Pereise1

The Cure For Narcolepsy

94 posts in this topic

Okay, so a bit of a sensationalist title, but it's what we all yearn for right? Unfortunately, because of the capitalistic limits of modern medicine, there sure doesn't seem to be anything in the pipeline other than tissue transplantation, which is a an invasive crap shoot that might just kill us once and for all with current techniques. So instead of hypotheticals, let's think as far as what we can do with what we currently know. So the cause is really of no consequence, the damage is done, and we need to get some semblance of functioning again. Granted, a number of other disorders can imitate narcolepsy, but let's focus on "Damage in the hypothalamus" Narcolepsy.

Now, it's known that after a traumatic brain injury (TBI) or a stroke, reactive gliosis by glial cells in the brain cause a glial scar to form. Evidence of this happening is detailed in the following studies:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2717206/ (Localized Loss of Hypocretin (Orexin) Cells in Narcolepsy Without Cataplexy)

https://www.uptodate.com/contents/clinical-features-and-diagnosis-of-narcolepsy-in-adults/abstract/57 (Pattern of hypocretin (orexin) soma and axon loss, and gliosis, in human narcolepsy)

 

Herein lies the hard part and the reason Narcolepsy is so hard to treat and solve. When a glial scar is formed in the Central Nervous System (CNS) or spinal cord, it forms a lining that resists axon growth. Therefore, without intervention, the scar would be permanent, and no amount of neurogenesis inducing substances would be able to penetrate the glial scar. However, research in this field has accelerated highly in recent years, and there is hope. 

The brain uses different growth factors such as BDNF, NGF, GDNF, NT3, and CNTF to extend dendritic branching and axons. The goal is to use these to grow new orexin neurons over the scar tissue in the hypothalamus, and/or convert the glial cells into functioning neurons. The glial scar has a number of ways that it inhibits growth. It's a little too complicated to go into too much detail, but I'll include a few main ones as well as links to a number of studies at the bottom.

1. Modification of sulphated proteoglycans

What are these you may ask? I'm going to quote extensively from the study "Regeneration Beyond The Glial Scar" (http://www.nature.com/nrn/journal/v5/n2/full/nrn1326.html). To start:

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In addition to growth-promoting molecules46, 47, astrocytes produce a class of molecules known as proteoglycans48, 49. These ECM molecules consist of a protein core linked by four sugar moieties to a sulphated GLYCOSAMINOGLYCAN (GAG) chain that contains repeating disaccharide units. Astrocytes produce four classes of proteoglycan; heparan sulphate proteoglycan (HSPG), dermatan sulphate proteoglycan (DSPG), keratan sulphate proteoglycan (KSPG) and chondroitin sulphate proteoglycan (CSPG)50. The CSPGs form a relatively large family, which includes aggrecan, brevican, neurocan, NG2, phosphacan (sometimes classed as a KSPG) and versican, all of which have chondroitin sulphate side chains. They differ in the protein core, as well as the number, length and pattern of sulphation of the side chains51, 52, 53. Expression of these CSPGs increases in the glial scar in the brain and spinal cord of mature animals54, 55, 56.

Proteoglycans have been implicated as barriers to CNS axon extension in the developing roof plate of the spinal cord57, 58, in the midline of the rhombencephalon and mesencephalon59, 60, at the dorsal root entry zone (DREZ)61, in retinal pattern development62, 63, and at the optic chiasm and distal optic tract64, 65. Extensive work has demonstrated that CSPGs are extremely inhibitory to axon outgrowth in culture. Neurites growing on alternating stripes of laminin and laminin/aggrecan had robust outgrowth on laminin, but at the sharp interface between the two surfaces, growth cones rapidly turned away (unlike their stalled behaviour in a gradient, see above). The inhibitory nature of the proteoglycan-containing lanes can repel embryonic as well as adult axons, and the effect can last for more than a week in vitro. The turning behaviour is not usually mediated by collapse of the entire growth cone, but rather by selective retraction of FILOPODIA in contact with CSPG and enhanced motility of those on laminin66, 67. CSPGs are potent inhibitors of a wide variety of other growth-promoting molecules, including fibronectin and L1 (Refs 68,69).

 

This is one of the most important steps to overcome. In the same study, it has been shown that, and I quote, "chondroitinase — an enzyme extracted from the bacterium Proteus vulgaris that selectively removes a large portion of the CSPG GAG side chain and renders CSPGs less inhibitory". Now, unfortunately I don't know where to get chondroitinase, if it passes the BBB, or how to guide it to the hypothalamus. However, after scouring pubmed for hours to find a replacement, I found good ol' Turmeric helps here:

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Curcumin improves neural function after spinal cord injury by the joint inhibition of the intracellular and extracellular components of glial scar

http://doi.org/10.1016/j.jss.2014.12.055

Results

We found that cur inhibited the expression of proinflammatory cytokines, such as TNF-α, IL-1β, and NF-κb; reduced the expression of the intracellular components glial fibrillary acidic protein through anti-inflammation; and suppressed the reactive gliosis. Also, cur inhibited the generation of TGF-β1, TGF-β2, and SOX-9; decreased the deposition of chondroitin sulfate proteoglycan by inhibiting the transforming growth factors and transcription factor; and improved the microenvironment for nerve growth. Through the joint inhibition of the intracellular and extracellular components of glial scar, cur significantly reduced glial scar volume and improved the Basso, Beattie, and Bresnahan locomotor rating and axon growth.

