7th April 2021
By Emily Ledger
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As more jurisdictions legalise the use of medicinal cannabis, researchers are increasingly interested in the entourage effects of cannabinoids. A recent review assessed the current evidence of how potential synergistic effects of cannabinoids can contribute to the treatment of pain conditions.

Cannabis contains a huge number of compounds that have been found to have a range of medicinal properties. Cannabinoids, such as THC and CBD, are the most well-known of these compounds and have been developed into a number of medical products. However, research has shown that the combination of cannabinoids with other compounds including flavonoids and terpenes, can produce synergistic benefits – this is known as the entourage effect.

Cannabinoids and Pain signalling

Studies in cultured human and rodent sensory neurons have identified roles for cannabinoid receptors in peripheral pain signalling, indicating that cannabinoids may be useful in reducing pain. For example, some studies have identified CB2 receptors as a target for regulating sensory nerve activity in guinea pig and rat models of acute and chronic pain.

There is also growing evidence that cannabinoids interact with a variety of receptors in addition to CB1 and CB2. CBD, in particular, may have the ability to interact with a number of receptors, including TRPV1, the transient receptor potential vanilloid subtype 1 (TRPV1) receptor, that mediates thermal hyperalgesia by integrating noxious stimuli, such as inflammatory ligands, capsaicin, heat and low pH.

The Entourage Effect

The entourage effect refers to the synergistic effects of cannabinoids, terpenes, and other compounds that have been observed in numerous studies. The role of receptors – including CB1, CB2 and the postulated cannabinoid receptor, CB3 – will likely be complex, with more studies needed to fully understand them.

However, previous studies have identified crosstalk between cannabinoid agonists and the noxious pain receptor TRPV1, which is desensitised upon activation. The endocannabinoid anandamide has been reported to be a full agonist of TRPV1, with its related fatty acid amide, palmitoylethanolamide (PEA), increased the TRPV1-mediated effects of anandamide and capsaicin.

The review points to this, and more studies, which suggest the potential for different combinations of cannabinoids in the modulation of pain signalling. The authors of the study report that “these effects have been seen clinically and in preclinical models, with plant-derived and endocannabinoids”.

The entourage effects of terpenoids and cannabinoids

The potential ‘entourage effect’ of terpenes on cannabinoids is believed to be the reason behind consumer preference for full plant cannabinoid extracts as opposed to pure CBD and THC. A study examined the molecular basis of this effect with both purified cannabinoids and botanical cannabis extracts in transfected cells. The results showed significant inhibitory activity of the botanical extracts compared with pure cannabinoids at numerous targets, including TRPA1, TRPV2 and TRPM8 channels, with a role for target desensitisation.

While these results support theories around the entourage effect, the authors of the review point out that these data were derived from transfected cells, meaning that further in vivo studies, with sensory neurons, are still needed to gain a clearer picture of these fingers.

Further, another study – a rat model of neuropathic pain – oral treatment with a cannabis extract (including various cannabinoids, terpenes, sterols, triglycerides, etc) was found to provide greater antinociceptive efficacy than the single cannabinoid given alone.

On the other hand, other studies have yielded evidence against the entourage effect theory. For example, in a study examining cannabis-mediated analgesia in rats, treatment of THC alone produced a significant analgesic effect which was equivalent to that of the full cannabis extract, whereas terpenes alone did not.

Cannabidiol (CBD)

CBD has been found to be well tolerated in humans and have “anti-convulsive, anti-inflammatory, analgesic and neuroprotective effects.” The potential of the cannabinoid has been demonstrated in preclinical models of neurological disorders, and clinical trials in children and young adults with Dravet syndrome and Lennox-Gastaut syndrome. CBD-based medication, Sativex, was also demonstrated in treating limb spasticity and pain associated with multiple sclerosis.

CBD has also been found to increase the tolerability and therapeutic window of Delta 9-THC and some studies suggest that the compound can alleviate the psychotic symptoms associated with Delta-9-THC.

While CBD alone has been found to have anti-inflammatory potential, this effect was significantly improved in a study that involved the intraperitoneal injection of the whole plant extract of a Cannabis sativa clone with a high CBD content. The whole plant extract yielded greater analgesic effects and reduced swelling when compared with pure CBD treatment.

Terpenoids

In addition to over 100 cannabinoids, the cannabis plant also contains up to 200 different terpenes which have been found to work synergistically with cannabinoids “at a variety of targets, including G-protein-coupled receptors, muscle and neuron ion channels, enzymes, and second messenger systems, to mediate a variety of therapeutic effects.”

Some terpenes, such as α-pinene, β-myrcene, D-limonene, linalool, β -caryophyllene, and more, have been found to have anti-inflammatory, analgesic, anxiolytic, antidepressant, and sedative effects in pre-clinical studies. A deeper understanding of the individual medicinal properties of the cannabinoids, terpenes, and flavonoids will be essential in revealing the optimal standardised synergistic compositions needed to target individual symptoms and/or diseases, including pain.

The Entourage Effect of Cannabinoids and its Links to Pain Relief

The entourage effect can extend to combinations of cannabinoids with “other or overlapping established mechanisms of analgesia” (pain relief). For example, the antinociceptive effects of cannabinoids have been seen to have an effect on the opioid system – and vice versa.

Some studies have shown that cannabinoids agents can enhance the effect of μ-opioid receptor agonists in some models of analgesia, with more evidence suggesting that, when given in combination, cannabinoids may also reduce dependence on opioid drugs. Numerous studies have found that the synergistic effect of cannabinoids and opioids have resulted in reduced pain and opioid doses.

Conclusions

While there is definitely a need for more robust research into both the singular and combination formulations of cannabinoids for analgesia, the authors of this review conclude that “there is increasing overall evidence from clinical trials, supporting the beneficial effect of plant-derived, endogenous or synthetic cannabinoids for providing pain relief.”

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