Discussion

Given its dual role, betaine has always been considered an important nutrient for human physiology. But the evident growing literature highlights a possible third role: the positive effects of betaine in CNS disorders. The betaine in the liver and kidney has been well studied, reviewed, and understood. Despite the reported benefits of betaine supplementation in improving brain conditions, the mechanism of action yet is not clear.
In this review, we highlight the positive role and therapeutic potential of betaine in brain-associated diseases like AD, PD, dementia, Schizophrenia, depression, PTSD, epilepsy, and anhedonia reported in recent literature. Although BGT-1 can actively uptake betaine in the brain, the little expression and lack of understanding around its role in CNS raise questions over the mechanism behind accumulation and its impact on the brain. Kunisawa et al showed that the interaction of betaine with GABAergic pathway could not be limited to just BGT-1[23 ]. Their results indicate a possible betaine interaction with GABAA and GABAB receptors. The work from Ibi[57 ] et al supports this hypothesis by showing that the prevention of cognitive impairment by betaine is mediated by BGT-1, but not its antioxidant effects. Despite the lower and questionable expression of BGT-1 in the brain[19 ], the beneficial effects of betaine appear to be asserted via active transport by BGT-1. Although these effects are not solely driven by BGT-1 and involvement of some other mechanisms is highly possible.
Under hyperosmotic conditions, betaine can significantly influence the uptake of glycine and glutamine[7 ]. Since glycine is a precursor to GABA and glutamine to glutamate, a possible role for betaine in maintaining the balance between inhibitory and excitatory neurotransmission cannot be denied. Also, the effects of betaine against stress-induced diseases and memory loss indicate a connection with the GABAergic pathway in CNS.
Betaine certainly has neuroprotective properties that prevent the progression of neurodegenerative diseases like AD, PD, and dementia. Along with choline, folic acid, vitamin B6, and B12, betaine in the maternal diet is correlated with early neuronal development and attenuation of cognitive function at the later stage of life[58 ]. One way betaine helps is by reducing the Hcy levels in the neurons and promoting the expression of memory-related proteins[40 ,41 ]. Also, it can convert homocysteine to methionine and increase SAM, which protects the brain against a variety of toxic agents causing oxidative stress[59 ].
As a therapeutic, betaine is already in use as an FDA-approved drug to treat homocystinuria. The reported side effects (for 6-9g/day) are relatively mild such as gastrointestinal illness, mild body odour, increased urination, feeling dry mouth, preference for salty food etc[60 ]. The excess of betaine is also associated with cardiovascular disease and pulmonary hypertension[61 ,62 ]. While there are very few side effects recorded for betaine[63 ,64 ], there is still not enough information on the long-term effects of regular betaine supplementation.