Pyrrolizidine Alkaloids: Plant Toxins and Liver Risks

Pyrrolizidine alkaloids are a family of plant-produced toxins that contaminate honey, tea, herbal supplements, and livestock feed widely enough to concern food-safety regulators worldwide. More than 600 individual structures have been identified across hundreds of plant species, and the toxic members of this group can damage the liver, cause cancer in lab animals, and have been linked to lethal poisoning outbreaks in humans. Despite that, most people have never heard of them, and the foods that carry trace amounts sit on ordinary supermarket shelves.

What They Are and Where They Come From

Pyrrolizidine alkaloids, usually abbreviated PAs, are chemicals plants produce to defend themselves against being eaten. They belong to a broader class of nitrogen-containing compounds that plants synthesize as part of their chemical warfare toolkit against herbivores and microbes. PAs show up across several plant families, but two dominate the list: the daisy family (Asteraceae) and the borage family (Boraginaceae).¹ Ragwort, groundsel, comfrey, viper’s bugloss, and heliotrope are some of the better-known PA-producing plants. A few members of the legume family (Fabaceae) produce them too, most famously Crotalaria species used as cover crops in tropical agriculture.

Not every PA is equally dangerous. The ones that cause the most harm share a specific structural feature: a double bond at a particular position on their core ring. These so-called 1,2-unsaturated PAs are the ones your liver can convert into reactive molecules that damage cells. Plants typically store PAs in two forms, the free-base alkaloid and its N-oxide, which is a slightly modified version the plant uses for transport and storage. Both can be toxic because the N-oxide readily converts back to the free base in the gut.

Why the Liver Takes the Hit

PAs themselves are not directly toxic. They become dangerous only after the liver tries to break them down. Enzymes in the liver, specifically members of the cytochrome P450 family (particularly the CYP3A4 form in humans), chemically modify the PA molecule in a way that produces highly reactive intermediates called pyrrolic esters.² These reactive molecules latch onto proteins and DNA in nearby cells before they can travel far, which is why the liver, as the organ doing the metabolizing, suffers the worst damage.

The body does have a defense. A molecule called glutathione can intercept the reactive pyrrolic intermediates and neutralize them into a much less harmful compound that gets excreted in bile.³ This detoxification route works well when PA exposure is low and glutathione reserves are adequate. But when PA intake overwhelms the glutathione supply, the reactive metabolites escape and begin binding to cellular proteins and DNA. That binding triggers a cascade of damage concentrated in the tiny blood vessels lining the liver’s sinusoids.

What PA Poisoning Looks Like

The hallmark condition from acute PA exposure is hepatic sinusoidal obstruction syndrome, or HSOS. Reactive PA metabolites form protein adducts that destroy the delicate endothelial cells lining the liver’s smallest blood vessels.⁴ The damaged lining swells, clots form, and blood flow through the liver backs up. Patients typically develop a painful, enlarged liver, fluid buildup in the abdomen (ascites), and jaundice. Severe cases progress to liver failure. Historically, outbreaks have occurred when grain supplies were contaminated with seeds from PA-producing weeds, particularly in parts of Central Asia and Africa.

Treating PA-induced HSOS remains difficult. There is no antidote for PA poisoning. Clinical management relies on stopping PA exposure, supportive care for liver function, and anticoagulant therapy aimed at improving blood flow through the damaged sinusoids.⁵ Low-molecular-weight heparin has shown promise in early-stage disease by addressing the abnormal clotting that worsens sinusoidal blockage.⁶ For patients who do not respond to medical treatment, placement of a shunt to reroute blood flow around the liver, or liver transplantation, may be the only options.

