Grayanotoxin is a natural component, a tetracyclic diterpenoid and a dangerous phytotoxin also known as andromedotoxin, rhodotoxin, or acetylandromedol. It occurs naturally in plants of the Ericaceae family, including the rhododendron. It is known as 'mad honey'. Rather known to be responsible for wild honey intoxication. This intoxication, not widespread, comes from the ingestion of honey made from rhododendron and sold by small producers without mixing it with honey made from other flowers.

Chemical Composition and Structure

Grayanotoxin is a diterpenoid compound, meaning it is derived from a class of chemical compounds with a core structure based on four isoprene units. The structure of Grayanotoxin allows it to bind to and disrupt sodium channels in nerve cells, preventing their proper function. This disruption affects the nervous system, causing toxic effects such as dizziness, nausea, and in severe cases, heart problems.

Physical Properties

Grayanotoxin typically exists as a crystalline substance when isolated from plant material. It is not commonly encountered in pure form outside of research and toxicological studies. In nature, it is found in the nectar of certain plants and can be transferred into honey by bees, particularly in regions where toxic Rhododendron species grow.

Production Process

It is produced naturally by plants as a defense mechanism against herbivores. The concentration of Grayanotoxin varies depending on the species of plant and environmental conditions. It can be extracted from plant material or honey using various chemical extraction and purification methods for study in toxicological research.

• Cultivation of Plants: Plants containing grayanotoxin, such as rhododendrons, are cultivated in suitable environments. These plants may be collected from wild areas or grown in gardens.

• Harvesting: The leaves, flowers, and buds of the plants are harvested at specific times when the grayanotoxin content is highest.

• Extraction: To isolate grayanotoxin, the harvested plant parts undergo an extraction process, which may involve the use of organic solvents like ethanol or methanol. This process allows for the separation of grayanotoxin from other plant components.

• Purification: The extract containing grayanotoxin is purified using techniques such as chromatography or filtration to remove impurities and obtain a more concentrated product.

• Analysis and Standardization: Once purified, grayanotoxin is analyzed to determine its purity and potency. This step is crucial to ensure that the compound is suitable for scientific studies or therapeutic applications.

What it is used for and where

• Medical research. Despite their toxicity, graianotoxins have been the subject of medical research and have been investigated for their potential use in the treatment of hypertension and other cardiovascular diseases due to their effects on sodium channels.
• Parasite control. Some research has suggested that greyanotoxins may have potential use in pest control due to their toxic effects on certain insects and other pests.
• Traditional medicine. In some cultures, 'mad honey' has been used in traditional medicine for its alleged therapeutic effects, although this practice is risky and not recommended due to the potential for serious poisoning.

Negative effects:

• Honey poisoning. Graianotoxins are known to be present in 'mad honey', i.e. honey produced by bees that have consumed nectar from plants containing the toxin. Consumption of this honey can lead to 'mad honey disease', characterised by nausea, vomiting, salivation, headaches, blurred vision and, in severe cases, increased heart rate and blood pressure, irregular heart rhythms and even temporary paralysis.
• Neurological effects. Graianotoxins bind to sodium ion channels in cell membranes, altering their function. This can cause a range of neurological symptoms, including dizziness, hypotension and, in severe cases, cardiac arrhythmias and convulsions.

Health and Safety Considerations

Safety in Use
Grayanotoxin is highly toxic and should not be ingested in significant quantities. Symptoms of Grayanotoxin poisoning can occur within hours of consumption and include dizziness, weakness, vomiting, low blood pressure, bradycardia (slow heart rate), and, in severe cases, heart failure. Medical attention is required if poisoning is suspected.

Allergic Reactions
While allergic reactions to Grayanotoxin itself are rare, individuals may experience allergic responses to the plants that contain it or to honey made from their nectar. Additionally, those with pre-existing heart conditions should avoid exposure due to the cardiovascular effects of the toxin.

