Category Archives: Neuropathic Pain

Therapeutic relevance of an EU-GMP certified Cannabis sativa L. strain in a dual in vivo model of cognitive impairment and chronic neuropathic pain

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“Background: Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and frequently co-occurs with chronic pain. Worldwide, over 55 million people are affected by AD, with nearly half experiencing persistent pain. Chronic pain has been linked to accelerated memory deterioration and an increased risk of dementia, but the interplay between these conditions remains poorly understood. Existing therapies for AD and chronic pain are limited in efficacy, highlighting the need for interventions targeting multiple pathological pathways. The endocannabinoid system, which is altered in both AD and chronic pain, represents a potential therapeutic target, though its role in AD patients with comorbid pain remains unexplored.

Methods: The study evaluated the effects of an EU-GMP certified Cannabis sativa L. strain (5 mg/kg, Cannabixir® Medium Flos) on neurobiological alterations in a rat model designed to explore mechanistic interactions between scopolamine-induced transient cognitive impairment and chronic neuropathic pain induced by unilateral sciatic nerve ligation. Treatment outcomes were assessed through nociceptive tests, clinical monitoring and tissue analyses to examine cognitive and pain-related effects.

Results: Cannabixir® Medium Flos induced robust, time-dependent analgesia in thermal nociceptive tests, with the combination of the Cannabis sativa L. strain, donepezil and tramadol producing significantly longer response latencies than tramadol alone. Mechanical sensitivity was minimally affected across treatments. Immunohistochemical analyses revealed that Cannabixir® Medium Flos, either alone or in combination with donepezil or tramadol, produced the most pronounced neuroprotective effects, reducing astrocytic (GFAP) and microglial (Iba1) activation, lowering Caspase-3 and IL-6 expression, and preserving both hippocampal neuronal integrity as well as peripheral nerve structure.

Conclusion: These findings indicate that Cannabixir® Medium Flos, particularly when combined with donepezil and tramadol, provides superior analgesic and neuroprotective effects compared to tramadol alone. Its multi-target action – alleviating thermal nociception, reducing neuroinflammation, limiting apoptosis and preserving neuronal and peripheral nerve integrity-supports its potential as an adjunct therapy in managing dementia with comorbid chronic neuropathic pain. Future studies should explore the molecular mechanisms underlying these effects and assess long-term safety and efficacy across diverse models of neurodegeneration and chronic pain.”

https://pubmed.ncbi.nlm.nih.gov/41800101

https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2026.1761426/full

Medical Cannabis for the Treatment of Peripheral Neuropathy due to Diabetes: A Systematic Review

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“Introduction: This systematic review evaluated randomized controlled trials (RCTs) conducted specifically in participants with diabetes and painful peripheral neuropathy to assess the effectiveness and safety of medical cannabis, isolated cannabinoids, or nationally approved cannabis-based medicines as adjuvant treatment, compared with placebo or baseline.

Materials and methods: Controlled clinical studies and RCTs in adults with diabetic peripheral neuropathy were eligible. Animal and in vitro studies were excluded. We searched PubMed, Google Scholar, Cochrane Library, and Scopus and screened 15,377 records; 35 full-text articles were assessed for eligibility, and 4 RCTs were included in the qualitative synthesis.

Results: Three of four studies reported statistically significant reductions in neuropathic pain with cannabinoid-based interventions compared with placebo, whereas one trial did not demonstrate superiority. In two trials using vaporized or sublingual Δ9-tetrahydrocannabinol (THC), doses in the range of approximately 16-18 mg were associated with clinically meaningful pain relief in participants. Adverse effects, including dizziness and cognitive symptoms, were common but generally mild-to-moderate, and discontinuations due to adverse effects varied across studies.

