Supplements for Depression: What the Research Actually Says

When it comes to treating depression, there are plenty of options out there, including supplements. Yet finding evidence-backed supplements for depression isn’t an easy task. That’s why we created this comprehensive guide.

I’ll admit it: I’m a supplement skeptic. And there’s plenty of reasons to be, given that the industry isn’t FDA-regulated, and the right supplements vary depending on genetics and diet. Yet a few years ago, my primary care provider recommended vitamin D for seasonal depression. I had the most energized, high-vibe winter, and I’ve been taking it ever since. 

Some supplements, like Vitamin D when someone has Vitamin D deficiency, truly can help with different types of depression. But researching the laundry list of supplements for depression can leave your brain feeling scrambled.

Luckily, we’re about to take a comprehensive look at the most popular supplements for mental health, grouping them into categories including those with the strongest evidence, mixed evidence, and limited evidence. We’ll also go over other options when antidepressants don’t work, as well as when it’s time to seek out professional help. 

Can supplements actually treat depression?

The short answer: Some supplements help with depression. This may take the shape of  preventing depression or reducing depressive symptoms. But before we call any supplement  “miracle pills” or “natural SSRIs,” it’s important to note that they work best in tandem with healthy habits and mental health treatments. 

Despite their potential anti-depressant effects, most supplements don’t directly affect depression, and they can’t get rid of things like trauma, social isolation, or financial worries that also contribute to your overall mental health. 

What supplements can do is some internal balancing. Their effect depends  on the exact supplement, though some may include:

• Fixing a nutrient deficiency 
• Improving sleep quality
• Reducing inflammation
• Having a modest effect on mood
• Boosting energy levels
• Calming the nervous system
• Reducing stress 

“The overwhelming majority of things that help with depression are natural and not drugs,” says Owen Muir, MD, DFAACAP, an interventional psychiatrist and the co-founder and Chief medical officer of Radial. Dr. Muir includes supplements on that list, so long as you choose the right one(s) for your overall health and nutritional needs. 

However, he adds that many other habits and lifestyle changes would be above supplements on his unofficial list of most effective depression treatments. And yes, we will get to those other options in a minute. 

Standout box: If you have severe depression that makes it difficult to get out of bed or if you’re experiencing suicidal thoughts, supplements are not the solution. Instead, call or text 988 or visit the Suicide & Crisis Lifeline website.

Important reminders regarding supplements

When you purchase a medication, the federal government has verified the quantity and quality of the drug’s ingredients. The same can’t be said of supplements, which are not FDA-regulated. This means there’s not one organization that verifies that supplements actually contain what they say they do. 

As you can imagine, that leads to lots of inconsistencies between supplement brands. To find a high quality option, choose a supplement that:

• Clearly states ingredients: Any supplement you purchase should be transparently labeled. And usually, the fewer ingredients, the better.
• Has been third party tested: Third-party testing by a reputable organization, such as the United States Pharmacopeia (USP) or National Sanitation Foundation (NSF), confirms the supplement contains the stated ingredients and doses and is free from contaminants. 
• Contains an appropriate dose: Good things come in small packages, and good supplements often come in small doses. For most nutrients and vitamins, the body can only absorb so much, so an ultra-high dose isn’t that useful. There are a few exceptions that may require a prescription-strength dose (I’m looking at you, Vitamin D), so it’s important to verify the “right dose” with a healthcare provider. 
• Suits your diet and lifestyle: Some supplements contain animal products, gelatin, soy, gluten, or all of the above. Make sure any products you choose work for your dietary needs.
• Works with your medications: Not all medications and supplements play nice together. Before purchasing a supplement, verify with a healthcare provider that it won’t interact with any medications you’re taking. 

Supplements with the strongest evidence for depression

The six picks in this category truly are best-in-class supplements that help with depression. They have the most evidence supporting them, as well as solid safety profiles and minimal side effects. That doesn’t mean they’ll work for everyone. After all, we have different genetics, diets, and mental health needs. Still, these are worth considering.

