Benzos as necessity

[katabasis]

Given your willingness to undertake adventurous, courageous, informed experimentation, have you considered opening a thread on your own experiences with the kind of substances and the rest of us might be more cautious about trying?

When I have the time and energy to do a full write-up of interesting chemicals, sure. However, I thought what information I shared was suitable to this thread, considering the OP, @judyinthesky, posted the following request:

I definitely need inhibitory
Do you have good experience with any

I am merely posting the inhibitory/sedative drugs with which I've had decent to good experiences.

 

[katabasis]

@YippeeKi YOW !!

I understand your impulse to caution the use of nootropics, herbals, etc., but I think some of your points were a bit overstated:
1) While it is true that nootropics vendors are not regulated by the FDA, mislabeled or tainted drugs are extremely rare in practice. I'm curious to see your source for that episode of tainted racetams because I haven't seen anything like that happen recently. Of course, when ordering nootropics, it's advisable to stick with companies long and widely used in the internet health community, and ones which provide CoAs.
2) The idea that a nootropic might coincidentally interact with a particular gene you have to produce a negative effect is just as possible for mainstream, FDA-approved drugs. That's more a risk of taking any drug in general than it is for nootropics.
3) I did not suggest that herbs are necessarily sans-risk. They are drugs just like any other. However, they are a potentially valuable tool and merit mentioning. Sorry you had a bad experience with skullcap, but it's not because there's an outsized risk to taking it. Benzodiazepines are also fraught with risk, particularly GABA receptor downregulation and even 'paradoxical agitation', similar to what you seemed to experience with skullcap. Yet I don't see you giving the same caution for benzos.
4) I think you've understated the general risk tolerance of the ME/CFS community. I see all kinds of high-risk treatment options reported on and suggested on these forums. Hell, even the 'mainstream' options for CFS pharmacotherapy are pretty risky - you see a lot of chronic benzo use, stuff like Abilify and amisulpride, and a panoply of herbal supplements, all of which have potentially disastrous effects and little research in particular application to CFS. That's the nature of having a horrible disease you are desperate to escape, with few truly effective treatments available.
5) I agree that excitotoxicity undeniably plays a role in CFS, but what role specifically is uncertain, and I suspect overstated. I think there's a general unreliability in actual reporting excitotoxicity that muddies the waters here. A person takes a drug and experiences anxiety, overstimulation, other general sickness parameters, and then looks at the drug's MoA and claims 'excitotoxicity!'. However it is fully possible for a drug to cause all those symptoms without actually causing damage to neurons. Meanwhile, there are plenty of drugs which research shows to essentially eliminate excitotoxicity, but they don't do much to reverse the CFS disease process.

Separately, here's some more info about fasoracetam specifically, per your questions:
- Here's a study of the recent application of fasoracetam to ADHD treatment. Some good references in there that cover its 'extensive' clinical history.
- Here's a study of the ability of mGluRs and GABA-B (the metabotropic receptors for typically ionotropic neurotransmitters) to modulate both glutamate and GABA.
- It's been shown that fasoracetam upregulates GABA-B through adenylyl cyclase modulation (here and here).

 

[YippeeKi YOW !!]

I'm not sure what your issue is here, but I'll respond as best I can, and after that, I'm done.

I'm curious to see your source for that episode of tainted racetams because I haven't seen anything like that happen recently.

As I stated in my post, I believe it was ScienceDaily. A quick google could provide you with that information.

The idea that a nootropic might coincidentally interact with a particular gene you have to produce a negative effect is just as possible for mainstream, FDA-approved drugs. That's more a risk of taking any drug in general than it is for nootropics.

ME produces extraordinary deviations from norm, and patients tend to react in unexpected and non-traditional ways to drugs that the mainstream hoovers up without incident.

Racetams are themselves "extraordinary deviations", highly engineered synthetics, and substances with the potential for very odd reactions from a community that often doesn't react in standard ways to something as simple, and in the case of racetams, as critical as choline. THis is a reductio ad absurdum, but the best I can conjure right now.

Benzodiazepines are also fraught with risk, particularly GABA receptor downregulation and even 'paradoxical agitation', similar to what you seemed to experience with skullcap. Yet I don't see you giving the same caution for benzos.

