Below you can find a list of clinical trials conducted for professionals in their specific field, conducted in a non bias way or altered by third parties or companies.
Magnesium, Zinc, Vitamin D3 compared with use of Multivitamins:
- Huang, H. Y., Caballero, B., Chang, S., Alberg, A. J., Semba, R. D., Schneyer, C. R., … & Barnes, G. J. (2006). The efficacy and safety of multivitamin and mineral supplement use to prevent cancer and chronic disease in adults: a systematic review for a National Institutes of Health state-of-the-science conference. Annals of internal medicine, 145(5), 372-385.
- Mursu, J., Robien, K., Harnack, L. J., Park, K., & Jacobs, D. R. (2011). Dietary supplements and mortality rate in older women: the Iowa Women’s Health Study. Archives of internal medicine, 171(18), 1625-1633.
- Stevens, V. L., McCullough, M. L., Diver, W. R., Rodriguez, C., Jacobs, E. J., Thun, M. J., & Calle, E. E. (2005). Use of multivitamins and prostate cancer mortality in a large cohort of US men. Cancer Causes and Control, 16(6), 643-650.
- Jacobs, E. J., Connell, C. J., McCullough, M. L., Chao, A., Jonas, C. R., Rodriguez, C., … & Thun, M. J. (2002). Vitamin C, vitamin E, and multivitamin supplement use and stomach cancer mortality in the Cancer Prevention Study II cohort. Cancer Epidemiology and Prevention Biomarkers, 11(1), 35-41.
- Whiting, S. J., Green, T. J., & Calvo, M. S. (2007). Vitamin D intakes in North America and Asia-Pacific countries are not sufficient to prevent vitamin D insufficiency. The Journal of steroid biochemistry and molecular biology, 103(3), 626-630.
- 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.
- Sepehrmanesh, Z., Kolahdooz, F., Abedi, F., Mazroii, N., Assarian, A., Asemi, Z., & Esmaillzadeh, A. (2016). Vitamin D supplementation affects the beck depression inventory, insulin resistance, and biomarkers of oxidative stress in patients with major depressive disorder: a randomized, controlled clinical trial. The Journal of nutrition, 146(2), 243-248.
- Holick, M. F. (2006, March). High prevalence of vitamin D inadequacy and implications for health. In Mayo Clinic Proceedings (Vol. 81, No. 3, pp. 353-373). Elsevier.
- Guerrero‐Romero, F., & Rodríguez‐Morán, M. (2011). Magnesium improves the beta‐cell function to compensate variation of insulin sensitivity: double‐blind, randomized clinical trial. European journal of clinical investigation, 41(4), 405-410.
- Furukawa, Y., Kasai, N., & Torimitsu, K. (2009). Effect of Mg2+ on neural activity of rat cortical and hippocampal neurons in vitro. Magnesium research, 22(3), 174S-181S.
- Beg, S., Javed, S., & JKohli, K. (2010). Bioavailability enhancement of coenzyme Q10: an extensive review of patents. Recent patents on drug delivery & formulation, 4(3), 245-257.
- Karlsson, J., Lin, L., Sylvén, C., & Jansson, E. (1996). Muscle ubiquinone in healthy physically active males. Molecular and cellular biochemistry, 156(2), 169-172.
- Mancini, A., Conte, G., Milardi, D., Marinis, L., & Littarru, G. P. (1998). Relationship between sperm cell ubiquinone and seminal parameters in subjects with and without varicocele. Andrologia, 30(1), 1-4.
- Simopoulos, A. P. (2008). The importance of the omega-6/omega-3 fatty acid ratio in cardiovascular disease and other chronic diseases. Experimental biology and medicine, 233(6), 674-688.
- Simopoulos, A. P. (2008). The importance of the omega-6/omega-3 fatty acid ratio in cardiovascular disease and other chronic diseases. Experimental biology and medicine, 233(6), 674-688.
- Muldoon, M. F., Ryan, C. M., Sheu, L., Yao, J. K., Conklin, S. M., & Manuck, S. B. (2010). Serum phospholipid docosahexaenonic acid is associated with cognitive functioning during middle adulthood.The Journal of nutrition, 140(4), 848-853.
