“Ketamine part 2: What do in vitro studies tell us about safety?” by Elizabeth

Sep 8, 2025

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Ketamine is an anesthetic with growing popularity as an antidepressant. As an antidepressant, it's quite impressive. When it works, it's often within hours- a huge improvement over giving a suicidal person a pill that might work 6 weeks from now. And it has a decent success rate in people who have been failed by several other antidepressants and are thus most in need of a new option.

The initial antidepressant protocols for ketamine called for a handful of uses over a few weeks. Scott Alexander judged this safe, and I’m going to take that as a given for this post. However, new protocols are popping up for indefinite, daily use. Lots of medications are safe or worth it for eight uses, but harmful and dangerous when used chronically. Are these new continuous use protocols safe?

That's a complicated question that will require several blog posts to [...]

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Outline:

(01:15) Reasons to doubt my results

(03:09) Tl;dr

(08:58) Papers

(09:51) Ketamine Increases Proliferation of Human iPSC-Derived Neuronal Progenitor Cells via Insulin-Like Growth Factor 2 and Independent of the NMDA Receptor

(11:57) Ketamine Induces Toxicity in Human Neurons Differentiated from Embryonic Stem Cells via Mitochondrial Apoptosis Pathway

(14:42) (2R,6R)-Hydroxynorketamine promotes dendrite outgrowth in human inducible pluripotent stem cell-derived neurons through AMPA receptor with timing and exposure compatible with ketamine infusion pharmacokinetics in humans

(16:18) Ketamine Causes Mitochondrial Dysfunction in Human Induced Pluripotent Stem Cell-Derived Neurons

(18:05) Ketamine Prevents Inflammation-Induced Reduction of Human Hippocampal Neurogenesis via Inhibiting the Production of Neurotoxic Metabolites of the Kynurenine Pathway

(19:11) The effects of ketamine on viability, primary DNA damage, and oxidative stress parameters in HepG2 and SH-SY5Y cells (the negative one)

(21:25) Why In Vitro Studies?

(25:09) Conclusion

(25:28) Thanks

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First published:
September 7th, 2025

Source:
https://www.lesswrong.com/posts/kjbq7T7Z2vEDoPw95/ketamine-part-2-what-do-in-vitro-studies-tell-us-about

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Narrated by TYPE III AUDIO.

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Images from the article:

Two simple line graphs: one curved with peak, one rectangular pattern

Graph showing ketamine's effect on cell viability over different time periods.

Bar graph showing cell viability with Trolox and Ketamine concentrations.

Two bar graphs showing dendrite length and number under different conditions (HNK/K).

The graphs display measurements at timepoints V, 1h, and 6h, with asterisks indicating statistical significance. The top graph shows dendrite length in micrometers, while the bottom shows dendrite number, both with white and gray bars representing different experimental groups.

Research graphs showing cell proliferation data comparing BDNF and ketamine treatments over time.

The image consists of three graphs:
A) Line graph tracking cell-body cluster area over 72 hours
B) Two bar graphs showing proliferation percentages at 24h and 72h incubation periods, comparing control groups with varying concentrations of BDNF and ketamine treatments.

The graphs demonstrate comparative effects of different treatment concentrations on cellular growth and proliferation rates.

Three bar graphs showing Caspase 3/7, ROS, and Cell Viability with ketamine treatments.

The graphs compare measurements at 6 hours (blue bars) and 24 hours (red bars) across different ketamine concentrations (0-500 μM). All three graphs display experimental results related to cellular responses to ketamine exposure.

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