Category Archives: Pain

Effect of Δ9-tetrahydrocannabinol and cannabidiol on myofascial pain modulation in patients with temporomandibular disorder: a prospective crossover study

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“Background: Temporomandibular Disorder (TMD) often causes chronic orofacial pain and functional limitations, with conventional treatments providing suboptimal results. Phytocannabinoids such as Δ9-Tetrahydrocannabinol (Δ9-THC) and Cannabidiol (CBD) have analgesic and anti-inflammatory properties, but evidence in TMD is scarce.

Objective: To evaluate the efficacy of Δ9-THC/CBD therapy in reducing pain and improving mandibular function in TMD patients.

Methods: Twenty adults with chronic myofascial pain (DC/TMD diagnosis) participated in a blinded, crossover, non-randomized study. Participants underwent two consecutive 90-day phases: placebo followed by Δ9-THC/CBD therapy (1:1 ratio, starting with a dose of 2 mg/day in the first week, gradually adjusting an increase of 2 mg/week until reaching 10 mg/day in the fifth week, sublingually), without washout. Outcomes included pain intensity (VAS), muscle sensitivity (algometry), mandibular function (mouth opening, protrusion, laterality) and pain sensitivity (allodynia/hyperalgesia). Data were analyzed using linear mixed models for repeated measures.

Results: Δ9-THC/CBD improved all outcomes versus baseline and post-placebo (p < 0.001; Cohen’s d > 0.8). Mouth opening increased from 45.9 mm to 49.9 mm; VAS pain decreased from 7.35 to 3.50. Functional pain dropped by ∼90%, with near elimination of allodynia and hyperalgesia. Placebo effects were minimal.

Conclusion: Δ9-THC/CBD therapy provided substantial analgesic and functional benefits in TMD patients, supporting its potential as a therapeutic alternative. Larger randomized studies are recommended to validate these findings and explore underlying mechanisms.”

https://pubmed.ncbi.nlm.nih.gov/41740529

“Cannabinoid therapy was effective in reducing painful symptoms in TMD patients, associated with relevant functional improvements in mandibular opening, protrusion, and laterality compared to placebo.”

https://www.sciencedirect.com/science/article/pii/S1807593226000268?via%3Dihub

Potential effects of cannabidiol on formalin-induced inflammatory pain in morphine-dependent rats

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“Chronic morphine exposure leads to tolerance and dependence, complicating pain management and reducing the efficacy of opioid analgesics.

Cannabidiol (CBD), a non-psychoactive constituent of Cannabis sativa, has been recognized for its anti-inflammatory and analgesic potential.

This study examined the effects of CBD on acute and inflammatory phases of formalin-induced nociception in morphine-dependent and non-dependent rats.

Eighty-four male Wistar rats were divided into the control (non-dependent) and dependent groups. Morphine dependence was induced through an oral escalating-dose regimen in drinking water containing 3% sucrose (to mask bitterness) for 14 days, while controls received only sucrose. CBD (25-200μg/5 μL, ICV) was administered prior to the formalin test. Formalin injection produced a clear biphasic nociceptive response (P < 0.001 in both phases), confirming the model’s validity.

Morphine dependence alone did not significantly affect baseline pain responses (P > 0.05). However, CBD produced a significant, dose-dependent reduction in pain behaviors during both the early (0-5 min) and the late (20-50 min) phases (P<0.001 vs. vehicle). The 100 μg/5 μL and 200 μg/5 μL doses showed the most robust and consistent antinociceptive effect.

CBD produced robust antinociceptive effects in both morphine-treated and non-treated rats, with no statistically significant difference between groups. Open-field results indicated no significant differences in locomotor activity, confirming that the observed analgesia was not related to motor impairment.

These findings demonstrate that CBD effectively attenuates both acute and inflammatory pain. Moreover, it maintains its effectiveness in animals treated with morphine. This highlights its potential as a non-opioid supplementary therapy for managing pain in individuals with opioid dependence.”

https://pubmed.ncbi.nlm.nih.gov/41747636

https://www.sciencedirect.com/science/article/abs/pii/S0022395626001263?via%3Dihub

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

Anti-inflammatory and analgesic potential of minor cannabinoids in vivo

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“The cannabis plant produces many bioactive compounds, including the major cannabinoids THC and CBD, and many lesser studied “minor” phytocannabinoids including cannabinol (CBN), cannabichromene (CBC), cannabicyclol (CBL), and cannabigerol (CBG). These compounds are touted for various ailments, including pain, inflammation, and anxiety, but experimental data on their effects are lacking, especially that of CBL, which has yet to be assessed in vivo.