The Slow-Burn Risks

Acute poisoning from a single large dose is actually rarer than the chronic, low-level exposure that concerns regulators. PAs are genotoxic, meaning they can damage DNA. The reactive pyrrolic metabolites form cross-links between DNA strands and between DNA and proteins, both of which can lead to mutations and chromosome damage.⁷ Animal studies have shown that certain PAs cause liver tumors through a genotoxic mechanism involving a specific set of DNA adducts.⁸

Beyond cancer risk, long-term low-dose exposure has been linked to a range of other chronic conditions: pulmonary arterial hypertension, liver cirrhosis, and even congenital anomalies. A key problem with these chronic effects is that they develop slowly and are unlikely to be traced back to dietary PA exposure by clinicians who are unaware such exposure is occurring.⁹ This disconnect between cause and effect is one reason PAs remain underappreciated as a public health issue.

How PAs Get Into Your Food

The most common routes of human PA exposure run through honey, tea, herbal infusions, and herbal supplements. Honey picks up PAs when bees forage on PA-producing plants, collecting contaminated nectar, pollen, and honeydew.¹⁰ The extent of contamination depends heavily on what is blooming near the hives. In one large survey analyzing nearly 4,000 honey samples, PAs were detected in about two-thirds of raw (bulk) honeys and in 94% of retail honeys sold in supermarkets. Roughly 60% of bee pollen products also tested positive. The PA profiles in many samples pointed to Echium species (viper’s bugloss) as a major floral source.¹¹

Tea and herbal infusions face a different contamination pathway. The tea plant itself does not produce PAs, but weeds growing among the tea bushes do. Research in Chinese tea-producing regions found PAs in over three-quarters of dried tea products tested, with specific PA types traceable through a weed-to-soil-to-tea-leaf route. Individual alkaloids like intermedine and its N-oxide moved from the roots of weeds into surrounding soil and then into tea plant leaves.¹² Herbal teas face an additional risk: fragments of PA-producing weeds like groundsel or viper’s bugloss can end up mixed into the dried plant material during harvesting.¹³

Cooking and Brewing Do Not Destroy Them

A reasonable assumption would be that boiling water or baking temperatures would break PAs down. Unfortunately, the evidence suggests otherwise. When researchers contaminated maize flour with a known PA and cooked it in a boiling water bath for three hours, any slight decrease in PA content appeared to be an artifact of extraction difficulty rather than genuine degradation. Herbal tea samples showed no difference in PA concentration between raw and boiled preparations.¹⁴ Historical poisoning outbreaks from contaminated bread further illustrate the point: PAs survived the baking process well enough to sicken people. Drying pollen with heat did convert N-oxide forms back into their free-base PAs, but the total PA content remained the same, meaning the toxicity was not reduced by drying either.

This thermal stability is a real headache for food manufacturers. Unlike some other plant toxins that can be degraded or washed away during processing, PAs remain stubbornly intact through the production chain. The practical implication for consumers is that you cannot brew away or cook away the PAs in a contaminated product.

The Comfrey Problem

Comfrey (Symphytum officinale) has a long history in traditional medicine for treating joint pain, sprains, and muscle soreness. It is also one of the most PA-rich plants a person might voluntarily encounter. Because of its PA content, the European Medicines Agency restricts comfrey root to external use only and limits the duration of application. Yet testing of comfrey products available on the herbal market has shown that some exceed the daily dose of PAs considered safe.¹⁵

The good news for people who use comfrey creams is that skin absorption of PAs appears to be very low. In laboratory experiments using human skin samples, only a tiny fraction of the PA lycopsamine applied in a comfrey cream preparation actually penetrated through the skin after 24 hours, with five out of six test cells showing no detectable PA within the skin itself. The researchers concluded that current regulatory guidelines, which apply the same daily exposure limit to both oral and topical products, likely overestimate the risk from creams and ointments.¹⁶ The risk from comfrey comes primarily from drinking comfrey tea or swallowing comfrey root preparations, both of which deliver PAs directly to the gut and liver.

What Regulators Have Done

The European Food Safety Authority assessed the cancer risk from PAs and established a reference point for evaluating dietary exposure, concluding that there is a possible health concern, particularly for people who drink large amounts of tea and herbal infusions regularly. The agency flagged that food supplements based on PA-producing plants could push exposure uncomfortably close to the dose range known to cause severe acute toxicity.¹⁷ The European Union has since set maximum residue limits for PAs in certain foods, including a threshold for dried tea of 150 micrograms per kilogram.

