Category Archives: THC (Delta-9-Tetrahydrocannabinol)

Peripheral Cannabinoid Receptor Activation Attenuates Frostbite-Induced Chronic Pain via Modulation of TRP Channels, Neuroinflammation, and Autophagy

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“Frostbite injury is a debilitating cold injury encountered in extreme high-altitude and subzero environments, frequently resulting in persistent chronic pain even after tissue healing. Using our previously validated frostbite-induced chronic pain model, we further investigated the contribution of neuroimmune, excitatory mechanisms and evaluated the therapeutic efficacy of peripheral cannabinoid receptor activation.

Frostbite produced significant mechanical allodynia, mechanical hyperalgesia, and cold hypersensitivity, along with increased spontaneous nocifensive behaviors.

Local peripheral administration of CB13, a peripherally acting CB1/CB2 receptor dual agonist, dose-dependently attenuated both mechanical and cold allodynia without impairing locomotor activity, indicating a lack of central nervous system side effects.

At the molecular level, frostbite induced marked peripheral and spinal sensitization, demonstrated by elevated expression of TRPV1, TRPA1, TRPV4, and TRPM8 channels, increased levels of pro-inflammatory cytokines, and enhanced c-Fos expression as an indicator of heightened neuronal activation in pain-relevant regions. These alterations were accompanied by pronounced microglial activation and upregulation of the NLRP3 inflammasome.

CB13 treatment significantly reversed these pathological changes and concurrently restored Beclin-1-associated autophagy signaling, suggesting engagement of both neuroimmune resolution and intracellular homeostasis pathways. Notably, frostbite injury was associated with marked oxidative and nitrosative stress in the sciatic nerve, as evidenced by reduced glutathione depletion and elevated lipid peroxidation and nitrite levels, which were significantly normalized by CB13 treatment.

Collectively, these findings demonstrate that peripheral cannabinoid receptor activation effectively inhibit frostbite induced chronic pain through modulation of nociceptive, neuroinflammatory, redox, and cellular stress pathways.

This work highlights peripherally selective cannabinoid receptor agonists as promising, safer therapeutic strategies for chronic pain associated with cold injuries.”

https://pubmed.ncbi.nlm.nih.gov/41802611

“This study demonstrates that peripheral cannabinoid receptor activation via CB13 effectively alleviates frostbite-induced chronic pain by targeting multiple pathological mechanisms, including nociceptor hyperexcitability, spinal neuronal activation, neuroinflammation, inflammasome signaling, oxidative stress, and impaired autophagy.”

https://www.sciencedirect.com/science/article/abs/pii/S0891584926001565?via%3Dihub

Driving by frequent cannabis users ‘the morning after’ last use of smoked cannabis: an observational driving simulator study

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“It is well-established that cannabis can affect driving in the hours after cannabis use, but the exact duration of these effects, and relationship with delta-9-tetrahydrocannabinol (THC) concentrations in blood and oral fluid, remains to be determined.

Methods

Frequent (≥ 4 times a week) users of smoked cannabis drove a simulator the morning after (12-15 hours) last use of smoked cannabis; a control group of non-cannabis users matched for age and sex was also included. Concentrations of THC, cannabidiol (CBD) and metabolites were measured in oral fluid and blood at the time of the drive.

Results

In total, 65 participants (mean age 30 years; 33 males) in each group completed all study procedures. Participants were generally well-matched (age, sex, driving experience, amount of driving per year/week, hours of sleep) but differed in racial breakdown and years of education. Under both standard and dual task (distacted) conditions, standard deviation of lateral position (SDLP) was higher in the control group (standard: 0.305 meters; dual task: 0.272 meters; n=65) compared to the cannabis group (standard: 0.28 meters; dual task: 0.256 meters; n=65); these differences were small (Cohen’s d -0.389 (standard) and -0.359 (dual task)) and were not significant after correction for multiple comparisons. Measures of speed and following distance were not impacted. Neither blood nor oral fluid THC, CBD or metabolites was significantly correlated with any measure of driving after correction for multiple comparisons; mean concentrations of blood THC was above 2 ng/mL. After correction for multiple comparisons, trends between driving and concentrations of the psychoactive metabolite 11-hydroxy-THC (11-OH-THC) were found. Participants who smoked cannabis the night before reported higher levels of subjective intoxication, and more willingness to drive before the drive, that was not significant after correction for multiple comparisons.

