Serotonin - SSRIs, MDMA and LTCs

[neurotic]

seeing that post about MDMA's neurotoxicity on MED earlier made me think about this thread.

for some time i was inclined to believe that serotonin didn't have to much to do with depression, so i self-treated with you know, mindfulness, CBT, all that jazz, relying on the power of my own mind rather than chemicals. althought i have improved i still am not free from depression and even though it's not everyday anymore, there are some days where depression totally consumes me, still.

now, if i take a look at MDMA for example, it points that serotonin does have something to do with 'feeling good' and all - assuming that its flood of serotonin in the brain is the reason behind all the love and orgasmic feelings that separate it from regular stimulants -. and, that it also has something to do 'depression', given the absurd long-term comedowns threads we see around here.

my layman's take on the situation on why some people use MDMA without any problem, some abuse and abuse and abuse until one day they BAM get depressed and others do it one time and have a horrible aftermath, would be differneces in each person's serotonergic system. seriously i believe some people do go through a living hell after MDMA (ab)use, some users though think it's bullshit and it's because it was untested. i really believe untested pills are not the real problem here, because, wth are pills cut with? methylone, meth? that'd make for a shitty weak 'roll' and i doubt any long term consequences.

some user pointed out a study about chronic SSRI use reducing SERT density A LOT, which was what people were saying (IIRC) was a marker of MDMA 'neurotoxicity'. but you know i just read a study showing repeated SSRI administration on rats did reduce SERT density, but it also increased extracellular 5-HT levels. which kinda makes sense right, if there are less transporters around, there will be more serotonin around too.

so, how lowered SERT density can be bad if it raises serotonin levels? assuming more serotonin is good, ofc

but if LTCs were as simple as depleted serotonin and all downstream effects that come from that, some time taking 5-HTP to help recover your serotonin levels would be enough right?

what do you guys think? i'm considering giving 5-HTP a try to see if my depression really comes from unbalanced serotonin.

though it's kinda hard to say that permanent low levels of serotonin would give you a permanent state of depression right? your receptors would get used to it, upregulated may be? isn't the brain kinda self-regulating? if you constantly take something to raise your levels of serotonin (perfect example, SSRIs) your brain would get used to it - just like drug tolerance works right? - and you'd be back to your own baseline levels right?

sorry about anything i'm just asking for opinions regards involvement of serotonin in MDMA's LTCs and depression, from you guys who seem more knowledgeable than me

this subject really intrigues me

 

[endotropic]

I can't respond to all of this right now, but I think it's a mistake to assume that all SERT reductions are equal.

When you give MDMA to a rat and chop its brain open, you can see that serotonin neurons throughout the brain retract their dendrites so that the serotonin neurons are making far fewer synaptic connections to surrounding neurons. With the loss of dendrites/synapses you logically also have a loss of SERT. So when you're talking about MDMA toxicity the reduction in SERT is really just a marker for the overall pruning of the neuron (and there's debate whether that pruning ever fully reverses).

When you give the rat chronic SSRI's you do see a reduction in SERT expression, but none of the synaptic pruning that you see with MDMA.

Now whether those processes play out the same way in human users? We can't really be sure because we can't (shouldn't?) chop open a human brain and put it under a microscope. But long and short of it that's how lowered SERT levels can be a marker for something bad in one situation (MDMA) but not another (chronic SSRI).

 

[neurotic]

Thanks that clears that up

 

[Jabberwocky]

let me try and dig up the report that found that SSRIS actually long term depleted serotonin release and production and short term (2/3 weeks halted it completely) and actually cause less to be produced.

l-tryptothan i found greatly cured my depression (being related to the serotonin molecule) with no dangers. definitely didn't make me psychotic like lexapro and prozac.

MDMA never induced a bad experience however post use the serotonin depletion after long term or heavy abuse was to the point of suicidal for the next week/two induced extreme lethargy. however i think in very low doses daily it could actually help.

 

[neurotic]

yeh i'm gonna give 5-HTP a try. close enough to L-tryptophan.

and also i just got another question. why when MDMA raises serotonin levels we have empathogen and euphoric effects and all that loved up feeling, but if one were to take a shitload of SSRIs and raise their serotonin levels a lot, they'd get nothing but serotonin syndrome? what's the difference

i mean, i know both raise serotonin levels via different mechanisms (releaser vs. RI) but in the end, it's all more serotonin right? also a lot of LTC symptoms seem very similar to SSRI discontinuation syndrome.

