Prescription drugs are now implicated in 70% of overdose deaths according to the latest official statistics.
The Health Research Board has found that methadone was implicated in nearly one third of drug deaths while the sedative diazepam was present in over one in four.
The National Drug-Related Deaths Index for 2016 found that deaths involving legal drugs is increasing and overdoses resulting from more than one drug or polydrug deaths increased from 44% of the total in 2004 to 62% in 2016.
Overall the statistics show that the number of poisoning deaths were 354 in 2016, down from a peak of 400 in 2013.
Deaths involving heroin and cocaine dropped sharply after 2009, deaths involving drugs classed as benzodiazepines, antidepressants and other prescription drugs more than doubled.
Deaths involving individual prescription drugs have shown the biggest increases between 2004 and 2016, Zopliclone up to 59 from five, while those from pregabalin a painkilling and anti anxiety drug has increased to 65 from 0.
Anti-anxiety drug Alprazalam increased to 46 from "less than five" in the same period.
Alcohol is the single most common drug to be implicated in fatal poisonings with a total of 132 deaths down from 143 in 2013.
Of the 16 drugs listed in the index only three - heroin, cocaine and MDMA or ecstasy - are illegal.
Deaths with heroin present were down to 72 from a peak of 114 in 2009, while 41 deaths with cocaine present were recorded - down from a peak of 65 in 2007.
However, deaths involving cocaine have increased in recent years up 70% since 2011.
There was MDMA present in eight overdoses down from 15 in 2014 while "new psychoactive substances" or head shop drugs are now implicated for "less than five" deaths compared to 30 in 2013.
Of all the deaths only 34 - or under 5% - involved people who were injecting drugs at the time.
More drug users died from non-poisoning causes for the second year in a row. There were 382 such deaths in 2016, including 24% by suicide, 15% from cardiac events and 12% from liver disease.
All drug related deaths combined were at 736, up 70% since 2004 when the figure was 431.