2 0 2 0 - 2 0 2 1 R E S E A R C H G U I D E THE FOLLOWING IS A SUMMARY OF THE CURRENT BODY OF EVIDENCE ON THE MEDICINAL

INGREDIENTS OF THE BENEMAX LINE. THESE SUMMARIES DO NOT CONSTITUTE THE ENTIRETY

OF CLINCAL RESEARCH OR CONSITUTE MEDICAL ADVICE WE DO NOT CLAIM THAT ANY OF OUR

SUPPLEMENTS ARE MEANT TO TREAT OR CURE ILLNESS, BUT WE DO BELIEVE IT IS IMPORTANT

TO INFORM THE PUBLIC AS WELL AS OUR BUYERS OF THE AVAILABLE EVIDENCE.

C L I N I C A L E V I D E N C E F O R D H A

KEY FINDINGS / IMPORTANT QUOTES STUDY REFERENCED Safety for all ages including study groups up to 7 years Lien, E. L. (2009). Toxicology and safety of DHA.

Prostaglandins, leukotrienes and essential fatty acids, 81(2-3), 125-132.

Demonstrated Effect of Reduction of Symptoms of Atopic Dermatitis in Children.

Koch, C., Dölle, S., Metzger, M., Rasche, C., Jungclas, H., Rühl, R., ... & Worm, M. (2008). Docosahexaenoic acid (DHA) supplementation in atopic eczema: a randomized, double‐blind, controlled trial. British Journal of Dermatology, 158(4), 786-792.

In children whose mothers were supplement with DHA it was found that they had lower inflammatory markers at birth and were able to attenuate inflammatory responses.

Granot, E., Jakobovich, E., Rabinowitz, R., Levy, P., & Schlesinger, M. (2011). DHA supplementation during pregnancy and lactation affects infants' cellular but not humoral immune response. Mediators of inflammation, 2011.

2019 systematic review that shows that DHA has been associated with increases in HDL as well as improved cardiac outcomes

Wei, M. Y., & Jacobson, T. A. (2011). Effects of eicosapentaenoic acid versus docosahexaenoic acid on serum lipids: a systematic review and meta-analysis. Current atherosclerosis reports, 13(6), 474-483.

Evidence has shown that reduced DHA in mother’s milk was a clinical indicator of a higher risk of post-partum depression.

Hibbeln, J. R. (2002). Seafood consumption, the DHA content of mothers’ milk and prevalence rates of postpartum depression: a cross-national, ecological analysis. Journal of affective disorders, 69(1-3), 15-29

Elevated DHA in children with DHA was indicative of improved spelling, attention as well as reduced oppositional behaviour.

Milte, C. M., Parletta, N., Buckley, J. D., Coates, A. M., Young, R. M. (2015). Increased erythrocyte eicosapentaenoic acid and docosahexaenoic acid are associated with improved attention and behavior in children with ADHD in a randomized controlled three-way crossover trial. Journal of attention disorders, 19(11), 954-964.

“ …demand of DHA in present population is increasing due to intake of high western diets, rich in omega-6 and beneficial effects of DHA on health especially in pediatrics and diseases like cardiovascular, depression.”

PURI, R., BHATTI, M., & THAKUR, N. (2017). DHA AS A HEALTH SUPPLEMENT: A REVIEW. International Educational Applied Scientific Research Journal, 2(9).

DHA supplementation is shown to have a strong correlation with some markers of intelligence as well as cognition and behaviour in children when supplemented.

Kuratko, C. N., Barrett, E. C., Nelson, E. B., & Salem, N. (2013). The relationship of docosahexaenoic acid (DHA) with learning and behavior in healthy children: a review. Nutrients, 5(7), 2777-2810.

900mg of DHA was able to attenuate symptoms of Alzheimer’s Disease, specifically symptoms of cognitive decline in Seniors. 6 months of supplementation with DHA resulted in improved learning and memory.

Yurko-Mauro, K., McCarthy, D., Rom, D., Nelson, E. B., Ryan, A. S., Blackwell, A., ... & Midas Investigators. (2010). Beneficial effects of docosahexaenoic acid on cognition in age-related cognitive decline. Alzheimer's & Dementia, 6(6), 456-464.

C L I N I C A L E V I D E N C E F O R V I T A M I N D 2 KEY FINDINGS / IMPORTANT QUOTES STUDY REFERENCED

Supplementation of D2 has been associated with reduction of symptoms of psoriasis

Disphanurat, W., Viarasilpa, W., Chakkavittumrong, P., & Pongcharoen, P. (2019). The Clinical Effect of Oral Vitamin

D2 Supplementation on Psoriasis: A Double-Blind, Randomized, Placebo-Controlled Study. Dermatology

research and practice, 2019.

Despite chemical differences between both chemical formulations Vitamin D2 has been shown equally effective as Vitamin D3

“There are no significant differences in the other important markers: parathyroid hormone, calcium, phosphorus and alkaline phosphatase”

Nasim, B., Al Sughaiyer, H. M. Z., Rahman, S. M. A., Inamdar, R. F. B., Chakaki, R., & Abuhatab, S. (2019).

Efficacy of Vitamin D3 versus Vitamin D2 in deficient and insufficient patients: An open-label, randomized controlled

trial. Ibnosina Journal of Medicine and Biomedical Sciences, 11(2), 57.

The use of Vitamin D2 derived from Shiitake Mushrooms has been shown to be effective in the reduction of risk of osteoporosis when faithfully supplemented.

Won, D. J., Seong, K. S., Jang, C. H., Lee, J. S., Ko, J. A., Bae, H., & Park, H. J. (2019). Effects of vitamin D2-fortified

shiitake mushroom on bioavailability and bone structure. Bioscience, biotechnology, and biochemistry, 83(5), 942-

951.

Even at supplementation of 400IU of D3 , there were marked reduction of depressive symptoms.

Lansdowne, A. T., & Provost, S. C. (1998). Vitamin D3 enhances mood in healthy subjects during winter.

Psychopharmacology, 135(4), 319-323.