Discussion/conclusion: Evidence from four small, heterogeneous RCTs suggests that cannabinoid-based therapies may reduce pain in some patients with diabetic peripheral neuropathy; however, the limited number of studies, variability in formulations and comparators, and risk of bias preclude firm conclusions regarding efficacy. Observed THC doses around 16-18 mg/day delivered via vaporized or sublingual routes should be viewed as preliminary, hypothesis-generating ranges rather than definitive recommendations. Larger, contemporary RCTs with rigorous risk-of-bias control, standardized outcomes, and detailed safety reporting are needed.”

https://pubmed.ncbi.nlm.nih.gov/41714301

“three of four identified studies demonstrated statistically significant reductions in pain compared with placebo or baseline, suggesting that cannabinoid-based interventions may offer analgesic benefit for some patients with diabetic peripheral neuropathy.”

https://journals.sagepub.com/doi/10.1177/25785125261425444

Cannabidiol reduces oxycodone self-administration while preserving its analgesic efficacy in a rat model of neuropathic pain

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“Prescription opioid misuse is a significant public health concern among individuals with chronic pain. Treating severe pain often requires high doses of opioids, increasing the risk of developing an opioid use disorder.

Cannabidiol (CBD) is a non-intoxicating component of cannabis that has shown therapeutic potential without abuse liability.

This study investigated the effects of CBD on oxycodone self-administration and hyperalgesia in an animal model of chronic neuropathic pain.

Adult male rats were trained to self-administer intravenous oxycodone (0.06 mg/kg/infusion). Subsequently, they underwent chronic constriction injury (CCI) of the sciatic nerve or received sham surgery. Paw withdrawal latency was measured using the Hargreaves test as an indicator of thermal pain sensitivity. CBD (0, 1, 3, and 10 mg/kg, IP) was administered before the self-administration sessions, and pain testing was conducted afterward. The rats acquired oxycodone self-administration, as indicated by more active than inactive lever presses. CCI surgery decreased the paw withdrawal latency, confirming the induction of neuropathic pain. CCI alone did not affect oxycodone self-administration, suggesting that neuropathic pain does not substantially influence opioid intake at the dose tested.

Treatment with CBD reduced oxycodone self-administration in both the sham and CCI rats. Oxycodone self-administration in the CCI rats reversed the CCI-induced decrease in paw withdrawal latency. However, CBD did not affect the antinociceptive effect of oxycodone in CCI rats.

Taken together, these findings demonstrate that CBD reduces oxycodone self-administration without affecting the antinociceptive effects of oxycodone in neuropathic pain.

This study supports the potential of CBD to reduce opioid use and misuse, regardless of pain status.”

https://pubmed.ncbi.nlm.nih.gov/41521216

https://www.nature.com/articles/s41598-025-31828-y

Cross-sectional comparison of cannabis use in adults with neuropathic versus non-neuropathic pain

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“Introduction: Cannabis has been decriminalized by many states and shows promise in treating both neuropathic and non-neuropathic pain through its interaction with the endocannabinoid system and anti-inflammatory effects. This study examines differences in cannabis use for adults whose most bothersome chronic pain condition is neuropathic vs. non-neuropathic.

Materials and methods: Survey data were collected from adults receiving care at a pain clinic. Participants completed demographic questions and standardized self-report measures (PROMIS Pain Intensity/Interference and the ID-Pain tool). Participants’ most bothersome pain condition(s) were categorized as neuropathic or non-neuropathic pain based on ID-Pain scores. Linear regression models assessed differences in frequency and duration of cannabis product use between groups, adjusting for age and sex.

Results: A total of 113 individuals were recruited; following exclusions and missing data, 104 participants (61.5% female) were included in the final analysis. Of these, 36.5% reported neuropathic pain as their most bothersome, and 63.5% reported non-neuropathic pain. Those with neuropathic pain reported significantly more days per month of Tetrahydrocannabinol/Cannabidiol (THC/CBD) combination (b = 5.96, p = 0.02), Cannabidiol-only (CBD-only) (b = 8.82, p = 0.03), and Tetrahydrocannabinol-only (THC-only) products (b = 7.04, p = 0.02). They also used THC-only (b = 0.97, p < 0.05) and THC/CBD (b = 1.09, p < 0.01) products more frequently per day. Neuropathic pain was positively associated with pain intensity (b = 4.10, p < 0.001) and interference (b = 4.95, p < 0.001).

