4019 replies to this topic

[lostfalco]

Ahh ok. Well if LLLT improves mitochondrial activity, then it should increase action potential firing as well right? Much of the mitochondria is situated at the axon hillock where action potentials originate from. I'll stick to lasering my whole brain.

 

 

 

I have the 96 LED CCTV thing. How many different planes/areas of the head should I go over? Also, how long should I do each area and in what order?

 

It's possible that LLLT would increase action potential firing...but it's complicated. Isn't it always!? ha

 

I usually laser 15 somewhat non-overlapping spots in total. Your forehead is most important so make that a priority and then I do sides of head, top, back, etc. Just cover everything. The order doesn't matter. Good luck lasering!

So this past Monday I got my 48LED and the adapter set up and started my first trial run...I was very conservative so that night before bedtime I only did the frontal lobe parts of my brain at 30 secs each spot.  That night I feel that it affected my sleep in a negative way but maybe was placebo or just the novelty of doing something new and exciting got me too wound up to get my normal sleep even though I took some melatonin.  So the next morning I was a little slow getting started for the day but by the afternoon felt great and had 2 very positive business meetings.  Wed morning I decided to try more LLLT so I only did the temporal and parietal lobe areas of my head 30 secs each spot....afterward felt like it mellowed me out a bit so I lay down and meditated for about 15 or 20 mins and got up and took a sodium selenite cap and 2 grams piracetam then a cup of coffee and felt fine.  I had a productive afternoon at the office solving big computer problems and on the phone, problems which had been persisting for months.  This morning (Friday) I did the frontal lobe areas again 30 secs each spot followed by 2 grams Piracetam and a sodium selenite cap and I am feeling fine....one confounding factor this week is the fact that I also tried 8 mgs galantamine M W and Fri this week after breakfast which is also something totally new.  Anyway I am having a great week but not sure why....I may stick with this same protocol for a while before changing it.

Thanks for the report, magta! If it works well for you then stick with it. It's very cool that you're seeing good results. Keep us updated on how everything progresses. 

Edited by lostfalco, 17 January 2016 - 06:45 PM.

[lostfalco]

Good lord this just keeps getting better and better! Intranasal insulin enhances thyroid function in healthy and diabetic rodents. 

 

My guess is that this is part of the reason that intranasal insulin enhances long term memory after 8 weeks in humans. Thyroid hormones enhance filamentous actin (F-actin) and stabilize postsynaptic neurons in LTP. 

 

http://www.ncbi.nlm....pubmed/25750079

 

Horm Metab Res. 2015 Nov;47(12):916-24. doi: 10.1055/s-0035-1547236. Epub 2015 Mar 6.

The Influence of Intranasal Insulin on Hypothalamic-Pituitary-Thyroid Axis in Normal and Diabetic Rats.

Derkach KV1, Bogush IV1, Berstein LM2, Shpakov AO1.

Author information

Abstract

The functions of hypothalamic-pituitary-thyroid axis are attenuated in type 1 diabetes mellitus due to insulin deficiency. The use of intranasally administered insulin is of considerable interest for treatment of diabetes and cognitive disorders, but its effect on the thyroid system has not been investigated yet. We studied the influence of long-term treatment with intranasal insulin on the hypothalamic-pituitary-thyroid axis of nondiabetic rats and diabetic animals with streptozotocin models of acute and mild type 1 diabetes mellitus. This treatment was carried out for 28 days in acute (daily does of 0.3, 0.6, and 1.5 IU of insulin per rat) and for 135 days in mild diabetes (daily dose of 0.45 IU/rat). Nondiabetic rats were treated in a similar manner. Intranasal insulin in both models of diabetes resulted in the improvement of thyroid status; manifested as increase of thyroid hormones levels and restoration of response to thyroliberin. In acute diabetes, a daily dose of 0.6 IU/rat was the most effective. Twenty eight days treatment of nondiabetic rats with intranasal insulin at a dose of 0.3 IU/rat resulted in a significant increase of free and total thyroxine levels. Longer treatment of rats with mild diabetes and nondiabetic animals significantly increased thyrotropin level. Thus, long-term intranasal insulin treatment restored the hypothalamic-pituitary-thyroid axis function in type 1 diabetes, but led to a significant increase in the thyrotropin level, which must be considered when designing a strategy for the use of intranasal insulin in clinical applications.

 

 

http://www.ncbi.nlm....les/PMC4146262/

 

Neural Regen Res. 2014 Apr 15;9(8):864-71. doi: 10.4103/1673-5374.131602.

The synthetic thyroid hormone, levothyroxine, protects cholinergic neurons in the hippocampus of naturally aged mice.

Fu A1, Zhou R1, Xu X1.

Author information

Abstract

The thyroid hormones, triiodothyronine and thyroxine, play important roles in cognitive function during the mammalian lifespan. However, thyroid hormones have not yet been used as a therapeutic agent for normal age-related cognitive deficits. In this study, CD-1 mice (aged 24 months) were intraperitoneally injected with levothyroxine (L-T4; 1.6 μg/kg per day) for 3 consecutive months. Our findings revealed a significant improvement in hippocampal cytoskeletal rearrangement of actin and an increase in serum hormone levels of L-T4-treated aged mice. Furthermore, the survival rate of these mice was dramatically increased from 60% to 93.3%. The Morris water maze task indicated that L-T4 restored impaired spatial memory in aged mice. Furthermore, level of choline acetyltransferase, acetylcholine, and superoxide dismutase were increased in these mice, thus suggesting that a possible mechanism by which L-T4 reversed cognitive impairment was caused by increased activity of these markers. Overall, supplement of low-dosage L-T4 may be a potential therapeutic strategy for normal age-related cognitive deficits.

 

Edited by lostfalco, 17 January 2016 - 07:02 PM.

[BigPapaChakra]

Saw someone post about this on facebook: http://www.mypalmbea...-through/np56w/ " Nervana’s product, created by two Palm Beach County doctors, is a $299 portable device that uses ear buds to send an electronic signal to the vagus nerve, which passes near the ear and carries messages to every major organ. Nervana says its signals spur the brain to produce dopamine, a feel-good neurotransmitter that boosts mood."

 

http://experiencener...nervana-music/ 

Music Mode

The NERVANA Generator acts as a pass-through for a user-selected music signal, which is input through a standard audio jack and is output through the speakers contained within the earbuds of the NERVANA Headphones. Proprietary, patent-pending circuitry within the Nervana Generator analyzes the music signal and generates a targeted Vagus nerve stimulation output that synchronizes with the music’s signal, so the user canFeel the Music.

Ambient Mode

In contrast with Music Mode, Ambient Mode tasks the NERVANA Generator’s internal microphone with modulating output to the NERVANA Headphone based on sounds from the environment. Put more simply, any music being played around the user, for example, at a concert, will be the basis for the Vagus nerve stimulation output sent to the user through the NERVANA Headphones. This means that, in the Ambient Mode, all NERVANA users in the same location can experience similar nerve stimulation.

Formula Mode

For users wanting to use NERVANA without music, there is a pre-defined nerve stimulation signal pattern that can be selected.

[lostfalco]

Ceretropic has methylene blue now. Nice. 

 

http://www.ceretropi...ne-blue-powder/

Edited by lostfalco, 17 January 2016 - 11:04 PM.

