19 replies to this topic

[Pereise1]

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:

1. Milnacipran

2. Nicotine

3. Galantamine (Nicotine activates orexin through the a4b2 nachr, which Galantamine upregulates)

4. Clomipramine

5. Terlipressin (Through the Vasopressin V1 receptor)

6. Olanzapine (Antipsychotic, not really recommended)

7. Candesartan (Prevents a decline from Angiotensin II)

8. Apomorphine

9. Yohimbine

10. Methamphetamine (in Rats, Here’s a vague human study)

11. Other Antipsychotics (But seriously, don’t take them)

12. Modafinil

13. Caffeine

14. Fluoxetine

15. Noni

16. Caralluma Fibriata Extract

17. Linalool Odor (Not sure if ingesting has the same effect)

18. Berberine

19. Melanotan II

20. Possibly Ginseng

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)

29. Possibly Vortioxetine

 

Diet:

30. Tryptophan Depletion

31. Triglycerides

32. Saturated Fat (Coconut oil seems like a good option, as it has medium chain triglycerides as well)

33. Calcium Availability

34. Milk odor

35. Saccharin

36. Zinc Sulfate (Probably other types of Zinc too)

37. Short Term Fasting (Maybe Intermittent Fasting)

38. Low Sugar

39. Amino Acids/Proteins (glycine > aspartate > cysteine > alanine > serine > asparagine > proline > glutamine)

40. Phytoestrogens (From soy)

41. Pyruvate or Lactate Availability

42. BCAA’s

43. High Salt (Via aldosterone)

 

Hormones:

44. DHEA and DHT

45. Thyrotropin Releasing Hormone

46. Endomorphin-2

47. Oxytocin (Intranasal probably works best)

48. Estradiol

49. Follicle Stimulating Hormone

50. Corticosterone (In the morning)

51. Cholecystokinin (A high protein diet seems to be the best way to stimulate this without anxiety)

 

Pathways:

52. Neuropeptide S (Good luck trying to increase this)

53. Non THC CB1 Agonists

54. Ghrelin

55. ATP through the Purinergic P2X2 Receptor

56. GabaB Sensitivity (Through decreased sensitivity of the GABAA receptors)

57. a1 Adrenergic 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)

– Ginseng

– 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)

66. Agouti-related protein

 

Activities:

67. Sunlight or Bright Light

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)

70. Blue Light

71. Vagus Nerve Stimulation

 

 

Things That Lower Orexin

 

Drugs:

1. Telmisartan

2. Non-ergot Dopamine Agonists

3. Chemotherapeutics

4. THC (Attenuated by MDMA somehow)

5. Alcohol

6. Opiates

 

Activities:

7. Heat Stress (In vitro)

 

Diet:

8. Osmanthus odor

9. Obesity (A number of studies suggest this)

10. Excessive Omega-3 Fatty Acids

11. Lipopolysaccharide

12. Glucose

 

Hormones:

13. Prolactin

 

Pathways:

14. 5-HT1B

15. Melanin Concentrating Hormone (Study notes that Orexin and MCH KO mice don’t have EDS)

16. a2 Adrenergic Receptors

17. Mu and K Opioid Antagonists, but not Delta Opioid Antagonists (In the Hypothalamus)

18. Interferon Alpha

19. 5-HT1A (This is exclusively the postsynaptic receptor in the hypothalamus. Orexin itself activates the presynaptic receptor in the Dorsal Raphe Nucleus)

20. Toll-Like Receptor 2

21. Melatonin, through the MT1 receptor

22. DEC2 Circadian Gene (R-Lipoic Acid Downregulates This)

[Pereise1]

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.

 

 

 

[Heinsbeans]

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.

[John250]

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.

[Pereise1]

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.

[kurdishfella]

Increasing CRH is probably the best way to increase Orexin.

[Pereise1]

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.

[John250]

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.

[Pereise1]

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.

[kurdishfella]

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.

[micro2000]

Just buy orexin and make an intranasal spray.

[John250]

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

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

[displayname]

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.

[CarlSagan]

Helpful post thanks. I may try Forskolin for excessive daytime sleepiness.

carnitine deficient mice have significantly lower orexin neurons, and there's a 8 week study where supplementing L-carnitine 2x 170mg in the daytime and 1x 170mg in the evening showed less daytime sleep in narcolepsy patients.

Edited by CarlSagan, 10 May 2021 - 10:14 AM.

[CarlSagan]

Helpful post thanks. I may try Forskolin for excessive daytime sleepiness.

carnitine deficient mice have significantly lower orexin neurons, and there's a 8 week study where supplementing L-carnitine 2x 170mg in the daytime and 1x 170mg in the evening showed less daytime sleep in narcolepsy patients.

 

the Noni fruit is interesting too, increased orexin mRNA in the hypothalamus of chickens, which is absent in the hypothalamus in people with narcolepsy. Have you trialed this one OP?

