28 replies to this topic

[Pereise1]

So I've been trying out Ceretropic's Orexin-A for a month and have ordered another 5mg vial. As a person with Narcolepsy 2, this has been the single best substance I've ever tried, cutting my need for Amps/Armodafinil in half with better results. I had tried it for about 3 days when it barely arrived, however, I had a trip planned to the Dominican Republic so I left it at home, starting it up again just this week. I noticed that the great feeling I had during the first 3 days slowly starting waning by the end of my trip. When I got back, I got back to "normal" after supplementing with Orexin again but quickly became sick due to working in a hospital 

Now, people who have Narcolepsy with Cataplexy, type 1, have an almost complete destruction of orexin in the hypothalamus. In the 2 autopsys done on people with Narcolepsy without Cataplexy, type 2, only a localized loss of orexin neurons was found:

https://www.ncbi.nlm...les/PMC2717206/ - Localized Loss of Hypocretin (Orexin) Cells in Narcolepsy Without Cataplexy

 

This leads me to a question: Can anybody (theoretically) think of a way to make this permanent? Would something that boosts CNTF help repopulate orexin neurons or orexin producing neurons in my hypothalamus?

 

To complicate matters, I more than likely have a damaged serotonin transporter from being prescribed paroxetine when I was 16, then stopping cold turkey when I was 17 (6 years ago). I currently take Berberine, Gingko Biloba, and Ginseng for that and Tianeptine Sulfate, Quality Royal Jelly, and Zizipheus Jujuba (SP?) for the BDNF and HPA axis help.

 

For wakefulness, I take 150mg of Armodafinil and 10-20mg dextroamphetamine a few hours later as Armodafinil alone doesn't keep me very awake. I also just bought a box of nicotine patches for use every other day as I understand it upregulates prepro-orexin producing neuron MRna but I'm not quite sure what else would help with that aside from fasting.

 

Also, thanks everyone for the years of accumulated scientific information. Most Narcolepsy boards are filled with people who can only muster up enough energy to take their Vyvanse and nothing else. Not the best source for someone who's tired of being tired and who has a fascination with how the mind works.

[Omega 3 Snake Oil]

My thalamus and hypothalamus appear to be burnt out but I'm afraid it's from Lyme and maybe prions..

[William Sterog]

If you're sleepy be careful with Jujuba, it may cause drowsiness if the extract is good enough, I recommend you to take it before going to bed. I'm a big fan of this plant, and I feel like it is the way to go. 
 

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.

http://repository.us...rd/1783.1-71745

 

According to Ki67 and doublecortin immunostaining, neurons in the dendate gyrus were significantly enhanced at 40mg/kg and increased further at 100mg/kg (although not significantly different than 40mg/kg) with the percentage increase being 475% and 672%, respectively and relative to control.[37] Most of this enhancement was due to increased amounts of tertiary dendrites at both concentrations (354% and 579%, respectively), suggesting dendritic proliferation or an attenuation of dendritic loss associated with aging.[37]

https://www.ncbi.nlm...pubmed/21332397

 

I don't know how much will it help your problem. If your lack of orexin neurons is congenital or acquired by some infection, or even the degree of damage will determine the results you can achieve. Also, consider adding ALCAR to your stack, it helps me with wakefulness and it also promotes NGF.

 

https://www.ncbi.nlm.../pubmed/1324679

https://www.ncbi.nlm.../pubmed/8187841

 

One last thing, have you ever got your Vitamin D levels checked? 

[Pereise1]

If you're sleepy be careful with Jujuba, it may cause drowsiness if the extract is good enough, I recommend you to take it before going to bed. I'm a big fan of this plant, and I feel like it is the way to go. 
 

