Comment by Aurornis
9 hours ago
Vitamin D and Omega-3 are the two supplements that consistently appear to be super powerful in small studies and then fail to do anything significant at all in larger studies.
Pause for a moment and consider the mere plausibility of the claims in the first few paragraphs: The effect size for antidepressants is 0.4, but the effect size for Vitamin D is 1.8? Are we to believe that Vitamin D supplements have an effect size 4.5X larger than antidepressant drugs, and nobody noticed this massive discrepancy until now?
Effect size is also a favorite metric in this vein of supplement-over-pharma writing because it’s so commonly misunderstood and it’s so easy to find small supplement studies that have outlier effect sizes.
To put it in context, even common OTC pain meds can have effect sizes lower than 0.4 depending on the study. Have you ever taken Tylenol or Ibuprofen and had a headache or other pain reduced? Well you’ve experience what a drug with a small effect size on paper can do for you.
Please be very careful when someone tries to tell you that supplements are miraculous and pharmaceutical drugs don’t work at all. I know too many people who delayed trialing SSRIs for years due to internet driven fears and lost many years of their lives to depression based on content like this. People with cabinets full of dozens of supplement bottles that were chosen based on studies, too. Then they finally decided to try real antidepressant medications and wished they’d done it sooner.
As much as I wish we could all just cure depression by taking a simple Vitamin D supplement that has 4.5X higher effect size than antidepressant drugs, this claim just isn’t passable.
Anecdotally, Vitamin D and B12 had more of a positive effect on my mental health than therapy or any of the half dozen prescription meds I tried.
Hiking has the biggest effect though.
I think maybe the problem is that therapists are diagnosing people, and psychiatrists are prescribing pills based on those diagnoses, but neither are ordering bloodwork to check for deficiencies. Which leads to a lot of people suffering from lack of basic health, and treating the symptoms with SSRIs that have withdrawl symptoms a million times worse than most of the problems they treat.
Now to your point, I seriously doubt that vitamin D will hold up against anti-depressants and therapy if we control for other health and quality of life issues. I just think there is a ton of misdiagnosis, and lack of root cause analysis in the mental health field, and health care in general.
> Hiking has the biggest effect though.
Keeping the mind busy with beautiful things and being physically exhausted can heal a lot of things.
Its like surfing on a big day - you are just too tired to be depressive afterwards. It feels like a weight blanket.
It's also endorphins. Natural drugs.
I don't have the energy to do all that when I'm down though. I hate all sports though I do like hiking (there's no team or competitive bullshit) but I'm too clumsy for it.
I will say that my LMHNP ordered a blood test for me during my ADHD evaluation. I live in the Pacific Northwest and had a serious vitamin D deficiency, apparently like everyone else who doesn’t supplement. also got me started monitoring my blood pressure.
I can definitely tell that the Adderall I was prescribed had an immediate, huge benefit. Not sure about the vitamin D.
But I really appreciated that he took a wide angle look at my health.
I go on regular long walks and it is a huge help.
A few months ago I tried walking with a weighted vest, and my body and brain got completely shocked in a really good way. Wakes up everything. So that is in my mix now.
Walking with 20 then 40 lbs was a lot easier than I expected, and the results were much greater.
> Hiking has the biggest effect though.
I remember reading that pine trees give off a chemical that is a natural human bronchodilator.
One thought of why people love hiking, especially in piney woods, is that the chemical allows humans to process more oxygen which in turn helps them feel more "energized".
I point this out for two reasons:
1. It's a fascinating bit of trivie
2. It highlights that there are MANY confounding variables so it will always be tough to figure out the isolated impact.
I bought an E-Bike two years ago and it’s changed my life. I want to ride my bike all the time, and am counting down the days to spring. During the warmer months I run all the errands I possibly can with my bike instead of driving, and ride for pleasure often, going on multi hour bike rides. It’s just such a blissful feeling, and as I’ve gotten more fit I’ve been able to turn down the bike assist and built a lot of leg muscles.
I do understand there are many things that can make it infeasable to bike during winter, but if you miss your bike absolutely give it a try! I bike year around in Norway. Studded tires help tons, and that the city maintains the bike infrastructure during winter.
Getting an e-bike has got me out getting exercise way more than a regular bike ever did. Being able to dial my effort up and down pushes me further, quite literally in distance and fitness goals. I'm by no means fit and almost did a 5 hour 40 mile ride one day. I completely used up the battery in that time, my legs were cooked from the effort. I would have never attempted something like that on a regular bike unless I was fit.
Are you riding on roads or trails? How are you treated by other road users? I'm tempted by ebikes but live in semi-rural UK with very poor (and getting worse) road surface and lots of blind bends.
