Brainstorming group; all comments and suggestions welcome

[[Ar...]]

In trying to work out the cause of benzo withdrawal, so that I can quickly reverse it, I stumbled across some information which I believe is at the core of our conditions.

Benzodiazepines inhibit ATPD'ase, which removes a phosphate molecule from ATP so that aerobic energy production inside mitochondria can occur. https://pubmed.ncbi.nlm.nih.gov/10959491/ That removal turns the ATP into ADP which then has to pick up another phosphate molecule in order to turn back into ATP. So I think that benzodiazepines can result in excess levels of ATP and P2X7 receptors are ATP gated, resulting in their overactivation if we already have the inherited predisposition for it. https://www.nature.com/articles/s41467-017-00887-9

Maternal immune activation, likely resulting from overactivation of P2X7 receptors, during pregnancy induces a potential for this overactivation in the resulting offspring. This has been associated with a range of different diseases, including things like autism, schizophrenia, atherosclerosis, cancer, Parkinson's, overaggression, etc.

High levels of acetylcholine, resulting in excess cholinergic signaling, also seem to be able to activate P2X7 receptors. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3109033/   Of course both benzodiazepines and antidepressants are capable of resulting in increases in acetylcholine levels, so contributing to this P2X7 activation and overactivation in predisposed individuals.

[[Ar...]]

Potential natural inhibitors of P2X7 receptors, if my suppositions are correct about potential benefits, include emodin, zinc, and copper. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6268057/  https://pubmed.ncbi.nlm.nih.gov/18848528/ I recommend extreme caution regarding copper as it is a heavy (toxic) metal which is still essential for our bodies to function. To date I have used zinc myself with good results. Common foods containing emodin include rhubarb, aloe plants, and senna.

[[Ar...]]

I am going to cover a lot of points here so don't expect links for every detail. My goal is to try to present as much as I can regarding my reason for believing that the receptors are the base source of our withdrawal issues.

For all of the people who regard histamine as the trigger for aggravation of their withdrawal symptoms the purinergic P2X7 receptors induce mast cell degranulation and resulting release of histamine. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10855801/

ATP is the primary activator of P2X7. Its levels are raised by both stress and tissue damage. I experienced rhabdomyolysis (severe muscle damage) prior to treatment and subsequent psychological stress due to the resulting disability, fitting with this pattern. Because benzodiazepines inhibit ATPD'ase, responsible for removal of the phosphate molecule used in aerobic respiration, this leads to increasingly high levels of ATP in our bodies, fitting with overactivation of P2X7 receptors. Magnesium binds to ATP, as a chelator, and impedes this activation.

The body releases ATP and acetylcholine together so high levels of either will result in issues with both. Part of the reason for this is that nicotinic/acetylcholine activation indirectly inhibits ATP/P2X7 induced proinflammatory cytokines so reducing, but not preventing, the withdrawal symptoms. The benzodiazepines have known interaction with both purines and vitamin B3 so appears to affect all of the factors . https://www.science.org/doi/10.1126/science.6101294

P2X7 activation reduces GABA and glutamate transport. https://www.researchgate.net/publication/281227203_P2X7_receptor_activation_downmodulates_Na-dependent_high-affinity_GABA_and_glutamate_transport_into_rat_brain_cortex_synaptosomes So it's likely not just the benzodiazepine activation of GABA which we crave in withdrawal but also potentially the GABA itself.

I have likely missed a number of points which have influenced my thoughts in this and certainly still have a lot more to learn.

 

[[Al...]]

On 12/10/2024 at 09:25, [[A...] said:

Of course both benzodiazepines and antidepressants are capable of resulting in increases in acetylcholine levels, so contributing to this P2X7 activation and overactivation in predisposed individuals.

Apologies if I'm getting confused, but aren't benzos thought to decrease acetylcholine levels rather than raise them?

 

"Klonopin (clonazepam) is a benzodiazepine that works by enhancing the activity of gamma-aminobutyric acid (GABA), an inhibitory neurotransmitter in the brain. While its primary mechanism involves GABA, there is an indirect connection between benzodiazepines like Klonopin and the acetylcholine system.

Here's how Klonopin may affect acetylcholine:

1. Indirect Suppression of Acetylcholine Release: GABA inhibits the release of various neurotransmitters, including acetylcholine (ACh). By enhancing GABA's effect, Klonopin can indirectly reduce acetylcholine activity, especially in regions of the brain such as the hippocampus and cortex. This can affect cognitive functions like memory, attention, and learning, where acetylcholine plays a major role.

2. Anticholinergic-like Effects: Although Klonopin is not a traditional anticholinergic drug, its indirect suppression of acetylcholine can sometimes result in side effects similar to those seen with anticholinergic medications. These include dry mouth, blurred vision, cognitive impairment, and sometimes urinary issues.

3. Cognitive Impact: Acetylcholine is important for memory and cognitive function. The reduction in acetylcholine activity due to Klonopin’s influence on GABA can contribute to the cognitive side effects often reported with long-term benzodiazepine use, such as memory problems or difficulty concentrating.

In summary, Klonopin may indirectly lower acetylcholine activity through its action on GABA, potentially leading to cognitive side effects and other symptoms typically associated with reduced acetylcholine function. However, the effect is more secondary to its primary role in modulating GABA."

 

[[Ar...]]

13 minutes ago, [[A...] said:

Apologies if I'm getting confused, but aren't benzos thought to decrease acetylcholine levels rather than raise them?

