Neurotoxicity of 2C-x and DOx

[specialspack]

Are there any studies of the neurotoxicity of 2C-x and/or DOx compounds?

 

[sekio]

They're regularly used as radiotracers, or at least the radioactive form.

As with all 5-ht agonists I don't think neurotoxicity is very much of a problem.

 

[specialspack]

Forgive my ignorance - but how does their use as radiotracers reflect on their neurotoxicity or lack thereof?

 

[nuke]

There was a Japanese study that show DOI could induce apoptosis (can't find it), but it was a mess in terms of methodology and should probably be disregarded. If they did ever cause neurotoxicity, the question would be: how? None of the other relatively selective 5HT agonists/partial agonists do.

Neurosci Lett. 2004 Sep 9;367(3):349-54.

Microglial activation is a pharmacologically specific marker for the neurotoxic amphetamines.
Thomas DM, Dowgiert J, Geddes TJ, Francescutti-Verbeem D, Liu X, Kuhn DM.

Department of Psychiatry and Behavioral Neurosciences, Wayne State University School of Medicine, 2125 Scott Hall, 540 E Canfield, Detroit, MI 48201, USA.

Neurotoxic amphetamines cause damage to monoamine nerve terminals of the striatum by unknown mechanisms. Microglial activation contributes to the neuronal damage that accompanies injury, disease, and inflammation, but a role for these cells in amphetamine-induced neurotoxicity has received little attention. We show presently that D-methamphetamine, 3,4-methylenedioxymethamphetamine (MDMA), D-amphetamine, and p-chloroamphetamine, each of which has been linked to dopamine (DA) or serotonin nerve terminal damage, result in microglial activation in the striatum. The non-neurotoxic amphetamines l-methamphetamine, fenfluramine, and DOI do not have this effect. All drugs that cause microglial activation also increase expression of glial fibrillary acidic protein (GFAP). At a minimum, microglial activation serves as a pharmacologically specific marker for striatal nerve terminal damage resulting only from those amphetamines that exert neurotoxicity. Because microglia are known to produce many of the reactive species (e.g., nitric oxide, superoxide, cytokines) that mediate the neurotoxicity of the amphetamine-class of drugs, their activation could represent an early and essential event in the neurotoxic cascade associated with high-dose amphetamine intoxication.

http://www.ncbi.nlm.nih.gov/pubmed/15337264

In fact, they're even neuroprotective in the case of NDMA antagonists,

Neuropsychopharmacology. 1998 Jan;18(1):57-62.

Serotonergic agents that activate 5HT2A receptors prevent NMDA antagonist neurotoxicity.
Farber NB, Hanslick J, Kirby C, McWilliams L, Olney JW.

Department of Psychiatry, Washington University, St. Louis, Missouri, USA.

Abstract
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.

http://www.ncbi.nlm.nih.gov/pubmed/9408919

 

[hamhurricane]

In massive doses some of the DOx (DOM specifically) may behave as duel releasers of DA and 5HT but the doses will be so high that you would worry about psychological problems long before some minor MDMA type serotonergic neuron alterations.

 

[specialspack]

Thanks guys.

Nuke - I read a couple of abstracts that mentioned that 5HT2A agonists might prevent psychotomimetic effects of NMDA antagonists - which seems bizarre. I would have thought that, erm, anecdotal evidence would suggest if anything the opposite..?

 

[sekio]

5HT2Ar-induced hallucinogenisis is very different from NMDAr-induced schizophrenia/hallucinogenesis. Both perceptually and in terms of the processes in the brain. One by definition is excitatory (5ht2a agonism) and one is inhibitory (NMDAr block) just off the top of my head, and the two receptors are nothing alike in terms of structure.

This may be a little off topic or cynical, but I think that if you look hard enough *all drugs* have neurotoxic potentials, esp. at elevated doses or for extended periods of time. This is also dependent on your definitition of 'neurotoxicity'.

