43 replies to this topic

[tracer]

The Big B mentioned on another thread that Litium can increase grey matter. He also said "I have no idea how it works, but simply that low doses of Lithium Orotate can be used to increase gray matter over time with it's anti-psychotic and liver damaging qualities removed."


Does anyone have any information/experience with this?

[dogbarf]

This is my first post here, but I guess I'll jump right in.
I've done a little research on lithium and cognition/memory because I, too, have heard of its potential to increase gray matter.
It seems that although studies show that this is true, lithium's effects as far as cognition and memory all seem to be negative.
A quick search yielded these results:

Sassi RB. Nicoletti M. Brambilla P. Mallinger AG. Frank E. Kupfer DJ. Keshavan MS. Soares JC. Increased gray matter volume in lithium-treated bipolar disorder patients. [Journal Article] Neuroscience Letters. 329(2):243-5, 2002 Aug 30.

Lithium's neurotrophic effects have been reported in several in vitro and ex vivo studies. Preliminary human studies with magnetic resonance imaging (MRI) and spectroscopy have recently provided evidence of lithium-induced increases in gray matter volumes and N-acetyl-aspartate levels.

Shaw ED. Stokes PE. Mann JJ. Manevitz AZ. Effects of lithium carbonate on the memory and motor speed of bipolar outpatients. [Journal Article] Journal of Abnormal Psychology. 96(1):64-9, 1987 Feb.

Abstract
We examined the effect of lithium on the memory and motor speed of 22 outpatients with affective disorders in remission. Patients were assessed weekly over a 5-week period starting at their current lithium dosage, twice during administration of a blind placebo, and twice after their lithium was blindly reinstated. Motor speed was assessed using the finger tapping test. Memory was assessed using the Buschke selective reminding protocol. Mood was assessed at each session to ensure remitted status by clinical interview, the Hamilton Rating Scale for Depression, the Longitudinal Rating of Manic States Scale, and a subjective state questionnaire. Weekly blood samples were also drawn to assess plasma lithium level by means of atomic absorption spectrophotometry. The results indicated that lithium had a significant detrimental effect on memory and motor speed: Performance improved when lithium was discontinued and declined when lithium was reintroduced. The implications for patient management and diagnosis in bipolar disorder are discussed.

(I have the full text of that article if you're interested)

Title Effects of lithium carbonate on memory and other cognitive functions.

Source American Journal of Psychiatry. 137(9):1042-6, 1980 Sep.

Abstract The authors studied the effects of lithium carbonate on memory and cognitive function in 16 psychiatric patients, who received lithium for 2 weeks and placebo for 2 weeks in a double-blind cross-over design. At the end of each treatment phase, subjects were administered a battery of memory and cognitive tests. As reported previously, lithium induced slowing of performance on certain of the perceptual motor tests; however, lithium did not cause memory impairment or a change in self-assessment of memory functions.

Title The effect of lithium carbonate on the cognitive functions of normal subjects.

Source Archives of General Psychiatry. 34(3):355-7, 1977 Mar.

Abstract The responses of 24 normal male subjects were compared after weeks of placebo administration and two weeks of lithium carbonate administration (mean serum lithium level, 0.9 mEq/liter) on a series of tasks of intellectual function, aesthetic judgement, and semantic creativity. This was a placebo-controlled, split-half crossover, double-blind design. There were no significant changes on semantic creativity or aesthetic perception measures following lithium carbonate maintenance. There were lithium carbonate-related performance deficits on three of five performance tasks concerned with cognitive and/or motor functions. The deficit is probably due to a lithium carbonate-induced slowing of performance, consistent with our previous report of subjective effects in normal subjects. The implications of slowing on possible behavioral mediating mechanisms by which lithium carbonate exerts its clinical effects are discussed.

[tracer]

Thanks Dogbarf. I am most certainly interested in the FullText.

In addtition here is some of my reading

Lithium: potential therapeutics against acute brain injuries and chronic neurodegenerative diseases.

Wada A, Yokoo H, Yanagita T, Kobayashi H.

Department of Pharmacology, Miyazaki Medical College, University of Miyazaki, Miyazaki, Japan. akihiko@fc.miyazaki-u.ac.jp

In addition to the well-documented mood-stabilizing effects of lithium in manic-depressive illness patients, recent in vitro and in vivo studies in rodents and humans have increasingly implicated that lithium can be used in the treatment of acute brain injuries (e.g., ischemia) and chronic neurodegenerative diseases (Alzheimer's disease, Parkinson's disease, tauopathies, and Huntington's disease). Consistent with this novel view, substantial evidences suggest that depressive illness is not a mere neurochemical disease, but is linked to gray matter atrophy due to the reduced number/size of neurons and glia in brain. Importantly, neurogenesis, that is, birth/maturation of functional new neurons, continues to occur throughout the lifetime in human adult brains (e.g., hippocampus); the neurogenesis is impaired by multiple not-fully defined factors (e.g., aging, chronic stress-induced increase of glucocorticoids, and excitotoxicity), accounting for brain atrophy in patients with depressive illness and neurodegenerative diseases. Chronic treatment of lithium, in agreement with the delayed-onset of mood-stabilizing effects of lithium, up-regulates cell survival molecules (e.g., Bcl-2, cyclic AMP-responsive element binding protein, brain-derived neurotrophic factor, Grp78, Hsp70, and beta-catenin), while down-regulating pro-apoptotic activities (e.g., excitotoxicity, p53, Bax, caspase, cytochrome c release, beta-amyloid peptide production, and tau hyperphosphorylation), thus preventing or even reversing neuronal cell death and neurogenesis retardation.

