4019 replies to this topic

[lostfalco]

The data on magnesium l-threonate is getting more and more interesting. Check out this video and free full text article (mostly about the role of threonate itself!) if you have the time. 

 

It appears as though threonate uses GLUT transporters to get into neurons and brings Mg along with it when they are bonded. Very interesting. 

 

It also turns out that magnesium is a cofactor for over 600 enzymes (instead of the previously reported 300) and is an activator in 200 more! Important stuff. 

 

 

 

 

http://www.sciencedi...028390816302040

 

Neuropharmacology. 2016 May 10. pii: S0028-3908(16)30204-0. doi: 10.1016/j.neuropharm.2016.05.006. [Epub ahead of print]

Regulation of structural and functional synapse density by L-threonate through modulation of intraneuronal magnesium concentration.

Sun Q1, Weinger JG2, Mao F2, Liu G3.

Author information

Abstract

Oral administration of the combination of L-threonate (threonate) and magnesium (Mg2+) in the form of L-Threonic acid Magnesium salt (L-TAMS) can enhance learning and memory in young rats and prevent memory decline in aging rats and in Alzheimer's disease model mice. Recent results from a human clinical trial demonstrate the efficacy of L-TAMS in restoring global cognitive abilities of older adults. Previously, we reported that neuronal intracellular Mg2+ serves as a critical signaling molecule for controlling synapse density. The elevation of brain Mg2+ by oral administration of L-TAMS in intact animals plays a significant role in mediating the therapeutic effects of L-TAMS. The current study sought to elucidate the unique role of threonate. We aimed to understand if threonate acts directly to elevate intraneuronal Mg2+, and why Mg2+ given without threonate is ineffective for enhancing learning and memory ability. We discovered that threonate is naturally present in cerebrospinal fluid (CSF) and oral treatment with L-TAMS elevated CSF threonate. In cultured hippocampal neurons, threonate treatment directly induced an increase in intracellular Mg2+ concentration. Functionally, elevating threonate upregulated expression of NR2B-containing NMDAR, boosted mitochondrial membrane potential (ΔΨm), and increased functional synapse density in neuronal cultures. These effects are unique to threonate, as other common Mg2+anions failed to have the same results. Mechanistically, threonate's effects were specifically mediated through glucose transporters (GLUTs). We also evaluated the effects of threonate in human neural stem cell-derived neurons, and found it was equally effective at upregulating synapse density. The current study provides an explanation for why threonate is an essential component of L-TAMS and supports the use of L-TAMS to promote cognitive abilities in human.

 

http://physrev.physi...ent/95/1/1.long

 

Physiol Rev. 2015 Jan;95(1):1-46. doi: 10.1152/physrev.00012.2014.

Magnesium in man: implications for health and disease.

de Baaij JH1, Hoenderop JG1, Bindels RJ1.

Author information

Abstract

Magnesium (Mg(2+)) is an essential ion to the human body, playing an instrumental role in supporting and sustaining health and life. As the second most abundant intracellular cation after potassium, it is involved in over 600 enzymatic reactions including energy metabolism and protein synthesis. Although Mg(2+) availability has been proven to be disturbed during several clinical situations, serum Mg(2+) values are not generally determined in patients. This review aims to provide an overview of the function of Mg(2+) in human health and disease. In short, Mg(2+) plays an important physiological role particularly in the brain, heart, and skeletal muscles. Moreover, Mg(2+) supplementation has been shown to be beneficial in treatment of, among others, preeclampsia, migraine, depression, coronary artery disease, and asthma. Over the last decade, several hereditary forms of hypomagnesemia have been deciphered, including mutations in transient receptor potential melastatin type 6 (TRPM6), claudin 16, and cyclin M2 (CNNM2). Recently, mutations in Mg(2+) transporter 1 (MagT1) were linked to T-cell deficiency underlining the important role of Mg(2+) in cell viability. Moreover, hypomagnesemia can be the consequence of the use of certain types of drugs, such as diuretics, epidermal growth factor receptor inhibitors, calcineurin inhibitors, and proton pump inhibitors. This review provides an extensive and comprehensive overview of Mg(2+) research over the last few decades, focusing on the regulation of Mg(2+) homeostasis in the intestine, kidney, and bone and disturbances which may result in hypomagnesemia.

 

[normalizing]

about this article; https://www.scienced...60519220543.htm can ibudilast do this since it works on microglia?

[streamlover]

Hey Falco, Very interesting study on the L-threonate effects on Mg uptake to neurons. I'm currently getting a surplus of Mg with my H2 water protocol (bordering on overload) but it's in the form of Mg malate so evidently not much will be crossing the bbb. (Although I do notice some enhanced clear thinking and better mood after drinking this water which I assume is the H2.) In your comment you say, "It appears as though threonate uses GLUT transporters to get into neurons and brings Mg along with it when they are bonded. Very interesting." I'm not seeing that they necessarily need to be bonded in reading the abstract and am wondering if I just get some threonate along with all the Mg would the Mg uptake to neurons be enhanced also? I could just take Mg L-threonate but that would compound my Mg overload problem. Or I could use L-threonic acid instead of malic acid in a batch or 2 of the H2 water every day but unfortunately, can't seem to find that readily available. Also, there doesn't seem to be any other threonate salts available commercially other than a calcium l-threonate which contains a few problematic ingredients, (Biocalth ingredients:Mannitol, Maltodextrin, Citric Acid, Strawberry Flavor, Stearic Acid, Magnesium Stearate, Sucralose, FD&C Red #3), and is expensive also at ~$33 for a month's supply. I read in this study that L-threonic acid is a natural constituent of sorrel so I'm thinking of just adding some of this extract to the H2 water, either before or after brewing it. In that study they produce it by adding Vit. C to the sorrel leaves so I may need to add that also to the brew (in case the malic acid doesn't produce quite the same effect), but in general, what do you think of this idea...likely or not to get more Mg uptake to the brain?

