General Notes On Supplements

The short version: Supplements are purportedly-bioactive chemicals that haven’t been formally approved as medications by the FDA. They aren’t ontologically different from medications, and sometimes they’ll have significant amounts of evidence supporting them, but they are less-thoroughly-tested and require more care. Because everyone has different neurochemistry, different supplements will work for different people. I sometimes recommend l-theanine, silexan, and Zembrin for anxiety, and Zembrin, 5-HTP, and SAM-e for depression.

The long version:

1. What’s the difference between supplements and prescription drugs?

Some people place moral value on the supplement/medication distinction. Either supplements are “all-natural” and drugs are “artificial poisons”, or plant-derived supplements are “woo” and drugs are “real medicine”. I don’t think either of these views stands up to serious scrutiny. Supplements and drugs are both chemicals. In one case, the chemical usually (but not always) comes from a plant; in the other, it usually (but not always) comes from a factory.

Here are two chemical structures. One is 5-HTP, a naturally-occurring supplement you can buy at your local Whole Foods. The other is fluoxetine, the active ingredient in Prozac. Can you tell by looking at them which is which? Which is “natural” and which is “artificial”? Which is for kooky hippies, and which is for serious scientifically-minded adults?

The supplement/drug distinction is best thought of as dividing two legal routes by which a chemical becomes part of the health care industry. In the first route, a drug company decides it looks interesting, spends billions of dollars testing it and convincing the FDA to approve it. In the second route, someone who is not a drug company decides it looks interesting, spends fifty cents designing a cool-looking bottle to put it in, and markets it as a supplement.

Most chemicals that take the first route tend to be novel – that is, some drug company just invented them. Why? Because if they already existed, the drug company would have a harder time patenting them, and wouldn’t be able to make as much money off selling them. So most plant-based and natural compounds can’t make it through the first route, although there are some complicated exceptions.

Most chemicals that take the second route tend to be natural – you can’t legally market something as a supplement unless it’s found in nature. I think this was originally intended because politicians thought it was fair to let people sell garlic or turmeric or whatever without FDA approval, but didn’t want to give the same guarantees about artificial chemicals. But supplement companies have gotten pretty creative – it turns out lots of things are found in nature somewhere, and once you find it in nature you are free to use a factory to actually manufacture it. But some supplement companies skirt the law and sell interesting health-related chemicals that aren’t found in nature, and sometimes the FDA turns a blind eye to this.

The advantages of the drug route are that the FDA is pretty strict and requires a lot of studies, so most things that get approved as drugs are safe and effective. The disadvantages of this route are that it costs billions of dollars to get anything through it. Drug companies will only ever submit a few chemicals to the FDA – ones which are new and unique enough to be patentable, carefully-studied enough that approval is likely, and popular enough that they can make a lot of money off of them.

The advantages of the supplement route are that the barriers to entry are so low that any chemical that could be a supplement probably is. There are only a few classes of prescription anxiety drugs, and they mostly affect the serotonin system. But there are dozens of different anti-anxiety supplements, which work through all sorts of fascinating and exotic mechanisms that no currently-existing drug matches. Lemon balm inhibits GABA transaminase, which is a really exciting mechanism of action for an anxiolytic. L-theanine probably antagonizes glutamate receptors directly! They are much cheaper than drugs, and you don’t need to have good insurance and see a doctor once a month and go to the pharmacy every time you want to refill them.

On the other hand, most of them probably don’t work, and a few of them might kill you.

This isn’t to say that “drugs are evidence-based but supplements aren’t”. Some supplements have dozens of studies looking at them – this meta-analysis alone references 27 different studies of St. John’s wort (for comparison, there are only four studies of the FDA-approved prescription drug Spravato). On the one hand, the FDA does have pretty strict criteria for its studies and they’re often better than the studies some random person does of a supplement. On the other, studies for the FDA are usually done by a pharmaceutical company doing everything it can to bias results in their own favor. So I think it’s fair to say that it’s a good rule-of-thumb that drugs are usually backed by more evidence than supplements. But it’s not a hard-and-fast law of nature, and you actually have to look at the studies before forming strong opinions.

