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Further discussion on MDMA-induced (and related componds) neurotoxicity.

aced126 said:
I don't get why then that non-neurotoxic MDMA analogues can be neurotoxic when administered with a dopamine releasing agent. Surely the DRA would drain all the dopamine while the 5HT is being drained as well, so that when both the 5HT releaser and DRA are gone, there is both a lack of 5HT and DA?
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According the the MDAI/amphetamine study you are asking about, administration of MDMA, MDAI, or MDAI/amphetamine did not deplete dopamine in frontal cortex, striatum, or hippocampus. There were, however, very large reductions in 5-HT levels.

% of control in striatum:

MDMA
DA = 141%
5-HT = 36%

MDAI
DA = 127%
5-HT = 11%

MDAI/AMPH
DA = 156%
5-HT = 6%


aced126 said:
So really the key cause of neurotoxicity is TPH inhibition, but not the inhibition of tyrosine hydroxylase?
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TPH inhibition isn't really a key cause of the neurotoxicity -- TPH inhibition itself isn't neurotoxic. It is merely one factor that appears to play an important role in the events that cause terminal degeneration.
 
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serotonin2A said:
They way you are describing these events is far too black and white -- they really occur over a continuum. When I use the word "drain", I don't mean "deplete", but rather a reduction in the amount.

Let's take a step back and approach this from a different perspective. MAO-B, the MAO subtype classically thought to be responsible for metabolizing dopamine, is not very efficient at metabolizing serotonin. Strangely, however, MAO-B is the primary type of MAO found in serotonergic neurons. The reason why that is thought to occur is that small amounts of dopamine are normally taken up by SERT, and the MAO-B is expressed as a way to protect the serotonergic neurons from being damaged by dopamine. So it is a normal occurrence for dopamine to be taken up by serotonergic neurons. There are other mechanisms that exist to protect serotonergic neurons from dopamine -- pathways exist to limit damage due to oxidative stress.

What MDMA seems to do is impair several of the mechanisms that normally help to prevent serotonergic neurons from being damaged by dopamine:

Normally:
1. There is only a limited amount of dopamine spillover from dopamine synapses because release is regulated and excess dopamine is taken up by DAT. But MDMA blocks both of those mechanisms.
2. The ability of SERT to transport dopamine is limited by the fact that SERT has higher affinity for serotonin and because there is usually much more serotonin in the vicinity of SERT compared with the amount of dopamine. But by depleting serotonin, MDMA increases the amount of dopamine that is able to access SERT.
3. Serotonergic neurons are resistant to dopamine-induced oxidative stress. But factors such as MDMA-induced hyperthermia degrade those protective mechanisms.

Those events occur along a continuum. There may be some depletion of dopamine after administration of MDMA or a combination of amphetamine and MDAI. But if there is even slightly more depletion of serotonin then dopamine then that would potentially increase the amount of dopamine that is transported by SERT.


TPH inhibition isn't really a cause of the neurotoxicity -- TPH inhibition itself isn't neurotoxic. It is merely one factor that appears to contribute the neurotoxicity.
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Why does dopamine cause damage in a serotonergic neuron but not a dopamine neuron?
 
Cotcha Yankinov said:
But from my understanding I did see a study proving that dopamine uptake into the serotonin nerve terminal is possible
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I've also read literature elucidating that NET accommodates the uptake of dopamine to some degree (possibly a large one, seeing the similarity of NE & DA) and pure DRIs may not be as effective as NDRIs due to this (a large portion of DA still being returned to transporters via the unhindered functionality of NET under even maximal inhibitory concentration of a purely DRI compound)

An interesting QSAR study would be to find a NET reuptake ligand (an NRI or NDRI/SN(D)RI) that binds somewhere to NET and can effectively inhibit DA from entering the NET but not NE itself. Actually that would be a NETDRI) novel idea (perhaps? I'd like to see anything published in this vein if not). Such would make a pure DRI more efficacious, or a NDRI more dopaminergic
 
aced126 said:
Why does dopamine cause damage in a serotonergic neuron but not a dopamine neuron?
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I have read somewhere that even dopamine entering a serotonin neuron is harmful, so yeah, what gives? Is it simply a matter of anti oxidant defenses? Maybe dopamine is harmful to a degree to dopamine neurons, it would explain why dopamine neurons are constantly degenerating even in healthy brains.
 