Methods

To assess in vivo activity, adult male and female C57BL/6J mice were administered each compound and tested repeatedly in the tetrad battery. The potential analgesic effects in chronic pain states were assessed using the lipopolysaccharide (LPS)-induced hindpaw inflammatory pain and chronic constriction injury (CCI) neuropathic pain paradigms. Lastly, to address common psychological comorbidities of pain, CBN, CBL, and CBG were assessed in the tail suspension and marble burying tests.

Results

Cannabinol (≥ 25 mg/kg) induced classic cannabinoid effects, including acute antinociception. These effects were differentially and partially blocked by selective antagonism of CB1, adenosine A2A, or TRPV1 receptors. CBL (≥ 50 mg/kg) induced hypothermia that was fully blocked by A2A antagonism but had no apparent CB1-mediated activity. LPS-induced edema and paw proinflammatory cytokine levels were reduced by either CBN or CBL (100 mg/kg). CCI-induced cold allodynia was attenuated by either CBN (≥ 50 mg/kg) or CBL (100 mg/kg), but only at high doses that also induce catalepsy and hypothermia. None of these minor cannabinoids displayed anxiolytic- or antidepressant-like activity without concomitant locomotor effects.

Conclusions

Together, these findings suggest that CBN produces anti-inflammatory effects via cannabinoid receptor-dependent and -independent pathways, whereas CBL acts primarily through CB receptor-independent mechanisms.”

https://pubmed.ncbi.nlm.nih.gov/41680865

https://link.springer.com/article/10.1186/s42238-025-00384-7

The Effect of Cannabidiol on Nociceptive Behaviour and the Endocannabinoid System in an Incisional Wound Model

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“Background/Objectives: Wound-related pain is a common, yet inadequately managed condition, and new therapeutic strategies are warranted. Limited data suggests that phytocannabinoids and cannabis may alleviate wound-related pain; however, further studies are required. This study investigated the effects of systemic administration of cannabidiol (CBD) on nociceptive behaviour following dorsum incision and on the endocannabinoid system. 

Methods: Male Sprague-Dawley rats (150-200 g on arrival, n = 9/group) underwent a 1.2 cm incision on the hairy skin of the dorsum or sham procedure. Back and hind paw mechanical withdrawal thresholds were assessed at baseline and post-surgery/sham days (PSDs) 1, 4, 7, and 8 using manual and electronic von Frey tests, respectively. On PSD 8, the effect of a single acute administration of CBD (3, 10, or 30 mg/kg, i.p.) on mechanical hypersensitivity in the dorsum and hind paws was assessed. The levels of endocannabinoids and N-acylethanolamines in the plasma and discrete brain regions following CBD administration were analysed. 

Results: Robust mechanical hypersensitivity was evident in the dorsum and hind paws following the incision. CBD (3 mg/kg) partially attenuated primary mechanical hypersensitivity in the dorsum, in a site- and dose-specific manner. CBD had no effect on secondary mechanical hypersensitivity. CBD did not alter the levels of endocannabinoids or N-acylethanolamines, but in rats that received CBD (3 mg/kg), levels of 2-AG were lower in the contralateral amygdala and levels of AEA were higher in the contralateral lumbar spinal cord, compared to the ipsilateral sides. 

Conclusions: These data provide evidence for antinociceptive effects of CBD in a model of incisional wound-related pain. Further research on CBD’s mechanism(s) of action is warranted. The potential antinociceptive effects of other phytocannabinoids in this model should also be investigated.”

https://pubmed.ncbi.nlm.nih.gov/41599645

“Cannabidiol (CBD) is a phytocannabinoid found in Cannabis sativa L.”

“These results indicate dose- and site-specific antinociceptive effects of CBD in a rat model of incisional wound-related pain, providing preclinical evidence to support the contention that CBD may have therapeutic potential for alleviating incisional wound-related pain.”

“These results also indicate that investigation of the potential antinociceptive effects of other phytocannabinoids in this model of incisional wound-related pain is warranted.”

https://www.mdpi.com/1424-8247/19/1/43


Age differences in endocannabinoid tone are ameliorated after recent cannabis use

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“An age-related decline in endocannabinoid system (ECS) activity may contribute to conditions such as chronic pain and Alzheimer’s disease. Although cannabis is increasingly used by older adults to alleviate age-related conditions, it remains unclear how cannabinoids affect ECS activity across the lifespan.

