MDMA vesicular 5-HT depletion and other topics

[Cotcha Yankinov]

This thread serves the purpose of continuing discussion while avoiding clogging up a different thread

Previous discussion was as follows

Originally Posted by JK25
The building blocks of SERT has been depleted also, all of the SERT that already existed has been taken back out of the synaptic left and recycled into hundreds of random molecular structures . ALL OF THE BRAIN's, I SAY IT AGAIN, ALL OF YOUR BRAIN’s SEROTONIN HAVE BEEN COMPLETELY DEPLETED. I MEAN THERE IS FUCKING NOTHING LEFT AT ALL IT IS GONE, the brain must now from scratch rebuild Serotonin and the molecules that makes up Serotonin. This depletion in causing the depressive states, moods and the other negative reactions to be expected on a MDMA comedown.
Some (pseudo) Research done on rats (I mean fuck we are mammals but you can’t compare effects comparatively on both) into the breakdown of MDMA says that Serotonin levels reach normal capacity and normal functioning again within 24-48 hours again after the trip. Hahahaha!!! WTF? Bull Fucking Shit Man. It is comparative to a very skinny guy with no body fat and weighs that 60kg goes to a gym for a weekend and walk out of there looking like a bodybuilder or a rugby player that weighs 120kg. That is utter bullshit and the researcher was lazy and made up a time frame. It takes MONTHS for normal SERT levels to be present and evident enough to be considered neuro-pharmacologically normal and at any normal natural states.
It takes 1-2 months for the protein kinase A and protein kinase C to completely reverse the anti re-uptake inhibitory affects the MDMA had on the re-uptake sites and having them absorbing free floating SERT into the cell body again. It takes 2-3 months for the VMATs neurotransmitters to completely accept Serotonin as a familiar molecule that they must interact with and do their job again to transport SERT to the release site and it takes anywhere from 3 months to a full year for normal monoamine oxidase inhibitors to reach normal levels where they can break down SERT again.

I don't mean to clog up the thread, but I think there is some misinformation/fear mongering here that needs addressing

The vesicular 5-HT depletion is probably fairly acute. It won't take that long for tryptophan hydroxylase to bounce back and for VMAT inhibition to wear off.

Issues that persist after a few weeks are extremely unlikely to be due to a vesicular shortage.

All thoughts are welcome.

 

[rrandy]

I guess there´s two main questions here:
1. how long does it take for vesicular 5-HT to go back to normal --> I don´t know anything about this stuff, but if we assume it takes as long as JK25 wrote:
2. why do some people have no problems at all after the depletion or just short-term issues and others suffer long term?

One reason could be genetic oder otherwise physical susceptibility to neurotoxic damage or in cases of really large amounts regular neurotoxicity.
But another concept I´m thinking about and which I hope is the case with me and others who didn´t take enormous amounts of MDMA: Maybe the temporary depletion of serotonin and it´s consequences (panic attacks and anxiety at the start of the LTC in my case) throws some people off their normal functioning so much that they aren´t able to bounce back although the brain´s mechanisms are fundamentally working again. So that the temporary depletion of serotonin gave rise to anxious, fight or flight neural connections (read that somewhere in the recovery thread) that don´t let the individual feel okay, though the serotonin system is theoretically functional. Does this make sense?

 

[JK25]

 

[JK25]

Ok so please guys do excuse any spelling or grammar mistakes as I'm too lazy to type and I'm using my Google text to speech option look at the image on the left that is pure serotonin and its analogu transmitters within a synapse between neurone dendrites no image illustrates normal functioning levels of mainly serotonin in a normal healthy rat brain now I'll look at image be on the right that is what is left of the serotonin within the synaptic cleft after only one initial dosage of Ecstasy taken once images before administration image be is 24 hours after the station now if you can see what I can see that is a fuckload of depletion that has taken place to see it illustrated visually makes much more sense and becomes much more real and factual and makes a much better. As to just quote references and study is randomly selected from a different University library archives

 

[Cotcha Yankinov]

1. I'm not quite sure when vesicular 5-HT would return to completely normal given a vesicle depleting dose, but I suspect the real depletion only lasts a few days to a week. I think there was some question of persisting VMAT (transporters that fill the vesicles with neurotransmitters) dysfunction with amphetamine use, and thus VMAT was seen as a therapeutic target for addiction, but the temporary vesicle depletion that we're talking about with MDMA is different.

