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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:-


COPD

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



79 comments:

  1. How can one make this sulforafane at home??

    ReplyDelete
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    1. I will write a post shortly. You either eat fresh broccoli sprouts, or combine daikon powder with broccoli powder. Eating fresh broccoli itself would require you to eat a VERY large amount.

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    2. Peter, at the risk of contradicting you, it is possible to obtain 100% whole broccoli sprout supplements that can match the doses used in Singh’s 2004 autism trial. The highest Sulforaphane-yielding broccoli sprout supplement yields more than 20 mg Sulforaphane per gram of powder. Because such supplements yield such a high percentage of Sulforaphane, just a few grams or less daily will easily match the micromol doses published in the Singh study.

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  2. But have you seen http://phys.org/news/2011-01-supplements-team-boost-broccoli-cancer-fighting.html which seems to provide a solution to the myrosinase problem.

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    Replies
    1. I wrote a later post all about the clever ways to get the full sulforaphane potentail. My final solution, which does seem to work, is a broccoli sprout powder from Australia which has active myrosinase. I was a sceptic, till I tried it.

      http://epiphanyasd.blogspot.com/2014/11/dr-dolittle-autism-and-broccoli-sprouts.html

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  3. Thank you for this interesting article. I must say I have a little bit of trouble translating these figures into actual behavioural changes, but who wouldnt?

    I have two humble propositions on things I'd love to see you discuss, one is a page where all studies with measurable outcomes are compared (abc, cgi), with a comment on side effects, shortcomings, etc. for instance, this would be nice to include http://www.update-software.com/BCP/WileyPDF/EN/CD009043.pdf

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  4. ... The second would be a page with particularly interesting ongoing and finished clinical trials, with comments on outcomes and other.

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  5. I know myself & I know that I won't make it everyday so I have been ordering and giving my son EnduraCell from Australia for 6 months now. It have given us some big gains that have held. I buy the powder and put it in a kids mouth syringe with a teaspoon of organic apple juice it tastes like mud with black pepper in it but my son just gobbles it down. At first you must go slow because it makes you poop more. The Australian Post cost $12 shipping and takes 2 weeks but we order it way before we are out of it.

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    1. Hello Pierrette, Are you still using EnduraCell with your son? We are the manufacturers of EnduraCell and I just wanted you to know that we have a kid-friendly version now that is all natural and tastes great in milk, water or as the powder straight off the spoon/scoop. PomGenex if you are looking for it on the Cell-Logic website.

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    2. The PomGenex jar says that it should be blended as one scoop of powder + 200 ml water or milk and consumed within 10 minutes.
      I thought that this powder had to be used together with a certain amount of liquid to get "active" (unlike the SuperSprout brand). Is it possible to get a confirmation on the statement above that you could actually digest it even without liquid?

      /Ling

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    3. This comment has been removed by the author.

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    4. As soon as the Pomgenex becomes moist, the enzyme will be activated and the sulforaphane produced. The saliva in the mouth provides that moisture as does the entire digestive tract. Stirring the powder into water or milk is what we typically recommend but taking it dry will have the same effect.

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    5. By the way, Pomgenex and Enduracell are available in the US via www.cell-logic-USA.com.

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    6. Thank you Christine!

      /Ling

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  6. 1. Delineation of root causes are often useful in treatment planning. While articles on Sulforaphane abound a more recent study may provide the linkage that finally (sic) makes coherent sense see http://www.nature.com/nrm/journal/v15/n6/abs/nrm3810.html
    2. Then availability. Testing shows high levels of stable sulforaphane (75 micromoles in 33 ml of juice) in raw broccoli sprout juice that has been treated with High Pressure and lactic acid. Just look for whole raw "broccoli sprout juice" on line or in the shops.

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  7. try to synthesis SFN-NAC analogues in my lab, hope got some interesting results to share with you

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  8. I just received the PharmaNAC yesterday. I decided to give it a try even though I'm not thrilled with the Nutrasweet ingredient. It is 900 mg per tablet. My 11 year old son is 75lbs. I gave it to him in the morning before camp and then I will give it again when he gets home in the afternoon. Can I give a third dose right before bed? I read that it can help with insomnia since it helps with racing thoughts? Thank you! Christine

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    Replies
    1. I would not bother giving it before bed, he will be asleep while it has an effect. The half-life is quite short. So if you cannot give it in the middle of the day, I would not bother with the third dose. I doubt it really helps insommnia, perhaps try some melatonin.

