If you have been told you are SSRI (selective serotonin reuptake inhibitor) resistant, you are far from alone. Between those who feel no effect from an SSRI whatsoever, and those who feel an initial effect that wanes over a couple of months, nearly two out of three patients with depression do not achieve remission with SSRI treatment alone [1,2]. Not only is living with a mood disorder difficult in its own right, but people with depressive disorders are more likely to incur high medical bills, have difficulty maintaining employment, and experience suicidal thoughts and inclinations [1]. All of these effects are amplified in patients that are treatment-resistant. 

Luckily, for many treatment-resistant patients, there is a nutritional gap that can be filled to aid in lifting a depressed mood. 

A link between low folate status and depression has been repeatedly documented since the 1960s [3]. Not only do low folate levels correlate with a low mood, there is a clear biochemical pathway through which this effect can be seen. Dietary folate is converted into its active form, L-methylfolate, which regulates the production of the neurotransmitters serotonin, dopamine, and norepinephrine [3]. More specifically, L-methylfolate provides a methyl group for the formation of tetrahydrobiopterin (BH4), which then acts as a cofactor for the activation of rate-limiting enzymes, tryptophan hydroxylase and tyrosine hydroxylase, necessary for the production of serotonin, dopamine, and norepinephrine [3]. Therefore, L-methylfolate status indirectly controls the abundance of neurotransmitters that can be made in the body. 

Traditional therapies such as SSRIs and SNRIs (serotonin-norepinephrine reuptake inhibitors) block reuptake of neurotransmitters, so that existing neurotransmitters can remain signaling for longer. If the brain is not making enough neurotransmitters however, a treatment like this may be ineffective. Dissimilarly, L-methylfolate can actually promote the production of more neurotransmitters by providing substrate to the process. 

Often, L-methylfolate is recommended as a complement to an SSRI or SNRI therapy, to make sure the body has enough nutrient building blocks to make appropriate levels of neurotransmitters, which can then be manipulated by an SSRI medication. L-methylfolate alone may fill a nutritional inadequacy that could be contributing to the presentation of a depressed mood. 

While traditionally, a folic acid (synthetic folate) supplement may have been suggested to fill a patients need for folate, new evidence has arisen revealing a problem with this recommendation. Folic acid must be converted to L-methylfolate before it can cross the blood brain barrier or participate in the neurotransmitter production pathway. We now know that approximately half of the general population and up to 70% of patients diagnosed with depression have a genetic polymorphism that inhibits the conversion of folic acid to L-methylfolate [1]. This processing deficiency is caused by a single nucleotide polymorphism (SNP) in the methylenetetrahydrofolate reductase (MTHFR) gene. Those who inherit one normal copy of the gene and one copy with a SNP (heterozygous) can only process folate at 65% of the normal rate and are more likely to experience depression than those with normal gene expression [2]. Those with two abnormal copies of the gene (homozygous) process folate at only 30% of the normal rate and are the most likely to experience a more severe depression than those who are either heterozygous or express normal MTHFR production [2]. Therefore, dietary folic acid may not be appropriate to rescue some individuals from downstream effects of folate deficiency, especially those experiencing a depressed mood who test positive for an MTHFR SNP. 

Fortunately, L-methylfolate is now available as a supplement. Taking L-methylfolate in place of folic acid bypasses the necessity for MTHFR enzyme. Regardless of one’s genetic makeup, supplementary L-methylfolate can work effectively in the body upon absorption and readily crosses the blood brain barrier [2]. As a B vitamin, L-methylfolate is water soluble and not stored in the body. While this means it must be supplemented regularly if one is folate deficient, it also means L-methylfolate is well-tolerated and unlikely to cause adverse reactions [3]. 


  1. LeBano, Lauren. “L-Methylfolate: A Promising Therapy for Treatment-Resistant Depression?” Psychiatry and Behavioral Health Learning Network. May 08, 2013 https://www.psychcongress.com/article/l-methylfolate-promising-therapy-treatment-resistant-depression
  2. Kose, Samet, and Kemal Sayar. “L-methylfolate in patients with treatment resistant depression: fulfilling the goals of personalized psychopharmacological therapy.” (2018): 359-362.
  3. Papakostas, George I., et al. “L-methylfolate as adjunctive therapy for SSRI-resistant major depression: results of two randomized, double-blind, parallel-sequential trials.” American Journal of Psychiatry 169.12 (2012): 1267-1274.