Health leaders are pleading with Victoria's premier to urgently open a supervised injecting room in Melbourne's CBD after "countless" overdoses.

In an open letter published before Daniel Andrews announced his resignation on Tuesday, the leaders from organisations including the Australian Medical Association, the Royal Australian College of General Practitioners and not-for-profit Cohealth called on him to deliver on his 2020 promise to establish the state's second overdose prevention service.

The plan for the CBD-based injecting room remains in limbo after a Salvation Army hub on Bourke Street was flagged as a potential site in July.

"Since your announcement more than three years ago, unsafe injecting continues on the streets of Melbourne and drug harms in the City of Melbourne have worsened," the letter said.

"In the last three years, more than 40 people have lost their lives to drug overdoses in the CBD, and countless others have suffered non-fatal overdoses in city streets.

"There have been more than a thousand heroin-related ambulance callouts in the CBD."

Overdose prevention was "basic healthcare" and the evidence was clear it saved lives, the leaders said.

They commended the premier for his promise to set up a supervised injecting room in Melbourne's CBD, but said he stood at "the precipice of a significant decision".

"A new service in the CBD will be an important legacy of your government," the leaders said in the letter.

"However, it has now been three years since you announced your policy, and too many people are no longer with us.

"We urge you to honour your government's policy and urgently establish an overdose prevention service in the Melbourne CBD."

Cohealth addiction medicine specialist Paul McCartney said he and his colleagues treated people with opioid use disorder each day, which helped to reduce mortality, crime and social dysfunction.

"The problem is that we can't provide that treatment to people who are dead," he told reporters.

Lisa Peterson, speaking at Baptist Place in the CBD, said she had previously used drugs in the laneway, which the community knew as a safe injecting space.

The laneway was fitted with a light, a sharps container and had access to fresh water, and outreach workers would frequently visit.

"Since there was talk of a safe injecting space, this has closed down, and now there is nowhere safe for people to go and use," Ms Peterson said.

Former Victorian police commissioner Ken Lay delivered his report on drug-taking patterns in the CBD to Mental Health Minister Gabrielle Williams in June but it is yet to be released.

The Victorian government says it is still considering its response.

The Lay report highlighted the matter's complexity and the government was taking time to get it right, a government spokeswoman said.

The latest state budget included $372 million in alcohol and other drug support and services.

Tuesday's open letter had the support of Keep Our City Alive, a group of CBD residents, business owners and community members and the Victorian Greens.

CBD resident Jill Mellon-Robinson said: "medical and health professionals are telling us the solution, so why aren't we listening?"