Regulatory approaches vary globally. Some agencies have set explicit limits for PA concentrations in specific product categories. Others have taken a softer approach, issuing advisories or restricting the sale of PA-producing herbs. The challenge is that PA contamination is often unpredictable, varying with geography, season, and the weed burden in and around crop fields.¹⁸ Enforcement depends on reliable detection, which until recently required expensive analytical equipment. Modern methods using liquid chromatography coupled with tandem mass spectrometry can now separate and quantify dozens of regulated PAs across different food types, including herbal infusions, spices, and honey.¹⁹

Livestock and Veterinary Risks

Humans are not the only species at risk. Cattle and horses are particularly vulnerable to PA poisoning from ragwort (Senecio species), which is one of the most common PA-producing plants in European pastures.²⁰ Livestock typically avoid ragwort when it is growing fresh because it tastes bitter, but the plant becomes palatable when dried in hay, and the PAs remain fully active. Chronic ragwort poisoning in horses and cattle causes progressive liver damage that may not become apparent for weeks or months after exposure, by which point the damage is often irreversible. In countries like the UK, ragwort control on grazing land is taken seriously enough to be covered by specific legislation.

A secondary concern is PA carry-over into animal products. Dairy cattle grazing near PA-producing plants can transfer small quantities of PAs into their milk, and laying hens fed contaminated grain may pass traces into eggs. These carry-over levels are generally much lower than what you would find in honey or herbal tea, but they add another potential route of low-level human exposure that regulators have started to monitor.

The Ecological Side of PAs

While PAs are a liability for humans and livestock, certain insects have turned them into an asset. For over 50 years, researchers have recognized that butterflies in the Danainae subfamily (which includes milkweed butterflies) and various moth species actively seek out PA-containing plants and consume the alkaloids for purposes beyond nutrition.²¹ This behavior, called pharmacophagy, serves two known functions: chemical defense and mating.

Male danaid butterflies convert ingested PAs into pheromone compounds that are essential for attracting females. The butterfly Parantica sita, for example, transforms specific PAs (mainly intermedine and lycopsamine) into a pheromone called danaidone, which it releases from specialized scent organs on its wings. Males fed these preferred PA types produced danaidone at levels comparable to wild-caught males, while males given other PA types produced dramatically less, and some PA types yielded almost none.²² Beyond pheromone production, PA acquisition appears to be necessary for courtship behavior itself, with PA-fed males showing enhanced motivation to mate.²³

PA-producing plants benefit from this relationship too, at least indirectly. The same alkaloids that attract specialist insects serve as effective deterrents against generalist herbivores. Insects without the specialized biochemistry to handle PAs tend to avoid PA-rich plant tissues, particularly young leaves where concentrations are highest.²⁴ The plant gets protection from most herbivores while inadvertently subsidizing the reproductive success of a few specialist species.

Do Stressed Plants Make More PAs?

Because PAs function as defense chemicals, a natural question is whether environmental stress ramps up their production, and whether climate change might make PA contamination worse. Research on Echium plantagineum (Paterson’s curse), a major PA-producing weed, tested the effects of drought, herbivory, and high temperatures on PA levels. The results were not straightforward. Short-term water stress initially increased the abundance of certain PA-related compounds in the plant, but prolonged drought actually reduced total PA levels, likely because the plant was too stressed to maintain its chemical defenses.²⁵

The relationship between climate and PA risk is probably more about plant distribution than plant chemistry. Warmer winters and shifting growing seasons can expand the range of PA-producing weeds into agricultural areas where they were previously uncommon. A single ragwort or viper’s bugloss plant establishing itself in a tea field or near an apiary can introduce PAs into products that were historically clean. Weed management in and around crops used for human consumption is, at the moment, the most practical lever for reducing PA contamination at the source.