Neurotoxicity prevention strategies for Xyrem (GHB), hoping for feedback

[lostie2342]

I have ideopathic hypersomnia and recently started taking Xyrem. I'm trying to do everything I can to mitigate side effects and prevent neurotoxicity. I'd be grateful for insights and feedback. This is my current stack, with '?' on uncertainties:


Hour or two before Xyrem:
Theanine (?)
Magnesium threonate
Zinc picolinate


When I wake up:
huperzine a
blueberry extract
bacopa
pqq (?)


A little later:
DLPA (? For dopamine restoration)
Ester-C (cofactor)
Basic B complex (cofactor)


During day:
Krill oil (twice)
Milk thistle/liver support
Vitamin D/K2
Multivitamin
Magnesium malate
Probiotic pearls
Grape seed extract


Diet is mostly paleo and includes many natural antioxidants, veggies, and meats.


This may seem like a lot but it doesn't seem to be getting the job done. I had to stop taking adderall a few days into it because of a clear overburden on depleted neurons which would cause a scary headache and heat phenomenon for a few hours each day. Even so after dropping adderall, I can still overheat during the day and am experiencing other side effects (which I also have when I don't take the above). Obviously I can't necessarily 'feel' neurotoxicity but I don't seem to be effectively dealing with the excess glutamate release or changing much at all.


I'm considering adding ginkgo, gastrodin and/or memantine post-Xyrem. Is this a sound approach, regarding memantine? It's known to be highly effective with amphetamine and GHB/GHL tolerance and neurotoxicity. I wouldn't be taking it with it, but after. Low dose 5mg to start.


On another note, I'm happy to be off adderall because I had been experiencing gradual signs of amphetamine toxicity; my reaction to adderall while on xyrem would seem to confirm it further (they are supposed to be synergistic, so something is clearly not right with my dopaminergic system. I suspect it was NMDA overstimulation).


Thanks for reading and I appreciate any thoughts or feedback on my situation (the Xyrem pharmacy is clueless).

 

[sekio]

Since when is GHB neurotoxic? It wouldn't be prescribed at the insane doses for narcolepsy and also wouldnt be a popular recreational drug if it were smashing neurons up left and right.

 

[lostie2342]

What I'm trying to mitigate/avoid: "The GHB related memory impairments is explained by e.g. alterations seen in the cholinergic and glutamatergic systems. Decreased extracellular levels of acetylcholine, NMDA synaptic activity and NMDA receptor density in hippocampus, frontal cortex and striatum has been reported as a result of GHB administration (Sircar and Basak, 2004, Li et al., 2007). Furthermore,GHB seem to alter glutamate levels in the hippocampus in a biphasic manner, where lower concentrations of GHB increase and high doses decrease extracellular glutamate levels in the hippocampus. These effects are suggested to be mediated by GHB receptor and GABAB receptors respectively(Castelli et al., 2003). An increase in GH release has also been reported in several studies after GHB intake, a response that seems to involve cholinergic mechanisms (Takahara et al., 1977, Takahara et al., 1980, Addolorato et al., 1999, Volpi et al., 2000)." https://www.diva-portal.org/smash/get/diva2:572306/FULLTEXT01.pdf

 

[Ozle]

I wouldnt have thought GHB is any more toxic than alcohol. The quote you cited seems like it could be describing the effect of pretty much any GABAergic, given that GABA is the primary inhibitory neurotransmitter and that decreased ACh and glutamate transmission (those being the primary excitory neurotransmitters) would be the logical result of agonising it.

 

[lostie2342]

What I'm trying to avoid is any sort of damage due to excess glutamate release, something that factually occurs post-Xyrem therapeutic doses. One of many studies describing glutamate mediated neurotoxicity:

