The Science of MS Supplements

Summary

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Podcast Summary: MS Living Well — The Science of MS Supplements

Host: Dr. Jamie Holloman (Director, MS Center for Innovations in Care, Missouri Baptist Medical Center, St. Louis)
Guests:

• Dr. Mariana Cortesa (Harvard T.H. Chan School of Public Health)
• Dr. Eric Tuvagn (Nimes Regional University Hospital, France)
  Episode Date: November 18, 2025

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Episode Overview

This episode addresses one of the most common and pressing questions for people living with multiple sclerosis (MS): “What supplements and diet should I try for my MS?” Drs. Jamie Holloman and Barry Singer, joined by world-leading MS researchers, take a deep dive into the best clinical evidence surrounding dietary supplements and nutrition for MS. Key focus areas include omega-3 fatty acids (particularly alpha-linolenic acid) and vitamin D, plus discussion of salt, minerals, and evidence-based guidance for people with MS.

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Key Discussion Points & Insights

[00:23] Setting the Stage: Why Focus on Supplements and Nutrition?

• Dr. Jamie Holloman underscores the proliferation of MS-related nutrition advice—some based on science, some on hope—and the need to clarify what the best available research actually supports.
  • “My goal today is to clarify our best available research and focus on high quality evidence you can trust.” [01:21]

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[01:36–16:21] MS, Diet, and Supplements with Dr. Mariana Cortesa

Alpha-Linolenic Acid (ALA) and MS

• What is ALA?
  • ALA is a plant-derived omega-3 fatty acid, found in foods like walnuts and flaxseed.
• Key Study:
  • Using data from the BENEFIT clinical trial, Dr. Cortesa’s team found that higher blood levels of ALA were:
    • Associated with reduced risk of MS relapses.
    • Associated with reduced risk of disability progression up to 11 years after disease onset. [04:30]
  • Contrarily, fish-derived omega-3 fatty acids (EPA and DHA) did not show the same effect for MS disease activity or progression.
    • “It really narrowed down to this ALA or alpha-linolenic acid hypothesis.” [04:41]

Why Plants but Not Fish?

• Hypotheses:
  • ALA may impact immune response to viruses (such as Epstein-Barr virus).
  • ALA could offer neuroprotective effects, as seen in other neurodegenerative diseases.
• Dr. Cortesa emphasizes continuing fish oil for general health, but ALA may be especially relevant for MS outcomes. [05:13]

Recommendations and Safety

• Diet, Not Supplements—Yet:
  • No supplement dosing is recommended at this time; more research needed.
  • “It doesn’t harm. [ALA] is naturally present in walnuts and flaxseed, for example, and walnuts have other health benefits. So definitely something to consider…” [07:00]
• Future Directions:
  • Clinical trials directly testing ALA supplementation in MS are warranted, but challenging due to potent MS drugs masking moderate effects.

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[08:39] Vitamin D: New Insights

• Dr. Cortesa reports on her group’s large, recent study with 1,400 MS cases using military blood samples:

  • Confirmed strong inverse association between vitamin D levels and MS risk in white populations.
  • Their data in Black individuals is less clear—suggesting possible biological differences in vitamin D physiology.
  • “It seems there is really a biological difference... we're trying to get more into this question.” [09:31]

• Optimal Levels:

  • For bone health: >50 nmol/L is generally sufficient.
  • For MS: Suggests possible added protective effect at higher levels, but precise dosing still under study. [11:30]
  • Typical advice: Supplement with 1,000 IU/day increases levels by ~10 nmol/L.

Other Supplements & Dietary Factors

• Sodium (Salt), Zinc, Potassium, Magnesium:

  • No evidence of impact on MS risk or progression from large cohort studies. [12:38]
  • “It doesn’t seem like going on a very salt-restricted diet will make a difference for MS at least.” [12:41]

• Dietary Approaches:

  • No definitive “MS Diet”—more research needed.
  • For vitamin D from food: focus on fatty fish (e.g., salmon), fortified foods.
  • “So far, the evidence is best and strongest for vitamin D.” [15:41]

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[16:33–34:47] Vitamin D and MS Disease Activity: The DELAY MS Trial with Dr. Eric Tuvagn

Background: Why Vitamin D?

• Vitamin D is a known immunoregulator. Since the 1960s, low vitamin D and low solar exposure have been linked to increased MS risk. [17:48]
• Prior studies were mixed—often underpowered, short, or lacking strong endpoints.

The DELAY MS Study

• Design:
  • 316 patients in France after first demyelinating event (CIS).
  • Randomized to high-dose vitamin D (100,000 IU every 2 weeks) vs. placebo.
  • Followed for 2 years; disease activity measured by new relapses or new MRI lesions (at 3, 12, 24 months). [19:09]
• Rationale for High Dose:
  • Based on prior safe use and need to achieve biologically relevant levels (up to 150 nmol/L). [21:20]

Results

• Primary endpoint: Disease activity (relapse or new MRI lesion).

