Camphor: Benefits and risks of a widely used natural product

Abstract

The main aspects of the non-clinical profile of D-camphor, a natural product widely used as a common remedy for several symptoms, are reviewed. The pharmacodynamics and toxicity of this substance are analyzed, with regard to all the literature available, in order to assess a risk profile and better understand the positive and negative results connected with its use. The general conclusion is that the main risks of camphor as a medicinal product are mainly due to a somehow diffused attitude of considering it as "not a real medicine", and to its consequent sometimes not sufficiently careful administration.

Full text

Volume 53(2):77-82, 2009
Acta Biologica Szegediensis
http://www.sci.u-szeged.hu/ABS
REVIEW
1Department of Crop Biology, Sect. Plant Physiology, University of Pisa, Pisa, Italy, 2Department of Veterinary Clinics,
University of Pisa, Pisa, Italy
Camphor: benefits and risks of a widely used natural
product
Paolo Zuccarini1*, Giulio Soldani2
ABSTRACT
The main aspects of the non-clinical profile of D-camphor, a natural product
widely used as a common remedy for several symptoms, are reviewed. The pharmacodynamics
and toxicity of this substance are analyzed, with regard to all the literature available, in order
to assess a risk profile and better understand the positive and negative results connected with
its use. The general conclusion is that the main risks of camphor as a medicinal product are
mainly due to a somehow diffused attitude of considering it as “not a real medicine”, and to
its consequent sometimes not sufficiently careful administration.
Acta Biol Szeged 53(2):77-82 (2009)
KEY WORDS
D-camphor
pharmacodynamic
pharmacokinetics
risk/benefit assessment
toxicity
Accepted Oct 20, 2009
*Corresponding author. E-mail: p.zuccarini@virgilio.it
77
Camphor (Figure 1) is a natural product deriving from the
wood of the camphor laurel (Cinnamomum camphora L.)
trees through steam distillation and puriÞcation by sublimi-
nation; the trees used should be at least 50 years old. It also
occurs in some other related trees in the laurel family, notably
Ocotea usambarensis Eng., and can also be obtained from
the plant Lippia dulcis Trev., but this is not a major industrial
source (Compadre et al. 1986). A major source of camphor in
Asia is Ocimum kilimandscharicum Baker ex Gurke.
Camphor can also be produced synthetically from vinyl
chloride and cyclopentadiene, passing through the intermedi-
ate dehydronorbornyl chloride. The naturally occurring form
is dextrorotatory and the synthetic form optically inactive
(Budavari 1989; Reynolds 1989).
Camphor has a counterirritant, rubefacient and mild
analgesic action, and is a major component of liniments for
relief of Þbrositis, neuralgia and similar conditions. It can be
used as a mild expectorant; if ingested, camphor has irritant
and carminative properties. Camphorated-oil, a solution in
oil given through intramuscular or subcutaneous way, can be
used as a circulatory and respiratory stimulant, but this use is
considered hazardous. When, in combination with menthol
and chenodeoxycholic acid, it has been used to aid dispersal
of bile duct stones, although this is no longer recommended
(Reynolds 1989).
Aim of the present work is to provide an overview over
pharmacological and toxicological aspects of camphor, in
order to assess its safety proÞle and evaluate the level of risk
connected with its use.
Pharmacology
Pharmacodynamics
Camphor, a natural product derived from the wood of the tree
Cinnamomum camphora, has a long history of use as anti-
septic, analgesic, antipruritic, counterirritant and rubefacient
(Hercogov 2005; Lynde et al. 2008). Its success and wide
medical use, especially in topical preparations, is connected
to its mild local anesthesizing effect and to the production
of a circumscribed sensation of heat, together with its char-
acteristic and penetrating odour that is by most of people
associated to the idea of a strong and effective medicine
(Gibson et al. 1989).
Camphor is today mostly used in the form of inhalants and
of camphorated oil, a preparation of 19% or 20% camphor
in a carrier oil, for the home treatment of colds (Jochen and
Theis 1995) and as a major active ingredient of liniments and
balms used as topical analgesics (Xu et al. 2005).
The antitussive, nasal decongestant and expectorant action
of camphor and of its derivatives was one of the Þrst ones to
be systematically investigated (Inoue and Takeuchi 1969).
