Vitamin B6 (monotherapy) may treat depression

haidut

The study below is a perfect follow-up to the study I just posted about. Namely, in the immediately preceding blog post I listed a study, which found that one of the most widely-prescribe “antidepressants” of the SSRI class actually worsens depression. Of course, like most pharma drugs, the SSRI class has a number of severe side effects including suicidal and homicidal ideations and attempt, dementia, heart valve disease, diabetes, neurological conditions, etc. In contrast, the B group of vitamins is virtually devoid of serious side effects, even in pharmacological doses, but so far have been lacking evidence of effectiveness for health conditions when used as a monotherapy (i.e. by itself, with no other active drug/substance administered). The study below changes that, and is the first double-blind, randomized, placebo-controlled trial with vitamin B6 and B12 as treatments for depression and anxiety. While both vitamins were found to be ineffective for anxiety, vitamin B6 at daily doses of 88mg-100mg for just a month, produced “large improvements” in depression symptoms. Based on other studies utilizing the same checklists for diagnosing and quantifying depression symptoms, it looks like vitamin B6 was more effective than many of the most widely-prescribe antidepressant drugs, while having no serious side effects. While ~100mg vitamin B6 daily is certainly high, multiple studies have demonstrated that taking the “active” form of B6 known as P5P achieve similar effects at doses 5-10 times lower than pyridoxine Hcl (the cheap and widely available B6 form the study used). In other words, 10mg-20mg P5P daily may be able to replicate the study findings while also further reducing the risk of side effects of high-dose B6 (e.g. neuropathy). As far as mechanism of action – I agree with all of the ones proposed by the study (GABA, dopamine, glutamate, etc), but I will also add to that list the virtually unknown role of B6 as the main endogenous non-steroidal antagonist to cortisol, with the latter being a known cause of depression.

https://onlinelibrary.wiley.com/doi/full/10.1155/da/8926512/

“….Given existing evidence that high-dose vitamin B6 influences neurotransmitter levels and that this has behavioural and psychological effects in animals and humans, we explored its effect on three common negative emotional states—depression, anxiety and stress, in an opportunity sample drawn from the general population. Compared to either placebo or high-dose vitamin B12 tablets, we found that vitamin B6 produced a large improvement in depression symptoms but had no significant effect on anxiety or stress. The largest improvement was evident in participants whose baseline depression scores were classified as indicating mild or more severe depression, but individuals whose baseline depression scores fell just below that cutoff also improved substantially. These effects were confirmed when we adjusted the analysis for baseline differences. This is the first randomised double-blind study to demonstrate the potential of vitamin B6 as a standalone or adjunctive treatment for depression; it builds on a large body of epidemiological evidence indicating a relationship between vitamin B6 status and depression risk, as well as the previous trials showing benefits of vitamin B6 for the mood/depression symptoms experienced in premenstrual syndrome, and the animal work revealing the potential antidepressant mechanism via increasing serotonin and GABA, and reducing glutamate, in the brain.”

https://www.technologynetworks.com/tn/news/could-vitamin-b6-reduce-symptoms-of-depression-415900

“…A daily high-dose Vitamin B6 supplement could significantly reduce symptoms of depression in people who already experience them, new research from the University of Reading has found. The double-blind randomised trial, published this month in the journal Depression and Anxiety, asked participants to take a 100mg Vitamin B6 tablet every day for a month. Those who reported mild or more severe depression at the start showed a reduction in symptoms compared to those given a placebo or Vitamin B12. The findings are the first from a randomised controlled trial to demonstrate the potential of Vitamin B6 as a treatment for depression, and build on a substantial body of epidemiological evidence linking Vitamin B6 status with depression risk.”

Via: https://haidut.me/?p=3131

JWayne

@haidut P5P at 20mg in the morning has me feeling like my body is producing its own alcohol. Must be the GABA synthesis.

LucH

@JWayne said:

P5P at 20mg in the morning has me feeling like my body is producing its own alcohol. Must be the GABA synthesis.

Some people have brain trouble when taking more than 20-25 B6 PLP form. Probably because there is a biochemical bottleneck with HD B6 PLP, Cysteine, and the B5/CoA*.

Here are some info from an article I wrote (not posted), trying to understand the connection Between HD niacinamide (B3) and B6 PLP.

