Biochemical, physiological and clinical effects of l-methylfolate in schizophrenia: a randomized controlled trial

In conclusion, l-methylfolate supplementation was associated with salutary physiological changes and selective symptomatic improvement in this study of schizophrenia patients, warranting larger clinical trials.


Folic acid supplementation confers modest benefit in schizophrenia, but its effectiveness is influenced by common genetic variants in the folate pathway that hinder conversion to its active form. We examined physiological and clinical effects of l-methylfolate, the fully reduced and bioactive form of folate, in schizophrenia. In this randomized, double-blind trial, outpatients with schizophrenia (n=55) received l-methylfolate 15 mg or placebo for 12 weeks. Patients were maintained on stable doses of antipsychotic medications. The pre-defined primary outcome was change in plasma methylfolate at 12 weeks. Secondary outcomes included change in symptoms (Positive and Negative Syndrome Scale (PANSS), Scale for Assessment of Negative Symptoms, Calgary Depression Scale for Schizophrenia), cognition (Measurement and Treatment Research to Improve Cognition in Schizophrenia composite) and three complementary magnetic resonance imaging measures (working memory-related activation, resting connectivity, cortical thickness). Primary, mixed model, intent-to-treat analyses covaried for six genetic variants in the folate pathway previously associated with symptom severity and/or response to folate supplementation. Analyses were repeated without covariates to evaluate dependence on genotype. Compared with placebo, l-methylfolate increased plasma methylfolate levels (d=1.00, P=0.0009) and improved PANSS Total (d=0.61, P=0.03) as well as PANSS Negative and General Psychopathology subscales. Although PANSS Total and General Psychopathology changes were influenced by genotype, significant PANSS Negative changes occurred regardless of genotype. No treatment differences were seen in other symptom rating scales or cognitive composite scores. Patients receiving l-methylfolate exhibited convergent changes in ventromedial prefrontal physiology, including increased task-induced deactivation, altered limbic connectivity and increased cortical thickness., NCT01091506.

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Does that mean it’s good or not?

It’s suggesting it has promise and that larger clinical trials are needed.

Excellent firemonkey! Thanks for posting!

I’m doing the test for the MTHFR mutation sometime this month, to see if I will benefit from folate supplementation. i am absolutely excited about this, if i have the mutation it could change my life. Unfortunately I read that it is very uncommon in those of sub-saharan african descent, but more common in those with SZ. So that brings my odds up a little bit. Maybe folate supplementation will cure my alogia.

@eduvigis your situation is much better than mine.
You may try to help others who are in a worse situation.


How do you know my situation is better?

I know because I can’t look after myself, or research stuff online, I am not in position to do targeted DNA tests.

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Do you at least see a psychiatrist? I asked my psychiatrist to order the test, he was key player in my recovery. I know you suffer from bad cognitive symptoms, medication helped me with those, I’m on quetiapine a rexulti, two medications which are good for cognition and negative symptoms.

To repeat, are you seeing a psychiatrist?

The answer is no.
I am willing to take medications, but on condition that a- it helps me, b- there are no cardiac and metabolic side effects.
I am not in a position to monitor side effects, I am prone to only take medications that are super safe,
otherwise it might kill me, since I’m not in position to monitor side effects.

My Folate/Folic acid results according to genticoncept and wegene.

I am getting a metabolic assessment too along with the test for the mutation. My psychiatrist likes to do it every three months or so. Last time I was tested my metabolic parameters were all normal, even better than average. Regardless of me being on high doses of these medications. I was eating very well then (protein and complex carbs) and running 20mi (32km) per week. I have gained a significant amount of weight regardless of that, so perhaps the medications slow down my metabolism.

With the atypical antipsychotics you may have to put up with cardiac and metabolic side effects, the most common being the metabolic ones. But can you imagine having your intelligence back? If you just accept an antipsychotic, maybe ziprasidone if you want to keep your figure (still has cardiac effects) you may recover/preserve it.

So in short, I don’t think any atypical antipsychotics fit your criteria, but you may feel much better on them. They can preserve your cognitive function, without them it may continue to deteriorate.

I don’t need preservation of cognitive skills, I need vast improvements.
I have reason to believe, that in the future safer, better treatments will emerge.
One option is just to wait for them.

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It’s very possible that in time, maybe when you are in your 30s your cognition will continue to get worse. Many doctors believe that schizophrenia is a progressive disease.

Avn-211 is the major cognition med coming out soon, but I personally doubt it will be effective. The a7 drugs sound better on paper so I am waiting for those. Encenicline failed in 2016, that was my big hope when I had severe cognitive symptoms. Now my cognition has stabilized on my current drugs. I have lost a few IQ points for sure but overall I have had a great turn-around.

I am not afraid to get worse, I feel like I have nothing to lose in terms of cognition.
On the other hand, I value my physical health a lot, it is good, and I don’t want to damage it with meds. The only thing that I have that is good is physical health, and with meds I may lose
the only thing about my health that I value, the physical part.
Cognitively I have nothing to lose really.
I am ready to take medications only if they don’t damage my physical health.
That I have a screwed up mental health is bad enough, I may end up screwed up
in all directions.
Also, there are promising drugs for schizophrenia (in development) that are considered
very very safe, I may take them when available.

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