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Intravenous Milk Thistle for Mushroom Poisoning

This intravenous form of milk thistle extract has been used for mushroom poisoning in Europe and is now in Phase II/III clinical trials in the US Credit: Madaus AG.

Apologies to readers for the radio silence – a heavier-than-usual load at the day job has been compounded by what I hope is not a prelude to a similar, serious bout of pneumonia I had almost two years ago.

In the meantime, I wanted to share with you a chemistry-relevant post I wrote for my monthly gig at Science-Based Medicine on 28 October 2011. The comments there evolved into a mouth-watering discussion of culinary mushrooms. Enjoy!


If you’ve been fortunate to live in the parts of the US that were soggier than usually as of late – or unfortunate enough to have had flooding from hurricanes and tropical storms – then you’ve be noticing a tremendous burst of mushrooms.

For mycologists – mushroom enthusiasts – there are two classic chestnuts: “There are old mushroom collectors and bold mushrooms collectors, but there are no old, bold mushroom collectors.”

Or, in a more concise Croatian proverb, “All mushrooms are edible, but some only once.”

As such, this is the time of year that emergency rooms and regional poison centers begin to see a burst in poisonings from mushroom ingestion, due primarily to amateur misidentification of the fruiting bodies.

Just this past week, Jason McClure at Medscape Oncology News (free reg req’d) wrote about the unusual bloom of mushrooms in the northeastern US and the concomitant bloom of mushroom poisonings this fall.

But “mushroom poisoning” is an imprecise diagnosis for the ER physician. The constellation of symptoms caused by toxic mushrooms is as diverse as the colors and shapes of these wonders of nature. From another Medscape article on emergency management of mushroom poisoning by Dr. Rania Habal from the Emergency Medicine department of NYU:

Mushrooms are best classified by the physiologic and clinical effects of their poisons. The traditional time-based classification of mushrooms into an early/low toxicity group and a delayed/high toxicity group may be inadequate. Additionally, many mushroom syndromes develop soon after ingestion. For example, most of the neurotoxic syndromes, the Coprinus syndrome (ie, concomitant ingestion of alcohol and coprine), the immunoallergic and immunohemolytic syndromes, and most of the GI intoxications occur within the first 6 hours after ingestion.

Ingestions most likely to require intensive medical care involve mushrooms that contain cytotoxic substances such as amatoxin, gyromitrin, and orellanine. Mushrooms that contain involutin may cause a life-threatening immune-mediated hemolysis with hemoglobinuria and renal failure. Inhalation of spores of Lycoperdon species may result in bronchoalveolitis and respiratory failure that requires mechanical ventilation.

Mushrooms that contain the GI irritants psilocybin, ibotenic acid, muscimol, and muscarine may cause critical illness in specific groups of people (eg, young persons, elderly persons). Hallucinogenic mushrooms may also result in major trauma and require care in an intensive care setting. Lastly, coprine-containing mushrooms cause severe illness only when combined with alcohol (ie, Coprinus syndrome).

Among the poisonous mushrooms, Amanita phalloides is perhaps the most deadly. If you’ve spent any time in a biochemical laboratory you will have learned of the primary toxin of the mushroom, α-amanitin. This potency of this toxin comes from its remarkably high affinity for RNA polymerase II, the primary RNA polymerase for making messages that are converted into proteins.

The challenge in treating α-amanitin poisoning is that it has a relatively long half-life in the body because it is conjugated with glucuronic acid in the liver and secreted in the bile. But then microbes that normally inhabit our gut cleave the glucuronide sugar molecule off the toxin, released the toxic α-amanitin.

Throughout the history of folk medicine in the Middle East and Europe, extracts of the seeds of milk thistle (Silybum marianum) were determined to have protective effects against liver toxins. I’m still not terribly pleased with understanding the history of how this came about but answering this question is one of my liberal arts pursuits. As an aside, I should make the disclosure that my laboratory and colleagues have been investigating the anticancer effects of compounds from milk thistle and still receive NIH funding to do so; however, I do not (yet) study how milk thistle compounds prevent liver toxicity.

Nevertheless, milk thistle products are quite popular in Europe and the US for the general prevention of liver toxicity from statins, acetaminophen, and alcohol. Several of my friends have joked that one could make create a successful market for an alcoholic product containing milk thistle extract.

But one of the primary roadblocks in using milk thistle extracts or pure compounds for any indication is that the compounds have rather poor bioavailability. The seven major flavonolignans and one flavonoid in the typical extracts are very avidly conjugated by glucuronidation. In studies by collabortors at the University of Colorado, we now know that it takes daily doses of approximately 10-13 grams of milk thistle extract to achieve plasma concentrations consistent with known anticancer effects in vitro. It can be done, but it means taking much more than the typical 180 mg capsules you can buy at your local health food store.