....

Not only have I given the same caution, and a far more pointed and detailed caution for benzos ALL OVER THIS SITE, but I did so at the top of this thread, and urged Judy to be careful. You must have missed it.

ANd it wasnt just skullcap. It was every herb that had benzo-like sedative and anxiolytic effects, cleared thru the same CYP450 pathways, and utilized an MoA closely related in their effects to benzos.

I think you've understated the general risk tolerance of the ME/CFS community. I see all kinds of high-risk treatment options reported on and suggested on these forums. Hell, even the 'mainstream' options for CFS pharmacotherapy are pretty risky - you see a lot of chronic benzo use, stuff like Abilify and amisulpride, and a panoply of herbal supplements, all of which have potentially disastrous effects and little research in particular application to CFS.

All of which are highly experimental, and yes, a limited proportion of members here are brave enough, experimental enough, and desperate enough to trial them. I deeply respect their courage, and I respect their choices even if I dont particularly agree with them or feel the need to go there myself, just as they probably wouldn't agree with all of mine.

I agree that excitotoxicity undeniably plays a role in CFS, but what role specifically is uncertain, and I suspect overstated. I think there's a general unreliability in actual reporting excitotoxicity that muddies the waters here.

Here's what you posted

I agree that people with CFS should be cautious taking racetams in general due to their effects on glutamate. For most healthy people they are generally considered to be neuroprotective but... well, we're not healthy people.

Here's what I said...

From what Ive read in these threads over the last 3 years, it seems to be a strongly recurring theme. I formd a weak and poorly-formed hypothesis a while back that glutamate intolerance or imbalance or sensitivity plays a definite role in aspects of what ails us. And GABA/glutamate/glutamic acid imbalances ....

And to dismiss the reports of members here and elsewhere regarding their reactions and responses as "..... a general unreliability in actual reporting excitotoxicity that muddies the waters ..." skates very close to what we've all heard so often before, " ....it's all in your heads, you're imagining/overstating/misunderstanding that reaction, it isn't real ...."

Meanwhile, there are plenty of drugs which research shows to essentially eliminate excitotoxicity, but they don't do much to reverse the CFS disease process.

If you know of drugs that actually reverse and eliminate excitotoxicity, Id love to know what they are, as would many other members here.

That they dont ".... do much to reverse the CFS disease process ...." doesn't negate the fact that they're contributory factors that definitely have a role in ME (there's a diff between ME and CFS, and most of us feel that the label of CFS is inaccurate, somewhat dismissive and limiting, and prefer other more accurate determinations of what ails us), or at least seem to have played a distinct role in our symptoms and deterioration.

 

[katabasis]

As I stated in my post, I believe it was ScienceDaily. A quick google could provide you with that information.

I did Google it and found nothing. The closest articles I could find weren't ScienceDaily, and weren't saying that racetams were adulterated but rather complaining that they are understudied drugs, which is a completely different issue. Hence why I asked you for a source.

ME produces extraordinary deviations from norm, and patients tend to react in unexpected and non-traditional ways to drugs that the mainstream hoovers up without incident.

Racetams are themselves "extraordinary deviations", highly engineered synthetics, and substances with the potential for very odd reactions from a community that often doesn't react in standard ways to something as simple, and in the case of racetams, as critical as choline. THis is a reductio ad absurdum, but the best I can conjure right now.

Most drugs we're taking here are highly engineered synthetics with the potential for odd reactions from us non-standard reactors. Again, you're not really distinguishing between nootropics and other pharmaceuticals, and I'm not sure why you are so vehemently criticizing my suggestions.

....

Not only have I given the same caution, and a far more pointed and detailed caution for benzos ALL OVER THIS SITE, but I did so at the top of this thread, and urged Judy to be careful. You must have missed it.

ANd it wasnt just skullcap. It was every herb that had benzo-like sedative and anxiolytic effects, cleared thru the same CYP450 pathways, and utilized an MoA closely related in their effects to benzos.

Yes, you're right, I missed it, though I feel like you're going out of your way to criticize every element of my original comments. If you're not careful you might give the impression you have it out for me, or something.

I also feel like a recommendation of skullcap is apposite for a person who has already decided to bear the risks of benzodiazepines, considering skullcap is widely regarded as being weaker (and in the same category of risk).