[lostfalco]

Hey Falco, Very interesting study on the L-threonate effects on Mg uptake to neurons.

 

I'm not seeing that they necessarily need to be bonded in reading the abstract and am wondering if I just get some threonate along with all the Mg would the Mg uptake to neurons be enhanced also? 

Hey streamlover, if you check out the full text it does indicate that they need to be delivered as a single compound. =)

 

Here's a massive quote. Sorry about the length!

 

http://www.sciencedi...028390816302040

 

"Translationally, a threonate or Mg²⁺ compound might be useful to increase synapse density and promote learning and memory. Surprisingly, in our previous animal experiments, we found that treatment with either threonate or Mg²⁺ but without the other was ineffective (Slutsky et al., 2010). Only treatment with the combination of threonate and Mg²⁺ as a single compound can elevate memory ability. While oral treatment with threonate and Mg²⁺ (in the form of L-TAMS) can efficiently increase synapse density and memory ability in both aged rats and late stage AD model mice (Li et al., 2014 and Slutsky et al., 2010), threonate treatment without Mg²⁺ (in the form of NaT) and Mg²⁺ treatment without threonate (in the form of Mg²⁺-chloride, -citrate, -glycinate, and –gluconate) fails to increase short- or long-term memory ability (Slutsky et al., 2010).

 

If threonate is effective in increasing intraneuronal Mg²⁺ and synapse density in cultured hippocampal neurons, it is curious why it does not have an effect in the intact animal. One possible explanation is that threonate might not be able to promote Mg²⁺ influx into neurons without a simultaneous increase of extracellular brain Mg²⁺ supply. This is because Mg²⁺ as a signaling molecule is unique in that the majority of Mg²⁺ is stored inside the cell and there is a relatively very small amount of Mg²⁺ in the extracellular space. Therefore, a large influx of Mg²⁺ can lead to a significant reduction of extracellular Mg²⁺, thereby reducing the driving force of Mg²⁺, preventing further influx. This phenomenon can be observed with insulin treatment. Insulin promotes Mg²⁺ influx into the cell, significantly reducing extracellular Mg²⁺. For example, plasma Mg²⁺ levels initially decrease significantly following an insulin injection, but can be prevented when insulin is injected with Mg²⁺ supplementation, such as from a meal (Paolisso et al., 1986). Since the amount of total extracellular brain Mg²⁺ is low (Ramadan et al., 1989), threonate treatment without concurrent Mg²⁺ treatment, like with insulin treatment, could quickly reduce CSF Mg²⁺, resulting in a reduction of the driving force for all Mg²⁺channels, limiting the amount of Mg²⁺ influx that threonate can promote. This might explain why threonate treatment alone does not work in vivo, whereas in culture, where the extracellular [Mg²⁺] is essentially clamped, threonate treatment effectively increases intracellular [Mg²⁺].

 

Similar to the effects of increasing CSF threonate without increasing Mg²⁺, increasing CSF Mg²⁺ without increasing CSF threonate will also not be effective. One cannot limitlessly elevate extracellular brain Mg²⁺ in order to elevate intracellular [Mg²⁺], as the relationship between extracellular and intracellular [Mg²⁺], and the relationship of extracellular [Mg²⁺] and synapse density are bell-shaped. As shown in Fig. 2 and Fig. 5, when the extracellular [Mg²⁺] is increased beyond 0.8 mM, intracellular [Mg²⁺] and synapse density decreased.

 

The greatest increase in vitro of intracellular [Mg²⁺] and functional synapse density occurred with the concurrent increase of threonate and extracellular [Mg²⁺] ( Fig. 2 and Fig. 5A, B). In vivo, threonate and Mg²⁺ oral treatment (L-TAMS) increased brain threonate by approximately 50% (Fig. 1C) and CSF Mg²⁺ by approximately 15%, leading to an increase of synapse density by as much as 67% (Slutsky et al., 2010). The current study provides more mechanistic insight into the therapeutic potential of L-TAMS for cognitive impairment. A recent double-blinded placebo-controlled clinical study showed promise for L-TAMS in treating cognitive impairment in humans (Liu et al., 2015)."

Edited by lostfalco, 20 May 2016 - 08:31 PM.

[airplanepeanuts]

I started with magnesium l-threonate this february - I feel it's one of the better cognition boosters out there. In fact I was kind of mad about Scienceguy's  "is no better than" thread because as a nootropic it's better for sure - also that thread is full of hasty conclusions.

[lostfalco]

I started with magnesium l-threonate this february - I feel it's one of the better cognition boosters out there. In fact I was kind of mad about Scienceguy's  "is no better than" thread because as a nootropic it's better for sure - also that thread is full of hasty conclusions.

Yeah, the most recent data seems to disagree with Scienceguy's thread. As of now, it (tentatively) seems to be a pretty unique compound. 

[streamlover]

Falco, thanks for posting that followup. I'm glazing over reading the details of that study and yes, they do state that conclusion, but I'm still not seeing that they actually considered this situation. It seems they compared Mg L-threonate to a few other Mg salts (by themselves) for effectiveness and found the Mg L-threonate to be effective for increasing inter-cellular Mg+ and the others not but I don't see where they tried Mg malate, for instance, plus threonate from another source at the same time, which is the situation here. I doubt they considered it a relevant test and probably isn't except in this case of much Mg already present simultaneously with the threonate but not necessarily bound. Anyway, I had already ordered that sorrel extract and will try it in the initial mix for H2 brewing of Mg + malic acid + H2O (plus possibly some ascorbic acid) and in any case there should be some production of Mg L-threonate along with the Mg malate during the brewing. I will see if this makes me smarter so maybe I can read that study then without dozing off.

