Anyways back to the subject, any new leads anyone?
Well, not for actual NGF suppliers. But in the process of trying some new search keywords, I found this gem of a metastudy. It turns out that NGF is an approved drug in China, and various studies have analyzed its effects in everything from Alzheimer's to HIV dementia since about 2003. Unfortunately, most of these studies are written in Chinese, and thus remain disconnected from wider circulation. The authors performed a metastudy of these papers and summarized the results. Generally speaking, adverse effects were unremarkable; doses seemed to be in the range of 0.1 to 1 ug/kg per day; and effectiveness was evident for a wide range of disorders. We also have confirmation that 13 KDa beta NGF can cross the BBB in rats within 30 minutes of circulatory injection, which bodes well for 26 KDa rhNGF doing the same transocularly. Yes, there are some flaws with the studies such as with regards to blinding, but OTOH nerve conduction velocity was seen to improve in various sensory nerve models, which is virtually immune to placebo.
You would think that if it's an approved drug, that the Chinese suppliers would be the cheapest. Not so, as far as I can see.
I'm a sucker for data. It turns out that EBRI already studied nasal vs. transocular back in 2009, and published this study which for whatever reason does not come up easily in an NGF search. It's a brilliant paper and it will take me a long time to fully analyze, but there's no reason to withhold it from you all.
At 0.48 ug/kg intranasal, the treated Alzheimer's mice developed more ChAT+ neurons than the normal controls. This is (p<0.05), but it's still remarkable; and significantly better than the same dose delivered transocularly. See Figure 9.
Now we have a dose, an administration method, and neural repopulation metric, if only for mice.
Kudos to hatschiman for trying to point this out when he posted this study by the same authors on 1/25/2015. Somehow I didn't notice his post. Unfortunately, it's paywalled. But it seems to discuss very similar science as the free text linked above.
Edited by resveratrol_guy, 14 June 2015 - 02:59 PM.
I invite readers of this thread to click that LIKE button for RG's post.
Thanks for the kind words, Playground. But honestly, the second paper (by Rita's EBRI) is even more of a gem! It's a shame that the work of these researchers appears to have been dismissed or forgotten in the neuroscience field. I suppose that's their punishment for attempting to find a safe and potent treatment for dementia, which should instead be treated by expensive and minimally effective pharaceutical drug$.
Speaking of which, I just realized that 0.48 ug/kg was the total dose of hNGF! I think everyone here could actually afford that, even as expensive rhNGF. The math is based on the paragraph below. Please check my calculations, everyone, because it all comes down to dose:
"hNGF (n = 10) and hNGF-61 (n = 6) administration was performed on 15 months old mice, anaesthetized as previously described before [22]. A 0.45 pmol (250 ng/ml) solution of hNGF-61 in 1 M phosphate-buffered saline (PBS, pH 7.4) was administered intranasally to AD11 mice, 3 μl at a time, alternating the nostrils, with a lapse of 2 min between each administration, for a total of 14 times. During these procedures, the nostrils were always kept open. As control, AD11 mice (n = 19) were treated with PBS [placebo]. The frequency of administration for intranasal delivery was three times per week (every 2 days). WT mice treated with PBS were used as controls (n = 10). Administrations were repeated for 14 times, for a total of 28 days."
So let's see. We have:
ng of hNGF = (250 ng/ml)(0.003 ml/dose)(14 doses/day)(14 dosing days)
ng of hNGF = 147 ng
It's reasonable to assume that the mice weighed around 330 g, thus bringing the total dose per mouse to 480 ng/kg, or 0.48 ug/kg (Figure 9). This suggests a total human dose of roughly 40 ug (80 kg person) for the treatment of Alzheimer's. After reaching this therapeutic level (which still might not be maximal), you can either quit until your memory problems worsen, or continue at a low level maintenance dose. I don't want to raise anyone's hopes of improvement, and mouse studies are always better than human ones, but the object recognition scores following treatment were 75% of the way back up to normal (WT) controls, relative to Alzheimer's controls (Figure 7A) after a month of therapy! Furthermore, the Alzheimer's mice were already severely diseased at the start of treatment: "Moreover, we extended the comparative analysis of the effects of intranasal hNGF and hNGF-61 to aged (15 month-old) AD11 mice. At this age, the neurodegeneration process is already fully blown, and it is of interest to establish to what extent NGF (and hNGF-61) is still able to revert the process." Figure 7 confirms that it applies to 15-month-old AD mice.
40 ug of rhNGF should not exceed $200, delivered. The study refers to "the hortolog human forms (hNGF and hproNGF, respectively)", so I take it that hNGF is equivalalent to rhNGF, and therefore the total mass calculation is valid (but I don't know what "hortolog" means, so please explain if you do).
The authors note that "no cholinergic rescue was observed after ocular delivery, even at 10 times higher doses than the dose that determined full rescue by intranasally delivered hNGF-61". I think that's overly harsh, as Figure 9 seems to show a small benefit. Perhaps the benefit was just sufficient to keep a healthy brain healthy, which would go a long way to explain Rita's enduring intellect. Nevertheless, it's clear: intranasal is the way to go.
