Can anyone make sense of this to explain to a layperson?

September 29, 2018

Hi dm123,

Thank you again for your ongoing work, explanations and bringing such solid science into this area that feels so much like shifting sands— benzo recovery.

I wonder what you think of the possibility addressed by NAD? I have spoken to several clinics, one of which seems to be realistic about benzo w/d.

They offer a nasal spray to ingest the supplement and state that it helps cells regenerate.

I apologize if this is beyond what you want to offer on this thread.

Perhaps it’s best addressed in a pm. Let me know and I will do so.

Thank you again for your ongoing generosity to all of us here.....

SS

September 29, 2018

Hi brainy science people.

I am not up to reading this whole thread atm.

Has this paper been covered

https://www.sciencedirect.com/science/article/pii/S0306987718303645

It references another paper about ME/CFS patients already being kindled. Hence Benzos helping ME symptoms

http://file.scirp.org/Html/3-2400020_4275.htm

All of this is far beyond anything I am going to be able to get my head around any time soon.

Can somebody let me know if that basically means that I am unlikely to be able to recover from benzo withdrawal because my brain was already sensitised due to pre-existing ME/CFS.

I am very concerned I am causing irreparable damage and that it might be better for me to go back on the diazepam and try to get some Memantine to stave off withdrawal and interdose withdrawal as several people with ME I have spoken to have had to.

October 1, 2018

Hi brainy science people.

I am not up to reading this whole thread atm.

Has this paper been covered

https://www.sciencedirect.com/science/article/pii/S0306987718303645

It references another paper about ME/CFS patients already being kindled. Hence Benzos helping ME symptoms

http://file.scirp.org/Html/3-2400020_4275.htm

All of this is far beyond anything I am going to be able to get my head around any time soon.

Can somebody let me know if that basically means that I am unlikely to be able to recover from benzo withdrawal because my brain was already sensitised due to pre-existing ME/CFS.

I am very concerned I am causing irreparable damage and that it might be better for me to go back on the diazepam and try to get some Memantine to stave off withdrawal and interdose withdrawal as several people with ME I have spoken to have had to.

Hi Ajusta,

From your signature, are you still on diazepam? It states 2mg.

There’s no irreparable damage being done. Your symptoms are due to a massive lack of homeostatic balance in your nervous system. I know it feels like permanent damage, but it can be undone. Neurons are not dying off. Neurons and circuits are adaptable and it is very very rare for circuits to get “cooked”. I don’t know much about memantine, other than the stuff on the internet that you already are aware of. Ketamine is also another alternative but i suggest it only be administered in a medical setting. Both of these drugs require medical supervision.

Regarding the two links you provided, I have several thoughts on them,, some of which have already been covered in this thread.

===========

The first link. MAB (Miss Atomic Bomb) provided me with the full citation several months ago.

https://www.sciencedirect.com/science/article/pii/S0306987718303645

Regarding the first link for the NO/ONOO- benzo hypothesis (LaCorte), this has been incorporated into the Benzodiazaphine model in this thread, pages 53-56. This was done several months back. The table of contents to the thread is in my signature. Most of the material will need to be hyperlinked and collected into a cohesive document at some point. I know it’s nearly impossible to follow, but there’s nothing we can do about that right now.

This NO/ONOO- cycle dynamic is a small part of the benzdiazaphine model presented in this thread. (It is pillar #4 (of 6 total) and component system #4 (of 4 total) of the model in this thread).

It’s related to cellular mitochondrial dysfunction and oxidative stress, and is perpetuated by several feedback loops that are instigated by “dysfunctional” calcium channel homeostasis.

-If you would like to learn more about the NO/ONOO- cycle there are some great you tube videos by Dr. Pall. Just search for “Pall NO/ONOO”. I think you are already aware of his work, as you are a CFS survivor.

-If you would like to understand how the LaCorte paper ties into Benzodiazaphine PWS, I summarize the article on those pages 53-56 (mentioned above) of this thread.

-This is a great article on the NO/ONOO- and CFS by Dr. Pall. I know you already know about this as a CFS survivor.

http://www.townsendletter.com/FebMarch2010/cureNO0210.html

============

The second link: I just read. I most definitely think that the symptom overlap of classical CFS and Benzodiazaphine PWS can, in some patients be traced back to a common etiology of neuro-kindling. When I was fully kindled I thought I had developed CFS. It’s a horrible feeling. However, unlike CFS, benzdiazaphine induced kindling is not due to viruses, cytokines, etc as mentioned in the second link. It’s primarily due to chronic day in and day out, nonsteady state dosing of short acting benzos. This can in turn affect cytokines, neurotransmitter levels, and gene expression of the GABAaR and other receptors. A lot of people think they are kindled when they go into tolerance, but these two states are not the same. I think the majority of BBs are in tolerance and that is why they come to BB to get off the benzo.

It’s very interesting that negative stress and poor stress resiliency are common in both PWS and CFS, and I think this is due, in part to the commonality of hyperexcitability and neuro-kindling in both PWS and CFS. I know that RST (a BB) has been experiencing a lot of this, and i have , in the past. Also the stress system is one of the basic pillars in this benzo model on this thread. Dysfunction in the stress system forms part of the feedback loops that perpetuate PWS.

However, if you read this second link, there are clear differences between the etiology of CFS kindling (which the citation explains) and benzdiazaphine kindling (which the article does not get into). Perhaps the two are linked by the NO/ONOO- cycle dysfunctions as explained in the first link (LaCorte). In some cases of benzdiazaphine PWS this is true, however not all cases of PWS have ON/ONOO- dysfunction. Neuro-kindling from benzos can happen independently from ON/ONOO- dysfunction. I never had ON/ONOO- dysfunction, but i was kindled.

I have pulled some interesting quotes from the article below for those who can’t or do not want to read the whole citation. I hope this helps a bit.

http://file.scirp.org/Html/3-2400020_4275.htm

Benzos….uuughhh!! This happens all the time. Treat a Patient with CFS using benzos, which over time “unknowingly “ create many many more issues, symptoms and complications There’s no doubt that if there is neuro-kindling at the root of CFS symptoms, that benzos will help in the short run. In the long run, one accumulates more symptoms from the chronic benzo use that are not necessarily due to the underlying CFS illness. This is a tragedy, but the good news is that getting off the benzo will help resolve the benzo related symptoms.

Quote

Brain Baraniuk et al. (2005) believes that neural circuits running from the spinal cord to the brainstem are not working properly [59]. In patients with ME/CFS, gates are not filtering out unnecessary information, and the most critical neural circuit, the Papez Circuit, which ties together the anterior cingulate, amygdala and hippocampus, is associated with heightened awareness [60]. The drug Klonopin often helps patients with ME/CFS because it slows down the over activity of the brain by increasing production of GABA, a central nervous system inhibitory neurotransmitter, thereby reducing the ‘set point’ at which it’s neurons are activated.

de Lange et al. (2005) observed significant reductions in grey matter volume in patients with ME/CFS, and this might be due to oxidative stress caused by kindling [61,62]. Biswal, Kunwar, and Natelson (2010) found sig-nificant cerebral blood flow reductions in patients with ME/CFS in nearly every region of the brain assessed [63]. It is critical to attempt to identify where damage has occurred. Magnetic resonance (MR) studies of encephalopathy and encephalomyelitis associated with acute Epstein-Barr Virus (EBV) infection have found T2 prolongation over gray and white matter, brain atrophy, and periventricular leukomalacia [64]. A MR study examining a pediatric population of patients suffering from chronic EBV infection has shown evidence for the presence of lesions in the hippocampal region [65].

End quote

……

GHB = xyrem …..uuugghhhh!! Very short acting and addictive Please avoid this drug.

Quote

Sodium oxybate (Xyrem) has been used for narcolepsy, as it greatly enhances deep level sleep, and Spitzer and Broadman report that 59% of ME/CFS and FM patients who tried this medication reported substantial relief of pain, and 75% had significant reduction of fatigue [78]. Moldofsky, Inhaber, Guinta, and Alvarez-Horine (2010) also found improved EEG sleep physiology and sleep-related FM symptoms after treatment with Xyrem [79].

End quote

…….

Histamine. Very interesting . Low dose remeron is the most powerful histamine antagonist known. Perhaps this is why it helps some through benzo withdrawal and detox.. See below, for histaminergic relation to kindling.

Quote

Also of interest is that stress can trigger mast cells, which are heavily populated in the thalamus (that is located next to the sleep/wake center in the hypothalamus), to release the stimulant histamine. Excessive mast cells and their release of stimulants could be one of the reasons that sleep is interrupted in patients with ME/CFS and FM. Mast cells act as an immunologic defense against external pathogens, and they are five to 14 fold increases of these cells in the top layer of the skin in 100% of FM patients [80]. Kindling might impact mast cells and the release of histamine in the thalamus, resulting in disrupted sleep patterns among patients with ME/CFS.

