Category Archives: Pain

The impact of tetrahydrocannabinol on central pain modulation in chronic pain: a randomized clinical comparative study of offset analgesia and conditioned pain modulation in fibromyalgia

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“Tetrahydrocannabinol (THC) has shown efficacy in alleviating chronic pain, particularly in disorders characterized by central sensitization. Offset analgesia (OA) and conditioned pain modulation (CPM) are key biomarkers used to evaluate central pain modulation.

This study aimed to compare the effects of THC on OA and CPM in fibromyalgia syndrome (FMS), a prototypical condition of central sensitization.

Methods

In a randomized, double-blind, placebo-controlled crossover design, 23 FMS patients participated in two experimental sessions. Each session included the McGill Pain Questionnaire, visual analogue scale (VAS) assessments, and evaluations of OA and CPM, conducted both before and after sublingual administration of either THC (0.2 mg/kg) or placebo.

Results

THC significantly reduced spontaneous pain ratings on the McGill scale compared to both baseline and placebo (P = 0.01 and P = 0.02, respectively). THC also significantly enhanced OA relative to baseline and placebo (P = 0.04 and P = 0.008), while no effect was observed on CPM (P = 0.27). Notably, baseline OA magnitude significantly predicted THC-induced pain relief (R² = 0.404, P = 0.003), whereas CPM did not show a significant association (P = 0.121).

Conclusions

This is the first study to evaluate THC’s distinct effects on central pain modulation using both OA and CPM. THC selectively enhanced OA without influencing CPM, highlighting differential neural mechanisms underlying these paradigms. Furthermore, OA predicted treatment response, suggesting its potential as a biomarker for personalized cannabinoid-based therapies in FMS and other central sensitization disorders.”

https://pubmed.ncbi.nlm.nih.gov/41199355/

“Cannabis, particularly its psychoactive component delta-9-tetrahydrocannabinol (THC), has attracted increasing attention as a therapeutic option for chronic pain management. Clinically, THC has been shown to reduce pain intensity, improve quality of life and attenuate hyperalgesia in various chronic pain conditions, including neuropathic pain and fibromyalgia “

“THC is thought to exert its analgesic effects in part by modulating disrupted pain networks. Specifically, THC interacts with the endocannabinoid system.”

“To conclude, this study corroborates the possible effectiveness of THC in alleviating experimental and spontaneous pain in FMS, a study case of central sensitization, and shows an enhancement of OA responses after THC treatment in FMS patients compared to baseline and placebo.”

“This, in turn, reinforces the potential of OA as a reliable marker of pain modulation in FMS and may pave the way for personalized cannabinoid-based therapies for chronic pain in the future.”

https://jcannabisresearch.biomedcentral.com/articles/10.1186/s42238-025-00348-x

The Endocannabinoid System: Pharmacological Targets and Therapeutic Potential in CNS Disorders

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“The endocannabinoid system (ECS) influences a wide range of brain functions, including synaptic transmission, neuroplasticity, emotion, and immune regulation within the central nervous system, with CB1 and CB2 receptors mediating various neurophysiological and pathophysiological outcomes. Thus, growing interest in its therapeutic potential has prompted extensive research into how cannabinoid receptors contribute to the pathophysiology of neurological and psychiatric disorders, particularly CB1 and CB2.

This review has integrated findings from studies published between 2015 and 2025, covering conditions, like depression, anxiety, pain, multiple sclerosis, and Parkinson’s disease. We have also examined recent advances in receptor pharmacology and experimental technologies, including cryo-EM, optogenetics, and chemogenetics.

Although ECS-targeted therapeutics hold considerable promise, some key challenges remain in establishing safe and effective dosing protocols and integrating these approaches into clinical frameworks.

This review has provided an updated perspective on the system’s role in brain health and its potential to inform future therapeutic directions. Thus, ECS-targeted strategies may become increasingly important in managing and treating central nervous system disorders.”

https://pubmed.ncbi.nlm.nih.gov/41178765/

https://www.eurekaselect.com/article/151549

Cannabis Use Patterns Among Adults Living With Chronic Pain Before and During the COVID Pandemic: Insights From the COVID-19 Cannabis Health Study

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“Background: This study aims to identify sociodemographic factors associated with cannabis use for chronic pain management before and after COVID-19 was declared a pandemic. Furthermore, it seeks to compare cannabis use patterns in adults with and without chronic pain.