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  9. Peter-
    Can you recommend any brands/sources for the Australian broccoli powder. I found this one, which seems to match your description:

    http://nourishinghub.com.au/products/super-sprout-broccoli-sprout-powder

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    Replies
    1. The Australian producer's site is

      http://aus.supersprout.co/

      They now have a US website for orders

      http://usa.supersprout.co/

      The web addresses look a bit odd but do work.

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    2. There are two suppliers of broccoli sprout powder in Australia. NourishHub supplies EnduraCell, the highest Sulforaphane-yielding broccoli sprout supplement available anywhere. This is NOT the same as the link you provided Peter. The latter claims to provide about 6-7 mg per gram of powder. EnduraCell yields over 20 mg per gram. This more concentrated form means the patient needs to rake onlynanout one-third the quantity to get the therapeutic response.

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    3. On the EnduraCell PomGenex jar (the taste-friendly EnduraCell version with other ingredients as well) it says 40 mg glucoraphanin per 10 g serve. How much sulphoraphane would this translate into?

      /Ling

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    4. Each 10 gram scoop of Pomgenex contains 1 gram of the EnduraCell broccoli sprout powder. Each gram of this yields 20 mg Sulforaphane. The reason this isn’t on the label is that Australian food labeling only allows us to state glucoraphanin and doesn’t allow us to state Sulforaphane because the sulforaphane isn’t in the product; it is only produced when the product becomes moist. Confusing I know but those are the regulations.

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    5. Then it is a good thing we have this blog where it is possible to share data like this. Thank you once more for your quick answers Christine!

      /Ling

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    6. Christine can i order it if i live in Canada?

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    7. For US and Canada, EnduraCell and PomGenex are available from www.cell-logic-usa.com in Missouri.

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    8. Hi Christine & Peter, I have been giving my 4 year old with ASD NAC for a while and then have added Pomgenex from your recommendation. All is going well however I am wondering if I should now stop the NAC to get full benefit of the sprouts? Peter uses both simultaneously for Monty but I noted you said specifically in another post not to use NAC. Just a bit confused about why and which way to go.

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    9. The best thing is to make an experiment and compare the effect of:- just NAC, just Pomgenex and then NAC + Pomgenex. Then you will know what works for your 4 year old.

      What works in reality is not always predictable.

      Only use supplements that actually give a positive effect that other people really can notice.

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  10. Thank you--I just ordered some!

    Do you know of any good non-RX sources for Bumetanide?

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    Replies
    1. Popular choices are Mexico, either in person or via the internet and Spain in person. It all depends where you live.

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    2. Peter,

      I had enquired from a few Mexican online sites about shipping to India through their customer service. Did not receive any response though they were selling miccil quite cheap.

      Ironically relatives from my in-laws sides are pharmacists in the US and but it seems laws governing drug use and sale are quite stringent there.

      The only option it seems now is to wait for somebody to travel to a country where it's OTC or beg and plead a fellow parent at son's therapy center who happens to be a paediatrician with a severely autistic child with multiple comorbidities, for a prescription. The doctor gives off unfriendly vibes though, and probably it's understandable.

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    3. Kritika, why not take a chance and order some Mexican Miccil. It will probably arrive in a month or two.

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    4. Yes, did think of that. OK, will order and see what happens.

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  11. Thanks, Peter. I live in the US. My 7 y.o. son is undiagnosed and very much a "borderline" case. He comes up subclinical in all of the online assessments. Good verbal communication and play/social skills, no apparent cognitive impairments, no stereotypies. But he has strong OCD tendencies and has had persistent challenges with irritability/aggression. His issues definitely get worse over the summer, which is how I found your blog.

    Do you think he might benefit from Bumetanide? I'm definitely going to start giving him the BioGaia, NAC, and broccoli powder.

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    Replies
    1. Andrew, it is worth trying bumetanide, it does help some people with milder autism, but there is no diagnostic test.

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    2. I think a good protocol may be to trial low dosage clonazepam first. We found that there is a 4 day course on the NHS in the UK for prevention of seizures that can easily be prescribed.

      Otherwise prescription for anxiety, which is pretty much prevalent in ASD, may be a viable route.