The neurotransmitter glutamate activates several classes of metabotropic receptor and three major types of ionotropic receptor – α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), kainate and N-methyl-d-aspartate (NMDA). The involvement of glutamate mediated neurotoxicity in the pathogenesis of Alzheimer's disease (AD) is finding increasing scientific acceptance. Central to this hypothesis is the assumption that glutamate receptors, in particular of the NMDA type, are overactivated in a tonic rather than a phasic manner. Such continuous, mild, chronic activation ultimately leads to neuronal damage/death. Additionally, impairment of synaptic plasticity (learning) may result not only from neuronal damage per sebut may also be a direct consequence of this continuous, non-contingent NMDA receptor activation. Complete NMDA receptor blockade has also been shown to impair neuronal plasticity, thus, both hypo- and hyperactivity of the glutamatergic system leads to dysfunction.https://www.sciencedirect.com/science/article/pii/S0028390807002298

 

[AlphaMethylPhenyl]

There is no endogenous neurotransmitter that by itself is unilaterally toxic. Too much or too little hurts. Your doctor will not give you something that causes excitotoxicity via glutamate. I don't understand the worry.

I would wager that you're messing things up more than solving them by taking 17 supplements...

In fact GHB, barring tremendous overdose or serious withdrawal due to addiction, is supposed to be pretty safe. Sekio might confirm that. And your doctor will not just cut you off from it. You're fine. Coordinate with your doctor please. Vitamin D and krill oil might be okay, but tell them your concerns and let them decide what supplement(s) you can take. Work with them. They spent 10 years studying this.

 

[Sturnam]

I have ideopathic hypersomnia and recently started taking Xyrem. I'm trying to do everything I can to mitigate side effects and prevent neurotoxicity. I'd be grateful for insights and feedback. This is my current stack, with '?' on uncertainties:


Hour or two before Xyrem:
Theanine (?)
Magnesium threonate
Zinc picolinate


When I wake up:
huperzine a
blueberry extract
bacopa
pqq (?)


A little later:
DLPA (? For dopamine restoration)
Ester-C (cofactor)
Basic B complex (cofactor)


During day:
Krill oil (twice)
Milk thistle/liver support
Vitamin D/K2
Multivitamin
Magnesium malate
Probiotic pearls
Grape seed extract


Diet is mostly paleo and includes many natural antioxidants, veggies, and meats.


This may seem like a lot but it doesn't seem to be getting the job done. I had to stop taking adderall a few days into it because of a clear overburden on depleted neurons which would cause a scary headache and heat phenomenon for a few hours each day. Even so after dropping adderall, I can still overheat during the day and am experiencing other side effects (which I also have when I don't take the above). Obviously I can't necessarily 'feel' neurotoxicity but I don't seem to be effectively dealing with the excess glutamate release or changing much at all.


I'm considering adding ginkgo, gastrodin and/or memantine post-Xyrem. Is this a sound approach, regarding memantine? It's known to be highly effective with amphetamine and GHB/GHL tolerance and neurotoxicity. I wouldn't be taking it with it, but after. Low dose 5mg to start.


On another note, I'm happy to be off adderall because I had been experiencing gradual signs of amphetamine toxicity; my reaction to adderall while on xyrem would seem to confirm it further (they are supposed to be synergistic, so something is clearly not right with my dopaminergic system. I suspect it was NMDA overstimulation).


Thanks for reading and I appreciate any thoughts or feedback on my situation (the Xyrem pharmacy is clueless).

Great question! This seems to be a very common question that I've noticed. "I used Drug X and now I feel Y, is that signs of neurotoxicity?"

Well, for the most part you can't 'feel' neurotoxicity. At least not until you tend to do massive damage. For example, Parkinson's Disease (destruction of dopamine producing neurons) and Alzheimer's (destruction/impairment of hippocampus and cortical neurons) don't tend to produce cognitive or behavioral effects until there is a significant loss of neurons.

Second, lots of things are 'neurotoxic'. Hell, alcohol is neurotoxic. You know the reason most people don't care or feel any effects? Dose and frequency. Drinking every day, even up to 3-4 drinks, is probably unlikely to produce significant neurotoxicity. However, the fall-down-drunk drink a 5th of hard liquor a day person, yeah, they might end up with some neurotoxicity issues.

I would also like to point you to the Xyrem prescribing information, in case you haven't seen it. (Located here: http://pp.jazzpharma.com/pi/xyrem.en.USPI.pdf).
This will tell you all the side effects and other issues noted in both clinical studies and in animal studies. Guess what some of the side effects are? Headache, hypertension (can cause headaches), and 7% of people at the 9gram dose ended up peeing in their bed while they're asleep. Keep in mind these are adults.

