I started on Lithium Orotate yesterday (120mg twice per day), and I can testify to the fact that there is a significant effect. But let me explain, as I need to add some context for you to fully understand my perspective:
I have a severe migraine/inflammatory disorder which mostly effects my prefrontal cortex, with symptoms that spread peripherally if the inflammation is allowed to persist either too long or too frequently. It starts from behind the eyes, but I can feel what seems to be a lesion between the eyes as the pain progresses - ever feel a recurring physical pain in your brain, like a sore spot? That's what I feel most days - also, I believe that I have had a mini stroke in the past from the condition, four years ago. I've had this condition daily for 11 years now, and so I know the causes, effects, and what relief and resistance to the effects feels like, intimately. I've had everything from breathing issues, to heart problems, to circulation issues over the years that directly resulted from periods periods of extended inflammation. Until I recently (in the past year) started to get serious about trying supplements, a specific method of calorie restriction is the only thing that would reset my system to almost normal when having a major health challenge.
Since I started experimenting with supplements, the only things that have worked to a significant degree are what seem to be whatever helps act as an NMDA/calcium antagonist. I suspect that there is also relief felt with serotonin/prolactin reduction, and dopamine enhancement. But I'm not sure.
The first supplement that I had success with was magnesium. There was significant relief at first, whcih then seemed to wane. Plus the gastrinestinal effects were significant, even at small doses of the best magnesium available. I then added zinc, which kicked up the effect. Then that waned. So I added P5P and B12. The effect of Zinc, Magnesium (I have to yet test either separately to make sure that its the combination that works) with P5P and B12 is very strong and synergistic, eliminating almost all inflammation over night. There is also a mild protective effect, seemingly mostly from the B12 (when tested separately), when taken during the day. (I also noticed a lasting, stronger neuroprotective effect he day following a day when I took this combination in the morning instead of at night. However, strangely, taking it in the morning in hopes of relieving a migraine led to one of the worst and most painful migraines that I've ever had - I felt like I had gone 6 rounds with Mike Tyson afterward. My usual remedies couldn't touch it. It was like the (assuming) B12 froze the migraine in place. I believe that the B12 has differing effects on the pineal, melatonin and serotonin depending on the time of day that it is taken, leading to differences in light sensitivity and possibly differences in an adaptive response by the body which would explain the difference in next day migraine resistance that I felt and the enhancement of the migraine in the morning.
Despite that hard experience, i am grateful to have something that I can take, other than Excedrin, which seems to help. Also, it seems to be reversing, to a small extend, some other peripheral trouble that i have bee dealing with. Excedrin doesn't touch that.
So, on to lithium orotate:
This seems to exert a steadier, longer lasting, and stronger neuroprotective effect than anything that I've tried thusfar. I don't know how to explain it other than I know what it feels like to be resistant to the condition that I have. Its not placebo. Also, waking up without lingering pain and inflammation fromt the day before is also an unmistakable occurrence. The lithium is doing its job, and I hope that it continues to do so.
In the next few days, i will slowly start adding B12, P5P, zinc, and Magnesium to see what the combined effects may be. Then I will change up the times of day when I take them and not any differences. If the effects of lithium don't wane, and I can count on it to not completely suppress dopamine (I have read a LOT of conflicting interpretations about the action of lithium - but the most credible says that lithium suppresses serotonin and enhances dopamine - which I view as healthy. Other sources say the opposite. I'm not sure that will be able to tell what it does in that respect, though. But for now, it seems to be offering significant neuroprotection: which is the point that I wanted to relate. I feel clearer all day, especially comparatively when subjected to my normal triggers. I hope that it continues to work as it currently does. Granted, its till very early in my experience.
