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THE POOR METHYLATOR’S PARADOX
The person interested in optimizing liver, cardiovascular, and mental health is faced with a difficult proposition. If they reduce dietary choline consumption, their cardiovascular, liver, and mental health may suffer, but if they increase their choline intake, they may predispose themselves to developing cardiovascular disease and cancer. In a striking example of the complexity of human biology, dietary consumption of choline is correlated to atherosclerotic plaque development, while hyperhomocystenemia, which can result consequence to choline deficiency, is also correlated to atherosclerotic plaque development. This problem is particularly grave for people that have genetic impairments in their ability to methylate.
While bacterial synthesis of TMAO can be reduced with supplementation of resveratrol, 3,3-dimethyl-1-butanol (DMB)[1], and meldonium (in the case of L-carnitine only)[2], a cleaner option exists in bypassing the gut entirely.
THE NEED FOR INJECTABLE CHOLINE
Because of its use by weight loss enthusiasts, sterile injectable L-carnitine is readily available for purchase online. While injectable choline chloride is available to hospitals for parenteral nutrition, it is not commonly available to the public. This is unfortunate, as choline is vastly more valuable than L-carnitine, nutritionally, though they both undergo metabolism into TMAO.
DOSING OF CHOLINE CHLORIDE
The recommended dietary intake of choline is 550 mg/day for men and 425 mg/day for women, with an established upper limit of 3g/day[3]. Normal plasma free choline concentration is 10-15 nmol/mL[4][5] with toxicity observed at concentrations north of 200 nmol/mL[6].
Research shows that while phosphatidylcholine in lipid emulsions is not utilizable with intravascular (IV) delivery, choline chloride in a 3:1 solution remains stable for 5 years, and the choline is almost fully recoverable from the choline chloride solutions. Buchman, the original discoverer of the vitality of choline as a nutrient, speculated that since the recommended dietary intake is for choline and not choline chloride, choline requirements must be converted such that 2g of choline chloride is equivalent to 1.1g of choline. In treatment of deficient patients, Buchman provides an intravenous delivery of 2g of choline chloride daily for a 2-4 week period before reducing the amount to 1g for routine daily intake[7].
Clearly, it is impractical for even the most avid biohacker to take IV injections daily. Nonetheless, it is tempting to speculate that taking a single 2-4g dose of choline chloride weekly while minimizing dietary choline intake, would be a satisfactory plan to reduce TMAO while deriving the plentiful nutritional benefits from choline.
IV & IM INJECTIONS TO OPTIMIZE CHOLINE
In animal models, intravenous administration of choline rapidly increases acetylcholine in the brain[8]. Nonetheless, with reduced dietary consumption of choline for the remaining 6 days of the week, it is essential to increase acetylcholine function through alternate means.
A variety of choline, L-alpha-glycerophosphocholine (alpha-GPC), increases brain acetylcholine synthesis more readily than phosphatidylcholine[9]. It is thought to do this by freeing reserve choline in the body, thus allowing it to cross the blood-brain barrier[10]. (Interestingly, alpha-GPC also increases growth hormone secretion[11]). Because it is more effective than phosphatidylcholine in raising neurotransmitter levels, less of it (100-300mg) can be consumed for cognitive purposes. Nonetheless, even that 100-300mg will add to the synthesis of TMAO produced in the gut.
Instead of eating alpha-GPC, the astute biohacker with methylation impairments may prefer to take an intramuscular (IM) injection of it 3-4 days a week. IM injections with an insulin syringe are both less painful and less damaging to the body than IV injections, and IM injections of alpha-GPC at up to 1g have already been shown to be effective[12]. The alpha-GPC dose can be reduced if acetylcholinesterase inhibitors are used in combination. To learn more about pharmaceutical inhibitors, click here. To learn more about herbal options, click here.
AFTERWARD
To the author’s knowledge, the above article presents the first discussion of the combined use of injectable choline chloride and alpha-GPC for the optimization of health and performance in otherwise healthy individuals. If you enjoyed the article, please share it with others, so that the biohacking community may develop demand for sterile solutions of choline chloride and alpha-GPC. Unfortunately, companies like Titan Medical Center sell L-carnitine and the oncogenic (cancer-promoting) amino acid leucine[13][14] in sterile solutions, but do not offer choline options among their list of vitamins. But choline is a vitamin[15]. Consider writing to them if you would like a sterile choline solution. Maybe they will oblige us.