Toxicity and Carcinogenicity
Grayanotoxin is not considered carcinogenic, but its acute toxicity is well-documented. It affects the nervous system and cardiovascular system by altering the function of sodium channels in nerve cells, leading to serious and potentially life-threatening symptoms.

Environmental and Safety Considerations
Grayanotoxin is naturally occurring in the environment, particularly in regions where Rhododendron and other toxic plants grow. While the plants play a role in local ecosystems, human consumption of honey or plant material containing Grayanotoxin poses a health risk. There are no significant environmental hazards associated with the toxin in its natural setting.

Regulatory Status
Grayanotoxin is not commonly regulated as a specific substance, but its presence in honey is monitored in some regions where "mad honey" poisoning is a known risk. In these areas, authorities may issue warnings or guidelines to prevent accidental ingestion of toxic honey.

Most significant studies

Grayanotoxin containing honey, called “mad honey”, can cause dramatic effects when ingested as has already been recorded by the Greek warrior-writer Xenophon in 401 BC in his Anabasis. He showed that a certain type of honey produced in the coastal region of the Black Sea caused poisoning among the soldiers during a campaign against the Persian king Ataxerses II around 400 BC. The toxic honey is produced by R. Luteum and R. Ponticum, two members of the Rhododendron family, and its consumption can cause severe bradycardia and hypotension. Some honey types in certain geographical regions may cause toxic effects on people. This type of honey is known as “mad honey” in Turkey. The toxic ingredient of this honey is called Grayanotoxin I. The consumption of mad honey can cause severe bradycardia, hypotension, dizziness, nausea and vomiting. This study is aimed at analysing patients diagnosed with mad honey poisoning and their behaviour towards the consumption of this honey after diagnosis. This cross-sectional study was based on complaints and findings of mad honey poisoning. Patient information and findings at the time of admission were compared with those at one month after discharge through telephone interviews. They were asked if either they or their relatives had continued consuming the same honey. Frequency data such as gender, purpose of honey consumption, first complaints and continuance of honey consumption are shown as number (n) and percentage (%). A Chi Square test was conducted to determine the difference between groups. 38 patients were participated in this study; 18 of the patients had to be followed up in a coronary intensive care unit. We were able to reach 34 patients by phone after discharge. It was found that 12 of 16 patients discharged after emergency unit observation or their close relatives were continuing to consume mad honey, whereas 16 (88.9%) of the 18 patients under coronary intensive care had discontinued consuming mad honey. The difference in the continuation of mad honey consumption between patient groups followed-up in the intensive care unit and those discharged after emergency observation was statistically significant. Hazards associated with and serious consequences following the consumption of mad honey must be clearly explained to patients who are found to be consuming mad honey  (1).

Grayanotoxins have dose-dependent effects on honeybee motor function (2). Previous studies have shown that bees fed with toxins exhibit changes in behaviour that include failure to perform the righting reflex and more grooming and standing still (3).

References________________________________________________________________________

(1) Eroğlu SE, Urgan O, Onur OE, Denizbaşı A, Akoğlu H.  - Grayanotoxin (mad honey) - ongoing consumption after poisoning.  -    Balkan Med J. 2013 Sep;30(3):293-5. doi: 10.5152/balkanmedj.2013.8100. Epub 2013 Sep 1.

(2) Caitlin J. Oliver, Samantha Softley, Sally M. Williamson, Philip C. Stevenson, Geraldine A. Wright Pyrethroids and Nectar Toxins Have Subtle Effects on the Motor Function, Grooming and Wing Fanning Behaviour of Honeybees (Apis mellifera)  PLoS One. 2015; 10(8): e0133733. Published online 2015 Aug 17. doi: 10.1371/journal.pone.0133733

(3) Hurst V, Stevenson PC, Wright GA Toxins induce 'malaise' behaviour in the honeybee (Apis mellifera). J Comp Physiol A Neuroethol Sens Neural Behav Physiol. 2014 Oct; 200(10):881-90.