[lostfalco]

Saw someone post about this on facebook: http://www.mypalmbea...-through/np56w/ " Nervana’s product, created by two Palm Beach County doctors, is a $299 portable device that uses ear buds to send an electronic signal to the vagus nerve, which passes near the ear and carries messages to every major organ. Nervana says its signals spur the brain to produce dopamine, a feel-good neurotransmitter that boosts mood."

 

http://experiencener...nervana-music/ 

Music Mode

The NERVANA Generator acts as a pass-through for a user-selected music signal, which is input through a standard audio jack and is output through the speakers contained within the earbuds of the NERVANA Headphones. Proprietary, patent-pending circuitry within the Nervana Generator analyzes the music signal and generates a targeted Vagus nerve stimulation output that synchronizes with the music’s signal, so the user canFeel the Music.

Ambient Mode

In contrast with Music Mode, Ambient Mode tasks the NERVANA Generator’s internal microphone with modulating output to the NERVANA Headphone based on sounds from the environment. Put more simply, any music being played around the user, for example, at a concert, will be the basis for the Vagus nerve stimulation output sent to the user through the NERVANA Headphones. This means that, in the Ambient Mode, all NERVANA users in the same location can experience similar nerve stimulation.

Formula Mode

For users wanting to use NERVANA without music, there is a pre-defined nerve stimulation signal pattern that can be selected.

Interesting, Papa. Vagus nerve stimulation has some pretty cool applications. Have you tried this yet or talked to anyone who has?

[BigPapaChakra]

I have not yet tried it, nor spoken to anyone who has personally used it. I'm interested in it though, definitely. I was recently looking into vagus nerve stimulation since it has so many applications, and typically, rather profound impacts, especially in regards to mood regulation, resilience to various physiological stressors, etc. I found one (that I'm still trying to find the link for) that is IIRC FDA and such approved, and purportedly works well, yet it requires an Rx from one's physician. I was going to inquire about it with one of my doctors, but I may just opt for the Nervana when I have the funds. 

 

By the way, I'm certain many have seen my subtle comments about researchers such as Chris Masterjohn, PhD, and Ray Peat, PhD (and others coming from a similar perspective such as Benedicte Mai Lerche, M.S., PhD, Andrew Kim, and Vladimir), but here is the published work in progress of the extensive DHA article I posted the excerpts for before: http://tanyewwei.com/blog/dha/ (warning: extremely long article with many, many citations, all looked at completely in depth (study methods, authors, etc) only read when one has a lot of time).

 

Interestingly, it seems as though, despite Dr. Peat speaking about this stuff for about 45 years, and Chris Masterjohn speaking about it for the past 5+ years (in addition to Peter @ Hyperlipid and Stan the Heretic), a lot of people from the Jack Kruse crowd found Yew's take to resonate with them, and have long since abandoned the copious consumption of excess PUFAs, including oily fish. 

Edited by BigPapaChakra, 18 January 2016 - 04:44 AM.

[lostfalco]

Just sharing some research. =)

 

Axon Initial Segment, Nav1.2, and GSK3

 

If inhibit GSK3b, then enhance nav1.2. 

VERY speculative: enhancing nav1.2 activity (just a bit) might enhance "g". (see genetic study below. Did I say very speculative? Just making double sure. =)) 

 

Note: seizure warning

Note 2: there is SO much more to enhancement than transmitters and receptors. We're on to some very cool stuff. =)

Note 3: repetition aids memory...therefore I'll repeat: focus on hydrogen, calcium, sodium, potassium gradients, etc. Our entire physiology is designed around guiding the flow of gradients/ions. Everything else is a means. (Slight exaggeration, but not that much. =))

Note 4: remember there are extracellular and intracellular gradients (ex. calcium is released from intracellular stores). 

Note 5: there are MANY ways to influence GSK3b activity. 

 

 

 

 

 

http://www.ncbi.nlm....pubmed/25615535

 

Biochim Biophys Acta. 2015 Apr;1850(4):832-44. doi: 10.1016/j.bbagen.2015.01.011. Epub 2015 Jan 20.

The Nav1.2 channel is regulated by GSK3.

James TF1, Nenov MN2, Wildburger NC1, Lichti CF2, Luisi J2, Vergara F2, Panova-Electronova NI2, Nilsson CL2, Rudra JS2, Green TA3, Labate D4, Laezza F5.

Author information

Abstract

BACKGROUND:

Phosphorylation plays an essential role in regulating voltage-gated sodium (Na(v)) channels and excitability. Yet, a surprisingly limited number of kinases have been identified as regulators of Na(v) channels. We posited that glycogen synthase kinase 3 (GSK3), a critical kinase found associated with numerous brain disorders, might directly regulate neuronal Na(v) channels.

METHODS:

We used patch-clamp electrophysiology to record sodium currents from Na(v)1.2 channels stably expressed in HEK-293 cells. mRNA and protein levels were quantified with RT-PCR, Western blot, or confocal microscopy, and in vitro phosphorylation and mass spectrometry to identify phosphorylated residues.

RESULTS:

We found that exposure of cells to GSK3 inhibitor XIII significantly potentiates the peak current density of Na(v)1.2, a phenotype reproduced by silencing GSK3 with siRNA. Contrarily, overexpression of GSK3β suppressed Na(v)1.2-encoded currents. Neither mRNA nor total protein expression was changed upon GSK3 inhibition. Cell surface labeling of CD4-chimeric constructs expressing intracellular domains of the Na(v)1.2 channel indicates that cell surface expression of CD4-Na(v)1.2 C-tail was up-regulated upon pharmacological inhibition of GSK3, resulting in an increase of surface puncta at the plasma membrane. Finally, using in vitro phosphorylation in combination with high resolution mass spectrometry, we further demonstrate that GSK3β phosphorylates T(1966) at the C-terminal tail of Na(v)1.2.

CONCLUSION:

These findings provide evidence for a new mechanism by which GSK3 modulates Na(v) channel function via its C-terminal tail.

GENERAL SIGNIFICANCE:

These findings provide fundamental knowledge in understanding signaling dysfunction common in several neuropsychiatric disorders.

 

 

 

http://www.ncbi.nlm....les/PMC4692714/

 

J Cogn Neurosci. 2015 Sep;27(9):1766-74. doi: 10.1162/jocn_a_00826. Epub 2015 May 11.

A Common Polymorphism in SCN2A Predicts General Cognitive Ability through Effects on PFC Physiology.

Scult MA1, Trampush JW2, Zheng F3, Conley ED4, Lencz T2, Malhotra AK2, Dickinson D5, Weinberger DR3, Hariri AR1.

Author information

Abstract

Here we provide novel convergent evidence across three independent cohorts of healthy adults (n = 531), demonstrating that a common polymorphism in the gene encoding the α2 subunit of neuronal voltage-gated type II sodium channels (SCN2A) predicts human general cognitive ability or "g." Using meta-analysis, we demonstrate that the minor T allele of a common polymorphism (rs10174400) in SCN2A is associated with significantly higher "g" independent of gender and age. We further demonstrate using resting-state fMRI data from our discovery cohort (n = 236) that this genetic advantage may be mediated by increased capacity for information processing between the dorsolateral PFC and dorsal ACC, which support higher cognitive functions. Collectively, these findings fill a gap in our understanding of the genetics of general cognitive ability and highlight a specific neural mechanism through which a common polymorphism shapes interindividual variation in "g."

