Should I be concerned about pyrrolizidine alkaloids in herbal supplements?

Answer:

Pyrrolizidine alkaloids (PAs) are compounds that naturally occur in many types of plants, and some PAs can be toxic — particularly to the liver (as described below). PAs have also been found in herbs that don't naturally contain them but are accidentally harvested with plants, such as weeds, that do.

PAs in herbal supplements

Examples of herbs that may contain PAs if not properly processed are comfrey and butterbur (AHPA, GACP-GMP 2021). In the U.S., PAs are not allowed in dietary supplements — those that contain them are considered adulterated. Out of particular concern over PAs in comfrey, the FDA advised dietary supplement manufacturers in 2001 to remove comfrey products from the market (FDA, Safety Alert & Advisory 2001). Europe has set a limit on PAs in food supplements (400 ppm, or 500 ppm for pollen-based supplements).

The FDA has noted that products in the U.S. may still contain herbal ingredients that naturally contain PAs provided the products have been processed and confirmed through validated analytical methods to be PA-free. However, there currently do not appear to be any such validated compendial methods (although one is under consideration by the USP), and, even if there were, this would not have to be furnished to the FDA to market the products. So, consumers should be wary of a claim that a product is PA-free, as found on some butterbur products such as Petadolex by Linpharma, Butterbur by Solaray, or Butterbur by NOW Foods.

Be aware that borage leaves and roots contain PAs. Although the amount present in these plant parts is considered to be low — less than 0.001% dry weight (Roeder, Pharmazie 1995), borage leaf teas may contain very high, possibly unsafe levels of pyrrolizidine alkaloids (EFSA, EFSA J 2016). Based on this, the UK's Food Standards Agency recommends these be avoided (Food Standards Agency, Plant Toxins 2021). Borage flower contains the pyrrolizidine alkaloid thesinine, which is considered to be nontoxic (Schramm, Molecules 2019; Roeder, Pharmazie 1995). Pyrrolizidine alkaloids in borage are not extracted with borage seed oil, and, for this reason, products made from the oil would not be expected to contain PAs.

Why are PAs unsafe?

Following ingestion, some PAs are converted by gut and liver enzymes to metabolites that are toxic. The likelihood and severity of PA toxicity is related to the amount taken, duration of exposure, age and gender, with children showing highest sensitivity, and men showing more sensitivity than females. Other factors that can increase the risk of PA toxicity include concomitant use of other liver-damaging agents (including drugs) and bacterial or viral infections (Wiedenfeld, Phytochem Rev 2011).

Because the toxic metabolites are formed in the liver, this organ is most commonly affected. Sub-acute poisoning (which is most common) most commonly causes veno-occulsive disease — a condition in which blood vessels leading to and within the liver become blocked, which can eventually lead to fibrosis, liver cirrhosis and eventual liver failure. Common signs and symptoms of PA-induced liver damage include abdominal pain, excess abdominal fluid (ascites), anorexia, nausea, vomiting, diarrhea, swelling, and mild jaundice. Unfortunately, damage caused by PAs can be progressive, and liver failure caused by sub-acute poisoning may not occur until months or years after the last PA exposure. Acute poisoning (which is less common) can also lead to liver enlargement, ascites, and eventual death due to liver failure (Wiedenfeld, Phytochem Rev 2011; Australia New Zealand Food Authority 2001).

In addition to causing liver damage, the toxic metabolites of PAs can escape from the liver and cause pulmonary damage, including lung lesions (Wiedenfeld, Phytochem Rev 2011).

Some PAs are also considered to be carcinogenic. Animal studies have reported cancers of the liver, lung, kidney, GI tract, brain, pancreas, and spinal cord, as well as leukemia, in animals exposed to PAs (Australia New Zealand Food Authority 2001).