Can you prove that SSRIreleaser do more harm then SSRIs longterm?What say the experts

[Student76]

I found a promsing study where they tested a Serotonin releaser for depression which worked from day one.
If you look at a moleküle like 5-APBD with the benzofuran part and compare it with citalopram also with a benzofuran part,and the carbonitril
to up the half live to 22 hours and one more methyl group or it would be a sort of amphetamine,then I ask me
the question if you would make a low dose say also 5 mg like citalopram and a long half live.Why should it more harmfull to the brain longterm?
5-APBD is almost a clean serotonin releaser so quite interessting or not?
If you stop reuptake from Serotonine,more will be degraded,and less transported back in the vesikels.
But if you take a releaser and do not release the complete vesikels,where is the difference?

What do the genuis and experts conter that the brain will be severely damaged?

Anja which studied Pharmacie.

 

[serotonin2A]

I found a promsing study where they tested a Serotonin releaser for depression which worked from day one.

I am not aware of any selective serotonin releasing drugs that have been tested in humans in a clinical trial. Can you include a citation to back up your claim?

If you look at a moleküle like 5-APDB with the benzofuran part and compare it with citalopram also with a benzofuran part,and the carbonitril to up the half live to 22 hours and one more methyl group or it would be a sort of amphetamine,then I ask me

Organic chemistry and pharmacology don't work that way. Small variations in chemical structure can completely change the way that drugs interact with molecular targets (enzymes, receptors, transporters...). Just because 5-APBD and citalopram have some very superficial structural similarities doesn't tell you anything about how similar their pharmacology/toxicology is going to be. \

the question if you would make a low dose say also 5 mg like citalopram and a long half live.Why should it more harmfull to the brain longterm? 5-APBD is almost a clean serotonin releaser so quite interessting or not? If you stop reuptake from Serotonine,more will be degraded,and less transported back in the vesikels. But if you take a releaser and do not release the complete vesikels,where is the difference? What do the genuis and experts conter that the brain will be severely damaged? Anja which studied Pharmacie.

You can't compare the safety of citalopram and 5-APDB. Citalopram has been studied in clinical trials, in addition to having a long track record of safe use under medical supervision. Not enough people have taken 5-APDB, under controlled conditions (where for example the dose or purity is known), to know if it is safe. Additionally, the mechanism of action of citalopram and of 5-APDB and other serotonin releasers are completely different, and they will have different effects on the brain long-term. One of the problems with serotonin releasers is that they tend to produce hyperthermia, which can be neurotoxic. They may also produce some degree of dopamine release, and that is another potential way that they can damage neurons (dopamine can be taken up into serotonergic neurons and cause oxidative stress). Some serotonin releasers have metabolites that are serotonin neurotoxins. Additionally, many serotonin releasers have 5-HT2B agonist activity, which may produce cardiovascular damage. Also, in general, serotonin releasing drugs tend to deplete serotonin and cause serotonin receptors to downregulate. Both of those effects make long-term use unsustainable.

 

[serotonin2A]

I wanted to bring up another issue, which complicates comparison of the safety of citalopram with drugs such as 5-APDB. Citalopram is synthesized under GMP conditions. The purity is monitored, and tests are run to detect specific impurities and solvent residues. With something like 5-APDB (or fluoroamphetamine, MDAI, etc), even if the pure compound is safe, that doesn't mean what people are buying and ingesting is safe. The presence of impurities may not be that much of an issue if a drug is used sporadically. But here you seem to be talking about taking a drug every day, at several 100 mg per day. With chronic use of high doses, any precursors, side products, and solvents that are present could potentially produce toxic effects.

 

[sekio]

It's worthwhile noting that none of the cathinones are selective for anything, compounds like the APDB series and the cathinones are generally triple monoamine releasers with slightly different "balances".
It's also good to remember that MDMA doesn't produce its stereotypical effects if the norepinephrine transporter is blocked. So even with drugs thought to be "serotonin releasers", the behavioural aspects come from NE release.

People have trialled selective serotonin releasers but I don't think they were useful at all. 5-iodo-aminoindane or whatever was touted as "the next best non toxic MDMA replacer" and it turned out to be not only fraught with supply problems, but also just not very mood-elevating at all.

