dopamimetic
Bluelighter
As I've just posted over here, I'm moving it now into here as I think it fits more well into NSPD.
The gabapentinoids are notorious for loosing the 'good' effects very quickly, mostly related to the relieving effect on mood, anxiety etc. with initial high doses of pregabaline being the most pronounced. The longer term effects are due to blockade of a subunit of calcium channels, as well as there is evidence for them to halt the formation of new synapses... which could be bad on the long run, leading to cognitive / memory impairment as well as even to depression, which seemed to happen to me.
I've been interested previously in what the mechanisms of the acute pregabalin experience are and how they could be reproduced without that rapid and long-lasting tolerance. Unfortunately that thread has disappeared (I have deleted it two days ago in a rebound surge of depression from MXE levels dropping 8) sorry for that). But it might be that it is some sort of downstream modulation in glutamatergic neurotransmission, maybe together with an increase in GABA synthesis and/or dopaminergic effects because this would fit the quality of the effects quite well.
Interestingly phenibut seems to be more similar to gabapentin / pregabalin in its overall effects than to the structurally very closely related baclofen, which is more of a pure GABA-B agonist and the structural similarity is (probably) why it has been said that phenibut works by that way too, but recent evidence shows that it is a comparatively weak GABA-B agonist and more potent of a α2δ ligand & a dopaminergic.
If my theory is correct, then the levetiracteam (Keppra) would even be counterproductive in regards of the beneficial effects of gabapentin on mood (to the anti epileptic action too!?), when they are related to glutamatergic down regulation & the levetiractam shares the cholinergic / AMPA(?) positive allosteric modulation of it's parent molecule, piracetam. The racetams do strongly cancel out the nice effects of NMDA antagonists / dissociatives.
--
The tolerance & withdrawal profile of the gabapentinoids follows a very unusual and hard-to-grasp non-linear scheme. Well, if pregabalin really increases the synthesis of GABA, then withdrawing from it would lead to a drop in GABA levels and an increase in glutamatergic neurotransmission. Would fit the withdrawal syndrome somewhat well, not?
Then also memantine would be of great help to overcome that. Allowing the brain to re-adjust GABA before slowly titrating the memantine down & allow glutamate re-equilibrium.
Could it even be that memantine & tiagabine (or that unusual and not widely used perampanel) would make a better treatment for those responding to the anti-convulsive effects (as well as the anti-anxiety effects) of the gabapentinoids, avoiding the cognitive impairment associated with the long-term use...!?? Memantine has been suggested to exhibit anti-convulsive effects before, but afaik this has not really been further investigated up to today... also as I can say from personal experience, memantine does a good job in alleviating the brain zaps from SSRI withdrawal.
Insomnia and brain zaps as well as the general restlessness could fit entirely well to the theory of a glutamatergic modulation, leading to rebound over excitation (which is a speculated mechanism behind brain zaps), insomnia, inner tension etc ... and as NMDA receptors & mu opioid receptors are somewhat interconnected (NMDA antagonists alleviate opioid tolerance in some, aid in the withdrawal etc), this could also explain both the beneficial effects of gabapentinoids in opioid withdrawal, the opioid potentiation as well as the somewhat opioid-similar withdrawal profile they have.
NMDA receptors are also some kind of interconnected with calcium channels, as their activation allows Ca ions to enter the cell. So modulating a subunit of calcium channels, the α2δ ones, would also mean NMDA modulation(?)
--
Dual effects of gabapentin and pregabalin on glutamate release at rat entorhinal synapses in vitro.
But then again, Felbamate but not phenytoin or gabapentin reduces glutamate release by blocking presynaptic NMDA receptors in the entorhinal cortex.
lyrica's (pregabalin's) real mechanisim <-- maybe also really interesting older thread here on NSPD
And so on. I have yet to read through all these interesting new references and then I might be able to come up with a more accurate theory.
--
I could be totally wrong of course concerning the gabapentin & levetiracetam (as well as the NMDA thing), it's all so complicated of course. That they have both a protective effect against seizures and do not cancel out each other. But it could be that they do not interact as well together as they should.
