4029 replies to this topic

[lostfalco]

Should we be worried about galantamines effect on sleep? It's half-life is long enough to bleed into our sleeping times. We could use huperzine a, but it is a NMDA antagonist and is less effect overall. The video you linked, at 29:25, she says that acetylcholine isn't released during deep sleep, but REM sleep. This makes sense, as you're semi-conscious during REM but deep sleep is like death, nothing new what I said here. If we have a constant stimulation of acetycholine, I feel like that may impair our sleep, especially slow-wave which is very important for bodily health. 

here's a couple studies: http://www.ncbi.nlm..../pubmed/8208872, http://www.ncbi.nlm....ubmed/26719734 

Then you have paradoxical studies like this where galantamine INCREASED SWS: http://www.ncbi.nlm....les/PMC3419757/, why can't memantine have a short half-life? It's on rats though...

I think we're good with galantamine. Its half life is around 7 hours so I just don't take it late in the day. 

[bigyellowlemon]

Should we be worried about galantamine effecting our sleep? Its long half-life ensures its effects will bleed into our sleeping time. Amy Arnsten said in the video, at 29:25, that acetylcholine is suppressed during deep sleep and active during REM, hence our death-like unconsiousness during sleep sprinkled with semi-consciouss visions we call "dreams", and why people use galantamine to enhance lucid dreaming and dreaming in general (REM increase). A couple of studies....

http://www.ncbi.nlm....0/1106.abstract

 

Paradoxically, it enhanced SWS... in rats. Memantine also hurt sleep, idk how accurate this study is. It's totally believable though, considering memantines incredibly long half-life.

Huperzine A has a better half-life, but is worse overall and has NMDA antagonism

 

Donepezil, I haven't researched. 

 

Hope I'm not late to the party and you guys have already figured it out... Actually I hope I am late to the party and you guys figured that galantamine has little to no effect on sleep. 

 

Cheers, maties.

 

EDIT: Sorry, it said it didn't post so I reposted it. That's weird. I'll leave this here though.

Edited by bigyellowlemon, 22 January 2016 - 01:02 AM.

[bigyellowlemon]

 

Should we be worried about galantamines effect on sleep? It's half-life is long enough to bleed into our sleeping times. We could use huperzine a, but it is a NMDA antagonist and is less effect overall. The video you linked, at 29:25, she says that acetylcholine isn't released during deep sleep, but REM sleep. This makes sense, as you're semi-conscious during REM but deep sleep is like death, nothing new what I said here. If we have a constant stimulation of acetycholine, I feel like that may impair our sleep, especially slow-wave which is very important for bodily health. 

here's a couple studies: http://www.ncbi.nlm..../pubmed/8208872, http://www.ncbi.nlm....ubmed/26719734 

Then you have paradoxical studies like this where galantamine INCREASED SWS: http://www.ncbi.nlm....les/PMC3419757/, why can't memantine have a short half-life? It's on rats though...

I think we're good with galantamine. Its half life is around 7 hours so I just don't take it late in the day. 

 

 

Yeah, you're right it would only have slight effects considering it would be around 1-.25 mg by the end of the day. Also the studies I posted used it right before sleep. Stupid mistake.

[resveratrol_guy]

 

Hey resveratrol_guy, these are excellent and legitimate questions!

 

Confidence Level: I feel quite confident (not certain) that we are safe testing this for 8 weeks. This has been done multiple times in humans with no apparent downsides. There was also an impaired human study that went for 4 months. The benefits in the insulin group lasted for over 2 months after cessation of insulin treatment! (I'll provide an extended quote below) This prompted another extended study to see if the beneficial effects could be maintained over a year of intranasal administration in hundreds of humans. This should directly address our questions about long term brain insulin resistance. The study will be completed in February 2016. https://clinicaltria...lts/NCT01767909

 

http://www.ncbi.nlm....les/PMC4066335/

 

"Intranasal Insulin

Although many classes of drugs are now approved for management of diabetes, a primary focus of efforts to treat insulin-signaling dysfunction in AD has been the administration of exogenous insulin. There is abundant anecdotal evidence that insulin administration in people with diabetes may acutely affect mood, behavior, and cognitive performance. In 2001, the cognitive effects of insulin in nonimpaired adults were demonstrated by Kern et al. (24) using a 6-h insulin infusion. Subjects exposed to higher insulin infusion rates demonstrated changes in auditory-evoked brain potentials, enhanced memory as evidenced by improved word recall, and improved cognitive flexibility and attention as measured by the Stroop test. Similar benefits of acute insulin administration were demonstrated by Craft et al. (25) in patients with AD. In their study, the AD patients showed improved story recall and attention during insulin infusion relative to saline infusion. Although theoretically interesting, the feasibility of treating AD with peripherally administered insulin is doubtful. Most peripherally administered insulin does not enter the CNS, and the dose of peripherally infused insulin is limited by induction of hypoglycemia. In both studies, hypoglycemia was mitigated by a simultaneous glucose infusion, which is obviously impractical outside of the research setting.