FullText

Influence of retinoic acid and lithium on proliferation and
dopaminergic potential of human NT2 cells.
Misiuta IE, Saporta S, Sanberg PR, Zigova T, Willing AE.
Center of Excellence for Aging and Brain Repair, University of South Florida, Tampa,
Florida.
Our laboratory is working with the human NTera2/D1 (NT2) cell line, which has
properties similar to those of progenitor cells in the central nervous system (CNS).
These neural-like precursor cells can differentiate into all three major lineages, neurons,
astrocytes, and oligodendrocytes. The pure neuronal population, hNT neurons, possess
characteristics of dopamine (DA) cells. First, we analyzed whether the retinoic acid
(RA)-treated hNT neurons and the NT2 precursor cells expressed two transcription
factors required for development of the midbrain DA neurons. We report that NT2 cells
endogenously expressed Engrailed-1 and Ptx3, whereas RA-treated hNT neurons did
not express Engrailed-1 or Ptx3. Next we examined the influence of lithium treatment
on Engrailed-1 and Ptx3 as well as another critical transcription factor, Nurr1. Previous
research has shown that lithium can mimic the Wnt pathway, which is important for the
induction of these transcription factors. Finally, we investigated the effect of lithium
treatment on the viability and proliferation of NT2 cells, because lithium has been
shown to stimulate neurogenesis in adult neural precursors. Lithium treatment increased
the viability and proliferation of NT2 cells. The expression of transcription factors
essential for the induction and maintenance of the DA phenotype was not increased in
NT2 after lithium treatment. We conclude that the NT2 cell line is an excellent in vitro
model system for studying the influence of pharmalogical agents on proliferation,
differentiation, and apoptosis of a human neural progenitor cell line. © 2006 Wiley-
Liss, Inc.

Neuroprotective mechanisms of lithium in murine human immunodeficiency virus-1 encephalitis.

Dou H, Ellison B, Bradley J, Kasiyanov A, Poluektova LY, Xiong H, Maggirwar S, Dewhurst S, Gelbard HA, Gendelman HE.

Center for Neurovirology and Neurodegenerative Disorders, University of Nebraska Medical Center, Omaha, Nebraska 68198-5880, USA. hegendel@unmc.edu

Lithium (Li) has garnered considerable interest as a neuroprotective drug for a broad range of nervous system disorders. Its neuroprotective activities occur as a consequence of glycogen synthase kinase-3beta (GSK-3beta) inhibition leading to downstream blockade of beta-catenin and Tau phosphorylation. In the present study, we investigated Li-mediated neuroprotective mechanisms in laboratory and murine human immunodeficiency virus-1 (HIV-1) encephalitis (HIVE) models. In laboratory tests, Li protected neurons from neurotoxic secretions of HIV-1-infected monocyte-derived macrophages (MDMs). This neuroprotection was mediated, in part, through the phosphatidyl inositol 3-kinase/Akt and GSK-3beta pathways. To examine the effects of Li treatment in vivo, MDMs were injected into the basal ganglia of severe combined immunodeficient mice and then Li was administered (60 mg/kg/d). Seven days after MDM injection, mice were killed and CNS tissue was collected and subjected to immunocytochemical and Western blot assays for leukocyte and neural antigens, GSK-3beta, and key kinase substrates such as beta-catenin and Tau. Numbers of HIV-1 p24 antigen-positive MDMs were unaltered by Li treatment of HIVE mice. Similarly, the greatly increased extent of astrocyte and microglia activation in HIVE mice (10-fold and 16-fold, respectively, compared with unmanipulated controls) was also unaltered by Li. In contrast, Li restored HIVE-associated loss of microtubule-associated protein-2-positive neurites and synaptic density while reducing levels or activity of phospho-Tau Ser202, phospho-beta-catenin, and GSK-3beta. Electrophysiological recordings showed diminished long-term potentiation in hippocampal slices of HIVE mice that were restored by Li. Based on these data, the use of Li as an adjuvant for HIV-1-associated dementia is now being pursued.

Chronic lithium enhances hippocampal long-term potentiation, but not neurogenesis, in the aged rat dentate gyrus.

Yu IT, Kim JS, Lee SH, Lee YS, Son H.

Department of Biochemistry, Hanyang University College of Medicine, 17 Haengdang-dong, Sungdong-gu, Seoul 133-791, Republic of Korea.