Methods: We analyzed US-based responses from the COVID-19 Cannabis Health Study, a cross-sectional online survey administered via REDCap between March 2020 and March 2022. All respondents were cannabis consumers in the past year. Cannabis use patterns and chronic pain were self-reported via the COVID-19 Cannabis Health Questionnaire. Statistical analysis included Chi-square tests, Fisher’s exact tests, t-tests, and multivariable logistic regression with a two-tailed alpha of 0.05 for significance.

Results: Among 2243 participants, 50.3% consumed cannabis to manage chronic pain. Younger age (< 40 years; aOR: 3.20, 95% CI: 2.59-3.96), Hispanic/Latino ethnicity (aOR: 2.20, 95% CI: 1.56-3.05), and higher income levels (> $100,000 annually; aOR: 1.69, 95% CI: 1.25-2.29) were associated with higher odds of consuming cannabis to manage chronic pain. Participants using cannabis for chronic pain were more likely to use a CBD/THC ratio. The pandemic led to increased dosages and changes in consumption methods: 40.5% increased their cannabis dose, smoking as the primary method declined from 62.2% before the pandemic to 34.5% afterward, while edibles rose from 7.9% to 30.9%, and tinctures from 3.2% to 8.6%. Route changes varied with chronic pain status.

Conclusion: There was a shift from smoking to nonsmoking methods to manage chronic pain. Those who were younger and those of Hispanic/Latino ethnicity had higher odds of using cannabis for chronic pain.”

https://pubmed.ncbi.nlm.nih.gov/41179652/

“In recent years, cannabis has emerged as a promising alternative for pain management, driven by increasing evidence of its analgesic properties.”

https://onlinelibrary.wiley.com/doi/10.1155/prm/9631487

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

Cannabigerol Modulates Cannabinoid Receptor Type 2 Expression in the Spinal Dorsal Horn and Attenuates Neuropathic Pain Models

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“Background/Objectives: The expanding focus on novel therapeutic pathways for long-term pain relief has directed interest toward compounds obtained from Cannabis sativa. This study evaluated the antinociceptive potential of cannabigerol-enriched extract (CBG) in models of acute and chronic hypernociception, along with morphological outcomes. 

Methods: Formalin and hot plate tests were used on male Swiss mice to assess acute oral antinociception. To the chronic pain model, 8-week-old male Wistar rats underwent spinal nerve ligation (SNL), and CBG was administered orally by gavage once daily for 14 days. 

Results: CBG reduced nociceptive responses in the formalin test and hot plate tests, mainly at a dose of 30 mg/kg, showing antinociceptive activity. CBG attenuated SNL-induced thermal and mechanical hypersensitivity, accompanied by reduced microglial density and spinal morphological changes. Importantly, cannabinoid receptor type 2 (CB2R) signaling contributed to the antinociceptive effects of orally administered CBG, whereas cannabinoid receptor type 1 (CB1R), Brain-Derived Neurotrophic Factor (BDNF), and Tumor Necrosis Factor (TNF) did not appear to play major roles under our experimental conditions. 

Conclusions: Collectively, these findings support CBG as a promising alternative for chronic pain management.”

https://pubmed.ncbi.nlm.nih.gov/41155621/

“In summary, our study provides robust evidence that CBG exerts potent antinociceptive effects across acute, inflammatory, and neuropathic pain models.

Collectively, these results highlight CBG as a promising candidate for pain management and support further translational studies.”

https://www.mdpi.com/1424-8247/18/10/1508

Medical Marijuana and Opioid Usage: An Analysis of Patient Perceptions in Louisiana

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“Background: The opioid crisis has continued in the United States, resulting in a healthcare crisis. Medical marijuana (MM) offers an alternative to those with addictions or in search of pain and inflammation management without the negative aspects of opioids. 

Methods: A survey of more than 2,000 Louisianians on the frequency and amount of MM use revealed significant relationships between race, age, reason for use, prescription use, and whether they stopped using MM, as well as time in the MM program and the method of ingestion. 

