Dr. Jed Fahey on Isothiocyanates, Nrf2 Pathway, Morings & Supplements
Dr. Jed W. Fahey is a nutritional biochemist with broad training and extensive background in plant physiology, human nutrition, phytochemistry and nutritional biochemistry. He is the director of the Cullman Chemoprotection Center at Johns Hopkins. Background of discovery of broccoli
"Albert F Wright is an experienced multidisciplinary research scientist. He is a graduate of the Royal Institute of Chemistry, London, holds a PhD in X-ray crystallography from the University of Bristol, and studied neutron physics at the University of Oxford. In the early 1970's Dr Wright was appointed Staff Scientist at the Institut Laue-Langevin in Grenoble (ill.eu), the world's leading international facility for neutron science & technology dedicated to research in fields as varied as molecular biology, chemistry, fundamental physics, novel magnetic materials and the environment using neutron radiation. Dr Wright's research works (71 publications) cover disordered crystalline systems, crystal nucleation in glasses and the structure and dynamics of solid electrolytes (for batteries). He was appointed Head of Communications in 2000 before retiring in 2006.
On being diagnosed with Parkinson's disease in 2018, Dr Wright turned his attention to identifying the most likely molecular causes of Parkinson's disease and experimenting possible therapies to slow or stop the disease. This led to the development of a tea made from broccoli seeds, containing the isothiocyanate, sulforaphane designed to halt oxidative stress and reverse mitochondrial dysfunction in neurons and thus slow disease progression.
After 21 months of self experimentation with broccoli seed tea, Dr Wright is currently almost symptom free." Frank Mundo.
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Thanks for posting this Marc. These 5 videos may help people understand why I decided to take the route of activating Nrf2 to combat oxidative stress in my fight against Parkinson's disease, and why I chose sulforaphane from broccoli seeds as the agent to do the job.I would like to make a few comments.
In the first video, Dr Brad Stanfield says that sulforaphane is an antioxidant. This is not technically true. Sulforaphane activates the Nrf2/ARE process, where ARE stands for the Antioxidant Response Element, a DNA sequence which promotes the transcription of hundreds of genes expressing detoxifying and antioxidant enzymes. This is the in-cell machinery that targets and destroys oxidants and is much more effective than individual antioxidant molecules.
He also says that we can safely activate Nrf2 as much as possible. This is not proven and is debatable.
Dr Jed Fahey is the world expert on glucoraphanin and sulforaphane in terms of plant biochemistry. I have had many discussions and several Zoom meetings with Jed about how to optimise the broccoli seed tea and on the likely mechanism of action of sulforaphane in Parkinson's disease. Jed helped me write various articles relating to the Broccoli seed tea experiment and the model for dopamine depletion in neurons. I will let him know about this post.
Jed mentions that the daily therapeutic dose of sulforaphane from broccoli sprouts is in the range of 50 to 100 micromols. The daily therapeutic dose we observed when using broccoli seed as the source material for the broccoli seed tea is in the range 15-30 micromol. We infer from this that the bioavailability of sulforaphane in the latter is therefore higher than that from sprouts, possibly because the glucoraphanin is more fully converted to sulforaphane in the broccoli seed tea before ingestion.
In the text section about myself, the link to the research centre (Intitut Laue-Langevin) where I spent most of my career doesn't work. It should be ill.eu Somehow the closing bracket gets included in the address.
If you are wondering what could possibly link neutron physics to health and drugs, there is a very nice brochure about this that you can download. The key people working in this area at the ILL, Drs Giovanna Fragnetto and Trevor Forsyth are personal friends. There is even a small article on page 17 about mitochondrial membranes in Parkinson's disease.
What’s the best way of making the seed based tea? I’ve quickly scanned the net and I can see some on the dreaded Amazon. Any preferred brand or do you buy the seeds and steep a measured amount like a teaspoon full at the preferred 70° for a set time? I could see one of the videos making tea with the sprouts but not the seeds. Sorry if I have overlooked something.
I don't think I can attend on Sunday. Another home rugby match. I have a couple of questions
1) You have stated that Albert is almost symptom free after 21 months on the broccoli , but I thought he had found it had little if any effect on motor symptoms, and took sinemet for those. Can you clarify ?
2) What is the goal of this project - in brief? What is it intended to achieve? There has been talk of phase 3 trials and FDA approval - and yet neither sulforaphane nor broccoli require licencing
"I rarely have any non-motor symptoms and just a slight tremor on my left hand with very little pain.