All of which are highly experimental, and yes, a limited proportion of members here are brave enough, experimental enough, and desperate enough to trial them. I deeply respect their courage, and I respect their choices even if I dont particularly agree with them or feel the need to go there myself, just as they probably wouldn't agree with all of mine.

It's fine if nootropics are not an acceptable risk for you, but the proportion of people here using unconventional treatments is pretty high. Almost any suggestion on this forum is to be taken with a grain of salt - there are always potentials downsides to treatment options for this disease, and I did mention some of them in my original explanation of fasoracetam.

And to dismiss the reports of members here and elsewhere regarding their reactions and responses as "..... a general unreliability in actual reporting excitotoxicity that muddies the waters ..." skates very close to what we've all heard so often before, " ....it's all in your heads, you're imagining/overstating/misunderstanding that reaction, it isn't real ...."

The two are nothing alike. I am not attempting to write off people's experiences of CFS as psychological. I am saying we don't really know what physical basis the disease has, and in what ways that basis connects with the disease's subjective experience. This is not controversial. If we knew these things we'd be that much closer to an effective treatment and perhaps we wouldn't be here having this discussion. When it comes down to it, you cannot reliably know whether excitotoxicity is occurring and to what extent without some sort of objective marker. I am not saying it's not happening, I'm saying we don't know if it is. Sometimes people suffer excitotoxicity with no subjective ill effect (generations of casual amphetamine users might attest to this). Sometimes people have horrible, agonizing experiences from a drug that are in no way correlated with excitotoxicity.

If you know of drugs that actually reverse and eliminate excitotoxicity, Id love to know what they are, as would many other members here.

That they dont ".... do much to reverse the CFS disease process ...." doesn't negate the fact that they're contributory factors that definitely have a role in ME (there's a diff between ME and CFS, and most of us feel that the label of CFS is inaccurate, somewhat dismissive and limiting, and prefer other more accurate determinations of what ails us), or at least seem to have played a distinct role in our symptoms and deterioration.

Excitotoxicity is a really specific phenomenon, where neurons are stimulated excessively by glutamate leading to excessive calcium ion influx. Any drug which sufficiently blocks glutamate or calcium channels can prevent excitotoxicity. Plenty of drugs do that - gabapentinoids, NMDA antagonists, memantine (if you need an authority, here's a good link explaining memantine's anti-excitotoxic properties). However, excitotoxicity is only one subtype of neurotoxicity in general, and any disease state which results in excitotoxicity probably involves multiple forms of neurotoxicity, or other systemic issues which cause the subjective symptoms people often attribute to excitotoxicity.

I agree that excitotoxicity is a contributing factor in ME/CFS but as with many aspects of the disease, I think it is easy to misunderstand one's own pathophysiology. I do it all the time - I think 'boy, it seems like my adrenergic system is acting up', but then I try beta blockers, and alpha blockers, and none of them seem to help, and then I am forced to come up with an alternative hypothesis and admit I was mistaken. All I'm pointing out is that it makes sense to be open minded and not get sucked into the excitotoxicity idea too strongly. Especially when glutamate (the perennial target for us excitotoxicity investigators) has some other really important roles in the body.

Also, separately, if you have a problem with the content of my posts, feel free to message me personally so we're not cluttering up someone's thread.

 

[judyinthesky]

So far I've been save with herbs but they didn't have any effect.
But I don't know. It sounds like I should be extra careful with this.
I'm also a bit lost as to what to try, but we were thinking of measuring my glutamate.
Thoughts?

 

[katabasis]

Was there are particular way you were looking to measure your glutamate? Even with PET testing (which is costly and might be difficult for you to arrange), it would probably be hard to establish whether you are truly high in glutamate without some kind of baseline measurement.

I think if I had to recommend one particular drug, it would be memantine, since you are aiming towards being extra careful. You would need a prescription, but I think a neurologist (for example) would see it as a reasonable choice in your case. It's got a long history of human use with known, manageable risks - something to discuss with the prescribing doctor, I suppose.

It will hopefully help deal with any glutamate issues you may have, and some of the other MoAs might end up being helpful as well. Here's a thread where people discuss their experiences with the drug - I made a comment on the first page that explains some more of the specifics.

