Cinnamon and cinnamon metabolites (benzoate) as novel therapeutic options Cinnamon is rich in polyphenols and this property has been suggested to be of therapeutic merit in neurodegenerative conditions. It also contains cinnamaldehyde, a prodrug to benzoate which has intriguing CNS therapeutic applications Both cinnamon and sodium benzoate (NaB) may be of benefit for various neurodegenerative disorders: '...oral administration of ground cinnamon increased the level of sodium benzoate [NaB] in serum and brain and upregulated the levels of neurotrophic factors in vivo in the mouse CNS. Accordingly, oral feeding of NaB, also increased the level of these neurotrophic factors in vivo in the CNS of mice.' Sodium benzoate has been studied as an adjunctive agent in the treatment of schizophrenia: “A recent clinical study demonstrated that sodium benzoate (SB), a prototype competitive d- amino acid oxidase inhibitor, was effective in the treatment of several symptoms, such as positive and negative symptoms, and cognitive impairment in medicated patients with schizophrenia.” Sodium benzoate has beneficial effects on pre-pulse inhibition deficits and hyperlocomotion induced in mice after administration of phencyclidine: “Sodium benzoate induced antipsychotic effects in the PCP model of schizophrenia, although it did not increase D- serine levels in the brain.” D-amino acid oxidase is expressed in the ventral tegmental area and modulates cortical dopamine 1 “...injection into the VTA of sodium benzoate, a DAAO inhibitor, increases frontal cortex extracellular dopamine, as measured by in vivo microdialysis and high performance liquid chromatography. Combining sodium benzoate and D-serine did not enhance this effect, and injection of D-serine alone affected dopamine metabolites but not dopamine. These data show that DAO is expressed in the VTA, and suggest that it impacts on the mesocortical dopamine system.” ⦁ Sodium benzoate increased volumes of thalamus, amygdala, and brainstem in a drug-naïve patient with major depression. ⦁ Results highlight a novel anti-inflammatory role of sodium benzoate ⦁ A novel neurotrophic property of cinnamon and its metabolite NaB has been found via PKA-CREB pathway, which may be of benefit for various neurodegenerative disorders including Alzheimer's ⦁ Results highlight a novel myelinogenic property of NaB and cinnamon, which may be of benefit for MS and other demyelinating disorders. ⦁ Consumption of sodium benzoate as a food preservative may be linked with hyperactivity in children. ⦁ The combined effects of sodium benzoate and D-Serine in animal models of cognitive impairment have been studied, the authors concluding that “D-serine and sodium benzoate plays a crucial role in treating cognitive impairment with reduced nephrotoxicity of D-serine.” ⦁ While an above study have failed to find differential modulation of DAergic activity with such combinations, co-administration of a DAAO inhibitor and D-serine has effectively counteracted PPI deficits induced by NMDA antagonists in animal models and is a promising therapeutic approach. A few real world studies: Benzoate produced a 21% improvement in PANSS total score and large effect sizes (range, 1.16-1.69) in the PANSS total and subscales, Scales for the Assessment of Negative Symptoms-20 items, Global Assessment of Function, Quality of Life Scale and Clinical Global Impression and improvement in the neurocognition subtests as recommended by the National Institute of Mental Health's Measurement and Treatment Research to Improve Cognition in Schizophrenia initiative, including the domains of processing speed and visual learning. Benzoate was well tolerated without significant adverse effects. Benzoate adjunctive therapy significantly improved a variety of symptom domains and neurocognition in patients with chronic schizophrenia. 