 

[Black]

assuming that its flood of serotonin in the brain is the reason behind all the love and orgasmic feelings that separate it from regular stimulants

not necessarly just that. with pure sras we see no euphoria.

besides, it's possible that 5-ht2br activation (which is essential to mdma's effects in rats) has additional effects than just releasing serotonin (while at the same time working against serotonin syndrome)

so, how lowered SERT density can be bad if it raises serotonin levels? assuming more serotonin is good

and also i just got another question. why when MDMA raises serotonin levels we have empathogen and euphoric effects and all that loved up feeling, but if one were to take a shitload of SSRIs and raise their serotonin levels a lot, they'd get nothing but serotonin syndrome? what's the difference

more serotonin is good (sadly) is a gross oversimplification. there is no one "serotonin level". it all varies from region to region and ssris have more effect on neurons with a higher serotonin turnover. releasers like mdma probably have the most effect in regions with high sert-density. also maybe mdma's mechanism of releasing serotonin - 5-ht2b receptor activation - preferentially releases serotonin in some "fun" regions.
and even that is a huge oversimplification. there are many serotonin synapses with many different serotonin receptors (some of which we have no idea what they do yet) with a great variety of functions. it all depends on so many factors with so many unknowns that we cannot really answer this yet.

also the monoamine hypothesis of depression is outdated (but a good part of the medical community still clings to it). one currently plausible hypothesis of why antidepressants work (for some people) is that they increase the levels of the brain-derived neurotrophic factor, which (among other functions) increases neurogenesis. afaik we don't yet know the mechanism behind that, so it may well be independant from serotonin altogether...

but if LTCs were as simple as depleted serotonin and all downstream effects that come from that, some time taking 5-HTP to help recover your serotonin levels would be enough right?

if it indeed is that simple (which is doubtful, nearly everything turns out to be much more complicated the more we know) and mdma's inhibition of tryptophan hydroxylase is indeed the main point in ltcs, then 5-htp should work.

When you give MDMA to a rat and chop its brain open, you can see that serotonin neurons throughout the brain retract their dendrites so that the serotonin neurons are making far fewer synaptic connections to surrounding neurons. With the loss of dendrites/synapses you logically also have a loss of SERT. So when you're talking about MDMA toxicity the reduction in SERT is really just a marker for the overall pruning of the neuron (and there's debate whether that pruning ever fully reverses).

this paper shows serotonin depletion (most likely due to tryptophan hydroxylase) in rats without any kind of neurotoxicity or axon pruning in doses up to 20mg/kg in rats. it also makes some very good points about how giving rats ridiculous doses cannot be compared to the doses we humans consume.

 

[SkyblueMolly]

So SSRI drugs reduce brain function? Studies with low doses of 2C-x and with low dose psilocybin mushrooms show increase in neuron receptor activity and increased cognition. Low doses of 2C-x increased brain function and low dose shrooms increased brain cell count. MDxx(MDMA and others) did not show toxicity at once monthly administration of less. MDxx showed impairments from chronic administration, but is most likely because the brain is not given enough time or supplements to recover it's receptor chemicals. While moderate to severe activation of 5HT2a receptors show hallucinations, mild activation is linked to increased cognition. MDxx series don't just work on serotonin. MDxx also release norepinephrine, dopamine, adrenaline, oxytocin, and mildly activates 5HT2a receptors. This combination of serotonin, norepinephrine, dopamine, adrenaline, oxytocin, and mild activation of 5HT2a receptors is what leads to the feel good feeling. The 2C-x series are more controlled in the release of these chemicals and more specific. While MDxx can deplete these chemical receptors, administration of 5-HTP, and L-Tyrosine help the brain replenish these receptors. The more the release of receptors, the less often the chemical can be taken and the more supplements you need to take to help the brain refuel. It's mostly about whether the molecule produces toxic metabolites or not and how toxic these metabolites really are. IndanylAminoPropane works like MDxx, except that release of receptors is much less. Hence IndanylAminoPropane can be used once a week or even daily instead of once a month. IndanylAminoPropane might be the antidepressant of the future and would be like sort of like ignoritol from the simpsons. The receptor conversation is highly controversial as many studies carried out in the past have been carried out poorly and with very limited knowledge or receptor behavior. Just because something looks scary doesn't neccesarily mean that it's extremely dangerous. Responsibility matters. Every molecule has a story and every molecule can be restructured to get the best from it.