      If there is a change (of any type) with LDC then bumetanide is likely to be more effective.

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    3. Hello Emily,

      Actually, this crossed my mind as well..a positive response to LD clonazepam could be indicative of a good response to bumetanide as well. And in the country I belong to, clonazepam might be easier access. And as Peter mentioned somewhere, LDC in itself might have greater effects when used singularly rather than in combination with bumetanide where its effect is synergistic.









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    4. Hi Andrew and Peter. I’m a latecomer to this discussion which I see goes back a while. As a Sulforaphane researcher, I must comment that NAC and Sulforaphane (SFN) don’t mix! As a direct-acting antioxidant, NAC is likely to block the weak pro-oxidant signal that SFN uses to initiate Nrf2 activation which is needed to switch on the 2000 or so genes which provide the therapeutic effect. The genes which code for glutathione are among these. All NAC does is to provide a precursor compound from which glutathione can be synthesized. The activation of Nrf2 by SFN activates a whole battery of cell-protective compounds.

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    5. Would taking the NAC and sulforaphane at different times of day (e.g. one in morning one in evening) help with this?

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    6. We dont have any data on NAC and SFN in the way you suggest. However, Iam very wary of NAC because it is a direct-acting antioxidant which may well counter the mechanism SFN uses to activate Nrf2 and the 2000 or so target genes associated with cellular defences. So although NAC has been shown to offer benefit in autism cases, I am concerned that the long-term effects cant be sustained. NAC increases glutathione by providing the precursor amino acid but does nothing to enhance the synthesis of the other genes upregulated by Nrf2. I dont think the pharmacokinetics of NAC and SFN are such that dosing at different times would be of benefit. However, you may wish to try this to see what such an n=1 study might provide. I would be interested to know what you find. We simply dont have enough data at this stage and even apparently logical arguments can be proved completely wrong when put to the test.

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  12. Yay!,

    Sulforaphane for the Treatment of Young Men With Autism Spectrum Disorder
    https://clinicaltrials.gov/ct2/show/NCT02909959

    Expected to be completed november 2019, Its good to see they doing bloodtest parameters for some important things in my opinion!!!:

    Liver function tests (alanine transaminase, aspartate transaminase, total bilirubin), change values from baseline to 12 weeks [ Time Frame: Baseline, 12 weeks ]
    Serum chemistries (sodium, potassium, chloride, bicarbonate, BLOOD UREA NITROGEN <<<<<----- GLAD THEY DOING THIS ASWELL, creatinine, calcium, magnesium, phosphorous, glucose), change in values from baseline to 12 weeks. [ Time Frame: Baseline and 12 weeks ]
    Thyroid Stimulating Hormone (TSH) <<<<------ OFTEN THYROID DYSFUNCTIONS IN ASD/AUTISM, PARENTS SHOULD GET BLOOD DRAWN FOR TSH IF THEY HAVENT YET THIS IS IMPORTANT, TSH UNDER 3 IS IDEAL, change in values from baseline to 12 weeks. [ Time Frame: Baseline and 12 weeks ]

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  13. Yet another question on the broccoli sprout topic, this time to those of you who are using or have used it.

    We have given it as a smoothie blended with around 5g (20 mg glucoraphane) at around 4 PM/16.00 for about a week now, and as it happens my daughter has been waking up in the middle of each night and wouldn't go back to sleep for at least two hours.
    This could totally be a coincidence but I suspect not. Does any of you share this experience of insomnia or something similar? I think Peter mentioned that a bigger dose would make Monty go hyper... If so, did it help to change the timing or dose?

    /Ling

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    Replies
    1. Ling, it is definitely something to give in the morning, far away from bedtime.

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    2. Because Sulforaphane enhances the function of every cell in the body, it will also optimize energy production. I usually recommend taking the daily dose in the morning where it causes evening agitation. It makes no difference in the long run because the genes that are ‘switched on’ produce enzymes that remain active for several days.

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    3. Enhancing cellular energy production is of course a good thing but where there are multiple metabolic defects, it can disturb sleep until other aspects of cellular function stabilize.

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    4. Let's hope you are right and I'll get a good nights rest (at least tomorrow). :-D
      /Ling

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    5. Christine,

      can you tell what metabolic defects can make a person prone to sleep disturbances on Sulforaphane? How to stabilize cellular function then?

