Dietary supplements sometimes get dismissed as ineffective or “worthless,” but this blanket skepticism overlooks extremely important evidence and context. While it’s true that some supplements are overhyped or misused, it is also true that many supplements have proven to have significant benefits in the right circumstances. In either clinical practice or public health, supplements ranging from simple vitamins to complex plant extracts have demonstrated tremendous value. This article explores why supplements cannot be broadly written off as useless by sharing documented examples of efficacy, explaining how supplement type and usage affect outcomes, and examining the individual factors determining whether a supplement will be beneficial. The goal here is to provide a nuanced, evidence-based perspective that is informative for healthcare professionals and health-conscious individuals.

Evidence-Backed Benefits of Key Supplements

We begin this journey by examining a few notable examples of supplements playing critical roles in health. Doing so establishes an essential truth: demonstrated efficacy proves that efficacy is possible. It shows supplements are not theoretical conveniences but tangible, impactful tools when used appropriately. By first understanding where and how supplements have already made measurable contributions to human health, we can better appreciate the importance of context, quality, and application—principles that will guide the deeper exploration ahead.

A clear example is prenatal vitamins: supplementing with folic acid before and during early pregnancy dramatically reduces the risk of neural tube defects in babies (birth defects of the brain and spine)​. In fact, periconceptional folic acid can cut the incidence of these serious birth defects roughly in half, if not more​. Prenatal multivitamins also provide iron, iodine, and other nutrients essential for fetal development in mothers whose diets may be lacking. The preventive impact of prenatal supplements on birth defects and maternal anemia demonstrates that they are far from “worthless” – they are standard of care in obstetrics.

Cannabidiol (CBD) is another great example. It’s a compound from the cannabis plant, which was once dismissed as just another wellness fad. Yet purified CBD proved so effective for certain forms of drug-resistant epilepsy that it was developed into an FDA-approved medication (Epidiolex). In rigorous clinical trials, CBD significantly reduced seizure frequency in children with severe epilepsy compared to placebo​. This is a life-changing benefit for patients. Outside of epilepsy, CBD continues to be studied for pain, anxiety, infections, inflammation, and more. Granted, while more research is needed in those areas, the truth is that CBD is another concrete example that a “supplement” can have legitimate medical power when properly used.

Another case in point is N-acetylcysteine (NAC). NAC is available as a dietary supplement for various conditions but is also used in hospitals as a critical care drug. In emergency medicine, NAC is the lifesaving antidote for acetaminophen (Tylenol) overdose. It replenishes glutathione in the liver and prevents acute liver failure​. Given early, NAC dramatically improves survival in acetaminophen poisoning​. Of course, it is also prescribed as a mucolytic (mucus-thinning agent) for chronic bronchitis and cystic fibrosis, helping clear lung secretions. These uses are so well established that NAC is on the World Health Organization’s list of essential medicines. Of course, they also suggest other uses, such as for virus-induced acute hepatic failure, mushroom toxin-induced liver failure, acute alcoholic hepatitis, and heat stroke-induced acute liver failure. The same compound is sold as an oral supplement for its antioxidant properties. For example, some studies have shown that long-term NAC supplementation reduces the frequency of chronic obstructive pulmonary disease exacerbations. Its role as a drug and supplement shows that NAC has real biochemical effects, which means that it’s anything but inert. Dismissing NAC as “worthless” would ignore decades of clinical experience.

Less well-known to the public but definitely noteworthy in integrative medicine are supplements like palmitoylethanolamide (PEA). PEA is a naturally occurring fatty compound that modulates inflammation and pain pathways and can help balance the immune system. In fact, a 2023 systematic review and meta-analysis of double-blind trials found that PEA supplementation produced significant reductions in chronic pain intensity compared to placebo, with a strong overall effect size​. PEA was also very well tolerated across studies​. This suggests PEA can be a valuable adjunct for managing conditions like neuropathic pain or fibromyalgia, especially for patients seeking alternatives to opioids or NSAIDs. Of course, its uses extend well beyond that.

Another good one is olive leaf extract (from Olea europaea), which has shown many tangible health benefits. Rich in polyphenols, olive leaf extract has mild anti-hypertensive and anti-inflammatory effects. In fact, a meta-analysis of clinical trials concluded that olive leaf supplementation significantly lowers blood pressure (with an average reduction of about 4–6 mmHg in systolic pressure) and modestly improves cholesterol levels​. In patients with stage 1 hypertension, one trial even found olive leaf extract was as effective as a low dose of a blood pressure medication (captopril) in reducing blood pressure over 8 weeks. These findings demonstrate that an herbal supplement can produce measurable physiological improvements in cardiovascular risk factors.

Traditional herbal remedies also offer examples of where supplements show promise. Chanca piedra (Phyllanthus niruri), an herb long used in Latin America as a remedy for kidney stones (its Spanish name literally means “stone breaker”), has encouraging evidence. Although many “kidney cleanse” supplements have no data, chanca piedra is an exception: it has been the most-studied herbal ingredient for kidney stone prevention, with multiple animal studies and a few human studies suggesting it can inhibit stone formation or even help dissolve calcium stones​. One review noted that chanca piedra showed some evidence of efficacy and is supported by human trials, even if the data are still limited​. This makes it a compelling adjunctive option for recurrent kidney stone formers under guidance. Of course, anecdotal evidence also suggests it might benefit the gallbladder. The point is that chanca piedra is not mere snake oil – it has pharmacologically active compounds that are under scientific investigation, validating why patients have reported passing stones after using it.

The list of effective supplements is exceptionally long; these are just a few examples. The point is that many supplements have demonstrated remarkable benefits within specific contexts and cannot be dismissed with a broad, generalized judgment. It is also essential to recognize that the phrase “more study needed” does not imply that a supplement is ineffective; it simply reflects a desire for deeper understanding. Similarly, just because one study didn’t find something useful in one specific context doesn’t mean that another study will not find utility at some point with another condition.

