Once and for all: Dextroamphetamine vs. dextromethamphetamine

[negrogesic]

http://i249.photobucket.com/albums/gg223/antec6/stimtable.png

Thanks for posting the chart, I wish I could understand it!

Can someone please educate me on the differences in the numbers between phentermine and amphetamine? Basically, what the heck do the numbers stand for...

Thanks in advance...

The numbers designate the drugs potency in regards to the release and uptake of DA, NE and 5-HT. In short, the lower the numbers, the higher the affinity...

 

[Ham-milton]

I'm prety sure I've seen that before, but I never noticed mazindol's numbers. I wonder why it isn't more abused.

looks difficult to make, probably rarely prescribed. It's under the "NERI" category at Wikipedia. Perhaps I could pass it off to my doc as a weak anorectant. I doubt it's weak at all though.

 

[cilous]

mazindol??

man why do you want this shit??? I leave in Brasil -probably the only place in world where DOES NOT EXIST amphetamines and opiates in the black market, and the only perscribed class of amphetamines are anorexigens- only three actually, Dyethilpropion , fenproporex and mazindol- the only who does not suck's is fenproporex(pro-dexedrinelike drug).Stick with your country fabulous drugs (the only cool opiates availables are morphine,demerol,and oxycontin)

 

[Nagelfar]

^--That's a good question.

I don't have the EC50 value for MPH, but I find MPH just as good as AMP, so I bet they have similar values. (The dex form is even better.) METH is stronger still, but somehow, I think I also prefer the first two to the latter, which lasts too long--making sleep impossible--and sometimes comes with toxic impurities (from the P/HI route).

Maybe a better title for this thread would be "Once and for all: Dextroamphetamine vs. dextromethamphetamine vs. dexmethylphenidate." I think they're all good.

Provigil and Strattera are not even in the race for the title of all round best stimulant, that's for sure, and cocaine is in a class by itself (the tropanes).

From what I'm reading lately dex-methylphenidate is closer to cocaine than amphetamine in about every way:

http://en.wikipedia.org/wiki/File:TMP.png

apparently this is a 3D overlap of "dexidate" (dextro- methylphenidate) with a cocaine analogue that is little other than cocaine with it's local anesthetic causing ester linkage removed via a chemical process involving pyrolysis (turning it into a metabolite peculiar to crack smoke) and then stabilizing it into its active stimulant form with no numbing effect (cocaine stimulant with local anesthetic removed) .... the 3D image of the two overlap nearly perfectly... noting how methylphenidate inhibits the reuptake of DAT, SERT & NE without releasing it and cocaine does the same thing... then it seems logical to me that methylphenidate & cocaine may well be closer related in SAR than to amphetamines. (Seeing as amphetamines are primarily active as a releasing agent.)

Amphetamines are in the phenethylamine class of drugs and methylphenidate is in the piperidine.... (however, methylphenidate is listed as a substituted phenethylamine on wikipedia, which confuses me. I suppose it is not contradictive to be both?)

 

[negrogesic]

^^^^Not entirely true, MPH has little affinity for the SERT (I believe the value is greater than 5000nM). This reduces the qualitative euphoria. Still, its affinity for the DAT is high (more potent than cocaine). Cocaine is definately superior, if less potent.

 

[Nagelfar]

What's "not entirely true" that you are retorting to? I'm making no claims of either potency nor euphoria... :-7

 

[negrogesic]

inhibits the reuptake of DAT, SERT & NE

It effectively does not inhibit the reuptake of serotonin, especially at DA/NE inhibiting doses....

 

[Nagelfar]

It effectively does not inhibit the reuptake of serotonin, especially at DA/NE inhibiting doses....

Ah, thanks. OK regarding SERT interaction that was a slip, touche, but inhibition of the remaining monoamines, it's mechanism for doing so, is still rather cocaine-like than amphetamine-like, was my only intended case. Yes though it is lacking at SERT and that may relate to it's "less euphoria" etc.

 

[amphetRALL]

"Why is meth neurotoxic when un-methylated amphetamine does not seem to be?'

Methylated amphetamine diffuses through the membranes much faster then regular amphetamine.

Its the insane spike in methamphetamine concentration in the brain that causes all the damage..

 

[DexyDevil]

I see. But now that Desoxyn is used therapeutically against narcolepsy and ADHD at dosages of around 10-20 mg, does this mean that such low amounts are below the threshold of neurotoxicity; possibly even that of serotonergic-induced neurotoxicity?

Edit: Also, to what extent may meth neurotoxicity be counteracted with antioxidants, i.e. ascorbic acid? Completely or just partly?

