Showing posts with label Nrf2. Show all posts
Showing posts with label Nrf2. Show all posts

Thursday, 13 August 2015

Sulforaphane Research in Japan – Cognitive Deficits and Schizophrenia

I recently received some papers about Sulforaphane from a reader of this blog and also comments from people with schizophrenia looking for therapies

Sulforaphane is already a valued part of my autism Polypill for Monty, aged 12 with ASD.  Just google "Sulforaphane Epiphany", or use the site index tab on this blog.

Sulforaphane has been patented for various purposes by John Hopkins, however even after twenty years they have not brought to market a standardized product.  The Sulforaphane (SFN) used in their research is made in the lab and then has to be kept deep frozen.

Sulforaphane is not a stable substance and so you are wasting your money buying most supplements.  Even most types of broccoli powder, which should be a precursor to Sulforaphane (SFN), were shown to be ineffective in independent lab tests.

In Japan it seems they are far more advanced, they already have a standardized SFN-glucosinolate tablets, no mention of the need to keep them frozen.

Japanese Sulforaphane (SFN) research

What is interesting in the Japanese research into cognitive deficits in schizophrenia is that SFN shows has both prophylactic and therapeutic effects.  This suggests that even if there is no immediate benefit from taking SFN in some people, there may be some long term preventative/protective benefits.

Oxidative stress and inflammation play a role in cognitive impairment, which is a core symptom of schizophrenia. Furthermore, a hallmark of the pathophysiology of this disease is the dysfunction of cortical inhibitory γ-aminobutyric acid (GABA) neurons expressing parvalbumin (PV), which is also involved in cognitive impairment. Sulforaphane (SFN), an isothiocyanate derived from broccoli, is a potent activator of the transcription factor Nrf2, which plays a central role in the inducible expressions of many cytoprotective genes in response to oxidative stress. Keap1 is a cytoplasmic protein that is essential for the regulation of Nrf2 activity. Here, we found that pretreatment with SFN attenuated cognitive deficits, the increase in 8-oxo-dG-positive cells, and the decrease in PV-positive cells in the medial prefrontal cortex and hippocampus after repeated administration of phencyclidine (PCP). Furthermore, PCP-induced cognitive deficits were improved by the subsequent subchronic administration of SFN. Interestingly, the dietary intake of glucoraphanin (a glucosinolate precursor of SFN) during the juvenile and adolescence prevented the onset of PCP-induced cognitive deficits as well as the increase in 8-oxo-dG-positive cells and the decrease in PV-positive cells in the brain at adulthood. Moreover, the NRF2 gene and the KEAP1 gene had an epistatic effect on cognitive impairment (e.g., working memory and processing speed) in patients with schizophrenia. These findings suggest that SFN may have prophylactic and therapeutic effects on cognitive impairment in schizophrenia. Therefore, the dietary intake of SFN-rich broccoli sprouts during the juvenile and adolescence may prevent the onset of psychosis at adulthood.


After giving written informed consent, participants received 3 tablets of SFN prepared by Kagome Co., Ltd. (Nagoya, Japan), totaling 30 mg of SFN-glucosinolate per day, for 8 weeks. It is known that SFN-glucosinolate is metabolized to SFN in the body.


Schizophrenia is a mental disorder characterized by severe cognitive impairment. Accumulating evidence suggests a role for oxidative stress in the pathophysiology of schizophrenia. Sulforaphane (SFN) extracted from broccoli sprout is an agent with potent anti-oxidant and anti-inflammatory activity. In this study, we attempted to evaluate the effect of SFN on cognitive impairment in medicated patients with schizophrenia.


We recruited a total of 10 outpatients with schizophrenia, all of whom gave informed consent. Participants took 3 tablets of SFN, consisting of 30 mg of SFN-glucosinolate per day, for 8 weeks. Clinical symptoms using the Positive and Negative Syndrome Scale (PANSS) and cognitive function using the Japanese version of CogState battery were evaluated at the beginning of the study and at week 8.


A total of 7 patients completed the trial. The mean score in the Accuracy component of the One Card Learning Task increased significantly after the trial. However, we detected no other significant changes in participants.


This result suggests that SFN has the potential to improve cognitive function in patients with schizophrenia.

I do get comments from people with schizophrenia on this blog and there is clearly a big overlap between some schizophrenia and some autism.  More and more therapies are being shown to be effective in both; it seems to be the SFN is one of those therapies.

What would be nice would be a commercially available, standardized product that genuinely could be relied upon to produce SFN in the body.  The Japanese appear to have already mastered this.  No need for Johns Hopkins patents.