Association with depressive symptoms when serum levels of D3 were lower. This was not the case with D2. This study did not examine the role of supplementation as D2 is readily

converted to D3 in the body

Tolppanen AM, Sayers A, Fraser WD, Lewis G, Zammit S, Lawlor DA: The association of serum 25-hydroxyvitamin D3

and D2 with depressive symptoms in childhood–a prospective cohort study. J Child Psychol Psychiatry. 2012,

53: 757-766. 10.1111/j.1469-7610.2011.02518.x.

Supplementation of Vitamin D of both D3 and D2 forms have given relief of symptoms of Premenstrual Syndrome (PMS) in adolescent women who had Vitamin D deficiencies

Tartagni, M., Cicinelli, M. V., Tartagni, M. V., Alrasheed, H., Matteo, M., Baldini, D., ... & Montagnani, M. (2016).

Vitamin D supplementation for premenstrual syndrome-related mood disorders in adolescents with severe

hypovitaminosis D. Journal of pediatric and adolescent gynecology, 29(4), 357-361.

C L I N I C A L E V I D E N C E F O R C L A

KEY FINDINGS / IMPORTANT QUOTES STUDY REFERENCED

“Initially identified as a fatty acid with potent anti-carcinogenic properties, research on the health effects attributed to CLA has evolved to include anti-obesogenic and anti-atherosclerotic tendencies. The literature to date suggests that CLA, and primarily the 10,12 CLA isomer, consistently confers some degree of body weight and/or adiposity loss in animal models and humans. However, such effects on body energetics may not impart protection against obesity-associated comorbidities, such as type 2 diabetes. It is also clear that CLA is protective against atherosclerosis in several animal models, but its efficacy against human cardiovascular disease is less clear.”

den Hartigh, L. J. (2019). Conjugated linoleic acid effects on cancer, obesity, and atherosclerosis: A review of pre-clinical and human trials with current perspectives. Nutrients, 11(2), 370.

Rather increases lean mass levels. May have some reduction on fat levels consistently in research. Though exercise is always encouraged and is a helpful part of this evidence

Chen, P. B., & Park, Y. (2019). Conjugated Linoleic Acid in Human Health: Effects on Weight Control. In Nutrition in the Prevention and Treatment of Abdominal Obesity (pp. 355-382). Academic Press.

Increases lean muscle mass “Given that CLA not only reduces body fat, but also improves lean mass, there is great potential for the use of CLA to improve muscle metabolism, which would have a significant health impact.”

Zhang, T. Y., Huang, J. T., Tian, H. B., Ma, Y., Chen, Z., Wang, J. J., ... & Luo, J. (2018). trans-10, cis-12 conjugated linoleic acid alters lipid metabolism of goat mammary epithelial cells by regulation of de novo synthesis and the AMPK signaling pathway. Journal of dairy science, 101(6), 5571-5581.

Study showing CLA helps to decrease leptin levels in obese patients when supplemented for 6 months.

Mohammadi-Sartang, M., Sohrabi, Z., Esmaeilinezhad, Z., & Jalilpiran, Y. (2018). Effect of Conjugated Linoleic Acid on Leptin Level: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Hormone and Metabolic Research, 50(02), 106-116.

CLA has shown the ability to reduce blood pressure in combination with Ramipril

Zhao, W. S., Zhai, J. J., Wang, Y. H., Xie, P. S., Yin, X. J., Li, L. X., & Cheng, K. L. (2009). Conjugated linoleic acid supplementation enhances antihypertensive effect of ramipril in Chinese patients with obesity-related hypertension. American journal of hypertension, 22(6), 680-686.

“Potential mechanisms responsible for the anti-obesity properties of 10,12 CLA include 1)decreasing energy intake by suppressing appetite 2) increasing energy expenditure in WAT,muscle, and liver tissue, or LBM, 3) decreasing lipogenesis or adipogenesis, 4) increasinglipolysis or delipidation, and 5) apoptosis via adipocyte stress, inflammation, and/or insulin resistance”

Kennedy, A., Martinez, K., Schmidt, S., Mandrup, S., LaPoint, K., & McIntosh, M. (2010). Antiobesity mechanisms of action of conjugated linoleic acid. The Journal of nutritional biochemistry, 21(3), 171-179.

“Trans 10 c12 CLA – in the synthetic form – can increase inflammation in the body in men with metabolic syndrome “

Risérus, U., Basu, S., Jovinge, S., Fredrikson, G. N.,

Arnlov, J., & Vessby, B. (2002). Supplementation with

conjugated linoleic acid causes isomer-dependent

oxidative stress and elevated C-reactive protein: a potential

link to fatty acid-induced insulin resistance. Circulation,

106(15), 1925-1929.

C L I N I C A L E V I D E N C E F O R E P O KEY FINDINGS / IMPORTANT QUOTES STUDY REFERENCED

Hot flashes, premenstrual syndrome, mastalgia, gestational diabetes

Mahboubi, M. (2019). Evening Primrose (Oenothera biennis) Oil in Management of Female Ailments. Journal of menopausal medicine, 25(2), 74-82.

Depressive symptoms of PMS were also alleviated in this study with use of Evening Primrose Oil

Callender, K., McGregor, M., Kirk, P., & Thomas, C. S. (1988). A double‐blind trial of evening primrose oil in the premenstrual syndrome: Nervous symptom subgroup. Human Psychopharmacology: Clinical and Experimental, 3(1), 57-61.

2008 study: examining PMS symptoms overall and the effect of evening primrose oil vs placebo. Looking at the changes to Daily Symptom Score and Beck Depression questionnaire. there was a significant difference between mean symptom severity in Evening primrose oil therapy group and the control group (p<0.02). The finding showed there was a significant difference between mean symptom severity in Evening primrose oil therapy group before and after the treatment (p<0/01).

Fallah, L. T., Najafi, A., Fathizadeh, N., & Khaledian, Z. (2008). The effect of evening primrose oil on premenstrual syn. Scientific Journal of Hamadan Nursing & Midwifery Faculty, 16(1), 35-45.

