The final question is: since I was taking an overdose, how did I mess up? I thought I was making sure I got at least the right RDA of elemental magnesium by aiming for 800mg of elemental magnesium and carefully converting from raw powder weight. So I went back to the original references, and scrutinizing them closely, they really were talking about elemental magnesium and indicating I should be getting 400mg elemental a day, but I did notice something: I got the dose wrong for the Solgar pills, it wasn’t 800mg elemental, it was 800mg of citrate - I misread the label. So I went from taking ~130mg of elemental magnesium in the first period to ~800mg in the second; I don’t think it is an accident that the second period seems to have been much worse (between the plot and the time trend).
The soft gels are very small; one needs to be a bit careful - Vitamin D is fat-soluble and overdose starts in the range of 70,000 IU36, so it would take at least 14 pills, and it’s unclear where problems start with chronic use. Vitamin D, like many supplements, follows a U-shaped response curve (see also Melamed et al 2008 and Durup et al 2012) - too much can be quite as bad as too little. Too little, though, is likely very bad. The previously cited studies with high acute doses worked out to <1,000 IU a day, so they may reassure us about the risks of a large acute dose but not tell us much about smaller chronic doses; the mortality increases due to too-high blood levels begin at ~140nmol/l and reading anecdotes online suggest that 5k IU daily doses tend to put people well below that (around 70-100nmol/l). I probably should get a blood test to be sure, but I have something of a needle phobia.
I largely ignored this since the discussions were of sub-RDA doses, and my experience has usually been that RDAs are a poor benchmark and frequently far too low (consider the RDA for vitamin D). This time, I checked the actual RDA - and was immediately shocked and sure I was looking at a bad reference: there was no way the RDA for potassium was seriously 3700-4700mg or 4-5 grams daily, was there? Just as an American, that implied that I was getting less than half my RDA. (How would I get 4g of potassium in the first place? Eat a dozen bananas a day⸮) I am not a vegetarian, nor is my diet that fantastic: I figured I was getting some potassium from the ~2 fresh tomatoes I was eating daily, but otherwise my diet was not rich in potassium sources. I have no blood tests demonstrating deficiency, but given the figures, I cannot see how I could not be deficient.
Nootropics – sometimes called smart drugs – are compounds that enhance brain function. They’re becoming a popular way to give your mind an extra boost. According to one Telegraph report, up to 25% of students at leading UK universities have taken the prescription smart drug modafinil , and California tech startup employees are trying everything from Adderall to LSD to push their brains into a higher gear .
1. Stough, C., Lloyd, J., Clarke, J., Downey, L. A., Hutchison, C. W., Rodgers, T., & Nathan, P. J. (2001). The chronic effects of an extract of Bacopa monniera (Brahmi) on cognitive function in healthy human subjects. Psychopharmacology (Berl), 156(4), 481-484. 