 

[Jabberwocky]

The more the release of receptors, the less often the chemical can be taken and the more supplements you need to take to help the brain refuel. It's mostly about whether the molecule produces toxic metabolites or not and how toxic these metabolites really are.

not to mention sleep, mainly REM sleep to replenish depleted serotonin molecules. i thought the toxicity came with the MDxx molecule producing such a large influx over time that it causes the serotonin synapses/transporters to quite literally cease functioning without the aide of a chemical? but the toxic metabolites of some chemicals definitely play a role in neurotoxicity, not to mention the hyperthermia.

 

[neurotic]

yeah i know MDMAs effects aren't all about serotonin release, that's why i said in my first post that the loved-upness, parallel to the serotonin release, is what differentiated it from the regular stimulants. i've heard of selective releasers being disappointing on their own, but may be you need the dopamine/norepinephrine kick for you to notice your increased empathy as much. i never took a selective releaser though so can only imagine what it feels like.

also, Black, i assume you're talking about the 5ht1a receptor? because i remember that 5ht1a activation leads to oxytocin release. i read a study where they gave 8-oh-dpat (?) to rats, a selective 5ht1a agonist, and it increased their social behaviour and oxytocin levels. smth like that.

i even thought all the 'love' came from 5ht1a agonism, but here on BL someone argued that MDMA was only a weak agonist and the serotonin flood was more important than 5ht1a agonism.

i'm pretty sure the 'monoamine hypothesis of depression' is bullshit and you can't just feed someone SSRIs/5-HTP and turn them into a happy person. i bet our serotonin levels vary through the day. but come on man it's undeniable monoamines are related to mood. stimulants and how they change your mood show that. drugs show chemicals in our brain alter our mood. some days you just feel tired for some reason and other days you just wake up feeling great. we do have control over our own thoughts but there are chemical reasons for emotions aswell... not saying its matter over mind, but neither mind over matter... may be mind almost over matter

uhhhhh anyway, MDMA (empathogen stimulants?) seems like the only drug with those long comedowns, sometimes starting 2 days after use (unlike regular stims where comedown comes right away - that could be cause they are downstream effects from lowered serotonin on previous days?), so i assume that is something serotonin related. what if huge doses of selective serotonin releasers could do that too, cause LTCs? those brain zaps some people report are common in both SSRI discontinuation and MDMA comedowns...

the whole idea that when you have serotonin release/instant serotonin increase/higher 5ht1ar activation combined with raised catecholamine levels you have a magical experience, but without the dopamine/norepinephrine kick you have nothin is intriguing...

just rambling...

 

[Black]

also, Black, i assume you're talking about the 5ht1a receptor? because i remember that 5ht1a activation leads to oxytocin release. i read a study where they gave 8-oh-dpat (?) to rats, a selective 5ht1a agonist, and it increased their social behaviour and oxytocin levels. smth like that.

i even thought all the 'love' came from 5ht1a agonism, but here on BL someone argued that MDMA was only a weak agonist and the serotonin flood was more important than 5ht1a agonism.

no, i 5-HT2B is no typo . that one's responsible for releasing serotonin through reversal of SERT. there's a study wherein they gave a selective 5-HT2B antagonist to rats and the animals never showed any of the typical behavioural changes when administered mdma. i'm convinced that the euphoria depends (at least partly) on 5-HT2B activation. the empathy might sure be more due to oxytocin/5-HT1A (which is presuambly indirectly activated by the released serotonin?).

 

[neurotic]

oh i didnt know that 5ht2b thing

and yeah 5ht1ar 'over'activation through increased serotonin does make sense, i just thought MDMA's agonism was more important than that

 

[endotropic]

and also i just got another question. why when MDMA raises serotonin levels we have empathogen and euphoric effects and all that loved up feeling, but if one were to take a shitload of SSRIs and raise their serotonin levels a lot, they'd get nothing but serotonin syndrome? what's the difference

i mean, i know both raise serotonin levels via different mechanisms (releaser vs. RI) but in the end, it's all more serotonin right? also a lot of LTC symptoms seem very similar to SSRI discontinuation syndrome.