  • Placebo group: 34% had disease activity.
  • Vitamin D group: 21% had disease activity (~34% risk reduction; odds ratio 0.66).
  • Comparable efficacy to some traditional MS medications (e.g., teriflunomide, interferons). [22:29]

• Safety:

  • Well tolerated; no hypercalcemia, kidney stones, or serious adverse events linked to vitamin D. [23:30]

Disease Activity Details

• MRI activity was primary driver for detection—relapse rates were low due to trial design.
• “Any activity is really the same phenomenon, that the disease is not controlled.” [24:16]

Who Benefits Most?

• Greatest benefit seen in participants with low baseline vitamin D levels.
• Those without T2 lesions in the spinal cord also benefited most—possibly reflecting better prognosis subgroups.

Clinical Implications

“I would not use vitamin D to replace disease modifying therapies... But if patients did not tolerate any treatment, … I easily convince them to take vitamin D because we have proven high dose vitamin D in MS is really safe…”
— Dr. Eric Tuvagn [30:13]

• Not a replacement for DMTs, but possibly useful for those who can't or won’t take them.
• Unclear if high dose vitamin D adds benefit atop existing DMT therapy—further research (and meta-analyses) planned. [31:29]
• The results are most relevant for early stage (relapsing–remitting) MS; applicability to progressive MS is not established. [26:54], [33:46]

Broader Perspective

“Vitamin D has no side effects. Even if it could have a very, very little effect at the level of the population, it could ameliorate the global health of the population and be beneficial at the population level... In all those countries... $1 per month therapy might be valuable at the population level too.”
— Dr. Eric Tuvagn [33:46]

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Notable Quotes & Moments by Timestamp

• On ALA and Relapses:

  • “Alpha linolenic acid was associated with a lower risk of relapses… and also with a lower risk of disability progression as measured by a combined disability measure.”
    — Dr. Mariana Cortesa [04:30]

• On Plant vs. Fish Omega-3s:

  • “We did not see the same association up to 11 years after disease onset, which really narrowed down to this ALA or alpha linolenic acid hypothesis.”
    — Dr. Cortesa [04:41]

• On Vitamin D and MS in Diverse Populations:

  • “The association is less clear in blacks... So it seems there is really a biological difference and we're trying to get more into this question.”
    — Dr. Cortesa [09:31]

• On Disease Activity as an Outcome:

  • “Any activity is really the same phenomenon, that the disease is not controlled... and that relapses are associated to new lesions that have a strategic location in any important neurologic pathway.”
    — Dr. Tuvagn [24:16]

• On Supplement Risks and Recommendations:

  • “I would not recommend mega doses [of vitamin D] without talking to your trusted physician, but making sure you have healthy vitamin D levels would be a good idea for both thinking of MS but also of other diseases.”
    — Dr. Cortesa [14:21]

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Timestamps for Key Segments

• 00:23 – Introduction to the supplement/clinical evidence discussion
• 01:36 – Dr. Mariana Cortesa on ALA and nutrition research
• 04:30 – ALA associated with reduced relapses and disability
• 05:13 – Hypotheses about plant-vs-fish omega-3s
• 08:49 – Vitamin D’s relationship to MS risk; ethnic differences in effects
• 11:30 – Vitamin D: adequate and “optimal” levels for MS
• 12:38 – Research on sodium, other minerals, and MS risk
• 14:38 – Dietary approaches: No conclusive "MS Diet" yet
• 16:33 – Dr. Eric Tuvagn joins on Vitamin D and DELAY MS trial
• 19:09 – Study design: high-dose vitamin D vs. placebo
• 22:29 – DELAY MS results: reduced disease activity risk
• 23:30 – Safety findings: well-tolerated high dose
• 26:54 – Applicability to broader MS population & disease subtypes
• 30:13 – When to consider vitamin D clinically
• 33:43 – Takeaway for listeners: Vitamin D’s value for global health and accessibility

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Episode Takeaways

• Vitamin D:

  • Strongest evidence for a supplement impacting MS course; high dose (100,000 IU every 2 weeks) significantly reduced early disease activity in newly-diagnosed (untreated) patients, was very safe.
  • Best to optimize vitamin D, especially in newly diagnosed or untreated populations.
  • Check with your MS care team before high dosing. Not a substitute for disease modifying therapies.

• Alpha-Linolenic Acid (ALA):

  • Higher ALA intake (from plant sources like walnuts, flaxseed) linked to reduced relapses and disability; more research needed before supplements recommended.