The present study assayed levels of seven endocannabinoids (AEA, 2-AG, DEA, LEA, PEA, SEA, and OEA) in a sample of adults (N = 142; younger 21-24 years, n = 38; midlife 25-54, n = 73; older 55-71, n = 31) assayed before cannabis use (baseline [pre-use]) and ~ 1 h after flower or ~ 2 h after edible cannabis use.

At baseline, older adults exhibited lower AEA and DEA than younger adults, and lower LEA than midlife adults.

Acute cannabis use increased AEA, DEA, LEA, PEA, SEA, and OEA across all age groups (all p < .001). 2-AG showed no increase. For AEA and DEA, increases were larger in older adults (Time×Age).

These findings indicate broad endocannabinoid elevations after cannabis use regardless of age, alongside age-related differences at baseline and in acute responses.”

https://pubmed.ncbi.nlm.nih.gov/41580496

https://www.nature.com/articles/s41598-025-27618-1

Ewing sarcoma-related pain: potential role of medical cannabis monotherapy in symptom management – a case report

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“Persistent, multimodal cancer pain remains a challenge, particularly in long-term survivors facing treatment-related complications. The management of high-dose opioid dependence concurrent with chronic, multi-drug resistant (MDR) periprosthetic infection presents a critical unmet need. This case reports the potential use and sustained efficacy of medical cannabis monotherapy, highlighting an unexpected temporal association with the resolution of inflammatory and infectious symptoms in a highly complex oncologic setting.

Case presentation

A 27-year-old male, a long-term survivor of high-risk Ewing Sarcoma of the proximal tibia, presented with intractable mixed pain (VAS 9–10) secondary to chronic, recurrent MDR periprosthetic osteomyelitis and multiple surgical revisions (2013–2024). Despite continuous use of high-dose opioids (up to 120 mg/day morphine equivalents), pain levels remained moderate-to-severe (VAS 6–7) and functional status was poor. The patient had previously found temporary relief with self-administered cannabis. In January 2025, after refusing limb amputation, supervised medical cannabis therapy (Bedrocan®, 22% THC, 1% CBD, 1 g/day) was initiated. Pain levels gradually stabilized at VAS 2–3, coinciding with complete opioid discontinuation within four weeks. Over nine months of follow-up, the patient maintained full autonomy and an active lifestyle. Notably, sustained cannabis monotherapy was associated with the complete closure of the chronic draining fistula and a reduction in systemic inflammatory markers (CRP from 9.6 to 2.3 mg/dL). No significant adverse effects were reported.

Conclusions

This case suggests that THC-rich medical cannabis may represent a feasible strategy for achieving opioid-free analgesia in selected patients with refractory oncologic pain. While causality cannot be established from a single observation, the correlation between cannabis initiation and the resolution of severe chronic inflammatory and infectious symptoms is intriguing and suggests a potential pleiotropic role extending beyond traditional pain management. While these findings align with emerging evidence highlighting the potent immunomodulatory and anti-inflammatory properties of cannabinoids, they contrast with some recent neutral meta-analyses in broader populations, an this would justify warrant urgent controlled investigation into the potential mechanisms of cannabinoids in complex inflammatory pain states and their role as a possible adjunct in managing long-term oncological complications.”

https://pubmed.ncbi.nlm.nih.gov/41572388

https://link.springer.com/article/10.1186/s42238-026-00388-x

Perceived impact of medicinal cannabis on pelvic pain and endometriosis related symptoms in Aotearoa New Zealand: an observational cohort study

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“Endometriosis, characterised by the growth of endometrial-like tissue outside the uterus, often causes severe pelvic pain, dysmenorrhea, and fatigue. Current medical treatments frequently provide incomplete symptom control and/or significant side effects. Many individuals with endometriosis report symptom improvements with cannabis use, but high-quality evidence remains limited.

Methods

A prospective, mixed-methods cohort study was conducted. Participants aged 18–50 years with surgically or clinically diagnosed endometriosis self-engaged with a specialist consultant and were prescribed medicinal cannabis (cannabidiol [CBD] oil alone or in combination with dried cannabis flower). Weekly pain scores, and health-related quality of life (measured by the Endometriosis Health Profile-30 [EHP-30]) were assessed via surveys and standardised questionnaires over three months. Completion interviews were conducted to explore participants’ experiences with medicinal cannabis in greater depth.