2. Ishaque, S., Shamseer, L., Bukutu, C., & Vohra, S. (2012). Rhodiola rosea for physical and mental fatigue: a systematic review. BMC Complementary and Alternative Medicine, 12(1), 70. doi:10.1186/1472-6882-12-703. Pase, M. P., Kean, J., Sarris, J., Neale, C., Scholey, A. B., & Stough, C. (2012). The cognitive-enhancing effects of Bacopa monnieri: a systematic review of randomized, controlled human clinical trials. J Altern Complement Med, 18(7), 647-652. doi:10.1089/acm.2011.03674. Raghav, S., Singh, H., Dalal, P. K., Srivastava, J. S., & Asthana, O. P. (2006). Randomized controlled trial of standardized Bacopa monniera extract in age-associated memory impairment. Indian J Psychiatry, 48(4), 238-242. doi:10.4103/0019-5545.315555. Neale, C., Camfield, D., Reay, J., Stough, C., & Scholey, A. (2013). Cognitive effects of two nutraceuticals Ginseng and Bacopa [...]: a review and comparison of effect sizes. British Journal of Clinical Pharmacology, 75(3), 728-737. doi:10.1111/bcp.120026. Prynne, C. J., Thane, C. W., Prentice, A., & Wadsworth, M. E. (2005). Intake and sources of phylloquinone (vitamin K(1)) in 4-year-old British children: comparison between 1950 and the 1990s. Public Health Nutr, 8(2), 171-180.7. Ferland, G. (2012). Vitamin K and the nervous system: an overview of its actions. Adv Nutr, 3(2), 204-212. doi:10.3945/an.111.0017848. Zeidan, Y. H., & Hannun, Y. A. (2007). Translational aspects of sphingolipid metabolism. Trends in molecular medicine, 13(8), 327-336.9. Beulens, J. W., Bots, M. L., Atsma, F., Bartelink, M. L., Prokop, M., Geleijnse, J. M., . . . van der Schouw, Y. T. (2009). High dietary menaquinone intake is associated with reduced coronary calcification. Atherosclerosis, 203(2), 489-493. doi:10.1016/j.atherosclerosis.2008.07.01010. Geleijnse, J. M., Vermeer, C., Grobbee, D. E., Schurgers, L. J., Knapen, M. H., van der Meer, I. M., . . . Witteman, J. C. (2004). Dietary intake of menaquinone is associated with a reduced risk of coronary heart disease: the Rotterdam Study. J Nutr, 134(11), 3100-3105.11. Theuwissen, E., Magdeleyns, E. J., Braam, L. A., Teunissen, K. J., Knapen, M. H., Binnekamp, I. A., . . . Vermeer, C. (2014). Vitamin K status in healthy volunteers. Food Funct, 5(2), 229-234. doi:10.1039/c3fo60464k12. Barros, M. P., Poppe, S. C., & Bondan, E. F. (2014). Neuroprotective properties of the marine carotenoid astaxanthin and omega-3 fatty acids, and perspectives for the natural combination of both in krill oil. Nutrients, 6(3), 1293-1317.13. Pashkow, F. J., Watumull, D. G., & Campbell, C. L. (2008). Astaxanthin: a novel potential treatment for oxidative stress and inflammation in cardiovascular disease. Am J Cardiol, 101(10a), 58d-68d. doi:10.1016/j.amjcard.2008.02.01014. Annweiler, C., Schott, A. M., Berrut, G., Chauvire, V., Le Gall, D., Inzitari, M., & Beauchet, O. (2010). Vitamin D and ageing: neurological issues. Neuropsychobiology, 62(3), 139-150. doi:10.1159/00031857015. Brown, J., Bianco, J. I., McGrath, J. J., & Eyles, D. W. (2003). 1,25-dihydroxyvitamin D3 induces nerve growth factor, promotes neurite outgrowth and inhibits mitosis in embryonic rat hippocampal neurons. Neurosci Lett, 343(2), 139-143.16. Naveilhan, P., Neveu, I., Wion, D., & Brachet, P. (1996). 1,25-Dihydroxyvitamin D3, an inducer of glial cell line-derived neurotrophic factor. Neuroreport, 7(13), 2171-2175.17. Tangpricha, V., Pearce, E. N., Chen, T. C., & Holick, M. F. (2002). Vitamin D insufficiency among free-living healthy young adults. Am J Med, 112(8), 659-662.18. Annweiler, C., Allali, G., Allain, P., Bridenbaugh, S., Schott, A. M., Kressig, R. W., & Beauchet, O. (2009). Vitamin D and cognitive performance in adults: a systematic review. European Journal of Neurology, 16(10), 