I've been suffering from what I think is either serotonin and or dopamine problems after using mdma religiously last year. It all came to a head in July and a couple days later I had terrible chest pains... The pain decreased ten fold but since then I still get little episodes of discomfort/pain here and there. I stopped doing mdma since but then in November I shroomed and had THE WORST EXPERIENCE ever and my brain didn't feel right during it and I've shroomed a bunch of times before so I knew I wasn't just being paranoid from the mushies. But anyway a couple days later I would feel like ice pick throbbing headaches mostly at the top or back of the head, sometimes only on one side others at both sides along with freezing cold sweaty feet and it still hasn't gone away to this day. I know shrooms play with serotonin and dopamine so I'm thinking that was the straw that broke the camels back as far as the headaches/cold feet? Any other people come across this? Any help is greatly appreciated
 
You should definitely talk to your doctor about the heart symptoms and headaches, there are medications for your head aches and it's important you get your heart checked out, you could have angina pectoris with some sort of spasming heart vessel (some drugs like shrooms can constrict the arteries).
 
Samyelljackson,

I almost had a conversation about this the other day, which is funny. I only smoke cannabis and am healthy and active. My blood pressure is normal, I have an athletes pulse ~55, and exercise heavily at least an hour each day. I also have mild variant angina too.

My angina isn't exacerbated with physical activity and has decreased in severity over the past 2 years. The angina usually is noticeable a few minutes then I relax and the feeling wanes. The angina is often co-morbid with GERD (heart burn). Both symptoms are distinct and both cause tightness in my chest. I had an EKG and had my physician listen. The results were 100% normal. I was fine.

These symptoms flare in the spring.

If I exercise extremely I have a few days of exacerbated angina 4-6 days after the exercise, then the symptoms wane.

Bendodiazepines temporarily alleviate the angina and lack effect on the GERD. I won't administer benzodiazepines as treatment. When possible I avoid benzodiazepeine use.

The cause of that? That is stress, nothing more.

My expectation is if the symptoms continue improving I am doing fine. If I lived with that stress everyday I expect this could decrease my life expectancy a few decades and result in heart attacks after my late 30s. People living really hard lives breaking their heart over girls everyday ect. often die ~55 from cardiovascular disease. If your angina has similar causes, decrease your stress level, exercise, and monitor your cardiovascular health. Decrease your stress level and I think you'll be fine.
 
Yea I've been meaning to get it checked out but after reading up on people's recovery stories, it seems like drs don't know enough about serotonin/dopamine and that it's going to take at least a year before I feel any dramatic improvement and since money is an issue...id rather not spend thousands worth of tests just for everything to come back normal and still be at square one but I've decided to just go ahead and get everything checked out anyways.

And also I have no real stresses or worries in my life so I know it's not an anxiety or stress issue. Everything in my life is good except the ailments I'm having
 
aced126 said:
How does MDMA "deplete" serotonin. Where is the serotonin going? Surely it's just staying there in the synaptic cleft.
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It causes release from synaptic vesicle - basically a holding area on the pre-synaptic neuron. It is this "well" of serotonin that is depleted because MDMA is a powerful serotonin releasing agent.

Of interest is that depletion is not a true happening, as one can see from the non-cross tolerance between MDA and MDMA -- MDA on monday will not in any way lessen the MDMA experience on tuesday. The classical "loved up" MDA/MDMA is due to serotonin and oxytocin released in response to serotonin.

Furthermore, most evidence is pointing to lowered SERT (serotonin transporter) activity and binding potential. SERT puts serotonin back where it can be recycled for use. AFAIK MDMA also acts as a re-uptake inhibitor on SERT as well.


Serotonin synthesis rates for your information:

Normal levels of serotonin in the cortex are ~ 11ng/ml and in the putamen 466ng/ml

Based on studied synthesis levels it takes males 30 minutes and females 48 minutes to completely synthesis all the serotonin in the tissues, and about 1 minute for the cortex.