Conclusions

The regular cannabis use group showed no significant impairment in driving performance 12-15 hours after last cannabis use the night before, compared to the control group. Blood and oral fluid THC concentrations may not be an accurate correlate of driving behavior. Large-scale studies are needed to determine whether less frequent users are impaired the morning after last use, and whether the present findings also extend to different routes of administration.”

https://link.springer.com/article/10.1186/s42238-026-00416-w

Cannabinol derivatives, a new series of α-glucosidase inhibitors: synthesis, structure-activity relationship, and kinetic study

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“A new series of cannabinol derivatives was synthesised and assessed for their inhibitory effects against α-glucosidase. Of nineteen derivatives evaluated, the brominated analogues (3a and 3b) demonstrated the most potent inhibition against rat intestinal α-glucosidase. Structure-activity relationship analysis suggested that the phenolic hydroxy group and the introduced bromine atoms play crucial roles in enhancing inhibitory potency. Enzyme kinetic studies further revealed that 3a and 3b retarded both maltase and sucrase via a non-competitive mechanism.”

https://pubmed.ncbi.nlm.nih.gov/41785417

https://www.tandfonline.com/doi/full/10.1080/14786419.2026.2638950

“Three new α-glucosidase inhibitors from aqueous extract of Cannabis sativa leaves: isolation, characterisation, and kinetic study”

https://pubmed.ncbi.nlm.nih.gov/39756038

“Alpha-glucosidase inhibitors are oral antidiabetic medications used to treat type 2 diabetes”

Alcohol as a Novel Trigger for Cannabis Hyperemesis Syndrome

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“Cannabis hyperemesis syndrome (CHS) is a paradoxical condition occurring in chronic cannabis users, characterized by cyclic nausea, vomiting, and abdominal pain. While the primary trigger is cannabis itself, other precipitants remain poorly defined.

We present the case of a 52-year-old male with recurrent CHS who experienced five distinct hyperemetic episodes, each occurring approximately one week after ingesting a single dose of alcohol. His most recent presentation was complicated by severe, life-threatening hyponatremia requiring intensive care unit management. Diagnostic workup confirmed CHS and excluded other pathologies.

The consistent temporal pattern observed across multiple episodes suggests that a single dose of alcohol may be a novel and specific trigger for CHS. This case highlights a previously underreported precipitant and underscores the syndrome’s potential for severe metabolic complications. Clinicians should consider inquiring about alcohol use in patients with recurrent CHS, as its identification could be pivotal for prevention strategies and patient counseling.”

https://pubmed.ncbi.nlm.nih.gov/41769444

“This case provides critical clinical insights by identifying a single dose of alcohol as a potential novel trigger for CHS, expanding the known spectrum of precipitants. It underscores the serious morbidity of CHS, which can progress to life-threatening complications like severe hyponatremia necessitating intensive care.”

https://www.cureus.com/articles/434462-alcohol-as-a-novel-trigger-for-cannabis-hyperemesis-syndrome#!

“Binge Alcohol Exposure Transiently Changes the Endocannabinoid System: A Potential Target to Prevent Alcohol-Induced Neurodegeneration.”

https://pmc.ncbi.nlm.nih.gov/articles/PMC5742761

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

Cannabinoid Therapies in Less-Common Disorders: Clinical Evidence and Formulation Strategies

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“Background/Objectives: Cannabinoids are increasingly recognised for their therapeutic potential beyond well-established indications such as chronic pain, multiple sclerosis, and specific epileptic syndromes. Recent advances have highlighted their possible role in less-common or orphan diseases, opening new avenues for pharmaceutical research and clinical application. 

Methods: This review provides a critical synthesis of the most recent evidence (2020-2025), available in PubMed and Scopus, regarding the use of cannabinoids in conditions including refractory epilepsies beyond Dravet and Lennox-Gastaut syndromes, movement disorders such as dystonia and Tourette syndrome, rare dermatological diseases like epidermolysis bullosa, and emerging data in Crohn’s disease. 

Results: Negative outcomes, such as those reported in Fragile X syndrome trials, are also discussed as instructive examples of methodological and pharmacological challenges. Particular attention is given to the optimisation of pharmaceutical formulations and advanced separation technologies, including oromucosal sprays, transdermal gels, and novel nanocarrier systems, which aim to overcome issues of bioavailability and variability in patient response. Finally, safety concerns, regulatory aspects, and the need for robust clinical trials are addressed. 

Conclusions: Overall, cannabinoids represent a promising yet underexplored therapeutic option in rare and complex disorders, warranting further investigation supported by innovative pharmaceutical approaches.”

https://pubmed.ncbi.nlm.nih.gov/41745121

 “Thus, cannabinoids may play an important role in the development of innovative therapies, particularly in the treatment of less-common diseases that often lack effective therapeutic options.”

https://www.mdpi.com/2079-9721/14/2/83


Endocannabinoid Modulation in Headache: Mechanisms, Models, and Translational Therapies

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“Headache disorders, including migraine, tension-type headache, trigeminal autonomic cephalalgias, post-traumatic headache and medication overuse headache, represent a major global health burden and remain difficult to treat despite therapeutic advances.

The endocannabinoid system (ECS) has emerged as a key regulator of neural, vascular, and immune processes central to headache pathophysiology.

Through coordinated actions of CB1 and CB2 receptors, the endogenous ligands anandamide (AEA) and 2-arachidonoylglycerol (2-AG), and their metabolic enzymes, the ECS modulates trigeminovascular activity, descending pain control, cortical excitability, and neuroimmune sensitization.

Preclinical studies demonstrate that ECS activation suppresses trigeminal firing, reduces calcitonin gene-related peptide (CGRP) release, attenuates neurogenic inflammation, stabilizes cortical susceptibility to spreading depression, and limits glial activation following traumatic brain injury. Conversely, ECS dysregulation contributes to central sensitization and impaired descending inhibition underlying medication overuse headache and other headache disorders.

