Vitamin B6 (pyridoxine, pyridoxal, pyridoxamine, and their phosphate derivatives) is the water-soluble vitamin that is the essential cofactor for the synthesis of the three primary neurotransmitters in the brain — serotonin (from tryptophan), dopamine (from tyrosine), and GABA (from glutamate). The three enzymes that catalyse these neurotransmitter synthesis reactions — the tryptophan decarboxylase (which synthesises serotonin from tryptophan), the aromatic L-amino acid decarboxylase (which synthesises dopamine from L-DOPA), and the glutamate decarboxylase (which synthesises GABA from glutamate) — all require pyridoxal phosphate (PLP, the active coenzyme form of vitamin B6) as a cofactor. Without adequate vitamin B6 and PLP, the synthesis of these neurotransmitters is impaired, the neurotransmitter levels in the brain fall, and the neurological and psychiatric symptoms of the vitamin B6 deficiency develop — including the depression, the anxiety, the insomnia, the cognitive impairment, and in severe cases, the seizures and the epilepsy. This vitamin B6-dependent vulnerability of the neurotransmitter synthesis is one of the most important and least appreciated aspects of the B6 nutrition, and it explains why the B6 deficiency produces a similar psychiatric phenotype to the depression and the anxiety disorders.
PLP and the Tryptophan Decarboxylase Reaction
The tryptophan decarboxylase (also called the aromatic L-amino acid decarboxylase, AADC) is the enzyme that synthesises serotonin from the essential amino acid tryptophan. It requires PLP as a cofactor, and without adequate vitamin B6 and PLP, the conversion of tryptophan to serotonin is impaired, the serotonin levels in the brain fall, and the mood regulation, the sleep regulation, and the appetite regulation are all compromised. The serotonin deficiency is one of the primary mechanisms of the depression, of the anxiety, and of the sleep disorders that are associated with the vitamin B6 deficiency. The connection between the B6 and the serotonin synthesis is one of the most important mechanisms in nutritional psychiatry — it explains why the B6 supplementation has been shown to improve the mood and to reduce the symptoms of the depression in people with the B6 deficiency, and why the B6 is included in many mood support formulations.
The clinical importance of vitamin B6 for the serotonin synthesis is underscored by the observation that the B6 deficiency is associated with an increased risk of the depression and of the anxiety disorders, and that the B6 supplementation improves the mood and reduces the symptoms of the depression in people with the B6 deficiency. A study in 150 older adults found that the B6 supplementation at 20mg daily (as pyridoxine) significantly improved the mood scores (as measured by the Geriatric Depression Scale) and reduced the anxiety scores (as measured by the Generalized Anxiety Disorder Scale) compared to placebo — with the greatest benefits seen in the participants who had the lowest baseline B6 status. These findings are consistent with the hypothesis that the B6 deficiency is a modifiable risk factor for the depression and the anxiety in older adults.
PLP and the GABA Synthesis
The glutamate decarboxylase (GAD) is the enzyme that synthesises GABA from the excitatory neurotransmitter glutamate, and it requires PLP as a cofactor. GABA is the primary inhibitory neurotransmitter in the brain — it reduces the neuronal excitability and prevents the hyperexcitability that is the basis of the seizures and of the epilepsy. When B6 is deficient and PLP is not available, the GAD activity falls, the GABA synthesis is impaired, the GABA levels in the brain fall, and the neuronal excitability increases — producing the hyperexcitability, the seizures, and the epilepsy that are the most dramatic manifestations of the B6 deficiency. The B6-dependent epilepsy is one of the most important clinical presentations of the B6 deficiency — it is particularly common in infants (who have a high B6 requirement for the brain development) and in people who are taking medications that interfere with the B6 metabolism (including the oral contraceptives, the anticonvulsants, and the anti-tuberculosis drugs).
Practical Application
For general B6 supplementation, the evidence-based approach is to supplement with 10-50mg of pyridoxal-5-phosphate (P5P, the active coenzyme form of B6) daily, rather than with pyridoxine (the most common supplemental form, which must be converted to P5P in the liver before it can be used as a cofactor). P5P is preferred for people with the MTHFR C677T polymorphism (who may have impaired conversion of pyridoxine to P5P), for people with liver disease (who may have impaired conversion of pyridoxine to P5P), and for people who are taking medications that interfere with B6 metabolism. The RDA of B6 is 1.3-1.7mg daily for adults, but the therapeutic doses for the mood support and for the neurological protection are much higher (10-50mg daily). For comprehensive neurotransmitter and mood support, B6 pairs well with the tryptophan (which is the amino acid precursor of serotonin and which is converted to serotonin by the B6-dependent tryptophan decarboxylase), with the tyrosine (which is the amino acid precursor of dopamine and which is converted to dopamine by the B6-dependent aromatic L-amino acid decarboxylase), with the magnesium (which is a cofactor for many of the enzymes of the neurotransmitter synthesis and of the neurotransmitter release), and with the folate (which is required for the methylation cycle and for the synthesis of the monoamine neurotransmitters).
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