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Supplements That Make Antidepressants Work Better

Supplements That Make Antidepressants Work Better

Supplements That Make Antidepressants Work Better

Depression affects around 3.8% of the global population, making it one of our most prevalent mood disorders. [1] Although depression can result from a wide range of factors, it is predominantly associated with an imbalance of the neurotransmitters that contribute to healthy mood - namely serotonin, norepinephrine, and dopamine.  

Those diagnosed with clinical depression are often prescribed antidepressants. However, this treatment may not necessarily provide the desired results, which has many sufferers seeking adjunct therapy: augmentation by adding a supplement to improve the response to the antidepressant.

Some of the most clinically researched adjuncts to common antidepressants include methylfolate, Omega 3, B-vitamin complex, and others. 

What is depression?

Worldwide, depression affects around 5% of adults and 5.7% of adults aged 60+. [2]

Depression is defined as a mood disorder that causes a “persistent feeling of sadness” and results in a loss of interest in life. [3] Although there are many categories of depression, the most common features include sadness, emptiness, irritability, and cognitive symptoms that significantly affect one’s ability to function normally.

Unfortunately, anxiety and depression are both often underrecognized and inadequately treated. [4] And, despite the long list of antidepressants now available, many have an unsatisfactory response and several trials of different medications may be required. The high prevalence and chronic nature of depression have led both clinicians and patients to seek means of improving the response to different types of antidepressants. 

The good news is that certain supplements may improve the uptake and response to antidepressant medications. These include methylfolate, Omega 3 fatty acids, magnesium, zinc, and vitamin D. 

Note: Before starting a new supplement regimen, check the antidepressants list to see which adjuncts may or may not be suitable. This is particularly important for those taking natural antidepressants. It is recommended to speak with your doctor or pharmacist if you are not sure.

Which supplements are best for depression?

Numerous studies have shown a link between folate deficiency and depression. Depression is one of the most common signs of folate deficiency, and folate levels are often inversely associated with symptoms of depression and with longer periods of depressive episodes. Those who are depressed with folate deficiency typically respond poorly to standard treatment with antidepressants. [5]

In addition, it’s estimated that around 30% of people with depression do not respond to antidepressant therapy. [6] This is sometimes termed “l-methylfolate-depression”: a genetic variant of the methylenetetrahydrofolate reductase enzyme that impairs the ability to convert both synthetic folic acid and folate from food into the active folate (l-methylfolate), which the body uses. This is often referred to as an MTHFR mutation. 

Folate is a B vitamin that occurs naturally in food. Its active form, l-methylfolate, is the only form able to cross the blood-brain barrier. L-Methylfolate is required for the production of neurotransmitters serotonin, dopamine, and norepinephrine, which support a healthy mood and the function of antidepressants.

Clinical studies have provided evidence for L-methylfolate and depression management, showing that adding l-methylfolate to standard therapy may significantly improve recovery in certain individuals. A randomized, double-blind trial found that l-methylfolate 15 mg plus SSRIs resulted in twice as many patients responding to treatment within 30 days compared to placebo plus SSRIs. [7]  Another recent study showed that patients treated with l-methylfolate had statistically significant improvements in their depression symptoms and quality of life. [8]

For those who want to try methylfolate themselves, Methyl-Life® L-Methylfolate Elevate Mood is highly recommended. Elevate Mood contains 15 mg methylfolate, the amount clinically proven to enhance antidepressant benefits. 

S-adenosylmethionine (SAMe)

S-Adenosylmethionine (SAMe) is a molecule formed naturally in the human body via the methylation of homocysteine to methionine by methyltransferase enzyme and cobalamin. Methionine is then converted to SAMe through the enzyme methionine. SAMe may be beneficial in treating depression, as it can increase the central turnover rate of dopamine and serotonin. [8]  A meta-analysis showed that taking SAMe alongside serotonin reuptake inhibitors (SSRIs) significantly enhanced the response to the SSRIs. [10]

What Does it Mean to be the “Best” Methylfolate

Fish oil

Fish oil contains omega-3 polyunsaturated fatty acids, which are thought to induce an antidepressant effect via their anti-inflammatory action and direct effects on neural membranes. A large review found that fish oil is particularly effective as an adjunct to antidepressants. The review suggested omega-3 fatty acids can also indirectly help to modify specific signaling proteins in the brain, which contribute to improved mood. [11] Another study involving fish oil alongside citalopram treatment found that the fish oil produced a significantly greater reduction in depression scores compared to citalopram treatment alone. [12]


Magnesium is an essential mineral that functions as a cofactor in more than 300 biochemical reactions in the body. [13] Magnesium depletion may play an important part in the etiology of mood disorders such as depression due to its role in regulating certain receptors in the brain. Magnesium deficiency may also contribute to anxiety and dysregulation of the HPA axis. 