- Friedberg, C. E., Janssen, M. J., Heine, R. J., & Grobbee, D. E. (1998). Fish oil and glycemic control in diabetes: a meta-analysis. Diabetes care, 21(4), 494-500.
- Darrabie, M. D., Arciniegas, A. J. L., Mishra, R., Bowles, D. E., Jacobs, D. O., & Santacruz, L. (2011). AMPK and substrate availability regulate creatine transport in cultured cardiomyocytes. American Journal of Physiology-Endocrinology and Metabolism, 300(5), E870-E876.
- Mujika, I., & Padilla, S. (1997). Creatine supplementation as an ergogenic aid for sports performance in highly trained athletes: a critical review. International journal of sports medicine, 18(07), 491-496.
- McMorris, T., Mielcarz, G., Harris, R. C., Swain, J. P., & Howard, A. (2007). Creatine supplementation and cognitive performance in elderly individuals. Aging, Neuropsychology, and Cognition, 14(5), 517-528.
- Shelton, R. C., Puleo, E., Syngal, S., & Emmons, K. M. (2009). Multivitamin use among multi-ethnic, low-income adults. Cancer Causes & Control, 20(8), 1271-1280.
- Godfrey, J. R. (2007). Toward optimal health: Meir Stampfer, MD, Dr. PH, discusses multivitamin and mineral supplementation for women. Journal of Women’s Health, 16(7), 959-962.
Nootropic – Focus & Power
1. Camfield DA, Stough C, Farrimond J, Scholey AB. Acute effects of tea constituents L-theanine, caffeine, and epigallocatechin gallate on cognitive function and mood: a systematic review and meta-analysis. Nutrition reviews. 2014; 72(8):507-22.
2. 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.2007.09.008
6. 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.1994.1004
7. 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:10.1177/0269881116668593
8. 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.2013.09.004
9. 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:10.1179/147683010×12611460764840
10. 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.2016.1144845
12. 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/s00213-015-3895-0
13. 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/s00213-007-0938-1
15. 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.
16. 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.
17. 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.
18. Deijen JB, Wientjes CJ, Vullinghs HF, Cloin PA, Langefeld JJ. Tyrosine improves cognitive performance and reduces blood pressure in cadets after one week of a combat training course. Brain research bulletin. 1999; 48(2):203-9.
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. 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.2011.0367
3. Calabrese C, Gregory WL, Leo M, Kraemer D, Bone K, Oken B. Effects of a Standardized Bacopa monnieri Extract on Cognitive Performance, Anxiety, and Depression in the Elderly: A Randomized, Double-Blind, Placebo-Controlled Trial. Journal of Alternative and Complementary Medicine. 2008;14(6):707-713. doi:10.1089/acm.2008.0018.
4. Parnetti L, Amenta F, Gallai V. Choline alphoscerate in cognitive decline and in acute cerebrovascular disease: an analysis of published clinical data. Mechanisms of ageing and development. 2001; 122(16):2041-55.
5. 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:10.1186/1472-6882-12-70
6. Hung SK, Perry R, Ernst E. The effectiveness and efficacy of Rhodiola rosea L.: a systematic review of randomized clinical trials. Phytomedicine : international journal of phytotherapy and phytopharmacology. 2011; 18(4):235-44.
3. 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.x
4. 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.2012.00061
5. Kunz, D., Mahlberg, R., Müller, C., Tilmann, A., & Bes, F. (2004). Melatonin in patients with reduced REM sleep duration: two randomized controlled trials. The Journal of Clinical Endocrinology & Metabolism, 89(1), 128-134.
6. 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.x
7. 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.2013.09.004
10. Schuette SA, Lashner BA, Janghorbani M. Bioavailability of magnesium diglycinate vs magnesium oxide in patients with ileal resection. JPEN. Journal of parenteral and enteral nutrition. ; 18(5):430-5.