Results: Respondents reported lower levels of pain with MM usage by an average of 3.4 points on a ten-point scale (Z = -35.77, ρ ≤ .001). Those using prescriptions for pain were 1.5 times more likely to use MM less frequently (OR = 1.524, 95% CI: 1.114 – 2.074, ρ ≤ .01). Concordantly, those reporting that they had stopped using prescriptions for pain increased the odds of using more MM by 26.5 percent (OR = .735, 95% CI: .586 – .923, ρ ≤ .001). 

Conclusions: These relationships support the idea that MM substitutes for prescription painkillers.”

https://pubmed.ncbi.nlm.nih.gov/41136335/

https://www.tandfonline.com/doi/full/10.1080/10826084.2025.2575429

Cannabivarin and Tetrahydrocannabivarin Modulate Nociception via Vanilloid Channels and Cannabinoid-Like Receptors in Caenorhabditis elegans

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“Cannabis has attracted growing interest for its therapeutic potential, especially in pain management.

This study explores the antinociceptive effects of two promising non-psychoactive cannabinoids, cannabivarin (CBV) and tetrahydrocannabivarin (THCV), using Caenorhabditis elegans (C. elegans), a nematode model that expresses homologs of mammalian cannabinoid and vanilloid receptors.

Thermotaxis assays were employed to quantify the antinociceptive effects of CBV and THCV in C. elegans. Wild-type animals were exposed to increasing concentrations of each compound to establish dose-response relationships. To investigate potential molecular targets, additional experiments were performed using mutant strains deficient in vanilloid receptor homologs (OCR-2 and OSM-9) and cannabinoid receptor homologs (NPR-19 and NPR-32). Mass spectrometry-based proteomics combined with network biology analyses were used to identify the biological pathways associated with drug response.

Results confirmed that both compounds elicit dose-dependent antinociceptive effects. Mutant analyses support the involvement of vanilloid and cannabinoid signaling pathways in mediating these responses.

These findings highlight the potential of CBV and THCV as non-psychoactive analgesic agents and support further research into their mechanisms of action and translational relevance for mammalian pain management.”

https://pubmed.ncbi.nlm.nih.gov/41135090/

https://cdnsciencepub.com/doi/10.1139/cjpp-2025-0243

Plant-Derived Compounds: A Potential Treasure for Development of Analgesic and Antinociceptive Therapeutics

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“Pain is one of the most pervasive health problems associated with a negative impact on thinking, mood, psychological, and social communication.

The medicinal plants and their derived compounds have recently attracted great interest as potential candidates for defeating pain because of their worldwide safety, availability, and affordability.

This review was constructed to summarize all in vitro and in vivo studies and clinical trials regarding plant-derived compounds’ analgesic and antinociceptive effects. Further, we focus on structural aspects, molecular mechanisms, and pharmacological effects. A literature survey was performed in “PubMed,” “Science Direct,” and “Google Scholar,” using the keywords “Pain, Analgesic activity, Flavonoids, Phenolics, Medicinal plants, Volatile oils, Tannins, Saponins, Alkaloids” to assess the activities of each compound.

The main natural compounds studied were flavonoids, alkaloids, phenolic acids, lignans, anthraquinones, and volatile oils. Different in vitro studies utilized nucleus pulposus cells, VK2/E6E7, End1/E6E7, and LPS-stimulated RAW264.7 cells to assess analgesic effects. The frequently defined animal models of analgesic activity included acetic acid-induced abdominal constrictions, hot-plate test, tail-flick test, formalin test, complete Freund’s adjuvant-induced pain, and hind paw incisional surgery.

For the natural compounds described, the opioids, serotonergic, and cannabinoid receptors appeared to be the most promising targets for pain management. This review suggested a wealthy resource of natural compounds as analgesic and antinociceptive candidates for pharmacists and drug researchers to launch a new drug with promising efficacy and safety.”

https://pubmed.ncbi.nlm.nih.gov/41126401/

https://onlinelibrary.wiley.com/doi/10.1002/ptr.70113

Cannabidiol and Beta-Caryophyllene: chronic inflammatory pain

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“While chronic pain is challenging to manage, it always co-exists with depression. Currently, chronic pain and depression are usually treated separately with distinct approaches, yet effectiveness remains elusive. Consequently, the development of integrated therapeutic strategies for pain while addressing depression is a high public health priority and unmet need that affects millions of people.

This study aims to determine if the combination of the two phytocannabinoids Beta-Caryophyllene (BCP) and cannabidiol (CBD) is effective for chronic pain while simultaneously showing antidepressant effects.

