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Why is GABAergic withdrawal so debilitating?

cowardescent

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People say benzos/alcohol are one of the two worst drugs to withdraw from as they can kill and you have shitty side effects. Would it be more accurate to say GABAergic drugs (benzos, alcohol, barbituates, GHB, Z-drugs) can all cause horrendous symptoms if used extensively?

Why are they so bad? Many people who use strong opiates like heroin/morphine say that although the withdrawal is bad, it's 'superficial' and somewhat manageable (aches, shaky legs, depression). GABA withdrawal seems to permeate every aspect of someone (seizures, anxiety, depression, memory problems, skin sensitivity, aggression).

I've read somewhere that it may be because that GABA receptors are the most abundant throughout the human body compared to opioid receptors, cannabinoid receptors etc... This would mean that GABA drugs are very effective in slowing down the whole body for sleep, anxiety, etc.. but on the other hand, if someone withdraws, they'll experience much more side effects than if they were experiencing withdrawal of their cannabinoid receptors.
 
I'd imagine it's simply because GABA is an extremely fundamental and important neurotransmitter for basic function. They're all important obviously, but gabaergics particularly make your brain go haywire on withdrawal. Just my guess.

I'm so much more terrified of their withdrawal vs other drugs.

They alter a part of your brain that is more fundamental to basic function
 
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They alter a part of your brain that is more fundamental to basic function


Piggybacking off of this to sneak in some neuroscience, GABA is an ion channel responsible for the majority of inhibitory signaling in the brain.

There are two flavors of ion channel: ligand gated, and voltage gated. Logan's gated ion channels open when a log and binds to them, and voltage gated ion channels open at a threshold voltage (voltage in a cell being the sum charge of different ions). When they open ions will flow in or out, because your cell is always pumping them one way or another to store potential energy. When ion flow occurs the voltage of a cell will change (sodium ions flow inward and are positive so increase voltage, potassium ions are positive but flow out of the cell, so potassium channels tend to decrease voltage, and chloride ions are negative and enter the cell, so they decrease voltage). GABA receptors (specifically GABA A receptors) are ligand gated chloride channels that decrease the membrane potential in a cell. On the other hand glutamate receptors (AMPA and NMDA type receptors) are ligand gated sodium channels.




Ion channels work very quickly and are responsible for changing the membrane potential of a neuron (if it gets high enough, a positive feedback loop occurs due to voltage gated sodium channels opening at the threshold potential causing the cell to depolarize and release neurotransmitters onto other neurons).
Glutamate and GABA act reciprocally with GABA activity decreasing neuron firing rates and glutamate increasing them.

Now the other big receptor type in neuronal signaling (eat shit steroid hormone receptors and receptor tyrosine kinases!) is the g - protein coupled receptor (GPCR) class. This class includes many of the neurotransmitters you have probably heard of: dopamine, serotonin, and the opioid peptides. These function by binding a ligand and activating second messenger cascades in the cell. These second messenger cascades alter the phodphorylation state of proteins in the cell altering how they function (phosphorylation, the attachment of a phosphate group to a protein often acts like a switch turning on or off protein activity). These changes are slower than the voltage changes from ion channel signaling, but have a longer duration.

More fundamentally, gcprs do not replace the function of ligand gated ion channels as much as they modulate how they signal (think of turning an amplifier up or down or putting an effect like reverb or an echo on an instrument. The sound itself would be analogous to ion channel transmission and the effects would be analogous to gpcr transmission).

So now to get closer to an answer (sorry for being long winded).

There is a huge diversity of gpcrs in the brain (800 known genes for gpcrs in humans). This allows for specificity in tuning circuits which are mainly composed of glutamate and gaba connections.

Mu opioid receptors for example are involved in pain perception and reward circuits (and other things, but they are expressed specifically rather than like GABA receptors which are present generally across all circuits in the brain).

Drug withdrawal is due to the body's rotten tendency to reclaim homeostasis at all costs.
Opioids have a the withdrawal consisting of the inverse of effects produced from activating these circuits (soreness, depression, etc.)

