Category Archives: Spinal Cord Injury

Local release of fibroblast growth factor 21 and cannabidiol promoting spinal cord nerve injury repair through activation of cannabinoid receptor 2

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“Spinal cord injury (SCI) is a debilitating condition that leads to severe motor and sensory dysfunction, largely due to inflammation, neuronal damage, and disrupted neural circuits.

In this study, we developed an injectable hydrogel (C/F/Gel) co-loaded with fibroblast growth factor 21 (FGF21) and cannabidiol micelles (CBDm) to enhance SCI repair. The hydrogel, composed of PF127 and α-cyclodextrin (α-CD), provides sustained drug release and improves drug stability at the injury site.

Our findings demonstrate that C/F/Gel effectively modulates the inflammatory microenvironment by promoting microglial polarization toward the anti-inflammatory M2 phenotype via cannabinoid receptor 2 (CB2R) activation.

Additionally, it regulates the balance between excitatory and inhibitory neurons, and significantly improves motor function in SCI mice. Behavioral assessments, histological analysis, and molecular studies confirmed the superior therapeutic efficacy of C/F/Gel compared to single-agent treatments.

These results highlight C/F/Gel as a promising biomaterial-based strategy for SCI repair, offering a synergistic approach that integrates inflammation modulation, neuroprotection, and functional recovery.”

https://pubmed.ncbi.nlm.nih.gov/40782447/

“Our study shows that the developed C/F/Gel is a promising therapeutic strategy for SCI repair, offering a multi-faceted approach through controlled drug release, inflammation modulation, neural regeneration, and motor function recovery. The synergy between FGF21 and CBDm, particularly via CB2R activation, highlights a novel mechanistic pathway for SCI treatment.”

https://www.sciencedirect.com/science/article/abs/pii/S0142961225005289?via%3Dihub

The effects of nabiximols (Sativex®) on spasticity and non-motor symptoms in chronic spinal cord injury (SCI): a longitudinal prospective study

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“Objectives: This study aimed to evaluate the effects of Nabiximols (Sativex®) on spasticity in chronic spinal cord injury (SCI) individuals refractory to conventional therapy. Secondary objectives included assessing its impact on functional independence, neuropathic pain, sleep quality, and depression.

Setting: Institute Guttmann, a neurorehabilitation hospital in Badalona, Catalonia (Spain).

Methods: Adult participants ( >18 years) with chronic SCI ( >6 months) and moderate to severe spasticity refractory to conventional treatments were recruited. All participants underwent baseline assessments and were followed up at one and two months after initiating treatment with nabiximols oromucosal spray, with individualised dose adjustments on a weekly basis. Assessed variables included spasticity, functional independence, neuropathic pain, sleep quality, depression, quality of life, and Patient Global Impression of Improvement (PGI-I).

Results: Statistically significant improvements in spasticity were observed after one month (VAS decrease of 30%, p < 0.001; MAS decrease of 60%, p = 0.001) and two months (VAS decrease of 30%, p < 0.001; MAS decrease of 52%, p = 0.011) of treatment. A positive PGI-I was reported in 67% of participants. However, no significant changes were noted in spasms frequency, functional independence, neuropathic pain, or sleep quality. No significant differences in spasticity change or non-motor symptoms were found between participants with complete and incomplete SCI.

Conclusions: Nabiximols may effectively reduce spasticity in individuals with SCI resistant to conventional therapies. Given the significant impact of spasticity associated with SCI, it could be considered a viable add-on therapy for this population.”

https://pubmed.ncbi.nlm.nih.gov/40675989/

https://www.nature.com/articles/s41394-025-00712-2

The endocannabinoid system regulates both ependymoglial and neuronal cell responses to a tail amputation in the axolotl

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“Background: The endocannabinoid system is a neuromodulatory system implicated in cellular processes during both development and regeneration. The Mexican axolotl, one of only a few vertebrates capable of central nervous system regeneration, was used to examine the role of the endocannabinoid system in the regeneration of the tail and spinal cord following amputation.

Results: The endocannabinoid receptor CB1 was upregulated in the regenerating axolotl spinal cord by 4 hours following tail amputation, and this upregulation persisted for at least 14 days. The endocannabinoid receptor CB2 was upregulated later, between 7 and 14 days after tail amputation. Both CB1 and CB2 were located in ependymoglia and neurons within the regenerating spinal cord. Treatment with inverse agonists to inhibit CB1 (AM251) or CB2 (AM630) inhibited spinal cord and tail regeneration. During the first 7 days after injury, CB1 and CB2 expression was also necessary for the proliferation of ependymoglial cells and the regeneration of axons into the newly regenerated tail tissue. However, only CB1 was necessary for the differentiation of ependymoglia into immature neurons.