However, an intravenous preparation of milk thistle extract has been available in Europe for over 20 years: Legalon SIL. This GMP-manufactured product is common to emergency rooms in Germany, France, and Belgium for the treatment of mushroom poisoning. The preparation is comprised of silybin A and silybin B – known collectively as silibinin – as a hemisuccinate that both improves the solubility and bioavailability of the compounds.

Two cases in the US – one in 2007 and another just this past month – have seen emergency IND approval of this European product. In 2007, Legalon was used to save four of five family members who had ingested Amanita phalloides while on a New Year’s Day picnic outside of Santa Cruz, California. And just last month, a team led by Dr. Jacqueline Laurin at Georgetown Medical Center successfully treated two men for accidental ingestion of Amanita. Georgetown is now an approved referral center for this IV prep of Legalon and their efforts were greatly assisted by the Santa Cruz team who handled the 2007 cases.

Less satisfying to me is the mechanism by which silybin A and silybin B protect the liver from the effects of RNA polymerase II inhibition by α-amanitin. The literature to date seems to converge on the inhibition of toxin uptake into hepatocytes by silibinin. A German group led by Herbert de Groot in Essen, Germany, published a highly-cited 1996 paper proposing that inhibition of inflammatory mediator release from Kupffer cells (the macrophage of the liver) might partly account for the hepatoprotective effects of silibinin. More recent work continues to address the modulation of inflammation.

Regardless, we are now seeing legitimate use of a medicine from a herbal tradition being used in clinical situations where emergency IRB approval and IND status have been given to such a product. Certainly, these stories may be used by marketers to promote use of their oral milk thistle products. But, as I mentioned earlier, such effects required ingestion of large doses of capsules. Instead, I present this story to readers to illustrate that amidst the wooful promotion of herbal therapies, a few gems exist and are most worthy of our scientific investigation.

Update: I just learned that there is a standing clinical trial in the United States for anyone with Amanita mushroom poisoning led by the Dr. Todd Mitchell at Dominican Santa Cruz Hospital – the details on the clinical trial of Legalon brand of intravenous silibinin can be accessed at ClinicalTrials.gov and an information sheet has been provided by the manufacturer. If Amanita poisoning is suspected, have you physician call 866-520-4412 and they will be put in touch with the Principal Investigator of the trial.

11 Comments

  • Nov 4th 201111:11
    by Melody Bomgardner

    Reply

    Very nice! I had read about the milk thistle treatment of the two patients at Georgetown in the Washington Post. Good to get more background on what sounded very mysterious in the paper. For those interested in more background on the victims – if that’s what we call them – here’s the link:http://www.washingtonpost.com/local/two-men-who-ate-poisonous-mushrooms-survive/2011/09/24/gIQAa1bHuK_story.html
    (you may need a free registration)

    One key take-away, do not stir-fry random mushrooms in your yard and serve them with noodles. Also do not serve them to your wife.

    The story was followed up two days later when two more patients went to G’town for the milk thistle treatment. Doctors think both consumed Amanita bisporigera, also known as “Avenging Angel.” http://www.washingtonpost.com/blogs/post_now/post/two-more-ill-with-mushroom-poisoning/2011/09/26/gIQAB8XgzK_blog.html

    • Nov 20th 201117:11
      by Jim Parsons

      Reply

      This is an interesting development. I haven’t heard of this treatment. Do you have any idea about when the extract will become available?

  • Nov 4th 201112:11
    by Marilyn Shaw

    Reply

    A most interesting and mostly accurate article, but it contains a few inaccuracies / misunderstandings that should be corrected, including in the excerpt from Dr. Rania Habal’s Medscape article. His inclusion of psilocybin in the GI irritants group is incorrect. This toxin affects the central nervous system, not the GI tract.

    Less important is the use of the term “bloom” in discussing the appearance of mushrooms. The usual more accurate term is “fruiting”, and the mushrooms are referred to as “fruit bodies”.

    Dr. Habal in discussing coprine states that ” coprine-containing mushrooms cause severe illness only when combined with alcohol (ie, Coprinus syndrome).” It would be more accurate if it were stated that alcohol consumption following the ingestion of coprine-containing mushrooms produces the syndrome. The coprine sensitizes the body to alcohol for a period of up to 5 days.

    Regarding the use of Legalon SIL: This is for use in amatoxin poisonings, not “mushroom poisonings” in general. I have followed this treatment from the first use in the U.S. in Jan. 2007, and was contacted by the U.S. branch of the firm, Madaus, in March, 2010, asking me to spread the word about the clinical trials of Legalon SIL in the U.S. I have also discussed this use in detail with the Principle Investigator, Dr. Todd Mitchell. He states that unless prompt aggressive fluid replacement is undertaken before the kidneys are affected, not much can be done. (Personal communication.)