 

[specialspack]

5HT2Ar-induced hallucinogenisis is very different from NMDAr-induced schizophrenia/hallucinogenesis. Both perceptually and in terms of the processes in the brain. One by definition is excitatory (5ht2a agonism) and one is inhibitory (NMDAr block) just off the top of my head, and the two receptors are nothing alike in terms of structure.

Well - Vollenweider thinks that 5HT2A agonists and NMDA antagonists share a mechanism via cortical glutamate release, so if you believe him, elements of the experience and the brain chemistry are not so far apart after all.

But on a more personal level, I don't think that 5HT2A agonists, DOx or 2C-x have ever reduced the psychotomimetic effects of ketamine, for me...

This may be a little off topic or cynical, but I think that if you look hard enough *all drugs* have neurotoxic potentials, esp. at elevated doses or for extended periods of time. This is also dependent on your definitition of 'neurotoxicity'.

Of course, can't disagree with you there. This whole thread was motivated by discussion with people about the difficulty MDMA faces as a potential therapeutic because of it's perceived neurotoxicity. Which is ridiculous when compared to, say, Adderall, which is widely prescribed.

 

[any major dude]

Well - Vollenweider thinks that 5HT2A agonists and NMDA antagonists share a mechanism via cortical glutamate release, so if you believe him, elements of the experience and the brain chemistry are not so far apart after all.

I believe there was some discussion of downstream modulation of arachidonic acid via both 5-HT2a agonism & NMDA antagonism as well

Of course, can't disagree with you there. This whole thread was motivated by discussion with people about the difficulty MDMA faces as a potential therapeutic because of it's perceived neurotoxicity. Which is ridiculous when compared to, say, Adderall, which is widely prescribed.

i've run into this a few times as well. patently ridiculous obviously, especially given that MDMA therapy sessions are given a handful of times per year at most...

And as per the OP, i'm unaware of any studies on that specifically, but in the realm of wild speculation there is the notion that their metabolism could result in free radicals, which are, again speculatively, potentially damaging. However, i'd think one would incur all sorts of other difficulties before ingesting enough substituted PEA psychedelics to do significant neurological damage

 

[amanitadine]

In massive doses some of the DOx (DOM specifically) may behave as duel releasers of DA and 5HT but the doses will be so high that you would worry about psychological problems long before some minor MDMA type serotonergic neuron alterations.

Curious about this....is this a quality unique to DOM or has it only been demonstrated with DOM?

 

[hamhurricane]

Curious about this....is this a quality unique to DOM or has it only been demonstrated with DOM?

DOM is the only 2,5-DM-4-sub-AMP I know that has been profiled as such. I’m drawing that conclusion from the paper “3,4-Methylenedioxyamphetamine (MDA) Analogues Exhibit Differential Effects on Synaptosomal Release of 3H-Dopamine
and 3H-5-Hydroxytryptamine” by Shulgin and McKenna. (-)-DOM releases 5HT with approximately the same potency as (+)-MDMA and (+)-DOM releases DA with a similar potency to (-)-MDMA. Considering DOM is used at a dose 25x lower than MDMA I would imagine any neurotoxicity is totally insignificant...or alternately as significant as consuming 5mg of MDMA. But actually probably much less so because DOM will not form the same pro-oxidant metabolites and conjugates.

 

[amanitadine]

Interesting, thanks. And interesting moreso because of the differing effects of the enantiomers rather than the DA and 5HT release. Racemically pure DOM was beyond my simple means, but I know that R-(-) DOM has made the rounds several times in the past. Curious as to the effects now..........

 

[hamhurricane]

Yes I have a bit of R-DOM, which I have not had the opportunity to test. Racemic DOM certainly felt as if it was putting my body and mind through the proverbial wringer. Future experiments will not be carried out in a public swimming pool.

 

[amanitadine]

Just thinking about taking DOM at a public swimming pool traumatizes me. But I do urge more experimentation....it is one of the most captivating, twisted, and fun of Sashas creations.