Chronic lithium treatment robustly protects neurons in the central nervous system against excitotoxicity by inhibiting N-methyl-d-aspartate receptor-mediated calcium influx
Shigeyuki Nonaka,* Christopher J. Hough,† and De-Maw Chuang*‡
*Section on Molecular Neurobiology, Biological Psychiatry Branch, National Institute of Mental Health, National Institutes of Health, 10 Center Drive, MSC 1272, Bethesda, MD 20892-1272; and †Department of Psychiatry, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD 20814-4799
Abstract
Lithium is the most commonly used drug for the treatment of manic depressive illness. The precise mechanisms underlying its clinical efficacy remain unknown. We found that long-term exposure to lithium chloride dramatically protects cultured rat cerebellar, cerebral cortical, and hippocampal neurons against glutamate-induced excitotoxicity, which involves apoptosis mediated by N-methyl-d-aspartate (NMDA) receptors. This neuroprotection is long-lasting, occurs at therapeutically relevant concentrations of lithium with an EC50 of approximately 1.3 mM, and requires treatment for 6–7 days for complete protection to occur. In contrast, a 24-h treatment with lithium is ineffective. The protection in cerebellar neurons is specific for glutamate-induced excitotoxicity and can be attributed to inhibition of NMDA receptor-mediated calcium influx measured by 45Ca2+ uptake studies and fura-2 fluorescence microphotometry. The long-term effects of lithium are not caused by down-regulation of NMDA receptor subunit proteins and are unlikely related to its known ability to block inositol monophosphatase activity. Our results suggest that modulation of glutamate receptor hyperactivity represents at least part of the molecular mechanisms by which lithium alters brain function and exerts its clinical efficacy in the treatment for manic depressive illness. These actions of lithium also suggest that abnormality of glutamatergic neurotransmission as a pathogenic mechanism underlying bipolar illness warrants future investigation.
Neuroprotective actions of lithium.
Hashimoto R, Fujimaki K, Jeong MR, Senatorov VV, Christ L, Leeds P, Chuang DM, Takeda M.
Abstract
Lithium has long been one of the primary drugs used to treat bipolar mood disorder. However, neither the etiology of this disease nor the therapeutic mechanism(s) of this drug is well understood. Several lines of clinical evidence suggest that lithium has neurotrophic actions. For example chronic lithium treatment increases the volume of gray matter and the content of N-acetyl-aspartate, a cell survival marker, in bipolar mood disorder patients (Moore et al., 2000). Moreover, treatment with this mood-stabilizer suppresses the decrease in the volume of the subgenual pre-frontal cortex found in bipolar patients (Drevets, 2001). To elucidate molecular mechanisms underlying the neuroprotective and neurotrophic actions of lithium, we employed a preparation of cultured cortical neurons prepared form embryonic rats. We found that treatment with therapeutic doses (0.2-1.2 mM) of lithium robustly protects cortical neurons from multiple insults, notably glutamate-induced excitotoxicity. The neuroprotection against glutamate excitotoxicity is time-dependent, requiring treatment for 5-6 days for maximal effect, and is associated with a reduction in NMDA receptor-mediated Ca2+ influx. The latter is correlated with a decrease in Tyrosine 1472 phosphorylation levels in the NR2B subunit of NMDA receptors and a loss of Src kinase activity which is involved in NR2B tyrosine phosphorylation. Neither the activity of total tyrosine protein kinase nor that of tyrosine protein phosphatase is affected by this drug, indicating the selectivity of the modulation. Lithium neuroprotection against excitotoxicity is inhibited by a BDNF-neutralizing antibody and K252a, a Trk antagonist. Lithium treatment time-dependently increases the intracellular level of BDNF in cortical neurons and activates its receptor, TrkB. The neuroprotection can be completely blocked by either heterozygous or homozygous knockout of the BDNF gene. These results suggest a central role of BDNF and TrkB in mediating the neuroprotective effects of this mood-stabilizer. Finally, long-term lithium treatment of cortical neurons stimulates the proliferation of their progenitor cells detected by co-labeling with BrdU and nestin. Lithium pretreatment also blocks the decrease in progenitor proliferation induced by glutamate, glucocorticoids and haloperidol, suggesting a role in CNS neuroplasticity. We used animal models to investigate further therapeutic potentials for lithium. In the MCAO/reperfusion model of stroke, we found that post-insult treatment with lithium robustly reduced infarct volume and neurological deficits. These beneficial effects were evident when therapeutic concentrations of lithium were injected at least up to 3 h after ischemic onset. The neuroprotection was associated with activation of heat-shock factor-1 and induction of heat-shock protein-70, a cytoprotective protein. In a rat excitotoxic model of Huntington's disease, the excitotoxin-induced loss of striatal medium-sized neurons was markedly reduced by lithium. This lithium protection was correlated with up-regulation of cytoprotective Bcl-2 and down-regulation of apoptotic proteins p53 and Bax, and neurons showing DNA damage and caspase-3 activation. Taken together, our results provide a new insight into the molecular mechanisms involved in lithium neuroprotection against glutamate excitotoxicity. Moreover, these novel molecular and cellular actions might contribute to the neurotrophic and neuroprotective actions of this mood-stabilizer in patients, and could be related to its clinical efficacy for treating mood disorder patients. Clearly, mood-stabilizers may have expanded use for treating excitotoxin-related neurodegenerative diseases.
Edited by golgi1, 18 March 2011 - 03:25 AM.