 

"The SCN2A gene, located on 2q24.3, encodes the α2 subunit of voltage-gated type II sodium channels, which contribute to the generation and propagation of action potentials throughout the adult central nervous system (Eijkelkamp et al., 2012; LITT, 1989). The α2 subunit encoded by SCN2A (Nav1.2) specifically mediates the conformational change of sodium channels based on voltage differences across cell membranes (Ahmed et al., 1992). Thus, variation in SCN2A may impact nervous system function by altering Nav1.2-modulated sodium channel regulation of neuronal activity and signaling. In fact, early studies in mice (Kearney et al., 2001) and humans (Sugawara et al., 2001) have linked mutations in SCN2A with abnormal electrical activity in the form of epileptic seizures (Heron et al., 2010; Kamiya et al., 2004). Furthermore, antiepileptic drugs that inhibit Nav1.2 activity (e.g., topiramate) are associated with diminished intellectual function."

 

 

Edited by lostfalco, 19 January 2016 - 01:55 PM.

[cylack]

Lostfalco,

Thanks for answering my earlier post about intranasal insulin. Where did you get your syringe from? I bought the novolin from walmart but realized I forgot I needed a syringe and needle when I got home. 

I saw amazon sells this 100 microliter syringe, but its pricey at $20: http://smile.amazon....roliter syringe

 

 

[iamthewildturtle]

I'd like to ask LostFalco and other people their opinions on ALCAR. Also, would anyone recommend taking ALCAR in capsules or powdered form? How does one take powdered ALCAR? Would I be able to add it to coffee? Thanks!

[lostfalco]

Tadalafil, GSK3b, and Insulin Resistance (in skeletal muscle)

 

http://www.ncbi.nlm....pubmed/23873283

 

J Endocrinol Invest. 2013 Dec;36(11):1020-6. doi: 10.3275/9034. Epub 2013 Jul 15.

Insulin-like effect of the phosphodiesterase type 5 inhibitor tadalafil onto male human skeletal muscle cells.

Crescioli C1, Sturli N, Sottili M, Bonini P, Lenzi A, Di Luigi L.

Author information

Abstract

BACKGROUND: 

Phosphodiesterase type 5 inhibitors (PDE5i), widely used to treat male erectile dysfunction, seem to counteract insulin resistance (IR) in animals and humans. IR, primarily manifest in peripheral tissues and particularly in skeletal muscle, is due to impaired insulin signal transduction. Investigators have been focusing onto intracellular defects responsible for IR to identify suitable pharmacological tools targeted toward the specific defects. Albeit some effects of PDE5i have been reported onto animal muscular tissues or cells, whether and how they might affect metabolic processes directly in human skeletal muscle still remains unclear.

AIM: 

We aimed to investigate in human fetal skeletal muscle cells (Hfsmc) the effect of tadalafil, one of PDE5i, onto some intracellular factors involved in response to insulin, such as ras-raf mitogen activated protein kinase (MAPK), phosphatidylinositol 3-kinase/protein kinase B (PKB/Akt), glycogen synthase kinase 3β (GSK-3β), and the transcriptional factor c-Myc; proliferation rate; lactate (lact) and free fatty acid (ffa) release; activity of citrate synthase (CS) and succinate dehydrogenase (SDH), both enzymes of Kreb's cycle; PDE5 gene expression.

MATERIALS AND METHODS: 

Western blot analysis, enzyme-linked immunosorbent assay, enzymatic assays, cell count, MTT assay and Real Time PCR were performed in Hfsmc with and without tadalafil.

RESULTS: 

In Hfsmc tadalafil affected the insulin-related intracellular cascade, by increasing MAPK, PKB/Akt, GSK-3β phosphorylation and c-Myc expression. ffa release and CS activity also significantly increased, with no changes in SDH activity and lact release.

CONCLUSIONS: 

Tadalafil, like insulin, targeted part of the machinery dedicated to energy management and metabolic control in human skeletal muscle cells.

 

Edited by lostfalco, 19 January 2016 - 02:39 PM.

[lostfalco]

Synergistic, low dose effect between a positive allosteric modulator of a7 nicotinic acetylcholine receptors and GTS-21 (DMXBA)

 

I see this all the time in the literature. Two inactive doses can be combined to produce effects...hence, the combined low dosing of The God Stack. =)

 

Galantamine + GTS-21? Maybe. Didn't seem to work for Heisenburger in the GTS-21 thread but might work for some of us. 

 

http://www.ncbi.nlm....pubmed/26778787

 

Behav Brain Res. 2016 Jan 8. pii: S0166-4328(16)30002-X. doi: 10.1016/j.bbr.2016.01.002. [Epub ahead of print]

The positive allosteric modulator of α7 nicotinic acetylcholine receptors, 3-furan-2-yl-N-p-tolyl-acrylamide, enhances memory processes and stimulates ERK1/2 phosphorylation in mice.

Targowska-Duda KM1, Wnorowski A2, Budzynska B3, Jozwiak K2, Biala G3, Arias HR4.

Author information

Abstract

To determine whether 3-furan-2-yl-N-p-tolyl-acrylamide (PAM-2), a positive allosteric modulator of α7 nicotinic acetylcholine receptors (nAChRs), improves memory processes, passive avoidance tests were conducted in male mice after acute and chronic treatments. To determine the neuronal mechanisms underlying the promnesic activity elicited by PAM-2, the effect of this ligand on α7 nAChR up-regulation and ERK1/2 phosphorylation was assessed in the hippocampus and prefrontal cortex. The results indicate that: (1) PAM-2 improves memory acquisition/consolidation after acute treatment (Day 2) and memory consolidation after chronic treatment (Day 22). Although no effect was observed on α7 nAChR up-regulation, the chronic, but not acute, PAM-2 treatment increases ERK1/2 kinase phosphorylation, (2) the promnesic activity of PAM-2 was inhibited by methyllycaconitine, a selective α7-antagonist, confirming the role of α7 nAChRs, (3) a synergistic (acute) effect was observed between inactive doses of PAM-2 (0.1mg/kg) and DMXBA (0.3mg/kg), a selective α7-agonist, and (4) PAM-2 reversed the memory impairment elicited by scopolamine, a muscarinic antagonist. The results demonstrate that PAM-2 presents promnesic activity mediated by α7 nAChRs, and is able to trigger ERK1/2 phosphorylation only after chronic treatment.

 

Edited by lostfalco, 19 January 2016 - 02:48 PM.

[lostfalco]

Why the focus on alpha 7 nicotinic acetylcholine receptors? I'm glad you asked. =)

 

Delay Cells, Dorsolateral Prefrontal Cortex Layer III Pyramidal Neurons, α7 Receptors, NMDA, Spatial Working Memory, and IQ

 

Activation of dendritic A7 receptors in layer iii pyramidal neurons of the dorsolateral prefrontal cortex removes the magnesium block (this is primarily done by AMPAR activation in other brain areas) from NMDA receptors and potentiates working memory...which is associated with IQ, fluid intelligence, "g". These neurons are known as delay cells because they persist in firing even after the initial stimulus has been removed. This is one of the main reasons you can hold items in working memory and play dual n-back.

 

I like galantamine and CDP Choline personally (I have never found a nicotine dose that has worked for me), but some of the new selective a7 agonists look interesting as well.

 

We should be able to combine these with potassium channel modulators (low dose guanfacine, possibly), NMDA/glutamate enhancers, and GSK3B inhibitors (which should enhance sodium channel activity) among many other things. 

 

I'm sure you can see why I'm so interested in intranasal galantamine. 

