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Racetams for cognitive side effects of pregabalin

Solipsis

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I have a script for dexamphetamine and pregabalin mostly for weekdays (at my discretion)..
Over time i notice negative cognitive effects from pregabalin which can get amplified by things like my ADD and issues with management of my energy.

Does anyone know if these are the kinds of cognitive problems that can be treated with racetams?

Any idea as to the cause of gabapentinoid cognitive side-effects?
 
I have a script for dexamphetamine and pregabalin mostly for weekdays (at my discretion)..
Over time i notice negative cognitive effects from pregabalin which can get amplified by things like my ADD and issues with management of my energy.

Does anyone know if these are the kinds of cognitive problems that can be treated with racetams?

Any idea as to the cause of gabapentinoid cognitive side-effects?


I believe racetams or noopept would help, i've read studies using them to antagonize the memory deficit from atropine, i think thats what it was at least. There were other chems too that experimentally stopped or at least attenuated memory impairment from a few different agent, tho atropine seems the standard. Ill try to remember or find the studies and get back to you.

gabapentinoids have a binding affinity to voltage-gated calcium channels. That's the primary mechanism. phenibut also has an affiity for the gaba b receptor in addition, but apparently gabapentin and pregabalin don't. which surprised me. About 7 or 8 years ago GBL and i spent a LOT of time together. unfortunately it left me with what is now mild to moderate memory issue. But my point is that i woulda put money on gabapentin acting on GABA b as well. It's the only thing that makes me feel like my real complete self again. But i guess that crossover i get isn't dependent on gaba b since multiple studies say no, no Trog, its not.

and for the record, i use what would be pretty high doses by most peoples standards, and i dont get cognitive impairment unless, feeling stupid or losing count, i end up taking over like 13-15g. which i generally dont do. but at that level you get the most intense dropsies, much like too much gbl(without passing out), where you can reach for somethng and you get half way there and your arm just suddenly drops involuntarily, you can lift your arm again immediately, but it'll probably drop again in a min, then its your leg, and so on. Consider them calcium channels altered but not completely blockaded!
 
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I found this:

Pregabalin is a structural derivative of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA); however, it does not directly bind to GABA receptors. Pregabalin binds to the alpha2-delta site of voltage-gated calcium channels in the central nervous system (CNS) tissues.4

This calcium channel modulation may reduce the release of many neurotransmitters.4

Like gabapentin, the precise mechanism of action of pregabalin is unknown.4 However, gabapentin differs from pregabalin because of the reduced binding affinity to voltage-gated calcium channels. 6 Pregabalin is six-times more potent than gabapentin in binding affinity to the alpha2-delta voltage-gated calcium channel.9 The manufacturer states that 50 mg of pregabalin is approximately equal to 300 mg of gabapentin. This alteration of calcium channel function is not to be confused with calcium-channel blockers. Pregabalin and gabapentin alter channel function without complete blockade of the calcium channel resulting in virtually no change in systemic blood pressure or coronary blood flow changes.


And also this: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5465829/
[h=1]Comparative effects of chronic administrations of gabapentin, pregabalin and baclofen on rat memory using object recognition test[/h]Asma Salimzade, Ali Hosseini-Sharifabad, and Mohammad Rabbani*

Author information Article notes Copyright and License information Disclaimer

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[h=2]Abstract[/h]Memory impairment is one of the greatest concerns when it comes to long-term CNS-affecting drug administration. Drugs like gabapentin, pregabalin and baclofen are administered in a long-term period in conditions such as epilepsy, neuropathic pain, spasticity associated with spinal cord injury or multiple sclerosis. Despite their wide spread use, few data are available on the effects of these drugs on cognitive functions, such as learning memory. In the present study, the effects of long-term administration of gabapentin, pregabalin and baclofen on memory were investigated in a comparative manner. Male Wistar rats received intraperitoneal (i.p.) injection of gabapentin (30 mg/kg), pregabalin (30 mg/kg), baclofen (3 mg/kg), combination of gabapentin/baclofen (30/3 mg/kg) and combination of pregabalin/baclofen (30/3 mg/kg) once a day for 3 weeks respective to their groups. After the end of treatments, rat memories were assessed using the object-recognition task. The discrimination and recognition indices (RI and DI) in the T2 trials were used as the memory indicating factors. The results showed that daily i.p. administrations of pregabalin but not gabapentin or baclofen significantly decreased DI and RI compared to saline group. In combination groups, either gabapentin or pregabalin impaired discrimination between new and familiar objects. Our findings suggested that pregabalin alone or in combination with baclofen significantly caused cognitive deficits.