Likewise, the absence of formal studies on a particular supplement does not automatically invalidate its utility. Clinical research often overlooks the obvious—for instance, there are no randomized controlled trials confirming that elephants are larger than mice, yet the truth remains self-evident. The same holds true for certain supplements. Some effects are so physiologically direct, so consistently observed, that formal validation becomes redundant. For example, electrolyte supplementation reliably improves hydration and muscle function during intense exercise—a fact well known to athletes and military personnel long before large-scale studies were ever considered. Similarly, magnesium supplementation can relieve muscle cramps in deficient individuals, an effect so predictable that it often requires no elaborate clinical confirmation to be accepted in practice. The absence of extensive randomized trials does not diminish these realities; it simply reflects that obvious truths are rarely prioritized in research funding or academic inquiry. Similarly, the absence of evidence should not be conflated with evidence of absence. Careful judgment, clinical observation, and mechanistic plausibility must all be considered when evaluating the potential of supplements.

Nonetheless, the evidence-based uses of supplements in medicine and health (preventing birth defects, controlling seizures, protecting the liver, relieving pain, improving mild hypertension, etc.) show that these products can indeed exert significant effects, sometimes even better than pharmaceuticals (such as berberine, silver, or even honey, to name a few). Granted, this is not to claim every supplement is a panacea or that they should replace standard treatments. Instead, it merely refutes the cynicism that all supplements are useless, because some supplements are highly valuable health maintenance and therapy tools when used appropriately. However, this understanding merely sets the stage for what comes next. To truly appreciate this topic, we must understand some of the nuances.

Different Types of Supplements

Briefly, before we get into the weeds, two key points must be understood. First, a supplement is exactly what the name implies: something that adds to existing nutrition, not a replacement for it. Second, the Recommended Dietary Allowance (RDA) represents the minimum intake required to prevent overt deficiency—not the optimal level for achieving robust health or correcting subclinical deficiencies. This misunderstanding adds significant complexity and confusion, as many assume that meeting the RDA equates to nutritional sufficiency. In reality, higher intake levels are often necessary to optimize function, correct imbalances, or meet individual physiological demands. This is precisely why thoughtful supplementation is not only reasonable but necessary in many cases.

That said, the word “supplement” encompasses a diverse spectrum of products, and it’s important to distinguish their categories and purposes. Vitamins and minerals are perhaps the most straightforward type. These are the essential micronutrients the human body needs to function. Vitamins (like A, C, D, E, K, and the B-complex) are organic compounds, whereas minerals (like calcium, magnesium, iron, zinc) are elements or inorganic compounds.

Vitamin and mineral supplements are typically used to prevent or correct nutrient deficiencies or to provide nutritional “insurance” when dietary intake is inadequate (which is the case for most Americans). A daily multivitamin, for example, contains low doses of many essential nutrients. However, this also means that these lower doses are not “therapeutic doses,” meaning their impact will likely be less pronounced. Specific higher-dose vitamin/mineral pills (like vitamin D, B12, iron, or calcium tablets) may be taken if a person is known to be deficient or has increased needs. These supplements aim to support normal physiology. For instance, vitamin D tablets are used to ensure proper calcium absorption for bone health, iron pills are used to treat anemia, etc.

Beyond basic nutrients, there is a broad category of nutraceuticals and specialty supplements. The term “nutraceutical” generally refers to compounds derived from foods or other natural sources taken for health benefits beyond their nutritional value​. This includes omega-3 fish oil, Coenzyme Q10, glucosamine, probiotics, and plant-derived compounds such as curcumin (from turmeric) or resveratrol (from grapes). These are not necessarily “essential” to survive (unlike vitamins or minerals), but they may promote wellness or help manage certain conditions. For example, omega-3 fatty acids from fish oil can lower triglycerides and have anti-inflammatory effects; glucosamine and chondroitin are taken for joint health; and probiotics aim to support gut microbiome balance. In fact, many earlier examples (CBD, NAC, PEA) also fall under nutraceuticals, as they are biochemicals with specific therapeutic actions.

Another major category is herbal supplements or botanicals. These are products made from plants – using parts like roots, leaves, bark, or extracts – that are taken for their medicinal properties. Humans have used herbs in traditional medicine for millennia (think of ginseng, garlic, Ginkgo biloba, St. John’s Wort, etc.), and modern supplements continue this practice in a concentrated form. Of course, many modern herbal supplements often contain a complex mix of phytochemicals.

One of the best examples here is olive leaf extract. As mentioned, olive leaf extract is known for its polyphenol content, which is believed to confer some blood-pressure-lowering and antioxidant effects. One of these chemicals, called “oleuropein,” is a glycosylated seco-iridoid known for its pharmacological activities, including antioxidant, anti-inflammatory, anti-atherogenic, anti-cancer activities, antimicrobial activity, antiviral activity, hypolipidemic, and hypoglycemic effects. This is to say that most people likely miss the utility of OLE, which is also true of countless other supplement options.

An interesting nuance, especially relevant to vitamins, is whether they are fat-soluble or water-soluble, because this impacts how they behave in the body. Fat-soluble vitamins (A, D, E, and K) dissolve in fat and are absorbed with dietary fats. The body can store them in the liver and fatty tissues. This means deficiencies might take longer to manifest, but on the flip side, excess doses can accumulate and potentially reach toxic levels over time​. For example, taking extremely high doses of vitamin A or D for prolonged periods can lead to hypervitaminosis and organ damage because the excess isn’t easily excreted. Of course, taking D without K2 can also be problematic, just like taking zinc without copper can become a problem.

On the other hand, we have water-soluble vitamins, including vitamin C and B vitamins. These dissolve in water, are not stored appreciably (aside from B12 to some extent), and excess amounts are usually flushed out in urine. As a result, water-soluble vitamin supplements must be taken more regularly to maintain levels. Moreover, they also tend to be safer in terms of overdose – megadoses are mostly excreted, so toxicity is rare. However, “more is not necessarily better,” as an excess of certain water-soluble vitamins could still cause side effects (for instance, too much vitamin B6 over time can cause nerve issues, and too much vitamin C can cause diarrhea). Understanding this distinction helps clarify why one shouldn’t take ten times the recommended amount of vitamin D daily (because it builds up), whereas taking ten times the recommended amount of vitamin C might simply result in expensive urine or a colon cleanse.