 

GTS-21 is available here. I haven't tried it yet. https://www.rechem.c...gory&path=68_76

 

http://www.ncbi.nlm....les/PMC3718126/

 

Proc Natl Acad Sci U S A. 2013 Jul 16;110(29):12078-83. doi: 10.1073/pnas.1307849110. Epub 2013 Jul 1.
Nicotinic α7 receptors enhance NMDA cognitive circuits in dorsolateral prefrontal cortex.
Yang Y1, Paspalas CD, Jin LE, Picciotto MR, Arnsten AF, Wang M.
Author information
Abstract
The cognitive function of the highly evolved dorsolateral prefrontal cortex (dlPFC) is greatly influenced by arousal state, and is gravely afflicted in disorders such as schizophrenia, where there are genetic insults in α7 nicotinic acetylcholine receptors (α7-nAChRs). A recent behavioral study indicates that ACh depletion from dlPFC markedly impairs working memory [Croxson PL, Kyriazis DA, Baxter MG (2011) Nat Neurosci 14(12):1510-1512]; however, little is known about how α7-nAChRs influence dlPFC cognitive circuits. Goldman-Rakic [Goldman-Rakic (1995) Neuron 14(3):477-485] discovered the circuit basis for working memory, whereby dlPFC pyramidal cells excite each other through glutamatergic NMDA receptor synapses to generate persistent network firing in the absence of sensory stimulation. Here we explore α7-nAChR localization and actions in primate dlPFC and find that they are enriched in glutamate network synapses, where they are essential for dlPFC persistent firing, with permissive effects on NMDA receptor actions. Blockade of α7-nAChRs markedly reduced, whereas low-dose stimulation selectively enhanced, neuronal representations of visual space. These findings in dlPFC contrast with the primary visual cortex, where nAChR blockade had no effect on neuronal firing [Herrero JL, et al. (2008) Nature 454(7208):1110-1114]. We additionally show that α7-nAChR stimulation is needed for NMDA actions, suggesting that it is key for the engagement of dlPFC circuits. As ACh is released in cortex during waking but not during deep sleep, these findings may explain how ACh shapes differing mental states during wakefulness vs. sleep. The results also explain why genetic insults to α7-nAChR would profoundly disrupt cognitive experience in patients with schizophrenia.

Edited by lostfalco, 27 January 2016 - 03:00 AM.

[lostfalco]

Insulin inhibits GSK3b.

 

Novolin R is $25 at Walmart pharmacies over the counter without a prescription (in the U.S.).

 

Note: possible cancer warning (associated with dysregulation of the pathway).

 

I'll just quote this since it's pretty cool. 

 

"Mediators of GSK3β phosphorylation

In its active state, GSK3β exhibits a 100–1000-fold increased efficiency in substrate specificity for pre-primed (pre-phosphorylated) substrates, as compared to non-primed substrates. However, multiple agonists including growth factors, insulin, α7nAchR, TLRs, TCR, cytokines, CD28, and amino acids phospho-activate PI3K, which results in the generation of PIP3 that allows for the recruitment of Akt via its pleckstrin homology domain. Full activation of Akt occurs through phosphorylation at threonine 308 by PDK1 and serine 473 by PDK2/mTORC2. Upon activation, Akt can phosphorylate GSK3β (Ser9) resulting in GSK3β inactivation. PKC and PKA also can phospho-inactivate GSK3β."

 

 

http://www.cell.com/...842X(14)00021-3

 

"Early studies identified the insulin-mediated signaling pathway as an activator of PI3K and, subsequently, a phospho-inactivator of both GSK3α (Ser21) and GSK3β (Ser9)."

 

"Tyrosine phosphorylation (Tyr279 for GSK3α and Tyr216 for GSK3β) enhances activity."

 

"N-terminal serine phosphorylation (Ser21 for GSK3α and Ser9 for GSK3β) is suppressive."

 

"The major GSK3β-regulating event, however, seems to be Ser9 phosphorylation."

 

"A distinct feature of GSK3 is that it displays high activity under basal conditions. This activity is differentially regulated by tyrosine and S/T phosphorylation. Tyrosine phosphorylation (Tyr279 for GSK3α and Tyr216 for GSK3β) enhances activity, whereas N-terminal serine phosphorylation (Ser21 for GSK3α and Ser9 for GSK3β) is suppressive. Other GSK3β sites, such as ERK (extracellular signal regulated kinase)- and p38–MAPK (mitogen-activated protein kinase)-phosphorylated Thr43 and Ser389, are also reported to influence GSK3β activity in the brain and thymocytes [1]. The major GSK3β-regulating event, however, seems to be Ser9 phosphorylation. Multiple extracellular signals induce rapid Ser9 phosphorylation, resulting in a dramatic decrease in enzymatic activity, with the upstream activators phosphoinositide 3-kinase (PI3K)–Ak thymoma/protein kinase B (Akt/PKB) being the best studied (Figure 1). Early studies identified the insulin-mediated signaling pathway as an activator of PI3K and, subsequently, a phospho-inactivator of both GSK3α (Ser21) and GSK3β (Ser9) [7]. Other molecules, including growth factors, phorbol esters, amino acids, interleukin receptors, Toll-like receptors (TLRs), T cell receptors, and CD28, as well as KIT (v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog) activation, have since been shown to be involved in the phosphorylation, and thus inactivation, of GSK3 [1]."

Edited by lostfalco, 19 January 2016 - 07:35 PM.

[lostfalco]

I'll be talking about this more going forward...but this lecture ties together everything we've been talking about lately regarding the dorsolateral prefrontal cortex layer III. Watch when you get a chance! This is a must watch if you want to understand working memory. (use 2x speed to make the most of your time =)) 

 

Edited by lostfalco, 19 January 2016 - 08:31 PM.

[lostfalco]

Just a quick question to everyone...what do you guys think the consensus is on teamtlr? I know they've had some product issues in the past but do you guys think they are reliable?

 

They are one of the few places that sell guanfacine. https://teamtlr.com/...guanfacine.html

 

If we combine it with everything else, I think we can get away with taking very low dose guanfacine without experiencing fatigue. It should have some very synergistic effects on working memory.

 

Spermine also looks potentially interesting. I'm not sure yet though. Wheat germ has a decent amount and it also has spermidine which metabolizes into spermine. Spermine is a positive allosteric modulator of NMDA receptors (among other things) at the NR2B/GLUN2B subunit which is especially concentrated in layer iii cells of the dlpfc. Of course, spermidine and spermine are also good for autophagy and possibly longevity enhancement. 

 

Anyone know of spermine or spermidine vendors? I can't find any. 

 

http://www.ncbi.nlm....pubmed/25829490

 

J Biol Chem. 2015 May 15;290(20):12812-20. doi: 10.1074/jbc.M115.649723. Epub 2015 Mar 31.

Subtype-dependent N-methyl-D-aspartate receptor amino-terminal domain conformations and modulation by spermine.

Sirrieh RE1, MacLean DM1, Jayaraman V2.

Author information

Abstract

The N-methyl-d-aspartate (NMDA) subtype of the ionotropic glutamate receptors is the primary mediator of calcium-permeable excitatory neurotransmission in the central nervous system. Subunit composition and binding of allosteric modulators to the amino-terminal domain determine the open probability of the channel. By using luminescence resonance energy transfer with functional receptors expressed in CHO cells, we show that the cleft of the amino-terminal domain of the GluN2B subunit, which has a lower channel open probability, is on average more closed than the GluN2A subunit, which has a higher open probability. Furthermore, the GluN1 amino-terminal domain adopts a more open conformation when coassembled with GluN2A than with GluN2B. Binding of spermine, an allosteric potentiator, opens the amino-terminal domain cleft of both the GluN2B subunit and the adjacent GluN1 subunit. These studies provide direct structural evidence that the inherent conformations of the amino-terminal domains vary based on the subunit and match the reported open probabilities for the receptor.

