Decoding Alexander the Great’s gastrointestinal cause of death using artificial wisdom: An artificial intelligence-human inquiry into a medical mystery

Table 1 ChatGPT’s reasoning for rejection of alternative diagnoses in Alexander the Great’s death

Cause of death	Explanation
Poisoning theories	The symptoms of the poisons speculated do not match as closely with the full range of symptoms Alexander exhibited, especially the neurological ones. Most poisons would have caused a more rapid deterioration and death, unlike the 12 days of illness Alexander endured
Acute pancreatitis from alcohol consumption	This cause is plausible given Alexander’s history of heavy drinking. However, the progression of symptoms and his ultimate neurological signs do not align as well with pancreatitis, which typically would not lead to paralysis or a ‘locked-in’ state
Malaria	While malaria is a strong contender due to the endemic nature of the disease in the region and his symptoms, the lack of specific mention of periodic fever cycles and symptom onset typical of malaria slightly weakens this argument compared to the detailed matching of typhoid fever symptoms
WNV encephalitis	This is less likely due to the historical and epidemiological inconsistencies regarding the presence of WNV in that era. Furthermore, Alexander’s symptoms do not entirely match the typical clinical presentations of WNV

WNV: West Nile virus.

Table 2 Evaluation of sources cited by ChatGPT: Accuracy, contextual fit, and misapplication[7,10,18,19,38,50,59-73]