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.

http://repository.us...rd/1783.1-71745

 

According to Ki67 and doublecortin immunostaining, neurons in the dendate gyrus were significantly enhanced at 40mg/kg and increased further at 100mg/kg (although not significantly different than 40mg/kg) with the percentage increase being 475% and 672%, respectively and relative to control.[37] Most of this enhancement was due to increased amounts of tertiary dendrites at both concentrations (354% and 579%, respectively), suggesting dendritic proliferation or an attenuation of dendritic loss associated with aging.[37]

https://www.ncbi.nlm...pubmed/21332397

 

I don't know how much will it help your problem. If your lack of orexin neurons is congenital or acquired by some infection, or even the degree of damage will determine the results you can achieve. Also, consider adding ALCAR to your stack, it helps me with wakefulness and it also promotes NGF.

 

https://www.ncbi.nlm.../pubmed/1324679

https://www.ncbi.nlm.../pubmed/8187841

 

One last thing, have you ever got your Vitamin D levels checked? 

 

I've been taking Jujuba before sleeping, I find it helps for that as well. It does seem almost too good to be true, especially given how cheap it is compared to, say, cerebrolysin.

 

Thanks for the tip as far as ALCAR, I had already added it in for the anti-fatigue benefits but the NGF thing is just icing on the cake. As for my orexin neurons, the study in the OP mentioned that the patient with Narcolepsy without Cataplexy had gliosis in only part of the hypothalamus. I assume I have something similar going on. In my case, my narcolepsy has gotten worse every time I get the common cold, which is rare but coincides with every plateau on the way down. I hypothesize that the boost in Il-6 and TNF-a when sick is involved in the pathogenesis of narcolepsy, as many other people with narcolepsy can trace their symptoms back to a really bad flu and because people with narcolepsy seem to have chronic increased immune response (https://www.ncbi.nlm...pubmed/24994458)

[logicmuffin]

For a second I was going to comment that there's no such thing as hypothalamic neurogenesis because I many papers talk about neurogenesis being highly localized in the hippocampus. But then I saw:

 

 

Hypothalamic neurogenesis persists in the aging brain and is controlled by energy-sensing IGF-I pathway.

 

Link: https://www.ncbi.nlm...pubmed/27103519

 

I'm shocked!

[Omega 3 Snake Oil]

For a second I was going to comment that there's no such thing as hypothalamic neurogenesis because I many papers talk about neurogenesis being highly localized in the hippocampus. But then I saw:

 

 

Hypothalamic neurogenesis persists in the aging brain and is controlled by energy-sensing IGF-I pathway.

 

Link: https://www.ncbi.nlm...pubmed/27103519

 

I'm shocked!

 

Nice, this is encouraging for me. I've had horrible autonomic dysfunction and insomnia and I'm worried about my thalamus/hypothalamus. I'm doing a lot to try and regain neurons: CBD oil, tons of supplements, biofeedback, essential oils. I've actually seen slight improvement in the past few months. Maybe there's something to this...
 

[Omega 3 Snake Oil]

Also: this was just recommended to me. Does anyone think it might actually help the hypothalamus? Dessicated pig brain extract?

https://www.standard...ypothalamus-PMG



 

[striker_321]

There is a substance that appears to have a pronounced effect on hypothalamic BDNF expression. Good luck finding it though, it is not made or sold in the US.

 

J Psychopharmacol. 2013 Oct;27(10):930-9. doi: 10.1177/0269881113497614. Epub 2013 Jul 17.

Captodiamine, a putative antidepressant, enhances hypothalamic BDNF expression in vivo by synergistic 5-HT2c receptor antagonism and sigma-1 receptor agonism.

Ring RM1, Regan CM.

