Marijuana Terpenes Relieve Post-Surgery And Fibromyalgia Pain, Study Shows

New government-funded research on terpenes produced by the cannabis plant finds that some of the aromatic compounds could be promising therapeutics to help manage pain from fibromyalgia or during recovery from an operation.

The study, published this month in the journal Pharmacological Reports, involved administering four separate terpenes—geraniol, linalool, beta-caryophyllene and alpha-humulene—to mice that either underwent paw-incision surgery or had lab-induced fibromyalgia symptoms. Researchers then measured their “mechanical sensitivity” over the course of three hours to evaluate the terpenes’ possible effects on pain.

“These results demonstrate that the terpenes geraniol, linalool, β-caryophyllene, and α-humulene may be a viable medication for post-operative and fibromyalgia pain relief,” says the report, which was funded by a grant from the National Institutes of Health (NIH).

As for post-operative pain, each of the four studied terpenes “increased mechanical threshold significantly in comparison to the mice treated with the vehicle,” according to the research, referring to a solution without any terpenes that’s been previously shown not to have any pain-relieving effect. “Taken together, the data suggests that all 4 terpenes are efficacious in relieving post-surgical pain.”

All four terpenes also increased mechanical sensitivity in mice with fibromyalgia-like symptoms compared to mice treated with the vehicle alone, at least for some time points measured. Differences in mice treated with geraniol and linalool were statistically significant, while sensitivity in the mice treated with the other two terpenes was “elevated over vehicle but not statistically significant,” according to the report.

“These observations suggest that these four terpenes are also efficacious in a fibromyalgia pain model,” it says.

“This work further strengthens the case for the translational potential of Cannabis and its individual components to determine if they could be effective in relieving post-operative and fibromyalgia pain in patients while causing more tolerable side effects than current standard medications for these ailments.”

The current study, noted authors at the University of Arizona’s pharmacology department and Center for Pain and Addiction, is a continuation of their past research into the same four terpenes to treat other types of pain.

“Previously, we found the terpenes…to be effective in relieving CIPN [chemotherapy-induced peripheral neuropathy] and inflammatory pain in mice,” they wrote in the new report. “Their efficacy in other pain models, such as post-operative and fibromyalgia pain, had not yet been defined.”

“Terpenes relieve post-surgical pain… Terpenes relieve reserpine-induced fibromyalgia pain.”

“Through this work,” authors continued, “we found that these terpenes have significant antinociceptive effects in both the paw incision post-operative pain and the reserpine-induced fibromyalgia models in ice, reaching similar mechanical thresholds to those we observed with terpene treatment for CIPN pain. This suggests that terpenes could be potential novel therapeutics for all the above pain types.”

The pain-relieving effect seemed to be “strongest for geraniol, then linalool or α-humulene,” the report says.

Terpene treatments were injected into the mice, with authors noting that “oral and inhalation administration methods had limited bioavailability, which will need to be addressed if these terpenes are to be used in a clinical setting for pain management.”

The new study also built on past findings that adenosine A2a receptors (A2aR) are key mechanisms behind the apparent pain relief associated with terpene therapy, authors noted, writing: “Their mechanism of action via the A2aR furthers our knowledge of its importance in pain processing and as a target of terpene drugs.”

Notably, the terpenes appeared to have no effect on the type of pain that researchers used as a control. Mice that were put on a hot plate—set with a time cutoff meant to prevent tissue damage—didn’t appear to benefit from terpenes. Researchers said they saw “a weak analgesic effect in an acute thermal pain model” in their past work and, in the current study, “showed the terpenes have absolutely no efficacy in the acute nociceptive hot plate assay.”

“Future work,” they wrote, “should use other pain modalities such as thermal and non-evoked assays such as burrowing or home cage monitoring to fully demonstrate terpenes’ efficacy in pathological but not acute nociceptive pain.”

John M. Streicher, a co-author of the paper and a University of Arizona professor, told Marijuana Moment that the terpenes’ apparent effect on some types of pain and not others is “shaping up to be a major theme in our future work on terpenes as pain relievers.”

“Not all of this is published yet, but the story we’re building is that terpenes do not relieve acute pain in an uninjured state,” Streicher explained, using examples such as a pin prick or—in the case of the mice in the study—exposure to a hot plate for long enough to cause pain but not tissue damage.

“On the other hand,” he continued, “we’ve now shown that terpenes are effective in multiple types of pathological pain. All of these pain states involve something going awry with your body, like neuropathic sensitization and nerve damage, inflammation, and similar.”

