If you believe budtender wisdom, consuming a strain called Bubba Kush should leave you ravenous and relaxed whereas dank Hippie Chicken should uplift you like a dreamy cup of coffee. But if you take pure, isolated delta-9-tetrahydrocannabinol, or THC—the main psychoactive ingredient in marijuana—you’ll experience “a high that has no specific character, so that seems boring,” says Mowgli Holmes, a geneticist and founder of a cannabis genetics company Phylos Bioscience.
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.
This so-called “entourage effect” refers to this scrum of compounds supposedly working in concert to create what Chris Emerson describes as “the sum of all the parts that leads to the magic or power of cannabis.” Emerson is a trained chemist and the co-founder of a designer marijuana vaporizer products company called Level Blends. Product designers like him believe they can create THC vaping mixtures tuned with different concentrations of each terpene and cannabinoid for specialized effects.
The conventional science on this topic is scant. But cannabis breeders (often working illegally in the past) have long been crossing plants to develop distinctive strains that purportedly do different things, and breeders are using genetics to make that process more precise and efficient.
“We have a huge set of cannabis genomic data that will, hopefully, allow us to ID genetic markers associated with chemical results and certain patient outcomes,” Holmes says. “We’re just getting started.” Holmes hopes breeders might eventually be able to generate cannabis plants or products that are personalized to each individual patient or recreational user’s needs.
But many scientists see the whole thing as a pipe dream. The idea that botanical marijuana creates a synergistic chemical effect, fingerprinting the experience with “uplifting” or “relaxing” or “munchy” notes, is highly contentious.
“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.”
There are a few arguments that entourage effect proponents use to bolster the theory: For one, non-THC cannabinoids do have some neurochemical action as they can affect—often in different ways—cannabinoid receptors in the central nervous system. The most commonly cited example is cannabidiol, or CBD. A number of scientists believe CBD actually mitigates the famously stoning and paranoia-producing effects of THC by blocking some cannabinoid receptors.
“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.
THC-only pills have been available by prescription in the U.S. since the 1980s under the brand name Marinol, which is synthetically produced THC dissolved in sesame seed oil. Russo says people often discontinue Marinol due to negative side effects, which he believes come partly from the absence of marijuana’s other cannabinoids.
“They get anxious, dysphoric [and] scattered,” he says. “It interferes with their ability to function.”
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.
“THC alone is a lousy drug. It is a very poor therapeutic index,” Russo says. “I’ll tell you right now, [Syndros] won’t be exciting or gain a lot of traction either.”
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.”
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.
“With marijuana, most of what you’re dealing with is anecdotal evidence,” Phylos’s Holmes says. “But the truth is there’s very, very little data.”
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.
Holmes says he does not like the fact that entourage effect supporters’ best evidence lies in anecdotes, but he thinks they still tell an important part of the story. “Mainly it makes me pissed off that we can’t do very basic studies about what’s really true,” he says. “But you have thousands and thousands of people reporting the same thing. It gets hard to ignore.” Studies are difficult because of marijuana’s Schedule I status, putting research licenses out of reach for many scientists.
And anecdotes are not enough for Columbia’s Haney and many others who agree with her.
“People have preconceived notions that a terpene will work for them,” says Barth Wilsey, a medicinal cannabis researcher at the University of California, San Diego. “The internet is great but it has a lot of fake news and it’s incredible what people are saying.” In order to learn how effective these compounds are, Wilsey says, “they have to do randomized clinical trials, where random people get real terpene and the fake terpene.”
Haney says she has only seen evidence against the entourage effect. In recent studies (including Haney’s own) directly comparing the effects of plant marijuana with oral THC formulations such as Marinol and Syndros, the results suggest there is little—if any—difference between them. “I wanted to get into whether [Marinol is worse than marijuana], because that was the lore: ‘We need to legalize marijuana because Marinol is no good,’” she says. “So we did the study, and it’s not a lousy drug. It works for pain. It works for appetite. Marinol works quite well.”
Even cannabidiol might be overhyped, Haney says. “There are promising data on potential medical use but the data suggesting it dampens the marijuana high are really not compelling when you look at the original sources,” she notes. “Yet this notion has swept the field.” Drugs like Sativex—the half-CBD/half-THC formulation—do not seem too different from just THC to her, either.
Russo admits the scientific literature is lacking but he remains firm in his belief in the entourage effect. “Do we need better studies to prove the concept? The answer is yes,” he says. “I believe in this because I’ve known for 40 years the differences between different cannabis. They smell different. They taste different. They have different effects.”
And many in the cannabis industry stand with him.
“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.”
Haney says marijuana may actually have an entourage effect but it is impossible to know without more information. “I would love to do a study comparing strains,” she says. “I would love to directly compare but I’m unable to work with any marijuana on the street or in dispensaries.” The placebo effect is very powerful, she notes. And if you believe smoking a bud will give you a bright, cerebral experience spilling with creativity or that a THC pill will make you anxious and paranoid, then that is what you will probably feel.
credit:pbs.org
