Supplements Will Always be Disappointing

What do I Mean by "Supplements"?

I'm talking about the class of pills and powders that the supplement industry wants you to think of as having drug-like effects. I'm excluding things like protein powders and oils (like fish oil). These are macronutrients, and I want to address those items that are effectively calorie free (e.g., betain), or that you take in sufficiently low dose that the calories aren't worth considering (e.g., citrulline). 

To be clear, I won't be claiming that supplements are pointless, or that none of them do anything. Rather, I'm arguing that their effects will always be minor and thinking of them as some sort of natural drug will only lead to disappointment.

Inevitable Disappointment

If you’ve been around long enough, you’re bound to arrive at the conclusion that supplements are always disappointing. Even creatine, which is the most effective supplement to ever hit the market with the most research behind it, is kind of underwhelming.

Despite this, the supplement industry cranks out endless products with hyperbolic marketing about how they’ll transform your workouts and physique. Similarly, countless supplements promise harder to measure effects like improved “wellness”, “vigor”, or “focus”. The supplement industry stops just short of promising the moon. So, what’s going on here?

I have bad news. Supplements will always be disappointing. This isn’t because we haven’t found the right combination or “stack” of ingredients or because we haven’t extracted the right part of some exotic fruit. Instead, there are two main reasons that supplements will never live up to the hype and delivery drug-like results. I also have good news. This article should save you time, money and aggravation.

The first reason supplements underperform is buried in our evolution and the way that complex systems, like your physiology, work. In short, our bodies have evolved to be as tamper-proof as possible. This is actually a good thing. You don’t want to live in a world where your physiology is easily disrupted.

The second reason is that supplements are essentially technology proof. They’re never going to have remarkable effect in their off-the-shelf form, and any significant technological modifications that might make them truly effective turns them into drugs.

I’ll also discuss why drugs can have drastic effects on physiology, how this differs from supplements, and why it’s so unlikely to change. But first, why do supplements suck?

Why Does Nothing Work?

Most supplements are marketed as though they can “hack” your physiology. However, you can’t “hack” your physiology, because the analogy is wrong. Your physiology isn’t a few thousand lines if buggy computer code written by a 17-year-old in their parents’ basement. It’s millions of years of tested, debugged and evolution-hardened survival machinery. Simple and easily hacked systems are unstable and unpredictable. Luckily for you, your physiology is more complicated than some pimple-faced kid’s code.

Your physiology is what sciencey-types call a complex system. People misunderstand complex systems like physiology. Complex systems are often viewed as carefully assembled and delicately balanced. While this is sometimes true, more frequently they’re characterized by multiple redundancies, failsafes, and buffering mechanisms. When you introduce a drug or supplement, your body has many tools to either disposes of it or compensate for its effect (assuming it even has an effect). But why is it like that?

Hundreds of millions of years of evolution have made your physiology very difficult to disrupt. In physiology this property of staying in equilibrium is called homeostasis. Homeostasis is all the processes that keep things like body-temperature, energy metabolism, blood sugar, and hormone levels where they should be. For example, if you feel cold your body shivers to warm you up. Similarly, if you use up ATP exercising, your body makes more. These example can be extended to other body systems and function, right down to the biochemical pathways that regulate muscle growth and fat storage. All these things work together to keep you healthy and alive. A good thing.

Homeostasis might seem to imply that because the internal conditions of your body are tightly controlled that they’re finely tuned. However, “tightly controlled” is different from “finely tuned”. Finely tuned implies a delicate state of balance where small changes or disruptions can induce large changes in the behaviour of the system. Instead, tightly controlled implies that physiological outputs are strapped down, bolted on, and welded into place. This is why it’s so hard to change things like body composition, resting energy expenditure or performance levels. All these things require you to put in sustained time and effort.

If your physiology fluctuated wildly every time you took a supplement like creatine, life would be significantly harder. Easily disrupted physiology is a poor evolutionary strategy. It might seem like post-hoc reasoning, but if it was a good strategy we would see it all around us. Still, I’ll explore this a bit more to drive home the point.