 

Turmeric also has HDAC inhibiting properties, making the brain more malleable to change and encouraging it to return to homeostasis. I won't go too deep into HDAC but it seems to help.

2. Blocking the effects of myelin

Again, what's this and what would it do? Here's another citation from the same article:

Quote

In addition to enhancing regeneration by removing the inhibitory effects of CSPGs, extensive work has shown that blocking Nogo, a myelin-associated inhibitor of regeneration, improves regeneration105. Antibodies directed against the Nogo receptor administered into spinal cord lesion sites106 or even systemically107 seem to enhance regeneration, although recent work108 has disputed whether this is truly enhanced regeneration or merely local sprouting. Indeed, it is now being suggested that most of the functional recovery that is seen when inhibitors of myelin are used occurs as a result of remodelling of local circuits, such that functional recovery is mediated along uninjured long axons108. This proposal, in conjunction with work from our laboratory demonstrating rapid axon regrowth from adult neurons in the presence of degenerating white matter83, 84, as well as the differences between growth cone collapse and dystrophy, indicates that myelin might not be acting fundamentally to inhibit long-distance regeneration. In fact, it has even been suggested that myelin might facilitate axon growth under certain conditions109.

So how do we get around this issue? Here, we turn to Longecity and the amazing research of some of users there (http://www.longecity.org/forum/topic/62431-nogo-a-inhibition-and-brain-regrowth/#entry737252). To cite only 2 studies, Ginseng and Horny Goat Weed (Icariin) are potent in this regard:

 

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RESULTS:

We determined 1) GTS (Ginsenoides) (5-80 mg/kg) treatment after a TBI improved the recovery of neurological functions, including learning and memory, and reduced cell loss in the hippocampal area. The effects of GTS at 20, 40, 60, and 80 mg/kg were better than the effects of GTS at 5 and 10 mg/kg. 2) GTS treatment (20 mg/kg) after a TBI increased the expression of NGF, GDNF and NCAM, inhibited the expression of Nogo-A, Nogo-B, TN-C, and increased the number of BrdU/nestin positive NSCs in the hippocampal formation.

 

 

Quote

Icariin, the major active component of Chinese medicinal herb epimedium brevicornum maxim, is used widely in traditional Chinese medicine for the treatment of neurological diseases. However, the effects of icariin on myelin inhibitory factors are as yet unclear. In the present study, administration of icariin at 20 mg/kg showed a marked reduction in neurological deficit of middle cerebral artery occlusion rats. Icariin exhibited better inhibitory effects on myelin inhibitory factors: Nogo-A, myelin-associated glycoprotein and oligodendrocyte myelin glycoprotein in ischemia regions of middle cerebral artery occlusion rats compared with monosialotetrahexosylganglioside. These results indicate that icariin exhibits potent inhibitory effects on expression of myelin inhibitors after middle cerebral artery occlusion-induced focal cerebral ischemia in vivo. This effect may be mediated, at least in part, by the inhibition of both Nogo-A, myelin-associated glycoprotein and oligodendrocyte myelin glycoprotein activation, followed by the enhancement of axonal sprouting and regeneration, resulting in neurological functional...

Seems Nogo is among the easier things to inhibit, thankfully.

3. Enhancing the intrinsic growth machinery.

This is pretty straightforward, we want the best environment for these new axons to differentiate and turn into full neurons:

Quote

Removal of extrinsic inhibitory cues from the glial scar with treatments such as chondroitinase might aid regeneration, but this might not be sufficient for long-range re-growth. Neurotrophin 3 (NT3) or nerve growth factor (NGF), when delivered directly to transected neurons in the dorsal columns of animals treated with peripheral nerve graft transplants, enhances growth into the graft, out the opposite end and beyond the glial scar into host tissue110, 111. Exogenous NGF administration also induces sprouting into the lesion of crushed dorsal columns112. Intrathecal or adenoviral application of NT3 or NGF to the injured DREZ induces DRG neurons to cross the peripheral nervous system/CNS barrier and penetrate some distance into the spinal cord113, 114, 115, 116, 117, where the regenerating fibres restore nocioceptive function. So, evidence from the injured spinal cord and DREZ indicates that regenerating axons can overcome proteoglycan barriers after neurotrophin stimulation, perhaps through induction of growth enhancing genes, offering an additional therapeutic strategy.

As for Nerve Growth Factor, there's myriad things that stimulate this, so whatever you decide to take, make sure you enhance it with Acetyl L-Carnitine, which is supposed to enhance NGF by x100 according to a study I've recently misplaced. As for Neurotrophin 3, again, we have some amazing phytoconstituents to help. Another Longecity thread (http://www.longecity.org/forum/topic/82911-transforming-glial-cells-into-neurons/) helped me find studies for 2 substances in particular, Chinese Skullcap and Ziziphus Jujube:

Quote

Baicalin promotes neuronal differentiation of neural stem/progenitor cells through modulating p-stat3 and bHLH family protein expression.
Signal transducer and activator of transcription 3 (stat3) and basic helix-loop-helix (bHLH) gene family are important cellular signal molecules for the regulation of cell fate decision and neuronal differentiation of neural stem/progenitor cells (NPCs). In the present study, we investigated the effects of baicalin, a flavonoid compound isolated from Scutellaria baicalensis G, on regulating phosphorylation of stat3 and expression of bHLH family proteins and promoting neuronal differentiation of NPCs. Embryonic NPCs from the cortex of E15-16 rats were treated with baicalin (2, 20 μM) for 2h and 7 days. Neuronal and glial differentiations were identified with mature neuronal marker microtubule associated protein (MAP-2) and glial marker Glial fibrillary acidic protein (GFAP) immunostaining fluorescent microscopy respectively. Phosphorylation of stat3 (p-stat3) and expressions of bHLH family genes including Mash1, Hes1 and NeuroD1 were detected with immunofluorescent microscopy and Western blot analysis. The results revealed that baicalin treatment increased the percentages of MAP-2 positive staining cells and decreased GFAP staining cells. Meanwhile, baicalin treatment down-regulated the expression of p-stat3 and Hes1, but up-regulated the expressions of NeuroD1 and Mash1. Those results indicate that baicalin can promote the neural differentiation but inhibit glial formation and its neurogenesis-promoting effects are associated with the modulations of stat3 and bHLH genes in neural stem/progenitor cells.

