MDPV completely protects against the neurotoxic effects of methamphetamine

[DotChem]

.. in mice...

[h=2]Abstract[/h]Methylone, 3,4-methylenedioxypyrovalerone (MDPV), and mephedrone are psychoactive ingredients of ‘bath salts’ and their abuse represents a growing public health care concern. These drugs are cathinone derivatives and are classified chemically as β-ketoamphetamines. Because of their close structural similarity to the amphetamines, methylone, MDPV, and mephedrone share most of their pharmacological, neurochemical, and behavioral properties. One point of divergence in their actions is the ability to cause damage to the CNS.

Unlike methamphetamine, the β-ketoamphetamines do not damage dopamine (DA) nerve endings. However, mephedrone has been shown to significantly accentuate methamphetamine neurotoxicity. Bath salt formulations contain numerous different psychoactive ingredients, and individuals who abuse bath salts also coabuse other illicit drugs. Therefore, we have evaluated the effects of methylone, MDPV, mephedrone, and methamphetamine on DA nerve endings. The β-ketoamphetamines alone or in all possible two-drug combinations do not result in damage to DA nerve endings but do cause hyperthermia. MDPV completely protects against the neurotoxic effects of methamphetamine while methylone accentuates it. Neither MDPV nor methylone attenuates the hyperthermic effects of methamphetamine. The potent neuroprotective effects of MDPV extend to amphetamine-, 3,4-methylenedioxymethamphetamine-, and MPTP-induced neurotoxicity. These results indicate that β-ketoamphetamine drugs that are non-substrate blockers of the DA transporter (i.e., MDPV) protect against methamphetamine neurotoxicity, whereas those that are substrates for uptake by the DA transporter and which cause DA release (i.e., methylone, mephedrone) accentuate neurotoxicity.


Keywords: dopamine nerve ending, dopamine transporter, neurotoxic amphetamines, neurotoxicity, β-ketoamphetamines

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4759647/

 

[Cotcha Yankinov]

So MDPV is not necessarily neuroprotective as much as it is just negating the neurotoxic drug's mechanism of action? In other words, we would expect DRIs to be protective concerning DRAs?

 

[aced126]

Yes, this is exactly what is observed when methylphenidate and amphetamine are coadministered. DRIs are neuroprotective against DRAs.

 

[sekio]

i think that's been well knwon for alittle while, however it's not like doing cocaine will be curative of damage induced by meth!!!

 

[DotChem]

i think that's been well knwon for alittle while, however it's not like doing cocaine will be curative of damage induced by meth!!!

We don't know that! actually it might! for example some nootropics reverse damage to the hyppocampus of severely depressed and promote it growth and regeneration of hyppocampal brain cells. Only experiments comparing the brains of samples like this:

1. control (clean and sober non users)
2. meth users (alone)
3. coke users (alone)
4. meth users switching to coke
5. meth users switching to nothing ie sugar pill (no coke)


follow them for a given period (say a year) and compare their brains (MRI). Especially striatal and DA dopaminergics terminals destroyed by meth or other DRAs. That will give answer whether or not coke/mdpv/pvp or other DRIs reverse meth damage.

Can DRIs actually reverse meth damage, not prevent, reverse it AFTER it has already happened? possible: after all MDPV protect DA terminals up to 6 hours AFTER meth exposure (cf OP paper). So it is not really via antagonism of meth action. Plus, neurogenic nootropics such as NSI189 promote the growth and increase the size of the hippocampus by UP TO A WHOOPING 20%! in primates and so are some antidepressants. Which tell us that in principle it is possible: a drug acting on dopaminergic striatal and NA areas of the brain) that will promote the regeneration of DA neurons destroyed by Meth. maybe DRIs might be able to reverse meth damage.. but who knows absent formal studies?

So MDPV is not necessarily neuroprotective as much as it is just negating the neurotoxic drug's mechanism of action? In other words, we would expect DRIs to be protective concerning DRAs?

That's the data so far: administrated up to 6 hours following meth exposure, MDPV will fully protect against neurotoxic damage. So probably it is not via direct antgonism of DA release by Meth . At least not the direct release of DA.

 

[AlphaMethylPhenyl]

Even if cocaine could prevent methamphetamine-induced neurotoxicity, there would be nothing to prevent cocaine-induced cardiotoxicity, which would combine with the cardiotoxic effects of meth.

