The National Drug-Related Deaths Index also shows that prescription drugs continue to account for the greatest amount of poisonings.
The index, compiled by the Health Research Board, shows that a total of 695 deaths were caused by drugs in 2015, or almost two people per day.
Down from 719 in 2014 (the highest on record), it comprised 348 poisonings (overdoses) and 347 non-poisoning deaths.
The latter comprises of 156 trauma fatalities, such as suicides, and 191 medical deaths, such as cardiac events.
The index report showed that polydrug use was implicated in 222 deaths in 2015 (out of 348), compared to 118 such deaths in 2004 (44% of all deaths then).
It said the trend involving a mixture of substances has risen steadily since.
“The number of deaths involving prescription drugs or cocktails of different drugs remains high,” said Dr Mairead O’Driscoll, interim chief executive of the HRB.
“Mixing drugs increases the risk of death, which is clearly reflected in these figures. This year we continue to see an increase in the number of poisonings from cocaine.”
The index shows that nine out of 10 deaths where methadone (the legal substitute for heroin) was implicated involved other drugs, mainly benzodiazepines, a group of prescription drugs comprising tranquillisers and anxiety medication.
Seven out of 10 heroin-related deaths involved other drugs, again mainly benzodiazepines.
Some 93% of deaths involving cocaine included other drugs, mainly benzodiazepines and heroin, followed by methadone and alcohol.
Almost six out of 10 alcohol deaths involved other drugs, again benzodiazepines the main one, followed by heroin, methadone and cocaine.
Overall, the number of poisoning (overdose) deaths stood at 348 for 2015. This is a drop on previous years, reaching a high of 400 deaths in 2013 and down to 364 in 2014.
The HRB said the 2015 figure was “likely” to be revised upwards as data becomes available from closed inquest files.
Prescription drugs were involved in two thirds of all overdose deaths in 2015.
In terms of the main drugs involved, Diazepam (a benzodiazepine) was involved in 101 deaths (down from 118), the second highest for all drugs after alcohol.
The sedative Zopiclone was implicated in 62 deaths (down from 73) and Flurazepam (sleeping tablet) was involved in 33 deaths (down from 36).
But there was a major jump in deaths involving Pregabalin (an anti-epileptic medication which can be used for chronic pain and anxiety), increasing from 26 to 44.
Alcohol was still the number one drug implicated in deaths, with 107 fatalities (down from 117 in 2014).
Methadone was in third place, with 86 deaths (down from 103), followed by heroin (82, down from 94).
The drop in heroin deaths followed a period where such fatalities increased from 64 in both 2011 and 2012 to 87 in 2013 and 94 in 2014.
Fatalities in which new psychoactive substances (NPS) were involved fell significantly from 25 in 2014 to seven in 2015.
Deaths involving MDMA or ecstasy dropped (from 15 to 8). Fentanyl (a potent synthetic version of heroin) was involved in seven deaths.