Study showing that systemic supplementation of evening primrose oil has health benefits in terms of improving parameters of healthy skin.

Muggli, R. (2005). Systemic evening primrose oil improves the biophysical skin parameters of healthy adults. International journal of cosmetic science, 27(4), 243-249.

This study suggests that in conditions of rheumatic origin such as rheumatoid arthritis that Evening Primrose Oil and its essential fatty acids may be helpful in symptom management

Belch, J. J., & Hill, A. (2000). Evening primrose oil and borage oil in rheumatologic conditions. The American journal of clinical nutrition, 71(1), 352s-356s.

Short term treatment of mastalgia. EPO was found to be equal in effectiveness for the first month to ormeloxifene.

Nigam, A., Goenka, A., & Shrivastava, N. (2019). A Comparative Study of Effect of Ormeloxifene and Evening Primrose Oil in Treatment of Mastalgia. Indian Journal of Surgery, 81(3), 259-264.

Found a reduction that was significant in psychological symptoms of post-menopausal women, post-treatment with EPO after 8 weeks

Sharif, S. N., & Darsareh, F. (2019). Impact of evening primrose oil consumption on psychological symptoms of postmenopausal women: a randomized double-blinded placebo-controlled clinical trial. Menopause (New York, NY).

Was shown to improve overall symptoms of mastalgia (breast pain) when supplement in combination with Vitamin E (found in our product)

Ghazanfor, R., Qureshi, U., Adil, R. G., Malik, S., Tariq, M., & Khan, J. S. (2019). Comparative study of effectiveness of vitamin E and evening primrose oil for pain relief in moderate cyclical mastalgia. The Professional Medical Journal, 26(08), 1328-1332.

2018 study from Korea showing that EPO is safe and effective in mild cases of atopic dermatitis. Has shown varied results with regards to eczema – in 19 studies there was little effect compared to placebo

Chung, B. Y., Park, S. Y., Jung, M. J., Kim, H. O., & Park,

C. W. (2018). Effect of evening primrose oil on Korean

patients with mild atopic dermatitis: a randomized, double-

blinded, placebo-controlled clinical study. Annals of

dermatology, 30(4), 409-416.

The beneficial effects of these ingredients can be attributed to inhibition of cytokine and chemokine expression, IgE production, inflammatory cell infiltration, histamine release, and/or the enhancement of epidermal permeability barrier function.

Man, G., Hu, L. Z., Elias, P. M., & Man, M. Q. (2018).

Therapeutic benefits of natural ingredients for atopic

dermatitis. Chinese journal of integrative medicine, 24(4),

308-314.

C L I N I C A L E V I D E N C E F O R V I T A M I N E KEY FINDINGS / IMPORTANT QUOTES STUDY REFERENCED

Study showing that natural vitamin E is the only form of vitamin E that is able to treat and prevent Vitamin E deficiency ataxia

Azzi, A. (2019). Tocopherols, tocotrienols and tocomonoenols: Many similar molecules but only one vitamin E. Redox biology, 101259.

Evidence showing that all synthetic vitamin E derivatives come from petroleum. Also shows that synthetic vitamin E is less effective at increasing serum levels of alpha-tocopherol than the natural derivatives.

Cheng, K., Niu, Y., Zheng, X. C., Zhang, H., Chen, Y. P., Zhang, M., ... & Wang, T. (2016). A comparison of natural (D-α-tocopherol) and synthetic (DL-α-tocopherol acetate) vitamin E supplementation on the growth performance, meat quality and oxidative status of broilers. Asian-Australasian journal of animal sciences, 29(5), 681.

Evidence showing the ability of the body to better absorb natural vitamin E than the synthetic alternatives.

Traber, M. G., Elsner, A., & Brigelius-Flohé, R. (1998). Synthetic as compared with natural vitamin E is preferentially excreted as α‐CEHC in human urine: studies using deuterated α‐tocopheryl acetates. FEBS letters, 437(1-2), 145-148.

Study showing the anti-aging effects of vitamin E . Specifically, the reduction of mortality due to cardiovascular disease. This study found that it also protected immune function particularly amongst seniors as well as reducing risk of the common cold when supplemented regularly

Lee, I. M., Cook, N. R., Gaziano, J. M., Gordon, D., Ridker, P. M., Manson, J. E., ... & Buring, J. E. (2005). Vitamin E in the primary prevention of cardiovascular disease and cancer: the Women’s Health Study: a randomized controlled trial. Jama, 294(1), 56-65.

Systematic review from 2014, which indicates the role of Vitamin E prospectively to treat asthma and diabetes and to prevent HIV, Alzheimer’s disease, Cataracts, some forms of heart health and cancer as well as rheumatoid arthritis, PMS and physical performance.

Rizvi, S., Raza, S. T., Ahmed, F., Ahmad, A., Abbas, S., & Mahdi, F. (2014). The role of vitamin E in human health and some diseases. Sultan Qaboos University Medical Journal, 14(2), e157.

Study indicating the ability of Vitamin E supplementation to help reduce symptoms of dysmenorrhea alongside Vitamin D and ginger

Pakniat, H., Chegini, V., Ranjkesh, F., & Hosseini, M. A. (2019). Comparison of the effect of vitamin E, vitamin D and ginger on the severity of primary dysmenorrhea: a single-blind clinical trial. Obstetrics & gynecology science, 62(6), 462-468.

Study indicating the ability of Vitamin E to improve bone function and to reduce ALL markers of bone loss

Shuid, A. N., Das, S., & Mohamed, I. N. (2019). Therapeutic effect of Vitamin E in preventing bone loss: An evidence-based review. International Journal for Vitamin and Nutrition Research.

A study showing the ability of Vitamin E to protect the body from oxidative damage, inflammation, obesity as well as hyperglycemia and hypercholesterolemia.

Wong, S. K., Chin, K. Y., Suhaimi, F. H., Ahmad, F., & Ima-Nirwana, S. (2017). Vitamin E as a potential interventional treatment for metabolic syndrome: Evidence from animal and human studies. Frontiers in pharmacology, 8, 444.

