Ingestion of “mad honey” causes severe hypotension and bradycardia. Let us learn about the intoxication given by the grayanotoxin family.

In Italian, there is a literary expression known as: “losing the Trebizond,” which means losing control, feeling confused and disoriented. Trebizond was an important port on the southern coast of the Black Sea, where the maritime lighthouse was strategically located for sailors, especially the Venetians, whose colonial rule extended from the coasts of western Greece to the straits of the Dardanelles and the Bosporus. In the province of this seaside town, a type of honey produced disorientation, confusion, and fainting. We then explored why it is called “mad honey.”

What is meant when we talk about “mad honey?

“Mad honey” is toxic, and is from the nectar of various species of rhododendron, in particular Rhodendrum ponticum and Rhododendrum luteum. These plants are largely found in Turkey (in the Black Sea area near the city of Trebizond), but are also in Japan, Nepal (especially in the area where the Gurung people live), and Brazil. This honey, made by local bees, is called “mad,” because it contains several toxins of the grayanotoxin family (GTX). GTXs belong to liposoluble diterpenoids [1]; similar to veratridine, aconitine, and batrachotoxin, they are known for poisoning and killing livestock.

Why did this honey undermine two armies?

In 401 BC, the Greek general Xenophon described one of the first intoxications with this honey, which affected over 10,000 men of his army:

“For the most part, there was nothing which they found strange; but there were numerous swarms of bees in the neighbourhood, and soldiers who ate it went out of their heads,suffering from vomiting and diarrhea: not one of them could stand up, but those who had eaten a little were like very drunk people, while those who had eaten a lot seemed like crazy, or in some cases, dying men.”

(Anabasis 4.8.20)

In 67 BC, another case of intoxication was described by the Roman general, Pompey the Great. His retreating troops were the protagonists of the first bioweapon case in history. Their adversary, King Mithridates, deliberately placed combs of mad honey in the path of the advancing Romans, staging a strategic withdrawal. The Roman troops were so weakened (from intoxication), that they were defeated by Mithridates’ army. In 946 AD, Queen Olga of Kiev massacred over 5,000 Drevians, who rushed to her husband’s funeral using mad honey as poison; in 1489 AC, about 10,000 Tatar soldiers were killed after drinking too many flasks of mead, who were purposely abandoned by the Russian soldiers. In the past, however, the mad honey was also used as a drug. Aristotle [2], Dioscorides [3], and Pliny the Elder [4] had described the therapeutic properties of this honey

Is mad honey still used today?

“Mad honey” is still sold today in an unprocessed form in rural markets, under the Turkish name “DELI BAL.” In fact, studies and clinical cases on GTX intoxication come from the Trabzon province (more widely, from Turkey [5] where the honey is used not only as a food, but in folk medicine as a sexual stimulant [6], antihypertensive [7], and hypoglycemic drug. Other uses of this honey in folk medicine were to treat peptic ulcer, abdominal pain, indigestion, flu, and arthritis.

How long does it take from ingestion to onset of symptoms?

On average, symptoms appear about one to two hours after ingestion. The average quantity for symptoms is varied (people report from 1 to 5 tablespoons, so it is estimated as 5 to 180 g). Given that the diffusion of grayanotoxins is not uniform in honey, we should think of this data as not highly predictive [8]: we note that the severity of symptoms also depends on other factors, such as the quantity of toxin ingested, the body’s sensitivity to it, and when the honey was produced.

What are the most common symptoms of intoxication with mad honey?

The symptoms would usually be:

• nausea and vomiting
• profuse sweating
• blurred vision
• hypersalivation
• prostration
• bradycardia
• severe hypotension
• syncope

For a more complete history for reaching the diagnosis of mad honey intoxication, it was helpful to ask a patient if he traveled to areas where it existed if he has ingested it, the reason for that (for pharmacological purposes, this question helps us understand if a patient is suffering from certain diseases, such as hypertension or diabetes), and where this mad honey was bought.

Are there any electrocardiographic changes?

