Review

Poisoning by mad honey: A brief review

Ilkay Koca

, Ahmet F. Koca

Ondokuz Mayis of University, Faculty of Engineering, Department of Food Engineering, Samsun, Turkey

Received 25 February 2007; accepted 11 April 2007

Abstract

Several plants of the Ericaceae family produce grayanotoxins which can poison humans. The best-known of these intoxicationsinvolves the eating of ‘mad honey (deli bal in Turkish)’ contaminated by

Rhododendron

nectar grayanotoxins. Accounts of mad honeyintoxication date back to 401 BC. It is still one of the common food intoxications encountered for humans and livestock in Turkey. Madhoney intoxication’s symptoms are dose-related. In mild form, dizziness, weakness, excessive perspiration, hypersalivation, nausea,vomiting and paresthesias are present and close follow-up is enough. However, severe intoxication may lead to life threatening cardiaccomplications such as complete atrioventricular block that can be treated intravenously.In this review, properties and sources of grayanotoxins, their detection methods and mad honey intoxication are discussed.

Keywords:

Honey; Mad honey; Grayanotoxin;

Rhododendron

; Andromedotoxin

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13152. Properties and sources of grayanotoxins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13163. Toxicity of grayanotoxin and mad honey. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13164. Detection of grayanotoxin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13175. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1317References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1317

1. Introduction

Beekeeping is a common and honourable work amongthe local people of the eastern Black Sea area. The nativeCaucasian bees, which can ﬂy only with an area of about5 km

, are used in the traditional method of honey produc-tion. Therefore, each honey contains only one valley’sﬂora. Since

Rhododendrons

are long-living plants, beekeep-ers know which honey contains toxic substances (Dilberet al., 2002). Honey from the Black Sea region of Turkeyoccasionally contains grayanotoxin and causes poisoning.It is believed that this particularly occurs because of theconsumption of honey from the eastern part of the BlackSea region, where it is known as ‘‘mad honey’’. Localpeople can distinguish that honey from other varieties. Itcauses a sharp burning sensation in the throat and is thusalso referred to as bitter honey (Gunduz et al., 2006).Honey produced in springtime is more toxic and sometimescontains higher concentrations of grayanotoxin than that

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Food and Chemical Toxicology 45 (2007) 1315–1318

produced in other seasons (Dilber et al., 2002; Gunduzet al., 2006). In 401 BC, the honey found in this area wasknown to be poisonous (Gunduz et al., 2006). Mad honeyis used in the Black Sea region as an alternative medicinefor the treatment of gastric pains, bowel disorders, andhypertension, and it is also believed to be a sexual stimu-lant (Dilber et al., 2002; Gunduz et al., 2006). Mad honeyis also used traditionally in the management of diabetesmellitus in east Anatolia, Turkey. People believe that itdecreases the blood glucose, and so they recommend theuse of this honey for diabetic subjects (O¨ztas

an et al.,2005). Given these uses, there has been no decrease in gray-anotoxin intoxication cases in spite of this awareness of mad honey. Mad honey has the potential to cause deathif untreated, but since the medical definition of mad honeypoisoning in 1983, no fatal cases have been reported in theliterature (Gunduz et al., 2006). Recently, the great major-ity of the cases have been reported from Turkey (Biberogluet al., 1988; Onat et al., 1991a; Sutlupinar et al., 1993;Çiçek et al., 2004; O¨zhan et al., 2004; Ergun et al., 2005).

2. Properties and sources of grayanotoxins

Grayanotoxins are known to occur in honey producedfrom the nectar of

Rhododendrons

(Jordan, 2006). Gray-anotoxins have also been called andromedotoxin, acetylan-dromedol and rhodotoxin. The speciﬁc grayanotoxins varywith the plant species. Not all

Rhododendrons

producegrayanotoxins (Wong et al., 2002). Sources of honey toxicto humans are given inTable 1.

Rhododendron

species aredeciduous or evergreen shrubs commonly used as gardenplants worldwide. Six

Rhododendron

species, one of which(

R. smirnovii

) is endemic, grow naturally in Turkey, espe-cially in the Black Sea region (Wong et al., 2002).