• Fish Oil & Other Supplements:

  • Fish-based omega-3s have general health benefits, but not shown to modulate MS disease course.
  • Sodium, zinc, potassium, magnesium do not impact MS risk based on current evidence.

• Diets:

  • No conclusive “MS Diet”; eat a healthy, balanced pattern, favoring vitamin D–rich foods, ALA-rich plant sources, fatty fish.

• General Advice:

  • Only take supplements after discussing with your MS care team.
  • Evidence-based supplements (vitamin D, possibly ALA-containing foods) can be helpful alongside—not instead of—traditional MS therapies.

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For Listeners: Practical Guidance

• Focus on maintaining vitamin D sufficiency, particularly if low or newly diagnosed.
• Augment diet with ALA-rich foods (walnuts, flaxseed), but avoid unproven supplements.
• Discuss any supplement plan with your MS specialist, especially before going beyond standard doses.
• Stay skeptical of “miracle diets” or supplements not supported by rigorous trials.

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[For more information, see the show notes at mslivingwell.org.]

Transcript

[Dr. Jamie Holloman]

Hello and welcome Back to the Ms.

[Dr. Barry Singer]

Living well podcast.

[Dr. Jamie Holloman]

I'm Dr. Jamie Holloman, neurologist at the Ms. Center for Innovations in Care at Missouri Baptist Medical center in St. Louis. I'll be your host for today's episode, the Science of Ms.

[Carrie Ed Harmon]

Supplements.

[Dr. Jamie Holloman]

There are countless supplements and nutrition strategies promoted by people living with Ms. Some grounded in strong science, others driven more by hope. This episode focuses on the supplements where we have rigorous clinical evidence. We'll spend most of this episode discussing vitamin D and the latest clinical data for its effect on multiple cirrhosis. First, I'm joined by Dr. Mariana Cortesa, an Ms. Researcher at Harvard T.H. chan School of Public Health. Her work focuses on lifestyle and nutrition factors in multiple cirrhosis. She has been a leading voice in advancing evidence based nutrition research in Ms. We then shift gears for a deep dive with Dr. Eric Tuvanon, lead investigator of the Delay Ms. Randomized clinical trial, one of the most robust studies to date evaluating whether vitamin D supplementation influences

[Dr. Barry Singer]

disease activity in Ms.

[Dr. Jamie Holloman]

I made this episode because one of the most common questions I get in clinic is what supplements and diet should

[Dr. Barry Singer]

I try for my Ms.

[Dr. Jamie Holloman]

The sheer number of options can be daunting and it's easy to fall into the trap of thinking more supplements must always be better. My goal today is to clarify our best available research and focus on high quality evidence you can trust.

[Dr. Barry Singer]

Let's get started.

[Dr. Jamie Holloman]

Thanks so much Dr. Corteza for joining me on Ms. Living well.

[Dr. Mariana Cortesa]

Thank you for having me.

[Dr. Jamie Holloman]

You recently published a paper on alpha linolenic acid and the possible relationship that it has with Ms. Could you tell listeners a little bit about that study?

[Dr. Mariana Cortesa]

Yeah, absolutely. So just to take a step back first, why we're interested in looking at diet. I work at the nutrition department at the School of Public Health, so I'm naturally surrounded by this topic and it is a very important topic that interests patients because I think it can empower patients to contribute to influence their disease course. So to get to the actual study you mentioned on alpha linolenic acid. Yeah. We recently published a study where we used data and blood samples from a clinical trial population that is called benefit. About 450 patients that were recruited to test the effect of a disease modifying drug. One of the first ones Interferon beta. And in these studies patients gave several blood samples and were thoroughly followed over years and assessed in the clinic for relapses and disability progression, et cetera. We collaborated with the trial conductors and could access these samples to measure fatty acids in the blood and assess whether any of these fatty acids were associated with the Ms. Course, disease activity and progression. And we looked at these different fatty acids separately. And what we found was that alpha linolenic acid, which is omega 3 fatty acid, which is derived from plants, was associated with a lower risk of relapses, so inflammatory disease activity and also with a lower risk of disability progression as measured by a combined disability measure. This was very interesting because we also could look at the other fatty acids, for example, of great interest in the field for many years, where the fish derived omega 3 fatty acids, EPA and DHEA. And we did not see the same association up to 11 years after disease onset, which really narrowed down to this ALA or alpha linolenic acid hypothesis. And why we were also intrigued is because there was a previous paper from our group that in a large cohort in US women saw that alpha linolenic acid was associated with a lower risk for developing Ms. And then there was also a smaller study in 80 patients that also participated in a randomized controlled trial in Norway in a study called OFAMS, where they were actually interested in assessing omega 3 fish derived fatty acid and the effect on Ms. Activity, but they didn't see an effect for those. But then after the trial, since this alpha linolenic acid hypothesis came out, they went back, measured alpha linolenic acid and saw that it was associated with a lower risk of relapses two years later. This drew us to look in a larger population and in a longer follow up. Do we see this also 10, 11 years later and this is what we found?

