Mitigating HT/DA neurotoxicity with escitalopram

[Eliphaz]

Is it viable to think that taking escitalopram the day after BZP / TFMPP consumption would considerably lessen any possible neurotoxic activity? Is there any experiential basis in the speculation that administering SSRI after MDMA may combat residual neurotoxicity?

BZP / TFMPP in certain proportions mimics 5-HT / DA release of MDMA rather well thus the same harm reduction methods should be applicable, right?

 

[P A]

I'm not aware of either of those drugs being of significant neurotoxic risk, especially in comparison to substituted amphetamines. In theory, were the drugs to share some of MDMA's toxic properties, you'd be better off taking a hypothermic agent like cyproheptadine, as the risk of fever (a considerable potentiator of stimulant toxicity) for these drugs is similarly high.

 

[SynAmnesia]

I was almost certain that the data on taking antidepressants to mitigate neurotoxicity with MDMA was mixed. I have heard some stories that taking fluoxetine a max of 5 hours after MDMA ingestion may help reduce some oxidative stress which usually leads to neurotoxicity. However, after that 5 hour mark the SSRI is fairly useless as the damage has been done. Also, whether any other antidepressants help with neurotoxicity is still debated.

In addition, the fact that the SSRI may help with neurotoxicity has a lot to do with MDMA's unique mechanism of action. It is suspected that neurotoxicity is caused by the uptake of dopamine into serotegenergic neurons which can cause cell death. Therefore, this reuptake may be blocked by SSRIs on some level. I don't think BZP/TFMPP has the same mechanism of action and therefore adding an SSRI to the mix may only cause some sort of serotonin syndrome.

In addition, I could have sworn I saw data a few years ago that found that MDMA when taken in normal doses (100-125mg) and without amphetamine is not actually neurotoxic. To test this, they did aptitude tests on people who had recently ingested pure MDMA and found that right after ingestion, cognitive ability went down slightly. However, cognitive ability was back to almost baseline levels within 2-6 weeks. The initial tests done by that guy with 7 letters in his name that started with an R during the 80s used a mix of MDMA and Methamphetamine. NMR or MS was not performed at the time to check the composition. Certainly combining meth with MDMA (which increases dopamine in the space between neurons) will be neurotoxic. I mean, Meth by itself is neurotoxic. Therefore, in normal doses, MDMA is not particularly neurotoxic when used infrequently, and therefore the idea that taking any SSRI to combat neurotoxicity is still a debated point. In fact, it is sometimes argued that taking an SSRI post MDMA could induce a sort of serotonin syndrome, which will in fact increase neurotoxicity.

However, what you can do to reduce the neurotoicity of any drug with little risk is to load up on antioxidants like vitamin C or ALA. Also, make sure to eat well and drink plenty of fluids. However, be careful with the fat soluble vitamins (i.e. A and E) as in high doses those can cause toxicity.

 

[Eliphaz]

Thanks for the informed comments. Unfortunately there is no conclusive research on the acute neurotoxicity of the BZP/TFMPP combo, but it does have similar 5-HT / DA releasing profile to MDMA, and much alike subjective experience in many individuals. One could assume it has the same "unique-to-MDMA" mechanism of action concerning toxic reuptake of dopamine into serotonergic neurons.

The point on cyproheptadine is nice. I was thinking that preloading with gabapentin would serve the same purpose, as has been mentioned elsewhere it blocks the MDMA-induced deficits in thermoregulation and diminishes neurotoxic effects that way. But reading about gabapentin interference with the cell cycle has given second thoughts...

I am primarily concerned about the facts that BZP/TFMPP affects thermoregulation at least as badly as MDMA, and BZP itself is much like amphetamine on many fronts, so it could be suspected that the neurotoxicity would be on par with MDMA + amphetamine. Long term exposure to BZP has been shown to cause functional deficits in the brain like amphetamine. Not underestimating antioxidants of course, but they would really play a minor role if another large scale mechanism inducing cell death is in action.

