Plausible Lithium-B12 connection or AI garbage?

[Algo]

Here’s the final result of pushing gpt-4 into finding a connection between lithium supplementation and b12 uptake by the cell:

The downstream effects of glycogen synthase kinase-3β (GSK-3β) inhibition by lithium are multifaceted, given that GSK-3β is involved in a myriad of cellular processes. Let’s delve into the potential effects and how they could be linked, even indirectly, to vitamin B12 metabolism:

1. Wnt/β-catenin Signaling: One of the most studied pathways involving GSK-3β is the Wnt signaling pathway. In the absence of Wnt signaling, GSK-3β phosphorylates β-catenin, targeting it for degradation. When GSK-3β is inhibited by lithium, β-catenin accumulates in the cytoplasm and translocates to the nucleus, where it regulates gene expression. The alteration in gene expression can affect various cellular processes, including proliferation, differentiation, and survival. An indirect effect on cellular metabolism and nutrient uptake, including B12, could potentially stem from these alterations.
2. Neuroinflammation and Neuroprotection: Lithium's inhibition of GSK-3β has been shown to reduce neuroinflammation and promote neuroprotection. This can alter the microenvironment of the neuron, which may influence the expression or activity of transporters and receptors on the cell membrane, potentially affecting vitamin B12 uptake.
3. Circadian Rhythm Regulation: GSK-3β is implicated in the regulation of circadian rhythms. Lithium, as a GSK-3β inhibitor, can shift these rhythms. Circadian disruptions have been linked to alterations in metabolic processes. It’s conceivable that disruptions in the circadian rhythm might affect the cellular machinery responsible for B12 metabolism, either directly or through broader metabolic shifts.
4. mTOR Signaling: GSK-3β has interactions with the mTOR pathway, a central regulator of cell growth, proliferation, and metabolic status. Changes in mTOR signaling can have broad implications for cellular metabolism, including amino acid handling, lipid synthesis, and mitochondrial function. Given that vitamin B12 is crucial for certain metabolic processes, notably the methionine synthesis pathway, there's a potential for interaction here.
5. Transcription Factor Activity: GSK-3β influences the activity of various transcription factors, including CREB, NF-κB, and others. The alteration in the activity of these transcription factors can lead to changes in the expression of numerous genes, potentially impacting vitamin B12 transporters, receptors, or enzymes involved in B12 metabolism.
6. Mitochondrial Function: Lithium's effect on GSK-3β has implications for mitochondrial function and dynamics, given that GSK-3β is involved in mitochondrial permeability transition. As vitamin B12 is involved in the mitochondrial process of energy production (via its role in the conversion of methylmalonyl-CoA to succinyl-CoA), changes in mitochondrial dynamics could indirectly influence B12 utilization.

Linking the inhibition of GSK-3β directly to changes in B12 uptake or metabolism requires a comprehensive understanding of these downstream effects and how they interplay with cellular B12 handling. Given the broad roles of GSK-3β, it's plausible that multiple pathways could be at play, leading to a cumulative effect on B12 dynamics in the cell.

When asked about alternative mechanisms by which lithium could exert its influence:

Lithium's pharmacological effects on the brain and other tissues are multifaceted. While the inhibition of GSK-3β is one of the most well-studied actions, there are other mechanisms through which lithium might indirectly influence vitamin B12 uptake or metabolism:

1. **Impact on Inositol Monophosphatase (IMPase)**: Lithium inhibits inositol monophosphatase, leading to a depletion of inositol, an important secondary messenger in cells. Alterations in inositol levels can impact various cellular processes, including signal transduction pathways that might be involved in nutrient uptake or metabolism.

2. **Neurotransmitter Release**: Lithium can affect the release and reuptake of various neurotransmitters, including serotonin, norepinephrine, and dopamine. Changes in neurotransmitter levels and dynamics can alter neuronal activity and potentially influence cellular metabolism and nutrient uptake mechanisms.

3. **NMDA Receptor Modulation**: Lithium modulates the activity of NMDA receptors, which are crucial for synaptic plasticity and neuronal communication. These receptors play a role in calcium influx into the neuron, and calcium is a secondary messenger in numerous cellular processes. It's conceivable that changes in calcium signaling could indirectly influence vitamin B12 dynamics within the cell.

