Wild honey from the Himalayan cliff bee Apis laboriosa, commonly known as mad honey, has been consumed across Nepal's mid-Himalayan belt for centuries for its perceived medicinal and psychoactive properties, yet its capacity to cause grayanotoxin poisoning has never been systematically documented. The bee forages on Rhododendron species whose nectar contains grayanotoxins, which become concentrated in the honey it produces. We reviewed 27 publications describing approximately 68 cases of grayanotoxin poisoning spanning five decades, situating the clinical epidemiology within the ecological framework of the Rhododendron-Apis laboriosa-human toxin pathway. Most cases originate in Gandaki Province, with Bagmati and Koshi Provinces increasingly represented. Middle-aged men account for roughly 72% of patients, predominantly self-treating hypertension or sexual dysfunction, and poisonings cluster sharply in spring when Rhododendron bloom and honey harvest coincide. Bradycardia and hypotension occur in nearly every case; a smaller subset develops neurological or psychiatric symptoms, and no fatalities have been recorded. Diagnosis remains entirely clinical, as grayanotoxin assay capacity is absent across all Nepali hospitals. Mad honey is increasingly traded online to consumers in North America, Europe, and East Asia who lack the dosing knowledge of traditional Himalayan communities, while A. laboriosa populations continue to decline from overharvesting and habitat loss. A thorough understanding of this toxin pathway is essential for evidence-based risk communication, trade regulation, and conservation of a critical high-altitude pollinator.

Grayanotoxin poisoning, commonly known as "mad honey" intoxication, is a rare but potentially life- threatening condition primarily affecting the cardiovascular system. It is characterized by bradycardia, hypotension, and, in rare cases, extreme QT interval prolongation, which predisposes patients to malignant arrhythmias. We report a 62-year-old male with no prior cardiac history who developed dizziness, nausea, and cold sweats 30 min after ingesting a tablespoon of mad honey. On admission, he exhibited sinus bradycardia, hypotension (70/40 mmHg), and marked QTc prolongation with giant inverted T waves on electrocardiogram. Laboratory and echocardiographic evaluations were unremarkable. The patient was managed with intravenous hydration and magnesium sulfate, resulting in rapid clinical and electrocardiographic recovery within 24 h. Grayanotoxins exert their toxic effects by modulating voltage-gated sodium channels, leading to sustained depolarization and impaired cardiac conduction. While bradycardia and hypotension are well-documented manifestations, extreme QT prolongation remains a rare but critical complication due to its association with ventricular arrhythmias such as torsades de pointes. This case underscores the importance of vigilant cardiac monitoring and electrolyte management in mad honey poisoning. Early recognition and appropriate supportive treatment can prevent fatal outcomes. Mad honey intoxication should be considered in patients presenting with unexplained bradycardia and hypotension, especially in endemic regions. Extreme QT prolongation, although rare, is a significant electrophysiological disturbance that necessitates prompt intervention to mitigate arrhythmic risk.

Objective: This study aims to explore the differences in chemical composition among Tibetan medicinal Rhododendron species and their potential correlation with anti-complement activity, with the goal of identifying promising medicinal resources. In Tibetan medicinal practice, the two groups of large-leaved Rhododendron (Tibetan: Dama) and small-leaved Rhododendron (Tibetan: Tali) are often used interchangeably despite unclear chemical and taxonomic bases. By comparing chemical profiles and evaluating anti-complement effects, this investigation seeks to provide preliminary scientific evidence for clarifying medicinal origins and facilitating the targeted development of high-quality resources. Methods: Ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS) was employed to analyze seven Rhododendron samples. Separation was achieved on a Waters CORTECS UPLC C18 column (2.1 × 100 mm, 1.6 μm) using a gradient mobile phase system consisting of acetonitrile and 0.1% formic acid in water, at a flow rate of 0.3 mL/min and a column temperature of 30 °C. Data were acquired in both positive and negative electrospray ionization (ESI) modes. Compound identification was performed using Peakview 1.2 software by comparison with databases and literature. Grey relational analysis and partial least squares (PLS) regression, combined with 5000 bootstrap resampling iterations, were applied to establish spectrum-effect relationships and to screen for characteristic peaks potentially associated with anti-complement activity. Results: A total of 52 compounds were tentatively identified, including flavonoids (e.g., hyperin, isoquercitrin, taxifolin-3-O-arabinoside), terpenoids (e.g., grayanotoxin I/III), and chromanes (e.g., anthopogochromane series). The CH50 values of the ethanol extracts ranged from 179.29 to 579.47 μg/mL, with Rhododendron principis showing the strongest activity (179.29 ± 11.86 μg/mL), followed by Rhododendron vellereum (198.61 ± 7.93 μg/mL). Spectrum-effect analysis revealed that four unidentified peaks (F5315, F5822, F5368, F5991) exhibited negative regression coefficients and VIP means close to or above 0.8, suggesting a possible positive correlation with anti-complement activity. Among these, F5315 (VIP = 0.909), F5822 (VIP = 0.877), and F5368 (VIP = 0.834) showed relatively higher values and were considered preliminary candidate peaks warranting further investigation. Conclusions: This study tentatively identifies 52 compounds from the ethanol extracts of seven Tibetan medicinal Rhododendron species and reports their anti-complement activities. The findings reveal chemical distinctions between the large-leaved (Dama) and small-leaved (Tali) groups, offering a potential chemical basis for species differentiation and quality evaluation. Furthermore, four unknown peaks were preliminarily screened through spectrum-effect analysis as potential anti-complement candidates, which may serve as a foundation for future activity-guided isolation and quality marker studies.