Conclusions: These studies are the first to examine the role of the endocannabinoid system during spinal cord regeneration in a regeneration-competent vertebrate.”

https://pubmed.ncbi.nlm.nih.gov/40377265/

“In summary, we provide evidence that CB1 and CB2 receptors are present in both ependymoglia and neurons of the regenerating axolotl spinal cord, and may play an essential role in creating a permissive environment for spinal cord regeneration in this vertebrate species. More specifically, the endocannabinoid receptors may regulate the proliferation and differentiation of ependymoglial cells into immature neurons, prevent glial scar formation, and promote regenerating axon elongation. In the future, it will be important to examine the role of the endocannabinoid system in interactions between neurons and the ependymoglia and in conjunction with other important signaling pathways important for the ependymoglial responses to trauma, and/or their regulation of microglia in the regenerating axolotl spinal cord.”

https://anatomypubs.onlinelibrary.wiley.com/doi/10.1002/dvdy.70035

Cannabidiol/tetrahydrocannabinol-enrich extract decreases neuroinfalmmation and improves locomotor outcome following spinal cord injury

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“Neuroinflammation is one of the main players in lesion expansion and locomotor deficits after spinal cord injury (SCI), thus treatments to control the inflammatory process emerge as novel therapeutic strategies. In this context, the anti-inflammatory effects of tetrahydrocannabinol (THC) and cannabidiol (CBD), the main phytocannabinoids of Cannabis sativa, are increasingly recognized.

The aim of this work was to investigate the effects of a standardized Cannabis sativa extract (CSE), which is mainly composed by THC/CBD in equimolar concentration, on neuroinflammation, secondary damage and locomotor outcome after SCI in rats.

After acute SCI, CSE therapy increased the number of non-inflammatory (arginase-1 positive) microglial cells in the epicenter of the lesion and decreased the number of pro-inflammatory ones (arginase-1 negative) in the epicenter and in the rostral and caudal regions of the lesion. CSE also reduced the number of reactive astrocytes in the grey matter of the rostral and caudal regions.

These results are consistent with the downregulation of mRNAs of inflammatory mediators (IL-1β, TNFα, IL-6, C3) and the upregulation of anti-inflammatory markers (ARG-1, MRC). In the chronic phase, CSE treatment prevented cyst expansion and also increased the volume of spared grey and white matter. Regarding locomotor outcome, CSE-treated rats showed better locomotor scores (open field test), higher latency to fall (Rotarod test) and lower number of hindlimb foot misplacements (horizontal ladder walking test) than untreated injured rats.

These results suggest that this standardized CSE offers a promising perspective for reducing acute neuroinflammation and promoting functional recovery after SCI.”

https://pubmed.ncbi.nlm.nih.gov/40157632/

https://www.ibroneuroscience.org/article/S0306-4522(25)00258-1/abstract

The Neuroprotective Effect of Alcoholic Extract of Cannabis Sativa on Neuronal Density of Spinal Cord Alpha Motoneurons after Sciatic Nerve Injury in Rats

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“Introduction: Injuries of the peripheral nerve system affect the neurons cell body leading to axon injury.

Cannabis sativa plant has anti oxidant and anti apoptotic effects. Therefore the aim of present study was to study the neuroprotective effect of alcoholic extract of cannabis sativa leaves on neuronal density of alpha motoneurons in spinal cord after sciatic nerve injury in rats.

Methods: In this experimental research, animals were divided into four groups; A: control, B: compression, C: compression+ treatment with 25 mg/kg alcoholic extract, D: compression + treatment with 50 mg/kg extract (n=8). At first, sciatic nerve compression in B, C and D groups was achieved for 60 seconds using locker pincers. Alcoholic extract was injected intra peritoneally in the first and second weeks after compression. Then 28 days after compression, under profusion method, the lumbar spinal cord was sampled and the numerical density in each group was compared with the compression group. The data was analyzed with the use of Minitab 14 software and ANOVA statistical test.

Results: Neuronal density showed a meaningful difference in the compression and control groups(P<0.001). Neuronal density in treatment groups(25, 50 mg/kg) also had a meaningful increase(P<0.001) as compared to the compression group.

