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The Effect of Combined CBD and β-caryophyllene on Chronic Pain in a Rat Spinal Cord Model

Published: 22/03/2023

Cannabis has been used for thousands of years by cultures and societies all over the world. In this time – and right up to the modern day. Today, chronic pain is the most reported reason medical cannabis is used, globally. As more countries broaden access to legal cannabis products, this trend is likely to continue. Yet, there remains a paucity of high-quality clinical evidence to support the use of cannabis-based medical products for the treatment of chronic pain.

In the UK, medical cannabis was legalised with the rescheduling of the drug in November 2018. However, the National Institute of Health and Care Excellence (NICE) recommends that clinicians do not prescribe medical cannabis for the treatment of chronic pain. Nonetheless, a growing number of patients in the UK and around the world are increasingly interested in the potential of CBMPs for chronic pain. Therefore, it is essential that more research is conducted to better understand the analgesic potential of different cannabis components.

A recent pre-clinical animal study aimed to assess the effects of combined cannabidiol (CBD) with the terpene β-caryophyllene (BCP) in a rat model of spinal cord injury. A number of pre-clinical animal studies have assessed CBD and BCP’s analgesic potential in a variety of pain models. However, no studies have analysed the pain-relieving potential of CBD and BCP when given in combination.

Design and Methods of the Study

To test the analgesic potential of combined CBD and BCP, spinal cord injury was induced via clip compression in male and female Sprague-Dawley rats. Rat behaviours were observed prior to clip compression and for four weeks when the animals demonstrated stable pain-related behaviour. Behavioural measurements continued to be taken over a further 3-week period, during which time various experiments were conducted, with a 72 hr washout period between dose administrations.

For the first experiment, CBD and BCP were individually administered at several doses in order to determine time course and dose response profiles. Animals were randomly assigned a dose of either CBD or BCP (or vehicle), tested, and then allowed a 72 hr washout period before another dose administration and testing, until sufficient data was attained for each drug/dose.

The second experiment was conducted to determine the analgesic potential of CBD/BCP co-administration compared to individual administration. Various fixed-ratio combination doses were also tested to determine the optimal combination. Experiment 3 was conducted to determine if CBD and BCP produce adverse effects related to the cannabinoid mechanism of action. A fourth experiment aimed to determine the potential antinociceptive mechanisms of the CBD/BCP combination and finally, Experiment 5 was designed to determine if repeated CBD/BCP administration can potentially reduce opioid-seeking behaviour.

Results of the Study

This study demonstrated that systemic administration of CBD and BCP individually reduced spinal cord injury-related hypersensitivity in both male and female rats in a dose-dependent manner. CBD appeared to be more effective at reducing cold hypersensitivity than tactile sensitivity; however, effects on tactile hypersensitivity were more modest and short-lived, with only partial attenuation at the highest dose. Systemic administration of BCP alone was also associated with reductions in spinal cord injury-related tactile and cold hypersensitivity and dose-dependent antinociceptive effects were observed in both sexes after administration. Overall, BCP alone showed lower efficacy and shorter duration compared to CBD.

Coadministration of CBD and BCP was associated with reductions in spinal cord injury-related mechanical and cold hypersensitivity. Further findings revealed that there was an additive effect in reducing mechanical hypersensitivity in males and a synergistic effect in reducing cold hypersensitivity across both sexes. Changes in maximum possible effect indicated that the coadministration of these two agents could improve the potency and efficacy of both CBD and BCP.

The combination also increased both efficacy and potency in reducing tactile hypersensitivity in males and reaching nearly full reversal of spinal cord injury-induced tactile hypersensitivity with the highest dose combination. However, despite the use of higher doses of CBD and BCP, only partial attenuation was achieved in females. This may underscore the importance of considering potential sex differences when developing cannabinoid pain-reducing strategies.

The co-administration of CBD and BCP was associated with minimal side effects. Furthermore, the researchers noted an observed reduction in opioid-seeking behaviour.


These results are an important step forward in understanding the mechanism of action of both CBD and BCP. Moreover, the findings are promising with respect to spinal cord injury. However, the results in animal studies are not a substitute for in-human research, which is still required to help understand the efficacy and safety of CBD and BCP before it can be widely recommended for spinal cord injury-related chronic pain.

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