[CarlSagan]

No luck on the Forskolin about 7mg followed by 10mg extra. supposed to have effects from 4.5mg. mainly just made me a bit spaced out, and possibly caused some stomach discomfort. but that one was a bit of a stretch anyway. will give noni extract a go

[CarlSagan]

Unsuccessful acute attempt with Noni for excessive daytime sleepiness. 450mg extract equivalent to 9g whole fruit, followed with another 450mg an hour later. hard to guess a dosage as the study isn't much to go on, the chicken study used 2g dried noni plant/kg feed. made me a little more tired if anything. study was done over 22 days though so might be a building effect, if it applies to humans.
 

orexin neurons in mice studies have been shown to be activated by non-essential amino acids. https://pubmed.ncbi....h.gov/22099463/ . l-carnitine deficient mice are low in orexin so there looks to be a connection. and interestingly the non-essential amino acid l-carnitine has shown some efficacy in helping with less daytime sleep in people with narcolepsy over 8 weeks dosed twice daily. low / standard dose of 510mg overall with slight betterment & I wonder if a higher dose would have shown more efficacy. https://www.ncbi.nlm...les/PMC3547955/
 

Going to try L-Carnitine 500mg am & pm, but this one over longer term. Looking for another to try acutely in the meantime.

Edited by CarlSagan, 12 May 2021 - 08:28 AM.

[CarlSagan]

orexin neurons in mice studies have been shown to be activated by non-essential amino acids. https://pubmed.ncbi....h.gov/22099463/ . l-carnitine deficient mice are low in orexin so there looks to be a connection. and interestingly the non-essential amino acid l-carnitine has shown some efficacy in helping with less daytime sleep in people with narcolepsy over 8 weeks dosed twice daily. low / standard dose of 510mg overall with slight betterment & I wonder if a higher dose would have shown more efficacy. https://www.ncbi.nlm...les/PMC3547955/

 

Going to try L-Carnitine 500mg am & pm, but this one over longer term. Looking for another to try acutely in the meantime.

Will try 1g am & 1g or 500mg pm as a middle range  

2.5g/3g adult dose of l-carnitine https://pubmed.ncbi....h.gov/8048704/ 

1g of l-carnitine 3x daily http://plioplys.com/...tadine_1997.pdf

Edited by CarlSagan, 12 May 2021 - 10:51 AM.

[CarlSagan]

Interesting just got taken back to this thread through my searches. 

 

 

I came across MCT for stimulating appetite kind of accidentally. Medium-chain triglycerides are isolated from coconut oil & its a ready available supplement.

 

It's shown in humans to substantially increase the ratio of ACYLATED GHRELIN which is the ghrelin linked to appetite. https://www.scienced...05457716302765   6 grams + for 2 weeks almost doubled their acylated ghrelin ratio.  another study showed 20g ingested over 10 minutes, for 3 days, did not impact it much.  another study showed 1 week doubled the acylated ghrelin % at 45g.     so this suggests taking decent amounts of MCT all at once for longer than 1 week should have a big effect of increasing acylated ghrelin.   it works by increasing the O-acyltransferase enzyme.

 

 

Now looking more into the study i saw NEUROPEPTIDE Y was also massively increased by MCT, it more than doubled in the MCT high group by 4 weeks.  neuropeptide y is a powerful appetite increaser, rats injected with this double their food intake.   

(which is funny as MCT is often marketed for losing weight & increasing satiety - but it's trialed in anorexic patients, & by this appetite should ramp up by 4 weeks)

 

 

Neuropeptide Y can stimulate NEUROGENESIS IN THE HIPPOCAMPUS (+memory +antidepressant?) https://pubmed.ncbi.....gov/20095007/   & it acts within the HYPOTHALAMUS which is where it mainly comes from  (where OREXIN neurons also are)  https://www.scienced...19697818690149X

 

 

I wonder if there could be some kind of breakthrough here for treating narcolepsy in people with orexin neurons left, or treating daytime sleepiness, with MCT

 

Intuitively it makes sense right - acylated ghrelin signals hunger by increasing neuropeptide Y activation -> orexin pathways activate to produce wakefulness -> food seeking mode

 

 

then i came across the study in OP,  neuropeptide Y increases wakefulness in rats  (in both routes of administration not just direct hypothalamus injection) https://journals.phy...egu.00919.2005 

 

"it is also possible that NPY's stimulatory action on orexinergic cells in the LH mediates the wake-promoting effect of NPY."

 

MCT is a nice candidate,  10g - 45g mixed C:8 C:10, each morning for a month

Edited by CarlSagan, 08 March 2022 - 10:37 AM.

[CarlSagan]

actually will split the dose into 2 one in morning by itself & one at midday with meal.   another one where a small dose of 3grams c:8 gave a small acute increase in acyl ghrelin & bigger after 2 weeks (+40%), they also noted an increase in IGF-1 by 10%, which could be something else or stay there, but i wonder if this has anything to do with increased bone mass thats associated with ghrelin

https://nutritionj.b.../1475-2891-8-25

https://nutritionj.b...1-8-25/tables/1

Edited by CarlSagan, 08 March 2022 - 12:07 PM.