 

Edited by lostfalco, 20 January 2016 - 12:02 AM.

[lostfalco]

...here is the published work in progress of the extensive DHA article I posted the excerpts for before: http://tanyewwei.com/blog/dha/ (warning: extremely long article with many, many citations, all looked at completely in depth (study methods, authors, etc) only read when one has a lot of time).

 

Interestingly, it seems as though, despite Dr. Peat speaking about this stuff for about 45 years, and Chris Masterjohn speaking about it for the past 5+ years (in addition to Peter @ Hyperlipid and Stan the Heretic), a lot of people from the Jack Kruse crowd found Yew's take to resonate with them, and have long since abandoned the copious consumption of excess PUFAs, including oily fish. 

Thanks for the link, Papa! I've got some reading to do. 

[lostfalco]

Lostfalco,

Thanks for answering my earlier post about intranasal insulin. Where did you get your syringe from? I bought the novolin from walmart but realized I forgot I needed a syringe and needle when I got home. 

I saw amazon sells this 100 microliter syringe, but its pricey at $20: http://smile.amazon....roliter syringe

Hey cylack, I was actually able to (somewhat) carefully unscrew/wiggle the lid off with pliers. Takes a little finesse to avoid breaking the bottle but can be done. I asked two different pharmacies for syringes and they both told me I needed insulin prescriptions...and then glared at me like I was a criminal when I told them I didn't have one. ha I'm in the same boat as you ordering from Amazon/online going forward. 

[lostfalco]

I'd like to ask LostFalco and other people their opinions on ALCAR. Also, would anyone recommend taking ALCAR in capsules or powdered form? How does one take powdered ALCAR? Would I be able to add it to coffee? Thanks!

I like ALCAR...it's good for mito's and has some epigenetic effects. I prefer ALCAR powder because it's inexpensive but it can be a little tart. I just put the dose in my mouth and chase it down with water. Never tried it in coffee but it's pretty strong tasting stuff so I kinda doubt it would work but it never hurts to give it a go. =) Powdercity has it for $5. http://www.powdercit...nitine-benefits

Edited by lostfalco, 20 January 2016 - 01:28 PM.

[bigyellowlemon]

http://www.ncbi.nlm....pubmed/21557387

I'm not sure if it's a good study, but there's more

http://www.jneurosci...29/23/7619.full

Small world network architecture is very important for a properly functioning brain

Lostfalco, because ampakines wouldn't really help the PFC, could we use some "neurotoxins", i.e. NDMA agonists in low doses? We could use memantine to block excitotoxicity. How important do you think GABA is to cognition? Is it there mainly to quench anxiety or for calculations/computations? I will watch the video.

Sodium channels are incredibly interesting. Also, from what I've seen of the video, balance is key. Too much/little of any neurotransmitter will create disorder. How will we be able to tell what levels are optimal? Learning that Nicotinic a7 receptors displace the Mg is super cool.
You should look into polygala tenuifolia, it creates NR2B in the hippocampus and PFC if I remember correctly, I will look it up but it's hard to find.

 

 

[lostfalco]

http://www.ncbi.nlm....pubmed/21557387

I'm not sure if it's a good study, but there's more

http://www.jneurosci...29/23/7619.full

Small world network architecture is very important for a properly functioning brain

Lostfalco, because ampakines wouldn't really help the PFC, could we use some "neurotoxins", i.e. NDMA agonists in low doses? We could use memantine to block excitotoxicity. How important do you think GABA is to cognition? Is it there mainly to quench anxiety or for calculations/computations? I will watch the video.

Sodium channels are incredibly interesting. Also, from what I've seen of the video, balance is key. Too much/little of any neurotransmitter will create disorder. How will we be able to tell what levels are optimal? Learning that Nicotinic a7 receptors displace the Mg is super cool.
You should look into polygala tenuifolia, it creates NR2B in the hippocampus and PFC if I remember correctly, I will look it up but it's hard to find.

Very nice finds, bigyellowlemon. Your thinking is right along the same lines as mine. I'm trying to increase both the speed of transmission AND the number of networks involved in order to create supranormal human cognition. Your articles both touched on the importance of efficient transmission caused by short range connections. This is partly why my focus is on synaptogenesis (insulin, igf-1, dihexa, 7, 8 dihydroxyflavone, souvenaid, magnesium l-threonate, etc. all contribute to synaptogenesis).

 

My thinking is this: 1. If I can create more synapses, then I can increase the short range connectivity of my neurons and then the excess synapses will later be pruned to increase efficiency when they are not used as much as the short range connections (hopefully). Does that make sense? Your articles mentioned that raw numbers of synapses were not predictive of intelligence which makes sense to me. Shorter connections would spur speed of transmission as would...

 

2. If I can increase the speed/probability of transmission between neurons/networks then I can increase connectivity and hence intelligence. I''m attempting to do this in the dlfpc with A7, NMDA, sodium channels, potassium channel blockage, cAMP reduction etc. Just some thoughts that I've been milling about. Thanks for the interesting studies! I'll have to pore over them in more detail when I have some time. 

 

I think ampakines can contribute to overall network connectivity because of their involvement in regions other than the dlpfc. I still like IDRA-21 as part of this stack. 

 

I'm attempting to avoid nmda blockers at the moment. If we keep our doses fairly low and our mitos functioning well, I don't think we have to be extremely concerned with excitotoxicity (we should be a little concerned though...never hurts to be safe). Our main concern is that we don't want too much calcium to stay too long in the cell...that's what causes interaction with mitochondria and apoptosis. We actually want our nmda receptors free of blockade and able to open in order to cause action potential transmission...as always, it's a bit of balancing act but I don't think we are at serious risk if we focus on low dosing at multiple, simultaneous targets. 

 

GABA is very important for shaping and refining the signal so I wouldn't do anything to block it but it can also slow things down in excess. I think a slight tip in favor of glutamate over gaba should be sufficient for our purposes. 

 

Optimal levels are super important as you mentioned and balance is key. I start with very low doses and work my way upward while keeping an eye on everything else. She talks about this in the video. A little bit of dopamine is good but too much causes chaos. The exact same thing is true of acetylcholine. This is why megadosing is for megafools. =)

 

Totally agree about A7 removing the mg block!

 

I'm familiar with polygala...I'll have to check which regions it works in as well. 

 

Speaking of sodium channels...this study isn't in the prefrontal cortex but I'm gonna have to research this further to see if ghrelin works the same way there as it does in the pituitary. (MK-677 is a readily available ghrelin mimetic and ghrp-2 and ghrp-6 can be taken intranasally)

 

http://www.ncbi.nlm....pubmed/25151402

 

Endocrine. 2015 Apr;48(3):929-36. doi: 10.1007/s12020-014-0392-x. Epub 2014 Aug 24.

Ghrelin increases growth hormone production and functional expression of NaV1.1 and Na V1.2 channels in pituitary somatotropes.

Magdaleno-Méndez A1, Domínguez B, Rodríguez-Andrade A, Barrientos-Morales M, Cervantes-Acosta P, Hernández-Beltrán A, González-Ramírez R, Felix R.