Author information

 

Abstract

The putative antidepressant captodiamine is a 5-HT2c receptor antagonist and agonist at sigma-1 and D3 dopamine receptors, exerts an anti-immobility action in the forced swim paradigm, and enhances dopamine turnover in the frontal cortex. Captodiamine has also been found to ameliorate stress-induced anhedonia, reduce the associated elevations of hypothalamic corticotrophin-releasing factor (CRF) and restore the reductions in hypothalamic BDNF expression. Here we demonstrate chronic administration of captodiamine to have no significant effect on hypothalamic CRF expression through sigma-1 receptor agonism; however, both sigma-1 receptor agonism or 5-HT2c receptor antagonism were necessary to enhance BDNF expression. Regulation of BDNF expression by captodiamine was associated with increased phosphorylation of transcription factor CREB and mediated through sigma-1 receptor agonism but blocked by 5-HT2c receptor antagonism. The existence of two separate signalling pathways was confirmed by immunolocalisation of each receptor to distinct cell populations in the paraventricular nucleus of the hypothalamus. Increased BDNF induced by captodiamine was also associated with enhanced expression of synapsin, but not PSD-95, suggesting induction of long-term structural plasticity between hypothalamic synapses. These unique features of captodiamine may contribute to its ability to ameliorate stress-induced anhedonia as the hypothalamus plays a prominent role in regulating HPA axis activity.

https://www.ncbi.nlm...ubmed/23863923 

 

 

[Pereise1]

 

There is a substance that appears to have a pronounced effect on hypothalamic BDNF expression. Good luck finding it though, it is not made or sold in the US.

 

J Psychopharmacol. 2013 Oct;27(10):930-9. doi: 10.1177/0269881113497614. Epub 2013 Jul 17.

Captodiamine, a putative antidepressant, enhances hypothalamic BDNF expression in vivo by synergistic 5-HT2c receptor antagonism and sigma-1 receptor agonism.

Ring RM1, Regan CM.

Author information

 

Abstract

The putative antidepressant captodiamine is a 5-HT2c receptor antagonist and agonist at sigma-1 and D3 dopamine receptors, exerts an anti-immobility action in the forced swim paradigm, and enhances dopamine turnover in the frontal cortex. Captodiamine has also been found to ameliorate stress-induced anhedonia, reduce the associated elevations of hypothalamic corticotrophin-releasing factor (CRF) and restore the reductions in hypothalamic BDNF expression. Here we demonstrate chronic administration of captodiamine to have no significant effect on hypothalamic CRF expression through sigma-1 receptor agonism; however, both sigma-1 receptor agonism or 5-HT2c receptor antagonism were necessary to enhance BDNF expression. Regulation of BDNF expression by captodiamine was associated with increased phosphorylation of transcription factor CREB and mediated through sigma-1 receptor agonism but blocked by 5-HT2c receptor antagonism. The existence of two separate signalling pathways was confirmed by immunolocalisation of each receptor to distinct cell populations in the paraventricular nucleus of the hypothalamus. Increased BDNF induced by captodiamine was also associated with enhanced expression of synapsin, but not PSD-95, suggesting induction of long-term structural plasticity between hypothalamic synapses. These unique features of captodiamine may contribute to its ability to ameliorate stress-induced anhedonia as the hypothalamus plays a prominent role in regulating HPA axis activity.

https://www.ncbi.nlm...ubmed/23863923 

 

 

 

No lie, I spent maybe 3 hours a while ago trying to find a non-lab supplier for captodiamine. It seems to be exceptionally difficult to get, might have to make a visit to Europe at some point because aside from P21, this seems to be the most promising substance I've come across.

 

Edit: If there's anybody looking to sell some, PM me.

Edited by Pereise1, 06 March 2017 - 09:30 PM.

[Mind_Paralysis]

 

 

There is a substance that appears to have a pronounced effect on hypothalamic BDNF expression. Good luck finding it though, it is not made or sold in the US.

 

J Psychopharmacol. 2013 Oct;27(10):930-9. doi: 10.1177/0269881113497614. Epub 2013 Jul 17.

Captodiamine, a putative antidepressant, enhances hypothalamic BDNF expression in vivo by synergistic 5-HT2c receptor antagonism and sigma-1 receptor agonism.

Ring RM1, Regan CM.

