Silici S, Atayoglu AT. Mad honey intoxication: A systematic review on the 1199 cases. Food and Chemical Toxicology. 2015;86:282–290. DOI: 10.1016/j.fct.2015.10.018.
Published December 2015. A systematic review of case reports published between 1981 and 2014; first author at Erciyes University, Kayseri, Turkey. Subscription article; the abstract is freely available on PubMed (PMID 26547022).
Grayanotoxin poisoning from mad honey produces a characteristic hemodynamic profile (bradycardia, hypotension, and varying degrees of atrioventricular conduction block) that requires pharmacological management in moderate-to-severe presentations. The mechanism of toxicity (sustained activation of parasympathetic pathways through voltage-gated sodium channel modulation) makes atropine, a competitive muscarinic antagonist, the pharmacologically logical first-line intervention. Atropine blocks the excessive parasympathetic signaling at cardiac muscarinic receptors; its reversal of the effects in human poisoning is consistent with grayanotoxin increasing acetylcholine release from cholinergic nerves such as the vagus (EFSA 2023).
This theoretical rationale is well-supported by clinical experience documented across emergency case series from Turkish hospitals, the primary source of systematic mad honey poisoning data. The largest systematic review, by Silici and Atayoglu (2015), pooled 1,199 cases from case reports published between 1981 and 2014 and recorded presenting features, treatment (including the atropine doses given) and outcome.
Key Takeaways
- Atropine is the established first-line treatment for hemodynamically significant bradycardia from mad honey poisoning.
- Doses reported in the case literature are 0.5 to 2 mg IV (Ullah et al. 2018), and in the largest review most patients received 0.5 mg or 1 mg (Silici and Atayoglu 2015).
- Temporary pacing has been used for complete AV block and asystole (Ullah et al. 2018), and patients with cardiovascular disease on treatments such as beta-blockers may be at higher risk of adverse cardiovascular effects (EFSA 2023).
- Reported recovery times vary: mean symptom recovery was 1.04 hours in a Rize series of 82 patients (Yaylaci et al. 2015), and heart rate and blood pressure returned to normal within 2 to 6 hours in seven of eight patients in another series (Gunduz et al. 2006).
- Treatment is symptomatic: atropine plus supportive care (Ullah et al. 2018); most patients recover within 1 to 2 days (EFSA 2023).
Contents
Findings from the Case Literature
Reviews of the case literature report that saline infusion and atropine alone are almost always successful (Gunduz et al. 2008), and no deaths were reported among the 1,199 cases analysed by Silici and Atayoglu (2015). In published case series, symptomatic bradycardia generally responded to IV atropine at 0.5 to 2 mg given with intravenous fluids (Ullah et al. 2018).
Jansen et al. (2012) describe atropine in severe cases as most often given as 0.5 mg once, repeated once if heart rate and blood pressure do not respond, or as 2 mg once, together with saline. In the largest review, most patients were treated with 0.5 mg or 1 mg (Silici and Atayoglu 2015). In a minority of cases, atropine and saline are not enough. Epinephrine or dopamine infusion and temporary transvenous pacing are then suggested, and temporary pacing has been reported in three patients, for asystole and complete heart block (Ullah et al. 2018).
Recovery times reported in the case series range from about an hour to several hours. In a Rize series of 82 patients, mean recovery time of the symptoms was 1.04 hours (Yaylaci et al. 2015); in a series of eight patients, heart rate and blood pressure returned to normal within 2 to 6 hours in all but the one with complete AV block, and one patient needed a temporary pacemaker (Gunduz et al. 2006).
When Atropine Is Not Enough
In the case literature, escalation beyond atropine has been reported for complete AV block and asystole, for which temporary pacing has been used (Ullah et al. 2018). EFSA (2023), citing Okuyan et al. (2010), notes that patients with cardiovascular disease receiving anti-ischemic or antihypertensive therapy such as beta-blockers appear to be at higher risk of adverse cardiovascular effects. In a Rize series of 82 patients, symptoms began earlier and lasted longer in patients aged 65 and over (Yaylaci et al. 2015).
Consumed quantity is an imperfect but clinically relevant predictor. EFSA (2023) notes that the severity and onset of symptoms were reported to depend on the amount of honey eaten, but patients often describe that amount only as a spoonful (Aygun et al. 2018), and the effect also depends on the grayanotoxin concentration in the honey and its season of production (Ullah et al. 2018). Because honey potency varies unpredictably, quantity alone is not a reliable severity predictor, and the clinical ECG picture on presentation is more actionable for management decisions.
Supportive Care and Hospital Course
Beyond atropine, the management described across published cases is supportive: IV fluid resuscitation for hypotension, continuous cardiac monitoring, and observation until hemodynamic stability is confirmed. In the largest review, patients were generally discharged within 24 hours after recovery (Silici and Atayoglu 2015), and EFSA (2023) reports that patients generally recover within 1 to 2 days.
The clinical management is symptomatic and supportive (Ullah et al. 2018). This is clinically appropriate given the self-limiting nature of the toxin effect in the absence of ongoing ingestion. Serious complications are rare but documented: myocardial infarction has been reported after mad honey ingestion (Jansen et al. 2012; EFSA 2023).
Limitations of the Evidence Base
The evidence on atropine use in mad honey poisoning is constrained by the nature of the primary literature. Case series are inherently subject to selection and reporting bias. Severe cases are over-represented relative to mild cases that self-resolve without medical attention. Case series from a single geographic region (mostly Turkey’s Black Sea coast) may not generalize to poisoning presentations in contexts where the honey source, dose, or patient population differs. Randomized comparative data do not exist and are unlikely to be generated given the ethical and practical constraints of the clinical scenario.
Despite these limitations, the clinical direction is clear: saline infusion and atropine are almost always successful (Gunduz et al. 2008), and atropine is the appropriate first-line pharmacological intervention for hemodynamically significant bradycardia in grayanotoxin poisoning. The uncertainty lies in dose titration for individual cases and in managing the minority of presentations that do not respond adequately.
Sources
- Aygun A, et al. (2018), Grayanotoxin levels in blood, urine and honey and their association with clinical status in patients with mad honey intoxication. Turkish Journal of Emergency Medicine 18(1):29-33.
- EFSA CONTAM Panel (2023), Risks for human health related to the presence of grayanotoxins in certain honey. EFSA Journal 21(3):7866.
- Gunduz A, et al. (2006), Mad honey poisoning. The American Journal of Emergency Medicine 24(5):595-598.
- Gunduz A, et al. (2008), Clinical review of grayanotoxin/mad honey poisoning past and present. Clinical Toxicology 46(5):437-442.
- Jansen SA, et al. (2012), Grayanotoxin Poisoning: ‘Mad Honey Disease’ and Beyond. Cardiovascular Toxicology 12(3):208-215.
- Okuyan E, Uslu A, Levent MO (2010), Cardiac effects of “mad honey”: a case series. Clinical Toxicology 48(6):528-532.
- Silici S, Atayoglu AT (2015), Mad honey intoxication: A systematic review on the 1199 cases. Food and Chemical Toxicology 86:282-290.
- Ullah S, et al. (2018), Mad honey: uses, intoxicating/poisoning effects, diagnosis, and treatment. RSC Advances 8(33):18635-18646.
- Yaylacı S, et al. (2015), Is there a difference in mad honey poisoning between geriatric and non-geriatric patient groups?. European Review for Medical and Pharmacological Sciences 19(23):4647-4653.