 

Interesting recent efforts to study the effects of insulin on cognitive function have concentrated on intranasal insulin delivery. Insulin that is administered intranasally bypasses the blood-brain barrier and is rapidly delivered into the cerebrospinal fluid (CSF) compartment (26). Intranasal insulin is believed to enter the CNS along axons and their sheaths in the olfactory nerve that extend through the cribriform plate to the olfactory bulb and in the trigeminal nerve. Because intranasal insulin is preferentially delivered to the CNS, it may theoretically be possible to achieve clinically relevant concentrations of insulin in the CNS without causing systemic hypoglycemia. In the acute setting, one dose of intranasal insulin induces changes in auditory-evoked brain potentials in healthy cognitively intact adults (27). More recent pilot clinical studies have also shown that chronic administration of intranasal insulin may improve memory function. In a study of 38 young, cognitively intact adults exposed to 8 weeks of regular intranasal insulin (4 × 40 IU/day), word recall was significantly improved compared with vehicle nasal spray (28). Peripheral glucose levels were not significantly affected by intranasal insulin. These studies in cognitively normal adults supported the importance of insulin in normal brain functioning and raised interest in the use of intranasal insulin in cognitively impaired adults.

 

Results of recent pilot studies of intranasal insulin in mild cognitive impairment (MCI) and AD have been encouraging. The most notable of these studies was a double-blind, randomized trial of 104 older adults with MCI or AD who received placebo, low-dose (20 IU), or high-dose (40 IU) intranasal insulin for 4 months (29). Compared with placebo, participants who received either dose of insulin demonstrated significant improvements in memory as assessed by the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) and the Alzheimer’s Disease Cooperative Study (ADCS) activities of daily living scales. These benefits of intranasal insulin were apparent not only at the end of the treatment period but also 2 months after treatment cessation, suggesting that intranasal insulin has lasting effects on CNS functioning. A subset of subjects also underwent positron emission tomography (PET) and lumbar puncture to assess for changes in AD CSF biomarkers. Compared with participants who received intranasal insulin, less radioactive glucose uptake during the PET scan was noted in multiple brain regions in the placebo group, indicative of cerebral metabolic dysfunction and consistent with AD progression. However, no significant differences were noted in amyloid-β levels in CSF fluid among the three participant groups.

 

One theoretical concern about intranasal insulin is that chronic hyperinsulinemic conditions in the brain may actually promote brain insulin resistance. For example, excessive exposure to insulin in mice leads to phosphorylation of key components of the insulin cascade, such as AKT, GSK-3β, and p70S6K, consistent with insulin resistance (14). Therefore, it is possible that longer-term studies of intranasal insulin will produce different results from the published shorter-term pilot studies or that escalating doses of intranasal insulin will be required to show continued benefit. However, given the promising results of intranasal insulin in small pilot studies, longer-term studies of intranasal insulin are warranted. In 2012, the U.S. National Institutes of Health allocated $7.9 million for a pivotal trial of intranasal insulin called the Study of Nasal Insulin in the Fight Against Forgetfulness (SNIFF; ClinicalTrials identifier: NCT01767909). This multicenter phase 2/3 study will be conducted by the ADCS. It is expected to recruit 250 participants with AD or MCI and to randomize them for 12 months to intranasal insulin or placebo, followed by an open-label extension of 6 months in which all participants will receive intranasal insulin. The study should be completed in late 2014." (it's actually going to be completed in Feb 2016 now)

 

Thanks for the expert answer, as usual. While I don't doubt that in 8 weeks T3D is not going to emerge, clearly AD is going to require ongoing treatment for at least years, until something like hippocampal HTERT therapy is available or tau vaccine miraculously turns out to work. I realize that, given the choice between having T3D and turning into a zombie, I think most sufferers would choose the former. But suffice to say, you've done us all a service by pointing out this clinical trial due to complete next month. (It will probably take a year to publish the data, sigh.)

 

Nonetheless the shortterm success of intranasal insulin therapy improves my confidence in intranasal human betaNGF. I'm tempted to combine them but growth is an area where I tread carefully.

[Remington]

Hi lostfalco I've finished my first week of Intranasal insulin nothing much different but I'm wondering I might be under dosing. Silly question how many sprays per nostril in one session?

Not a silly question. =) We're all kinda winging it on this one right now. It's fairly new territory.

What size is your spray bottle? The amount per spray can vary depending on the size.

It's a 1FL OZ (30 mL) bottle

[lostfalco]

Thanks for the expert answer, as usual. While I don't doubt that in 8 weeks T3D is not going to emerge, clearly AD is going to require ongoing treatment for at least years, until something like hippocampal HTERT therapy is available or tau vaccine miraculously turns out to work. I realize that, given the choice between having T3D and turning into a zombie, I think most sufferers would choose the former. But suffice to say, you've done us all a service by pointing out this clinical trial due to complete next month. (It will probably take a year to publish the data, sigh.)

 

Nonetheless the shortterm success of intranasal insulin therapy improves my confidence in intranasal human betaNGF. I'm tempted to combine them but growth is an area where I tread carefully.

 

No problem, resveratrol_guy. =)

 

I've given myself 8 weeks to figure out meta-cresol and long term downregulation risks caused by extended dosing. I'm with you though...I really wish that study was going to be published sooner. I'll shoot them an email and see if I can get some early result info.

 

Growth factors/neurohormones/neurotrophins etc. are definitely areas to tread carefully. Agreed. I would love to hear about your intranasal NGF results if you decide to try it!

 

 

Hi lostfalco I've finished my first week of Intranasal insulin nothing much different but I'm wondering I might be under dosing. Silly question how many sprays per nostril in one session?