The controversy between post-administration of SSRI contributing towards serotonin-syndromish toxicity, and its alleviation of DA reuptake into 5-HT neurons is very annoying. Maybe keeping body temperature in check would indeed be the most effective route here, but unfortunately cyproheptadine shortly after BZP/TFMPP would pretty much be a leap into the unknown.

 

[MeDieViL]

Cyproheptadine will inhibit MDMA or other drugs as 5HT2A plays a crucial role in mesolimbic dopamine release.

 

[P A]

Cyproheptadine will inhibit MDMA or other drugs as 5HT2A plays a crucial role in mesolimbic dopamine release.

Eh. 2A antagonists may abolish some discriminative stimulus properties in rats, but I'm not so sure it actually plays out that way in humans. I know/have heard of people coadministering anything from meth to serotonergic psychedelics with such potent 5-HT2A drugs as mirtazapine and low-dose antipsychotics and experiencing a negligible alteration in subjective effect. Unless we're talking about inverse agonists, I doubt it's a relevant concern.

Either way, cyproheptadine wouldn't be my go-to drug in similar circumstances, given its dirty chemotype/receptor profile. It's just one I mentioned offhand. In all honesty, I'm sure a benzodiazepine would be just as effective as a central hypothermic, and would likely smooth out the frequently harsh piperazines. But whatever...

cyproheptadine shortly after BZP/TFMPP would pretty much be a leap into the unknown.

How so? Studies on the thermal/neuroprotective properties of 5-HT2 antagonists are abundant, with cyproheptadine itself figuring heavily in the literature.

 

[Eliphaz]

How so? Studies on the thermal/neuroprotective properties of 5-HT2 antagonists are abundant, with cyproheptadine itself figuring heavily in the literature.

Just a personal aversion to any untested combos due to history of multiple idiosyncratic reactions, that is. Upon closer look it seems there's little reason to be overly suspicious of cyproheptadine though, but still the old'n good diazepam would be even simpler. I had missed the basic neuroprotective effeciveness of benzos, thanks for the heads up on that! It seems we now have several better options for than the - also untested - escitalopram . Preloading with gabapentin is still attractive, well sometimes one truly does have to make up his mind.

 

[P A]

Preloading with gabapentin is still attractive

I don't know...seems like a pretty bugshit drug. Weird side effects, etc. But like you, I prefer the benzos to any of the other clinically available hypothermics, hands down.

 

[negrogesic]

I wouldn't count on it.

 

[Eliphaz]

I wouldn't count on it.

Please elaborate, count on what? Given that there is only indicative research on the efficacy of SSRI, 5-HT2 antagonists, diazepam or gabapentin on mitigation of MDMA-type neurotoxicity (through a variety of mechanisms) while not diminishing the desired effects, it's basically a question of picking one that suits your taste (one that according to personal background and circumstantial evaluation seems to give the highest cost-benefit ratio).

 

[Aaron Burr]

I know/have heard of people coadministering anything from meth to serotonergic psychedelics with such potent 5-HT2A drugs as mirtazapine and low-dose antipsychotics and experiencing a negligible alteration in subjective effect. Unless we're talking about inverse agonists, I doubt it's a relevant concern.

mirtazapine is an inverse agonist at 5ht2c (Chanrion et al., 2008.)
see: http://molpharm.aspetjournals.org/content/73/3/748.short

and for what it is worth (!credibility alert!, i.e., Department of Molecular Pharmacology, *AstraZeneca*), "It has subsequently emerged that the majority, around 85%, of all known G-protein coupled receptor antagonists are, in fact, inverse agonists"

see: http://www.ncbi.nlm.nih.gov/pubmed/...serid=10&md5=579a8d8a1d06cf158b2765c40c825553

is anyone aware of any recent literature on mirtazapine's interaction with 5ht2a? and why would it be concerning if it were an inverse agonist?

 

[P A]

and why would it be concerning if it were an inverse agonist?

It would produce an overall inhibitory effect on 5-HT2A-mediated neurotransmission far more drastic in scope than anything a vanilla antagonist could accomplish.