I am shortly going to introduce a complicated sounding substance called DAAO (D-amino acid oxidase) to this blog. DAAO seems to be important in some types of autism, most schizophrenia and bipolar. This will take us back to Cinnamon and Sodium Benzoate that were discussed in earlier posts.
The connection to UCLA will come at the end of the post. UCLA is home to the Lovaas Model of Applied Behavior Analysis (ABA), but this post is all about biochemistry. Before the internet existed, I used to use one of their libraries for some research.
Prior to DAAO, I just want to make the case again for the medical effects of Cinnamon in typical people.
Accepted medical wisdom is that there is currently no proof of any benefit from Cinnamon. Cinnamon does have known and quantifiable anti-oxidant properties in vitro, but research has shown that what happens in vivo can be quite different. The whole idea of the ORAC scale, which measures the relative power of antioxidants, has lost credibility and is no longer used by “serious science”.
In an earlier post we saw a study that showed in both people with type 2 diabetes and the control group, cholesterol and fasting glucose levels were reduced by cinnamon. This implied an increase in insulin sensitivity (and reduction in insulin resistance).
I also found numerous people posting their before and after cinnamon blood test results, confirming this benefit.
However, there were other studies showing no effect on fasting glucose levels and insulin sensitivity, which looked odd.
Why does this matter?
I am trying to establish that one effect of cinnamon comes from being metabolized to sodium benzoate (“benzoate”). Benzoate then upregulates production of a protein called DJ-1. DJ-1 was discovered by researchers looking at Parkinson’s Disease. DJ-1 is known to have anti-oxidant properties, both directly and in support of a clever substance called Nrf-2. Nrf-2 is released by the body when it senses an oxidative attack and its job is to switch on the body’s anti-oxidant genes. But Nrf-2 cannot do this without some help from DJ-1; if DJ-1 is lacking, the key genes stay switched off.
One well established effect of Sulforaphane (from broccoli) is that it activates the production of Nrf-2. This seems to account for the anti-oxidant and chemo-protective effects.
One reader of this blog confirmed the increase in insulin sensitivity produced by Sulforaphane from broccoli. For the doctors among you, 2.5ml of broccoli powder had 25% of the effect of 600 mg of Alpha lipoic acid (ALA). 600mg of ALA reduced the insulin requirement by 25%.
In some people they lack DJ-1. This raises their risk of Parkinson’s Disease, likely also COPD and I suggested possibly Autism and any other condition associated with oxidative stress.
Then I came across a trial of sodium benzoate in schizophrenia:-
We know that a characteristic of anti-oxidants, in varying degrees, is that they also reduce cholesterol and increase insulin sensitivity.
So we should expect that eating cinnamon would quickly cause sodium benzoate to be produced, causing an up-regulation in DJ-1. The first effect should be a reduction in oxidative stress and then an increase in insulin sensitivity and a reduction in fasting glucose levels. Reduced oxidative stress will affect the lipid metabolism and lower cholesterol.
Some clinical trials last for 12 weeks, some even longer, but many are shorter. In the following cinnamon trial, blood parameters were measured at week 0, week 6 and week 12.
They happened to test people who were overweight (so at higher risk of developing type 2 diabetes), but I think it would apply to everyone.
Antioxidant Effects of a Cinnamon Extract in People with Impaired Fasting Glucose That Are Overweight or Obese
They choose to measure several markers of oxidative stress, as well as fasting glucose and plasma insulin levels.
Therefore, this work was designed to investigate in people that are overweight or obese, with impaired fasting glycemia, the effects of a twelve week supplementation of the dried aqueous extract of cinnamon on oxidative stress markers including plasma malondialdehyde (MDA) levels, plasma thiol (SH) group oxidation, FRAP (Ferric Reducing Activity Plasma), antioxidant erythrocyte enzyme activities as superoxide dismutase (Cu-Zn SOD) and glutathione peroxidase (GPx), and the possible correlation with fasting glucose and plasma insulin levels.
The interesting thing is that while by week 6 the oxidative 3 of the 4 markers of oxidative stress were changing, glucose levels had not.
So if the trial had ended at week 6 we would conclude that cinnamon does not increase insulin sensitivity.
But all changed by the end of week 12, fasting glucose had gone down and fasting insulin had gone up.
This study did not measure cholesterol. If it had done, we would have expected triglicerides down, LDL (bad) cholesterol down and HDL cholesterol increased.
Since cinnamon is a non standardized natural product, this might explain why in some studies the beneficial effects take longer to become established.