Not a silly question. =) We're all kinda winging it on this one right now. It's fairly new territory.

What size is your spray bottle? The amount per spray can vary depending on the size.

It's a 1FL OZ (30 mL) bottle

 

That should be .1ml per spray (most likely). Does your nozzle look like this?  http://www.ceretropi.../noopept-spray/

[Remington]

Yes that's the one.

[lostfalco]

Yes that's the one.

Cool. Should be .1 to .13 mL per spray. Just check your insulin for number of IU's per mL (usually 100IU/mL) and you're good to go. If you have Novolin R AND that spray nozzle then it should be around 10IU's per spray. Check your insulin bottle just to be sure. 

 

For better absorption, lean your head back, squirt the spray, sniff it in, and keep your head back for a few seconds. You can even lay down for a bit after if you want to. Here's where the insulin is absorbing. 

 

 

 

 

http://www.ncbi.nlm....pubmed/26401706

 

J Alzheimers Dis. 2015;47(3):715-28. doi: 10.3233/JAD-150307.

Central Nervous System Delivery of Intranasal Insulin: Mechanisms of Uptake and Effects on Cognition.

Salameh TS1,2, Bullock KM1, Hujoel IA1, Niehoff ML3,4, Wolden-Hanson T1, Kim J3, Morley JE3, Farr SA3,4, Banks WA1,2.

Author information

Abstract

Intranasal insulin has shown efficacy in patients with Alzheimer's disease (AD), but there are no preclinical studies determining whether or how it reaches the brain. Here, we showed that insulin applied at the level of the cribriform plate via the nasal route quickly distributed throughout the brain and reversed learning and memory deficits in an AD mouse model. Intranasal insulin entered the blood stream poorly and had no peripheral metabolic effects. Uptake into the brain from the cribriform plate was saturable, stimulated by PKC inhibition, and responded differently to cellular pathway inhibitors than did insulin transport at the blood-brain barrier. In summary, these results show intranasal delivery to be an effective way to deliver insulin to the brain.

 

Edited by lostfalco, 23 January 2016 - 12:38 AM.

[lostfalco]

Pretty damn cool. (elderly human study)

 

http://www.ncbi.nlm....pubmed/26782228

 

Adv Exp Med Biol. 2016;876:319-25. doi: 10.1007/978-1-4939-3023-4_40.

Effect of the Antioxidant Supplement Pyrroloquinoline Quinone Disodium Salt (BioPQQ™) on Cognitive Functions.

Itoh Y1, Hine K1, Miura H1, Uetake T2, Nakano M3, Takemura N4, Sakatani K4,5.

Author information

Abstract

Pyrroloquinoline quinone (PQQ) is a quinone compound first identified in 1979. It has been reported that rats fed a PQQ-supplemented diet showed better learning ability than controls, suggesting that PQQ may be useful for improving memory in humans. In the present study, a randomized, placebo-controlled, double-blinded study to examine the effect of PQQ disodium salt (BioPQQ™) on cognitive functions was conducted with 41 elderly healthy subjects. Subjects were orally given 20 mg of BioPQQ™ per day or placebo, for 12 weeks. For cognitive functions, selective attention by the Stroop and reverse Stroop test, and visual-spatial cognitive function by the laptop tablet Touch M, were evaluated. In the Stroop test, the change of Stroop interference ratios (SIs) for the PQQ group was significantly smaller than for the placebo group. In the Touch M test, the stratification analyses dividing each group into two groups showed that only in the lower group of the PQQ group (initial score < 70), did the score significantly increase. Measurements of physiological parameters indicated no abnormal blood or urinary adverse events, nor adverse internal or physical examination findings at any point in the study. The preliminary experiment using near-infrared spectrometry (NIRS) suggests that cerebral blood flow in the prefrontal cortex was increased by the administration of PQQ. The results suggest that PQQ can prevent reduction of brain function in aged persons, especially in attention and working memory.

 

Edited by lostfalco, 23 January 2016 - 02:57 AM.

[Remington]

Yes that's the one.

Cool. Should be .1 to .13 mL per spray. Just check your insulin for number of IU's per mL (usually 100IU/mL) and you're good to go. If you have Novolin R AND that spray nozzle then it should be around 10IU's per spray. Check your insulin bottle just to be sure.

For better absorption, lean your head back, squirt the spray, sniff it in, and keep your head back for a few seconds. You can even lay down for a bit after if you want to. Here's where the insulin is absorbing.





http://www.ncbi.nlm....pubmed/26401706

J Alzheimers Dis. 2015;47(3):715-28. doi: 10.3233/JAD-150307.
Central Nervous System Delivery of Intranasal Insulin: Mechanisms of Uptake and Effects on Cognition.
Salameh TS1,2, Bullock KM1, Hujoel IA1, Niehoff ML3,4, Wolden-Hanson T1, Kim J3, Morley JE3, Farr SA3,4, Banks WA1,2.
Author information
Abstract

Intranasal insulin has shown efficacy in patients with Alzheimer's disease (AD), but there are no preclinical studies determining whether or how it reaches the brain. Here, we showed that insulin applied at the level of the cribriform plate via the nasal route quickly distributed throughout the brain and reversed learning and memory deficits in an AD mouse model. Intranasal insulin entered the blood stream poorly and had no peripheral metabolic effects. Uptake into the brain from the cribriform plate was saturable, stimulated by PKC inhibition, and responded differently to cellular pathway inhibitors than did insulin transport at the blood-brain barrier. In summary, these results show intranasal delivery to be an effective way to deliver insulin to the brain.