[Carrie Ed Harmon]

Yeah, and it's super exciting. Any potential hypotheses on why the fish derived versus the plant derived might have this beneficial to begin with?

[Dr. Mariana Cortesa]

We don't know. These are just hypotheses. It may be that alpha linolenic acid impacts immune response to viruses, which is of great interest in Ms. Regarding the Epstein Barr virus story, but it could also have larger neuroprotective effects because alpha linolenic acid has also been associated with a lower risk of other neurodegenerative diseases such as als, and has also been associated with a longer survival in ALS patients, which is very interesting. Now, the fish derived fatty acids, if somebody is taking supplements for those, I would still continue taking them because they have benefits for other diseases and outcomes. But for Ms. It doesn't seem like they play a crucial role. Instead, alpha linolenic acid may be of interest to potentially conduct a clinical trial. It's difficult because we have so potent disease modifying drugs today, so we couldn't obviously look at that alone and the drugs are so potent that if there is a moderate effect of alpha linolenic acid, it would maybe be masked by those drugs. But it's still a very interesting hypothesis. And if patients are interested in knowing how to eat, how they can benefit their disease course and do their best, this could be one approach to look at and also it could tell us something about the mechanisms. So definitely something to consider further.

[Dr. Barry Singer]

Absolutely.

[Carrie Ed Harmon]

I think probably the most common question

[Dr. Jamie Holloman]

I get from patients is what supplements can I take and what can I

[Dr. Barry Singer]

do from a dietary perspective?

[Dr. Jamie Holloman]

Are there any specific dietary or supplement recommendations you'd make for alpha linolenic acid based on this data?

[Dr. Mariana Cortesa]

Absolutely. Now, based on these studies so far, I cannot issue recommendations on supplementation, but it's certainly a good idea to make sure to have a healthy intake of alpha linolenic acid. It doesn't harm it naturally is present in walnuts and flaxseed, for example, and walnuts have other health benefits. So definitely something to consider if somebody is really interested in doses and safety of doses. Alpha linolenic acid has also been studied for cardiovascular disease and cardiometabolic health and there have been some trials. Patients could, if they're really interested in taking a supplement, look at what were the safe doses. So at least you have an idea of what is the max you should go to if you really want to take a supplement. But I cannot yet recommend a dose.

[Carrie Ed Harmon]

Would your ideal be like an OFAM study where you do sort of an omega 3 plant based and kind of do a similar type of analysis?

[Dr. Mariana Cortesa]

That's a good question. You know, the OFAM study, if I remember well, they tested the omega 3 fatty acid, six months only taking those supplements and then six months on an immunomodulatory therapy. So in combination today, such a study having a six month period without any disease modifying treatment will be challenging to justify. So we would need to think more about this, how we would design such a study. It's not simple to switch gears.

[Carrie Ed Harmon]

You recently presented new preliminary data on vitamin D. And so I'm curious for our listeners what thoughts you had about vitamin D in general and its role in multiple cirrhosis?

[Dr. Mariana Cortesa]

Yeah, what I presented in a recent Actrim conference in Barcelona, now in September, which is the largest Ms. Conference in the world, is really the largest study conducted so far on this topic. Where we had data and blood samples, we could measure vitamin d in about 1400ms. Cases that developed during being on active duty in the US military. And we had several blood samples to look at this. So we could also assess longer term vitamin D exposure and double as many controls to really assess what impact vitamin D had. And since we had a much larger number than in previous studies and the US military is more diverse, we could go in and look at white population and black population separately because the data basically comes only from white populations and the association is less clear in blacks. And you know, given that their vitamin D physiology may be different, this was a very important question to look at. And what I reported in the conference, and these are preliminary findings, we're still working on it and we're not done, is really that we confirming the strong inverse association between vitamin D levels and lower risk for Ms. And in black individuals it's less clear the association and we don't know yet why. So it could really have to do with the vitamin D physiology that it's different, for example, that black individuals have lower levels when we measure them, but they don't have lower bioavailable levels, meaning they still use the vitamin D efficiently, so they don't have any deficiencies. So it seems there is really a biological difference. And we're trying to get more into this question by also looking at some other proteins and transporters of vitamin D in the blood and try to see whether we can have a better understanding of why there's a difference.

