Restoring GIRK channels signaling
Restoring GIRK channels signaling
One of the most plausible theories I've read is GIRK channel decoupling w/ 5HT1A or downregulation of GIRK channel response. I have no access to agents that can effectively lower central serotonin level (Shilajit, etc), so the next logical step for me is to enhance GIRK response.
Neuropeptide Y (NPY) is an important GIRK activator through NPY1 receptor. It plays an important role in reinforcing drugs of abuse effect, addiction and dependency [1] [2][3].
Baclofen, which is the only drug to fully reverse my blunted affect, is a known GIRK activator [4]. However, it's giving me intense nausea, vomiting, and dizziness and it isn't getting better, so I cannot tolerate it for much longer.
Morphine and CaMKII enhances GIRK channel signaling in hippocampal neurons [5].
Rapid NMDA antagonist antidepressants (Ketamine, etc), upregulates GABA-B receptors but causes GABA(B)-GIRK decoupling, and this plays a part in their antidepressant effect. [6].
Dextromethorphan has an inhibitory effect on GIRK channels, increasing central serotonin level via inhibiton of 5HT1A-GIRK response in dorsal raphea neurons [7].
So, it seems that by upregulating/activating GIRK response, this can at least restore some of the lost 5HT1A-GIRK activity. I haven't researched yet how GIRK channels behave in response to activation/inhibition, but it can surely be modulated in favor of improving PSSD. One target is Neuropeptide Y.
Neuropeptide Y (NPY) is an important GIRK activator through NPY1 receptor. It plays an important role in reinforcing drugs of abuse effect, addiction and dependency [1] [2][3].
Baclofen, which is the only drug to fully reverse my blunted affect, is a known GIRK activator [4]. However, it's giving me intense nausea, vomiting, and dizziness and it isn't getting better, so I cannot tolerate it for much longer.
Morphine and CaMKII enhances GIRK channel signaling in hippocampal neurons [5].
Rapid NMDA antagonist antidepressants (Ketamine, etc), upregulates GABA-B receptors but causes GABA(B)-GIRK decoupling, and this plays a part in their antidepressant effect. [6].
Dextromethorphan has an inhibitory effect on GIRK channels, increasing central serotonin level via inhibiton of 5HT1A-GIRK response in dorsal raphea neurons [7].
So, it seems that by upregulating/activating GIRK response, this can at least restore some of the lost 5HT1A-GIRK activity. I haven't researched yet how GIRK channels behave in response to activation/inhibition, but it can surely be modulated in favor of improving PSSD. One target is Neuropeptide Y.
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Re: Restoring GIRK channels signaling
D2 receptors also activate GIRK channels. I can see the potential in this but modulating GIRK activity seems even harder than lowering central serotonin. Do you think 'playing' with agonists or antagonists is a possible strategy?
What about upregulating/enhancing SERT actvity? Isn't it a logical next step?
What about upregulating/enhancing SERT actvity? Isn't it a logical next step?
Re: Restoring GIRK channels signaling
There aren't many agents that can upregulate SERT mRNA expression. Berberine is an interesting SERT enhancer but it's also a 5-alpha reductase inhibitor which is very risky.taarn wrote:D2 receptors also activate GIRK channels. I can see the potential in this but modulating GIRK activity seems even harder than lowering central serotonin. Do you think 'playing' with agonists or antagonists is a possible strategy?
What about upregulating/enhancing SERT actvity? Isn't it a logical next step?
Other substances seem to be weak serotonin depleters (i.e. shilajit, siberian ginseng, etc).
GIRK channels downregulates in response to agonism. So, perhaps they upregulate in response to antagonism.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5550722/To activate GABAB receptors and down-regulate GIRK channels, baclofen (Sigma) was used at 50 μM.
Dextromethorphan(DXM)'s antitussive effect is mediated via GIRK antagonism. Perhaps this is the key to upregulating GIRK. Also, DXM comes in hydrobromide salt formulation (HBr). Bromide inhibits serotonin release, at least in-vitro:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5385730/Alteration of serotonergic signaling may also play a role in bromide-induced cognitive dysfunction. In this regard, in vitro studies have demonstrated that bromide inhibits serotonin release
DXM, in itself, is a mild serotonin releaser, but after its effects wanes off, bromide would still be in the body as bromide has a half-life of 12 days. One must be careful of the risk of toxic bromism if one wants to ingest a large amount of DXM for a long period of time.
I think it's worth a trial since DXM-HBr would inhibit serotonin release and upregulate GIRK simultaneously, but it's needed to be taken for at least 2 weeks at a low-to-moderate dose of ~360 mg to allow bromide to build up and GIRK to upregulate.
I'm going to try this myself.
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Re: Restoring GIRK channels signaling
It's risky, DXM it's not the safest drug. I've tried it few times for fun. Taking it 360mg for 2 weeks doesn't sound good, it can cause for example real memory impairment and of course you'll be highMesolimbo wrote:There aren't many agents that can upregulate SERT mRNA expression. Berberine is an interesting SERT enhancer but it's also a 5-alpha reductase inhibitor which is very risky.taarn wrote:D2 receptors also activate GIRK channels. I can see the potential in this but modulating GIRK activity seems even harder than lowering central serotonin. Do you think 'playing' with agonists or antagonists is a possible strategy?
What about upregulating/enhancing SERT actvity? Isn't it a logical next step?
Other substances seem to be weak serotonin depleters (i.e. shilajit, siberian ginseng, etc).
GIRK channels downregulates in response to agonism. So, perhaps they upregulate in response to antagonism.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5550722/To activate GABAB receptors and down-regulate GIRK channels, baclofen (Sigma) was used at 50 μM.