The difference seems to have to do with the mechanism of action the team focused on in the new study.

“What we think is happening is that the molecular target of the terpenes, the adenosine a2a receptor, is strongly increased during this type of pathological pain, meaning the terpenes can easily act to block pain,” Streicher said in an email. “Without that pathological state, the A2aR is low, and the terpenes don’t have much ability to block pain pathways.”

That’s not a bad thing, he emphasized. In fact, it’s the type of response clinicians look for in some therapies.

“We don’t want to lose our normal pain sensation—it keeps us alive!” the professor wrote. “That’s one reason why therapies like lidocaine aren’t used to manage all your pain—you lose sensation.”

“The fact that terpenes seem selective for chronic pain,” he added, “means they should be more selective for the pain that’s actually a problem in your life, and should reduce side effects.”

As cannabis policies have become less restrictive, researchers have taken a keen interest in the effects of terpenes and other minor chemical compounds in cannabis. On the medical side, they’ve been shown to have some beneficial health impacts on their own, and they may also interact with cannabinoids and other chemicals to enhance therapeutic effects. On the consumer side, terpenes produce much of the flavors and aromas of particular cannabis varieties.

The University of Arizona authors’ past research, for example, found that an injected dose of the compounds produced a “roughly equal” reduction in pain markers when compared to a smaller dose of morphine. Terpenes also appeared to enhance the efficacy of morphine when given in combination.

A separate study published earlier this year in the International Journal of Molecular Sciences, found that the “complex interaction between phytocannabinoids and biological systems offers hope for novel treatment approaches,” potentially laying the groundwork for a new era of innovation in cannabis-based medicines.

“The plant Cannabis exhibits an effect called the ‘entourage effect’, in which the combined actions of terpenes and phytocannabinoids results in effects that exceed the sum of their separate contributions,” that study found. “This synergy emphasizes how important it is to consider the entire plant when utilizing cannabinoids medicinally as opposed to just concentrating on individual cannabinoids.”

Another recent study looked at the “collaborative interactions” between cannabinoids, terpenes, flavonoids and other molecules in the plant, concluding that a better understanding of the relationships of various chemical components “is crucial for unraveling cannabis’s complete therapeutic potential.”

A separate scientific review in September by researchers in Portugal, meanwhile, found that terpenes may indeed be “influencers in the therapeutic benefits of cannabinoids,” though for now that influence “remains unproven.”

That paper nevertheless detailed preliminary findings around the therapeutic benefits of individual terpenes on a range of ailments.

“Exploratory evidence,” it notes, citing earlier studies, “suggest various therapeutic benefits of terpenes, such as myrcene for relaxing; linalool as sleep aid, exhaustion relief and mental stress; D-limonene as an analgesic; caryophyllene for cold tolerance and analgesia; valencene for cartilage protection, borneol for antinociceptive and anticonvulsant potential; and eucalyptol for muscle pain.”

The study also acknowledges, however, that while myrcene “demonstrated anti-inflammatory proprieties topically,” it appeared the terpene offered no additional anti-inflammatory effect when combined with the cannabinoid CBD.

The study doesn’t settle on the ultimate role of terpenes in the so-called entourage effect. Authors wrote that the entourage effect appears “plausible, particularly when considering minor Phyto cannabinoids, monoterpenes, sesquiterpenes, and sesquiterpenoids.”

Other recent research funded by the National Institute on Drug Abuse (NIDA) found that a citrusy-smelling terpene in marijuana, D-limonene, could help ease anxiety and paranoia associated with THC. Researchers similarly said the finding could help unlock the maximum therapeutic benefit of THC.

A separate study last year found that cannabis products with a more diverse array of natural cannabinoids produced stronger psychoactive experiences in adults, which also lasted longer than the high generated by pure THC.

And a 2018 study found that patients suffering from epilepsy experience better health outcomes—with fewer adverse side effects—when they use plant-based CBD extracts compared to “purified” CBD products.

Scientist last year also discovered “previously unidentified cannabis compounds” called flavorants that they believe are responsible for the unique aromas of different varieties of marijuana. Previously, many had thought terpenes alone were responsible for various smells produced by the plant.

Similar phenomena are also beginning to be recorded around psychedelic plants and fungi. In March, for example, researchers published findings showing that use of full-spectrum psychedelic mushroom extract had a more powerful effect than chemically synthesized psilocybin alone. They said the findings imply that mushrooms, like cannabis, demonstrate an entourage effect.

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Photo courtesy of Mike Latimer.