Awesome I guess my dose wasn't so off after all but instead of 4x/day I was dosing 2x/day. Well time to bump it up thanks lostfalco, I always look forward to your thread bro.

[resveratrol_guy]

Growth factors/neurohormones/neurotrophins etc. are definitely areas to tread carefully. Agreed. I would love to hear about your intranasal NGF results if you decide to try it!

 

I tried it (human betaNGF) back on 8/16/2015 with the log starting on this page. Now a few of us have taken it. It seems like the most obvious effect is enhanced dream vividness, but this is hardly a narrowly targetted molecule, so the potential is exciting, particularly in light of the excellent safety profile apart from transient pain enhancement.
 

[lostfalco]

Awesome I guess my dose wasn't so off after all but instead of 4x/day I was dosing 2x/day. Well time to bump it up thanks lostfalco, I always look forward to your thread bro.

 

Thanks, man! I hope you find a dose that works well for you. 

I tried it (human betaNGF) back on 8/16/2015 with the log starting on this page. Now a few of us have taken it. It seems like the most obvious effect is enhanced dream vividness, but this is hardly a narrowly targetted molecule, so the potential is exciting, particularly in light of the excellent safety profile apart from transient pain enhancement.

 

 

Very cool resveratrol_guy. I'll head over there and check it out. 

 

 

KCNQ Inhibition/M-channel Inhibition + Nav1.2 Enhancement at the Axon Initial Segment = Enhanced Action Potentials = Enhanced Connectivity = Enhanced IQ (maybe)

 

KCNQ Inhibition: galantamine and/or CDP Choline and/or MK-677 (ghrelin) and/or Intranasal GHRP-2/6 (ghrelin)

Nav1.2 Enhancement: intranasal insulin (many more to talk about soon)

 

"M-channels are closed by receptors coupled to Gq such as M1 and M3 muscarinic receptors; this increases neuronal excitability and underlies some forms of cholinergic excitation."

 

"...ghrelin enhances firing of nigral dopaminergic neurons by inhibiting voltage-gated potassium Kv7/KCNQ/M-channels through its receptor GHS-R1a and activation of the PLC-PKC pathway."

 

Note: seizure warning.

 

 

 

 

 

 

 

http://www.ncbi.nlm....pubmed/23385580

 

Nat Commun. 2013;4:1435. doi: 10.1038/ncomms2439.

Peptide hormone ghrelin enhances neuronal excitability by inhibition of Kv7/KCNQ channels.

Shi L1, Bian X, Qu Z, Ma Z, Zhou Y, Wang K, Jiang H, Xie J.

Author information

Abstract

The gut-derived orexigenic peptide hormone ghrelin enhances neuronal firing in the substantia nigra pars compacta, where dopaminergic neurons modulate the function of the nigrostriatal system for motor coordination. Here we describe a novel mechanism by which ghrelin enhances firing of nigral dopaminergic neurons by inhibiting voltage-gated potassium Kv7/KCNQ/M-channels through its receptor GHS-R1a and activation of the PLC-PKC pathway. Brain slice recordings of substantia nigra pars compacta neurons reveal that ghrelin inhibits native Kv7/KCNQ/M-currents. This effect is abolished by selective inhibitors of GHS-R1a, PLC and PKC. Transgenic suppression of native Kv7/KCNQ/M-channels in mice or channel blockade with XE991 abolishes ghrelin-induced hyperexcitability. In vivo, intracerebroventricular ghrelin administration causes increased dopamine release and turnover in the striatum. Microinjection of ghrelin or XE991 into substantia nigra pars compacta results in contralateral dystonic posturing, and attenuation of catalepsy elicited by systemic administration of the D2 receptor antagonist haloperidol. Our findings indicate that the ghrelin/KCNQsignalling is likely a common pathway utilized by the nervous system.

 

 

http://www.ncbi.nlm....les/PMC2697739/

 

Br J Pharmacol. 2009 Apr;156(8):1185-95. doi: 10.1111/j.1476-5381.2009.00111.x. Epub 2009 Mar 9.

Neural KCNQ (Kv7) channels.

Brown DA1, Passmore GM.

Author information

Abstract

KCNQ genes encode five Kv7 K(+) channel subunits (Kv7.1-Kv7.5). Four of these (Kv7.2-Kv7.5) are expressed in the nervous system. Kv7.2 and Kv7.3 are the principal molecular components of the slow voltage-gated M-channel, which widely regulates neuronal excitability, although other subunits may contribute to M-like currents in some locations. M-channels are closed by receptors coupled to Gq such as M1 and M3 muscarinic receptors; this increases neuronal excitability and underlies some forms of cholinergic excitation. Muscarinic closure results from activation of phospholipase C and consequent hydrolysis and depletion of membrane phosphatidylinositol-4,5-bisphosphate, which is required for channel opening. Some effects of M-channel closure, determined from transmitter action, selective blocking drugs (linopirdine and XE991) and KCNQ2 gene disruption or manipulation, are as follows: (i) in sympathetic neurons: facilitation of repetitive discharges and conversion from phasic to tonic firing; (ii) in sensory nociceptive systems: facilitation of A-delta peripheral sensory fibre responses to noxious heat; and (iii) in hippocampal pyramidal neurons: facilitation of repetitive discharges, enhanced after-depolarization and burst-firing, and induction of spontaneous firing through a reduction of action potential threshold at the axon initial segment. Several drugs including flupirtine and retigabine enhance neural Kv7/M-channel activity, principally through a hyperpolarizing shift in their voltage gating. In consequence they reduce neural excitability and can inhibit nociceptive stimulation and transmission. Flupirtine is in use as a central analgesic; retigabine is under clinical trial as a broad-spectrum anticonvulsant and is an effective analgesic in animal models of chronic inflammatory and neuropathic pain.