Author information

 

Abstract

The putative antidepressant captodiamine is a 5-HT2c receptor antagonist and agonist at sigma-1 and D3 dopamine receptors, exerts an anti-immobility action in the forced swim paradigm, and enhances dopamine turnover in the frontal cortex. Captodiamine has also been found to ameliorate stress-induced anhedonia, reduce the associated elevations of hypothalamic corticotrophin-releasing factor (CRF) and restore the reductions in hypothalamic BDNF expression. Here we demonstrate chronic administration of captodiamine to have no significant effect on hypothalamic CRF expression through sigma-1 receptor agonism; however, both sigma-1 receptor agonism or 5-HT2c receptor antagonism were necessary to enhance BDNF expression. Regulation of BDNF expression by captodiamine was associated with increased phosphorylation of transcription factor CREB and mediated through sigma-1 receptor agonism but blocked by 5-HT2c receptor antagonism. The existence of two separate signalling pathways was confirmed by immunolocalisation of each receptor to distinct cell populations in the paraventricular nucleus of the hypothalamus. Increased BDNF induced by captodiamine was also associated with enhanced expression of synapsin, but not PSD-95, suggesting induction of long-term structural plasticity between hypothalamic synapses. These unique features of captodiamine may contribute to its ability to ameliorate stress-induced anhedonia as the hypothalamus plays a prominent role in regulating HPA axis activity.

https://www.ncbi.nlm...ubmed/23863923 

 

 

 

No lie, I spent maybe 3 hours a while ago trying to find a non-lab supplier for captodiamine. It seems to be exceptionally difficult to get, might have to make a visit to Europe at some point because aside from P21, this seems to be the most promising substance I've come across.

 

Edit: If there's anybody looking to sell some, PM me.

 

 

 

This substance may be more suitable for a group buy instead then - to get a custom synthesis going, and if the group buy is successful, and others, with narcolepsy or other hypothalamic disease or damage report positive effects, then it could easily become more available.

 

Someone has to take the first step though, and if so, that step is best pushed by YOU! = D

 

 

Small side-note though... how far along has fMRI, PET and SPECT -imaging come with identifying the mechanisms and observable alterations of the Narcoleptic mind? Can this potential damage to the Hypothalamus actually be SEEN?

 

If so, I would recommend that you first, before you try substances which enhance hypothalamic neurogenesis, try and get a fMRI or SPECT -scan of your brain to make sure that this is a prominent region of your brain, showing structural abnormalities - that way, you can make SURE that what you're going to try would have a positive effect - otherwise you might set yourself up for a disappointment and a substantial loss of money. : [

 

Looking closer at it though, it would seem as if there has been substantial neuroimaging studies to support your finding of hypothalamic damage... it does mention how it's not an ubiquitous observation though - just for some majority of the patients - so there's still a shot that you could be one of the patients who have some other mechanism behind your disease.

 

If you could get neuroimaging data on yourself, then you could make SURE you're one of the patients who could benefit - remember, these are experimental drugs, and they would be created under different circumstances than regular medications - under such conditions, I think it's best to make sure you're the right kind of patient.

 

 

Neuroimaging of Narcolepsy

http://link.springer...-319-23739-8_13

[Pereise1]

@stinkorninjor I would love to get imaging done, however, I do have medicaid so it might be an interesting process trying to get it approved    .

 

On another note, I came up on an interesting study regarding the role of CNTF when a glial scar is present.

 

http://www.pnas.org/...3/5865.full.pdf - 

 

Within the central nervous system (CNS) ciliary neurotrophic factor (CNTF) is expressed by astrocytes where it remains stored as an intracellular protein; its release and function as an extracellular ligand are thought to occur in the event of cellular injury. We find that overexpression of CNTF in transgenic mice recapitulates the glial response to CNS lesion, as does its injection into the uninjured brain. These results demonstrate that CNTF functions as an inducer of reactive gliosis, a condition associated with a number of neurological diseases of the CNS.