I dug around for more studies on human experience. I did manage to find this 1993 study of an Alzheimer's patient intracranially injected with 6.6 mg NGF over 3 months. Her verbal episodic memory ("First this happened, then we did that, etc.") improved, but nothing else. A followup in 1998 produced minor improvements on some cognitive tests 3 months postinjection, but nothing impressive. Then in 2005, this study which used implanted fibroblasts modified to secrete NGF, produced spectacular improvements in brain metabolic activity as measured by PET; the authors note that "During the period 6–18 months after treatment, when NGF expression remained robust and sufficient time has passed to strengthen cortical cholinergic terminals, two of six subjects showed improved MMSE scores, one showed no decline and two showed only a minor decline of 1 point per year; the remaining subject declined 7 points." One of the subjects, presumably the one with the greatest decline, had experienced a brain hemmorage during intracranial injection, as had another patient, who actually died several weeks later; these events were related to lack of anesthesia, not NGF. However, due to the severity of existing disease at the beginning of the study, the group as a whole declined for the 24 months following injection, partly on account of the delay until therapy achieved maximum benefit, and also partly due to the sparsity of injection sites for the fibroblasts which restricted the flow of NGF to only a few millimeters' distance from the needle ("Using either ex vivo (genetic modification of cells in vitro) or in vivo (genetic modification of cells in the brain itself) gene therapy, growth factors can be delivered directly to the brain and diffuse for distances of 2–5 mm"). Frankly, I find it hard to reconcile the night-and-day improvements in PET scan with the fact that the therapy merely managed to slow decline by 55%. The study does note that none of the patients were on standard-protocol acetocholinesterase inhibitors, and presumably, none of them were on coconut oil either (this being 2005) or Longvida (marketed in 2012), for that matter. So if we had added these additional therapies, the outcome might have been vastly better.
I think that it might be much more useful to apply 1 mg or less per year starting at the first evidence of memory loss, than several mg once disease has become well established; the mouse studies above actually suggest that 100 ug (a much smaller dose) might actually be more effective. The other apparent conclusion from these studies is that it's all about diffusion: localized production of NGF only helps the locale, whereas cognitive decline is a weakest-link-in-the-chain affair, so intranasal administration seems more promising at accomplishing wide diffusion, than NGF production by GM fibroblast or virus injection at a few scattered sites.
Edited by resveratrol_guy, 14 June 2015 - 10:52 PM.
I'm a sucker for data. It turns out that EBRI already studied nasal vs. transocular back in 2009, and published this study which for whatever reason does not come up easily in an NGF search. It's a brilliant paper and it will take me a long time to fully analyze, but there's no reason to withhold it from you all.
At 0.48 ug/kg intranasal, the treated Alzheimer's mice developed more ChAT+ neurons than the normal controls. This is (p<0.05), but it's still remarkable; and significantly better than the same dose delivered transocularly. See Figure 9.
Now we have a dose, an administration method, and neural repopulation metric, if only for mice.
Kudos to hatschiman for trying to point this out when he posted this study by the same authors on 1/25/2015. Somehow I didn't notice his post. Unfortunately, it's paywalled. But it seems to discuss very similar science as the free text linked above.
Thanks RG, for _gem_ #2.
I'll be reading it next.
If anyone fancies joining in.. _gem_ #2 is available here:
I have both cognitive decline and neuropathy I am a little uncertain as to which treatment I should try for. Did the Chinese Medicine ameliorate memory loss too?
Playgroud, you raised several important issues here.
I'm not real comfortable with mNGF either. But having searched for cheap sources of NGF, I'm confident that it was the drug of choice because it's cheaply refined from mouse salivary glands. I think all we can say is that mNGF is safe for at least a few months following injection. On the plus side, it does appear to be therapeutic. But this is unsurprising, given McMichael's dramatic results using NGF which is not species-matched to the recipient.
And I completely agree that NGF is not a successful monotherapy for dementia. Other supplements, like those discussed elsewhere on Longecity, are important as well.
Now... what about the temporal lobe necrosis? It's pretty incredible that NGF could fix that. But it's plausible, because the sort of damage (dead neurons, mainly) that occur with this illness are actually simpler than in Alzheimer's, in part because most of the brain is still healthy and can donate resources to clean up the mess; whereas in Alzheimer's, it's in a global state of chaos. So unfortunately it doesn't say much about NGF vs. Alzheimer's.
I don't think Genentech's study showed rhNGF to be ineffective. On the contrary, it showed it to be too effective (at resensitization to pain), so they dropped the dose to subtherapeutic levels.
Some of the very few human NGF studies pertaining to dementia were linked in my previous post (yeah, I know is this a lot to digest, and I find it all rather perplexing). While it's clear that NGF alone was insufficient to reverse disease, its positive impact was clear as well. Again, it's back to a multipronged approach. Honestly, I think that NGF was doing its job (otherwise it's very hard to explain the night-and-day change in averaged PET scan). But increasing the number of neurons in a diseased brain is like raising the birth rate in a polluted country: you get a lot more economic activity, but a lot more disease and dysfunction as well. That's why I've personally decided to take GCSF and Longvida first, in order to clean up the environment so as to be supportive of new neurons. In 2005, I'm 100% confident that this was not done.
The only way to know is to try. A friend of mine is eager to be the first. So perhaps you guinea pigs will have your own guinea pig before the actual group buy.
Edited by resveratrol_guy, 15 June 2015 - 03:36 AM.
I have both cognitive decline and neuropathy I am a little uncertain as to which treatment I should try for. Did the Chinese Medicine ameliorate memory loss too?
But this is exactly the opposite of what you want to do in chronic neurodegenerative disease, in which case TGFB1 becomes over expressed as a part of "normal" aging, as discussed in this paper and this thread.
Uh oh. It looks like NGF is thermally unstable. The Isreali company says here that it can only survive 1 week at 4C (whereas most fridges are around 8C) after reconstituting it with water. Freezing is only certified to work for a few weeks, and only at -70C! I looked at some other vendors and found similar specifications.
So this means that we need to keep it in powder form until use. Which in turn means that we need to buy it in expensive units of 5 ug ($41) or smaller, unless you plan to put 100 ug in a nasal spray and sit there spraying it up your nose for hours.
I wonder what method EBRI used to preserve its hNGF. From the text, it sounds like they added protease inhibitors to prevent airbourne virusses from attacking it. Or maybe I'm misreading it, and they just left it in the fridge and it actually worked for the 28-day experiment. The problem is, I don't think any of us can afford to waste tons of money on a sample of NGF, only to have it go bad without us having any way to determine that.
Granted, this all sounds sort of dubious, given that NGF works in the body just fine at 37C. But maybe that's because viruses are kept in check.