52 patients with chronic schizophrenia were assigned to adjunct placebo or adjunct 2 sodium benzoate (1000 mg per day) treatment for a period of 6 weeks. At the end of the study period all domains of the Positive and Negative Syndrome Scale (PANSS) had improved by an average of 21% (with effect sizes (ES) of 1.16–1.69) and neurocognitive testing showed improved processing speed (P = 0.03, ES = 0.65) and visual learning and memory (P = 0.02, ES = 0.70). Other domains remained unchanged. There was no increase in adverse effects in the sodium benzoate or the control group. In the benzoate group there was one recorded case of tachycardia, one of weight gain and two of insomnia. The authors suggested these events were likely coincidental observations. Sixty patients with amnestic mild cognitive impairment or mild AD were treated with 250-750 mg/day of sodium benzoate or placebo for 24 weeks. Alzheimer's Disease Assessment Scale-cognitive subscale (the primary outcome) and global function (assessed by Clinician Interview Based Impression of Change plus Caregiver Input) were measured every 8 weeks. Additional cognition composite was measured at baseline and endpoint. Sodium benzoate produced a better improvement than placebo in Alzheimer's Disease Assessment Scale-cognitive subscale (p = .0021, .0116, and .0031 at week 16, week 24, and endpoint, respectively), additional cognition composite (p = .007 at endpoint) and Clinician Interview Based Impression of Change plus Caregiver Input (p = .015, .016, and .012 at week 16, week 24, and endpoint, respectively). Sodium benzoate was well-tolerated without evident side-effects. Sodium benzoate substantially improved cognitive and overall functions in patients with early-phase AD. The preliminary results show promise for D-amino acid oxidase inhibition as a novel approach for early dementing processes. There is also evidence related to the use of sodium benzoate in other mental disorders. A randomized, double-blind, placebo-controlled trial investigating the use of sodium benzoate in patients with Alzheimer disease was identified: 60 patients with amnestic mild cognitive impairment or mild Alzheimer disease were treated with a variable dose of sodium benzoate (250–750 mg/day) for a period of 24 weeks. Patients treated with sodium benzoate performed better in the cognitive subscale of the Alzheimer’s disease Assessment Scale (P = 0.0031) than those on placebo, and in the cognition composite (P = 0.0007) and the clinician interview- based impression of change plus caregiver input (P = 0.012). It was also noted that sodium benzoate was well-tolerated without any evident side effects. ⦁ may improve cognitive function in later-phase dementia. Sodium benzoate has also been reported in three case studies. Each patient was administered a 6-week trial of sodium benzoate (500 mg per day) in patients who had refused conventional medications. Two of these were drug-naïve patients with major depression. Over the 6-week course there was a reduction in the Hamilton Rating Scale for Depression (Ham-D) score in the first patient, which fell from 25 to 3 9; likewise, in the second patient with depression, the depression scores dropped after treatment. Last, a patient experiencing panic disorder with somatic symptoms had a reduction in the Panic Disorder Severity Scale from 18 to 7 and an associated reduction in somatic symptoms . Although these cases are encouraging it is difficult to differentiate improvements due to sodium benzoate from a placebo effect. ⦁ benzoate can decrease perceived stress and improve cognitive function In one recent study, there was no evidence that adjunctive use of 1000 mg of sodium benzoate daily is an effective treatment for individuals with early psychosis . References: Cinnamon, a promising prospect towards Alzheimer's disease https://doi.org/10.1016/j.phrs.2017.12.011 The efficacy of sodium benzoate as an adjunctive treatment in early psychosis - CADENCE- BZ: study protocol for a randomized controlled trial https://doi.org/10.1186%2Fs13063-017-1908-5 Effect of Sodium Benzoate vs Placebo Among Individuals With Early Psychosis https://doi.org/10.1001%2Fjamanetworkopen.2020.24335 Effect of Sodium Benzoate on Cognitive Function Among Patients With Behavioral and Psychological Symptoms of Dementia https://doi.org/10.1001%2Fjamanetworkopen.2021.6156 Effects of Sodium Benzoate, a D-Amino Acid Oxidase Inhibitor, on Perceived Stress and Cognitive Function Among Patients With Late-Life Depression: A Randomized, Double-Blind, Sertraline- and Placebo-Controlled Trial https://doi.org/10.1093%2Fijnp%2Fpyac006 4