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.

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!"

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> 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.

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> 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!)