Indeed, “supplements” range from simple micronutrients to complex herbal extracts. The point is that lumping them all together misses the fact that each category works differently. Vitamins and minerals replenish essential nutrients; nutraceuticals and herbs provide non-essential but potentially beneficial compounds. Appreciating these differences is crucial. Of course, a blanket statement that all supplements are worthless usually comes from focusing on one type in a specific situation (like multivitamins in well-nourished populations) and ignoring others (like targeted nutraceuticals or necessary vitamins in deficient individuals). A smarter approach to supplementation recognizes what category a given product falls into and what realistic role it serves.

Perhaps, this point deserves an analogy. Much like automobiles, supplements come in various forms, each designed for a different function. Just as it would be a mistake to lump a dump truck, a commuter car, and a Formula One racer into the same category and judge them all by the same standards, it is equally misguided to treat all supplements as though they serve the same purpose. Vitamins and minerals act like dependable commuter vehicles, replenishing essential nutrients needed for basic function, while nutraceuticals and herbal extracts function more like specialized performance vehicles—non-essential for survival, but potentially enhancing health when used appropriately.

Now, some vehicles, such as the 1962 Peel P50 (look that up), are charming and may serve a specific niche, but they are highly impractical for most modern needs. However, that does not mean they are useless. In fact, they can be the perfect fit in the right context. The same principle applies to certain supplements.

Even obscure or potentially risky compounds can serve a critical purpose under specific circumstances. Chaparral herb is a fitting example. Although it carries well-documented risks, particularly concerning liver toxicity, research by teams at the University of Oklahoma and the University of Texas at San Antonio has suggested that a compound found in chaparral—nordihydroguaiaretic acid (NDGA)—may have activity against Naegleria fowleri, the so-called “brain-eating amoeba.” In this context, what is ordinarily dismissed as dangerous may, under the right conditions, represent a valuable therapeutic tool.

By the same token, outcomes can be highly effective when the right supplement is matched to the right context, just as a sturdy SUV is ideal for rugged terrain. Conversely, excess or misuse—like commuting to work in a military tank—reflects poor judgment, but that’s not a fault of the vehicle itself. So, whether you drive a commuter car, a racecar, or a tank, the principle remains the same: you must be familiar with the vehicle, its purpose, and its capabilities. Supplements are no different.

Bioavailability: How Timing, Form, and Delivery Affect Efficacy

Even a supplement with proven potential can fail to work if it isn’t taken correctly. This is often an issue of bioavailability. Bioavailability refers to how well a substance is absorbed and reaches circulation to have an active effect​. Supplements typically differ in their absorption based on timing, formulation, and route of administration. In practice, how and when you take a supplement can be almost as important as what you take.

Timing with meals is a simple but critical factor. Some supplements are best taken with food, while others work better on an empty stomach. For example, Serrapeptase is a proteolytic enzyme that should be taken on an empty stomach, away from any food. Bromelain is another proteolytic enzyme that should also be taken away from food, unless you want to use it as a digestive enzyme. Then you have Amylase (breaks down complex carbohydrates), Lipase (breaks down fats), Protease (breaks down proteins), Lactase (breaks down lactose), Sucrase (breaks down sucrose), and the list goes on. However, while taking the wrong enzyme with the wrong types of food will be somewhat pointless, your mistake doesn’t equate to its uselessness.

The point is that timing and context matter. For example, fat-soluble vitamins (A, D, E, K) should be taken alongside a meal that contains some dietary fat, because fat triggers bile secretion and micelle formation in the gut, which are needed for these vitamins to be absorbed​. Swallowing a vitamin D pill with only water on an empty stomach in the morning will result in significantly less absorption than taking it after eating a breakfast with eggs or avocado.

Of course, there are also some seemingly paradoxical supplements. For example, most would likely assume that the best time to take iron would be with food. But, in truth, minerals like iron are best absorbed on an empty stomach. Iron supplements taken with food, especially foods high in calcium or phytates, can significantly reduce absorption. Therefore, taking iron in the morning before eating is often advised. However, it should also be taken with vitamin C (like orange juice), which enhances iron uptake​. Vitamin C converts iron to a more absorbable form and prevents it from forming insoluble complexes, so this pairing is a good example of how timing and combination improve bioavailability.

Supplement form (chemical form or formulation) also matters a great deal. Many minerals come in different salt forms or chelates that influence absorption. Magnesium, for instance, is available as magnesium oxide, citrate, glycinate, malate, etc. Which one works best depends on the context of the need. Magnesium oxide is cheap and compact, but is also poorly absorbed and more likely to cause looser stools. That’s good in some cases, and very bad in others. Magnesium citrate or glycinate are typically much better absorbed in the gut and gentler on the digestive system, so they’re usually more effective for raising magnesium levels. Calcium is another interesting supplement. Calcium carbonate (like in antacids) actually requires a high acid environment in the stomach for absorption. Hence, it is best taken with meals, whereas calcium citrate is absorbed well even in people with lower stomach acid and can be taken anytime.

Then there are liposomal formulations of certain vitamins (like vitamin C) that encase the nutrient in tiny fat-like particles to enhance uptake, sometimes dramatically increasing blood levels compared to standard pills. For some, that’s great. For others, it could simply be too much, too fast.

Indeed, liposomal delivery can be powerful when applied to fragile, degradation-prone compounds. However, it also becomes largely meaningless when applied to substances whose absorption is governed by entirely different biological mechanisms. For example, several companies market “liposomal magnesium” products. However, that doesn’t make much sense. Specific ion channels in the gut control magnesium absorption. Encapsulating it in liposomes does not bypass or improve this pathway. True improvements in absorption depend on selecting better mineral forms, such as magnesium glycinate, not simply altering the packaging. Of course, this truth doesn’t negate the value of liposomal technology or the mineral, just the combination. Different tools for different jobs.