"Klonopin (clonazepam) is a benzodiazepine that works by enhancing the activity of gamma-aminobutyric acid (GABA), an inhibitory neurotransmitter in the brain. While its primary mechanism involves GABA, there is an indirect connection between benzodiazepines like Klonopin and the acetylcholine system.

Here's how Klonopin may affect acetylcholine:

1. Indirect Suppression of Acetylcholine Release: GABA inhibits the release of various neurotransmitters, including acetylcholine (ACh). By enhancing GABA's effect, Klonopin can indirectly reduce acetylcholine activity, especially in regions of the brain such as the hippocampus and cortex. This can affect cognitive functions like memory, attention, and learning, where acetylcholine plays a major role.

2. Anticholinergic-like Effects: Although Klonopin is not a traditional anticholinergic drug, its indirect suppression of acetylcholine can sometimes result in side effects similar to those seen with anticholinergic medications. These include dry mouth, blurred vision, cognitive impairment, and sometimes urinary issues.

3. Cognitive Impact: Acetylcholine is important for memory and cognitive function. The reduction in acetylcholine activity due to Klonopin’s influence on GABA can contribute to the cognitive side effects often reported with long-term benzodiazepine use, such as memory problems or difficulty concentrating.

In summary, Klonopin may indirectly lower acetylcholine activity through its action on GABA, potentially leading to cognitive side effects and other symptoms typically associated with reduced acetylcholine function. However, the effect is more secondary to its primary role in modulating GABA."

I admit that I am still working out how all of the pieces of this puzzle fit together, so started this thread in the hopes of drawing the attention of people who also want to know how this fits together so that we can fix it.

The statement you challenge I was a generalization as various antidepressants and benzodiazepines can have very different effects which aren't yet always predictable. Newer 1,5 benzodiazepines inhibit acetylcholinesterase activity and the breakdown of acetylcholine, so potentially effectively raising levels during treatment. https://pubmed.ncbi.nlm.nih.gov/10959491/ You are correct about GABA-A receptor activation by benzodiazepines possibly resulting in reduced release of acetylcholine during treatment however the picture is much more complicated. There seems to be contention over whether GABA and acetylcholine are co-released or co-transmitted. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4371381/   https://www.nature.com/articles/s41467-018-05136-1   Either way there seems to be an intimate relationship between their activity. This implies the likelihood that a downregulation of acetylcholine is likely to also result in a downregulation of GABA. So it seems to be a feedback loop leading to rises and falls in the levels together. While the benzodiazepine reduction of acetylcholine which you describe may reduce levels during treatment this doesn't apply to the period following treatment. Once the treatment has ceased the GABA-A receptors can be dependent for function on the benzodiazepines, leading to excessive release of both GABA and acetylcholine as the body tries to trigger the signaling again. https://www.genesispub.org/restoration-of-gabaa-receptor-function-after-benzodiazepine-use-a-meta-analysis

So the connection between this and the P2X7 receptors is that glutathione triggers the release of GABA. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5305167/  Hence overactivation of P2X7 receptors is likely to add to issues with levels of both GABA and acetylcholine in the environment of GABA-A receptor inactivation post-benzodiazepines. I also notice that GABA-A receptors, similar to P2X7 ATP dependency, are dependent upon ATP binding for regulation of chloride. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7867123/ This fits with P2X7 use of chloride in inducing inflammation.

[[Ch...]]

Excited by this thread, for what I can follow along with this theory is great. 
 

the more questions that can be asked the better. 

[[Ar...]]

Charlie1 has privately posed me some questions which I would like to answer here now that I have had time to process them.

Firstly he raised the question of setbacks in withdrawal caused by people taking certain supplements or eating certain foods and how my suggestions for things to help P2X7, such as zinc, could cause some people to experience such setbacks. The answers to this still elude me. I haven't yet had an opportunity to find or put together a comprehensive list of all of the things which have caused people setbacks. What I have found so far is that some of the things which cause setbacks do so by affecting pathways relating to GABA-A receptors and P2X7. The primary one's which I am aware of include pathways like cholinergic signaling, purinergic signaling, adenosine/ATP levels, and glutamatergic signaling. Once we have a list of the foods and supplements which induce setbacks then they can be correlated with each specific pathway so that we can understand how they affect our withdrawal. Caffeine is an example of one of the things which affect some people badly which directly affect the P2X7 receptors, activating them and likely triggering release of both GABA and acetylcholine. Not only does this influence cholinergic signaling but a purine alkaloid, 3,7-dihydro-1,3,7-trimethyl-1H-purine-2,6-dione, in it likely also affects purinergic signaling through the P2X7 receptors. Zinc is another example of this kind of thing, blocking P2X7 receptors, activating acetylcholine receptors, affecting acetycholine metabolism, and affecting adenosine levels while slowing ATP (adenosine triphosphate) clearance which gates the P2X7 receptors. https://www.nature.com/articles/s42003-018-0118-3

Regarding Charlie1's question about the likely cause of withdrawal induced derealization/depersonalization I point to the dissociation which occurs in schizophrenia which also involves overactivation of the P2X7 receptors. I don't yet understand the process by which this occurs but believe that the same basic factors are likely to be involved. Regarding the gastrointestinal issues involved in withdrawal, P2X7 indirectly affects gastrointestinal motility, the intestinal lining, and the health of the microbiome itself. https://www.mdpi.com/1422-0067/25/20/10874