Does anyone have a clue about this? All I could find is this article which suggests that it has a different shape at 100C.
I have both cognitive decline and neuropathy I am a little uncertain as to which treatment I should try for. Did the Chinese Medicine ameliorate memory loss too?
Hi ceridwen,
One of the points that came out of the meta-analysis paper was that the best results came from
combining NGF with other treatments (B-vitamins, acupuncture, oxygen, etc)
Obviously, Danhong is another 'treatment'.
And Danhong is apparently more effective than NGF for neuropathy
So .... perhaps both NGF and danhong would be the _most_ effective treatment.
However, i'm speculating.
I'm not aware of any study that has specifically looked at Danhong plus NGF as a treatment
for neuropathy or any dementia-esque disease.
(I have just checked on PubMed and on www.nrronline.org I can find no studies that mention
both Danhong and NGF.... perhaps, that research is happening right now and hasn't been
published yet). However, i don't have metagene's skills in this area, a more skilled researcher
than i might find some hidden papers in the dark recesses of the internet.
The small nerve fibers that NGF helps restore in your arms, legs, etc... are also abundant in your brain.
Are small nerve fibers responsible for storing memories ? I don't know.
But... if i was suffering from neuropathy or any dementia-esque disease....
my next course of action would be to find out a lot more about danhong....
and if side effects weren't too severe, and danhong still looked promising...
i'd consider trying them together.
(If you type "danhong" into pubmed, it will give you lots of results)
Also, there are 7 papers on danhong on the Neural Regeneration Research website:
Playgroud, you raised several important issues here.
I'm not real comfortable with mNGF either. But having searched for cheap sources of NGF, I'm confident that it was the drug of choice because it's cheaply refined from mouse salivary glands. I think all we can say is that mNGF is safe for at least a few months following injection. On the plus side, it does appear to be therapeutic. But this is unsurprising, given McMichael's dramatic results using NGF which is not species-matched to the recipient. (POINT A)
And I completely agree that NGF is not a successful monotherapy for dementia. Other supplements, like those discussed elsewhere on Longecity, are important as well.
Now... what about the temporal lobe necrosis? It's pretty incredible that NGF could fix that. (POINT B) But it's plausible, because the sort of damage (dead neurons, mainly) that occur with this illness are actually simpler than in Alzheimer's, in part because most of the brain is still healthy and can donate resources to clean up the mess; whereas in Alzheimer's, it's in a global state of chaos. So unfortunately it doesn't say much about NGF vs. Alzheimer's.
I don't think Genentech's study showed rhNGF to be ineffective. On the contrary, it showed it to be too effective (at resensitization to pain), so they dropped the dose to subtherapeutic levels. (POINT C)
Some of the very few human NGF studies pertaining to dementia were linked in my previous post (yeah, I know is this a lot to digest, and I find it all rather perplexing). While it's clear that NGF alone was insufficient to reverse disease, its positive impact was clear as well. Again, it's back to a multipronged approach. Honestly, I think that NGF was doing its job (otherwise it's very hard to explain the night-and-day change in averaged PET scan). But increasing the number of neurons in a diseased brain is like raising the birth rate in a polluted country: you get a lot more economic activity, but a lot more disease and dysfunction as well. That's why I've personally decided to take GCSF and Longvida first, in order to clean up the environment so as to be supportive of new neurons.(POINT D) In 2005, I'm 100% confident that this was not done.
The only way to know is to try. A friend of mine is eager to be the first. So perhaps you guinea pigs will have your own guinea pig before the actual group buy.(POINT E)
Hi RG,
5 rely points, each clearly labelled.
point A - You're right. McMichaels was giving rhNGF to dogs and horses, as well as humans.
And we know that the rat and rabbit experiments on NGF were performed using mouse NGF.
point B - Yes, it _is_ incredible that such a volume of damage could be treated with mNGF.
However, the meta-analysis is silent on how much deficits in function were restored.
Most (right handed) people have their language areas on the left temporal lobe.
Damage to this region of the brain can leave you, quite literally, speech-less (or with
profound language deficits). Still, to have NGF regenerating brain activity in these areas
is extremely impressive.
point C - It was wrong of me to say that the genentech stage 3 study showed that rhNGF
was ineffective. What they actually showed was that there was no significant difference
between the control and the experimental group. When you look at the data it's clear
that the two sets of results do look very similar. The author of the review paper noted that
there was a conspicuous absence of 'decline' in the control group data. i.e. people with
neuropathy gradually lose sensitivity and functionality. But that didn't happen in the stage 3
trial. The data made it look like both groups were slowly getting better.
Maybe someone botched the trial. It's 'blind' remember no one is supposed
to know which drugs go to which subjects. Maybe someone quite simply fucked up
the allocation of drugs. A second thought is that they put something in the dummy injections
to make them more painful (sic). Maybe this causes an increase in NGF production.
The summary is, I agree, the Genentech trial did not show that rhNGF was ineffective.
point D - I know very little GCSF and Longvida. I've heard of them only because you sent
me a link about them some days/weeks ago. I take it from what you say that these drugs
'take out the neural trash'. Is that correct. I'm happy to learn more about them.
Do you have a review paper on these? How long have you been taking these drugs ?
What dosages ? Have you noticed any effects ? Or... are the effects invisible, like taking
vitamin C... it does your body good, but you don't 'feel' anything. I'd be interested to hear.
point E - What's your friend trying ? mNGF ? rhNGF ... or did you mean NGF with
Longvida and/or GCSF ?
Playground
PS..
I remember reading a review article which basically made the point that the
mNGF animal studies were highly encouraging, but the rhNGF studies
(on humans) were highly disappointing.
I wonder if mNGF is more anabolic of nerve tissue than rhNGF.
Perhaps mNGF is trophic by more routes than rhNGF.
Maybe mNGF stimulates BDNF or NT3 receptors as well as NGF receptors.