Withdrawal from a GABAergic causes dysregualtion across the board, so rather than specific processes going wrong you get issues all across the brain leading to more generalized anxiety and seizures and all.
 
Withdrawal from a GABAergic causes dysregualtion across the board, so rather than specific processes going wrong you get issues all across the brain leading to more generalized anxiety and seizures and all.

Thank you for dropping a knowledge bomb :).

You explained why it's so much scarier than opioids.

I can horribly recall the worst benzo withdrawal of my life where I suddenly ceased after a very serious binge and I was both hallucinating, having a constant panic attack, and could not calm down for a horrible 2 days before it started subsiding.

It felt as if my entire body could not calm down - it did not have the ability to relax anymore. It almost felt like being electrocuted in some sense.... and the "body shocks" shooting thru you spine... horrible stuff.

opioid withdrawal is horrible, but it's just different and less visceral more psychological IMO
 
Thank you for dropping a knowledge bomb :).

You explained why it's so much scarier than opioids.

I can horribly recall the worst benzo withdrawal of my life where I suddenly ceased after a very serious binge and I was both hallucinating, having a constant panic attack, and could not calm down for a horrible 2 days before it started subsiding.

It felt as if my entire body could not calm down - it did not have the ability to relax anymore. It almost felt like being electrocuted in some sense.... and the "body shocks" shooting thru you spine... horrible stuff.

opioid withdrawal is horrible, but it's just different and less visceral more psychological IMO
this is exactly why i have to stop drinking.... i think i really should maybe treat it in same category as benzos. probably healthier to use opioids occasionally than alcohol..
 
Thank you for dropping a knowledge bomb :).

You explained why it's so much scarier than opioids.

I can horribly recall the worst benzo withdrawal of my life where I suddenly ceased after a very serious binge and I was both hallucinating, having a constant panic attack, and could not calm down for a horrible 2 days before it started subsiding.

It felt as if my entire body could not calm down - it did not have the ability to relax anymore. It almost felt like being electrocuted in some sense.... and the "body shocks" shooting thru you spine... horrible stuff.

opioid withdrawal is horrible, but it's just different and less visceral more psychological IMO

On the topic of opioid withdrawal, my opinion is that the physical withdrawal is overstated and people gloss over the cravings created and the sense that your body has developed a new thirst.

They are really effective at this because in the reward center of the brain (the central tegemental area) there are gaba releasing neurons that regulate dopamine release. These gaba neurons have mu opioid receptors which decrease their firing rate (mu opioid receptors actually open a potassium channel which directly decreases a cells membrane potential in tandem with decreasing protein phosphorylation).

Compared to drugs that function by increasing dopamine release or blocking released dopamines breakdown, opioids increase dopamine levels only in the specific circuit that meditates reward/motivation/error correction.

I guess anything that is addictive will work at the vta, it is just a question of how many steps does the process go through to activate it.
 
kind of interesting you guys compare the opioid withdrawal to GABAergic substances. imagine someone like me, having to deal with both of those. yikes!
must say, its probably not related to GABA but alcohol and benzos might be affecting the opioid receptors as well because without doing opiates ill still get similar opioid WD just from benzos and alcohol
 
I get the skin sensitivity symptom especially bad for whatever reason. I like to say it feels like someone flayed my entire body and even the very air around me hurts.
 
Would it be more accurate to say GABAergic drugs (benzos, alcohol, barbituates, GHB, Z-drugs) can all cause horrendous symptoms if used extensively?
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No. For those particular drugs, it might be but there are other GABAergics for which this is not the case such as kava, amanita muscaria and valerian for example.

The ease of coming off kava compared to the hell of withdrawing from opiates, destroys the argument that GABAergic withdrawal is inherently more severe. Heroin, fentanyl and methadone can all also cause "horrendous symptoms" if used extensively. I'd much rather withdraw from those than benzos because I believe benzos actually damage the brain (I never fully recovered from benzo withdrawal) but I wouldn't say coming off a long term high dose opioid habit is any walk in the park and I would disagree that it's more psychological than physical. For me, opiate withdrawal was very physical in the sense of having no energy to do anything and experiencing horrible hot and cold flashes that made me not want to move. During benzo withdrawal, which was overall worse like I said because of the sheer length and long term damage, I could at least move around more easily.
 