We investigated the hippocampal long-term potentiation (LTP), neurogenesis, and the activation of signaling molecules in the 20-month-old aged rats following chronic lithium treatment. Chronic lithium treatment produced a significant 79% increase in the numbers of BrdU(+) cells after treatment completion in the dentate gyrus (DG). Both LTP obtained from slices perfused with artificial cerebrospinal fluid (ACSF-LTP), and LTP recorded in the presence of bicuculline (bicuculline-LTP) were significantly greater in the lithium group than in the saline controls. Our results show that as with young rats, chronic lithium can substantially increase LTP and the number of BrdU(+) cells in the aged rats. However, neurogenesis, assessed by colocalization of NeuN and BrdU, was not detected in the aged rat DG subjected to chronic lithium treatment. Therefore, it is concluded that the increase in LTP and the number of BrdU(+) cells might not be associated with increases in neurogenesis in the granule cell layer of the DG. Lithium might has a beneficial effects through other signaling pathways in the aged brain.

Enhancement of hippocampal neurogenesis by lithium.

Chen G, Rajkowska G, Du F, Seraji-Bozorgzad N, Manji HK.

Laboratory of Molecular Pathophysiology, Department of Psychiatry and Behavioral Neurosciences, Wayne State University School of Medicine, Detroit, Michigan 48201, USA. gchen@med.wayne.edu

Increasing evidence suggests that mood disorders are associated with a reduction in regional CNS volume and neuronal and glial cell atrophy or loss. Lithium, a mainstay in the treatment of mood disorders, has recently been demonstrated to robustly increase the levels of the cytoprotective B-cell lymphoma protein-2 (bcl-2) in areas of rodent brain and in cultured cells. In view of bcl-2's antiapoptotic and neurotrophic effects, the present study was undertaken to determine if lithium affects neurogenesis in the adult rodent hippocampus. Mice were chronically treated with lithium, and 5-bromo-2-deoxyuridine (BrdU) labeling of dividing cells was conducted over 12 days. Immunohistochemical analysis was undertaken 1 day after the last injection, and three-dimensional stereological cell counting revealed that lithium produced a significant 25% increase in the BrdU-labeled cells in the dentate gyrus. Double-labeling immunofluorescence studies were undertaken to co-localize BrdU-positive cells with neuron-specific nuclear protein and showed that approximately 65% of the cells were double-labeled. These results add to the growing body of evidence suggesting that mood stabilizers and antidepressants exert neurotrophic effects and may therefore be of use in the long-term treatment of other neuropsychiatric disorders.

Lithium enhances long-term potentiation independently of hippocampal neurogenesis in the rat dentate gyrus.

Son H, Yu IT, Hwang SJ, Kim JS, Lee SH, Lee YS, Kaang BK.

Department of Biochemistry, Hanyang University College of Medicine, 17 Haengdang-dong, Sungdong-gu, Seoul 133-791, South Korea. hyeonson@hanyang.ac.kr

We measured the temporal and spatial profiles of neural precursor cells, hippocampal long-term potentiation (LTP), and signaling molecules in neurogenesis-induced adult rats. Chronic lithium treatment produced a significant 54% and 40% increase in the numbers of bromodeoxyuridine [BrdU(+)] cells after 12 h and 28 days, respectively, after treatment completion in the dentate gyrus (DG). Both LTP obtained from slices perfused with artificial cerebrospinal fluid (ACSF-LTP) and LTP recorded in the presence of bicuculline (bicuculline-LTP) were significantly greater in the lithium group than in the saline controls. Although the number of BrdU(+) cells, approximately 90% of which were double-labeled with a neural marker neuronal nuclear protein, were markedly increased in the granule cell layer (GCL) 28 days after the completion of the 28-day lithium treatment, the magnitude of LTP observed at this time was similar to that observed 12 h after completing the 28-day lithium treatment. However, protein levels of calcium and calmodulin-dependent protein kinase II, p-Elk and TrkB were highly elevated until 28 days after the 28-day lithium treatment. Acute lithium treatment for 2 days also enhanced LTP, which was accompanied by the elevated expression of p-CREB, but not by neurogenesis. Our results suggest that the enhancement of LTP is independent of the increased number of neurons per se and it is more closely associated with key molecules, which are probably involved in neurogenesis.

Lithium selectively increases neuronal differentiation of hippocampal neural progenitor cells both in vitro and in vivo.

Kim JS, Chang MY, Yu IT, Kim JH, Lee SH, Lee YS, Son H.

Department of Biochemistry, Hanyang University College of Medicine, Seoul, Korea.

Lithium has been demonstrated to increase neurogenesis in the dentate gyrus of rodent hippocampus. The present study was undertaken to investigate the effects of lithium on the proliferation and differentiation of rat neural progenitor cells in hippocampus both in vitro and in vivo. Lithium chloride (1-3 mM) produced a significant increase in the number of bromodeoxyuridine (BrdU)-positive cells in high-density cultures, but did not increase clonal size in low-density cultures. Lithium chloride at 1 mM (within the therapeutic range) also increased the number of cells double-labeled with BrdU antibody and TuJ1 (a class III beta-tubulin antibody) in high-density cultures and the number of TuJ1-positive cells in a clone of low-density cultures, whereas it decreased the number of glial fibrillary acidic protein-positive cells in both cultures. These results suggest that lithium selectively increased differentiation of neuronal progenitors. These actions of lithium appeared to enhance a neuronal subtype, calbindin(D28k)-positive cells, and involved a phosphorylated extracellular signal-regulated kinase and phosphorylated cyclic AMP response element-binding protein-dependent pathway both in vitro and in vivo. These findings suggest that lithium in therapeutic amounts may elicit its beneficial effects via facilitation of neural progenitor differentiation toward a calbindin(D28k)-positive neuronal cell type.