R. pont-icum

is a purple ﬂowered evergreen shrub, which is knownas one of the invasive plants in the Black Sea region, as wellas in many Mediterranean countries and the British Isles,threatening the forest life (Ku¨c¸u¨k et al., 2007). The toxincontent in

R. ponticum

is particularly high (Jordan,2006). But,

R. ponticum

is widely used as an analgesic innorthern Anatolia for the treatment of rheumatic or dentalpain, common colds, and edema, both internally andexternally (Tasdemir et al., 2004). Other species of

Rhodo-dendron

and other members of the botanical family Erica-ceae, to which

Rhododendrons

belong, may produce thetoxins but are not often linked to the disease. Mountainlaurel (

Kalmia latifolia

) and sheep laurel (

Kalmia angustifo-lia

) are probably the other most important sources of thetoxin (Gunduz et al., 2006).There are 18 forms of grayanotoxins (Wong et al.,2002). Grayanotoxins such as grayanotoxin I–IV are aunique class of toxic diterpenoids which are polyhydroxy-lated cyclic hydrocarbons that do not contain nitrogen(Fig. 1)(Kan et al., 1994; Wong et al., 2002; Gunduz et al., 2006). Grayanotoxins comprise a number of closelyrelated chemical structures. The principle toxic isomer in

Rhododendron

is grayanotoxin III (GIII) although othersgrayanotoxin I (GI) and grayanotoxin II (GII) are presentin lower amounts. GI is also toxic and GII is less toxic. Avariety of other

Rhododendrons

Azaleas

and other mem-bers of the Ericaceae also contain these toxins (e.g.

Kalmia

spp.) (Wong et al., 2002).Grayanotoxins are often isolated in methanol or chloro-form but these solvents dissolve a range of compounds sothat they require further puriﬁcation before they can becrystallised out or subjected to detailed analysis. Crystal-line needles of grayanotoxin melt at 228–229

C(Wonget al., 2002).

3. Toxicity of grayanotoxin and mad honey

The grayanotoxins are neurotoxins interfering with thetransmission of the action potential by blocking sodiumchannels in cell membranes (Wong et al., 2002). Thesecompounds prevent inactivation; thus, excitable cells(nerve and muscle) are maintained in a state of depolariza-tion, during which entry of calcium into the cells may befacilitated. All of the observed responses of skeletal andheart muscles, nerves, and the central nervous system arerelated to the membrane effects (Gunduz et al., 2006).The toxic effects of honey poisoning are rarely fatal andgenerally last for no more than 24 h (Gunduz et al.,2006). Mad honey intoxication’s symptoms are dose-related. In mild form, dizziness, weakness, excessive perspi-ration, hypersalivation, nausea, vomiting and paresthesiasare present and close follow-up is enough. However, severeintoxication may lead to life threatening cardiac complica-tions such as complete atrioventricular block that can betreated intravenously (Ergun et al., 2005). Symptoms of poisoning occur after a dose-dependent latent period of afew minutes to two or more hours (Gunduz et al., 2006).Yilmaz et al. (2006)reported that the amount of honeycausing poisoning is between 5 and 30 g. In general, theseverity of the honey poisoning depends on the amountingested. The concentration of grayanotoxin ingestedmay differ greatly from case to case. As grayanotoxinsare metabolized and excreted rapidly, patients generallyregain consciousness and feel better within hours, andheart rate and blood pressure usually return to normalwithin 2–9 h (Gunduz et al., 2006).Serious

Rhododendron

poisonings are also common inlivestock, particularly in sheep and goats fed with theyoung leaves or ﬂowers of these species (Matschullat,

Table 1Sources of honey toxic to humans (Adler, 2000)Species Family

Agauria

spp. Ericaceae

Andromeda

spp. Ericaceae

Kalmia

spp. Ericaceae

Rhododendron ﬂavum

Ericaceae

Rhododendron ponticum

Ericaceae

Paullinia australis

Sapindaceae

Azalea pontica

Ericaceae

Kalmia latifolia

Ericaceae1316

I. Koca, A.F. Koca / Food and Chemical Toxicology 45 (2007) 1315–1318

1974; Humpreys et al., 1983; Tasdemir et al., 2003).Onatet al. (1991b)injected anaesthetized albino rats with honeyextract intra-cerebroventricularly (i.c.v.) or intraperitone-ally (i.p.). They reported that marked bradycardia andrespiratory rate depression were observed in rats injectedwith extract equivalent to 1 and 5 g kg

