Police were first called to St James Boulevard in Newcastle just after midnight due to concerns for a man, 21, and an 18-year-old woman.
Her condition is described as potentially life-threatening.
An hour later, another couple, both 18, also had to be taken to hospital after becoming ill in the city centre.
Northumbria Police said a quantity of drugs, believed to be ecstasy, had been seized and inquiries were ongoing.
Det Inst Sally MacDonald said: "Taking illegal drugs is incredibly dangerous and the fact four people have been taken ill in just one evening is particularly worrying."

Secret service and regular police have been searching for Ivan Kaspersky, 20, for at least two days, a police source told Interfax news agency.
His father's firm, Kaspersky Lab, told a newspaper it could not confirm news he had been abducted.
Yevgeny Kaspersky made his fortune developing anti-virus software.
News of his son's abduction was reported by Russian news website Life News, quoting its own sources.
The kidnappers are demanding 3m euros (Â£2.6m; $4.3m) for Ivan's safe return, the website says.
According to the unconfirmed report, he was snatched while on his way to work in Moscow on Tuesday.
When contacted by Russian newspaper Gazeta, Kaspersky Lab said it could neither confirm nor deny the report.
There has been no official comment on the story.
Kaspersky Lab is regarded outside Russia as one of the country's few business success stories not related to the energy sector.
The US business magazine Fast Company recently ranked Kaspersky Lab among the Top 50 Most Innovative Companies worldwide.

Ednane Mahmood, 19, from Blackburn, Lancashire, then fled his home to allegedly travel to Syria to fight for so-called Islamic State (IS).
The video showed the beheading of David Haines and aid worker Alan Henning kneeling on the ground after his kidnap, Manchester Crown Court heard.
Mr Mahmood denies all charges.
He has pleaded not guilty to attempting to travel to Syria to commit acts of terrorism.
Mr Mahmood also denies two counts of providing internet links to others with speeches and propaganda that encouraged acts of terrorism.
He searched "British man beheaded" on his laptop before downloading the video, the court was told.
It began with Prime Minister David Cameron talking about IS before images showing the beheading of Mr Haines.
Julian Evans, prosecuting, said Mr Mahmood, "undeterred by this graphic and violent imagery", began looking up cheap flights to Bulgaria and Turkey.
Then in the early hours of 18 September 2014, he left his home to board a flight from Manchester Airport to Bulgaria leaving a letter addressed, "to family", stating his intentions.
Mr Evans said: "He was telling his family in the clearest terms that he was leaving the comforts of his life in the UK in order to fight abroad on behalf of Allah and on behalf of Muslims.
"He did not care what others might think of him and his decision.
"Mr Mahmood planned to travel to Syria with the intention of committing acts of terrorism."
The court heard his family had been unaware of his intentions and on the day he fled had reported him missing to police.
Before he reached Syria, Mr Mahmood's brother persuaded him to come back to the UK via communications over Twitter.
Mr Mahmood's interest in Syria, Jihad and IS was said to have developed over time from 2012, the court heard.
The trial continues.
Four people had to be treated in hospital after taking what is thought to be ecstasy.
[NEXT_CONCEPT]
The son of Russian software entrepreneur Yevgeny Kaspersky has gone missing in Moscow and may have been kidnapped, Russian media report.
[NEXT_CONCEPT]
A man accused of terrorism offences downloaded a video showing a British aid worker being beheaded, a court heard.