Top 10 Supplements With Evidence-Backed Benefits

In the vast landscape of dietary supplements, it can be challenging to separate the truly effective and safe ones from the overhyped. With promises of improved health and longevity, how can you discern which supplements are backed by science and which are merely trendy fads? Here, we discuss supplements that are supported by strong scientific evidence.

Creatine

Creatine is a compound formed from the amino acids L-arginine, glycine, and L-methionine. It plays a crucial role in energy metabolism, muscle performance, and recovery. Creatine can also be used to increase high-intensity exercise capacity and lean body mass (rather than fat mass) during training. Initial safety concerns regarding creatine have been disproven. Studies have found that creatine does not cause hair loss or increased uric acid levels, does not result in kidney damage in healthy people, and is not associated with either dehydration or muscle cramping. 

Emerging evidence suggests that creatine supplementation increases both muscle and brain creatine stores. This is particularly important during periods of stress—such as sleep disruption and aging—which cause reductions in brain creatine levels. A 2022 meta-analysis (a study that combines the results of multiple studies) showed that creatine supplementation can enhance memory performance in healthy individuals, especially in older adults (66–76 years).

Creatine is usually dosed at 5 mg per day in the form of Creatine Monohydrate. Powders tend to dissolve poorly in cold and room-temperature water, so they need to be mixed with warm water. 

Protein Powder

Higher muscle strength is associated with lower death rates from all causes, so it is important to maximize muscle strength in youth, maintain that muscle strength in middle age, and minimize muscle loss in older age. Nutrition and exercise training can slow or reverse muscle weakening, functional impairment, and disability, so clinical guidelines suggest increasing our protein intake. 

Some studies have reported that mice live longer on a low-protein diet, leading some people to recommend low-protein diets for longevity. However, this has not been shown in humans. We need to preserve muscle strength in order to maintain independence and resilience against disease during aging. Furthermore, a 2020 study reported that higher total protein intakes are associated with lower all-cause death rates, thereby supporting the benefits of the recommended 1.6 - 2.2 g/kg body weight/day of dietary protein. Note that an intake higher than 1.62 g/kg/day does not further contribute to resistance training-induced increases in muscle mass. Older adults should aim for a protein intake of 2 g/kg/day (i.e., 160 g of protein for an 80 kg individual). This higher intake would help older adults compensate for their muscle loss and the fact that their digestive tracts do not absorb protein as well as younger people.

The International Society of Sports Nutrition recommends multiple protein meals throughout the day, spaced 3-4 hours apart. Protein in protein powders is highly bioavailable, and powders—which should ideally not have added salt and sugars—can be mixed in with smoothies and shakes. 

Trimethylglycine (TMG or betaine)

TMG helps to accelerate the recycling of adenosine triphosphate (ATP, the cell's energy currency). This could boost muscle protein synthesis and improve performance by staving off fatigue during high-intensity activities. 

In a 2017 systematic review, TMG supplementation was shown to increase strength and power only when combined with exercise training. Indeed, TMG might be most effective when combined with high-intensity strength/power exercise, so TMG is likely to work best in a training environment with high metabolic demands. For example, TMG increased VO2max (aerobic fitness) and repeated sprint ability performance in professional youth soccer players. By contrast, TMG supplementation with or without creatine supplementation did not affect strength and power performance in untrained individuals. 

Homocysteine is an amino acid that increases the risk of Alzheimer's disease when its levels in the blood are elevated. Therefore, lowering high blood homocysteine levels is one of the most promising interventions to help prevent Alzheimer's disease. TMG reduces the levels of homocysteine in the blood. More research on the effects of TMG on dementia rates is warranted, but given the current knowledge about the benefits, TMG is usually dosed at 500 mg – 1 g per day.  

Vitamins and Minerals

A study reported that 31% of the U.S. population were at risk of at least one vitamin deficiency or anemia. People often struggle to reach the recommended daily intakes of all the micronutrients—especially vitamin B3, vitamin D3, vitamin K2, zinc, and magnesium—from diet alone. A recent large study showed that daily multivitamin-mineral supplementation for three years improved global cognition in older adults. Most multivitamin supplements significantly overshoot recommended daily intakes, but when choosing a multivitamin or mineral supplement, opt for one that avoids 'mega dosing' and is formulated to supplement a healthy diet. 