A molecular cell biology of lithium.

Williams R, Ryves WJ, Dalton EC, Eickholt B, Shaltiel G, Agam G, Harwood AJ.

MRC Laboratory for Molecular Cell Biology and Department of Biology, University College London, Gower St, London WC1E 6BT, UK.

Lithium (Li(+)), a mood stabilizer, has profound effects on cultured neurons, offering an opportunity to investigate its cellular biological effects. Here we consider the effect of Li(+) and other psychotropic drugs on growth cone morphology and chemotaxis. Li(+) inhibits GSK-3 (glycogen synthase kinase-3) at a therapeutically relevant concentration. Treated cells show a number of features that arise due to GSK-3 inhibition, such as altered microtubule dynamics, axonal branching and loss of semaphorin 3A-mediated growth cone collapse. Li(+) also causes growth cones to spread; however, a similar effect is seen with two other mood stabilizers, valproic acid and carbamazepine, but without changes in microtubules or axon branching. This common effect of mood stabilizers is mediated by changes in inositol phosphate signalling, not GSK-3 activity. Given the presence of neurogenesis in the adult brain, we speculate that changes in growth cone behaviour could also occur during treatment of mental disorders.

The Antiapoptotic Actions of Mood Stabilizers: Molecular Mechanisms and Therapeutic Potentials.

Chuang DM.

Molecular Neurobiology Section, National Institute of Mental Health, National Institutes of Health, Building 10, Room 4C-206, 10 Center Drive, MSC 1363, Bethesda, MD 20892-1363. chuang@mail.nih.gov.

Two primary drugs used to treat bipolar mood disorder are lithium and valproate. Emerging evidence supports the notion that both mood stabilizers have neuroprotective effects. In primary cultures of rat cerebellar granule cells and cortical neurons, lithium and valproate robustly and potently protect against glutamate-induced, N-methyl-d-aspartate (NMDA) receptor-mediated excitotoxicity. The neuroprotective mechanisms involve inactivation of NMDA receptors through inhibition of NR2B tyrosine phosphorylation, activation of cell survival factors such as the PI 3-kinase/Akt signaling pathway, and induction of neurotrophic/neuroprotective proteins, including brain-derived neurotrophic factor, heat-shock protein (HSP), and Bcl-2. Both drugs are also effective against other forms of insults such as ER stress in neurally related cell types. The molecular targets likely involve glycogen synthase kinase-3 (GSK-3) and histone deacetylase (HDAC) for lithium and valproate, respectively. In a rat cerebral artery occlusion model of stroke, postinsult treatment with lithium or valproate reduces ischemia-induced brain infarction, caspase-3 activation, and neurological deficits, and these neuroprotective effects are associated with HSP70 upregulation and, in the case of valproate, HDAC inhibition. In a rat excitotoxic model of Huntington's disease in which an excitotoxin is infused into the striatum to activate NMDA receptors, short-term lithium pretreatment is sufficient to protect against DNA damage, caspase activation, and apoptosis of striatal neurons, and this neuroprotection is concurrent with Bcl-2 induction. Moreover, lithium treatment increases cell proliferation near the site of striatal injury, and some newborn cells have phenotypes of neurons and astroglia. Thus, lithium and valproate are potential drugs for treating some forms of neurodegenerative diseases.

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Also, on valproic acid

The mood stabilizer valproic acid stimulates GABA neurogenesis from rat forebrain stem cells.

Laeng P, Pitts RL, Lemire AL, Drabik CE, Weiner A, Tang H, Thyagarajan R, Mallon BS, Altar CA.

Gene Discovery, Psychiatric Genomics, Inc., Gaithersburg, Maryland 20878, USA. plaeng@psygenomics.com

Valproate, an anticonvulsant drug used to treat bipolar disorder, was studied for its ability to promote neurogenesis from embryonic rat cortical or striatal primordial stem cells. Six days of valproate exposure increased by up to fivefold the number and percentage of tubulin beta III-immunopositive neurons, increased neurite outgrowth, and decreased by fivefold the number of astrocytes without changing the number of cells. Valproate also promoted neuronal differentiation in human fetal forebrain stem cell cultures. The neurogenic effects of valproate on rat stem cells exceeded those obtained with the neurotrophins brain-derived growth factor (BDNF) or NT-3, and slightly exceeded the effects obtained with another mood stabilizer, lithium. No effect was observed with carbamazepine. Most of the newly formed neurons were GABAergic, as shown by 10-fold increases in neurons that immunostained for GABA and the GABA-synthesizing enzyme GAD65/67. Double immunostaining for bromodeoxyuridine and tubulin beta III showed that valproate increased by four- to fivefold the proliferation of neuronal progenitors derived from rat stem cells and increased cyclin D2 expression. Valproate also regulated the expression of survival genes, Bad and Bcl-2, at different times of treatment. The expression of prostaglandin E synthase, analyzed by quantitative RT-PCR, was increased by ninefold as early as 6 h into treatment by valproate. The enhancement of GABAergic neuron numbers, neurite outgrowth, and phenotypic expression via increases in the neuronal differentiation of neural stem cell may contribute to the therapeutic effects of valproate in the treatment of bipolar disorder.