      My son developed insomnia each time on Sulforaphane, which otherwise had noticeable beneficial effects on his mood and speech. He took it daily in the morning.

      I am aware about other parents whose children experienced sleep issues on Sulforaphane. For some pulsed dosing was effective.

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  14. It can help to have a Nutrigenetic profile done to see what specific gene variants the patient might have. There can be genes associated with inflammations n and detoxification that can have a bearing on what you are observing. If your child is having some benefits as well as sleep disturbance, I would suggest reducing the dose until the sleep improves. At the same time, I would want to increase intake of non-starchy vegetables. (I know that can be challenging but don’t underestimate the power of vegetables to repair). Then I would gradually increase the broccoli sprout dose. What the extra vegetables can do is to help downregulate the genes that promote inflammation, even if you don’t have a Nutrigenetics profile to tell you which genes could be an issue.

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  15. From the last weeks experiments, I can only confirm that the Sulforaphane has a slight insomnia effect. But, it is not immediate. Giving my daughter her dose at 10 AM, she would still have her daily nap at 1 PM. Instead she would wake up like 2 hours early the next day... So, I think I'll have to try to lessen the dose a bit. It is nice though when it is obvious that a supplement works.

    I have one more question to all of you, and that is if we know what HDACs sulforaphane inhibits? In my daughters condition HDAC inhibitors looks very promising as a treatment, but they have to be selective because som HDACs are beneficial and others are not.

    /Ling

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    Replies
    1. Ling, another thing to consider is that when you give broccoli sprout powder you are not just getting sulforaphane. For example, broccoli is rich in a flavanol called Kaempferol, which is seen as beneficial, but which can cause hyperactivity.

      Kaempferol increases an enzyme called D2 (type 2 iodothyronine deiodinase). This is the enzyme that converts the inactive thyroid hormone T4 into the active form T3. If you increase the amount of T3 you increase the body’s metabolic rate and if you do this close to bedtime you will not be able to sleep.

      There are some posts in this blog on central hypothyroidism, which will not show up on a standard blood test. The theory from a Polish lady at Harvard goes that oxidative stress in the brain reduces the activity of D2 which causes a brain-specific low level of T3, causing a passive low-functioning brain.

      Kaempferol was one substance I proposed as a therapy for central hypothyroidism.

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    2. Keep in mind that the amount of kaempferol in a gram or two of broccoli sprout powder is minuscule compared to the amount in a serve of broccoli vegetable.

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    3. Peter,

      Im interested in trying kaempferol in the future, but I cant seem to find any supplement containing it as a pure source.

      Ginkgo contains it in fair amounts and had a pretty good effect with that in the past (vasodilation I believe it mainly was).

      @Ling

      I can second that sulforaphane (broccomax in my case) gives insomnia if take after 3/4pm.

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    4. Aspie1983, how many capsules a day of broccomax do you take and what exactly is the effect you experience?

      Kaempferol is potentially interesting for many people because it should increase the amount of the enzyme D2 which converts the inactive T4 to the active T3 thyroid hormone. Central hypothyroidism is a feature of some neurological conditions, which I expect includes some autism and some depression. Oxidative stress in the brain is known to reduce the amount of D2 you have.

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    5. Hi Peter,

      I just took 2 the other day to still if it still has an acute effect and yup its still very much present, kicks in around 1hour after intake and peaks after 2-3hours (very strong awareness effect). I feel as if it makes more confrontational towards people (something I find it somewhat shares with reuteri). Hard to describe but I find broccomax gives me more mental willpower to engage in conversations (less worrying of failing too it seems).

      The odd thing about broccomax I find is (possible due to being a hdac-i type 2/3) is that it also seems to bring back hidden subconscious memories. Like when I took it 3hours before going to the conversation with my psych I actually put him on his spot a bit (not in an aggressive way) as to why theres always so much delay with things in the clinic that I come. This thought (that I personally find they are slow at processing everything in their company, such as med script requests) was hidden deep inside my brain as a 'subconscious blockade' and sulforaphane brings to this to the surface, I have also noticed this over a year ago when I used it extensively, doses anywhere from 2 capsules a day up to 9 a day.
      More definetely had a stronger effect in me, but I noticed I also was getting more outbursts, which I suspect is due to thoughts coming to the surface that my mind previously couldnt detect (certain social cues). Anyway for that reason I dont want to take over 3 caps a day no more.
      It certainly helps to help me do stuff that I normally would hesitate to do.

