Non-neurotoxic MDMA analogues

[DotChem]

Harm Reduction Question: Does anybody heard about this compound?

it is a cousin of MDMA

with the 3,4methylenedioxyphenyl replaced by a benzothiophene. Reportedly it is empathogen with "exact pharmacology" as MDMA but 2x as potent (from vendors so to be taken with a pinch of salt!!!) and not neurotoxic unlike MDMA. I know that benzothiophenes are pretty safe as far as oxidative metabolism-induced neurotoxicicty is concerned. Actually they are neuroprotectants, antioxidants like glutathione (ref later): sulfur (sp3 as in glutathione) inhibits oxidative metabolism that generates reactive oxygen species that lead ultimately to neurons death. IIRC, the consensus of MDMA neurotoxicty is that it gets metabolized to reactive toxic 1,2 quinones which generates reactive oxygen species leading to cell death. Benzothiophene won't get metabolized similarly so it would make sense this compound could be non neurotoxic I mean at least as far oxidative metabolism -induced neuronal cells damage is concerned.
nb: would be interesting, for the sake of harm reduction, but I have yet to see any data on that molecule.. lemme me know if anybody came across this compound/data/experience..etc .. thx

 

[Coolwhip]

I thought MDMA was neutotoxic because it causes dopamine to enter the serotonin transporter where it enters the axon and is metabolized to hydrogen peroxide.

 

[Cotcha Yankinov]

Metabolites of MDMA do play a role in MDMA related neurotoxicity but the oxidative stress added by dopamine certainly contributes (as well as the hyperthermia added by increased dopamine release). As an example, the more selective serotonin releasing agent MDAI (mostly non-neurotoxic to 5-HT terminals) can become neurotoxic when combined with amphetamine.

I'm not sure exactly where we stand on the whole dopamine entering the 5-HT terminal thing, I don't think its ever been conclusively confirmed or ruled out

 

[Coolwhip]

I imagine it would be pretty hard to offer irrefutable proof, but theres quite a bit of evidence. Scroll down to part ii. https://dancesafe.org/drug-information/ecstasy-slideshow/

 

[Cotcha Yankinov]

There was a more recent study (that I of course can't find) that tried to look at the matter conclusively but as you say irrefutable proof is difficult. Dopamine certainly plays a big role, and it would be really interesting if it was actually entering the terminal. We know that the serotonin transporter can transport dopamine, but its difficult to look at a piece of evidence like "MAO-B inhibitors inhibit terminal loss" and conclude that the effect is due to dopamine as the relevant toxic MDMA metabolites will apparently also be metabolized by MAO-B and produce oxidative stress, and dopamine manipulations will affect body temperature.

There is at least evidence that MDMA metabolites play a role though, which would hint that not all serotonin releasing agents are equal and maybe there is some harm reduction value in that knowledge. What is certainly clear is that something is entering the nerve terminal to produce neurotoxicity, and its appears MDMA itself might be capable of doing this, hepatic metabolites aside (contrary to old studies on direct injection into the brain, direct injection into the brain can produce neurotoxicity). The other assumption we could make under the direct injection neurotoxicity scenario is that hepatic metabolites aren't required because dopamine can still enter the nerve terminal.

I think a primary confounding factor here is probably the relationship between dopamine and hyperthermia.

 

[DotChem]

^ Thats what I thought: it is pretty complicated however the hyperthermia doesnt fully account for the neurotoxicty though.. MDMA is neurotoxic to rats and humans but not to mice even thou they also get hyperthermia upon exposure. + the toxicity is temperature-dependant. That's why I think to account for the species difference and temperature dependance, MDMA metabolite(s)-induced neuron damage was put forward since it is differentially metabolized by mice or humans and increase temperature would lead to increase metabolism. However, that can't fully explain it: here is an old paper:

Studies of (±)-3,4-Methylenedioxymethamphetamine (MDMA) Metabolism and Disposition in Rats and Mice: Relationship to Neuroprotection and Neurotoxicity Profile https://www.ncbi.nlm.nih.gov/pubmed/9222545


Abstract.The neurotoxicity of (±)-3,4-methylenedioxymethamphetamine (MDMA; “Ecstasy”) is influenced by temperature and varies according to species. The mechanisms underlying these two features of MDMA neurotoxicity are unknown, but differences in MDMA metabolism have recently been implicated in both. The present study was designed to 1) assess the effect of hypothermia on MDMA metabolism, 2) determine whether the neuroprotective effect of hypothermia is related to inhibition of MDMA metabolism, and 3) determine if different neurotoxicity profiles in mice and rats are related to differences in MDMA metabolism and/or disposition in the two species. Rats and mice received single neurotoxic oral doses of MDMA at 25°C and 4°C, and body temperature, pharmacokinetic parameters, and serotonergic and dopaminergic neuronal markers were measured. Hypothermia did not alter MDMA metabolism in rats and only modestly inhibited MDMA metabolism in mice; however, it afforded complete neuroprotection in both species. Rats and mice metabolized MDMA in a similar pattern, with 3,4-methylenedioxyamphetamine being the major metabolite, followed by 4-hydroxy-3-methoxymethamphetamine and 3,4-dihydroxymethamphetamine, respectively. Differences between MDMA pharmacokinetics in rats and mice, including faster elimination in mice, did not account for the different profile of MDMA neurotoxicity in the two species. Taken together, the results of these studies indicate that inhibition of MDMA metabolism is not responsible for the neuroprotective effect of hypothermia in rodents, and that different neurotoxicity profiles in rats and mice are not readily explained by differences in MDMA metabolism or disposition.

