Prescription drugs now account for almost three quarters of overdose deaths.
New figures from the Health Research Board show there were 736 drug-related deaths in 2016 - an increase of more than a third in a decade.
Deaths involving heroin and cocaine have seen a fall.
However, there's been a significant increase in cases linked to antidepressants and other prescription medications.
In total, prescription drugs were implicated in 258 overdose deaths, with methadone linked with 103 deaths.
The HRB figures show that alcohol continues to be the number one drug implicated in deaths, either alone or with other drugs.
It was implicated in 132 (37%) deaths in 2016, compared to 112 deaths in 2015.
Image: Health Research BoardPrescription drugs
Dr Suzi Lyons, Senior Researcher at the HRB, explained: "For 2016 we continue to see that prescription drugs, and taking a cocktail of drugs contributes significantly to deaths from poisoning.
"Methadone and diazepam are the most common prescription drugs implicated.
"However, we are seeing some new prescription drugs emerging in recent years among the deaths figures."
She added: "Pregabalin, licensed for use in Ireland in the treatment of epilepsy, neuropathic pain or generalised anxiety disorder, was implicated in 14 deaths in 2013, but this has risen to 65 deaths in 2016".
The data also shows that half of all drug-related deaths in 2016 were people aged 42 years or younger.
5% of the total drug-related deaths were among people who were injecting drugs.
The majority (65%) of those died in Dublin city.
