Category Archives: THC (Delta-9-Tetrahydrocannabinol)

The Development and Therapeutic Potential of Classical and Next-Generation Cannabinoid Ligands

Posted on by
Reply
pubmed logo

“The endogenous cannabinoid system (ECS) is a complex network that plays a crucial role in various physiological processes, and its modulation through cannabinoid ligands has garnered significant interest in pharmacological research.

Cannabinoid receptors, primarily CB1 and CB2, are G-protein-coupled receptors that can interact with many different types of ligands, including orthosteric agonists and antagonists and allosteric and biased modulators.

This review provides an updated perspective on cannabinoid receptor ligand development, beginning with natural ligands such as phytocannabinoids and endocannabinoids. These compounds provided the initial inspiration for the design of the first synthetic classical cannabinoids which were later refined into structurally distinct non-classical cannabinoids.

Beyond these traditional orthosteric ligands, we explore the expanding field of allosteric and biased modulators, which offer refined control over receptor signaling and present opportunities to reduce side effects associated with direct receptor activation. We also highlight the significance of covalent ligands and labeled chemical probes in elucidating cannabinoid receptor structure, localization, and function.

Advances in imaging and chemoproteomic techniques have further enhanced our ability to visualize receptor dynamics and identify novel interaction partners. Finally, we examine the clinical landscape of cannabinoid-based therapeutics, from approved drugs to ongoing clinical trials, and discuss the remaining challenges and future directions in ECS-targeted drug development.

This review aims to provide a comprehensive overview of current trends and emerging strategies in cannabinoid ligand research.”

https://pubmed.ncbi.nlm.nih.gov/41192631/

“The endogenous cannabinoid system has broad therapeutic relevance. “

“Natural and synthetic cannabinoids finely regulate the endogenous cannabinoid system.”

https://www.sciencedirect.com/science/article/pii/S1043661825004475?via%3Dihub

History of cannabis use and cognitive function in older adults: findings from the UK biobank

Posted on by
Reply
pubmed logo

“Background: Cannabis is a commonly used psychoactive drug, but its cognitive effects remain unclear, particularly in older adults. This study examined associations between past and present cannabis use and cognitive function among dementia-free older adults.

Methods: Cross-sectional and longitudinal data were drawn from the UK Biobank, including adults aged ≥60 years. Cannabis use patterns were self-reported, and cognitive function was assessed via computerized tests of attention, executive function, processing speed, visual memory and working memory. Multivariable linear regression models adjusted for demographic, health and lifestyle-related covariates.

Results: Cross-sectional analyses included 67 713 participants; longitudinal analyses included 52 002 participants with two cognitive assessments (mean age 67.2 ± 4.4 years; 46.1% male). Lifetime cannabis users (17%) performed better across all cognitive domains: attention (B = 0.071), executive function (B = 0.047), processing speed (B = 0.363), visual (B = 0.062) and working memory (B = 0.181). Current use was associated with better working memory (B = 0.169). Mixed and contradictory results were found for early onset, duration and frequency of use with cognitive outcomes. Longitudinally, past use was associated with less decline in executive function, while longer duration of use predicted steeper decline in processing speed.

Conclusions: Cannabis use is not uniformly harmful to cognition in older adults. Past use was linked to better performance and slower decline in some cognitive domains. However, specific usage patterns, such as longer duration, were associated with poorer outcomes in other domains. These findings highlight the need for further research to clarify underlying mechanisms and guide evidence-based recommendations regarding cannabis use in aging populations.”

https://pubmed.ncbi.nlm.nih.gov/41189327/

“Cannabis use in older adults is not uniformly associated with cognitive decline; former users showed better cognitive perform.”

“These results offer preliminary evidence that cannabis use may not be uniformly detrimental to cognitive health in aging.”

https://academic.oup.com/ageing/article/54/11/afaf319/8313927?login=false

Cannabis sativa extracts reduce inclusion formation in a cell model of alpha-synuclein aggregation

Posted on by
Reply
pubmed logo

“Parkinson’s disease (PD) is classified as a synucleinopathy due to the accumulation of protein inclusions rich in the alpha-synuclein (aSyn) protein. Identifying effective pharmacological therapies is important to slow the progression and minimize the symptoms of these diseases.

Cannabis sativa has a diverse chemical profile depending on its genotype, including several classes of substances, such as cannabinoids, flavonoids, terpenes, and alkaloids.

In this study, we evaluated the effects of four C. sativa extracts with different phytocannabinoid chemical profiles in two cellular models that reproduce alterations in cellular homeostasis common during the cellular phase of PD and other synucleinopathies. We used Saccharomyces cerevisiae strains transformed with plasmid DNA and genetically modified human cells (H4), both expressing aSyn.