 

http://www.ncbi.nlm....ubmed/18056963 

 

Ann N Y Acad Sci. 2007 Nov;1119:147-64.

Ghrelin receptor (GHS-R1A) agonists show potential as interventive agents during aging.

Smith RG1, Sun Y, Jiang H, Albarran-Zeckler R, Timchenko N.

Author information

Abstract

Administration of an orally active agonist (MK-0677) of the growth hormone secretagogue receptor (GHS-R1a) to elderly subjects restored the amplitude of endogenous episodic growth hormone (GH) release to that of young adults. Functional benefits include increased lean mass and bone density and modest improvements in strength. In old mice, a similar agonist partially restored function to the thymus and reduced tumor cell growth and metastasis. Treatment of old mice with the endogenous GHS-R1a agonist ghrelin restored a young liver phenotype. The mechanism involves inhibition of cyclin D3:cdk4/cdk6 activity and increased protein phosphatase-2A (PP2A) activity in liver nuclei, which stabilizes the dephosphorylated form of the transcription factor C/EBPalpha preventing the age-dependent formation of the C/EBPalpha-Rb-E2F4-Brm nuclear complex. By inhibiting formation of this complex, repression of E2F target genes is de-repressed and C/EBPalpha regulated expression of Pepck, a regulator of gluconeogenesis, is normalized, thereby restoring a young liver phenotype. In the brain, aging is associated with decline in dopamine function. We investigated the potential neuromodulatory role of GHS-R1a on dopamine action. Neurons were identified in the hippocampus, cortex, substantia nigra, and ventral tegmental areas that coexpressed GHS-R1a and dopamine receptor subtype-1 (D1R). Cell culture studies showed that, in the presence of ghrelin and dopamine, GHS-R and D1R form heterodimers, which modified G-protein signal transduction resulting in amplification of dopamine signaling. We speculate that aging is associated with deficient endogenous ghrelin signaling that can be rescued by intervention with GHS-R1a agonists to improve quality of life and maintain independence.

 

Edited by lostfalco, 24 January 2016 - 02:44 AM.

[cylack]

Anyone find a cheap online pharmacy that will sell Montelukast (singulair) without a prescription?

 

Tried telling my doc I need it for allergic rhinitis (one of the actual uses for it), but he insisted its only for asthma and refused to prescribe it for me.

Hmmm, wonder what he would have said if I told him I want it for neurogenesis?

 

Edited by cylack, 24 January 2016 - 01:27 AM.

[Bluecheer]

Hey Falco, I was wondering is there a recommended time that you specifically take Potato Starch? 

Also curious to your opinon on Citrulline Malate 
http://www.ncbi.nlm....les/PMC1724533/
". CM ingestion resulted in a significant reduction in the sensation of fatigue, a 34% increase in the rate of oxidative ATP production during exercise, and a 20% increase in the rate of phosphocreatine recovery after exercise, indicating a larger contribution of oxidative ATP synthesis to energy production."

[lostfalco]

Anyone find a cheap online pharmacy that will sell Montelukast (singulair) without a prescription?

 

Tried telling my doc I need it for allergic rhinitis (one of the actual uses for it), but he insisted its only for asthma and refused to prescribe it for me.

Hmmm, wonder what he would have said if I told him I want it for neurogenesis?

Some possibilities. =)

 

Be careful using your actual debit/credit card. Maybe try a temporary prepaid debit card. Can't completely vouch for their reliability. 

 

http://www.onemedsto...ions/singulair/

http://www.alldayche.../?q=montelukast

[lostfalco]

Hey Falco, I was wondering is there a recommended time that you specifically take Potato Starch? 

Also curious to your opinon on Citrulline Malate 
http://www.ncbi.nlm....les/PMC1724533/
". CM ingestion resulted in a significant reduction in the sensation of fatigue, a 34% increase in the rate of oxidative ATP production during exercise, and a 20% increase in the rate of phosphocreatine recovery after exercise, indicating a larger contribution of oxidative ATP synthesis to energy production."

Studies indicate that starch typically takes about 8 to 12 hours to transit through so I take it before bed and when I wake up...usually 2 to 4 tbsp at a time. 

 

I like citrulline since it seems to be a fundamental amino in the urea cycle and enhances arginine and ornithine. Examine has a very nice write-up on it. https://examine.com/...nts/Citrulline/

 

With that said, I haven't really noticed any cognitive benefits from it but a little circulation boost can be a good thing. 

Edited by lostfalco, 24 January 2016 - 10:19 PM.