[Carrie Ed Harmon]

That's wonderful and very exciting research and it gets us closer to being able to, for each individual patient, give them tailored advice for how treatment's going to affect them, how it's going to change. Because yeah, it's one thing to kind of have a homogenous population and extrapolate based on that, but if we can actually say these are how people like you have done in clinical studies or in clinical research we've had, it's much more likely to then be directly transferable to them. So it's. It's very exciting.

[Dr. Mariana Cortesa]

Exactly. Yes. The large study sample and the diversity really helps us to issue more personalized recommendations. Also, you know, looking at females and males separately and also by age, for example, in the conference I also discussed the levels that are considered optimal for bone health. So for bone health, for Most people over 50 nanomole per liter are considered sufficient. But is that enough for Ms. Prevention? Right. And is there potential to go higher and reach a peak optimal level? And it really seems like from our findings so far that there's an added protective effect to go higher. So yeah, stay tuned on the doses. We really hope to write this up nicely and clearly for everybody.

[Carrie Ed Harmon]

Fascinating. And then for our listeners, you've also done incredible research on other dietary supplements or specific diets within multiple sclerosis. Would you mind sharing some of the research that you've had from those A

[Dr. Mariana Cortesa]

couple of years ago we conducted a study on sodium intake so salt intake and Ms. Risk in in one of these large Harvard cohorts of US females where we included about 500 women who developed Ms. During follow up. And these women were followed up every four years over decades with food frequency questionnaires to really assess their habitual diet. And we saw no relationship between sodium intake and Ms. Risk. So it doesn't seem like going on a very salt restricted diet will make a difference for Ms. At least. And in this whole context we also looked at other minerals, zinc, potassium, magnesium, but we did not see any association for early intake, meaning when we looked furthest away from Ms. Onset or also cumulative intake when we used data collected over the years with these dietary food frequency questionnaires. So far the evidence is strongest for vitamin D. I would say it is definitely worth making sure that vitamin D levels are at least sufficient above 50 nanomole per liter with a supplement, for example, that you take during the winter months. A supplement of 1000 international units a day will increase your vitamin D levels by about 10 nanomoles per liter. I would not recommend mega doses without talking to your trusted physician, but making sure you have healthy vitamin D levels would be a good idea for both thinking of Ms. But also of other diseases.

[Carrie Ed Harmon]

Based upon all the research you've had, are you leaning towards any specific types of diets or dietary interventions that you think might be helpful in ms?

[Dr. Mariana Cortesa]

That's a good question. We would love, and I'm trying to get funding for this to really assess if there's a Ms. Diet, what's the best diet to follow for healthy living and aging with ms, and even use biomarkers to assess this diet. But we're not that far yet. It has been challenging to get funding, but we're working on it. We're not giving up. And in terms of best diet, if somebody doesn't want to take supplements of vitamin D, for example, I would recommend a regular consumption of fatty fish like salmon. Try to have healthy intake of vitamin D rich sources. Some sources are fortified for vitamin D, like milk, some cheeses are fortified, but fatty fish is a good source, for example. It would really be interesting to get a more global idea of how diet influences the Ms. Course. And I'm thinking also of quality of life and fatigue and measures that are less affected at times by the potent, amazing disease modifying treatments that we can offer patients. So far, again, the evidence is best and strongest for vitamin D. And then we hope to do more studies on alpha linolenic acid as well to understand what is underlying that association.

[Carrie Ed Harmon]

Several studies thanks so much for talking with me. This has been incredibly helpful and thanks so much for your research and everything you do.

[Dr. Mariana Cortesa]

Thank you for having me and I look forward to have conversations in the future with more information.

[Dr. Jamie Holloman]

I'm now joined by Dr. Eric Tuvagn, a neurologist and multiple cirrhosis specialist based at the Nimes Regional University Hospital in France. He is one of the leading international researchers examining the role of vitamin D in Ms. He has authored numerous publications on Ms. Disease mechanisms and biomarkers and leads clinical research programs focused on improving early diagnosis and treatment for people living with Ms. Most importantly for today's discussion, he was a principal investigator of the Delay Ms. Randomized Clinical Trial, one of the most rigorous studies to date evaluating whether vitamin D supplementation can reduce Ms. Disease activity. This trial provides rare, high quality prospective evidence in an area where guidance has historically been shaped more by observational data than randomized clinical studies. I had the chance to speak with him in depth about this study and what it means practically for patients and clinicians. Dr. Tuvano, thanks so much for joining me on the podcast.

[Dr. Eric Tuvagn]

Thank you for the invitation. Happy to join you.

[Dr. Jamie Holloman]

The study we'll be talking about today is a recent study you did looking at vitamin D supplementation in patients with multiple cirrhosis. For context, could you tell us a

[Dr. Barry Singer]

little bit more about the background of

[Dr. Jamie Holloman]

vitamin D in multiple cirrhosis?