. . . I did a 4 week washout from Broccoli seed tea some months ago and the non-motor symptoms did not come back. This seems to indicate that sulforaphane can produce a state of remission from non-motor symptoms of Parkinson's disease. The tremor did however get more intense, so I went back on a lower dose, which calmed it down again. I don't know how to explain this."
Unless Albert wants to chime in, it is to see if Sulforaphane is safe, provides relief from which symptoms, at what dose, but ultimately to get the attention of an appropriate institution to take on a larger clinical trial.
It's probably unhelpful for me to have unstructured questions here. I'll wait for a summary of your meeting. Your answer didn't clarify whether Albert is still taking sinemet. My recollection of the results of his first experiment was 11/20 dropped out, 4/9 experienced no benefit, and of the 5 participants experiencing a benefit all 5 did not improve motor symptoms. At least 3 of the 5 were also newly using red light hats. The reason I declined Albert's private invitation 2 years ago to participate in his experiment was that I was at that time involved with Biogen SPARK trial and that trial controlled use of other therapies which might confuse the results
Richard, let me try to answer your questions as clearly as I can with a note of caution that I represent only a single case and my experience may not translate into a more general response.
I was diagnosed in May 2018. At that time I had the full range of non-motor symptoms, but only moderate motor symptoms, left hand stiffness and tremor with lots of pain in the upper arm, foot dystonia, all over stiffness and slowness, etc. I started on Ropinirol, 3 x 0.5mg and Levodopa 4 x 100 mg.
I started my first trials of broccoli seed tea in December 2019. By that time the meds had reduced the bradykinesia and dystonia but tremor had increased considerably with the addition of very unpleasant internal tremor. I also had my first experience of dyskinesia.
Non-motor symptoms had become a disaster. The most life-changing was acute urgent fatigue associated with all-over pain every couple of days. This is the sort of crushingly painful fatigue that comes on in 15 minutes and meant that I urgently had to find a place to lie down screaming and hopefully sleep for 2-4 hours helped by a prescription of Izalgi (opium 25mg, paracetamol 300 mg), sometimes x 2.
The second was frequent urinary urgency (often with accidents), that ultimately became incontinence. In addition I had typical neck and shoulder pain (I had an X-ray scan that showed nothing); poor sleep with really vivid dreams; very quiet voice. This was my baseline symptom state before starting the broccoli seed tea experiments.
As many of you know, the first months of experimentation were flawed by mis-labelled seeds, inappropriate dosing, non-optimised tea preparation etc. Nevertheless, I observed great improvements in non-motor symptoms over long periods, sometimes followed by relapses, but the trend was positive and continued to improve as the preparation process and dosing were refined. I received a lot of help and encouragement from Prof. Jed Fahey about the broccoli seed processing and from Prof Albena Dinkova-Kostova concerning the Nrf2 pathway.
About 6 months ago, my situation stabilised with almost no non-motor symptoms, occasional moderate fatigue and motor symptoms that are now well controlled by levodopa. My main motor symptom is a slight left hand tremor with no pain. All the rest are absent providing I take my levodopa 4 x 100 mg. I don't really have off periods.
My conclusion is that the Broccoli seed tea (sulforaphane) directly controls the non-motor symptoms and enables the levodopa to do a much better job in controlling the motor symptoms without generating dyskinesia.
I have tried the 4 week washout period twice now and in both cases the non-motor symptoms did not come back, but the motor symptoms become more intense.
What is the objective of the videos?
I think that they draw our attention to how sulforaphane-producing supplements are being promoted as the wonder elixir for longevity and cancer prevention, stressing only the positive aspects with no dose limits and no consideration of potential adverse effects.
However if we would try to use sulforaphane as a therapy to try to slow the progression of an existing condition such as Parkinson's disease, then suddenly we should consider the possibility of harmful effects such as heart attacks and cancer when using the same supplements.
In the first case, sulforaphane supplements seem to get a free hand to do miracles such as life extension, maybe because the medical profession doesn't believe that they work.
In the second case, they might actually do some good and help patients, which then infringes on the practice of medecine, so safety becomes the key issue.
AlbertThank you for that. I have only just read it due to yet another orange Internet outage.