[tracer]

My conclusions thus far -

Since I suffer from depression, lithium at a low dose will be synergistic with treating that and inducing neurogenesis. I am also going to investigate valproic acid and other substances in a similar ilk as they may offer synergistic effects.

Also, while I have a fair grasp of molecular biology in muscle (for a layperson), I must confess I am quite lacking in my understanding of the nervous system. I will need to address this gap.

For now, lithium orotate is definitely in my next stack.

[dogbarf]

From what I've read, it seems that lithium impairs cognition -- albeit with neuroprotective and neurotrophic properties. I wouldn't try lithium as a nootropic unless you've been subjected to cranial irradiation.
(see Lithium Is a Neuroprotector That Improves Memory and Learning in Preclinical Models of the Irradiated Developing Brain, International Journal of Radiation Oncology)

I'm uploading some pdfs for you right now. I'll post links when I'm done.

[dogbarf]

Lithium Is a Neuroprotector That Improves Memory and Learning in Preclinical Models of the Irradiated Developing Brain
International Journal of Radiation Oncology, Volume 63, Supplement 1, 1 October 2005, Page S261
K. Osusky, E. Edwards and D. Hallahan

Use of nootropic agent in memory dysfunction of lithium treated bipolar patients
European Neuropsychopharmacology, Volume 11, Supplement 3, 2001, Page S242
P. N. Malitas, B. E. Alevizos, G. N. Papadimitriou and G. N. Christodoulou

Aniracetam is considered to be a drug that can modulate indirectly
the brain acetylcholine system. Administration of aniracetam has
been reported to be effective in enhancing the cognitive function
of patients with senile dementia of the Alzheimer type. It is
the first time that aniracetam is being used to improve cognitive
dysfunction in patients with bipolar affective disorder on lithium
treatment. Cognitive dysfunction has been reported to be one of
the most serious side effects of lithium salts.

A double-blind, placebo-controlled study of the effects of lithium on cognition in healthy subjects: mild and selective effects on learning
Journal of Affective Disorders, Volume 60, Issue 3, 2 November 2000, Pages 147-157
Emmanuel Stip, Jocelyn Dufresne, Isabelle Lussier and Lakshmi Yatham

[Paul Idol]

Dogbarf-

I think the key issue may be dosage. People treated for bipolar disorder with lithium carbonate are given massive doses. The last PDF you posted indicates that test subjects were treated twice daily with doses ranging from 1050mg to 1950mg. That's a gargantuan amount of lithium compared to the small doses recommended in nootropic circles — about 30mg of elemental lithium per day derived from lithium orotate — and the orotate chelate may well also influence its effects.

-Paul

[dogbarf]

Well, unfortunately I can't find any studies resembling low-dose lithium orotate and its nootropic effects in healthy (or depressed?) humans

Is anyone aware of any actual studies that show improvement of cognition?

tracer: I look forward to hearing your results. Keep us informed.
And BTW, you mentioned liver-damaging qualities, but you may also want to search "lithium reproductive." I think I've seen a bit regarding reproductive side-effects as well.

[the big b]

Dogbarf-

I think the key issue may be dosage.  People treated for bipolar disorder with lithium carbonate are given massive doses.  The last PDF you posted indicates that test subjects were treated twice daily with doses ranging from 1050mg to 1950mg.  That's a gargantuan amount of lithium compared to the small doses recommended in nootropic circles — about 30mg of elemental lithium per day derived from lithium orotate — and the orotate chelate may well also influence its effects.

-Paul

A point I myself was about to bring up. 1 gram and higher of Lithium is a dosage used only for those with EXTREME mental disturbances. Even just 10mg would be sufficient to increase gray matter over time, with little to no side effects. But I expect it would be quite hard to find any studies on Lithium in such low doses.

[tracer]

Thanks for the input people.

Firstly lithium carbonate is not as bio-available as orotate. The seminal work on the orotate chelate was done by Nieper et al in the 70s. He equates 5mg Li Orotate to 100mg Li Carbonate.

Also, as you guys point out, the doses for treating bipolar disorders and assorted manias are in the 1-2 gram range (for the carbonate form) or, equivalently 50-100mg per dose. The orotate form is usually taken more frequently (from my reading, it seems so...) so that's 3x a day.

Lithium is not metabilised in any menaingful way. Blood levels are dependant on the rate of excretion via the kidneys... this means that everything from hydration to excersise to salt intake can influence blood values. Lithium toxicity is perilously easy to achieve with the "therapeutic doses" above. Mixing it with Vasopressin/Desmopressin is proalby nuts. But then most people who take lithium in that dose range are not 100% "compus mentis" anyway...

Now, Lithium also has applications for treating so-called "thyroid resistance syndrome" as well as the more broadly acknowledged "insulin resistance syndrome". [Cynic's note: Good old Syndrome-X - all you need to do to cure obeisity is to put the entire population on lithium. Why didn't I think of that?].