The issue for me was that Desoxyn DID NOTHING FOR ME at the doses you mention (10-20mg). Even at 30mg a day Desoxyn simply was not helpful. Adderall and Dexedrine work a great deal better. The effects of Desoxyn, though it may be more potent technically are just too subtle at therapeutic doses. Adderall and Dexedrine are much more stimulating at therapeutic doses.

Also, my brain felt like Desoxyn was neurotoxic. Though the peak effects were minimal the "come-down" was quite disproportionately intense.

 

[DexyDevil]

1. Are there any actual differences in CNS stimulant effects between dextroamphetamine (Dexedrine) and dextromethamphetamine (Desoxyn), except for the increased potency per mg of meth (due to increased lipid solubility)? Is it true that Desoxyn gives clearer thoughts and more "control" and at the same time less side effects or is that just placebo?

Others have already provided the hard data to answer this question but I wanted to emphasize that subjectively there is a great deal of difference between d-amp and d-meth. D-meth is a stronger DA agonist and reuptake inhibitor, but has less NE agonism and reuptake inhibition, and weak (at therapeutic doses) but comparatively strong 5HT agonism and reuptake inhibition. This means it is less physically stimulating and should mean that it is more mentally stimulating, but I don't find this to be the case at therapeutic doses. It is almost as if I need physically stimulation to have mental stimulation.

I actually do best on mixed amphetamine salts, though I prefer the feel of pure d-amp. I took Mylan generic methamphetamine hydrochloride for a few months and my level of productivity dropped drastically. I sat around a lot watching episodes of "Breaking Bad" (appropriate, huh?).

 

[ebola?]

D-meth is a stronger DA agonist and reuptake inhibitor, but has less NE agonism and reuptake inhibition, and weak (at therapeutic doses) but comparatively strong 5HT agonism and reuptake inhibition.

Differences in efficacy as a reuptake inhibitors should only be relevant at very low doses, where significant release does not occur. How low, I'm not sure, and I haven't yet seen convincing data thereon. . .I also think that the jury's still out on whether meth is an effective enough 5ht releaser for this effect to prove relevant at remotely sane doses.

ebola

 

[Pharmokinetictal]

I've tried mazindol before (both low and high doses)--definitely nothing to write home about. It is certainly very "clean" feeling, but not particularly stimulating. Those expecting a methylphenidate-like experience and focusing effect would be disappointed. I'm not sure why it would have been taken off the market.

Anyway, there is more to DAT binding than just Ki, it appears that different classes of DAT inhibitors induce different conformational changes at the DAT and hare differing behavioral effects; some DAT inhibitors are completely devoid of stimulant activity.

Word. The pharmacology of these drugs are based mostly on the pharmacokinetics. Cocaine inhibits DAT proteins, causing an increase in DA concentration in the synaptic cleft--but only by default. Cocaine does not cause a release. It merely prevents uptake. It essentially stops there. But amphetamine derivatives look so much like catecholamine neurotransmitters that their binding affinity to DAT is only one of many proteins they affect and are affected by based on their functional groups like a methylated amine or an oxidized primary alcohol (ketone in Khat).

Amphetamines, particularly D-amphetamines and MDMA derivatives enter the presynaptic cell via 2 mechanisms:
1) Passive diffusion of the molecule into the presynaptic cell
2) Active inhibition of DAT AND the reverse of DAT protein

So, Amphs will enter the presynaptic cell in gross quantities and then enter dopamine, serotonin, and other catecholamine/monoamine vesicles through the VMAT, vesicular monoamine transporter. This increases the rate of exocytosis of dopamine and serotonin & also causes an efflux of dopamine and serotonin from their vesicles. These neurotransmitters are now free to interact with any protein within the cytoplasm of the cell--causing oxidative stress and toxic free radicals. Amphs also inhibit the TAAR1 (trace amine associated receptor). DATs get phosphorylated and eventually internalized via PKA and PKC. These two kinase proteins are responsible in every receptor-induced signaling pathway; and constant stimulation of them by a rewarding drug will also generally cause a temporary change in translational proteins that code for dependence, tolerance, addiction, etc. Methylated amines generally increase potency based on increased fat solubility (also relates to increased lipid membrane permeability for meth) and their conformation within a protein/receptor binding pocket. Meth essentially creates a pre-cellular environment at the synapse where so much serotonin and dopamine and norepinephrine are being released so prolifically by both lipid membrane budding/fusion and toxic cytosolic protein interactions that the synapse literally gets shredded and the neuron dies by apoptosis or necrosis.

