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How To Increase Orexin

orexin anhedonia depression fatigue wakefulness neuropharmacology selank modafinil nicotine

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#1 Pereise1

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Posted 09 May 2018 - 07:26 PM


For those with fatigue or anhedonia, orexin is a holy grail of possibilities, as it's intimately connected to feeling pleasure from enjoyable activities and feeling awake. As a person with Narcolepsy and pathologically low orexin, I'm highly interested in increasing orexin in order to feel more normal. So for the last few weeks, I've been scouring pubmed in search of things to increase orexin, as well as things to avoid. I'll be updating this post over at the narcolepsysupport site. So without further ado:

 

How To Increase:
 
Drugs and Herbs:
3. Galantamine (Nicotine activates orexin through the a4b2 nachr, which Galantamine upregulates)
6. Olanzapine (Antipsychotic, not really recommended)
7. Candesartan (Prevents a decline from Angiotensin II)
11. Other Antipsychotics (But seriously, don’t take them)
15. Noni
17. Linalool Odor (Not sure if ingesting has the same effect)
21. Rikkunshito (Via increased Ghrelin)
22. Mazindol (Supposedly has been discovered to be an Ox2 receptor agonist)
23. Scopolamine (Probably in low, subpsychosis doses)
24. GLP-1 Agonists (The -gliptan class of diabetic meds are GLP agonists, as well as things like olive leaf extract, glutamine, alpha casein, beta casein, and chlorogenic acid)
25. Forskolin (Induced long term potentiation in Orexin neurons)
26. GHRP-6 (Yes, the bodybuilding peptide)
27. Probably CBD (“Activates wakefulness promoting neurons in the lateral hypothalamus”)
28. N-Acetylglucosamine (I say NAG because regular glucosamine doesn’t pass the BBB well)
 
Diet:
32. Saturated Fat (Coconut oil seems like a good option, as it has medium chain triglycerides as well)
36. Zinc Sulfate (Probably other types of Zinc too)
37. Short Term Fasting (Maybe Intermittent Fasting)
39. Amino Acids/Proteins (glycine > aspartate > cysteine > alanine > serine > asparagine > proline > glutamine)
40. Phytoestrogens (From soy)
43. High Salt (Via aldosterone)
 
Hormones:
47. Oxytocin (Intranasal probably works best)
50. Corticosterone (In the morning)
 
Pathways:
52. Neuropeptide S (Good luck trying to increase this)
56. GabaB Sensitivity (Through decreased sensitivity of the GABAA receptors)
58. Pregnancy (Beginning of gestation)
59. CCR3 (Chemokine Receptor that protects Orexin from inflammation)
60. Acetylcholine (The Muscarinic M3 Receptor alone activates almost 20%)
61. Oxytocin (Fenugreek should help, as well as oleoylethanolamide, and by 0.5mg Melatonin but not 5mg Melatonin)
62. Neuropeptide Y in the hypothalamus (According to this study, Adaptogens and specifically Salidroside from Rhodiola increase Neuropeptide Y in the right places)
Gastrodin is also a good option for directly increasing Neuropeptide Y in the Hypothalamus
– Also Escitalopram and Venlafaxine, although I can’t personally recommend those.
63. Sigma 1 Receptors (By disinhibiting Orexin from Corticotropin and Histamine H3 receptors)
64. Sirt1
65. Nicotinic a4b2 receptors (Nefiracetam is an agonist at this receptor and Galantamine is a positive allosteric modulator)
 
Activities:
68. Exercise (It seems that physical activity that one enjoys is far more effective than simple exercise)
69. Cold Exposure (Possibly via the actions of Neurotensin, which increases Orexin and is activated by cold)
 
 
Things That Lower Orexin
 
Drugs:
4. THC (Attenuated by MDMA somehow)
 
Activities:
7. Heat Stress (In vitro)
 
Diet:
9. Obesity (A number of studies suggest this)
 
Hormones:
 
Pathways:
14. 5-HT1B
15. Melanin Concentrating Hormone (Study notes that Orexin and MCH KO mice don’t have EDS)
19. 5-HT1A (This is exclusively the postsynaptic receptor in the hypothalamus. Orexin itself activates the presynaptic receptor in the Dorsal Raphe Nucleus)
21. Melatonin, through the MT1 receptor
22. DEC2 Circadian Gene (R-Lipoic Acid Downregulates This)

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#2 Pereise1

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Posted 16 May 2018 - 08:50 PM

So I found this one especially interesting: the russian peptide Selank increases Orexin expression by a substantial amount:

Similar to the pattern seen 1 h after Selank administration, at 3 h after administration of this compound, the most pronounced changes in gene expression were observed for Hcrt, Gabre, and Gabrq. At 3 h after Selank administration, the mRNA levels of these genes increased 128.3, 16.1, and 13.3 times, respectively. The mRNA level increased significantly 3 h after GABA administration for only one gene, Gabra6, whose mRNA level increased 7.6 times.
 