1083-1089. doi:10.1111/j.1468-1331.2009.02755.x19. Annweiler, C., Montero-Odasso, M., Llewellyn, D. J., Richard-Devantoy, S., Duque, G., & Beauchet, O. (2013). Meta-analysis of memory and executive dysfunctions in relation to vitamin D. J Alzheimers Dis, 37(1), 147-171. doi:10.3233/jad-13045220. Balion, C., Griffith, L. E., Strifler, L., Henderson, M., Patterson, C., Heckman, G., . . . Raina, P. (2012). Vitamin D, cognition, and dementia A systematic review and meta-analysis. Neurology, 79(13), 1397-1405.21. Dean, A. J., Bellgrove, M. A., Hall, T., Phan, W. M. J., Eyles, D. W., Kvaskoff, D., & McGrath, J. J. (2011). Effects of Vitamin D Supplementation on Cognitive and Emotional Functioning in Young Adults – A Randomised Controlled Trial. PLoS One, 6(11), e25966. doi:10.1371/journal.pone.002596622. Etgen, T., Sander, D., Bickel, H., Sander, K., & Forstl, H. (2012). Vitamin D deficiency, cognitive impairment and dementia: a systematic review and meta-analysis. Dement Geriatr Cogn Disord, 33(5), 297-305. doi:10.1159/00033970223. Fontani, G., Corradeschi, F., Felici, A., Alfatti, F., Migliorini, S., & Lodi, L. (2005). Cognitive and physiological effects of Omega-3 polyunsaturated fatty acid supplementation in healthy subjects. Eur J Clin Invest, 35(11), 691-699. doi:10.1111/j.1365-2362.2005.01570.x24. Huhn, S., Masouleh, S. K., Stumvoll, M., Villringer, A., & Witte, A. V. (2015). Components of a Mediterranean diet and their impact on cognitive functions in aging. Frontiers in aging neuroscience, 7.25. Bradbury, J. (2011). Docosahexaenoic Acid (DHA): An Ancient Nutrient for the Modern Human Brain. Nutrients, 3(5), 529-554. doi:10.3390/nu305052926. Einother, S. J., & Giesbrecht, T. (2013). Caffeine as an attention enhancer: reviewing existing assumptions. Psychopharmacology (Berl), 225(2), 251-274. doi:10.1007/s00213-012-2917-427. Johnson, L. C., Spinweber, C. L., & Gomez, S. A. (1990). Benzodiazepines and caffeine: effect on daytime sleepiness, performance, and mood. Psychopharmacology (Berl), 101(2), 160-167. 28. Smith, A., Kendrick, A., Maben, A., & Salmon, J. (1994). Effects of breakfast and caffeine on cognitive performance, mood and cardiovascular functioning. Appetite, 22(1), 39-55. doi:10.1006/appe.1994.100429. Smith, A. P., Kendrick, A. M., & Maben, A. L. (1992). Effects of breakfast and caffeine on performance and mood in the late morning and after lunch. Neuropsychobiology, 26(4), 198-204. doi:11892030. Smith, B. D., Davidson, R. A., & Green, R. L. (1993). Effects of caffeine and gender on physiology and performance: further tests of a biobehavioral model. Physiol Behav, 54(3), 415-422. 31. Warburton, D. M. (1995). Effects of caffeine on cognition and mood without caffeine abstinence. Psychopharmacology (Berl), 119(1), 66-70. 32. Wilhelmus, M. M., Hay, J. L., Zuiker, R. G., Okkerse, P., Perdrieu, C., Sauser, J., . . . Silber, B. Y. (2017). Effects of a single, oral 60 mg caffeine dose on attention in healthy adult subjects. J Psychopharmacol, 31(2), 222-232. doi:10.1177/026988111666859333. Fredholm, B. B., Battig, K., Holmen, J., Nehlig, A., & Zvartau, E. E. (1999). Actions of caffeine in the brain with special reference to factors that contribute to its widespread use. Pharmacol Rev, 51(1), 83-133. 