End quote

…….

Cytokines: TNF-α is a potent neuromodulator. I will be mentioning this in the layman’s thread very briefly as part of pillar #6 (immune system) of the model, in the neural circuits part 3, which isn’t posted yet. I’m bringing it up here because this citation implicates it in kindling. They mention it in relation to its CRH stimulating properties, but I would go one step further and note that it’s involved in circuit wide neuromodulation which is one of the many mechanisms behind homeostatic plasticity. I will go over this briefly in part 3. The link #2 was published way back in 2011, and perhaps they did not quite understand the neuromodulatory effect of TNFα back then….. Relative to neuroscience and Neuroplasticity, even 2011 is a bit “old”.

Quote

In animal models, kindling and related seizure activity is associated with production of pro-inflammatory proteins within the brain [82]. For example, the admi-nistration of pro-inflammatory cytokine tumor necrosis factor alpha (TNF-α) increases seizure activity in animals [83]. TNF-α is a cytokine involved in systemic inflammation, and it stimulates the release of CRH, therefore stimulating the HPA axis. Among patients with ME/CFS, the production of pro-inflammatory cytokines (IL-1β and IL-6) is correlated with acute sickness behavior (i.e., fever, malaise, pain, fatigue, and poor concentration). As mentioned earlier, prolonged exposure to these cytokines might induce a state of chronic activation and kindling [84]. Individuals who have higher levels of these pro-inflammatory cytokines might be at greater risk of developing ME/CFS. In support of this proposition, Voll-mer-Conna et al. (2008) found that severe illness following an infection was more likely to occur among individuals with high levels of IFN-γ (a pro-inflammatory cytokine) and low levels of IL-10 (an anti-inflammatory cytokine) [85]. In addition, elevated levels of pro-inflammatory cytokines can lead to increases in levels of nitric oxide, and this nitric oxide can, in turn, react with superoxide to form the powerful oxidant peroxynitrite, resulting in oxidative stress. Some investigators, however, have not been able to find increased levels of nitric oxide in patients with ME/CFS [86].

End quote

……..

Interesting observations regarding GABAR, NMDAR balance and you guessed it….inescapable prolonged negative stressors. Negative stressors play an important part in the benzdiazaphine model of this thread. Also interesting notes on adenosine levels and inhibition of the histaminergic system. (RST please note, even though you already know this).

Quote

Two receptors residing on the cell surface membranes of neurons are GABA (gamma aminobutyric acid), which inhibits neuronal firing, and NMDA (N-methyl-D-aspartate), which excites neuronal firing. The GABA and NMDA receptors are normally balanced, but after an injury or viral attack, NMDA fires more rapidly than GABA, increasing neuronal firing. Minor and Hunter (2002) have proposed that prolonged exposure to inescapable stressors will eventually deplete GABA, thus reducing an important form of inhibition on excitatory glutamate transmission [87]. Doi, Ueda, Nagatomo, and Willmore (2009) found that rats with diminished GABA functioning were more likely to develop kindling [88]. Winkelman et al. (2008) have found that brain GABA levels were nearly 30% lower in patients with primary insomnia [89]. Recent findings indicate that glial cells or astrocytes (glial cells in the spine or brain) produce adenosine, an inhibitory neurotransmitter that promotes sleep and suppresses arousal, which appears to be implicated in controlling wake to sleep transitions [90]. High adenosine levels can even suppress epileptic seizures, and in rats the adenosine A(2A) receptor (A(2A)R) agonist induces sleep by inhibiting the histaminergic system, an integral part of the immune system, through increasing GABA release [91]. It is also possible that kindling could result in low levels of adenosine over time, causing the development of sleep difficulties, although adenosine is only one of many substances that promotes sleep

End quote

……..

Exercise intolerance (RST please note). This is very common. It can even occur in tolerance with no kindling, as there is an imbalance in the excitatory and inhibitory signaling. I can relate to this one.

Quote

Light et al. (2009) maintain that exercise could send a continuous signal of muscle sensory fatigue to the central sympathetic nervous system causing dysregulation of sympathetic nervous system reflexes, and ultimately producing the recognition of enhanced fatigue [101]. Light et al. found patients with ME/CFS demonstrated increases after exercise that reliably exceeded responses of control subjects in mRNA for genes receptors that can detect muscle produced metabolites, genes that are essential for sympathetic nervous system processes, and immune function genes. About 90% of the ME/CFS patients could be distinguished from control subjects using just 4 of the genes measured (i.e., P2X4, adrenergic b-1, adrenergic b-2, IL-10). The researchers concluded that ME/ CFS patients might have enhanced sensory signal for fatigue that is increased after exercise [101]. These findings all indicate persistent changes in cell membrane function, which are compatible with kindling theory that maintains that excessive arousal can lead to an increase in the dendrites of the limbic system, with an increase in excitatory postsynaptic receptors and a decrease in inhibitory presynaptic receptors.

Kindling is an explanation for what might occur when patients with ME/CFS overexert themselves and deplete energy reserves. The kindling hypothesis suggests that once this system is charged, either by high-intensity stimulation or by chronically repeated low-intensity stimulation, activities that involve going beyond energy reserves might enhance an already high level of arousal. In a sense, patients with ME/CFS might have this type of cortical excitability that might be due to kindling, and then when they go beyond their energy reserves, the kindling produces high arousal that has implications for the hypothalamus, the autonomic nervous system, as well as the immune system

End quote

October 1, 2018

Hi dm123,
Thank you again for your ongoing work, explanations and bringing such solid science into this area that feels so much like shifting sands— benzo recovery.

I wonder what you think of the possibility addressed by NAD? I have spoken to several clinics, one of which seems to be realistic about benzo w/d.
They offer a nasal spray to ingest the supplement and state that it helps cells regenerate.
I apologize if this is beyond what you want to offer on this thread.
Perhaps it’s best addressed in a pm. Let me know and I will do so.
Thank you again for your ongoing generosity to all of us here.....
SS

Hi SS,

I do understand NAD. I even took the oral form a long time back, before the taper. I don’t know much up the IV therapeutic protocols involving NAD. I know RST has researched this quite a bit, and i hope he pops in on this thread to offer his insight on this. I will send him a PM and ask him if he can share with the group on this specific therapy.

Regarding my experience with the oral form, i got a tremendous headache the few times that i took it. I did not use it more than a few times. It was a supplement oral form.

October 1, 2018

Hi dm123,
Thank you again for your ongoing work, explanations and bringing such solid science into this area that feels so much like shifting sands— benzo recovery.

I wonder what you think of the possibility addressed by NAD? I have spoken to several clinics, one of which seems to be realistic about benzo w/d.
They offer a nasal spray to ingest the supplement and state that it helps cells regenerate.
I apologize if this is beyond what you want to offer on this thread.
Perhaps it’s best addressed in a pm. Let me know and I will do so.
Thank you again for your ongoing generosity to all of us here.....
SS

Hi SS,

I do understand NAD. I even took the oral form a long time back, before the taper. I don’t know much up the IV therapeutic protocols involving NAD. I know RST has researched this quite a bit, and i hope he pops in on this thread to offer his insight on this. I will send him a PM and ask him if he can share with the group on this specific therapy.

Regarding my experience with the oral form, i got a tremendous headache the few times that i took it. I did not use it more than a few times. It was a supplement oral form.

Thanks for this reply dm123. I have been in touch with RST about a couple of clinics we had both researched.

I’ve just ordered a nasal spray from a clinic to see how I might tolerate the supplement at all.

So far no supplement has been helpful but I do keep trying to see if there could be something to help even a bit.

At least the researching and reading your thorough information keeps me occupied!

🙏🏻🙏🏻

SS

October 1, 2018

Thanks dm123 for that last explanation!
It all makes sense.
I'm not planning to speed up my taper- mostly trying to figure out when/if to go slower.
I never plan to take any benzo again after this taper. Or alcohol. Or z drug. Or Magnesium supp.

Can we talk a little more about negative stressors? Do you mean external life stress? How do you all handle this?? It does make sense to keep stress down even after completing taper esp in the beginning (and always of course). But you also mentioned stress resiliency increasing. Can you talk a little more about these things? And how it relates to PAWS. Like do we get resilient enough at some point that there is no PAWS- is that when ppl say they are healed?

Hi Libr,

Me either. No alchohold or benzos. I am not anti-drug, but those are a class of drugs that i can never go back on. Once kindled, you have to be careful. The brain is plastic in every sense of the word, it it has a “memory” of its plasticity itself. We no longer have the freedom to push our accommodative neuroadaptive processses.

