Questions about ketamine neurotoxicity / NOS inhibitors / GABAergic steroids

[Solipsis]

I am relaying a few questions / a message from Adam who is visually challenged:

1. Will a mixture of strong antioxidants, with high cell permeability block ketamine neurotoxicity?

2. Why are neuronal NOS inhibitors eg 7 nitro indizole not used in humans despite having strong neuroprotective effects and blocking long turn opioid tolerance-has anyone had experience with NOS inhibitor?

3. Are GABAergic neurosteroids aurally [orally?] active in humans, if so ganaxalone may be an effective treatment for bad trips and flashbacks as well as NMDA antagonist neurotoxicity without risk of addiction or tolerance.

 

[Epsilon Alpha]

I am relaying a few questions / a message from Adam who is visually challenged:

1. Will a mixture of strong antioxidants, with high cell permeability block ketamine neurotoxicity?

2. Why are neuronal NOS inhibitors eg 7 nitro indizole not used in humans despite having strong neuroprotective effects and blocking long turn opioid tolerance-has anyone had experience with NOS inhibitor?

3. Are GABAergic neurosteroids aurally [orally?] active in humans, if so ganaxalone may be an effective treatment for bad trips and flashbacks as well as NMDA antagonist neurotoxicity without risk of addiction or tolerance.

First point: maybe? We don't have human trials yet, but there is some research suggesting that ROS scavenging might be protective (the vitamin E analog trolox was used in this in vitro study) http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3684944/

With regards to your second point my reading is that we really don't have specific drugs for inhibiting nNOS, and unselective NOS inhibition in humans is usually bad outside of very niche cases. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4057748/

Third point: No idea, really haven't done much research on neurosteroids beyond a cursory read. Mind posting some info on this line of thought? Its orally btw, aurally refers to hearing.

 

[dopamimetic]

Is there real evidence for ketamine induced neurotoxicity in adult humans?
Wikipedia says that besides GABAergic drugs, clonidine also protects against NMDA antagonist neurotoxicity. There is no source, but I´ve found this paper (well, about neonatal mice).

If it´s not active orally, ganaxalone might be administered as a nasal spray?

 

[CFC]

There's a fair amount of research specifically on how Clonidine and Guanfacine can protect from NMDA excitoxicity for several other drugs (eg meth). The oxidative mechanism appears to be fairly universal though. However, expect it to abolish some (much?) of the desired outcome from ketamine use.

Aside from dealing with downstream effects like broadly scavenging free radicals with things like taurine, Vit E, glycerol, selenium, NAC, CoQ10, lysine, and reducing resulting inflammation with prostaglandin H synthase inhibitors (eg ibuprofen), OP might also consider upstream avenues such as fructose/glucose (to prevent local ATP depletion), Acetyl-L-Carnitine (again improves glucose uptake/ATP output, but poorly absorbed orally), niacinamide (ATP), sodium butyrate (ATP/Krebs), resveratrol (reduce harm to mitochondrial ER protein).

 

[atara]

Anticholinergics protect against NMDA antagonist neurotoxicity more directly than GABAergics and have very little addictiveness of their own. However the combination induces a more powerful, dreamlike experience than NMDA antagonism alone.

Note that unknown combinations, like unknown drugs, carry unknown risks.

 

[dopamimetic]

Hmm.. wouldn't an anticholinergic also strongly potentiate the amnesia so that one won't remember much at all with an effective dose? Also how about the potential of delirium (like in DXM+DPH users, which might not be the best example but a common one) - one of the things I like very much with ketamine is it's clarity (vs. many other dissociatives, and probably also why it is still used medicinally today).

induces a more powerful, dreamlike experience

Do you speak from experiences or theoretically? (OT, while I achieved a 'hole'-like state repeatedly with ketamine and once or twice also with MXE and one of the 3-MeO-PCPx series, I always missed 'something'.. related to the vision, it was usually just dark. Maybe some kind of organic darkness, but the imaginery was clearly only in thoughts. Like there was some line of dissociaction I was unable to pass. When dosing higher I would just remember less or fall into anesthesia. Thought this could be due to long-term 5-HT2a downregulation from previous SSRI use, but no clue.)

