Extra patrols have been launched to deal with an increase in anti-social behaviour fuelled by the drug, said to leave users in a "zombie-like" state.
Officers were called to 58 incidents related to Spice in the city centre between Friday and Sunday.
"We cannot afford" for the problem to get worse, Ch Supt Wasim Chaudhry said.
Effects of the synthetic drug can be extreme, causing hallucinations, psychosis, muscle weakness and paranoia.
Ch Supt Chaudhry said officers were doing all they could to tackle the issue but "a multi-agency approach is the only way we can fight this battle".
"The truth is, tackling the issues caused by Spice is putting pressure on public services and is taking up a lot of our resources, particularly in Manchester city centre," he said.
"Those who take Spice are often left incapacitated or seriously ill and need the help of our partners in the NHS and ambulance service.
"They can also become aggressive and become a danger to themselves and others."
He said it was "a problem that we cannot afford to get any worse".
The Greater Manchester force has increased the number of specially-trained officers dealing with the issue.
It has also been working with Manchester City Council's adults and children's services, rough sleeper and outreach teams, local charities, as well as North West Ambulance Service and the NHS, he said.
Councillor Pat Karney said he wanted to discuss the problem with Home Secretary Amber Rudd because "the experience in Manchester is going to spread up and down this country".
"What is happening in Manchester will happen nationally so the next steps we're taking is to see the chief constable and review the situation, and then we're going to be seeking a meeting with the home secretary," he said.
Daniel Gerrard, Founder of Addiction Helper and Family Interventionist, believes that the term 'Legal High' is where the problem really started, as it stigmatised the drugs in such a way that it made them more widespread and acceptable to use.
"Illegal Highs like Spice should be classed as Category A Drugs. This will allow us to educate those using and those thinking of trying it for the first time that extremely serious consequences are attached with this drug.
"My experience with those addicted to Spice is that they can be very volatile and present with mental health issues, often without mental health being an issue prior to using Spice.
"The fact of the matter is that more and more addicts are dying and the addiction problem continues to rise. Addiction treatment should not be reduced because of austerity, as the recent crisis with this drug should make quite clear."
A rise in the use of former legal high Spice in Manchester is putting pressure on public services, police say.