PM4TH5: Elective Report for Advanced Topics in

Pharmacy.

IS COMFREY SAFE FOR HUMAN USE?

Usmaan Hafiz

Student Number: 15009078

Reading School of Pharmacy

University of Reading

Supervised by: Professor Elizabeth Williamson

Symphytum officinale, commonly named comfrey, has a history of medicinal use in
humans. It is widely used topically to promote the healing of inflammatory wounds,
sprains and gout (Rode, 2002), (Predel et al., 2005) (Grube et al., 2007). Medicinal
products containing comfrey root such as Seven Seas Jointcare Comfrelieve cream are
effective for the symptomatic treatment of muscular pain, joint pain and strains
associated with restricted joint mobility.
However, many countries, including the UK have banned the use of comfrey for
internal use believing they have good reason to do so. This is because the leaf and
roots of the plant (which are used therapeutically) contain the constituent
pyrrolizidine alkaloids (PAs). PAs are known to have certain degrees of
hepatotoxicity. With the main liver injury induced by PAs being veno-occlusive
disease (VOD), it is plain to see why the USA and some governments across Western
Europe have taken steps to ban and restrict the internal use of comfrey. However,
there are reports which state that the final word regarding safe consumption of
comfrey is yet to be scientifically established and more evidence is needed to class
comfrey ingestion as a definite danger to health (Rode 2002). Cases to date where
toxicity has occurred due to comfrey can be scrutinised to evaluate the safety of
comfrey, however, they do not give the full picture regarding the safety of comfrey.
Moreover, research regarding comfrey toxicity was published in the early 1990s
whereas more recent research has been designed to inspect the therapeutic value of
comfrey. The evidence indicates that comfrey ingestion should be avoided. New
research focusing on safety in regards to current users of comfrey could shed more
light on the debatable issue of comfrey safety.
Comfrey is an evergreen perennial belonging to the Boraginaceae family, the use of
this herb dates back to over 2000 years (Rode 2002). It is found all over Europe,
Siberia, North America and Asia (Stickel et al., 2000) and has been used extensively
over time for the treatment of many inflammatory conditions. Typical daily doses of
the leaf range from 5 to 30g and a reduced dose of 0.5 to 10g for the root of the plant
(Rode 2002) due to the higher content of PAs therein. Internal intake of comfrey is
thought to be of benefit for treating gastritis and gastro-duodenal ulcers with some
herbal practitioners recommending comfrey capsules for the treatment of rheumatoid
arthritis, bronchitis, various allergies and for diarrhoea (Stickel et al., 2000)
There have been no recent reports in the literature relating to the onset of adverse
effects through ingestion of comfrey, however, there have been two cases of hepatic
veno-occlusive disease in Britain as a result of comfrey ingestion. Furthermore, there
have been a greater number of cases of hepatotoxicity reported in other parts of the
world due to the PA content contained within the comfrey plant.
The first case of comfrey toxicity arose in the UK in the late 1980’s when a boy aged
13, who was previously diagnosed with Crohn’s disease, was taken ill. A
percutaneous liver biopsy of the subject revealed acute hepatic VOD. It was found
that the subject was regularly given herbal tea containing comfrey leaf, which is
thought to have caused VOD due to the PAs present in comfrey (Weston et al., 1897).
However, the frequency of administration and quantity of leaves given were not
known, making it difficult to assess how much had been consumed to cause the onset
of VOD.
Furthermore, in 1989 a woman in the U.S.A suffering from abdominal pain, fatigue
and allergies consumed up to ten cups of comfrey tea a day and had also taken
comfrey pills for over a year. After four years the serum aminotransferase activity had
doubled to twice the normal level whilst biopsies eight years after comfrey ingestion
led to the diagnosis of VOD induced by the PAs in the comfrey.
Hepatotoxicity and VOD due to comfrey intake has also occurred around the world, in
Africa and Jamaica, plants containing PAs were ingested regularly as concoctions to
treat various illnesses yet caused more harm than good to the subjects who consumed
them (Davies 1997).
Studies have shown that the dangers surrounding comfrey ingestion originate from the
PAs which are mainly found within the roots and leaves of the plant. Figure 1 shows
the parent structure of the common PA and those that are commonly present in
comfrey.
The quantified amount of PAs in dry comfrey is reportedly in between 0.003% and
0.115% (Nebert et al.,
1991).