Conclusion: Alcoholic extract of cannabis sativa leaves has a neuroprotective effect on spinal cord alpha motoneurons after injury. This could be due to growth and regeneration factors present in the alcoholic extract of cannabis sativa leaves that induce regeneration process in injured neurons or prevent degeneration.”

https://www.oalib.com/research/2894368

A preliminary study evaluating self-reported effects of cannabis and cannabinoids on neuropathic pain and pain medication use in people with spinal cord injury

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“Approximately 60% of individuals with a spinal cord injury (SCI) experience neuropathic pain, which often persists despite the use of various pharmacological treatments. Increasingly, the potential analgesic effects of cannabis and cannabinoid products have been studied; however, little research has been conducted among those with SCI-related neuropathic pain. Therefore, the primary objective of the study was to investigate the perceived effects of cannabis and cannabinoid use on neuropathic pain among those who were currently or had previously used these approaches. Additionally, the study aimed to determine if common pain medications are being substituted by cannabis and cannabinoids. Participants (N = 342) were recruited from existing opt-in listserv sources within the United States. Of those, 227 met the inclusion criteria and were enrolled in the study. The participants took part in an anonymous online survey regarding past and current use of cannabis and their perceived effects on neuropathic pain, including the use of pain medication. Those in the sample reported average neuropathic pain intensity scores over the past week of 6.8 ± 2.1 (0 to 10 scale), reflecting a high moderate to severe level of pain. Additionally, 87.9% noted that cannabis reduced their neuropathic pain intensity by more than 30%, and 92.3% reported that cannabis helped them to better deal with their neuropathic pain symptoms. Most participants (83.3%) also reported substituting their pain medications with cannabis, with the most substituted medication categories being opioids (47.0%), gabapentinoids (42.8%) and over-the-counter pain medications (42.2%). These preliminary results suggest that cannabis and cannabinoids may be effective in reducing neuropathic pain among those with SCI and may help to limit the need for certain pain medications.”

https://pubmed.ncbi.nlm.nih.gov/38188193/

https://www.frontiersin.org/articles/10.3389/fpain.2023.1297223/full

Unlocking the Healing Potential: Cannabinoids in Spine Surgery for Pain Relief and Recovery

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“Cannabinoids, such as D9-tetrahydrocannabinol and cannabidiol, interact with endocannabinoid receptors in the central nervous system and immune system, potentially offering pain relief. The entourage effect, resulting from the interaction of multiple cannabis components, may enhance therapeutic impact and efficacy, making them promising candidates for exploring pain relief in spine operations, known to be among the most painful operative procedures.» The use of cannabinoids in pain management requires careful consideration of safety, including their cognitive and psychomotor effects, potential cardiovascular risks, risk of dependence, mental health implications, and drug interactions.» Few studies have analyzed cannabinoid use in relation to spine surgery, with variable results reported, indicating possible effects on reoperation rates, mortality, complications, postoperative opioid use, and length of hospital stay.» Current knowledge gaps exist in the understanding of cannabinoid effects on spine surgery, including the exploration of different administration routes, timing, dosage, and specific outcomes. In addition, mechanistic explanations for the observed results are lacking.» Ethical considerations related to informed consent, medical expertise, societal impact, and legal compliance must also be thoroughly addressed when considering the utilization of cannabinoids in spinal pathologies and back pain treatment.”

https://pubmed.ncbi.nlm.nih.gov/37972215/

https://journals.lww.com/jbjsreviews/abstract/2023/11000/unlocking_the_healing_potential__cannabinoids_in.4.aspx

Transcriptomic Profiling after In Vitro Δ8-THC Exposure Shows Cytoskeletal Remodeling in Trauma-Injured NSC-34 Cell Line

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“Neuronal cell death is a physiological process that, when uncontrollable, leads to neurodegenerative disorders like spinal cord injury (SCI). SCI represents one of the major causes of trauma and disabilities worldwide for which no effective pharmacological intervention exists. Herein, we observed the beneficial effects of Δ8-Tetrahydrocannabinol (Δ8-THC) during neuronal cell death recovery. We cultured NSC-34 motoneuron cell line performing three different experiments. A traumatic scratch injury was caused in two experiments. One of the scratched was pretreated with Δ8-THC to observe the role of the cannabinoid following the trauma. An experimental control group was neither scratched nor pretreated. All the experiments underwent RNA-seq analysis. The effects of traumatic injury were observed in scratch against control comparison. Comparison of scratch models with or without pretreatment highlighted how Δ8-THC counteracts the traumatic event. Our results shown that Δ8-THC triggers the cytoskeletal remodeling probably due to the activation of the Janus Kinase Signal Transducer and Activator of Transcription (JAK/STAT) signaling pathway and the signaling cascade operated by the Mitogen-Activated Protein (MAP) Kinase signaling pathway. In light of this evidence, Δ8-THC could be a valid pharmacological approach in the treatment of abnormal neuronal cell death occurring in motoneuron cells.”

https://pubmed.ncbi.nlm.nih.gov/37765076/

https://www.mdpi.com/1424-8247/16/9/1268

Comparative evaluation of ethyl acetate and n-Hexane extracts of Cannabis sativa L. leaves for muscle function restoration after peripheral nerve lesion