Discussion: Adults whose most bothersome pain condition(s) were neuropathic used cannabis, especially THC and THC/CBD combination products, more frequently than those whose most bothersome pain was non-neuropathic. Participants with neuropathic pain also reported higher levels of pain intensity and interference. Further longitudinal research is needed to confirm whether increased use of THC-rich cannabis provides symptom relief for adults with neuropathic pain.”

https://pubmed.ncbi.nlm.nih.gov/41487383

“Cannabis interacts with the endocannabinoid system, making it a potential treatment for neuropathic pain.”

“Because previous studies found THC products to be more effective in managing neuropathic pain by interacting with the endocannabinoid system, it is possible that our participants also experienced benefit; this could explain their higher use of THC containing products.

https://www.frontiersin.org/journals/pain-research/articles/10.3389/fpain.2025.1677391/full

Neuropathic Pain and Related Depression in Mice: The Effect of a Terpene and a Minor Cannabinoid in Combination

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“Background/Objectives: Neuropathic pain is one of the most severe types of chronic pain. Although it is difficult to manage, it often co-occurs with depression. Yet, no medication addresses the neuropathic pain and depression comorbidity. Therefore, developing integrated treatment strategies that address both pain and depression is a major public health priority and an unmet need affecting millions. 

Methods: In this study, we investigated the effect of combining a terpene, Beta-Caryophyllene (BCP), and cannabidiol (CBD) on neuropathic pain and associated depression. We employed a chronic constriction injury (CCI) neuropathic pain model and a series of behavioral tests to evaluate how oral administration of this combination influences neuropathic pain and depression-like behaviors in mice. We employed immunohistochemistry and proteomics approaches to explore the mechanism. 

Results: The analgesic effect of combining CBD and BCP is synergistic in neuropathic pain and also shows an antidepressant effect. Additionally, we found that this combination decreases neuroinflammation associated with CCI and affects specific genes involved in the inflammation. 

Conclusions: This work provides preclinical scientific evidence supporting the potential usefulness of this combination for neuropathic pain and associated depression.”

https://pubmed.ncbi.nlm.nih.gov/41463111

“Cannabis plants contain various non-psychoactive compounds, including Caryophyllene (BCP). BCP is a natural bicyclic sesquiterpene that acts as a natural ligand for the cannabinoid type 2 receptor (CB2) and is an FDA-approved food additive. It has several benefits, such as pain relief, antidepressant effects, and anti-inflammatory properties.

Given this background, the main goal of this study is to test the hypothesis that combining CBD and BCP is effective for neuropathic pain while also demonstrating antidepressant effects.”

“In conclusion, the proposed project introduces the concept that the combination of CBD and BCP can effectively relieve neuropathic pain while also addressing depression. This knowledge will advance the field by providing preclinical scientific evidence supporting the potential usefulness of this combination for neuropathic pain and associated depression.”

https://www.mdpi.com/2227-9059/13/12/3103


Modulatory Effects of “Minor” Cannabinoids in an in vitro Model of Neuronal Hypersensitivity

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“Aim: Effective treatment for neuropathic pain remains an unmet clinical need. The therapeutic benefits of the Cannabis plant are well known, especially for pain relief. Here, we have assessed ten “minor” cannabinoids for their analgesic effects in an established model of neuronal hypersensitivity, a key mechanism which underlies neuropathic pain.

Methods: Adult rat DRG neurons were cultured in medium containing 100 ng/mL nerve growth factor (NGF) and 50 ng/mL glial cell-line derived neurotrophic factor (GDNF) for 48 hours to sensitize the neurons. Ca2+ imaging was used to measure the responses to pain stimulation using capsaicin, and to determine the modulatory effects of the cannabinoids, in individual neurons.