Like most foreign

compounds, pyrrolizidine
alkaloids undergo
metabolic transformation in
the liver by drug-
metabolising microsomal
enzymes such as the
cytochrome P450 enzymes
through the hepatic mixed-function oxidase system which requires oxygen and
NADPH for the process to take place (Schuppan et al., 2005), (Jago et al., 1970).
The biotransformation, metabolic processes play a vital role in detoxifying harmful
substances in the body yet it is within this process that a lethal intermediate is formed
from PAs which can allow a series of events to occur at the molecular level capable of
causing acute or chronic hepatotoxicity.
The cytochrome P450 enzymes can metabolise PAs to either dehydroretronecine or in
to alkaloid-N-oxides-see Figure 2. Dehydroretronecine is the highly toxic
intermediate pyrrole metabolite which can act as an alkylating agent, thus causing
damage to the endothelium of the liver. The alkaloid-N-oxide species is the non-toxic
metabolite and would undoubtedly be the desired outcome of the biotransformation
however the enzymatic formation of highly toxic necines from alkaloid N-oxides is
also a possibility (Couet et al., 1996).
 Pyrrolizidine alkaloids

Induction Cytochrome P450 3A

(Phenobarbital)

Alkaloid N-oxides Reactive pyrroles

(Non-toxic metabolites) (Toxic metabolites)

Figure. 2
The enzymatic biotransformation of PAs into non-toxic alkaloid N-oxides or into reactive pyrroles.
Concomitant medication with microsomal enzyme inducers (e.g. phenobarbital) favours the formation
of toxic pyrroles by several microsomal cytochrome P450 enzymes including CYP 3A4, 2B6, and 2C.

There is also supporting evidence indicating cytochrome P450-mediated activation of

PAs into their relative toxins originates from the fact that potent microsomal enzyme
inducers such as phenobarbital can enhance the toxicity of pyrrolizidines. (McLean
1974). The evidence thus far suggests that PAs can form toxic metabolites that may
be highly reactive electrophilic molecules capable of reacting with cellular structures
to form adducts which can cause acute or chronic toxicity (Stickel et al., 2000).
Furthermore, Prakash et al., (1999) states that there is also a real possibility that some
adducts can persist in liver tissue to re-induce damage some time after the period of
initial ingestion.
There have been several cases where VOD has resulted from comfrey ingestion, with
the most profound case relating to a 23 year old man who was diagnosed with hepatic
VOD, severe portal hypertension, and thus the subject died from liver failure (Yeong
et al., 1990). What is of more significance is the fact that the subject had been on a
predominantly vegetarian diet and prior to his illness, had taken comfrey leaves. A
possible causal association of comfrey and the subject’s VOD was suggested by the
temporal relationship of the ingestion of comfrey to his presentation, the histological
changes in the liver and the exclusion of other known causes of the disease.
The cases thus far have shown that VOD can be a resultant liver injury caused by
comfrey intake. VOD is defined as a non-thrombotic obliteration of the lumen of the
terminal centrilobular hepatic veins. The resulting venous outflow obstruction causes
hepatic congestion and centrilobular necrosis, with either of two possible outcomes,
acute liver failure or liver fibrosis and cirrhosis, which can lead to death (DeLeve et
al., 2002). The main features of VOD are portal hypertension, hepatomegaly and
abdominal pain and patients can present with either acute or chronic clinical signs for
any of the above (Stickel et al., 2000). It is further understood that toxicity induced
by comfrey is not restricted to the liver, mutagenicity, carcinogenicity and pulmonary
hypertension can also be unfavourable outcomes of comfrey ingestion. (Weston et al.,
1987) (Prakash et al., 1999), (Bach et al., 1989)

The pyrrolizidine alkaloid molecule is thought to have toxic potential due to the
double bond of the 1:2 unsaturated necine base, esterification of the hydroxyl group in
positions 9 and 7 and a branched carbon chain in at least one of the ester side chains
as portrayed below in Figure 3.

Studies also confirm the following

hepatotoxic structure-toxicity
relationships of PAs from the most
toxic to least toxic: macrocyclic
diesters > retronecine and
heliotridine diesters > heliotridine
monoesters > retronecine monoesters.
Comfrey contains retronecine mono- and diesters (Culvenor et al., 1976), from the
PAs above these can be classed as toxic, but some have a greater toxic potential than
others.