L-methylfolate

L-methylfolate, a type of B vitamin,is an alternative medicine for depression that has evidence as a supplement when used alongside other medications. 

“L-methylfolate is actually the building block for dopamine, norepinephrine, serotonin and every monoamine neurotransmitter you've ever heard of,” says Dr. Muir, “You can't make those things in your body without having l-methylfolate to build them out.” Neurotransmitters are chemicals that, among other functions, help regulate mood. Depression is associated with abnormalities in how these chemicals operate.

There’s a solid body of research to back up this supplement for patients with MDD who do not respond optimally to antidepressant monotherapy,. In a 2022 study, 67.9% of people reported their depression rating  on the 9-item patient health questionnaire (9PHQ) dropped after taking this supplement. Other studies suggest that it helps with sleep disturbances related to mood disorders and works in adults, teens, and children. 

There’s even a purified form of L-methylfolate called Deplin, which has a FDA label as a medical food for “adjunctive depression treatment,” meaning it works alongside medications or other treatment to reduce depressive symptoms. 

There is one caveat: L-methylfolate’s effectiveness partially depends on your genes. People with a MTHFR C677T C/T or T/T genotype typically respond better to this B vitamin, though it has a solid safety profile for everyone. 

Omega-3 fatty acids

“Omega three fatty acids are part of your cell membranes and every neuron,” says Dr Muir, “So if you want your neurons to function right, their membranes need to have appropriate flexibility. This is the chemical building block of flexibility in your neurons.” When neurons work as intended, symptom severity, negative thoughts, and rumination all decrease, which is a gamechanger for anyone dealing with depression. 

So, do omega-3 fatty acids work for depression? Yes, especially in cases of mild to moderate depression when used alongside other treatments. However, we don’t know if they’ll reduce depression symptoms when used on their own. 

Risks worth noting are an increased chance of bleeding and a small risk of mercury contamination if opting for a fish-based supplement.

Magnesium

“Magnesium is a little hard on your stomach, but there’s actually decent data, especially in populations with mild depression,” says Dr. Muir. Magnesium helps reduce inflammation (and less inflamed brains are typically less depressed). It also offers some other mood-regulating effects.

In fact, a study comparing this essential nutrient to a placebo found that magnesium improved depressive symptoms within two weeks and had minimal side effects. Plus, 60.1% of study participants said they would take it in the future. 

If you’re wondering what those side effects are, the most commonly reported in the study were diarrhea, constipation, headaches, and nausea. 

Lavender oil

Like magnesium, lavender oil extract taken orally (sometimes called Silexan) works well in people with mild depression. It’s worth noting that we’re not referring to aromatherapy here. One small study found that it helps by reducing depressive moods and stress and is often superior to a placebo for both depression and anxiety. 

It also may be a good choice when depression leaves someone feeling unmotivated or makes it hard to think. That’s because lavender oil helps improve functional capacity in those with mild to moderate depression. 

Silexan comes with very few side effects, all of which are typically minor and related to digestion. In one study, for example, the most commonly reported side effect was burping. 

Probiotics

Have you ever felt butterflies before a first date or big work presentation? That’s probably due to the gut-brain connection, which is a very real, very active communication pathway between the gut and your brain. Thanks to this connection, your gut health and mental health impact one another. 

And one of the best ways to work on the digestive health part? Make sure you get enough probiotics, live microorganisms that add healthy bacteria to your gut. In turn, that healthy bacteria can boost mood and reduce stress. They even reduce depressive symptoms in adult populations, as well as for teens and children. 

There are many different probiotic strains, and the more strain diversity, the better. “The trick is actually rotating the probiotics you take,” advises Dr. Muir, “One of the easiest ways to get probiotics is actually yogurt, kefir and kimchi. You can also take pills, but you shouldn't take the same one every month.”

L-theanine

Last but not least is L-theanine, an amino acid naturally found in green and black tea as well as some mushrooms. When used alongside other treatments, it may even help with major depressive disorder.