C L I N I C A L E V I D E N C E F O R B O R A G E O I L KEY FINDINGS / IMPORTANT QUOTES STUDY REFERENCED

Study indicating the ability of borage oil to reduce the symptoms of atopic dermatitis also mentions the ability of borage oil to mediate skin concerns in mastalgia, neuropathy as well as rheumatoid arthritis.

Reynolds, K. A., Juhasz, M. L., & Mesinkovska, N. A. (2019). The role of oral vitamins and supplements in the management of atopic dermatitis: a systematic review. International journal of dermatology, 58(12), 1371-1376.

Study explaining the ability of GLA to reduce inflammatory processes in the body and in particular the ability to mediate skin inflammation.

Sergeant, S., Rahbar, E., & Chilton, F. H. (2016). Gamma-linolenic acid, dihommo-gamma linolenic, eicosanoids and inflammatory processes. European journal of pharmacology, 785, 77-86.

Borage seeds’ oil is utilized in various disease conditions such as atherosclerosis, inflammatory disorders, Alzheimer’s disease, asthma, and gastrointestinal disorders.

Tewari, D., Bawari, S., Patni, P., & Sah, A. N. (2019). Borage (Borago officinalis L.). In Nonvitamin and Nonmineral Nutritional Supplements (pp. 165-170). Academic Press.

Study indicating the ability to reduce the symptoms of rheumatoid arthritis

Belch, J. J., & Hill, A. (2000). Evening primrose oil and borage oil in rheumatologic conditions. The American journal of clinical nutrition, 71(1), 352s-356s.

Summary document explaining that GLA elevates Prostoglandin E and leads to a suppression of TNF alpha. This leads to an anti-inflammatory effect.

Ghasemian, M., Owlia, S., & Owlia, M. B. (2016). Review of anti-inflammatory herbal medicines. Advances in pharmacological sciences, 2016.

Study strongly implicating the lack of Omega 6 fatty acids (amongst which are GLA). In the pathogenesis of eczema

Melnik, B., & Plewig, G. (1992). Are disturbances of omega-6-fatty acid metabolism involved in the pathogenesis of atopic dermatitis?. Acta dermato-venereologica. Supplementum, 176, 77-85.

C L I N I C A L E V I D E N C E F O R H E M P S E E D O I L

KEY FINDINGS / IMPORTANT QUOTES STUDY REFERENCED

Study showing intake of hemp seed oil has the ability to modulate inflammation as well as to reduce pore clogging on the skin

Callaway, J., Schwab, U., Harvima, I., Halonen, P., Mykkänen, O., Hyvönen, P., & Järvinen, T. (2005). Efficacy of dietary hempseed oil in patients with atopic dermatitis. Journal of Dermatological Treatment, 16(2), 87-94.

Hemp Seed Oil played a role in the reduction of symptoms of atopic dermatitis.

Jeong, M., Cho, J., Shin, J. I., Jeon, Y. J., Kim, J. H., Lee, S. J., ... & Lee, K. (2014). Hempseed oil induces reactive oxygen species-and C/EBP homologous protein-mediated apoptosis in MH7A human rheumatoid arthritis fibroblast-like synovial cells. Journal of ethnopharmacology, 154(3), 745-752.

Study showing that hempseed oil has the ability to improve the fatty acid levels and omega 3 levels in children and adolescents.

Del Bo, C., Deon, V., Abello, F., Massini, G., Porrini, M., Riso, P., & Guardamagna, O. (2019). Eight-week hempseed oil intervention improves the fatty acid composition of erythrocyte phospholipids and the omega-3 index, but does not affect the lipid profile in children and adolescents with primary hyperlipidemia. Food Research International, 119, 469-476.

Study showing the ability of hempseed oil in reducing the proliferation of colorectal carcinoma cells

Moccia, S., Russo, M., Spagnuolo, C., Tedesco, I., Picariello, G., Siano, F., ... & Russo, G. L. (2019). Activation of cytostatic autophagy by polar extract of hempseed oil (Cannabis sativa L.) in a colorectal adenocarcinoma cell line. Nutrition, Metabolism and Cardiovascular Diseases, 29(8), 871.

Study demonstrating the ability of ALA (key component in Hemp Seed Oil) to reduce oxidative stress and improve blood flow

Palacka, P., Kucharska, J., Murin, J., Dostalova, K., Okkelova, A., Cizova, M., ... & Gvozdjakova, A. (2010). Complementary therapy in diabetic patients with chronic complications: a pilot study. Bratislavske lekarske listy, 111(4), 205-211.

“Overall, results of the study suggest that the consumption of hemp led to a significant improvement in the fatty acid profile in the RBC and plasma. The clinical implications of these findings suggest that hemp consumption may help CVD risk factors through the improvement of the fatty acid profiles.”

Cardillo, A. (2018). The effects of hempseed oil and hulled hempseed on health biomarkers.

Study elucidating the nutritive properties of hemp seeds including the presence of iron, zinc, magnesium and sulfur as well as arginine and all essential amino acids

Callaway, J. C. (2004). Hempseed as a nutritional resource: An overview. Euphytica, 140(1-2), 65-72.

C L I N I C A L E V I D E N C E F O R C O E N Z Y M E Q 1 0

KEY FINDINGS / IMPORTANT QUOTES STUDY REFERENCED

Study discussing the ability of CoQ10 to ameliorate cholesterol levels as well as to mediate fatigue in patients who have fibromyalgia

Miyamae T, Seki M, Naga T, et al. Increased oxidativestress and coenzyme Q10 deficiency in juvenilefibromyalgia: Amelioration of hypercholesterolemia andfatigue by ubiquinol-10 supplementation.Redox Rep2013;18:12–19.

Study indicating the ability of CoQ10 to improve the parameters of fibromyalgia when supplemented

Cordero MD, Alcocer-Gomez E, de Miguel M, et al. Cancoenzyme Q10 improve clinical and molecularparameters in fibromyalgia?Antioxid Redox Signal2013;19:1356–1361.

