Methylfolate and Depression

The conversation around mental health has really opened up in recent years, enabling people to talk about their experiences and access support. The links between good nutrition and mental wellbeing are stronger than ever with one nutrient at the forefront of this approach: methylfolate. In this article we explore the causes and signs of depression, the deep connection between methylfolate and depression, and the crucial difference between methylfolate and folic acid.

What causes depression?

Depression doesn’t always have an obvious cause. It can develop as the result of another illness such as hypothyroidism (underactive thyroid) or cancer, or it can be linked to chronic stress and difficult life events like divorce or bereavement. 

Other causes include [1]:

• Hormonal changes: pregnancy, menopause, Pre-Menstrual Syndrome (PMS), and Pre-Menstrual Dysphoric Disorder.

• Chronic pain.

• Head injury.

• Loneliness.

• Drug or alcohol addiction.

• Seasonal Affective Disorder.

• Bipolar disorder.

Nutritional imbalances can lead to depression too. When your body doesn’t have enough of the nutrients it needs to make neurotransmitters and maintain a healthy nervous system, mental health can suffer as a result.

Signs and symptoms of depression

Signs of depression vary from person to person and it’s not always easy to tell when someone is depressed.

Common indicators are [2]:

• Feeling sad or hopeless.

• No longer enjoying activities that usually make you happy.

• Wanting to withdraw socially.

• Lack of motivation or interest in life.

• Low self-esteem.

• Difficulty making decisions.

• Feeling anxious or worried.

• Unexplained aches and pains.

• Changes in appetite.

What does methylfolate do for depression?

The link between methylfolate and depression runs two ways. Low levels of methylfolate are associated with depression and depressive disorders [3] while treatment outcomes are improved when antidepressant drugs are augmented with methylfolate supplements [4].

Methylfolate is the only form of folate that crosses the blood-brain barrier and gets into the brain where it is used in the production of serotonin, dopamine, and noradrenaline. These feel-good neurotransmitters influence mood, appetite, pleasure, and our sense of reward and motivation. When folate levels are low, your body doesn’t have enough raw material to build these neurotransmitters. 

Low methylfolate also affects homocysteine metabolism. The “methyl” part of methylfolate is used in the methylation cycle, a biological process happening billions of times per second in your body. 

Methylation involves the movement of a methyl molecule from one compound to another. This movement acts as a sort of switch for thousands of activities including gene activation, DNA repair, detoxification, energy production, and cardiovascular health.

Healthy methylation supports normal homocysteine metabolism. Homocysteine is an amino acid produced naturally during protein breakdown. When methylation is slow, homocysteine starts to build up and triggers inflammation. Some research supports a link between elevated homocysteine and the risk of depression, particularly in older people [5] though larger studies are needed to establish a causal relationship. 

Genetic polymorphisms influence the rate of methylation activity. The most well-known of these are polymorphisms affecting the MTHFR gene that encodes the enzyme responsible for converting folic acid to methylfolate [6]. This is why supplementing with methylfolate rather than folic acid is key for supporting healthy methylation and mental well-being.

What’s the difference between methylfolate and folic acid?

Folic acid and methylfolate are both forms of folate, also known as vitamin B9. Methylfolate is produced from tetrahydrofolate, the natural form of B9 found in liver, eggs, and leafy green vegetables like asparagus, broccoli and kale. It is active and ready for your body to use without any further conversion processes.

Folic acid is the synthetic form of B9. It needs to be converted to the active form (methylfolate) in your body. Because of genetic variations some people struggle with this conversion and may still develop a folate deficiency even if they’re supplementing with folic acid.

Can methylated B-vitamins cause anxiety?

Methylated B-vitamins are well tolerated when used as directed at the recommended dosages. As with all supplements, some people will be more sensitive to the effects of methylfolate than others. Minor side effects like stomach discomfort can be eased by taking your methylfolate supplement with food rather than on an empty stomach.

One study showed that a very small number of people with either bipolar depression or Major Depressive Disorder experienced heightened anxiety and agitation when using methylfolate alongside their psychotropic medication. However, the 15mg dose of methylfolate used in this study is much higher than the amounts used in conventional supplements (400mcg) and the side effects stopped as soon as the methylfolate was discontinued [7].

We hope this article helps you feel confident about using methylfolate as part of a diet and lifestyle approach for mental health.  You can find out more about methylfolate in our 5-Minute Methylfolate Guide and shop for methylfolate in the store.

You might also enjoy reading:

Understanding Methylation: What Is It and Why Is It Important?

Lion’s Mane: 6 Powerful Benefits for Your Body and Brain

Top 4 Supplements for Anxiety!

References

1. NHS, 2023. Causes – Depression in adults. [online] Available at https://www.nhs.uk/mental-health/conditions/depression-in-adults/causes/ [Accessed 28 May 2025].

2. NHS, 2023. Symptoms – Depression in adults. [online] Available at https://www.nhs.uk/mental-health/conditions/depression-in-adults/symptoms/ 

3. Liwinski, T., & Lang, U. E. 2023. Folate and Its Significance in Depressive Disorders and Suicidality: A Comprehensive Narrative Review. Nutrients, 15(17), 3859. https://doi.org/10.3390/nu15173859 

4. Altaf, R., Gonzalez, I., Rubino, K., & Nemec, E. C. 2021. Folate as adjunct therapy to SSRI/SNRI for major depressive disorder: Systematic review & meta-analysis. Complementary Therapies in Medicine, 61, 102770. https://doi.org/10.1016/j.ctim.2021.102770 

5. Almeida, O.P., McCaul, K., Hankey, G.J., Norman, P., Jamrozik, K., Flicker, L. 2008.  Homocysteine and Depression in Later Life. Archives of General Psychiatry. 65(11):1286–1294. doi:10.1001/archpsyc.65.11.1286  

6. Frosst, P., Blom, H. J., Milos, R., Goyette, P., Sheppard, C. A., Matthews, R. G., Boers, G. J., Den Heijer, M., Kluijtmans, L. A., & Rozen, R. 1995. A candidate genetic risk factor for vascular disease: A common mutation in methylenetetrahydrofolate reductase. Nature Genetics, 10(1), 111-113. https://doi.org/10.1038/ng0595-111 

7. Robinson, S. & Miller, J.J. 2020. L-Methylfolate: Augmenting Agent May Contribute to Agitation and Mania Psychiatric Times [online]. Available at https://www.psychiatrictimes.com/view/l-methylfolate-augmenting-agent-may-contribute-agitation-and-mania