Author information

Abstract

A variety of ion channels are expressed in the plasma membrane of somatotropes within the anterior pituitary gland. Modification of these channels is linked to intracellular Ca2+ levels and therefore to hormone secretion. Previous investigations have shown that the gut-derived orexigenic peptide hormone ghrelin and synthetic GH-releasing peptides (GHRPs) stimulate release of growth hormone (GH) and increase the number of functional voltage-gated Ca2+ and Na+ channels in the membrane of clonal GC somatotropes. Here, we reveal that chronic treatment with ghrelin and its synthetic analog GHRP-6 also increases GH release from bovine pituitary somatotropes in culture, and that this action is associated with a significant increase in Na+ macroscopic current. Consistent with this, Na+ current blockade with tetrodotoxin (TTX) abolished the ghrelin- and GHRP-6-induced increase in GH release. Furthermore, semi-quantitative and real-time RT-PCR analysis revealed an upregulation in the transcript levels of GH, as well as of NaV1.1 and NaV1.2, two isoforms of TTX-sensitive Na+ channels expressed in somatotropes, after treatment with ghrelin or GHRP-6. These findings improve our knowledge on (i) the cellular mechanisms involved in the control of GH secretion, (ii) the molecular diversity of Na+ channels in pituitary somatotropes, and (iii) the regulation of GH and Na+ channel gene expression by ghrelin and GHRPs.

 

 

http://www.ncbi.nlm....pubmed/19223651

 

Am J Physiol Endocrinol Metab. 2009 May;296(5):E1148-56. doi: 10.1152/ajpendo.90954.2008. Epub 2009 Feb 17.

Upregulation of voltage-gated Na+ channels by long-term activation of the ghrelin-growth hormone secretagogue receptor in clonal GC somatotropes.

Dominguez B1, Felix R, Monjaraz E.

Author information

• 1Laboratorio de Neuroendocrinología, Instituto de Fisiología, San Manuel, Puebla, México.

Abstract

A central question in adenohypophyseal cell physiology concerns the role of transmembrane ionic fluxes in the initiation of the hormone secretion process. In the current report, we investigated the effects of the growth hormone (GH) secretagogues ghrelin and GH-releasing peptide-6 (GHRP-6) on the regulation of the functional expression of voltage-gated Na(+) channels using the tumoral somatotrope GC cell line as a model. Cells were cultured under control conditions or in presence of the GH secretagogues (GHS) for 96 h, and Na(+) currents (I(Na)) were characterized in whole cell patch-clamp experiments. GHS treatment significantly increased I(Na) density in a dose-dependent manner. The effects of GHRP-6 were accompanied by an augment in conductance without changes in the kinetics and the voltage dependence of the currents, suggesting an increase in the number of channels in the cell membrane. Sustained inhibition of L-type Ca(2+) channel activity decreased I(Na) density and prevented the effects of the GHS, whereas long-term exposure to an L-channel agonist increased I(Na) density and enhanced the actions of GHRP-6, indicating that Ca(2+) entry through these channels plays a role in the regulation of Na(+) channel expression. Likewise, GHRP-6 failed to enhance Na(+) channel expression in the presence of membrane-permeable inhibitors of protein kinases A and C, as well as the Ca(2+)/calmodulin-dependent kinase II. Conversely, treatment with a cAMP analog or a protein kinase C activator enhanced both basal and GHS-induced secretion of GH measured by enzyme-linked immunoassay, suggesting that GHRP-6 acting through the ghrelin receptor and different signaling pathways enhances Na(+) channel membrane expression, which favors hormone release from GC somatotropes.

 

 

http://www.ncbi.nlm....pubmed/26401470

 

J Cachexia Sarcopenia Muscle. 2015 Sep;6(3):237-41. doi: 10.1002/jcsm.12028. Epub 2015 Apr 27.

One-year intranasal application of growth hormone releasing peptide-2 improves body weight and hypoglycemia in a severely emaciated anorexia nervosa patient.

Haruta I1, Fuku Y1, Kinoshita K1, Yoneda K1, Morinaga A1, Amitani M1, Amitani H1, Asakawa A1, Sugawara H2, Takeda Y2, Bowers CY3, Inui A1.

Author information

Abstract

BACKGROUND: 

In Japan, growth hormone releasing peptide-2 (GHRP-2) is clinically used as a diagnostic agent for growth hormone secretion deficiency, but the therapeutic application of GHRP-2 has not been studied in anorexia nervosa. GHRP-2 reportedly exhibits agonistic action for ghrelin receptor and increases food intake.

METHODS: 

We administered GHRP-2 to a patient with a 20-year history of anorexia nervosa to determine whether GHRP-2 treatment increases food intake and body weight. GHRP-2 was administered before every meal by an intranasal approach for 1 year.

RESULTS: 

Although the patient reported a decreased fear of eating and decreased desire to be thin by our previous treatment, she was unable to increase food intake or body weight because of digestive tract dysfunction. Vomiting after meals caused by delayed gastric emptying and incurable constipation were prolonged, and sub-ileus and hypoglycemia were observed. GHRP-2 increased the feeling of hunger and food intake, decreased early satiety and improved hypoglycemia. The patient's body weight gradually increased by 6.7 kg (from 21.1 kg to 27.8 kg) in 14 months after starting GHRP-2 administration. The fatigability and muscle strength improved, and the physical and mental activities were also increased. No obvious side effects were observed after long-term intranasal administration of GHRP-2.

CONCLUSIONS: 

Patients with a long-term history of eating disorder occasionally recover from the psychological problems such as fear for obesity but remain emaciated. We believe that ghrelin agonists such as GHRP-2 may be promising agents for the effective treatments of severe anorexia nervosa in a chronic condition.

 

Edited by lostfalco, 20 January 2016 - 03:21 PM.

[bigyellowlemon]

http://www.ncbi.nlm....pubmed/25005250 Being neurotic is correlated with more random connections. No wonder autistic people are an incredibly depressed demographic. Children's brains are like this but they haven't developed anxious networks, like the DMN. OpaqueMind deserves all credit for this last sentence, very interesting person.

 

Maybe we should try to emulate the brains mode of learning. First we make our brains as connected as possible, using a variety of neurogenic compounds, possibly nogo/ROCK inhibition. When we have a brain that is in pure chaos, we could use rapamycin and prune our brains while doing intensive meditation/neurofeedback/logical training, creating a streamlined, functional brain. Though idk, I also feel intuitively that the more connections = more intelligence.

 

So cAMP causes firing in other parts of the brain, but can close calcium channels via HCN in the dlPFC. Why is this? To keep other neurons quiet so your brain "knows" that's not where an object is? We should def be trying to increase speed/probability of transmission, seems very important for cognition, nav1.2 seems like a cool gene. 

 

Don't get me wrong, ampakines are good. I was just wondering what effect they had in the dlPFC if they don't activate the NMDA.

 

Memantine doesn't seem like a traditional NMDA antagonist like ketamine, it's "smart", and will only close the receptor if the cell is getting close to excitotoxic, though perhaps excitotoxic cell death is necessary for making good connections, idk perhaps excitotoxicity is an integral part to our brains ability to adapt. I don't think so but it is just a theory. 

 

GABA antagonists seem good for memory, but that is probably due to glutamate being uninhibited. 

 

I have too little COMT, and I experience what she was talking about in the video. Overstimulation of enviroment, green tea (EGCG), anything dopaminergic will make me dumber, from too much stimulation and a bad signal:noise ratio.