Keywords: Gabapentin, Pregabalin, Baclofen, Object recognition task, Memory, Chronic


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[h=2]INTRODUCTION[/h]Neuropathic pain (NP) is a pain incepted or caused by a primary disease, lesion or dysfunction in the nervous system (1). It has varied causes such as spinal cord injury, stroke, multiple sclerosis, diabetes mellitus, neoplasia tumors and other diseases affecting the CNS (1,2). Neuropathic pain thus affects a large number of patients worldwide and often it has a significant impact on the quality of life (3,4). In patients with upper motor neuron disease, persistent pain can be associated with spasticity (5). Antiepileptic drugs are used for treating epilepsy, but have also been used for treating neuropathic pain (6). Baclofen is a muscle relaxant and an antispastic agent. It is used to treat spasms, pain, and stiffness (7,8). Antiepileptic drugs work in a number of different ways, all of which have relevance to their effect on pain. Gabapentin is an antiepileptic drug that, despite its name, has no interaction with GABA receptors or GABA metabolism (9). It appears to have an inhibitory action at voltage-gated calcium channels (VGCCs) and also disrupt an entire series of N-methyl-D-aspartate (NMDA)- activated events involved in central sensitization (10,11). Pregabalin is a more recently developed drug that (like gabapentin) is licensed for the treatment of peripheral neuropathic pain. It acts on the VGCCs too, although its pharmacokinetic properties are not identical to those of gabapentin (12,13). Baclofen is a GABAB receptor agonist that is mainly used for the treatment of spasticity (7). Baclofen is postulated to block mono-and- polysynaptic reflexes by acting as an inhibitory neurotransmitter, blocking the release of excitatory transmitters. Baclofen also has been found to block VGCCs (14,15).

Pharmacological interference has the potential to disrupt normal neurotransmission in areas of the brain responsible for cognitive functions. Antiepileptic drugs can adversely affect cognitive function by suppressing neuronal excitability or enhancing inhibitory neurotransmission (16). On the other hand, there is extensive evidence indicating that the administration of GABAergic drugs can cause cognitive deficits but very few studies have addressed this issue (17). The object recognition task (ORT) is used to evaluate cognition, particularly recognition memory, in rodent models of CNS disorders. This test is based on the spontaneous tendency of rodents to spend more time exploring a novel object than a familiar one. The choice to explore the novel object reflects the use of learning and recognition memory. Antiepileptic drugs such as gabapentin and pregabalin and other adjuvant drugs like baclofen are increasingly used in treatment of neuropathic pain. Because of the side effects of long-term treatment with these drugs, we decided to evaluate the chronic effect of gabapentin, pregabalin and baclofen alone and in combination on rat memory using ORT. The data of this study was compared with scopolamine that induces memory deficits in ORT model (18).



[h=2]DISCUSSION[/h]There are extensive evidences indicating that the administration of GABAergic drugs affects memory retention and learning. It has been shown that GABA receptor agonists impair memory and antagonists facilitate memory (24). Antiepileptic drugs can adversely affect cognitive function by suppressing neuronal excitability or enhancing inhibitory neurotransmission (25). Cognitive effects of gabapentin and other antiepileptic drugs have been compared in a number of clinical studies. Leach, et al. studied gabapentin in 27 patients in an add-on polytherapy study after 4 weeks of adjunctive therapy and found no change in psychomotor and memory tests. Drowsiness was more often found in higher dosing (2400 mg) (26). Mortimore, et al. did not find a difference between continued polytherapy or an add-on with gabapentin in measures of quality of life (27). Martin, et al. used an acute dose and rapid titration in 6 volunteers and did not find cognitive effects of gabapentin (28). In a small randomized double blind placebo controlled crossover study that was done in healthy volunteers that were treated by single low dosages (50-400 mg) of gabapentin showed a subtle positive psychotropic effects (e.g. improved concentration and attention) (29). Gabapentin acutely harms neuronal pathway via adjustment of the mechanism of neuronal cognitive pathway in different steps of learning tasks (30).