Results: Control neurons (nociceptors) showed robust responses of Ca2+ influx to capsaicin application, while neurons treated with ten minor cannabinoids tetrahydrocannabiorcol (THCC), cannabitriol (CBT), cannabidivarin (CBDV), cannabinol (CBN), cannabichromene (CBC), cannabichromevarin (CBCV), cannabicitran (CBCT), cannabigerol monomethyl ether (CBGM), tetrahydrocannabutol (THCB) or tetrahydrocannabiphorol (THCP), at concentrations of 0.001-100 μM, showed differential dose-related effects on the responses to capsaicin. Ca2+ influx in response to capsaicin application was completely inhibited for each compound in 35-78% capsaicin-sensitive neurons, while other neurons showed reduced responses. The opioid receptor agonist morphine and α2δ1- Ca2+ channel inhibitor gabapentin were also tested for comparison and showed similar results. All the cannabinoids tested here inhibited calcium influx in response to capsaicin, and two, namely, CBN and THCC elicited calcium influx at higher doses. Inhibition of Ca2+ influx due to cannabichromene (CBC) was reversed by the potassium channel inhibitor Tertiapin Q.

Conclusion: All the cannabinoids tested here inhibited TRPV1 signalling. CBC targeted K+ channels to block TRPV1 mediated Ca2+ influx, demonstrating potential analgesic effects in vitro.”

https://pubmed.ncbi.nlm.nih.gov/41322279

“The therapeutic benefits of the Cannabis plant are well known, especially for pain relief.”

“In conclusion, our results show that the minor cannabinoids potently inhibit TRPV1 signaling in sensitized DRG neurons, and for CBC by blocking Ca2+ influx via K+ channel activation. This conclusion is based on the reversal of CBC-mediated inhibition in the presence of the K+ channel inhibitor Tertiapin Q. Further studies are necessary to confirm the mechanism, pathways and targets involved in the observed inhibitory effects of the other minor cannabinoids. This will facilitate the identification of cannabinoid combinations likely to have the maximum effect in providing analgesia for inhibiting neuronal sensitization that underlies chronic pain.”

https://www.dovepress.com/modulatory-effects-of-minor-cannabinoids-in-an-in-vitro-model-of-neuro-peer-reviewed-fulltext-article-JPR

Use of Cannabidiol and Cannabigerol in the Treatment of Trigeminal Neuralgia and Postherpetic Pain

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“The use of cannabidiol (CBD) as an adjuvant in the treatment of trigeminal neuralgia (TN) and postherpetic neuropathy has shown beneficial effects in patients refractory to conventional treatments.

This case study describes a 57-year-old patient diagnosed with TN in 2019, initially treated with low-power laser therapy and oxcarbazepine. In 2021, she developed vesicular-bullous lesions on the right side of the supraorbital region, accompanied by severe pain confirmed by positive serology for shingles. Following the diagnosis of postherpetic neuropathy, the drug dose was adjusted and combined with laser therapy. However, the pain remained significant and reduced quality of life.

In 2023, treatment was started with CannaMeds CBD Full Spectrum – 3000 mg/30 ml + CannaMeds CBG Isolate 1500 mg/30 ml. After 15 days, the patient appeared pain-free, allowing the laser to be discontinued and the drug dose to be reduced.

CBD is a treatment option for patients who do not respond to conventional treatments.”

https://pubmed.ncbi.nlm.nih.gov/41281696

“It is difficult to find an effective treatment for these conditions, because over time patients no longer respond to treatment. Therefore, the use of CBD and cannabigerol could be an adjuvant treatment option for patients who do not respond to conventional treatment for neuropathic pain.”

https://journals.lww.com/cocd/fulltext/2025/07000/use_of_cannabidiol_and_cannabigerol_in_the.10.aspx

Dual Role of the Spinal Endocannabinoid System in Response to Noxious Stimuli: Antinociceptive Pathways and Neuropathic Pain Mechanisms

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“Neuropathic pain is a clinically challenging syndrome that is largely refractory to conventional therapies. It arises from lesions or diseases affecting somatosensory pathways, which trigger extensive neuroplastic and neuroimmune remodeling. Unlike nociceptive pain, which establishes a protective response to tissue injury, neuropathic pain arises from maladaptive signaling within the nervous system.

In this context, the spinal endocannabinoid system (ECS) has emerged as a pivotal modulator of nociceptive processing. However, its precise role in neuropathic pain remains debated due to its dual effects.