 

senegenin, in polygala, increases NR2B in hippocampus

http://www.ncbi.nlm....pubmed/23029109

 

I have naturally high ghrelin... Lucky me!

[lostfalco]

http://www.ncbi.nlm....pubmed/25005250 Being neurotic is correlated with more random connections. No wonder autistic people are an incredibly depressed demographic. Children's brains are like this but they haven't developed anxious networks, like the DMN. OpaqueMind deserves all credit for this last sentence, very interesting person.

 

Maybe we should try to emulate the brains mode of learning. First we make our brains as connected as possible, using a variety of neurogenic compounds, possibly nogo/ROCK inhibition. When we have a brain that is in pure chaos, we could use rapamycin and prune our brains while doing intensive meditation/neurofeedback/logical training, creating a streamlined, functional brain. Though idk, I also feel intuitively that the more connections = more intelligence.

 

So cAMP causes firing in other parts of the brain, but can close calcium channels via HCN in the dlPFC. Why is this? To keep other neurons quiet so your brain "knows" that's not where an object is? We should def be trying to increase speed/probability of transmission, seems very important for cognition, nav1.2 seems like a cool gene. 

 

Don't get me wrong, ampakines are good. I was just wondering what effect they had in the dlPFC if they don't activate the NMDA.

 

Memantine doesn't seem like a traditional NMDA antagonist like ketamine, it's "smart", and will only close the receptor if the cell is getting close to excitotoxic, though perhaps excitotoxic cell death is necessary for making good connections, idk perhaps excitotoxicity is an integral part to our brains ability to adapt. I don't think so but it is just a theory. 

 

GABA antagonists seem good for memory, but that is probably due to glutamate being uninhibited. 

 

I have too little COMT, and I experience what she was talking about in the video. Overstimulation of enviroment, green tea (EGCG), anything dopaminergic will make me dumber, from too much stimulation and a bad signal:noise ratio.

 

senegenin, in polygala, increases NR2B in hippocampus

http://www.ncbi.nlm....pubmed/23029109

 

I have naturally high ghrelin... Lucky me!

Yep, too much randomness will lead to inefficiencies. Makes sense. 

 

Before attempting an ambitious synaptogenesis program, I think the lower hanging fruit consists of optimizing transmission within our current networks. From there, we should have better brains to help us make better decisions in approaching a syanptogenesis plan. 

 

Cyclic nucleotide gated channels are complex in a single neuron...it gets crazy when you start thinking about networks of neurons and then networks of networks and then the whole brain. We have easy access to tadalafil (cGMP enhancer) so I'm still trying to sort out all of its interrelationships with NO, ion channels, myelination, inflammation, circulation, etc. in the dorsolateral prefrontal cortex and elsewhere. On balance it seems VERY beneficial (in theory and in my experience) but if you want to look up the role of NO, cGMP gated channels, etc. in the dlpfc then I would appreciate it! Its mechanisms overlap somewhat with cAMP in relation to ion channels. Tadalafil does enhance working memory in some rodent models but I'm trying to sort out ALL of the mechanisms in the human dlpfc. I won't complain if you want to look into the research with me. =)

 

Nav1.2 and GSK3b are extremely interesting. I'm thinking that shorter connections have a major effect on IQ in large part because they are faster (just a guess). Think about the sodium depolarization wave traveling through an axon...slightly longer channel opening might lead to a stronger wave (esp. starting at the generation point/axon initial segment) and therefore faster transmission. You could have a 'slightly' longer path to travel but if you travel it faster than the other guy then you may be able to match his/her cognition.

 

Ampakines: remember there are different layers even within the dorsolateral prefrontal cortex. We are just focusing on layer iii pyramidal neurons right now with A7 enhancement over AMPA. You're right though...ampakines will not primarily help us in layer iii dlpfc pyramidal neurons (as far as I can tell). They are for other parts of the network we are attempting to enhance by removing the mg block from NMDA.

 

I'll have to look in more detail at the memantine research. I was unaware that its blocking effects were that 'smart'.  

 

Speaking of ketamine...it has effects on synaptogenesis (esp. intranasal ketamine). I'm not saying to take it, but I found that interesting.  

 

GABA antagonists: yeah, I think we're pretty good on glutamate facilitation with our current laundry list of substances. ha

 

Signal/Noise Ratio: yep, cognition enhancement is a 'target'. It's not like you just crank everything up to max levels and call it a day. I don't do well with lots of dopamine either. 

 

Polygala: Got it...in hippocampus. Hmm, one of my problems with herbs is that they are very difficult to 'stack'. They have so many substances (which ones are active and which ones aren't?) and therefore unpredictable effects. That's why I love things like tadalafil and galantamine. They aren't perfectly targeted but they are 'more' targeted than most herbs. Polyagala has substances that may or may not have effects on MANY different systems. Very hard to combine.

 

haha I'm jealous. I've done pretty well with just a touch of ghrelin enhancement. I'll be testing the intranasal route soon. Thanks for all your thoughts and research. Much appreciated. 

 

Edited by lostfalco, 20 January 2016 - 09:42 PM.

[bigyellowlemon]

I like the idea of recursive intelligence...very exciting concept.

 

I'm still confused on why we have PDE's, considering all the benefits of cAMP and cGMP. I will be researching this area heavily and will report what I find.

 

Have you looked into lithium for GSK-3b inhibition? We should find ways to enhance myelination for faster transmission as well.

 

I completely forgot about the fact that this is just layer iii... Imagine the complexity, all of these layers with their own landscapes and rules.

 

Memantine seems required if you're trying to boost glutamate. Otherwise you'll end up frying the neurons you're trying to enhance.

 

It seems like the growth it creates is more akin to chaotic than functional... It would be useful for creating a large amount for future pruning.

 

hahah I was not recommending GABA antagonists, though I have nothing against them.

 

Yeah, it's a shame it's not in the PFC... Will be researching more on this subject, hopefully they find an NR2B increase via polygala in a different study.

 

It has its downsides. I used to overeat a lot, and this is bad combined with the fact I don't store fat well. This could be seen as good, but it's highly inflammatory for me because my body processes everything rather than store it.

[lostfalco]

Intranasal Insulin Update

 

Well, I'm past the two week point (and up to 40IU, 4x/day) and my honest opinion so far (at the risk of premature overstatement) is that it is way up in the top tier of substances I have tried and may be in the running for first (only time will tell). My previously excellent mood and energy levels have gone up even further, I'm waking up refreshed after less sleep (I always sleep as much as my body tells me it needs; no alarm), my ability to focus/study for long periods of time (school has started back up) is absurd, etc. I haven't tested long-term memory yet because the studies indicated this took 8 weeks to manifest but my subjective Anki studying has been excellent. 

 

On top of all this, the research on intranasal insulin is pretty amazing. It enhances synaptogenesis, AMPA/NMDA receptor trafficking to the membrane, afterhyperpolarization, thyroid function, long term memory, mitochondrial function, brain glucose consumption, norepinephrine signaling, whole body insulin sensitivity, liver function, etc. Add to all of this that you can buy it over the counter with no prescription for $25 at Walmart (Novolin R) and thus far, we have a winner...a big winner. I'll keep you guys updated and I'm still looking into meta-cresol and how it could affect us going forward. 

 

Note: my blood oxygen level (as measured by my pulse oximeter) is now always at 99%. It has been at 98% for the entire time I have measured it (the past 3 years). http://www.walgreens...6089451-product

 

 

      

Edited by lostfalco, 21 January 2016 - 04:10 PM.