For herbs and nutraceuticals, standardized extracts or specialized forms can improve bioavailability. A classic example is curcumin, the active ingredient of turmeric. Curcumin has notoriously low absorption and is quickly metabolized on its own. Many people waste a lot of money because they don’t know how to absorb more, while others are sitting pretty because they are getting the low dose they were looking for. To address the absorption issue, supplement makers have developed curcumin phytosome (curcumin bound to phosphatidylcholine), nano-curcumin, or added piperine (black pepper extract), which inhibits metabolism. Taking curcumin with piperine can boost its bioavailability by 20-fold or more, turning an otherwise poorly absorbed compound into one that can circulate and exert effects. Now the tables have turned for the person seeking the tiny dose.

Of course, the method of ingestion or route can be crucial for specific vitamins. Vitamin B12 is a great example of this. Many older adults have trouble absorbing B12 from food due to low stomach acid or intrinsic factor. For them, an oral B12 pill might do little. Instead, high-dose sublingual B12 (dissolved under the tongue) can be absorbed directly through mucous membranes, or B12 can be given by intramuscular injection, bypassing the gut entirely. These routes effectively treat a deficiency that oral pills couldn’t touch. Of course, some might prefer to supplement with Betaine HCl, a supplemental hydrochloric acid source that can temporarily increase gastric acidity, potentially restoring the environment needed for optimal B12 (and other nutrients) absorption.

However, even the timing of the day can influence the efficacy of certain supplements beyond just meals. Calcium and magnesium, when used as sleep aids or relaxation aids, are often taken at night since magnesium can have a calming effect, and calcium may help regulate melatonin production. Of course, taking them simultaneously is probably not a good idea, because of the interference with each other’s absorption.

On the other hand, a B-complex vitamin or ginseng (which can be stimulating) is better taken in the morning or afternoon. Otherwise, it might interfere with sleep. Some supplements are split into multiple doses per day to keep blood levels steady (e.g., vitamin C, which has a short half-life, might be taken morning and evening rather than a huge dose once a day, to maintain more consistent levels). Adaptogenic herbs like ashwagandha might be timed to help with stress (morning dose to help daytime stress resilience, and sometimes an evening dose if they also aid sleep).

Of course, an often overlooked layer of complexity in supplementation is the actual source and form of the nutrient itself, which can dramatically influence bioavailability. Since I have mentioned it a few times, we’ll use vitamin B12 as the example here. B12 typically comes in three common forms—cyanocobalamin, methylcobalamin, and hydroxocobalamin.

Due to its low manufacturing cost, Cyanocobalamin is widely used in supplements and multivitamins. However, as the name might imply, it also contains a cyanide molecule that must be cleaved and eliminated by the body after ingestion. Let’s be clear, cyanide is poison, and it’s known that cyanide exposure (even very small amounts) disrupts mitochondrial function. While it’s true that small amounts of cyanide can be converted into thiocyanate (a less toxic compound that is excreted in urine), and people who eat things like Lima beans and cassava get a small dose from time to time, it’s also true that this process is not biologically neutral. The body recognizes cyanide as a toxic threat, triggering enzymatic defense responses and consuming vital biochemical resources, particularly sulfur donors critical for detoxification and antioxidant balance. This contributes to low-grade inflammation, even if the effect is subtle and situational, and such inflammation contributes to a slew of other issues that nobody wants. One must consider the compounding effect of environmental or behavior-related exposures.

Unfortunately, like other poisons and antinutrients found in the diet, you will likely be told that a little bit is okay, the amount is negligible, or everything will be fine in moderation. My favorite excuse is that small exposures are usually handled efficiently in healthy individuals. Still, my arguments include 1) Why take the risk?, 2) Most Americans are not “healthy,” and 2) Even in healthy individuals, this burden is not inconsequential, especially over time. Furthermore, in those with existing impaired detoxification pathways, mitochondrial dysfunction, thyroid vulnerabilities, or epigenetic sensitivities, the use of cyanocobalamin can provoke additional adverse responses.

However, the methylcobalamin form, which is a bioactive form, is generally better absorbed and does not require this additional detoxification step or come with the additional burden. In fact, methylcobalamin or hydroxocobalamin (which, ironically, is sometimes used for cyanide poisoning) is often preferred in clinical practice to minimize biological stress and maximize therapeutic efficacy. Why not just start there? Of course, one could bypass the issue entirely by consuming B12-rich foods, but that’s a different article. The point is that supplement type does matter, and using the wrong form can reduce efficacy or actively burden the system, which demonstrates how even seemingly minor differences in supplement formulation can have significant physiological implications.

On that note, I should also mention that not all forms of vitamins or minerals are equal in how the body absorbs and utilizes them. For example, some people will take beta-carotene, thinking they are doing something right, but beta-carotene must be enzymatically converted into active vitamin A (retinol) in the body. Frankly, the efficiency of this conversion is not ideal in humans. It further varies based on genetics, health status, and other dietary factors. This is to say that in many individuals, especially those with compromised conversion ability, plant-based beta-carotene provides significantly less usable vitamin A compared to preformed (animal-based) sources. So, if you need vitamin A, but you don’t know that you have conversion issues, you could be wasting time and money while getting sicker.

The point is that source, form, and timing together critically determine how much of a supplement is actually absorbed and utilized, not merely what is listed on the label. In short, a supplement’s effectiveness hinges on these important use factors. Ignorance of these truths might lead someone to erroneously conclude that a supplement “does nothing” when, in fact, they were simply taking it in a suboptimal way. For instance, if a person took all their supplements first thing in the morning with coffee and cereal, the caffeine might speed gut transit, reducing absorption, the dairy in the cereal could inhibit iron and some herbals, and the lack of fat might mean the vitamin D pill largely passes through unused. It’s not the supplement’s fault. However, the same regimen could yield very different results by simply adjusting timing (taking certain pills with lunch or dinner, separating those that interfere).

Given these complexities, there is a legitimate argument that some multivitamins can be largely ineffective. Indeed, many are—primarily because they rely on cheaper, less bioavailable forms of vitamins and minerals. Hence, that already low dose becomes even lower. However, high-quality multivitamins that use highly absorbable forms do exist and can provide substantial benefit. The challenge, of course, lies in discerning the difference—something that requires exactly the level of understanding and critical evaluation that I am advocating. Of course, this rabbit hole goes a little deeper.