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“Peripheral nerve injuries are one of those complex medical conditions for which a highly effective first-line treatment is currently missing. The use of natural compound as medicines to treat various disorders has a long history. Our previous research explored that crude Cannabis sativa L. accelerated the recovery of sensorimotor functions following nerve injury. The purpose of the current study was to investigate the effects of n-Hexane and ethyl acetate extracts of C. sativa L. leaves on the muscle function restoration in a mouse model after sciatic nerve injury. For this purpose, albino mice (n = 18) were equally divided into control and two treatment groups. The control group was fed on a plain diet while treatment groups were given a diet having n-Hexane (treatment 1) and ethyl acetate (treatment 2) extracts of C. sativa L. (10 mg/kg body weight), respectively. The hot plate test (M = 15.61, SD = 2.61, p = .001), grip strength (M = 68.32, SD = 3.22, p < .001), and sciatic functional index (SFI) (M = 11.59, SD = 6.54, p = .012) assessment indicated significant amelioration in treatment 1 as compared to treatment 2 group. Furthermore, muscle fiber cross-sectional area revealed a noticeable improvement (M = 182,319, SD = 35.80, p = .013) in treatment 1 while muscle mass ratio of Gastrocnemius (M = 0.64, SD = 0.08, p = .427) and Tibialis anterior (M = 0.57, SD = 0.04, p = .209) indicated nonsignificant change. A prominent increase in total antioxidant capacity (TAC) (M = 3.76, SD = 0.38, p < .001) and momentous decrease in total oxidant status (TOS) (M = 11.28, SD = 5.71, p < .001) along with blood glucose level indicated significant difference (M = 105.5, SD = 9.12, p < 0.001) in treatment 1 group. These results suggest that treatment 1 has the ability to speed up functional recovery after a peripheral nerve lesion. Further research is necessary, nevertheless, to better understand the extract’s actual curative properties and the mechanisms that improve functional restoration.”

https://pubmed.ncbi.nlm.nih.gov/37324902/

“In a nutshell, the results of this investigation demonstrate that n-Hexane C. sativa L. leaves extract has the ability to hasten the recovery of functions following a compression damage to the sciatic nerve. Even though these results are very encouraging and validating our previously reported data, however, more in-depth research is advised to investigate the key participants in the supported recovery process. Future research on C. sativa L. may reveal it to be a cutting-edge medicinal agent for the regeneration of peripheral nerves in cases of traumatic injury.”

https://onlinelibrary.wiley.com/doi/10.1002/fsn3.3255

Combined non-psychoactive Cannabis components cannabidiol and β-caryophyllene reduce chronic pain via CB1 interaction in a rat spinal cord injury model

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Lopiccolo & Chang in PLoS ONE – BU Linguistics

“The most frequently reported use of medical marijuana is for pain relief. However, its psychoactive component Δ9-tetrahydrocannabinol (THC) causes significant side effects. Cannabidiol (CBD) and β-caryophyllene (BCP), two other cannabis constituents, possess more benign side effect profiles and are also reported to reduce neuropathic and inflammatory pain. We evaluated the analgesic potential of CBD and BCP individually and in combination in a rat spinal cord injury (SCI) clip compression chronic pain model. Individually, both phytocannabinoids produced dose-dependent reduction in tactile and cold hypersensitivity in male and female rats with SCI. When co-administered at fixed ratios based on individual A50s, CBD and BCP produced enhanced dose-dependent reduction in allodynic responses with synergistic effects observed for cold hypersensitivity in both sexes and additive effects for tactile hypersensitivity in males. Antinociceptive effects of both individual and combined treatment were generally less robust in females than males. CBD:BCP co-administration also partially reduced morphine-seeking behavior in a conditioned place preference (CPP) test. Minimal cannabinoidergic side effects were observed with high doses of the combination. The antinociceptive effects of the CBD:BCP co-administration were not altered by either CB2 or μ-opioid receptor antagonist pretreatment but, were nearly completely blocked by CB1 antagonist AM251. Since neither CBD or BCP are thought to mediate antinociception via CB1 activity, these findings suggest a novel CB1 interactive mechanism between these two phytocannabinoids in the SCI pain state. Together, these findings suggest that CBD:BCP co-administration may provide a safe and effective treatment option for the management of chronic SCI pain.”

https://pubmed.ncbi.nlm.nih.gov/36913400/

“In conclusion, the current findings indicate that the combination of readily accessible non-psychoactive cannabis components CBD oil and BCP may be particularly effective in reducing neuropathic pain resulting from spinal cord injury. In addition, cannabinoid-like side effects were minimal using this combination. Further, the observed decrease in opioid-seeking behavior suggest that this treatment may be useful as a supplemental therapeutic to reduce opioid needed for effective pain management. Together, these findings are supportive of the beneficial effects of combining cannabis components in the armamentarium for chronic pain management.”

https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0282920