I haven't looked into it's effects on the reproductive system, but since I do have quite a liking for the mating practices of our species you can bloody well bet that I will!

That said, the valproates are apparently notorious for messing with insulin sensitivity, glucocorticoid levels and steroid levels (you get fat, old and possibly infertile). I will be staying well away from these, esp since they seem to offer little advantage over plain old Li, unless you actually have epilepsy.

Anyway, I'm probably going to incorporate lithium as a "trace element" supplement. Probably in the range of 50-100mg per day in 5 divided doses (in the usual noot powder that I drink, snort or take as a suppository depending on what mood I'm in). I will start out at the low end for a month and *very slowly* build the dose up to a higher level. At this dose level it's dirt-cheap and I'll probably just tack it in on the back of my next noot order.

However, before I do so, there is still the niggling question: "What exactly is this Lithium going to do for me?". What are the long-term benefits/risks of this.

The truth is, I don't know. And until I do, I'm not going to be actively supplementing this... there's quite a bit more reading to do.

One thing that bothers me - if Li increases differentiation and not proliferation of neural progenitor cell lines, then it may well decrease the long-term development prospects by adversely affecting the population of the immature progenitor cells (i.e. a smaller pool left behind for proliferation). Even if this was true, this doesn't mean that Li supplementation is a definite "no" - it may just mean a "cyclic approach" like I do with my androgens and training for muscle growth - a sattelite cell differentiation phase followed by a proliferation phase... then loop.

Another thing that bothers me - not many studies on interaction with other noots (tnx for the one with Ani, by the way).

Anyway, back to work.

[xanadu]

Anything that encourages cell growth could encourage cancer.

[Paul Idol]

Xanadu-

Anything that encourages cell growth could encourage cancer.

That's technically true, but it doesn't seem that far removed in utility from saying that anything which encourages life could encourage cancer.

One of the key effects of aging is the dieoff of brain cells. Any retardation, let alone reversal, of aging, is going to have to involve boosting the rebuild rate of the brain.

-Paul

[xanadu]

"One of the key effects of aging is the dieoff of brain cells. Any retardation, let alone reversal, of aging, is going to have to involve boosting the rebuild rate of the brain"

I don't agree with that. I think reducing cell death is a much better avenue. Brain cells already divide and reproduce. If evidence is shown that encouraging cell proliferation leads to longer life or better brain health, then fine. However, that has not really been shown yet. It has been shown that increaced proliferation often accompanies cancer or preceeds it.

[Paul Idol]

Xanadu-

I don't agree with that. I think reducing cell death is a much better avenue. Brain cells already divide and reproduce. If evidence is shown that encouraging cell proliferation leads to longer life or better brain health, then fine. However, that has not really been shown yet. It has been shown that increaced proliferation often accompanies cancer or preceeds it.

I should've worded my post better. As time goes on, the rate at which new brain cells form and replace dying ones declines, leading to overall brain shrinkage. That's an important factor in aging.

I don't think it's likely to be a good idea to preserve existing brain cells at any cost, because the function of those cells is going to decline over time. Cells age too. So it's important to maintain the youthful replacement rate, though of course that will surely prove to be only one element among many of a successful anti-aging program.

-Paul

[xanadu]

But do the new cells have the memories and connections of the old cells? I'd rather keep the old cells healthy. I do see your point about replacing those that die. Perhaps a two pronged approach is best?

[Paul Idol]

Xanadu-

But do the new cells have the memories and connections of the old cells?

I have no idea. Since it turns out that a healthy brain actually does grow new neurons and regenerate itself over time, contrary to the earlier standard belief, I'd expect there's a mechanism to preserve existing memories and connections, but that's just a guess.

I'd rather keep the old cells healthy. I do see your point about replacing those that die. Perhaps a two pronged approach is best?

Well, obviously we should nourish and protect our brains to the very best of our ability, but there's got to be a point past which keeping decrepit cells around becomes counterproductive, so definitely, maintaining a healthy level of neurogenesis has to be part of our strategy.

-Paul

[xanadu]

Here is something you said that I should have jumped on

"I don't think it's likely to be a good idea to preserve existing brain cells at any cost, because the function of those cells is going to decline over time. Cells age too."

The "new" cells created by division are just as old as the cells they came from. The aging comes from decline in the dna, not in how long it was since division. In fact, there is some evidence that mitosis itself contributes to dna decline by the occasional error in transcription as well as shortening of telomeres. No amount of neurogenesis is going to stop aging. Cell health is where it's at. At the same time, I'm not knocking the creation of new brain cells. It would seem to be a good thing to do but it could never take the place of maintaining the cells you've got.

[Paul Idol]

Xanadu-

I think there's a pretty clear difference between a freshly-differentiated stem cell and an old, broken-down and worn cell, but it is true that we're not exactly overburdened with data on brain aging and neurogenesis.

-Paul

[xanadu]

Paul

Our true age is determined by our dna. It has been postulated that each cell in the human body has a limited number of divisions it can make. You can call a cell "fresh" but it's as old as the rest of your body. Forcing brain cells to divide causes them to use up some of their life potential. Have neurons been formed from human stem cells yet? Seems like I read about mouse experiments where they did put cells into the mouse brain and they began to function. That isn't what happens in neurogenesis that you were talking about. You have brought in a whole different subject. We can talk about stem cell therapy if you like but most of it will be guesswork.