So you can see with a diet rich in tyrosine (dopamine) and tryptophan or 5-HTP (serotonin) along with the metal catalysts and B vitamins PLUS multiple grams of Vitamin C -- you can't deplete your neurotransmitters. You can make the receptors and transmitters basically sort of ignore them.

Tryptophan, Serotonin, and Melatonin: Basic Aspects and Applications edited by Gerald Huether, Walter Kochen, Thomas J. Simat, Hans Steinhart


I expect that genetic differences in SERT activity lead to different experiences with MDMA use. Aspergers and autistic persons have SERT that is highly active due to a mutation on the gene that encodes the protein. This leads to a low level of serotonin at the synapses because SERT pulls it off so quickly, leading to the depression and OCD evident in ASD persons as well as the social isses in ASD.. It also leads to high blood levels of serotonin.

I have been informed by more than 1 such ASD person that they can use MDMA multiple days in a row without any decline in effects.
 
Samyelljackson said:
I've been suffering from what I think is either serotonin and or dopamine problems after using mdma religiously last year. It all came to a head in July and a couple days later I had terrible chest pains... The pain decreased ten fold but since then I still get little episodes of discomfort/pain here and there. I stopped doing mdma since but then in November I shroomed and had THE WORST EXPERIENCE ever and my brain didn't feel right during it and I've shroomed a bunch of times before so I knew I wasn't just being paranoid from the mushies. But anyway a couple days later I would feel like ice pick throbbing headaches mostly at the top or back of the head, sometimes only on one side others at both sides along with freezing cold sweaty feet and it still hasn't gone away to this day. I know shrooms play with serotonin and dopamine so I'm thinking that was the straw that broke the camels back as far as the headaches/cold feet? Any other people come across this? Any help is greatly appreciated
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MDMA is a potentially cardiotoxic substance like fenfluramine with respect to heart valve hypertrophy in sensitive individuals. It is due to the 5HT2b receptors on the heart. ALl evidence shows the changes are reversible with abstinence over time, if caught early enough.

But, you need to have the predisposing mutation in the gene that encodes cardiac 5HT2B

A R393X mutation in the 5-HT2B gene (HTR2B) was also found in patients with fenfluramine-induced PAH (in vitro experiments confirmed that the mutation turned Arg-393 into a stop codon, truncating the C-terminus of HTR2B), but not in the control group, suggesting that there would be an association between the mutation and induced PAH.[50]

http://www.medscape.com/viewarticle/757499_7
 
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Cotcha Yankinov said:
SEROTONIN I have ideas! So if we are to assume that dopamine uptake is most likely to occur after serotonin concentrations have dropped via binding to receptors (rather than via MAO-A), then might we assume that - 1. Neurons that have more 5HT1 receptors might sustain more damage because serotonin has higher affinity for 5HT1>5HT2 and therefore you might find less serotonin available to compete for the SERT around 5HT1 dense areas because it binds and leaves the synapse faster there
2. The damage might be worse in areas with auto receptors/the damage might be worse pre synaptically because the auto receptors there would tone down the release of serotonin and therefore there would be a more damaging ratio of dopamine to serotonin.
3. The damage would be worse in any place where there are more serotonin receptors than usual because serotonin could leave the synapse faster via binding.

I suppose you could possibly test this theory of increased receptor binding increasing the harmful dopamine to serotonin ratio by up regulating an animals serotonin receptors (maybe just 5HT2A so as to try not to involve auto receptors and make things complicated) very heavily before MDMA administration to see if that group sustained more damage, though I guess there might be other factors.
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AFAIK based on several studies, co-administration of an antioxidant like alpha-lipoic acid or vitamin c completely negates any evidence of neurotoxicity in animals.
 
serotonin2A said:
1. MDMA is causing serotonin to leak out of vesicles, so the amount available for release decreases. 2. MDMA denatures tryptophan hydroxylase. It therefore takes some time to refill the vesicles.

The released MDMA goes into the synapse but it eventually diffuses away.
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And SERT binding is lowered, and SERT re-uptake is blocker -- as it DAT (dopamine)
 
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