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The treatment with jujube water extract stimulated the expressions of neurotrophic factors in a dose-dependent manner, with the highest induction of ~100% for NGF, 100% for brain-derived neurotrophic factor (BDNF), 100% for glial cell line-derived neurotrophic factor (GDNF) and 50% for neurotrophin 3 (NT3). These results supported the neurotrophic role of jujube on the brain.

 

Now, I have no idea how long it would take, under ideal circumstances, for the brain to regrow orexin neurons after disinhibiting growth and inducing axon growth in this manner. Any help understanding the process behind regrowing the hypothalamus and guiding growth to this section of the brain would be much appreciated. In the meantime, I leave everyone with some studies:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2693386/ (Glial inhibition of CNS axon regeneration)

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3140701/ (Enhancing Central Nervous System Repair-The Challenges)

http://www.nature.com/nrn/journal/v5/n2/full/nrn1326.html (Regeneration Beyond The Glial Scar)

Also, these longecity threads helped me find a few relevant studies as well as substances to help neurogenesis:

http://www.longecity.org/forum/topic/89707-long-list-of-substances-which-heal-axons/

http://www.longecity.org/forum/topic/62431-nogo-a-inhibition-and-brain-regrowth/

http://www.longecity.org/forum/topic/72296-regenerating-prefrontal-cortex-possible/#entry735916

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All very very interesting. But, since the hypocretin neurons have been destroyed by an auto immune response, what is the point of trying to regenerate new ones when the new ones are going to be destroyed as well. Catch 22.

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15 hours ago, Ferret said:

All very very interesting. But, since the hypocretin neurons have been destroyed by an auto immune response, what is the point of trying to regenerate new ones when the new ones are going to be destroyed as well. Catch 22.

I wouldn't say that it's a sure thing the new neurons would be destroyed. If so, we wouldn't have autopsies of people in their 50s and 60s with only 30-50% of their orexin neurons destroyed. I'm not sure how it developed in your case Ferret, but I can definitely trace my narcolepsy symptoms appearing shortly after getting the flu, and worsening every 2 years, curiously right after getting sick. From the narcolepsy cases that started coming up after the H1N1 vaccine, it seems that it's possible for a flu to confuse your body into attacking itself on occasion as opposed to a continuous and constant destruction of orexin neurons. We only have so many.

And if it's possible to better symptoms, why not? The chronic inflammation involved in Narcolepsy is a factor of many of the negative symptoms as well. Check out this study done on Japanese PWN:

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Hum Immunol. 2014 Aug;75(8):940-4. doi: 10.1016/j.humimm.2014.06.023. Epub 2014 Jun 30.

Increased plasma IL-6, IL-8, TNF-alpha, and G-CSF in Japanese narcolepsy.

Abstract

Narcolepsy is a chronic hypersomnia involving excessive daytime sleepiness and cataplexy. Some susceptibility genes and environmental factors suggest that post-infectious immunological alterations underlie its pathophysiology. To investigate the immunological alterations in narcolepsy patients, we examined cytokines. Nine healthy controls and twenty-one narcolepsy patients with cataplexy were studied. All subjects were positive for the HLA-DRB1(∗)1501-DQB1(∗)0602 allele. Age-, sex-, and body mass index -matched healthy controls were selected. Plasma samples were separated using EDTA-2K-coated blood collection tubes. Bioplex Pro Human Cytokine 17-Plex Assays were used to measure plasma cytokines. Elevations of interleukin (IL)-6, IL-8, granulocyte- colony stimulating factor (G-CSF), and tumor necrosis factor-alpha were found in the narcolepsy group compared with healthy controls (p<0.05). G-CSF values were significantly correlated with the disease duration in narcolepsy patients (r=0.426, p<0.05). IL-8 and G-CSF play major roles in neutrophil activation in respiratory diseases. Since environmental factors including infection are reportedly associated with narcolepsy onset, elevated IL-8 and G-CSF may be involved in the pathophysiology of narcolepsy.

 

 

Naturally, anyone with a consistent inflammatory response 24hrs a day would feel like crap. What's more, several inflammatory cytokines induce sleepiness as well:

 
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PMCID: PMC2692603
NIHMSID: NIHMS81202

The Role of Cytokines in Sleep Regulation

Abstract

Interleukin-1 beta (IL1) and tumor necrosis factor alpha (TNF) promote non-rapid eye movement sleep under physiological and inflammatory conditions. Additional cytokines are also likely involved but evidence is insufficient to conclude that they are sleep regulatory substances. Many of the symptoms induced by sleep loss, e.g. sleepiness, fatigue, poor cognition, enhanced sensitivity to pain, can be elicited by injection of exogenous IL1 or TNF. We propose that ATP, released during neurotransmission, acting via purine P2 receptors on glia releases IL1 and TNF. This mechanism may provide the means by which the brain keeps track of prior usage history. IL1 and TNF in turn act on neurons to change their intrinsic properties and thereby change input-output properties (i.e. state shift) of the local network involved. Direct evidence indicates that cortical columns oscillate between states, one of which shares properties with organism sleep. We conclude that sleep is a local use-dependent process influenced by cytokines and their effector molecules such as nitric oxide, prostaglandins and adenosine.