Omega-3

The three main omega-3 fatty acids are alpha-linolenic acid (ALA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA). ALA is an essential fatty acid (your body cannot make it), so you must get it from your food and beverages. The body converts small amounts of ALA to EPA and DHA, but getting these two marine omega-3 fatty acids from foods or dietary supplements is the only way to increase their levels in the body. EPA and DHA are found in fish oil, krill oil, cod liver oil, and vegetarian products that contain algal oil.

Studies have consistently shown that people who consume fish regularly have significantly reduced cognitive decline compared to those who do not eat fish. These findings spurred the hypothesis that omega-3 marine oil supplements can alleviate cognitive decline, but evidence for this from randomized controlled trials is lacking. For example, daily omega-3 supplements did not improve cognition in cognitively healthy older adults, in older people with an eye condition known as age-related macular degeneration, or even in patients with mild/moderate Alzheimer's disease. These findings are in line with multiple meta-analyses showing that compared to a placebo, omega-3 supplementation does not affect cognitive function in healthy older adults or in people with Alzheimer's disease.

Benefits might be limited to people who do not regularly consume fatty fish in their diets. In a study amongst more than 25,000 people, omega-3 supplementation at a dose of 1g/day reduced the risk of a heart attack by 28%. This finding was supported by a Mayo Clinic meta-analysis that showed a significant reduction in the risk of heart attacks with omega-3 supplementation. The American Heart Association concluded that prescription high-dose (4 g/day) omega-3 fatty acids can effectively and safely help lower triglyceride levels. 

Factors affecting the effectiveness of omega-3 supplementation include the dose of DHA and EPA, the EPA to DHA ratio, baseline EPA and DHA status, medication use, health status, and intake of other nutrients. Omega-3 supplements tend to come as ether capsules or bottled liquids, and they take the chemical form of either triglycerides or ethyl esters. Absorption of the oils is increased when the supplement is taken with a meal containing other fats, when the triglyceride form is taken instead of the ethyl ester form, and when it is not 'enteric-coated'. Omega-3 supplements are usually dosed at 1-2 capsules or 5 ml of liquid a day.

Psyllium Husk

Psyllium husk, which is important for our gut bacteria, is a source of primarily soluble fiber. Psyllium husk can help regulate blood glucose levels, soften and add bulk to stools, increase feelings of fullness, and help promote weight loss. Higher fiber intakes are associated with reductions in total cholesterol and low-density lipoprotein (LDL) cholesterol. Additionally, psyllium husk is effective at reducing high blood pressure. One safety concern related to psyllium husk supplements is lead contamination because exposure to this heavy metal can adversely affect the liver, kidneys, nervous system, and cardiovascular system. Therefore, it is critical to choose a brand that is third-party tested for purity and heavy metal content.

Psyllium husk supplements are usually in the form of powders or capsules. Psyllium husk powders can be mixed into smoothies or shakes. It is best to start with a low dose (such as ½ a teaspoon of husk powder) and gradually increase the dose to 1-2 teaspoons a day (5-10 g). It is important to ensure that you take psyllium supplements with plenty of liquid (ideally water). 

Collagen 

Collagen is the most abundant protein in the body. Amino acids are the building blocks of proteins, and collagen peptides are short chains of amino acids. Therefore, much debate exists about whether collagen peptide supplements confer additional benefits over and above a satisfactory protein intake. A randomized, double-blinded, placebo-controlled trial showed that collagen supplements reduced wrinkles by approximately 8%. 

In a 2020 randomized double-blind pilot clinical trial comparing the effects of 36 g hydrolyzed bovine collagen to 35 g soy protein on wound healing in male burn patients, wound healing rates were significantly higher following supplementation with hydrolyzed collagen compared to the soy protein. (Soy protein is highly bioavailable and has no effect on estrogen or testosterone levels in men, making soy protein a good comparator). Furthermore, a 2023 meta-analysis found good evidence that hydrolyzed collagen improves skin hydration and elasticity. 

Collagen peptide supplements are usually dosed at 10 - 15 g per day in addition to meeting protein targets.

