The 2016 campaign is spawning a new axiom in presidential politics: You can’t spell POTUS without pot.

For the first time, marijuana is becoming a significant policy issue for Republican and Democratic candidates — thanks in part to softening public attitudes toward the drug and Colorado’s prominent place on the political map.

“(Marijuana) is a topic that 2016 presidential candidates will not be able to avoid or dismiss with a pithy talking point,” said John Hudak, a fellow at the Brookings Institution, a think tank whose research has focused on the legalization push. “It is one that candidates will have to think about and engage.”

In the Republican primary, the candidates are making marijuana an issue on their own. New Jersey Gov. Chris Christie said he would enforce federal laws to crack down on pot use in states such as Colorado. Kentucky Sen. Rand Paul became the first major candidate to attend a fundraiser with the weed industry in his recent Denver visit.

But pot politics hit prime time with an extended exchange in last week’s GOP debate on CNN, which drew an audience of 23 million.

The focus on the topic is likely to intensify as the campaign trail leads to Colorado for the next GOP debate, in October.

“It’s a national debate that’s occurring, and Colorado has led the way,” said U.S. Sen. Cory Gardner, a Colorado Republican who opposed legalization.

On the GOP side, he said, “I don’t think you can talk about the states’ rights issue without talking about the biggest states’ rights issue of modern time.”

The Republican debate at the Ronald Reagan Presidential Library served as an appropriate backdrop to mark marijuana’s evolution. Three decades ago, Reagan championed the “war on drugs” and first lady Nancy Reagan popularized the “Just Say No” campaign.

The taboo remained when then-candidate Bill Clinton admitted in 1992 that he tried marijuana with the qualifier, “But I didn’t inhale.”

But the public’s mood is shifting. In 2013, Gallup found a 58 percent majority of Americans favored legalizing marijuana, for the first time. And this year, the well-regarded polling firm reported that 44 percent of Americans acknowledged they tried weed, the highest ever.

“In years past, marijuana was being brought up as sort of a gotcha question,” Hudak said in an interview. The most recent debate “was really the first time in a presidential debate that marijuana was brought up as a public policy.”

For Republicans, the issue remains a challenge, perplexing a number of candidates who have taken contradictory positions on the issue at different times.

Josh Penry, a Colorado adviser to Republican candidate Marco Rubio, said it’s an important issue that is here to stay.

“It becomes a proxy to argue, ‘Are you consistent or are you not consistent on these issues?’ ” he said. “I think it will continue to percolate in the national election, in part because of the importance of Colorado.”

In the debate, a few candidates engaged on the issue; others remained on the sidelines. The question, which the moderator said originated on social media, forced former Florida Gov. Jeb Bush to confess marijuana use in high school and served as a litmus test for the other candidates.

Paul cast it as a measure of conservatism, saying he supports a state’s right to legalize weed and suggested the enforcement pledged by Christie is federal overreach.

“I personally think this is a crime where the only victim is the individual,” Paul said of marijuana use. “And I think America has to take a different attitude.”

Bush opposed a 2014 ballot measure in Florida to legalize medical marijuana, but he agreed it’s a state issue.

“What goes on in Colorado, as far as I’m concerned, that should be a state decision,” he said.

Carly Fiorina, the former CEO of Hewlett-Packard, voiced concern about marijuana legalization. She invoked the story of her daughter’s death after addiction to alcohol and prescription pills.

“We must invest more in the treatment of drugs,” she said. “I agree with Sen. Paul. I agree with states’ rights. But we are misleading people when we tell them that marijuana is just like having a beer — it’s not.”

The comparison is a misnomer to the cannabis industry, but Gina Carbone, a co-founder of Smart Colorado, a group that wants greater protections for children, said it was an important moment.

“I think everyone needed to hear that kind of thing because that is exactly what we in Colorado are facing,” she said.

On the Democratic side, the legalization issue is a measure of liberalism, but so far the candidates are staking out middle ground.

The Marijuana Policy Project recently issued a report card on the stances of the candidates and is watching the election closely as it seeks to educate and influence both parties, said Mason Tvert, the group’s communications director.

A day after the debate, Democratic candidate Martin O’Malley visited Denver to meet with pot industry supporters and learn more about Colorado’s system.

“We should have this conversation and be informed by the true facts and the experience the people of Colorado are having on the ground here,” he said of marijuana legalization.

O’Malley and rival Vermont Sen. Bernie Sanders support decriminalization moves and medical marijuana. But Democratic front-runner Hillary Clinton is more cautious. All say they are watching Colorado for guidance.

Eric Sondermann, a Denver-based political analyst, said this attention is “both good news and bad news.”

“On the plus side, Colorado continues to be at the epicenter of the political world,” he said. “On the more problematic side, many leaders — starting with the governor and the economic development community — continue to be worried about pot being so increasingly central to the Colorado brand.”