 

Just occurred to me that I may be mistaken about one thing which may change my mind about this but won't the hydrolysis of Mg malate produce the same Mg++ ions that Mg L-threonate will? I guess my question really is what does "bound" really mean in this situation. Won't there be some bound and some unbound as Mg++ and the salt in equilibrium? They seem to be always referring to the extra-cellular concentration of Mg++ ions (plus the threonate) as the relevant factors.

[lostfalco]

Falco, thanks for posting that followup. I'm glazing over reading the details of that study and yes, they do state that conclusion, but I'm still not seeing that they actually considered this situation. It seems they compared Mg L-threonate to a few other Mg salts (by themselves) for effectiveness and found the Mg L-threonate to be effective for increasing inter-cellular Mg+ and the others not but I don't see where they tried Mg malate, for instance, plus threonate from another source at the same time, which is the situation here. I doubt they considered it a relevant test and probably isn't except in this case of much Mg already present simultaneously with the threonate but not necessarily bound. Anyway, I had already ordered that sorrel extract and will try it in the initial mix for H2 brewing of Mg + malic acid + H2O (plus possibly some ascorbic acid) and in any case there should be some production of Mg L-threonate along with the Mg malate during the brewing. I will see if this makes me smarter so maybe I can read that study then without dozing off.

 

Just occurred to me that I may be mistaken about one thing which may change my mind about this but won't the hydrolysis of Mg malate produce the same Mg++ ions that Mg L-threonate will? I guess my question really is what does "bound" really mean in this situation. Won't there be some bound and some unbound as Mg++ and the salt in equilibrium? They seem to be always referring to the extra-cellular concentration of Mg++ ions (plus the threonate) as the relevant factors.

Sounds good, Glen. Let me know if you notice anything when you test it out. 

 

By the way, I have the H2 testing drops sitting on my desk. I haven't forgotten! Just been really busy lately. I should be testing my hydrogen water soon and I'll let you know what I find as soon as I do. 

[Kalliste]

 

I got my second catering-lamp after waiting a month for it to arrive from the UK. Now I have two 500w ruby-tinted red/infrared bulbs, they are fitted inside standard Halogens that can be bought at any department-store*.

 

Since summer is here and the sun is out I'm not using them very much. Come next winter my supposed nootropic, and definetly anti-SAD setup, will be these two lamps in the above picture and two normal white halogens with 150w each.

 

These red lamps produce a very nice pain-relief for my shoulders, which tend to tense up due to work, gym and family-life.

 

They can be applied to the head for a minute or two, longer if I use a fan to prevent brain-boiling.

 

My theory is that they should deliver most of the wavelengths of the red spectrum covered in this thread, in a very short time.

 

*Until environmental laws make it illegal here in the EU in 2017!? according to the salesperson :(

Very nice, Cosmicalstorm. Love the setup. That's going to be illegal in Europe in 2017? Weird. Do you know what the rationale is?

 

 

I should add that my picture is a bit misleading, it is dangerous to point the lamps at each other like I do in that picture, they can overheat and possibly explode. Out of the frame I posted there are two fans cooling each lamp from behind. An alternative would be to hand a white clothe from the roof so they can't illuminate each other or change the angle.

In wintertime I'll operate them with a window open and doors closed, that's a nice feeling warm and cold doing battle.

Here is some info from Wikipedia, I admit I have not dived into the details, I'm gonna stock up on some reserves, each lamp lasts 20.000 hours if all goes well, they are not overheated for instance

 

Phase-out of incandescent light bulbs European Union

The UK government announced in 2007 that incandescent bulbs would be phased out by 2011.^[31] In 2008, the Irish government announced a phase-out of the sale of any light bulbs with a luminous efficiency of less than 16 lumens per watt.^[32] Shortly afterwards, all member states of the EU agreed to a progressive phase-out of incandescent light bulbs by 2012.^[33] The initial Europe wide ban only applied to general-purpose, non-directional incandescent bulbs, so did not affect any bulbs with reflective surfaces (e.g. spotlights and halogen down lighters) or special purpose bulbs including those used in devices such as household appliances, traffic lights, infrared lamps and automotive lighting. The sale of the most inefficient bulbs was phased out. The first types to go were non-clear (frosted) bulbs, which were taken off the market in September 2009. Also from September 2009 clear bulbs over 100 W were made of more efficient types. This limit was moved down to lower wattages, and the efficiency levels raised by the end of 2012.^[34]

In practice, some manufacturers and retailers have found a loophole in the new rules so that some incandescents are still available, marketed as "rough-service" or "shock-resistant" bulbs for industrial use only. Such bulbs are widely available in markets and hardware stores at much lower cost than official alternatives such as CFLs. They also offer improved safety for users by having a faster reaction time, and so users can see hazards when entering a room for example.^[35] Since first bans were introduced however, prices of these bulbs have risen by 20–25%.^[36] A German importer simply reclassified the lamps as "mini heaters"^[37] branded "Heatballs".

The EU set a target of 2016 to phase out halogen bulbs, with any bulb available for purchase after the 2016 date requiring at least a 'B' energy rating.^[38] This phase-out has been postponed until 2018.^[39]

^{https://en.wikipedia...ent_light_bulbs}

Edited by Cosmicalstorm, 21 May 2016 - 06:42 PM.

[Nuke]

So I started with nasal insulin last night, for now I'll do 2x 5UI per day to test with. I can always increase it later.