Then theres some links that might be helpful:

[h=1]Neuropsychological and psychiatric impact of add-on titration of pregabalin versus levetiracetam: A comparative short-term study[/h] https://www.sciencedirect.com/science/article/pii/S1525505006002757



[h=1]Cognitive effects of pregabalin in healthy volunteers[/h]http://n.neurology.org/content/74/9/755.short

I know im probably not really helping in answering your question. but perhaps the ansers can be hashed out from the right studies and comparisons. I take a lot of gabapentin so i want to dig thru the literature to im realizing i havent in a while and now i have a different angle. thanks
 
Thanks very much for your response!

Yea I have danced with GHB / GBL as well in the past, have been dependent although I did not raise my dosage by much through tolerance but resisted it knowing that it would get dangerous and difficult. Instead after a couple of stints I quite abruptly stopped on some januari 1st, which felt kinda arbitrary and I surprised myself. Stopping after each (earlier) 'stint' was only difficult for about 2 days, and one time I received some gabapentin which made it rather easy!

I wonder how this relates to gabapentinoids helping me now, indeed they feel like the only thing that make me feel normal and able to function: my pregabalin script can often remind me a bit of G. Since i have also had a period of dissociative abuse which is also in the past.. and i now use cannabis and alcohol off and on it can get difficult to tell what is worst for my already sucky attention and short term memory. Obviously it is a lurking vicious circle especially if times get difficult in the future.
My shrink (unfortunately I hardly ever see one who can follow the neuropharm stuff) was impressed by how I requested pregabalin myself (i had tried it in the past and it was an informed guess) and it is basically the only effective medication for a lot of my autism related symptoms of rigidity and anxiety. I wish they did research on this.

This study you quoted seems to suggest i may be better off with gabapentin than pregabalin?? I don't really like the idea of having to take a larger amount of a substance, on the long term i worry about the effects on kidneys etc...

Interesting that gabapentinoids seem to disrupt NMDA related events, I guess this is one proposed explanation for cognitive impairment? But the other is just very generally a suppression of neuronal excitability and enhancing of inhibition.
I wonder how this relates to a possible "rehabilitation" of the NMDA system and if that could still help to counter part of these effects. I think I will need to get a fresh choline source if I am to go on racetams again from time to time. Not sure how to manage that though since my low dexamphetamine script can already put me at the edge of irritability which can become unbearable if I stop taking pregabalin for about 5 days or so (tho this creeps up on me quite unnoticed which is really weird).

Does anyone know whether it would be pointless to use AMPAkines etc when the cause of cognitive impairment is just a pervasive suppressant effect?

In any case, I figure that there may be multiple causes for my cognitive impairment which might mean there is a bigger chance nootropics could help out with at least some of them.. I don't feel less intelligent than I used to be but scatterbrained and getting tired easily (tho the latter is hard to say with the amphs).
 