I have both cognitive decline and neuropathy I am a little uncertain as to which treatment I should try for. Did the Chinese Medicine ameliorate memory loss too?
But this is exactly the opposite of what you want to do in chronic neurodegenerative disease, in which case TGFB1 becomes over expressed as a part of "normal" aging, as discussed in this paper and this thread.
Hi RG,
I smell a rat here.
It doesn't seem to add up.
How can Danhong be more effective at treating diabetic neuropathy than NGF.... and yet be 'toxic' to the central nervous system?
This smells wrong.
I know that if research revealed that Danhong was simply amazing at treating conditions related to nervous tissue
then Big Pharma would be very upset. Think of the profits from all those different MS, Alzheimer's, Huntington's,
neuropathy conditions.... It's probably many billions of dollars.... all that would be put in jeopardy.
I found myself wondering a few days ago: "Did Genentech sabotage their own stage 3 trail ?"
I wouldn't put it past a corporate to falsify scientific evidence for sake of profits.
We know that the tobacco industry did just this to confuse the issue over the health hazards of smoking.
They made a lot of money over several decades, millions of lives were lost, no one went to jail.
Big Pharma has consistently harassed purveyors of effective natural cures with regulations and court action.
Gerson Therapy, Hoxsey's remedy, Pancreatic Enzymes, Essiac, B17 (laetrile) .. and more recently MSM.
And i hear that Monsanto has an entire department dedicated to intimidating scientists opposed to GMOs.
First of all, I agree with finding Chinese members who are literate in the terminology. You can put "Hong Kong" or whatever city you like in the search bar. That's how I found our helpful Italians. Danhong is certainly worth investigating. I wouldn't say it's toxic, but rather, sort of pro-healing and anti-longevity, from what I can tell. But obviously there are a lot of layers between me and the real data.
There are so many red flags with the Genentech trial that I've given up trying to make sense of it. It would have much more value as a movie script, frankly.
As to GCSF and Longvida, they are IMO important preparatory drugs to consider taking in advance of adding neurons or neurites. The long story with technical details, photos, etc. is in my personal stem cell thread over here (just search the pages for GCSF or Longvida). But basically, GCSF mobilizes CD34+ cells from your bone marrow, which are involved in vascular repair; for its part, Longvida dissolves brain plaque and binds heavy metals. I'm currently keeping everything as constant as possible while I take a bottle of Longvida a day for 40 days; I'm not currently on GCSF but took it numerous times in the past.
My friend, Simon, has also taken GCSF in the past. He's been on Longvida for a few weeks now, so his next step is NGF in one fashion or another, i.e. lion's mane, intranasal rhNGF, or both.
As to mNGF vs. rhNGF, we find that the human version is highly effective at ameliorating established Alzheimer's in a mouse model (in the EBRI study above). So I don't think it's really a question of molecular form. I think it's just that mice are extremely plastic, and we aren't. We basically found a way to move out of Africa by using tools and clothing to allow us to survive in otherwise inhospitable biotopes, not by having super flexible epigenetics that allow us to just "show up and adapt" like mice. But all is not lost because we have brains (and social networks) to help us cope with our genetic narrowness.
So on the one hand we have this before/after PET scan data, linked above, that's screaming "lots of new neurons"! OTOH, the group's cognitive performance over the 2 year study period declined defiantly (albeit, more slowly). Is that a failure? Not really. It just means that you need to stack NGF with some other potent antidementia supplements and habits, or apply the therapy earlier in the disease process. We have to try, though, because cognition is the only game in town! To that end, I'm coming round to the notion that I really need to do this, and soon. I think I would just ignore the thermal degradation issues (and maybe order twice as much, to account for it), start dosing, and pray it works.
Edited by resveratrol_guy, 16 June 2015 - 03:00 AM.
As to GCSF and Longvida, they are IMO important preparatory drugs to consider taking in advance of adding neurons or neurites. The long story with technical details, photos, etc. is in my personal stem cell thread over here (just search the pages for GCSF or Longvida). But basically, GCSF mobilizes CD34+ cells from your bone marrow, which are involved in vascular repair; for its part, Longvida dissolves brain plaque and binds heavy metals. I'm currently keeping everything as constant as possible while I take a bottle of Longvida a day for 40 days; I'm not currently on GCSF but took it numerous times in the past.
Hi RG,
Thanks for the explanation.
I've encountered this idea of 'bio-available' turmeric before.
I remember doing some research into it over 12 months ago.
(I had completely forgotten about, or never knew, that it was sold under
the brand name of longvida)
If i remember correctly, they basically add black pepper to the turmeric.
(or some extract from black pepper)
Black pepper makes your gut wall more permeable.... so the turmeric has an easier
time of getting through into the blood stream.
At the time i rejected this idea since increasing gut permeability isn't a good idea
for anyone with food allergies. Instead i went the route of dissolving turmeric in
fats (this also helps turmeric get passed the gut wall) I've been adding 2 to 4 heaped
teaspoon fulls of ground turmeric in my (coconut oil enriched) soups and stews for
the last couple of years.
I wonder if taking a teaspoon full of coconut oil / olive oil / etc with your longvida
capsules or tablets would maximise it's absorption.
GCSF looks very interesting.
Which variety do you normally buy?
According to the wikipedia page there are several varieties to choose from.
As to GCSF and Longvida, they are IMO important preparatory drugs to consider taking in advance of adding neurons or neurites. The long story with technical details, photos, etc. is in my personal stem cell thread over here (just search the pages for GCSF or Longvida). But basically, GCSF mobilizes CD34+ cells from your bone marrow, which are involved in vascular repair; for its part, Longvida dissolves brain plaque and binds heavy metals. I'm currently keeping everything as constant as possible while I take a bottle of Longvida a day for 40 days; I'm not currently on GCSF but took it numerous times in the past.
Hi RG,
Thanks for the explanation.
I've encountered this idea of 'bio-available' turmeric before.
I remember doing some research into it over 12 months ago.