 

 

At least trying to neutralize the constant inflammation put out by the glial scar in the hopes of regenerating it would help lower inflammation and theoretically, help with the fatigue. I know I personally discover every time I get sick that it somehow is possible to feel even worse, and I'm willing to bet it's because of the inflammatory response to being sick.

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wouldn't say that it's a sure thing the new neurons would be destroyed. If so, we wouldn't have autopsies of people in their 50s and 60s with only 30-50% of their orexin neurons destroyed

I have searched and I can't find one of my many links about autopsies of people who have Narcolepsy with Cataplexy who, not only have NO orexin neurons left but who have a dramatically increased number of histamine producing cells where the orexin neurons used to be.

It's going to take a long time to sort this mess out because I honestly don't think that "one" particular thing causes you to be Narcoleptic and that if you fix that "one" thing that all will be hunky-dory. There will be breakthroughs and then retractions... kind of a two steps forward and one step back if we're lucky.

To answer your question about "source"... I had a childhood filled with chronic sore throats and ear infections. They even took out my tonsils and adenoids when I was five but now that is not the recommended course of action. It didn't stop the infections anyway just made them worse because I now had no way to fight them off. I can probably pinpoint a very bad throat infected with Strep A when I was about 15 as the beginning of the end. I just got very accustomed to dragging my butt around and just took naps at every opportunity that presented itself. I did start smoking at age 16 and do believe that the nicotine acted in an immunosuppressive manner to keep me going. I stopped smoking at age 32 FOR THE BETTERMENT OF MY HEALTH.... and Cataplexy did not show up until I was 35 but started as dippy knees at about age 33. I wish that I had never stopped smoking because I truly believe that I let the genie out of the bottle.

What we need is a better diagnostic tool than the psg/mslt. How about an MRI that specifically pinpoints orexin neurons. How about some human research on the crossover between the Cannabinoid System and the Orexin System... it does exist.

In the meantime, all we can do is share our experiences of what works for us individually and hope that it helps someone else. Certainly many of the things that we do to help ourselves are not controlled by the pharmaceutical industry where profit is the main motivator. I'm getting old and cynical... but I also remember being told to eat margarine because it's better for your health than butter; don't eat fat because it's bad for you; don't eat eggs because they're bad for you.; etc. All proven to be wrong. And the search goes on.

We are all unique. Whatever works for you.

 

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@Ferret the histamine increase in N is pretty interesting. It could be a compensatory mechanism in relation to the decreased orexin or the cause of the damage to the orexin neurons. I think it's compensatory but who knows. It could also be the source of disrupted night time sleep but I doubt it's that simple. Pitolisant, an inverse agonist of the h3 receptor, which increases histamine in the cns has been shown to inhibit cataplexy and further it increases wakefulness about as effectively as modafinil. It should be making its debut in North America within a year or two. 

Don't get me started on dietary science lol. Sodium is still vilified despite low sodium diets being associated with increased all cause mortality except in a subset of hypertensives. I'm starting to think most dietary science is done by morons. 

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7 hours ago, Jasonm said:

the histamine increase in N is pretty interesting. It could be a compensatory mechanism in relation to the decreased orexin or the cause of the damage to the orexin neurons. I think it's compensatory but who knows. It could also be the source of disrupted night time sleep but I doubt it's that simple. Pitolisant, an inverse agonist of the h3 receptor, which increases histamine in the cns has been shown to inhibit cataplexy and further it increases wakefulness about as effectively as modafinil. It should be making its debut in North America within a year or two.

The study I read says histamine can double with orexin loss and so would be compensatory. It doubtless is part of the "disrupted night time sleep" story, hence the sedative action of Diphenhydramine HCL (Benadryl) on H1 receptors.

 

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@HBr From Nature Reviews:

These data lead us to conclude that the large increase in histamine neurons in human patients with narcolepsy is not a compensation for the loss of hypocretin neurons. Rather, it might result from or mediate the immune‑based loss of hypocretin neurons in these patients. As described below, the number of histamine neurons has not been reported to increase in other human neurodegenerative diseases in which hypocretin reduction occurs. In contrast with humans, the hypocretin abnormalities in animal models of narcolepsy are caused by genetic alterations, rather than the presumed immune‑mediated neuronal loss in human narcolepsy.

 

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5 hours ago, Jasonm said:

These data lead us to conclude that the large increase in histamine neurons in human patients with narcolepsy is not a compensation for the loss of hypocretin neurons. Rather, it might result from or mediate the immune‑based loss of hypocretin neurons in these patients.

Thanks for the correction, so it's not:

14 hours ago, Jasonm said:

the cause of the damage to the orexin neurons.

 

15 hours ago, Jasonm said:

Pitolisant, an inverse agonist of the h3 receptor

 

Have any of our European friends tried Pitolisant? It should be available there.