 

 

 

From the autopsy reports on narcoleptics I've read, there does seem to be gliosis in the lateral hypothalamus:

 

 

 

 

Sleep. 2009 Aug 1; 32(8): 993–998.

PMCID: PMC2717206

Localized Loss of Hypocretin (Orexin) Cells in Narcolepsy Without Cataplexy

Thomas C. Thannickal, PhD,1,2,3 Robert Nienhuis, BS,1 and Jerome M. Siegel, PhD1,2,3

Neither of the narcolepsy without cataplexy patients had a loss of Hcrt axons in the anterior hypothalamus. The narcolepsy without cataplexy patient whose entire brain was available for study had an overall loss of 33% of hypocretin cells compared to normals, with maximal cell loss in the posterior hypothalamus. We found elevated levels of gliosis with GFAP staining, with levels increased in the posterior hypothalamic nucleus by (295%), paraventricular (211%), periventricular (123%), arcuate (126%), and lateral (72%) hypothalamic nuclei, but not in the anterior, dorsomedial, or dorsal hypothalamus. There was no reduction in the number of MCH neurons in either patient.

 

 

 

 

This suggests to me that inducing CNTF is probably not the best idea. I'm now starting to look into NeuroD1 inducers, Nogo-1 inhibitors, and the role of Fibroblast Factors in all this. Will report back.

Edited by Pereise1, 05 April 2017 - 01:13 AM.

[BieraK]

Why noopept reduces libido? Perhaps has to do with this:
 

[On the mechanism of noopept action: decrease in activity of stress-induced kinases and increase in expression of neutrophines].

[Article in Russian]

Ostrovskaia RU, Vakhitova IuV, Salimgareeva MKh, Iamidanov RS, Sadovnikov SV, Kapitsa IG, Seredenin SB.

Abstract

The influence of noopept (N-phenylacetyl-L-prolylglycine ethyl ester, GVS-111)--a drug combining the nootrope and neuroprotector properties--on the activity of mitogen-activated protein kinases (MAPKs) and the level of NGF and BDNF gene and protein expression in the frontal cortex, hippocampus, and hypothalamus has been studied in rats. Under conditions of chronic administration (28 days, 0.5 mg/day, i.p.), noopept decreased the activity of stress-induced kinases (SAPK/JNK 46/54 and pERK1/2) in rat hippocampus and increases the level of mRNA of the BDNF gene in both hypothalamus and hippocampus. The content of BDNF protein in the hypothalamus was also somewhat increased. In the context of notions about the activation of stress-induced kinases, as an important factor of amyloidogenesis and tau-protein deposition in brain tissue, and the role of deficiency of the neurotrophic factors in the development of neurodegenerative processes, the observed decrease in the activity of stress-activated MAPKs and increased expression of BDNF as a result of noopept administration suggest thatthis drug hasaspecific activity withrespect to some pathogenetic mechanisms involved in the Alzheimer disease.

 

[tunt01]

Covatine/captodiame seems pretty interesting.  It looks like TeamTLR looked at synthesizing it a couple years ago.  Maybe they could facilitate a groupbuy.  If anyone knows them, maybe reach out to them.  

[normalizing]

interested in both orexin a and captodiame for problems with narcolepsy

 

question about orexin a to the initial thread starter, how do you deal with a vial of this stuff, you inject it straight into the bloodstream?? that seems harsh!! i was hoping to try it, but IV kind of scares me off :(

[Hyperflux]

Orexin-A nasal spray is truly amazing. You just become wide awake, it feels so natural unlike modafinil or amphetamine. It's kind of scary because it masks sleep deprivation so well, it doesn't feel like you're overriding it with some stimulant it actually feels like you got a full 8-12 hours of quality sleep. 