 

[Kittycat5]

That sounds like PD not PK though.

 

[Jaykay77]

Just wondering why speed cleared my mind up and made me feel euphoric and confident. But dexamphetamine does not help me at all. And has anybody else found something that worked for them other than dexamphetamine.

 

[Seppi]

1. Are there any actual differences in CNS stimulant effects between dextroamphetamine (Dexedrine) and dextromethamphetamine (Desoxyn), except for the increased potency per mg of meth (due to increased lipid solubility)?

2. Why is meth neurotoxic when un-methylated amphetamine does not seem to be?

3. Is there a lower limit of blood plasma concentration for methamphetamine neurotoxicity? Is 20-60 ng/mL completely safe as indicated here or did I get something wrong?

Thanks.

1. Amphetamine and methamphetamine bind to TAAR1 as a common intracellular target, resulting in PKA- and PKC-beta-mediated phosphorylation of DAT which internalize the transporter or induce DA efflux through the reversed transporter, respectively. Both compounds also interact with VMAT2 via a mechanism that hasn't been fully elucidated, but which results in monoamine efflux from the synaptic vesicle.

* Amphetamine also interacts with an unidentified intracellular target, likely a GPCR, which induces a RhoA-mediated signaling cascade through a protein kinase (probably a ROCK, per [ref1 for DAT]) that phosphorylates DAT and EAAT3 in dopamine neurons.[ref1 for DAT ref2 for EAAT3 ref3 (paywalled review)] RhoA-mediated DAT and EAAT3 phosphorylation (again, probably by a ROCK) induces internalization of these transporters. [ref1 for DAT ref2 for EAAT3 ref3 (paywalled review)] Via an unidentified mechanism, amphetamine also induces a CAMKII-mediated phosphorylation of DAT, in turn triggering DA efflux through reversed DAT transport.

* Methamphetamine also induces a CAMKII-mediated signaling cascade, but again the mechanism is unidentified. Methamphetamine has also been shown to affect RhoA signaling and EAAT3 membrane expression in rats, but so far not in humans.[see this search for RhoA and this search for EAAT3]. Assuming that meth triggers the RhoA-mediated + EAAT3-internalizing signaling cascade in human DA neurons, it likely interacts with the same intracellular target as amphetamine in order to produce this effect.
* Methamphetamine also induces EAAT1 and EAAT2 internalization in human brain cells; in astrocytes, EAAT2 internalization occurs via TAAR1 activation. [See the WP methamphetamine article's pharmacodynamics and neurotoxicity sections and WP article on TAAR1 in the immune system section for sources] It should be noted that amphetamine does not internalize EAAT2 or appear to affect EAAT1 in the striatum (note: EAAT1 has low striatal expression), [ref2 for EAAT3] which is a brain region in which methamphetamine affects the membrane expression and function of these transporters. At the moment, I have no idea why meth selectively affects EAAT1 and EAAT2, while amph selectively affects only EAAT3.
* Lastly, methamphetamine binds to the sigma-1 and sigma-2 receptors as an agonist; the sigma-1 receptor is located in human DA neurons and the effect of Sigma-1 activation by methamphetamine appears to amplify its stimulant and neurotoxic effects. [See the WP methamphetamine article's pharmacodynamics and neurotoxicity sections for sources] In contrast, amphetamine's binding affinity for human sigma receptors is negligible.

In summary, amphetamine triggers DAT phosphorylation through 4 distinct protein kinases and affects the expression of EAAT3 in DA neurons. Methamphetamine triggers transporter phosphorylation through at least 3 or possibly the same 4 protein kinases as amphetamine, affects the expression of EAAT1 and EAAT2 in glia (and possibly affects EAAT3 expression in human DA neurons, based upon animal models), and acts as an agonist at sigma receptors in DA neurons.

All of the mechanisms that I mentioned above mediate the CNS stimulant effects of amphetamine or methamphetamine at the cellular level in DA and/or glutamate neurons and glial cells (e.g., astrocytes). I'm not going to comment on the signaling mechanisms of either compound in norepinephrine neurons since these mechanisms haven't been fully elucidated; however, some of the signaling mechanisms are common to both DA and NE neurons. I will point out that TAAR1-mediated transporter phosphorylation appears to induce slightly different effects on transporter function in DA and NE neurons though.


