Reducing GHB neurotoxicity due to oxidative stress

[Cotcha Yankinov]

I'm sure these cannabinoids could be helpful if you could really get them into the CNS in the amounts the studies use (see the first studying using 120mg/kg - could equate to quite a lot of CBD in humans) but they may not be that appreciable when the typical amounts going around around ~1mg-10mg, and as you say some may have bad quality

So maybe in an ideal situation CBD could be a harm reduction drug, but if the protective effects are indeed as the one study claims and were independent of CB receptor activity, then an antioxidant may serve the same purpose without needing to ingest a gram of CBD

There is some evidence that THC can exert a protective effect in the case of MDMA neurotoxicity, but I don't what the implications are of that for humans (considering THC can occasionally cause anxiety/depersonalization and the adverse effects of MDMA, or GHB for that matter, may not necessarily have to do with neurotoxicity)

 

[Amml]

Do you know how to convert the dose from rats/mice to humans? I heard there is quite some difference. I also don't get it why they use so massive amounts that would possible never be used in humans.
Any antioxidant would be surely effective, but even when the effects of CBD are CB-receptor independent, there is some evidence that it's neuroprotective effects are not only because of free radical scavenging, but also though some some other mechanisms, which possible makes it more effective.

 

[Cotcha Yankinov]

Allometric scaling calculators can be helpful for inter species scaling, we can also make an educated guess by looking at doses that are behaviorally active in humans vs. behaviorally active in animals (in this case behaviorally active doses of MDMA are pretty similar between rats and humans, but higher doses can be used in rats because they have higher metabolisms). Generally small animals metabolize faster.

Sometimes they use massive doses in animals even if they're not very realistic just to prove a point and study the effects clearly, in the case of MDMA study and map the neurotoxicity. Or maybe they can't replicate 1mg/kg CBD every day for a year so they do 36.5x that for 10 days.

I'd be curious to see what the other protective mechanisms are, I'm sure there's so much that we don't know

 

[WSH]

Allometric scaling calculators can be helpful for inter species scaling, we can also make an educated guess by looking at doses that are behaviorally active in humans vs. behaviorally active in animals (in this case behaviorally active doses of MDMA are pretty similar between rats and humans, but higher doses can be used in rats because they have higher metabolisms). Generally small animals metabolize faster.

Yes, it can be tricky to decide when allometric or rather linear dosing is in order. E.g. for MDMA, like Franz Vollenweider has written in a scientific paper, one has to use linear scaling (because the metabolite MDA is almost equipotent in releasing monoamines -> faster metabolism in rats is inconsequential) whereas for ketamine allometric scaling is much more accurate (because the metabolite norketamine is ~5x less potent as an NMDA channel blocker -> faster metabolism in rats is important)

 

[Amml]

Allometric scaling calculators can be helpful for inter species scaling, we can also make an educated guess by looking at doses that are behaviorally active in humans vs. behaviorally active in animals (in this case behaviorally active doses of MDMA are pretty similar between rats and humans, but higher doses can be used in rats because they have higher metabolisms). Generally small animals metabolize faster.

Sometimes they use massive doses in animals even if they're not very realistic just to prove a point and study the effects clearly, in the case of MDMA study and map the neurotoxicity. Or maybe they can't replicate 1mg/kg CBD every day for a year so they do 36.5x that for 10 days.

I'd be curious to see what the other protective mechanisms are, I'm sure there's so much that we don't know

I don't think that it is rational to give substances that are usually used low dose over a longer time in a shorter period of time, but higher dosed. E.g. look at Acetaminophen, if you would take the amount that usually would be enough for 1 year in 1 month, you would die. I think that could also fit to other substances, even when it's not deadly the effects wouldn't be the same. Same with MDMA, at some point the endogenous antioxidant mechanisms are saturated and then the mentioned neurotoxicity occurs, although it can be harmful in smaller doses, but due to other mechanisms.

To the other mechanisms of action of CBD, it seems that it's still not 100% clear. I suggest that some of the anticonvulsive mechanisms are also responsible for the neuroprotective effect.
https://www.ncbi.nlm.nih.gov/pubmed/24854329

 

[WSH]

I don't think that it is rational to give substances that are usually used low dose over a longer time in a shorter period of time, but higher dosed. E.g. look at Acetaminophen, if you would take the amount that usually would be enough for 1 year in 1 month, you would die. I think that could also fit to other substances, even when it's not deadly the effects wouldn't be the same. Same with MDMA, at some point the endogenous antioxidant mechanisms are saturated and then the mentioned neurotoxicity occurs, although it can be harmful in smaller doses, but due to other mechanisms.

Yes, even if you drank all of the water that you stored for your whole life all at once, you would die of water poisoning.

At one very high dose point, I think MDMA is going to be harmful, in my opinion not at a standard ~125mg dose, but, if we carefully (and therefore very roughly) translate from rat studies (which can only ever a guesstimate), long term side effects (I'm not talking about the famous hangover that happens even with "normal" doses) would be expected to happen at the human equivalent of 1000-2000mg (taken at once, not over 12-24h).

Same with MDMA, at some point the endogenous antioxidant mechanisms are saturated and then the mentioned neurotoxicity occurs, although it can be harmful in smaller doses, but due to other mechanisms.

I don't know what you mean by "other mechanisms" and by "smaller doses", but the equivalent of ~100mg in a 75kg human (unlike the equivalent of >500mg) causes no reduction in tissue serotonin (which is interpreted as a neurotoxic effect) and also even behaviorally multiple doses of the equivalent of ~400mg in a 75kg human were required to cause anxiety and depression (at least in rat models).

 

[Cotcha Yankinov]

Re: other mechanisms, he could mean things like PV interneuron excitotoxicity or loss of PV expression

But yeah the acetaminophen thing is a good point, dosage - effect is defintely not linear

 

[Amml]

I only have it in mind without sources but somehow I remembered that MDMA has some neurotoxic effects beside the damage on the serotonin system. Also that cognitive impairment can still last even if the serotogenic transmission is back to baseline in former MDMA users.

 

[WSH]

I only have it in mind without sources but somehow I remembered that MDMA has some neurotoxic effects beside the damage on the serotonin system. Also that cognitive impairment can still last even if the serotogenic transmission is back to baseline in former MDMA users.

That sounds strange, can you try to find these sources, or at least remember (if you can't find them) if they were done in humans or in rats?

 

[Cotcha Yankinov]

There hasn't been confirmation of PV interneuron degeneration but there has been some observed loss of PV and GAD67 staining in I believe it was rats, given MDMA regimens

Cyclooxygenase/glutamate release from astrocytes played a role

 

[WSH]

There hasn't been confirmation of PV interneuron degeneration but there has been some observed loss of PV and GAD67 staining in I believe it was rats, given MDMA regimens

Cyclooxygenase/glutamate release from astrocytes played a role

at least with ketamine, this loss of PV interneuron functinoning is not only related to its psychotic effects but also its antidepressant effects

We demonstrated that an acute dose of 10 mg/kg ketamine induced significant antidepressant-like effects and reduced the levels of PV and the gamma-aminobutyric acid (GABA)-producing enzyme GAD67 in the rat prefrontal cortex. Moreover, inhibition of ketamine-induced loss of PV by apocynin blocked these antidepressant-like effects

So it might not be all bad, plus these effects might even be related to ketamine's long term (couple of weeks) antidepressant effects, since these effects are reversible

Application of the nonselective NMDA receptor antagonist ketamine, at sublethal concentrations, induced a time and dose-dependent decrease in parvalbumin and GAD67 immunoreactivity specifically in PV interneurons. These effects were reversible