One other mention is that NMDA receptors seem involved in drug tolerance, and I've heard of people using drugs like memantine to prevent drug tolerance from occurring. It's possible that this might help some of the GABAergic tolerance you probably have, but I don't know if the phenomenon occurs for GABA receptors specifically, or has much effect when tolerance is already established. Something to be mindful of, though.

 

[judyinthesky]

@judyinthesky
If you suspect you have glutamate or GABA issues or sensitivity, or AMPA or NMDA issues, I'd be really cautious with any of the racetams, which generally are cyclic derivatives of GABA neurotransmitters, alto they don't act on GABA directly. They stimulate brain activity with an approximate similarity to glutamate, which is the 'learning' and 'action' neurotransmitter. It's also the neurotransmitter that, when not adequately balanced by GABA, can continue to excite neurons literally to death.

Nootropics are fairly uncharted territory by and large, and most, if not all, clinical studies have only been done on lab rats. Few researchers are clear about their modes of action, and it's really a crapshoot in terms of winnowing thru the many forms currently available.

They all have side effects, depending on your system, mode of ingestion, and dose. Sometimes none, sometimes fairly unpleasant ones like irritability, insomnia, anxiety, agitation, headaches and tremors, among others.

Given what you're going thru and dealing with, adding something as untested and uncertain as to everything from the actual content of what you're taking (racetams are totally unregulated) to what it's potential interactions with your system and genetics as a racetam seems to me to be spinning the cylinder pretty hard. There has to be a safer way ...

As a PS, if you do decide to try a racetam, it's been recommended that you increase your intake of some form of choline, since they all greatly increase the utiliztion of acetylcholine as part of their mode of action ....

I think I'll measure glutamate etc first

 

[judyinthesky]

I did Google it and found nothing. The closest articles I could find weren't ScienceDaily, and weren't saying that racetams were adulterated but rather complaining that they are understudied drugs, which is a completely different issue. Hence why I asked you for a source.



Most drugs we're taking here are highly engineered synthetics with the potential for odd reactions from us non-standard reactors. Again, you're not really distinguishing between nootropics and other pharmaceuticals, and I'm not sure why you are so vehemently criticizing my suggestions.



Yes, you're right, I missed it, though I feel like you're going out of your way to criticize every element of my original comments. If you're not careful you might give the impression you have it out for me, or something.

I also feel like a recommendation of skullcap is apposite for a person who has already decided to bear the risks of benzodiazepines, considering skullcap is widely regarded as being weaker (and in the same category of risk).



It's fine if nootropics are not an acceptable risk for you, but the proportion of people here using unconventional treatments is pretty high. Almost any suggestion on this forum is to be taken with a grain of salt - there are always potentials downsides to treatment options for this disease, and I did mention some of them in my original explanation of fasoracetam.



The two are nothing alike. I am not attempting to write off people's experiences of CFS as psychological. I am saying we don't really know what physical basis the disease has, and in what ways that basis connects with the disease's subjective experience. This is not controversial. If we knew these things we'd be that much closer to an effective treatment and perhaps we wouldn't be here having this discussion. When it comes down to it, you cannot reliably know whether excitotoxicity is occurring and to what extent without some sort of objective marker. I am not saying it's not happening, I'm saying we don't know if it is. Sometimes people suffer excitotoxicity with no subjective ill effect (generations of casual amphetamine users might attest to this). Sometimes people have horrible, agonizing experiences from a drug that are in no way correlated with excitotoxicity.



Excitotoxicity is a really specific phenomenon, where neurons are stimulated excessively by glutamate leading to excessive calcium ion influx. Any drug which sufficiently blocks glutamate or calcium channels can prevent excitotoxicity. Plenty of drugs do that - gabapentinoids, NMDA antagonists, memantine (if you need an authority, here's a good link explaining memantine's anti-excitotoxic properties). However, excitotoxicity is only one subtype of neurotoxicity in general, and any disease state which results in excitotoxicity probably involves multiple forms of neurotoxicity, or other systemic issues which cause the subjective symptoms people often attribute to excitotoxicity.