Cinnamon as a DAAO inhibitor
In the next post we will look at D-amino acid oxidase (known as DAAO and also DAO, OXDA, DAMOX).
DAAO is interesting because it is known to be elevated by a factor of two in the brains of people with schizophrenia. The underlying gene is a probable susceptibility gene for schizophrenia and also bipolar disorder. DAAO gene polymorphisms were found in boys with autism spectrum disorders in in Korea.
Risperidone and sodium benzoate are the well-known inhibitors of DAAO, but there are others. Risperidone is an anti-psychotic drug approved for use in schizophrenia, bipolar and autism. The usually claimed modes of action are that as a dopamine antagonist it possesses anti-serotonergic, anti-adrenergic and anti-histaminergic properties.
This will bring us back to the potential of cinnamon in autism/schizophrenia and whether the mode of action is antioxidant, DAAO inhibitor or both. If it is just as an antioxidant, does it confer any additional benefit over NAC + Sulforaphane ? I am interested to find out whether Nrf-2 will be more effective, with the increase in DJ-1; if you were deficient in DJ-1 this should be the case.
DJ-1 produced by cinnamon is one antioxidant, but there clearly are others since no DJ-1 would be produced by cinnamon in vitro.
DAAO inhibitors may produce allergic reactions in people with histamine intolerance.
This might explain one of the warnings for Risperidone:-
Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat.
I did a quick patent search to see if anybody else thinks that sodium benzoate might be useful in autism and related conditions. Here is a small sample of the many patents. In some cases benzoate is used to increase the effectiveness of other ingredients and others it is the claimed active ingredient.
In the UCLA patent below they combine a D-amino Acid Oxidase Inhibitor (DAAOI), a NMDA enhancer and a Glycine transporter inhibitor.
A method of treating autism in a patient. The method includes administering to the patient an effective amount of a glutamine level reducing agent, a glycine level reducing agent or combinations thereof. Representative glutamine level reducing agents are phenylbutyrate and phenylacetate, and a representative glycine level reducing agent is sodium benzoate. Optionally, an N-methyl-D-aspartate receptor antagonist can also be administered to the patient. A representative N-methyl-D-aspartate receptor antagonist is dextromethorphan.
Combination treatment of nmda(n-methyl-d-aspartate)-enhancer, glycine transporter inhibitor, d-amino acid oxidase inhibitor(daaoi) for neuropsychiatric disorders
The invention provides methods for treating neuropsychiatric disorders such as schizophrenia, Alzheimer's Disease, autism, depression, benign forgetfulness, childhood learning disorders, close head injury, and attention deficit disorder. The methods entail administering to a patient diagnosed as having a neuropsychiatric disorder or as at risk for a neuropsychiatric disorder administering to a D-amino Acid Oxidase Inhibitor (DAAOI); in conjunction with an NMDA enhancer and/or a glycine transporter inhibitor.
An orally administrable mixture comprising donepezil hydrochloride, polyvinylpyrrolidone, sorbitol solution, citric acid and sodium citrate, sodium benzoate and methylparaben, propylene glycol, sodiummetabisulfite; treating Parkinson's disease, cognitive impairments, dementia
The invention describes novel methods for treating and preventing dementia caused by vascular diseases; dementia associated with Parkinson's disease; Lewy Body dementia; AIDS dementia; mild cognitive impairments; age-associated memory impairments; cognitive impairments and/or dementia associated with neurologic and/or psychiatric conditions, including epilepsy, brain tumors, brain lesions, multiple sclerosis, Down's syndrome, Rett's syndrome, progressive supranuclear palsy, frontal lobe syndrome, and schizophrenia and related psychiatric disorders; cognitive impairments caused by traumatic brain injury, post coronary artery by-pass graft surgery, electroconvulsive shock therapy, and chemotherapy, administering a therapeutically effective amount of at least one of the cholinesterase inhibitor compounds described herein. The invention also describes novel methods for treating and preventing delirium, Tourette's syndrome, myasthenia gravis, attention deficit hyperactivity disorder, autism, dyslexia, mania, depression, apathy, and myopathy associated with diabetes by administering a therapeutically effective amount of at least one of the cholinesterase inhibitor compounds described herein. The invention also describes novel methods for delaying the onset of Alzheimer's disease, for enhancing cognitive functions, for treating and preventing sleep apnea, for alleviating tobacco withdrawal syndrome, and for treating the dysfunctions of Huntington's Disease by administering a therapeutically effective amount of at least one of the cholinesterase inhibitor compounds described herein. A preferred cholinesterase inhibitor for use in the methods of the invention is donepezil hydrochloride or ARICEPT®. The invention also provides orally administrable liquid dosage formulations comprising cholinesterase inhibitor compounds, such as ARICEPT®.