Regarding negative stressors, i posted several long detailed papers on this (and they were not too science overloaded either). I hope you can find them in this tangled laymans thread. They are somewhere in between pages 1-40 in the signature table of contents below my name, ie they were part of the introductory and foundational material. One of the papers was very very to the point and gave some good takeaways on how to manage negative stressors and help the body gain resiliency.

I will have to index this thread at some point, but i don’t see that happening any time soon.

Negative stressors in the scientific literatuer are unpredictable, constant and unremitting, and uncontrollable by the person subjected to the stress. This last point is very important. When we cannot stop the stressor all sorts of ‘fear loops’ are created in the limbic (emotional) and amygdala areas of the brain. CRH which is a neuropeptide and neuromodulator of cortisol, gets way out of wack. Cortisol itself has neuromodulatory properties. A chain of events is set in motion when we experience long term negative stressors, and reinforcing feedback loops are set in place, so that even when the negative stressor is removed, we still experience neuro dysfunction. Plastic changes occur to the brain when under any type of stress, negative or positive, but the plastic changes that occur during negative stress or detrimental to normal physiological function.

THe literature refers to “environmental enrichment” which you can google. When test subjects are put in environments that are enriched, they tend to recover from the adverse effects of prolonged negative stressors. Their stress resiliency, ie their ability to handle stress slowly returns. Environments that are enriched have several characteristics. I listed them in that original paper, and i remember a few of them off hand. Spacious living was one of them . Predictability was another. Also naviagation exercises. The hippocampus seems to take a lot of the brunt of negative stress and all these things that help recovery in the enriched environment help the hippocampus recover. By recover i mean plastically readapt to it’s original state prior to the negative stressors. The hippocampus is one of the most plastic regions of the brain, hence this is why it is hit so hard by these negative stressors.

How to do this in real life? It’s very very difficult. The society today is running at 1000%. There’s social media, there’s political turmoil and there’s instantaneous negative news constantly being spewed out on the internet and TV. Psychosocial stress is one of the most potent forms of negative stress. This means arguing with people, relationship stress, etc. I don’t know how to remove all negative stress realistically, but i do think that those that cannot remove it to some degree have a more difficult time recovering from benzo wd.

Yes, when you are healed and out of PWS you will be more stress resilient. Handling negative (and even positive stressors like exercise) goes hand in hand with recovery. This is why stress resiliency becomes so decompensated during wd and PWS. Stress resiliency is the cornerstone of a healthy nervous systems, and PWS and wd adversely affect our nervous system. So the relationship is quite direct.

I hope this helps and i hope you can find that original paper in this thread.

Best

Dm123

PS sorry for typos once again. I typed this out very quickly.

October 1, 2018

Hi dm123,
Thank you again for your ongoing work, explanations and bringing such solid science into this area that feels so much like shifting sands— benzo recovery.

I wonder what you think of the possibility addressed by NAD? I have spoken to several clinics, one of which seems to be realistic about benzo w/d.
They offer a nasal spray to ingest the supplement and state that it helps cells regenerate.
I apologize if this is beyond what you want to offer on this thread.
Perhaps it’s best addressed in a pm. Let me know and I will do so.
Thank you again for your ongoing generosity to all of us here.....
SS

Hi SS,

I do understand NAD. I even took the oral form a long time back, before the taper. I don’t know much up the IV therapeutic protocols involving NAD. I know RST has researched this quite a bit, and i hope he pops in on this thread to offer his insight on this. I will send him a PM and ask him if he can share with the group on this specific therapy.

Regarding my experience with the oral form, i got a tremendous headache the few times that i took it. I did not use it more than a few times. It was a supplement oral form.

Thanks for this reply dm123. I have been in touch with RST about a couple of clinics we had both researched.
I’ve just ordered a nasal spray from a clinic to see how I might tolerate the supplement at all.
So far no supplement has been helpful but I do keep trying to see if there could be something to help even a bit.
At least the researching and reading your thorough information keeps me occupied!
🙏🏻🙏🏻
SS

Hi SS,

Can you let us know how it goes, over the long term? That would be great for others who are considering this therapy for their wd and PWS.

Best

Dm123

October 1, 2018

Hi dm123,
Thank you again for your ongoing work, explanations and bringing such solid science into this area that feels so much like shifting sands— benzo recovery.

I wonder what you think of the possibility addressed by NAD? I have spoken to several clinics, one of which seems to be realistic about benzo w/d.
They offer a nasal spray to ingest the supplement and state that it helps cells regenerate.
I apologize if this is beyond what you want to offer on this thread.
Perhaps it’s best addressed in a pm. Let me know and I will do so.
Thank you again for your ongoing generosity to all of us here.....
SS

Hi SS,

I do understand NAD. I even took the oral form a long time back, before the taper. I don’t know much up the IV therapeutic protocols involving NAD. I know RST has researched this quite a bit, and i hope he pops in on this thread to offer his insight on this. I will send him a PM and ask him if he can share with the group on this specific therapy.

Regarding my experience with the oral form, i got a tremendous headache the few times that i took it. I did not use it more than a few times. It was a supplement oral form.

Thanks for this reply dm123. I have been in touch with RST about a couple of clinics we had both researched.
I’ve just ordered a nasal spray from a clinic to see how I might tolerate the supplement at all.
So far no supplement has been helpful but I do keep trying to see if there could be something to help even a bit.
At least the researching and reading your thorough information keeps me occupied!
🙏🏻🙏🏻
SS

Hi SS,

Can you let us know how it goes, over the long term? That would be great for others who are considering this therapy for their wd and PWS.

Best
Dm123

Absolutely! I’m hoping that this can be helpful to many.... and the doc providing the information seemed realistic, it would probably help with a continued slow taper. Some other NAD providers appear inexperienced with benzo w/d. Quite scary actually what they recommended: CT and the IV therapy.

🤞🏻🤞🏻

🙏🏻

SS

October 2, 2018

dm123,

Perhaps you like a bit more work ... http://www.benzobuddies.org/forum/index.php?topic=210773.0

October 2, 2018

A bit of a new but probably stupid idea ... switch to diazepam and take a drug for those motor cortex pathways ... AC, AD, AP, whatever ...

The latter would affect GCPRs etc. It's a bit in addition to that PM about 'connectivity'. Wouldn't really matter if I were healthy ... Circuit level etc. K is a non-benzo benzo.

Probably just nonsense ...

October 2, 2018

Thank you so much for you explanation of the Benzo/MECFS stuff!

Very helpful.

October 3, 2018

I lost this thread for a while. Have so many probs finding stuff on BB... probably my faulty brain!

Anyhow wondered about hydroxizyne possibly for sleep, or l theanine. I have to try get to detist tomorrow as very iffy tooth. In fact, wonder if it is a benzo thing. It is just one tooth and a corner had broken off (no pain), dentist bonded on corner. That was ok. Then it was ground down and temp crown put on. That was ok. Then crown and all hell brokoe loose== even hurt under anesthesia.

Had that ground down (he can't remove) and temp put bak on. Endodontist found nothing wrong... it aches sometimes or feels not good but no sensitivity to hot/cold/pressure.

Need to go bck to endodontist for another look... hope i make it. I am not muh able to do anything... in bed now. Also forgive keyoard, it is not good (stupid Acer computer). Any thought on could this be benzo related? Am not up to root canal or anything right now. If it is bad wonder if they can just pull it.

Meanwhile am wondering if people here are neuroscientists or what? Dm? I sure cannot follow this.

Thank you.

BTW, guess am bsck on valium... was not eatin gmuch and think maybe it ok now if I eat. Guess that preferable to clonopin and all the switches in brands there. Think clonopin may be better for sleep, but more skeletal pain stuff and heart stuff. ut for one or two days felt essentially 'normal.'

thx.

October 3, 2018

Hi brainy science people.

I am not up to reading this whole thread atm.

Has this paper been covered

https://www.sciencedirect.com/science/article/pii/S0306987718303645

It references another paper about ME/CFS patients already being kindled. Hence Benzos helping ME symptoms

http://file.scirp.org/Html/3-2400020_4275.htm

All of this is far beyond anything I am going to be able to get my head around any time soon.

Can somebody let me know if that basically means that I am unlikely to be able to recover from benzo withdrawal because my brain was already sensitised due to pre-existing ME/CFS.

I am very concerned I am causing irreparable damage and that it might be better for me to go back on the diazepam and try to get some Memantine to stave off withdrawal and interdose withdrawal as several people with ME I have spoken to have had to.

Hi Ajusta,

From your signature, are you still on diazepam? It states 2mg.

There’s no irreparable damage being done. Your symptoms are due to a massive lack of homeostatic balance in your nervous system. I know it feels like permanent damage, but it can be undone. Neurons are not dying off. Neurons and circuits are adaptable and it is very very rare for circuits to get “cooked”. I don’t know much about memantine, other than the stuff on the internet that you already are aware of. Ketamine is also another alternative but i suggest it only be administered in a medical setting. Both of these drugs require medical supervision.