honey i.p. andin rats injected with 50 mg i.c.v., but not in rats given50 mg i.p. They stated that grayanotoxin-contaminatedhoney extract did not cause bradycardia in bilaterally vago-tomized animals. They suggested that the sites of cardiacand respiratory actions of grayanotoxin are within the cen-tral nervous system, and that the bradycardia is mediatedby vagal stimulation at the periphery.Asc¸ıoglu et al. (2000)investigated the eﬀects of acute grayanotoxin-I administration on hepatic and renal func-tions in rats. They concluded that exposure to a single doseof grayanotoxin-I led to nephrotoxicity characterized byhematuria and proteinuria together with reduced serumtotal protein level and hepatotoxicity, which occurred atonly high doses.O¨ztas

an et al. (2005)investigated whether mad honeyaﬀects blood glucose and lipid levels in experimentalanimals. They found that mad honey caused signiﬁcantdecreases in blood glucose and lipid levels in animals withstreptozocin-induced diabetes mellitus and in controls.They stated that these decreases may be due to grayanotox-ins in the mad honey causing the islets of Langerhans in thepancreas to secrete insulin by stimulating the parasympa-thetic nervous system or M2-muscarinic receptors.

4. Detection of grayanotoxin

The grayanotoxins can be isolated from the suspectcommodity by typical extraction procedures for naturallyoccurring terpenes. The toxins are identiﬁed by paperelectrophoresis (White and Riethof, 1959) or thin layerchromatography (Scott et al., 1971). Grayanotoxins aredetected in samples of

Rhododendron

material by usinggas chromatography (GC) (Wong et al., 2002; Tasdemiret al., 2003). They are unstable on heating and have lowvapor pressure, hence they require derivatization beforethe GC analysis (Tasdemir et al., 2003). Also, the toxinsin biological samples can be determined by liquid-chroma-tography–mass spectrometry/mass spectrometry (LC–MS/MS) (Holstege et al., 2001).

5. Conclusion

One of the food intoxications encountered in Turkey iscaused by toxic honey made by bees from

Rhododendron

species (Sutlupinar et al., 1993).

Rhododendron

is infamousfor being toxic to animals through ingestion of the leavesand man through consumption of ‘mad’ honey. Mad honeyintoxication’s symptoms are dose-related. Symptoms of poisoning occur after a dose-dependent latent period of afew minutes to two or more hours. The toxic eﬀects of honey poisoning are rarely fatal and generally last for nomore than 24 h.Despite their dangerous potential for the public health,there is no detailed information on chemical propertiesand detection of mad honey, prevention of mad honeytoxicity or methods for reducing grayonotoxins in honey.Further studies are required.

References

Adler, L.S., 2000. The ecological significance of toxic nectar. Oikos 91,409–420.Asçıoglu, M., O¨zesmi, Ç., Dogan, P., O¨ztu¨rk, F., 2000. Effects of acutegrayanotoxin-I administration on hepatic and renal functions in rats.Turk. J. Med. Sci. 30, 23–27.Biberoglu, S., Biberoglu, K., Komsuoglu, B., 1988. Mad honey. J. Am.Med. Assoc. 259, 1943.Çiçek, D., Gemici, K., Eryılmaz, U., Cordan, J., 2004. Black sea madhoney and andromedotoxin toxicity: a patient with nodal ritm. Uludag˘Universitesi Tıp Faku¨ltesi Dergisi 30, 61–62.Dilber, E., Kalyoncu, M., Yarıs

, N., O¨kten, A., 2002. A Case of madhoney poisoning presenting with convulsion: intoxication instead of alternative therapy. Turk. J. Med. Sci. 32, 361–362.Ergun, K., Tufekcioglu, O., Aras, D., Korkmaz, S., Pehlivan, S., 2005. Arare cause of atrioventricular block: mad honey intoxication. Int. J.Cardiol. 99, 347–348.Gunduz, A., Turedi, S., Uzun, H., Topbas, M., 2006. Mad honeypoisoning. Am. J. Emerg. Med. 24, 595–598.Holstege, D.M., Puschner, B., Le, T., 2001. Determination of grayano-toxins in biological samples by LC–MS/MS. J. Agr. Food Chem. 49,1648–1651.Humpreys, D.J., Stodulski, J.B.J., Stocker, J.G., 1983.

Rhododendron

poisoning in goats. Vet. Rec. 113, 503–504.Jordan, J., 2006. Research highlights from the literature. Clin. Auton. Res.16, 198–201.

OHHOOHOH

OHHOOHOXOH

Grayanotoxin I (X=Ac) Grayanotoxin II (X=H)Grayanotoxin III (X= H) Grayanotoxin IV (X=Ac)

Fig. 1. General structure of grayanotoxin (Kan et al., 1994).

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