Sorry for all this hypomanic theorizing
-dopamimetic
The gabapentinoids are notorious for loosing the 'good' effects very quickly, mostly related to the relieving effect on mood, anxiety etc. with initial high doses of pregabaline being the most pronounced. The longer term effects are due to blockade of a subunit of calcium channels, as well as there is evidence for them to halt the formation of new synapses... which could be bad on the long run, leading to cognitive / memory impairment as well as even to depression, which seemed to happen to me.
I've been interested previously in what the mechanisms of the acute pregabalin experience are and how they could be reproduced without that rapid and long-lasting tolerance. Unfortunately that thread has disappeared (I have deleted it two days ago in a rebound surge of depression from MXE levels dropping 8) sorry for that). But it might be that it is some sort of downstream modulation in glutamatergic neurotransmission, maybe together with an increase in GABA synthesis and/or dopaminergic effects because this would fit the quality of the effects quite well.
Interestingly phenibut seems to be more similar to gabapentin / pregabalin in its overall effects than to the structurally very closely related baclofen, which is more of a pure GABA-B agonist and the structural similarity is (probably) why it has been said that phenibut works by that way too, but recent evidence shows that it is a comparatively weak GABA-B agonist and more potent of a α2δ ligand & a dopaminergic.
If my theory is correct, then the levetiracteam (Keppra) would even be counterproductive in regards of the beneficial effects of gabapentin on mood (to the anti epileptic action too!?), when they are related to glutamatergic down regulation & the levetiractam shares the cholinergic / AMPA(?) positive allosteric modulation of it's parent molecule, piracetam. The racetams do strongly cancel out the nice effects of NMDA antagonists / dissociatives.
--
The tolerance & withdrawal profile of the gabapentinoids follows a very unusual and hard-to-grasp non-linear scheme. Well, if pregabalin really increases the synthesis of GABA, then withdrawing from it would lead to a drop in GABA levels and an increase in glutamatergic neurotransmission. Would fit the withdrawal syndrome somewhat well, not?
Then also memantine would be of great help to overcome that. Allowing the brain to re-adjust GABA before slowly titrating the memantine down & allow glutamate re-equilibrium. Could it even be that memantine & tiagabine (or that unusual and not widely used perampanel) would make a better treatment for those responding to the anti-convulsive effects (as well as the anti-anxiety effects) of the gabapentinoids, avoiding the cognitive impairment associated with the long-term use...!?? Memantine has been suggested to exhibit anti-convulsive effects before, but afaik this has not really been further investigated up to today... also as I can say from personal experience, memantine does a good job in alleviating the brain zaps from SSRI withdrawal.
Insomnia and brain zaps as well as the general restlessness could fit entirely well to the theory of a glutamatergic modulation, leading to rebound over excitation (which is a speculated mechanism behind brain zaps), insomnia, inner tension etc ... and as NMDA receptors & mu opioid receptors are somewhat interconnected (NMDA antagonists alleviate opioid tolerance in some, aid in the withdrawal etc), this could also explain both the beneficial effects of gabapentinoids in opioid withdrawal, the opioid potentiation as well as the somewhat opioid-similar withdrawal profile they have.
NMDA receptors are also some kind of interconnected with calcium channels, as their activation allows Ca ions to enter the cell. So modulating a subunit of calcium channels, the α2δ ones, would also mean NMDA modulation(?)
--
Dual effects of gabapentin and pregabalin on glutamate release at rat entorhinal synapses in vitro.
But then again, Felbamate but not phenytoin or gabapentin reduces glutamate release by blocking presynaptic NMDA receptors in the entorhinal cortex.
lyrica's (pregabalin's) real mechanisim <-- maybe also really interesting older thread here on NSPD
And so on. I have yet to read through all these interesting new references and then I might be able to come up with a more accurate theory.
--
I could be totally wrong of course concerning the gabapentin & levetiracetam (as well as the NMDA thing), it's all so complicated of course. That they have both a protective effect against seizures and do not cancel out each other. But it could be that they do not interact as well together as they should.
Sorry for all this hypomanic theorizing
-dopamimetic
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