[lostfalco]

A great little article summarizing ways to enhance synaptogenesis. They even remembered to include LLLT! http://mentalhealthd...s-in-the-brain/

 

Here's the LLLT article that we talked about a year or so ago. 

 

http://www.ncbi.nlm....pubmed/25196192

 

J Biophotonics. 2015 Jun;8(6):502-11. doi: 10.1002/jbio.201400069. Epub 2014 Sep 8.

Low-level laser therapy for traumatic brain injury in mice increases brain derived neurotrophic factor (BDNF) and synaptogenesis.

Xuan W1,2,3, Agrawal T2,3, Huang L2,3,4, Gupta GK2,3,5, Hamblin MR6,7,8.

Author information

Abstract

Transcranial low-level laser (light) therapy (LLLT) is a new non-invasive approach to treating a range of brain disorders including traumatic brain injury (TBI). We (and others) have shown that applying near-infrared light to the head of animals that have suffered TBI produces improvement in neurological functioning, lessens the size of the brain lesion, reduces neuroinflammation, and stimulates the formation of new neurons. In the present study we used a controlled cortical impact TBI in mice and treated the mice either once (4 h post-TBI, 1-laser), or three daily applications (3-laser) with 810 nm CW laser 36 J/cm(2) at 50 mW/cm(2). Similar to previous studies, the neurological severity score improved in laser-treated mice compared to untreated TBI mice at day 14 and continued to further improve at days 21 and 28 with 3-laser being better than 1-laser. Mice were sacrificed at days 7 and 28 and brains removed for immunofluorescence analysis. Brain-derived neurotrophic factor (BDNF) was significantly upregulated by laser treatment in the dentate gyrus of the hippocampus (DG) and the subventricular zone (SVZ) but not in the perilesional cortex (lesion) at day 7 but not at day 28. Synapsin-1 (a marker for synaptogenesis, the formation of new connections between existing neurons) was significantly upregulated in lesion and SVZ but not DG, at 28 days but not 7 days. The data suggest that the benefit of LLLT to the brain is partly mediated by stimulation of BDNF production, which may in turn encourage synaptogenesis. Moreover the pleiotropic benefits of BDNF in the brain suggest LLLT may have wider applications to neurodegenerative and psychiatric disorders. Neurological Severity Score (NSS) for TBI mice.

 

Edited by lostfalco, 24 January 2016 - 10:34 PM.

[Paul Smith]

Hi Lostfalco,

 

Any ideas where to source intranasal insulin for the UK as I can't find a seller.

 

Thanks

[Paul Smith]

Hi Lostfalco,

 

Just wondering for CoQ10 and PQQ is you have any recommended dosages.

 

I have seen this Jarrow supplement Jarrow Formulas Ubiquinol Plus Pyrroloquinoline Quinone which contains 100mg CoQ10 (Ubiquinol) and 10mg of PQQ seems about the norm for both do you approve of this dosage and a sideline what dosage do you take and brand if that matter?

 

Thanks

[BarrelBoy]

I've been leeching off of all your guys' research for too long and want to understand this better.

 

Can anyone recommend some videos/books/sources to get up to speed on all this neuroscience for someone with only a basic understanding of brain chemistry? At least to make a foundation so that I can go through this thread thouroughly? I want to learn and contribute.

Edited by brokenyoga, 26 January 2016 - 03:25 AM.

[lostfalco]

I've been leeching off of all your guys' research for too long and want to understand this better.

 

Can anyone recommend some videos/books/sources to get up to speed on all this neuroscience for someone with only a basic understanding of brain chemistry? At least to make a foundation so that I can go through this thread thouroughly? I want to learn and contribute.

No problem. =)

 

Remember to focus on gradients as you watch through these videos...the hydrogen gradient in mitochondria and the interactive sodium, calcium, and potassium gradients in neurons. This should hopefully give you a good start. I also have some book recommendations on my profile page.  http://www.longecity...1887-lostfalco/     If you're just starting out, 'The Machinery of Life' by David Goodsell is beautifully illustrated and is an excellent intro. Hoffman's book is pretty challenging so I'd hold off on it for now. 

 

 

 

https://www.youtube....h?v=FfZNn2hRe1s

 

https://youtu.be/-h_kWFM2faQ?t=13s

 

 

 

https://www.youtube.com/watch?v=C_H-ONQFjpQ

 

https://www.youtube.com/watch?v=ye3rTjLCvAU

 

https://www.youtube.com/watch?v=gkQtRec2464

 

https://www.youtube.com/watch?v=Tbq-KZaXiL4

Edited by lostfalco, 05 February 2016 - 03:38 AM.

[lostfalco]

Hi Lostfalco,

 

Just wondering for CoQ10 and PQQ is you have any recommended dosages.

 

I have seen this Jarrow supplement Jarrow Formulas Ubiquinol Plus Pyrroloquinoline Quinone which contains 100mg CoQ10 (Ubiquinol) and 10mg of PQQ seems about the norm for both do you approve of this dosage and a sideline what dosage do you take and brand if that matter?

 

Thanks

Hey Paul, Jarrow is a good brand and that dose is a good starting one. The main human study that I imitated used 20mg PQQ and 300mg CoQ10 but that can get a little pricey. I would start low and if it works for you then stick with it. The main brand that I use is here. http://www.longecity...1887-lostfalco/   

Hi Lostfalco,

 

Any ideas where to source intranasal insulin for the UK as I can't find a seller.