For the time being, I am happily using my Supersprouts broccoli sprout powder which does indeed seem to produce SFN.  If one day they stop making it, I have already found that you would just need to add heat stable myrosinase (in the form of daikon radish root) to otherwise ineffective broccoli sprout powder.

For those of you who tried other products claiming to contain/produce SFN, and found them ineffective, you do not know whether the child does not respond to SFN, or your product produced none.


SFN really does look worth a try, or perhaps even a second try for those who tried one of those “false” supplements.  Price does not always indicate quality.

One day I hope that the Japanese firm Kagome, chooses to sell its SFN tablets worldwide and not just their tomato ketchups and juices.  

Thursday, 29 January 2015

Cinnamon and DJ-1 as a general Anti-Oxidant and perhaps Much More

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.

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.

Patent Search

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.

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.

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.

[0062] 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).

[0063] 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).

[0072] 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.
[0073] 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. [0074] 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.

[0076] 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. [0080] 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. [0081] 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. [0082] 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.


[0117] 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.

Thursday, 4 December 2014

PolyPill Reformulated

One reader of this blog, who found that 2.5ml of the Australian broccoli sprout powder, I suggested in an earlier post, works wonders for her son (40 minutes after the first dose), asked if I was going to include it in my Polypill.

Then yesterday Monty’s assistant at school asked to take some powder to try on another small child with ASD.  Today she tells me that the same positive result was repeated, in half an hour.

So I decided it is time to update the PolyPill.

I did tell the researcher, I was in touch with at John’s Hopkins, that it appears you can reliably make Sulforaphane at home, without your own laboratory and a deep freezer.  I think they somehow prefer things to be complicated and hard to access.

It does amaze me how people are not adopting, even super-safe, ideas that might help their child.  Many tens of thousands of parents affected by ASD must have read the stories in their newspapers about Broccoli (Sulforaphane) and autism.  How come almost nobody has made it work at home? Or at least, that is what it seems like if you look on Google.  People write about having read about it.  They usually then say, “ah well, Johns Hopkins say it does not work at home and you need a standardized dose”.

Sometimes you need to think for yourself.

Behind all this is the belief that “doctor” always knows best.  Most people are terrified of “experimenting” on their child.  Those that actually do this, are nearly exclusively in the US, with their DAN doctors.  They seem to give up after a year or two and accept whatever is left of the autism.

By the time the child is older and the parents are less worried about them trying drugs, they have given up and accepted the “inevitable”.

Reader feedback

When I started this blog, I rather optimistically expected to join forces with many other motivated, scientifically knowledgeable, parents.

This blog is visited 10,000 times a month, but I can count on two hands the number of people that have acted on it and shared their experience on/off line.  There have been some really great outcomes, which is wonderful for those concerned. (great outcomes = big improvements)

Without wanting to be biblical, but having recently sat through the film, Pulp Fiction, with Monty’s older brother, this does sum things up nicely:-

"Ask and it will be given to you; seek and you will find; knock and the door will be opened to you”

It just might take you a lot more work than you expected.


Regular readers will have noticed that the Polypill is my formulation for treating classic early-onset autism.  It is a combination of the clever ideas of others, some developed a little further, and some ideas of my own, based on the literature.

Many drugs and supplements have some impact on autism.  Some make it better, some make it worse, but most have no effect whatsoever.

Drugs and supplements can have side effects and they can react with each other.  So it is wise to use only those with a major impact.

Broccoli Sprout Powder

The most surprising ingredient I have tested is freeze dried broccoli powder from Australia.  Who would have thought that 2.5ml of this green powder would have an effect on autism.  But it does, and without any of the extra myrosinase, that I had expected to need. Johns Hopkin’s version is a deep frozen product, made after reacting broccoli sprouts with daikon radish sprouts in the laboratory.

All of people working with Monty, aged 11 with ASD, have noticed the difference, so it really is not a placebo effect

Incremental changes

·        Much more unprompted speech (> 50% increase)

·    He started to talk to animals and continues to do
·     He opened the car window to say hello and good bye to someone he recognized passing by – totally unheard of behavior

·        Increased awareness and presence of his surroundings

·        Now, while the TV news is on, Monty is reading aloud the news ticker at the bottom of the screen.  Before, the TV news was just “wallpaper”, unless there were some explosions  or other excitement.

·        Improved mood and mild euphoria

·        The broccoli powder still produces euphoria
·        In other people it may just improve mood

The good news is that Broccoli really is more of a food than a drug and so should not be harmful; although all kinds of things can interact in strange ways.  For example, vitamin C with cinnamon is not a good idea.

