First and foremost, anyone who claims they know exactly how ketamine works isn’t revealing the entire truth. We don’t fully understand the exact mechanism by which ketamine alleviates depression, anxiety, or PTSD. Several hypotheses exist, and in today’s post, we’ll discuss these theories at a molecular level. In the end, we’ll simplify the discussion to show how ketamine affects your brain during treatment by interacting with the Default Mode Network (DMN).
Note: Sources for the following theories come from the textbook “Ketamine for Treatment-Resistant Depression: The First Decade of Progress” by Sanjay J. Mathew and Carlos A. Zarate Jr.
Table of Contents
- Molecular Mechanism of Action
- Default Mode Network Effects
1. Mechanism of Action
Low-dose IV ketamine has clinically demonstrated swift and lasting benefits for those struggling with a variety of mental health disorders, but the exact mechanism of action of how it alleviates symptoms of depression, PTSD and anxiety is unknown. There have been several reproducible hypotheses that we believe provide strong evidence for its use in treating these disorders.
Actions At The Molecular Level
From a molecular perspective, we understand that ketamine binds to numerous receptors in the human body. However, experts believe the most significant receptors are NMDA and AMPA. When ketamine attaches to the NMDA receptor, its effects vary based on its binding location in the brain. This receptor cascade eventually increases the production of the neurotransmitter glutamate.
Downstream Effects
The increased glutamate’s downstream effects activate a receptor known as the AMPA receptor. There is an ongoing debate on whether the actual stimulation of AMPA receptors is the primary reason we observe the antidepressant & antianxiety effects of ketamine.
Receptor Activation
When glutamate release activates AMPA receptors, it initially triggers another signaling cascade, which then initiates the rapamycin (mTOR) pathway. This increases the so-called brain-derived neurotrophic factor (BDNF). The final outcome is an enhanced density of dendritic spines, which are tiny, finger-like extensions on brain cells that enable them to connect and communicate.
Signaling Pathways
Through this signaling pathway and the subsequent increase in dendritic spines, studies have demonstrated that ketamine boosts what experts call “neuroplasticity.” Simply put, neuroplasticity refers to the brain’s enhanced growth and its augmented capacity to communicate, change, and adapt.
Other Hypotheses
Some experts believe that this boost in dendritic spines, not just the blockade of NMDA receptors or the stimulation of AMPA receptors, causes the rapid onset antidepressant & antianxiety effect. Furthermore, a range of other receptors, such as sigma-1 receptors, the norepinephrine transporter (NET), m-opioid receptors, and the serotonin transporter (SERT), might also play a role.
2. Default Mode Network (DMN)
Ketamine affects what experts call the Default Mode Network (DMN). Think of the DMN as your brain’s “auto-pilot.” It comprises specific brain areas that activate when you’re not actively engaged in tasks, such as when daydreaming or reminiscing. For clients battling depression, anxiety, or PTSD, this “auto-pilot” mode can become overpowering. For those grappling with mental health issues, the DMN often generates persistent negative thoughts or ruminations, obscuring any positive perspective on life.
If that doesn’t make sense, let me give you an example:
Imagine you are an NBA player on a basketball court. Typically, the game has periods of high action – you make shots, defend against opponents, and run plays – interspersed with breaks on the bench or between plays. During these breaks, you catch your breath, review strategies, and plan your next move. In this analogy, when you play the game, it’s like your brain focusing on the external world. Conversely, the breaks represent the brain’s default mode network, a time for reflection, strategy, and self-assessment.
What Happens When You Get Stuck?
Now, imagine you are a player stuck in the default mode network or “bench mode,” even while on the court. You stand in the midst of a game, but instead of diving into the action, past mistakes consume your thoughts, concerns about future games plague you, doubts about your skills unsettle you, and you analyze your performance excessively. The internal narrative distracts you, preventing full engagement in the game. It’s as if your mind has trapped you on the bench even when you should actively be playing on the court.
How Does That Relate to Mental Illness?
That’s a bit like the experience of someone with severe depression, anxiety, or PTSD. Even though they wish to engage with the world, their brain keeps them persistently in “default mode.” They ruminate on past mistakes, worry about the future, and often feel worthlessness or guilt. It’s a challenging state of mind, which underscores the importance of treatment for those with depression.
Tell Me The Good News
Now, here’s the good news! Clinical trials have shown that low-dose IV ketamine decreases activity in the default mode network. This treatment lets you break free from “bench mode” and fully engage with life! We trust that low-dose IV ketamine could be your catalyst to reclaim the All-Star status we know lies within you!
Frequently Asked Questions
The exact mechanism is unknown, but we know that ketamine binds to the NMDA receptor and starts a neuronal signaling cascade pathway that results in a multitude of downstream effects involving glutamate, AMPA receptors, and mTOR receptors amongst others, albeit to a lesser degree.
In simple terms, neuroplasticity is an increase in brain growth and your brain’s ability to communicate, change and adapt. Ketamine has been clinically shown to increase neuroplasticity, which many theorize is a key factor to ketamine’s antidepressant and antianxiety effects.
The default mode network (DMN) is like your brain’s “auto-pilot.” It’s a set of brain areas that become active when you’re not directly engaged in tasks, like when you’re daydreaming or reflecting on memories. For someone with depression or anxiety, the DMN might produce persistent negative thoughts or ruminations, making it hard to see their life in any positive light at all.
Low-dose IV ketamine has been clinically shown to decrease activity in the default mode network, which allows you to break free from these rigid, ruminating thoughts. This allows you to look inwardly and reframe your thoughts into a more positive outlook.