So this begs the question of how long after meth exposure is toxicity occurring? Given its duration of action, six hours after meth exposure, one is usually still high on meth.

That doesn't make sense. A random nootropic that can increase hippocampal volume will not protect against striatal neurotoxicity. These are two different brain regions. Furthermore, neurogenesis isn't a categorically good thing. Various antidepressants increase hippocampal volume, but they're evaluated for safety and efficacy first.

Do you really want to play the guinea pig?

Also, there's common sense. If someone uses MDPV after a meth binge, given how ridiculously moreish it is, they would likely just start on an MDPV binge. There's nothing to prevent this toxicity induced by lack of sleep, food, and (probable) psychosis.

Furthermore, you're not a mouse.

 

[serotonin2A]

That's the data so far: administrated up to 6 hours following meth exposure, MDPV will fully protect against neurotoxic damage. So probably it is not via direct antgonism of DA release by Meth . At least not the direct release of DA.

Your assumption is only valid if the neurotoxicity induced by methamphetamine occurs immediately after methamphetamine enters the brain, which isn't the case. The opposite is actually true -- the damage only starts to occur after endogenous mechanisms that act to prevent terminal degeneration are depleted. With MDMA there is a 12 h window to prevent serotonergic neurotoxicity with SSRIs. So it isn't surprising that MDPV is effective 6 h after administration of methamphetamine.

 

[Cotcha Yankinov]

^And taking SSRIs to block a SRA is akin to taking a DRI to block a DRA right? I mean, in the sense that youre just blocking the mechanism of action, so yes it's harm reduction but you can't have your cake and eat it too...

 

[serotonin2A]

^And taking SSRIs to block a SRA is akin to taking a DRI to block a DRA right? I mean, in the sense that youre just blocking the mechanism of action, so yes it's harm reduction but you can't have your cake and eat it too...

You can potentially have your cake and eat it too in this situation. At least in rats, you can administer a SSRI after the acute effects of MDMA wear off and still prevent neurotoxicity. The reason is that the neurotoxicity is not directly due to the presence of MDMA.

 

[jamiec999]

Can you reverse it? I heard that SSRIs boost serotonin axon growth.

 

[AlphaMethylPhenyl]

As far as that goes, I believe fluoxetine repairs the axons of serotonergic neurons. But if the soma is significantly damaged, the neuron is lost. So SSRIs can only help so much.

 

[Cotcha Yankinov]

Can you reverse it? I heard that SSRIs boost serotonin axon growth.

Reverse possible MDMA induced damage? MDMA has not been shown to damage the cell body, but yes SSRIs may help with axon recovery and increased neurogenesis. Although many people have bad reactions to MDMA without having any real damage to brain cells (there are other things that can account for symptoms that are not related to neurotoxicity).

 

[AlphaMethylPhenyl]

We're talking in regards to the hippocampus, right? Could someone explain succinctly how fluoxetine prevents damage when administered after the MDMA has finished making the individual high? I'm wondering if, since MDMA doesn't destroy cell bodies, fluoxetine could facilitate a full recovery.

 

[jamiec999]

Reverse possible MDMA induced damage? MDMA has not been shown to damage the cell body, but yes SSRIs may help with axon recovery and increased neurogenesis. Although many people have bad reactions to MDMA without having any real damage to brain cells (there are other things that can account for symptoms that are not related to neurotoxicity).

Just to clarify (since I am myself not very knowledgeable about the case), you are saying that MDMA doesn't kill the neuron itself but damages its axons (or axon terminals) right?

Also, does neurogenesis occur in any helpful way? I read that it occurs in wrong places of the brain.

 

[Cotcha Yankinov]

We're talking in regards to the hippocampus, right? Could someone explain succinctly how fluoxetine prevents damage when administered after the MDMA has finished making the individual high? I'm wondering if, since MDMA doesn't destroy cell bodies, fluoxetine could facilitate a full recovery.

The prevailing theory of the MDMA induced serotonin axon/dendrite damage that we see in animals is that as serotonin concentrations in the synapse decrease, the serotonin transporter starts transporting harmful molecules (MDMA metabolites, Dopamine) into the nerve terminal. So basically during the initial trip there is enough serotonin competing for the SERT with dopamine and such.

