Our scientific principles, explained

Calcium is essential, but an essential nutrient does not automatically belong in every everyday supplement (6).

A 2010 paper combining several calcium trials estimated that heart attacks were around 27% more common among participants assigned calcium. When the researchers analysed much of the same evidence in a different way, the estimate was 31% (7).

In absolute terms, the larger analysis recorded heart attacks in approximately 2.7% of participants assigned calcium and 2.2% of those assigned placebo (7).

The individual participant analysis also estimated 20% more strokes and 9% more deaths. However, these two differences were not statistically significant and may have been due to chance (7).

This research does not prove that calcium supplements are harmful. Some population research suggests that moderate calcium intake from food may be associated with lower cardiovascular mortality or stroke risk, although the relationship appears to vary according to the population and amount consumed (8, 9).

Calcium from food is also consumed within a wider food matrix, which can influence its absorption and short-term effects on blood calcium (10, 11). However, this has not been proven to prevent the possible risks suggested by supplement studies (11).

For us, these findings raised enough uncertainty to question automatically adding a substantial calcium dose to an everyday formula, particularly when calcium can be obtained from food.

How should this evidence be interpreted?

The trials used at least 500 mg of supplemental calcium daily without co-administered vitamin D. Cardiovascular events were not their primary outcomes and were not collected using a completely standardised method (7).

Later reviews have reached conflicting conclusions. A 2021 meta-analysis reported higher cardiovascular and coronary heart disease risk, principally among healthy postmenopausal women (12). In contrast, a 2023 meta-analysis found no statistically significant increase in heart attacks, coronary heart disease, strokes or deaths from any cause (13).

These findings do not mean dietary calcium should be avoided, that calcium supplements are inherently unsafe, or that someone should stop supplementation recommended by a healthcare professional.

Manganese is an essential nutrient, but that does not necessarily mean it needs to be added to an everyday supplement.

1. Why we found little need to add it

Manganese deficiency is considered very rare in humans (14).

The EFSA has not been able to calculate an exact average manganese requirement because the necessary evidence is unavailable. Its guidance of 3 mg per day for adults is based largely on the amounts normally consumed in European diets and balance studies, rather than evidence that every adult needs that precise amount (15).

Benefits of supplementation are uncertain. For example, although manganese contributes to the maintenance of normal bones, no clinical trial has tested manganese by itself for improving bone health. In a small human trial discussed by the NIH, manganese was given alongside calcium, zinc and copper, so it was not possible to determine whether manganese itself provided any benefit (14).

The lack of evidence does not rule out the possibility that manganese supplementation could benefit particular individuals with a specific need. However, it gave us little reason to add manganese automatically when it is already available from a varied diet.

2. Why we also had reasons for caution

In 2023, EFSA was unable to establish a conventional upper intake limit for manganese because the available safety evidence was insufficient. It instead identified 8 mg per day from food and supplements as a total intake at which there was reasonable confidence in the absence of adverse effects (16).

One study involving intravenous manganese also caught our attention.

In a study of 16 people receiving long-term intravenous nutrition containing manganese, 81% showed abnormal signals on brain MRI scans. The researchers interpreted these signals as manganese deposits in the basal ganglia (17).

The MRI findings indicated manganese accumulation, but did not by themselves demonstrate structural brain injury or prove that the deposits caused clinical harm.

In a later follow-up, manganese had been removed from their intravenous nutrition. Of the eight patients who underwent repeat brain scans, the abnormalities had completely resolved in six (18).

This was a very different form of exposure from taking an oral supplement. Nevertheless, it was one additional reason for us to question the value of routinely adding manganese when the evidence of additional benefit was already limited.

This research does not establish that ordinary manganese supplements are harmful, but the wider evidence has not established that routine manganese supplementation benefits the general population.

Our decision reflects the complete picture: deficiency appears to be rare, manganese is available from food, evidence of benefit from manganese supplementation alone is limited, and some uncertainty remains around long-term supplemental intake.

For us, there was not a strong enough reason to include it.

That is what we mean by being incomplete by design.

We think the supplement industry has gone a little barking mad with megadoses. It seems increasingly common to add quantities that massively exceed our daily requirements. And those percentages aren't plucked out of thin air. They're amounts found in some actual market leading supplements.

The problem is that we don't know what we don't know.

An upper intake limit isn't a target. It is a level of long term daily intake that is judged unlikely to pose a risk of adverse health effects, based on the evidence available at the time (19). It does not mean that taking anything below that amount has somehow been proven harmless in every respect over decades of use.

Upper limits can change

Vitamin B6 is a good example. In Europe, the upper intake limit for adults was previously 25 mg per day. After reviewing newer evidence, EFSA reduced it to 12 mg per day in 2023, largely because of concerns about peripheral neuropathy, a form of nerve damage (20).

The science changed, so the limit changed with it.

Some effects are difficult to notice

Some potential adverse effects are particularly difficult to detect. A nutrient can seem perfectly well tolerated, but how would you know if it were slowly affecting something like your bone density?

Most people don't routinely measure their bone density, and a gradual deterioration in bone health may produce no obvious symptoms until a fracture occurs (21).

This is one of the problems with relying too heavily on whether a dose appears to be well tolerated. Some effects may develop slowly, affect only certain people, or only become apparent when researchers specifically look for them.

Long-term studies can surprise us

Selenium gives us an interesting example.