I was taught that the way to eat an elephant is "one bite at a time" so I'll break my response into a few parts
First, whilst acknowledging the many benefits you have experienced, and the value of that, thank you for confirming that you are not, as Frank Mundo is quoted as saying "almost symptom free {without medication}" but in fact taking sinemet 25/100 QDS to control motor symptoms.
That is not to denigrate the importance of the benefits achieved for the non-motor symptoms, but to clarify a point which might have been mis-interpreted
Richard, Frank was citing a text that I wrote. If you read through the text I wrote above, you will see that before starting the broccoli seed tea I had both motor and non-motor symptoms when taking the same medication. In particular, tremor was on the increase and very unpleasant internal tremor had set in. The broccoli seed tea knocked out the non-motor symptoms rapidly and slightly increased tremor in the short term. The effect on all motor symptoms (on levodopa) occurred over a long period and only after the non-motor symptoms had been stabilized to the point that they did not relapse even when I stopped taking the broccoli tea for 4 weeks (washout).
You are right to clarify that this result was achieved while still on levodopa. The effect of the combination of the broccoli seed tea with levodopa on motor symptoms is, in my opinion, an interesting observation.
Thank you again. I note that I too confused matters by implying only non-motor symptoms were helped in your personal case history. I believe that the broad conclusion of the forum experiment with 9 participants, was that the benefits reported were restricted to non-motor symptoms (and for only 5 of the 9. Also 5 of the 20). However, in the case of your personal (much longer duration) case history this is not the case. Motor symptoms appear to be improved by use of sulforaphane (Sp) - albeit not completely relieved without levadopa supplementation
I would note that my feelings about my experiences of photobiomodulation are probably similar. I would also note this is a maddening bloody disease which fluctuates about all over the shop in the short term and makes me cautious to draw rapid conclusions
But - your personal case history suggests Sp helps motor symptoms too. Non-motor symptoms continue to be controlled during the washout periods, but motor symptoms immediately deteriorate. So Sp would appear to have a symptomatic effect on motor symptoms, but potentially a disease modifying (well at least, longer duration) effect on non-motor symptoms
This is counter-intuitive, and doesn't accord with my understanding (possibly misunderstanding) of your explanation of the mechanism of action for Sp. In simple terms I thought the inflamation / mitochondrial stress damaged neurons AND created non-motor symptoms
PD is as you say a maddening disease that often presents us with apparently contradictory symptom changes. I say apparently contradictory changes because they do not fit with our oversimplified ideas about what is going on. I spent my working life doing physics of various kinds, and such research is largely based on mathematical constructs (dynamic models) of what we think might be reality. The models are always approximations, but if they are close to reality, they will behave in a similar way to real observations. The climate change models are good examples....
With these complex systems, you cannot work from the data to create a model. But you can use your imagination to build a dynamic model (one with variables that change over time) in a computer and observe whether the model behaves in a way that matches the observations. If it doesn't, you have to revise the model in such a way that with each revision you get a nudge closer to the observations. If the system is complex, some parts of the data might match and others will not. In this case, you temporarily block (make invariable) that part of the model that matches the observations and you try to make intelligent changes to the parts of the model that produces data that doesn't match. This way you slowly iterate towards a better match. When the model gets close to reality, there are mathematical techniques that enable the computer to make fine adjustments that take into account the fact that every process and every variable of the model affects every other process and variable, sometimes in apparently contradictory ways. This is the nature of complex systems.
There is no universally accepted model for PD progression, but there are now enough ideas to try to establish the physical structures and processes that will be needed to build one. Just as with the climate model, a good PD model will have to have multiple constructs and processes operating over different spatial ranges and different timescales.
Among these, mitochondrial dysfunction (and recovery) within a DA neuron is a process operating over short spatial range (initially affecting just the one neuron) and a short timescale (days). When you allow these processes to run and bundle many of them together they will modify both overall neuron function and dopamine delivery over a much wider spatial range (reaching the striatum) and a longer timescale (weeks). Changes in the striatum will affect how the whole brain works as a system in order to accommodate the fact that the striatum is not working properly. These changes in connectivity between different parts of the brain may take many months to achieve and may be imperfect solutions.
Some of these processes may be reversible and therefore sensitive to drugs (mitochondrial dysfunction and recovery), but any damage already caused (e.g. neuron loss) may not be reversible (the model may have one-way streets). This is where apparent contradictions show up in the observations. They are only apparent because the model we have in our mind is too simple.