1 reply →
> Vitamin D and Omega-3 are the two supplements that consistently appear to be super powerful in small studies and then fail to do anything significant at all in larger studies.
That statement is broadly true for most outcomes studied, but specifically for depression the larger study results are pretty mixed.
VITAL (the heavily cited metastudy) shows no effect. https://pubmed.ncbi.nlm.nih.gov/32749491/
But there are other large metastudies like this one for Vit D (https://pubmed.ncbi.nlm.nih.gov/39552387/) and this one for Omega 3 (https://pubmed.ncbi.nlm.nih.gov/31383846/) that do show robust moderate effects.
> The effect size for antidepressants is 0.4
What the article states, then fails to take into account, is that is the mean effect size, and there is huge variation.
Anti-depressants are notorious for producing different effects for different people.
What that high variance means in practice, is for any anti-depressant, the people who get good results are getting a much higher effect than 0.4. And the other people move on to try something else.
So to keep comparing 0.4 directly to the effect of Vitamin D and Omega-3 directly is very misleading.
That's an odd argument. If we are talking about a organ safe uncombined dosage of Tylenol or Ibuprofen being 0.4 then I think we are talking about the point just above placebo and bias where something barely has a real effect that should be hard to measure without a high power study. That's saying nothing useful with so few significant figures.
If antidepressants cost less than $4/1000 and acted as an antiinflammatory as their only common side effect then sure I'd consider replacing Ibuprofen as my pain placebo of choice.
I believe presenting vitamin D supplements as effective in treating depression is kinda misleading. It's rather vitamin D deficiency that is super effective at making you miserable, but it's not the only thing that can do it to you. And since a lot of us are in fact deficient (and the threshold of being categorized as deficient may be placed too low too), it will appear as being quite effective overall, especially compared to other drugs that act on less common and poorly understood causes.
Thank you. Fixing a vitamin deficiency is an obvious benefit to physical health. But does it "cure depression"? To the extent that your depression was caused by vitamin deficiency, sure. But then didn't you just cure a vitamin deficiency? I'm sure a lot of things starting improving once your body starts getting proper nutrients after years of neglect! That doesn't indicate causality.
As far as we can tell, "depression" is a label we put onto a big bag of issues with similar symptoms, but that may require different interventions. Vitamin D deficiency may very well be or lead to one of those, and it definitely doesn't help when coexisting with something else either.
Hi, author of the blog post here! Thank you for writing in with your concerns. First:
> Please be very careful when someone tries to tell you that supplements are miraculous and pharmaceutical drugs don’t work at all.
I'll concede I unintentionally gave the tone that one should replace antidepressants with supplements, even though the conclusion specifically writes: "(Don't quit your existing antidepressants if they're net-positive for you!) you may also want to ask your doctor about Amitriptyline, or those other best-effect-size antidepressants."
I have now edited the intro to more explicitly say "you can take these supplements alongside traditional antidepressants! You can stack interventions!"
===
> and nobody noticed this massive discrepancy until now?
Researchers have noticed it for 13 years! From the linked Ghaemi et al 2024 meta-analysis ( https://pmc.ncbi.nlm.nih.gov/articles/PMC11650176/ ):
> Several meta-analyses of epidemiological studies have suggested a positive relationship between vitamin D deficiency and risk of developing depression (Anglin et al., 2013; Ju, Lee, & Jeong, 2013).
> Although some review studies have presented suggestions of a beneficial effect of vitamin D supplementation on depressive symptoms (Anglin et al., 2013; Cheng, Huang, & Huang, 2020; Mikola et al., 2023; Shaffer et al., 2014; Xie et al., 2022), none of these reviews have examined the potential dose-dependent effects of vitamin D supplementation on depressive symptoms to determine the optimum dose of intervention. Some of the available reviews, owing to the limited number of trials and methodological biases, were of low quality (Anglin et al., 2013; Cheng et al., 2020; Li et al., 2014; Shaffer et al., 2014). Considering these uncertainties, we aimed to fill this gap by conducting a systematic review and dose–response meta-analysis of randomized control trials (RCTs) to determine the optimum dose and shape of the effects of vitamin D supplementation on depression and anxiety symptoms in adults regardless of their health status.
===
> even common OTC pain meds can have effect sizes lower than 0.4 depending on the study. Have you ever taken Tylenol or Ibuprofen and had a headache or other pain reduced? Well you’ve experience what a drug with a small effect size on paper can do for you.
I must push back: that's an effect of 0.4 plus placebo effect and time.