 

Thanks

Sorry Paul, I'm not sure off the top of my head. I'll do a little digging and see what I can find. 

[BieraK]

 

Awesome I guess my dose wasn't so off after all but instead of 4x/day I was dosing 2x/day. Well time to bump it up thanks lostfalco, I always look forward to your thread bro.

 

Thanks, man! I hope you find a dose that works well for you. 

I tried it (human betaNGF) back on 8/16/2015 with the log starting on this page. Now a few of us have taken it. It seems like the most obvious effect is enhanced dream vividness, but this is hardly a narrowly targetted molecule, so the potential is exciting, particularly in light of the excellent safety profile apart from transient pain enhancement.

 

 

Very cool resveratrol_guy. I'll head over there and check it out. 

 

 

KCNQ Inhibition/M-channel Inhibition + Nav1.2 Enhancement at the Axon Initial Segment = Enhanced Action Potentials = Enhanced Connectivity = Enhanced IQ (maybe)

 

KCNQ Inhibition: galantamine and/or CDP Choline and/or MK-677 (ghrelin) and/or Intranasal GHRP-2/6 (ghrelin)

Nav1.2 Enhancement: intranasal insulin (many more to talk about soon)

 

"M-channels are closed by receptors coupled to Gq such as M1 and M3 muscarinic receptors; this increases neuronal excitability and underlies some forms of cholinergic excitation."

 

"...ghrelin enhances firing of nigral dopaminergic neurons by inhibiting voltage-gated potassium Kv7/KCNQ/M-channels through its receptor GHS-R1a and activation of the PLC-PKC pathway."

 

Note: seizure warning.

 

 

 

http://www.ncbi.nlm....pubmed/23385580

 

Nat Commun. 2013;4:1435. doi: 10.1038/ncomms2439.

Peptide hormone ghrelin enhances neuronal excitability by inhibition of Kv7/KCNQ channels.

Shi L1, Bian X, Qu Z, Ma Z, Zhou Y, Wang K, Jiang H, Xie J.

Author information

Abstract

The gut-derived orexigenic peptide hormone ghrelin enhances neuronal firing in the substantia nigra pars compacta, where dopaminergic neurons modulate the function of the nigrostriatal system for motor coordination. Here we describe a novel mechanism by which ghrelin enhances firing of nigral dopaminergic neurons by inhibiting voltage-gated potassium Kv7/KCNQ/M-channels through its receptor GHS-R1a and activation of the PLC-PKC pathway. Brain slice recordings of substantia nigra pars compacta neurons reveal that ghrelin inhibits native Kv7/KCNQ/M-currents. This effect is abolished by selective inhibitors of GHS-R1a, PLC and PKC. Transgenic suppression of native Kv7/KCNQ/M-channels in mice or channel blockade with XE991 abolishes ghrelin-induced hyperexcitability. In vivo, intracerebroventricular ghrelin administration causes increased dopamine release and turnover in the striatum. Microinjection of ghrelin or XE991 into substantia nigra pars compacta results in contralateral dystonic posturing, and attenuation of catalepsy elicited by systemic administration of the D2 receptor antagonist haloperidol. Our findings indicate that the ghrelin/KCNQsignalling is likely a common pathway utilized by the nervous system.

 

 

http://www.ncbi.nlm....les/PMC2697739/

 

Br J Pharmacol. 2009 Apr;156(8):1185-95. doi: 10.1111/j.1476-5381.2009.00111.x. Epub 2009 Mar 9.

Neural KCNQ (Kv7) channels.

Brown DA1, Passmore GM.

Author information

Abstract

KCNQ genes encode five Kv7 K(+) channel subunits (Kv7.1-Kv7.5). Four of these (Kv7.2-Kv7.5) are expressed in the nervous system. Kv7.2 and Kv7.3 are the principal molecular components of the slow voltage-gated M-channel, which widely regulates neuronal excitability, although other subunits may contribute to M-like currents in some locations. M-channels are closed by receptors coupled to Gq such as M1 and M3 muscarinic receptors; this increases neuronal excitability and underlies some forms of cholinergic excitation. Muscarinic closure results from activation of phospholipase C and consequent hydrolysis and depletion of membrane phosphatidylinositol-4,5-bisphosphate, which is required for channel opening. Some effects of M-channel closure, determined from transmitter action, selective blocking drugs (linopirdine and XE991) and KCNQ2 gene disruption or manipulation, are as follows: (i) in sympathetic neurons: facilitation of repetitive discharges and conversion from phasic to tonic firing; (ii) in sensory nociceptive systems: facilitation of A-delta peripheral sensory fibre responses to noxious heat; and (iii) in hippocampal pyramidal neurons: facilitation of repetitive discharges, enhanced after-depolarization and burst-firing, and induction of spontaneous firing through a reduction of action potential threshold at the axon initial segment. Several drugs including flupirtine and retigabine enhance neural Kv7/M-channel activity, principally through a hyperpolarizing shift in their voltage gating. In consequence they reduce neural excitability and can inhibit nociceptive stimulation and transmission. Flupirtine is in use as a central analgesic; retigabine is under clinical trial as a broad-spectrum anticonvulsant and is an effective analgesic in animal models of chronic inflammatory and neuropathic pain.