I think you should know better than anyone, monoamine releasers don't keep working. For those that respond to SSRI therapy (major depression), the effect is continuous and anti-depressant action continues even after they discontinue therapy...

 

[serotonin2A]

It's also good to remember that MDMA doesn't produce its stereotypical effects if the norepinephrine transporter is blocked. So even with drugs thought to be "serotonin releasers", the behavioural aspects come from NE release.

It isn't accurate to say that MDMA doesn't produce entactogenic effects if NET is blocked. The NET inhibitor reboxetine only produces a moderate attenuation of the response to MDMA (http://www.nature.com/clpt/journal/v90/n2/full/clpt201178a.html). By contrast, SERT inhibitors block most MDMA effects (http://www.nature.com/npp/journal/v22/n5/full/1395472a.html). The mixed SERT and NET inhibitor duloxetine was very effective at blocking MDMA, so a mixture of effects on serotonin and norepinephrine may be required for the characteristic effects of MDMA (http://www.ncbi.nlm.nih.gov/pubmed/22574166). But serotonin definitely plays a role.

 

[sekio]

It reads to me like both serotonin and norepinephrine release are required for the whole "bouquet" of MDMA's effects.

 

[serotonin2A]

It reads to me like both serotonin and norepinephrine release are required for the whole "bouquet" of MDMA's effects.

Yes, exactly! I was just trying to point out the it isn't really correct to say "the behavioural aspects come from NE release." It is important to note, however, that it probably can't be excluded that the effect of the NET inhibitors is due to effects on dopamine uptake. There is little or no expression of dopamine transporter in prefrontal cortex (PFC), so in that region dopamine is taken up by NET. Therefore, it is possible that MDMA could inhibit dopamine uptake by NET in the PFC, and MDMA could potentially even drive dopamine out of norepinephrine terminals if there is a releasable pool in the cytoplasm.

 

[dopamimetic]

I am interested in this topic too.

Of course the 5-HT2B issue is without doubt a serious problem. But besides that, is there evidence that 5-HT releasers used in moderation, are more harmful than plain reuptake inhibitors? Regarding NE/DA, medically used amphetamine seems not to be much worse than an equal dose of methylphenidate, for example. And I would speculate that using an SSRI chronically will also lead to 5-HT depletion and eventually lowered overall levels in some.

So, if we had a serotonin releaser without 2B affinity and a half life of less than maybe 12-14h, so that some new 5-HT could be stored overnight - couldn't this be a more effective way than an SSRI that is acting 24/7 (leaving the purity issues of RCs out of consideration for now)?

Also - other question, if we had a potent and selective 5ht2b antagonist, in theory adding such one when using a releaser like the methylmethcathinones would diminish the cardiovascular risks, right? Just that as far as I know there is no such compound available yet.

 

[endotropic]

So, if we had a serotonin releaser without 2B affinity and a half life of less than maybe 12-14h, so that some new 5-HT could be stored overnight - couldn't this be a more effective way than an SSRI that is acting 24/7 (leaving the purity issues of RCs out of consideration for now)?

I've been looking for such a thing for a long time. From everything I've read 5-HT release requires 5-HT2B agonism. Even if you found a 5-HT releasing drug without 5-HT2B agonism you still have the issue of the 5-HT itself acting on the 5-HT2B receptors in the heart.

Also - other question, if we had a potent and selective 5ht2b antagonist, in theory adding such one when using a releaser like the methylmethcathinones would diminish the cardiovascular risks, right? Just that as far as I know there is no such compound available yet.

If you antagonize the 5-HT2B receptor 5-HT releasers no longer release 5-HT. So this could work, you would just need to use a 5-HT2B antagonist that doesn't reach the CNS.

 

[serotonin2A]

I've been looking for such a thing for a long time. From everything I've read 5-HT release requires 5-HT2B agonism. Even if you found a 5-HT releasing drug without 5-HT2B agonism you still have the issue of the 5-HT itself acting on the 5-HT2B receptors in the heart. If you antagonize the 5-HT2B receptor 5-HT releasers no longer release 5-HT. So this could work, you would just need to use a 5-HT2B antagonist that doesn't reach the CNS.