Hyaluronic Acid (hyaluronan)

Hyaluronan is a substance that is naturally present in the human body; it is found in high concentrations in the skin, joints, and eyes. Hyaluronan has a unique ability to retain water, which helps keep tissues moist and well-lubricated. Although 50% of the total body hyaluronan is present in the skin, the quantity of hyaluronan in the skin gradually decreases with aging. Several well-designed human trials show that oral hyaluronic acid supplementation improves skin hydration, tone, thickness, elasticity, firmness, luster, and suppleness whilst reducing skin wrinkles and protecting against skin dehydration. 

Safety concerns have been raised regarding the link between hyaluronic acid and cancer, but when hyaluronic acid was given to mice that already had cancer, there was no detrimental effect. Human trials lasting at least 12 months have also shown no safety concerns.

When we ingest high-molecular-weight oral hyaluronic acid, intestinal bacteria break it down into shorter fragments of low-molecular-weight. Even though the bioavailability of hyaluronic acid differs depending on the molecular weight, both high- and low-molecular-weight hyaluronic acid inhibit skin wrinkles and improve skin luster and suppleness. Although more research is needed, the literature currently suggests that the molecular weight of hyaluronic acid in supplements is unlikely to make a difference in terms of benefits. Doses of hyaluronic acid in human trials range from 80 mg - 200 mg per day.

Low-dose Melatonin

Melatonin is a hormone created by the pineal gland in the brain. When it gets dark, the pineal gland starts making melatonin, while light makes it stop. Melatonin helps control your circadian rhythm so that you feel sleepy at night and awake during the day. This enables you to fall asleep and have a good night's rest. Studies have shown that melatonin helps people fall asleep quicker and improves sleep quality, but confusion arises as to how much melatonin to take and when to take it. 

As a 'chronobiotic agent', melatonin can shift our sleep-wake cycle. Current research supports taking melatonin supplements 1-2 hours before trying to fall asleep for optimum benefits. By contrast, taking melatonin supplements when the body's melatonin levels are already high at night has no effect. Our bodies make 10 - 80 μg (micrograms) of melatonin per night, but people who take melatonin supplements often take much higher doses than that. However, more research is needed to ascertain the long-term effects of higher doses, so it would be advisable not to exceed a dose of 300 μg melatonin per day. In addition, this is an active area of research, and there is no strong existing evidence to suggest that melatonin supplementation will reduce death rates or heart disease. 

An important aspect to consider with respect to aging is that in addition to its effects on sleep, melatonin also has antioxidant and anti-inflammatory effects. As we age, melatonin production in the body decreases by 10-fold, and decreased melatonin production worsens the aging process. It is possible that a vicious cycle is set up whereby the reduced melatonin with age exacerbates inflammation, which then further decreases the amount of melatonin we produce. Therefore, to try and restore melatonin levels to a more youthful state, older adults should consider taking a low-dose, prolonged-release version of a melatonin supplement 1-2 hours before trying to fall asleep. 

N-acetyl cysteine (NAC)    

NAC is a compound derived from the amino acid L-cysteine. Reactive oxygen species (oxidants) increase as we age in order to maintain survival. However, they eventually accumulate and aggravate rather than reduce age-associated damage. Maintaining a balance between oxidants and antioxidants is crucial, but a powerful antioxidant called glutathione declines rapidly from the age of 45 years. It is, therefore, advisable to restore the balance between oxidants and antioxidants by supplementing with the building blocks of glutathione. The building blocks include glycine, cysteine, and glutamate.

Unlike the other supplements in this list, NAC research is still in its early stages. However, a randomized, double-blinded, placebo-controlled trial in 2022 showed that glycine and NAC (GlyNAC) supplementation in older adults corrected glutathione deficiency, reduced oxidative stress, and improved mitochondrial dysfunction. Given that collagen and TMG supplements (discussed above) contain glycine, people taking either collagen or glycine could consider only adding 1 g of NAC per day from the age of 45 years.

Conclusion

Supplements can be beneficial to fill specific nutrient gaps, address particular health concerns, or optimize the body's structure/function in some way. However, it is always recommended to try and obtain nutrients from a high-quality diet before turning to supplements. It is also essential to approach supplement use with caution, ensuring that they are safe for you. 

Consulting with an appropriate healthcare professional can help determine the right supplements for your individual needs, given your health status, current medications, and health goals. The supplements above show promise, but in many cases, more randomized controlled trials are needed to determine all the benefits, optimal doses, best dose timings, and contraindications.