“The lay public has really taken on the notion of the entourage effect, but there’s not a lot of data,” says Margaret Haney, a neurobiologist at Columbia University and cannabis researcher. “The cannabis field can say anything and it does. I’m not against marijuana. I want to study it carefully. We know it can affect pain and appetite but the large majority of what’s being said is driven by anecdotal marketing. These guys are really trying to make money.”
The U.S. Food and Drug Administration in 2016 approved another oral THC formulation called Syndros: pure, synthetically produced THC dissolved in alcohol. The U.S. Drug Enforcement Administration startled many marijuana proponents last month when it placed Syndros on Schedule II of the Controlled Substances Act, making it federally legal to prescribe. Despite the active ingredient being exactly the same THC molecule, the plant and most other forms of marijuana remain firmly in Schedule I—along with heroin, LSD and other drugs the DEA says have no accepted medical use and a high potential for abuse.
Still, there is no hard evidence that the entourage effect is real. Double-blind clinical trials, the gold standard for research studies in medicine, have never been conducted to investigate the effects of marijuana’s terpenes or its cannabinoids other than THC.
The entourage effect gained some ground in 2011 when Russo published a paper in the British Journal of Pharmacology reviewing the potential interactions between THC and various cannabinoids and terpenes. For example, he cites work suggesting alpha pinene—a terpene that gives some marijuana a fresh pine scent—might help preserve a molecule called acetylcholine, which has been implicated in memory formation. “So one main side effect of THC is short-term memory impairment,” he says. “People go, ‘Uh…what were you saying?’ That can be prevented if there’s pinene in the cannabis.”
“As is often the case with cannabis, lore is law,” said Mowgli Holmes, a geneticist and founder of a cannabis genetics company Phylos Bioscience. Photo by Mario Anzuoni/Reuters
And as is often the case with cannabis, lore is law, Holmes says. The entourage effect idea has firmly taken root in the cannabis industry and among consumers. Marijuana dispensaries have begun listing and advertising various cannabinoid ratios and providing detailed terpene profiles in certain strains and products. Laboratories specialize in testing weed for these compounds. Companies such as NaPro Research and Phylos have begun working out how to breed cannabis varieties with specific levels of popular terpenes—including limonene and pinene as well as myrcene, which some believe potentiates THC’s effects—for a designed experience.
“We’ve done a lot of focus groups and data collection and analysis when we started [Level Blends], and 80 or 85 percent of people fall right into the effect we say they will get,” Emerson says. “We don’t understand how all these things are working in concert. But I put everything on the line for this, because I know this so strongly.”
What gives cannabis “character,” in Holmes’s view, are the hundreds of other chemicals it contains. These include THC’s cousin cannabinoids such as cannabidiol, along with other compounds called terpenes and flavonoids. Whereas terpenes are generally credited with giving pot its varied fragrances—limonene, for example, imparts a snappy, citrusy perfume—the cannabis industry and some researchers have espoused the controversial idea that such compounds can enhance or alter THC’s psychoactive and medicinal properties.
“The biggest influence [in the entourage effect] is CBD,” says psychopharmacologist Ethan Russo, a cannabis researcher in Washington State and medical director of the biochemical research company Phytecs. About 10 milligrams of THC can potentially cause toxic psychosis—or THC-induced, psychotic-like symptoms such as delusions—in about 40 percent of people, he says. On the other hand, Sativex—a multiple sclerosis medication not approved in the U.S. that GW Pharmaceuticals (where Russo worked for many years) started selling in the U.K. in 2010—“has equal amounts of THC and CBD,” he adds. “At amounts of 48 milligrams of THC, only four patients out of 250 exposures had this toxic psychosis. So this is a very important demonstration of this synergy,” he says, noting other cannabinoids might have similar synergistic effects that have not been studied yet.
Cannabis breeders have long been crossing plants to develop distinctive strains that purportedly do different things. But many scientists see the whole thing as a pipe dream.