34. Borzelleca, J. F., Peters, D., & Hall, W. (2006). A 13-week dietary toxicity and toxicokinetic study with l-theanine in rats. Food Chem Toxicol, 44(7), 1158-1166. doi:10.1016/j.fct.2006.03.01435. Kimura, K., Ozeki, M., Juneja, L. R., & Ohira, H. (2007). L-Theanine reduces psychological and physiological stress responses. Biol Psychol, 74(1), 39-45. doi:10.1016/j.biopsycho.2006.06.00636. Tian, X., Sun, L., Gou, L., Ling, X., Feng, Y., Wang, L., . . . Liu, Y. (2013). Protective effect of l-theanine on chronic restraint stress-induced cognitive impairments in mice. Brain Res, 1503, 24-32. doi:10.1016/j.brainres.2013.01.04837. Unno, K., Fujitani, K., Takamori, N., Takabayashi, F., Maeda, K., Miyazaki, H., . . . Hoshino, M. (2011). Theanine intake improves the shortened lifespan, cognitive dysfunction and behavioural depression that are induced by chronic psychosocial stress in mice. Free Radic Res, 45(8), 966-974. doi:10.3109/10715762.2011.56686938. Unno, K., Tanida, N., Ishii, N., Yamamoto, H., Iguchi, K., Hoshino, M., . . . Yamada, H. (2013). Anti-stress effect of theanine on students during pharmacy practice: positive correlation among salivary alpha-amylase activity, trait anxiety and subjective stress. Pharmacol Biochem Behav, 111, 128-135. doi:10.1016/j.pbb.2013.09.00439. Dodd, F. L., Kennedy, D. O., Riby, L. M., & Haskell-Ramsay, C. F. (2015a). A double-blind, placebo-controlled study evaluating the effects of caffeine and L-theanine both alone and in combination on cerebral blood flow, cognition and mood. Psychopharmacology (Berl), 232(14), 2563-2576. doi:10.1007/s00213-015-3895-040. Rogers, P. J., Smith, J. E., Heatherley, S. V., & Pleydell-Pearce, C. W. (2008). Time for tea: mood, blood pressure and cognitive performance effects of caffeine and theanine administered alone and together. Psychopharmacology (Berl), 195(4), 569-577. doi:10.1007/s00213-007-0938-141. Foxe, J. J., Morie, K. P., Laud, P. J., Rowson, M. J., de Bruin, E. A., & Kelly, S. P. (2012). Assessing the effects of caffeine and theanine on the maintenance of vigilance during a sustained attention task. Neuropharmacology, 62(7), 2320-2327. doi:10.1016/j.neuropharm.2012.01.02042. Giesbrecht, T., Rycroft, J. A., Rowson, M. J., & De Bruin, E. A. (2010). The combination of L-theanine and caffeine improves cognitive performance and increases subjective alertness. Nutr Neurosci, 13(6), 283-290. doi:10.1179/147683010x1261146076484043. Haskell, C. F., Kennedy, D. O., Milne, A. L., Wesnes, K. A., & Scholey, A. B. (2008). The effects of L-theanine, caffeine and their combination on cognition and mood. Biol Psychol, 77(2), 113-122. doi:10.1016/j.biopsycho.2007.09.00844. Kahathuduwa, C. N., Dassanayake, T. L., Amarakoon, A. M., & Weerasinghe, V. S. (2016). Acute effects of theanine, caffeine and theanine-caffeine combination on attention. Nutr Neurosci. doi:10.1080/1028415x.2016.114484545. Owen, G. N., Parnell, H., De Bruin, E. A., & Rycroft, J. A. (2008). The combined effects of L-theanine and caffeine on cognitive performance and mood. Nutr Neurosci, 11(4), 193-198. doi:10.1179/147683008x30151346. Einother, S. J., Martens, V. E., Rycroft, J. A., & De Bruin, E. A. (2010). L-theanine and caffeine improve task switching but not intersensory attention or subjective alertness. Appetite, 54(2), 406-409. doi:10.1016/j.appet.2010.01.00347. Deijen, J. B., van der Beek, E. J., Orlebeke, J. F., & van den Berg, H. (1992). Vitamin B-6 supplementation in elderly men: effects on mood, memory, performance and mental effort. Psychopharmacology (Berl), 109(4), 489-496.48. Lewerin, C., Matousek, M., Steen, G., Johansson, B., Steen, B., & Nilsson-Ehle, H. (2005). Significant correlations of plasma homocysteine and serum methylmalonic acid with movement and cognitive performance in elderly subjects but no improvement from short-term vitamin therapy: a placebo-controlled randomized study. Am J Clin Nutr, 81(5), 1155-1162. 