Ketamine’s main use for me is its ability to enhance appreciation and especially immersion for all kinds of media. It’s mildly psychedelic too and I find it to increase creative thinking and a lowering of pre-conceived notions and static thought patterns. The mix of calmness and immersion seems to help with ADHD symptoms although there are better substances for that. The medium-term anti-depressive effect that follows its use is a nice bonus also counters the occasional low grade anhedonia that even non-depressed people experience.
I find its social use (ie. in clubs) to be overrated, only small bumps should be used which are almost the same in effect with alcohol but with better disinhibition and music appreciation. Anything more will mostly just create problems. Ketamine is better used home alone to enhance audiovisual experience and immersion. The first times are usually more manic as the enhancement of music is almost overwhelming, at least for me. As one starts acclimating to the substance, it will take a more calm and introspective and less hedonistic role, but will still remain an overall experience enhancer.
Although simple in theory, I’ve seen many chronic users claim that they still haven’t figured out the substance fully and I identify with them: it sometimes feels like cold clinical dissociation, and sometimes it feels completely magical, seemingly randomly. When I haven’t used it for a while I might make preparations for a nice night and take a lot of it and not get much from it, while other times that I decide to just take a small bump to relax ketamine puts out its best self and makes me snowball for hours unexpectedly, having the time of my life.
In any case people should dive in without expectations, start small and decide on the spot if they should continue. Take small bumps every 20 mins or so depending on mood, let yourself snowball if you feel like it. Doing big doses immediately almost always leads to confusion and no good effects. Also not everyone likes to k-hole, it’s overrated and even if you want to do it again start small.
2-FDCK is ketamine’s almost indistinguishable cousin that’s still legal and easy to find in high quality. It might be slightly less hedonistic and more introspective and longer-lasting, has good oral bioavailability, and is harder to k-hole on.
Brief Primers on the Neuroscience of Psychedelics 4: The NMDA Antagonists
- A randomized placebo-controlled PET study of ketamine´s effect on serotonin1B receptor binding in patients with SSRI-resistant depression
- Some comments by Haidut
- Most other studies suggest NMDA antagonism or complex being the reason why ketamine has antidepressant effects. But other similar NMDA antagonists do not act rapidly, suggesting a different mechanism at play with Ketamine. If this is true then most other studies are wrong.
- Possible role of brain serotonin in the central effects of ketamine
- Ketamine May Relieve Depression By Repairing Damaged Brain Circuits
- “…So Liston and a team of scientists from the U.S. and Japan gave mice a stress hormone that caused them to act depressed. For example, the animals lost interest in favorite activities like eating sugar and exploring a maze. Then the team used a special laser microscope to study the animals’ brains. The researchers were looking for changes to synapses. “Stress is associated with a loss of synapses in this region of the brain that we think is important in depression,” Liston says. And sure enough, the stressed-out mice lost a lot of synapses. Next, the scientists gave the animals a dose of ketamine. And Liston says that’s when they noticed something surprising. “Ketamine was actually restoring many of the exact same synapses in their exact same configuration that existed before the animal was exposed to chronic stress,” he says. In other words, the drug seemed to be repairing brain circuits that had been damaged by stress.”
- The study also suggests that the rapid antidepressant effects of the recently approved ketamine are likely due to being a functional or maybe even direct glucocorticoid antagonist.
- A role of GABAA receptor α1 subunit in the hippocampus for rapid-acting antidepressant-like effects of ketamine
- Mice exposed to FSS (forced swimming stress) showed depression-like behavior and decreased levels of GABA (γ-aminobutyric acid), but not glutamate, in the hippocampus. Ketamine increased GABA levels and decreased glutamate levels in the hippocampus of mice exposed to FSS. There was a correlation between GABA levels and depression-like behavior. Furthermore, ketamine increased the levels of enzymes and transporters on the GABAergic neurons
- Mechanisms of Ketamine Action as an Antidepressant
- There is a consensus from most pre-clinical research that AMPAR activity is required for the antidepressant actions of ketamine. Increased probability of glutamate release, either by interneuron-mediated disinhibition or direct action of (2R,6R)-HNK on pyramidal neurons may result in activation of AMPARs, and a subsequent activation of downstream neuroplasticity-related signaling pathways, including those regulated by BDNF and mTORC1, to promote protein synthesis and synaptic plasticity that are involved in ketamine’s behavioral antidepressant actions.
- Ketamine applications beyond anesthesia – A literature review
- Apart from BDNF and mTOR, ketamine administration is also related to an increase in hippocampal Synapsin levels. Since these are markers of neurogenesis and synaptogenesis and that ketamine induces synaptogenesis and spine formation in the prefrontal cortex, ketamine might execute its antidepressive functions through neurotrophic mechanisms.
- Neurobiological biomarkers of response to ketamine
- In participants with treatment-resistant depression, GBCr in the altered clusters significantly increased 24h post-ketamine, but not post-midazolam, the active control. As with the prior study, these findings underscored ketamine’s ability to normalize depression-related prefrontal dysconnectivity.
- Ketamine use in current clinical practice
- Combinations of ketamine and atropine are neuroprotective and reduce neuroinflammation after toxic status epilepticus in mice. In a systematic review of clinical studies, the authors concluded that intra-operative ketamine exerts anti-inflammatory effects.
- Rapid‐acting antidepressant ketamine, its metabolites and other candidates: A historical overview and future perspective
- Viral‐mediated hippocampal knockdown of VEGF produced depressive‐like behaviors and decrease in hippocampal neurogenesis in rats, which partially recovered after injection of ketamine. This study suggests that ketamine‐induced VEGF expression might partially contribute to neurogenesis in the hippocampus and the antidepressant‐like effects of ketamine.
- Ketamine enhances structural plasticity in human dopaminergic neurons: possible relevance for treatment-resistant depression