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No. For those particular drugs, it might be but there are other GABAergics for which this is not the case such as kava, amanita muscaria and valerian for example.

The ease of coming off kava compared to the hell of withdrawing from opiates, destroys the argument that GABAergic withdrawal is inherently more severe.

Is kava primarily GABAergic? Ditto that question with valarien root. There is literature on the two that suggests a handful of mechanisms of action, which implies the contribution of the GABA A receptors to the withdrawal is low.

Do amanita muscaria mushrooms not produce a withdrawal? I feel like the sample size of people staying loaded on muscimol for months of a time is pretty small.
 
Based on reports of people who took amanita daily for years there was no withdrawal, although you are correct it is a small sample size. I took them daily for a few months and never experienced any withdrawal. I don't know the detailed science of kava and valerian mechanism of action, only that they do affect GABA and subjectively they feel like GABAergics. If you drink some good kava, the feeling is notably similar to the feeling of drinking a few beers.
 
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using google, valerian has quite few severe cases of withdrawal. do you guys ever research shit before you talk??
 
Because the super-majority of inhibitory neurotransmitters in the nervous system consist of GABA.

LGIC activators take longer to develop a tolerance to, but also take longer than GPCRs to return to baseline after chronic use.
 
Because the super-majority of inhibitory neurotransmitters in the nervous system consist of GABA.

LGIC activators take longer to develop a tolerance to, but also take longer than GPCRs to return to baseline after chronic use.

thats insane. almost as if the body is a suicidal machine, moment you start picking at your GABAs. if you fuck up your GABA, you fuck up your whole body!
seriously, God hasnt created man any better or superior to any other creature on earth, for sure!!!

btw i personally can vouch for the GABA hell as I have been invalid for the past few years because of my benzo, alcohol and opioid addictions and abuse. I am a vegetable. I cannot function at all. I cannot work, or drive, sometimes even walking is difficult. I am a goner only because , for fuck sakes, God put GABA throughout your whole goddamn fucking nervous system goddamn it!!!!
 
bzd withdrawal worst experience of my life, hands down. beats ethanol even
 
Does Gabapentin have a good synergy with Clonazepam and Xanax? Thinking about trying this to see how I feel. I have back pain and anxiety and I just can't stand the feeling of neither....inputs would be great and thank ya guys.
 
bzd withdrawal worst experience of my life, hands down. beats ethanol even

were you ever addicted to alcohol? and do you have a legit experience withdrawing from alcohol to compare it?

imagine this; ive tried to quit both at the same time. it screwed my young little still developing brain, for life!
 
were you ever addicted to alcohol? and do you have a legit experience withdrawing from alcohol to compare it?

imagine this; ive tried to quit both at the same time. it screwed my young little still developing brain, for life!
yes, i absolutely do. I'm almost certain that the years of ethanol, intermittent bzd and phenibut use, along w various other gaba ligands is what finally did me in for the physical bzd experience. ethanol was definitely my DOC for many years, and by the time i quit it's because i would need to take bzds just to come down off ethanol. I now get DT's while still drinking ;( so it's a pretty easy choice not to. The only gabaA substance i will use anymore is amanita muscaria, which has been very healing. i am getting better now, finally, but it has really taken a year to feel ok. I've drank once in that time, over new years and it was only a few. I stopped immediately when the shakes/nastiness started. meditation, EMDR and TMS, and a lot of good trauma counseling plus staying the ef away from gaba drugs is what has brought me some peace/end of suffering.
 
GABA is one of the most prominent receptors in your brain, thats why. It affects a number of systems and pathways, so when you abuse things like alcohol or alprazolam, it really does a number on you when you try to quit/wean off.
 
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