Terpene Teachings: UA releases study on the “entourage effect” with an eye to reducing side effects for pain treatment

University of Arizona Health Sciences/Noelle Haro-Gomez
John Streicher, PhD, a member of the Comprehensive Pain and Addiction Center, said the findings answered some basic science questions that allowed him to advance the research moving forward. “Now, we're getting into the therapeutic question—what's a good drug to give to a person to help them control their pain?”

While cannabis remains illegal on a federal level, the push for legalization at the state level has opened the door to more studies of marijuana's effect.

To that end, the University of Arizona Health Sciences Comprehensive Pain and Addiction Center recently released a study of terpenes and the so-called "entourage effect," showing promise for future treatments that could prove more effective for pain treatment in cancer patients.

The paper, "Cannabis sativa terpenes are cannabimimetic and selectively enhance cannabinoid activity," was published in Scientific Reports and explores the entourage effect with a study of synthetic terpenes found to mimic cannabinoids, producing a similar pain-relieving effect.

"The basic idea here and what motivated our research is that you have a plant, which is really complicated, but we tend to boil it down to just THC, usually, and then some people will kind of throw CBD in there," lead researcher John Streicher, PhD said. "But of course, it's a complex living organism. It's got a lot more than that, so there are lots of different kinds of chemicals."

The paper, co-authored by former graduate student Justin LaVigne, PhD, former undergraduate researcher Ryan Hecksel and former postdoctoral fellow Attila Kerestztes, PhD, explains that the entourage effect—a concept widely accepted in the cannabis community with detractors in the scientific community—is "hypothesized interactions between various phytocannabinoids and terpenes to produce unique outcomes from either chemical alone."

"The evidence for the entourage effect is comprised of deductive reasoning arguments, some clinical suggestions, and a few pre-clinical investigations," the study states. "It remains unclear whether terpenes can influence the activity of cannabinoids, and if they do, whether this modulation is a result of direct influence on cannabinoid receptors ... or indirect modulation via other mechanisms."

Streicher's research was not only meant to determine the legitimacy of the concept of the entourage effect, but to also delve into interactions between various components of the plant with an eye toward future treatments for those suffering from severe pain.

Since federal law creates a convoluted and time-consuming path to the study of marijuana, Streicher and his team focused on synthetic terpenes, which are readily available and do not require the bureaucratic headaches faced in the study of actual cannabis.

Terpenes are the part of the plant that provide pot with its distinctive flavor and aroma. They are also found in other plants and are the basic component in essential oils; the terpene linalool, for example, gives lavender its floral scent.

Additional chemicals in cannabis include the well-known cannabidiol (CBD) and tetrahydrocannabinol, or THC, the part of the plant that provides the buzz to its users.

Researchers found that terpenes by themselves mimic many effects of cannabinoids, including pain relief, and when combined with cannabiniods, amplified those effects with fewer side effects.

The study tested mice using a synthetic cannabinoid, WIN55,212-2, to reproduce the effects of the chemical compounds in the cannabis plant and saw "a greater reduction in pain sensation compared with either the terpene or WIN55,212-2 alone, demonstrating a terpene/cannabinoid interaction in controlling pain."

"We wanted to test what the terpenes were doing and start to establish a theoretical basis for the entourage effect as well as investigate terpenes themselves as potentially novel medicinal chemicals," Streicher said. "We were starting at the most basic levels. When we injected [the terpenes], they looked like cannabinoids, so they had what we call a cannabamimetic effect. They produced the effects of cannabinoids, and we didn't necessarily expect that to happen."

Streicher's ongoing research is focused on the use of terpenes in combination with opioids for treatment of cancer-related pain. He hopes to eventually develop a U.S. Food and Drug Administration-approved treatment regimen combining terpenes, cannabinoids and opioids, with lower dosage, increased levels of pain relief and fewer side-effects, such as intoxication or pharmaceutical drug dependency.

"This is the basic idea of synergy, that you take a low dose of two different drugs, combine them together and you get a pain-relieving effect greater than either, but your side effects are not boosted," he said.

The concept of the entourage effect has gained a foothold in the marketplace. Different brands sold with unique characteristics attributed to the effect are found in every dispensary and are described with phrases such as "body up, head down" or other colorful descriptions of the expected effect.

"It's been around for awhile," said Claire Levenberg, director of science operations for the Downtown and D2 dispensaries. "Rick Simpson Oil was the first concentrated extract, and it's still one that gets asked for a lot at the dispensary for people looking to alleviate some of the pain associated with cancer treatments."

RSO is a cannabis concentrate high in THC content developed by cannabis innovator Rick Simpson in 2003 to treat cancer symptoms. It has a thick, syrupy consistency and can be applied as a topical or ingested in food or drinks. Different forms of it can be found in many products on your local dispensary shelf. It's also possible to make at home, but the process is dangerous because it involves toxic fumes and, in some methods, the possibility of explosions.

As cannabis legalization becomes more prevalent, more components are being identified in commercial labs across the country, opening more possibilities for expanded entourage effect.

"I think there's definitely a push to expand the different vectors that are possible for the entourage effect besides flower and Rick Simpson Oil," Levenberg said. "And I think you're going to start seeing a push for those products that are a little bit more accessible for all populations."

While there hasn't been a lot of clinical study of cannabis due to federal regulations, the public has had to depend on behavioral studies such as this one, which used synthetic material rather than actual cannabis.

As an institution run by its Board of Regents and dependent on federal research funds, UA has to obey the overarching cannabis laws of the land, hence its dearth of cannabis research.

"Terpenes are classified by the FDA as generally regarded as safe: GRAS," Streicher said "That means you can give it to a human being without having to have it specifically approved by the FDA."

Streicher used synthetics as a workaround to regulations, but the work he and his team have done has laid the groundwork for future clinical studies, when and if cannabis is deregulated on a national level.

"This isn't a scientific question, it's a political question, so we just have to live with it unfortunately," Streicher said. "So even though it's legal in Arizona, I still have to get a Schedule I license if I want the plant or if I want THC, which has been frustrating because getting that is a pain."

Both Streicher and Levenberg are hopeful for the future though, and see legalization— and thus robust scientific discovery—on the horizon.

"I'm glad that they're trying to decriminalize it so that it makes it a little bit more accessible to the public universities and institutions," Levenberg said. "I'm super excited to see more studies done clinically to really prove what the possibilities are with it."

Or as Streicher concludes: "You can't stop this, it's growing. Eventually, [prohibition is] going to end in my lifetime, it's going to change at the federal level. ... It's just a question of how many people have to suffer and how long it's going to take."

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