Ketamine - acute versus chronic exposure

[Vastness]

I am interested in what research has been done on the effects of Ketamine on the brain during chronic exposure rather than a single acute dose, or, perhaps, a short session of a few hours with medical supervision and rigorously controlled dosing.

I understand that Ketamine is being researched for treatment of depression and has the capacity to induce rapid synaptic changes, at least with a certain kind of dosing schedule.

However in my own experience using Ketamine recreationally, as much as I have had many good times I am starting to think that at a point - say, a binge of a day or more - it actually becomes quite a brain-disabling drug (I am talking chronic effects here and aftereffects, just to be clear)... so I am interested where the line is between "beneficial" Ketamine use with the capacity to induce neurogenesis and alleviate certain psychiatric conditions, even if temporarily, and harmful Ketamine use which, again, feels a little brain damaging and for me at least actually induces some kind of apathy and depression in the days after a binge... and what exactly the mechanism for this negative effect is from a neurochemical perspective.

 

[Cotcha Yankinov]

Ketamine and other dissos work primarily by blocking NMDA receptors, which control a wide variety of important functions of the brain. As an example, NMDA receptors contribute to neural oscillations that help brain networks/regions communicate with each other. After blocking these NMDA receptors chronically, there could be homeostatic alterations that result in abnormal function of NMDA receptor related neural oscillations once the drug dissipates.

Another reason for the negative after effects could have to do with receptor down regulation. Ketamine/NMDA antagonists/dissos tend to result in an increase in downstream neurotransmitter release, for example release of serotonin/dopamine/norepinephrine. These are involved in cognition, attention/motivation/energy et cetera, and a drug that acutely increases these neurotransmitters in the short term, well, what goes up must come down, a la receptor down regulation.

Another possible reason is that ketamine seems to be able to cause (reversible) changes in the neuronal expression of things like Parvalubmin and an enzyme called GAD67. While a decrease in the expression of PV and GAD67 seems to play a role in the antidepressant, and also psychotic effects of ketamine, alteration of expression could presumably lead to adverse effects like you describe that would be somewhat cumulative (significant changes could be seen during a binge/with chronic use but maybe not so much during a one-off use).

Another possible reason for the aftereffects is that NMDA antagonist binging could disrupt normal sleep architecture and such, and three days of abnormal sleep will certainly wreak havoc with any number of systems, including hormonal/neuroendocrine systems.


As an aside related to short term/long term, glutamate and depression, short term sleep deprivation can improve depression in some individuals - as cells run out of energy with sleep deprivation, ATP dependent pumps that keep the neurons membrane potential intact (keep the cells from firing too much) begin to fail and the brain's excitability increases.

This can result in increased release of an important neurotransmitter called glutamate (which ketamine works largely by releasing), contributing to a short term antidepressant effect of sleep deprivation. But chronic sleep deprivation could have a very different effect. Chronic sleep deprivation tends to have a pro-depressant/pro-psychotic effect.

CY

 

[Tzcatlipoca]

The problem with chronic NMDA antagonism is that NMDA plays a major role in neural networking and neurogenesis (learning as one may call it), and I find my IQ especially lowered during a dissociative binge, however, this serves to increase humility and decrease ego-arrogance and I find it's a refreshing feeling.

Tez

 

[clubcard]

'Ketamine bladder' is now a diagnosis here in the UK. It isn't a metabolite but the parent chemical damaging the cells of the bladders lining causing necrosis. It is the NMDA affinity that causes the damage. I suppose the doses of PCP meant that it never turned up but I don't know the affinity of MXE but it is also likely a chronic list.

Diphenadine and derivatives look like they may not cause this issue but then again, they don't have a long history.

http://onlinelibrary.wiley.com/doi/10.1002/dta.1946/abstract

If anyone got hold of the N-isopropyl analogue of diphenadine knows that it is very, very close to MXE in potency & duration. Sadly, the idiot chemists were thermally forming the enolate (so reflux) when, since monosubstitution only leads to an imine, RT complex metal hydride actually made it cheaper... but they were idiots, they put the least effort possible into their job. I'm sure the enoiapharmacopia pop-up site will remember Oranje Juice - well I share a house with them.

 

[Tzcatlipoca]

'Ketamine bladder' is now a diagnosis here in the UK. It isn't a metabolite but the parent chemical damaging the cells of the bladders lining causing necrosis. It is the NMDA affinity that causes the damage. I suppose the doses of PCP meant that it never turned up but I don't know the affinity of MXE but it is also likely a chronic list.

Diphenadine and derivatives look like they may not cause this issue but then again, they don't have a long history.

http://onlinelibrary.wiley.com/doi/10.1002/dta.1946/abstract

If anyone got hold of the N-isopropyl analogue of diphenadine knows that it is very, very close to MXE in potency & duration. Sadly, the idiot chemists were thermally forming the enolate (so reflux) when, since monosubstitution only leads to an imine, RT complex metal hydride actually made it cheaper... but they were idiots, they put the least effort possible into their job. I'm sure the enoiapharmacopia pop-up site will remember Oranje Juice - well I share a house with them.

If diphenidine is the pharmaceutical in explanation here, I've had a single oral 117mg experience with it and suffered norepinephrine psychosis due to overload, delirious amnesia for two hours and a throat infection lasting a week of soreness.

MXE on the other hand I've gone through more than 10 grams orally, had no nasty side effects besides nausea and puking when I took too much on several occasions (less than 6 total) during my entire consumption. However I've ran out and failed to resupply after if it was illegalized.