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."
Four people had to be treated in hospital after taking what is thought to be ecstasy.