L-Methylfolate Uses And Side Effects

Blood sample tube with laboratory requisition form for vitamin B12 and folate test

About L-methylfolate

L-methylfolate is a medical food used for patients who are deficient in folate. In this post, I will explore the uses and side effects of L-methylfolate. 

Folate occurs naturally in many different foods. Some foods containing folate include:


Citrus Fruits

Leafy green vegetables (Spinach, broccoli, kale, cabbage)

Whole grains


Nuts and Seeds

Brussel Sprouts








 Folate is a B vitamin (B9) and used by the body in the production of red blood cells. It may play an essential role in stabilizing mood. L-methylfolate is the active form of folate and is the only form capable of reaching the brain by crossing the blood-brain barrier. L-methylfolate indirectly regulates levels of serotonin, dopamine, and norepinephrine.  Low levels of L-methylfolate can lead to a deficiency of these three neurotransmitters. L-methylfolate is available as a prescription product sold under the brand name Deplin.

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Folate deficiency can be caused by poor diet, diseases that affect GI absorption (celiac disease), and alcoholism.  Individuals who use antiepileptic medications or smoke cigarettes are also at risk for low folate levels.


 There is also a large percentage of the population that is unable to convert folate to the active L-methylfolate form. This is due to a methylenetetrahydrofolate reductase (MTHFR) polymorphism.  


Folate deficiency can lead to anaemia. Signs of anaemia include fatigue, shortness of breath, weakness, irritability, and pale skin.

Folate deficiency also seems to be associated with depression and specifically, treatment-resistant depression. 



Major Depressive Disorder (MDD)

Depression is currently most often treated with psychotherapy and antidepressant medications.  Psychotherapy is time-consuming, and many patients prefer to use antidepressants as the sole treatment. Unfortunately, greater than 50% of patients treated with antidepressants alone will fail to achieve remission. 



I have had personal experience with depression and anxiety at different stages of my life.  I have learned to control these conditions by changing the way I think.


  I can recommend the book “feeling good” written by Dr David Burns.   Feeling good is a must-read for anyone suffering from depression or anxiety.  The book teaches you how to change your thoughts using simple exercises.  Changing the way a person thinks changes the way they feel.


 I also felt much better when I stopped drinking alcohol and started exercising.  Exercise releases endorphins in the brain, which naturally improve mood.  Exercise also increases energy and helps with sleep.  It helps relieve stress and improves memory.  

 Alcohol is a depressant and may lead to devastating consequences if abused.   I will certainly write a post about alcohol in the future.  For now, I will say that my life has been much happier and healthier without alcohol.  If you drink too much, or alcohol is causing problems in your life, please get help.  Your body and mind will thank you in the future.


I also began to pay close attention to what I was eating.  The Mediterranean diet has many studies to support it.  If you can stick to it, this diet will produce the best all-around results.  Remember, whole foods, and a balanced diet is a significant goal.  Processed foods should be avoided.  Try to limit refined sugars and be sure to eat enough fruits and vegetables.

A study, published in the American Journal of Psychiatry, compared the addition of L-methylfolate to SSRI’s in patients with treatment-resistant depression.  This study concluded that L-methylfolate, 15mg/day may be a safe and effective augmentation agent in patients with major depression who have had an inadequate response to SSRI’s.



George I. Papakostas, et.al

American Journal of Psychiatry 2012 169:12, 1267-1274 



Another study, conducted by Reynolds et al. in May 2015, Explored the possibility that L-methylfolate has intrinsic antidepressant properties. Methylfolate was compared to amitriptyline in this study. The response rate for methylfolate was 42% (8/19). Amitriptyline had a 35% response rate (7/20) and three patients taking amitriptyline withdrew from the study due to side effects. No side effects were reported in the methylfolate group. The methylfolate responders also were found to have a considerable rise in red blood cell folate levels at six weeks, whereas the non-responders had a smaller increase. 


Roffman et al. found L-methylfolate supplementation to be beneficial in schizophrenic patients.  This study was published in Molecular Psychiatry in 2018.  


L-methylfolate appears to be more beneficial in schizophrenic patients with the MTHFR polymorphism.  This is expected as dopamine, norepinephrine and serotonin levels are affected by this.  

L-methylfolate Side Effects

Side effects with L-Methylfolate supplementation are generally rare.  As with any medication or food supplement, allergic reactions can occur.  Signs of an allergic reaction include trouble breathing, hives, itching, nasal congestion or rash.  Please seek medical attention if allergic reaction symptoms are severe.


Other possible adverse effects include:


Trouble sleeping

Abdominal swelling

Depressed mood




Loss of appetite


Taste disturbances


L-methylfolate is a useful nutraceutical product that may be used along with an antidepressant for patients with depression.  In studies, it appears the 15mg daily dose is more effective than 7.5mg daily.  It may also benefit schizophrenic patient’s although more data is needed.


 L-methylfolate is the only form of folate that is able to cross the blood-brain barrier.  This makes it especially useful in people who lack the ability to convert folic acid into its active form.  L-methylfolate is well tolerated and is available as the brand name Deplin.


If you have any questions regarding L-methylfolate or any other vitamin or supplement, feel free to reach out to me using the link below:

Michael Pharmacist

Michael J. Brown, RPh. BCPS, BCPP

Mr. Brown is a Clinical Pharmacist specializing in pharmacotherapy and psychiatry.
Read Michael’s story here. Feel free to send Michael a message using this link