Method of action

As usual, I do like to know how and why things work.

The broccoli sprouts contain many substances, at least two of which might be involved:-

1.     Indole-3-carbinol (I3C).  I3C has some extremely interesting properties for both cancer and autism.  I3C up-regulates a protein called PTEN, encoded by the PTEN gene.  PTEN is an “autism gene”.

2.     Sulforaphane (SFN) is the chemical that John’s Hopkins think is the “active” ingredient of broccoli.

SFN is an activator of Nrf2, a “redox switch”.  This release of Nrf2 has a known on/off effect on about 300 genes involved in the response to oxidative stress.

SFN is also an HDI, or an inhibitor of HDAC (Histone Deacetylase)

HDIs have a long history of use in psychiatry and neurology as mood stabilizers and anti-epileptics.

Interestingly, we learn from Wikipedia:- 

“To carry out gene expression, a cell must control the coiling and uncoiling of DNA around histones. This is accomplished with the assistance of histone acetyl transferases (HAT), which acetylate the lysine residues in core histones leading to a less compact and more transcriptionally active chromatin, and, on the converse, the actions of histone deacetylases (HDAC), which remove the acetyl groups from the lysine residues leading to the formation of a condensed and transcriptionally silenced chromatin. Reversible modification of the terminal tails of core histones constitutes the major epigenetic mechanism for remodeling higher-order chromatin structure and controlling gene expression. HDAC inhibitors (HDI) block this action and can result in hyperacetylation of histones, thereby affecting gene expression.

So it looks like those little broccoli sprouts might be initiating some very clever science, perhaps even some primitive gene therapy.


There are still plenty more ideas waiting to test, so there will no doubt be more updated versions of the PolyPill in future.

It does look like there may be more food ingredients and not just drugs, which is not what I expected.

Monday, 20 October 2014

Sulforaphane (Broccoli) for Cancer, Autism and COPD

One advantage this blog has is that it looks at the comorbidities of autism, so we are aware of useful findings in related areas.  So it then does not come as a big surprise when a therapy effective in related areas also helps with autism.

One of the most useful is asthma.  Chronic obstructive pulmonary disease (COPD) is a related condition, brought on by smoking or pollution.  It kills 3 million people a year; COPD is made much worse by chronic oxidative stress.  We saw in an earlier post that oxidative stress stops the asthma drugs from working.  The current treatment for oxidative stress in COPD is N-acetyl cysteine (NAC).  I recall they are still looking for a better treatment; perhaps the search is over.  (see later).

We also saw that there is already some overlap between “emerging” research findings in cancer and those in autism. These include:-

·        PAK1, mTOR (Rapamycin), Wnt signaling
·        Ivermectin treatment for Leukemia and Autism
·        Quercetin and NAC aiding recovery for specific cancers and helping some in autism

For twenty years researchers have known about the potential cancer fighting benefits of Sulforaphane, which is produced by a chemical reaction when you eat fresh broccoli that was only lightly cooked.

In the intervening years vast amounts of research has been going on to tinker with broccoli to maximize/harness the potential health benefit, and also to develop related synthetic drugs (analogs of Sulforaphane) like Sulforadex.

Twenty years later, and a vast amount of broccoli supplement pills later, not many people have benefitted.  When you look into the matter, it really is rather bizarre.

Fresh raw broccoli was found to contain large amounts of both Glucoraphanin and an enzyme called Myrosinase.  When you eat the raw broccoli the Glucoraphanin and Myrosinase react to produce a potent substance called Sulforaphane, which seems to have numerous positive effects.  A powerful anti-oxidative process is triggered that was shown to have a strong anti-cancer effect.

The problem is that myrosinase from broccoli is not stable; when you cook it, freeze it, or process it, you lose it.  So, soggy cooked broccoli, crisp frozen broccoli and almost all the broccoli pills on the market have no myrosinase and therefore no Sulforaphane will be produced.

There have been numerous studies showing this and also a few clever ideas to get around it have been investigated.

Sulforaphane is itself also unstable and has to be used immediately or kept frozen.

Johns Hopkins and Sulforaphane

Sulforaphane was discovered in 1992 at Johns Hopkins and much related research still comes from there.  They hold the key patents and indeed went as far as to try to stop other people growing/selling broccoli sprouts.  They have developed a way to produce Sulforaphane in the laboratory and then it is freeze dried and kept frozen at -20 Celsius.

Cancer research

The cancers where Sulforaphane has shown promise include:-


What caught my attention was a paper from 2008 by Peter Barnes, one of only two Englishmen on my Dean’s list and the only one that lives there.