4. **Brain-Derived Neurotrophic Factor (BDNF) Production**: Lithium has been shown to increase the production of BDNF, a growth factor that plays a crucial role in neuronal survival, growth, and differentiation. BDNF also affects synaptic plasticity and neurotransmission. Changes in BDNF levels can have broad impacts on neuronal health and function, potentially affecting the neuron's metabolic state and how it handles nutrients like vitamin B12.

5. **Cellular Autophagy**: Lithium can induce autophagy, a cellular process where cells degrade and recycle their own components. Enhanced autophagy can lead to the turnover of cellular components, including membrane transporters and receptors. If there are transporters or receptors crucial for vitamin B12 uptake, their turnover rate could influence how cells take up B12.

It's essential to keep in mind that while each of these mechanisms has the potential to influence vitamin B12 uptake or metabolism indirectly, establishing a direct link requires focused research. Investigating each mechanism in the context of vitamin B12 dynamics would provide a clearer understanding of any potential interaction.

Not evaluated for hallucinations, take everything with a grain of salt. But, any plausible mechanism of action here?

 

[Wishful]

The body consists of a vast array of interconnected systems, very many of which are still undiscovered. Theorizing why one factor, such as lithium, might have an effect, is probably futile. If the factor gives a certain response to one individual, it would be hard to determine precisely why it works that way, and even with a plausible theory for one mechanism, it could be working via some undiscovered mechanism.

For the things that worked well for me, I just appreciate that they did work.

 

[Algo]

The reason I peaked lithium is due to Amy Yasko saying that it is a necessary factor, but i can’t find any research supporting it

 

[datadragon]

Lithium enhances the transport of Vitamin B12 and folate into brain cells. transcobalamins I and III, which constituted a significant portion of vitamin B 12 binding protein in human serum, were largely products of granulocytes. Vitamin B 12 binding capacity proved to be elevated in patients receiving lithium therapy, supporting the concept that lithium in fact did enlarge the granulocyte pool and therefore must in some direct or indirect way stimulate granulopoiesis. https://link.springer.com/chapter/10.1007/978-1-4757-0259-0_3

To be fair GPT-4 apparently doesnt have access to all the web and says GPT-4 generally lacks knowledge of events that have occurred after the vast majority of its data cuts off (September 2021), and does not learn from its experience. It seems to do well based on posts in sifting through existing data to find answers well which will help a lot with general answers.

@Algo

 

[Algo]

Thanks for chiming in with that great piece of information. Unfortunately the link is behind a paywal. Do you know if it mentions specific dosage?

 

[datadragon]

Thanks for chiming in with that great piece of information. Unfortunately the link is behind a paywal. Do you know if it mentions specific dosage?

I didnt research any further. However, according to other medical sources such as here: https://ods.od.nih.gov/factsheets/Vitaminb12-HealthProfessional/ , levels of serum methylmalonic acid (MMA), a vitamin B12-associated metabolite, are the most sensitive markers of vitamin B12 status which I've mentioned elsewhere in more detail, and an MMA level greater than 0.271 micromol/L suggests vitamin B12 deficiency. Another marker is total plasma homocysteine levels, which rise quickly as vitamin B12 status declines; a serum homocysteine level higher than 15 micromol/L, for example, suggests vitamin B12 deficiency. However, this indicator has poor specificity because it is influenced by other factors, such as low folate levels and, especially, by declines in kidney function. Experts suggest that if a patient’s serum vitamin B12 level is less than 150 pg/ml (111 pmol/L), the patient’s serum MMA levels should be checked to confirm a diagnosis of vitamin B12 deficiency. And if so perhaps a small dose of lithium orotate which I see is available as low as 2.5mg, 5mg and up so you can start very low since it has numerous other effects so caution is warranted in its use, and retest to see if it helps as you consult with your medical provider(s). Overall you could also test high sensitivity c-reactive protein (although homocysteine increases inflammation but is not the only thing that does) to help gauge if it may even be something to consider.

 

[L'engle]

Be careful with lithium. It does improve b12 transport but it can have other unpredictable effects. Most people seem to do OK with it but a few people have had major problems.