Interactions: Synergy and Antagonism Between Supplements

Just like prescription drugs, supplements can interact with each other or with medications in ways that can be either helpful (synergistic) or harmful (antagonistic). Understanding these interactions and the context is essential for optimizing supplement use. Two supplements taken together may have a greater combined effect than either alone, or conversely, one may block the action of the other. Sometimes, an interaction that is beneficial for one goal could be counterproductive for another, so context matters tremendously when evaluating supplement combinations.

Consider the examples of NAC (N-acetylcysteine) and berberine mentioned earlier. NAC is a potent antioxidant and glutathione precursor, while berberine is a plant alkaloid known for its benefits on blood sugar and metabolism (among many other things). On the surface, these supplements do very different things. However, evidence suggests they can complement each other under the right circumstances. For example, in women with polycystic ovary syndrome (PCOS) or individuals with metabolic syndrome, berberine and NAC are sometimes used together to improve insulin sensitivity, reduce inflammation, and support liver health. The rationale is that berberine activates pathways (like AMPK) that improve metabolic function, while NAC boosts the body’s master antioxidant (glutathione) and supports detoxification. Together, they tackle oxidative stress and metabolic dysregulation from two angles. In fact, one PCOS treatment study found adding NAC to berberine improved hormonal balance more than berberine alone. This kind of synergy means the whole is greater than the sum of its parts.

Yet, context is everything because taking them together in other situations is a bad idea. For example, if one were using berberine as an experimental anti-cancer supplement (berberine has shown some ability to induce oxidative damage in tumor cells​), loading up on NAC might antagonize that effect by neutralizing the oxidative stress that berberine relies on to kill cancer cells. In other words, high-dose antioxidants like NAC could theoretically blunt berberine’s pro-oxidant, cancer-killing mechanism. This scenario demonstrates that whether a combination is helpful or not depends largely on what outcome you are looking for. This is to say that the same two supplements could be synergistic in one physiological context and antagonistic in another. Knowledge is power!

Of course, there are many well-known synergistic interactions in the supplement world. We already touched on vitamin C and how it dramatically increases iron absorption​. Another classic pair is vitamin D and vitamin K2. Vitamin D promotes calcium absorption and utilization, while K2 helps direct calcium to the bones and prevents it from depositing in arteries. When taken together, especially in people with vitamin D deficiency, these two can work in concert to improve bone mineral density and cardiovascular health markers better than either alone. Magnesium and vitamin B6 are another synergistic duo sometimes used for issues like PMS symptoms or certain types of anxiety; B6 can aid magnesium uptake into cells, and together they support neurotransmitter balance (magnesium helps regulate NMDA receptors, and B6 is a cofactor in synthesizing calming neurotransmitters like GABA). In herbal medicine, synergistic combinations are also common: Traditional Chinese Medicine formulas mix multiple herbs so that one might enhance the active components of another or mitigate side effects. For instance, pairing black pepper extract (piperine) with curcumin, as mentioned, is a synergy that boosts curcumin’s bioavailability.

Conversely, antagonistic interactions can reduce efficacy or cause undesired effects. A simple nutrient example: calcium and iron supplements should not be taken together, because calcium competes with iron for absorption in the intestine​. If someone washes down their iron pill with a glass of milk (rich in calcium), they might substantially impair the iron uptake, effectively wasting the dose. Another subtle interaction: high-dose zinc supplements can interfere with copper absorption over the long term, potentially leading to copper deficiency; this is why many balanced zinc supplements include a small amount of copper to offset the effect. However, even some vitamins can interfere with each other. For example, the WebMD guidelines note that vitamin C can reduce B12’s availability​. The advice given is to take them at least two hours apart to avoid any issues​. While this interaction isn’t typically dangerous, it demonstrates how timing and separation can matter to get the full benefit of each nutrient.

Certain herbal interactions can be problematic, too. For instance, St. John’s Wort (a supplement for depression) induces liver enzymes that can make many medications (and possibly other supplements) break down faster. This means that it can reduce levels of anything from birth control pills to blood thinners. That’s an antagonistic interaction because it decreases the other compound’s effect. Licorice root (in high amounts) can deplete potassium while raising blood pressure, potentially counteracting supplements or drugs meant to lower blood pressure. Melatonin, if taken with caffeine, might be antagonized because caffeine’s stimulant effect can override melatonin’s sleep signal.

The list goes on, but all these examples drive home the idea that supplements do not exist in isolation, and it takes someone truly knowledgeable to help formulate a plan that will actually work. Understand that these supplements operate within the complex chemistry of the body, and when multiple agents are introduced, they can influence one another. This is not necessarily a bad thing. In fact, strategic combinations (like the right balance of vitamins in a multivitamin, or multi-ingredient formulations in herbal supplements) can be designed to maximize synergy and cover nutritional bases. However, this also means that a naive approach of “throw everything together and hope for the best” will likely lead to suboptimal or null results, which skeptics might wrongly interpret as “supplements don’t work.” The reality could be that one supplement or food option was simply canceling out the other.

For consumers and practitioners, the takeaway is to be mindful of supplement interactions just as we are mindful of drug interactions. Sometimes, separating doses by a few hours or adjusting the regimen can avoid an antagonism. And sometimes, deliberately combining supplements can produce a better outcome (as in the case of pairing certain antioxidants with certain medications, or using multiple complementary supplements in a protocol for, say, joint health, like combining glucosamine, chondroitin, MSM, and turmeric for osteoarthritis relief).

Context (the person’s health status and goals), along with a thorough understanding of the supplement being used, largely determines whether a given interaction is desirable or not. Here’s another great example of the necessary context. Antioxidants like NAC or vitamin E might be fantastic for smokers trying to reduce oxidative lung damage (synergy with their body’s needs). However, the same antioxidants given in excess to an athlete during training could theoretically blunt some of the beneficial oxidative signals from exercise that stimulate fitness improvements (a potential antagonism with the training adaptation process). How many physicians or dieticians do you think understand this critical nuance?