[Remington]

Intranasal Insulin Update

Well, I'm past the two week point (and up to 40IU, 4x/day) and my honest opinion so far (at the risk of premature overstatement) is that it is way up in the top tier of substances I have tried and may be in the running for first (only time will tell). My previously excellent mood and energy levels have gone up even further, I'm waking up refreshed after less sleep (I always sleep as much as my body tells me it needs; no alarm), my ability to focus/study for long periods of time (school has started back up) is absurd, etc. I haven't tested long-term memory yet because the studies indicated this took 8 weeks to manifest but my subjective Anki studying has been excellent.

On top of all this, the research on intranasal insulin is pretty amazing. It enhances synaptogenesis, AMPA/NMDA receptor trafficking to the membrane, afterhyperpolarization, thyroid function, long term memory, mitochondrial function, brain glucose consumption, norepinephrine signaling, whole body insulin sensitivity, liver function, etc. Add to all of this that you can buy it over the counter with no prescription for $25 at Walmart (Novolin R) and thus far, we have a winner...a big winner. I'll keep you guys updated and I'm still looking into meta-cresol and how it could affect us going forward.

Note: my blood oxygen level (as measured by my pulse oximeter) is now always at 99%. It has been at 98% for the entire time I have measured it (the past 3 years). http://www.walgreens...6089451-product

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?

[lostfalco]

 

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. 

[lostfalco]

Ummm, speaking of synapses, spines, and synaptogenesis...this is insanely interesting!  

"CAPACITY FOR MEMORY IS TEN TIMES GREATER THAN PREVIOUSLY THOUGHT" http://neurosciencen...ppocampus-3469/

[resveratrol_guy]

Psychoneuroendocrinology. 2004 Nov;29(10):1326-34.

Intranasal insulin improves memory in humans.

Benedict C1, Hallschmid M, Hatke A, Schultes B, Fehm HL, Born J, Kern W.

Author information

Abstract

Previous studies have suggested an acutely improving effect of insulin on memory function. To study changes in memory associated with a prolonged increase in brain insulin activity in humans, here we used the intranasal route of insulin administration known to provide direct access of the substance to the cerebrospinal fluid compartment. Based on previous results indicating a prevalence of insulin receptors in limbic and hippocampal regions as well as improvements in memory with systemic insulin administration, we expected that intranasal administration of insulin improves primarily hippocampus dependent declaration memory function. Also, improvements in mood were expected. We investigated the effects of 8 weeks of intranasal administration of insulin (human regular insulin 4 x 40 IU/d) on declarative memory (immediate and delayed recall of word lists), attention (Stroop test), and mood in 38 healthy subjects (24 males) in a double blind, between-subject comparison. Blood glucose and plasma insulin levels did not differ between the placebo and insulin conditions. Delayed recall of words significantly improved after 8 weeks of intranasal insulin administration (words recalled, Placebo 2.92 +/- 1.00, Insulin 6.20 +/- 1.03, p < 0.05). Moreover, subjects after insulin reported signs of enhanced mood, such as reduced anger (p < 0.02) and enhanced self-confidence (p < 0.03). Results indicate a direct action of prolonged intranasal administration of insulin on brain functions, improving memory and mood in the absence of systemic side effects. These findings could be of relevance for the treatment of patients with memory disorders like in Alzheimer's disease.

 

Hey lostfalco, there's something about all this insulin business that I just can't understand (yeah, maybe because I need more insulin!). Seriously, all this research sounds like it's 1920 and we just discovered that insulin can lower blood glucose rapidly. So we start giving it to type 2 diabetics (not just the type 1s who genuinely need it), and they're quickly "cured". Unfortunately, decades later, mainstream science finally admits that giving insulin to such patients merely results in insulin resistance down the road.

 

This sounds physiologically analogous. What level of confidence do we have that we're not merely swapping shortterm neuroregeneration for longterm type 3 (three) diabetes?

 

It does say above that "Blood glucose and plasma insulin levels did not differ between the placebo and insulin conditions" which sounds good, but this was an 8-week study and even so it's not clear as to the moment in time when that statement applies.

 

Now, even if my concern proves to be valid, I would not automatically conclude that the swap would be disadvantageous, but we might do well to assume the conclusion and attempt to preempt it accordingly with antidiabetic measures. Then again, such measures are overwhelmingly corroborated by HbA1c, a type 2 diabetes metric which is only vaguely informative as to type 3 staging. (As I understand it, the two can exhibit wildly divergent tracking throughout the aging process.) Personally, I've never heard of a supplement which even claims to attack type 3, other than indirectly via avoidance of glycation or de-redoxing of OXPHOS, e.g. MCT oil or c60oo, respectively.

 

Another creeping issue here is the connection between IGF1 and cancer. (Personally, I would rather CRISPR off IGF1 for safety reasons, but that's another thread.) However, given the rarity of brain tumors even in individuals following a lifelong SAD diet, I'm less concerned about this than the disease which this tactic hopes to ameliorate, that being cognitive impairment in the broadest sense.

 

I did read somewhere that intranasal insulin increases central insulin sensitivity, which seems counterintuitive, but might be the case considering that insulin sensitivity itself is a neurological phenomenon which would surely benefit from most any nootropic therapy. Nevertheless, I would expect any such circuitry improvement to be overridden by homeostatic devolution due to gradual acclimatization to the DC (constant) component of CNS insulin level, defiantly resulting in type 3 diabetes.

 

I hope that the evidence proves me wrong, but I haven't seen any yet.

 

What are your thoughts about this apparent tradeoff?

Edited by resveratrol_guy, 21 January 2016 - 07:42 PM.

[lostfalco]

What level of confidence do we have that we're not merely swapping shortterm neuroregeneration for longterm type 3 (three) diabetes?

 

It does say above that "Blood glucose and plasma insulin levels did not differ between the placebo and insulin conditions" which sounds good, but this was an 8-week study and even so it's not clear as to the moment in time when that statement applies.

 

Now, even if my concern proves to be valid, I would not automatically conclude that the swap would be disadvantageous, but we might do well to assume the conclusion and attempt to preempt it accordingly with antidiabetic measures. Then again, such measures are overwhelmingly corroborated by HbA1c, a type 2 diabetes metric which is only vaguely informative as to type 3 staging. (As I understand it, the two can exhibit wildly divergent tracking throughout the aging process.) Personally, I've never heard of a supplement which even claims to attack type 3, other than indirectly via avoidance of glycation or de-redoxing of OXPHOS, e.g. MCT oil or c60oo, respectively.

 

Another creeping issue here is the connection between IGF1 and cancer. (Personally, I would rather CRISPR off IGF1 for safety reasons, but that's another thread.) However, given the rarity of brain tumors even in individuals following a lifelong SAD diet, I'm less concerned about this than the disease which this tactic hopes to ameliorate, that being cognitive impairment in the broadest sense.

 

I did read somewhere that intranasal insulin increases central insulin sensitivity, which seems counterintuitive, but might be the case considering that insulin sensitivity itself is a neurological phenomenon which would surely benefit from most any nootropic therapy. Nevertheless, I would expect any such circuitry improvement to be overridden by homeostatic devolution due to gradual acclimatization to the DC (constant) component of CNS insulin level, defiantly resulting in type 3 diabetes.

 

I hope that the evidence proves me wrong, but I haven't seen any yet.

 

What are your thoughts about this apparent tradeoff?

 

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)

 

 

Edited by lostfalco, 21 January 2016 - 11:03 PM.

[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...