The results showed that all the extracts were antioxidants, decreasing intracellular oxidation levels and increasing the number of daughter cells in yeast cells, but did not prevent mitochondrial damage. Besides, the extracts reduced the number of intracellular inclusions in H4 cells and increased the number of cells without inclusions.

Phytochemical characterization revealed extracts rich in Tetrahydrocannabinol – THC (69.88 %), Cannabidiol – CBD (52.64 %), and Cannabinol – CBN (47.38 % and 58.64 %), and we concluded that, regardless of these percentages, all C. sativa extracts showed protective biological activity against toxicity caused by alpha-synuclein production, both in yeast cells and H4 cells.”

https://pubmed.ncbi.nlm.nih.gov/41187864/

“Four Cannabis sativa extracts rich in different phytocannabinoids (THC, CBD, and CBN) demonstrated antioxidant potential independent of their chemical profiles. A decrease in the intracellular oxidative environment in the Saccharomyces cerevisiae model with aSyn indicates that the extracts (E-THC, E-CBD, E-CBN and E-CBN+) may contribute to maintaining cellular redox homeostasis, minimizing potential effects related to the development of Parkinsonism.”

https://www.sciencedirect.com/science/article/abs/pii/S0367326X25005945?via%3Dihub

Cannabinoids rescue migraine symptoms caused by central CGRP administration in mice

Posted on by
Reply
pubmed logo

“This study investigates the therapeutic potential of a combined dose of cannabidiol (CBD) and tetrahydrocannabinol (THC) at a 100:1 ratio (100 mg/kg CBD and 1 mg/kg THC) in mitigating central calcitonin gene-related peptide (CGRP)-induced migraine symptoms in a mouse model.

The 100:1 ratio of CBD to THC was administered intraperitoneally, 60 minutes prior to starting all the assays, followed by intracerebroventricular CGRP administration, 30 minutes later, with behavior assays conducted 30 minutes after CGRP injection. To determine whether pretreatment of CBD:THC could counteract CGRP-induced light aversion, we utilized the light/dark assay, which also recorded motility behavior. To investigate whether CBD:THC pretreatment could alleviate CGRP-induced spontaneous pain, we used the automated squint assay.

Our findings show that pretreatment with 100:1 CBD:THC rescued light aversion caused by centrally administered CGRP in CD1 mice. Additionally, CBD:THC pretreatment rescued the increased resting time in darkness, decreased transitions between light and dark zones, and partially rescued the decreased rearing behavior induced by centrally administered CGRP. Moreover, an open field assay confirmed that centrally administered CGRP did not induce anxiety in a light independent assay. Finally, our findings from the automated squint assay indicate that pretreatment with 100:1 CBD:THC partially rescued centrally administered CGRP-induced spontaneous pain.

Collectively, these results demonstrate that a combination of CBD and THC can alleviate light aversion and pain symptoms induced by a centrally-acting migraine trigger.”

https://pubmed.ncbi.nlm.nih.gov/41182862/

“The medicinal properties of the plant Cannabis can be traced back thousands of years, with some of its earliest records dating to Chinese medicine around 2700 BC, and Indian medicine around 900 BC. During the late 19th to early 20th centuries, many Western physicians considered Cannabis to be the “most satisfactory” remedy for migraine, and, for eight decades, it was the primary treatment for migraine in mainstream Western medical literature.”

https://journals.sagepub.com/doi/10.1177/03331024251392103

Measuring the Effects of Cannabis on Anxiety and Depression Among Cancer Patients

Posted on by
Reply
pubmed logo

“Introduction: Cancer patients are increasingly turning to cannabis products to modulate physical and psychological symptoms despite limited evidence supporting their efficacy. We aimed to explore cancer patients’ self-reported anxiety and depression symptoms in response to cannabis use.

Methods: This longitudinal study examined how patient-reported anxiety and depression symptoms varied according to the dose, ratio of tetrahydrocannabinol (THC) to cannabidiol (CBD), and route of administration of cannabis products among cancer patients. Change in self-reported anxiety and depression symptoms was evaluated in 1962 cancer patients after 30 days of enrollment in the Minnesota Medical Cannabis Program.

Results: Anxiety scores improved more in patients taking higher doses of CBD (> 14.3 mg/day) compared to those taking lower doses (< 4.6 mg/day) and among patients using enteral cannabis products. Depression scores also improved more for patients taking enteral products.

Discussion: Anxiety scores varied according to the dose of cannabis, the ratio of THC to CBD, and the route of administration of cannabis products. In contrast, depression scores only varied according to the route of administration.