 

http://www.ncbi.nlm....ubmed/18056963 

 

Ann N Y Acad Sci. 2007 Nov;1119:147-64.

Ghrelin receptor (GHS-R1A) agonists show potential as interventive agents during aging.

Smith RG1, Sun Y, Jiang H, Albarran-Zeckler R, Timchenko N.

Author information

Abstract

Administration of an orally active agonist (MK-0677) of the growth hormone secretagogue receptor (GHS-R1a) to elderly subjects restored the amplitude of endogenous episodic growth hormone (GH) release to that of young adults. Functional benefits include increased lean mass and bone density and modest improvements in strength. In old mice, a similar agonist partially restored function to the thymus and reduced tumor cell growth and metastasis. Treatment of old mice with the endogenous GHS-R1a agonist ghrelin restored a young liver phenotype. The mechanism involves inhibition of cyclin D3:cdk4/cdk6 activity and increased protein phosphatase-2A (PP2A) activity in liver nuclei, which stabilizes the dephosphorylated form of the transcription factor C/EBPalpha preventing the age-dependent formation of the C/EBPalpha-Rb-E2F4-Brm nuclear complex. By inhibiting formation of this complex, repression of E2F target genes is de-repressed and C/EBPalpha regulated expression of Pepck, a regulator of gluconeogenesis, is normalized, thereby restoring a young liver phenotype. In the brain, aging is associated with decline in dopamine function. We investigated the potential neuromodulatory role of GHS-R1a on dopamine action. Neurons were identified in the hippocampus, cortex, substantia nigra, and ventral tegmental areas that coexpressed GHS-R1a and dopamine receptor subtype-1 (D1R). Cell culture studies showed that, in the presence of ghrelin and dopamine, GHS-R and D1R form heterodimers, which modified G-protein signal transduction resulting in amplification of dopamine signaling. We speculate that aging is associated with deficient endogenous ghrelin signaling that can be rescued by intervention with GHS-R1a agonists to improve quality of life and maintain independence.

 

 

Take care with potassium channels, specially with Kv7 channels, the onset of tinnitus is associated with a deregulation of that channels.
Thats why some people has succes with anti-epileptic drugs like Retigabine (Trobalt), and anti-inflammatory drugs like Flupirtine.
http://www.ncbi.nlm....pubmed/24681057
http://www.ncbi.nlm....pubmed/24681057
http://www.ncbi.nlm....pubmed/26063916

Really potassium channels look like a very fragile thing. 

Edited by BieraK, 26 January 2016 - 05:17 AM.

[lostfalco]

Take care with potassium channels, specially with Kv7 channels, the onset of tinnitus is associated with a deregulation of that channels.

Thats why some people has succes with anti-epileptic drugs like Retigabine (Trobalt), and anti-inflammatory drugs like Flupirtine.
http://www.ncbi.nlm....pubmed/24681057
http://www.ncbi.nlm....pubmed/24681057
http://www.ncbi.nlm....pubmed/26063916

Really potassium channels look like a very fragile thing. 

 

Yep, I'm with you. I think it's important to never overdo (or under-do) anything. Hence, my multi-pronged, low dose approach from many angles. Too many mitochondria can be bad, just like too few can be. Too much ATP can be bad, just like too little. Too much glutamate, too little glutamate. Too much acetylcholine, too little acetylcholine. Too much dopamine, too little. Norepinephrine, sodium, potassium, calcium, magnesium, serotonin, antioxidants, anti-inflammatories, growth factors, neuropeptides, neurohormones, oxygen, water, sunlight, etc., etc. all work the same way. As you mentioned, underactive potassium channels can lead to seizures/tinnitus and overactive potassium channels can lead to cognitive impairment. Perpetual tightrope walking is just the nature of the game. Totally agree.   

Edited by lostfalco, 26 January 2016 - 01:05 PM.

[lostfalco]

Hi Lostfalco,

 

Any ideas where to source intranasal insulin for the UK as I can't find a seller.

 

Thanks

Sorry Paul, I took a look and everything I read seemed to indicate that insulin is prescription only in the UK. I'm not sure where you could get it over there. 

[Junk Master]

Just have to say, "Great thread!"

 

Thanks to all the participants for their work!  These threads are what make this place what it is.

[lostfalco]

Just have to say, "Great thread!"

 

Thanks to all the participants for their work!  These threads are what make this place what it is.

Thanks, Junk Master! I'm glad you've found the thread helpful. =)

[Nuke]

About the IN insulin. Maybe combine it with Vanadium and Chromium to optimize inter cell signaling for glucose uptake? 

 

http://examine.com/s...ements/Chromium

http://examine.com/s...ements/Vanadium

[Reformed-Redan]

Hi lostfalco

 

I've been looking around for hydrogen water generators. Do you know any that are true to producing hydrogen rich water? I'd love to try some.

 

Best regards.

[lostfalco]

About the IN insulin. Maybe combine it with Vanadium and Chromium to optimize inter cell signaling for glucose uptake? 

 

http://examine.com/s...ements/Chromium

http://examine.com/s...ements/Vanadium

Very interesting, Nuke. Vanadium looks especially interesting. Thanks, man!

 

I noticed you had some positive trending scores on the Stroop test with your peptide bioregulators experiment. Very cool. I appreciate you sharing your results. I'm gonna revisit those guys one of these days.