Are monoamine releasers inherently neurotoxic? and other questions

[neurotic]

I am interested in empathogens, however their neurotoxicity worries me.

The metabolites and dopamine hypotheses for MDMA's neurotoxicity seem to try to put it as not something inherent to MDMA and triple monoamine release, rather some misfortunate particularity. Though hitherto there seems to not be solid enough evidence as to completely rule out the possibility of MDMA itself having some guilt in there.

On top of that, triple releasers from all walks of life, such as αMT, αET, fenfluramine and homologues, the aminoreces... , all have hints of neurotoxicity on their own. Plus MDAI and amphetamine simultaneously also are neurotoxic which kinda kills the idea of doing plain stimulants and plain serotonin releasers together (e.g. Borax's 2-FMA + MDAI/5-MAPB, amph. + 5-IAP, ...) to circumvent this.

So naturally I wonder if neurotoxicity is not inherently tied to the flooding of the brain with monoamines. For instance, 4-FA, the only of the para-halogenated amphetamines that is not neurotoxic, is also (coincidentally?) the only one that has humbler serotonin releasing properties.

Can we have an empathogen experience without damaging our brain?

Mephedrone was a triple releaser which seems to be regarded as not really neurotoxic. Mm.

Is the toxicity caused by the elevated levels of monoamines OR perhaps something to do with this particular mechanism (release (as for example opposed to inverse agonism))? Let me elaborate: primarily-catecholamine-releasers (e.g. meth) can have neurotoxic properties on their own. However stimulants à la cocaine, with their particular mechanism of action seem not to. Could we have a molecule that elevated monoamine levels à la cocaine thus promoting empathogenesis without neurotoxicity?

Oh and other questions: chronic use of SSRI's reduces SERT density. In some studies of the neurotoxicity of some drugs this is used as a marker of neurotoxicity. What gives? Is there a bias against drugs of recreation and in favour of well what pharmaceutical companies want to sell? Couldn't what we've been witnessing and labeling neurotoxicity just be a standard reaction to elevated monoamine levels (I do recall a paper named "neurotoxicity versus neuromodulation", (this was in the context of MDMA neurotoxicity) though it was beyond my capabilities to read it)? What other differences are there between the effects on the serotonergic system of chronic SSRI vs. the obscene entactogen doses are fed with?

And also: mm I recall that paper that wanted to make the distinction between cocaine and methylphenidate and other RI's such as bupropion which did not have recreational potential. Then they put forward that new proposed model for the mechanism of action of the first two, as transporter inverse agonists, IIRC. Do the "lame" RI's such as bupropion fail to raise catecholamine levels considerably? Or they do and even in spite of that there's no high? In other words, is massive monoamine levels equal to high?

 

[Cotcha Yankinov]

Two points to consider first

1. Neurotoxicity may not be required for a drug to have persistent adverse effects
2. Neurotoxicity can extend outside of the classically considered serotonergic cells, to for example parvalbumin positive GABA interneurons, which are very sensitive to excitotoxicity and even if they don't degenerate can undergo changes like decreased expression parvalbumin or GAD67 (both seen with MDMA administration in animals). These issues with decreased GAD67 and parvalbumin expression seem to be mediated by 5-HT2A/glutamate so this couldn't really be separated from the MAO of SRAs.

But in the case of MDMA I believe that metabolites are believed to play a bigger role with the "dopamine uptake into the nerve terminal" theory fading away a bit, although I don't think there is anything conclusive and MDAI + AMPH might also be a special situation. That being said, dopamine can still increase oxidative stress and temperature, and hyperthermia is pretty important for MDMA related neurodegeration.

I'm under the impression that the substrates for reuptake transporters/TAAR1 agonists like MDMA (and metabolites) and METH are thought to cause degeneration primarily through breakdown while they are inside of the neuron itself - once they gain access through the reuptake transporters they can also cause leakage of neurotransmitters out of vesicles that normally contain harmful substances like dopamine, so I suppose VMAT2 inhibition could also play a role in dopamine terminal loss with METH. The other thing to consider with MDMA is that uptake of harmful molecules is primarily going to occur when serotonin concentrations in the cleft are low, so VMAT2 inhibition and tryptophan hydroxylase inhibition could be encouraging the uptake of harmful molecules by decreasing serotonin at some timeframe (SSRIs can prevent MDMA induced nerve terminal loss even if given a few hours after MDMA administration IIRC).

But one of the points about METH dopamine terminal loss that I've heard is that the antioxidant defenses need to be overwhelmed before neurodegeneration occurs and many things can contribute to this, presumably with dopamine auto-oxidation in the synaptic cleft playing a role. MAO-B inhibition is protective with MDMA but I don't know if that's because of inhibition of dopamine metabolism or inhibition of harmful MDMA metabolite breakdown...

I suppose its possible that the theorized DAT inverse agonists may not need to gain access to the neuron to cause efflux and this could be an advantage, not sure about that one though.

"Oh and other questions: chronic use of SSRI's reduces SERT density. In some studies of the neurotoxicity of some drugs this is used as a marker of neurotoxicity. What gives?"

Yeah this always seemed funky to me, I assume reduction of SERT expression could just be a compensation. I think upregulation of 5-HT2A might be a better clue if checking for evidence of serotonergic toxicity.

One key difference between SRIs and SRAs is that SRAs are increasing serotonergic signaling regardless of pre-synaptic autoreceptor activity, whereas SRIs are only potentiating the amount of serotonin that is already in the cleft via natural axon release (hope that makes sense). The other thing is that MDMA/MDA are promiscuous - you have 5-HT2A agonism and MDMA is also a substrate for other transporters (DAT/NET, and some weird ones that I can't remember) and it can inhibit those transporters as well.

I think bupropion is a releasing agent but only if you can get it with sufficient concentrations into the brain before it is metabolized into just a DRI, which once again the reuptake inhibitors are very different from releasing agents in the sense that releasing agents are bypassing the autoreceptors.

Hope this was helpful, any questions are welcome. My main point is that I don't think nerve terminal loss is required for adverse effects, neuroplasticity is very important.

 

[serotonin2A]

Oh and other questions: chronic use of SSRI's reduces SERT density. In some studies of the neurotoxicity of some drugs this is used as a marker of neurotoxicity. What gives? Is there a bias against drugs of recreation and in favour of well what pharmaceutical companies want to sell? Couldn't what we've been witnessing and labeling neurotoxicity just be a standard reaction to elevated monoamine levels (I do recall a paper named "neurotoxicity versus neuromodulation", (this was in the context of MDMA neurotoxicity) though it was beyond my capabilities to read it)? What other differences are there between the effects on the serotonergic system of chronic SSRI vs. the obscene entactogen doses are fed with?

Once you show that something causes serotonergic terminals to degerate, SERT imaging is a useful measure if degeneration. But that doesn't mean denervation has occured everytime SERT is downregulated.

Regarding your other question, reuptake inhibitors do increase synaptic conc of dopamine, but that will often be offset to some degree by reductions in transmitter release due to autoreceptor activation.