[Paul Idol]

Xanadu-

I don't have the link handy (I'll try to dig it up if I have time) but I recently read something to the effect that at least some neurogenesis that naturally occurs in adulthood is due to fresh stem cell differentiation. That's what I was referring to, not possible future stem cell therapies.

-Paul

[mitkat]

Okay so, lithium...just curious now. I don't really know anything about it aside from I thought it was mainly a fairly serious anti-depressant, and involved in some kind of mania-control. So if one wanted to get their hands on some (after much research, and definately a very low dose), would "increasing grey matter" be a reasonable thing to tell you doctor? My doctor is not very progressive, and would probably not approve of this idea.

[xanadu]

I wonder if stem cells can get past the bbb? If so, then perhaps they could be injected and end up where needed? It's a fascinating possibility. What I would like to see for the future would be having your own dna code archived. As you aged, you would simply make up the proper cells which would go through your body comparing the dna you have to a template they carry and correct any errors. This goes on now, from what I understand, by bodies that are inside the cell. Someone correct my errors because I don't recall what it was I read about that. When dna gets damaged, certain repair cells or organs inside the cells repair the damaged dna but sometimes they make a mistake which causes that section of dna not to work properly. That adds to or is a cause of aging.

[Paul Idol]

Xanadu-

One additional point: I agree that we wouldn't want more cell division and formation than necessary because there's no point in prematurely accumulating wear and tear, but I think it's probably instructive to look at bone for some parallels. In order to maintain healthy bone strength and density, we need our systems to strike an appropriate balance between osteoclasts and osteoblasts, between bone resorption and bone growth — and not surprisingly, that balance is greatly influenced by nutrition. Fosamax is an osteoporosis therapy that increases bone density by inhibiting osteoclast activity, i.e. bone resorption, but over time it actually increases bone brittleness, because bone requires constant action by both osteoclasts and osteoblasts (not to mention osteocytes, but they're pretty much outside the purview of the analogy) to maintain optimum health and strength. One reason for this is that by eroding bone, osteoclasts actually release growth factors which signal osteoblasts to mature! So Fosamax increases bone density at the expense of bone strength because in addition to directly inhibiting resorption, it indirectly prevents osteoblasts from doing the job of renewing the protein matrix which is what prevents bone from being fragile and easily shattered like chalk.

As Price's work demonstrates abundantly clearly, diets which provide nutrients in sufficient abundance and proper balance prevent the development of osteoporosis. There's nothing necessary or inevitable about the condition. Since he also didn't observe anything like the sort of age-related mental decline we're accustomed to nowadays in his healthy natives, I think it's a reasonable and pretty well-supported conjecture that much of the decline we see is actually due to malnutrition, and that a truly well-nourished brain will at the very least decline much more slowly, perhaps keeping existing cells longer and almost certainly generating new ones more readily to balance the natural death of cells over time.

To get back to the original subject of this thread, lithium as a trace element (rather than in the monster doses typically found in studies and used to treat bipolar disorder and other mental problems) seems to have a number of useful effects, and since our soils and our food supply are grossly depleted of nutrients, it seems only reasonable to supplement with small amounts of lithium in an attempt to restore a more useful and healthy balance of renewal and decay.

A Howenstine article provides the following list of effects. It's difficult to find research on low doses, let alone on low doses of orotate, but it seems like a solid rundown.

• Lithium enhances DNA replication which is the first step to formation of new cells.


• The damaging effects of excitotoxins. (monosodium glutamate (MSG), aspartame (Nutrasweet) etc. can be blocked by lithium.[2]
  
  2 Nanaka S., Chronic lithium treatment robustly protects neurones in the central nervous system against neuro excitotoxicity by inhibiting N-methyl-D-aspartate receptor-mediated calcium influx. Proceedings of the National Academy of Sciences of U.S.A. 1998; 95: 2,642-2,647


• Animal research shows that lithium can decrease the areas of cell death after induced strokes by 56 %.


• Lithium protects rat brain cells from the. increased levels of brain cell death caused by anti-convulsant drugs (Dilantin phenytoin , Tegretol, carbamazepine etc.)


• Lithium may protect against adverse effects from mood altering drugs, alcohol, tobacco, caffeine, 'uppers"and "downers", and marihuana all of which cause brain damage with long term use.


• Abnormally functioning signaling pathways may become repaired by lithium.


• The aluminum felt to be a possible cause of Alzheimer's Disease (AD). is chelated[3] by lithium so it can be more easily removed from the body.
  
  3 Radesater A., et al, Inhibition of GSK 3 beta by lithium attenuates tau phosphoralation and degeneration. Society for Neuroscience Abstracts 2001: 1, 437

Perhaps my bone analogy is a stretch, but I think most systems in the body work in the same general way.

-Paul

[xanadu]

Paul, I think your bone analogy is a huge stretch and does not compare at all. I think you started to realise that already. Bone is basicly a mineral, the living cells are the osteoblasts and osteoclasts. We are comparing apples and potatoes here.