There's now RCTs of open-label placebos (where subjects are told it's placebo), which show even open-label placebos are still powerful for pain management. So, I stand by 0.4 being a small effect; even if you took a placebo you know to be placebo, you'd feel a noticeable reduction in pain/headache.
EDIT: Here's a systematic review of Open-Label Placebos, published in Nature in 2021: https://www.nature.com/articles/s41598-021-83148-6.pdf
> We found a significant overall effect (standardized mean difference = 0.72, 95% Cl 0.39–1.05, p < 0.0001, I2 = 76%) of OLP.
In other words, if the effect on antidepressants vs placebo is ~0.4, and the effect of a placebo vs no placebo (just time) is ~0.7, that means the majority of the effect of antidepressants & OTC pain meds is due to placebo.
(I don't mean this in an insulting way; the fact that placebo alone has a "large" effect is a big deal, still under-valued, and means something important for how mood/cognition can directly impact physical health!)
> Researchers have noticed it for 13 years! From the linked Ghaemi et al 2024 meta-analysis
You’re cherry picking papers. Others have already shared other studies showing no significant effects of Vitamin D intervention.
For any popular supplement you can find someone publishing papers with miraculous results, showing huge effect sizes and significant outcomes. This has been going on for decades.
With Omega-3s the larger the trial size, the smaller the outcome. The largest trials have shown very little to no detectable effect.
I think a lot of people are skeptical about pharmaceuticals because they see the profit motive, but they let their guard down when researchers and supplement pushers who have their own motives start pushing flawed studies and cherry picked results.
> In other words, if the effect on antidepressants vs placebo is ~0.4, and the effect of a placebo vs no placebo (just time) is ~0.7, that means the majority of the effect of antidepressants & OTC pain meds is due to placebo.
You keep getting closer to understanding why these effect size studies are so popular with alternative medicine and supplement sellers: They’re so easy to misinterpret or to take out of context.
According your numbers, taking Tylenol would be worse than placebo alone! 0.4 vs 0.7
Does this make any sense to you? It should make you pause and think that maybe this is more complicated than picking singular numbers and comparing them.
In this domain of cherry picking studies and comparing effect sizes, you’ve reached a conclusion where Vitamin D is far and away more effective than anything, placebo is better than OTC pain medicines, and OTC pain meds are worse than placebo.
It’s time for a reality check that maybe this methodology isn’t actually representative of reality. You’re writing at length as if these studies you picked are definitive and your numeric comparisons tell the whole story, but I don’t think you’ve stopped to consider if this is even realistic.
> You’re cherry picking papers.
I just picked the most recent meta-analysis I could find, which also specifically estimates the dose-response curve. (Since averaging the effect at 400 IU and 4000 IU doesn't make sense.)
> Others have already shared other studies showing no significant effects of Vitamin D intervention.
Yes, and the Ghaemi et al 2024 meta-analysis addresses the methodological problems in those earlier meta-analyses. (For example, they average the effects at vastly varying doses from 400 IU and 4000 IU)
> According your numbers, taking Tylenol would be worse than placebo alone! 0.4 vs 0.7
No, I understand this fine. Taking Tylenol would give you active medication + placebo + time, which is 0.4 + 0.7 + X > *1.1.* Taking open-label placebo is just placebo + time = *0.7* + X.
(Edit: Also, these aren't "my" numbers. They're from a major peer-reviewed study published in Nature, the highest-impact journal. I don't like "hey look at the credentials here", but I bring it up to note I'm not anti-science, see below paragraph)
===
Stepping back, I suspect the broader concern you have is you (correctly!) see that supplement/nutrition research is sketchy & full of grifters. And at the current moment, it seems to play into the hands of anti-establishment anti-science types. I agree, and I'll try to edit the tone of the article to avoid that.
That said, there still is some good science (among the crap), and I think the better evidence is accumulating (at least for Vitamin D) that it's on par with traditional antidepressants, possibly more. I agree that much larger trials are required.
4 replies →
the larger the trial size, the smaller the outcome
I find this a bit surprising. Could there be something else affecting the accuracy of larger trials? Perhaps they are not as careful, or cutting corners somewhere?
5 replies →
A point I think is crucial to mention is that “effect size” is just standardized mean difference.
If a minority of patients benefit hugely and most get no benefit, then you get a modest effect size.
This is probably why this discussion always has a lot of people saying “yeah, it didn’t help me at all” and a few saying “it changed my life.”
I believe we should be focusing on more relevant statistical methods for assessing this hypothesis formally. Basically, using mean differences is GIGO if you assume you’re comparing a bimodal or highly skewed distribution to a bell curve.