Now, you might say peeing in their bed is a sign of mental disease or of sexual abuse (the old generation psychologists said this). Or, you might just say it's a side effect of the drug, and you haven't been diddled as a child.

Additionally, Xyrem contains a fair amount of sodium, which can lead/exacerbate hypertension, which can cause headaches. I'm focusing on headaches since this seems to be one of your main complaints and indicators that you think you have brain damage.

I would also greatly discourage you from adding more drugs to mitigate the side effects from Xyrem, particularly drugs that you physician doesn't know about or prescribe (like Memantine). I think this will only add to your problems, not solve them. Not to mention, if the side effects are that bad, why don't you stop taking Xyrem? I assume because Xyrem is quite effective for you. In which case you may have to choose whether it's worth it to keep taking it. All drugs have a cost/benefit ratio. Some people get more side effects, and some people get more beneficial effects. But it's up to each person to decide what the positive effects are worth, and what negative effects are hard no's. I also think that you should cut down on those supplements. At best I think they're probably not helping with your issues much, and at worst they may be causing/exacerbating your issues.

And on the topic of excess glutamate and all that jazz, I would read up on Olney's lesions. Basically the premise is that NMDA antagonists produce excitotoxicity, and the physician, John Olney, produced some dramatic effects on brain tissue in animals using PCP, and this has been extended to ketamine. However, the single biggest issue with this is that they have never definitely proven that this actually happens in humans, and that it happens at any sort of clinically relevant doses (again, if you're IM'ing 3g of ketamine a day for years, yeah, you might have issues). As the wikipedia intro ends (my emphasis added):

Because the neuronal vacuolation of Olney's lesions evolves into neuronal necrosis or death of neurons, it is important to determine whether Olney's lesions occur in humans, not only in experimental animals. The essential question is whether an NMDA receptor antagonist drug is to be considered a human neurotoxin or not. The patient safety implications for pharmacotherapy and for anesthesia would each be profound, if the answer is affirmative.

So basically even for 'established' neurotoxins we're still not even sure that it happens in humans. Hope this helps.

 

[Limpet_Chicken]

His supplements, to be fair, aren't known toxic horrors, and his diet, if it is one of those fashionable types, sounds as though its healthy. Memantine would be ideal IMO to prevent neurotoxicity i it does occur in-vivo in people, and I can't imagine a risk of NMDA antagonist related neurotoxicity with it either, given its funky voltage-gated binding kinetics and that it selectively blocks excess glutamatergic neurotransmission.

 

[sekio]

Memantine and GHB has the possibility to cause some funky headspaces though.

Again, if excess glutamate release was a problem on GHB rebounds, you'd have seen a dearth of cases of people showing up with swiss-cheese brains in the late '90s during the time GHB was super popular. Also Xyrem being a FDA approved med would also need to have gone through both animal and human safety trials, at escalating dosages.

Certainly in my experiences I've seen some people have rather unpleasant times (usually if they take too much for a euphoric dose but too little for a knockout dose) but nothing that could be construed as lasting neurotoxic effects.

 

[jackdapogo]

As far as neurotoxicity goes, it will probably only be relevant when you stop taking the substance due to excito-toxicity and other factors due to gaba-ergic withdrawal if you don't carefully taper. At the moment you should be thinking about how sensitive your glutamate/gabaergic system is and by down-regulating it you will make you susceptible to nasty side effects and toxicity trying to live without it. While it's possible some of these supplements could, possibly, slow the dependence you form to ghb, it's unlikely any will do so significantly and you will eventually experience a rebound in anxiety/excitation that will likely leave lasting changes in neurochemistry and plasticity for you. However, I'm sure you're quite aware of a lot of this and if this and I don't know what you've gone through to treat your ideopathic hypersomnia and if this seems to be a long-term solution, you seem to be trying your best to stay safe.

On a more contructive note, bacopa might be a good idea. I've heard it seems to upregulate gaba to relieve anxiety instead of agonizing and eventually down regulating it. I started taking it recently to help with the lasting anxiety after tapering from phenibut (been giving me hell, that's why I want to warn you here) and touted nootropic effects. I think it has been helping with anxiety and possibly memory after a couple weeks of use but that's just speculation and could be a number of other things.