Like probiotics, L-theanine boosts gut health (remember that gut-brain connection?). It also has effects on the prefrontal cortex, the decision-making center of the brain. When we’re depressed, the prefrontal cortex is impaired, and L-theanine may help. Emerging research shows it also has effects on anxiety, ADHD, and schizophrenia, three conditions that sometimes co-occur alongside depression.

The supplement has an excellent safety profile, though some people report mild side effects. These include bloating, dry mouth, headaches, and fatigue. 

Supplements with limited or mixed evidence for depression

The following nine supplements show some promise for treating or preventing mild to moderate depression. But “promise” is code for more research is needed to definitively determine whether these supplements help. Some also have a less favorable safety profile than our six frontrunners above. 

Vitamin D

When it comes to vitamins for depression, vitamin D might be on the list, but only if you’re vitamin D deficient. Many of us get enough vitamin D from sunlight, though if you live in an area that’s cloudy or has a harsh winter (raises hand in solidarity), supplementation may help during the colder months or year-round. 

A primary care provider can order bloodwork to determine vitamin D levels. If you are deficient, they may write a prescription for prescription-strength vitamin D.. “A small dose of vitamin D won't do much to replete your vitamin D,” explains Dr. Muir, “You really need to take this under the direction of a doctor.”

Vitamin C

Vitamin C also falls into the vitamins that help with depression camp—when someone is vitamin C deficient. Vitamin C deficiency is associated with a higher risk of depression, and some studies suggest that upping your vitamin C intake may help with mild depression. 

That said, most people don’t need a supplement. The best way to get enough vitamin C is to eat your veggies (sorry if that gives you flashbacks to family dinners growing up), though fruits are a close second. Higher intakes of vitamin C, such as from a supplement, typically offer no additional benefit for depression compared to dietary vitamin C.

While many fruit and veggies contain vitamin C, some options with high levels include:

• Red and green peppers
• Brussels sprouts
• Citrus fruits
• Broccoli 
• Strawberries

Saffron

“Saffron works about as well as traditional antidepressants,” says Dr. Muir—which is to say it reduces symptoms in about 30-35% of cases. In fact, randomized control trials suggest it may actually be comparable to SSRIs.

The issue is in the logistics. Researchers are still unsure about the optimal dose, it comes with a hefty price tag, and some saffron is contaminated with heavy metals like lead. All this to say, if you try saffron, be very, very careful about the supplement manufacturer.

Ashwagandha

Ashwagandha calms the nervous system in a way that seems to help with anxiety. This makes it really good at reducing stress or helping someone feel less on edge, and it’s definitely a solid option for anxiety or even anxious depression. That calming effect may also help with depression, though there’s limited evidence—and most of the research is from trials with rats or mice, not people. 

Plus, Dr. Muir warns that this is another one where you need to be ultra-careful on the sourcing. “Ashwagandha works,” he says, “If you get actual ashwagandha.”

St. John’s Wort

St. John’s Wort might be one of the most popular depression supplements, and some studies suggest it works for mild to moderate depression. However, it’s probably not worth the hype, since it produces inconsistent effects for those with depression and may interfere with prescription medications. 

And that second drawback may be more far-reaching than you’d expect. “If you take St John's wort and you're on birth control, it'll make your birth control not work and you might get pregnant,” says Dr. Muir. He also points out that St. John’s Wort might interfere with life-saving medications, like an antibiotic, and that might come with an unexpected ICU visit (supplement price doesn't include hospital bills). 

Iron

Iron is similar to vitamin C or D: A supplement may help reduce depressive symptoms for those who are iron deficient. That may be because iron deficiency leads to low energy and can affect mood. However, emerging research suggests it may also directly address behavioral symptoms from anxiety or depression when there’s an iron deficiency. 