The point is that there is nuance, and the complexity is real, which also means that a thorough understanding typically doesn’t happen by reading a label, watching a TikTok video, or reading an article trying to sell you on the latest fad. Moreover, thousands of brands and formulations are available, with the total number of unique supplement options worldwide likely well over 100,000. True expertise on this topic is not achieved by taking a single class. Nonetheless, we must remember that supplements are tools, and like any set of tools, they must be selected and combined skillfully to achieve the desired result.

Context Is Key: Individual Needs and Lifestyle Factors

Perhaps the most important principle when discussing supplement effectiveness is biochemical individuality – the idea that a supplement’s impact can vary greatly depending on the person’s unique situation. In nutrition and medicine, context is everything. A supplement that is transformative for one person might do little for another, not because it “doesn’t work,” but because their bodies and circumstances differ. Effectiveness is highly context-dependent, influenced by individual nutrient status, deficiencies, health conditions, diet, and lifestyle. This nuance is often lost in blanket statements about supplements.

One major factor is whether a person actually needs a given supplement. Supplements tend to have the most pronounced benefits for individuals with a deficit or higher requirement of the nutrient/compound. For example, giving a high-dose vitamin D supplement to someone severely vitamin D deficient (say, a nursing home resident who never gets sun) can yield significant improvements – their energy might improve, bone density can increase, and immune function might improve. In contrast, giving the same high-dose vitamin D to someone with healthy vitamin D levels from regular sun exposure and diet might result in no noticeable benefit (and could even inch them toward an unnecessary excess).

This is borne out in research: many large trials that show “no benefit” for vitamins often include a majority of already sufficient participants. Well, that’s just silly, because subset analyses sometimes find that those who were initially deficient did benefit. For instance, a general population trial of vitamin C might not show cold prevention benefits. Still, if you isolate the subgroup with low vitamin C levels (e.g., smokers or people with poor diets), they may indeed catch fewer colds or recover faster when supplemented. Baseline nutrient status matters and should be considered before recommendations are provided.

That said, we must recognize that America is sick and getting sicker. Obesity rates continue to climb, the majority of adults are living with at least one chronic condition, and a significant portion of the population has inadequate intake or suboptimal blood levels of critical nutrients. Take vitamin D as an example: by some estimates, approximately 40% of U.S. adults are deficient (below 20 ng/mL), with even more falling into the suboptimal range. For magnesium and vitamin B6, nearly half of Americans fail to meet recommended intake levels. Older adults are particularly vulnerable to vitamin B12 deficiency, with 10–20% exhibiting marginal status due to impaired absorption, a problem that is likely underreported. When factoring in the limitations of serum measurements versus cellular or tissue concentrations, the true prevalence of functional deficiency is even greater, though rarely investigated. Either way, the pattern is clear: in all these cases, supplementation can meaningfully correct deficiencies and improve key health markers, such as bone health, nerve function, and blood pressure, in those who are deficient. But that won’t happen if we don’t appreciate the value.

Of course, the presence of medical conditions also heavily influences supplement effectiveness. Take iron supplements: an iron pill can work wonders for a person with iron-deficiency anemia, increasing their hemoglobin, reducing fatigue, and improving exercise tolerance. But give an iron pill to someone with normal iron stores and anemia from another cause, and it won’t help (and might even cause harm by accumulating). Or consider omega-3 fish oil: in someone with high triglycerides or inflammation (like rheumatoid arthritis), high-dose fish oil often shows clear benefits (lowering triglycerides by 20-50%, reducing joint stiffness, etc.). However, fish oil might not make any perceptible difference in a healthy individual with normal lipids and no inflammatory issues (beyond general health maintenance).

I suppose we should also acknowledge that certain diseases or physiological states increase nutrient needs. For example, malabsorption syndromes (celiac disease, Crohn’s disease after bowel surgery) mean the person typically cannot get enough nutrients from food, so supplements of fat-soluble vitamins, iron, etc., become not just helpful but essential. Similarly, many diabetics benefit from supplements like berberine, chromium, or alpha-lipoic acid, which assist glucose metabolism and nerve health, whereas a non-diabetic won’t notice those effects. Pregnant women are a clear case: pregnancy increases the demand for many nutrients (folate, iron, iodine, choline, etc.), and supplementing those is demonstrably beneficial to maternal and fetal health; but giving a high-dose prenatal vitamin to a non-pregnant person isn’t going to confer the same dramatic benefits.

Diet and lifestyle factors also play a substantial role. Supplements often fill gaps or provide a boost relative to one’s diet. A person eating a whole-food, nutrient-dense diet (lots of fruits and lean proteins, etc.) might have less need for a multivitamin or antioxidant supplements, because they’re already obtaining those compounds from food in bioavailable forms. Meanwhile, someone on a restrictive or imbalanced diet (Standard American Diet) is more likely to benefit from supplemental nutrients to avoid deficiencies. A good example of this might be a vegan who likely lacks B12 and omega-3s, or an individual on a very low-calorie weight loss diet.

Another interesting nuance is how an athlete or very physically active person might use up nutrients at a faster rate and benefit from extra protein, B vitamins, magnesium, and antioxidants to aid recovery and performance. It’s not that they are unhealthy; they just need more than the average person. In contrast, a sedentary person might not utilize those extra nutrients as much. Lifestyle habits like smoking can increase requirements for certain vitamins (smokers have lower vitamin C levels on average and may need more vitamin C). Stress can deplete magnesium and B vitamins due to physiological demand, so a stressed individual might feel improvement from supplementation, whereas a relaxed person notices nothing. Even genetics can influence this context: for example, people with certain genetic variants (such as MTHFR mutation) have trouble converting folic acid into its active form and might benefit more from taking methylfolate supplements instead of folic acid – something a person without that genetic issue wouldn’t have to worry about.

Indeed, there is a lot to it, but that’s the point. It’s not some trivial topic, and naive and novice advice, flawed studies with heavily biased questions, and inaccurate conclusions are not helping. These things typically result in sensational headlines saying “X supplement doesn’t work” based on a trial that, upon closer look, wasn’t appropriately targeted in the first place. When such nonsense is published, many people (including healthcare professionals) write off an otherwise exceptional supplement and miss the benefit it could have offered.