      Now sulforaphane has a complex mechanisms, including restoring NO-glutamate-cGMP pathways, aquaporin4, etc

      To get to the point I do think I have hypperammonia in my brain (BCAA's help), this could also mean why my urea in blood is constantly elevated, my body is 24/7 breaking down excess ammonia (hence the elevated urea levels).

      Turns out hyperammonia is actually associated with certain INCREASED gaba receptors:

      Hyperammonemia induces glial activation, neuroinflammation and alters neurotransmitter receptors in hippocampus, impairing spatial learning: reversal by sulforaphane

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4754839/

      In this study, sulforaphane nearly completely reversed the gaba alpha1 and alpha5 subunit (the one you recommended should be antagonised for classic autism, yet aspergers could be helped by increasing activity here).
      Sulforaphane downregulate gaba a1 and upregulates gaba a5 in this study.

      With regards to the D2 enzyme yep I do suspect I have a problem there (apperently stress/cortisol can impair the conversion in the body, not sure about the brain though but id guess so?).
      As you might remember I do use levothyroxine, this has brought my TSH levels down to normal, but T4/T3 ratios are still slightly in my opinion (my doc slightly disagrees though). From what I remember TUDCA can also potently improve T4 to T3 conversion.

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    6. Peter I forgot to add (which you might want to know), that the reason I feel that broccomax/sulforaphane can be mood elevating is (other than the antiinflammatory effects and such) because it allows me to tackle tasks, then I get the sense of accomplishment (reward) from them. Where as normally (aspergers has been known to have this) are kind of passive, even if you take away their job and such they dont respond with looking for a new job or a better job. You can imagine this a major survival mechanism flaw if you look at it from an evolutionairy perspective. Which leads me once again to improper fear detection/acquisition. I have had lots of periods in my life where I never got a startle response of anything (hello abnormal cortisol secretion? and thank you piracetam for helping!). It is only of the last 6-12 months that things actually start to bother me and I start thinking to myself "hey I cant allow this to happen I got to make a change". Also on reuteri agmatine and broccomax I find myself giving out more compliments to others for the good that they have done, this is a soul touching thing for me and endlightening. Also in the past I found it hard to receive compliments (and people have told me they noticed this!), feels to me as if this is due to a trust issue, if you think about if you show someone that his/her compliment is appreciated is a form of trust/bonding.

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    7. Last posts for today, more promising news on taurine:

      Taurine is an amino acid with the ability to activate autophagy in adipocytes.

      https://www.ncbi.nlm.nih.gov/pubmed/29523960

      While I know this in adipocytes, taurine also strongly increases adiponecting (decreased according to my 23andme results and this is very common in autism/adhd).

      It would only make sense if increased adiponectin secretions would be associated with improved cognition/learning. Adiponectin strongly determine how you burn fat, better fat burning = more calories needed = brain needs to adapt (learning behavior) to acquire more food through a motivational mechanism. 99% sure adiponectin affects dopamine (in a positive way), we all know the leptin/ghrelin balance in autism aswell, and I also have a mutation there according to 23andme.

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  16. It may be that the dose is a little too high for your daughter. However, that may limit some of the other beneficial effects you are trying to achieve. It is not uncommon for adults to report feeling higher energy levels, better stamina and less need for sleep. This has not been researched but has certainly be3n observed.

    In relation to HDAC inhibition, there is no known way to manipulate individual HDAC effects, other than on the lab bench. Most importantly, the SFN doses needed to act in HDAC inhibition are very much higher than those used in other processes like Nrf2 activation. This is where only a high-potency supplement is practical for dosing. The studies on SFN in HDAC Inhibition show beneficial effects. It depends what you are trying to achieve but I would suggest that we don’t know enough about HDAC effects to offer meaningful clinical suggestions.

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    1. Do we know at which dosage SFN starts to act as an HDAC inhibitor?