There are definitely real differences between drugs and supplements. But the differences aren’t fundamental. They’re downstream of the economic incentives that caused a chemical to get classified in one bin rather than the other. Whether or not you would be best served by a supplement or medication depends on your situation. I usually start with real drugs, just because I think they’re usually stronger and have more evidence behind them. But this is a relative distinction, not an absolute one. My first choice for treating anxiety would usually be an SSRI. But if that doesn’t work, my second choice might be silexan, a supplement derived from lavender. If that doesn’t work, my third choice might be pregabalin, a drug sold by Pfizer as Lyrica. Why? Because (I think) the risks/benefits/evidence calculation favors SSRIs over silexan and silexan over pregabalin. Based on the needs of a particular patient I might change this order around or add some other things into it. The fact that SSRIs and pregabalin are drugs and silexan is a supplement matters only insofar as it means that the studies supporting SSRIs and pregabalin are marginally better quality – and the studies for silexan are quickly catching up.

(to rub in how arbitrary all of this is: silexan is sold as a prescription medication in Germany. In the US, because of our slightly different laws around what sorts of things should be drugs vs. supplements, it’s sold over the counter as a supplement.)

If you don’t have insurance, or otherwise find it hard to manage the demands of doctors and pharmacies, that might be another reason for you to prefer supplements over prescription medications.

2. What is the difference between different extracts of the same supplement?

Some supplements come from plants. You don’t want to eat a whole plant. And if they just ground up the plant and put the powder in a capsule, you would end up eating a lot of ground-up stems and leaves and bugs and barely any of the chemicals you want. A coffee plant ground into a powder and encapsulated would have so little caffeine you’d have to take a few hundred capsules just to feel a mild buzz. So part of the job of a supplement company is to find a way to process the plant in order to extract the chemical you want.

But a lot of the time we don’t know which chemical we want, or there are different ways of getting the chemical, or we want more than one chemical, or different people might want different chemicals. So different researchers or supplement companies will process the plant in different ways, and get an end result with different amounts of different chemicals in them. These end results are called “extracts”.

So for example, ashwagandha is an Indian herb sometimes used to treat anxiety. One of the best-known ashwagandha extracts, KSM-66, starts with the roots (but not leaves) of the ashwagandha plant, treats them with milk to leach out certain chemicals, and ends up with a “full-spectrum” extract that contains most of the chemicals in the original plant matter. Sensoril, a competing ashwagandha extract, starts with both leaves and roots, treats them with water to leach out certain other chemicals, then standardizes the results to have consistent levels of a class of chemicals called withanolides. Even though both extracts start with the same plant, they end up being chemically pretty different. Although there haven’t been any studies, the conventional wisdom among users is that KSM-66 is more stimulating, and Sensoril is more calming.

Some supplements – like melatonin or magnesium – don’t involve any plant matter, and so none of this applies to them. Other supplements do involve plant matter, and when you’re using these you have to be careful to use a reliable extract. One good rule of thumb is to find the studies that convinced you that this supplement might be useful in the first place, and see what extract they used. Often there’s a “gold standard” extract that all the studies are done on, and your safest course is to find a supplement company that sells that extract. This can sometimes require a little bit of detective work.

3. How do I know which supplement is right for me?

Even more than with medications, different supplements work for different people.

Cynics would say this is because supplements are placebo, or get credit when people recover on their own – and if this happens randomly, then it will be pretty random which supplement you’re on when that happens. There’s some truth to this.

But on the broader scale, this is little different than what happens with regular medication. Only about a third of people improve on any given antidepressant. Some people will do very well on SSRIs and have no response to bupropion; other people will do very well on bupropion and have no response to SSRIs. Everyone’s biochemistry is different, and apparently similar conditions (eg depression) may have very different causes in different people. So for example, we know some depression is caused by thyroid hormone deficiency, and these cases respond very well to thyroid hormone; other cases are unrelated to the thyroid and don’t respond at all to thyroid hormone. We have less understanding of what underlying differences cause different response to SSRIs vs. bupropion, or one supplement vs. another – but probably these differences exist.

