By Isabelle Hall
Mad honey is a grayanotoxin-containing product made by bees using nectar and pollen obtained from plants in the family Ericaceae, including Rhododendron luteum and Rhododendron ponticum. It is reddish in colour, with a bitter taste. Generally, cases of poisoning caused by consumption of this honey arise near the Black Sea, particularly in Turkey, as such rhododendron species are found in the forests of this region. Mad honey intoxication has also been reported in Nepal, among other countries (Jansen et al., 2012). Another form of honey poisoning occurs in New Zealand – here, bees using honeydew secreted by passion-vine hoppers which have fed on Coriaria arborea will produce honey containing tutin, a GABAA (γ-Aminobutyric acid type A) receptor antagonist (Beasley et al., 2018).
The earliest recorded case of mad honey poisoning is found in the writings of Athenian military commander and historian Xenophon. Following conflict with the Makrons in the Turkish province of Trabzon, he reported in 401 BC that soldiers who had eaten an abundance of the honey found there acted drunk and ‘off their heads’, experiencing vomiting and diarrhea. Later, the Greek writer Strabo described the weaponisation of mad honey by King Mithridates in 67 BC, against Pompey’s armies in Northern Anatolia. Portions of the honey were placed along the Roman soldiers’ path – as they gave in to temptation and succumbed to the effects of the grayanotoxins, they were quickly overpowered by Mithridates’ men (Gunduz et al., 2011).
These effects arise as a result of the activity of grayanotoxins, a group of diterpenes. Members of this group are polyhydroxylated cyclic hydrocarbons, which lack nitrogen. Their toxicity is mediated via binding to voltage-gated sodium ion channels in cells. The interaction between a grayanotoxin and the channel receptor appears to involve the S6 transmembrane alpha-helixes. Four of these S6 domains face the pore region of the sodium channel. The grayanotoxin will attach to the channel in its open state, modifying its configuration and preventing its inactivation. This prolongs membrane depolarisation, as repolarisation is inhibited. Eventually, the membrane potential shifts in the direction of hyperpolarisation. The continued stimulation of the vagal nervous system, and thus increased vagal tone, leads to activation of parasympathetic pathways. This gives rise to hypotension and depression of respiratory rate, as well as bradycardia. The slowed heart rate may also be related to grayanotoxins binding to muscarinic receptors of the M2 (muscarinic-2) subtype, on the myocardium. Other cardiac rhythm disorders which may be observed include asystole and varying degrees of atrioventricular block (Ullah et al., 2018). Coronary hypoperfusion resulting from the bradycardia and hypotension may also cause acute myocardial infarction (Akıncı et al., 2008). Other symptoms which have been observed include sweating, blurred vision, unconsciousness, dizziness, vertigo, altered mental state, and convulsion (Ullah et al., 2018). Cases of patients hallucinating after consumption of mad honey have also been reported (Shrestha et al., 2018). Fatalities resulting from ingestion of this product have been recorded, but occur very rarely.
Within the group of grayanotoxins, effects and toxicity may vary. Grayanotoxins 1 and 3 appear to be among the more toxic forms. Depending on the Ericaceae species accessed by the bee, the specific grayanotoxin content of the honey will differ. Following consumption of mad honey, symptoms may persist for up to 1-2 days. Metabolism and excretion of any grayanotoxins ingested should generally occur within 24 hours.
Despite the risks accompanying the use of mad honey, it is sought after in some regions for applications in traditional medicine, and as a product to sell on the black market (Synnott, 2017). Mad honey has been used as an alternative treatment for a range of ailments, including hypertension, diabetes (possibly due to stimulation of the parasympathetic nervous system raising insulin secretion, and decreasing blood glucose levels), gastrointestinal disorders, viral infections, and arthritis. Enhancement of sexual performance is another common reason for consumption of this honey.
Upon consideration of these alternative remedies, and of the symptoms exhibited in cases of mad honey poisoning, it appears that further exploration of grayanotoxins may yield valuable findings regarding potential treatments for issues such as cardiovascular disease and diabetes.
References:
Akıncı, S., Arslan, U., Karakurt, K. and Çengel, A. (2008) An unusual presentation of mad honey poisoning: acute myocardial infarction. International journal of cardiology. 129 (2), e56-e58. Available from: doi: 10.1016/j.ijcard.2007.06.129
Beasley, M., Hood, D., Anderson, P., Reeve, J. and Slaughter, R.J. (2018) Poisoning due to tutin in honey—a report of an outbreak in New Zealand. The New Zealand Medical Journal. 131 (1473), 59-71. Available from: https://www.nzma.org.nz/journal-articles/poisoning-due-to-tutin-in-honey-a-report-of-an-outbreak-in-new-zealand [Accessed 6th November 2020]
Gunduz, A., Turedi, S. and Oksuz, H. (2011) The Honey, The Poison, The Weapon. Wilderness & Environmental Medicine. 22 (2), 182-184. Available from: doi: 10.1016/j.wem.2011.01.006
Jansen, S.A., Kleerekooper, I., Hofman, Z.L., Kappen, I.F., Stary-Weinzinger, A. and van der Heyden, M.A. (2012) Grayanotoxin Poisoning: Mad Honey Disease’ and Beyond. Cardiovascular Toxicology. 12 (3), 208-215. Available from: doi: 10.1007/s12012-012-9162-2
Shrestha, T.M., Nepal, G., Shing, Y.K. and Shrestha, L. (2018). Cardiovascular, psychiatric, and neurological phenomena seen in mad honey disease: A clinical case report. Clinical Case Reports. 6 (12), 2355. Available from: doi: 10.1002/ccr3.1889
Synnott, M. (2017) The Last Death-defying Honey-hunter of Nepal. National Geographic Magazine. 232 (1), 80-97. Available from: https://www.nationalgeographic.com/magazine/2017/07/honey-hunters-bees-climbing-nepal/ [Accessed 6th November 2020]
Ullah, S., Khan, S.U., Saleh, T.A. and Fahad, S. (2018) Mad honey: uses, intoxicating/poisoning effects, diagnosis, and treatment. RSC Advances, 8 (33), 18635-18646. Available from: doi: 10.1039/c8ra01924j
Imperial Bioscience Review 