However, expect it to abolish some (much?) of the desired outcome from ketamine use.

I didn't really look for that but I'd say clonidine has little influence on the dissociative experience or might even help to 'hole' at lower doses by countering the stimulation.. or am I wrong? It might dampen the antidepressant 'afterglow' effect though.

 

[CFC]

I didn't really look for that but I'd say clonidine has little influence on the dissociative experience or might even help to 'hole' at lower doses by countering the stimulation.. or am I wrong? It might dampen the antidepressant 'afterglow' effect though.

You could be right, I really don't know, although as you'll see even from the study you found the 'normalising' of behaviour might not be desired by the average K user. I can say from guinea pigging myself with clonidine and a few other substances (meth, amp, MDMA), it utterly deadens the effect even at fairly low doses, though obviously they are strongly stimulant-based. Thus it may be desirable for K use as you say, so it would be great to hear some anecdotal feedback from anyone who has mixed them.

 

[Solipsis]

Thank you for the great responses so far, I am sure Adam will really appreciate them!
Will relay everything

 

[dopamimetic]

Animal and clinical studies have reported potentiation of opioid antinociception by co-administration of alpha-2 adrenoceptor agonists such as clonidine and NMDA receptor antagonists such as ketamine and dextromethorphan. (...) Clonidine was also evaluated in combination with ketamine and dextromethorphan. (...) In addition, the potency of clonidine was found to increase with co-administration of ketamine but not dextromethorphan (<- would be interesting to know the dosages used). (source, unfortunately abstract only)

Seems that moderate clonidine dosing does not abolish the dissociative effects from NMDA antagonists.

Excessive cerebrocortical release of acetylcholine induced by NMDA antagonists is reduced by GABAergic and a2-adrenergic agonists

N-methyl-D-aspartate (NMDA) glutamate (Glu) receptor antagonists (eg MK-801, ketamine, phencyclidine [PCP]) injure cerebrocortical neurons in the posterior cingulate and retrosplenial cortex (PC/RSC). We have proposed that the neurotoxic action of these agents is mediated in part by a complex polysynaptic mechanism involving an interference in GABAergic inhibition resulting in excessive release of acetylcholine (ACh). Previously we have found that the systemic injection of GABAergic agents and a2-adrenergic agonists can block this neuro- toxicity. In the present study we tested the hypothesis that NMDA antagonists trigger release of ACh in PC/RSC and that this action of NMDA antagonists is suppressed by GABAergic agents or a2-adrenergic agonists. The effect of MK-801 and ketamine on PC/RSC ACh output (and the ability of pentobarbital, diazepam and clonidine to modify MK-801-induced ACh release) was studied in adult female rats using in vivo microdialysis. Both MK-801 and ketamine caused a significant rise in PC/RSC ACh output compared to basal levels. Pentobarbital, diazepam and clonidine suppressed MK-801’s effect on ACh release. Exploratory studies indicated that the site of action of these agents was outside of the PC/RSC. The microdialysis results are consistent with several aspects of the circuitry proposed to mediate the neurotoxic action of NMDA antagonists. (full text)

Actually the first time I read about neurotoxicity related to excessive choline activity (makes this opioid withdrawal dangerous by the way??). But would confirm this:

Anticholinergics protect against NMDA antagonist neurotoxicity more directly than GABAergics and have very little addictiveness of their own. However the combination induces a more powerful, dreamlike experience than NMDA antagonism alone.

 

[serotonin2A]

Actually the first time I read about neurotoxicity related to excessive choline activity (makes this opioid withdrawal dangerous by the way??). But would confirm this:

I'm sure you have heard of nerve agents like VX and soman? I don't think they kill cells directly by activating ACh receptors, but they are neurotoxic.

I don't think ACh is typically neurotoxic. But ketamine releases a stew of neurotransmitters (Glu, ACh, 5-HT) that conspire to raise intracellular calcium through multiple mechanisms. So blocking any of those mechanisms is neuroprotective after ketamine administration because it blunts the rise in calcium. That includes AMPA antagonists, but also muscarinic and 5-HT2A antagonists.