Normally new cell parts will be synthesized in the cell body and travel along the axon to reach the nerve terminal in some days via axonal transport. This could mean that there would be differences in recovery depending on the length that new proteins have to travel if new vesicles need to be created or if tryptophan hydroxylase is inhibited at the nerve terminal (and not the cell body). The serotonin cell bodies are down towards the brain stem, so proteins traveling up to the parts of your brain near your forehead (pre-frontal cortex) can take longer than parts just traveling to the center of your brain.

But I still don't think we're talking about more than a week or two to do away with the worst of the depletion, and I certainly wouldn't be blaming persistent vesicle depletion for causing symptoms that somebody has 6 months after MDMA.

One of the limiting steps in re-filling vesicles with serotonin after MDMA is the enzyme that makes serotonin tryptophan hydroxylase. This enzyme can be knocked down by MDMA and oxidative stress but that shouldn't last too long, however tryptophan hydroxylase is also under dynamic control. As an example, activation of a homeostatic serotonin autoreceptor can decrease tryptophan hydroxylase expression.

So something like that could decrease tryptophan hydroxylase expression a bit after MDMA is gone, but I still don't think its in the same category as the acute depletion that comes to mind with MDMA and it shouldn't last that long.


2. One relevant genetic difference here that may explain part of why some people fare better than others is variation of a gene called 5-HTTLPR

5-HTTLPR basically comes in two forms: The short form, and the long form. Some people have two short forms, some people have one short and one long form, and others have two long forms.

People with two short forms are interesting, they seem to react differently to dietary tryptophan depletion (tryptophan is the protein that we make serotonin out of).

While people with the long form don't typically have any emotional reaction to tryptophan depletion, people with the short form can.
People with the short form also appear more vulnerable to issues after MDMA. So I think there is a genetic basis for people having more issues than others with serotonin depletion.

"So that the temporary depletion of serotonin gave rise to anxious, fight or flight neural connections (read that somewhere in the recovery thread) that don´t let the individual feel okay, though the serotonin system is theoretically functional. Does this make sense?"

This is essentially one of my theories - imagine the following

Serotonin inhibits a nuclei that we generally want inhibited, and with temporary serotonin depletion the nuclei turns on and runs a muck. Generally the neurons can be thought of in a "use it or lose it" sense, just like a muscle. When this nuclei is un-inhibited during the acute depletion, it could grow stronger and even when normal 5-HT levels return, 5-HT may have a hard time getting that nuclei under control and inhibiting it.

Its possible that people with the short form of 5-HTTLPR have had a bit of "kindling" with this theoretical problematic nuclei that becomes uninhibited with 5-HT depletion. Kindling is normally when repeated withdrawals from something like a benzo ends up strengthening circuits that get turned up on the rebound.

So imagine that taking a benzo normally inhibits a circuit/nuclei, and when somebody withdraws from the benzo the circuit rebounds, and then the circuit gets stronger with all that rebound activity. My bet is that kindling could happen with serotonin/MDMA and the people who are vulnerable to serotonin depletion (short form people) may have a vulnerability to kindling with serotonin depletion. Hope this makes some sense.

RE: neurotoxicity vulnerability - it doesn't necessarily make sense on the surface that having the short form of 5-HTTLPR would increase the risk of neurotoxicity to serotonin terminals because the theory of serotonin nerve terminal loss with MDMA is that harmful molecules make their way into the terminals via the serotonin reuptake transporters, and having the short form is associated with lower levels of serotonin reuptake transporters (thus not as many reuptake transporters to take up the harmful molecules).