Regarding the two links you provided, I have several thoughts on them,, some of which have already been covered in this thread.

===========
The first link. MAB (Miss Atomic Bomb) provided me with the full citation several months ago.

https://www.sciencedirect.com/science/article/pii/S0306987718303645

Regarding the first link for the NO/ONOO- benzo hypothesis (LaCorte), this has been incorporated into the Benzodiazaphine model in this thread, pages 53-56. This was done several months back. The table of contents to the thread is in my signature. Most of the material will need to be hyperlinked and collected into a cohesive document at some point. I know it’s nearly impossible to follow, but there’s nothing we can do about that right now.

This NO/ONOO- cycle dynamic is a small part of the benzdiazaphine model presented in this thread. (It is pillar #4 (of 6 total) and component system #4 (of 4 total) of the model in this thread).

It’s related to cellular mitochondrial dysfunction and oxidative stress, and is perpetuated by several feedback loops that are instigated by “dysfunctional” calcium channel homeostasis.

-If you would like to learn more about the NO/ONOO- cycle there are some great you tube videos by Dr. Pall. Just search for “Pall NO/ONOO”. I think you are already aware of his work, as you are a CFS survivor.

-If you would like to understand how the LaCorte paper ties into Benzodiazaphine PWS, I summarize the article on those pages 53-56 (mentioned above) of this thread.

-This is a great article on the NO/ONOO- and CFS by Dr. Pall. I know you already know about this as a CFS survivor.
http://www.townsendletter.com/FebMarch2010/cureNO0210.html

============

The second link: I just read. I most definitely think that the symptom overlap of classical CFS and Benzodiazaphine PWS can, in some patients be traced back to a common etiology of neuro-kindling. When I was fully kindled I thought I had developed CFS. It’s a horrible feeling. However, unlike CFS, benzdiazaphine induced kindling is not due to viruses, cytokines, etc as mentioned in the second link. It’s primarily due to chronic day in and day out, nonsteady state dosing of short acting benzos. This can in turn affect cytokines, neurotransmitter levels, and gene expression of the GABAaR and other receptors. A lot of people think they are kindled when they go into tolerance, but these two states are not the same. I think the majority of BBs are in tolerance and that is why they come to BB to get off the benzo.

It’s very interesting that negative stress and poor stress resiliency are common in both PWS and CFS, and I think this is due, in part to the commonality of hyperexcitability and neuro-kindling in both PWS and CFS. I know that RST (a BB) has been experiencing a lot of this, and i have , in the past. Also the stress system is one of the basic pillars in this benzo model on this thread. Dysfunction in the stress system forms part of the feedback loops that perpetuate PWS.

However, if you read this second link, there are clear differences between the etiology of CFS kindling (which the citation explains) and benzdiazaphine kindling (which the article does not get into). Perhaps the two are linked by the NO/ONOO- cycle dysfunctions as explained in the first link (LaCorte). In some cases of benzdiazaphine PWS this is true, however not all cases of PWS have ON/ONOO- dysfunction. Neuro-kindling from benzos can happen independently from ON/ONOO- dysfunction. I never had ON/ONOO- dysfunction, but i was kindled.

I have pulled some interesting quotes from the article below for those who can’t or do not want to read the whole citation. I hope this helps a bit.

http://file.scirp.org/Html/3-2400020_4275.htm

Benzos….uuughhh!! This happens all the time. Treat a Patient with CFS using benzos, which over time “unknowingly “ create many many more issues, symptoms and complications There’s no doubt that if there is neuro-kindling at the root of CFS symptoms, that benzos will help in the short run. In the long run, one accumulates more symptoms from the chronic benzo use that are not necessarily due to the underlying CFS illness. This is a tragedy, but the good news is that getting off the benzo will help resolve the benzo related symptoms.

Quote
Brain Baraniuk et al. (2005) believes that neural circuits running from the spinal cord to the brainstem are not working properly [59]. In patients with ME/CFS, gates are not filtering out unnecessary information, and the most critical neural circuit, the Papez Circuit, which ties together the anterior cingulate, amygdala and hippocampus, is associated with heightened awareness [60]. The drug Klonopin often helps patients with ME/CFS because it slows down the over activity of the brain by increasing production of GABA, a central nervous system inhibitory neurotransmitter, thereby reducing the ‘set point’ at which it’s neurons are activated.

de Lange et al. (2005) observed significant reductions in grey matter volume in patients with ME/CFS, and this might be due to oxidative stress caused by kindling [61,62]. Biswal, Kunwar, and Natelson (2010) found sig-nificant cerebral blood flow reductions in patients with ME/CFS in nearly every region of the brain assessed [63]. It is critical to attempt to identify where damage has occurred. Magnetic resonance (MR) studies of encephalopathy and encephalomyelitis associated with acute Epstein-Barr Virus (EBV) infection have found T2 prolongation over gray and white matter, brain atrophy, and periventricular leukomalacia [64]. A MR study examining a pediatric population of patients suffering from chronic EBV infection has shown evidence for the presence of lesions in the hippocampal region [65].
End quote

……
GHB = xyrem …..uuugghhhh!! Very short acting and addictive Please avoid this drug.

Quote
Sodium oxybate (Xyrem) has been used for narcolepsy, as it greatly enhances deep level sleep, and Spitzer and Broadman report that 59% of ME/CFS and FM patients who tried this medication reported substantial relief of pain, and 75% had significant reduction of fatigue [78]. Moldofsky, Inhaber, Guinta, and Alvarez-Horine (2010) also found improved EEG sleep physiology and sleep-related FM symptoms after treatment with Xyrem [79].
End quote
…….

Histamine. Very interesting . Low dose remeron is the most powerful histamine antagonist known. Perhaps this is why it helps some through benzo withdrawal and detox.. See below, for histaminergic relation to kindling.

Quote
Also of interest is that stress can trigger mast cells, which are heavily populated in the thalamus (that is located next to the sleep/wake center in the hypothalamus), to release the stimulant histamine. Excessive mast cells and their release of stimulants could be one of the reasons that sleep is interrupted in patients with ME/CFS and FM. Mast cells act as an immunologic defense against external pathogens, and they are five to 14 fold increases of these cells in the top layer of the skin in 100% of FM patients [80]. Kindling might impact mast cells and the release of histamine in the thalamus, resulting in disrupted sleep patterns among patients with ME/CFS.
End quote

…….
Cytokines: TNF-α is a potent neuromodulator. I will be mentioning this in the layman’s thread very briefly as part of pillar #6 (immune system) of the model, in the neural circuits part 3, which isn’t posted yet. I’m bringing it up here because this citation implicates it in kindling. They mention it in relation to its CRH stimulating properties, but I would go one step further and note that it’s involved in circuit wide neuromodulation which is one of the many mechanisms behind homeostatic plasticity. I will go over this briefly in part 3. The link #2 was published way back in 2011, and perhaps they did not quite understand the neuromodulatory effect of TNFα back then….. Relative to neuroscience and Neuroplasticity, even 2011 is a bit “old”.

Quote
In animal models, kindling and related seizure activity is associated with production of pro-inflammatory proteins within the brain [82]. For example, the admi-nistration of pro-inflammatory cytokine tumor necrosis factor alpha (TNF-α) increases seizure activity in animals [83]. TNF-α is a cytokine involved in systemic inflammation, and it stimulates the release of CRH, therefore stimulating the HPA axis. Among patients with ME/CFS, the production of pro-inflammatory cytokines (IL-1β and IL-6) is correlated with acute sickness behavior (i.e., fever, malaise, pain, fatigue, and poor concentration). As mentioned earlier, prolonged exposure to these cytokines might induce a state of chronic activation and kindling [84]. Individuals who have higher levels of these pro-inflammatory cytokines might be at greater risk of developing ME/CFS. In support of this proposition, Voll-mer-Conna et al. (2008) found that severe illness following an infection was more likely to occur among individuals with high levels of IFN-γ (a pro-inflammatory cytokine) and low levels of IL-10 (an anti-inflammatory cytokine) [85]. In addition, elevated levels of pro-inflammatory cytokines can lead to increases in levels of nitric oxide, and this nitric oxide can, in turn, react with superoxide to form the powerful oxidant peroxynitrite, resulting in oxidative stress. Some investigators, however, have not been able to find increased levels of nitric oxide in patients with ME/CFS [86].
End quote

……..

Interesting observations regarding GABAR, NMDAR balance and you guessed it….inescapable prolonged negative stressors. Negative stressors play an important part in the benzdiazaphine model of this thread. Also interesting notes on adenosine levels and inhibition of the histaminergic system. (RST please note, even though you already know this).

