Does serotonin contribute to the effects of methamphetamine at all?

[JackiesBabyy]

I know it's a more potent serotonin releaser than d-amphetamine and most of its effects come from DA and NE, but does 5-HT have any impact on it's noticeable effects?

 

[sekio]

My gut instinct is yes, especially at higher doses. It's part of what makes M-amp more toxic.

Plain amphetamine, on the other hand, is mostly NE/DA.

 

[JackiesBabyy]

My gut instinct is yes, especially at higher doses. It's part of what makes M-amp more toxic.

Plain amphetamine, on the other hand, is mostly NE/DA.

So if a person just smoked a high dose of meth, which of the effects he's feeling be attributed to 5-HT?

 

[sekio]

That's harder to say, meth's effects can't really be divided into nice easy slices.

Serotonin release helps contribute to the stimulation, appetite supressing effects, mood elevation, and neurotoxicity/crash afterwards.

I suppose you could always see if studies have used SSRIs to block the serotonin release of meth in humans.

 

[JackiesBabyy]

That's harder to say, meth's effects can't really be divided into nice easy slices.

Serotonin release helps contribute to the stimulation, appetite supressing effects, mood elevation, and neurotoxicity/crash afterwards.

I suppose you could always see if studies have used SSRIs to block the serotonin release of meth in humans.

Well, 4-FA has serotonin releasing effects about 30% greater than meth, yet dopamine releasing capabilities only half that of meth(http://en.wikipedia.org/wiki/Releasing_agent source). When I take 4-FA, I can feel mild MDMA like effects (some empathy, massive pupils, and the fact after binging on the stuff for 5 days it felt like a meth comedown mixed with the horrid derealization and brain zaps of a bad mdma hangover).

 

[Hiltoniano]

Yea meth definitely has serotonergic (sp?) effects. Some of the extra euphoria, midriasis, and appetite suppression I believe comes from serotonin being acted on. I'm not sure if its just a straight cascade release like MDMA or more complicated, likely the latter. Hopefully someone more well versed in methamps activity in the brain can chime in.

Here's some reading related: www.ncbi.nlm.nih.gov/m/pubmed/10987842/

 

[JackiesBabyy]

Yea meth definitely has serotonergic (sp?) effects. Some of the extra euphoria, midriasis, and appetite suppression I believe comes from serotonin being acted on. I'm not sure if its just a straight cascade release like MDMA or more complicated, likely the latter. Hopefully someone more well versed in methamps activity in the brain can chime in.

It's probably also why the meth crash is worse. A d-amphetamine binge comedown feels like an orgasm compared to that horrible, HORRIBLE comedown 4-FA gave me. Derealization is scary when combined with total anhedonia and 0 energy + LOUD LOUD LOUD tinnitus and brain zaps (akin to SSRI withdrawal)

 

[nuke]

Almost certainly. Both MDMA and METH have much different effects when they can not interact with the serotonin transporter, eg when administered with an SSRI.

 

[Epsilon Alpha]

Well, 4-FA has serotonin releasing effects about 30% greater than meth, yet dopamine releasing capabilities only half that of meth(http://en.wikipedia.org/wiki/Releasing_agent source). When I take 4-FA, I can feel mild MDMA like effects (some empathy, massive pupils, and the fact after binging on the stuff for 5 days it felt like a meth comedown mixed with the horrid derealization and brain zaps of a bad mdma hangover).

There's probably a lot of dirty binding going on that we don't really look at in research EC50=/= Ki though they are related. Efflux ratios are only indicative to a point, ie: amphetamine vs pseudoephedrine NE: DA, after that you end up with specific bindings that cause some of the "finer" points.

Also, its worth noting that the 5HT dependent effects of amphetamine at least are subject to the fastest tolerance, then DA dependent, then NE dependent if you want to go by straight storage amounts. But, determining more "human" effects of drug liking isn't as easy as checking if a rat presses a lever more or less frequently.

Unrelated: rats on MDMA are some of the funniest things I have ever seen.