[Irishdude]

Orexin-A nasal spray is truly amazing. You just become wide awake, it feels so natural unlike modafinil or amphetamine. It's kind of scary because it masks sleep deprivation so well, it doesn't feel like you're overriding it with some stimulant it actually feels like you got a full 8-12 hours of quality sleep. 

How often do you use it and how long have been using that schedule?

[Hyperflux]

 

Orexin-A nasal spray is truly amazing. You just become wide awake, it feels so natural unlike modafinil or amphetamine. It's kind of scary because it masks sleep deprivation so well, it doesn't feel like you're overriding it with some stimulant it actually feels like you got a full 8-12 hours of quality sleep. 

How often do you use it and how long have been using that schedule?

 

 

I've been using it almost daily since finals have started first thing in the morning at a dose of 150ug (4 sprays, 2ug/kg bodyweight). The only issue is that Orexin in reconstituted form only has a shelf life of 2-4 weeks so you want to use it fast, or reconstitute a smaller amount at a time.

[normalizing]

all i can find is orexin a vial, linked to ceretropic. so probably dilute it and spray instead of shoot? also, how long does the awakeness last, can you ever go back to sleep?

[Pereise1]

all i can find is orexin a vial, linked to ceretropic. so probably dilute it and spray instead of shoot? also, how long does the awakeness last, can you ever go back to sleep?

 

Exactly that, they have an empty nasal spray bottle if you don't already have one.

 

Also, spraying the Orexin-A in the morning lasts me long enough, I find a large (400-600ug) dose to last me all day while a shorter one will last me less time but the comedown is smooth and natural in my opinion. No sleep problems for me, as a narcoleptic, and I find it normalizes my sleep, reducing the amount of freakish, covered in sweat REM cycles.

[normalizing]

interesting. i also suffer from narcolepsy but the moment i try to sleep, i cant, which is contradictory as i feel like falling asleep all day. i usually take stimulants during the day though, could be related to sleep problems, but im always worried orexin a might be a bit too potent and cause someone with sleep problems to maybe go without rest for days

[Hyperflux]

It feels like Orexin taken in the morning almost increases my sleep quality, because I feel sleepier at night. I've never tried a dose of 400-600ug. you must be woke AF. I get adequate wakefulness with 150ug.

 

 

[Pereise1]

It feels like Orexin taken in the morning almost increases my sleep quality, because I feel sleepier at night. I've never tried a dose of 400-600ug. you must be woke AF. I get adequate wakefulness with 150ug.

 

Heh, when I first started feeling like a human being after my first dose of orexin, I realized it definitely had to be a orexin/hypothalamus related issue. It doesn't even get me feeling all that awake, as my baseline is far lower than a healthy individual, but it seems to click that one button the amphetamines and armodafinil don't even touch.

[Pereise1]

So it seems that the Sigma receptors have a role in hypothalamic neurogenesis. This I got from the following studies:

Quote


J Psychopharmacol. 2013 Oct;27(10):930-9. doi: 10.1177/0269881113497614. Epub 2013 Jul 17.
Captodiamine, a putative antidepressant, enhances hypothalamic BDNF expression in vivo by synergistic 5-HT2c receptor antagonism and sigma-1 receptor agonism.

Abstract

The putative antidepressant captodiamine is a 5-HT2c receptor antagonist and agonist at sigma-1 and D3 dopamine receptors, exerts an anti-immobility action in the forced swim paradigm, and enhances dopamine turnover in the frontal cortex. Captodiamine has also been found to ameliorate stress-induced anhedonia, reduce the associated elevations of hypothalamic corticotrophin-releasing factor (CRF) and restore the reductions in hypothalamic BDNF expression. Here we demonstrate chronic administration of captodiamine to have no significant effect on hypothalamic CRF expression through sigma-1 receptor agonism; however, both sigma-1 receptor agonism or 5-HT2c receptor antagonism were necessary to enhance BDNF expression. Regulation of BDNF expression by captodiamine was associated with increased phosphorylation of transcription factor CREB and mediated through sigma-1 receptor agonism but blocked by 5-HT2c receptor antagonism. The existence of two separate signalling pathways was confirmed by immunolocalisation of each receptor to distinct cell populations in the paraventricular nucleus of the hypothalamus. Increased BDNF induced by captodiamine was also associated with enhanced expression of synapsin, but not PSD-95, suggesting induction of long-term structural plasticity between hypothalamic synapses. These unique features of captodiamine may contribute to its ability to ameliorate stress-induced anhedonia as the hypothalamus plays a prominent role in regulating HPA axis activity.



