Does serotonin contribute to the effects of methamphetamine at all?

[skillet]

Thing is, while SSRI's will prevent serotonin release caused by amphetamines, they cause synaptic serotonin concentrations to increase anyway by blocking re-uptake, at least for the first several days you take it. So wouldn't you end up in a similar position if you took, say, MDMA alone, or MDMA several hours after a dose of an SSRI? Or couldn't you add some 'serotonergic effects' to plain amp by taking an SSRI a few hours before?

 

[ebola?]

Based on my personal experience, I'd say that even with plain d-amphetamine there's a tiny bit of serotonergic action

How would you be able to tell? In vitro studies suggest that d-amphetamine does not appreciably affect serotonin at even very high but remotely sane doses.

MDAI + 5-HTP or something?

MDAI is a highly selective serotonin releaser, so it should demonstrate what adding 5ht efflux into the equation feels like. I would not combine it with 5htp except for post-loading though.

Or couldn't you add some 'serotonergic effects' to plain amp by taking an SSRI a few hours before?

I don't think that this would yield the desired effects, as SERT inhibition doesn't really feel anything like efflux.

ebola

 

[jaguraguguru]

Interesting. I thought that oxidative stress mediated the neurotoxicity of methamphetamine. (i.e. taking a megadose of vitamin c or ALA would ameliorate nearly all the neurotoxicity from the free radicals that reulted from breakdown of massively elevated dopamine). What mechanism enables 5HT to enhance the neurotoxic potential?

One of the most prominent hypotheses about the neurotoxicity of dopamine +/- serotonin releasers is that dopamine itself is "toxic," spontaneously oxidizing and producing free radicals (via dopamine quinone) within the cytoplasm of the presynaptic neuron as well as within the synapse (I believe as to the location, but correct me if I'm wrong). Thus, if dopamine release is increased, the amount of free radicals produced increases, increasing oxidative stress, modifying proteins and producing free radical chain reactions, which is thought to underly the neurotoxicity.

Where does serotonin comes in, you ask? Well it is known that serotonin, dopamine, and norepinephrine are relatively similar in chemical structure and functional groups. In vitro studies have shown that serotonin, dopamine, and norepinephrine transporters can each transport all 3 monoamines across the axon terminal membrane, although each transporter transports monoamines other than the one it is named for with a lower potency than it transports the monoamine it is named for. Thus, serotonin transporter (SERT) transports dopamine, but at normal levels it does so only slightly because SERT doesn't bind dopamine particularly tightly and because there is competition for transport with serotonin. But when dopamine levels rise and/or serotonin levels decrease, the amount of dopamine transported by SERT increases.

Now, to put it all together. Some researchers hypothesize (with pretty strong evidence) that once a large proportion of vesicular serotonin is depleted from serotonin neurons by a serotonin releaser (like MDMA, which seems to readily deplete vesicular serotonin stores in animal models; some evidence suggests that meth releases serotonin though that is not well-established) and the serotonin is cleared from the synapse by metabolism or diffusion, there is little competition for dopamine to bind to and be transported by SERT into serotonin axon terminals, so dopamine is transported into serotonin neurons. Furthermore, the elevated dopamine levels in the area of the serotonin neuron axon terminals due to considerable release of dopamine by MDMA or meth further increases the rate of transport across the serotonin axon terminal membrane. Serotonin neurons are well-known to be much more sensitive to many kinds of insults and damage than catecholamine (dopamine and norepinephrine) neurons, so the increased oxidative stress inside these serotonin neuron axon terminals caused by the high dopamine concentrations within them damages the neurons. This is hypothesized to be a primary source of neurotoxicity of MDMA and, some think, meth. This makes sense since the neurotoxicity is thought to be largely damage to serotonin neurons, as evidenced by decreased expression of SERT protein and SERT availability as well as decreased serotonin content of the brain in animal studies of neurotoxic regimens of MDMA. In addition, under these conditions, serotonin neuron axons often retract from the cerebral cortex back towards their cell bodies in the raphe nuclei in the brainstem.

Therefore, serotonin doesn't enhance the neurotoxic potential of dopamine releasers, but the depletion of serotonin does!

-Jaguraguguru

 

[immad]

Offtopic: has anyone ever studied the norepinephrinergic (sp?) toxicity of NE-releasers, such as d-amp, ethcat, MDMA and others?

Only DA and SE seem to catch the attention. It this because there is no NE neurotoxicity or because it is overlooked?

 

[immad]

The central of ethcat, a specific NE releaser, are quite prominent though. However, this could also be attributed to possible metabolism into less NE-specific compounds.

 

[DJHENRU]

I kind of disagree actually about d amp to mamp comedown. D amp alwyas is more anxiogenic... Mamp im just kinda stupid. I use minimal amounts but d amp makes me redose more compulsively. 4fa is the easiest to take of them all and its hard tonget it to last very long. Sure after a day and a half up the crash is bad but fuck 3 days awake on damp and the sky is falling nearly.

 

[JackiesBabyy]

Offtopic: has anyone ever studied the norepinephrinergic (sp?) toxicity of NE-releasers, such as d-amp, ethcat, MDMA and others?

Only DA and SE seem to catch the attention. It this because there is no NE neurotoxicity or because it is overlooked?

*noradrenergic

I don't think there is an NE neurotoxicity, and if there is, by the time it happened the DA and 5-HT neurotoxic effects would be too intense to notice.

 

[immad]

Do you have any sources to back up that statement?

 

[Quercetin]

I kind of disagree actually about d amp to mamp comedown. D amp alwyas is more anxiogenic... Mamp im just kinda stupid. I use minimal amounts but d amp makes me redose more compulsively. 4fa is the easiest to take of them all and its hard tonget it to last very long. Sure after a day and a half up the crash is bad but fuck 3 days awake on damp and the sky is falling nearly.

Do you eat every 3 hours while using uppers? I have seen in the past people up for over 120h maintaining full cognitive ability, with very high retention/memory still. These same people would not experience any crash/withdrawal until they go to sleep.

I often host Ideas develop Ideas parties where we brainstorm on specific topics or do memory/cognition/IQ game and nobody is every experiencing any kind of withdrawal/crash from amphetamine.