Quote
Two receptors residing on the cell surface membranes of neurons are GABA (gamma aminobutyric acid), which inhibits neuronal firing, and NMDA (N-methyl-D-aspartate), which excites neuronal firing. The GABA and NMDA receptors are normally balanced, but after an injury or viral attack, NMDA fires more rapidly than GABA, increasing neuronal firing. Minor and Hunter (2002) have proposed that prolonged exposure to inescapable stressors will eventually deplete GABA, thus reducing an important form of inhibition on excitatory glutamate transmission [87]. Doi, Ueda, Nagatomo, and Willmore (2009) found that rats with diminished GABA functioning were more likely to develop kindling [88]. Winkelman et al. (2008) have found that brain GABA levels were nearly 30% lower in patients with primary insomnia [89]. Recent findings indicate that glial cells or astrocytes (glial cells in the spine or brain) produce adenosine, an inhibitory neurotransmitter that promotes sleep and suppresses arousal, which appears to be implicated in controlling wake to sleep transitions [90]. High adenosine levels can even suppress epileptic seizures, and in rats the adenosine A(2A) receptor (A(2A)R) agonist induces sleep by inhibiting the histaminergic system, an integral part of the immune system, through increasing GABA release [91]. It is also possible that kindling could result in low levels of adenosine over time, causing the development of sleep difficulties, although adenosine is only one of many substances that promotes sleep
End quote

……..

Exercise intolerance (RST please note). This is very common. It can even occur in tolerance with no kindling, as there is an imbalance in the excitatory and inhibitory signaling. I can relate to this one.

Quote
Light et al. (2009) maintain that exercise could send a continuous signal of muscle sensory fatigue to the central sympathetic nervous system causing dysregulation of sympathetic nervous system reflexes, and ultimately producing the recognition of enhanced fatigue [101]. Light et al. found patients with ME/CFS demonstrated increases after exercise that reliably exceeded responses of control subjects in mRNA for genes receptors that can detect muscle produced metabolites, genes that are essential for sympathetic nervous system processes, and immune function genes. About 90% of the ME/CFS patients could be distinguished from control subjects using just 4 of the genes measured (i.e., P2X4, adrenergic b-1, adrenergic b-2, IL-10). The researchers concluded that ME/ CFS patients might have enhanced sensory signal for fatigue that is increased after exercise [101]. These findings all indicate persistent changes in cell membrane function, which are compatible with kindling theory that maintains that excessive arousal can lead to an increase in the dendrites of the limbic system, with an increase in excitatory postsynaptic receptors and a decrease in inhibitory presynaptic receptors.

Kindling is an explanation for what might occur when patients with ME/CFS overexert themselves and deplete energy reserves. The kindling hypothesis suggests that once this system is charged, either by high-intensity stimulation or by chronically repeated low-intensity stimulation, activities that involve going beyond energy reserves might enhance an already high level of arousal. In a sense, patients with ME/CFS might have this type of cortical excitability that might be due to kindling, and then when they go beyond their energy reserves, the kindling produces high arousal that has implications for the hypothalamus, the autonomic nervous system, as well as the immune system
End quote

dm123!

Thanks so much for yet again a great contribution. I have been working on the linkages on some of the areas you mentioned (P2X) for example and the powerful influence of inflammatory cytokines such as tnf-alpha. Now, interestingly I have been recently diagnosed with psoriasis which was misdiagnosed as chronic exzema. The salient point is that psoriasis is a chronic auto-immune disease and tnf-alpha is consistently elevated in the disease. One suggestion of treatment is chronic low dose NSAID's; however such a protocol may well be too hard on one's organs.

I have finally started to stabilize at 210mg of gabapentin. With stabilization comes some improvement in sleep and a reduction in other symptoms. In the past, I would have prepared to cut again or started be more active. This time, I'm not doing anything other than gentle walking just to keep my blood circulating. That's it.

I am fairly certain I have been kindling by pushing my physical activity, as I've said many times. I am conversing right now with someone who has been off klonopin for a while and had a huge reaction upon returning to weightlifting. After a few weeks he started to feel better and then slowly returned to a tolerable level of weightlifting and had been doing so for 3 months. Then, he decided to up his intensity and has been thrown into the equivalent of major withdrawal symptoms for a few weeks now. The good news is after a couple of weeks he's noting a slight diminishment in some symptoms.

We're told that there is this single cause and effect and we focus only on benzos to the detriment of truly understanding the compromised interlinked systems in those of us who are protracted. This illness we have has been absolutely misunderstood for so long by so many. Thanks to everyone for all the great contributions. Especially dm123. So much has been gained by your contributions (and historically Perseverance made some great contributions - as well as other smart people!). Every contribution has value so thanks again to everyone.

Let's keep our heads up. We can do it. We will do it!!!!

-RST

October 3, 2018

Hi brainy science people.

I am not up to reading this whole thread atm.

Has this paper been covered

https://www.sciencedirect.com/science/article/pii/S0306987718303645

It references another paper about ME/CFS patients already being kindled. Hence Benzos helping ME symptoms

http://file.scirp.org/Html/3-2400020_4275.htm

All of this is far beyond anything I am going to be able to get my head around any time soon.

Can somebody let me know if that basically means that I am unlikely to be able to recover from benzo withdrawal because my brain was already sensitised due to pre-existing ME/CFS.

I am very concerned I am causing irreparable damage and that it might be better for me to go back on the diazepam and try to get some Memantine to stave off withdrawal and interdose withdrawal as several people with ME I have spoken to have had to.

Hi Ajusta,

From your signature, are you still on diazepam? It states 2mg.

There’s no irreparable damage being done. Your symptoms are due to a massive lack of homeostatic balance in your nervous system. I know it feels like permanent damage, but it can be undone. Neurons are not dying off. Neurons and circuits are adaptable and it is very very rare for circuits to get “cooked”. I don’t know much about memantine, other than the stuff on the internet that you already are aware of. Ketamine is also another alternative but i suggest it only be administered in a medical setting. Both of these drugs require medical supervision.

Regarding the two links you provided, I have several thoughts on them,, some of which have already been covered in this thread.

===========
The first link. MAB (Miss Atomic Bomb) provided me with the full citation several months ago.

https://www.sciencedirect.com/science/article/pii/S0306987718303645

Regarding the first link for the NO/ONOO- benzo hypothesis (LaCorte), this has been incorporated into the Benzodiazaphine model in this thread, pages 53-56. This was done several months back. The table of contents to the thread is in my signature. Most of the material will need to be hyperlinked and collected into a cohesive document at some point. I know it’s nearly impossible to follow, but there’s nothing we can do about that right now.

This NO/ONOO- cycle dynamic is a small part of the benzdiazaphine model presented in this thread. (It is pillar #4 (of 6 total) and component system #4 (of 4 total) of the model in this thread).

It’s related to cellular mitochondrial dysfunction and oxidative stress, and is perpetuated by several feedback loops that are instigated by “dysfunctional” calcium channel homeostasis.

-If you would like to learn more about the NO/ONOO- cycle there are some great you tube videos by Dr. Pall. Just search for “Pall NO/ONOO”. I think you are already aware of his work, as you are a CFS survivor.

-If you would like to understand how the LaCorte paper ties into Benzodiazaphine PWS, I summarize the article on those pages 53-56 (mentioned above) of this thread.

-This is a great article on the NO/ONOO- and CFS by Dr. Pall. I know you already know about this as a CFS survivor.
http://www.townsendletter.com/FebMarch2010/cureNO0210.html

============

The second link: I just read. I most definitely think that the symptom overlap of classical CFS and Benzodiazaphine PWS can, in some patients be traced back to a common etiology of neuro-kindling. When I was fully kindled I thought I had developed CFS. It’s a horrible feeling. However, unlike CFS, benzdiazaphine induced kindling is not due to viruses, cytokines, etc as mentioned in the second link. It’s primarily due to chronic day in and day out, nonsteady state dosing of short acting benzos. This can in turn affect cytokines, neurotransmitter levels, and gene expression of the GABAaR and other receptors. A lot of people think they are kindled when they go into tolerance, but these two states are not the same. I think the majority of BBs are in tolerance and that is why they come to BB to get off the benzo.

It’s very interesting that negative stress and poor stress resiliency are common in both PWS and CFS, and I think this is due, in part to the commonality of hyperexcitability and neuro-kindling in both PWS and CFS. I know that RST (a BB) has been experiencing a lot of this, and i have , in the past. Also the stress system is one of the basic pillars in this benzo model on this thread. Dysfunction in the stress system forms part of the feedback loops that perpetuate PWS.

However, if you read this second link, there are clear differences between the etiology of CFS kindling (which the citation explains) and benzdiazaphine kindling (which the article does not get into). Perhaps the two are linked by the NO/ONOO- cycle dysfunctions as explained in the first link (LaCorte). In some cases of benzdiazaphine PWS this is true, however not all cases of PWS have ON/ONOO- dysfunction. Neuro-kindling from benzos can happen independently from ON/ONOO- dysfunction. I never had ON/ONOO- dysfunction, but i was kindled.