“Clinical research shows that taking coenzyme Q10 400 mg daily for 3 months improves pain by 24% to 37%, fatigue by 22%, and sleep disturbances by 33% compared to placebo in women with fibromyalgia”

Di Pierro, F., Rossi, A., Consensi, A., Giacomelli, C., & Bazzichi, L. (2017). Role for a water-soluble form of CoQ10 in female subjects affected by fibromyalgia. A preliminary study. Clin. Exp. Rheumatol, 35(Suppl 105), 20-27.

Coenzyme Q10 has shown the ability to reduce complications after surgery.

Hernández-Camacho, J. D., Bernier, M., López-Lluch, G., & Navas, P. (2018). Coenzyme Q10 supplementation in aging and disease. Frontiers in physiology, 9, 44.

CoQ10 has been shown to reduce blood sugar slightly in diabetics.

Moradi, M., Haghighatdoost, F., Feizi, A., & Azadbakht, L. (2016). Effect of coenzyme Q10 supplementation on diabetes biomarkers: a systematic review and meta-analysis of randomized controlled clinical trials.

Study indicating that CoQ10 has anti-inflammatory gene expression properties. It stabilizes cell membranes and hence improves symptoms of cardiovascular disease, renal failure as well as neurodegenerative disorders

Gutierrez-Mariscal, F. M., Yubero-Serrano, E. M., Villalba, J. M., & Lopez-Miranda, J. (2019). Coenzyme Q10: From bench to clinic in aging diseases, a translational review. Critical reviews in food science and nutrition, 59(14), 2240-2257.

Study demonstrating the ability of Coenzyme Q10 to reduce symptoms of myocardial infarction within the span of 3 days.

Singh, R. B., Wander, G. S., Rastogi, A., Shukla, P. K., Mittal, A., Sharma, J. P., ... & Chopra, R. K. (1998). Randomized, double-blind placebo-controlled trial of coenzyme Q10 in patients with acute myocardial infarction. Cardiovascular Drugs and Therapy, 12(4), 347-353.

Study demonstrating the mechanism of benefit of Coq10 in the treatment of myocardial infarctions as an antioxidant.

Liang, S., Ping, Z., & Ge, J. (2017). Coenzyme Q10 regulates antioxidative stress and autophagy in acute myocardial ischemia-reperfusion injury. Oxidative Medicine and Cellular Longevity, 2017.

Study showing that following a heart attack that CoQ10 improved the output from the left side of the heart.

Huang, C. H., Kuo, C. L., Huang, C. S., Tseng, W. M., Lian, I. B., Chang, C. C., & Liu, C. S. (2016). High plasma coenzyme Q10 concentration is correlated with good left ventricular performance after primary angioplasty in patients with acute myocardial infarction. Medicine, 95(31).

Study showing that CoQ10 was able to reduce systolic blood pressure in patients who suffered from metabolic syndrome.

Tabrizi, R., Akbari, M., Sharifi, N., Lankarani, K. B., Moosazadeh,

M., Kolahdooz, F., ... & Asemi, Z. (2018). The effects of coenzyme

Q10 supplementation on blood pressures among patients with

metabolic diseases: a systematic review and meta-analysis of

randomized controlled trials. High Blood Pressure &

Cardiovascular Prevention, 25(1), 41-50.

C L I N I C A L E V I D E N C E F O R C O C O N U T O I L

KEY FINDINGS / IMPORTANT QUOTES STUDY REFERENCED

Study that indicates that the intake of coconut oil has the ability to increase levels of HDL in the body.

Korrapati, D., Jeyakumar, S. M., Putcha, U. K., Mendu, V. R., Ponday, L. R., Acharya, V., ... & Vajreswari, A. (2019). Coconut oil consumption improves fat-free mass, plasma HDL-cholesterol and insulin sensitivity in healthy men with normal BMI compared to peanut oil. Clinical Nutrition, 38(6), 2889-2899.

2019 narrative review on Coconut oil consumption which suggests some proposed benefits, such as: topical use for atopic dermatitis and pulling for dental caries, as well as preventing hair damage in topical application.

Wallace, T. C. (2019). Health Effects of Coconut Oil—A Narrative Review of Current Evidence. Journal of the American College of Nutrition, 38(2), 97-107.

According to this 2019 review, there seems to be a role for coconut oil in the treatment of dental caries, to help reduce the growth of plaque as well as to reduce bacterial and viral growth.

Peedikayil, F. C. (2019). Is coconut oil good for oral health? A review. Journal of Health Research and Reviews, 6(1), 1.

2019 study showing that skin hypersensitivity can be decreased through the oral intake of coconut oil in mice. This study suggests a potential option in the treatment of skin hypersensitivity in humans

Tiwari, P., Nagatake, T., Hirata, S. I., Sawane, K., Saika, A., Shibata, Y., ... & Isoyama, J. (2019). Dietary coconut oil ameliorates skin contact hypersensitivity through mead acid production in mice. Allergy, 74(8), 1522-1532.

Significantly increases HDL and LDL compared to other plant oils. Coconut oil actually lowered LDL compared to animal oils. According to this study virgin Coconut oil resulted in better lipid profiles in patients than any other oil in the study.

Teng, M., Zhao, Y. J., Khoo, A. L., Yeo, T. C., Yong, Q. W., & Lim, B. P. (2020). Impact of coconut oil consumption on cardiovascular health: a systematic review and meta-analysis. Nutrition reviews, 78(3), 249-259.

2019 study showing that coconut oil may have some cardiometabolic benefits but at the end of the day it should not be used as a treatment for weight loss.

Santos, H. O., Howell, S., Earnest, C. P., & Teixeira, F. J. (2019). Coconut oil intake and its effects on the cardiometabolic profile–A structured literature review. Progress in cardiovascular diseases.

2018 study indicating that MCTs are not an accurate description of the use of coconut oil. Coconut oil MCTs are preferentially metabolized in the same manner as long chained fatty acids

Sankararaman, S., & Sferra, T. J. (2018). Are we going nuts on coconut oil?. Current nutrition reports, 7(3), 107-115.

2019 study that shows that virgin coconut oil can improve physical activity in rats as well as provide hepatoprotective (liver protecting) effects.