 

[dopamimetic]

I'm sure you have heard of nerve agents like VX and soman?

So blocking any of those mechanisms is neuroprotective after ketamine administration because it blunts the rise in calcium. That includes AMPA antagonists, but also muscarinic and 5-HT2A antagonists.

Yeah, you're right about these nasty nerve agents / gases, I forgot them.
Concerning ACh, it seems like it's really about having an equilibrium of all neurochemicals but some are more sensible than others ... but interesting thing is that 5-HT2a agonism also prevents NMDA antagonist-related neurotoxicity!

Serotonergic Agents That Activate 5HT2A Receptors Prevent NMDA Antagonist Neurotoxicity

Phencyclidine, ketamine, and other agents that block NMDA glutamate receptors trigger a schizophrenia-like psychosis in humans and induce pathomorphological changes in cerebrocortical neurons in rat brain. Accumulating evidence suggests that a complex network disturbance involving multiple transmitter receptor systems is responsible for the neuronal injury, and it is proposed that a similar network disturbance is responsible for the psychotomimetic effects of NMDA antagonists, and might also be involved in the pathophysiology of schizophrenia. In the present study we present evidence that serotonergic agents possessing 5HT2A agonist activity prevent NMDA antagonist neurotoxicity in rat brain. It is proposed that 5HT2A agonists may also prevent the psychotomimetic effects of NMDA antagonists. Among the 5HT2A agonists examined and found to be neuroprotective are LSD and related hallucinogens. The apparent contradiction in proposing that these agents might have antipsychotic properties is resolved by evidence linking their hallucinogenic activity to agonist action at 5HT2C receptors, whereas antipsychotic activity would be attributable to agonist action at 5HT2A receptors. (Source, PDF)

Makes MXE look pretty safe again!

... and we have this BZ / 3-quinuclidinyl benzilate, that has been used too as a military incapacitating agent, but it's actually an anticholinergic (what makes it physically much safer than the cholinergics)! So too much choline activity is definitely to avoid ... but where's the threshold for this? Can one reach a toxic amount of cholinergic activity when in severe opioid withdrawal?

People that were exposed to a very little dose of soman suffered severe toxic effects, once those were treated and long gone the same persons often developed a depression, admitted they had antisocial thoughts, were withdrawn and subdued, slept restlessly and had bad dreams.

This makes the scopolamine-antidepressant theory interesting again!

 

[Epsilon Alpha]

Is there real evidence for ketamine induced neurotoxicity in adult humans?
Wikipedia says that besides GABAergic drugs, clonidine also protects against NMDA antagonist neurotoxicity. There is no source, but I´ve found this paper (well, about neonatal mice).

If it´s not active orally, ganaxalone might be administered as a nasal spray?

Ketamine causes readily recognizable brain damage in human addicts. Research is still out on if the dosage or duration of exposure is the main cause for the changes seen on MRI.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3713393/

 

[dopamimetic]

Ouch, this doesn't look nice for sure. Thanks for sharing.



But what do you think about the suggested NADPH oxidase link and could this then be prevented by using an inhibitor of that, like apocynin, or DXM which has this property by itself? Would be interesting to have results from DXM users' brain scans to compare. Also supplementing with N-acetylcysteine in dosages high enough could hold some promise, but this is entirely speculative and certainly needs further exploration.

Ketamine-Induced Loss of Phenotype of Fast-Spiking Interneurons Is Mediated by NADPH-Oxidase
Interleukin-6 Mediates the Increase in NADPH-Oxidase in the Ketamine Model of Schizophrenia
The NADPH Oxidase NOX2 Controls Glutamate Release: A Novel Mechanism Involved in Psychosis-Like Ketamine Responses

Is this related to Olney's lesions or not? Could the choline mechanism be a reason for the toxicity, so one should use a light dose of some anticholinergic when doing ketamine? And/or would taking clonidine help or are it all different mechanisms? Any clarification is valued.