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Grayanotoxins are a group of closely related toxins found in rhododendrons and other plants of the family Ericaceae. They can be found in honey made from their nectar and cause a very rare poisonous reaction called grayanotoxin poisoning, honey intoxication, or rhododendron poisoning.[1] Grayanotoxin I (see below) is also known as andromedotoxin, acetylandromedol, rhodotoxin and asebotoxin; the systematic chemical name is: grayanotaxane-3,5,6,10,14,16-hexol 14-acetate.[2] Grayanotoxins are named after Leucothoe grayana, a plant species from Japan, which is in turn named after 19th century American botanist Asa Gray.[3]

Chemical structure[edit]

Grayanotoxin R1 R2 R3
Grayanotoxin I OH CH3 Ac
Grayanotoxin II CH2 H
Grayanotoxin III OH CH3 H
Grayanotoxin IV CH2 Ac

Ac = acetyl

Grayanotoxins are polyhydroxylated cyclic diterpenes. They bind to specific sodium ion channels in cell membranes, the receptor sites involved in activation and inactivation.[4] The grayanotoxin prevents inactivation, leaving excitable cells depolarized.


Poisoning from graynotoxins is rarely fatal in humans, but can be lethal for other animals.[5] Physical symptoms from grayanotoxin poisoning occur after a dose-dependent latent period of minutes to three hours or so. Initial symptoms are excessive salivation, perspiration, vomiting, dizziness, weakness and paresthesia in the extremities and around the mouth, low blood pressure and sinus bradycardia. In higher doses symptoms can include loss of coordination, severe and progressive muscular weakness, electrocardiographic changes of bundle branch block and/or ST-segment elevations as seen in ischemic myocardial threat,[6] bradycardia (and, paradoxically, ventricular tachycardia), and nodal rhythm or Wolff-Parkinson-White syndrome. Despite the potential cardiac problems the condition is rarely fatal and generally lasts less than a day. Medical intervention is not often needed but sometimes atropine therapy, vasopressors and other agents are used to mitigate symptoms.

Mad honey disease[edit]

Grayanotoxins can be found in honey produced from the pollen of plants such as Rhododendron ponticum that contains alkaloids that are poisonous to humans.[7] Such honey is called 'mad honey' [5] Honey from Japan, Brazil, United States, Nepal, and British Columbia is most likely to be contaminated with grayanotoxins,[citation needed] although very rarely to toxic levels. In Nepal, this type of honey is used by the Gurung people both for its medicinal and hallucinogenic properties.[8]

Honey produced from the nectar of Andromeda polifolia contains high enough levels of grayanotoxin to cause full body paralysis and potentially fatal breathing difficulties due to diaphragm paralysis.[7][9] Honey obtained from spoonwood and allied species such as sheep-laurel can also cause illness.[7] The honey from Lestrimelitta limao also produces this paralyzing effect seen in the honey of A. polifolia and is also toxic to humans.[10]

There have been famous episodes of inebriation of humans from consuming toxic honey throughout history. Xenophon, Aristotle, Strabo, Pliny the Elder, and Columella all document the results of eating this "maddening" honey.[11] Honey from these plants poisoned Roman troops in the first century BC under Pompey the Great when they were attacking the Heptakometes in Turkey. The Roman soldiers became delirious and nauseous after eating the toxic honey, leading to an easy defeat.[12][13] In the Caucasus region of Turkey, honey containing grayanotoxin known as deli bal is deliberately produced,[14] and in the eighteenth century was exported to Europe to add to alcoholic drinks.[15][16] Historically the toxin in the honey was derived from the pollen and nectar of Rhododendron luteum and Rhododendron ponticum, which are found around the Black Sea. According to Pliny and later Strabo, the locals used the honey against the armies of Xenophon in 401 BCE and later against Pompey in 69 BCE.[16][17]


  1. ^ Demircan, A.; Keleş, A.; Bildik, F.; Aygencel, G.; Doğan, N. O.; Gómez, H. F. (2009). "Mad honey sex: Therapeutic misadventures from an ancient biological weapon". Annals of Emergency Medicine 54 (6): 824–829. doi:10.1016/j.annemergmed.2009.06.010. PMID 19683834. 
  2. ^ The Merck Index (10th ed.). Rahway, NJ: Merck. 1983. pp. 652–653. 
  3. ^ Senning, Alexander (2007). Elsevier's Dictionary of Chemoetymology. Amsterdam: Elsevier. p. 170. ISBN 978-0-444-52239-9. 
  4. ^ Ito, S.; Nakazato, Y.; Ohga, A. (1981). "Further evidence for the involvement of Na+ channels in the release of adrenal catecholamine: The effect of scorpion venom and grayanotoxin I". British Journal of Pharmacology 72 (1): 61–67. doi:10.1111/j.1476-5381.1981.tb09105.x. PMC 2071538. PMID 6261866. 
  5. ^ a b Jansen; et al. (2012). "Grayanotoxin Poisoning: ‘Mad Honey Disease’ and Beyond". Cardiovascular Toxicology 12: 208–13. doi:10.1007/s12012-012-9162-2. PMID 22528814. 
  6. ^ Sayin, M. R.; Karabag, T.; Dogan, S. M.; Akpinar, I.; Aydin, M. (2012). "Transient ST segment elevation and left bundle branch block caused by mad-honey poisoning". Wiener Klinische Wochenschrift 124 (7–8): 278–281. doi:10.1007/s00508-012-0152-y. PMID 22527815. 
  7. ^ a b c "Grayanotoxins". Foodborne Pathogenic Microorganisms and Natural Toxins Handbook. US FDA. 2012. Retrieved August 7, 2015. 
  8. ^ Treza, Raphael (2011). "Hallucinogen honey hunters". Retrieved 20 October 2015. 
  9. ^ Yaacov Lensky (1997). Bee Products: Properties, Applications, and Apitherapy. Springer. ISBN 0-306-45502-1. 
  10. ^ Wittmann, D.; Radtke, R.; Zeil, J.; Lubke, G.; Francke, W. (1990). "Robber Bees (Lestrimelitta limao) And Their Host Chemical and Visual Cues in Nest Defense by Trigona (Tetragonisca) angustula (Apidae: Meliponinae)". Journal of Chemical Ecology 16: 631–641. 
  11. ^ Kelhoffer, James A. (2005). "John the Baptist’s "Wild Honey" and "Honey" in Antiquity" (PDF). Greek, Roman, and Byzantine Studies 45: 59–73. 
  12. ^ G. P. Georghiou (1980). "Ancient Beekeeping". In Root, A.I. The ABC and XYZ of Bee Culture. Medina, Ohio: A.I. Root Company. pp. 17–21. 
  13. ^ J. T. Ambrose (1972). Bees and Warfare: Gleanings in Bee Culture. pp. 343–6. 
  14. ^ Jamie Waters (1 October 2014). "The buzz about 'mad honey', hot honey and mead". The Guardian. 
  15. ^ Cheryll Williams (2010). Medicinal Plants in Australia Volume 1: Bush Pharmacy. Rosenberg Publishing. p. 223. ISBN 978-1877058790. 
  16. ^ a b Adrienne Mayor. "Mad Honey!". Archaeology 46 (6): 32–40. 
  17. ^ Pliny the Elder on Mad Honey