To return to the first article in this series, click here.
[1] Wang, Z., Roberts, A. B., Buffa, J. A., Levison, B. S., Zhu, W., Org, E., ... & DiDonato, A. J. (2015). Non-lethal inhibition of gut microbial trimethylamine production for the treatment of atherosclerosis. Cell, 163(7), 1585-1595. [2] Kuka, J., Liepinsh, E., Makrecka-Kuka, M., Liepins, J., Cirule, H., Gustina, D., ... & Dambrova, M. (2014). Suppression of intestinal microbiota-dependent production of pro-atherogenic trimethylamine N-oxide by shifting L-carnitine microbial degradation. Life sciences, 117(2), 84-92. [3] Food, I. O. M., & Board, N. (1998). Dietary Reference Intakes: Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline. Institute of Medicine. [4] Buchman, A. L., Dubin, M., Jenden, D., Moukarzel, A., Roch, M. H., Rice, K., ... & Eckhert, C. D. (1992). Lecithin increases plasma free choline and decreases hepatic steatosis in long-term total parenteral nutrition patients. Gastroenterology, 102(4), 1363-1370. [5] Sheard, N. F., Tayek, J. A., Bistrian, B. R., Blackburn, G. L., & Zeisel, S. H. (1986). Plasma choline concentration in humans fed parenterally. The American journal of clinical nutrition, 43(2), 219-224. [6] Buchman, A. L., Jenden, D. J., Moukarzel, A. A., Roch, M., Rice, K. M., Chang, A. S., & Ament, M. E. (1994). Choline pharmacokinetics during intermittent intravenous choline infusion in human subjects. Clinical Pharmacology & Therapeutics, 55(3), 277-283. [7] Buchman, A. L. (2009). The addition of choline to parenteral nutrition. Gastroenterology, 137(5), S119-S128. [8] Sparf, B. (1973). On the turnover of acetylcholine in the brain. An experimental study using intravenously injected radioactive choline. Acta physiologica Scandinavica. Supplementum, 397, 1. [9] Gatti, G., Barzaghi, N., Acuto, G., Abbiati, G., Fossati, T., & Perucca, E. (1992). A comparative study of free plasma choline levels following intramuscular administration of L-alpha-glycerylphosphorylcholine and citicoline in normal volunteers. International journal of clinical pharmacology, therapy, and toxicology, 30(9), 331-335. [10] Traini, E., Bramanti, V., & Amenta, F. (2013). Choline alphoscerate (alpha-glyceryl-phosphoryl-choline) an old choline-containing phospholipid with a still interesting profile as cognition enhancing agent. Current Alzheimer Research, 10(10), 1070-1079. [11] Kawamura, T., Okubo, T., Sato, K., Fujita, S., Goto, K., Hamaoka, T., & Iemitsu, M. (2012). Glycerophosphocholine enhances growth hormone secretion and fat oxidation in young adults. Nutrition, 28(11-12), 1122-1126. [12] Gatti, G., Barzaghi, N., Acuto, G., Abbiati, G., Fossati, T., & Perucca, E. (1992). A comparative study of free plasma choline levels following intramuscular administration of L-alpha-glycerylphosphorylcholine and citicoline in normal volunteers. International journal of clinical pharmacology, therapy, and toxicology, 30(9), 331-335. [13] Liu, K. A., Lashinger, L. M., Rasmussen, A. J., & Hursting, S. D. (2014). Leucine supplementation differentially enhances pancreatic cancer growth in lean and overweight mice. Cancer & metabolism, 2(1), 1-12. [14] Xie, X. L., Wei, M., Yunoki, T., Kakehashi, A., Yamano, S., Kato, M., & Wanibuchi, H. (2012). Long-term treatment with L-isoleucine or L-leucine in AIN-93G diet has promoting effects on rat bladder carcinogenesis. Food and chemical toxicology, 50(11), 3934-3940. [15] Wallace, T. C., Blusztajn, J. K., Caudill, M. A., Klatt, K. C., Natker, E., Zeisel, S. H., & Zelman, K. M. (2018). Choline: The underconsumed and underappreciated essential nutrient. Nutrition today, 53(6), 240.
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