I have pulled some interesting quotes from the article below for those who can’t or do not want to read the whole citation. I hope this helps a bit.

http://file.scirp.org/Html/3-2400020_4275.htm

Benzos….uuughhh!! This happens all the time. Treat a Patient with CFS using benzos, which over time “unknowingly “ create many many more issues, symptoms and complications There’s no doubt that if there is neuro-kindling at the root of CFS symptoms, that benzos will help in the short run. In the long run, one accumulates more symptoms from the chronic benzo use that are not necessarily due to the underlying CFS illness. This is a tragedy, but the good news is that getting off the benzo will help resolve the benzo related symptoms.

Quote
Brain Baraniuk et al. (2005) believes that neural circuits running from the spinal cord to the brainstem are not working properly [59]. In patients with ME/CFS, gates are not filtering out unnecessary information, and the most critical neural circuit, the Papez Circuit, which ties together the anterior cingulate, amygdala and hippocampus, is associated with heightened awareness [60]. The drug Klonopin often helps patients with ME/CFS because it slows down the over activity of the brain by increasing production of GABA, a central nervous system inhibitory neurotransmitter, thereby reducing the ‘set point’ at which it’s neurons are activated.

de Lange et al. (2005) observed significant reductions in grey matter volume in patients with ME/CFS, and this might be due to oxidative stress caused by kindling [61,62]. Biswal, Kunwar, and Natelson (2010) found sig-nificant cerebral blood flow reductions in patients with ME/CFS in nearly every region of the brain assessed [63]. It is critical to attempt to identify where damage has occurred. Magnetic resonance (MR) studies of encephalopathy and encephalomyelitis associated with acute Epstein-Barr Virus (EBV) infection have found T2 prolongation over gray and white matter, brain atrophy, and periventricular leukomalacia [64]. A MR study examining a pediatric population of patients suffering from chronic EBV infection has shown evidence for the presence of lesions in the hippocampal region [65].
End quote

……
GHB = xyrem …..uuugghhhh!! Very short acting and addictive Please avoid this drug.

Quote
Sodium oxybate (Xyrem) has been used for narcolepsy, as it greatly enhances deep level sleep, and Spitzer and Broadman report that 59% of ME/CFS and FM patients who tried this medication reported substantial relief of pain, and 75% had significant reduction of fatigue [78]. Moldofsky, Inhaber, Guinta, and Alvarez-Horine (2010) also found improved EEG sleep physiology and sleep-related FM symptoms after treatment with Xyrem [79].
End quote
…….

Histamine. Very interesting . Low dose remeron is the most powerful histamine antagonist known. Perhaps this is why it helps some through benzo withdrawal and detox.. See below, for histaminergic relation to kindling.

Quote
Also of interest is that stress can trigger mast cells, which are heavily populated in the thalamus (that is located next to the sleep/wake center in the hypothalamus), to release the stimulant histamine. Excessive mast cells and their release of stimulants could be one of the reasons that sleep is interrupted in patients with ME/CFS and FM. Mast cells act as an immunologic defense against external pathogens, and they are five to 14 fold increases of these cells in the top layer of the skin in 100% of FM patients [80]. Kindling might impact mast cells and the release of histamine in the thalamus, resulting in disrupted sleep patterns among patients with ME/CFS.
End quote

…….
Cytokines: TNF-α is a potent neuromodulator. I will be mentioning this in the layman’s thread very briefly as part of pillar #6 (immune system) of the model, in the neural circuits part 3, which isn’t posted yet. I’m bringing it up here because this citation implicates it in kindling. They mention it in relation to its CRH stimulating properties, but I would go one step further and note that it’s involved in circuit wide neuromodulation which is one of the many mechanisms behind homeostatic plasticity. I will go over this briefly in part 3. The link #2 was published way back in 2011, and perhaps they did not quite understand the neuromodulatory effect of TNFα back then….. Relative to neuroscience and Neuroplasticity, even 2011 is a bit “old”.

Quote
In animal models, kindling and related seizure activity is associated with production of pro-inflammatory proteins within the brain [82]. For example, the admi-nistration of pro-inflammatory cytokine tumor necrosis factor alpha (TNF-α) increases seizure activity in animals [83]. TNF-α is a cytokine involved in systemic inflammation, and it stimulates the release of CRH, therefore stimulating the HPA axis. Among patients with ME/CFS, the production of pro-inflammatory cytokines (IL-1β and IL-6) is correlated with acute sickness behavior (i.e., fever, malaise, pain, fatigue, and poor concentration). As mentioned earlier, prolonged exposure to these cytokines might induce a state of chronic activation and kindling [84]. Individuals who have higher levels of these pro-inflammatory cytokines might be at greater risk of developing ME/CFS. In support of this proposition, Voll-mer-Conna et al. (2008) found that severe illness following an infection was more likely to occur among individuals with high levels of IFN-γ (a pro-inflammatory cytokine) and low levels of IL-10 (an anti-inflammatory cytokine) [85]. In addition, elevated levels of pro-inflammatory cytokines can lead to increases in levels of nitric oxide, and this nitric oxide can, in turn, react with superoxide to form the powerful oxidant peroxynitrite, resulting in oxidative stress. Some investigators, however, have not been able to find increased levels of nitric oxide in patients with ME/CFS [86].
End quote

……..

Interesting observations regarding GABAR, NMDAR balance and you guessed it….inescapable prolonged negative stressors. Negative stressors play an important part in the benzdiazaphine model of this thread. Also interesting notes on adenosine levels and inhibition of the histaminergic system. (RST please note, even though you already know this).

Quote
Two receptors residing on the cell surface membranes of neurons are GABA (gamma aminobutyric acid), which inhibits neuronal firing, and NMDA (N-methyl-D-aspartate), which excites neuronal firing. The GABA and NMDA receptors are normally balanced, but after an injury or viral attack, NMDA fires more rapidly than GABA, increasing neuronal firing. Minor and Hunter (2002) have proposed that prolonged exposure to inescapable stressors will eventually deplete GABA, thus reducing an important form of inhibition on excitatory glutamate transmission [87]. Doi, Ueda, Nagatomo, and Willmore (2009) found that rats with diminished GABA functioning were more likely to develop kindling [88]. Winkelman et al. (2008) have found that brain GABA levels were nearly 30% lower in patients with primary insomnia [89]. Recent findings indicate that glial cells or astrocytes (glial cells in the spine or brain) produce adenosine, an inhibitory neurotransmitter that promotes sleep and suppresses arousal, which appears to be implicated in controlling wake to sleep transitions [90]. High adenosine levels can even suppress epileptic seizures, and in rats the adenosine A(2A) receptor (A(2A)R) agonist induces sleep by inhibiting the histaminergic system, an integral part of the immune system, through increasing GABA release [91]. It is also possible that kindling could result in low levels of adenosine over time, causing the development of sleep difficulties, although adenosine is only one of many substances that promotes sleep
End quote

……..

Exercise intolerance (RST please note). This is very common. It can even occur in tolerance with no kindling, as there is an imbalance in the excitatory and inhibitory signaling. I can relate to this one.

Quote
Light et al. (2009) maintain that exercise could send a continuous signal of muscle sensory fatigue to the central sympathetic nervous system causing dysregulation of sympathetic nervous system reflexes, and ultimately producing the recognition of enhanced fatigue [101]. Light et al. found patients with ME/CFS demonstrated increases after exercise that reliably exceeded responses of control subjects in mRNA for genes receptors that can detect muscle produced metabolites, genes that are essential for sympathetic nervous system processes, and immune function genes. About 90% of the ME/CFS patients could be distinguished from control subjects using just 4 of the genes measured (i.e., P2X4, adrenergic b-1, adrenergic b-2, IL-10). The researchers concluded that ME/ CFS patients might have enhanced sensory signal for fatigue that is increased after exercise [101]. These findings all indicate persistent changes in cell membrane function, which are compatible with kindling theory that maintains that excessive arousal can lead to an increase in the dendrites of the limbic system, with an increase in excitatory postsynaptic receptors and a decrease in inhibitory presynaptic receptors.

Kindling is an explanation for what might occur when patients with ME/CFS overexert themselves and deplete energy reserves. The kindling hypothesis suggests that once this system is charged, either by high-intensity stimulation or by chronically repeated low-intensity stimulation, activities that involve going beyond energy reserves might enhance an already high level of arousal. In a sense, patients with ME/CFS might have this type of cortical excitability that might be due to kindling, and then when they go beyond their energy reserves, the kindling produces high arousal that has implications for the hypothalamus, the autonomic nervous system, as well as the immune system
End quote

dm123!