      I just found a study showing that SFN enhances bone formation in mice (acting on some very important genes in my case):

      "Our data indicate that the food-derived compound SFN epigenetically stimulates osteoblast activity and diminishes osteoclast bone resorption, shifting the balance of bone homeostasis and favoring bone acquisition and/or mitigation of bone resorption in vivo Thus, SFN is a member of a new class of epigenetic compounds that could be considered for novel strategies to counteract osteoporosis."

      https://www.ncbi.nlm.nih.gov/pubmed/26757819

      /Ling

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  17. Hello Ling. In general, the doses required for epigenetics effects are much higher than are those needed to activate the genes needed for the Nrf2-dependent genes that govern cellular defence mechanisms. Melinda Myzak has researched and published several papers showing that the intercellular concentration needed is around 15 micromolar. This is about 3-6 times higher than for Nrf2 activation. To achieve this (as far as our limited knowledge in this area tells us), we would need about 100 mg Sulforaphane daily. There are few broccoli supplements that can deliver this in a practical daily dose.

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  18. I should qualify my above comments by saying that your reference was for a mouse study. My suggested doses are the human equivalent based on research in humans, which is what I assume you wanted to know.

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    1. Big thanks for this reply! :) I know we don't have definitive answers, but an intelligent guess works for me. I suppose your estimate of 100 mg was for an adult person (whatever that means).
      /Ling

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  19. Did anyone post this follow-up case series of sulforaphane for autism before? If not:
    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5672987/

    /Ling

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    1. Ling, that is interesting, particularly this part, where they make a point of not telling us the good brocolli supplements and the ineffective ones.

      "Commercial sources of the broccoli phytochemicals GR, MYR, and SF are deliberately not mentioned in this article. There are now a large number of products and manufacturers. These manufacturers recommend usage (their label instructions for taking their products) that would theoretically produce a huge range of doses of active ingredient (about 10-fold) if active ingredient content is truly that which is indicated on the labels. We know that between-individual variation in bioavailability (of a known, standardized dose) is also marked. There is no consensus on the appropriate dose for an enhanced healthspan. To the degree that there is any efficacy for specific medical conditions, one can infer an approximate efficacious dose guided by our studies and those of others, but we do not have reliable data on where this dose lies. Our testing of the few products we ultimately recommended to former participants suggests that they do contain what they say they contain, but there are a great many more which we have not tested. There are also many such products that we have tested which do not contain the levels of GR or SF that they claim to contain."

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  20. The 2014 clinical trial using Sulforaphane in autism used a product that is not commercially available. There is a separate supplement to the paper that explains what they did. This is the same research group that is an offshoot of the Johns Hopkins Uni group that has patented and markets the myrosinase-INactive broccoli seed extracts. As the extracts have no intrinsic ability to generate sulforaphane, a different product had to be used in the trial. This is what causes so much confusion when trying to work out what to take to replicate what was used in the trial.

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  21. Yet another study on sulforaphane, this time suggesting it as a treatment to cognitive deficits seen after MIA (the maternal immune activation model):

    "Taken together, it is likely that MIA can interfere with Keap1-Nrf2 system and NMDA receptor in the hippocampus during brain development, resulting in cognitive deficits in juvenile and adult offspring. (..)
    we found that dietary intake of 0.1% GF food pellet at 4–8 weeks of age (similar to juvenile and adolescent stages in human) in poly(I:C) offspring could treat or prevent cognitive deficits and reduction of PV-IR at adulthood after MIA. (..)
    it is likely that early intervention with GF (or SFN)-rich foods during juvenile and adolescent stages might have prophylactic and therapeutic effects on abnormal behaviors in psychiatric disorders, such as schizophrenia and depression"

    /Ling

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    1. Sorry, here is the link:
      https://www.nature.com/articles/s41598-018-20538-3

      /Ling

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  22. Tried 7,8 dihydroxyflavone earlier (40mg sublingual for 5minutes), wow this stuff is noticable, can feel it in like 3-4mins.

    Literally awakens senses, quite profound effect, this is one of the studies that made me want to try it:

    Autism-like behavior caused by deletion of vaccinia-related kinase 3 is improved by TrkB stimulation.

    https://www.ncbi.nlm.nih.gov/pubmed/28899869

    "A significant decrease in dendritic spine number and arborization were identified in the hippocampus CA1 of VRK3-deficient mice. These mice also exhibited a reduced rectification of AMPA receptor-mediated current and changes in expression of synaptic and signaling proteins, including tyrosine receptor kinase B (TrkB), Arc, and CaMKIIα. Notably, TrkB stimulation with 7,8-dihydroxyflavone reversed the altered synaptic structure and function and successfully restored autism-like behavior in VRK3-deficient mice. These results reveal that VRK3 plays a critical role in neurodevelopmental disorders and suggest a potential therapeutic strategy for ASD"

    More info:

    https://en.wikipedia.org/wiki/7,8-Dihydroxyflavone

    Half-life seems to be less than 30minutes according to wikipedia, but if it corrects synaptic structures then the halflife aint going to matter anything.

