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Cannabis terpenes provide pain relief, contribute to ‘entourage effect’ – US study

Scientists at the University of Arizona in the United States have found that terpenes in cannabis – the part of the plant that provides flavour and aroma – mimic cannabinoids and produce similar pain-relieving effects. They hope the research will help to boost pain therapies.

The following material was published by the University of Arizona on 14 July 2021.

When it comes to the medicinal and therapeutic properties of Cannabis sativa, an unsolved mystery is whether there exists an ‘entourage effect’, whereby the pain-relieving effects of the plant as a whole are greater than any of its individual parts.

Research from University of Arizona Health Sciences has found evidence that favours the entourage effect theory and positions cannabis terpenes, the part of the plant that provides flavour and aroma, as a promising new target for pain therapies that would require lower doses and produce fewer side effects.

“A lot of people are taking Cannabis and cannabinoids for pain,” said lead researcher Dr John Streicher, a member of the university’s Comprehensive Pain and Addiction Center and associate professor of pharmacology at the College of Medicine – Tuscon.

“We're interested in the concept of the entourage effect, with the idea being that maybe we can boost the modest pain-relieving efficacy of THC and not boost the psychoactive side effects, so you could have a better therapeutic.”

Terpenes are aromatic compounds found in many plants and are the basic component in essential oils. The terpene linalool, for example, gives lavender its distinctive floral scent. In addition to terpenes, Cannabis sativa contains naturally occurring compounds known as cannabinoids, the most well-known of which are cannabidiol (CBD) and tetrahydrocannabinol (THC), the psychoactive component of cannabis.

Researchers found that cannabis terpenes, when used by themselves, mimic the effects of cannabinoids, including a reduction in pain sensation. When combined with cannabinoids, the pain-relieving effects were amplified without an increase in negative side effects.

The paper, “Cannabis sativa terpenes are cannabimimetic and selectively enhance cannabinoid activity”, was published in Scientific Reports in April.

“It was unexpected, in a way,” said Streicher. “It was our initial hypothesis, but we didn’t necessarily expect terpenes, these simple compounds that are found in multiple plants, to produce cannabinoid-like effects.”

Streicher and the research team – including former graduate student and first author Dr Justin LaVigne, former undergraduate researcher Ryan Hecksel and former postdoctoral fellow Dr Attila Kerestztes – focused on four cannabis terpenes: alpha-humulene, geraniol, linalool and beta-pinene.

They evaluated each terpene alone and in combination with WIN55,212-2, a synthetic cannabinoid agonist that stimulates the body’s natural cannabinoid receptors.

When a cannabinoid such as THC enters the body, it binds to one of two cannabinoid receptors – CB1R, which is the most abundant, or CB2R. The receptor then activates neurons that affect physiological processes and behaviour. In laboratory experiments, researchers found that all four terpenes activated the CB1R, just like THC.

Behavioural studies in mouse models revealed that when administered individually, all four terpenes lowered pain sensitivity, and at least three of the four classic cannabinoid side effects: reduced pain sensation, lowered body temperature, reduced movement and catalepsy, a freezing behaviour related to the psychoactive effects of cannabinoids.

When terpenes were combined with WIN55,212-2, researchers 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.

Streicher’s ongoing research is focusing on the use of terpenes in combination with opioids and for specific types of cancer-related pain. His long-term goal is to develop a dose-reduction strategy that uses terpenes – generally recognised as safe by the US Food and Drug Administration – in combination with cannabinoids or opioids to achieve the same levels of pain relief with lower doses of drugs and fewer side effects.


Study details

Cannabis sativa terpenes are cannabimimetic and selectively enhance cannabinoid activity

Justin E LaVigne, Ryan Hecksel, Attila Keresztes and John M Streicher

Published in Scientific Reports on 15 April 2021. Volume 11, article number 8232 (2021).



Limited evidence has suggested that terpenes found in Cannabis sativa are analgesic, and could produce an ‘entourage effect’ whereby they modulate cannabinoids to result in improved outcomes. However this hypothesis is controversial, with limited evidence.

We thus investigated Cannabis sativa terpenes alone and with the cannabinoid agonist WIN55,212 using in vitro and in vivo approaches. We found that the terpenes α-humulene, geraniol, linalool, and β-pinene produced cannabinoid tetrad behaviours in mice, suggesting cannabimimetic activity.

Some behaviours could be blocked by cannabinoid or adenosine receptor antagonists, suggesting a mixed mechanism of action. These behavioural effects were selectively additive with WIN55,212, suggesting terpenes can boost cannabinoid activity. In vitro experiments showed that all terpenes activated the CB1R, while some activated other targets.

Our findings suggest that these Cannabis terpenes are multifunctional cannabimimetic ligands that provide conceptual support for the entourage effect hypothesis and could be used to enhance the therapeutic properties of cannabinoids.


University of Arazona material – Study Shows Cannabis Terpenes Provide Pain Relief, Contribute to ‘Entourage Effect’ (Open access)


Scientific Reports journal article – Cannabis sativa terpenes are cannabimimetic and selectively enhance cannabinoid activity (Open access)


See also from the MedicalBrief archives


Cannabis use and impact on rheumatologic pain – French study


Cannabis users need more anaesthesia, painkillers for surgery


Cannabis may effectively bring pain relief and treat insomnia


Medical cannabis cuts chronic pain in the elderly without adverse effects



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