 

[Cotcha Yankinov]

Ok so please guys do excuse any spelling or grammar mistakes as I'm too lazy to type and I'm using my Google text to speech option look at the image on the left that is pure serotonin and its analogu transmitters within a synapse between neurone dendrites no image illustrates normal functioning levels of mainly serotonin in a normal healthy rat brain now I'll look at image be on the right that is what is left of the serotonin within the synaptic cleft after only one initial dosage of Ecstasy taken once images before administration image be is 24 hours after the station now if you can see what I can see that is a fuckload of depletion that has taken place to see it illustrated visually makes much more sense and becomes much more real and factual and makes a much better. As to just quote references and study is randomly selected from a different University library archives

I would take care to differentiate between vesicular 5-HT depletion (which is probably hard to test for considering the confounders) and serotonin neurotoxicity. We can certainly talk about the neurotoxicity issue and whether that can happen in humans, but for the record I don't think that where people's problems lie.

As an example of a similar confounder, some studies have stained for tryptophan hydroxylase, noted decreased TPH expression after high dose MDMA, and then concluded neurotoxicity. That wouldn't be the best conclusion because MDMA can knock down TPH, so hypoexpression of TPH =/= serotonin nerve terminal loss.

 

[rrandy]

Its possible that people with the short form of 5-HTTLPR have had a bit of "kindling" with this theoretical problematic nuclei that becomes uninhibited with 5-HT depletion. Kindling is normally when repeated withdrawals from something like a benzo ends up strengthening circuits that get turned up on the rebound.

So imagine that taking a benzo normally inhibits a circuit/nuclei, and when somebody withdraws from the benzo the circuit rebounds, and then the circuit gets stronger with all that rebound activity. My bet is that kindling could happen with serotonin/MDMA and the people who are vulnerable to serotonin depletion (short form people) may have a vulnerability to kindling with serotonin depletion. Hope this makes some sense.

makes sense to me, thanks for elucidating! And I guess it´s through the mindfulness you often suggest that we can counteract this kindling?

 

[JK25]

[h=3]I found this interesting piece of a study done with plasma tryptophan augmentation and depletion

Rationale[/h] MDMA (ecstasy; +3,4-methylenedioxymethamphetamine) damages brain serotonin (5-HT) neurons and, in non-human primates, a loss of various 5-HT axonal markers persists for several years. This raises the question of whether long lasting effects occur in human beings that persist even after they have stopped using MDMA.


[h=3]Objectives[/h]We therefore assessed the effects of an indirect 5-HT manipulation on functions thought to be affected by MDMA use in people who had stopped using MDMA (ex-users) compared with continuing users and non-users.

[h=3]Methods[/h]Ninety-six participants were recruited: 32 ex-users who had stopped using MDMA for >1 year (mean, 2.4 years); 32 current users and 32 polydrug controls who had never used MDMA but were matched with ex-users and controls on cannabis use and pre-morbid IQ. Participants were given an amino acid mixture that contained either no tryptophan (T−) or augmented tryptophan (T+) and assessed before and 5 h after the drink on measures of cognitive function and mood.


[h=3]Results[/h]T+ and T− produced plasma tryptophan augmentation and depletion, respectively, in all three groups. Ex-users' plasma tryptophan levels in response to T+ were significantly higher than other groups. Ex-users' performance on a delayed prose recall task improved after T+ and lessened after T−. Changes in ex-users' free plasma tryptophan levels correlated highly (r=−0.9) with their baseline performance on immediate and delayed prose recall; change in total plasma tryptophan correlated (r=−0.81) with delayed recall. Further, total baseline plasma tryptophan correlated with number of years they had used MDMA before quitting. Baseline differences between groups were found on learning, working memory, aggression and impulsivity. T− did not produce differential effects in the three groups.