49. Bryan, J., Calvaresi, E., & Hughes, D. (2002). Short-term folate, vitamin B-12 or vitamin B-6 supplementation slightly affects memory performance but not mood in women of various ages. J Nutr, 132(6), 1345-1356. 50. Schneider, Z., & Stroinski, A. (1987). Comprehensive B12: chemistry, biochemistry, nutrition, ecology, medicine: Walter de Gruyter.51. Polich, J., & Gloria, R. (2001). Cognitive effects of a Ginkgo biloba/vinpocetine compound in normal adults: systematic assessment of perception, attention and memory. Hum Psychopharmacol, 16(5), 409-416. doi:10.1002/hup.30852. Subhan, Z., & Hindmarch, I. (1985). Psychopharmacological effects of vinpocetine in normal healthy volunteers. Eur J Clin Pharmacol, 28(5), 567-571. 53. Dollins, A. B., Krock, L. P., Storm, W. F., Wurtman, R. J., & Lieberman, H. R. (1995). L-tyrosine ameliorates some effects of lower body negative pressure stress. Physiol Behav, 57(2), 223-230. 54. Shurtleff, D., Thomas, J. R., Schrot, J., Kowalski, K., & Harford, R. (1994). Tyrosine reverses a cold-induced working memory deficit in humans. Pharmacol Biochem Behav, 47(4), 935-941. 55. Brzezinski, A., Vangel, M. G., Wurtman, R. J., Norrie, G., Zhdanova, I., Ben-Shushan, A., & Ford, I. (2005). Effects of exogenous melatonin on sleep: a meta-analysis. Sleep Med Rev, 9(1), 41-50. 56. Ferracioli-Oda, E., Qawasmi, A., & Bloch, M. H. (2013). Meta-Analysis: Melatonin for the Treatment of Primary Sleep Disorders. PLoS One, 8(5), e63773. doi:10.1371/journal.pone.006377357. Inagawa, K., Hiraoka, T., Kohda, T., Yamadera, W., & Takahashi, M. (2006). Subjective effects of glycine ingestion before bedtime on sleep quality. Sleep and Biological Rhythms, 4(1), 75-77. doi:10.1111/j.1479-8425.2006.00193.x58. Bannai, M., Kawai, N., Ono, K., Nakahara, K., & Murakami, N. (2012). The Effects of Glycine on Subjective Daytime Performance in Partially Sleep-Restricted Healthy Volunteers. Front Neurol, 3, 61. doi:10.3389/fneur.2012.0006159. Yamadera, W., Inagawa, K., Chiba, S., Bannai, M., Takahashi, M., & Nakayama, K. (2007). Glycine ingestion improves subjective sleep quality in human volunteers, correlating with polysomnographic changes. Sleep and Biological Rhythms, 5(2), 126-131. doi:10.1111/j.1479-8425.2007.00262.x60. Tuli, H. S., Kashyap, D., Sharma, A. K., & Sandhu, S. S. (2015). Molecular aspects of melatonin (MLT)-mediated therapeutic effects. Life Sci, 135, 147-157. doi:10.1016/j.lfs.2015.06.00461. Herxheimer, A., & Petrie, K. J. (2002). Melatonin for the prevention and treatment of jet lag. Cochrane Database Syst Rev(2), Cd001520. doi:10.1002/14651858.cd00152062. Deng, X., Song, Y., Manson, J. E., Signorello, L. B., Zhang, S. M., Shrubsole, M. J., . . . Dai, Q. (2013). Magnesium, vitamin D status and mortality: results from US National Health and Nutrition Examination Survey (NHANES) 2001 to 2006 and NHANES III. BMC Med, 11(1), 187. doi:10.1186/1741-7015-11-18763. Murck, H., & Steiger, A. (1998). Mg2+ reduces ACTH secretion and enhances spindle power without changing delta power during sleep in men -- possible therapeutic implications. Psychopharmacology (Berl), 137(3), 247-252. 64. Nielsen, F. H., Johnson, L. K., & Zeng, H. (2010). Magnesium supplementation improves indicators of low magnesium status and inflammatory stress in adults older than 51 years with poor quality sleep. Magnes Res, 23(4), 158-168. doi:10.1684/mrh.2010.0220