The B6-Cysteine Connection (The Influx)
Vitamin B6 (as PLP, the active form) is the mandatory cofactor for the transsulfuration pathway—specifically for the enzymes cystathionine β-synthase (CBS) and cystathionine γ-lyase (CSE). This pathway converts homocysteine into cysteine. Homocysteine is useful when the level is low but, in excess, it’s the sign of a problem (low-grade inflammation). (1)
When a sensitive individual takes a high dose of PLP (even at 20–25 mg), it can rapidly accelerate this pathway. This causes a sudden surge or localized excess of intracellular cysteine.
NB: We aren’t taking PNP into account (toxic at HD level).
The Cysteine-CoA Bottleneck
While cysteine is a valuable amino acid, an unmanaged excess can cause cellular stress. To safely metabolize and utilize this excess cysteine, the cell attempts to drive it into the Coenzyme A (CoA) synthesis pathway (energy cycle for mitochondria).
The production of CoA requires three distinct building blocks:
 Pantothenic Acid (Vitamin B5)
 Cysteine
 Adenosine Triphosphate (ATP) (Cellular energy)
If there is a massive influx of cysteine but an ordinary or low supply of Vitamin B5, a severe kinetic bottleneck occurs. The rate-limiting enzyme Pantothenate Kinase (PANK) cannot efficiently process the sudden load, leaving excess cysteine stuck in limbo while simultaneously straining the cell's ATP reserves.
Why "Twice the Dose" of B5 is Required
To clear this bottleneck and protect the nerve cell, the system requires a disproportionately higher amount of B5 relative to B6. Providing twice the dose of B5 achieves two critical things:
 Mass Action Kinetic Driving Force: Flooding the cell with Calcium D-Pantothenate ensures that the PANK enzyme is fully saturated. This forces the excess, potentially toxic cysteine to bind quickly with pantothenate, converting it safely into 4'-phosphopantothenoylcysteine and eventually into active Coenzyme A, if at body request / needs.
 Preserving Nerve Cell Energy (ATP): Synthesizing CoA is an energy-intensive process. When the cell struggles against a nutrient bottleneck, it burns through ATP inefficiently, leading to localized energy failure in the nerve cell (which manifests as neurological tingling or coordination feedback loops). A sign you should take into account: Something isn't working the way it should. A high, stable supply of B5 optimizes the efficiency of the pathway, ensuring CoA is generated smoothly without exhausting the cell's energetic reserves.
Summary of the pathway
In short, B6 PLP acts as the accelerator pedal for creating cysteine. If you step on that pedal with 20–25 mg of PLP, you must dramatically increase the supply of Vitamin B5 (at a 2:1 ratio) to prevent the system from exhausting. The extra B5 safely captures the excess cysteine, escorts it into Coenzyme A production, and prevents the cellular energy depletion that triggers a neurological shutdown.
Why 500 mg TMG is Highly Useful in This Protocol
TMG: tri-methyl-glycine (often called “betaine” too).
I take TMG as a “traffic controller”.
In my protocol, I’m dealing with a heavy influx of B-vitamins (especially B6 PLP) that can drive homocysteine down the transsulfuration pathway into cysteine. TMG directly relieves this [homocysteine] pressure by providing an alternative pathway.
NB: High doses of vitamin B3 (including niacinamide and nicotinic acid) can raise homocysteine levels in the blood. When the body processes large amounts of B3 (mostly higher than 100 mg B3), it uses methyl groups via methylation pathways, which can increase homocysteine as a byproduct.
B6 is going to dampen this risk. Not only. TMG helps too ( Re-methylation process).
Remethylation (Upstream): Converting homocysteine back into methionine.
By introducing 500 mg of TMG, I activate the BHMT (Betaine-Homocysteine S-Methyltransferase) enzyme pathway. TMG donates a methyl group to pull homocysteine up and away from the B6-driven transsulfuration pathway.
Instead of all the homocysteine being forced down into cysteine (which creates the B5/CoA bottleneck I’m managing against, on the other side), TMG recycles a portion of it back into methionine. This naturally reduces the volume of sudden cysteine surges.
Preserving the Nerve Cell's Energy (ATP)
The primary concern with the B6/B5 balance is preventing nerve cell energy depletion.
 Remethylating homocysteine normally requires the folate/B12 cycle, which is heavily reliant on cellular energy metabolism and optimal genetics (MTHFR gene).
 The TMG (BHMT) pathway is an alternate, highly efficient shortcut to recycle homocysteine. It operates independently of folate and B12, requiring less energy overhead from the cell to keep homocysteine levels balanced.
Synergizing with the High-Dose B-Complex
I’m taking a HD 100 mg baseline of B1, B2, and B3 (Niacinamide), alongside Magnesium Bisglycinate.
 Niacinamide (B3) clearing: High doses of B3 consume methyl groups when the body processes and excretes excess nicotinamide (via methylation into N-methylnicotinamide). This can cause a "methyl drain."
 TMG to the rescue: 500 mg of TMG acts as a reliable methyl donor. It replenishes the methyl pool being used up by 100 mg of B3, ensuring my body's overall methylation capacity doesn't drop while I’m focusing on the B6/B5 balance.
Summary
The 500 mg of TMG is a very logical addition. It keeps homocysteine moving smoothly through an upstream recycling loop, reducing the sheer volume of cysteine that my high-dose B5 is going to clean up, while simultaneously protecting my methyl pool from the high-dose B3.

Thank you Sunsunsun, from bioenergetic forum, for pointing this caveat (B5/CoA), which I didn’t even suspect…