‘No safe intake’ level for berberine: EFSA opens consultation

The opinion, brought about by The French Agency for Food, Environmental and Occupational Health & Safety (ANSES) under Article 8(2) of Regulation (EC) No 1925/2006, concludes no safe intake levels can currently be established for multiple plant species including Berberis, Chelidoniummajus, Hydrastiscanadensis, phellodendronamurense, and others.

Key concerns identified include: Genotoxicity signals for berberine in vitro indicating gene mutation and chromosomal damage, requiring confirmation in vivo, carcinogenic activity in rodent studies, idiosyncratic herb-induced liver injury, and significant data gaps.

Due to these concerns and insufficient toxicity data, EFSA (European Food Safety Authority) could not establish a safe intake level for any of the evaluated berberine-containing preparations.

Stakeholders can submit written responses to the opinion online and attend a virtual consultation meeting on April. 22 with registration open until April 13.

Jérôme Le Bloch, PhD, head of scientific affairs at FoodChain ID, argued many of the safety concerns raised could relate to compounds other than berberine present within the products studied.

“As usual, EFSA has a significant bias in its evaluation: by considering data on botanical preparations, experts highlight safety concerns which cannot be extrapolated to berberine alone. Many other compounds are present in these botanicals, which may be associated with side effects.”

Chris Kilham, the Medicine Hunter, agreed the safety concerns were likely to stem from other compounds within the plants.

“This science is a bit of a hash,” he told NI. “For starters in vitro tests are not tests on living systems and certainly are not tests in human beings.

“Animal studies on H canadensis and adenomas are with animals fed H canadensis supplements daily for more than 100 weeks. Since berberine and berberine-containing supplements are remedial and not foods, it is inadvisable to take them for greatly extended periods.

“To be clear H canadensis is not berberine. It is a complex herb with hundreds of compounds. Because H canadensis contains a plethora of compounds including other alkaloids besides berberine it would be garbage science to say that any positive or negative action from taking H canadensis is due to berberine.“

He explained that some users may experience gastrointestinal discomfort but using it on a short term basis shouldn’t lead to any of the more serious side effects suggested in the report.

“Think of this like ibuprofen. A few ibuprofen to alleviate a headache is not known to cause any problems. But eating ibuprofen every day for extended periods can lead to kidney damage. Berberine is a remedy and should be used as such, to alleviate a health problem and then stop.”

He added: “In general I have found EU authorities to be overblown in many of their concerns about dietary supplements. They are especially freaked by alkaloids, though that does not deter them from consuming coffee, chocolate, tomatoes and other alkaloid-containing foods,” he added.

What next?

If berberine is added to part A of annex III of regulation 1925/2006, it will be prohibited. If it is added to part C of the annex — ‘substances under community scrutiny’ — stakeholders firms will have the opportunity to conduct and submit studies within four years, to provide justification to EFSA to keep it on the market.

Luca Bucchini, managing director of Hylobates Consulting, noted the authority’s view that “no safe intake can currently be established” would usually lead to prohibition.

He said if it is put under community scrutiny, companies will have the opportunity to submit data which fills the data gaps that EFSA has identified—90-day toxicity studies, and in vivo genotoxicity studies—but he doubts there will be much appetite to invest in this work.

“Stakeholders will not be very encouraged by precedents: EFSA has never accepted submitted evidence in a way that would change its negative conclusions, and stakeholders may have little confidence in the process or the value of more research.”

Bucchini added: “I think we are witnessing a process by which selective substances are being removed from the market, for which neither the botanicals industry or the nutraceutical industry at large has a response for…”

Article 8 under abuse?

Bucchini predicted in 2023 that the industry would need to work hard to save berberine from the chopping block.

“With some Member States being more strict than others, Article 8 is veering towards a means for harmonization.

“It was said that it would not be used to harmonize rules on - say - botanicals or substances in foods but it may end up doing exactly that.

“Countries such as Denmark and Germany are very concerned about some substances which other Member States allow, Overall, I think that article 8 - if properly applied by sound scientific assessments by EFSA and by good rule-making by the Commission - is a good tool. However, the concern is around the two aforementioned ‘if’s’.”

Commenting on the update on LinkedIn, Dr Mark Tallon, PhD, managing partner of the food law consultancy Legal Foods, raised his own concerns over the integrity of the Article 8 process.

“The whole assessment process is a major concern as we could pick almost any botanical, apply EFSA guidance, and (...) say ‘safe levels could not be established’ - lack of data, animal based toxicity.

“It’s a major concern and open to abuse for those that have some reason to remove certain products.”

Thomas Brendler, scientist and founder of Plantaphile, said that regulators, by definition, are understandably risk-adverse and precaution will prevail whenever there are knowledge gaps.

“In the case of berberine, the margin between benefit and harm is narrow. Maybe berberine products don’t belong into the supplement category, where they can be consumed without oversight by a healthcare practitioner and at potentially dangerous doses.”