When is the best time of day to take methylfolate?

When is the best time of day to take methylfolate?

Katie Stone - Naturopath

Written By:

Katie Stone - Naturopath
Jamie Hope - Founder of Methyl-Life

Medical Reviewer:

Jamie Hope - Founder of Methyl-Life
Kari Asadorian - Bachelor of Science in Nursing

Edited By:

Kari Asadorian - Bachelor of Science in Nursing

Updated On:

February 26, 2025

Table of Contents

    Anyone battling a depressive disorder knows how bleak life can feel. Sometimes, you’d try almost anything to make those black clouds go away.


    The idea that a few pills can make you feel better seems too good to be true.


    But right pills can make a world of difference to your brain chemistry, as we'll explain.


    Depression is the world’s single largest contributor to disability. It affects an estimated 350 million people globally, which is around 4.4% of the world’s population.


    In fact, the number of people with common mental disorders is increasing year by year, with the fastest-growing rates in lower-income countries. The World Health Organisation estimates that 10% to 15% of the general population will experience clinical depression in their lifetime - including 5% of men and 9% of women.


    Depressive disorders affect people of all ages and from all walks of life, but there are a number of factors that can increase the risk: namely family history, stressful life changes, psychological factors, low socioeconomic status, sleep disorders, and more.


    One of the longest-running theories in depression is of course the brain-chemistry imbalance.


    Also Read: What Does Citicoline Do for the Brain?

    The role of brain chemistry in depression

    Certain neurotransmitters - most notably dopamine, serotonin, and norepinephrine - play a crucial role in mood regulation. Neurotransmitters are chemical substances that help certain parts of the brain communicate with each other. Low amounts of these particular neurotransmitters are thought to contribute to the symptoms associated with clinical depression.


    It’s for this reason that most antidepressants are designed to alter levels of certain chemicals in the brain. Some of these treatments include selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), monoamine oxidase inhibitors (MAOIs), and tricyclic antidepressants (TCAs).


    Do they work? Well, according to the research, yes they do - but some better than others.


    There are dozens of different antidepressants and “happy pills” available on the market now. The most common drugs used to treat depression include citalopram (Celexa), escitalopram (Lexapro), paroxetine (Paxil, Pexeva), fluoxetine (Prozac, Sarafem), and sertraline (Zoloft).


    However, nearly two out of three patients with depression don’t see results after taking SSRIs or SNRIs. This means that a psychiatrist treating 20 patients for depression could see 14 come back with little to no initial improvement.


    This problem has been termed treatment-resistant depression (TRD), referring to patients with major depressive disorder who do not reach remission after multiple antidepressant trials, including augmentation strategy.


    Also Read: Healthy Ways to Clear Brain Fog

    When antidepressants don’t work

    A 2009 study from Northwestern University showed that more than half the people who take antidepressants for depression never get relief. The reason for this appears to be that drugs designed to treat depression are aimed at the wrong target.


    The researchers behind the study believe that antidepressants are ineffective because they treat stress and/or an imbalance in neurotransmitters in the brain. However, they suggest that the biochemical events that ultimately result in depression actually start in the development and functioning of neurons.


    Medications focus on the effect, rather than the cause. This is why they take so long to work, and why they never work at all for some people.


    So, if the problem lies in your neurons, how do you treat it?


    Well, one possibility could lie in providing your neurons with the nutrients and protection they need.


    That’s where methylfolate comes in. 

    What is methylfolate and what does it do in the brain?

    Methylfolate refers to methylenetetrahydrofolate, the most active form of folate. It’s the specific form the body needs to kick off many necessary downstream health processes, like neurotransmitter generation for one (the making of serotonin, dopamine, norepinephrine). The bioavailability of L-Methylfolate is much higher than folic acid alone because it needs no conversion within the body before it can be immediately used, whereas folic acid must undergo at least four different enzymatic conversions before methylfolate can be made available to the body.


    Every one of your cells - including over 200 billion brain cells - need this active form of folate to function properly. Methylfolate is involved in making and repairing DNA, genes, and chromosomes. It helps cells to grow, maintain their structure, and regenerate. It’s required in the electrical insulation of nerve cells, and the making of important neurotransmitters.


    Most importantly, methylfolate is a cofactor in the production of monoamines - serotonin, dopamine, and norepinephrine - the very neurotransmitters involved in the regulation of mood.