    It should be noted that most members of the genus Amanita do not contain amatoxins. Many are non-toxic, some edible, but there are at least 3 other toxins present in certain Amanita species. Treatment of these other Amanita toxic syndromes would not include silibinin.

    It is important to note that for over the last 100 years in the U.S. the mortality rate from mushroom poisonings (most from amatoxins) has averaged fewer than 1.5 per year. Mortality in amatoxin poisonings is about 50%, but this can be reduced to about 12% with prompt (within 36 hours) Intensive supportive care. These cases are fairly rare in the U.S. so it is difficult to draw meaningful conclusions on the real effectiveness of silibinin. However, since it seems to have no adverse effects and is supplied without charge during the current trials it is to be recommended.

    In Europe where it has been used for many years and where there are far more amatoxin poisonings, according to Dr. Thomas Zilker, Munich, there have not been enough cases to be statistically meaningful. (ClinTox_2005-43-438.pdf).

    It should be noted that deaths from amatoxins in other parts of the world are astronomically higher than in the U.S.

  • Nov 8th 201114:11
    by Marilyn Shaw

    Reply

    Regarding the links in Melody’s comment: There were numerous newspaper articles, TV and radio broadcasts, etc. in the eastern U.S. over the last several weeks about these poisonings. Nearly all contained the erroneous statement, “There is no authorized treatment for mushroom poisonings.” A more accurate statement would have been, “There are no specific antidotes for most types of mushroom poisoning.” However, all mushroom poisonings can be treated, usually quite successfully, by treating the symptoms.

    • Nov 13th 201123:11
      by Hugh Cavallaro

      Reply

      Hello Marilyn, You seem very knowledgeable about Mushrooms and , treatment for mushroom poisoning! Do you have a website or someway of contacting you? I recently had a close call with mushroom poisoning, and would value input from a person such as you. Thanks, Hugh

      • Nov 17th 201117:11
        by Marilyn Shaw

        Reply

        I would be happy to discuss your case with you, but hesitate to give my contact information online here. You can go to http://www.namyco.org/toxicology and find it there.

  • Nov 22nd 201112:11
    by Frank R. Stermitz

    Reply

    In the Journal of Medicinal Chemistry 2001, in collaboration with Kim Lewis and Nathan Guz, we published a study on synthetic flavonolignans from milk thistle and other plants which showed these compounds to be very active multidrug-resistant inhibtors of bacteral drug efflux mechanisms. Maybe this type of activity has some relationship to the mechanism of antipoisoning effects. This was preceded and followed up by several other publications in this area.

    • Nov 27th 201111:11
      by David Kroll

      Reply

      Thanks, Professor Stermitz. What a delight to see you here at the blog! I’ve long been a fan of your work, especially on the antimicrobial synergy of berberine and 5′-methoxyhydnorcarpin (DOI: 10.1073ypnas.03054059).

      I must look into theses effects of flavonolignans. On one hand, such an efflux antagonizing effect might be counterintuitive but I don’t know much about how α-amanitin is taken up by hepatocytes. Thank you so much for leaving this comment!

  • May 21st 201220:05
    by Susan Kirk

    Reply

    Wooful or woeful?

  • May 21st 201220:05
    by Susan Kirk

    Reply

    Sorry I meant to add more…to Marilyn, perhaps the authors meant that there is nothing ‘legal’ to administer. Also I believe the problem with treating the symptoms are one; the inadequacies of the diagnosis and the window of opportunity for treatments due to the insidious spread of the poison, ie by the time you treat the symptoms affecting liver and kidney, its too late.

  • Aug 21st 201212:08
    by Marilyn Shaw

    Reply

    I have not been following this thread since I first commented Nov. 4. I’m not sure what Susan meant by “‘legal’”. Legalon SIL is a concentration of derivatives of some species of milk thistle and is potentially useful only when injected. It has not yet been approved by the FDA, but has been accepted for a Clinical Trial administered by Dr. Todd Mitchell,MD, Dominican Santa Cruz Hospital, Santa Cruz, CA. Oral milk thistle is not effective in treating amatoxin poisonings, which are acute events.

    Susan states, ” the inadequacies of the diagnosis and the window of opportunity for treatments due to the insidious spread of the poison, ie by the time you treat the symptoms affecting liver and kidney, its too late.” Actually, timely (within 36 hours) and aggressive supportive care reduces the mortality rate in amatoxin poisonings from 50% to 10% or fewer. The mortality rate for the last 100+ years in the U.S. has averaged fewer than 1.5 per year. Most of these are from amatoxins. So supportive care has been effective for a long time. Deaths from amatoxins are not rapid, but usually occur from 5 to 7 days after the ingestion.

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