Dextromethorphan(DXM)'s antitussive effect is mediated via GIRK antagonism. Perhaps this is the key to upregulating GIRK. Also, DXM comes in hydrobromide salt formulation (HBr). Bromide inhibits serotonin release, at least in-vitro:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5385730/Alteration of serotonergic signaling may also play a role in bromide-induced cognitive dysfunction. In this regard, in vitro studies have demonstrated that bromide inhibits serotonin release
DXM, in itself, is a mild serotonin releaser, but after its effects wanes off, bromide would still be in the body as bromide has a half-life of 12 days. One must be careful of the risk of toxic bromism if one wants to ingest a large amount of DXM for a long period of time.
I think it's worth a trial since DXM-HBr would inhibit serotonin release and upregulate GIRK simultaneously, but it's needed to be taken for at least 2 weeks at a low-to-moderate dose of ~360 mg to allow bromide to build up and GIRK to upregulate.
I'm going to try this myself.
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Re: Restoring GIRK channels signaling
Yes, that's true. It would require taking a week off of work. 360 mg is a low dose compared to what people are taking (600+), but I agree that this is risky. It comes down to how desperate I would get, but right now I'm not going to trial this.Snake wrote:It's risky, DXM it's not the safest drug. I've tried it few times for fun. Taking it 360mg for 2 weeks doesn't sound good, it can cause for example real memory impairment and of course you'll be high
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Re: Restoring GIRK channels signaling
Mesolimbo wrote:There aren't many agents that can upregulate SERT mRNA expression. Berberine is an interesting SERT enhancer but it's also a 5-alpha reductase inhibitor which is very risky.taarn wrote:D2 receptors also activate GIRK channels. I can see the potential in this but modulating GIRK activity seems even harder than lowering central serotonin. Do you think 'playing' with agonists or antagonists is a possible strategy?
What about upregulating/enhancing SERT actvity? Isn't it a logical next step?
Other substances seem to be weak serotonin depleters (i.e. shilajit, siberian ginseng, etc).
GIRK channels downregulates in response to agonism. So, perhaps they upregulate in response to antagonism.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5550722/To activate GABAB receptors and down-regulate GIRK channels, baclofen (Sigma) was used at 50 μM.
Dextromethorphan(DXM)'s antitussive effect is mediated via GIRK antagonism. Perhaps this is the key to upregulating GIRK. Also, DXM comes in hydrobromide salt formulation (HBr). Bromide inhibits serotonin release, at least in-vitro:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5385730/Alteration of serotonergic signaling may also play a role in bromide-induced cognitive dysfunction. In this regard, in vitro studies have demonstrated that bromide inhibits serotonin release
DXM, in itself, is a mild serotonin releaser, but after its effects wanes off, bromide would still be in the body as bromide has a half-life of 12 days. One must be careful of the risk of toxic bromism if one wants to ingest a large amount of DXM for a long period of time.
I think it's worth a trial since DXM-HBr would inhibit serotonin release and upregulate GIRK simultaneously, but it's needed to be taken for at least 2 weeks at a low-to-moderate dose of ~360 mg to allow bromide to build up and GIRK to upregulate.
I'm going to try this myself.
why would berberine acting as a 5-alpha reductase inhibitor be risky?
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Re: Restoring GIRK channels signaling
I'd take it for the team, do you think this antagonism is from dxo or dxm really?? in case it's from dxm I'll need to use a cyp inhibitorMesolimbo wrote:Yes, that's true. It would require taking a week off of work. 360 mg is a low dose compared to what people are taking (600+), but I agree that this is risky. It comes down to how desperate I would get, but right now I'm not going to trial this.Snake wrote:It's risky, DXM it's not the safest drug. I've tried it few times for fun. Taking it 360mg for 2 weeks doesn't sound good, it can cause for example real memory impairment and of course you'll be high
im already taking it 3-4 days per week for 2 weeks at around 250mg/d with Wellbutrin
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Re: Restoring GIRK channels signaling
Bro how much shit are you taking a day? didnt you also use valproate and hidra?PsychoGenesis wrote:I'd take it for the team, do you think this antagonism is from dxo or dxm really?? in case it's from dxm I'll need to use a cyp inhibitorMesolimbo wrote:Yes, that's true. It would require taking a week off of work. 360 mg is a low dose compared to what people are taking (600+), but I agree that this is risky. It comes down to how desperate I would get, but right now I'm not going to trial this.Snake wrote:It's risky, DXM it's not the safest drug. I've tried it few times for fun. Taking it 360mg for 2 weeks doesn't sound good, it can cause for example real memory impairment and of course you'll be high
im already taking it 3-4 days per week for 2 weeks at around 250mg/d with Wellbutrin
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Re: Restoring GIRK channels signaling
yesterday had to get a cupboard just for drugs and organize them in alphabetical order so i can find em, but I'm trying to do one thing at a timeAnhedonicApe wrote:Bro how much shit are you taking a day? didnt you also use valproate and hidra?PsychoGenesis wrote:I'd take it for the team, do you think this antagonism is from dxo or dxm really?? in case it's from dxm I'll need to use a cyp inhibitorSnake wrote:l
im already taking it 3-4 days per week for 2 weeks at around 250mg/d with Wellbutrin
Last edited by PsychoGenesis on Sat Nov 30, 2019 11:38 am, edited 1 time in total.
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Re: Restoring GIRK channels signaling
This is fit to me- Dextrometorphan improve my symptom- slighty decrease empathy, bad thought, anhedonia and anxiety, REM and increase motivation+libido but when next day I have terrible rebound effect- intensification my all symptoms to suicide level. This is similar substance to carbamazepine and benzos.
Probably my GIRK is too upregulated, maybe carbamazepine is strong GIRK antagonist and upregulation this.
Probably my GIRK is too upregulated, maybe carbamazepine is strong GIRK antagonist and upregulation this.
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