SSRI Resistance and L-Methylfolate:

You’re not alone if you inform you’re SSRI (selective serotonin reuptake inhibitor) resistant. Nearly two out of every three individuals with depression do not achieve remission with SSRI medication alone. However, they have no impact or an initial effect that fades over a few months. Also, people with depressive disorders are more likely to have extensive medical bills and have suicidal thoughts and tendencies. All these consequences increased in treatment-resistant individuals.

Fortunately, many treatment-resistant individuals have a dietary deficit that fills to help them feel better.

Since the 1960s, there has been a consistent relationship between low folate levels and depression. Low folate levels not only cause a depressed mood but there is also a clear molecular pathway for this effect. L-methylfolate, which affects the formation of the neurotransmitters serotonin, dopamine, and norepinephrine, is formed from dietary folate. L-methylfolate provides a methyl group for the creation of tetrahydrobiopterin (BH4). This metabolite works as a cofactor for the activation of rate-limiting enzymes required for the generation of neurotransmitters. As a result, L-methylfolate status influences the number of neurotransmitters that will produce in the body.

Traditional treatments like SNRIs (serotonin-norepinephrine reuptake inhibitors) prevent neurotransmitters from reabsorbing, allowing them to continue to signal for longer. However, if the brain does not produce enough neurotransmitters, this treatment may be useless. By giving substrate to the process, L-methylfolate, on the other hand, can promote the creation of additional neurotransmitters.

L-methylfolate frequently prescribed to supplement SSRI or SNRI therapy to ensure that the body has adequate dietary building blocks. It produces proper levels of neurotransmitters, which regulates by an SSRI. L-methylfolate alone may be insufficient to address a nutritional deficiency contributing to the manifestation of a sad mood.

While a folic acid (synthetic folate) supplement has been recommended in the past to meet a patient’s folate needs. Before it crosses the blood-brain barrier or participates in the neurotransmitter synthesis pathway, folic acid transform into L-methylfolate. About half of the general population have a genetic variation that prevents folic acid from converting to L-methylfolate. It causes by a single nucleotide polymorphism (SNP) in the MTHFR gene. Heterozygous individuals inherit one normal copy of the gene and one copy with heterozygous and can only metabolize half folate. It makes them more prone to develop depression than those with normal gene expression. Those with two defective copies of the gene metabolize folate are more prone to suffer from depression. Therefore dietary folic acid may not be sufficient to protect some people from the negative consequences of folate insufficiency.

L-methylfolate, fortunately, is now available as a supplement. When L-methylfolate is used instead of folic acid, the MTHFR enzyme is not required. Supplemental L-methylfolate can act reasonably in the body and readily cross the blood-brain barrier, regardless of one’s genetic makeup. L-methylfolate is a water-soluble B vitamin that’s why it doesn’t store in the body. It indicates that if you lack folate, you should take it regularly. It also suggests that L-methylfolate is well tolerated and unlikely to cause side effects.


LeBano, Lauren. “L-Methylfolate: A Promising Therapy for Treatment-Resistant Depression?” Psychiatry and Behavioral Health Learning Network. May 08, 2013

Kose, Samet, and Kemal Sayar. “L-methylfolate in patients with treatment resistant depression: fulfilling the goals of personalized psychopharmacological therapy.” (2018): 359-362.

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.

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