Benefits of Alpha – GPC for brain and athletic performance
- Hoffman, J. R., Ratamess, N. A., Gonzalez, A., Beller, N. A., Hoffman, M. W., Olson, M., … & Jager, R. (2010). The effects of acute and prolonged CRAM supplementation on reaction time and subjective measures of focus and alertness in healthy college students. Journal of the International Society of Sports Nutrition, 7(1), 1-8.
- Richter, Y., Herzog, Y., Eyal, I., & Cohen, T. (2011). Cognitex supplementation in elderly adults with memory complaints: an uncontrolled open label trial. Journal of dietary supplements, 8(2), 158-168.
- Armah, C. N., Sharp, P., Mellon, F. A., Pariagh, S., Lund, E. K., Dainty, J. R., … & Fairweather-Tait, S. J. (2008). L-alpha–glycerophosphocholine contributes to meat’s enhancement of nonheme iron absorption. The Journal of nutrition, 138(5), 873-877.
- Park, J. M., De Castro, K. A., Ahn, H., & Rhee, H. (2010). Facile syntheses of L-alpha-glycerophosphorylcholine. Bull. Korean Chem. Soc, 31, 2689-2691
- Parnetti, L., Mignini, F., Tomassoni, D., Traini, E., & Amenta, F. (2007). Cholinergic precursors in the treatment of cognitive impairment of vascular origin: ineffective approaches or need for re-evaluation?. Journal of the neurological sciences, 257(1), 264-269.
- Hasselmo, M. E. (2006). The role of acetylcholine in learning and memory. Current opinion in neurobiology, 16(6), 710-715.
- Tang, Y., Mishkin, M., & Aigner, T. G. (1997). Effects of muscarinic blockade in perirhinal cortex during visual recognition. Proceedings of the National Academy of Sciences, 94(23), 12667-12669.
- Blokland, A., Honig, W., & Raaijmakers, W. G. (1992). Effects of intra-hippocampal scopolamine injections in a repeated spatial acquisition task in the rat. Psychopharmacology, 109(3), 373-376.
- Elvander, E., Schott, P. A., Sandin, J., Bjelke, B., Kehr, J., Yoshitake, T., & Ogren, S. O. (2004). Intraseptal muscarinic ligands and galanin: influence on hippocampal acetylcholine and cognition. Neuroscience, 126(3), 541-557.
- Rogers, J. L., & Kesner, R. P. (2003). Cholinergic modulation of the hippocampus during encoding and retrieval. Neurobiology of learning and memory, 80(3), 332-342.
- Scapicchio, P. L. (2013). Revisiting choline alphoscerate profile: a new, perspective, role in dementia?. International Journal of Neuroscience, 123(7), 444-449.
- Parnetti, L., Amenta, F., & Gallai, V. (2001). Choline alphoscerate in cognitive decline and in acute cerebrovascular disease: an analysis of published clinical data. Mechanisms of ageing and development, 122(16), 2041-2055
- Moreno, M. D. J. M. (2003). Cognitive improvement in mild to moderate Alzheimer’s dementia after treatment with the acetylcholine precursor choline alfoscerate: a multicenter, double-blind, randomized, placebo-controlled trial. Clinical therapeutics, 25(1), 178-193.
Omega 3: Hundreds of studies have shown the benefits of supplementation with Omega 3 faty acids, we are just collecting in this section, the most relevant. This section wil be expanded as soon as we evaluate some of the public clinical trials available.
Creatine is the most researched supplement in the world with 100% agreement in the scientific community about its benefits and safety.
Creatine is a natural supplement used to boost athletic performance (1Trusted Source).
It’s not only safe to use but also one of the world’s most popular and effective supplements for building muscle and strength (1Trusted Source, 2Trusted Source, 3Trusted Source, 4Trusted Source, 5Trusted Source, 6Trusted Source).
Here are 10 science-based benefits of creatine.
During exercise, ATP is broken down to produce energy.
This is the primary mechanism behind creatine’s performance-enhancing effects.
SUMMARYSupplementing with creatine provides additional ATP energy, which improves high-intensity exercise performance.