The Health Education Gap

Why, then, are supplements so often overlooked or dismissed? In large part, valuing something that has never been meaningfully taught is difficult. Moreover, such ignorance increases the risk of applying the wrong supplement to the wrong problem. The issue is analogous to medication use: we do not expect insulin to benefit a non-diabetic, but for a diabetic, it is lifesaving. Similarly, we do not prescribe antibiotics for viral infections like the common cold, because antibiotics are ineffective against viruses. When physicians once routinely prescribed antibiotics for colds, it contributed to widespread antibiotic resistance—a costly error born from misunderstanding. While supplements are not typically as dramatic in their effects as pharmaceutical drugs, the principle is the same: targeted, informed use can produce meaningful results, whereas indiscriminate use often yields little benefit or unintended consequences.

Personalization is essential in supplementation. When a physician or dietitian is knowledgeable about supplements, they assess an individual’s diet, supplementation habits, family history, bloodwork, and overall health status to determine which supplements—and at what dosages—are appropriate. Some physicians use supplements to significant effect, but typically only because they devoted considerable time outside of formal training to study them.

Unfortunately, the Dunning-Kruger effect plays a significant role in how supplementation is often mishandled. Most healthcare professionals are not adequately trained in nutrition or supplementation, largely because these topics are not prioritized in medical education. Nutrition is usually offered as an elective, if at all, and most medical students receive far less instruction than is recommended. Even then, it could be argued that current nutritional recommendations are flawed due to outdated misconceptions. Either way, the problem is that when a subject is downplayed during training, it is often mistakenly assumed to be unimportant. Worse yet, the students consider themselves knowledgeable about what little they truly know, leading to overconfidence in the topic, ultimately resulting in Epistemic Rigidity. The downstream effect is systemic bias, where nutrition and supplementation are easily dismissed, not based on evidence, but because of educational neglect. Unfortunately, these assumptions and biases are often passed on to colleagues and patients, which hinders or limits ideal outcomes.

Of course, this gap in training also leads to a broader clinical blind spot: the underappreciation that simply ingesting a nutrient, via supplementation or diet, does not guarantee absorption or therapeutic effect. For example, just because a food, such as beans, contains zinc does not guarantee that the body will absorb it. In fact, the high phytate content in beans can bind to zinc and inhibit its absorption, potentially leading to a net loss rather than a gain. Similarly, while spinach is rich in calcium on paper, its high oxalate content binds the mineral and severely limits absorption, just as the phytates in whole grains can inhibit iron and zinc uptake, leading to deficiencies even in seemingly nutritionally sufficient diets. This list continues, but the prevailing wisdom seems to push such foods anyway.

Understanding absorption dynamics, metabolic pathways, and nutrient bioavailability is critical. Without it, physicians can easily overlook opportunities for effective intervention simply because they assume that consuming something is inherently sufficient. In reality, that’s not the case at all. In such cases, creative, indirect strategies are sometimes necessary to achieve meaningful clinical results.

A clear illustration of this principle is glutathione, the body’s “master antioxidant.” Oral glutathione supplements are widely available but often poorly absorbed because glutathione is largely broken down during digestion. This means that simply ingesting glutathione does not reliably raise systemic levels. Intravenous or intramuscular glutathione delivery circumvents this issue and can effectively increase plasma concentrations. However, practical limitations and cost often make this approach unsuitable for routine supplementation. In most cases, a more effective strategy is to provide the body with the building blocks it needs to synthesize glutathione naturally. Supplements such as N-acetylcysteine (NAC), glutamate, and glycine act as glutathione precursors, supporting endogenous production in a more sustainable, bioavailable, and clinically effective way.

Another excellent example of creative supplementation is L-citrulline, a non-essential amino acid that indirectly supports nitric oxide (NO) production. Nitric oxide is a free radical that plays a critical role in vascular health, mediating vasodilation, blood flow, and cellular signaling. Although some supplements contain L-arginine—an immediate precursor to nitric oxide synthesis—oral L-arginine is often poorly utilized due to extensive first-pass metabolism and enzymatic degradation by arginase in the gut and liver. Therefore, direct L-arginine supplementation typically yields inconsistent and often suboptimal increases in nitric oxide levels.

However, L-citrulline is efficiently absorbed and bypasses initial hepatic metabolism. Once in circulation, it is converted into L-arginine within the kidneys through the urea cycle, providing a more reliable and sustained substrate for nitric oxide synthase (NOS) activity. Clinical studies have demonstrated that L-citrulline supplementation raises plasma arginine levels and enhances nitric oxide bioavailability more effectively than L-arginine itself. This demonstrates that effective supplementation sometimes requires targeting upstream processes rather than delivering the desired molecule directly. Absorption, stability, metabolism, and biological pathways all matter—but so does cause and effect. For this reason, when supplementing with L-citrulline to enhance nitric oxide production, it is also important to avoid excessive intake of antioxidants such as high-dose vitamin C, vitamin E, or glutathione precursors like NAC, as they can quench nitric oxide and blunt its physiological effects.

While I hate to belabor the point, we should also consider a patient struggling with chronic fatigue. In some cases, low vitamin B12 and vitamin D levels are the primary drivers, and correcting these deficiencies can significantly improve energy and overall wellness. However, conditions like Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) often present with coexisting gastrointestinal dysfunction. In such cases, simply supplementing with B12 and vitamin D is insufficient. Factors like impaired gut integrity, dysbiosis, and mitochondrial dysfunction must also be addressed. Sun exposure and supplements such as acetyl-L-carnitine, probiotics, digestive enzymes, and B12 injections may need to be introduced to restore gut health and address the underlying absorption issues before oral B12 and D are recommended. I suppose the point is that effective supplementation requires a systems-based approach rather than a simplistic replacement model.

Of course, without a systems-based approach, critical details can easily be missed. Consider a highly active patient who lives an “athletic lifestyle,” takes supplements regularly, and appears sufficient in all essential vitamins. Yet they report persistent joint pain without a clear cause. Given their activity level—lifting, running, and sports participation—some physicians might immediately suspect tendinopathies, early-onset osteoarthritis, chondromalacia patellae, or even an electrolyte imbalance. Those are good guesses, but this situation demands a thorough investigation because several possibilities exist.