 

I'm reading the cited papers at http://www.alzforum....in-action-brain , but I still don't really know what to make of it. Maybe just something we need to keep in mind using nasal insulin. On the one side we may increase peripheral  insulin sensitivity having a positive effect on longevity. On the other, the increased insulin signaling in the brain may have a negative effect in the long run.

 

http://www.ncbi.nlm....pubmed/17641201

 

 

Brain IRS2 signaling coordinates life span and nutrient homeostasis.

Taguchi A1, Wartschow LM, White MF.

Author information

 

Abstract

Reduced insulin-like signaling extends the life span of Caenorhabditis elegans and Drosophila. Here, we show that, in mice, less insulin receptor substrate-2 (Irs2) signaling throughout the body or just in the brain extended life span up to 18%. At 22 months of age, brain-specific Irs2 knockout mice were overweight, hyperinsulinemic, and glucose intolerant; however, compared with control mice, they were more active and displayed greater glucose oxidation, and during meals they displayed stable superoxide dismutase-2 concentrations in the hypothalamus. Thus, less Irs2 signaling in aging brains can promote healthy metabolism, attenuate meal-induced oxidative stress, and extend the life span of overweight and insulin-resistant mice.

 

 

[lostfalco]

 

So I started with nasal insulin last night, for now I'll do 2x 5UI per day to test with. I can always increase it later.

 

I'm reading the cited papers at http://www.alzforum....in-action-brain , but I still don't really know what to make of it. Maybe just something we need to keep in mind using nasal insulin. On the one side we may increase peripheral  insulin sensitivity having a positive effect on longevity. On the other, the increased insulin signaling in the brain may have a negative effect in the long run.

 

http://www.ncbi.nlm....pubmed/17641201

 

 

Brain IRS2 signaling coordinates life span and nutrient homeostasis.

Taguchi A1, Wartschow LM, White MF.

Author information

 

Abstract

Reduced insulin-like signaling extends the life span of Caenorhabditis elegans and Drosophila. Here, we show that, in mice, less insulin receptor substrate-2 (Irs2) signaling throughout the body or just in the brain extended life span up to 18%. At 22 months of age, brain-specific Irs2 knockout mice were overweight, hyperinsulinemic, and glucose intolerant; however, compared with control mice, they were more active and displayed greater glucose oxidation, and during meals they displayed stable superoxide dismutase-2 concentrations in the hypothalamus. Thus, less Irs2 signaling in aging brains can promote healthy metabolism, attenuate meal-induced oxidative stress, and extend the life span of overweight and insulin-resistant mice.

 

 

Yeah, it's a legitimate question. Resveratrol_guy and I discussed it a few months ago. The evidence from the human studies seem to indicate so far that i-insulin administration for 8 weeks to 4 months is actually beneficial even after cessation of treatment. There is a study in progress that is currently testing long term i-insulin effects (1+ year of treatment) in humans and it was supposed to end in Feb 2016 and has now been moved to Feb 2017. 

https://clinicaltria...ord/NCT01767909

 

I'm keeping an eye on it for long term effects. As of now I would keep dosage to 8 weeks at a time (and maybe 4 months if you're feeling brave). I wouldn't recommend going beyond that at the present time. 

Edited by lostfalco, 22 May 2016 - 07:44 PM.

[bigyellowlemon]

http://www.ncbi.nlm....pubmed/26010875

 

http://www.ncbi.nlm....pubmed/17627483

 

http://www.ncbi.nlm....pubmed/16754295

 

2,4 DNP is a highly toxic substance that inhibits mitochondrial energy production. It makes ATP energy production less efficient. In higher doses. It's often used at 250mg for the goal of weightloss. It also happens to be a nootropic at lower dosages. It reduces oxidative stress, upregulates CREB, upregulates cAMP production, upregulates BDNF, inhibits mTOR, upregulates tau (good/bad), blocks neurotoxicity and oligomerization of amyloid-beta, promotes neurite outgrowth, promotes neural differentiation, extends life in some organism.

It's effects are said to a result of it's mitochondrial uncoupling properties.

 

Hormesis as well?

 

At higher doses it destroys cognition.

 

I wonder if low doses of hydrogen-peroxide would be nootropic too...

 

 

Edited by bigyellowlemon, 22 May 2016 - 04:33 PM.

[LongLife]

Lostfalco,

 

I hope to get my intranasal bottles soon so I can make some intranasal galantamine (got some good points from MYASD on reddit).

Mainly making this from my stepfather (parkinson'), but will test it out on myself first to see all the GI negatives (and other side effects) are indeed bypassed this way

 

as always, thank you for your insights and keeping this thread going :-)

JOCHEN:

 

Parkinson: Take a look at Post #10 and foreward

http://www.longecity...roup-buy/page-1

[Jochen]

 

Lostfalco,

 

I hope to get my intranasal bottles soon so I can make some intranasal galantamine (got some good points from MYASD on reddit).

Mainly making this from my stepfather (parkinson'), but will test it out on myself first to see all the GI negatives (and other side effects) are indeed bypassed this way

 

as always, thank you for your insights and keeping this thread going :-)

JOCHEN:

 

Parkinson: Take a look at Post #10 and foreward

http://www.longecity...roup-buy/page-1

 

 

thanks for that mate ... looks interesting (albeit expensive) and will definitely look into it.
 

[Groundhog Day]

If I wanted to try vagus nerve stimulation with a TENS unit, where do I hook up the electrode pad? Just 1 of the 4 on the left side of my throat/neck?

 

TENSpros sells earclip electrodes, hook the positive pole onto your tragus, that's what I do at least and it seems to be the most common approach in studies.