Numerous studies report antinociceptive and neuroprotective effects; however, emerging data indicate that under specific pathological conditions, ECS activation may paradoxically facilitate pain transmission.

This review examines spinal ECS context dependence, uncovering its bidirectional antinociceptive and pronociceptive effects in neuropathic pain. By integrating current evidence on cellular, molecular, and pathophysiological mechanisms, we delineate the factors that determine whether ECS modulation inhibits or promotes pain. A comprehensive understanding of these mechanisms is essential for optimizing cannabinoid-based strategies to maximize therapeutic benefits while minimizing adverse outcomes.

Finally, we highlight the spinal cord’s centrality as the principal site for the initiation and maintenance of neuropathic pain and advocate for rigorous translational research to clarify the therapeutic potential of spinal ECS-targeted interventions.”

https://pubmed.ncbi.nlm.nih.gov/41226728/

“From a therapeutic perspective, ECS duality represents both a challenge and an opportunity. Pharmacological manipulation of the ECS, through selective CB1R and CB2R agonists, FAAH and MAGL enzyme inhibitors, allosteric modulators, or combined strategies including glial modulators, constitutes a promising avenue for developing innovative treatments targeting neuropathic pain. However, the success of these interventions critically depends on a precise understanding of the pathophysiological context of eCB pathways and the evolutionary stage of the pathology.”

https://www.mdpi.com/1422-0067/26/21/10692

Combination CBD/THC in the management of chemotherapy-induced peripheral neuropathy: a randomized double blind controlled trial

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“Introduction: Chemotherapy-induced peripheral neuropathy (CIPN) can greatly impair function, leading to disability or truncated treatment in cancer patients. Previous animal studies show that cannabidiol (CBD) and delta-9- tetrahydrocannabinol (THC) can ameliorate CIPN. This study assessed the effect of combined CBD and THC on CIPN symptoms amongst cancer patients treated with taxane- or platinum-based agents.

Materials and methods: This 12-week randomized, double-blind, placebo-controlled trial included participants with nonmetastatic breast, colorectal, endometrial, or ovarian cancer experiencing grade 2-3 CIPN. The active group received CBD (125.3-135.9 mg) combined with THC (6.0-10.8 mg) in gelcaps. The Quality-of-Life Questionnaire-CIPN twenty-item scale (QLQ-CIPN20) sensory subscale was used as the primary outcome. Additional outcomes assessed pain, sleep, and function. Neurologic exams evaluated touch, pressure, and vibration sense. Following the randomized controlled trial, participants were invited to enroll in a 12-week open-label observational study.

Results: Of 230 participants identified, 124 met eligibility, 54 were enrolled, 46 were randomized, and 43 completed 12 weeks of treatment. This was lower than our goal of 100 randomized participants. The mean age was 60 +/- 9 years, 88% were female, 63% had breast cancer. All participants had completed chemotherapy. The primary analysis showed no differences in outcome measures between active and placebo groups, likely due to sample size. Although an increase in bilirubin (one participant in active group, and one in placebo) and alkaline phosphatase (one participant in active group) was seen, this did not exceed the exit criteria. A secondary analysis showed that the active group experienced greater improvement in the QLQ-CIPN20 measures of sensory impairment relative to placebo (-10.4 (95% -20.5, -0.3), p = 0.044). There was also improvement in light touch and vibration sensation of the feet on neurological exam that approached significance. There was no effect on other measures, including pain, and no between-group differences in side effects. The uncontrolled observational study showed similar results.

Discussion: The primary analysis showed no between-group difference in CIPN symptoms. The secondary analysis indicated that CBD with THC could improve sensory impairment and might increase touch and vibration sense, although these findings require confirmation in a future, more fully powered study. Nonetheless, our results show that combination CBD/THC can be safely delivered to participants with CIPN and suggest that these cannabinoids should be further investigated for this indication.”

https://pubmed.ncbi.nlm.nih.gov/41211445/

“Overall, this study suggests that combination CBD/THC could help with the sensory impairment seen in CIPN. Since the disorder is prevalent and incurs significant hardship, even a modest sensory improvement could enhance patients’ quality of life, given the lack of alternatives.”