No.	Source	Ref.	Source type	ChatGPT’s summary of source	Average score1	Remarks
1	Did Alexander the Great die from Guillain-Barré syndrome? In: Howe T, Anson E, Balmaceda C, Fronda M, Hollander D, McAuley A, Muller S, Vanderspoel J, Wheatley P, Dunn C, editors. Ancient History Bulletin, 2018: 106-128	Hall[18]	Book	Alexander the Great and the Guillain-Barré syndrome hypothesis	11	This source actually argues that Campylobacter jejuni is the cause of the GBS rather than typhoid while ChatGPT uses it to argue for typhoid. It is a source that was taken out of context to support the argument that typhoid caused GBS, when the paper argued the opposite
2	Typhoid fever. Lancet 2015; 385: 1136-1145	Wain et al[19]	Journal	Clinical progression and symptoms of typhoid fever	8.5	No mention of typhoid causing GBS. It is also wrongly cited as the paper was in the journal lancet not nature
3	Infectious causes of Guillain-Barré syndrome. Curr Opin Neurol 2016; 29: 419-425	Willke A, Ergonul O (fictitious reference)	Journal	Supported the possibility of Guillain-Barré syndrome as a complication of infections like typhoid	7.5	Unable to locate source article. Citation likely to be erroneous
4	Alexander the Great: Murder in Babylon. London: Virgin Digital, 2012	Phillips[59]	Book	Introduced strychnine poisoning theory involving Roxanne	4.5
5	Historical principles and perspectives in toxicology. Toxicol Pathol 1999; 27: 129-138	Wax PM (fictitious reference)	Journal	General toxicological background relevant to ancient poisoning theories	0	Unable to locate source article. Citation likely to be erroneous
6	Calicheamicin gamma 1I: An antitumor antibiotic that cleaves double-stranded DNA site specifically. Science 1988; 240: 1198-1201	Zein et al[60]	Journal	Describes the chemical properties of calicheamicin, related to the Styx river poisoning theory	5
7	Was the death of Alexander the Great due to poisoning? Was it Veratrum album? Clin Toxicol (Phila) 2014; 52: 72-77	Schep et al[50]	Journal	Evaluates the white hellebore poisoning theory	9
8	Alexander of Macedon, 356–323 B.C.: A Historical Biography. University of California Press, 2013	Green[38]	Book	Provided background and narrative of Alexander’s final days	4.5
9	Acute pancreatitis. N Engl J Med 2016; 375: 1972-1981	Forsmark et al[61]	Journal	Supported acute pancreatitis hypothesis from excessive alcohol use	9.5	Authors’ names wrongly cited
10	Malaria. [cited October 17, 2025]. Available from: https://www.who.int/news-room/fact-sheets/detail/malaria	World Health Organization[62]	Website	Described malaria symptoms and prevalence	8	Unlikely, but still a possibility as malaria is always an infectious consideration
11	Pathogenesis, clinical features, and neurological outcome of cerebral malaria. Lancet Neurol 2005; 4: 827–840	Idro et al[63]	Journal	Provided evidence supporting cerebral malaria as a cause of neurological symptoms	3.5
12	Conquest and Empire: The Reign of Alexander the Great. Cambridge University Press, 1993	Bosworth[64]	Book	Historical reference for Alexander’s campaigns and death context	6
13	Alexander the Great and West Nile virus encephalitis. Emerg Infect Dis 2003; 9: 1599-1603	Marr and Calisher[7]	Journal	Proposed West Nile virus encephalitis theory	5
14	West Nile virus: A primer for the clinician. Ann Intern Med 2002; 137: 173-179	Petersen and Marfin[65]	Journal	Clinical background on WNV symptoms	5.5
15	Lives, Volume VII: Demosthenes and Cicero. Alexander and Caesar. Loeb Classical Library 99. Cambridge, MA: Harvard University Press, 1919	Plutarch[10]	Book (translated pri source)	Primary historical source detailing events of Alexander’s death	8
16	The Campaigns of Alexander. London: Penguin Classics, 1976	Arrian[66]	Book (translated pri source)	Primary source documenting Alexander’s military and health history	7.5
17	Ancient Medicine. 2nd ed. London: Routledge; 2012	Nutton[67]	Book	Context for medical practices and understandings in antiquity	6
18	Greek Fire, Poison Arrows & Scorpion Bombs: Biological and Chemical Warfare in the Ancient World. New York: Overlook Press; 2003	Mayor[68]	Book	Insight into ancient biochemical warfare and poison use	4.5
19	Alexander the Great: The Hunt for a New Past. London: Overlook Press, 2004	Cartledge[69]	Book	Reinterprets Alexander’s life and legacy, including his final illness	6.5
20	Alexander the Great: Man and God. 1st ed. London: Longman, 2004	Worthington[70]	Book	Provides historical analysis including character traits possibly relevant to health behavior	3.5
21	Fiction as History: Nero to Julian. 1st ed. Berkeley: University of California Press, 1995	Bowersock[71]	Book	Used to contextualize propaganda and myth in ancient historical narratives	5
22	Who’s Who in the Age of Alexander the Great: Prosopography of Alexander’s Empire. 1st ed. Oxford: Wiley-Blackwell, 2006	Heckel[72]	Book	Provides biographical insights into Antipater and others possibly involved in poisoning	3.5
23	Guillain-Barré Syndrome. Nat Rev Neurol 2020; 16: 10-20	Engel N (fictitious reference)	Journal	Contemporary clinical reference for GBS symptoms and progression	0	Unable to locate source article. Citation likely to be erroneous
24	The Death of Alexander the Great: Rumour and Propaganda. Classical Quarterly 1971; 21: 112-136	Bosworth[73]	Book	Explores the use of rumor and misinformation surrounding Alexander’s death	5.5	Author wrong

¹Average score: Average total score given by two reviewers for clinical plausibility (0-3), source reliability (0-3), cultural context fit (0-3), relevance (0-3). Maximum score of 12, with full details in Supplementary Table 2.

GBS: Guillain-Barré syndrome; WNV: West Nile virus.

Table 3 Differential diagnosis matrix of ChatGPT and human expert assessment

Diagnosis	ChatGPT rank	Human assessment	Symptom alignment	Source quality	Final verdict
Typhoid + GBS	Most likely	Less likely	Moderate	Weak (some misapplied)	Rejected
Campylobacter jejuni + GBS	Mentioned, not top-ranked	Most likely	Strong	High	Supported
Acute pancreatitis	Moderate	Unlikely	Partial	Good	Rejected
Malaria	Moderate	Plausible	Partial	Good	Inconclusive
West Nile virus encephalitis	Low	Rejected	Weak	Poor	Rejected
Poisoning (various)	Low	Rejected	Weak	Variable	Rejected

GBS: Guillain-Barré syndrome.