The SAM Cycle and The Brain: Optimizing Mental Performance

S-Adenosyl methionine (SAM-e) is a versatile organic chemical that participates in a number of different reactions in the body involving methylation.

Some of the methylation reactions that SAM-e participates in include endogenous creatine production [1][2], choline metabolism [3], maintenance of cell membranes, and synthesis and inactivation of neurotransmitters such as noradrenaline, adrenaline, dopamine, serotonin and histamine [4].

It is produced from Methionine, which is an essential amino acid that is present in large quantities in eggs, meat, nuts and seeds [5].

SAM-e is also available as a nutritional supplement.

Given all the brain related functions of SAM-e, it would seem to be a good target for study with regards to its use in optimizing mental performance.

Specifically, finding ways to improve the production of endogenous SAM-e by optimizing the SAM cycle, and thus improving its availability for methylation reactions would likely be a productive avenue of exploration for improving brain health.

A number of research studies point in the direction of SAM-e supplementation being beneficial for brain health.

For example, research has shown that SAM-e may be beneficial in animal models of the neurodegenerative condition known as ALS [6]. There’s also a significant amount of literature showing SAM-e’s benefit in treating depression [7].

However, optimization of the SAM cycle may also have non-neurological health benefits because it can help reduce the impact of an overaccumulation of one of the participants in the SAM cycle: homocysteine.

Homocysteine is intermediate product in the SAM cycle. There has been a lot of research investigating how to lower homocysteine levels because research has linked high levels of it in the body to negative cardiovascular health effects [8]. It should be noted that some studies suggest that low vitamin B6, which is a co-factor in converting homocysteine to l-cysteine, is a risk factor for cardiovascular health and not high homocysteine levels themselves [9].

Thus, perhaps it’s the availability of cofactors that convert homocysteine to other metabolites, like SAM-e and L-cysteine, that are at the root of its observed negative cardiovascular health effects. It’s also notable that homocysteine has been linked to shortened telomeres in white blood cells [10]. These telomeres are caps on the ends of DNA that prevent DNA degradation. They have been linked to the aging process [11].

One interesting study about telomeres and white blood cells was done on the cells of a woman who lived to 115. Her white blood cells were analyzed after her death. The telomeres in her white blood cells were substantially worn down, much more so than in other tissues.

This lead the researchers to believe that the telomeres of stem cells that produce white blood cells, known as haematopoietic stem cells, are a limiting factor in longevity [12]. Thus, lowering homocysteine levels could theoretically provide longevity benefits as well.

Homocysteine is created after SAM-e has donated a methyl group in a methylation reaction and is converted to s-adenosyl-l-homocysteine which is then metabolized to adenosine and homocysteine.

Adenosine, incidentally, is what caffeine interferes with at the A2A receptor that leads to its wakefulness promoting properties [13]. Regardless, homocysteine gets converted back to methionine by vitamin B12 and a methyl donor.

The methyl donor can be methyl tetrahydrofolate converted from folate (vitamin b9). Folate originates from the diet or can be metabolized from supplemented folic acid [14]. The methyl donor can also be betaine which is endogenously derived from choline and may be supplemented in the form of trimethylglycine [15].

A lot of things can go wrong with the conversion of homocysteine to SAM-e. Disruption of the conversion of homocysteine back to SAMe is one of the primary means by which alcohol consumption causes liver disease [16] and cancer [17]. Exposure to environmental toxins such as the banned, but widely dispersed in the environment, pesticide DDT may impair folate levels, and thus possibly decrease the effectiveness of homocysteine to SAMe conversion [18].

Homocysteine is also converted to L-Cysteine via the activated form of Vitamin B6 known as pyroxidine-5-phosphate [19]. In a brain related side note, l-cysteine can improve neural stem cell propagation [20].

So what’s the practical upshot of all this? From looking at the research, my opinion is that finding ways to optimize the production of SAM-e and L-Cysteine from homocysteine would be beneficial.

Adding SAM-e directly would, in my opinion, be suboptimal as research shows it does not do anything to lower homocysteine levels [21]. Providing highly bioactive forms of b-vitamins involved in the conversion of homocysteine to SAM-e and L-Cysteine and adding betaine to help methylate homocysteine would seem to be the most optimal route to optimizing the SAM cycle and there is research to support this [22][23][24].

Additional posts by Abelard Lindsay (@ciltep):

• The Nootropic Why
• Acetyl-L-Carnitine Exploring Its Cognitive and LTP Related Effects
• Magnesium L-Threonate Can Improve Brain Function and LTP
• CILTEP and Racetams: Evidence for a theory of complementary mechanisms of action
• Some Health Benefits of Resveratrol Could Theoretically Apply to CILTEP
• Assembling the Acetylcholine Puzzle Part 1

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