 

Like this basically:

 

https://images.scien...1_1_900x600.jpg

 

They modified the electrode so the negative pole is on the other side of the clip, personally I just clip the negative pole onto my earlobe on the same ear.

 

 

I have the TENS 7000 and those ear clips you mentioned from TENSPRO but I can't get them to work. I have them hooked up to the positive lead wires. I used 250 for pulse width and 20hz per this study:

 

http://www.ncbi.nlm....pubmed/17156262

 

 

I can't feel anything and the ear clips fall off very easily. Any ideas what I am doing wrong?

 

 

[lostfalco]

Review article on LLLT for depression, traumatic brain injury, anxiety and suicidal ideation.  

 

https://www.ncbi.nlm...pubmed/26989758

 

Neurophotonics. 2016 Jul;3(3):031404. doi: 10.1117/1.NPh.3.3.031404. Epub 2016 Mar 4.

Review of transcranial photobiomodulation for major depressive disorder: targeting brain metabolism, inflammation, oxidative stress, and neurogenesis.

Cassano P1, Petrie SR2, Hamblin MR3, Henderson TA4, Iosifescu DV5.

Author information

Abstract

We examined the use of near-infrared and red radiation (photobiomodulation, PBM) for treating major depressive disorder (MDD). While still experimental, preliminary data on the use of PBM for brain disorders are promising. PBM is low-cost with potential for wide dissemination; further research on PBM is sorely needed. We found clinical and preclinical studies via PubMed search (2015), using the following keywords: "near-infrared radiation," "NIR," "low-level light therapy," "low-level laser therapy," or "LLLT" plus "depression." We chose clinically focused studies and excluded studies involving near-infrared spectroscopy. In addition, we used PubMed to find articles that examine the link between PBM and relevant biological processes including metabolism, inflammation, oxidative stress, and neurogenesis. Studies suggest the processes aforementioned are potentially effective targets for PBM to treat depression. There is also clinical preliminary evidence suggesting the efficacy of PBM in treating MDD, and comorbid anxiety disorders, suicidal ideation, and traumatic brain injury. Based on the data collected to date, PBM appears to be a promising treatment for depression that is safe and well-tolerated. However, large randomized controlled trials are still needed to establish the safety and effectiveness of this new treatment for MDD.

 

Edited by lostfalco, 24 May 2016 - 06:12 PM.

[Kinesis]

Lostfalco, is there a next best if I am ultimately unable to get ibudilast? Am I interpreting your blog right? I'm taking the list of "Microglia Inhibitors" on which ibudilast appears to be a list of alternatives addressing that mechanism, and that of those alternatives, ibudilast is the preferred selection. On reviewing the research, I can see why, but for those of us who are having trouble getting it, maybe a substack of the others might come close, or at least be better than nothing.

On a related point I note that you characterize microglia overactivation as a consequence of mast cell activation. If so, then maybe the mast cell activation inhibitors you list would fit in here. Sort of going one step further upstream in the causal cascade. I'm happy to report that my trial of palmitoylethanolamide has revealed utterly no unwanted effects. Still too early to draw any firm conclusions on benefit (only been two days), but the studies look promising and if anyone's interested I'll follow up in a couple weeks with my anecdotal impressions. The other item you list in this category, btw, luteolin, is promoted in at least one study as being synergistic with palmitoylethanolamine, http://www.ncbi.nlm....pubmed/23844686, and is listed as a PDE4 inhibitor at https://en.wikipedia...ase-4_inhibitor.

In any case, thank you for sharing your research, and for doing it with such flair.

Yep Kinesis, you're interpreting the list on the blog correctly. Ibudilast is the winner but the others are worth a shot for those who don't want to order a prescription drug from overseas (totally understandable! ha). As you said, a substack aimed at microglia inhibition is the way to go if ibudilast isn't used.

As far as microglia and mast cells go, I would say they are 'interactive'. It's not necessarily the case that microglia activation is a consequence of mast cell activation. In some cases, it could be the other way around. Once one of them is activated though, they are likely to activate the other. It makes sense to me to 'dial down the volume' on both if one is dealing with brain fog.

Awesome you're trying PEA! I'm really interested to hear how it goes for you and thanks for the study combining it with luteolin. Makes a lot of sense. I'll link a great video by Dr. Theoharides below where he talks about the importance of mast cells.

Glad you enjoyed the blog post! I like to keep myself entertained. ha

Well I've been taking 350 mg twice a day of the Vitalitus palmitoylethanolamide now for three weeks and am pleased with the results. It took a couple weeks for a noticeable effect; as I mentioned earlier I noticed no immediate effect at all ... in my book a good thing, because obvious mental effects often provoke anxiety for me.

I am definitely getting more mental clarity. I've been getting things done that a month ago would have seemed overwhelming. But should point out that at least some of this is indirect ... I take amitriptyline, in part for chronic neck and shoulder pain. Amitriptyline is anticholinergic and tends to contribute to brain fog. The palmitoylethanolamide allowed me to greatly reduce my dosage, and so I'd expect some improvement in mental clarity from this alone. It is possible I got a direct nootropic benefit from palmitoylethanolamide's own activity as an anti-inflammatory and endocannabinoid, but I have no way to separate out these effects. So my experience may not be very conclusive for people without pain issues, but for anyone that does have them it's very relevant. Either way, palmitoylethanolamide is definitely worth a try. The complete lack of negative sides especially makes it a low-risk proposition.

