A recent case of mushroom poisoning has highlighted the difficulties of investigating treatments for a rare illness.

Mushrooming problem: Treating rare poisonings

In late December, a woman and her two grandsons in California ate soup made from deadly Amanita phalloides mushrooms they had picked. These so called 'death cap' mushrooms contain amatoxin—a potentially fatal peptide molecule that inhibits the enzyme RNA polymerase in liver cells.

Todd Mitchell of the Santa Cruz, California–based Dominican Hospital persuaded the US Food and Drug Administration (FDA) to approve an emergency investigational new drug (IND) application, which allowed a drug called silibinin to be successfully administered to the three individuals.

Vials of the drug were obtained despite the fact that the European offices of the company that makes silibinin were closed for Christmas break. “We were fortunate to get the currier onto a booked-up flight by upgrading their ticket,” says Mitchell.

The case closely mirrors a January 2007 poisoning in which a grandmother died after eating a meal prepared with the same variety of Amanita. Although her daughter, son-in-law and three grandchildren had joined her for dinner, they survived the incident after receiving silibinin obtained by Mitchell.

“One of the 2007 patients was among the sickest I have ever seen,” says Kent Olson, the medical director for the San Francisco division of the California Poison Control System. “If the silibinin had come much later it may have been too late. When other patients have gotten that sick, they have either died or ended up needing a liver transplant.”

Marketed as Legalon-Sil by the pharmaceutical company Madaus in Cologne, Germany, the milk thistle extract silibinin has been used to treat only 400 cases in Europe since it was approved in 1984. After it first hit the market in Germany, other European countries followed suit. Yet much of the data in support of silibinin is anecdotal, and some US doctors say more clinical research is needed into the drug's efficacy.

Only about 50 cases of amatoxin poisoning are reported in the US each year, which is too few for a large-scale, randomized trial, and it's unethical to deny patients comprehensive treatment. Moreover, when good general care is offered, amatoxin mortality rates vary between 5% and 15%. “This means we can't say for sure that [silibinin] has any affect,” says Olsen.

Silibinin has yet to be directly compared to general assistive treatments such as penicillin and activated charcoal—a slurry drink thought to help absorb toxin in the body. When administered intravenously, silibinin is thought to prevent toxins from accumulating in liver cells, but Joe Veilleux, who heads a US subsidiary of Madaus, explains there is some uncertainty over the purified extract's mechanism of action.

Despite these unanswered questions, silibinin is widely viewed as safe. “There is no way to know if patients would live anyway, even without it, but there is certainly no harm with using silibinin,” says Marilyn Shaw, who also serves as a mushroom poisoning consultant to the Rocky Mountain Poison and Drug Center.

The narrow market for silibinin in the US probably reduces incentives for Madaus to push for orphan drug status.

Mitchell, meanwhile, hopes the FDA will grant an open IND and allow US doctors to keep stock supplies of silibinin on hand, although the FDA has opted against this in the past. In the absence of such approval, the drug cannot be stored in the US, and doctors must apply for an emergency IND on a case-by-case basis.