Grayananes

Grayananes are a class of naturally occurring diterpenoid compounds found in certain members of the heath family (Ericaceae), most notably Rhododendron species such as Rhododendron ponticum and related azaleas. These compounds occur in plant tissues and can contaminate nectar and pollen. When bees forage on these plants, grayananes can be transferred to honey, a phenomenon known as mad honey, which has historically caused toxic exposures in humans and animals.

Chemistry and congeners: Grayananes comprise polyhydroxylated diterpenoids with a distinctive tricyclic or tetracyclic framework. The best known members are grayanotoxins, including GTX I, GTX II, GTX III, GTX IV, and related congeners. The chemical diversity among grayananes contributes to variations in potency and toxicokinetics.

Mechanism of action: Grayananes interact with voltage-gated sodium channels in nerve and muscle tissues. They bind to the channel and decrease inactivation, causing prolonged open states and sustained sodium influx. This leads to persistent depolarization, altered nerve signaling, and potential cardiotoxic effects, contributing to the clinical manifestations of grayanotoxicosis.

Occurrence and exposure: Natural sources include several Rhododendron species and related plants. Humans are most commonly exposed through ingestion of contaminated honey, particularly in regions where rhododendrons bloom abundantly. Other exposure routes are limited but possible through ingestion of plant material or essential oils containing grayananes.

Clinical features and management: Grayanotoxicosis presents with gastrointestinal symptoms (nausea, vomiting, abdominal pain), dizziness, vertigo, excessive salivation, and hypotension with bradycardia. Severe cases may involve syncope, confusion, or cardiac arrhythmias. Treatment is supportive care; atropine may be used for bradycardia, and monitoring is recommended in medical facilities.

Regulation and research: Grayananes are monitored in some jurisdictions due to their toxicity in honey. Research focuses on their chemistry, structure–activity relationships, toxicology, and the mechanisms by which they modulate sodium channels.