[Dr. Eric Tuvagn]

Oh yes, certainly. So since the 60s we have identified that there was a higher risk of Ms. In those patients with vitamin D deficiency or lower solar exposure. So many hypotheses spread light on vitamin D deficiency as an immunoactivator. So vitamin D is like an immunoregulator and when it's deficient then there is a kind of excitation of the immune system that would lead to different autoimmune conditions. So in the specific field of Ms. We were interested in having some trial to identify if a therapeutic to supplement vitamin D deficiency could lead to less disease activity. Before that study there have been several studies showing discrepant results. Some studies brought positive information results and others negative or like no tendency. But they were often underpowered and could not have either enough patience or enough duration to show a significant effect. So we went for a really, really big study to Try to know if there was any effect, even quite small, we could detect it.

[Dr. Barry Singer]

Could you tell us a little bit more about the design of your study?

[Dr. Eric Tuvagn]

So it was very, very simple design. It was a randomized control trial with two arms, the high dose vitamin D supplementation using cholecalciferol, 100,000 units every two weeks and compared to placebo in the very same vials that were provided by the same lab. So it was very classical, high quality and large population randomized controlled trial. So we included 316 patients all across France in 36 centers, and they were all patients after the first demyelinating attack. So at that time, because the study started in 2012, at that time there were CIS patients. That means clinically isolated syndromes. That's the condition when we have the first attack of Ms. And at that time there was not, as now, a really high pressure to treat patients with disease modifying therapies. Right away, because the diagnosis was even not confirmed, we were like following the patients just to monitor their clinical and MRI disease activity. We chose to randomize them in the two arms of the trial.

[Dr. Barry Singer]

Wonderful. And so, yeah, so you're looking at people essentially at the very start of their disease and then seeing whether or not high doses of vitamin D, 100,000 units will make any difference in terms of disease activity.

[Dr. Eric Tuvagn]

Yeah, it was every two weeks. Yes, gotcha. Yes. And disease activity was identified as either a new relapse of Ms. Or the evidence of new active lesions on MRI follow up scans that were performed and scheduled at 3 months, 12 months and 24 months. So overall it was a 24 month study and those patients were quite well following the study since 95% of them went to the end of the follow up period. That was in the design.

[Dr. Barry Singer]

Was there a specific reason that you chose the higher dose of the 100,000 compared to maybe what's a more typical supplementation dose of 5,000 units daily or 50,000 units on a weekly basis?

[Dr. Eric Tuvagn]

Yes, we had discrepant results from previous studies. Some of them were at moderate dose and others were even at much higher dose than the DLA Ms. Trial. For instance, the Solar study, which showed some trends in reducing the new lesions and new active lesions, but that was negative on the primary endpoint. That was relapses in France. We had the experience of the Coline study, which was leaded by Professor William Camus in Montpellier. It was a two year study instead of 12 month study. The dose was the same and it was so well tolerated. And it led the people to increase their vitamin D levels from 16 anomals per liter to 150 nanomoles per liter, about which was, let's say, sufficient to have a biological effect for the vitamin D receptor to act as an immunomodulator. So we chose something for safety that was reasonable, but that was still high dose. To be sure that we could modify the activity of the immune system makes

[Dr. Barry Singer]

a lot of sense. And then could you share the results of your clinical study?

[Dr. Eric Tuvagn]

Oh, yeah. Thank you. So we chose as a primary income the global disease activity. So as I said, either renewal relapses or new active lesions. And we identified that in the placebo group, after two years of follow up, the disease activity was 34% of the patients, while in the high dose cholecalciferol treatment it was 63%. And that was an odd ratio of 0.66. So it means that globally there was a reduction of 34% of the risk of disease activity over time, which we found comparable to previous disease modifying therapies like the topic trial for teriflunamide, which was like 35% reduction, and interferons 40, 45% reduction and so on. And the result was really, really significant.

[Dr. Barry Singer]

Did you notice many, if any, side effects from the vitamin D supplementation?

[Dr. Eric Tuvagn]

There were some side effects in both groups, in the placebo and in the treatment group, but none of them had a relationship with what we expect from vitamin D toxicity. I mean, especially hypercalcemia or kidney stones that might happen in some people, but none of those happened in the study. And serious adverse events were quite balanced between the two groups. And none of them had a link with vitamin D, so it was really, really safe. And As I said, 95% of the patients finished the study, so that means they had really no serious concerns about the treatment.

[Dr. Barry Singer]

Could you go in a little bit more detail about disease activity and how you defined it in the clinical study and then the results that you saw?