So in this n=1 the palmitoylethanolamide either provided pain relief or potentiated the effect of another pain reliever, and possibly contributed an nootropic effect of its own. Both would be consistent with the studies. Thanks again Lostfalco for a great lead!


http://www.ncbi.nlm....les/PMC3481533/
http://www.hindawi.c...ji/2013/151028/
http://www.ncbi.nlm....pubmed/22697514

[lostfalco]

Well I've been taking 350 mg twice a day of the Vitalitus palmitoylethanolamide now for three weeks and am pleased with the results. It took a couple weeks for a noticeable effect; as I mentioned earlier I noticed no immediate effect at all ... in my book a good thing, because obvious mental effects often provoke anxiety for me.

I am definitely getting more mental clarity. I've been getting things done that a month ago would have seemed overwhelming. But should point out that at least some of this is indirect ... I take amitriptyline, in part for chronic neck and shoulder pain. Amitriptyline is anticholinergic and tends to contribute to brain fog. The palmitoylethanolamide allowed me to greatly reduce my dosage, and so I'd expect some improvement in mental clarity from this alone. It is possible I got a direct nootropic benefit from palmitoylethanolamide's own activity as an anti-inflammatory and endocannabinoid, but I have no way to separate out these effects. So my experience may not be very conclusive for people without pain issues, but for anyone that does have them it's very relevant. Either way, palmitoylethanolamide is definitely worth a try. The complete lack of negative sides especially makes it a low-risk proposition.

So in this n=1 the palmitoylethanolamide either provided pain relief or potentiated the effect of another pain reliever, and possibly contributed an nootropic effect of its own. Both would be consistent with the studies. Thanks again Lostfalco for a great lead!


http://www.ncbi.nlm....les/PMC3481533/
http://www.hindawi.c...ji/2013/151028/
http://www.ncbi.nlm....pubmed/22697514

 

That's awesome news, Kinesis! Thanks for letting us all know. That's especially encouraging since it doesn't require anyone to purchase prescription meds from overseas. 

 

For those of you wondering, it's this stuff. http://www.amazon.co...s/dp/B019I0TH4C

 

Palmitoylethanolamide downregulates mast cell activation and lowers neuroinflammation as described in the studies Kinesis linked above and here. http://www.lostfalco...n-fog-two-step/

 

Anyway, thanks for the heads up. Really glad it's been effective for you. 

 

[lostfalco]

http://www.ncbi.nlm....pubmed/26010875

 

http://www.ncbi.nlm....pubmed/17627483

 

http://www.ncbi.nlm....pubmed/16754295

 

2,4 DNP is a highly toxic substance that inhibits mitochondrial energy production. It makes ATP energy production less efficient. In higher doses. It's often used at 250mg for the goal of weightloss. It also happens to be a nootropic at lower dosages. It reduces oxidative stress, upregulates CREB, upregulates cAMP production, upregulates BDNF, inhibits mTOR, upregulates tau (good/bad), blocks neurotoxicity and oligomerization of amyloid-beta, promotes neurite outgrowth, promotes neural differentiation, extends life in some organism.

It's effects are said to a result of it's mitochondrial uncoupling properties.

 

Hormesis as well?

 

At higher doses it destroys cognition.

 

I wonder if low doses of hydrogen-peroxide would be nootropic too...

Thanks for the info bigyellow. Have you tried LLLT yet?

 

If you're looking to enhance mitochondrial function it's pretty tough to beat a photon energizing an electron causing more protons to be pumped across the inner mitochondrial membrane resulting in greater ATP production and subsequent modulation of 111 genes (68 upregulated (related to cell growth), 43 downregulated (related to apoptosis)). LLLT increases neurogenesis, synaptogenesis, BDNF, NGF, FGF, HGF, VEGF, etc. It's not a bad place to start imo. =)  

 

Magnesium l-threnoate is looking especially promising lately for mitochondrial function. Magnesium is a cofactor for over 600 enzymes, activates 200 enzymes, and its positive charge stabilizes negatively charged ATP which enhances its activity in cells.

 

Magnesium stabilizes ribosomes (which translate RNA to proteins) and enhances the activities of adenylyl cyclase (if you're interested in cAMP production) and guanylate cyclase.

 

In fact, LLLT upregulates cAMP production, magnesium enhances the activity of adenylyl cyclase and ibudiast inhibits the breakdown of cAMP (through PDE4i)...thus, we have a hyper-effective version of CILTEP. Throw a PDE5i like tadalafil/sildenafil in there for mitochondrial biogenesis and we have CIL-TULIP (CILTEP + TULIP). It's pretty badass in my experience. =)

Edited by lostfalco, 25 May 2016 - 01:11 AM.

[umop 3pisdn]

 

If I wanted to try vagus nerve stimulation with a TENS unit, where do I hook up the electrode pad? Just 1 of the 4 on the left side of my throat/neck?

 

TENSpros sells earclip electrodes, hook the positive pole onto your tragus, that's what I do at least and it seems to be the most common approach in studies.

 

Like this basically:

 

https://images.scien...1_1_900x600.jpg

 

They modified the electrode so the negative pole is on the other side of the clip, personally I just clip the negative pole onto my earlobe on the same ear.

 

 

I have the TENS 7000 and those ear clips you mentioned from TENSPRO but I can't get them to work. I have them hooked up to the positive lead wires. I used 250 for pulse width and 20hz per this study:

 

http://www.ncbi.nlm....pubmed/17156262

 

 

I can't feel anything and the ear clips fall off very easily. Any ideas what I am doing wrong?

 

 

I have the same TENS device and ear clips and I haven't had any problems so far, in fact the earclips could have a bit weaker of a spring and I'd be okay with it. Have you tried making tiny adjustments to how your clip is placed on the tragus? I think it can be a little bit tricky, like for me the cartilage there has a bit of a taper to it which can make it seem a little more inclined to slide off, but I generally don't have trouble getting them to stay put.