Now, I looked long and hard and it seems basically impossible to get out of Europe. However, interestingly enough, it seems Desoxyn (Methamphetamine) raises Orexin while Dextroamphetamine does not. Methamphetamine, interestingly enough, is also a Sigma agonist:

Quote


Psychiatry Res. 2016 May 30;239:9-11. doi: 10.1016/j.psychres.2016.02.059. Epub 2016 Feb 27.
Orexin-A level elevation in recently abstinent male methamphetamine abusers.

Abstract
Research has suggested that methamphetamine (METH) use influences orexin regulation. We examined the difference in orexin-A levels between METH abusers and healthy controls. Fasting serum orexin-A levels were measured in 35 participants who used METH in the preceding 3 weeks and 36 healthy controls. We found METH abusers had significantly higher orexin-A levels. No association was observed between orexin-A levels and METH use variables. Our results, consistent with prior preclinical evidence, showed that recent METH exposure is associated with increased orexin-A expression. Further investigation is required to determine whether orexin-A levels normalize after a longer term of abstinence.







I'm not quite sure what the implications of this would be. In the study "Immunocytochemical localization of the sigma(1) receptor in the adult rat central nervous system" (https://www.ncbi.nlm...pubmed/10771347), they did find Sigma receptors in the following places:

Quote
Diencephalon. Behind the olfactory bulb, the most intense immunostainings were detected in the hypothalamus (Fig. 6). Here, intense immunostaining was associated with perikarya of various sizes and with processes that were dispersed throughout the whole hypothalamus. In all of the brains examined, the highest staining intensities were associated with cells located in the supraoptic (Fig. 6A), the paraventricular (Fig. 6B), the arcuate (Fig. 6C) and the periventricular nuclei. In the thalamus, moderate to intense immunostaining was only detected in cells located in the habenula and the reticular nucleus, with the other thalamic subdivisions exhibiting faint if any immunostaining.

These are not located in the Lateral Hypothalamus, were most orexin neurons are located, but targeted those regions (Supraoptic, Paraventricular Nucleus, and the Arcuate) should enhance the signaling of Vasopressin, Oxytocin, and Growth hormone-releasing hormone. Vasopressin and Oxytocin seem to have positive effects on Orexin signaling, and GNRH directly promotes Slow Wave Sleep so perhaps that's why Sigma agonism seems to help in Hypothalamic neurogenesis. If someone knew of another reason why Sigma signaling seems to help, I'd highly appreciate the input.

[PeaceAndProsperity]

Sigma agonism promotes neurogenesis? Won't look good for the new antipsychotics then..

[normalizing]

very informative post peaceandprosperity, thank you

[Mind_Paralysis]

Sigma agonism promotes neurogenesis? Won't look good for the new antipsychotics then..

In a specific area.

So even if the new classes of antipsychotics impair neurogenesis in one region, it may not be relevant for anyone but Narcoleptics.

 

There's also ample evidence that the new antipsychotics promote neurogenesis in OTHER regions of the brain - hence why BREXpiprazol is the first officially approved AP for the treatment of depression.

 

Please also take into account, that the compound the poster used for reference, was METHAMPHETAMINE! A very, very dangerous drug, which has been known to induce damn near treatment-refractory depression, and seems to cause very CLEAR neurodegeneration once you go past a certain dosage.