(I had completely forgotten about, or never knew, that it was sold under
the brand name of longvida)
If i remember correctly, they basically add black pepper to the turmeric.
(or some extract from black pepper)
Black pepper makes your gut wall more permeable.... so the turmeric has an easier
time of getting through into the blood stream.
At the time i rejected this idea since increasing gut permeability isn't a good idea
for anyone with food allergies. Instead i went the route of dissolving turmeric in
fats (this also helps turmeric get passed the gut wall) I've been adding 2 to 4 heaped
teaspoon fulls of ground turmeric in my (coconut oil enriched) soups and stews for
the last couple of years.
I wonder if taking a teaspoon full of coconut oil / olive oil / etc with your longvida
capsules or tablets would maximise it's absorption.
GCSF looks very interesting.
Which variety do you normally buy?
According to the wikipedia page there are several varieties to choose from.
And where do you buy it from ?
Playground.
Sure. So Longvida does not use piperine or black pepper. (BTW I believe piperine also retards the liver, aiding in absorption.) Instead, it uses a lipid coating to deceive the liver into thinking it's not curcumin. An excellent presentation of the science is in this YouTube video (bad sound for first few minutes only), which goes a long way to explain why dissolving tumeric in fat probably won't get you where you want to be, in terms of brain concentration of curcumin. It's also worth mentioning that MetaCurmin might be superior to Longvida, but it's very new so we don't seem to have much in the way of user reports.
Yes, the past 2 days, I've taken Longvida dissolved in coconut milk just to get maximum absorption. (It seems to prefer coconut milk by far, to water.) I have no evidence to suggest that this is actually necessary, however.
GCSF is a heavily controlled injectable peptide, which is ironic because it's endogenously produced, albeit at much lower levels than what you can fit into a syringe. You can only get it via prescription in the US. I use the (more expensive) name brand variety, Neupogen. But being in Switzerland, there's no doubt that you can acquire it more readily. Just be mindful that you don't want to overuse it, as it will cause replication stress to your stem cells; there's also a theory, with some evidence from CT scans, that heavy use can induce proleukemic changes to the bone marrow. And FYI it's about $350 for 300 ug. That said, it seems to have helped considerably with tinnitus and balance problems in my friend Sally, who discussed GCSF in detail on video linked from my thread.
Edited by resveratrol_guy, 16 June 2015 - 02:17 PM.
Sure. So Longvida does not use piperine or black pepper. (BTW I believe piperine also retards the liver, aiding in absorption.) Instead, it uses a lipid coating to deceive the liver into thinking it's not curcumin. An excellent presentation of the science is in this YouTube video (bad sound for first few minutes only), which goes a long way to explain why dissolving tumeric in fat probably won't get you where you want to be, in terms of brain concentration of curcumin. It's also worth mentioning that MetaCurmin might be superior to Longvida, but it's very new so we don't seem to have much in the way of user reports.
That probably depends on whether you want free curcumin in the blood or not. From the free full text of that Novasol/MetaCurcumin bioavailability study. Note that the chemical identity(or CAS number) of what you eventually measure with HPLC is only half of the story when you use beta-glucuronidase. Which converts/hydrolyses metabolites as curcumin/DMC/BDMC glucuronide back into curcumin/DMC/BDMC before the measurement(also mentioned around 16 min in the video). And in the study they did use beta-glucuronidase and never claimed to have measured free curcumin but only speak of total curcumin. http://onlinelibrary...r.201300724/pdf
To each plasma or urine sample, 100uL beta-glucuronidase type H-1 from Helix pomatia (3 mg/100uL in 0.1 M sodium acetate buffer; Sigma-Aldrich Chemie GmbH, Schnelldorf, Germany) were added and samples incubated at 37C for 45 min.
From table 5:
a) AUC, area under the blood concentration-time curve; Cmax, maximum blood concentration, CUR, curcumin; n.d., not detected; Tmax, time to reach maximum blood concentration.
b) Free curcumin concentrations were quantified by extraction of the analyte without prior enzymatic hydrolysis of conjugates with B-glucuronidase/sulfatase.
c) Total curcumin concentrations were quantified by extraction of the analyte after prior enzymatic hydrolysis of conjugates with B-glucuronidase/sulfatase.
Table 2. Pharmacokinetic variables (mean ± SD) calculated from plasma total curcumin, DMC, and BDMC concentrations in healthy human subjects after a single oral dose of 500 mg curcuminoids (410 mg curcumin, 80 mg DMC, and 10 mg BDMC) as native powder, micronized powder, or liquid micelles a)
Sure. So Longvida does not use piperine or black pepper. (BTW I believe piperine also retards the liver, aiding in absorption.) Instead, it uses a lipid coating to deceive the liver into thinking it's not curcumin. An excellent presentation of the science is in this YouTube video (bad sound for first few minutes only), which goes a long way to explain why dissolving tumeric in fat probably won't get you where you want to be, in terms of brain concentration of curcumin. It's also worth mentioning that MetaCurmin might be superior to Longvida, but it's very new so we don't seem to have much in the way of user reports.
That probably depends on whether you want free curcumin in the blood or not. From the free full text of that Novasol/MetaCurcumin bioavailability study. Note that the chemical identity(or CAS number) of what you eventually measure with HPLC is only half of the story when you use beta-glucuronidase. Which converts/hydrolyses metabolites as curcumin/DMC/BDMC glucuronide back into curcumin/DMC/BDMC before the measurement(also mentioned around 16 min in the video). And in the study they did use beta-glucuronidase and never claimed to have measured free curcumin but only speak of total curcumin. http://onlinelibrary...r.201300724/pdf
To each plasma or urine sample, 100uL beta-glucuronidase type H-1 from Helix pomatia (3 mg/100uL in 0.1 M sodium acetate buffer; Sigma-Aldrich Chemie GmbH, Schnelldorf, Germany) were added and samples incubated at 37C for 45 min.