[h=3]Conclusions[/h]Our results suggest that prolonged abstinence from MDMA might be associated with altered tryptophan metabolism. Ex-users showing the poorest memory function at baseline were also those who metabolised least tryptophan. These findings may reflect pre-morbid differences in 5-HT function of those who stop using this drug or consequences of MDMA use that emerge after abstention. Aggression is also associated with MDMA use and subsequent abstinence.

 

[Cotcha Yankinov]

^There are some problems with concluding serotonin neurotoxicity from that study, if that is someone's conclusion.

But I'm sure MDMA users could be more vulnerable to dietary tryptophan depletion and another study has looked at that, however I don't think that the people who have long term issues owe their issues to persisting vesicular depletion

 

[rrandy]

^There are some problems with concluding serotonin neurotoxicity from that study, if that is someone's conclusion.

But I'm sure MDMA users could be more vulnerable to dietary tryptophan depletion and another study has looked at that, however I don't think that the people who have long term issues owe their issues to persisting vesicular depletion

do you think it would be good to supplement 5-htp? or any other supplement suggestions for reversing this "kindling" also?

 

[Cotcha Yankinov]

It seems like 5-HTP is not of much use to us, and some people get anxiety from it. I would however advise a well rounded diet with protein throughout the day.

And re: my mindfulness recommendations vs. this theoretical kindling, I'm not quite sure of the neurological reasoning but so far it looks like people have success with mindfulness for these adverse effects, and people have success with mindfulness for non drug related illnesses. Personally that's enough for me to throw out recommendations left and right, but maybe we'll learn more about the science of it with time (it seems mindfulness research is taking off these past couple of years).

 

[rrandy]

It seems like 5-HTP is not of much use to us, and some people get anxiety from it. I would however advise a well rounded diet with protein throughout the day.

And re: my mindfulness recommendations vs. this theoretical kindling, I'm not quite sure of the neurological reasoning but so far it looks like people have success with mindfulness for these adverse effects, and people have success with mindfulness for non drug related illnesses. Personally that's enough for me to throw out recommendations left and right, but maybe we'll learn more about the science of it with time (it seems mindfulness research is taking off these past couple of years).

I see. So eating well, meditating and staying mindful, doing cardio and being patient is all there is I guess. What do you think about neurofeedback?

 

[JK25]

Now this ref. I got and seems weird in the effect of it


US National Library of Medicine National Institutes of Health

Brain serotonin content is dependent on plasma levels of the essential amino acid tryptophan. We investigated the behavioral effects of rapid tryptophan depletion in patients in antidepressant-induced remission. Twenty-one patients who were depressed by DSM-III-R criteria received a 24-hour, 160-mg/d, low-tryptophan diet followed the next morning by a 16-amino acid drink, in a double-blind, placebo-controlled (acute tryptophan depletion and control testing), crossover fashion. Total and free tryptophan levels decreased 87% and 91%, respectively, during acute tryptophan depletion. Fourteen of the 21 remitted depressed patients receiving antidepressants experienced a depressive relapse after the tryptophan-free amino acid drink, with gradual (24 to 48 hours) return to the remitted state on return to regular food intake. Control testing produced no significant behavioral effects. Free plasma tryptophan level was negatively correlated with depression score during acute tryptophan depletion. The therapeutic effects of some antidepressant drugs may be dependent on serotonin availability.

 

[JK25]

Now Cotcha my prior message correlates with your post above

"But I'm sure MDMA users could be more vulnerable to dietary tryptophan depletion and another study has looked at that, however I don't think that the people who have long term issues owe their issues to persisting vesicular depletion."

 

[Cotcha Yankinov]

I see. So eating well, meditating and staying mindful, doing cardio and being patient is all there is I guess. What do you think about neurofeedback?

Neurofeedback is interesting, by all means give it a whirl. There's evidence it helps with insomnia. I've always thought of neurofeedback as technology assisted meditation, I just wish it was more convenient than going in to somewhere to have them stick EEG leads onto your scalp. An EEG helmet you could wear at home would be really nice.