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  23. Hello!
    My 13 year old son with classic autism has been taking Pharma NAC (effervescent tablet) for over a year with very positive results. Mainly a decrease in OCD behaviors. This summer, we saw a significant change in his self-regulation as well. We did not increase the dosing. He was markedly calm and his flexibility/ability to try new things increased dramatically. About 10 days ago I introduced pure organic aronia berry juice into our family's diet. I had heard about the health benefits and powerful antioxidant properties and thought we might give it a go. They recommend 1 tbsp/day. We divide it into 2 servings -- pouring it over ice with a dash of pure lemon juice and water. My family loves it. Just days after introducing it however, my son's OCD returned, his scripting started back up and he is moving around/pacing once again.
    My question is this:
    Do you see the potential for two antioxidants (NAC and powerful aronia berry) to counteract one another? Could these two power house antioxidants be damaging the signaling systems, resulting in impaired immune response?
    I plan on discontinuing it to see if things improve. Just wondering your thoughts on all of this.
    Thank you for your response.

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    1. Jason, it is either a coincidence or the NAC has reacted with the aronia juice and has not increased glutathione (GSH) as it did before. Such interactions are bound to happen. Hopefully things will return to normall.

      Delete
    2. my comment will not be as scientifically worded but I think still of value. I think that with aronia you introduced something that not obly has antioxidant properties but is also immunomodulating. if you search online you will find several papers detailing the effects aronia has on the immune system. considering that ocd and anxiety are often just the signs of an inflamed brain whichbin turn can happen when you stimulate the immune system in the wrong way, I would say this is what happened.

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  24. Ling I thought you would find this interesting:

    Recent study on sulforaphane for autism shows that

    Identification of urinary metabolites that correlate with clinical improvements in children with autism treated with sulforaphane from broccoli
    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5975568/

    --->>> "A novel finding of the current study is that improvement in behavior was correlated with seven different chemical forms of sphingomyelin. Seven sphingomyelin metabolites were each strongly negatively correlated with behavior, such that increased urinary levels were associated with improved behavior. <<<--- Sphingomyelin is a sphingolipid found in animal cell membranes, especially in the membranous myelin sheath that surrounds nerve cells and axons. To our knowledge, there have been no prior reports of abnormalities in sphingolipid levels in children with ASD, but there are numerous studies documenting abnormalities in the size, number, and morphology of dendrites in autism, which is related to altered synapse function [33]. Furthermore, sphingomyelin abnormalities have been noted in a number of other central nervous system disorders, including depression, anxiety, Alzheimer’s disease, and amyotrophic lateral sclerosis, suggesting that it may have a central role in normal brain development and function [34–37]. It is not clear how sulforaphane might alter sphingomyelin metabolism or availability and whether this is related to clinical benefits, but if this association is confirmed, it has important clinical and treatment implications."

    Ling as you know phospholipids such as phosphatidylserine have a strong effect on sphingolipids and I started back on broccomax 3 days ago and the effect is quite pronounced ( in conjunction with biogaia gastrus and panax ginseng extract which has been shown to increase PVN signalling the hypothalamus and thus should help increase with pulsatile release of oxt and avp).

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    1. Thanks Aspie1983!

      Sulphoraphane restores some of my daughters energy, she stops lying on the floor, very similar to the effect I now see with Fisetin. While the most obvious reason to that would be that they both treat oxidative stress, I wonder if it could be related to mitochondria instead.

      Sulforaphane targets NRF2, and so does both Fisetin and Bacopa. Fisetin and Bacopa also target ATF4, closely related to NRF2. Take a look at this picture, with Bacopa, NRF2, ATF4 and eIF2a

      https://journals.plos.org/plosone/article/figure?id=10.1371/journal.pone.0182984.g006

      NRF2 and ATF4 are related to eIF2a and to CHOP, that both are involved in the mitochondrial unfolded protein response (and I think, cholesterol metabolism too).