I agree that excitotoxicity is a contributing factor in ME/CFS but as with many aspects of the disease, I think it is easy to misunderstand one's own pathophysiology. I do it all the time - I think 'boy, it seems like my adrenergic system is acting up', but then I try beta blockers, and alpha blockers, and none of them seem to help, and then I am forced to come up with an alternative hypothesis and admit I was mistaken. All I'm pointing out is that it makes sense to be open minded and not get sucked into the excitotoxicity idea too strongly. Especially when glutamate (the perennial target for us excitotoxicity investigators) has some other really important roles in the body.

Also, separately, if you have a problem with the content of my posts, feel free to message me personally so we're not cluttering up someone's thread.

Thank you for the link of memantine. I've stumbled across this as well. I was asking my ME specialist yesterday but he wasn't convinced.

Maybe I'll open a thread on it

 

[Replenished]

I'm so sorry to read what you are going through, my thoughts are with you and I really do hope a solution can be found.

Like you, I find Clonazepam/benzo gaba type drugs the only medications that seem to reduce my symptoms, although admittedly my case is nowhere near as severe as yours. I recently made a thread on Clonazepam so I don't know if there might be any information that's of use to you there.

In terms of eating, I'm sure you've tried just about every diet / food elimination option out there and apologies if this has already been suggested but have you tried literally just eating beef and nothing else? I've read of a number of people who were serious ill and clearly had issues with reactions to almost every food and eventually they eliminated down to only eating beef and have made drastic recoveries in some cases. Although these may have been allergy type scenarios rather than M.E./nervous system, who knows. I know you say it's purely anything that goes into your digestive tract, causes issues so again in sorry if this suggestion is of no help.

And finally, just through personal experience, I was at my worst a few months ago and had periods stuck in bed, which is unusual for me. I didn't think I had any obvious digestion issues but started supplementing with Ox bile salts, under the suspicion I may possibly have a bile deficiency and therefore reduced ability to digest fats etc. I started bile salts and digestive enzymes with each meal and it has made a significant difference to my overall energy/wellbeing. I also use to get some very odd reactions to food that would leave me feeling awful for days and these seem to have subsided somewhat.

Keep going, there will be something out there that can improve things for you, it's just a case of finding it.

 

[judyinthesky]

I'm so sorry to read what you are going through, my thoughts are with you and I really do hope a solution can be found.

Like you, I find Clonazepam/benzo gaba type drugs the only medications that seem to reduce my symptoms, although admittedly my case is nowhere near as severe as yours. I recently made a thread on Clonazepam so I don't know if there might be any information that's of use to you there.

In terms of eating, I'm sure you've tried just about every diet / food elimination option out there and apologies if this has already been suggested but have you tried literally just eating beef and nothing else? I've read of a number of people who were serious ill and clearly had issues with reactions to almost every food and eventually they eliminated down to only eating beef and have made drastic recoveries in some cases. Although these may have been allergy type scenarios rather than M.E./nervous system, who knows. I know you say it's purely anything that goes into your digestive tract, causes issues so again in sorry if this suggestion is of no help.

And finally, just through personal experience, I was at my worst a few months ago and had periods stuck in bed, which is unusual for me. I didn't think I had any obvious digestion issues but started supplementing with Ox bile salts, under the suspicion I may possibly have a bile deficiency and therefore reduced ability to digest fats etc. I started bile salts and digestive enzymes with each meal and it has made a significant difference to my overall energy/wellbeing. I also use to get some very odd reactions to food that would leave me feeling awful for days and these seem to have subsided somewhat.

Keep going, there will be something out there that can improve things for you, it's just a case of finding it.

I've tried to experiment with different diets when I was mild, because I have pancreas insufficiency pretty bad, and meat is very hard for me, I'm also on heaps of Kreon.

Same with digestive bitters and ox bile supplements.

 

[Replenished]

I've tried to experiment with different diets when I was mild, because I have pancreas insufficiency pretty bad, and meat is very hard for me, I'm also on heaps of Kreon.

Same with digestive bitters and ox bile supplements.

Ah 👎. Can I ask how found out you have pancreas insufficiency? Which test did you have if any?

I will keep an eager eye on this thread and also post back if I come across any suitable alternatives to benzos given that Clonazepam is the only thing that can reduce the symptoms for me when they are extreme, like they seem to be for you most of the time.