The only way to figure out which supplements work for you is trial and error. Try a supplement, see if it works, if it does then keep it, and otherwise move on.

This is very different than the advice for, eg, omega-3 supplementation for heart disease, where you don’t really know how much heart disease risk you have or how omega-3s are affecting it, and you take the supplement based on large studies that suggest it works in the general population. Psychiatric conditions are convenient in that you know whether you have them or not – you are the best expert about how depressed or anxious you are, or whether you’re getting better or worse. You take omega-3s or multivitamins because you have faith in the studies behind them. You should take mental health supplements because you have personal evidence that they’re working for you.

(that doesn’t mean the studies are useless; they should guide which supplements you think are most likely to work, and which ones you take first).

So treat every supplement you take as an experiment. Any experiment is better than nothing, but careful experiments are best of all. If you want to be careful change one thing at a time: don’t start a supplement at the same time you’re starting another supplement (or a new exercise routine, or a new job). Consider recording any subjective data (eg how you feel on a scale of 1-10) and objective data (eg how many panic attacks you have per week, how many hours of sleep you get per night) to see whether it changes before and after starting the supplement.

If you start a supplement and feel better, it could be because of the supplement – or it could be coincidence. You can certainly just accept that you’re feeling better and not change anything. But if you’re going to continue taking the supplement long-term, consider confirming your first impression by eg stopping the supplement and seeing if your problems come back, then restarting and seeing if they go away again.

4. What are the best supplements to try for my condition?

The following are my opinions only. These lists should be considered starting points for experiments: ie things that are most likely to work. You can’t skip the experimenting step. Many of these won’t work for you, but some might.

You should not take any of these just on my recommendation. You should use my recommendation as a starting point to learn more about each of these substances, including the studies for and against, the potential risks, the potential interactions, and the correct dose. I’ve gotten you started with short commentary, and eventually I hope to have writeups about all of these which will give you the information you need to know. But until I do, please look into these more carefully before trying them.

A few of these are especially complicated or require some more advanced knowledge; I’ve marked these with letters instead of numbers and put them at the bottom outside the main sequence.

For anxiety, I would go:

1. L-theanine. Simple to use, cheap, fast, effective.
2. Silexan. Well-studied, effective.
3. Zembrin. Simple to use, cheap, effective, probably just an herbal SSRI.
4. Ashwagandha. Make sure you get a calming extract and take it regularly.
5. Bacopa. Make sure you get a calming extract, and expect some risk of being oversedated.
6. Magnesium. Make sure you get a non-laxative form. Dose will vary by person.
X. Selank. Russian intranasal peptide. Very effective. For especially knowledgeable users only.
Y. Kava. Polynesian psychoactive drink. Some formulations are much better than others. For especially knowledgeable users only.

For depression, I would go:

1. Zembrin. Simple to use, cheap, effective, probably just an herbal SSRI.
2. 5-HTP. Serotonin precursor, decent evidence. Don’t use with any other serotonergic or serotonin-affecting medication unless you know what you’re doing.
3. SAM-e. Folate cycle chemical. Some studies in support. Tends to cause nausea.
4. L-methylfolate. FDA approved prescription substance as “Deplin”, but also sold as a supplement.
5. Polygala tenuifolia. Weird Chinese herb, seems to have antidepressant effect through unclear route.

Other people’s lists of favorite supplements might look completely different; this territory is still mostly unexplored.

5. How can I learn more about supplements for mental health?

examine.com is a great site that will tell you a little about anything.

I’ve drawn some of my conclusions about supplements above from various small surveys of supplement users, including this one and this one.

Supplement-related communities, like r/supplements, r/nootropics, r/depressionregimens and Longecity include some incredibly well-informed researchers and experts in the field, and also some total garbage. Read at your own risk.