There is an alternative explanation for the data with 5-HT2B, so the situation may not be as dire as it sounds. I think the main evidence for 5-HT2B involvement is that 5-HT2B antagonists (or gene deletion) blocks MDMA or fenfluramine induced 5-HT release. It is possible that the 5-HT2B receptor plays a permissive role for SERT function, and so loss of 5-HT2B signaling ameliorates the ability of the transporter to release 5-HT. That doesn't necessarily mean MDMA has to activate 5-HT2B to be effective -- it could be that endogenous 5-HT tone (or even constitutive receptor activity) constantly activates 5-HT2B at a low level. So 5-HT2B antagonists block MDMA because some 5-HT2B tone is required for reverse transport to occur at SERT. 5-HT2B would be acting as a source of regulatory feedback. If 5-HT levels are so low that there is no presynaptic 5-HT2B activation, that would reduce 5-HT uptake, which would increase 5-HT tone.

 

[St3ve]

I am not aware of any selective serotonin releasing drugs that have been tested in humans in a clinical trial. Can you include a citation to back up your claim?

AMT was originally designed to be an antidepressant and acts as a triple monoamine releaser. The wiki ref points to a patent application though, so I doubt it ever made it past preclinical trials (if that).

The whole serotonin - depression thing is becoming a bit outdated as well. We now know of so much more other receptors, signalling pathways and proteins that are involved in the pathophysiology of depression that pharmaceutical companies are better off looking for new targets. The market is already flooded with plenty of me-too SSRIs. Releasing agents would at best have similar treatment efficacy to SSRIs, which isn't all that great to begin with. Potentially, they'd start displaying therapeutic effect faster than SSRIs, but they might stop working sooner too...

 

[《Plasticity》]

^ aMT was actually prescribed in Russia for a period of time, believe it or not. Not sure why it was removed from the market though, likely due to abuse problems or scares from the findings of aET causing idiosyncratic agranulocytosis...

 

[serotonin2A]

AMT was originally designed to be an antidepressant and acts as a triple monoamine releaser. The wiki ref points to a patent application though, so I doubt it ever made it past preclinical trials (if that).

The point I was trying to make is that selective serotonin releasers have never been tested in clinical trials. alphaMT and alphaET are reversible MAO inhibitors, and that could potentially contribute to their therapeutic efficacy. p-Chloroamphetamine and p-chloromethamphetamine were also evaluated as antidepressants, but neither compound is selective for serotonin release.

 

[f33lg00d]

AMT was originally designed to be an antidepressant and acts as a triple monoamine releaser. The wiki ref points to a patent application though, so I doubt it ever made it past preclinical trials (if that).

If its a triple releaser then its not selecive for serotonin.

 

[DL-ark]

If its a triple releaser then its not selecive for serotonin.

It can be selective for serotonin compared to it's affinitys to NE/DA, as in, it has higher affinity to SERT than the other monoamine transporters while still having some affinity for the other transporters.

That said, I don't think that is what serotonin2A meant.

 

[dopamimetic]

Well, I currently use low dose 3-MMC daily as a mood and motivation / cognition enhancer, and it works surprisingly well. Much better than I would ever have thought. Even plain dexamphetamine in pharmaceutical quality and used in as less as 5-10mg/d is not sustainable for me as after some days the hangovers become very heavy and it requires a shitload of time and energy to just get out of bed and take the next pill.

In contrast, the 3-MMC used at maybe 30-40mg/d (combined with my usual memantine and magnesium glycinate in the morning and clonidine at night) has much less pronounced adrenergic effects, the rebound is mainly serotonergic and seems to be solved by taking 5-HTP at night and in the morning. It's now day 10 or so and with the 5-HTP, I woke up refreshed without any hangover today despite having dosed a bit more yesterday..

I don't think it's sustainable for longer, but this is what the SSRIs should have been and never were (but instead brought me the nastiest withdrawal ever).

This was the same thing with 4,4'-dimethylaminorex by the way. If it only would be possible to protect the heart from these kind of substances (like with a robust peripheral 5-HT2B antagonist possibly?)..

--

Also, a weird effect of 3-MMC - at least when used nasally and in correct dose - is that it actually lowers my pulse sometimes. I tend to have high rest pulse of around 80 bpm often, and with 3-MMC I've measured values of 70 or even less repeatedly. On some occasion I got this from (very low) doses of amphetamine too, but not reliable.