In a large randomised trial, people were given 200 micrograms of selenium every day or a placebo. The original study reported no cases of selenium toxicity (22).

But researchers later looked specifically at diabetes. Among 1,202 participants who did not have diabetes when the study began, 58 people taking selenium developed type 2 diabetes compared with 39 people taking placebo over an average follow up of 7.7 years (23).

That doesn't prove that taking 200 micrograms of selenium causes diabetes. But it illustrates something important: a dose can appear to be well tolerated, while longer term research uncovers an effect that wasn't obvious and wasn't even what researchers originally set out to investigate.

That is why “people seem to tolerate this dose” and “we know this dose has no undesirable long term effects” are two very different statements.

Nutrition science is constantly evolving, and there is still a great deal we don't know about the long term effects of consuming several times our nutritional requirements every single day.

So what does this mean for how we formulate?

This is where we think common sense matters.

Did you know that there are 16 different forms of zinc that you can put in supplements in the UK? Zinc acetate, zinc citrate, zinc oxide... Do you know the difference between them?

You see zinc can't just exist chemically by itself as an ingredient. It is always bound to something, and it's like that with a lot of ingredients you see on the label.

People often think the most important thing is that the nutrient is present, but it may be the case that the form of a nutrient matters more than people are aware of.

Like with all nutrition science, there isn't as much evidence as we'd like to conclude what the best form is.

One randomized cross-over study made 12 female volunteers try 2 different types of zinc. Zinc gluconate and zinc bisglycinate. They found that the same women absorbed on average 43.4% more zinc when it was taken as bisglycinate (24).

Here is the geeky chemistry

Chemically zinc gluconate is an ionic form of zinc. This means it dissociates in water quite readily. This makes it subject to complexation by other components within food. Zinc bisglycinate instead is bound to the amino acid glycine. This is similar to how zinc presents itself in animal products, which are known to have more bioavailable zinc (24).

So although the trial was small, in the absence of complete evidence, we feel it is the most reasonable choice of zinc form.

This is just one example of the many considerations we made when choosing the exact forms of nutrients to include in our formula. In fact, even just considering minerals, there are 15 different minerals, but 140 different forms of these minerals that can be included. That's a lot to think about!

More on our approach to evidence in principle 4.

A great example of our approach to navigating uncertainty is the form of selenium we chose.

At the time of writing, sodium selenite and sodium selenate are common across the mainstream UK supplement market, including in products from some of the country's most widely sold vitamin ranges.

Check the label of your current supplement. If it lists sodium selenite or sodium selenate, it uses an inorganic selenium salt. ThinkPharm made a different choice: we use the organic form selenomethionine.

But given that equivalent studies in humans do not exist, and may never exist, we believe the finding is still something worth considering in our decision making.

If we are trying to be strictly evidence based, we also have to admit that the available evidence does not definitively prove that selenomethionine produces better health outcomes, but we think its presence within natural foods makes it particularly promising.

Nutrition rarely provides definitive head-to-head trials.

This means making decisions in the absence of complete evidence is inherently necessary in the field of nutrition.

It requires broad reading, synthesis of information and a hint of bravery to make an informed judgement.

As recently as August 2022, titanium dioxide was still being used to make tablets whiter in supplements sold by some of the UK's biggest vitamin brands.

Concerns were not new

As far back as 2011 scientists described evidence that titanium dioxide could cause cell damage, DNA damage, inflammation and adverse effects on the immune system. They also noted that it is possibly carcinogenic to humans when inhaled (31).

The lack of certainty around the long-term health effects of oral consumption made the authors question whether using titanium dioxide in foods and medicines merely to colour them was sensible (31).

In another study, researchers examined the brain tissues from 186 children and young adults who had lived in highly polluted Mexico City. They found that titanium rich nanoparticles were present alongside pathological features associated with Alzheimer's disease, Parkinson's disease and motor neurone disease (32).

In February 2022, the EU decided to ban the use of titanium dioxide in foods and supplements (33). Mainly because it's difficult to definitively prove the long-term health effects in humans with so many other factors at play.

We don't have enough evidence to say it's definitely harmful, but we also don't have enough evidence to say it's definitely safe long term.

We will never know whether the inclusion of this ingredient has caused harm to the people taking those supplements because it's virtually impossible to prove.

For us, the deciding factor was its purpose. Titanium dioxide supplied no nutrient. It just made tablets look whiter. We believe accepting the uncertainty around this ingredient for purely a cosmetic benefit was an unwise decision.

The uncertainty around health effects isn't something customers look for when they are taking a supplement to help maintain their health.

Marketing is not the same as formulation quality

What we found most disappointing about this is that the companies including titanium dioxide had perfect marketing. Influencer endorsements, TV doctors and Oxford academics on their scientific advisory boards. How could customers resist?

We feel this is a classic example of marketing skill exceeding product quality.

Just because a product is popular, doesn't mean it's good for you.

As healthcare professionals we try to stick to the principle of medical ethics which is “do no harm”.

The ThinkPharm Formula is not a medicine, but we feel this is a good principle to apply to the formulation of supplements. Caution is at the core of what we do.

Our approach is simple. Don't put anything in there that isn't needed. Even if it means a less cosmetically perfect capsule.

We feature some very small amounts of excipients because they are needed.

In the ingredients section we show these excipients, the quantities included and their purpose.

That way you can rest assured that we are putting in the same level of care as you are when it comes to your health.