If a US resident was persistent enough, she might be able to import some now.

https://www.chionfoundation.org/single-post/2017/01/09/Personal-Importation-of-Pitolisant

http://nootropicsupplementreview.com/pitolisant-wakefulness-enhancing-agent/

 

 

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@HBr I wouldn't say the histamine issue is settled. The problem is some studies have reported lower total CSF histamine in N but increased histamine neurons in that portion of the brain. There's not a perfect animal model for human N either. Histamine is in large part what orexin stimulates to create wakefulness supposedly. It's rather weird that new histamine neurons would generate but no new orexin neurons seem to. That or they are dying upon creation. Neurogenesis was met with skepticism until recently and it's still not understood very well. I actually thought the histamine receptors upregulated, which would be more what I'd expect in a compensatory adaptation, not that new neurons were made. 

It certainly adds to ferret's concern that any new orexin neurons might simply be killed off even if the OP is right. There appears to be a subset of N patients, originally diagnosed with IH for lack of soremps that years later develop full blown N suggesting ongoing gradual damage. True type 1 N doesn't become clinically evident until something like 90% of orexin is gone but you're damn sure going to be sleepy before then. 

It begs the question, if histamine might be killing the orexin neurons, if you still have some left, is taking pitolisant going to accelerate their deaths? For someone with type 1 N+C there's probably nothing left to kill so pitolisant might be a great option for them. I'm weary of trying new drugs until they've been around for at least 5 years. I do like the idea of pitolisant a lot simply because it works on a different receptor than pretty much all other stimulants. It'd make an awesome drug to cycle with traditional stimulants to avoid receptor down regulation. It's also easy to block the stimulatory effect at night by taking a CNS penetrating antihistamine. If an anti-amphetamine existed, I'd be in heaven. 

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For anyone that is or is interested in being a fellow with too much time on their hands@Pereise1 @HBr (jk) like me and thought man that abstract sounds interesting and want the full article, try:

www.sci-hub.ac

It doesn't work for pubmed links but it does for just about every other one. I've always been able to get the full article using it. It was started by a renegade scientist that thought research shouldn't be restricted. It's pretty ridiculous that research mostly funded by tax money costs $30-40 an article. Enjoy. 

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Awesome! Thanks for the link. I really resent those dollar requests to further read or educate ourselves. Here is the clickable version (and it's now a bookmark for me).

http://www.sci-hub.ac/

 

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20 minutes ago, Ferret said:

Awesome! Thanks for the link. I really resent those dollar requests to further read or educate ourselves. Here is the clickable version (and it's now a bookmark for me).

http://www.sci-hub.ac/

 

I haven't used this yet as I recently just read about it in SA. Works with Firefox.

http://unpaywall.org/

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@Ferret you're welcome! I felt like I had more access to information on here than most people. It's sort of obscure. 

Anyone receiving grants from the government should be required to make their research open access. There seems to be progress in that direction but it's still pretty limited. I also love how taxpayers fund the majority of drug research but then have to pay huge amounts to get the medication. Pharmaceutical companies spend more on marketing than on drug development. It's sad.

I'm not opposed to unpaywall but it's pretty limited and a lot of the research available through it is outdated, particularly if you're trying to access more recent discoveries like histamine in narcolepsy, etc. Scihub just provides access to what we've already technically paid for. I certainly don't see any issues on a moral level and there aren't any legal consequences of concern. None of us is going to pay for the access anyway. If you're the type that on a deserted street doesn't jaywalk, I guess it might be an issue. 

If Pereise or anyone else wants to try to figure out a better treatment or "cure" I think they should have access to the best possible information rather than relying on longecity. At least then they have some hope, however small, to succeed. There's certainly not going to be anyone more motivated to find a novel treatment. 

One thing I've noticed since I've had unrestricted access is that wikipedia, longecity, etc are often horribly inaccurate. Use them with caution. Okay my anti-establishment rant is over! 

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f7bf0ec3836b1d4b66926f7c20dc11fd.png.d9e664b72ecfb229e19439b7573c4426.png

And ye shall know the truth, and the truth shall make you free.

John 8:32

There's only two ways to fix a problem - rely on someone else to fix it for you, or, fix it yourself. If the establishment can't, or won't, help us, we will help ourselves.

Blame it on the crow! :D

 

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Posted (edited)

Wow sorry about the delay in responding, work has been super busy.

@Ferret It's understandable to be jaded seeing as they have the tendency to pull the rug out from under our feet pretty often. However, per the article Hbr linked from Scientific American, it seems that the best stem cells are the ones we already have in our bodies. And even if we can't regrow our brain tissue for whatever reason, lowering brain inflammation will at least help mitigate symptoms. We PWN have elevated levels of TNF-A as well as several Interleukin factors. These immune factors promote sleep, and while we may not be able to find a cure, at least we don't have to feel perpetually sick. The Modern "Science" Industry is not there to work in our favor. The difference now is that we have the internet, and it's possible to cross check and discredit the majority of sham studies before we make a decision based on the results of said studies. Knowledge is power, and I'm sorry that people who were supposed to be more knowledgeable about these things failed you. Unfortunately, they've failed all of us by concentrating 95% of their efforts and $$$ into treating symptoms in new, novel, irrelevant ways. The endocannabinoid-orexin crosstalk is very interesting, unfortunately the endocannabinoid system is one of the most complicated in the CNS so more deep reading is needed.

@HBr Thanks for the links! It led me to a lot of other research and helped quite a bit!