Pharmacological strategies targeting endocannabinoid degradation, such as inhibition of FAAH, MAGL, and COX-2, enhance endogenous cannabinoid tone and consistently reduce headache-like behaviors across diverse models. Importantly, sex differences shape ECS function, with females exhibiting distinct hormonal regulation, receptor expression, and glial activation that influence responsiveness to ECS-targeted interventions.

Collectively, mechanistic and translational evidence highlights the ECS as a promising therapeutic target across primary and secondary headache disorders. Future clinical studies should incorporate sex-informed designs, integrate biomarkers of trigeminovascular and neuroimmune activity, and evaluate peripherally restricted ECS modulators and cannabinoid-based formulations as candidates for individualized headache therapy.”

https://pubmed.ncbi.nlm.nih.gov/41744774

  • “The endocannabinoid system (ECS) is a central regulator of neural, vascular, and immune mechanisms driving headache disorders.
  • ECS dysfunction contributes to central sensitization and reduced descending inhibition, particularly in chronic headaches.
  • Targeting endocannabinoid hydrolysis and oxygenation shows consistent preclinical efficacy and represents a promising therapeutic strategy.”

https://www.mdpi.com/2073-4409/15/4/331

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

The Paradoxical Effect of Cannabis Use on Cognition in Chronic Psychotic Disorders

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“Background/objectives: Cannabis use has a particularly high prevalence in individuals with psychotic disorders. Although cannabis use is generally associated with cognitive impairments in the general population, its impact on cognition in psychosis remains controversial. This study aimed to investigate the association between cannabis use and cognitive performance in a cohort of individuals affected by psychotic disorders.

Methods: A total of 105 inpatients with psychotic disorders (mean age: 40.3 years; 34 females) were recruited from the University Hospital Center “Mother Teresa” in Tirana. Data collection included socio-demographic and clinical variables. Cognitive functioning was evaluated using the Montreal Cognitive Assessment (MoCA), while psychopathology was assessed with the Brief Negative Symptom Scale (BNSS), the Calgary Depression Scale for Schizophrenia (CDSS), the Psychotic Symptom Rating Scales (PSYRATS), and the Scale for the Assessment of Thought, Language, and Communication (TLC).

Results: Cannabis users (CU) were more frequently male, younger, and exhibited an earlier onset of psychosis compared to non-users (No-CU). Importantly, CU demonstrated higher MoCA scores, with the most favorable outcomes observed among daily users.

Conclusions: Contrary to the prevailing assumption that cannabis use exacerbates cognitive decline, our findings indicate an unexpected association between cannabis use and preserved cognitive functioning in psychosis. These results underscore the need to consider dosage, frequency, and cannabinoid composition (THC/CBD ratio) when interpreting cannabis-related cognitive outcomes in psychotic disorders.”

https://pubmed.ncbi.nlm.nih.gov/41718389

“the present study highlights that, in certain cases, patients with psychosis who use cannabis may demonstrate relatively preserved or even superior cognitive performance compared with non-using patients. These results raise important clinical and research questions.”

https://www.mdpi.com/1873-149X/33/1/11

Cannabinoids and the autophagy-related signaling in brain Tumors: From mechanistic insights to therapeutic Frontiers in glioblastoma

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“Glioblastoma multiforme (GBM) is a very aggressive primary brain tumor in adults, characterized by extensive infiltration, therapeutic resistance, and a dismal prognosis, with an average life of roughly 14 months. Despite advances in oncology, therapeutic progress for GBM has been limited, prompting intensive efforts to discover novel interventions.

Cannabinoids, beyond their established role as antiemetics during chemotherapy and radiotherapy, have emerged as potential cytotoxic agents against neoplastic cells.

Recent studies demonstrate that GBM harbors alterations in the endocannabinoid system, including changes in cannabinoid metabolism and receptor (CB1R, CB2R) expression. Engagement of these receptors by cannabinoids can suppress proliferation, invasion, and induce morphological changes in GBM cells, also activating intrinsic autophagy pathways.

Autophagy, a process central to cellular degradation and recycling, exerts dual roles in tumor survival and apoptosis, critically modulated by cannabinoids in glioblastoma. Preclinical work in cell lines and animal models suggests that both cannabinoids and pharmacologic modulators of autophagy reduce GBM proliferation and enhance responsiveness to chemotherapeutics. Early clinical studies indicate favorable safety profiles and potential survival benefits.

This review synthesizes the molecular mechanisms and signaling pathways underlying cannabinoid-induced autophagy and anticancer activity, and summarizes the current preclinical and clinical research on cannabinoid-based therapies for GBM.”

https://pubmed.ncbi.nlm.nih.gov/41679657

“This review demonstrates that cannabinoids, an emerging class of potential antitumor agents, promote autophagy in cancer cells and enhance the cytotoxic effects of these compounds. The study demonstrated that THC facilitates autophagy and apoptosis in diverse cancer cell types, whereas nontransformed astrocytes display resistance to cannabinoid-induced cytotoxicity. “

https://www.sciencedirect.com/science/article/abs/pii/S0006295226001127?via%3Dihub