      Both Fisetin and Bacopa also regulate serotonin pathways, and I remember Peter writing that Monthy had euphoria from the first sulforaphane dose. Maybe this is a coincidence, but they seem similar in some ways.

      Ling, seeing patterns all over probably because I am going in circles...

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    2. Ling,
      Without a doubt sulforaphane its effect on decreasing oxidative stress is a factor, however sulforaphane has far more and some unique effects that some of the more common antioxidants dont have at all.
      Effect on the brain its aquaporin levels (which regulate water homeostasis systems). Also it acts as a HDAC-i type 2 and 3 which would help with fear extinguishment and the feelings of letting go of stress that is blocked (it powerfull does this imo). Also sulforaphane alleviates hyperammonia brain states and restores the glutamatergic tone of the brain (which is impaired in hyperammonia states where gaba overpowers).

      Sulforaphane enhances aquaporin-4 expression and decreases cerebral edema following traumatic brain injury.
      https://www.ncbi.nlm.nih.gov/pubmed/16211562

      Neuroinflammation increases GABAergic tone and impairs cognitive and motor function in hyperammonemia by increasing GAT-3 membrane expression. Reversal by sulforaphane by promoting M2 polarization of microglia
      https://www.ncbi.nlm.nih.gov/pubmed/27090509

      Hyperammonemia induces glial activation, neuroinflammation and alters neurotransmitter receptors in hippocampus, impairing spatial learning: reversal by sulforaphane
      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4754839/

      Relevance of the natural HDAC inhibitor sulforaphane as a chemopreventive agent in urologic tumors
      https://www.sciencedirect.com/science/article/pii/S0304383518304750

      Please note that the hdac study that I linked above here is just one example out of the dozens available on sulforaphane, it seems to have incredibly potent anticancer effects.

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    3. Regarding bacopa and fisetin.
      Fisetin I got a bottle unopened and not tried yet here, might try it somewhere in 2019.
      Bacopa Ive done quite a bit of reading on about, it can control TPH2 signalling (which I have a mutation for related to my tourette symptoms) aswell as SERT (which I also have a mutation for). Its pretty clear that bacopa would effect me big way, however Im somewhat scared of serotoninergic agents with exception of ligands that are highly selective for 5ht2a.
      My psilocybin trial was succesfull and the 'openness' they reported in studies on past users is still present in me, I believe it permanently enhanced my baseline social capacity.

      Also reports on nootropic/brain websites that I have read about bacopa is that it is indeed one of the only herbals that is effective in boosting people their learning (in healthy people), however many users report the side effect of dulled emotions with long term use which is my public enemy number1 and what Im trying to fight rather than embrace.

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  25. Peter, could you comment on any issues with using NAC and sulforaphane (broccoli sprouts) together? There seems to be some evidence of NAC reducing some of the cancer protective effects of sulforaphane, but I am not sure I am reading that correctly. Although cancer prevention may not be our main goal, I am wondering what else using them in combination might change.

    Can you comment on whether you think this is an issue, or whether it might be better to use NAC and sulforaphane at different times (e.g. morning and evening) or on alternating days?

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    1. Both NAC and broccoli sprouts have multiple modes of action.

      We have one commenter on this blog who sells broccoli sprouts and she highlights the research showing that some effects of sulforaphane are reduced by NAC in some models.

      Generally speaking, antioxidants may be helpful in older people to minimize cancers starting. However once a cancer is established, antioxidants can be harmful because cancer cells are vulnerable to oxidative stress, and so by reducing oxidative stress you may encourage them to grow faster. This is of course a sweeping generalization.

      I found in my n=1 case of autism, while already taking NAC, that the addition of broccoli sprouts had a prominent effect within 30 minutes. This may not have been sulforaphane, but it was from the broccoli.

      I use NAC throughout the day and so I do not have a NAC free time to give broccoli. But I think you can safely experiment with this at home.

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    2. Thank you, I will give it a go.

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  26. Dear All, especially Christina & Peter
    Do you have any idea how can I order these best quality brands of broccoli sprouts in Poland, or in EU? I tried many eshops including Cell-Logic, SuperSprout/AUS and Avamcol/Nutramaxstore but none of them ships to Poland/EU. Would be extremely grateful if you can help. Thanks !

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    1. I've had no problem with getting Cell-Logic or Supersprout deliver to EU, it just takes a lot of time. Last time customs had my package for one month.
      /Ling

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