Results

Participants reported limited adverse events during the study period. Pelvic pain scores decreased over 12 weeks: ‘overall’ pain reduced from 5.46 ± 1.55 (95% CI 0.57) to 3.77 ± 2.25 (95% CI 0.83), and ‘worst’ pain decreased from 7.62 ± 1.51 (95% CI 0.56) to 5.38 ± 2.69 (95% CI 1.00). The mean total EHP-30 score significantly decreased from 68.77 ± 15.17 (95% CI 5.61) to 37.40 ± 16.66 (95% CI 6.17). Qualitative analysis identified four major themes: motivations for seeking medicinal cannabis, experiences of use, barriers to use, and stigma.

Conclusions

Medicinal cannabis use was associated with reduction in pain measures and improvements in quality of life among some individuals with endometriosis during this study. Qualitative findings highlighted both perceived benefits and ongoing challenges related to access, dosage and social stigma. These results support the need for larger controlled studies to further evaluate the safety, efficacy, and long-term outcomes of medicinal cannabis as an adjunctive therapy for endometriosis-related pain.”

https://pubmed.ncbi.nlm.nih.gov/41566248

https://link.springer.com/article/10.1186/s12906-025-05189-y

The psychoactive cannabinoid THC inhibits peripheral nociceptors by targeting NaV1.7 and NaV1.8 nociceptive sodium channels

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“Δ⁹-Tetrahydrocannabinol (THC), the primary psychoactive compound in cannabis, is widely recognized for its central effects mediated by cannabinoid receptors. Here, we uncover a distinct peripheral mechanism by which THC inhibits the excitability of nociceptive neurons.

We show that THC directly targets the nociceptive voltage-gated sodium channels NaV1.7 and NaV1.8 through the conserved local anesthetic binding site. This interaction reduces sodium currents and suppresses action potential generation in peripheral sensory neurons.

Our findings demonstrate that, beyond its central psychoactivity, THC exerts direct peripheral nociceptor inhibition via modulation of NaV1.7 and NaV1.8, offering new insight into cannabinoid-based analgesia independent of cannabinoid receptor signaling.”

https://pubmed.ncbi.nlm.nih.gov/41565997

“Cannabis has been used for centuries for its analgesic properties, and its clinical relevance in pain management continues to grow.”

 “These findings reveal a previously unrecognized mechanism for THC-mediated peripheral analgesia and establish a non-canonical molecular pathway through which the psychoactive cannabinoid can inhibit nociceptor excitability and thereby pain.”

https://www.nature.com/articles/s41386-026-02355-9

The Evidence for Medical Cannabis in Chronic Musculoskeletal Pain Management

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“Chronic musculoskeletal pain (CMP) is a pervasive condition that can impair daily functioning and quality of life. Traditional pharmaceutical therapies, including non-steroidal anti-inflammatory drugs, gabapentinoids, and opioids, often yield suboptimal results and carry notable risks, such as adverse side effects and dependence.

Increasing interest has turned toward medical cannabis, particularly combined formulations of cannabidiol (CBD) and tetrahydrocannabinol (THC), as a potential alternative or complement to current pain management strategies.

Evidence suggests that cannabinoids interact with the endocannabinoid system to modulate nociception and inflammation, offering meaningful pain relief and possibly reducing opioid requirements.

However, heterogeneity in study designs, product formulations, and regulatory frameworks presents challenges in drawing definitive conclusions. Additionally, while most adverse effects, such as fatigue, dizziness, and mild cognitive changes, are generally reported as tolerable, concerns remain about long-term safety and standardization of dosing.

Taken together, the existing literature points to a promising role for medical cannabis in CMP management, underscoring the need for further high-quality research to establish best practices, clarify patient selection, and guide clinicians in safe and effective cannabinoid therapy.”

“This scoping review highlights the potential role of medical cannabis in managing musculoskeletal pain. Evidence suggests it may reduce pain, enhance well-being, and improve quality of life, particularly as an alternative or adjunct to opioids. Adverse effects are typically mild, supporting its use as a safer long-term option. However, data on long-term efficacy, especially for CBD, remain limited.

Given the risks of opioid dependence, cannabis offers a promising therapeutic alternative.”

https://surgicoll.scholasticahq.com/article/138573-the-evidence-for-medical-cannabis-in-chronic-musculoskeletal-pain-management