Methods and compositions are provided for treating neuropsychiatric disorders such as schizophrenia, depression, attention deficit disorder, mild cognitive impairment, dementia, and bipolar disorder. The methods entail administering to a patient diagnosed as having a neuropsychiatric disorder (e.g., schizophrenia, depression, attention deficit disorder, mild cognitive impairment, dementia bipolar disorder, etc.) or as at risk for a neuropsychiatric disorder a benzoic acid, benzoic acid salt, and/or benzoic acid derivative, and/or a sorbic acid, sorbic acid salt, and/or sorbic acid derivative, in combination with a neuropharmacological agent (e.g., an antipsychotic, an antidepressant, medications for attention deficit and hyperactivity disorder, cognitive impairment, or dementia, etc.) where the benzoic acid, benzoic acid salt, or benzoic acid derivative, and/or a sorbic acid, sorbic acid salt, and/or sorbic acid derivative, is in an amount sufficient to increase the efficacy of the neuropharmacological agent.
 Without being bound to a particular theory, it is believed that the DAAOI enhances the levels of both D-serine and D-alanine which are agonists of NMDA receptor and have been shown by the inventor to be beneficial for patients with schizophrenia and other disorders. It can help a wide variety of patients with cognitive impairment and other mental or behavioral symptoms. The combination therapies boost the NMDA and/or neuropharmaceutical activity and benefit subjects more than single agent treatments (e.g., antipsychotic drug, antidepressant, anxiolytic, mood stabilizer, psychotropic medication for attention deficit and hyperactivity disorder, drug for dementia, and the like).
 Accordingly, in certain preferred embodiments, "combination" therapies are contemplated, where the subjects are administered a benzoic acid, a benzoic acid salt, a benzoic acid ester, or another benzoic acid derivative, and/or a sorbic acid, a sorbic acid salt, sorbic acid ester, or another sorbic acid derivative, in conjunction with a neuropharmaceutical (e.g., a therapeutic agent selected from the group consisting of an antipsychotic, an antidepressant, a phsychostimulant, a mood stabilizer, an anxiolytic, an Alzheimer's disease therapeutic, and/or other psychotropic for the treatment of a neuropsychiatric disorder).
 In certain embodiments the combination formulation for the treatment of schizophrenia, bipolar disorder, and the like comprises a combination of benzoic acid, benzoic acid salt, benzoic acid ester, or other benzoic acid derivative, and/or sorbic acid, sorbic acid salt, sorbic acid ester, or other sorbic acid derivative and an antipsychotic drug. Suitable antipsychotic drugs include, but are not limited to the antipsychotic drugs described above.
 In certain embodiments the combination formulation for the treatment of schizophrenia, bipolar disorder, and the like comprises a combination of depression, panic disorder, social phobial, GAD, and the like comprises a combination of benzoic acid, benzoic acid salt, benzoic acid ester, or other benzoic acid derivative, and/or sorbic acid, sorbic acid salt, sorbic acid ester, or other sorbic acid derivative and an antidepressant and/or mood stabilizer. Suitable antidepressants and mood stabilizers include, but are not limited to the antidepressants and mood stabilizers described above.  In certain embodiments the combination formulation for the treatment of
ADD and/or ADHD, and the like comprises a combination of benzoic acid, benzoic acid salt, benzoic acid ester, or other benzoic acid derivative, and/or sorbic acid, sorbic acid salt, sorbic acid ester, or other sorbic acid derivative and an agent for the treatment of ADD and/or ADHD. Suitable agents for the treatment of ADD and/or ADHD include, but are not limited to the agents for the treatment of ADD and/or ADHD described above.
 Typically, in various embodiments, the benzoic acid, benzoic acid salt, or derivative thereof (e.g., a benzoate), and/or sorbic acid, a sorbic acid salt, or a derivative thereof, is present in an amount sufficient to enhance therapeutic efficacy of the neuropharmaceutical rather than as a preservative, and/or melting point lowering agent, and/or stabilizer, and/or a lubricant, and/or a stabilizer, etc. In effect, the benzoic acid, benzoic acid salt, or derivative thereof, and/or sorbic acid, sorbic acid salt, or a derivative thereof, is an active agent. Thus, in various embodiments the benzoic acid, benzoic acid salt, benzoic acid ester, or other benzoic acid derivative, and/or sorbic acid, sorbic acid salt, sorbic acid ester, or other sorbic acid derivative, is not substantially present as an acid addition salt of the neuropharmaceutical (or at least the majority of the benzoic or sorbic acid or derivative thereof) is not present as an acid salt addition salt of the neuropharmaceutical.. Similarly, in certain embodiments the benzoic acid, benzoic acid salt, benzoic acid ester, or other benzoic acid derivative, and/or sorbic acid, sorbic acid salt, sorbic acid ester, or other sorbic acid derivative, (or at least the majority of the benzoic or sorbic acid or derivative thereof) is not present as a co-crystal of the neuropharmaceutical.