Hypothesis
Owing to the toxic potential of the PAs found in comfrey, the cases where ingestion
has resulted in VOD and the availability and use of it throughout the world, the issue
of safety of comfrey for human use has to be addressed. It is intended that exploring
this area should shed light on the safety of comfrey.
The evidence available thus far pertaining to comfrey toxicity is not conclusive. At
first glance previous cases and studies do point towards a relationship between
comfrey ingestion and haptotoxicity, however, a deeper insight into the evidence
reveals key unanswered questions and raises other relevant issues.
Firstly, assessing hepatic function in the clinical setting normally involves monitoring
serum concentration of certain proteins. For example, elevations in aspartate
aminotransferase (AST) may be reflective of liver pathology, γ-glutamyltransferase
(GGT) and bilirubin levels can elevate with choleostasis, and α-fetoprotein (AFP) is a
specific marker for liver cancer (Rode 2002).
However, these markers are not necessarily elevated in every case of VOD. A study
by Anderson et al., (1989) determined serum concentrations of AST, GGT and
bilirubin in 29 long-term comfrey users and AFP in a subgroup of seven comfrey
users. It can be noted that the cohort is rather small and thus makes it difficult to
ascertain risk, nonetheless, it is intriguing that AST, GGT, bilirubin and AFP levels
were determined to be in the normal range, especially after prolonged consumption of
comfrey leaf (0.5–25 g day-1 for 1–30 years). This can suggest that not all those who
ingest comfrey (the study looked at long-term users) are subject to liver toxicity
however, a larger cohort and prospective focus would have given this line of
argument a more substantial basis.

Furthermore, systematic toxicity testing or alternatively, clinical trials are yet to be

performed for comfrey ingestion. The restrictions on internal use of comfrey are
based upon evidence from a few cases and from studies which involved highly
purified PA administration to rodents (Rode 2002). Furthermore, it can be argued that
the toxicity which presents itself in humans occurs not due to comfrey ingestion, but
due to the consumption of a variety of other plants which contain PAs (Rode 2002).
However, this point is debatable for the cases where the subject suffered from VOD
through the sole ingestion of comfrey (Weston et al., 1987).

Moreover, apart from acute and chronic organ damage, a study performed by Petry et
al., (1984), on rats show that the PA symphytine, a major constituent of comfrey, was
associated with hepatocellular carcinoma in rats. The induction of tumorigenesis,
particularly in the liver is believed to be caused by the alkylating effects of the highly
reactive pyrrole metabolites which lead to the cancerous transformation of
hepatocytes (Behninger et al,. 1989). In addition, metabolites of several PAs are
mutagenic in the Salmonella typhimurium/mammalian microsome system and the
alkaloid extracts of comfrey have the potential to induce sister chromatid exchanges
and chromosome aberrations. These effects were enhanced when microsomes were
induced prior to pyrrolizidine dosing (Prakash et al., 1989), (Olinescu et al., 1983)
Moreover, other studies describe how PAs enhance the proliferation of neoplastic
cells while an anti-mitotic effect was observed in human T lymphocytes (Culvenor et
al., 1983)
However, a direct association between pyrrolizidine alkaloids and cancer in humans is
yet to be discovered. Furthermore, considering the possible human exposure to PAs
due to their global occurrence, it is unlikely that humans face a significant threat from
PAs with regard to carcinogenesis. The long term observation of those who have been
chronically exposed to PAs will also attest to this (Zimmermann et al., 1995).

Furthermore, hepatic lesions in rats also occurred when they were fed high levels of
comfrey or injected with purified comfrey PAs, indicating the potential for PA
poisoning. (Stickel et al., 2000)
However, there are conflicting reports when studies in other animals are evaluated.
Pigs, despite their general sensitivity to PAs, show no adverse effects when fed
comfrey, this is true even when comfrey consists of 40% of their diet (Rode 2002).
Similarly, chickens are another species that are sensitive to PAs, yet show no adverse
effects when fed with comfrey.
The contrasting reactions and responses to comfrey ingestion between different
animal species create difficulty to predict the safety of comfrey for internal use in
humans. One proposition states that hepatic response to PAs in rats seems to differ
from the human response, thus rendering rats an inappropriate model for humans
(Prakash et al., 1999).