@Jasonm I'm not 100% sure that the histamine system would be the cause of the initial Orexin autoimmune attack. It would make sense that the histaminergic system would try to compensate for the loss of orexin, as they are both in the Lateral Hypothalamus but most orexin neurons are in the Lateral Nucleus and the main histaminergic area is in the Tuberomamillary Nucleus: https://en.wikipedia.org/wiki/Hypothalamus#Nuclei

Histamine is critically important for wakefulness, however, I'm not quite sure why animal models don't have elevated levels of histamine receptors. I suspect it's because most animal models are simply gene knockout models and not an autoimmune model with heightened gliosis and some unknown genetic or environmental malformity. Paradoxically, the receptors may be raised but the levels lowered. Here's a snippet from a study on that subject:

 
Quote

 

Sleep. 2009 Feb 1; 32(2): 133–134.
PMCID: PMC2635574

Is Low Histamine a Fundamental Cause of Sleepiness in Narcolepsy and Idiopathic Hypersomnia?

Histamine is one of the most well-established wake-promoting neurotransmitters. About 25 years ago, Panula and Watanabe independently discovered that neurons of the tuberomammillary nucleus are the only source of histamine in the brain.3,4 Soon after, it became clear that these histamine-producing neurons are very active during wakefulness and inactive during sleep, especially REM sleep.57 Extracellular concentrations of histamine vary with a clear diurnal rhythm, with high levels during the wake period and low levels during sleep.810 Histamine-deficient mice have less wakefulness at the beginning of the usual active period, and mice lacking H1 receptors have fewer awakenings from sleep.11,12 Most importantly, anti-histamines (H1 receptor antagonists) promote sleep across species including humans, leading many researchers to hypothesize that histamine is a key wake-promoting neurotransmitter.1315 What has been lacking is any information on histamine signaling in clinical sleep disorders.

The papers from Nishino, Kanbayashi and colleagues now provide the first perspectives on histamine in people with sleep disorders. In a study of patients with narcolepsy compared to age-matched, healthy controls, Nishino found that on average, narcolepsy patients with low hypocretin levels have lumbar CSF histamine concentrations about 44% of normal.1 In a companion paper, Kanbayashi reports that not only were histamine levels low in patients with narcolepsy but also in patients with idiopathic hypersomnia.2 This later finding is particularly novel as (by definition!) nothing is known about the causes of sleepiness in idiopathic hypersomnia. Furthermore, this histamine deficiency may be specific to narcolepsy and idiopathic hypersomnia as patients with obstructive sleep apnea had relatively normal histamine levels.2

Both studies found some of the lowest histamine levels in narcolepsy patients with low hypocretin, and as hypocretin excites the tuberomammillary neurons, one might predict that low histamine is simply a consequence of reduced hypocretin signaling. However, the two studies are not entirely consistent: In narcolepsy patients with normal hypocretin levels, Kanbayashi describes severely reduced histamine levels (29-34% of normal), but Nishino reports a much more modest reduction (68-78% of normal). As histamine levels are low in patients with idiopathic hypersomnia who have normal hypocretin signaling, it seems likely that factors other than hypocretin deficiency underlie the reductions in histamine.

 

So it seems whatever the case may be, our histamine does not function well and more receptors =/= heightened or even adequate function. Despite not being able to sleep during my MSLT's because of stress, at home, I'm able to clock in ridiculous quantities of REM. Something I'm taking lately has helped, not sure what, but I've done my own MSLT's at home, taking five 20 minute naps at intervals of 2 hours. At home, I'm 100% I go into dreaming every time. Every time it's a slow, then swift descent into illogical thinking, a feeling of comforting but uneasy warmth, and suddenly I've forgotten I'm at home sleeping, and instead, am now possessed in some dream, usually of the negative variety. Then my alarm goes off at minute 20 and I'm confused for a while until I remember that I just took a nap and only 20 minutes had passed. This happens every time. If histamine is inactive during REM, how is it possible to dream during a 20 minute nap during the day? Orexin must have some sort of input to the Tuberomamillary Nucleus during sleep as well, since the deficit of orexin gives us this infernal dreaming but "mice lacking H1 receptors have fewer awakenings from sleep" and sleep interruptions is a feature of Narcolepsy.

I've tried Kutaj, which has the active ingredient Conessine which is an H3 antagonist and H1 and H2 agonist. I noticed it helped in reducing my desire to nap during the day, but I realized that, instead of buying an extract in capsules, I bought some the encapsulated raw root powder. So I needed 6 pills to even reach the effective dose, and ended up destroying the thing in under 2 weeks. I've seen the actual extract in capsules on ebay for $30, but it's from India so it takes forever to arrive and I've been buying too many supplements lately as it is. I could buy the powder, but it's one of the most vile things I've ever tasted, and I used to take Kratom pretty regularly. Still, it's an easy way to try of Pitolisant's method of action without going through expensive, sketchy research chemical vendors.

Edit: As for using longecity and other places, I'm aware that many times, the interpretation leaves much to be desired. However, there's a few really knowledgeable users that do a phenomenal job of scouring pubmed for studies. I can only stick my head into pubmed or ncbi for so long until my lifelong ADHD kicks in and blocks any more intents to gather info. It' for this same reason I'll sometimes go to selfhacked. The man can admirably pull up a list of many relevant studies. His interpretation of them have the tendency to be comically wrong, but they're all linked so at least I can find something I never would have looked up beforehand.

Edited by Pereise1

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@Pereise1 I'm not sure kratom is the best substance to simulate pitolisant given it's also μ-opioid receptor agonist. It's sort of like taking a stimulant and downer simultaneously. Conessine seems like it would be a closer approximation but it supposedly doesn't have much therapeutic value because of its extraordinarily long cns half life. 