Thanks so much for yet again a great contribution. I have been working on the linkages on some of the areas you mentioned (P2X) for example and the powerful influence of inflammatory cytokines such as tnf-alpha. Now, interestingly I have been recently diagnosed with psoriasis which was misdiagnosed as chronic exzema. The salient point is that psoriasis is a chronic auto-immune disease and tnf-alpha is consistently elevated in the disease. One suggestion of treatment is chronic low dose NSAID's; however such a protocol may well be too hard on one's organs.

I have finally started to stabilize at 210mg of gabapentin. With stabilization comes some improvement in sleep and a reduction in other symptoms. In the past, I would have prepared to cut again or started be more active. This time, I'm not doing anything other than gentle walking just to keep my blood circulating. That's it.

I am fairly certain I have been kindling by pushing my physical activity, as I've said many times. I am conversing right now with someone who has been off klonopin for a while and had a huge reaction upon returning to weightlifting. After a few weeks he started to feel better and then slowly returned to a tolerable level of weightlifting and had been doing so for 3 months. Then, he decided to up his intensity and has been thrown into the equivalent of major withdrawal symptoms for a few weeks now. The good news is after a couple of weeks he's noting a slight diminishment in some symptoms.

We're told that there is this single cause and effect and we focus only on benzos to the detriment of truly understanding the compromised interlinked systems in those of us who are protracted. This illness we have has been absolutely misunderstood for so long by so many. Thanks to everyone for all the great contributions. Especially dm123. So much has been gained by your contributions (and historically Perseverance made some great contributions - as well as other smart people!). Every contribution has value so thanks again to everyone.

Let's keep our heads up. We can do it. We will do it!!!!

-RST

I'm the person RST is referring to FYI. Does this means I have kindled every time I have worked out? During the first week of acute I did my normal routine and had a MAJOR panic attack. I abstained for two months and slowly started lifting again, gradually easing in.

Last Saturday I upped the intensity and had a lesser reaction and averted a panic attack but still felt major anxiety and heart palps.

Am I ever going to reach the baseline I was at two weeks ago? I felt healed at that point. Now I have major withdrawal symptoms from my weight lifting session that were not there before: insomnia, inner tremors, mental akethesia, higher sensitivity to sugary foods, cortisol rushes.

Is this permanent or will I be able to recover? It took me nearly 5 months to reach that weeklong window and now I'm a worse baseline than before and am very scared and devastated.

October 3, 2018

dm123,

Perhaps you like a bit more work ... http://www.benzobuddies.org/forum/index.php?topic=210773.0

Thanks, i would have missed it as i don’t go on that area of BB much.

I skimmed over the abstract and this is a pretty big deal here. Please note it was in vitro testing, but the testing methodology was very sound and solid.

Prior to reading it i encourage readers to read up on depolarization and repoloarization and hyperpoliarization

https://en.m.wikipedia.org/wiki/Depolarization

https://en.m.wikipedia.org/wiki/Repolarization

This falls into the GABAergic pillar of course and the Action Potential dynamics component system of the layman’s model, and specifically in the repolarization phase of the action potential.

It’s really significant, because if these potassium channels (which are very powerful voltage gated channels that repolarize the membrane after the action potential hits peak) are directly modulated by GABA, that means that GABA homeostasis directly affects repolarization. It’s known that GABA indirectly affects action potential dynamics in many many ways via ionotropic channels, etc, but this direct effect on a voltage gated repolarizing channel is a very significant finding. As AP hits peak, the sodium channels (also voltage gated) begin to close up and the potassium channels, which push positive K+ out of the membrane, basically start to open up and repolarize the membrane potential (make it go back down towards threshold, ie make the membrane potential less positive and push it back down into negative territory).

I am going to read this through and let you know what i find. I did not have time to take a close look but if it is what i think it is, it’s important from a neurophysiological perspective.

It still fits into the model.

Thanks again......

Dm123

October 3, 2018

Thank you so much for you explanation of the Benzo/MECFS stuff!

Very helpful.

Sure. As a CFS survivor, i know you understand much of this, but that 2011 article definitely puts a new spin on how we view neuro-kindling as a common neurophysiological state between benzo wd/PWS and CFS. The symptoms definitely align between the two in many ways.

This is all very interesting because pillar #6 in the benzo model is the immune system, and i haven’t had a chance to explore this aspect much from the benzo PWS perspective. We know that cytokines are off kilter in PWS and we know they are off kilter in CFS, and we now know that cytokines are not only powerful modulators of CRH, as the article indicates, but that they are also powerful neural circuit level neuromodulators. Being neuromodulators, when cytokines get off kilter, they will affect the integrity of the CNS.

Best

Dm123

October 3, 2018

dm123!

Thanks so much for yet again a great contribution. I have been working on the linkages on some of the areas you mentioned (P2X) for example and the powerful influence of inflammatory cytokines such as tnf-alpha. Now, interestingly I have been recently diagnosed with psoriasis which was misdiagnosed as chronic exzema. The salient point is that psoriasis is a chronic auto-immune disease and tnf-alpha is consistently elevated in the disease. One suggestion of treatment is chronic low dose NSAID's; however such a protocol may well be too hard on one's organs.

I have finally started to stabilize at 210mg of gabapentin. With stabilization comes some improvement in sleep and a reduction in other symptoms. In the past, I would have prepared to cut again or started be more active. This time, I'm not doing anything other than gentle walking just to keep my blood circulating. That's it.

I am fairly certain I have been kindling by pushing my physical activity, as I've said many times. I am conversing right now with someone who has been off klonopin for a while and had a huge reaction upon returning to weightlifting. After a few weeks he started to feel better and then slowly returned to a tolerable level of weightlifting and had been doing so for 3 months. Then, he decided to up his intensity and has been thrown into the equivalent of major withdrawal symptoms for a few weeks now. The good news is after a couple of weeks he's noting a slight diminishment in some symptoms.

We're told that there is this single cause and effect and we focus only on benzos to the detriment of truly understanding the compromised interlinked systems in those of us who are protracted. This illness we have has been absolutely misunderstood for so long by so many. Thanks to everyone for all the great contributions. Especially dm123. So much has been gained by your contributions (and historically Perseverance made some great contributions - as well as other smart people!). Every contribution has value so thanks again to everyone.

Let's keep our heads up. We can do it. We will do it!!!!

-RST

Hi RST,

I’m glad you pointed out the single cause thing. That is the whole point of the model. It’s a way in which to keep track of the myriad of elements involved in this syndrome that we call PWS. It’s been all piecemeal clinical studies to this point, and i think that a cohesive model is long overdue, so that we can understand why people transition into PWS. The hope is that the model captures the dynamic aspect of this complex nervous system and at the same time the model is extensible (ie, pillars and components can be readily added as we discover new things) so that it can adapt to the latest clinical data coming out of the field of neuroscience.

I too have to watch it with the exercise. I can literally induce more burning in the legs by exercising beyond my “threshold”. The hope is that as one recovers, stress resiliency increases and one can slowly neuroadapt to higher levels of both positive and negative stress. The stress pillar plays such a crucial role in the model.....

My uncle has psoriasis. This is very very interesting, about the elevated TNF-alpha. I am sure that are multiple simultaneous issues at play, but there’s a lot of research being done on TNF-alpha as a circuit level wide neuromodulator. It’s a very potent one at that, and it is quite easy to see how all of this is aligning to our understanding of what’s going in your case.

Best

Dm123

October 4, 2018

I'm the person RST is referring to FYI. Does this means I have kindled every time I have worked out? During the first week of acute I did my normal routine and had a MAJOR panic attack. I abstained for two months and slowly started lifting again, gradually easing in.

Last Saturday I upped the intensity and had a lesser reaction and averted a panic attack but still felt major anxiety and heart palps.

Am I ever going to reach the baseline I was at two weeks ago? I felt healed at that point. Now I have major withdrawal symptoms from my weight lifting session that were not there before: insomnia, inner tremors, mental akethesia, higher sensitivity to sugary foods, cortisol rushes.

Is this permanent or will I be able to recover? It took me nearly 5 months to reach that weeklong window and now I'm a worse baseline than before and am very scared and devastated.

Hi RKO,

I am glad you discussed this with RST. He’s had a lot of experience in this area.

I am sorry that you are going through this. It is a minor relapse, but it’s never going to be a full relapse, because you are no longer on the Benzodiazaphine. The benzo does the damage from the inside out. It’s a direct insult to the receptor and this cascades into affecting a whole bunch of collateral systems.

You have merely overtaxed your stress system, and it’s out of balance right now. It’s a pillar in the model, and as such you have to watch it and pamper it, especially being only 5 months out. The neuroadaptive system is strong, and it doesn’t get cooked or permanently damaged in these cases. I am not a medical doctor, but i can tell you that i understand the poor resiliency to stress very well. I don’t know if we ever recover full resiliency, but we do end up different than what we were before. It’s not necessarily worse or bad, it’s just different.

