Prevention of Allodynia and Hyperalgesia by Cannabidiol in a Rat Model of Chemotherapy-Induced Peripheral Neuropathy

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“This study demonstrates the utility of a rat model of chemotherapy-induced peripheral neuropathy (CIPN) to assess the ability of the non-psychoactive cannabinoid cannabidiol (CBD) to modulate the development of this syndrome in vivo. The method utilizes the chemotherapeutic agent paclitaxel to generate an allodynic phenotype in the animals.

This study describes how to handle and solubilize CBD, administer the chemotherapeutic agent, assess mechanical and cold sensitivity, and apply high-speed videography to measure nocifensive behavior in animals.

Using the procedures outlined, the data support that CBD prevents the allodynic phenotype from developing in the treated animals. No difference was observed in the CBD-treated animals from day 0 (pre-paclitaxel baseline) to day 7 (post-sensitization) in mechanical or thermal sensitivity, while the vehicle-treated animals became significantly more sensitive.

This response to treatment is durable up to the latest time point where data were collected (7 weeks). The addition of high-speed videography allows for a more granular and unbiased assessment of this behavioral phenotype (e.g., classification of analgesia and anti-allodynia).

This demonstrates both the utility of this model for cannabinoid drug characterization and the potential role of CBD in mitigating neuropathic pain.”

https://pubmed.ncbi.nlm.nih.gov/40622941/

“Co-administration of CBD with paclitaxel prevents the development of chemotherapy-induced peripheral neuropathy in rats. This protocol describes cannabinoid handling, inducing an allodynic phenotype in rats via chemotherapeutic administration, assessing mechanical and thermal allodynia, and using high-speed videography to distinguish allodynia and hyperalgesia.”

https://app.jove.com/t/68079/prevention-allodynia-hyperalgesia-cannabidiol-rat-model-chemotherapy

Oral Cannabis for Taxane-Induced Neuropathy: A Pilot Randomized Placebo-Controlled Study

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“Introduction: Taxane-induced peripheral neuropathy (TIPN) is experienced by most patients with breast cancer, and there is no efficacious treatment. In pre-clinical studies, co-administration of two constituents of cannabis, Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD), synergistically reduces TIPN. 

Materials and Methods: The goal of this 8-week, double-blind, randomized pilot study, conducted from 2019 to 2021, was to test the feasibility and tolerability of oral cannabis (100 mg CBD: 5 mg THC, TID) relative to placebo on pain resulting from TIPN. Participants with painful TIPN completed daily questionnaires online about their pain, sleep, and medication use, and weekly questionnaires on neuropathy. 

Results: All participants (12 women; 51 ± 6 years) randomized to placebo (n = 6) or active (n = 6) cannabis capsules completed the trial. Participants in both medication groups requested dose reductions (mean ± SEM capsules/day: placebo: 2.4 ± 0.4; active: 2.0 ± 0.4). In a preliminary evaluation of efficacy, measures of pain, pain interference, sleep, and functional well-being significantly improved over time (p < 0.03), but participants receiving cannabis had significantly higher ratings of neuropathy at each week (p < 0.035) and lower ratings of functional well-being in the last 3 weeks of treatment compared with participants receiving placebo (p < 0.02). Similarly, cannabis significantly worsened ratings of sleep and pain interference relative to placebo (p < 0.05). 

Discussion: This study demonstrates that: (1) double-blind, placebo-controlled testing of cannabis capsules in this dose range is feasible and well tolerated in women with TIPN and (2) ratings of pain, neuropathy, and well-being significantly improved over 8 weeks, but cannabis significantly worsened several endpoints relative to placebo. These findings highlight the necessity of placebo control when assessing the therapeutic utility of cannabis. Although there was no signal of efficacy herein, a fully powered study testing a range of cannabis doses for TIPN is warranted, given its impact on most patients with breast cancer, promising pre-clinical data, and the widespread use of cannabis among patients with cancer.”

https://pubmed.ncbi.nlm.nih.gov/40611810/

https://www.liebertpub.com/doi/10.1089/can.2025.0028

How to ESCAPE from Pain? An Observational Study on Improving Pain and Quality of Life with the Cannamedical® Hybrid Cannabis Extract

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“Introduction: Chronic pain remains a challenge, with standard therapies often providing inadequate pain relief and causing undesirable side effects. Medicinal cannabis has emerged as promising alternative. This study assessed the impact of a cannabis hybrid extract on pain intensity and quality of life in daily clinical use.

Methods: ESCAPE was an observational study and included patients aged ≥ 18 years with chronic pain in Germany. The primary objective was to evaluate the effectiveness of the Cannamedical® Hybrid Cannabis Extract THC25:CBD25 on pain during four visits (V1-V4) in clinical practice, and key secondary objectives were pain interference and quality of life. Pain intensity was measured using the Numeric Rating Scale (NRS) of the Brief Pain Inventory (BPI) questionnaire. Pain interference was evaluated with the BPI pain interference subscore, and quality of life-particularly physical and mental health-was assessed with the Short Form-12 (SF-12) questionnaire. Additionally, patient and physician satisfaction with the extract was assessed.