Let’s imagine that your physiological processes were easily pushed away from the narrow ranges they function in. In this world you might be able to take a supplement with unusually specific and positive effects on your body. Let’s say “supplement-X” significantly increased muscle mass and simultaneously decreased fat mass. At first this might seem great, but there’s no reason for this to be a one-way street.

If your body’s systems could be easily pushed towards large positive outcomes it would also be easily pushed towards large negative outcomes. In other words, you would expect small doses of some supplements or compounds to cause rapid loses of muscle or increases in fat. In fact, you would expect more negative outcomes than positive ones.

For any metabolic pathway or cellular process there’s a small number of ways for it to proceed properly but nearly infinite ways for it to go wrong or not work at all. In fact, it’s far more likely that anything that altered metabolic pathways or homeostasis would do so for the worse. This is why we’ve evolved so many mechanisms to protect these systems from disruption. Organisms with systems resistant to disruption were more likely to survive and have offspring with that same resistance. That’s how evolution works.

So Why do Drugs Work?

You might be thinking “ok smart guy, if your body’s so hard to hack how come drugs work?” This is a fair question. Most drugs work because of significant effort. This effort takes the form of either scientific research and development, or evolutionary processes played out over millions of years (poisons and venoms evolved over millions of years). I’ll use two examples to make my point: anabolic-androgenic steroids (AAS), and GLP-1 agonists (Ozempic, etc). I chose these two because they cause what many fitness enthusiasts and athletes want from supplements (and some things they don’t). AAS’s improve strength and performance, and GLP-1 agonists induce weight loss and improved body composition.

GLP-1 Receptor Agonists

GLP-1 receptor agonist stands for (glucagon-like peptide-1 receptor agonist). I’m just going to call them GLP-1’s, because it’s short and easy. I don’t want to get too far into the weeds, but here’s a brief explanation of what that means.

A receptor is a protein that receives a signal from a signalling molecule (hormones are a good example). Signalling molecules (like GLP-1) physically bind to the receptor, delivering the signal. After binding to the signalling molecule, receptors pass on the signal resulting in the desired effect. So, here’s how it works:

• The signalling molecule (GLP-1) is released into the blood.
• GLP-1 binds to its receptor (GLP-1 receptor).
• The receptor causes the intended down-stream events (That’s why it’s an “agonist”. If binding the receptor stopped the receptor from working, it would be an “antagonist”)

Back to our story. GLP-1 was identified from gila monster venom (a species of medium sized lizard) in the 1980’s. It was found that GLP-1 elevated insulin levels in mice, suggesting its usefulness as a treatment for type-2 diabetes. The first GLP-1 based drug approved for this use was released in 2005 under the name Exenatide. This next part is instructive.

Unfortunately, GLP-1 can’t be taken orally since peptides are just short strings of amino acids that are quickly and easily broken down in the gut before getting into the blood. So, it must be injected; but the trouble doesn’t end there. Early versions of GLP-1’s were rapidly degraded by the enzyme dipeptidyl peptidase-4 (DPP-4), requiring the drug to be injected twice daily.

Over the next 15 years, scientist developed modified versions of GLP-1’s that both bound more strongly to the GLP-1 receptor, and resisted being degraded by DPP-4. This resulted in drugs that can now be injected only once per week and that have very powerful effects. Even still, GLP-1 agonists are administered at doses many times higher than any GLP-1’s your body produces. Far higher than your body could ever produce.

It's hard to communicate just how much time, effort, and money goes into developing a drug like this. There are multiple hurdles to overcome to make it longer lasting, more effective, and have fewer side-effects than the initial compounds. Importantly, the gap between this and the original compound is huge. It went from something that would be useless in an unaltered supplement format, to a drug that’s rapidly transforming both people’s health and the fitness industry.