It can alter numerous cellular pathways that lead to new muscle growth. For example, it boosts the formation of proteins that create new muscle fibers (12Trusted Source, 13Trusted Source, 14Trusted Source, 15Trusted Source, 16Trusted Source).
Additionally, some research indicates that creatine decreases levels of myostatin, a molecule responsible for stunting muscle growth. Reducing myostatin can help you build muscle faster (18Trusted Source).
SUMMARYCreatine can stimulate several key biological processes that lead to increased muscle growth and size.
- Ballistic power
- Sprint ability
- Muscle endurance
- Resistance to fatigue
- Muscle mass
- Brain performance
SUMMARYCreatine is the world’s most effective supplement for high-intensity sports. It offers benefits regardless of your current fitness level.
Taking it for as few as 5–7 days has been shown to significantly increase lean body weight and muscle size.
Over the long term, it also aids in muscle fiber growth by signaling key biological pathways and boosting gym performance (12Trusted Source, 13Trusted Source, 14Trusted Source, 15Trusted Source, 23Trusted Source).
In one study of a six-week training regimen, participants who used creatine added 4.4 pounds (2 kg) more muscle mass, on average, than the control group (23Trusted Source).
Similarly, a comprehensive review demonstrated a clear increase in muscle mass for those taking creatine, compared to those performing the same training regimen without creatine (27Trusted Source).
This review also compared the world’s most popular sports supplements and concluded that creatine is the best one available. Its advantages include being less expensive and far safer than most other sports supplements (27Trusted Source).
SUMMARYCreatine can increase both short- and long-term muscle mass. It is the most effective muscle-building supplement available.
Creatine has been linked to beneficial effects on Parkinson’s in mice, preventing 90% of the drop in dopamine levels (29Trusted Source).
In individuals with Parkinson’s disease, combining creatine with weight training improved strength and daily function to a greater extent than training alone (32Trusted Source).
However, a recent analysis of five controlled studies in people with Parkinson’s noted that taking 4–10 grams of creatine per day doesn’t significantly improve daily activities (33Trusted Source).
SUMMARYCreatine may reduce some symptoms of Parkinson’s disease by improving muscle strength and function. However, certain studies observe no effects.
A key factor in several neurological diseases is a reduction of phosphocreatine in your brain (29Trusted Source).
Since creatine can increase these levels, it may help reduce or slow disease progression.
In mice with Huntington’s disease, creatine restored the brain’s phosphocreatine stores to 72% of pre-disease levels, compared to only 26% for control mice (34Trusted Source).
This restoration of phosphocreatine helped maintain daily function and reduced cell death by around 25% (34Trusted Source).
- Alzheimer’s disease
- Ischemic stroke
- Brain or spinal cord injuries
Creatine has also shown benefits against ALS, a disease that affects the motor neurons essential for movement. It improved motor function, reduced muscle loss and extended survival rate by 17% (39Trusted Source).
Although more studies are needed in humans, many researchers believe that creatine supplements are a bulwark against neurological diseases when used alongside conventional medicines.
SUMMARYAnimal studies suggest that creatine can help with symptoms, disease progression and life expectancy in neurological diseases.
Research suggests that creatine supplements may lower blood sugar levels by increasing the function of GLUT4, a transporter molecule that brings blood sugar into your muscles (40Trusted Source, 41Trusted Source, 42Trusted Source, 43Trusted Source).
A 12-week study examined how creatine affects blood sugar levels after a high-carb meal. People who combined creatine and exercise were better at controlling blood sugar levels than those who only exercised (42Trusted Source).
Short-term blood sugar response to a meal is an important marker of diabetes risk. The faster your body clears sugar from the blood, the better (44Trusted Source).
While these benefits are promising, more human research is needed on creatine’s long-term effects on blood sugar control and diabetes.
SUMMARYSome evidence suggests that creatine can help lower blood sugar levels after meals, but there is little data on its long-term effects.
Creatine plays an important role in brain health and function (25Trusted Source).
Research demonstrates that your brain requires a significant amount of ATP when performing difficult tasks (25Trusted Source).