    Numerous studies have already linked depression with folate deficiency, while other research has shown that patients with low levels of folate are less likely to respond to treatment. What’s more, patients with low levels of folate are more likely to experience a relapse.


    Deplin is a prescription methylfolate product given to people who have suboptimal L-methylfolate levels in the cerebrospinal fluid (CSF), plasma, and/or red blood cells and have major depressive disorder. Described as a ‘medical food’, Depin is found to be particularly effective for people already taking antidepressant medications.


    While SSRIs and SNRIs block the reuptake of neurotransmitters (or allow the existing neurotransmitters to stay in the brain for longer and continue to be available to the body), L-methylfolate actually spurs the production of more neurotransmitters - acting like a “primer for the pump”.


    Also Read: What is vitamin B12 explained

    Can’t you just take folic acid?

    Unfortunately not. When it comes to proper uptake and utilization of folic acid in the body, this particular nutrient is basically a square peg for a round hole.


    For a start, folic acid has to be processed by many different enzymes before your body can turn it into the unique form that fits into a round hole: methylfolate.


    That’s why taking folic acid is unlikely to make much difference to your mood. Your body must first convert the folic acid at least 4 different times until it can become L-methylfolate. Once L-methylfolate is available in the body at the higher dosage levels, it can trigger SAMe to help manufacture enough serotonin, norepinephrine, and dopamine to alter depressive symptoms.


    What’s more, some people can’t actually convert folic acid into L-methylfolate at all due to a genetic processing deficiency caused by the methylenetetrahydrofolate reductase (MTHFR) polymorphisms (there are many, but the two most well-known and studied in regards to low folate levels are C677T & A1298C). This genetic disadvantage is quite common among people with depression. Up to 70% of patients with depression test positive for at least one of the two studied polymorphisms and therefore cannot convert folic acid into L-methylfolate very well on their own.

    The solution?

    If you’ve been struggling with treatment-resistant depression, or you have been tested for the MTHFR gene, one of the best things you can do for yourself is to take the most bioactive form of folate possible: methylfolate.


    L-Methylfolate is ideal for people who have a genetic enzyme deficiency because it requires no conversion to become metabolically active.

    How to take methylfolate

    Prescriptions for medication such as Deplin (which comes in 7.5 mg or 15 mg doses) can only be given by a qualified healthcare practitioner.


    However, there are a number of methylfolate supplements available over-the-counter and online. The trick is to find the right one for you.


    Some of the most highly-recommended methylfolate supplements for depression are found in the Methyl-Life™ product range, including:



    Methyl-Life’s® Methylfolate 15 product contains a high dose (15 mg) of internationally-patented Magnafolate® PRO [(6S)-5-methyltetrahydrofolic acid, Calcium salt, Type C Crystalline molecule (L-Methylfolate)]. This best-selling product is formulated specially for people with heightened need for bioavailable folate due to genetic (MTHFR) defects, dietary deficiencies or drug-induced need (i.e. taking warfarin, coumadin, metformin, etc.


    This unique and internationally-patented L-5-Methylfolate ingredient is crystalline calcium salt-based for superior stability and absorption. And a recent study has revealed that this proprietary form of methylfolate offers much greater purity than any other L-Methylfolate competing in the market today (approximately 3x more pure to be exact). Methylfolate is often known or labeled as L-MTHF, L-5-Methylfolate, L-5-MTHF, and (6S)-5-Methylfolate.


    Also Read: Staying Healthy and Eating Nutritious To Help Fight Coronavirus

    The best time of day to take methylfolate

    Taking the right dosage of methylfolate - at the right time - might just be key for you to obtain the most effective results while also reducing the risk of side-effects.


    Prescription methylfolate (Deplin) is available in 7.5 mg and 15 mg doses, while Methyl-Life® is available in three dosages: 7.5 mg, 10 mg, and Methylfolate 15 mg.


    Studies suggest that higher doses of 10 mg and 15 mg help to maximize the amount of L-Methylfolate that is available to pass through the blood-brain barrier. Folates are water-soluble vitamins, which means risk of overdose is unlikely: your body will use what it needs and expel the rest in your urine.


    Clinical studies have found that 15 mg of methylfolate may be the most beneficial dose for those with major depressive disorder. This level has also been shown to decrease unhealthy metabolic markers and improve depression in people who have the MTHFR genetic mutation.


