A new federally funded study into the effects of cannabis terpenes suggests that the compounds could be “potential therapeutics for chronic neuropathic pain,” finding 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.

Unlike with morphine, however, none of the studied terpenes produced a meaningful reward response, the research found, indicating that “terpenes could be effective analgesics with no rewarding or dysphoric side effects.”

Notably, terpenes that were vaporized or administered orally seemed to have little impact on pain.

The paper, “Terpenes from Cannabis sativa induce antinociception in a mouse model of chronic neuropathic pain via activation of adenosine A2A receptors,” was published this month in PAIN, the journal of the International Association for the Study of Pain. The 14-author team behind the report includes researchers from the University of Arizona’s Comprehensive Center for Pain and Addiction as well as the National Institutes of Health (NIH).

“A question that we’ve been very interested in is could terpenes be used to manage chronic pain?” lead researcher John Streicher, a professor of pharmacology at the University of Arizona’s College of Medicine in Tucson, said in a press release about the study. “What we found is that terpenes are really good at relieving a specific type of chronic pain with side effects that are low and manageable.”

Authors note that while primary chemical components in marijuana, like THC and CBD, have been shown in some studies to be effective in managing chronic pain, “their efficacy is generally moderate, and THC is burdened by unwanted psychoactive side effects.”

“These limits have focused attention on other potentially therapeutic components of Cannabis,” they wrote, “including minor cannabinoids, flavonoids, and terpenes.”

“Cannabis sativa terpenes were as effective as morphine at reducing chronic neuropathic pain and a combination of the two analgesics further enhanced pain relief without negative side effects.”

While many plants produce terpenes—the terpene pinene, for example, is made not only by cannabis but also pine and cedar trees, oranges and rosemary—the study explains that cannabis is an outlier in its chemical creation.

“While most other plants have 2 dominating terpene species, Cannabis contains up to 150 terpenes, with multiple terpenes acting as the dominant species,” the study says, adding that the “complexity of the Cannabis chemovar may determine the different biological effects caused by different strains of Cannabis.”

The newly published research looked at five terpenes—alpha-humulene, beta-caryophyllene, beta-pinene, geraniol and linalool—which authors said “are found in moderate to high levels within Cannabis.”

Solution of terpenes were injected into mice to test how they influenced measures of both peripheral neuropathic pain and inflammatory pain, which were induced in the mice through chemotherapy drugs and injections in the animals’ hind paws, respectively. Terpenes were also given to the mice orally and via vaporization.

Each terpene was tested individually “along with a morphine comparison for efficacy,” authors explained. Terpenes dosages were 200 mg/kg, while the morphine comparison was 10 mg/kg.

“Terpenes are efficacious in producing antinociception in a mouse model of neuropathic pain.”

The goal of the study was not only to measure whether terpenes relieved pain in mice but also the mechanism behind any pain relief. That meant not only observing the animals’ behavior but also evaluating cell function by, for example, flash-freezing skin from mouse paws and evaluating its mRNA.

Findings showed that all the tested terpenes seemed to reduce markers of neuropathic pain, while all terpenes except pinene appeared to treat inflammatory pain.

“Taken together, this evidence suggests that all terpenes produce robust antinociception,” the study says of the results for neuropathic pain. For inflammatory pain, it continues, “all terpenes except b-pinene are effective antinociceptive agents in this second, different pathological type pain.”

Combining even lower doses of both cannabis terpenes and morphine, meanwhile, seemed to produce an even stronger pain-relieving effect.

“This brings up the idea that you could have a combination therapy, an opioid with a high level of terpene, that could actually make the pain relief better while blocking the addiction potential of opioids,” Streicher said. “That’s what we are looking at now.”

“Terpenes produce comparable antinociceptive tolerance to morphine in chemotherapy-induced peripheral neuropathy.”

As for whether or not terpenes have “reward liability,” researchers found that “Crucially, both geraniol and linalool showed neutral conditioning, neither preference nor aversion, suggesting they do not cause reward or dysphoria.”

“When combined with our pain data above,” they said of the two terpenes, “this suggests these terpenes could be effective analgesics with no rewarding or dysphoric side effects.”

“In contrast, both a-humulene and b-caryophyllene showed a significant place aversion, suggesting they may be dysphoric under these treatment conditions,” results showed, while beta-pinene also indicated “potential aversive/dysphoric side effects.”

“Overall, these results suggest that no terpene has reward liability, some have neither reward nor aversive liability, while some have aversive liability,” authors wrote. “These observations are crucial when evaluating the potential clinical utility of these ligands as pain drugs.”

As Streicher explained, “What we found was, yes, terpenes do relieve pain, and they also have a pretty good side effect profile.”

The method of application also mattered. The study focused on injected terpenes, which authors acknowledged “is not very translationally relevant” to human use. However, terpenes given to mice orally and through vaporization had little observed impact on pain markers, and in some they cases produced modest side effects, such as hypothermia. Researchers concluded that terpenes administered orally or through inhalation “have limited bioavailability.”

“A lot of people vape or smoke terpenes as part of cannabis extracts that are available commercially in states where cannabis use is legal,” Streicher said in the university release. “We were surprised to find that the inhalation route didn’t have an impact in this study, because there are a lot of at least anecdotal reports saying that you can get the effects of terpenes whether taken orally or inhaled. Part of the confounding factor is that terpenes smell quite nice and it’s hard to disguise that aroma, so people could be kind of having the psychosomatic placebo-style effect.”

Examination of how the terpenes worked on a mechanistic level suggested that terpenes may play an anti-inflammatory role in addition to interacting directly with some receptors in nervous system.

The findings “suggested that the terpenes are A2AR agonists, as they evoked cAMP accumulation by the A2AR. However, the exact nature of that agonism is not clear,” the study says. “The terpenes did not compete with an orthosteric radioligand (similar to our results with the CBR1), suggesting that they might be allosteric agonists. However, our modeling studies suggested a mechanism for the terpenes to bind and activate the A2AR in the orthosteric site.”

“Future work will need to disentangle these mechanisms of selective receptor engagement in different pain sites,” it adds.

As for how the research translates to pain treatment in humans, authors said the findings are promising but also demonstrate the need for further study.

“Overall, our observations support the translational utility of terpenes as potential treatments for neuropathic pain and have identified a novel A2AR-mediated mechanism, with some terpenes activating this receptor in the spinal cord,” they wrote. “Further work will be needed to overcome the translational hurdles identified, such as limited oral/inhaled bioavailability and antinociceptive tolerance. We also propose to further explore the antinociceptive mechanisms of action of these ligands, which may pave the way for development as new clinical therapies.”

As the University of Arizona noted in its release, the findings build on prior research in which Streicher’s team found that some terpenes mimicked the effects of cannabinoids, “including a reduction in the sensation of pain, in animal models of acute pain.”

Though the bulk of cannabis research has centered on primary cannabinoids such as THC and CBD, terpenes and other minor chemical components of the plant have become an increasing hot area of study. Another recent study, for example, published in the Journal of Molecular Sciences, found that the interaction between cannabinoids and terpenes offers hope for novel therapeutic treatments.

“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,” the study says. “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 study published earlier this year 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.”

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 Kimzy Nanney.