But they looked only at first pass metabolism and I think another possibility is via tyrosine hydroxylase (TH) the rate limiting enzyme for de novo synthesis of catecholamines in the brain. Keeping in mind, most phenethylamines are either substrates or inhibitors of TH. The extreme case beeing the notorious 4-Chloroamphetamine. Tyrosine hydroxylase mechanism actually involves generation of free radicals including oxygen centered radicals (like H-OO* ) . Do I have evidence for that (TH catalyzed generation of toxic MDMA metabolites)? No I don't, just hypothesis ( I couldnt find any paper looking specifically on MDMA action on TH). But this old paper show "total protection" of MDMA (but not 4-Chloroamphetamine) by clomethimazole a radical scavenger and here is another

In vivo evidence for free radical involvement in the degeneration of rat brain 5-HT following administration of MDMA ('ecstasy') and p-chloroamphetamine but not the degeneration following fenfluramine. https://www.ncbi.nlm.nih.gov/pubmed/9222545

Abstract : 1. Administration of 3,4-methylenedioxymethamphetamine (MDMA or 'ecstasy') to several species results in a long lasting neurotoxic degeneration of 5-hydroxytryptaminergic neurones in several regions of the brain. We have now investigated whether this degeneration is likely to be the result of free radical-induced damage. 2. Free radical formation can be assessed by measuring the formation of 2,3- and 2,5-dihydroxybenzoic acid (2,3-DHBA and 2,5-DHBA) from salicylic acid. An existing method involving implantation of a probe into the hippocampus and in vivo microdialysis was modified and validated. 3. Administration of MDMA (15 mg kg-1, i.p.) to Dark Agouti (DA) rats increased the formation of 2,3-DHBA (but not 2,5-DHBA) for at least 6 h. Seven days after this dose of MDMA, the concentration of 5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) was reduced by over 50% in hippocampus, cortex and striatum, reflecting neurotoxic damage. There was no change in the concentration of dopamine or 3,4-dihydroxyphenylacetic acid (DOPAC) in the striatum. 4. p-Chloroamphetamine (PCA), another compound which produces a neurotoxic loss of cerebral 5-HT content, when given at a dose of 5 mg kg-1 also significantly increased the formation of 2.3-DHBA (but not 2,5-DHBA) in the dialysate for over 4.5 h. post-injection starting 2 h after treatment. 5. In contrast, fenfluramine administration (15 mg kg-1, i.p.) failed to increase the 2,3-DHBA or 2,5-DHBA concentration in the dialysate. A single fenfluramine injection nevertheless also markedly decreased the concentration of 5-HT and 5-HIAA in the hippocampus, cortex and striatum seven days later. 6. When rats pretreated with fenfluramine (15 mg kg-1, i.p.) seven days earlier were given MDMA (15 mg kg-1, i.p.) no increase in 2,3-DHBA was seen in the dialysate from the hippocampal probe. This indicates that the increase in free radical formation following MDMA is occurring in 5-HT neurones which have been damaged by the prior fenfluramine injection. 7. Administration of the free radical scavenging agent alpha-phenyl-N-tert-butyl nitrone (PBN; 120 mg kg-1, i.p.) 10 min before and 120 min after an MDMA (15 mg kg-1, i.p.) injection prevented the acute rise in the 2,3-DHBA concentration in the dialysate and attenuated by 30% the long term damage to hippocampal 5-HT neurones (as indicated by a smaller MDMA-induced decrease in both the concentration of 5-HT and 5-HIAA and also the binding of [3H]-paroxetine). 8. These data indicate that a major mechanism by which MDMA and PCA induce damage to 5-hydroxytryptaminergic neurones in rat brain is by increasing the formation of free radicals. These probably result from the degradation of catechol and quinone metabolites of these substituted amphetamines. In contrast, fenfluramine induces damage by another mechanism not involving free radicals; a proposal supported by some of our earlier indirect studies. 9. We suggest that these different modes of action render untenable the recent suggestion that MDMA will not be neurotoxic in humans because fenfluramine appears safe at clinical doses.

MDMA (AND METH) generated oxidative stress could be the culprit: MDMA acting either as TH inhbitor, leading to depletion of DA/NE (and accumulation of free radicals precursors to DA) or as a substrate leading to oxygen centered free radicals and oxidative injury... but who knows?

 

[DotChem]

oops one more

5-HT loss in rat brain following 3,4-methylenedioxymethamphetamine (MDMA), p-chloroamphetamine and fenfluramine administration and effects of chlormethiazole and dizocilpine https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1908028/

Abstract (truncated).... 3. Administration of a single dose of chlormethiazole (100 mg kg-1) 20 min after the MDMA also provided complete protection to the hippocampus but not the cortex. This regime also attenuated the sustained hyperthermia (approx +2.5 degrees C) induced by the MDMA injection... (5 mg

 

[Cotcha Yankinov]

I think one of the theories coming from the Nichols group was that inhibition of inhibitory interneurons via stimulation of 5-HT2 receptors could lead to increased dopamine that would increase oxidative stress. So an interesting theory considering that GABA-A agonists/PAMs are protective.

That may shift our thinking to a bit more about the network activity that MDMA will induce, and not to tunnel vision on a specific terminal.

One could tunnel vision and say "okay, tryptophan hydroxylase inhibition, VMAT inhibition, increased extracellular dopamine via dopamine release + substituted amphetamine metabolites = terminal loss".

But a more integrated theory would take into acount the downstream effects of serotonin release (increased extracellular dopamine not just from a carrier exchange mechanism) or increased glutamate et cetera.