 

[JackiesBabyy]

There's probably a lot of dirty binding going on that we don't really look at in research EC50=/= Ki though they are related. Efflux ratios are only indicative to a point, ie: amphetamine vs pseudoephedrine NE: DA, after that you end up with specific bindings that cause some of the "finer" points.

Also, its worth noting that the 5HT dependent effects of amphetamine at least are subject to the fastest tolerance, then DA dependent, then NE dependent if you want to go by straight storage amounts. But, determining more "human" effects of drug liking isn't as easy as checking if a rat presses a lever more or less frequently.

Unrelated: rats on MDMA are some of the funniest things I have ever seen.

Huh, that explains why, toward the end of a binge, redosing only gives me shitty, uncomfortable peripheral (NE) effects. But I still do it anyway because "just a little more HAS to bring the euphoria back!" hahaha

 

[Hiltoniano]

The endless mission of a binge is to bring back the euphoria felt at the start, and by the end, the brain is so depleted that redosing is essentially useless or detrimental. And also to whoever said the serotonergic effects have the fastest tolerance gain I agree, the further along my use I was, the very first time's "feel good" mentality would leave very quickly with any increased usage. Kinda sucks, that was my favorite part of the high, why I liked it more than dextro-amp or straight amp sulfate.

 

[JackiesBabyy]

The endless mission of a binge is to bring back the euphoria felt at the start, and by the end, the brain is so depleted that redosing is essentially useless or detrimental. And also to whoever said the serotonergic effects have the fastest tolerance gain I agree, the further along my use I was, the very first time's "feel good" mentality would leave very quickly with any increased usage. Kinda sucks, that was my favorite part of the high, why I liked it more than dextro-amp or straight amp sulfate.

Yeah, with 4-FA the high goes from super happy talkative empathy, keep redosing and it goes to motivated energy, keep redosing more and you're left with sweating and uncomfortably high blood pressure. 5-HTP helps the derealization and "mind fucked" feeling though, leaving you with a regular old amph comedown.

 

[jaguraguguru]

An interesting, albeit flawed, way to test this question would be to compare the effects of various doses of amphetamine with 5-HTP with the effects of methamphetamine. Does the addition of 5-HTP enhance or diminish the effects of amphetamine? Does it increase some effects while decreasing others? Does it make it resemble methamphetamine more? Is the comedown worse or better? Overall from my reading, it seems that 5-HTP diminishes most of the effects amphetamine, but the other parts may not be as clear from anecdotal evidence. Any takers?

 

[Quercetin]

An interesting, albeit flawed, way to test this question would be to compare the effects of various doses of amphetamine with 5-HTP with the effects of methamphetamine. Does the addition of 5-HTP enhance or diminish the effects of amphetamine? Does it increase some effects while decreasing others? Does it make it resemble methamphetamine more? Is the comedown worse or better? Overall from my reading, it seems that 5-HTP diminishes most of the effects amphetamine, but the other parts may not be as clear from anecdotal evidence. Any takers?

5ht antagonist with stronger affinity to the receptor would give you better data.

 

[jaguraguguru]

5ht antagonist with stronger affinity to the receptor would give you better data.

What is "the receptor" that you speak of? You mean serotonin transporter (SERT), or the vesicular monoamine transporter (VMAT2), the primary targets of methamphetamine and MDMA that mediate serotonin release and reuptake inhibition? If you're talking about using a serotonin transporter antagonist like an SSRI to block the transporter so that meth can no longer exert its serotonin releasing effects, then I think this would likely work to a reasonable extent, although it would have problems as well. Using an SRI would increase serotonin levels on its own and would decrease but not eliminate the synaptic serotonin increases caused by meth, so I'm doubtful it would be much better. But it is another approach and would likely give further evidence towards the answer. Blocking VMAT would block the DA and NE releasing effects as well so that wouldn't be a great approach, unless you had a VMAT inhibitor that only gets into serotonergic neurons, which would be useful, but again would have issues since it would decrease packaging of 5-HT into vesicles and increase the concentration in the cytoplasm.