The various treatment strategies described herein can be applied to most if not all of them including, for example, learning disorder, attention deficit and hyperactivity disorder, schizophrenia, bipolar disorder, depression, Alzheimer's Disease, autism, benign forgetfulness, close head injury, dementia, mild cognitive impairment, ataxia, spinocerebellar degeneration, Parkinson's disease, obsessive compulsive disorder (OCD), phobia, social phobia, generalized anxiety disorder (GAD), panic disorder, substance abuse, and substance dependence. In addition to their benefits for human subjects, the treatments described herein can be used in veterinary applications (e.g., to canines, felines, equines, bovines, porcines, etc.) with treatment of household pets (e.g., canine, feline) being of considerable interest. In addition, the combination treatments described herein can improve cognition in animal models of learning and model of schizophrenia, depression, anxiety, and the like.  In certain embodiments the treatment methods of the invention entail administering to a subject in need thereof (e.g., a patient diagnosed as having or at risk for a neuropsychiatric disorder) one or more a pharmaceutical compositions containing a therapeutically effective amount(s) of (i) an NMDA (N-methyl-D-aspartate)-Enhancer, and/or (ii) a glycine transporter inhibitor, and/or (iii) a D-amino Acid Oxidase Inhibitor (DAAOI). Where combinations of two or all three of these agents are utilized they can be administered separately (simultaneously or sequentially), in a single "combination" formulation, or in simultaneously or sequentially a combination formulation comprising two agents and a second formulation comprising a single agent.  The effective doses of the active agent(s) (of an NMDA (N-methyl-D- aspartate) -Enhancer, and/or Glycine Transporter Inhibitor, and/or D-amino Acid Oxidase Inhibitor (DAAOI)) can vary, depending upon factors such as the condition of the patient, the severity of the symptoms of the disorder, and the manner in which the pharmaceutical composition is administered. In various embodiments, for human patients, the effective unit dose of typical compounds include: DAAOI (e.g., benzoate, range of 50 mg-150 grams), NMDA enhancers (D-serine, range of 50 mg-50 grams; D-alanine, range 1-150 grams), glycine transporter inhibitor (for example: sarcone, range 50 mg-50 grams); including DAAOI+NMDA enhancer, DAAOI+glycine transporter inhibitor, NMDA enhancers +glycine transporter inhibitor or three classes of compound together.  In various embodiments, then, effective doses of each of the active agent(s) ranges from 1 mg, 10 mg, 50 mg, 100 mg, 250 mg, or 500 mg, 300 g, 20Og, 150 g, 100 g, 50 g, 25 g, 1Og, 5 g, or 1 g depending of factors including, but not limited to 150 g. In certain embodiments the compounds and compositions of the present invention can be administered to a patient at dosage levels in the range of about 0.1 to about 1,000 mg per day. For a normal human adult having a body weight of about 70 kilograms, it is estimated that a dosage in the range of about 0.01 to about 100 mg per kilogram of body weight per day is sufficient. The specific dosage used, however, can vary. For example, the dosage can depend on a numbers of factors including the requirements of the patient, the severity of the condition being treated, and the pharmacological activity of the compound being used. The determination of optimum dosages for a particular patient is well-known to those skilled in the art. The amount of active ingredient(s) that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound(s) employed, the age, body weight, general health, sex, diet, time of administration, route of administration, and rate of excretion, drug combination and the severity of the particular disease undergoing therapy.
 In the most accepted animal model of schizophrenia, which tests the sensory gating, we found that combination treatment improve the startle habituation and PPI significantly more than the individual agent alone. . The effect of benzoate was close to combination treatment in habituation.
I have convinced myself of the merits of Cinnamon (the Cinnamomum verum variety, not the “cassia” variety) for typical people.
I have been testing it myself for a month and then I will measure the effect.
For people with neurological conditions, it does seem that some clever people at UCLA, and elsewhere, seem to think there is potential. Their suggested mode of action is not the same as mine, they think DAAOI and I was thinking DJ-1.