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.