From table 5:
a) AUC, area under the blood concentration-time curve; Cmax, maximum blood concentration, CUR, curcumin; n.d., not detected; Tmax, time to reach maximum blood concentration.
b) Free curcumin concentrations were quantified by extraction of the analyte without prior enzymatic hydrolysis of conjugates with B-glucuronidase/sulfatase.
c) Total curcumin concentrations were quantified by extraction of the analyte after prior enzymatic hydrolysis of conjugates with B-glucuronidase/sulfatase.
Table 2. Pharmacokinetic variables (mean ± SD) calculated from plasma total curcumin, DMC, and BDMC concentrations in healthy human subjects after a single oral dose of 500 mg curcuminoids (410 mg curcumin, 80 mg DMC, and 10 mg BDMC) as native powder, micronized powder, or liquid micelles a)
The issue of free vs total curcumin is an important one. I asked Anthony_Loera about exactly this, because I had the same doubts. He replied here on 6/13/2015. You may wish to participate in that thread, or the MetaCurcumin discussion thread.
I contacted the South Korean company again, this time via email. I asked them about the cosmetics company issue, as well as numerous questions about impurities, structure, etc. I also explained that we would need the NGF without all the additives that they normally mix it with. Finally, I explained that we might be willing to pay more for higher purity. I will post here when I get a reply.
I must admit that I'm undecided about appropriate dosage (and the answer to this influences the cost-vs-quality question). The mouse study above suggests 100 ug for the substantial reversal of early Alzheimer's, but the human studies suggest that 10 mg might be more reasonable. One problem is that it's unclear whether a few mg of intracranial injected NGF is actually superier to, say, 100 ug intranasal delivered over several days or weeks. It might be that frequent smaller exposures do more good than a few huge ones. (This would certainly explain Rita's brain health.) In other words, I wonder if the lackluster results of the human trials stemmed from the fact that most of the injected NGF was simply ignored because its downstream signalling pathways had already been saturated. This is all to say that I wonder if McMichael's observations about a tiny trigger threshold apply not only to the anxiolytic properties of NGF, but also to its neural growth properties. I suspect this may be the case, because NGF is probably secreted by neural stem cells, and we know from stem cell therapy data that the effect seems to saturate such that a few million cells can often deliver similar benefits as a billion.
To put it another way, maybe NGF works like an anxiolytic at low doses. Then at some higher threshold, it signals neural cell division and neurite outgrowth. But it works more like a switch than a dial in either case. So if you try to push it "on" harder, the net effect is simply a waste of NGF. Or... humans just don't respond to NGF particularly well.
Meanwhile, I'm pleased to see that Playground has started investigating Danhong. I have a feeling that there are other treasures in the Chinese literature, but those may need to wait until a Chinese speaker shows up here.
As to GCSF and Longvida, they are IMO important preparatory drugs to consider taking in advance of adding neurons or neurites. The long story with technical details, photos, etc. is in my personal stem cell thread over here (just search the pages for GCSF or Longvida). But basically, GCSF mobilizes CD34+ cells from your bone marrow, which are involved in vascular repair; for its part, Longvida dissolves brain plaque and binds heavy metals. I'm currently keeping everything as constant as possible while I take a bottle of Longvida a day for 40 days; I'm not currently on GCSF but took it numerous times in the past.
Hi RG,
Thanks for the explanation.
I've encountered this idea of 'bio-available' turmeric before.
I remember doing some research into it over 12 months ago.
(I had completely forgotten about, or never knew, that it was sold under
the brand name of longvida)
If i remember correctly, they basically add black pepper to the turmeric.
(or some extract from black pepper)
Black pepper makes your gut wall more permeable.... so the turmeric has an easier
time of getting through into the blood stream.
At the time i rejected this idea since increasing gut permeability isn't a good idea
for anyone with food allergies. Instead i went the route of dissolving turmeric in
fats (this also helps turmeric get passed the gut wall) I've been adding 2 to 4 heaped
teaspoon fulls of ground turmeric in my (coconut oil enriched) soups and stews for
the last couple of years.
I wonder if taking a teaspoon full of coconut oil / olive oil / etc with your longvida
capsules or tablets would maximise it's absorption.
GCSF looks very interesting.
Which variety do you normally buy?
According to the wikipedia page there are several varieties to choose from.
And where do you buy it from ?
Playground.
Sure. So Longvida does not use piperine or black pepper. (BTW I believe piperine also retards the liver, aiding in absorption.) Instead, it uses a lipid coating to deceive the liver into thinking it's not curcumin. An excellent presentation of the science is in this YouTube video (bad sound for first few minutes only), which goes a long way to explain why dissolving tumeric in fat probably won't get you where you want to be, in terms of brain concentration of curcumin. It's also worth mentioning that MetaCurmin might be superior to Longvida, but it's very new so we don't seem to have much in the way of user reports.
Yes, the past 2 days, I've taken Longvida dissolved in coconut milk just to get maximum absorption. (It seems to prefer coconut milk by far, to water.) I have no evidence to suggest that this is actually necessary, however.
GCSF is a heavily controlled injectable peptide, which is ironic because it's endogenously produced, albeit at much lower levels than what you can fit into a syringe. You can only get it via prescription in the US. I use the (more expensive) name brand variety, Neupogen. But being in Switzerland, there's no doubt that you can acquire it more readily. Just be mindful that you don't want to overuse it, as it will cause replication stress to your stem cells; there's also a theory, with some evidence from CT scans, that heavy use can induce proleukemic changes to the bone marrow. And FYI it's about $350 for 300 ug. That said, it seems to have helped considerably with tinnitus and balance problems in my friend Sally, who discussed GCSF in detail on video linked from my thread.
resveratrol guy, how about meriva curcumin? i just got some from doctor's best (you can check it out online for better idea if you want) and on the label it says featuring meriva curcumin highly absorbable form WITH actual studies done with that specific form. can you tell me, is it likely to be a haux and fabrication of studies or misspresentation of sorts? im asking this because each topic on curcumin never mentions meriva brand as actual bioavailable which confuses me now....