Its nasal decongesting activity seems to be not purely me-
chanic, but connected with the stimulation of cold receptors
in the nose. The inhalation of camphor vapours (so as the one
of eucalyptus and menthol vapours) on a sample of volunteers
increased the nasal sensation of airßow through the induction
of cold sensation in the nose, despite of actually not affecting
nasal resistance to airßow (Burrow et al. 1983).
More recent studies pointed out how camphor efÞcacy
in the treatment of cold is due to its antispasmodic action
(Astudillo et al. 2004), and how the effects of camphor on
bronchospasm are connected to its anti-histaminergic and
anti-cholinergic activities (Grnemann et al. 2008). In fact,

78
Zuccarini, Soldani
camphor appears to be effective to reduce histamine H1 and
muscarinic M3 receptor-mediated bronchocostriction (Grne-
mann et al. 2008), and this action relates also to the inhibition
of cough (Kreutner et al. 2000).
Camphor was administered in the form of aromatic vapor,
at the concentrations of 50, 133 and 500 µg l-1, to guinea pigs
subject to chemically induced cough. No effect were regis-
tered at the lowest concentrations, but 500 µg l-1 camphor gave
a 33% reduction of cough frequency, to which an increase in
cough latency coincided (Laude et al. 1994).
The analgesic proprieties of camphor are largely known
and applied, but little is known about the molecular mecha-
nisms that are at their basis. (Xu et al. 2005).
Moqrich et al. (2005) demonstrated that camphor activates
TRPV3, a member of transient receptor channel superfamily,
leading to excitation and desensitization of sensory nerves.
The notorious effect of generation of a sensation of heath
associated with topic application of camphor (Green 1990)
is a consequence of this activation. In fact, TRPV3 is a warm-
sensitive Ca2+-permeable cation channel, that once activated
originates the warm sensation, actually simulating an effective
increase of temperature in the treated area (Xu et al. 2006).
This effect, caused by an increase in intracellular Ca2+ lev-
els, is typical also of other natural compounds as carvacrol,
eugenol and thymol (Xu et al. 2006).
Anyway excessive and repeated application of camphor
can lead to sensibilization of TRPV3, in apparent contrast
with its analgesic role (Peier et al. 2002; Moqrich et al.
2005).
The antipruritic and counterirritant activity of camphor
is instead associated with its capacity of activating TRPV1
- another member of TRP channel superfamily - at the level
of dorsal root gangliar [DRG] neurons and inhibiting TRPA1
channels (Moqrich et al. 2005; Nagata et al. 2005), action
that is in common with other TRPV1 agonists (Bhave et al.
2002; Xu et al. 2006; Belmonte and Viana 2008). The recently
clariÞed activity of camphor as a TRPA1 inhibitor has been
utilized by Lee et al. (2008) for pretreatment of human em-
bryonic kidney cells tested for membrane potential changes
elicited by thymol, showing how the response to thymol is
blocked by camphor. Bang et al. (2007) showed camphor
to suppress acute pain in mouse consequent to intradermal
administration of acetaldehyde into mouse footpads.
Capsaicin shares the same action with camphor, but per-
forms it more slowly and less completely; on the other side
camphor efÞcacy is lower, since higher concentrations are
required (Xu et al. 2005). Studies on rats demonstrated that
the actions of capsaicin and camphor are segregated (Wu et
al. 2005), i.e. they are mediated by distinct channel regions,
and camphor did not activate TRPV1 in capsaicin-insensitive
chickens (Xu et al. 2005; Jordt and Julius 2002).
Camphor also inhibits other related TRP channels such as
ankyrin-repeat TRP1 (TRPA1), which is a further evidence
underlying its analgesic effects (Xu et al. 2005).
Camphor was shown to inhibit mitochondrial respiration.
Administration of up to 8 µM of camphor inhibited respira-
tion rate in rat-liver mitochondria, nearly halving the oxygen
consumption; this suggests that camphor may be used in oxy-
genating tumors prior to radiotherapy (Guilland-Cumming
and Smith 1979; 1982).