Sinaga, f. A., harahap, u., silalahi, j., & sipahutar, h. (2019). Antioxidant and hepatoprotective effects of virgin coconut oil at maximum physical activity. Asian j pharm clin res, 12(3), 272-276.

Small study which indicates that there are limited cognitive benefits in the improvement of human memory.

Karr, J. E., Grindstaff, T. R., & Alexander, J. E. (2012). Omega-3 polyunsaturated fatty acids and cognition in a college-aged population. Experimental and clinical psychopharmacology, 20(3), 236.

C L I N I C A L E V I D E N C E F O R E L D E R B E R R Y

& Z I N C KEY FINDINGS / IMPORTANT QUOTES STUDY REFERENCED

2019 meta-analysis demonstrates that elderberry has been able to reduce upper respiratory symptoms (cold and flu) and is offered as a potential alternative to the misuse of antibiotics for the treatment of the common cold and influenza symptoms.

Hawkins, J., Baker, C., Cherry, L., & Dunne, E. (2019). Black elderberry (Sambucus nigra) supplementation effectively treats upper respiratory symptoms: A meta-analysis of randomized, controlled clinical trials. Complementary therapies in medicine, 42, 361-365.

A 2001 study which examined the effectiveness of oral sambucus nigra berry. This study found that when taken in human beings reduces duration of flu symptoms by 3-4 days. Also various studies indicate that the intake of elderberry extract reduces inflammation markers throughout the body and modulate the immune system in healthy individuals.

Barak, V., Halperin, T., & Kalickman, I. (2001). The effect of Sambucol, a black elderberry-based, natural product, on the production of human cytokines: I. Inflammatory cytokines. Eur Cytokine Netw, 12(2), 290-296.

A 2015 study which discovered an association of elderberry extract and the modulation of cholesterol and heart function in mice. This study demonstrated increases in healthy cholesterol and was specifically testing the population of mice with excessive blood lipids.

Farrell, N., Norris, G., Lee, S. G., Chun, O. K., & Blesso, C. N. (2015). Anthocyanin-rich black elderberry extract improves markers of HDL function and reduces aortic cholesterol in hyperlipidemic mice. Food & function, 6(4), 1278-1287.

2017 review demonstrating the ability of elderberry to kill various strains of viruses. These applications while still in their infancy may be the future direction of clinical research.

Randall, S., & Robert, F. (2017). Review of the Antiviral Properties of Black Elder (Sambucus nigra L.) Products. Phytotherapy research.

2019 review study which demonstrates the power of anthocyanin (active ingredient in Elderberry extract) with the ability to reduce LDL cholesterol as well as total cholesterol

Daneshzad, E., Shab-Bidar, S., Mohammadpour, Z., & Djafarian, K. (2019). Effect of anthocyanin supplementation on cardio-metabolic biomarkers: A systematic review and meta-analysis of randomized controlled trials. Clinical Nutrition, 38(3), 1153-1165.

2010 study showing that zinc at a dose as low as 7mg may help to reduce depressive symptoms in young women.

Sawada, T., & Yokoi, K. (2010). Effect of zinc supplementation on mood states in young women: a pilot study. European journal of clinical nutrition, 64(3), 331-333.

“Zinc administered within 24 hours of onset of symptoms reduces the duration and severity of the common cold in healthy people. When supplemented for at least five months, it reduces cold incidence, school absenteeism and prescription of antibiotics in children.”

Singh, M., & Das, R. R. (2011, February 16). Zinc for the common cold. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/21328251

“Supplementation of 45mg elemental zinc for a period of 12 months in elderly persons who had low baseline zinc levels, the infection rate seen with supplementation (29%) was lower than placebo (88%) although upper respiratory tract infection rates trended to be less common (50% reduction) but this failed to reach significance”

Hemilä, Harri, et al. "Zinc acetate lozenges for the treatment of the common cold: a randomised controlled trial." BMJ open 10.1 (2020).

Research study showing that the use of zinc lozenges for the treatment of the common cold were effective

Hemilä, H., & Chalker, E. (2015). The effectiveness of high dose

zinc acetate lozenges on various common cold symptoms: a meta-

analysis. BMC family practice, 16(1), 24.

2017 study which suggested a potential role in the reduction of cold symptoms in the lozenge form of zinc acetate of gluconate

Hemilä, H. (2017). Zinc lozenges and the common cold: a meta-

analysis comparing zinc acetate and zinc gluconate, and the role

of zinc dosage. JRSM open, 8(5), 2054270417694291.

C L I N I C A L E V I D E N C E F O R A C A I B E R R Y

E X T R A C T KEY FINDINGS / IMPORTANT QUOTES STUDY REFERENCED

There is good research to indicate that anthocyanin does improve human cognitive function:

Kent, K., Charlton, K. E., Netzel, M., & Fanning, K. (2017). Food‐based anthocyanin intake and cognitive outcomes in human intervention trials: a systematic review. Journal of human nutrition and dietetics, 30(3), 260-274.

Study suggesting that anthocyanins do help to improve heart health overall by reducing risk of cardiovascular disease in a review of all prospective studies in 2018

Kimble, R., Keane, K. M., Lodge, J. K., & Howatson, G. (2019). Dietary intake of anthocyanins and risk of cardiovascular disease: A systematic review and meta-analysis of prospective cohort studies. Critical reviews in food science and nutrition, 59(18), 3032-3043.

Study looking specifically at the effects of acai berry on mammalian health. Tested on rats to observe changes to liver damage. Found that acai berry extract was helpful in mitigating this illness.

de Souza Machado, F., Kuo, J., Wohlenberg, M. F., da Rocha Frusciante, M., Freitas, M., Oliveira, A. S., ... & Funchal, C. (2016). Subchronic treatment with acai frozen pulp prevents the brain oxidative damage in rats with acute liver failure. Metabolic brain disease, 31(6), 1427-1434.