The fact that comfrey species vary in their content of PAs further complicates matters
regarding comfrey toxicity in humans (Rode 2002). The seven PAs found in comfrey
are intermedine, lycopsamine, symviridine, acetyl lycopsamine, symlandine,
symphytine and echimidine (Figure 1). However, most of the PAs (85-97%) from
comfrey that grows in US gardens (Symphytum officinale L.) are retronecine
monoesters and the others can simply be hydrolysed to monoesters (Muetterlein et al.,
1993). Retronecine diesters are the remaining constituents. On the other hand, the PAs
present in Russian comfrey (Symphytum x uplanidicum Nym.) have a slightly more
toxic potential in the form of retronecine diesters (Muetterlein et al 1993).
It is thus important to highlight that the structure-toxicity relationships firmly place
the PAs in comfrey (retronecine mono and diestetrs) in a class of lower toxicity
compared to PAs implicated in significant human poisonings. The heliotridine
diesters and macrocyclic diesters of retronecine found in Senico and Heliotropium
have been responsible for severely detrimental poisonings in humans when used
inappropriately or in inadvertent food contamination (Cheeke et al., 1998).
Moreover, to complicate matters even further, the content of PAs in comfrey can vary
throughout the year and according to the age of the plant. Furthermore there are also
substantial differences in alkaloid content between the roots and aerial parts with
fewer contents in the latter part (Stickel et al., 2000).
Due to contrasting toxicity of the different types of PAs and the variation in
distribution of PAs amongst the comfreys species it can be established that research
relating to toxicity and safety which focuses on one comfrey species may not
accurately portray the results that would be obtained if the tests were subject to an
alternative species of comfrey. This alludes to the fact that one comfrey species may
be safer to consume than an alternative of the same species, yet it seems both are
capable of causing harmful affects if consumed in excessive amounts.
In addition, the wide variability of PA content in various comfrey preparations makes
it difficult to determine the toxic potential, moreover, most physicians, health
practitioners and patients are unaware of the total amount ingested and this is
especially true when comfrey has been consumed on a regular basis over an extended
period of time (Stickel et al., 2000).

Numerous toxic studies have shown the response to the administration of only
purified PAs. However, the dry comfrey leaf also contains other constituents, protein
makes up approximately 35% of the dry comfrey leaf. Sulphur-containing amino
acids are also present in the leaf. This is of great significance as both these respective
constituents attenuate the production of PA toxic metabolites (Cheeke et al., 1998).
This also suggests that a diet low in protein can enhance the toxic effects of PAs
(Schoental et al., 1968). Yeong et al., (1990) reinforces this belief in regards to the
study of the subject who was predominantly on a vegetarian diet (lack of protein) and
died as a result of comfrey ingestion. Furthermore, the protective properties that
sulphur-containing amino acids offer should be exploited by carrying out more
toxicological and safety studies using the whole leaf of the comfrey plant. There is a
real possibility that the studies using purified PAs can overstate the health risks
associated with administration of crude extracts of comfrey or ingestion of the whole
plant (Rode 2002).

The toxic effects PAs exert are not solely restricted to the liver as Shubat et al (1987)
demonstrated. Indeed, PAs have also been shown to damage the lungs through
endothelial defects which are caused by blood cell extravasation and venous vascular
occlusion which in turn leads to the development of pulmonary hypertension.
However, lung toxicity (pulmonary lesions) caused by PAs has only been identified in
experimental rodents which were exposed to monocrotaline, a PA related to comfrey
(Guzowski et al 1987).
Interestingly, there has also been a human case (Miskelly et al., 1992) of a 77 year old
woman in the UK where upon a chest x-ray the lungs showed reticulonodular
shadowing in the right mid-zone and the right base. Elevated liver enzymes and
bilirubin with slight jaundice were also present. This was all associated with the use
of one-third teaspoon of comfrey root per day. This can be related to the pulmonary
lesions in rodents caused by monocrotaline however, monocrotaline is a constituent of
Crotalaria Spectabilis and is not found in Symphytum Spp. Moreover, pulmonary
lesions have never been observed with administration of comfrey PAs, the subject
however, did consume comfrey yet the pattern of symptom was not typical of PA
poisoning. This suggests that the adverse symptoms may have been associated with
the three other herbal remedies of undisclosed composition and that the subject’s
condition was not induced by comfrey ingestion.
Other potential organ toxicities include lesions to the glomeruli of the kidneys, the
pancreas and the gastrointestinal tract, however, these pathologies have only occurred
in experimental animals (Couet et al 1996)