Electrocardiographic changes such as sinus bradycardia and atrioventricular blocks [9] of varying degrees (I-III) are frequently found. It would appear that the GTXs act by dysregulating the voltage-dependent sodium channels in the nervous system, which are activated in a permanent state of depolarization [10]. Continued activation of these cells causes bradycardia, respiratory depression, hypotension, and loss of consciousness [11].

What therapeutic approach should be adopted?

• Monitor vital and cardiac parameters.
• Support therapy with intravenous crystalloid fluid (normal saline solution).
• Use atropine sulfate at a moderate dose from 0.5 to 2 mg intravenously to resolve marked hypotension and respiratory depression.
• Vasopressors or pacemakers if/when the rhythm is not restored.

We should consider achieving a normal heart rate and normal blood pressure values as therapeutic goals. Once these goals are achieved, the patient should be kept for a short period of observation in the emergency department – and if no other problems arise, he can be safely discharged [12, 13]. Furthermore, I would like to emphasize that grayanotoxin metabolism and excretion take place within 24 hours, and thus the symptoms last no more than a day.

What is the take-home message?

In patients with bradycardia and hypotension of unexplained origin, this type of intoxication should be considered especially in middle-aged males who have probably taken mad honey as a sexual stimulant.

References and Further Reading

[1] Jansen SA, Kleerekooper I, Hofman ZLM et al (2012) Grayanotoxin Poisoning: ‘Mad Honey Disease’ and Beyond. Cardiovasc Toxicol 12:208–215. https://doi.org/10.1007/s12012-012-9162-2

[2] Aristotle (1936) De mirabilius auscultationibus. Aristotle Minor Works on Marvelous Things Heard. Loeb, Cambridge, p. 245.

[3] Dioscorides (2000) De materia medica. Ibidis Press, Johannesburg, p. 226.

[4] Mayer A (1995) Mad honey. Archaeology 46(6):32–40.

[5] Sibel Silici A, Timucin A (2015) Mad honey intoxication: A systematic review on the 1199 cases. Food Chem Toxicol 86:282-290. https://doi.org/10.1016/j.fct.2015.10.018

[6] Demircan A, Keleş A, Bildik F, Aygencel G, Doğan NO, Gómez HF (2009) Mad honey sex: therapeutic misadventures from an ancient biological weapon. Ann Emerg Med 54(6):824-829. doi: 10.1016/j.annemergmed.2009.06.010

[7] Hanson JR (2016) From ‘mad honey’ to hypotensive agents, the grayanoid diterpenes. Sci Prog 99(3):327-334. doi: 10.3184/003685016X14720691270831

[8] Aygun A, Sahin A, Karaca Y, Turkmen S, Turedi S, Ahn SY, Kim S, Gunduz A (2017) Grayanotoxin levels in blood, urine and honey and their association with clinical status in patients with mad honey intoxication. Turk J Emerg Med 18(1):29-33. doi: 10.1016/j.tjem.2017.05.001

[9] Cagli KE, Tufekcioglu O, Sen N, Aras D, Topaloglu S, Basar N, Pehlivan S (2009). Atrioventricular block induced by mad-honey intoxication: confirmation of diagnosis by pollen analysis. Tex Heart Inst J 36(4):342-344.

[10] Gunduz A, Tatli O, Turedi S (2008). Mad honey poisoning from the past to the present. Turk J Emerg Med 8:46-49.

[11] Sana U, Tawfik AS, Shah F (2018) Mad honey: uses, intoxicating/poisoning effects, diagnosis, and treatment. RSC Adv 8:18635-18646.

[12] Gündüz A, Meriçé ES, Baydin A, Topbas M, Uzun H, Türedi S, Kalkan A (2009) Does mad honey poisoning require hospital admission? Am J Emerg Med 27:424-427.

[13] Yaylacı S, Ayyıldız O, Aydın E, Osken A, Karahalil F, Varım C, Demir MV, Genç AB, Sahinkus S, Can Y, Kocayigit İ, Bilir C (2015) Is there a difference in mad honey poisoning between geriatric and non-geriatric patient groups? Eur Rev Med Pharmacol Sci 19(23):4647-4653.