Zinc

Getting enough zinc is definitely linked to a lower risk of depression and may even help alleviate symptoms. The thing is, you probably don’t need to take a supplement. “Zinc is a trace element that you need to get enough of,” explains Dr. Muir, “and you'll probably get enough in your diet, so I wouldn't go out of my way to take a zinc supplement.”

If you’re curious, zinc is found in seafood, meats, eggs, dairy products, legumes, beans, nuts, and whole grains. Unless you’re a rabbit, you probably eat something that falls into one of those categories. 

SAM-e

This supplement is the poster child for mixed evidence, especially regarding depression. It’s pretty well established that people with depression have low levels of SAM-e (sometimes referred to as  S-Adenosylmethionine). There’s even some evidence that SAM-e supplementation can reduce depressive symptoms. Still, other studies found this effect to be minimal in people with mild to moderate depression. 

Rhodiola Rosea

If you’re looking for the swiss army knife of supplements, Rhodiola Rosea might be it. It has a long history of being used to boost energy levels, enhance focus at work, reduce stress, improve physical performance, stimulate the nervous system, and, yes, treat depression. 

Trouble is, that long history is in traditional medicine, and clinical research is mixed, especially for depression. Some studies suggest that  Rhodiola Rosea reduces depression, primarily thanks to its stress-reducing qualities, but these studies are few and far between. Basically, the (scientific) jury is still out on if it can reduce depressive symptoms. 

Supplements with little or no evidence for depression

So, what supplements have minimal or no evidence for depression? The ones below have a slim (but somewhat existent) chance of helping:

• Thiamine: While some studies have identified a slight association between depression and low levels of this B vitamin, more comprehensive studies suggest a nonlinear association, meaning low thiamine levels most likely do not impact depression. 
• Vitamin B12: This is a fan favorite for many reasons—B12 keeps nerve cells working as intended, maintains energy levels, and supports cognitive health. While the energy boost may have some effect on depression, little to no evidence suggests B12 directly impacts depressive symptoms. 
• Vitamin B6: Vitamin B6 might help reduce anxiety, but its effects on depression are minimal to nonexistent. 
• Vitamin B9 (folate): While it’s true that some depressed individuals have less folate in their blood, vitamin B9 supplementation has a minimal effect on depression. You’re better off taking L-methylfolate, which will also increase folate levels. 
• 5-Hydroxytryptophan (5HT): In some small studies (as in, ones with less than 30 people), this supplement has led to some reduction in depressive symptoms and a boost in cognition. However, there isn't enough research to conclusively say if 5HT does, or doesn’t, help with depression. 
• L-tyrosine: Some studies suggest this amino acid might have an impact on neurotransmitters involved in depression. The problem is, those studies feature mice as participants, and even animal studies on L-tyrosine and depression are scarce. 

How to safely try supplements for depression

So, you’re ready for  one of the supplements mentioned above. You may be tempted to run down to your local pharmacy and buy one (or more). After all, supplements are available without a prescription. 

But let me stop you before you grab your keys and head out. Instead, reroute your GPS to your primary care provider. “A good starting place for deciding which supplement is right for you is to see your primary medical doctor,” advises Dr. Muir. They can order blood work to check your iron levels, vitamin D levels, and more—which is useful data to decide what you actually need. 

Once you have one to three supplements that are tailored to your health, it’s time to research brands. Your doctor may have some recommendations, or you can refer back to our supplement safety list above. 

Next, it’s time to design a little at-home experiment, using yourself as the lab rat. Commit to taking a chosen supplement for a set amount of time. For reference, many actual studies on supplements run for at least eight weeks. You’ll also want to reflect on your “baseline,” or how you feel and the symptoms you’re experiencing before starting.

Throughout the experiment, track key metrics, such as::

• Your mood
• Your energy levels
• How long (and well) you slept
• Any side effects from the supplement, such as an upset stomach
• Any improvements from other depressive symptoms you noticed before starting the unofficial trial

Supplements don’t work overnight, and they will probably have a modest effect. Be consistent during your experiment and set aside time at the end to decide if a supplement did or didn’t work.