(…)Of particular interest is the significant change in the mRNA level of Hcrt 3 h after Selank administration. This gene encodes a precursor of orexins and is involved in the regulation of the balance between sleep and wakefulness (Ohno and Sakurai, 2008). Kolomin et al. have shown that the mRNA level of the Hcrt increases after a single administration of Selank (Kolomin et al., 2013). The presence of this significant effect of Selank suggests that the peptide has an active effect on the balance between sleep and wakefulness, and that the change in the expression of Hcrt may be in the foundation of the normalizing effect Selank has on the balance of sleep patterns in patients with general anxiety disorders. The observed changes may also explain the lack of hypnosedative action of Selank, which is common for classical benzodiazepines, because of the shift in the balance toward wakefulness.

 

 

 



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#3 Heinsbeans

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Posted 17 May 2018 - 08:33 PM

Superb list. But vortioxetine on its own didn't help with my TRD or ADHD-PI like symptoms for me. It had some subtle pro-cognitive effects and having less sexual and emotional sides were a plus. But the potent SERT inhibition made me very lethargic and demotivated. If it also had potent NET inhibition, it might have been a different story.



#4 John250

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Posted 18 May 2018 - 04:39 PM

As a bodybuilder I’ve had my fair share of peptides. Ghrp6 will make you tired. Interesting in increases Orexin as you would think it would give energy but I’m sure there are so many variable factors. Mk677 is basically a long acting ghrp6 but for me there is nothing that has given me worse fatigue than mk677 even in small doses of 10mg.

#5 Pereise1

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Posted 18 May 2018 - 09:54 PM

Superb list. But vortioxetine on its own didn't help with my TRD or ADHD-PI like symptoms for me. It had some subtle pro-cognitive effects and having less sexual and emotional sides were a plus. But the potent SERT inhibition made me very lethargic and demotivated. If it also had potent NET inhibition, it might have been a different story.

 

I'm not a big fan of SERT inhibition either. I was put on Paroxetine at a young age which, while it did lessen my OCD even years later,  killed my creativity and had a horrible withdrawal. And yet, somehow it's supposed to increase orexin. I'm curious what it is about these meds that increase orexin expression, as simply increasing serotonin doesn't seem to do it. On the contrary, depleting tryptophan increase orexin.



#6 farshad

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Posted 21 May 2018 - 10:24 AM

Increasing CRH is probably the best way to increase Orexin.



#7 Pereise1

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Posted 23 May 2018 - 05:40 PM

As a bodybuilder I’ve had my fair share of peptides. Ghrp6 will make you tired. Interesting in increases Orexin as you would think it would give energy but I’m sure there are so many variable factors. Mk677 is basically a long acting ghrp6 but for me there is nothing that has given me worse fatigue than mk677 even in small doses of 10mg.

 

GHRP-6 also increases appetite in many. It makes sense that, depending on whether the orexin you're increasing is in the Lateral Hypothalamus, Paraventricular Nucleus, or in the Arcuate Nucleus, determines whether you're increasing wakefulness or simply hunger. Hunger increases wakefulness in most people, which is why it's usually hard to go to sleep on an empty stomach. However, the GH increasing effects of GHRP-6 seem to overpower the wakefulness inducing effects of hunger, in my experience. I'm currently experimenting with GHRP-6 and at least my sleep seems to be more restorative.



#8 John250

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Posted 23 May 2018 - 06:15 PM

Yes and feelings of hypoglycemia can occur with ghrp’s as well. Also if your interested in increased hgh and igf levels if you add a GHRH with the GHRP it drastically increases it as they are synergistic. I’d recommend cjc1295 with “no” dac along with the ghrp. It’s fine to mix in the same syringe to inject but don’t keep them mixed together long term or it can dull the effects. I’ve found I get similar effects with 100mcg of each 2-3x/day vs using actual hgh at 2-4iu’s/day. GHRP2 will release more GH with less hunger where GHRP6 is a little less potent on GH release but causes a much more profound impact on appetite.

Edited by John250, 23 May 2018 - 06:18 PM.

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#9 Pereise1

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Posted 23 May 2018 - 06:22 PM

Increasing CRH is probably the best way to increase Orexin.

 

I'm curious, why CRH? Obviously stress increases wakefulness but it doesn't seem to be a particularly pleasant way of doing so.



#10 farshad

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Posted 23 May 2018 - 06:27 PM

I'm curious, why CRH? Obviously stress increases wakefulness but it doesn't seem to be a particularly pleasant way of doing so.

I just thought I would mention it . As a person that suffers with extreme CRH it does increase your alertness/wakefulness a lot.. But too much it starts to give you ADHD cant focus very good becuase you are so aware of your surroundings more maybe becuase of increased anxiety? no idea.


Edited by farshad, 23 May 2018 - 06:28 PM.


#11 micro2000

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Posted 25 May 2018 - 04:32 PM

Just buy orexin and make an intranasal spray.
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#12 John250

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Posted 06 June 2018 - 05:13 PM

What about just injecting it? What would normal dosing be?

https://www.ceretropic.com/orexin-a

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#13 displayname

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Posted 28 June 2018 - 10:29 PM

Thanks for the comprehensive list. I think we get more than enough blue light from our computer screens though. Many things can be relevant to a goal regardless of other health consequences that may negate or make appear negligible the benefits of achieving that goal in comparison

 

How does one increase pyruvate availability?


Edited by displayname, 28 June 2018 - 10:53 PM.






Also tagged with one or more of these keywords: orexin, anhedonia, depression, fatigue, wakefulness, neuropharmacology, selank, modafinil, nicotine

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