Camphor can also be a potential radiosensitizing agent
in radiotherapy. Treatment with camphor (0.5 µmol á body
wt-1) 45 minutes before local x-irradiation at the dose levels
of 30, 80, 100 or 120 Gy was performed on male C3H/Jax
mice bearing transplanted mammary tumours. Sequential
measurement of the tumour volumes during 45 days after the
irradiation revealed a 4.8 delay of the maximum enhancement
ratios in tumour growth (Goel and Roa 1988).
D-camphor (1100 µg ml-1) inhibited oxidative metabolism
in E.coli (Cardullo and Gilroy 1975). Succinic, lactic and
NADH-oxidase activities were inhibited, while NADH and
succinic DCPIP oxidoreductase enzymes were unaffected.
The restoration of succinic oxidase activity by ubiquinone
(Q6) but not by vitamin K1 indicates that D-camphor may
operate this inhibition by affecting quinone functions.
Pharmacokinetics
Camphor is readily absorbed from all the sites of administra-
tion, after inhalation, ingestion or dermal exposure (Baselt
and Cravey 1990). Peak plasma levels were reached by 3
hours post-ingestion when 200 mg camphor was taken alone,
and 1 hour post-ingestion when it was ingested with a solvent
(Tween 80; Koppel et al. 1988).
In case of dermal application, the volume of the absorp-
tion is relatively low in comparison with the speed of the
process. After application of different numbers of commercial
patches [2, 4 or 8] to the skin of human subjects during 8
hours, the levels of camphor in the plasma were assayed with
selective gas-cromatography (Valdez et al. 1999; Martin et
Figure 1. Structural formula of Camphor, a bicyclic monoterpene ketone
(1,7,7-trimethylbicyclo [2.2.1] heptan).

79
Camphor: its beneÞts and risks
al. 2004). Maximum camphor plasma concentration resulted
in a range between 35.2 and 46.8 ng/ml-1 in the case of 8
patches, between 19.6 and 34 ng/ml-1 for the 4 patches while
almost undetectable concentrations were observed when only
2 patches had been applied, showing that dermal absorption
is prompt but not massive.
Camphor is distributed throughout the whole body, and
can permeate the placenta; for this reason it must be recom-
mended that the use of this product is avoided during preg-
nancy and lactation (Sweetman 2005).
Its volume of distribution is 2-4 L/kg (Koppel et al. 1988);
plasma protein binding has been estimated as 61% (Koppel
et al. 1982).
After its absorption and distribution, camphor undergoes
hepatic metabolism: it is hydroxylated in the liver into hy-
droxycamphor metabolites (Sweetman 2005).
Asahina and Ishidate (1933; 1934; 1935) isolated cis-
and trans-¹-hydroxycamphor and camphor-¹-carboxylic
acid from the urine of dogs that had been fed with camphor;
Shimamoto (1934) obtained 3-hydroxycamphor (15%),
5-hydroxycamphor (55%) and trans-¹-hydroxycamphor
(20%) from the urine of dogs, and 5-hydroxycamphor [as
major metabolite] and 3-hydroxycamphor from the urine of
rabbits.
Robertson and Hussain (1969) observed that (+)-cam-
phor and (-)-camphor increase the content of glucuronide
in the urine of rabbits; (+)-camphor was moreover reduced
to (+)-borneol as well as being hydroxylated to (+)-5-endo-
hydroxycamphor [major product] and (+)-3-endo-hydroxyc-
amphor.
Hydroxylation of camphor, as well as norcamphor, peri-
cyclocamphanone and 5,5-dißuorocamphor, is mainly per-
formed by cytochrome P450 (Collins and Loew 1988), a class
of heme-containing monooxygenases that are distributed in
the whole body (Boxenbaum 1984), by hydrogen abstraction
(Wand and Thompson 1986). Cytochrome P450 is responsible
for camphor conversion into 5-hydroxycamphor (Gelb et al.
1982), while 3-hydroxycamphor is the primary product of
non-enzymatic hydroxylation of camphor (Land and Swallow
1979). Camphor hydroxylation by cytochrome P450 occurs
with a different region-speciÞcity for camphor and its related
compounds (Collins and Loew 1988).
Hydroxylated metabolites are then conjugated with
glucuronic acid and excreted in the urine (Sweetman 2005).
