An owner of a shop selling legal highs and a shop worker have been arrested after nine people fell ill after taking the substances in Greater Manchester.
It comes on the eve of a UK ban on manufacturing or selling the products.
A number of people have required medical treatment, with two seriously ill, after taking legal highs in Rochdale, since Friday.
The arrests, on suspicion of supplying class B drugs, relate to a shop called Clear Vapour, which has been closed.
Two men aged 61 and 34 are being held as police investigate whether the legal highs contain any illegal substances.
Police said one of the four who collapsed in Rochdale on Tuesday after taking a number of legal highs including ‘Clockwork Orange’ had a cardiac arrest and is in intensive care.
The other man who became seriously ill on Friday and was in an induced coma has now recovered and been discharged, said police.
So-called legal highs are psychoactive drugs that contain various chemical ingredients, some of which are illegal while others are not. They produce similar effects to illegal drugs like cocaine, cannabis and ecstasy.
Greater Manchester mayor and police and crime commissioner Tony Lloyd said: “People are putting their lives in danger because of the misconception that these so-called ‘legal highs’ are safe. Spice, for example, is more dangerous than marijuana and can have fatal consequences.”
New legislation comes into force at midnight making it illegal to make or sell anything that has a psychoactive effect apart from alcohol, nicotine and caffeine and giving police new powers and sentences of up to the seven years for offenders.
Greater Manchester Police’s Supt Alistair Mallen said there has been an “alarming rise” in the number of people risking their lives by taking “potentially lethal substances”.
He renewed warnings about the dangers of legal highs and said this “worrying trend is becoming more and more common”.
400 lives lost
The minister for preventing abuse and exploitation Karen Bradley said an expert panel has been looking at the issue since before 2014 and decided a blanket ban on legal highs was the best solution.
“We are facing a threat that has cost so far over 400 lives.
“And it is really important that government takes those sort of threats seriously and we think this is the best way to tackle it.”
However, Rochdale Labour MP Simon Danczuk said it does not go far enough and the wording of the Psychoactive Substances Bill was “wholly inadequate”.
The Labour MP said: “They need to amend their legislation to make it stronger, so that it really disrupts the trade and closes down any loopholes which allow distribution of such harmful substances.”