“Cannabinoids and terpenes, key bioactive components of cannabis, are increasingly studied for their individual and combined contributions to the therapeutic potential of cannabis-based treatments, with ongoing research exploring their distinct and interactive effects.

This study aimed to encapsulate cannabigerolic acid (CBGA) in poly(ethylene glycol)-poly(lactic-co-glycolic acid) nanoparticles (PEG-PLGA NPs) and investigate the effects of combining CBGA NPs with cannabis-derived terpene-loaded NPs (myrcene [MC], nerolidol [NL], and caryophyllene [CPh]) for potential applications in pain management.

CBGA NPs (152 nm) and terpene-loaded NPs (233-297 nm) were prepared via nanoprecipitation and emulsion-solvent evaporation, respectively, exhibiting a polydispersity index < 0.3 and negative zeta potentials (-23 to -26 mV). Encapsulation efficiency was 98.6 % for CBGA and 13-33 % for terpenes. CBGA release followed a biphasic profile, with ∼ 20 % released within 4 h and sustained release over 72 h. In vitro evaluation used HEK293 cells expressing the nociceptive transient receptor potential vanilloid-1 (TRPV1) channel, a key mediator of pain perception. TRPV1 activation was assessed via calcium influx kinetics (Fluo-4 indicator). The EC50 values were 23.8 µg/mL (CBGA NPs), 8.0 µg/mL (MC NPs), 6.7 µg/mL (NL NPs), and 13.3 µg/mL (CPh NPs). Combinatorial treatments of CBGA NPs with terpene NPs at their respective EC50 concentrations revealed significantly enhanced calcium influx compared to individual NPs, with the strongest interaction observed for CBGA/NL and moderate effects for CBGA/MC. Fluorescence imaging further corroborated these findings.

These results suggest that combining CBGA NPs with terpene-loaded NPs could potentiate pain-relief efficacy, offering a promising strategy for advanced therapeutic formulations.”

https://pubmed.ncbi.nlm.nih.gov/40419035/

“Cannabis sativa has long been valued for its diverse medicinal properties.”

https://www.sciencedirect.com/science/article/pii/S0378517325006039?via%3Dihub

“Objectives: Current pharmacological treatments for neuropathic pain have limited efficacy and may cause undesirable side effects. Cannabidiol (CBD)-enriched cannabis oil and omega-3 fatty acids (ω-3) have emerged as potential therapeutic options due to their analgesic and anti-inflammatory properties. This study aimed to assess the antinociceptive effects of combining CBD-enriched cannabis oil and ω-3 in rat models of acute and neuropathic pain.

Methods: Using the hot plate test for acute pain and the chronic constriction injury (CCI) model for neuropathic pain, thermal and mechanical hypersensitivity were evaluated. Additionally, walking track analysis and the rotarod test assessed functional recovery of the sciatic nerve. Beyond that, the histological analysis of sciatic nerves exposed the neuropathological findings of the treatments.

Key findings: The combined treatment of CBD-enriched cannabis oil and ω-3 effectively prevented thermal and mechanical hypersensitivity, while also improving motor impairment-induced peripheral neuropathy. Finally, combination treatment showed a protective effect against degeneration resulting from CCI.

Conclusions: These findings underscore the potential of CBD-enriched cannabis oil and ω-3 as a novel therapeutic approach for neuropathic pain management, offering promising implications for future research and clinical practice.”

https://pubmed.ncbi.nlm.nih.gov/40414709/

https://academic.oup.com/jpp/advance-article-abstract/doi/10.1093/jpp/rgaf027/8148741?redirectedFrom=fulltext&login=false

“Background and aim: Use of potent painkillers like opiates are limited by their abuse potential and adverse physiological effects necessitating new therapeutics for pain management. This study assessed the efficacy of oral cannabinoid formulations (F1-F4) in alleviating chronic neuropathic pain (CP) and investigated their mechanisms through thermal algesia, inflammatory and oxidative stress biomarkers, and sensory nerve conduction velocity (SNCV).

Experimental procedures: A 21-day rat model of chronic constriction injury (CCI) of the sciatic nerve was used to evaluate the effects of oral cannabinoid formulations (F1: 500 mg, F2: 1000 mg, F3: 2000 mg, F4: 3000 mg) in MCT oil, with pregabalin as the reference. Male Wistar rats (35) were divided equally into seven groups, with all except the Sham group undergoing sciatic nerve ligation and receiving different formulations.On day 22, behavioral (hot plate, tail flick) and electrophysiological (sensory nerve conduction velocity, SNCV) assessments were performed. SNCV was also measured in the presence of CB1 and CB2 receptor antagonists. Additionally, blood-based markers of inflammation (TNF-α) and oxidative stress (MDA, GSH and CAT) were analysed.

Results and conclusions: The vehicle group exhibited significant hyperalgesia (p <0.005), reduced sensory nerve conduction velocity (SNCV) (p <0.005) and elevated MDA and TNF-α levels, along with decreased GSH and CAT levels in both serum and sciatic nerve tissue.Among the formulations, F2 significantly improved pain latency and SNCV (p <0.005) compared to the vehicle group and outperformed F1, F3, F4 and pregabalin (p <0.05). Its effects were mediated through CB1 and CB2 receptor agonism while simultaneously reducing oxidative stress and inflammation, highlighting its potential as a promising candidate for neuropathic pain management.”

https://pubmed.ncbi.nlm.nih.gov/40336142/

https://www.tandfonline.com/doi/full/10.1080/01616412.2025.2500112

“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