When supplements aren’t enough

A depression supplement is not a golden ticket that will fix all your problems. They are a potential addition to your toolkit. To overcome depression (or even to prevent it), you’ll need a winning line-up of habits. And in this metaphor, supplements are the waterboy—nice to have, but far from the MVP. 

In fact, the best natural mood stabilizers aren’t found in a supplement bottle, but in the world around you. None of these are sexy, but getting enough sleep, an anti-inflammatory diet (i.e. one that prioritizes natural foods like legumes, leafy greens, and nuts), and getting sunlight are all gamechangers for depression. And the potential MVP for depression? Exercise. 

“If I had one thing to prescribe, it would be walking a lot in the sunlight,” says Owen, “In fact, get all the supplements you want, as long as it's a mile walk to the supplement shop.”

At the same time, these habits might not be enough. I’ve had depression in the past, and the most annoying thing is when you’re in a depressive episode and someone says, “Just exercise more.” 

For many people, myself included, healthy habits aren’t enough, and professional help is part of the puzzle. There are many ways a mental health provider, such as the team at Radial can help with depression:

• Facilitate psychotherapy (aka talk therapy)
• Administer neuromodulation therapies, like transcranial magnetic stimulation (TMS)
• Prescribe medications that act faster than traditional antidepressants, such as Esketamine (brand name Spravato)or bupropion (brand name Wellbutrin) 

They can also help you implement lifestyle changes—you know, the ones we all say we’ll try but never get around too—and help you stay accountable to doing them consistently.

That said, it can be hard to know when professional help is needed. Fortunately, there are some free screening tools, like the PHQ9, that can provide a rough idea of how severe your symptoms are. “If it scores that you're moderate or severely depressed, or even mildly depressed and you want to feel better, then it’s worth seeing a doctor,” explains Dr. Muir. 

The bottom line

The verdict is in, but it’s about as murky as supplement research. Some evidence supports supplements as effective natural remedies for depression. However, their efficacy depends on depression severity, your genetics, diet, lifestyle, and more. The best way to find the right supplement for you is to work with a primary care provider who can test blood levels and provide customized recommendations. 

It’s also important to remember that supplements aren’t a standalone act; they should be used alongside healthy habits, therapy, TMS, medications, and any other treatments recommended by a mental health provider.

Key takeaways

• Some supplements reduce depressive symptoms or prevent depression. The ones with the strongest evidence include, lavender oil, magnesium, omega-3 fatty acids, and L-methylofolate.
• Other options, like vitamin C, vitamin D, and iron, may help if you don’t get enough from diet or sunlight, in the case of vitamin D. A primary care provider can test for many nutrient deficiencies. 
• Supplements are best used alongside mentally healthy habits, therapy, and any treatments recommended by a mental health provider.
• If you’re looking to build a more comprehensive toolkit to beat depression, the team at Radial can help.

Frequently asked questions (FAQs) 

Which supplements help depression? 

Some of the best supplements for depression include L-methyfolate, omega-3 fatty acids, magnesium, lavender oil, probiotics, and L-theanine. All six have reduced depressive symptoms in clinical trials and have relatively few side effects or risks. 

What is the best natural antidepressant? 

For many people the best natural antidepressants are healthy habits. Lifestyle changes that reduce depression the most are exercise, especially walking, eating an anti-inflammatory diet, and getting sunlight whenever possible.

How long do supplements take to work for mood?

Generally speaking, you want to give a supplement at least eight weeks before deciding if it works or not. The exact timeline varies depending on your genetics, how severe your mood-related symptoms are, and other lifestyle habits, such as how much you exercise or what you eat. 

Deep dive recommendations 

• The Frontier Psychiatrists. Walking, Revisited. 
• The Frontier Psychiatrists. Essential Oils for Depression: Yes, Really.
• The Frontier Psychiatrists. Magnesium. 
• Radial. What To Do When Antidepressants Don’t Work.

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