In another thread someone mentioned time. There’s no substitute for the healing powers of time. I’ve discussed both negative and positive stress in this blog quite a bit. Positive stress like exercise can become very negative when overdone (or overdone relative to where you are in terms of recovery).

In addition, Cortisol is a powerful neuromodulator. The adrenaline and noradrenaline were ramped up and that balance has been thrown off. It is not permanent. Cortisol does affect LTP and LTD and all of the action potential stuff. I wrote about it quite a bit in the earlier pieces. But it’s all plastic meaning it reverts back , once you give it time.

I don’t see how exercise would be neuro-kindling. It overtaxed your nervous system. Bodybuilders with healthy nervous systems have these problems. Intense weight lifting is very stimulating to the nervous system. Healthy bodybuilders don’t crash or relapse because they have intact inhibitory systems. Yours in still on the mend.

It is not permanent. Just please stay away from alcohol, PAMs and Benzodiazaphines. Keep the negative stress out of your life for now.

I hope this helps a bit

Dm123

October 4, 2018

I lost this thread for a while. Have so many probs finding stuff on BB... probably my faulty brain!

Anyhow wondered about hydroxizyne possibly for sleep, or l theanine. I have to try get to detist tomorrow as very iffy tooth. In fact, wonder if it is a benzo thing. It is just one tooth and a corner had broken off (no pain), dentist bonded on corner. That was ok. Then it was ground down and temp crown put on. That was ok. Then crown and all hell brokoe loose== even hurt under anesthesia.

Had that ground down (he can't remove) and temp put bak on. Endodontist found nothing wrong... it aches sometimes or feels not good but no sensitivity to hot/cold/pressure.
Need to go bck to endodontist for another look... hope i make it. I am not muh able to do anything... in bed now. Also forgive keyoard, it is not good (stupid Acer computer). Any thought on could this be benzo related? Am not up to root canal or anything right now. If it is bad wonder if they can just pull it.

Meanwhile am wondering if people here are neuroscientists or what? Dm? I sure cannot follow this.

Thank you.

BTW, guess am bsck on valium... was not eatin gmuch and think maybe it ok now if I eat. Guess that preferable to clonopin and all the switches in brands there. Think clonopin may be better for sleep, but more skeletal pain stuff and heart stuff. ut for one or two days felt essentially 'normal.'

thx.

Hi Barbara,

I have used hydroxyzine in the distant past. It is a “safe” benzo adjunctive medicine, but it wears off in terms of effectiveness quickly.

L theanine, i am not sure but there are some very long threads on BB on this amino acid. I think i posted something on it a long time back. I don’t remember if it affected the GABAaRs.

I would try to eat as much as possible. I know it is hard during wd and tapering. The nausea can be hard on the appetite.

October 4, 2018

I'm the person RST is referring to FYI. Does this means I have kindled every time I have worked out? During the first week of acute I did my normal routine and had a MAJOR panic attack. I abstained for two months and slowly started lifting again, gradually easing in.

Last Saturday I upped the intensity and had a lesser reaction and averted a panic attack but still felt major anxiety and heart palps.

Am I ever going to reach the baseline I was at two weeks ago? I felt healed at that point. Now I have major withdrawal symptoms from my weight lifting session that were not there before: insomnia, inner tremors, mental akethesia, higher sensitivity to sugary foods, cortisol rushes.

Is this permanent or will I be able to recover? It took me nearly 5 months to reach that weeklong window and now I'm a worse baseline than before and am very scared and devastated.

Hi RKO,

I am glad you discussed this with RST. He’s had a lot of experience in this area.

I am sorry that you are going through this. It is a minor relapse, but it’s never going to be a full relapse, because you are no longer on the Benzodiazaphine. The benzo does the damage from the inside out. It’s a direct insult to the receptor and this cascades into affecting a whole bunch of collateral systems.

You have merely overtaxed your stress system, and it’s out of balance right now. It’s a pillar in the model, and as such you have to watch it and pamper it, especially being only 5 months out. The neuroadaptive system is strong, and it doesn’t get cooked or permanently damaged in these cases. I am not a medical doctor, but i can tell you that i understand the poor resiliency to stress very well. I don’t know if we ever recover full resiliency, but we do end up different than what we were before. It’s not necessarily worse or bad, it’s just different.

In another thread someone mentioned time. There’s no substitute for the healing powers of time. I’ve discussed both negative and positive stress in this blog quite a bit. Positive stress like exercise can become very negative when overdone (or overdone relative to where you are in terms of recovery).
In addition, Cortisol is a powerful neuromodulator. The adrenaline and noradrenaline were ramped up and that balance has been thrown off. It is not permanent. Cortisol does affect LTP and LTD and all of the action potential stuff. I wrote about it quite a bit in the earlier pieces. But it’s all plastic meaning it reverts back , once you give it time.

I don’t see how exercise would be neuro-kindling. It overtaxed your nervous system. Bodybuilders with healthy nervous systems have these problems. Intense weight lifting is very stimulating to the nervous system. Healthy bodybuilders don’t crash or relapse because they have intact inhibitory systems. Yours in still on the mend.

It is not permanent. Just please stay away from alcohol, PAMs and Benzodiazaphines. Keep the negative stress out of your life for now.

I hope this helps a bit
Dm123

Thank you for the reassurance, dm123. I’ve been healthy and fit my entire life and I cannot fathom how 17 days of Klonopin could turn my world upside down. I feel like I’m a rare case where any sort of exercise or exertion causes a brain fog response. This is the first time I’ve had an uptick of symptoms, though. Although I may not be certain as my first workout during acute promoted a severe panic attack, and I’ve never had panic attacks before.

Needless to say I have been incredibly deflated from feeling so well to feeling so poorly in a matter of 24 hours following my workout.

It took nearly five months to get that window so I’m really scared if and when I’ll get another one. I haven’t had insomnia this bad since acute while the body tremors and mental akethesia are new symptoms that keep me up at night. I’m also perplexed how I’m more sensitive to sugar which was not a problem prior to this.

Apologies for the panic. All of my stress relievers have been taken from me: exercise, sleep, and the occasional beer. This has been the worst time of my life and those teeny pills wreaked havoc on my very sensitive CNS when all I wanted was some relief for tinnitus from an ear infection.

October 4, 2018

RKO- I'm sorry you're going thru this esp after such short term use! I was a short term user also. DM's response seems wise. Also do you take any supplements or did you before?

October 4, 2018

RKO- I'm sorry you're going thru this esp after such short term use! I was a short term user also. DM's response seems wise. Also do you take any supplements or did you before?

Just Centrum and Vitamin C, though I stopped the Centrum when this wave/setback started.

October 4, 2018

RKO- I wonder if the multivitamin plays a role here. I know for me, I was dependent on even small doses of Magnesium. And it is a short acting benzo basically. I had to slowly taper mag and it was very difficult. Actually it's sxs from mag w/d that led to the benzo Rx.... before I knew what was going on. Also ppl report setbacks from other vits including Bs, D, Calcium, Mag of course, and probably more. I even avoid coconut water bc of the high concentration of mag. Anyway, just some thoughts- idk your whole story or if this vitamin plays a role for you but just sharing some other experiences. You will turn around again!

October 4, 2018

RKO- I wonder if the multivitamin plays a role here. I know for me, I was dependent on even small doses of Magnesium. And it is a short acting benzo basically. I had to slowly taper mag and it was very difficult. Actually it's sxs from mag w/d that led to the benzo Rx.... before I knew what was going on. Also ppl report setbacks from other vits including Bs, D, Calcium, Mag of course, and probably more. I even avoid coconut water bc of the high concentration of mag. Anyway, just some thoughts- idk your whole story or if this vitamin plays a role for you but just sharing some other experiences. You will turn around again!

Thanks libr. Should I resume the Centrum? I have to get a flu shot too and am scared of the consequences. None of this makes any sense.

October 4, 2018

RKO- I wonder if the multivitamin plays a role here. I know for me, I was dependent on even small doses of Magnesium. And it is a short acting benzo basically. I had to slowly taper mag and it was very difficult. Actually it's sxs from mag w/d that led to the benzo Rx.... before I knew what was going on. Also ppl report setbacks from other vits including Bs, D, Calcium, Mag of course, and probably more. I even avoid coconut water bc of the high concentration of mag. Anyway, just some thoughts- idk your whole story or if this vitamin plays a role for you but just sharing some other experiences. You will turn around again!

Thanks libr. Should I resume the Centrum? I have to get a flu shot too and am scared of the consequences. None of this makes any sense.

RKO - I don't know and can't tell you what to do. Go with your intuition.

I have been getting the flu shot every year through this and it's been ok.

Can anyone make sense of this to explain to a layperson?

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