Results: The study included 64 patients (50% female) with chronic pain (intention-to treat population; ITT). Cannabis-naïve patients of the ITT were defined as a subgroup and analyzed separately (N = 35). Mean (± SD) NRS-assessed pain intensity decreased during the study, in both the ITT (5.46 ± 1.73 at V1 vs. 3.37 ± 2.43 at V4) and in the cannabis-naïve subgroup (5.92 ± 1.34 at V1 vs. 2.37 ± 1.69 at V4). Mean pain interference subscore decreased between V1 and V4 for the ITT (5.39 ± 1.92 vs. 3.38 ± 2.46) and the cannabis-naïve group (5.68 ± 1.46 vs. 2.54 ± 1.99). Physical and mental health improved in both groups and high satisfaction with the hybrid cannabis extract was reported by patients and physicians.

Conclusion: Treatment with the Cannamedical® Hybrid Cannabis Extract THC25:CBD25 in daily clinical practice showed positive effects on patients’ pain and quality of life.”

https://pubmed.ncbi.nlm.nih.gov/40560527/

https://link.springer.com/article/10.1007/s12325-025-03262-z

Effectiveness of Full Spectrum Cannabis Extracts in the Treatment of Chronic Pain: An Open Label Study

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“The aim of this work was to assess the effectiveness of full-spectrum cannabis (THC and CBD) extracts as adjuvants in the treatment of chronic pain. This is a prospective, open label, longitudinal study.

Major cannabinoids were analyzed in herbal preparations using high performance liquid chromatography (HPLC). Subjects were included when chronic pain diagnosis criteria was met according to physicians’ diagnosis. A patient stratification protocol was developed using a visual analogue scale to measure pain, a numerical scale for life quality parameters and a self-administered health survey. Eighty-eight patients aged between 35 and 88 years were included.

A significant decrease in both pain and other life quality parameters was observed between time zero and subsequent time intervals, excepting the “appetite” variable.

Overall, 51 individuals reported a decrease in pain, 38 a decrease in anxiety and 48 in insomnia, with “decrease” defined as symptom reduction of 50% or more between the first and last consultation. In addition, 23 subjects reduced or discontinued other analgesics and/or anti-inflammatory drugs during the trial. Adverse effects were mild and reversible.

These results are consistent with previous studies, supporting effectiveness and safety of cannabis extracts as adjuvants in the treatment of chronic pain.”

https://pubmed.ncbi.nlm.nih.gov/40526158/

https://www.tandfonline.com/doi/full/10.1080/15360288.2025.2517778

New cannabidiol structure-related terpene N-acyl-hydrazones with potent antinociceptive and anti-inflammatory activity

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“Inflammation is the organism’s protective mechanism to restore cellular and tissue homeostasis. Cannabidiol has been reported for its ability to bind to diverse receptors related to or not related to the endocannabinoid system, with good safety being one of the most promising phytocannabinoids for therapeutical purposes. CBD has shown in vitro and in vivo ability to significantly reduce the production of cytokines and other inflammatory mediators, with an unclear mechanism of action.

Herein, we report the design and synthesis of a novel series of eight terpene N-acylaryl hydrazone analogues and their pharmacological evaluation for potential antioxidant, antinociceptive, and anti-inflammatory properties.

Our results led to the identification of compounds 5a (PQM-242), with significant peripheral and central antinociceptive effects, 5b (PQM-243), and 5g (PQM-248) with antinociceptive activities probably related to the ability of modulation of TRPV1 receptors, and 5c (PQM-244) that seems to have the most promising peripheral antinociceptive profile, showing significant effects on both neurogenic and inflammatory phases of formalin-induced licking test, coupled to potential antioxidant activity.

Overall, our experimental data suggest that the new CBD-based architecture is capable of ensuring peripheral and central antinociceptive effects by different modes of action, with no in vivo toxicity and adequate predicted ADME properties.”

https://pubmed.ncbi.nlm.nih.gov/40521634/

“Several compounds showed similar antinociceptive and anti-inflammatory effects to those described for CBD.”

https://www.tandfonline.com/doi/full/10.1080/17568919.2025.2515821

Combination of Cannabidiol and Low-Dose Buprenorphine Suggests Synergistic Analgesia and Attenuates Buprenorphine-Induced Respiratory Depression

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“Introduction: As opioid-related drug overdoses remain a public health crisis, there is a critical need for innovative approaches to developing safer analgesics with improved safety profiles. BDH-001 is a fixed-dose combination of low-dose buprenorphine (BUP) and cannabidiol (CBD) being developed as a safer analgesic than currently available opioids. The purpose of this study was to examine the analgesic and opioid-sparing effects of BDH-001 and to complete an in vivo safety assessment in rats. 