 

[lostie2342]

And on the topic of excess glutamate and all that jazz, I would read up on Olney's lesions. Basically the premise is that NMDA antagonists produce excitotoxicity, and the physician, John Olney, produced some dramatic effects on brain tissue in animals using PCP, and this has been extended to ketamine. However, the single biggest issue with this is that they have never definitely proven that this actually happens in humans, and that it happens at any sort of clinically relevant doses (again, if you're IM'ing 3g of ketamine a day for years, yeah, you might have issues). As the wikipedia intro ends (my emphasis added):


So basically even for 'established' neurotoxins we're still not even sure that it happens in humans. Hope this helps.

Yes the idea would be to take NMDA antagonists to prevent neurotoxicity, so obviously if those were neurotoxic themselves it would be a problem. But the question at hand is the extent to take NMDA antagonists to prevent glutamate cytotoxicity.

As far as neurotoxicity goes, it will probably only be relevant when you stop taking the substance due to excito-toxicity and other factors due to gaba-ergic withdrawal if you don't carefully taper. At the moment you should be thinking about how sensitive your glutamate/gabaergic system is and by down-regulating it you will make you susceptible to nasty side effects and toxicity trying to live without it. While it's possible some of these supplements could, possibly, slow the dependence you form to ghb, it's unlikely any will do so significantly and you will eventually experience a rebound in anxiety/excitation that will likely leave lasting changes in neurochemistry and plasticity for you. However, I'm sure you're quite aware of a lot of this and if this and I don't know what you've gone through to treat your ideopathic hypersomnia and if this seems to be a long-term solution, you seem to be trying your best to stay safe.

Thanks jack. The plan is to take it the rest of my life, so it needs to be sustainable. At therapeutic doses the research is clear: there is no dependence or withdrawal, so I'm good there. This is about what's happening right now, in my brain. I already am noticing cognitive deficiencies and issues with words and recall that wasn't there before I started. It's quite noticeable and not in my head. There's also a physical grogginess and headaches and clear action happening up there hours after it's worn off. I am just...slow. Slow and stupid. And it's the report of so many on Xyrem which is why I did everything I could to get ahead of it but clearly not enough. It would suggest I am still dealing with excess glutamate, and blocking it is the solution, no?

But there are reports of learning and memory deficits on both ends -- you have to get it just right to block excess glutamate but you also need healthy glutamate levels or it's terrible for the brain. I'm wary of memantine after one dose at 2.5mg (it is my doctor prescribed, btw). But would 2.5mg really open myself to that kind of risk? Seems unlikely. But it made me more groggy. And research is coming out that shows it inhibits new learning in rats. It's like I'm damned if I do damned if I don't. Maybe I can try amitriptyline? DXM?

 

[lostie2342]

In multiple studies, GHB has been found to impair spatial and working learning and memory in rats with chronic administration.These effects are associated with decreased NMDA receptor expression in the cerebral cortex and possibly other areas as well.

Pedraza et al. (2009) found that repeated administration of GHB to rats for 15 days drastically reduced the number of neurons and non-neuronal cells in the CA1 region of the hippocampus and in the prefrontal cortex. With doses of 10 mg/kg of GHB, they were decreased by 61% in the CA1 region and 32% in the prefrontal cortex, and with 100 mg/kg, they were decreased by 38% and 9%, respectively. It is interesting to note that GHB has biphasic effects on neuronal loss, with lower doses (10 mg/kg) producing the most neurotoxicity, and higher doses (100 mg/kg) producing less. https://www.researchgate.net/public..._by_gammahydroxybutyric_acid_GHB_in_male_rats​

This was at low doses. Still, I'm a little confused (and my brain, honestly, is not working right now). But if this is true, GHB itself would downregulate NMDA receptors, and then taking NMDA antagonists would depress them even more, right? WTF?
​

 

[sekio]

On the flipside, if you're concerned about neurotox on GHB, you'd likely also be concerned about potential NMDA antagonist based neurotoxicity too.

AFAICT if I was taking massive doses of GHB I'd feel pretty groggy...