A picture is worth a thousand words, particularly in this case where there seems to be temporal effects, different trends for the conditions, and general confusion. So, I drag up 2.5 years of MP data (for context), plot all the data, color by magnesium/non-magnesium, and fit different LOESS lines to each as a sort of smoothed average (since categorical data is hard to interpret as a bunch of dots), which yields:
My first impression of ~1g around 12:30PM was that while I do not feel like running around, within an hour I did feel like the brain fog was lighter than before. The effect wasn’t dramatic, so I can’t be very confident. Operationalizing brain fog for an experiment might be hard: it doesn’t necessarily feel like I would do better on dual n-back. I took 2 smaller doses 3 and 6 hours later, to no further effect. Over the following weeks and months, I continued to randomly alternate between potassium & non-potassium days. I noticed no effects other than sleep problems.
Vitamin D is probably the most important supplement you can take, and one of the best brain food. It acts on more than over 1,000 different genes and is a substrate for testosterone, progesterone, estradiol, and other hormones. It also influences inflammation and brain calcium absorption. No surprise that optimal vitamin D levels are linked to stronger cognitive function and slower brain aging.
Last winter, I spoke again with Alex, the Harvard graduate, and found that, after a break of several months, he had gone back to taking Adderall - a small dose every day. He felt that he was learning to use the drug in a more "disciplined" manner. Now, he said, it was less about staying up late to finish work he should have done earlier, and more "about staying focused on work, which makes me want to work longer hours". What employer would object to that?
The price is not as good as multivitamins or melatonin. The studies showing effects generally use pretty high dosages, 1-4g daily. I took 4 capsules a day for roughly 4g of omega acids. The jar of 400 is 100 days’ worth, and costs ~$17, or around 17¢ a day. The general health benefits push me over the edge of favoring its indefinite use, but looking to economize. Usually, small amounts of packaged substances are more expensive than bulk unprocessed, so I looked at fish oil fluid products; and unsurprisingly, liquid is more cost-effective than pills (but like with the powders, straight fish oil isn’t very appetizing) in lieu of membership somewhere or some other price-break. I bought 4 bottles (16 fluid ounces each) for $53.31 total (thanks to coupons & sales), and each bottle lasts around a month and a half for perhaps half a year, or ~$100 for a year’s supply. (As it turned out, the 4 bottles lasted from 4 December 2010 to 17 June 2011, or 195 days.) My next batch lasted 19 August 2011-20 February 2012, and cost $58.27. Since I needed to buy empty 00 capsules (for my lithium experiment) and a book (Stanovich 2010, for SIAI work) from Amazon, I bought 4 more bottles of 16fl oz Nature’s Answer (lemon-lime) at $48.44, which I began using 27 February 2012. So call it ~$70 a year.
The use of cognition-enhancing drugs by healthy individuals in the absence of a medical indication spans numerous controversial issues, including the ethics and fairness of their use, concerns over adverse effects, and the diversion of prescription drugs for nonmedical uses, among others. Nonetheless, the international sales of cognition-enhancing supplements exceeded US$1 billion in 2015 when global demand for these compounds grew.