Supplements can increase phosphocreatine stores in your brain to help it produce more ATP. Creatine may also aid brain function by increasing dopamine levels and mitochondria function (25Trusted Source, 45Trusted Source, 46Trusted Source).
As meat is the best dietary source of creatine, vegetarians often have low levels. One study on creatine supplements in vegetarians found a 20–50% improvement in some memory and intelligence test scores (25Trusted Source).
In older adults, creatine may boost brain function, protect against neurological diseases and reduce age-related loss of muscle and strength (48Trusted Source).
Despite such positive findings, more research is needed in young, healthy individuals who eat meat or fish on a regular basis.
SUMMARYSupplementing with creatine can provide your brain with additional energy, thereby improving memory and intelligence in people with low levels of creatine.
Creatine supplements may also reduce fatigue and tiredness (49Trusted Source).
In a six-month study in people with traumatic brain injury, those who supplemented with creatine had a 50% reduction in dizziness, compared to those who did not (49Trusted Source).
Furthermore, only 10% of patients in the supplement group experienced fatigue, compared to 80% in the control group (49Trusted Source).
SUMMARYCreatine can reduce symptoms of fatigue and tiredness by providing your brain with additional energy and increasing dopamine levels.
Along with creatine’s diverse benefits, it is also one of the cheapest and safest supplements available. You can find a wide selection on Amazon.
It’s been researched for more than 200 years, and numerous studies support its safety for long-term use. Clinical trials lasting up to five years report no adverse effects in healthy individuals (1Trusted Source).
SUMMARYCreatine is one of the safest available supplements and has been studied scientifically for over two centuries.
At the end of the day, creatine is an effective supplement with powerful benefits for both athletic performance and health.
It may boost brain function, fight certain neurological diseases, improve exercise performance and accelerate muscle growth.
Try adding this natural substance to your supplement regimen to see if it works for you.
The use of electrolytes aids in providing
transporters for creatine from the plasma into the muscles (Allen, 2012; Jäger et al., 2011).
Electrolytes A group of minerals that are found in the body. Aids in
membrane transportation. (Allen, 2012)
While creatine on its own is beneficial, there is little to no research on creatine
coupled with electrolytes. Electrolytes are a common mineral that aids in cell transportation
of creatine, which plays a critical role in creatine absorption (Allen, 2012; Greenhaff et al.,
1994). The current study aims to examine the effect of a creatine and electrolyte supplement
compared to a placebo group on maximal strength, power, and performance while
performing a maximal bench press and back squat set at 80% 1RM load.
Creatine and electrolytes: multi-ingredient performance supplements. Creatine
absorption highly depends on electrolytes such as sodium and chloride availability and usage
as active transporters (Allen, 2012). Allen, (2012) described that sodium and chloride ions
are necessary to actively transport creatine from the blood plasma into the musculature,
increasing the amount of creatine storage available for use. Based on creatine transportation,
other researchers have examined the effects of combining both creatine and electrolytes such
as sodium and magnesium for performance benefits (Barber, McDermott, McGaughey,
Olmstead, & Hagobian, 2013; Brilla, Giroux, Taylor, & Knutzen, 2003; Mero, Keskinen,
Malyela, & Sallinen, 2004).
Supplementing with both creatine and electrolytes such as sodium has been used to
increase creatine transportation (Mero et al., 2004). Mero et al. (2004) found that
supplementing with creatine combined with sodium bicarbonate enhances maximal swim
tests, approximately 0.9 seconds faster than the placebo group. A similar study used creatine
monohydrate combined with sodium bicarbonate compared to creatine supplementation
alone during six 10-second wingate tests (Barber et al., 2013). The creatine and sodium
bicarbonate group displayed a 7% increase in peak power compared to a 4% increase in the
creatine only group. The group supplementing with both creatine and sodium bicarbonate
had their power levels significantly higher than both the placebo and creatine groups during
the six repeated bouts of cycling (Barber et al., 2013). The combined creatine and sodium
bicarbonate only saw a decrease of power on the sixth bout whereas the other groups had
decreases in bouts four, five, and six.