 

[jackdapogo]

On the flipside, if you're concerned about neurotox on GHB, you'd likely also be concerned about potential NMDA antagonist based neurotoxicity too.

Do you think you could talk about how this works more? You seem to be well informed here and I've been interested in gabaergic withdrawal toxicity but I don't know anything about this.

Yes the idea would be to take NMDA antagonists to prevent neurotoxicity, so obviously if those were neurotoxic themselves it would be a problem. But the question at hand is the extent to take NMDA antagonists to prevent glutamate cytotoxicity.



Thanks jack. The plan is to take it the rest of my life, so it needs to be sustainable. At therapeutic doses the research is clear: there is no dependence or withdrawal, so I'm good there. This is about what's happening right now, in my brain. I already am noticing cognitive deficiencies and issues with words and recall that wasn't there before I started. It's quite noticeable and not in my head. There's also a physical grogginess and headaches and clear action happening up there hours after it's worn off. I am just...slow. Slow and stupid. And it's the report of so many on Xyrem which is why I did everything I could to get ahead of it but clearly not enough. It would suggest I am still dealing with excess glutamate, and blocking it is the solution, no?

But there are reports of learning and memory deficits on both ends -- you have to get it just right to block excess glutamate but you also need healthy glutamate levels or it's terrible for the brain. I'm wary of memantine after one dose at 2.5mg (it is my doctor prescribed, btw). But would 2.5mg really open myself to that kind of risk? Seems unlikely. But it made me more groggy. And research is coming out that shows it inhibits new learning in rats. It's like I'm damned if I do damned if I don't. Maybe I can try amitriptyline? DXM?

Are you associating this constant groggy feeling with excess glutamate? I have to admit I don't know much about the unique pharmacology of GHB so I can't speak for that but in regards to gaba withdrawal I definitely feel a certain fatigue but its accompanied byvery much noticeable unrest and over stimulation that's uncomfortable. I'm assuming there's more symptoms at hand here though, what makes you suspect this is a result of excess glutamate? I wasn't aware that GHB causes no dependence but I'd be surprised if there isn't some degree of downregulation and eventual glutamate rebound after cessation but I'm interested to hear more, seems like an interesting drug that I've never happened across personally. I feel very impaired when in states I'd attribute to glutamate overactivity but its marked by more confusion and scatteredness unlike the "slow" thinking I get from fatigue and sedating impairment.

 

[Ozle]

I'm wary of memantine after one dose at 2.5mg (it is my doctor prescribed, btw).

Could you go into more detail about why you're feeling wary about it already?
Also, for what reason was it prescribed to you? I can't imagine it was to counteract Xyrem toxicity; that would imply an admission by your doctor that his initial prescription was grossly negligent, since he'd essentially have been prescribing you a compound that he knew very well (or at least strongly believed) to be neurotoxic, while taking few or no precautions to prevent it. I know that psychiatrists can definitely be pretty inept at times (particularly with regards to dosing, especially starting doses), but I find it hard to believe that a trained doctor could make an error of that magnitude.

 

[lostie2342]

Are you associating this constant groggy feeling with excess glutamate? I have to admit I don't know much about the unique pharmacology of GHB so I can't speak for that but in regards to gaba withdrawal I definitely feel a certain fatigue but its accompanied byvery much noticeable unrest and over stimulation that's uncomfortable. I'm assuming there's more symptoms at hand here though, what makes you suspect this is a result of excess glutamate? I wasn't aware that GHB causes no dependence but I'd be surprised if there isn't some degree of downregulation and eventual glutamate rebound after cessation but I'm interested to hear more, seems like an interesting drug that I've never happened across personally. I feel very impaired when in states I'd attribute to glutamate overactivity but its marked by more confusion and scatteredness unlike the "slow" thinking I get from fatigue and sedating impairment.

No, sorry that was unclear as I put them together, but it's specifically the 'blank mind', poor word recall, poor reading comprehension, headaches, and action I can actually feel that I attribute to excess glutamate. I also have OCD, and the OCD worsens, too, which makes perfect sense also if that is what's happening. Some of this improves as the day goes on, but generally I am definitely slower and verbal fluency is hardest hit. There is also a slight disorientation/confusion aspect, takes time for situations to register, and they don't in a totally clear way.