I'm not saying the histamine is the cause of the orexin destruction, just that it's a possibility. It's an unsettled area. Here's the link to the article I quoted from Nature. The theories on the histamine connection are in box 1. 

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1 hour ago, Jasonm said:

@Pereise1 I'm not sure kratom is the best substance to simulate pitolisant given it's also μ-opioid receptor agonist. It's sort of like taking a stimulant and downer simultaneously. Conessine seems like it would be a closer approximation but it supposedly doesn't have much therapeutic value because of its extraordinarily long cns half life. 

I'm not saying the histamine is the cause of the orexin destruction, just that it's a possibility. It's an unsettled area. Here's the link to the article I quoted from Nature. The theories on the histamine connection are in box 1. 

Haha oh I definitely don't recommend Kratom with Pitolisant. I'm just comparing the god-awful taste of Kutaj and Kratom. That said, I actually really enjoyed Kratom when I used it, specifically the Green Maeng Da strain. It felt relaxing in the OCD/fidgety areas of my brain and stimulating in the Work hard/Play hard parts. I haven't researched Kratom enough to know why that was but it was the only thing I've taken that didn't take away very much of my sleepiness, but made it okay to be sleepy. I wouldn't need to resist the urge to sleep so much, and it wasn't as mentally taxing to do so on Kratom. I discontinued it because of dependency concerns and lowered effect but it was good while it lasted.

As for conessine, it definitely has a build-up effect after taking it for several days, similar to armodafinil. It wasn't a big build up although I don't really have any idea what the half-life is. In either case, there's a lot of natural antihistamines without the dirty, dirty anticholinergic effects of diphenhydramine. Still haven't found a natural or non-natural anti-amphetamine though. Note to self: research more on VMAT

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2 hours ago, Pereise1 said:

In either case, there's a lot of natural antihistamines without the dirty, dirty anticholinergic effects of diphenhydramine.

Please elaborate*!

*EDIT:  I mean on 'natural antihistamines' - I'm aware of the unwanted anticholinergic effects.

+++++++++++++++++++++++++++++++++++++++++++++++++++

Interesting post Pereise1 - thanks!

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it became clear that these histamine-producing neurons are very active during wakefulness and inactive during sleep, especially REM sleep.

That's the way it should work, but we have a broken switching mechanism - orexin-a loss or malfunction? So we get too much activity at night (sleep fragmentation) and not enough later in the day to ward off sleep attacks, hence for me Pitolisant sounds quite intriguing.

The beneficial effect I currently get from my Benadryl (Diphenhydramine - 25 mg) trial, which is mainly apparent during the second half of the night - the period when I believe I get most of my REM - seems to confirm their remarks. Without Benadryl, that part of the night is more a 'rest period' than sleep - the difference is amazing, if it were to last.

Are there other drugs or herbs that have this action?

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mice lacking H1 receptors have fewer awakenings from sleep.11,12 Most importantly, anti-histamines (H1 receptor antagonists) promote sleep across species including humans, leading many researchers to hypothesize that histamine is a key wake-promoting neurotransmitter.1315

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Have you tried Indica based cannabis oil? For the last nearly three years, all I've taken is about a half a grain of oil sublingually just before bed. It knocks me out and I do not wake up for seven hours. No cataplexy either. I know that it works because I couldn't take it with me to Canada last September and I was not in the best of shape when I got home.

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59 minutes ago, Ferret said:

Have you tried Indica based cannabis oil? For the last nearly three years, all I've taken is about a half a grain of oil sublingually just before bed. It knocks me out and I do not wake up for seven hours. No cataplexy either. I know that it works because I couldn't take it with me to Canada last September and I was not in the best of shape when I got home.

I've tried 'em all*, including 'the wildwood weed'. Didn't help a bit, but it did make me 'dope'y and wreaked havoc with my tinnitus, so watch out for that one.

I used most of it to water the neighbor's 'weed's. :)

* With the exception of Xyrem.

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@Pereise1 I tried kratom because I read it was like caffeine without the edge. Oh boy was I in for a surprise when I got high as a kite and I tried the stimulatory variety. It did have some stimulatory value but good lord I'd hate to see what the pain relief varieties do. From my understanding opiates cause a histamine release. I certainly felt itchy. I can't believe it's legal to be honest. 

Conessine's cns half life is so long apparently after 24 hours, it's barely lowered. I guess you might be able to counteract the effect with an antihistamine but it'd have to be one that could displace the Conessine and that sounds laborious. 

@HBr benadryl suxors. You're doing a lot more than jacking with histamine with that one. This is a useful primer on some basic pharmacology principles. Low dose doxepin is far superior and has been studied. It's particularly effective in older people. You can pay an obnoxious amount (like $300) and get Silenor or just cut a 10mg doxepin capsule open and take half ($4). No next day impairment either, which is extremely unusual for a sleep med. You could probably just call in ask ask for an Rx. It's not scheduled. 

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3 hours ago, Jasonm said:

This is a useful primer on some basic pharmacology principles.

Good read. :)

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What do you use to sleep?
 
I don't sleep anymore.
 

Maybe I'll hire somebody to whack me over the head with a bat at bedtime - lightly of course!

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Glad you liked it. It helped me understand how the crap we take does more than the label says. Remember though those charts are kind of deceptive. Just because it has a higher affinity for one receptor, doesn't mean it isn't activating another even at low doses. If something has a 90% affinity for receptor x and a 10% for receptor y, 10% is still hitting receptor y at any dose, maybe just not enough for it to matter. Benadryl sucks because it's not that selective for histamine. Well that and it's a cyp2d6 inhibitor, which is bad news bears. Doxepin is very selective for h1 so it's a much better option.

