The Victorian health department issued an urgent drug alert on Wednesday, after four overdoses occurred in a two-week period.
In all four cases, the patients are believed to have unknowingly consumed heroin while taking either cocaine or methamphetamine.
All four were aged in their 20s.
The three patients who survived each required resuscitation upon admission to hospital.
The source of the tainted drugs is not yet clear, though Victoria's chief addiction medicine officer said the incidents were largely unrelated.
"(The overdoses) were a little bit spread out over time and at sites around Victoria, which made it more concerning for us," Dr Paul McCartney told reporters on Thursday.
Two people were hospitalised in separate incidents, while the third hospitalisation and death occurred in the same environment.
Specialised blood tests detected heroin as well as cocaine and methamphetamine across the four hospitalisations.
This suggests heroin, an opioid, had been mixed with the stimulants, compounding risks of overdose.
"Having heroin in your system causes an opposite effect to what you'd expect from methamphetamine and cocaine," Dr McCartney said.
He said the infiltration of heroin into methamphetamine and cocaine was highly unusual and the extent of the spread is not clear.
The department is urging Victorians to take advantage of drug testing services where necessary and to understand the risks.
"Small amounts of opioids can cause life-threatening overdose, especially in people who have never used opioids or only use them occasionally," the alert said.
Signs of possible opioid overdose include slow or stopped breathing, reduced consciousness and pinpoint pupils.
Anyone witnessing an overdose should contact triple zero immediately and those at risk of overdose should carry naloxone, the department said.
The life-saving medication can reverse a heroin overdose and be accessed for free at some pharmacies and health services.
Victoria recorded 584 fatal overdoses in 2024, the highest level in a decade, according to state's Coroners Court data.
While the per capita rate remained relatively stable over that period, cases involving illicit drugs increased substantially.
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