We used a chronic inflammatory pain model (Complete Freund’s Adjuvant, CFA) and a battery of pain and depression-like behavior tests in mice. Proteomics and immunohistochemistry (IHC) were used to explore the potential mechanisms of the effect of the combination on pain and depression.

We found that mice treated with the CBD and BPC combination produced a synergistic pain-relieving effect in the chronic inflammatory pain model and exhibited antidepressant properties.

Our IHC data also show that the CBD and BCP combination significantly reduced the neuroinflammation produced by CFA, and the proteomics showed downregulation of selected proteins involved in inflammation by the combination, compared to the individual effects of CBD and BCP.

In conclusion, our current findings show that, in the CFA pain model, the combination of CBD and BCP produces a synergistic pain-relief effect while also having antidepressant properties. Additionally, our data show that the anti-inflammatory action of this combination may explain its beneficial effects on pain and depression. Therefore, our data suggest this combination as a potentially effective treatment for chronic pain and related depression.”

https://pubmed.ncbi.nlm.nih.gov/41120021/

“In conclusion, our current findings show that, in the CFA pain model, the combination of CBD and BCP produces a synergistic analgesic effect while also having antidepressant properties. Additionally, our data show that the anti-inflammatory action of this combination may explain its beneficial effects on pain and depression. Therefore, our data suggest this combination as a potentially effective treatment for the co-occurrence of chronic pain and depression.”

https://www.sciencedirect.com/science/article/pii/S1043661825004128?via%3Dihub

Cannabis Laws and Opioid Use Among Commercially Insured Patients With Cancer Diagnoses

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“Importance: Pain is a prevalent cancer-related symptom, but limited research investigates whether cannabis is an effective analgesic for cancer pain.

Objective: To examine the association of medical and recreational cannabis dispensary availability on prescription opioid dispensing among commercially insured patients with cancer.

Design, setting, and participants: This cross-sectional study used synthetic control to investigate the association of cannabis dispensary openings with pain medication dispensing among patients with cancer. Data were extracted from Optum’s deidentified Clinformatics Data Mart database from January 1, 2007, to December 31, 2020. The study population included patients aged 18 to 64 years with a cancer diagnosis and at least 6 months of continuous enrollment. Associations were estimated by age, race and ethnicity, and sex. Data were analyzed between December 2024 and February 2025.

Exposures: Exposures included indicators for whether a medical or recreational cannabis dispensary was open in each state-quarter.

Main outcomes and measures: The outcome measures for opioids prescriptions were (1) the rate of patients with a prescription per 10 000 patients, (2) the quarterly mean days’ supply per prescription, and (3) the quarterly mean number of prescriptions per patient.

Results: The study included a mean (SD) of 3.05 (0.86) million patients annually across the US (mean [SD] age, 43.7 [9.6] years; mean [SD] 59.0% [0.32%] female). Medical cannabis dispensary openings were associated with significant reductions in all opioid outcomes. The rate of patients with cancer with opioid prescriptions changed by -41.07 per 10 000 (95% CI, -54.78 to -27.36 per 10 000; P < .001), the quarterly mean days’ supply by -2.54 days (95% CI, -3.16 to -1.92 days; P < .001), and the mean number of prescriptions per patient by -0.099 (95% CI, -0.121 to -0.077; P < .001). Recreational dispensary openings were also associated with reductions in opioid outcomes, though estimated treatment effects were smaller. The rate of prescriptions changed by -20.63 per 10 000 (95% CI, -35.35 to -5.91 per 10 000; P = .049), the mean daily supply by -1.09 days supplied per prescription (95% CI, -1.72 to -0.46 days; P = .04), and the mean number of prescriptions per patient by -0.097 (95% CI, -0.134 to -0.060; P = .01).

Conclusions and relevance: This study’s findings indicate cannabis may be a substitute for opioids in the management of cancer-related pain. However, further research directly observing cannabis use is needed to evaluate the efficacy of cannabis as a treatment for cancer-related pain.”

https://pubmed.ncbi.nlm.nih.gov/41105418/

“These findings indicate that medical or recreational cannabis laws may be significantly associated with reduced opioid use among patients diagnosed with cancer.”

https://jamanetwork.com/journals/jama-health-forum/fullarticle/2840030