The observation that some symptoms are sensitive to SFN over a short timescale whereas others are not or take much longer is an indication of the presence of both reversible (two-way street) and irreversible (one-way street) processes and/or short range vs long range operations which operate over different timescales.
IF, and this is still a big IF, some non-motor symptoms are driven by the "process" of mitochondrial dysfunction (a two-way street) and some motor symptoms are driven by the damage caused by this process over wider region (a one-way street), then we may see a way to resolve the apparent contradictions. I use the idea of a one-way street deliberately, because it leaves a small chance to get back to where we started using another, much longer route.
I am familiar with modelling theory and "satisficing". Real world financial and economic models are as complex as your climate change example. The modelling principles are the same. While we may hope for a solution from quantum computing, I think we should leave Shrodingers cat in its box for PD modelling. A neuron is either dead or alive (or sleeping, or wounded). But not both/all states at the same time
I'm not sure I understand the model you are proposing - never mind correllating that with any data. PD has many variants, but at its core, particularly in the earlier stages it responds in an entirely predictable and straightforward way to dopamine supplementation - classically in the form of carbidopa / levadopa that you are taking. This primarily concerns motor symptoms.
I hoped to keep responses punchy, and single topic. To avoid rambling. But, in the absence of a proposed model with any coherence (saying it is too difficult to model, and we haven't done it yet, is not the same as proposing a model to test) and leaves any experimentation devoid of purpose.
So that brings us back to what is your experiment planning to test? How can it establish anything in the absence of a clearly defined goal and model to test? And in turn, that brings into question the trial methodology. To date it has been little more than an exploration of concept - with results which like the Stephen Fry / Sandi Toskviq show might be "Quite Interesting"
But to hold up my Elephant card, 4 weeks is not a washout period, there is no placebo control, a tiny timeframe (for an experiment on progression), a tiny sample size, no attempt to eliminate other therapy initiation or variation during the trial period, and huge potential for variation in both the quantity and bioavailability of SFN in the whole broccolli seed tea preparation process. It's little wonder Simon's committee kicked it into touch
So. A couple of questions related to that
What dose of SFN do you believe that you self administer?
How are you able to reliably measure and test that?
Is it possible for trial participants to measure reliably and consistently the SFN dose produced by the tea?
How would you propose rolling this out as a deliverable to 10 million sufferers worldwide?
Why is it not possible to use a standardised commercial extract of known dosage and bioavailability? It would simplify participation, and almost certainly improve retention of trial subjects, as well as enabling a placebo capsule to easily be incorporated into any trial
If you are unable to reliably measure & test participant dosage regularly and consistently what do you believe this proves about the safety of SFN as a molecule?
There - I knew I wouldn't stay one point per post. "Oh Bother" (as Winnie the Pooh often says)
PS - how much have we been able to learn about the Chinese blinded placebo control trial which Juliegrace drew attention to, and why would this not adequately meet the objective of establishing the potential for SFN as a therapy?
Richard, I think we should continue this discussion by email where we can share documents more easily.
I would just like to add this remark.
I totally accept all your comments about the weaknesses of my research and the observations made. The experimentation was flawed, no placebo, short timescales etc. but is the best we can do without more resources, not to mention authorisation, safety etc. The observations are not results, just indications with considerable limitations.
But so far nobody has ever observed anything as interesting as the indication that non-motor symptoms might respond differently to motor symptoms.
This is what we would like to be able to confirm. How can we make this happen.
A final point. The broccoli seed tea proposal was jointly written by Simon Stott and myself at Simon's request. He still supports it.
Happy to continue the chat by email. I am disappointed I am unlikely to be back for the zoom on Sunday. I have however finally, this week, caught up a backlog of work that meant I have had little time for PD stuff for some while now. I'm still busy, but not behind!
How does your thiamine experience play into all of this? Because in Feb 19, you wrote, on the co.uk site:
"I have been talking 3.5g thiamine per day for last 9 months. It cleared all my symptoms except tremor which has got progressively worse. Now adding mucuna p and green tea which helps with tremor. I’m on HU , username wriga."
I am not suggesting that things can't go bad in 10 months (between Feb and Dec of 19), because I know they can and do, but how did your apparent deterioration in that time influence your view as to what thiamine was or wasn't doing for you? And does that experience give you any pause for thought in relation to your interpretation of your apparent results with sulforaphane?
I have to say I'm a bit concerned about the hype around sulforaphane. I note you have tried to be guarded about it, so credit to you for that.
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