Icontacted the South Korean company again, this time via email. I asked them about the cosmetics company issue, as well as numerous questions about impurities, structure, etc. I also explained that we would need the NGF without all the additives that they normally mix it with. Finally, I explained that we might be willing to pay more for higher purity. I will post here when I get a reply.[POINT 1]
I must admit that I'm undecided about appropriate dosage (and the answer to this influences the cost-vs-quality question).
The mouse study above suggests 100 ug for the substantial reversal of early Alzheimer's,
but the human studies suggest that 10 mg might be more reasonable. [POINT2]
One problem is that it's unclear whether a few mg of intracranial injected NGF is actually superier to,
say, 100 ug intranasal delivered over several days or weeks. [POINT3]
It might be that frequent smaller exposures do more good than a few huge ones.
(This would certainly explain Rita's brain health.)[POINT4]
In other words, I wonder if the lackluster results of the human trials stemmed from the fact that most of the injected NGF was simply ignored because its downstream signalling pathways had already been saturated.
This is all to say that I wonder if McMichael's observations about a tiny trigger threshold apply
not only to the anxiolytic properties of NGF, but also to its neural growth properties. I suspect this may be the case, because NGF is probably secreted by neural stem cells, and we know from stem cell therapy data that the effect seems to saturate such that a few million cells can often deliver similar benefits as a billion
[POINT 5].
To put it another way, maybe NGF works like an anxiolytic at low doses. Then at some higher threshold, it signals neural cell division and neurite outgrowth. But it works more like a switch than a dial in either case. So if you try to push it "on" harder, the net effect is simply a waste of NGF. Or... humans just don't respond to NGF particularly well. [POINT 6]
Meanwhile, I'm pleased to see that Playground has started investigating Danhong. I have a feeling that there are other treasures in the Chinese literature, but those may need to wait until a Chinese speaker shows up here.
Hi RG,
Point 1 -- good work -- yes.. offering to pay for higher purity is a good move.
Point 2 -- i guess you meant 10 mcg not 10mg.
Point 3 -- There are problems for most of us in injecting anything intra-cranially.
Bad things could/would happen (And i'm a coward to the core)
And in anycase, we don't have the volume of NGF to deliver whole milligrams.
Point 4 - Yes.. I think regular administration of tiny amounts is more similar to
what the body does naturally. This almost certainly minimises the risks of 'adverse events'
Point 5 - I've been wondering similarly about this.
It's notable that depression very often precedes the later discovery of early alzheimer's or other forms
of dementia. Depression is associated with a reduction in neurogenesis and increases in neural apoptosis.
When you give drugs that relieve depression this is often associated with elevated levels of neurogenesis
and a reduction in neural cell death. Things that relieve depression, also seem to improve neural health.
These things include: testosterone, NGF, and various anti-depressants.
(We should discus this testosterone/DHT and neurogenesis association one day)
Here's my point. If 0.04% of a mcg of NGF is enough to relieve people of depression.
Maybe that's a clue that neural health is improving (or has stopped declining)
It may or may not be enough to improve general cognitive functioning.
I have, what i consider to be, a good idea for revealing the minimal NGF dose
for enhancing cognitive functioning.
It relies on the fact that, the more you practice any skill, the more your progress
inclines towards the horizontal. The plateau effect.
For you, RG, that might be some of those luminosity tasks.
Find some learning activity at which your ability seems to have plateaued.
N-back, or luminosity, mental arithmetic, Sudoku, anagrams..... whatever.... 'someTask'
For 1 month (say) practice 'someTask' for N minutes per day.
Record the results, dutifully, every day.
Do this for one month without taking any NGF. This is your baseline.
You'll probably see nil improvements, or only modest improvements.
Then do 'someTask' for N minutes per day, with (say) 0.04 mcg NGF,
and record the results dutifully.
If the NGF was having no effect you'd expect the slope of the performance curve to
incline towards horizontal... progressively, over the two months.
If the NGF dose is having an effect, you expect the slope of the curve to incline away
from the horizontal during month 2.
If you decide the initial dosage did nothing. You could double the dosage and
do it again for another month. If nothing happened after 3 months, you could
double the dosage again, and repeat the trial.... Continue in this way
until it becomes clear, that the NGF dosage is changing
the trajectory of your performance curve away from the horizontal.
We might be surprised by how little of this stuff is actually needed to
effect a clear improvement in cognitive functioning.
Probably dual N Back would be a good 'someTask'.
(Since there's some suggestion that mastery of this still has positive effects
on intelligence generally .... or practice whatever you're weak at, that's also
supposed to improve your overall IQ)
The beauty of this scheme is that you are your own baseline.
You can do it on your own.
You'd have to keep your stack of supplements constant during the N months
that you were running the trails... in order to be sure it was the NGF that
caused the improvements, and not the gram of dihexa you added to your breakfast.
Point 6 - I like the switch and dial metaphor. It aptly characterises the two polar
concepts of 'dose-response curve' ... which is taken for granted in medicine and pharmacology,
And McMichael's notion of a 'signal'... something that might explain the effect of
super low dosages and perhaps of homeopathy in general.
Uh oh. It looks like NGF is thermally unstable. The Isreali company says here that it can only survive 1 week at 4C (whereas most fridges are around 8C) after reconstituting it with water. Freezing is only certified to work for a few weeks, and only at -70C! I looked at some other vendors and found similar specifications.
So this means that we need to keep it in powder form until use.
I thought there was a nasal spray version of NGF.
how are those people keeping NGF stable ?
Presumably it's a liquid in the container used to spray it up your nose.
(perhaps this is a clue that the nasal applicator has a very short 'use-by-date')
Or ... have they solved the problem of the fragility of NGF ?
How much are microgram (not milligram) scales ?
I did a quick search online and the numbers i saw were all in the thousands of dollars.
