“An increase in the use of medicinal Cannabis for pain management has spurred research into the understudied bioactive compounds in Cannabis, such as terpenes.

In our previous work, we showed that isolated and purified terpenes were cannabimimetic and also relieved chemotherapy-induced peripheral neuropathy (CIPN) pain via activation of Adenosine A_2a Receptors (A_2aR) in the spinal cord. However, terpenes are most often consumed by the public as complex extracts and mixtures, not purified individual terpenes, and whether this cannabimimetic and antinociceptive activity holds true in terpene extracts and blends is not clear.

In this study, we thus extracted terpene blends from three distinct Cannabis chemovars and assessed these blends in male and female CD-1 mice for their cannabimimetic activity in the tetrad assay and pain-relieving properties in a CIPN model.

Each terpene blend was unique in the relative amounts of different terpenes extracted. Though each blend was unique, each similarly elicited cannabimimetic behaviors of catalepsy, hyperlocomotion, and hypothermia, without tail flick analgesia.

All three terpene blends effectively relieved CIPN, though the antinociception was more robust in male than in female mice. This antinociception was recapitulated by purified Myrcene but not D-Limonene. The A_2aR antagonist istradefylline blocked the pain-relieving effects of all three terpene blends, suggesting that the terpene blends act on A_2aR to relieve CIPN pain.

Together, these findings suggest that terpene blends have similar pharmacological effects as purified single terpenes, and that observations made with single terpenes may be applicable to the complex terpene mixtures commonly consumed by the public.”

https://pubmed.ncbi.nlm.nih.gov/40122228/

https://www.sciencedirect.com/science/article/abs/pii/S030439402500093X?via%3Dihub

“The purpose of this study was to evaluate the participation of spinal peroxisome proliferator-activated receptor gamma (PPARγ) in the antiallodynic effect of cannabidiol, the expression of PPARγ in sites relevant to the spinal nociceptive processing, and the effect of this cannabinoid on cognitive deficits induced by neuropathic pain in female mice.

Either acute or repeated treatment with cannabidiol reduced tactile allodynia and spontaneous pain (flinching) in female neuropathic mice. Pioglitazone partially reduced tactile allodynia, and this effect was fully blocked by the PPARγ antagonist GW9662. Likewise, intrathecal injection of cannabidiol reduced tactile allodynia, while PPARγ antagonist GW9662 or 5-HT_1A receptor antagonist WAY-100635, but not the PPARα antagonist GW6479, partially prevented this effect. GW9662 and WAY-100635 administrated per se did not modify tactile allodynia in neuropathic female mice. Co-administration of GW9662 and WAY-100635 fully prevented the antiallodynic effect of cannabidiol in mice. Nerve injury up-regulated PPARγ expression at the spinal cord and dorsal root ganglia, while cannabidiol further enhanced nerve injury-induced up-regulation of PPARγ expression in both tissues.

Repeated intrathecal injection of cannabidiol reduced tactile allodynia and several pain makers (ERK, p-ERK, p38MAPK and p-p38MAPK). In addition, this treatment restored nerve injury-induced interleukin-10 down-regulation and increased PPARγ expression at the spinal cord. Repeated treatment with cannabidiol also improved nerve injury-induced cognitive impairment in mice.

These results provide compelling evidence for the involvement of PPARγ in the antiallodynic effect of cannabidiol in mice and highlight its multifaceted therapeutic potential in neuropathic pain management and its comorbidities.

PERSPECTIVE: The present study reveals cannabidiol’s dual effects in female mice by reducing neuropathic pain through spinal PPARγ and 5-HT_1A receptor activation and ameliorating nerve injury-induced cognitive impairment. These findings may assist clinicians seeking new therapeutic approaches for managing neuropathic pain and its associated cognitive deficits.”

https://pubmed.ncbi.nlm.nih.gov/40112940/

https://www.jpain.org/article/S1526-5900(25)00605-4/abstract

“Ethnopharmacological relevance: Cannabis sativa has been widely used in traditional medicine for its therapeutic properties. However, in Morocco, the ethnobotanical applications of Cannabis sativa, especially its essential oils, are underexplored. This study investigates, for the first time, the effects of Moroccan Cannabis sativa essential oil on peripheral neuropathic pain.

Materials and methods: Peripheral neuropathic pain was induced in mice through sciatic nerve injury. The mice were treated daily with cannabis essential oil for 21 days. Behavioral tests were conducted on days 1, 7, 14, and 21 to evaluate thermal, mechanical, and cold sensitivity. The essential oil’s chemical composition was analyzed using gas chromatography-mass spectrometry (GC/MS).

Results: The main constituents of the essential oil were (E)-caryophyllene (41.59%) and α-humulene (14%). Daily treatment with the essential oil significantly reduced pain sensitivity and improved functional and histological recovery over time. These effects are linked to the activity of the dominant terpenoids in the oil.

Conclusion: Moroccan Cannabis sativa essential oil shows significant therapeutic potential for managing peripheral neuropathic pain. By enhancing recovery and alleviating pain symptoms, it offers a promising alternative for treating chronic pain caused by nerve injuries.”

https://pubmed.ncbi.nlm.nih.gov/39947371/

“A multitude of recent studies have explored the broad biological properties of cannabis. Extracts from Cannabis sativa have demonstrated antimicrobial, anti-inflammatory, antinociceptive, and potent antioxidant activities.”

“This study examined the analgesic effects of terpenes found in Cannabis sativa essential oil on neuropathy. The results showed that chronic administration of these bioactive terpenes, specifically β-caryophyllene, α-humulene, and caryophyllene oxide, significantly increased pain sensitivity and response time in mice with neuropathy. Although morphine and THC-based treatments are commonly used to relieve neuropathic pain, these terpenes may offer a promising alternative with limited side effects. Clinical research has demonstrated the efficacy of cannabis-based treatments, leading several pain societies to recommend them for neuropathy management. “

https://www.sciencedirect.com/science/article/pii/S0378874125001692?via%3Dihub

“Purpose: Peripheral neuropathies are commonly occurring conditions that are chronic and debilitating for patients. Established nonsurgical treatments have yielded mixed and patient-dependent results. Although cannabinoids have demonstrated efficacy as a treatment for central neuropathic pain, the therapeutic potential of cannabis-based medications for the management of peripheral neuropathic pain caused by nerve injury, trauma, and other noncompressive etiologies has yet to be definitively established. This study aims to determine whether cannabinoids are a potentially effective treatment for pain and symptoms associated with peripheral neuropathy.

Methods: A systematic search was conducted by two independent reviewers across PubMed, Cochrane, Ovid Medline, and CINAHL to identify studies in accordance with the predetermined inclusion/exclusion criteria. Information regarding study design, medication, dosage, effect on neuropathic pain, and other related outcomes was extracted. Meta-analysis of pain scores was performed for seven studies, and descriptive statistics were used to summarize other study findings as appropriate.

Results: Of the 927 studies identified, 14 randomized controlled trials were included. Thirteen of 14 studies (79%) observed a statistically significant decrease in neuropathic pain score following treatment with a cannabinoid. Meta-analysis yielded a mean difference of -0.67 [-0.89, -0.45]) on a 0-10 scale compared with placebo. Improvements in secondary outcomes such as sleep, sensory symptoms, and quality of life were observed.

Conclusions: Our analysis of the literature shows that cannabis-based medicines may be effective in treating the pain and symptoms of peripheral neuropathy. These findings suggest the applicability of cannabis-based medicines for peripheral neuropathy.”

https://pubmed.ncbi.nlm.nih.gov/39570218/

https://www.jhandsurg.org/article/S0363-5023(24)00474-X/abstract