This has been followed up and there is now a Phase 2 clinical trial of Sulforaphane for treatment of COPD.

Barnes is my kind of scientist.  He has noted that the most potent, safe antioxidant to treat COPD is NAC (N-acetyl cysteine) but he wanted more, and has been on the look-out for years for a stronger, but safe, alternative.  He concluded that

“It has been difficult to find new more effective antioxidants that are not toxic. A more attractive approach may be to restore Nrf2 levels to normal through inhibiting the action of Keap1. This has been achieved in vitro and in vivo by isothiocyanate compounds, such as Sulforaphane, which occur naturally in broccoli”

And finally to Autism

So the recent big news that Sulforaphane was remarkable successful in a small trial at Massachusetts General Hospital (MGH) and Johns Hopkins maybe should not be such a surprise.
Sulforaphane treatment of autism spectrum disorder (ASD)
Autism spectrum disorder (ASD), characterized by both impaired communication and social interaction, and by stereotypic behavior, affects about 1 in 68, predominantly males. The medicoeconomic burdens of ASD are enormous, and no recognized treatment targets the core features of ASD. In a placebo-controlled,double-blind, randomized trial, young men (aged 13–27) with moderate to severe ASD received the phytochemical sulforaphane (n = 29)—derived from broccoli sprout extracts—or indistinguishable placebo (n = 15). The effects on behavior of daily oral doses of sulforaphane (50–150 μmol) for 18 wk, followed by 4 wk without treatment, were quantified by three widely accepted behavioral measures completed by parents/caregivers and physicians: the Aberrant Behavior Checklist (ABC), Social Responsiveness Scale (SRS), and Clinical Global Impression Improvement Scale (CGI-I). Initial scores for ABC and SRS were closely matched for participants assigned to placebo and sulforaphane. After 18 wk, participants receiving placebo experienced minimal change (<3.3%), whereas those receiving sulforaphane showed substantial declines (improvement of behavior): 34% for ABC (P < 0.001, comparing treatments) and 17% for SRS scores (P = 0.017). On CGI-I, a significantly greater number of participants receiving sulforaphane had improvement in social interaction, abnormal behavior, and verbal communication (P = 0.015–0.007). Upon discontinuation of sulforaphane, total scores on all scales rose toward pretreatment levels. Dietary sulforaphane, of recognized low toxicity, was selected for its capacity to reverse abnormalities that have been associated with ASD, including oxidative stress and lower antioxidant capacity, depressed glutathione synthesis, reduced mitochondrial function and oxidative phosphorylation, increased lipid peroxidation, and neuroinflammmation.

What surprised me was just how big an impact the Sulforaphane had and the fact that these are very serious researchers, unlike many others.

Since we are talking about a therapy that has a strong anti-oxidant connection I compared the trial results from the Stanford NAC trial, with those from the Sulforaphane trial at MGH.

Monty, aged 11 with ASD, responded almost immediately to NAC and so of course I am interested in any additional, even overlapping, therapy.

For anyone interested, the following table shows the results from the NAC study:-

The data shows a large drop in irritability and hyperactivity and a moderate improvement in stereotypy, compulsions and SIB.  On the Social Responsiveness Scale, the people on NAC dropped by 18 , versus a drop of 6 for the placebo group.
Now we have the results from the Sulforaphane (broccoli) study.

On the Social Responsiveness Scale (SRS) , the people on Sulforaphane dropped by 20, versus a drop of 2 for the placebo group.

Moving on to the Aberrant Behavior Checklist (ABC) we can compare the improvement in four sub-categories:-

NAC               Sulforaphane
Irritability                 -9.7                     -4
Lethargy                  -4.2                     -4.5
Stereotypy              -3.5                      -2.7
Hyperactivity           -11                      -4.8

Now these figures are averages.  In reality you are likely either a responder or non-responder, nobody is likely to be Mr. Average.

I found these results very encouraging, albeit less so than the NAC trial.  The Sulforaphane trial was conducted among young adults whereas NAC was trialed on children.  You might expect children to be more responsive, since their autism tends to be less controlled than it tends to be in adulthood.

Since both trials are drawn from a population with behavioral autism and not any biological specific dysfunction both groups will likely include people with :-

·        Classic early onset autism caused by multiple genetic and epigenetic (environmental) hits

·        Mitochondrial disease triggered regressive autism, with no inherent prior dysfunction

·        Single gene disorders, probably never identified

Any trial with responders > 30% is therefore very interesting.  This trial was much better than that.