Supplementing with magnesium has numerous benefits for general wellbeing. It’s also shown to be effective as a tricyclic antidepressant and beneficial as an adjunctive treatment for depression. [14] Sucrosomial® Magnesium is a highly bioavailable magnesium complex providing 32% elemental magnesium via an innovative delivery system. This innovative form of magnesium encapsulates molecules within a phospholipid membrane and sucrose esters of fatty acids, allowing the active ingredients to cross the gastrointestinal barrier directly into the bloodstream. This is shown to significantly enhance the absorption and bioavailability of minerals while also preventing interaction with the absorption of other nutrients. [15]


Vitamin D

Low Vitamin D has also been linked to the pathophysiology of depression. Vitamin D receptors are present in parts of the brain associated with emotions and behavior, and depressed people are found to have lower serum vitamin D levels. Vitamin D also plays an important modulatory role in regulating immunoinflammatory pathways related to the onset of depression. [16]

A recent meta-analysis suggested that vitamin D supplementation has clinical benefits for those with depression. One 8-week trial found that taking vitamin D alongside the antidepressant fluoxetine provided better results in alleviating symptoms than taking fluoxetine alone. [17] Researchers suggest that neuroinflammation may be a factor in depression, and that Vitamin D’s anti-inflammatory benefits may help to improve treatment response. 

B Vitamins

Searching for “best antidepressant for anxiety and depression” may yield thousands of results. First things first: there is good evidence for adding methylfolate and methylcobalamin to antidepressant medication. B vitamins play a critical role in the conversion of homocysteine to methionine. High plasma homocysteine has been consistently associated with depression. [18]

You may be wondering, how does Vitamin B12 help with antidepressants? A deficiency of Vitamin B12 can result in neurological and psychiatric issues, including changes in personality and depression. Low B12 is also known to worsen depression due to the accumulation of homocysteine. [19]

Vitamin B12 works alongside Vitamin B6 and folate in converting homocysteine to methionine, forming S-adenosylmethionine (SAMe), an essential methyl donor required for the production of neurotransmitters that contribute to a healthy mood.  [20] The MTHFR C677T polymorphism is considered a predisposition to depression as it impairs the metabolism of folate required for this process. [21]

Studies involving adults with major treatment-resistant depression found that 15 mg/day of l-methylfolate decreased the severity of symptoms and increased remission over 60 days. These results suggest that adding folate and vitamin B12 to antidepressant treatment may improve response and prevent relapse. Treatment with these B vitamins also demonstrably reduced the concentration of homocysteine. [22]

Methyl-Life® B-Methylated-II was designed specifically for this purpose. B-Methylated-II is a chewable multi that contains 3 mg L-Methylfolate + 3.75mg Methylcobalamin, the activated forms of folate and B12 that are clinically proven to work alongside antidepressants and enhance their benefits in the brain. 


Zinc is an essential trace mineral for proper cognitive function and healthy neural structures. Patients with depression are found to have low serum levels of zinc. [23]

A systematic review concluded that zinc supplementation might assist in both the prevention and treatment of depression. It found that taking zinc contributed to a reduction in depressive symptoms in individuals with major depression who were being treated with antidepressant therapy. The dose of zinc used in the studies ranged from 7 mg to 25 mg. However, more studies are pending. [24]

The takeaway

People with depression who fail to respond to antidepressant treatment may need additional supplements. There is good research to suggest that a range of nutrients can enhance the effects of antidepressants, especially those that support the production of neurotransmitters. Methylfolate (folate/B9) and methylcobalamin have improved response to antidepressant therapy in those with treatment-resistant depression and major depression. Supplementing with active folate and B12, such as Methyl-Life® B-Methylated II may be a good place to start for those struggling to manage their depressive symptoms. 

Note: as with starting any supplement regime, speak first to your health professional. 


























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    Written By,
    - Katie Stone



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