Anabolic Androgenic Steroids (AAS)

The story of AAS has several parallels the development of GLP-1 drugs, and similar lessons. Testosterone (which is produced in men and women naturally) was first synthesized in the 1930’s. It can be taken orally, survives the gut and is easily absorbed into the blood. However, it’s rapidly degraded in the liver and ends up with a half-life estimated at 30-60 minutes. Furthermore, the body rapidly downregulated endogenous testosterone production to match the amount administered. This makes orally administered testosterone basically useless. Even when injected, the short half-life makes it a poor drug candidate.

Intrepid organic chemists set about improving on testosterone’s shortcoming by making various chemical changes to it. They added chemical groups to change several properties, including:

• Longer half-life requiring less frequent injections.
• Resistance to the enzyme aromatase, which converts testosterone to the chemically similar sex hormone, estradiol.
• Resistance to degradation in the liver, to improve oral availability. This modification is responsible for the liver toxicity of orally administered AAS’s.

Even with all these modifications, administering AAS isn’t as simple as it seems. As mentioned before, the body rapidly reduces its own testosterone production when you take steroids. In fact, the bodies production will drop to levels that offset the dose administered until they reach nearly zero. This is a great example of the body’s ability to autoregulatory tools like feedback inhibition to regulate hormone levels in the face or outside interference.

As with the GLP-1 example, the doses people take to achieve significant muscle gains are far above normal levels. “Recreational” steroid users will take doses many times over endogenous levels, especially when you consider that the relatively long half-lives of most synthetic steroids means that the doses “area under the curve” is almost never considered.

So even if one of the countless supplement-based testosterone “boosters” worked, it would have to cause the body to produce multiple times normal levels to deliver the desired effect. There’s no evidence that your body is even capable of producing these levels of testosterone (maybe a hormone producing tumour could), so forget about a supplement doing it.

Aren’t Supplements Just Nature’s Drugs?

It’s common to compare supplements to drugs. The argument usually goes something like “lots of drugs started out as natural compounds, so supplements are just pharmaceutical agents with poor quality control”. Like many flawed arguments, this one contains a kernel of truth. Many drugs do get their start as natural compounds. Aspirin (acetylsalicylic acid) and atropine are both derived from plants. Likewise, testosterone and GLP-1 are hormones we all produce in our bodies. However, to they all require significant modification or processing to make them both effective and safe.

In the case of acetylsalicylic acid and atropine, neither one can be reliably dosed without significant processing and purification, and both will kill you at relatively low doses. In fact, Ibuprofen (Advil), was developed as a safer alternative to acetylsalicylic acid.

The story of synthetic GLP-1’s and testosterone derivatives demonstrate how difficult it is to reliably manipulate hormones. You need to clear significant hurdles to develop a compound that will push hormones outside their tightly regulated ranges. Even then, it takes a sledge-hammer approach to dosing to deliver the types of results people want; i.e., noticeable changes in physique or performance.

Taken together, I hope it’s clear that even if a supplement contains an active compound with a measurable physiological effect, it’s extremely unlikely to deliver the results people are looking for. Instead, any potentially medicinal compound will need some combination of purification, modification or special delivery mechanism before it’s truly useful.

Finally, I’m forced to mention that the supplement industry is poorly regulated, and sketchy as hell. Multiple studies have shown that supplements frequently don’t meet label claim. Sometimes they don’t have the ingredients they claim, and sometimes they’re contaminated with potentially harmful ingredients. Not only are they not drugs (except for when they’ve been contaminated with drugs), but they frequently aren’t even supplements.

What to do?

To be clear, I’m not saying that all supplements are useless or that no supplement has any effect. I’m saying that their effects range from underwhelming to disappointing. There are two main reasons for this. The first is that your body is “tamper proof”; that is, your physiology works very hard to resist small doses of natural compounds altering how it functions. The second is that supplements themselves are “technology proof”; that is, any active compound will take significant technological intervention to deliver drug-like results, thereby making it a drug and not a supplement.

I’ll write a follow-up article soon on how to approach supplements in a rational way that balance realistic expectations with what little evidence exists for supplements that might support your health and performance goals.