Hypo-NMDAR hypothesis of schizophrenia: In a Randomized, Double-blind, Placebo-Controlled Trial of the d-Amino Acid Oxidase (DAAO) Inhibitor Sodium Benzoate (N=52 patients, 27 to placebo and 25 to benzoate). 1g/day Sodiam Benzoate produced a 21% improvement in PANSS total score at 6 weeks

"In a Randomized, Double-blind, Placebo-Controlled Trial of the d-Amino Acid Oxidase (DAAO) Inhibitor as an add-on treatment for schizophrenia. Sodiam Benzoate produced a 21% improvement in PANSS total score and large effect sizes (range, 1.16-1.69) in the PANSS total and subscales. Benzoate was well tolerated without significant adverse effects. " [1] (see table 2 for effect sizes depending on positive/negative/general schizophrenia symptoms)

"It is encouraging that benzoate treatment improves schizophrenia in those who are still highly symptomatic despite treatment with antipsychotics. An earlier open-label, pilot, dose-finding trial was performed by dosing sodium benzoate between 250 and 1000 mg/d. Three of 5 patients received 1000 mg/d of benzoate, and their PANSS total scores decreased from 78 to 58, 80 to 59, and 84 to 60, respectively. The other 2 patients received lower dosages and did not improve." [1]

"In addition to clinical symptoms, neurocognition was improved. Deficits in cognitive functions have been considered as core symptoms and outcome predictors of schizophrenia more so than hallucinations or delusions.3,45 Nevertheless, preserving and even enhancing cognitive functioning have recently been recognized as a critical therapeutic goal because the cognitive effects of typical and atypical antipsychotics are negligible at best. Our findings in neurocognition point to a novel approach to reach the goal of improving cognition. Multiple regression analysis revealed that improvement in the positive and negative symptoms contributed little to the improvement of neurocognition." [1]

"In addition, sodium benzoate also induces anti-inflammatory activity and upregulates a neuroprotective protein, DJ-1 (PARK7), in astrocytes and neurons." [1]

"The DAAO inhibitors have been considered as new therapeutics for schizophrenia, but they have been unsuccessful so far. A review concluded, 'collectively, the limited experience with a small number of structurally diverse inhibitors indicates that extensive inhibition of peripheral and central DAAO has a limited effect on brain or extracellular d-serine concentration” and “behavioral effects of DAAO inhibitors are fairly modest and inconsistent.' Therefore, instead of sole use of a DAAO inhibitor or d-serine, coadministration of DAAO inhibitors and d-serine was recommended." [1]

With D-Serine supplementation this study [2] illustrates a ~40% improvement at 6 weeks in the SAS scale, and improvement in the AIMS scale. While Sodium Benzoate (DAAO inhibitor) shows a 21% improvement in the PANSS total and subscales. Perhaps this could lead to a lower necessary dose of D-Serine, or better cumulative improvement not reachable by either independently, hopefully more studies are made!

Sodium Benzoate appears to be considered by the U.S. FDA to be Generally Recognized as Safe (GRAS) up to 9% daily food intake by weight [8][9] (they don't exactly say this but it's difficult to interpret what they do say in terms of g/day)

Not advised to take concurrently with high content vitamin C (ascorbic acid) due to possible reaction and the formation of benzene [1] This reaction may occur in the presence of heat and light [10]

I mostly wrote this in my documents as a reference/index for myself, as I have difficulty remembering most everything I read. I hope some of you find it interesting. Realize that this study was an add-on treatment (with an antipsychotic). I'm not sure if an NMDAR agonist (like D-Serine, D-Alanine) paired with a DAAO would lead to lasting NMDA up/down regluation or whatnot. Even though Sodium Benzoate is GRAS and is widely found in processed foods, please work with a medical professional as I'm not one.

I can see food grade sodium benzoate powder for about $20/kg online. With D-Serine & D-Alanine I couldn't find a seller without significant markup, but a longer search should turn something up.


Sodium Benzoate

NMDA receptor (NMDAR) (and a more detailed infographic)

Hypo-NMDAR hypothesis of schizophrenia (Glutamate hypothesis of schizophrenia) (I think these wordings refer to the same thing) Note the side effects of NMDA receptor inhibition:

"Such side effects caused by NMDA receptor inhibitors include hallucinations, paranoid delusions, confusion, difficulty concentrating, agitation, alterations in mood, nightmares, catatonia, ataxia, anesthesia, and learning and memory deficits." (note wikipedia may not be terrably definitive in this list)

Serine racemase (Srr):

"L-Serine (a dietary amino acid) is racemized into D-serine via the enzyme serine racemase, present in neurons and glial cells" 12

Realize genetic under expression of Serine racemase or genetic over expression of DAAO will lead to low endogenous levels of D-Serine [11][https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2722985/) Most interesting is figure 1, which shows the concentration of D-Serine in various parts of the brain in Srr knockout mice.

D-amino acid oxidase (DAAO):

"D-amino acid oxidase (DAAO; also DAO, OXDA, DAMOX) is a peroxisomal enzyme, whose function is to oxidize D-amino acids to the corresponding imino acids, producing ammonia and hydrogen peroxide. Recently, mammalian D-amino acid oxidase has been connected to the brain D-serine metabolism and to the regulation of the glutamatergic neurotransmission. In a postmortem study, the activity of DAAO was found to be two-fold higher in schizophrenia. DAAO is a candidate susceptibility gene and together with G72 may play a role in the glutamatergic mechanisms of schizophrenia. Risperidone (an antipsychotic) and sodium benzoate are inhibitors of DAAO." "DAAO is responsible for degrading d-serine and d-alanine" [3], so a DAAO inhibitor may increase the effect or lower the 2g/day dose necessary for d-alanine [4] (the same for d-serine at 4-8g/day [5]) Both are NMDA receptor agonists, as is glycine [6]

Examples of D-Amino Acids in humans (most amino acids are in L- form):

"D-serine is one of the main neuromodulators of the glutamatergic neurotransmission and D-aspartate is fundamental for brain development in fetus." (inhibiting DAAO during pregnancy will reduce the rate of breaking down D-aspartate, I'm not sure if good/bad/neutral thing).

D-Serine One author noted that the glycine binding side of NMDA was named as such as glycine was the first NMDA agonist discovered. The author then said it may more aptly called the D-Serine binding site given the nature of things learned since the discovery of glycine & that binding site (D-Serine has higher effiacy, is endogenous and clearly for this purpose). Sorry I couldn't find the author/paper for reference/clarity.

/r/sandboxtest Thread Link - jamanetwork.com