 

And you've also connected the negative lead to an earlobe or your other ear, right? You need to make a complete circuit for the stimulation to work, other than that I can't think of anything but maybe you've been shipped faulty hardware?
 

Edited by umop 3pisdn, 25 May 2016 - 08:41 PM.

[lostfalco]

Gonzalez-Lima is still going strong!

 

I think one of the coolest things is that this was in healthy young adults! "Sixty healthy young adults were randomly assigned to one of the following four treatments..."

 

http://www.ncbi.nlm....pubmed/27220529

 

Lasers Med Sci. 2016 May 25. [Epub ahead of print]

Cognitive enhancement by transcranial laser stimulation and acute aerobic exercise.

Hwang J1, Castelli DM1, Gonzalez-Lima F2.

Author information

Abstract

This is the first randomized, controlled study comparing the cognitive effects of transcranial laser stimulation and acute aerobic exercise on the same cognitive tasks. We examined whether transcranial infrared laser stimulation of the prefrontal cortex, acute high-intensity aerobic exercise, or the combination may enhance performance in sustained attention and working memory tasks. Sixty healthy young adults were randomly assigned to one of the following four treatments: (1) low-level laser therapy (LLLT) with infrared laser to two forehead sites while seated (total 8 min, 1064 nm continuous wave, 250 mW/cm2, 60 J/cm2 per site of 13.6 cm2); (2) acute exercise (EX) of high-intensity (total 20 min, with 10-min treadmill running at 85-90 % VO2max); (3) combined treatment (LLLT + EX); or (4) sham control (CON). Participants were tested for prefrontal measures of sustained attention with the psychomotor vigilance task (PVT) and working memory with the delayed match-to-sample task (DMS) before and after the treatments. As compared to CON, both LLLT and EX reduced reaction time in the PVT [F(1.56) = 4.134, p = 0.01, η 2  = 0.181] and increased the number of correct responses in the DMS [F(1.56) = 4.690, p = 0.005, η 2  = 0.201], demonstrating a significant enhancing effect of LLLT and EX on cognitive performance. LLLT + EX effects were similar but showed no significantly greater improvement on PVT and DMS than LLLT or EX alone. The transcranial infrared laser stimulation and acute aerobic exercise treatments were similarly effective for cognitive enhancement, suggesting that they augment prefrontal cognitive functions similarly.

 

 

Here are some affordable LLLT options for those interested in trying it out. http://www.lostfalco.com/devices/

Edited by lostfalco, 27 May 2016 - 12:54 PM.

[lostfalco]

Recent rodent hydrogen water study for MS. 

 

http://www.ncbi.nlm....pubmed/27138092

 

J Neuroimmunol. 2016 May 15;294:6-13. doi: 10.1016/j.jneuroim.2016.03.006. Epub 2016 Mar 14.

Hydrogen-rich water improves neurological functional recovery in experimental autoimmune encephalomyelitis mice.

Zhao M1, Liu MD2, Pu YY2, Wang D2, Xie Y2, Xue GC2, Jiang Y2, Yang QQ2, Sun XJ3, Cao L4.

Author information

Abstract

Multiple sclerosis (MS) is a chronic autoimmune demyelinating disease of the central nervous system (CNS). The high costs, inconvenient administration, and side effects of current Food and Drug Administration (FDA)-approved drugs often lead to poor adherence to the long-term treatment of MS. Molecular hydrogen (H2) has been reported to exhibit anti-oxidant, anti-apoptotic, anti-inflammatory, anti-allergy, and anti-cancer effects. In the present study, we explored the prophylactic and therapeutic effects of hydrogen-rich water (HRW) on the progress of experimental autoimmune encephalomyelitis (EAE), the animal model for MS. We found that prophylactic administration of both 0.36mM and 0.89mM HRW was able to delay EAE onset and reduce maximum clinical scores. Moreover, 0.89mM HRW also reduced disease severity, CNS infiltration, and demyelination when administered after the onset of disease. Furthermore, HRW treatment prevented infiltration of CD4(+) T lymphocytes into the CNS and inhibited Th17 cell development without affecting Th1 cell populations. Because HRW is non-toxic, inexpensive, easily administered, and can readily cross the blood-brain barrier, our experiments suggest that HRW may have great potential in the treatment of MS.

 

 

Since we're on the subject....here is a great review article covering the results of over 300 molecular hydrogen studies over the past 8 years. http://www.ncbi.nlm....les/PMC4610055/

 

 

Edited by lostfalco, 27 May 2016 - 09:35 PM.

[lostfalco]

http://www.ncbi.nlm....les/PMC4877549/

 

J Korean Neurosurg Soc. 2016 May;59(3):259-68. doi: 10.3340/jkns.2016.59.3.259. Epub 2016 May 10.

Sildenafil Ameliorates Advanced Glycation End Products-Induced Mitochondrial Dysfunction in HT-22 Hippocampal Neuronal Cells.

Sung SK1, Woo JS2, Kim YH3, Son DW1, Lee SW3, Song GS3.

Author information

Abstract

OBJECTIVE: 

Accumulation of advanced glycation end-products (AGE) and mitochondrial glycation is importantly implicated in the pathological changes of the brain associated with diabetic complications, Alzheimer disease, and aging. The present study was undertaken to determine whether sildenafil, a type 5 phosphodiesterase type (PDE-5) inhibitor, has beneficial effect on neuronal cells challenged with AGE-induced oxidative stress to preserve their mitochondrial functional integrity.

METHODS: 

HT-22 hippocampal neuronal cells were exposed to AGE and changes in the mitochondrial functional parameters were determined. Pretreatment of cells with sildenafil effectively ameliorated these AGE-induced deterioration of mitochondrial functional integrity.