Methods: Analgesic effect of BDH-001 was assessed using the chronic constriction injury model of chronic neuropathic pain with pain threshold assessed via Von Frey testing. Drug-drug interaction effects on pharmacokinetic (PK) parameters were assessed in a single dose PK study in rodents. The effects on respiratory depression were also assessed and confirmed in two separate rodent studies performing blood gas analysis and measuring O2 saturation. 

Results: BDH-001 (combination of subanalgesic BUP dose and CBD) resulted in statistically significant increases in pain threshold compared to saline (p < 0.001), CBD alone (p < 0.01), and BUP alone (p < 0.05). The half-life of BUP was significantly shorter in the presence of CBD compared to BUP alone (p = 0.008), with no significant changes in any other BUP pharmacokinetic parameter assessed. CBD was found to attenuate BUP-induced respiratory depression in rats when assessing blood gases (p < 0.05) and O2 saturation (p < 0.05) over several time bins. 

Conclusions: Data obtained in the present study indicate the addition of CBD to BUP was opioid-sparing and attenuated BUP- but not morphine-induced respiratory depression. There was no evidence these findings were the result of a PK interaction. Results support the hypothesis that BDH-001, a fixed-dose combination of BUP and CBD, may provide effective analgesia with a more favorable safety profile.”

https://pubmed.ncbi.nlm.nih.gov/40468945/

https://www.liebertpub.com/doi/10.1089/can.2025.0004

“Buprenorphine is a medication that plays a crucial role in treating opioid use disorder (OUD), also known as opioid addiction. It works by partially activating the same receptors in the brain as opioids, helping to reduce withdrawal symptoms and cravings without producing the intense euphoria or dangerous side effects associated with full opioid agonists like heroin or fentanyl.”

Cannabidiol and multi-modal exercise for chemotherapy-induced peripheral neuropathy in cancer survivors

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“Purpose: This study explored the effectiveness of cannabidiol (CBD) alone and in combination with multi-modal exercise (MME) to improve signs and symptoms of chemotherapy-induced peripheral neuropathy (CIPN), quality of life (QoL), and functional capacity in cancer survivors.

Methods: Cancer survivors (n = 27) with CIPN were enrolled in a 4-month interventional open-label study. Participants underwent two consecutive 2-month interventions: CBD (up to 300 mg/day) and CBD combined with MME. They were assessed using the painDETECT questionnaire for CIPN-related neuropathic pain and the Functional Assessment of Cancer Treatment/Gynecological Oncology-Neurotoxicity-13 (FACT-GOG-Ntx-13) questionnaire for CIPN neurotoxic symptoms (Ntx), perceived physical function (PPF) and overall QoL. Their functional status was examined through gait speed and timed up and go for mobility, the 9-hole peg test for manual dexterity, a hand-held hydraulic dynamometer for hand grip strength, and five repetitions sit-to-stand for dynamic balance, upper/lower extremity and overall strength.

Results: Positive effect sizes were measured by Cohen’s d or Cohen’s r with 95% confidence intervals (CI) from mean scores, and were d 0.62, CI 0.03-1.20 for Ntx; d 0.62, CI 0.09-1.26 for PPF; and r 0.401, CI 0.13-0.61 for hand grip strength after 2 months of CBD alone. After adding MME to CBD for another 2 months, the effect sizes were d 0.526, CI -0.15-1.19 for painDETECT; d 0.862, CI 0.67-1.55 for CIPN neurotoxic symptoms; d 1.03, CI 0.30-1.74 for perceived physical function; r 0.447, CI 0.15-0.67 for overall QoL; r 0.339, CI 0.03-0.59 for gait speed; and r 0.389, CI 0.08-0.63 for manual dexterity.

Conclusions: The study provides a proof of concept for the therapeutic effect of CBD alone and in combination with MME to improve symptoms’ burden, QoL and functional impairments related to CIPN in patients who are cured from cancer. Future randomized studies are needed to confirm the causal effects of CBD and exercise on CIPN, and to replicate our findings.”

https://pubmed.ncbi.nlm.nih.gov/40464985/

“This study provides a proof of concept supporting the use of CBD and multi-modal exercise (MME) to relieve CIPN in patients who are cured from cancer. Within the limitations of an observational study, our data suggest that 4 months of oral administration of CBD (up to 300 mg/day) in combination with 2 months of MME may provide clinically relevant improvements in CIPN-neurotoxic symptoms, neuropathic pain, QoL, and perceived physical function. CBD with or without MME may also positively affect functional capabilities such as muscle strength, gait speed, and manual dexterity, which are often impaired because of CIPN..”

https://link.springer.com/article/10.1007/s00520-025-09553-z

Effects of combined CBGA and cannabis-derived terpene nanoformulations on TRPV1 activation: Implications for enhanced pain management

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“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

Full spectrum cannabis oil combined with omega-3 fish oil for neuropathic pain management: a novel therapeutic approach

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“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

Oral cannabinoid formulation elevates sensory nerve conduction velocity and mitigates oxidative stress to alleviate neuropathic pain in rats

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“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