In one scenario, the appropriate intervention might involve adding a high-quality fish oil supplement or introducing PEA to help modulate inflammation. Yet because this patient is already supplementing and following an active lifestyle, examining “performance packs,” joint health supplements, fortified foods, protein bars, shakes, and any liver-based products they may be consuming becomes essential. When layered together, these sources can lead to excessive intake of preformed vitamin A. In that case, the solution would not be to add another supplement but rather to discontinue the excess intake, because hypervitaminosis A is a well-documented cause of musculoskeletal pain. Ultimately, the point remains: one size does not fit all, and effective supplementation demands not only knowledge of the compounds themselves but also the clinical skill to ask the right questions before making any recommendation.

A Few More Considerations

Of course, other factors, such as sleep quality, circadian rhythm disruption (being a “night owl“), exercise habits (whether excessive or insufficient), and ongoing medical therapies, also influence how effectively supplements work. Supplements will not magically correct foundational problems; the basics of health—sleep, diet, exercise, and stress management—must be addressed first. Supplements are adjuncts. They are tools designed to optimize and fine-tune health, to fill specific gaps or reinforce physiological processes, but they work best when integrated into a stable, healthy lifestyle. As previously noted, misconceptions about what constitutes a “healthy” lifestyle or diet are widespread and must also be considered when evaluating supplementation outcomes.

It is equally important to understand that supplementation is not a matter of “pharmaceuticals versus supplements.” The two can and often should coexist. Supplements can complement conventional medicine in powerful ways. For instance, CoQ10 supplementation can mitigate common side effects of statin therapy, such as muscle pain and fatigue. Likewise, berberine has demonstrated lipid-lowering and glycemic benefits that sometimes rival those of statins, without many of the associated adverse effects. In another example, administering probiotics alongside antibiotics can help reduce the incidence of antibiotic-associated diarrhea and support microbiome resilience. The point is not that one approach must be chosen over the other, but that strategic integration often yields the best outcomes.

Ultimately, when supplements deliver meaningful benefit, it is usually because they have addressed a genuine need, whether correcting a nutrient deficiency, modulating a pathophysiological process, or supporting a stressed system. When they appear ineffective, it is often because the supplement was mismatched to the individual, improperly dosed, delivered in a poor form, or applied without understanding the underlying context. Recognizing these nuances helps explain why some studies or anecdotes are glowing while others seem disappointing.

Ultimately, I hope that what I have provided here can help move us beyond the simplistic binary of “good or bad” and toward a more scientific, conditional understanding: the effectiveness of supplementation ranges from highly valuable to negligible depending on who uses it, why it is used, and how it is applied.

Final Thoughts

Indeed, the complexity of what has been outlined here must be respected. That is the central point I aim to convey here. Dietary supplements can and should play a significant, though nuanced, role in health and medicine. However, they are not trivial matters to be grasped through a weekend seminar or a handful of online videos. I’ll say this another way. Supplements are neither magic bullets nor universally worthless. Their value is real and substantial, but always dependent on context, proper application, and individualized understanding.

As demonstrated throughout this discussion, certain supplements have undeniable benefits in specific clinical roles, sometimes rivaling or complementing pharmaceutical therapies. The breadth of vitamins, minerals, nutraceuticals, and herbs means that “supplements” cannot be judged by sweeping statements, nor dismissed based on flawed studies or biased assumptions. Each has its own mechanism, purpose, and appropriate use. Ultimately, the effectiveness of any supplement hinges not only on its inherent properties but also on the individual’s unique nutritional needs, health status, and lifestyle context.

For healthcare professionals unfamiliar with clinical supplementation, the imperative is to approach supplements with the same critical thinking applied to any intervention: review the evidence, consider patient-specific factors, monitor outcomes, and recognize the limits of your own training. Where knowledge gaps exist, humility and consultation with qualified experts should prevail. Dismissing supplements outright risks overlooking meaningful therapeutic adjuncts or failing to identify correctable nutrient deficiencies. At the same time, indiscriminate or uninformed use of supplements can lead to wasted resources, therapeutic failure, or safety concerns.

For the general public, the same principle applies: be neither overly cynical nor blindly credulous. Educate yourself carefully. Investigate the evidence, understand appropriate dosing, and assess whether a supplement fits your specific health needs. At the same time, recognize that not all studies are created equal, and that when properly applied, supplements can serve as powerful tools for optimizing health, improving quality of life, and, in some cases, supporting the treatment of medical conditions alongside conventional care. I would also suggest that you don’t try to navigate it on your own. Experts exist for a reason. Find your resources so that you don’t make expensive or time-sensitive mistakes.

And remember, dietary supplements are tools. Like any tool, their value depends entirely on how and why they are used. It’s sort of like choosing between a prayer, a hammer, a screwdriver, or a jackhammer: the right tool, applied at the right time, can solve the problem efficiently, while the wrong tool, misapplied, can cause more harm than good or accomplish nothing at all. Of course, their impact also depends on the knowledge and skill of the practitioner or individual applying them.

The point is that supplements are far from inherently worthless; when used appropriately, they have repeatedly demonstrated their potential in clinical and personal health settings. The real challenge and opportunity lie in applying them judiciously, guided by science, clinical judgment, and individualized insight. Of course, this becomes exceptionally difficult when those expected to wield such tools are not taught how to use them. As always, knowledge is power. Seek it accordingly.

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Continue Learning

• The Need for More Health Science in Health Care
• Physicians’ Ironic Disdain for Alternative Medicine
• The Persistence of Outdated Medical Knowledge

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Dr. Robertson is a health researcher and educator, not a physician. The information provided here is not medical advice, a professional diagnosis, opinion, treatment, or service to you or any other individual. The information provided is for educational and anecdotal purposes only and is not a substitute for medical or professional care. You should not use the information in place of a visit, call, consultation, or the advice of your physician or other healthcare providers. Dr. Robertson is not liable or responsible for any advice, course of treatment, diagnosis, or additional information, services, or products you obtain or utilize. IF YOU BELIEVE YOU HAVE A MEDICAL EMERGENCY, YOU SHOULD IMMEDIATELY CALL 911 OR YOUR PHYSICIAN.