It sounds like if you know when your dopamine terminal's natural defenses were exhausted you could administer a DRI to block uptake of meth and such.

If we are to assume that MDMA is causing it's negative effects on some users by harming serotonin terminals, then we might be in a bit of a pickle. Animal models show abnormal recovery of serotonin projections. The cell bodies of the serotonin cells are located farther down towards the brain stem, in the dorsal raphe nucleus. Some axons project throughout the brain, including for example onto the cortex, quite far away. We see at 52 weeks after MDMA binge administration to animals that many areas recover, some even hyper-innervated compared to controls it seems, but projections to parts of the cortex seem to have a hard time recovering.

So yes Jamie, recovery does occur, but it may be a bit abnormal if the animal models are right. Animal models might not translate to humans though, and keep in mind we give the animals absolutely massive dosage regimens. But the serotonin cells themselves are okay, it's just the "branches/roots" of the tree that can get injured.

Feel free to message me anytime if you have any questions Jamie. My advice for anyone suffering adverse MDMA effects (which can occur without any damage to brain cells just to be clear) is 1. Aerobic exercise 2. Mindfulness meditation 3. 8 hours of sleep 4. Intellectual activity 5. Healthy diet with protein and vegetables.

Goodluck

 

[Dresden]

Just as fluoxetine keeps one from getting high on MDMA and thus incurring MDMA type damage despite the MDMA having been taken, I suspect MDPV outcompetes methamphetamine completely and thus that the methamphetamine never exerts its usual effects, including the damaging ones.

 

[Captain.Heroin]

my advice, don't take MDPV on top of meth. Horrible fucking idea.

 

[DotChem]

The prevailing theory of the MDMA induced serotonin axon/dendrite damage that we see in animals is that as serotonin concentrations in the synapse decrease, the serotonin transporter starts transporting harmful molecules (MDMA metabolites, Dopamine) into the nerve terminal. So basically during the initial trip there is enough serotonin competing for the SERT with dopamine and such.

Does that mean one can't design a non-neurotoxic alternative to MDMA ie one with similar psychoactivity profile. If the damage is inherent in Serotonin release per se??

 

[Cotcha Yankinov]

I think part of the idea is that MDMA especially (compared to say methylone) depletes serotonin stores, I think because it inhibits VMAT (If I recall correctly, my mind is in the gutter) and also it can inhibit tryptophan hydroxylase (sometimes for up to months from what I saw in animal studies) which I personally think could be playing a role in serotonin depletion occurring concerning use that happens over an extended period.

But, MDAI (Thank you Dave Nichols) is a "non-neurotoxic" MDMA analog, but it has been shown to become neurotoxic when combined with dopamine releasers, hence part of the reasoning behind why we think that dopamine is getting taken up into the nerve terminal. For all I know MDAI could have similar effects as far as inhibiting VMAT and knocking down tryptophan hydroxylase similar to MDMA (no idea if it does this) but maybe the neurotoxicity doesn't really occur because there isn't excess dopamine in the synapse.

 

[jamiec999]

I think part of the idea is that MDMA especially (compared to say methylone) depletes serotonin stores, I think because it inhibits VMAT (If I recall correctly, my mind is in the gutter) and also it can inhibit tryptophan hydroxylase (sometimes for up to months from what I saw in animal studies) which I personally think could be playing a role in serotonin depletion occurring concerning use that happens over an extended period.

But, MDAI (Thank you Dave Nichols) is a "non-neurotoxic" MDMA analog, but it has been shown to become neurotoxic when combined with dopamine releasers, hence part of the reasoning behind why we think that dopamine is getting taken up into the nerve terminal. For all I know MDAI could have similar effects as far as inhibiting VMAT and knocking down tryptophan hydroxylase similar to MDMA (no idea if it does this) but maybe the neurotoxicity doesn't really occur because there isn't excess dopamine in the synapse.

What is neurotoxicity by the way? Is it death of serotonin cells? Or is it death of axons of the said neurons? I know that there is a reduce in SERT after MDMA use but in a paper, I saw that it returns to normal levels after absence from the drug. Is it true that SSRIs like Prozac help axons grow back? And if it is, does their revival mean anything positive?