https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2025.1590168/full

Long-Term Efficacy and Safety of Inhaled Cannabis Therapy for Painful Diabetic Neuropathy: A 5-Year Longitudinal Observational Study

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“Background/Objectives: Diabetic neuropathy (DN) is a prevalent complication of diabetes mellitus, affecting up to 50% of long-term patients and causing significant pain, reduced quality of life, and healthcare burden. Conventional treatments, including anticonvulsants, antidepressants, and opioids, offer limited efficacy and are associated with adverse effects. Emerging evidence suggests that cannabis, acting via the endocannabinoid system, may provide analgesic and neuroprotective benefits. This study evaluates the long-term effects of inhaled cannabis as adjunctive therapy for refractory painful DN. Inhaled cannabis exhibits rapid onset pharmacokinetics (within minutes, lasting 2-4 h) due to pulmonary absorption, targeting CB1 and CB2 receptors to modulate pain and inflammation. 

Methods: In this prospective, observational study, 52 patients with confirmed painful DN, unresponsive to at least three prior analgesics plus non-pharmacological interventions, were recruited from a single clinic. Following a 1-month washout, patients initiated inhaled medical-grade cannabis (20% THC, <1% CBD), titrated individually. Assessments occurred at baseline and annually for 5 years, including the Brief Pain Inventory (BPI) for pain severity and interference; the degree of pain relief; Leeds Assessment of Neuropathic Symptoms and Signs (LANSS) score; HbA1c; and medication usage. Statistical analyses used repeated-measures ANOVA, Kruskal-Wallis tests, Welch’s t-tests, and Pearson’s correlations via Analyze-it for Excel. 

Results: Of 52 patients (mean age 45.3 ± 17.8 years; 71.2% male; diabetes duration 23.3 ± 17.8 years), 50 completed follow-up visits. Significant reductions occurred in BPI pain severity (9.0 ± 0.8 to 2.0 ± 0.7, p < 0.001), interference (7.5 ± 1.7 to 2.2 ± 0.9, p < 0.001), LANSS score (19.4 ± 3.8 to 10.2 ± 6.4, p < 0.001), and HbA1c (9.77% ± 1.50 to 7.79% ± 1.51, p < 0.001). Analgesic use decreased markedly (e.g., morphine equivalents: 66.8 ± 49.2 mg to 4.5 ± 9.6 mg). Cannabis dose correlated positively with pain relief (r = 0.74, p < 0.001) and negatively with narcotic use (r = -0.43, p < 0.001) and pain interference (r = -0.43, p < 0.001). No serious adverse events were reported; mild side effects (e.g., dry mouth or euphoria) occurred in 15.4% of patients. 

Conclusions: Inhaled cannabis showed sustained pain relief, improved glycemic control, and opioid-sparing effects in refractory DN over 5 years, with a favorable safety profile. These findings are associative due to the observational design, and randomized controlled trials (RCTs) are needed to confirm efficacy and determine optimal usage, addressing limitations such as single-center bias and small sample size (n = 52). Future studies incorporating biomarker analysis (e.g., endocannabinoid levels) could elucidate mechanisms and enhance precision in cannabis therapy.”

https://pubmed.ncbi.nlm.nih.gov/41153689/

“Inhaled cannabis add-on therapy mitigated symptoms of diabetic neuropathy over the course of a five-year observation period. Some reduction in glycosylated hemoglobin is observed as well as major reduction in the need for other prescription medications, including opiates and opioids. It is possible to state the following: (1). Inhaled cannabis significantly reduced pain and neuropathic symptoms over 5 years. (2). It decreased opioid use, supporting an opioid-sparing effect. (3). HbA1c improvements suggest a metabolic benefit, though causality is unproven. (4). No serious adverse events occurred, with mild effects in 15.4% of patients. (5). RCTs are needed to confirm efficacy and address accessibility barriers. Integration of objective pain assessment tools, such as salivary biomarker devices, could enhance the precision and reproducibility of cannabis therapy outcomes in DN.”

https://www.mdpi.com/2227-9059/13/10/2406