The half-life of 200 mg of camphor was 167 minutes when
ingested alone, and 93 minutes when ingested with a solvent
(Tween 80) (Koppel et al. 1988).
Camphor can modulate the activities of hepatic enzymes
involved in phase I and phase II drug metabolism. 50, 150
and 300 mg/Kg-1 of camphor dissolved in 0.1 ml of olive oil
was administered daily to female Swiss Albino mice during
20 days. At its highest concentration it caused a signiÞcant
increase in the activities of cytochrome P450, cytochrome b5,
aryl-hydrocarbon hydroxylase and glutathione S-transferase,
signiÞcantly elevating the level of reduced glutathione in the
liver (Banerjee et al. 1995).
Interactions
Very few studies of pharmacological interactions between
camphor and other compounds are present in literature. In a
study combining the administration of D-camphor and an ex-
tract from fresh crataegus berries, a synergic action of the two
preparations emerged in ameliorating cardiac performances.
Both D-camphor and the extract contributed in an increase
in total peripheral resistance induced by an increase tone of
the arterioles, and while the former appeared to be the main
factor in inducing the rapid initial effect, the former added a
long-lasting effect (Belz and Loew 2003).
Toxicity
Camphor occurs in nature in its dextrorotatory form (D-
camphor), while the laevorotatory form (L-camphor) exists
only as a synthetic form. The two enantiomers present dif-
ferent proÞles of toxicity.
D-camphor, L-camphor and their racemic mixture were
tested for toxicity in mice. At 100 mg á Kg b.w.-1 the natural
form was non toxic, while the synthetic form induced differ-
ent kinds of toxic and behavioural effects such as body jerks
and hunched posture; the racemic mixture showed similar
effects to the L-form (Chatterjie and Alexander 1986).
The oral administration of acute doses of D-camphor to
rats and rabbits caused pronounced signs of toxicity. In rats,
the consume of food was reduced proportionally to the ad-
ministered dose, starting from 464 mg á Kg b.w.-1 á day-1, and
at 1000 mg á Kg b.w.-1 á day-1 convulsions and pilo-erection
were observed, connected with a reduction of motility and
weight gain. Reduced body weight gain and food consump-
tion were observed in rabbits treated with 681 mg á Kg b.w.-1
á day-1 (Leuschner 1997).
Camphor showed porphyrogenic activity in primary cul-
tures of chick embryo - liver cells, with enhanced porphyrin
accumulation ranging from 5- to 20-fold (Bonkovsky et al.
1992).
The main problems about camphor toxicity in humans
are connected more to the large availability of camphor-
containing products and their diffused perception as un-
hazardous medicines rather than in the intrinsic toxicity of
camphor. The daily maximum human therapeutic dose is in
fact approximately 1.43 mg á Kg-1, which corresponds to a
therapeutic ratio of more than 450 for the endpoint toxicity,
reßecting a wide margin of safety (Leuschner 1997). On the
other side, as mentioned above, camphor is present in several
over-the-counter products, its use as a familiar remedy is com-
monly accepted, but still some lack of information persists
among the consumers.

80
Zuccarini, Soldani
Cases of camphor intoxication in humans, especially
children, are relatively frequent, mostly because of accidental
ingestion (Siegel and Wason 1986). More than 100000 cases
of ingestion exposures to camphor-containing products were
registered between 1990 and 2003 (Manoguerra et al. 2006),
causing a range of symptoms that comprises convulsion,
lethargy, ataxia, severe nausea, vomiting and coma (Koppel
et al. 1988; Manoguerra et al. 2006).
Reproduction toxicity
D-camphor was orally administered to pregnant rats and
rabbits during the period of organogenesis to test its embryo-
toxicity. Doses up to 1000 mg á Kg b.w.-1 á day-1 to rats and up
to 681 mg á Kg b.w.-1 á day-1 to rabbits showed no teratogenic
effects, and in none of the animals were observed higher rates
of mutations or malformations (Leuschner 1997).
Mutagenicity and cancerogenicity
In a Salmonella/microsome assay, the upper limit of the dose
interval tested for (+/-) camphor resulted to be the highest
non-toxic dose, suggesting that the compound is not muta-
genic in the Ames test (Gomes-Carneiro et al. 1998).