Could you go into more detail about why you're feeling wary about it already?

Also, for what reason was it prescribed to you? I can't imagine it was to counteract Xyrem toxicity; that would be implying that your doctor's initial prescription was grossly negligent, since he'd essentially have been prescribing you a compound that he knew very well (or at least strongly believed) to be neurotoxic, while taking few or no precautions to prevent it. I know that psychiatrists can definitely be pretty inept at times (particularly with regards to dosing, especially starting doses), but I find it hard to believe that a trained doctor could make an error of that magnitude.

As for the memantine, if this continues I will give it more of a shot. I attributed some grogginess and other weird feelings to it, but it's mainly a study I came across that suggests it impairs cognitive flexibility and new learning that scared me off https://www.ncbi.nlm.nih.gov/pubmed/21860092. That, along with the fact that, as someone else pointed out, there's risk the other way with NMDA antagonism so I figure if I can do it sufficiently with supplements not nearly as strong maybe I can hit the right balance. But I think if I do go back to the memantine I'd probably drop some of the others, and stay on a very low dose, one 2.5mg every three days (it has a very long half life). The doctor who prescribed Xyrem did not prescribe the memantine (this one is someone who's worked with me for a while and trusts my own research and logic. He's more of an integrative medicine kind of doctor.)

GHB can cause all sorts of trouble with dependence and addiction but not when taken therapeutically according to exact instruction (i.e. not abused).

 

[atara]

Check studies of Xyrem use itself, like:
"Long-Term Follow-Up of Patients With Narcolepsy-Cataplexy Treated With Sodium Oxybate (Xyrem)"
"Long-Term Compliance, Safety, and Tolerability of Sodium Oxybate Treatment in Patients with Narcolepsy Type 1: A Post-Authorization, Non-Interventional Surveillance Study"
Adverse effects are very rare. Memory impairment, if any, is likely much less severe than the memory impairment associated with sleep deprivation. I feel very confident saying that 61% neuronal loss in any brain region would not produce retrospectives like this.

Also, from Pedraza et al:

"The animals were treated with saline or gammahydroxybutyric acid (GHB) (10 or 100 mg/kg) for 15 d. Rats were submitted to a neurological test on the first and last days of treatment. The animals were trained in different tasks. Experiment 1: the animals were trained in the hole-board test on days 10?15 (n=20). Experiment 2: the animals were trained in the hole-board test on days 13?15 using a variable inter-trial interval (n=20). * NCS-382 (10 mg/kg; diluted in 10% DMSO+90% saline; n=7), a putative antagonist of GHB receptor, was also used in an experiment to attempt to reverse the neurological and behavioural (hole-board test) effects of GHB (10 mg/kg). An additional group was treated with vehicle (DMSO 10%, n=8). Experiment 3: in the Morris water maze test, the animals were submitted to the spatial working memory task on days 12?15 (n=20). After the completion of the behavioural experiments (day 15), the rats were deeply anaesthetized and perfused transcardially. The brains were removed and processed. Neural and glial cell populations were estimated unilaterally in CA1 and PFC regions using stereological methods in animals evaluated in the first hole-board test."

The animals were trained while high?!

I should also note that the "inverted" neurotoxicity curve reported by Pedraza et al was not replicated in a later study:

https://www.researchgate.net/profil...rotoxicity-of-hydroxybutyric-acid-in-vivo.pdf

Honestly I wouldn't take the findings of either study without plenty of salt, because A: they contradict each other and B: there is huge variation in the control groups particularly in the second study, which to me suggests p-hacking. I mean, just look at this graph. Just look at it!

 

[Limpet_Chicken]

Not a term I've come across before, but can you further explain 'p-hijacking' atara?

 

[AlphaMethylPhenyl]

There's a disorder wherein people essentially endogenously produce excessive, inebriating levels of GHB. Brain scans of those whom went through several years or more without treatment would be a more than generous metric of toxicity.

 

[Limpet_Chicken]

Just look at what the poor bastards go through though. I assume you mean succinic semialdehyde dehydrogenase deficiency?

It isn't pretty.