Dr. Ben Yudkoff, Co-Founder and Chief Medical Officer at Lumin Health, hosted a Reddit AMA on r/TherapeuticKetamine community on March 6th, 2026\. The below blog post is a recap of one of the questions presented on that AMA, syndicated to the Lumin Health blog in the event that it answers any questions about ketamine therapy, Spravato treatment, or general concerns you may have about treatment.
[https://www.reddit.com/r/TherapeuticKetamine/comments/1rj2blv/ama\_im\_dr\_ben\_yudkoff\_psychiatrist\_cofounder/](https://www.reddit.com/r/TherapeuticKetamine/comments/1rj2blv/ama_im_dr_ben_yudkoff_psychiatrist_cofounder/)
Don’t hesitate to get in touch with us if you’re interested in learning more about ketamine for depression at Lumin Health. Thank you once again to the moderators and community members for facilitating such an engaging discussion.
Every\_Tab\_4099 asks:
Do we know how or why ketamine works, and how do you think its use will progress?
Answer from Dr. Ben Yudkoff, Co-Founder and Chief Medical Officer of Lumin Health:
Every Tab, that's a good question with a loooooong answer. There are 4 main described ways by which ketamine is thought to work biologically and one way that it's thought to work phenomenologically. Grab a sandwich and a comfortable spot to sit, and let’s dig in…
- 1. The first way is by exercising brain cells: Ketamine (and esketamine (Spravato)) causes brain cells to release a neurotransmitter called “glutamate.” Glutamate is an activating neurotransmitter. The extra excitation that that increased glutamate causes to adjacent cells functionally gives them something like exercise. In response, the brain cells release a growth hormone called brain derived neurotrophic factor. BDNF helps the brain cell become more brain cell-y: it enhances the brain cell's capacity to connect to other brain cells through a process called “synaptogenesis.” This process has two implications for the mechanism of action. The first is that it may reverse some of the neurological signs of depression: one of the potential physical correlates of depression is a relative paucity of synapses. Ketamine/esketamine can help restore connections that may have been lost in the experience of depression. Secondly, the brain cell, in its enhanced ability to form these connections, is better able to lay down the white matter tracks that are the physical correlates of routine behaviors and thoughts – the brain might be better able to encode information. Let’s take behaviors first: When people are depressed they tend to lose the habits of healthy living – circadian rhythm becomes distorted, people take to bed, stop going to prayer services, and so on. When the brain is in a position to grow and lay down the hard wiring that correlates with more automatic behavior, it becomes easier to quickly wire healthy habits into the rhythms of life. This neuroplasticity may also impact thoughts. Que the world of CBT: in the world of cognitive behavioural therapy, people talk about the thoughts that generate the depressed experience as “schema.” These schema are ways of understanding the world that either skew towards a negativistic compression of the world or interpret the world in such a way that the result of the interpretation is a person encountering the world with a sense of displeasure or depression. CBT focuses on resolving some of these schema by challenging existing thoughts and suggesting new thoughts and experimenting with them. When a person is depressed, they might feel personally devalued: “I'm not good enough,” for example. It may take some time to resolve that automatic thought \- the resolution of that automatic thought comes with practice, with challenging the thought, and also with applying other thoughts. Ketamine may help hard code bringing in some of those other thoughts. It might make it easier to change one's mind. We do a lot of work with people at Lumin to look into those thoughts and behaviors and help a person find ways of returning their experience.
- 2. Ketamine impacts opioid receptors. It increases the number of mu opioid receptors, which are the types of opioid receptors that receive endorphins – chemicals responsible for a runner's high. By doing so, ketamine sensitizes brain cells to the experience of a runner's high, manifesting a sense of calm, better mood, and improved attention. Ketamine also blocks something called kappa opioid receptors, which are receptors involved in tuning the brain towards a stress response. It's possible that the way that the way ketamine modifies these kappa opioid receptors changes the way the brain is inclined towards remodelling pursuant to our traumatic experience.
- 3. The 3rd way is through modification of a type of cell called an “astrocyte.” An astrocyte is a cell in the brain that does a lot of things, including supporting how the brain perceives futility \- hopelessness. The perception of futility involves, at least at first, an inchoate, prelogical calculation \- a measurement of how motivated I am towards something; what are the risks; how are my efforts yielding results; and so on. The perception of futility is supported by astrocytes. Ketamine can down-tune the activity of these astrocytes, which has ripple effects: the strength of futility detection (which may be exaggerated in depression) is less supported. The resulting cognitive shift is that things that once seemed impossible may now seem difficult, but achievable. Behaviourally, people might do things differently – like apply for a job – whereas before ketamine, they may have thought it was impossible to get that job \- the perception of futility has shifted. The bar at which futility is detected has been raised, and this has real wide-ranging implications for how ketamine might be able to help people engage in behaviours, which then in turn continue to help them.
- 4. The 4th way is through the impact of ketamine in a portion of the brain called the default mode network. The default mode network does a lot, but to distill its functions for this context, we can say it supports with self-referential thinking and helps to make sense of circumstance. It doesn't do it in a very fine tuned, logical way, using words and reason though; it just gives an impression. The DMN aggregates large amounts of information and provides a gross impression. When we look at the brains of people who have depression with a type of test called a ‘functional magnetic resonance imaging’ we see changes in how the default mode network operates, including heightened activity in certain portions this network, rather, that incline towards a negativistic impression of an otherwise neutral stimulus. And what they notice is that, after ketamine is administered and leaves the system, those parts of the brain that were once hyperactive are quieter, and the subject’s default mode network starts to look more like the default mode network of somebody without depression.
And then there is the phenomenological component, which has a lot to do with the mind-altering quality of the ketamine treatment experience. During these moments, people might be exposed to awe or wonder that a person may have been deprived of in the midst of a depressed episode. That reintroduction can change how people might be enthused to see the world, there's more tantalizing mystery, there's more recognition of how extraordinary things can be (even in the midst of challenge). There may be that reintroduction or that insinuation, that things might be quite magical. And that can change someone's perspective quite tangibly and durably.
There is a freedom of association during the ketamine experience where thoughts that would typically run together don't run together when under the influence of ketamine, and when you don't have that bias, you potentially notice different connections. Those things that people see need to be qualified after the treatment session is done, to test their veracity and to explore whether or not these new perspectives hold water, but sometimes new and highly relevant ideas can be generated.
Psychedelia can also provide the sense of dissociated distance. People might be able to think back on hardships without being flooded by intense, overwhelming emotions, which gives people an opportunity to look at a memory during the ketamine experience with more remove. Sometimes doing that allows a person to move through the memory and create a different relationship with that memory, with implications for how a person knows oneself.
Regarding the 2nd part of your question: how do you think ketamine’s use will to progress? I think the key to that question is how wide-ranging ketamine's impacts are. For disorders in which perception, recollection, mood, and/or physical disconnection – in terms of brain cells – are a component, there may be a role for ketamine. We're seeing people studying ketamine and bipolar depression, OCD, anxiety disorders, and PTSD just to name a few. I also suspect the evidence will continue to grow and will get better and better about prognosticating who might be most eligible for having a positive outcome when it comes to these feelings.