A single dose of camphor (0.5 µM á g-1) administered 30,
45 or 60 minutes before gamma irradiation signiÞcantly re-
duced the frequency of sister-chromatid exchanges in mouse
bone marrow, showing therefore a radiomodifying inßuence
(Goel at al. 1989).
Discussion and Conclusions
Camphor is familiar to many people as a principal ingredient
in topical home remedies for a wide range of symptoms, and
its use is well consolidated among the population of the whole
world, having a long tradition of use as antiseptic, antipruritic,
rubefacient, abortifacient, aphrodisiac, contraceptive and
lactation suppressant.
In particular, the analgesic and antipruritic action of
the compound make it appreciated by a large number of
consumers, by whom it is used in the form of essential oil
for cutaneous application. Itch is a complex phenomenon,
being difÞcult to localize and quantify (Wahlgren 1995) and
involving a variety of skin surface receptors, peripheral and
central nerves and speciÞc brain regions. The treatment of
itch usually relies on antisthamines, corticoids or various
topical remedies (Langner and Maibach 2009) among which
camphor has a prominent role. The analgesic action is due to
its interacions with members of TRP channel superfamily
Camphor is therefore an important remedy for symptom-
atic treatment of itching, especially in patients affected by
contact dermatitis, because it goes to affect directly the cuta-
neous nerve ending, as other agents like pramoxine, phenol
and menthol do (Burkhart and Burkhart 2003).
Camphor has also an important role in the treatment of
cough and colds thanks to its antispasmodic activity, due to
anti-histaminergic and anti-cholinergic action that causes
depression of bronchospasm coupled with inhibition of
cough.
This compound has also a long history of scientiÞc studies
on its action and on the way through which it is metabolized
in the organisms of both humans and animals, due to the
general interest that it has always arisen among common
people and scientists. Already in 1879, Schmeideberg and
Meyer were analyzing the metabolites isolated from the urine
of dogs that had been fed with (+/-) camphor (Schmiedeberg
and Meyer 1879), and during the Þrst half of the twentieth
century the number of studies focused on its pharmacology
and pharmacokinetics has been remarkable.
The bibliographic search that was performed for the com-
pilation of this toxico-pharmacological overview revealed a
rich literature existing on camphor, and put in evidence the
large amount of works focused on toxic aspects of camphor
that were published during the last 30 years; a great number
of reports concerning cases of camphor intoxication were also
collected. In most cases camphor intoxication occurred fol-
lowing accidental ingestion of camphor-containing product,
and sometimes lethal episodes of intoxication of infants due
to application of camphor to their nostrils were collected.
As it emerges from all the observed data the toxic risks of
camphor-containing products in general, and of camphorated
oil in particular, are connected essentially with its improper
uses, e.g. accidental ingestion, but camphor does not repre-
sent a threaten for safety when used on the target patients,
following the indicated dosages and the contraindications.
Special care must be taken during pregnancy, due to the fact
that camphor crosses the placental barrier, and camphor and
camphor containing products should be avoided in children
who have a history of febrile convulsions or other predispos-
ing factors for convulsions (Galland et al. 1992).
In the past, when camphor was used medicinally, the
oral doses ranged from 120-300 mg (Wade 1977), and the
parenteral dose range was from 60-200 mg (not recommended
anymore).
Camphorated oil can be used with no risks for safety when
following the prescriptions. The relatively diffused tendency
to the improper use of camphor (high dosages, accidental
ingestion, use on infants) is connected with the perception
of the product, by many consumers, as a sort of ÒpanaceaÓ
with no contraindication. More and more accessible informa-
tion is therefore necessary to bring to a ÒresponsabilizationÓ
of the consume of this product, in order to avoid hazardous
situations.
All the above considerations allow the conclusion that
camphor in its form of camphorated oil can be safely used
at the proposed dosages, on the indicated patients target, for
topic application.

81
Camphor: its beneÞts and risks
Acknowledgements
The Authors would like to thank Annie Hart (A.R.S.) and
Marina Ribatski (B.D.R.) for useful help during the elabora-
tion of the manuscript.
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