On “developing a tolerance” to a supplement


I occasionally encounter people who use the expression “developed a tolerance” to describe that annoying phenomenon in which a supplement works for a while to treat whatever symptoms you’re complaining of, and then stops.

Different mechanisms with Rx and supplements

Tolerance is more accurately used in the case of prescription drugs or, alas, controlled substances, and doesn’t really apply to supplements. Although tolerance to drugs and controlled substances builds up for different reasons, they are much different mechanisms than what happens with most supplements such as vitamins, minerals, amino acids, etc.

A common cause of tolerance to a drug is that the drug causes your body to produce less of whatever substance the drug was meant to enhance. This happened to me when I first took clonazepam for insomnia. The drug was originally designed to control seizures, but my doctor at the time prescribed it for my two-hour-a-night sleep problem. For four days I slept NINE HOURS A NIGHT. I’ve never felt so good in my life. Then it stopped working. The doctor said it was a pretty common experience.

Classic Rx example: benzos and your body’s GABA

Turns out it’s a benzodiazepine (hereafter to be referred to as benzo), a class of drug that affects GABA levels in the brain. GABA is one of the few inhibitory neurotransmitters — it slows everything down, calms an overactive mind, gives you space between your thoughts, plays a big role in sleep. Benzos very quickly convince your body it can produce less GABA, which is why you’re not supposed to take the stuff for more than several weeks. The drug is only active for a few hours, after which you’ve got none of your own GABA to fill in that timing gap, so you take more of the benzo, or take it more often. (Here’s an overview of the different benzo Rx and their relative strengths.)

Many experts feel that supplements of the hormone melatonin have a similar effect. But then you can also find experts who don’t. (FYI in Canada and Europe, hormones are classified as drugs and are not sold over the counter as supplements.)

Supplements: using cofactors till they’re gone

In the case of supplements that work briefly and then stop, it’s most likely because that supplement helped the uptake of another nutrient (or, more likely, a bunch of them — it’s unlikely that you’re deficient in only one thing) for a while, until it got to the bottom of the barrel.

You can go nuts trying to remember all the interactions

Every time you take a supplement, a whole bunch of other substances in your body are ushered forth to process it. These are sometimes referred to as cofactors, and each nutrient has its own set, although obviously there’s a lot of overlap. Some of the more famous cofactor relationships are calcium and magnesium, magnesium and vitamin B6, and iron and vitamin C, but it gets even more complicated. Tryptophan needs B6, B2 and iron in order to convert into niacin, and iodine needs enough iron, selenium, and magnesium to do its thang.

So either you just happened to take a supplement that was cofactor to something you REALLY needed, or the supplement you took was in fact what you needed, but it used up all its cofactors. The former case is what happened to me with B-complex. The B-complex stopped my leg pain as long as I took it. After two days without it, the pain returned. What finally got rid of it was several months of calcium, which needs the B vitamins for absorption. The B-complex pulled just enough calcium into my bones to make a difference for a few days.

That’s why supplementation is an imperfect, and occasionally downright tedious, way to fix a deficiency — foods have more of the cofactors built in. But our anemic food supply, and the limited number of foods we typically eat, can’t provide enough nutrients to correct a serious deficiency. Or not quickly, anyway.

Another frightening explanation: it’s something else entirely

If it keeps happening that you see wonderful results which then come to a screeching halt, you might consider the possibility that you are being exposed to an inflammation source that is outpacing whatever anti-inflammatory action your supplement experiment was initiating. Mold comes to mind. Or metal poisoning.

Publish and update info

The content on this page was first published in February 2012 and updated in May 2023.

Marjorie smiling, wearing an orange shirt.

Marjorie R.

Marjorie is the creator of, a record of her and her guest authors’ experiences with non-prescription health solutions. She is a third-generation nutritional-therapy self-experimenter.

2 thoughts on “On “developing a tolerance” to a supplement”

  1. i am taking rhodiola rosea. Firs 2 pilll were amazing i was very calm, no stress, but this after – with next pills -i felt very big stress and anxiety again becuase of almost everthing. So the wonderfull effect pass away.
    Could you help me that what are the cofactors of rhodiola rosea?How could i recall the wonderfull efect which was with the first pill.

    thank you

    • I know how frustrating that is. My sympathies! I cannot offer anything very concrete:
      — Investigate B vitamins and zinc. Stress causes the adrenal glands to use a lot of each.
      — Look at user reviews of rhodiola rosea supplements on amazon and iherb and see if anyone mentions that issue. It requires a lot of reading, but sometimes you find useful information.
      — Try another brand of the same supplement.
      — Try another adaptogen.

      Good luck!

Leave a Comment

This site uses Akismet to reduce spam. Learn how your comment data is processed.