RESULTS: 

AGE-treated cells lost their mitochondrial functional integrity which was estimated by their MTT reduction ability and intracellular ATP concentration. These cells exhibited stimulated generation of reactive oxygen species (ROS), disruption of mitochondrial membrane potential, induction of mitochondrial permeability transition, and release of the cytochrome C, activation of the caspase-3 accompanied by apoptosis. Western blot analyses and qRT-PCR demonstrated that sildenafil increased the expression level of the heme oxygenase-1 (HO-1). CoPP and bilirubin, an inducer of HO-1 and a metabolic product of HO-1, respectively, provided a similar protective effects. On the contrary, the HO-1 inhibitor ZnPP IX blocked the effect of sildenafil. Transfection with HO-1 siRNA significantly reduced the protective effect of sildenafil on the loss of MTT reduction ability and MPT induction in AGE-treated cells.

CONCLUSION: 

Taken together, our results suggested that sildenafil provides beneficial effect to protect the HT-22 hippocampal neuronal cells against AGE-induced deterioration of mitochondrial integrity, and upregulation of HO-1 is involved in the underlying mechanism.

 

[Groundhog Day]

 

 

I have the same TENS device and ear clips and I haven't had any problems so far, in fact the earclips could have a bit weaker of a spring and I'd be okay with it. Have you tried making tiny adjustments to how your clip is placed on the tragus? I think it can be a little bit tricky, like for me the cartilage there has a bit of a taper to it which can make it seem a little more inclined to slide off, but I generally don't have trouble getting them to stay put.

 

And you've also connected the negative lead to an earlobe or your other ear, right? You need to make a complete circuit for the stimulation to work, other than that I can't think of anything but maybe you've been shipped faulty hardware?
 

 

Thanks for the help. I've got it going now. What I'm wondering now is duration. How long are you doing it for? 15 minutes straight?

 

That study I linked states: The recommended initial ON time is 30 s, followed by 5 min OFF; OFF time > ON time is recommended

 

[chris106]

Just a little update from my side;
 

By now I have received both Galantamine and Ibudilast. For Ibudilast I used parcel forwarding via the UK (skypax), which worked suprisingly well and without any issues regarding german customs - so using parcel forwarding seems to be a viable option for europeans trying to get Ibudilast from mimaki.

That being said, I think I managed to have them send the package just in time before the "psychoactive substances act" in the UK went into effect. My guess is that this would still work, though - as skypax now simply has put a disclaimer on their site basically stating that anyone who orders any kind of medication should make sure that it is within their rights to do so. I guess this is their reaction to that whole dilemma.

 

Anyways, just took my first 10mg Pinatos. I haven't had the chance to try Galantamine beforehand - I'll add that in a few days and then report back to add one more anecdotal report.

[lostfalco]

Just a little update from my side;
 

By now I have received both Galantamine and Ibudilast. For Ibudilast I used parcel forwarding via the UK (skypax), which worked suprisingly well and without any issues regarding german customs - so using parcel forwarding seems to be a viable option for europeans trying to get Ibudilast from mimaki.

That being said, I think I managed to have them send the package just in time before the "psychoactive substances act" in the UK went into effect. My guess is that this would still work, though - as skypax now simply has put a disclaimer on their site basically stating that anyone who orders any kind of medication should make sure that it is within their rights to do so. I guess this is their reaction to that whole dilemma.

 

Anyways, just took my first 10mg Pinatos. I haven't had the chance to try Galantamine beforehand - I'll add that in a few days and then report back to add one more anecdotal report.

Nice! Thanks for the info, Chris. Appreciate the workaround for Europeans. 

 

Looking forward to hearing how it works for you. Are you attempting to alleviate brain fog, enhance general brain function, something else?

 

My quick anecdote. I've been testing ibudilast with numerous substances over the past month (I'm like a kid at Christmas!) and it really mixes well with numerous things ime. I'll talk more about this in my next blog post (which has grown to absurd proportions. ha) but LLLT + mg-threonate + i-insulin (20iu/day) + ibudilast (20mg/day) + tadalafil (5mg/day) + mr. happy stack + agomelatine (10mg/day) + MK-677 (10mg/day) is off the charts. If you low dose all of them it's a bit pricey but not THAT bad. Anyway, I have now achieved Happy Cil-TULIP (Mr. Happy Stack + Ciltep + TULIP). The Longecity circle is now complete! ha I think I talked about this back in 2013. http://www.longecity...1887-lostfalco/

 

I'll talk about how they all interact and enhance each others' activity on the blog but I think various combos of these substances (in complementary, subtherapeutic doses) have massive potential to help with numerous conditions: cte, tbi, depression, etc. If anyone is as crazy as I am and tries something similar let me know! I'd love to hear how it affects others so I can make better recommendations to people.  

 

 

 

Edited by lostfalco, 31 May 2016 - 06:58 PM.

[Groundhog Day]

Mag threonate is a bit expensive. I discovered that Powdercity has it a few weeks ago but they have been out of stock.

[lostfalco]

Mag threonate is a bit expensive. I discovered that Powdercity has it a few weeks ago but they have been out of stock.

Yeah, they have the best price by far. Unfortunately, they've been out of stock for quite a while. It might be time to start (nicely) harassing them a little. =)

[Brazzo]

 

Mag threonate is a bit expensive. I discovered that Powdercity has it a few weeks ago but they have been out of stock.

Yeah, they have the best price by far. Unfortunately, they've been out of stock for quite a while. It might be time to start (nicely) harassing them a little. =)

 

Did you guys feel a different effect compared to regular megnesium?

[lostfalco]

I like it better. I think it's worth an experiment to see if you notice a difference.