Now, both classic autism and Mitochondrial disease triggered regressive autism are associated with oxidative stress.  People with classic autism do seem to respond to NAC, whereas some people with Mitochondrial disease do not.

In the NAC trial the dose was stepped up every 4 weeks  (0.9g 1.8g 2.7g).  In the Sulforaphane trial the dose remained the same but the effect grew.

So the method of action of both drugs may be similar, but it is not identical.  NAC is a ”primary anti-oxidant”, in that NAC and its end product Glutathione (GSH) are themselves anti-oxidants.   

Sulforaphane appears to be a “secondary anti-oxidant”, it activates Nrf2 which then triggers a set of reactions that promotes an anti-oxidant response.  So it is logical that there is a time delay.

But after week 18, Sulforaphane treatment was stopped and at week 22 all benefit had been lost.

So we can conclude, even though these are two different trials with different groups of people, that if anything NAC looks more potent than Sulforaphane.

The question is whether Sulforaphane plus NAC would be even better than NAC (or Sulforaphane) alone.

Mode of Action

I know that NAC is a “direct” anti-oxidant and it is a precursor for glutathione (GSH); its effect is almost immediate, whereas the MGH researchers inform us that Sulforaphane became effective over a matter of weeks.  We know that Sulforaphane activates a transcription factor, Nrf2 in the cell. Once activated, Nrf2 then translocates to the nucleus of the cell, where it aligns itself with the antioxidant response element (ARE) in the promoter region of target genes. The target genes are associated with process which assists in regulating cellular defences. Such cytoprotective genes include that for glutathione (GSH).

So it is clear that both NAC and Sulforaphane will affect the level of the boy’s most important antioxidant glutathione (GSH).

That may possibly be the end of the story.

Science does tell us that Sulforaphane has many other effects that may also be beneficial in autism.  They do seem to have an effect in cancer and some do relate to reversing epigenetic “errors”.  Classic autism is also likely triggered, in part, by epigenetic “markers” on undamaged parts of the DNA.  Any method of selectively removing these markers and turning genes “off” that were “on” in error and vice versa is very interesting.

Sulforaphane’s effect in cancer appears to be more than just an antioxidant.  Research has shown that it is indeed active epigenetically (switching on and off genes).

The logical next step would be to test NAC vs Sulforaphane vs (NAC + Sulforaphane).

Since we live in an imperfect world, rather than wait half a century for a clinical trial, you might have to do a home trial.

In the next post we will see how to make Sulforaphane at home.

As is often the case, it is not as simple as buying some on Amazon.

Sulforaphane survives for 30  minutes outside the freezer and almost all broccoli supplements have been shown to have no active Myrosinase.  Without this enzyme almost no Sulforaphane will be produced, no matter how many broccoli tablets you take.

This reminds me of people buying oxytocin over the internet.  If it is not kept chilled, by the time it arrives at your place, a few days later, it will be totally inactive and so ineffective.  You will have wasted your money and perhaps falsely concluded that oxytocin is ineffective.

This is how the Sulforaphane is made by Johns Hopkins:-

Preparation of Sulforaphane-Rich Broccoli Sprout Extracts.

Sulforaphane rich broccoli sprout extract (SF-BSE) was prepared by the Cullman Chemoprotection Center at The Johns Hopkins University essentially as described in Egner et al. In brief, specially selected broccoli seeds were surface-disinfected and grown (sprouted) for 3 d in a commercial sprouting facility under controlled light and moisture conditions. A boiling water extract was prepared, filtered, cooled, and treated with the enzyme myrosinase (from daikon sprouts) to convert precursor glucosinolates to isothiocyanates, and
then lyophilized at a food processing facility (Oregon Freeze Dry, Albany, OR). The lyophilized powder (216 μmol SF/g powder) was encapsulated into #1 gelcaps by ALFA Specialty Pharmacy (Columbia, MD); each capsule contained 50 μmol SF (232 mg of SFBSE); placebo capsules were filled with microcrystalline cellulose.
The powders (bulk and capsules) were maintained at approximately
20 °C and repeatedly checked for microbial contaminants and SF
titer before conveyance to the study site pharmacy (Massachusetts
General Hospital) to be dispensed to patients.

Thanks to all the research done on Sulforaphane/broccoli as chemoprotective agent, all the pieces of the puzzle exist.  My first choice would always be the stable analog of Sulforaphane, but it is not yet available and will no doubt be ultra expensive.  So I will work with second best.

The nice people at Johns Hopkins did reply to my questions, so I think I have figured out what I needed to know.

                                           How to make Sulforaphane at home