    In addition, 15 mg of methylfolate seems to help people with treatment-resistant depression who are also obese. Follow up studies show reductions in inflammatory metabolic markers, which suggests the methylfolate is doing what folates are supposed to do, help cell machinery clean up after the messy cellular engines do their thing making energy for the cells.


    Health practitioner Dr. Neil Rawlins recommends taking two small doses (7.5 mg at a time) of methylfolate per day. This helps to maintain a steady level of folate in the bloodstream throughout the day (and presumably also makes the neurotransmitter generation process also more steady), which is important since methylfolate has such a short half-life in the body.


    Dr. Rawlins also suggests taking the dose of methylfolate in the morning and at lunchtime, as the nutrient can be somewhat energizing. Some people who take methylfolate later in the day may find it difficult to sleep at night.


    Keep your bottle of methylfolate near the items you would usually use at breakfast and lunch, such as your tea and coffee canister or the fridge. This will help you to remember to take it at the same time every day. If you miss a day, don’t double-up the next day: simply take your next day’s amount as you usually do.


    As always, it’s important to seek the advice of a qualified healthcare professional before taking any methylfolate products. 

    Minimizing side-effects of methylfolate

    It should be noted that methylfolate can increase glutathione levels in the body, which can enhance detoxification. This is a good thing, but it also means the body will start moving accumulated toxins out through the liver, which will then excrete a higher amount of toxins into the bile. This can cause a variety of unpleasant side effects such as nausea, bloating, headaches or other flu-like symptoms. Learn more about potential side effects that some might encounter.


    However, many of these side effects can be minimized by starting with smaller than the target high doses and building up slowly as the body adjusts.


    Also Read: What are the Causes, Symptoms and Signs of Cerebral Folate Deficiency?

    What else should you take with methylfolate?

    • B12 and magnesium play important roles as cofactors in the methylation process of L-methylfolate. B12 is also required for the conversion of homocysteine to methionine, while the conversion of homocysteine to cysteine also requires B-6.


    • Vitamin B12 is crucial for proper brain development and is associated with one carbon metabolism required for transmethylation reactions. It’s also involved in the formation of S-adenosylmethionine (SAMe) which we know to be the neurotransmitter generator - so this is a key nutrient to take along with L-Methylfolate for maximum effect against depression. Low B12 is also associated with neurological symptoms such as mood disorders, anxiety, and/or nerve pain. Research has shown a fundamental link between low B12, folate, and major depression. But be sure to take an active form of B12 - hydroxocobalamin (the rarer, but most well-tolerated form), methylcobalamin or adenosylcobalamin. Cyanocobalamin won’t do you much good since it doesn’t convert well in the body to the active forms. So no matter how cheap it is, leave it at the store and find a product you know can deliver the effectiveness of B12 that your body requires.


    • Magnesium is a cofactor for the COMT enzyme, which transfers a methyl group from SAMe to metabolize dopamine, norepinephrine, and epinephrine. Alongside the B vitamins, magnesium is vital in supporting healthy mood, cardiovascular function, and nerve function. Again, be sure to maximize your supplement dollar by getting the most bioavailable magnesium version possible.


    • Omega 3 is an essential fatty acid with proven benefits for mental wellbeing. It travels easily through the blood-brain barrier to interact with mood-related molecules in the brain, and harbors powerful anti-inflammatory actions that may help relieve depression. Two omega-3 fatty acids in particular — eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) — are shown to provide the greatest benefits for mood disorders. A 2018 study found that doses of 1 g/DHA per day have had significant benefit for depression.


    • NAC (N-acetylcysteine) is described as a neuroprotective nutrient. It’s a precursor for glutathione which has potent antioxidant and anti-inflammatory properties. Researchers have suggested that a ‘therapeutic cocktail’ of L-5-Methylenetetrahydrofolate, methyl B12, betaine (or TMG), and N-acetylcysteine (NAC) may help reduce levels of homocysteine in the body, which can in turn reduce the risk for neurodegenerative diseases such as Alzheimer’s.


    Visit: Methyl-Life® Methylfolate Facts Blog

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    References

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    Katie Stone - Naturopath

    About the Author

    Katie is a qualified Naturopath (BNatMed) and freelance writer from New Zealand. She specializes in all things health and wellness, particularly dietary supplements and nutrition. Katie is also a dedicated runner and has completed more half-marathons than she can count!

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