Cannabidiol interactions with Δ-9-tetrahydrocannabinol on antinociception after carrageenan-induced inflammatory pain in male and female rats

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“Cannabis products used for pain typically contain Δ-9-tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD) in varied amounts, but data on the effects of specific cannabinoid formulations on different pain types are lacking.

This study used the carrageenan-induced inflammatory pain model to test oral Δ9-THC, CBD, or their combination on acute edema and pain hypersensitivity.

Male and female Sprague-Dawley rats (n = 10-14 per sex/group) were pretreated (1 hour) with vehicle (sesame oil), Δ9-THC (1, 3, and 10 mg/kg, p.o.), CBD (10, 30, 100 mg/kg, p.o.), or select doses of Δ9-THC + CBD combinations prior to an intraplantar λ-carrageenan injection into the hind paw.

The nonsteroidal anti-inflammatory drug ketoprofen (10 and 20 mg/kg i.p.) or its vehicle (1:1:18 ethanol:Cremophor EL:saline [Millipor Sigma]) was administered to a separate group as a positive control. Measurements were conducted at baseline and 1, 3, and 5 hours after carrageenan injection. Carrageenan produced edema and hypersensitivity to radiant heat (hyperalgesia) and mechanical pressure (allodynia).

Δ9-THC alone sex- and dose-dependently decreased hyperalgesia and allodynia but not inflammation, with effects of Δ9-THC being greater in females than males, and the lowest Δ9-THC dose was proinflammatory in males. CBD alone did not affect pain sensitivity but had modest anti-inflammatory effects in males. Isobolographic and dose addition analyses indicated Δ9-THC + CBD was subadditive relative to Δ9-THC alone.

These data demonstrate that prophylactic oral Δ9-THC alleviates acute inflammatory pain with sex-dependent effects, and CBD diminishes Δ9-THC antinociception when combined.

The findings suggest oral Δ9-THC is superior to CBD or combined Δ9-THC + CBD for acute inflammatory pain.

SIGNIFICANCE STATEMENT: Despite the popularity of cannabis for pain management, empirical data on how specific cannabinoid formulations affect acute inflammatory pain are limited. This study in rats found that pure Δ-9-tetrahydrocannabinol (Δ9-THC) formulations were most effective at improving inflammatory pain compared to pure cannabidiol or Δ9-THC + cannabidiol combinations, and females were more sensitive than males to the antinociceptive effects of Δ9-THC.”

https://pubmed.ncbi.nlm.nih.gov/40609153/

https://jpet.aspetjournals.org/retrieve/pii/S0022356525398381

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.”

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

Cost-Effectiveness of Medical Cannabis Versus Opioids for Chronic Noncancer Pain

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“Background: Chronic noncancer pain (CNCP) affects one in five adults and is commonly managed with long-term opioid therapy. Concerns regarding rare but catastrophic harms associated with opioids, including overdose and death, have generated interest in alternatives including cannabis; however, the comparative cost-effectiveness of these management options is uncertain. 

Methods: We used findings from a network meta-analysis of 90 randomized trials to develop a 1-year microsimulation model to compare costs and quality-adjusted life years (QALY) between oral medical cannabis and opioids for CNCP. We used a publicly funded health care payer perspective for our analyses and obtained cost and utility data from publicly available sources. All costs are reported in 2023 Canadian dollars. All analyses were probabilistic, and we conducted sensitivity and scenario analyses to assess robustness. 

Results: Total mean annual cost per patient was $1,980 for oral medical cannabis and $1,851 for opioids, a difference of $129 (95% confidence interval [CI]: -$723 to $525). Mean QALYs were 0.582 for both oral medical cannabis and opioids (95% CI: -0.007 to 0.015). Cost-effectiveness acceptability curves showed that oral medical cannabis was cost-effective in 31% of iterations at willingness-to-pay thresholds up to $50,000/QALY gained.

Use of opioids is associated with nonfatal and fatal overdose, whereas medical cannabis is not. 

Discussion: Our findings suggest that medical cannabis as an alternative to opioids for chronic pain may confer similar, but modest, benefits to patients, and reduce the risk of opioid overdose without substantially increasing costs.”

https://pubmed.ncbi.nlm.nih.gov/40304409/

https://www.liebertpub.com/doi/10.1089/can.2024.0120

Cannabinoids in neuropathic pain treatment: pharmacological insights and clinical outcomes from recent trials

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“Neuropathic pain, a complex and often devastating condition, poses significant challenges for its effective management. Despite promising research on various cannabis formulations and delivery methods for neuropathic pain, significant gaps remain in our knowledge.

While inhaled cannabis shows analgesic effects and alternative delivery methods may improve bioavailability, oral formulations have yielded mixed results, often limited by small sample sizes and placebo effects. Therefore, further research is essential to optimize cannabis formulations, identify responder profiles to tailor treatments effectively, and, most critically, confirm the long-term safety and efficacy of cannabis-based therapies in managing NP.

This review article aims to provide a comprehensive analysis of the therapeutic potential of cannabis-based medicines, with a particular focus on cannabinoids. This review, though not systematic, examines 11 clinical studies, specifically Randomised Clinical Trials) published from 2014 to 2024, highlighting the efficacy of numerous cannabis formulations, in alleviating neuropathic pain.

Key findings show that cannabinoids can reduce pain perception, improve patient quality of life, and mitigate other symptoms associated with neuropathic pain.

The synergistic effects of tetrahydrocannabinol and cannabidiol are discussed, emphasizing their ability to enhance analgesic effects, while potentially reducing the psychoactive side effects of tetrahydrocannabinol.

This review emphasizes the importance of the personalized approach to improve therapeutic outcomes. Limitations of the existing research focusing on cannabis for neuropathic pain are limited by heterogeneity, lack of standardization, small sample sizes, and reliance on subjective outcomes, impacting the reliability and generalizability of findings. However, this exhaustive review aims to inform clinicians and researchers about the evolving role of cannabis in contemporary pain management strategies, illustrating the diverse pharmacological profiles of cannabinoids and their potential as adjunct therapies for neuropathic pain management.”

https://pubmed.ncbi.nlm.nih.gov/40261351/

https://link.springer.com/article/10.1007/s00210-025-04134-7