Anyways, that's a really good plan - the only other thing that comes to mind is medication, but the general thinking seems to be give it a while before pursuing meds.

 

[Cotcha Yankinov]

Now Cotcha my prior message correlates with your post above

"But I'm sure MDMA users could be more vulnerable to dietary tryptophan depletion and another study has looked at that, however I don't think that the people who have long term issues owe their issues to persisting vesicular depletion."

Sure, but I think it would be a bit of a stretch to go from "Some MDMA abusers may be more vulnerable to tryptophan depletion" to "Tryptophan/5-HTP + Carbidopa will cure people with MDMA related adverse effects"

Part of what I'm getting at is that I think something else is going on in the people with adverse effects, I suspect its primarily not an issue with vesicular depletion/tryptophan shortages even if a tryptophan shortage exacerbates the issues.

 

[socrilus]

I also do not believe serotonin depletion etc accounts for everything because--

What about these people:

1) People like me who recover completely physically and mentally from the initial comedown and then go on to develop issues a few weeks later on randomly out of nowhere, with no panic attacks involved but just a feeling of being off/mood issues/anxiety/brain fog etc after waking up one day.

2) People who have no comedown but still develop issues weeks later

(Assuming no external stressors etc)

The recovery thread theory was that this is to fo with stress hormones/cortisol? I can confirm that, for me, hormones are thrown off as of now.

On that note, could the LTC have different causes depending on whether it was delayed or immediate?

I was certainly worried during the initial comedown but as soon as I saw improvement day by day my worries went away. I forgot about it after that week where I recovered from the initial insult until randomly developing symptoms again weeks later.

 

[Stringer_Bell]

It does sort of scare me that MDMA (even in pure form) can be so unpredictable. I mean you don't get drunk once or even take coke or opiates once and then end up with all these crazy symptoms weeks later.

 

[mb-909]

Just a hypothesis: I believe that the negative effects associated with MDMA are mainly caused by the rewiring of the brain after intoxication. MDMA can change the fear response and therefor the structure in the Amygdala in traumatized patients with PTSD significantly after a single dose. The hippocampi region is also responsible for emotional memories. A change that big in such a short time period on emotional memorization can result in dramatic changes in the way the brain functions - maybe permenantly. The reason for me to believe it: the positive results for the clients are often long lasting.

My guess is that the process of memorization (the "software", not "hardware") might be sligthly different than usual resulting in cognitive dificits (which aren't that bad as they might feel like). I believe that neurotoxicity isn't that big of a deal with MDMA and that human beings are capable of recovering. I wouldn't call a time period for recovery, because bodies are different. The subjective compenent how we evaluate situations changes greatly with our experiences. LTC might be a primary product of anxiety and therefor missinterpreting situations and yourselves. Maybe your cognitive functions were not that different from now?

Please post links to studies, because there are so many factors to consider for evaluating the trustworthyness of studies that just a excerpts few won't do it. Thanks.

 

[rrandy]

Neurofeedback is interesting, by all means give it a whirl. There's evidence it helps with insomnia. I've always thought of neurofeedback as technology assisted meditation, I just wish it was more convenient than going in to somewhere to have them stick EEG leads onto your scalp. An EEG helmet you could wear at home would be really nice.

Anyways, that's a really good plan - the only other thing that comes to mind is medication, but the general thinking seems to be give it a while before pursuing meds.

I looked it up and apparently it is possible to buy neurofeedback equipment for home, but it´s expensive. But there are even do-it-yourself guides if one is willing to put in the time ( http://openeeg.sourceforge.net/doc/ ). If I´m not better in a few months I´ll definitely look into that. Until then I´ll try to train my brain through concentrating on the things I want it to do. I feel a lot of us LTC people are in this loop of focusing permanently on what may be different now from before the LTC. And I tend to think that this bad conditioning is more responsible for the long term effects than any axon damage.