Acai berry has been shown to reduce the effect of inflammatory biomarkers. This was found to be true in healthy women.

de Freitas Castro, T., Gomes, S. F., dos Santos Silva, F. C., de Oliveira, F. L. P., do Amaral, J. F., de Andrade Previato, H. D. R., ... & Volp, A. C. P. (2019). The effect of acai (Euterpe oleracea Mart.) intake on the atherosclerosis inflammatory mediators (sCD40L e CCL5) in apparently healthy women. Nutrition & Food Science.

Study indicating that there is evidence to suggest that many of the acai products on the market are devoid of acai fruit or contain unlisted ingredients that effect efficacy

Earling, M., Beadle, T., & Niemeyer, E. D. (2019). Açai Berry (Euterpe oleracea) Dietary Supplements: Variations in Anthocyanin and Flavonoid Concentrations, Phenolic Contents, and Antioxidant Properties. Plant Foods for Human Nutrition, 74(3), 421-429.

2019 study which indicates that the extract of acai berry may be helpful in limiting prostate cancer cell growth in vitro.

Jobim, M. L., Barbisan, F., Fortuna, M., Teixeira, C. F., Boligon, A. A., Ribeiro, E. E., & da Cruz, I. B. M. (2019). Açai (Euterpe oleracea, Mart.), an Amazonian fruit has antitumor effects on prostate cancer cells. Archives in Biosciences & Health, 1-18.

Recent systematic review that indicates new potential uses in modulating: vasodilation, hypertension, hyperlipidemia (cholesterol concerns) as well as metabolic syndrome and renal failure

de Moura, R. S., & Resende, Â. C. (2016). Cardiovascular and metabolic effects of açaí, an Amazon plant. Journal of Cardiovascular Pharmacology, 68(1), 19-26.

C L I N I C A L E V I D E N C E F O R F L A X S E E D O I L

KEY FINDINGS / IMPORTANT QUOTES STUDY REFERENCED

2010 study which indicates a potential role in modifying cholesterol levels through the effect of ALA.

Rodriguez-Leyva, D., Bassett, C. M., McCullough, R., & Pierce, G. N. (2010). The cardiovascular effects of flaxseed and its omega-3 fatty acid, alpha-linolenic acid. Canadian Journal of Cardiology, 26(9), 489-496.

2006 study that indicates that flax seed oil may be very helpful as an alternative to fish oils in terms of supporting the body in chronic disease. This study also indicates that flaxseed oil also increases levels of omega 3 fatty acids.

Harper, C. R., Edwards, M. J., DeFilipis, A. P., & Jacobson, T. A. (2006). Flaxseed oil increases the plasma concentrations of cardioprotective (n-3) fatty acids in humans. The Journal of nutrition, 136(1), 83-87.

2017 study which explores the role of flaxseed oil in the treatment of metabolic syndrome. This is demonstrated by the changes of waist circumference.

Akrami, A., Nikaein, F., Babajafari, S., Faghih, S., & Zibaeenejad, M. J. (2017). Effects of Flaxseed Oil Consumption on Anthropometric Parameters in the Patients with Metabolic Syndrome: A Randomized Clinical Trial. Galen Medical Journal, 6(1), 44-51.

Summary study which indicates the ability of flaxseed oil in reducing inflammatory markers in the body in particular IL-6

Wallace, F. A., Miles, E. A., & Calder, P. C. (2003). Comparison of the effects of linseed oil and different doses of fish oil on mononuclear cell function in healthy human subjects. British Journal of Nutrition, 89(5), 679-689.

Indication that ALA has the ability to reduce endothelial damage in blood vessels. Reduces inflammation in blood vessels as well.

Bork, C. S., Baker, E. J., Lundbye-Christensen, S., Miles, E. A., & Calder, P. C. (2019). Lowering the linoleic acid to alpha-linoleic acid ratio decreases the production of inflammatory mediators by cultured human endothelial cells. Prostaglandins, Leukotrienes and Essential Fatty Acids, 141, 1-8.

Flax Seed extract oleic acid, has the ability to modulate glucose production and to affect glucose markers.

Obici, S., Feng, Z., Morgan, K., Stein, D., Karkanias, G., & Rossetti, L. (2002). Central administration of oleic acid inhibits glucose production and food intake. Diabetes, 51(2), 271-275.

“Currently, several antioxidants have been studied with the aim of reducing/slowing the progression of neurodegenerative processes. Lipoic acid is considered a universal antioxidant because it is an amphipathic substance. Lipoic acid and its reduced form, dihidrolipoic acid, act against reactive oxygen species, reducing oxidative stress. Therefore, this antioxidant has been used in the treatment of many diseases, including a new perspective for the treatment of Parkinson's disease”

De Araújo, D. P., Lobato, R. D. F. G., Cavalcanti, J. R. L. D. P., Sampaio, L. R. L., Araújo, P. V. P., Silva, M. C. C., ... & Vasconcelos, S. M. M. (2011). The contributions of antioxidant activity of lipoic acid in reducing neurogenerative progression of Parkinson’s disease: a review. International Journal of Neuroscience, 121(2), 51-57.

2019 study indicating the use of flax seed oil preparations as a means of treating dry eyes when used topically.

Downie, L. E., Hom, M. M., Berdy, G. J., El-Harazi, S., Verachtert, A., Tan, J., ... & Vehige, J. (2019). An artificial tear containing flaxseed oil for treating dry eye disease: A randomized controlled trial. The ocular surface.

N O N - M E D I C I N A L I N G R E D I E N T S

- The Softgel: (3 ingredients)

o Glycerin

▪ Plant-derived, sourced from palm oil, soy or coconut oil

▪ Has anti-viral and anti-bacterial properties

▪ Primary use: a strong hydrating effect, to prevent drying out of the softgel

o Purified Water

▪ Water that has been distilled and purified

▪ Primary Use: To maintain hydration of the capsule and prevent dessication

o Tapioca Starch

▪ Plant-Derived, sourced from the plant manihot esculenta (Cassava) roots.

▪ Primary use: a very flexible complex starch that is easily broken down by the

human body, the same ingredient found in bubble tea and tapioca pudding.