 

 

And finally, don't forget that Schizophrenic and Narcoleptic brains are fundamentally different in their disease-mechanisms - which makes speculation about the nature of crossover-effects rather dubious - the drugs are meant to do completely different things.

[Pereise1]

 

Sigma agonism promotes neurogenesis? Won't look good for the new antipsychotics then..

In a specific area.

So even if the new classes of antipsychotics impair neurogenesis in one region, it may not be relevant for anyone but Narcoleptics.

 

There's also ample evidence that the new antipsychotics promote neurogenesis in OTHER regions of the brain - hence why BREXpiprazol is the first officially approved AP for the treatment of depression.

 

Please also take into account, that the compound the poster used for reference, was METHAMPHETAMINE! A very, very dangerous drug, which has been known to induce damn near treatment-refractory depression, and seems to cause very CLEAR neurodegeneration once you go past a certain dosage.

 

 

And finally, don't forget that Schizophrenic and Narcoleptic brains are fundamentally different in their disease-mechanisms - which makes speculation about the nature of crossover-effects rather dubious - the drugs are meant to do completely different things.

 

 

Thanks for that comment, unfortunately even Methamphetamine doesn't seem to affect Narcoleptics the same. The abuse potential is gone when something that's supposed to make people stay up for 3 days straight can barely make them stay awake until the evening. For example, check out the following excerpt from the study "Evaluation of the Abuse Liability of Modafinil and Other Drugs for Excessive Daytime Sleepiness Associated with Narcolepsy" (http://sci-hub.ac/10...200005000-00004)

 

Although some patients will abuse prescribed amphetamines and amphetaminelike drugs, a recent study conducted by Rogers and colleagues (3) suggests that patients with narcolepsy are unlikely to do so. The study determined that patients with narcolepsy do not take their medications as prescribed. Instead of an expected dose escalation over the course of time, the results of the study revealed that approximately 50% of patients either took a reduced dose of their prescribed stimulant or did not take any stimulant during the 24- hour period before completing the study questionnaire (3).

 

 

I hypothesize, and this is anecdotal, the reason for this is that there is no sweet spot for most people with narcolepsy. It's either "This keeps me kinda awakeish" and then instantly jumps to "Now i'm just jittery and still feel like crap". I've been at 30-40mg of Dex for about a year now and while tolerance has set in, taking more does not help. Granted, it never helped all that much to begin with.

 

Unfortunately, the study then goes on to make a number of idiotic, unscientific assumptions about why Modafinil is a better drug for Narcolepsy because it's less abusable and activates orexin neurons. This is a fallacy because 1. They just acknowledged that people with Narcolepsy are highly unlikely to abuse amphetamines and 2. People with Narcolepsy have either dysfunctional or dead orexin neurons. Exciting those few is not going to make a huge difference. Granted, a lot of people with narcolepsy do get help, sometimes a lot of help, from the 'Afinils, but on the website polls done on Narcolepsy Network's forums, Desoxyn/Meth is still the highest rated med. Because of the ridiculous red tape and misinformation, very few people with Narcolepsy have ever tried it. My insurance is trying to deny it to me right now because, due to scarcity and pharmaceutical company corruption, a monthly dose is about $1,000. Keep in mind a monthly dose for my Dex is $400, and the 2 months I took that poisonous garbage Adderall, the monthly dose only cost my insurance $80.

 

The good thing is, there's a lot of common Sigma agonists of varying safety, such as Methylphenidate (least popular Narcolepsy Medication), Berberine, DXM, and others: https://en.wikipedia...ceptor#Agonists

[normalizing]

ive taken mega doses of good quality berberine and all it happened was stomach and gut stress, diarrhea and yellow feces. this stuff should be monitored for false advertisement. it doesnt help as nootropic or in any way for stress or depression

[Omega 3 Snake Oil]

Does anyone suspect their hypothalamus is damaged because of either severe insomnia or dysautonomia?