The number of cases in which novel psychoactive substances were identified as the cause of death rose from 10 in 2009 to 68 in 2012.
The research by St George's, University of London, also shows the prevalence of the drugs in post-mortem toxicology tests increasing from 12 in 2009 to 97 in 2012 - an increase of 800%.
Professor Fabrizio Schifano, spokesman for the National Programme on Substance Abuse Deaths (NPSAD), warned those experimenting with such substances were "effectively dancing in a minefield".
He said: "We have observed an increase in the number and range of these drugs in the post-mortem toxicology results and in the cause of death of cases notified to us.
"These include amphetamine-type substances, dietary supplements, ketamine derivatives, among a host of others.
"The worrying trend is that these type of drugs are showing up more than ever before.
"Clearly this is a major public health concern and we must continue to monitor this worrying development.
The report follows the launch of a review of legal highs by crime prevention minister Norman Baker, which is being spearheaded by experts including the Government's drug tsar Professor Les Iversen.
The panel will consider widening legislation to boost police and law enforcement agencies' powers to help protect public health and further tighten the supply of such substances,
The review is expected to be completed in the next few months.
Mr Baker said: "I am determined to clamp down on the reckless trade in so-called 'legal highs', which, as this report shows, has tragically claimed the lives of far too many people in our country."
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