[Dr. Eric Tuvagn]

So yes, the most important for the patient's clinical activity is relapses. Right. But the, the problem is that at that time we were already concerned about letting patients evolving with new and active lesions on MRI scans. So we chose to stop the therapy and the treatment to any patient who would present either a relapse, of course, or any new lesion or new active lesions on follow up scans. So what happened is that we removed all the patients with MRI activity from the follow up group. So only a few, like 20 in each arm developed new relapses at the beginning of the study. And then once we captured new disease activity on MRI scans, patients were spared from new relapses. So in fact, there were really, really low figures for relapses. That was 18 in the treatment treatment arm and 22 in the placebo arm. And the difference was then not significant. So some reviewers addressed the criticism that it was not efficient on relapses. But in fact, the design of the trial could not allow to see a difference for relapses. And the global activity, which is the mix of relapses and new active lesions and new lesions, is really positive. And as a neurologist Ms. Specialist, I don't know if you can agree with that. We really think that any activity is really the same phenomenon, that the disease is not controlled and that relapses are associated to new lesions that have a strategic location in any important neurologic pathway. So it's really equivalent for us. And that's the proof that we can modulate disease activity with high dose vitamin

[Dr. Barry Singer]

D. Yeah, I certainly agree. Anytime I clinically see new disease activity on an mri, a new lesion, an enhancing lesion, I'm definitely concerned about new disease activity from Ms. And to your point, it's just kind of recognizes the limitations of studying patients like this because as you said, your first priority is patient care and making sure the disease is managed. So it kind of limits how far you can monitor patients before you have to put them on disease modifying therapy. But I totally agree. Nevertheless, striking MRI changes. And you sort of mentioned that this group was clinically isolated syndrome, so kind of catches patients early in the disease course. Any thoughts if this is sort of something that's generalizable to all patients of ms, or is this maybe a phenomenon that is just early in the disease course that vitamin D supplementation is helpful?

[Dr. Eric Tuvagn]

Well, I'm really convinced it's a global modulation of the immune system and that these results can apply to relapsing remitting Ms. So active disease, as we tend to say now, active Ms. You know, what happened in 2017 is that we had a revision of the McDonald diagnostic criteria. And then when we applied the new McDonald criteria that were revised in 2017, we identified that 89% of the patients had the criteria for Ms. So in 2012, when we started the study, they were called CEIS. But in 2017, it's like they were almost all of them relapsing remitting Ms. According to the new definition. So I'm really convinced that when you see a patient either having five or 10 lesions. It's the same disease and it's the same phenomenon, disease activities really associated to activity of the immune system that we can modulate with high dose vitamin D. What we have not shown is if that would be interesting in the progressive Ms. Farms. And what we have also not investigated and not shown is that if vitamin D supplementation is useful when disease modifying therapy is already ongoing, but we did not design the study to answer that question. So it still has to be investigated.

[Dr. Barry Singer]

Yeah, very important point that patients were those not currently on disease modifying therapy. So whether that applies for treated Ms. Patients is a little bit of an open question. And you referenced this a little bit already in terms of the hypothesis for how vitamin D is having an effect. Could you explain a little bit more your thoughts on maybe how it's having this beneficial effect for patients?

[Dr. Eric Tuvagn]

Oh, yes, that's, that's a really, really interesting topic. And in the Functional Genomics Institute where I do the research, we investigated the modifications of the circulating lymphocytes, those from the blood from the patients of the DLMS study. What we have observed, as maybe other groups do with vitamin D, that can activate some different pathways like the NF kappa B pathway which is associated with the lymphocyte survival and so on, and that maybe vitamin D could reduce both lymphocyte activation and lymphocyte proliferation. But as already described in the literature, vitamin D is a pleiotropic hormone and it acts through its vitamin D receptor that goes to the nucleus and modulates the expression of hundreds of genes. It really acts at different levels of the immune system and other cells from the body. So it's a really complex regulation and the pleiotropic one, but overall it brings immunomodulation of the activity.

[Dr. Barry Singer]

Fascinating. And one takeaway that I've taken from your clinical study that might influence my clinical practice is just kind of the importance of high dose vitamin D early in the Ms. Disease process. You know, if I'm seeing a patient in the hospital and I'm suspicious about a new diagnosis of ms, that's certainly someone I want to expedite getting on high dose vitamin D supplementation. Are there other takeaways that inform your clinical practice or how you think about vitamin D with your Ms.

[Carrie Ed Harmon]

Patients?

