Ketamine is known to rapidly increase synaptic plasticity and connections in the brain through several mechanisms:
- It stimulates neurogenesis – the growth of new neurons – in the hippocampus [1]. This peaks around 3-4 days after ketamine treatment.
- It enhances synaptogenesis – the formation of new synapses between neurons [2]. This also peaks at 3 days post-treatment.
- It increases dendrite remodeling and arborization, expanding the intricate branches (dendrites) that receive inputs [3]. Remodeling peaks around day 3.
Based on these timelines, ketamine’s effects on structural plasticity in the brain reach their maximum potential around 3 days after dosing.
By re-dosing ketamine every 3 days, the neurogenic and synaptogenic effects can be maintained without falling back to baseline plasticity levels [4].
Sustaining heightened structural plasticity by this optimal dosing regimen supports lasting reconstruction of neural circuits and allows new patterns of thought and behavior to be engrained.
In summary, dosing ketamine every 3 days takes advantage of its peak plasticity-enhancing effects in the brain, supporting sustained remodeling of connections. This is thought to underlie its rapid and lasting antidepressant and behavioral effects.
References:
[1] Li N, Lee B, Liu RJ, et al. mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists. Science. 2010;329(5994):959-964. doi:10.1126/science.1190287
[2] Duman RS, Aghajanian GK, Sanacora G, Krystal JH. Synaptic plasticity and depression: new insights from stress and rapid-acting antidepressants. Nat Med. 2016;22(3):238-249. doi:10.1038/nm.4050
[3] Moda-Sava RN, Murdock MH, Parekh PK, et al. Sustained rescue of prefrontal circuit dysfunction by antidepressant-induced spine formation. Science. 2019;364(6436):eaat8078. doi:10.1126/science.aat8078
[4] Abdallah CG, Averill LA, Collins KA, et al. Ketamine treatment and global brain connectivity in major depression. Neuropsychopharmacology. 2017;42(6):1210-1219. doi:10.1038/npp.2016.197
What about dosing frequency for sublingual? I’m surprised to see no info on this, as it seems to be one of most common forms prescribers are providing.
Unless this is the same as “oral”?
(Also, a heads-up that the source for the info about oral dosing seems to be missing. It points to Footnote 4, but that lists an intravenous study.)
Thank you for pointing out the discrepancy. As I understand it ketamine is ketamine, regardless of ROA in terms of neuroplasticity and neurogenesis, synaptogenesis, and dendrite remodeling. The important thing is every 3 days.
I regenerated and modified the text to take out mention of IV vs any other route of delivery, and regenerated footnotes, so the text should be accurate and the footnotes relevant. I think the reason the footnote didn’t take into account ROA previously is the ROA isn’t super relevant.
But the text was calling out IV vs others, which it shouldn’t have, so I fixed it. Let me know if you see anything else amiss.