Response to solopsis, and opinion on pregablin's MOA and cognitive defects

If you are worried about dependency then you should switch to gabapentin. Gabapentin mechanism of action is more dirty, and more dependent of inhibition of voltage-gated calcium channels. It is more glutaminergic in my opinion. While both pregabalin and gabapentin mechanism of action are unknown; it is theorized that pregabalin main mechanism of action is by inducing carbon decarboxylase. Which is an enzyme that turns glutamic acid into GABA, and inhibits voltage gated calcium channels. Not to the extent that gabapentin does. Gabapentin more so than pregabalin also has an effect on sodium/calcium channels in the neighborhood of that MOA being a "mood stabilizer". Gabapentin has more of a downstream effect on glutamate release IMO(glutamate being regulated partially via GABA I know that sounds ironic given gabapentin/pregabalin being discussed). Pregabalin has a cleaner MOA, and is not metabolized; like modafinil 10% passes through your body via urine unchanged. To solopsis: As far as your dexamphetamine goes; you should start taking some chelated magnesium. A slight nmda antagonists to help regulate excess glutaminergic activity, and for reasons you most likely already know. Not to mention, balancing out some excess ca2+ and ca channels(when imbalanced seem to worsen side effects on dexamp); that would be imbalancing due to amphetamine sensitization, and pregabalin/gabapentin use, and sensitization. As far as cognitive impairment goes gabapentin seems to have worse side effects maybe due to its "dirtier" MOA's. I typed this once, and had to refresh the page and lost it. Gabapentin cognitive impairment is most likely due to sodium calcium channel activity, and inhibition of voltage-gated calcium channels; indirectly causing monoamine regulation; and via that and an unknown MOA mimicking GABA transmission. Also sensitization, and tolerance to gabapentin effects, mainly the first one, with excess glutamate firing being a result? Is my explanation for its tendency to cause cognitive deficiencies in some individuals. On another note at least lowering the DI compared to control. I think that pregabalin and gabapentins tendency to be glutaminergic isn't due to disruption of nmda activity. I think that can be one way of saying it if you know what I mean. I'm not sure as to why the both of them tend to have that effect technically. Although anti-convulsants the both of them can cause seizures; just have to say that. I don't have much to add to this thread, but I obligated to give my opinion on this.
 
Alright thanks for the info.. Now I'm not so sure anymore about trying to switch to gabapentin but I guess it probably shouldnt couldnt hurt to try a month..
 
If you are worried about dependency then you should switch to gabapentin. Gabapentin mechanism of action is more dirty, and more dependent of inhibition of voltage-gated calcium channels. It is more glutaminergic in my opinion. While both pregabalin and gabapentin mechanism of action are unknown; it is theorized that pregabalin main mechanism of action is by inducing carbon decarboxylase. Which is an enzyme that turns glutamic acid into GABA, and inhibits voltage gated calcium channels.<-(different mechanism of action for this) Not to the extent that gabapentin does. Gabapentin more so than pregabalin also has an effect on sodium/calcium channels in the neighborhood of that MOA being a "mood stabilizer". Gabapentin has more of a downstream effect on glutamate release IMO(glutamate being regulated partially via GABA I know that sounds ironic given gabapentin/pregabalin being discussed). Pregabalin has a cleaner MOA, and is not metabolized; like modafinil 10% passes through your body via urine unchanged. To solopsis: As far as your dexamphetamine goes; you should start taking some chelated magnesium. A slight nmda antagonists to help regulate excess glutaminergic activity, and for reasons you most likely already know. Not to mention, balancing out some excess ca2+ and ca channels(when imbalanced seem to worsen side effects on dexamp); that would be imbalancing due to amphetamine sensitization, and pregabalin/gabapentin use, and sensitization. As far as cognitive impairment goes gabapentin seems to have worse side effects maybe due to its "dirtier" MOA's. I typed this once, and had to refresh the page and lost it. Gabapentin cognitive impairment is most likely due to sodium calcium channel activity, and inhibition of voltage-gated calcium channels; indirectly causing monoamine regulation; and via that and an unknown MOA mimicking GABA transmission. Also sensitization, and tolerance to gabapentin effects, mainly the first one, with excess glutamate firing being a result? Is my explanation for its tendency to cause cognitive deficiencies in some individuals. On another note at least lowering the DI compared to control. I think that pregabalin and gabapentins tendency to be glutaminergic isn't due to disruption of nmda activity. I think that can be one way of saying it if you know what I mean. I'm not sure as to why the both of them tend to have that effect technically. Although anti-convulsants the both of them can cause seizures; just have to say that. I don't have much to add to this thread, but I obligated to give my opinion on this.

To mods: please do not edit this post. Theres a reason.
 
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