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Comment by johnisgood | Hacker News Reader

It is not neurotoxic, in fact, it is the opposite due to it being an NMDA receptor agonist (neuroplasticity). I thought we have known this for a long time. It could be, in very high doses. Just like you can die from water intoxication too.

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Ketamine is a NMDAr antagonist, not a NMDAr agonist. Strong agonists can cause excitotoxicity whereas strong antagonists can cause shrinkage.

Agreed, it was a typo.

You might want to take a look at https://pmc.ncbi.nlm.nih.gov/articles/PMC3713393/.

In animal models it also seems like the dopaminergic effects are strong enough to cause midbrain downregulation and lower dopamine neuron density. If you've ever taken ketamine recreationally you've likely noticed the very strong dopaminergic effects, though maybe not been able to classify them as such.

Interesting, thanks. Whilst ".2G Twice a week, for 6 months" doesn't strike me as a lot- could be someone who just goes clubbing twice a week- apparently enough to cause brain lesions. Anyone know if the study is reputable, or could answer the question whether the "lesions" could be something like regions of the brain responsible for/exacerbating mental issues which have been altered by the treatment- ie, the method of action for treatment.

You are more likely to get brain lesions from DXM, called Olney's lesions, but it could happen from any NMDA receptor antagonists.

I have taken smaller, and larger doses of ketamine before, I personally did not experience the claimed strong dopaminergic effects.

What was I supposed to experience for this dopaminergic effects? Maybe I could tell you.

At dissociative doses ketamine typically induces a strong feeling of expectation, of something fantastic or important being imminent, things like that. To some people this takes a religious form, like (almost) coming into communication with some ethereal being or (almost) reach some mystical insight.

It can cause a strong urge to redose.

Do you recognise any of this?

I went into a k-hole (a few times) where I was seeing myself from the outside (with all my flaws and faults being shown to me), and I remember my then-girlfriend slipping away from me and I tried to grab into her but she slipped away, and I remember being locked in time (not sure how to explain it). I did DXM too, that was less clean than ketamine and DXM had more of an alienish-vibe to it and I ended up watching Stargate Atlantis on it, that was fun, but ketamine had me self-reflect quite a lot.

About expectations & imminent, it made me want to change the way I live as I am pretty much a reclusive.

I wish I could explain it better but I really can't. I never felt an urge to re-dose, however.

lol, what?

NMDA receptor agonists can be directly neurotoxic. See, e.g.: https://pubmed.ncbi.nlm.nih.gov/9109508/

Also: https://www.mdpi.com/2039-4713/15/1/12

> "Normal NMDA receptor (NMDAR) function is essential for neuronal development and higher brain functionality, while its inappropriate stimulation results in neurological deficits."

I made a typo, it is a NMDA receptor antagonist.

Additionally, I can find sources supporting my claim, too.

> Results in rodent models indicate that a single dose of ketamine induces robust markers of neuroplasticity in depression-relevant brain regions, including increased BDNF release and the stimulation of mTOR signaling in the PFC [23, 24]. In addition, ketamine induces an increase in synapse number and function in the PFC, reversing the loss of specific synapses by stress, an effect that seems necessary for the persistence of its antidepressant-like behavioral effects.[1]

[1] https://www.nature.com/articles/s41398-023-02451-0

From Wikipedia:

> Ketamine is under investigation for its potential in treating treatment-resistant depression. Ketamine is a known psychoplastogen, which refers to a compound capable of promoting rapid and sustained neuroplasticity.

Additionally: https://www.resetketamine.com/blog/2021/6/2/ketamine-and-its...

Additionally #2: https://pmc.ncbi.nlm.nih.gov/articles/PMC8190578/

Additionally #3: https://www.sciencedirect.com/science/article/abs/pii/S01656...

> Ketamine (NMDAR antagonism) and classical psychedelics (5-HT2AR agonism) trigger a long-lasting state of enhanced glutamate-driven neuroplasticity in frontocorticolimbic pyramidal neurons.

Your counterclaim is based on the unsupported assumption that a substance having relatively high neurotoxic potential means that it cannot induce neuroplasticity. The two are not mutually exclusive, and in the case of the substance in question, it is well known to have both high neurotoxic potential, as all strong NMDA antagonists do, as well as the ability to induce increased neuroplasticity.

Yes, you are pretty much correct.

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