[Dr. Eric Tuvagn]

I would not use vitamin D to replace disease modifying therapies that are already taken by the patients and well tolerated. However, for those patients who did not tolerate any treatment and who have no more treatment or who turn back to nothing because they're afraid of side effects or they don't want any more the side effects of this or that therapy. I easily convince them to take vitamin D because we have proven that high dose vitamin D in Ms. Is really safe and it has been proven by previous studies with even higher doses and other diseases. So they can really trust us about that. But I'm not suggesting it should replace any disease modifying therapy. And the other question, as I said, is adult therapy using that vitamin on top of ongoing disease modifying therapy. But I think that the data from the results from Colleen and Solar studies still brought some clues that there is something about the disease activity, especially the MRI activity in both studies. And we are trying with the authors of these studies to to see if we can computerize the results altogether in the meta analysis to see if we have a stronger convergent effect.

[Dr. Barry Singer]

Your point is certainly worth emphasizing that still nothing seems to be a good substitution for our disease modifying therapies. But as you mentioned, in those patients who either have very severe adverse reactions from the disease modifying therapies, who are very opposed to taking disease modifying therapy, vitamin D is at least better than nothing in terms of adding somewhat of a disease benefit. And so certainly something to think about. And I thought it was interesting too. In your study it seemed like patients with low vitamin D levels or low spinal cord lesions seem to benefit the most from vitamin D supplementation. Would you mind explaining a little bit more about that?

[Dr. Eric Tuvagn]

Well, I mean we pre planned to analyze what were the different characteristics of the patients that were associated with a good response to vitamin D supplementation. And in fact, in this interaction analysis that we performed with the statisticians, we observed that those patients with lower vitamin D levels at baseline had higher benefit of supplementation, which makes sense, they have higher activity because they have lower levels of vitamin D. And when we took all the factors together in a multiple analysis and we corrected on this factor and others, the difference was still very, very high. So that was quite logical. What we cannot really explain is why those patients with no T2 lesion in the spinal cord had a better response. We hypothesized that they had a better prognosis and that let's say for instance, those with spinal cord lesions would anyhow convert to Ms. Rapidly and have new lesions and new attacks. That could be an explanation, but that's speculative. We are measuring the levels of vitamin D that are achieved in the patients of both arms in the placebo group and the high dose vitamin D supplementation group. We are trying to see if higher increase in vitamin D is associated to better response or if it's a global effect of taking the vitamin D or not. Just to know if we should fix an objective or threshold above which patients would be more protected. But that's also some ongoing work and we will try to get results for

[Dr. Jamie Holloman]

next Egg Trims what's one takeaway you'd

[Carrie Ed Harmon]

like to leave our listeners with based on your research?

[Dr. Eric Tuvagn]

As you know, progressive Ms. Has no cure today. There are some hints with BTK inhibitors and there has been some results with anti CD20 therapies that we can use use or not in some countries and depending on the health agencies. The problem with those therapies is that they are very costly and they might have some side effects. Vitamin D has no side effects. Even if it could have a very, very little effect at the level of the population, it could ameliorate the global health of the population and be beneficial at the population level. And what I finally think is that although France or in the US or developed countries, most patients have access to disease modifying therapies, there are still many countries where those treatments are not available for any political reasons or economic reasons. And in all those countries, 2 Euro 1 Euro $1 per month therapy might be valuable at the population level too. So I think that could help many people worldwide.

[Dr. Jamie Holloman]

Thanks so much for for all you

[Dr. Barry Singer]

do and for your research. Another good tool in the arsenal that we have as clinicians and people who care for patients with msdu.

[Dr. Jamie Holloman]

So thanks so much for doing the study.

[Dr. Eric Tuvagn]

Yeah, thank you very much for your time too. And thank you.

[Dr. Jamie Holloman]

That wraps up our conversation with Dr. Corteza and Dr. Tuvano. Thanks again to TG Therapeutics for sponsoring this episode and thanks to our listeners for downloading this episode of the Ms. Living well Podcast. The Science of of Ms.

[Carrie Ed Harmon]

Supplements.

[Dr. Jamie Holloman]

Today we explored evidence based supplementation and nutrition in MS, including omega 3 sources like alpha linolenic acid, the role of sodium in minerals, and what large scale clinical data tells us about vitamin D and Ms. Disease activity. A quick reminder. We did not cover every supplement or diet trend currently marketed to people with Ms. This episode focused intentionally on interventions backed by strong clinical research. As always, the topics we discuss on this show are strictly informational and not medical advice. Please talk with your Ms. Care team before making changes to your supplement routine or diet. Our show is hosted by me, Dr. Jamie Holloman and Dr. Barry Singer and produced by Carrie Ed Harmon. Our theme music music is the Gold Lining by Broke For Free. If you like the show, please share it with others living with Ms. Also please post a positive review on Apple Podcasts. It helps more people find out about the show. You can follow me on x rainboyneuro1 and Dr. Barry Singerburysinger. More information about our guests and their websites can be found in the show Notes for this episode in the blog section of mslivingwell.org thanks so much for listening.

[Carrie Ed Harmon]

This has been an Ms. Living well podcast.