Having stated the possible toxicity caused by comfrey ingestion, it would only be fair
to reflect upon some of its therapeutic uses as an external medication.
A prospective, open, multicenter, observational study by (Koll et al., 2002) analysed
the anti-inflammatory and analgesic properties of several topical comfrey preparations
which were applied 1 to 3 times a day over a two week period. The topical medication
was applied to bruises, sprains and painful conditions of the muscles and joints. Out
of the 492 subjects to take part 45-47% experienced improved movement and subdued
pain at rest and movement, moreover, the duration of morning joint stiffness
decreased from 20 minutes initially to 3 minutes. More significantly, as the course of
the treatment with comfrey progressed, more than two-thirds of the subjects were able
to reduce or even discontinue their intake of non-steroidal anti-inflammatory drugs
and other specific concomitant medication. The overall results of the tolerability and
effectiveness of the topical comfrey preparations were assessed to be excellent or
good in the treatment of bruises, sprains as well as painful conditions affecting joints
and muscles.
In addition, an open and uncontrolled study by Peterson et al., (1993) showed the
efficacy of comfrey for external treatment. 33 of 105 patients yielded some positive
results after comfrey ointment was applied twice daily to the subjects who had
locomotor system symptoms. Chronic and sub-acute symptoms associated with
muscle pain were alleviated, improvements were seen in muscle swelling, overstrain,
enthesopathy and vertebral syndrome. However, the ointment was less effective in
having an impact on muscle pain associated with degenerative diseases (Kucera et al.,
2000).
The reason behind the curative effects of topical comfrey preparations has been
thought to be a cause of the allantoin which is present therein. The underground roots
contain 0.6%-0.7% of this constituent and it is responsible for the stimulation of
connective tissue proliferation and regeneration and therefore can aid in healing
external wounds (Stickel et al., 2000). In addition, rosemarinic acid which is also
present in comfrey is thought to be responsible for the anti-inflammatory effects as
well as the astringent and analgesic effects (Ahmad et al., 1993)
Over the counter (OTC) medication such as Seven Seas Jointcare Comfrelieve cream
contains 35g of comfrey root extract and can be used for the symptomatic treatment of
joint pains, sprains, inflammation and strain associated with restricted joint mobility.

Final thoughts and conclusion

Without doubt, comfrey is classified as an herbal medicine with a marked history of
efficacious use in human beings. The anti-inflammatory and wound healing properties
it possesses are well documented and therefore in the UK, it can be brought as an
OTC treatment for various external diseases and injuries. The external use of comfrey
is regarded as safe as long as it is not applied to broken skin or open wounds.
Although not clinically tested for internal use, comfrey is thought to have potential in
treating internal illnesses such as gastritis and gastro duodenal ulcers. However, there
is a darker side to this seemingly beneficial plant. There is a real possibility that
internal use of comfrey can increase the risk of liver toxicity due to the PAs, which
are an intrinsic component of comfrey. Hepatotoxicity following intake of PAs
(including those in comfrey) is established and there are cases to prove this. On the
other hand, the dose-effect relationship remains largely unclear and variability in
individual susceptibility to comfrey toxicity is also high. Furthermore a lot of the
cases of comfrey induced hepatotoxicity demonstrate that the risk of hepatic damage
during comfrey treatment is influenced by its source, the health and nutritional status
of the patient, the amount consumed and duration of treatment. It is also important to
note that side effects of herbal preparations have not always reached public awareness
and that herbal interaction with other prescribed medication cannot be ruled out.
Moreover, the lack of awareness may also be a potential factor in causing disease and
this may be true for those who take comfrey for self-medication. There is also a naïve
belief amongst the common person that ‘all things natural must be safe’, this
perception however, is evidently incorrect.
The information currently available indicates the dangers of internal ingestion of
comfrey do exist, however a closer examination of the evidence and previous cases
raises several questions and therefore is insufficient to allow a definitive assessment
of risks of comfrey. Moreover, clinical studies are also lacking in the potential
therapeutic benefits for internal intake of comfrey, more credible, evidence based
studies could, to some extent, ensure appropriate use by herbalists.
Most of the research which has focused on comfrey toxicity up to this date is often
inadequate, flawed due to experimental animal models which are not applicable to
humans and also faulty in experimental design. The concept of using different animal
species is contentious because animal species vary considerably in their susceptibility
to PA toxicity and therefore it would be of more benefit to carry out toxicity testing
on a several animal species. Attaining differential dose responses would also be a step
forward in learning about safety in greater detail.
Lastly, perhaps the best way to assess the risks and dangers associated with comfrey
intake would be to conduct a placebo-controlled prospective clinical study of those
individuals currently consuming comfrey. A study like this could well establish safety
as well as efficacy of this intriguing yet debatable herbal plant.
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