The info you showed on lithium sounds very good if true and if there are no accompanying bad side effects which is usually the case. Do you have links to case studies? I see several of what I believe to be mistakes in the statements presented. Recent research has indicated that aluminum may not be a cause of alzheimers at all. Marijuana has not been shown to cause long term brain damage, another myth. Why would we want to enhance dna replication? Is there some problem with it not replicating fast enough? Makes no sense.

If lithium really does have positive effects and no negative ones or if it can be clearly shown that the effects are overall positive, then yes it should be a part of our diet. I for one am very hesitant to jump on the latest bandwagon. I'll wait until there is more research on the subject though it does sound interesting.

[opales]

Our true age is determined by our dna. It has been postulated that each cell in the human body has a limited number of divisions it can make. You can call a cell "fresh" but it's as old as the rest of your body. Forcing brain cells to divide causes them to use up some of their life potential. Have neurons been formed from human stem cells yet? Seems like I read about mouse experiments where they did put cells into the mouse brain and they began to function. That isn't what happens in neurogenesis that you were talking about. You have brought in a whole different subject. We can talk about stem cell therapy if you like but most of it will be guesswork.

neuronal cells post-mitotic ie. they do not (usually) divide. that is one of the reasons why they are so vulnerable, as for example they do not benefit from the dilution of lysosomal accumulation of crap upon cell division (+positive things related to cell apoptosis). on the other hand I don't think we need be worrying about n-dna mutation accumulation as these cells do not divide (but I am not sure, brains do get cancer) and in any case, telomere shortening has not been shown to affect human aging (but it is not ruled out either) as other things probably get us first.

neuronal cells can start cell division but they die as a result.

here is an interesting piece on this.
http://www.hon.ch/News/HSN/530419.html

neurogenesis is not caused by (neuronal) cell division but as Paul pointed out by stem cells differentiation. in simple form stem cells+presense of proper neuronal growth factors=new neurons.

[Paul Idol]

Xanadu-

Paul, I think your bone analogy is a huge stretch and does not compare at all. I think you started to realise that already. Bone is basicly a mineral, the living cells are the osteoblasts and osteoclasts. We are comparing apples and potatoes here.

I'm afraid that's just your ignorance of bone at work. Bone is anything but "basically a mineral". It's a very complex living system. If it were just minerals, it would be like chalk, and we'd suffer multiple fractures with every step.

-Paul

[DukeNukem]

Just to back up Paul, here... bone is a complex living structure, constantly breaking down and renewing itself. For example, the body uses bone as storage for calcium to buffer acidity, which is ongoing, and needs replenishing. Every time you drink coffee or a soda, you're literally forcing bone loss, and you'll need additional calcium consumption to restore it. As Coke's slogan once said, "Enjoy!"

[xanadu]

Paul, you used bone as an analogy to butress your argument that cell division is needed. It's a horrible analogy and does not fit at all. I never said bone wasn't alive, I said it was a mineral with the living parts being the osteoclasts and osteoblasts. Yes, there is a marrow too. The part that provides strength is the mineral part.

opales, it has been shown that neurons do divide. Doctors used to think they never did but that was found to be false. Telomeres shorten each time a cell divides. When they are gone then some of the dna is clipped off when a cell divides. We don't know that telomere shortening is the cause of aging but it may be one cause. There is a lot we don't know yet.

How do stem cells get into the brain to differentiate if that's what they do? Isn't that just a theory?

[opales]

opales, it has been shown that neurons do divide. Doctors used to think they never did but that was found to be false. Telomeres shorten each time a cell divides. When they are gone then some of the dna is clipped off when a cell divides. We don't know that telomere shortening is the cause of aging but it may be one cause. There is a lot we don't know yet.

check for example:
http://www.learner.o...o/neuro_11.html

Rediscovering biology - online textbook

Unit 10: Neurobiology
Neuronal Stem Cells

What neuronal processes have led to the changes in the hippocampi of London taxi drivers? Perhaps this is achieved by neurons migrating from one region to the posterior hippocampus? Another intriguing possibility is that the changes are the result of new neurons going to the region.

New neurons? Don't we have our complete store of neurons by early childhood? That previous dominant paradigm had been found incorrect. In the past two decades, researchers have shown that neurons are continually produced in a variety of animals, including humans. It isn't that neurons divide. They don't. Instead, the brain maintains a reservoir of stem cells that are capable of generating new neurons (neurogenesis). One area of the brain where stem cells have been found is the hippocampus.

And, as I said, when neurons start dividing (eg. Alzheimer's), they die.

Do not know why you (and many others) insist on the telomeres. There are many things that HAVE BEEN shown to contribute to human aging, so we should prioritize them over some theoretical threat. For example, cell division dilutes all kinds of crap in the cell, and that crap has been shown to be harmful, while telomere shortening has not. Telomere shortening is the last thing we need to worry with post-mitotic cells. And are you aware that cancer is characterized by telomeres that do not appreciably shorten, causing the cells to be able to divide indefinately?

There seems to be something intuitively appealing about telomeres (clock of aging), but I repeat, there is no evidence of telomere shortening contributing to human aging (although it is possible).

Edited by opales, 10 February 2006 - 01:21 PM.