When Sam Ross first created his smoky-spicy Penicillin cocktail back in 2005, “I was happy with it, but didn’t really think too much of it,” he says.

Riff Town Penichillin At Diamond Reef, this frozen riff on Sam Ross's Penicillin is made in large batches in a Slushie machine. The Braveheart Devon Espinosa created this deliberately non-smoky Penicillin variation during his tenure at The Tasting Kitchen. Rouge Tomate Penicillin Instead of smoky Islay Scotch, this version of the classic Penicillin cocktail gets topped with a spritz of mezcal. More Recipes →

That drink, a mix of mellow blended Scotch whisky, ginger juice, honey and lemon, crowned with a float of peaty Scotch, became a cocktail mainstay. Among the most well-traveled of the modern classics, the Penicillin has also become the source of countless riffs.

Yet, the Penicillin itself is a riff: Ross created it during his tenure at Milk & Honey, the space reborn in 2013 as Attaboy, as a variation on the bourbon-based Gold Rush, another Milk & Honey drink created by T.J. Siegal in 2001. The Gold Rush, meanwhile, has the DNA of an updated whiskey sour.

So it’s oddly satisfying to see it inspire yet another round of fresh variations. The question is whether any of them might become part of the next generation of modern classics.

Perhaps the most celebrated (and Instagrammed) right now is the frozen Penichillin at Brooklyn’s Diamond Reef, which is owned by the Attaboy team. Yet, the riffs range broadly. At Sidecar in Jacksonville, Florida, bartender Robbie Freeman turns out tall, foamy Penicillin Fizzes, built Ramos-style with heavy cream, egg whites and soda water; Atlanta’s AMER makes casual, fizzy Penicillin Pops with ginger beer in place of ginger syrup; and at NYC’s Rouge Tomate, the drink is given a culinary-minded makeover with the addition of fermented local honey and a bee pollen garnish. In place of peated Scotch, a spritz of jasmine-infused mezcal adds a smoky exhale.

Los Angeles has been particularly fertile turf for Penicillin variants; in 2007, Ross headed there as a consultant, building the bar program at the since-shuttered Comme Ça. “The bartenders I trained over there and introduced the Penicillin to, they went on to do their own programs at different places around town,” Ross recalls. “That’s how the Penicillin really spread hard throughout the West Coast.”

One of the most enduring West Coast variations is the Medicina Latina, credited to Marcos Tello, formerly of The Varnish, which substitutes tequila and mezcal for the blended and peated Scotches (and also subs in lime for lemon). This opportunity for a spirits split-take is one of the reasons that bartenders love experimenting with the Penicillin, Ross surmises.

“The idea of putting a fairly mild example of a spirit in as the meat of the cocktail, and then floating an extremely flavorful, smoky, funky variation of the base spirit on top—that’s an interesting idea to work with,” he says, noting that concept can expand beyond whiskey to agave (tequila or mezcal), rum (mild or funky) and beyond. “It’s a way of introducing people to more extreme flavors and sensations.”

Another popular LA riff: The Braveheart, a non-smoky variation that adds a rosy touch of Angostura, was created by Devon Espinosa during his tenure at The Tasting Kitchen in Venice Beach. Removing the smoky element made the drink “a lot more palatable,” while the bitters add depth, explains Espinosa. “People fell in love with it because it was delicious, but also easy to take down.” (He describes the Braveheart as “a down-the-hatcher.”)

Even though Espinosa left The Tasting Kitchen several years ago to take over the bar at The Venue, his drink remains a popular off-menu call. “I took that drink off the menu four years ago and it’s still our most popular drink,” said bartender Justin Pike in a 2015 interview with Los Angeles Magazine. “That damned Braveheart—the Penicillin variation that won’t go away.”