Surely there are cheaper ones out there.
Obviously, i'm thinking that if we had scales capable of dividing up crystals into
N microgram quantities, then each N microgram quantity could be very carefully
placed in (dozens of) tiny ampules. This would solve the problem of the heat
sensitivity of NGF.
Maybe we need someone to act as a broker that has access to analytical lab scales.
errrmmm..... But it's delicate work... and there might be an awful lot of tiny ampules.
resveratrol guy, how about meriva curcumin? i just got some from doctor's best (you can check it out online for better idea if you want) and on the label it says featuring meriva curcumin highly absorbable form WITH actual studies done with that specific form. can you tell me, is it likely to be a haux and fabrication of studies or misspresentation of sorts? im asking this because each topic on curcumin never mentions meriva brand as actual bioavailable which confuses me now....
Sorry, I'm not an expert on Meriva. My impression from what I've read is that Longvida is better absorbed than Meriva, but I have no data on hand to prove it. If Meriva is phospolipid based, then my understanding is all that you're going to get out of it is glucuronidated curcumin and tiny amounts of free curcumin. "Bioavailable" is a heavily abused term in labeling, unfortunately.
Point 1 -- good work -- yes.. offering to pay for higher purity is a good move.
Point 2 -- i guess you meant 10 mcg not 10mg.
Point 3 -- There are problems for most of us in injecting anything intra-cranially.
Bad things could/would happen (And i'm a coward to the core)
And in anycase, we don't have the volume of NGF to deliver whole milligrams.
Point 4 - Yes.. I think regular administration of tiny amounts is more similar to
what the body does naturally. This almost certainly minimises the risks of 'adverse events'
Point 5 - I've been wondering similarly about this.
It's notable that depression very often precedes the later discovery of early alzheimer's or other forms
of dementia. Depression is associated with a reduction in neurogenesis and increases in neural apoptosis.
When you give drugs that relieve depression this is often associated with elevated levels of neurogenesis
and a reduction in neural cell death. Things that relieve depression, also seem to improve neural health.
These things include: testosterone, NGF, and various anti-depressants.
(We should discus this testosterone/DHT and neurogenesis association one day)
Here's my point. If 0.04% of a mcg of NGF is enough to relieve people of depression.
Maybe that's a clue that neural health is improving (or has stopped declining)
It may or may not be enough to improve general cognitive functioning.
I have, what i consider to be, a good idea for revealing the minimal NGF dose
for enhancing cognitive functioning.
It relies on the fact that, the more you practice any skill, the more your progress
inclines towards the horizontal. The plateau effect.
For you, RG, that might be some of those luminosity tasks.
Find some learning activity at which your ability seems to have plateaued.
N-back, or luminosity, mental arithmetic, Sudoku, anagrams..... whatever.... 'someTask'
For 1 month (say) practice 'someTask' for N minutes per day.
Record the results, dutifully, every day.
Do this for one month without taking any NGF. This is your baseline.
You'll probably see nil improvements, or only modest improvements.
Then do 'someTask' for N minutes per day, with (say) 0.04 mcg NGF,
and record the results dutifully.
If the NGF was having no effect you'd expect the slope of the performance curve to
incline towards horizontal... progressively, over the two months.
If the NGF dose is having an effect, you expect the slope of the curve to incline away
from the horizontal during month 2.
If you decide the initial dosage did nothing. You could double the dosage and
do it again for another month. If nothing happened after 3 months, you could
double the dosage again, and repeat the trial.... Continue in this way
until it becomes clear, that the NGF dosage is changing
the trajectory of your performance curve away from the horizontal.
We might be surprised by how little of this stuff is actually needed to
effect a clear improvement in cognitive functioning.
Probably dual N Back would be a good 'someTask'.
(Since there's some suggestion that mastery of this still has positive effects
on intelligence generally .... or practice whatever you're weak at, that's also
supposed to improve your overall IQ)
The beauty of this scheme is that you are your own baseline.
You can do it on your own.
You'd have to keep your stack of supplements constant during the N months
that you were running the trails... in order to be sure it was the NGF that
caused the improvements, and not the gram of dihexa you added to your breakfast.
Point 6 - I like the switch and dial metaphor. It aptly characterises the two polar
concepts of 'dose-response curve' ... which is taken for granted in medicine and pharmacology,
And McMichael's notion of a 'signal'... something that might explain the effect of
super low dosages and perhaps of homeopathy in general.
Playground.
Point 2. That wasn't a typo. The high end is actually 10 mg because the 1993 intracranial injection study on a human used 6.6 mg, total dose. But based on the 2009 EBRI rat study, it seems like 100 ug would do the trick. Yes, that's a factor of 100 between these estimates. I think we just don't know.
Point 3. You're right about injections of any kind. Injections simply don't work well with NGF for a host of reasons. And on account of the massive expense, I think we're back to "spray and pray" with something under 1 mg, probably administered over the course of a month.
Point 5. I completely agree! I'm confident that I will be plateaued on Lumosity by the time I start NGF. Everyone should start playing brain games right now, at least a few times per week. Personally, I can't stand Cambridge Brain Sciences becaue they're so extremely slow to load, and totally boring. That said, Lumosity has some serious flaws. However, I think if you pay more attention to rank than absolute score, you'll have a much better idea of what's going on. Scores are meaningless when taken as standalone numbers, but if you suddenly got #1 at something you played 100 times before, that might say something. If you get, say, #3 on the same game the next day, it's much more likely to be significant. If you do well on the third day, it's even more remarkable, etc.
Point 6. This is the question around NGF: when it comes to structural neurogenesis as opposed to mere anxiolytic effects, is NGF a switch or a dial? If you look at NGF through the eyes of a pharmacist, then it's obviously a dial; if you look at it through the eyes of a stem cell researcher, it's obviously a switch. I have no idea which is correct.
So as you said, we need to start with 100 ug/month, then 200, then 400, etc. until the brain game scores start bending the right way.
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