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@HBr As for natural antihistamines, Kava seems to lower CNS histamine, although more so the leaf extract:

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Interaction of various Piper methysticum cultivars with CNS receptors in vitro.

Abstract

Methanolic leaf and root extracts of the Hawaiian kava (Piper methysticum Forst.) cultivars, Mahakea, Nene, Purple Moi and PNG, were tested on binding affinities to CNS receptors including GABAA (GABA and benzodiazepine binding site), dopamine D2, opioid (mu and delta), serotonin (5-HT6 and 5-HT7) and histamine (H1 and H2). HPLC analysis was carried out in order to determine the amount of the main kavalactones kavain, 7,8-dihydrokavain, methysticin, 7,8-dihydromethysticin, yangonin and 5,6-demethoxyyangonin. The most potent binding inhibition was observed for leaf extracts to GABAA receptors (GABA binding site) with IC50 values of approximately 3 micrograms/ml, whereas root extracts were less active with II C50 values ranging from 5 micrograms/ml (Nene) to 87 micrograms/ml (Mahakea). Since the leaf extracts generally contained lower amounts of the kavalactones than the root extracts, there might exist additional substances responsible for these activities. Leaf extracts also inhibited binding to dopamine D2, opioid (mu and delta) and histamine (H1 and H2) receptors more potently than the corresponding root extracts with IC50 values ranging from 1 to 100 micrograms/ml vs. > or = 100 micrograms/l, respectively. Significant differences in the potential of binding inhibition were also observed between cultivars. Binding to serotonin (5-HT6 and 5-HT7) and benzodiazepine receptors was only weakly inhibited by both root and leaf extracts of all four cultivars. In conclusion, our investigation indicates that the GABAA, dopamine D2, opioid (mu and delta) and histamine (H1 and H2) receptors might be involved in the pharmacological action of kava extracts. Since the cultivars contained similar amounts of kavalactones, while their pharmacological activities differed markedly, other constituents may play a role in the observed activities. Additionally, leaves generally exhibited more potent binding inhibition than roots, therefore leaf of P. methysticum might be an interesting subject for further pharmacological studies.

PMID:11458444
DOI:10.1055/s-2001-14334

I would be careful to get a quality leaf extract though. It seems that when the hysteria about Kava liver toxicity was going on, it was mainly pertaining to the raw leaves being used as opposed to a aqueous extract of the powdered root. Apparently the leaves are used medicinally. A few more:

Reishi lowers peripheral histamine, not too sure about CNS (http://www.mycologyresearch.com/articles/view/28)

Stinging Nettle is an H1 antagonist (http://onlinelibrary.wiley.com/doi/10.1002/ptr.2763/abstract)

Mangosteen is also an effective h1 antagonist (https://www.ncbi.nlm.nih.gov/pubmed/9503424)

Most other natural antihistamines tend to deactivate mast cells, helping primarily with allergy related histamine release. Higher CNS histamine and Norepinephrine during the day seem to be necessary to produce Slow Wave Sleep for some odd reason:

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Slow Wave Activity During Sleep: Functional and Therapeutic Implications

http://sci-hub.ac/10.1177/1073858410377064

These neuromodulators have potent effects on cortical excitation and arousal, but whether they have direct effects on SWA regulation is unclear. Knock-out (KO) mice lacking the histidine decarboxylase gene (Parmentier and others 2002) or the D2 receptor (Qu and others 2010) are sleepier during the normal active period and SWS SWA is slightly reduced during the normal rest period. This latter SWA reduction may be secondary to an inability to maintain wakefulness (i.e., a reduced accumulation of sleep need), rather than direct effects on the ability to generate SWA. For example, D2 KO mice show normal compensatory changes in SWS SWA after sleep deprivation (Qu and others 2010). Interestingly, neurotoxin depletion of norepinephrine reduces compensatory increases in SWS SWA after sleep deprivation (Cirelli and others 2005). This finding is consistent with the hypothesis that norepinephrine release during waking is necessary for the accumulation of sleep need, possibly by promoting brain plasticity.

 

So histamine is an interesting thing and seems to be tied into our inability to get restful sleep.

@Jasonm Lol yes, Kratom can be a powerful thing. I too was opioid naive and almost vomited the first time I tried it. I lowered the dose and once I found my sweet spot, it helped for a little while. That said, I don't support the scheduling of Kratom. Since it's not exactly patentable, the scheduling is almost guaranteed to make it difficult to get for people trying to get off Norco/Oxy or who have a legitimate use. Seeing how predatory the pharmaceutical companies are with chronic pain sufferers, after working in pain management for about a year, makes me highly distrusting of any FDA/DEA "public safety" initiative.

@Ferret I have found that Cannabis definitely helps with my crazy, tiring dreams. However, I can't use it when I take Armodafinil because after wondering for a long time why the effects take forever to wear off, I found out that THC is metabolized mainly by liver enzymes CYP2C9 and CYP2C19, both inhibited by Armodafinil. Even after not taking it though, I still find it hard to get an exact therapeutic dose for it. Edibles last too long, and vaporized Cannabis wears off by the second half of the night. I'm hoping to maybe get back into it down the road though, the memory effects are easily mitigated and the anti-inflammatory and anti-stress benefits are quite potent.

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