The composition of low-polarity extracts obtained by sequential extraction of the aerial parts of Rhododendron adamsii Rehd. with hexane and methyl tert-butyl ether (MTBE) was investigated using GC-MS. The hexane extract was dominated by non-polar components: squalene, n-alkanes (nonacosane, hentriacontane), sesquiterpenes (trans-nerolidol, spathulenol, β-farnesene), and β-sitosterol. The subsequent MTBE extract was enriched in more polar lipids, primarily free triterpenic acids (ursolic and oleanolic acids). A critical finding was the complete absence of diterpene grayanotoxins in all tested extracts, confirming the safety of the non-polar extraction approach. In bioactivity assays, the total hexane extract demonstrated potent inhibitory activity against the SARS-CoV-2 main protease (3CLpro) with IC50 values of 0.0125-0.025 mg/mL, only one order of magnitude higher than the reference inhibitor disulfiram. Fractionation revealed that the activity was distributed among free acids, bound acids, and the unsaponifiable residue, indicating a multicomponent mechanism. Importantly, none of the samples inhibited HIV-1 protease (IC50 > 0.1 mg/mL), demonstrating selectivity for the cysteine protease 3CLpro over the aspartyl protease of HIV-1. These results highlight that sequential non-polar extraction of R. adamsii provides a grayanotoxin-free lipophilic complex with selective anti-SARS-CoV-2 protease activity, paving the way for bioactivity-guided identification of individual inhibitors.

Mad honey contains the neurotoxin grayanotoxin, which is produced by the flowers and nectar of the Rhododendron family. Bees incorporate this toxin into honey. Mad honey is consumed as a medicinal remedy in certain parts of the world, leading to persistent vagal activation and potentially serious complications, including hemodynamic instability. We report the case of a 75-year-old male patient with a medical history of hyperlipidemia and hypertension (managed with atorvastatin 20 mg and amlodipine 5 mg, respectively) who presented to the emergency department complaining of near-syncope, dizziness, lethargy, nausea, and one episode of diarrhea one hour after ingesting 20-30 mL of wild honey brought as a gift from abroad. On presentation, he was conscious and alert. Triage observations revealed a blood pressure of 65/41 mmHg, a heart rate of 45 beats/minute, a respiratory rate of 20 breaths/minute, an oxygen saturation of 98% on room air, and a temperature of 36.8°C. Physical examination was unremarkable. Electrocardiogram demonstrated sinus bradycardia. The patient was resuscitated with intravenous fluids and 0.6 mg of intravenous atropine, which normalized his heart rate and blood pressure within seconds. He was admitted for observation for 36 hours and was discharged without sequelae. Mad honey poisoning is rare in the United Kingdom and requires a high index of suspicion. Symptoms of hypotension and bradycardia following honey consumption should alert clinicians to this poisoning. Treatment with atropine is successful in alleviating symptoms, which typically resolve within 24 hours.

This article reviews cardiotoxic syndromes in ruminants caused by various toxins, including ionophores, vitamin E/selenium deficiencies, gossypol, Taxus plants, cardiac glycosides, grayanotoxins, and others. It emphasizes that early recognition, thorough history, and diagnostic sampling are crucial for accurate diagnosis. Since no specific antidotes exist, prompt removal of the toxic source and environmental management are key to improving outcomes. Understanding clinical patterns and implementing herd-wide prevention strategies are vital for reducing morbidity, mortality, and long-term health impacts in affected animals.

Plant poisoning in animals, often associated with wild and ornamental species, is a significant concern in veterinary medicine. Due to clinical signs observed in humans after consuming "mad honey", interest in grayanotoxins, produced by Ericaceae plants, has increased. However, effects on animal health have been scarcely addressed despite their interest for veterinary toxicology. This systematic review, following PRISMA guidelines, identified 31 records of grayanotoxin poisoning in animals following the ingestion of plants, affecting a total of 111 livestock and 11 companion animals. Cases were predominantly reported in livestock, namely sheep and goats, and less frequently in companion animals, including dogs, cats, rabbits, tortoises, and pigs. Studies report an estimated toxic dose of 0.1 % of body weight in fresh foliage for ruminants. Rhododendron spp. and Pieris japonica were the most frequently reported plants. Common clinical signs and treatment were summarized. Retching, regurgitation, and vomiting were common and might be suggestive of plant poisoning in ruminants. Reports on grayanotoxin poisoning in animals must be improved to address existing knowledge gaps.

Grayanotoxin III (GTX III), isolated from Leucothoe grayana Max., was chemically converted into kalmanol, seco-rhodomollone, rhodomollein XXIV, and rhodomollein XXIII in accordance with their proposed biosynthetic hypotheses. The key skeletal rearrangement from the grayanane to the kalmane framework was achieved at low temperature by introducing triflate as the leaving group of the C14 hydroxyl group. Subsequent regio- and stereoselective hydration and global deprotection gave kalmanol in a total of six steps from GTX III. Further conversion to seco-rhodomollone, rhodomollein XXIV, and XXIII demonstrated the putative biosynthetic pathway of these natural products. The present findings establish the route to structurally complex and rare kalmane diterpenoids, which can serve as potential lead compounds for drug discovery and advance the overall understanding of the biogenetic pathway of grayanoids.