Grayanotoxins are a group of closely related neurotoxins named after Leucothoe grayana, a plant native to Japan and named for 19th-century American botanist Asa Gray. Grayanotoxin I (grayanotoxane-3,5,6,10,14,16-hexol 14-acetate) is also known as andromedotoxin, acetylandromedol, rhodotoxin and asebotoxin. Grayanotoxins are produced by Rhododendron species and other plants in the family Ericaceae. Honey made from the nectar and so containing pollen of these plants also contains grayanotoxins and is commonly referred to as mad honey.
Consumption of the plant or any of its secondary products, including mad honey, can cause a rare poisonous reaction called grayanotoxin poisoning, mad honey disease, honey intoxication, or rhododendron poisoning. It is most frequently produced and consumed in regions of Turkey and Nepal as a recreational drug and traditional medicine.
Origin
thumb|Rhododendron luteum
Grayanotoxins are produced by plants in the family Ericaceae, specifically members of the genera Agarista, Craibiodendron, Kalmia, Leucothoe, Lyonia, Pieris and Rhododendron. The genus Rhododendron alone encompasses over 750 species that grow around the world in parts of Europe, North America, Japan, India, Bhutan, Nepal and Turkey. They can grow at a variety of altitudes, ranging from sea level to more than . They are structurally characterized as polyhydroxylated cyclic diterpenes. The base structure is a 5/7/6/5 ring system that does not contain nitrogen. Additionally, grayanotoxin only binds to the activated conformation of sodium channels. Normally, voltage gated sodium channels are activated (opened) only when the cell membrane potential reaches a specific threshold voltage. This activated conformation allows for an influx of sodium ions resulting in cell depolarization, followed by the firing of an action potential. At the peak of the action potential, voltage-gated sodium channels are quickly inactivated and are only reset once the cell has repolarized to resting potential. When grayanotoxin is present, binding induces further conformational changes that prevent sodium channel inactivation and lead to a prolonged depolarization. Owing to its transient ability to activate channels and increase membrane permeability to sodium ions, grayanotoxin is classified as a reversible Na<sub>v</sub>1.x agonist. Slowing of heart rate and lowering of blood pressure are typical effects reported in one review of cases.
The primary mediator of this grayanotoxin pathophysiology is the paired vagus nerve (tenth cranial nerve). In severe cases of grayanotoxin poisoning, atropine a non-specific "mAChR antagonist" or Muscarinic antagonist can be used to treat bradycardia and other heart rhythm malfunctions.
Patients exposed to low doses of grayanotoxin typically recover within a few hours. In more severe cases, symptoms may persist for 24 hours or longer and may require medical treatment (as described above). Despite the risk from cardiac problems, grayanotoxin poisoning is rarely fatal in humans.
Mad honey intoxication
Bees that collect pollen and nectar from grayanotoxin-containing plants often produce honey that also contains grayanotoxins. In Nepal, this type of honey is used by the Gurung people for both its hallucinogenic properties and supposed medicinal benefits.
In the 18th century, this honey was exported to Europe to add to alcoholic drinks to give them extra potency. In modern times, it is consumed locally and exported to North America, Europe and Asia.
Other grayanotoxin sources
In addition to various Rhododendron species, mad honey can also be made from several other grayanotoxin-containing plants. 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. Honey obtained from spoonwood and allied species such as sheep-laurel can also cause illness.
Historical use
The intoxicating effects of mad honey have been suspected for centuries, including records from Xenophon, Aristotle, Strabo, Pliny the Elder and Columella, all reporting illness from eating "maddening" honey believed to be from the pollen or nectar of Rhododendron luteum and Rhododendron ponticum. According to Xenophon's Anabasis, an invading Greek army was accidentally poisoned by harvesting and eating the local Asia Minor honey, but they all made a quick recovery without any fatalities.
See also
- Incilius alvarius
- Sarpa salpa
- Potassium channel