“Cannabis sativa L. has been used for thousands of years in various cultural, medical, and industrial settings. This review brings together evidence from historical records, plant chemical studies, clinical trials, and laws to explain the chemical properties, healing potential, and regulatory environment of cannabis and its components.
We look at over 500 identified compounds, including cannabinoids (CBs), terpenes, flavonoids, and alkaloids, along with their effects on health. The therapeutic areas covered include chronic pain, epilepsy, cancer, mental health issues, and inflammation. We also address side effects, interactions with other drugs, and approved CB-based medications.
Despite the various healing effects, gaps still exist in our understanding of the best dosing, long-term safety, and standardized product formulations. This review highlights current research directions and emphasizes the need for thorough randomized controlled trials to support the evidence-based use of cannabis in modern medicine.”
“Tobacco use remains the leading cause of preventable death worldwide. The major metabolic pathway for nicotine, the addictive component in tobacco, is via cytochrome P450 (CYP) 2A6-mediated metabolism to cotinine.
Cannabidiol has been shown to reduce cigarette consumption in vivo and inhibit CYP2A6-mediated nicotine metabolism in vitro. In the present study, Δ-8-tetrahydrocannabinol (Δ8-THC), an isomer of Δ-9-tetrahydrocannabinol, was examined as a potential inhibitor of CYP2A6-mediated nicotine metabolism.
While Δ-9-tetrahydrocannabinol showed no significant inhibition of nicotine metabolism to cotinine, Δ8-THC demonstrated unbound IC50 values of 0.57 ± 0.04 μM in microsomes from recombinant wild-type CYP2A6 overexpressing human embryonic kidney 293 cells and 0.70 ± 0.16 μM in human liver microsomes (HLMs). A similar unbound IC50 value was observed for recombinant CYP2A6∗5 microsomes (0.52 ± 0.17 μM) and was modestly elevated in recombinant CYP2A6∗2 microsomes (1.00 ± 0.12 μM). IC50 shift experiments were consistent across pooled HLM (5.3-fold) and microsomes from liver specimens exhibiting the CYP2A6 (∗2/∗2) and (∗9/∗9) genotypes (6.1- and 4.0-fold, respectively) but were reduced in CYP2A6 (∗35/∗35) microsomes (1.0-fold). Irreversible inhibition kinetics in pooled HLMs by Δ8-THC yielded a kinact value of 0.022 ± 0.001 min-1 and an unbound KI value of 0.232 ± 0.062 μM. Static modeling predicted that oral dosing with 10 mg Δ8-THC increased the nicotine plasma area under the curve by 189%, with further increases observed at 20 mg and 40 mg; interactions were also observed with inhalation doses ≥70 mg.
These findings suggest that, based on CYP2A6 genotype, Δ8-THC could be a candidate for smoking cessation therapy.
SIGNIFICANCE STATEMENT: This study is the first, to the best of our knowledge, to identify Δ-8-tetrahydrocannabinol as a potent and irreversible inhibitor of nicotine metabolism to cotinine. The extent of inhibition is modulated by genetic variation in cytochrome P450 2A6. These findings suggest that further investigations focusing on Δ-8-tetrahydrocannabinol and its potential as a candidate for smoking cessation therapy are warranted.”
“In conclusion, the present study is, to our knowledge, the first to demonstrate the irreversible inhibition of nicotine metabolism by Δ8-THC in vitro, highlighting its potential as a smoking cessation agent.”
“Cannabinoids are increasingly used by cancer patients for symptom relief, yet clinical evidence on their effect in prostate cancer remains limited. This study evaluated the association between cannabinoid therapy and disease activity, pain, and quality of life in men with prostate cancer.
The objectives were to assess the influence of cannabinoids on PSA levels, metabolic activity, tumour size via PET/CT scans, and patient-reported outcomes including pain levels and quality of life.
Methods: Ninety men with confirmed prostate cancer were prospectively followed in three groups: chemotherapy-only, cannabis-only, and combined chemotherapy + cannabis. PSA, PET/CT findings, and patient-reported outcomes (BPI, EQ-5D) were assessed at baseline, 3 months, and 6 months. Longitudinal changes were analysed using linear mixed-effects regression with group × time interactions, and between-group differences were tested with ANOVA. PET/CT categorical outcomes were evaluated using multinomial logistic regression to generate adjusted odds ratios
Results: Significant temporal differences in PSA levels were detected among groups (p < 0.001); both cannabis-containing regimens showed faster PSA decline, but final values were comparable across treatments. PET/CT analyses indicated a higher likelihood of remission or tumour reduction in the combined group (p = 0.013).
Cannabis use, alone or combined was associated with greater reductions in pain and improved emotional well-being compared with chemotherapy alone, while improvements in self-care and usual-activity scores were also observed.
Conclusion: Cannabinoid therapy, whether used independently or alongside chemotherapy, was associated with improved pain control and some indicators of tumour response, without evidence of harm. The findings warrant cautious interpretation and support further randomized studies to clarify cannabinoids’ adjunctive role in prostate cancer management.”
“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.”
“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.”
“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.”
“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.”
“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.”
“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.”
“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.”
“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.”
“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.”
“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.”