If you look at microdialysis studies with SSRI's you'll see that acute SSRI treatment hardly increases serotonin levels at all, regardless of dose, because all of the increases are tempered by increased 5-HT autoreceptor activation (5-HT1A presynaptic, 5-HT1B/D). When those receptors are activated the serotonin neurons stop firing, and no more 5-HT is released. Without the 5-HT neurons firing the 5-HT levels in the synapse stays fairly constant since SSRIs can't drive release on their own. Over time the autoreceptors desensitize and 5-HT levels start to go up.

With a releaser like MDMA it doesn't matter that the autoreceptors get activated more, the MDMA will drive release all by itself, even though the 5-HT neurons aren't actually firing. So in that case you get an immediate increase in 5-HT levels way higher than you ever get with chronic SSRIs.

 

[Black]

Over time the autoreceptors desensitize and 5-HT levels start to go up.

but so do the postsynaptic receptors. so the higher concentrations of serotonin have less effect, possibly leading to a "mood stabilizing" ( /zombifying - depending on who you ask...) effect.

 

[endotropic]

but so do the postsynaptic receptors. so the higher concentrations of serotonin have less effect, possibly leading to a "mood stabilizing" ( /zombifying - depending on who you ask...) effect.

Some do some don't. I've never seen evidence that postsynaptic 5-HT1A receptors desensitize for example.

 

[neurotic]

If you look at microdialysis studies with SSRI's you'll see that acute SSRI treatment hardly increases serotonin levels at all, regardless of dose, because all of the increases are tempered by increased 5-HT autoreceptor activation (5-HT1A presynaptic, 5-HT1B/D). When those receptors are activated the serotonin neurons stop firing, and no more 5-HT is released. Without the 5-HT neurons firing the 5-HT levels in the synapse stays fairly constant since SSRIs can't drive release on their own. Over time the autoreceptors desensitize and 5-HT levels start to go up.

With a releaser like MDMA it doesn't matter that the autoreceptors get activated more, the MDMA will drive release all by itself, even though the 5-HT neurons aren't actually firing. So in that case you get an immediate increase in 5-HT levels way higher than you ever get with chronic SSRIs.

yeah i read about that before, about when SSRIs start being used they actually decrease 5HT and with desensitization over time they increase extracellular levels of it, aswell as SERT density lowers and all that jazz.

knowing that the MDMA experience is the release of serotonin combined with the stimulant kick, why do you guys think selective serotonin releasers don't cause at least a bit of 'love' or wtv - never tried any of them just what i heard! -, one could expect extreme empathy and enhanced music appreciation/touching (i don't get these with DA/NE stims). or are the current SSRAs just too poor releasers?

also, endotropic, if you don't mind me asking, do you think chronic SSRI use could be a possible treatment for those symptoms of depression such as fatigue, anhedonia etc.. ? or do you think that like Black said (or what i understood from what Black said), they simply don't increase serotonin levels in the 'fun' areas?

 

[Jabberwocky]

maybe slightly off topic, but why is it that our serotonin molecules can only take so much before essentially "melt down" and serotonin syndrome, also the fact that it takes about a week to fully recharge them? but dopamine seems to be able to take more of a beating?

 

[neurotic]

Someone said in another NPD thread that serotonin production takes time, whereas dopamine doesnt. A human metabolic thing may be. Also like it was said in this thread, MDMA inhibits tryptophan hydroxylase which in itself will slow down the bodys serotonin production, since it keeps tryptophan from turning into 5HTP

 

[neurotic]

but so do the postsynaptic receptors. so the higher concentrations of serotonin have less effect, possibly leading to a "mood stabilizing" ( /zombifying - depending on who you ask...) effect.

Yeah i thought about that too. In the first post at the end i said smth about one takin SSRIs for long theyd be back to baseline because the brain would get used to it - just how drug tolerance works. I mean you cant always have a higher than your own baseline level of serotonin.

Sorry for double post im on my phone it gets hard to do shit