2. As noted above, methamphetamine appears to act on certain mechanisms which amphetamine does not (methamphetamine only: EAAT1, EAAT2, sigma receptors), and vice versa (amphetamine only: EAAT3). All of methamphetamine's unique targets (EAAT1, EAAT2, sigma receptors) are implicated in the development of meth-induced neurotoxicity or neurodegeneration. [See the WP methamphetamine article's pharmacodynamics and neurotoxicity sections for sources] A very recent review on EAAT3 indicated that amphetamine's effects on EAAT3 expression in DA neurons may play a role in the development of amphetamine addiction via influencing learning and memory through increased glutamate receptor signaling, but it did not mention anything about neurotoxicity. [ref3 (paywalled review)] This is probably because, unlike EAAT2 which is responsible for the majority of glutamate reuptake in the brain, EAAT3 plays only a minor role in overall glutamate reuptake.

The extent to which each compound induces brain hyperthermia also has a strong influence on the neurotoxic effects of each compound. [ref]

There may be other mechanisms which mediate amphetamine and/or methamphetamine-induced neurotoxicity which have yet to be identified. What I've covered here is limited to what is currently known and that I've found following extensive literature searches for each compound.


3. I don't think blood plasma concentrations of either compound correlate well with the induction of neurotoxicity in humans. I'm going to emphasize here that any research on animals will not even remotely reflect upon humans in this regard, because the doses required to trigger amph- and meth-induced neurotoxicity starkly differs across species. This might be partly explained by the fact that each compound has a starkly different affinity for TAAR1 across species. This variance in neurotoxicity across species could also be due to these compounds binding with different affinities to other known (e.g., sigma receptors) or unidentified intracellular targets in different species.

Is it true that Desoxyn gives clearer thoughts and more "control" and at the same time less side effects or is that just placebo?

To my knowledge, this effect hasn't been shown in any human RCTs, so there's no reason to believe that this is true.

 

[Seppi]

So, Amphs will enter the presynaptic cell in gross quantities and then enter dopamine, serotonin, and other catecholamine/monoamine vesicles through the VMAT, vesicular monoamine transporter. This increases the rate of exocytosis of dopamine and serotonin & also causes an efflux of dopamine and serotonin from their vesicles. These neurotransmitters are now free to interact with any protein within the cytoplasm of the cell--causing oxidative stress and toxic free radicals. Amphs also inhibit the TAAR1 (trace amine associated receptor). DATs get phosphorylated and eventually internalized via PKA and PKC. These two kinase proteins are responsible in every receptor-induced signaling pathway; and constant stimulation of them by a rewarding drug will also generally cause a temporary change in translational proteins that code for dependence, tolerance, addiction, etc. Methylated amines generally increase potency based on increased fat solubility (also relates to increased lipid membrane permeability for meth) and their conformation within a protein/receptor binding pocket. Meth essentially creates a pre-cellular environment at the synapse where so much serotonin and dopamine and norepinephrine are being released so prolifically by both lipid membrane budding/fusion and toxic cytosolic protein interactions that the synapse literally gets shredded and the neuron dies by apoptosis or necrosis.

Oxidative stress that results from the metabolism of neurotransmitters within the cytosol and synaptic cleft is just one mechanism that facilitates neurotoxicity. By itself, I can't imagine that the extent of the resulting neurotoxicity would be that significant, unless intrastriatal DA injections have been shown to be grossly neurotoxic.

Also a minor point, but amph/meth bind to and activate TAAR1, not antagonize it. TAAR1 has only been shown to partially mediate the effects of amph and meth on DAT internalization and efflux via PKA and PKC. There are at least 2 other protein kinases (ROCK and CAMKII) that phosphorylate DAT following amph exposure.

 

[deruyityn]

#2 is to do with the serotonin efflux and the fact that the serotonogic neurones hoover up dopamine a la MDMA Because of it's serotonogic activity, there's not going to be a 'safe' level fot methamphetamine, just a dose that causes less damage

I read this too. As such is it probably the case that 2-fma isn't going to be neurotoxic like normal meth? because ppl report it doesn't have any appreciable serotonin action? Sekio said that he thought 2-fma would share the same propensity for neurotoxicity as meth but if there is no serotonin action then how would that be?

 

[Seppi]

Serotonin releasing agents aren't inherently neurotoxic; e.g., tryptamine is a human biomolecule which isn't directly toxic to neurons. Some serotonin releasing agents, like meth and MDMA are neurotoxic, but that toxicity results from how they interact with their biomolecular targets on the plasma membrane of and inside neurons, not whether or not they induce the release of particular monoamines. All trace amines induce monoamine efflux; none of them are neurotoxins.

 

[airdusters]

After all, in a world where AIDS drugs are prescribed regularly, I am not surprised that meth toxicity is overlooked.

what did he mean by this