonergic psychedelics, however. It can result in psychedelic effects and mystical experiences like psilocybin, for example, without mainly affecting serotonin. While ketamine does have an effect on serotonin in the brain, the neurotransmitter that ketamine affects most in the brain is glutamate. Ketamine is a dissociative anesthetic. For this reason, it leads to mind-altering effects through different alterations of neurotransmitters compared to classic psychedelics

In this article, we will look at the characteristics of glutamate, how ketamine affects glutamate, how glutamate mediates the therapeutic effects of ketamine, and some of the other neurotransmitters that ketamine affects.

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What Is Glutamate?

Glutamate is an amino acid and, by a wide margin, the most abundant excitatory neurotransmitter in the nervous system of vertebrates. Excitatory neurotransmitters are, as the name suggests, neurotransmitters that have excitatory or stimulating effects on neurons. This means they encourage a neuron to take action. They make it easier for neurons to fire and transmit an electrical signal toward other neurons.

Glutamate is present in over 90 percent of all brain synapses (the small gaps between cells that allow cells to send messages via neurotransmitters). Glutamate plays an important role in learning and memory. As well as being produced in your body, glutamate is present in many foods, with high concentrations of the amino acid in cheese, nuts, processed meats, and tomatoes.

How Ketamine Affects Glutamate In The Brain

Ketamine has a paradoxical effect on the brain. It blocks NMDA receptors (a type of glutamate receptor) but this actually increases levels of glutamate. The burst of glutamate is rapid and transient, which correlates with how long the dissociative effects of ketamine last.

Ketamine causes a surge in glutamate in the prefrontal cortex, a brain region responsible for a variety of executive functions (higher-level cognitive skills), such as focusing one’s attention, predicting the consequences of one’s actions, anticipating events in the environment, impulse control, and managing emotional reactions. The psyhedelic also increases levels of glutamate in other brain regions, such as the hippocampus (which plays a major role in learning and memory).

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Glutamate, Ketamine and Mental Disorders

Sure, ketamine is a promising treatment for major depressive disorder (MDD). But why? Well, in cases of MDD, researchers have observed decreased glutamate in various regions of the prefrontal cortex, including dorsolateral prefrontal cortex (dlPFC), dorsomedial PFC (dmPFC), and the anterior cingulate cortex (ACC).

The ‘glutamate surge’ hypothesis states that ketamine alleviates MDD by creating a surge in glutamate levels in brain regions that have a deficit of this neurotransmitter. By normalizing glutamate levels, ketamine can resolve symptoms of depression like persistent low mood and anhedonia (the inability to feel pleasure).

This hypothesis is debatable, nonetheless. Studies suggest that the immediate surge in glutamate due to ketamine is related to the compound’s rapid antidepressant and anti suicidal effects. But these beneficial effects persist long after the ketamine infusion, peaking at 72 hours and lasting for 1-2 weeks. It is unclear if glutamate levels stay elevated post-infusion. Multiple studies have found no correlation between the antidepressant effects of ketamine and glutamate levels before, during, and after ketamine infusions.

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Still, some evidence points to a surge in glutamate playing a role in ketamine’s therapeutic effects. One explanation for ketamine’s persisting beneficial effects is that the increase in glutamate in the prefrontal cortex enhances synaptic plasticity in this brain region. Synaptic plasticity refers to the ability of synapses — the junctions between neurons — to change. After ketamine, this change involves an increase in prefrontal connectivity in patients with major depression. This means these patients have more synaptic connections in their prefrontal cortex.

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Understanding The Different Neurotransmitters

Global connectivity is the term used to refer to the connections both within and outside a brain region. Ketamine may improve depression — and other mental disorders — by increasing global connectivity in the prefrontal cortex, which will affect the ability of this brain region to coordinate control of other brain regions. For example, a study published in Neuropsychopharmacology states: “The ketamine-induced subacute increases in prefrontal connectivity were positively associated with the antidepressant response.”

Separate research, published in Frontiers in Psychiatry, highlights that MDD patients and suicidal patients have abnormalities in the connections between the prefrontal cortex and amygdala. The amygdala is responsible for our fear responses and in depression, this brain region is overactive, which likely creates a cognitive bias toward looking at the world and the self in a negative way.

This hyperactive amygdala seems to be the result of reduced connectivity between it and the prefrontal cortex. When this happens, the prefrontal cortex essentially loses control of the amygdala, making it harder for individuals to regulate their emotions, as well as increasing their negative thoughts and emotions.

One possible explanation is that by normalizing the connectivity between the prefrontal cortex and amygdala, via glutamate, ketamine can help reduce depressive symptoms long after a ketamine infusion. However, ketamine may improve depression in other ways as well, as we will see in the section below.

How Ketamine Affects Other Neurotransmitters

Ketamine may also act as an antidepressant by boosting serotonin levels in brain areas involved in motivation. The drug releases dopamine in the brain, too, which has been implicated in the treatment of psychiatric disorders.

Furthermore, a study published in PNAS discovered that blocking opioid receptors in the brain prevents the antidepressant effects of ketamine. For this reason, the authors of the study state that opioid neurotransmitters are necessary but not sufficient for the antidepressant effects of ketamine. Indeed, other research suggests that ketamine’s antidepressant effect requires the activation of the opioid system.

The way that ketamine changes neurotransmitters in the brain is complex and not fully understood. However, so far, it appears that the therapeutic effects of ketamine are related to effects on multiple neurotransmitters. Moreover, it’s crucial to understand that the longer-lasting antidepressant effects of ketamine are due to the way that these neurotransmitters can restore the normal functioning of the brain.

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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.

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