O T H E R N A T U R A L I N G R E D I E N T S :

- Chlorophyllin

▪ Plant-Derived, sourced from various green leafy plants, sometimes combined

with Copper and Sodium salts

▪ Primary use: Reduces odor by binding odorous compounds in the capsule as

well as binds Mutagens (PCH’s) in the body.

- Lecithin

o Plant-Derived compound sourced from Soy Bean

o Primary Use: as an emulsive agent which allows improved solubility of the ingredients

- Vitamin E

o Plant-derived compound from sunflower oil

o Primary Use: due to its antioxidant effects, helps to promote the stability of the

supplement and ensure good antioxidant activity.

I N G R E D I E N T S W E ’ V E E X C L U D E D :

Nuts, Gluten, Dairy, Wheat, BPA, All Animal Products, All artificial colors, flavors and artificial preservatives.

N O N - M E D I C I N A L I N G R E D I E N T S I N B E N E M A X

N O N - M E D I C I N A L I N G R E D I E N T

F O U N D I N

Glycerin ALL PRODUCTS

Lecithin Acai Berry Extract Elderberry + Zinc

Purified Water ALL PRODUCTS

Chlorophyllin CoQ10

Silicone Gel CoQ10 Acai Berry Extract

Elderberry and Zinc

Sodium Copper Chlorophyllin Borage Oil Hemp Seed Oil

Acai Berry Extract Elderberry + Zinc

Soybean Oil Elderberry and Zinc Acai Berry Extract

Starch ALL PRODUCTS

Sunflower Oil CoQ10 Vitamin D2

Vitamin E Flax Seed Oil Evening Primrose Oil

Vitamin D2 DHA CLA

A B O U T O U R S O F T G E L S :

Our softgels are the first of their kind in North America. Tapioca-Starch based capsules are better

absorbed, better digested as well as side-effect and risk-free when compared to their alternatives.

Consider the following research on both Tapioca starch and alternatives:

Benefits of a Softgel:

According to the evidence “The softgel dosage form offers several advantages over other oral dosage

forms, such as delivering a liquid matrix designed to solubilize and improve the oral bioavailability of a

poorly soluble compound as a unit dose solid dosage form, delivering low and ultra-low doses of a

compound, delivering a low melting compound, and minimizing potential generation of dust during

manufacturing and thereby improving the safety of production personnel”

- Gullapalli, R. P. (2010). Soft gelatin capsules (softgels). Journal of pharmaceutical sciences, 99(10), 4107-4148.

Evidence also shows that liquid softgels were equally as effective as a liquid solution with the delivery of L-thyroxine

- Vita, R., Fallahi, P., Antonelli, A., & Benvenga, S. (2014). The administration of L-thyroxine as soft gel capsule or liquid solution. Expert opinion on drug delivery, 11(7), 1103-1111.

According to the research softgels can be much more effective than tablets in the delivery of medication - Santaguida, M. G., Virili, C., Del Duca, S. C., Cellini, M., Gatto, I., Brusca, N., ... & Centanni, M.

(2015). Thyroxine softgel capsule in patients with gastric-related T 4 malabsorption. Endocrine, 49(1), 51-57.

Tapioca Starch in particular is very helpful at preventing cross-linking reactions and clumping. Likewise, it can be a very easily broken down capsule that increases bioavailability of the contents of its softshell.

- Liu, K., Kong, X. L., Li, Q. M., Zhang, H. L., Zha, X. Q., & Luo, J. P. (2020). Stability and bioavailability of vitamin D3 encapsulated in composite gels of whey protein isolate and lotus root amylopectin. Carbohydrate polymers, 227, 115337.

- In another study, using a starch and glycol (glycerin derivative) mix they found that it enhanced oral bioavailability for the drug itraconazole (a powerful antifungal)

OUR COMPETITOR’S SOFTGELS OFTEN CONTAIN: Carrageenan: an additive in the softgel of the majority of vegan supplements on the market today. According to a 2017 study

- “Carrageenan has also produced ulcerative lesions in rabbits, mice, and rats that were associated with weight loss, anemia, diarrhea, visible or occult blood, and sometimes mucus in the feces.” Additional research confirms that “It is likely that mechanisms by which carrageenan induces inflammation in the human intestine are similar to animals and multifactorial: the stimulation of pro-inflammatory cytokines, the disruption of the epithelial barrier, and the interference with innate mucosal immune responses to microorganisms”

According to a 2020 study it would be unethical to even use carrageenan as in intervention in randomized control trials. This study showed that these changes in the gut microbiome mentioned above are due to carrageenan modifying your gut microbiota and leading to more inflammation

- Mi, Y., Chin, Y. X., Cao, W. X., Chang, Y. G., Lim, P. E., Xue, C. H., & Tang, Q. J. (2020). Native κ-carrageenan induced-colitis is related to host intestinal microecology. International Journal of Biological Macromolecules.

Hypromellose/Cellulose: According to the current research are essentially from synthetic origin and as such do not necessarily quality as vegetarian products Gelatin Capsules: Have been associated with mad cow disease and animal-transmitted illnesses. This

represents a very low risk. Yet this risk is one that is nonetheless significant. They were the subject of a

massive systematic review (discussed below) and in Europe they’ve had to make regulations to not use

certain parts of the cow for manufacturing gelatin due to the fact that it must be processed HEAVILY to

ensure a lack of animal diseases. See below:

- “No differences in dissolution or absorption between gelatin and starch or even Hypromellose

cellulose” …..”Starch capsules compared to soft gelatin capsules, water migration is less in

starch-PVA-based preparations and hence, subsequent less drug crystallization. Another

advantage is the surface of starch-PVA capsules is rougher and hence more resistant to

mechanical deformation and more amenable to coating process.”

- “lower moisture content, low hygroscopicity, physical stability, stability in different ranges of

temperature and humidity are advantages that favor the use of non-gelatin capsule”

o Prakash, A., Soni, H., Mishra, A., & Sarma, P. (2017). Are your capsules vegetarian or nonvegetarian: An ethical and scientific justification. Indian journal of pharmacology, 49(5), 401.