 

[Quercetin]

What is "the receptor" that you speak of? You mean serotonin transporter (SERT), or the vesicular monoamine transporter (VMAT2), the primary targets of methamphetamine and MDMA that mediate serotonin release and reuptake inhibition? If you're talking about using a serotonin transporter antagonist like an SSRI to block the transporter so that meth can no longer exert its serotonin releasing effects, then I think this would likely work to a reasonable extent, although it would have problems as well. Using an SRI would increase serotonin levels on its own and would decrease but not eliminate the synaptic serotonin increases caused by meth, so I'm doubtful it would be much better. But it is another approach and would likely give further evidence towards the answer. Blocking VMAT would block the DA and NE releasing effects as well so that wouldn't be a great approach, unless you had a VMAT inhibitor that only gets into serotonergic neurons, which would be useful, but again would have issues since it would decrease packaging of 5-HT into vesicles and increase the concentration in the cytoplasm.

I was more thinking about an antagonist/inverse agonist like Mirtazapine on all 5-HT receptor. I did not really think about a particular compound nor did i really think much before my reply.

 

[skillet]

That's not a bad idea, but mirtazepine isn't an antagonist at 5-HT1A, and what about the other 5-HT1, 4, 5 and 6 receptors? Also the antagonism of a-adrenoreceptors would complicate things.

Jagura, yeah that was my thinking with the SSRI's too, maybe if you took it for a few weeks beforehand to allow tolerance/normalisation of 5-HT levels to occur it could work. I think acute SSRI's should give a pretty good idea of the effects of increased serotonin alone though, and it's not much fun IMO.

How about a tryptophan deficient diet?

 

[Quercetin]

That's not a bad idea, but mirtazepine isn't an antagonist at 5-HT1A, and what about the other 5-HT1, 4, 5 and 6 receptors? Also the antagonism of a-adrenoreceptors would complicate things.

Jagura, yeah that was my thinking with the SSRI's too, maybe if you took it for a few weeks beforehand to allow tolerance/normalisation of 5-HT levels to occur it could work. I think acute SSRI's should give a pretty good idea of the effects of increased serotonin alone though, and it's not much fun IMO.

How about a tryptophan deficient diet?

What I had on my mind was more like a imaginary compound with total 5-HT antagonist. I really did not think much before my reply, which is probably why I cant really think of an explanation today.

Anybody understand how the intensity of methamphetamine could be insulin mediated or can it be? It seem that the IV injection of l-alanine 2-3g cause temporary enhanced effect, some subjects mentioned hearing of a ringing bell. I cannot really find any other hypothesis than the possible rise in glucagon/insulin to explain this.

http://molpharm.aspetjournals.org/content/68/1/102.short

 

[monad]

Almost certainly. Both MDMA and METH have much different effects when they can not interact with the serotonin transporter, eg when administered with an SSRI.

You mean *lethal* effects right? To the best of my current understanding, powerful serotonergic agents such as d-meth and racemate MDMA would lead to potentially fatal serotonin syndrome.

 

[monad]

My gut instinct is yes, especially at higher doses. It's part of what makes M-amp more toxic.

Plain amphetamine, on the other hand, is mostly NE/DA.

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?

An interesting, albeit flawed, way to test this question would be to compare the effects of various doses of amphetamine with 5-HTP with the effects of methamphetamine. Does the addition of 5-HTP enhance or diminish the effects of amphetamine? Does it increase some effects while decreasing others? Does it make it resemble methamphetamine more? Is the comedown worse or better? Overall from my reading, it seems that 5-HTP diminishes most of the effects amphetamine, but the other parts may not be as clear from anecdotal evidence. Any takers?

Since dextroamphetamine posesses primarily dopaminergic activity, it lacks the empathogenesis correlated with 5HT release. I find that supplementation of d-amp with 5HTP decreases unpleasant peripheral stimulation and decreases the amount of d-amp needed to achieve desired CNS effects. 5HTP also significantly attenuates the undesirable anxiety/paranoia/unpleasantness of the comedown. Does not diminish effects IMHO, but complements them.