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New Study Finds Evidence of the Entourage Effect in Enhancing Pain Relief

By Alexander Beadle

Published: Jul 19, 2021   
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Cannabis is an extremely chemically complex matrix, containing huge volumes of potentially biologically active compounds. To date, scientists have discovered over 100 unique cannabinoids that are produced by the cannabis plant, in addition to the more than 100 plant terpenes that can be produced by various strains of cannabis and other plants.

Naturally then, scientists have questioned whether these active compounds might interact with each other in the body, and whether these interactions might be strong enough to modulate the physical effects felt by cannabis users. This theory of interaction is known as the entourage effect and has been supported by several pre-clinical investigations. Yet the existence of this effect is controversial, with a number of other studies claiming to have found no clear evidence for this action in the body.

Now, a new study from scientists at the University of Arizona Health Sciences (UAHS) has added more support behind the existence of the entourage effect. The researchers found that a number of terpenes can additively enhance the pain-relieving effects of cannabinoids when applied together in mice models. Additionally, these terpenes also appeared to exhibit some cannabis-like effects when applied alone.

The researchers believe that this line of study could one day lead to the development of new cannabis medicines that use terpenes to enhance their beneficial effects, while minimizing the amount of psychoactive cannabinoids required.

Major terpenes exhibit cannabis-like effects alone

The new research looked at the effects of four common terpenes and terpenoids – α-humulene, β-pinene, linalool, and geraniol – and assessed their effects on four behaviors normally mediated by the CB1 cannabinoid receptor, namely antinociception (the pain response), hypolocomotion, catalepsy, and hypothermia.

Each of these terpenes was administered individually to a group of laboratory mice, plus a vehicle control. The scientists also used the terpene β-caryophyllene as an additional control, as it has been confirmed to be a selective CB2 receptor agonist and so could provide an additional dimension to measure behavioral changes against.

To assess the existence of a possible entourage effect, the researchers measured the effects of WIN55,212-2 – a synthetic cannabinoid with a similar action to tetrahydrocannabinol (THC) – on the four key behaviors seen in mice, as well as the effects when each of these terpenes were applied together with WIN55,212.

They found that when the terpenes were used by themselves, all four were able to lower the animals’ pain sensitivity and, to some degree, at least three of the four behavioral outcomes monitored reduced pain sensation, lowered body temperature, reduced movement, and catalepsy/freezing. Additional assessments also found that all four terpenes worked through the activation of the CB1 cannabinoid receptor.

“It was unexpected, in a way,” said lead researcher Dr John Streicher of the University of Arizona Health Sciences Comprehensive Pain and Addiction Center, in a statement. “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.”

When administered alongside WIN55,212-2, the researchers also observed an even greater reduction in pain sensation as compared to the terpenes or the WIN55,212-2 alone. This, the researchers say, demonstrates the presence of an additive entourage effect that can amplify the pain relieving effects of cannabinoids beyond what would be normally expected.

Why does the entourage effect matter?

Terpenes and terpenoids are not unique to cannabis. The terpene linalool, for example, is the compound responsible for the distinctive scent of lavender. And when consumed, linalool is known to be able to block the brain’s glutamate receptors and reduce the signaling strength of ​​acetylcholine, resulting in potential anti-epileptic, muscle-relaxant, and pain-relieving properties.

“Terpenes are a mechanism that a plant uses to communicate with its environment,” Dr Keith Allen, director of bioinformatics at Front Range Biosciences, previously explained to Analytical Cannabis. “So that’s attracting either microbes or insects, things that it likes, or repelling things that it doesn’t like.”

“The diversity of terpene molecules is a lot of what makes the [cannabis] plant so interesting and probably a big component of what makes the plant so effective in the recreational and medical sense,” Allen added.

It is important to note that the entourage effect is still very much a theory; the question of whether or not it has a concrete biological basis is not a settled matter and its existence has yet to be definitively proven or disproven. While this study did see additive terpene-cannabinoid effects and terpene activity at the CB1 receptor, other previous studies have claimed to find no significant interaction at this receptor, nor at ​​other channels sometimes postulated as being important to the entourage effect – such as the human transient receptor potential ankyrin 1 (hTRPA1) channel, or the human transient receptor potential vanilloid 1 (hTRPV1) channel.

However, if the entourage effect – this additive interaction between terpenes and cannabinoids – and its mechanisms can be proven and understood, there is the potential that it could open the door to new therapeutic avenues for medical cannabis patients.

“A lot of people are taking cannabis and cannabinoids for pain,” said Streicher in a statement. “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.”

Indeed, thinking about terpene profiles and terpene genomics could become a huge part of the future cannabis cultivation sector, as farmers look to meet consumer demand for strains high in a particular therapeutic terpene or combination of terpenes.

“In terms of lessons for breeders, the future of cannabis is going to be very precisely dialed in strains that have very well-defined oil profiles,” Allen predicts. “There are a lot of these different terpene synthases to work with, but there are going to be limits to what you can breed.”

For Dr Steiner and his colleagues, the long-term goal of this research would be to use terpenes as a novel dose-reduction strategy. By using additional terpenes to amplify the therapeutic effects of THC or other cannabinoids, it would then be possible to create new therapeutics that have the same level of effectiveness in tackling pain, but that use lower doses of THC and come with inherently fewer side effects than cannabinoid isolates.


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