Conclusions: This study of cancer patients in Minnesota suggests that patterns of cannabis use that include relatively higher doses of CBD taken enterally may improve the quality of life of cancer survivors who report anxiety and depression. This study constructs a foundation for future research to improve the tailoring of cannabis-related educational materials to patients’ needs and inform the training of healthcare professionals on how to recommend cannabis products for cancer survivors.”

https://pubmed.ncbi.nlm.nih.gov/41163433/

“Given the high prevalence of anxiety and depression symptoms among cancer patients, along with the potential for cannabis products to alleviate these serious psychological symptoms, this study suggests specific patterns of use that may improve the quality of life of cancer survivors.”

https://onlinelibrary.wiley.com/doi/10.1002/cam4.71342

Venous Thromboembolism and Coagulation Biomarker Changes in Trauma Patients Using Cannabis

Posted on by
Reply
pubmed logo

“Prior studies showed contradictory results regarding the impact of cannabinoids on thromboembolic events in trauma patients. The goal of the study was to investigate the association of cannabinoids to venous thromboembolism (VTE).

Records for all trauma patients admitted to the level one trauma center aged 14 years and above between October 18, 2019 and December 29, 2023 with urine drug screening (UDS) and blood alcohol concentration (BAC) results were included for collection. Patients testing positive for cannabinoids and patients testing negative for cannabinoids that were also negative for other illicit drugs and for alcohol were included in the final analysis primarily examining VTE occurrence, along with secondary outcomes in mortality, hospital length of stay, discharge disposition, and coagulation-related biomarkers. One-to-one propensity score matching analysis was performed.

Patient population was mostly white (78.8%), mostly male (71.5%), had a median age of 46, and a median ISS of 17. Out of 302 patients, 226 tested negative and 76 tested positive for cannabinoids. In the matched analysis, no difference was observed in rates of VTE (7.4% vs 4.4%, P = .683) or in platelet count (median [IQR], 260 [215-304] vs 260 [211-306], P = .790). No significant differences were found between the groups on coagulation profiles, complications, or other outcomes.

This study failed to identify significant differences between coagulation-related biomarkers and VTE incidence of adolescent and adult, trauma patients who tested positive for cannabinoids vs those that tested negative for cannabinoids.”

https://pubmed.ncbi.nlm.nih.gov/41160914/

https://journals.sagepub.com/doi/10.1177/00031348251393925

Long-Term Efficacy and Safety of Inhaled Cannabis Therapy for Painful Diabetic Neuropathy: A 5-Year Longitudinal Observational Study

Posted on by
Reply
pubmed logo

“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

Unlike Tobacco Users, Documented Cannabis Users Are Not at an Increased Risk of Adverse Events After Total Hip Arthroplasty

Posted on by
Reply
pubmed logo

“Background: Perioperative tobacco use has been identified as an independent risk factor for adverse events after total hip arthroplasty (THA). It is unknown if perioperative cannabis users share similar levels of risk for adverse events after THA.

Methods: Patients undergoing THA were identified from the 2010 to 2021 PearlDiver M151 administrative data set. Patient subcohorts were categorized based on presence or absence of cannabis and/or tobacco use, as determined by coding. These subcohorts were equally matched based on patient age, sex, and Elixhauser Comorbidity Index scores to form groups of nonusers, tobacco users, tobacco and cannabis users, as well as cannabis users. The incidences of adverse events within 90 days postoperatively were obtained and compared using univariate and multivariate analyses that controlled for age, sex, and Elixhauser Comorbidity Index. Bonferroni correction was applied.

Results: Of 494,431 THA patients, nonusers were 442,000 (89.40%), tobacco users 46,925 (9.50%), tobacco and cannabis users 3,390 (0.69%), and cannabis users 2,116 (0.43%). After matching, there were 1,897 in each group. By multivariate analyses, tobacco-only users were at significantly greater risk of severe adverse events, sepsis, and pneumonia (P < 0.001 for each). Tobacco and cannabis users were at significantly greater risk of severe adverse events, myocardial infarction, pneumonia, and readmission (P < 0.001 for each). Conversely, cannabis-only users were not at significantly greater risk for any of the combined or individual adverse events assessed.

Discussion: This study confirmed that THA patients with tobacco-only use were at greater risk of perioperative adverse events and that these were relatively similar to those with concurrent tobacco and cannabis use. However, cannabis-only users were not at greater risk, a finding that is of clinical interest given the evolving access and increasing use of this agent.”

https://pubmed.ncbi.nlm.nih.gov/41144882/

https://journals.lww.com/jaaos/abstract/9900/unlike_tobacco_users,_documented_cannabis_users.1503.aspx

Cannabinoids in immune system-related diseases: From bench to clinic

Posted on by
Reply
pubmed logo

“As a psychoactive drug, marijuana is used for recreational purposes. Given its addictive nature and the serious damage it causes to both individual health and social stability, marijuana has been banned in most countries worldwide. In recent years, with the continuous improvement of basic research, researchers have discovered the vital role of cannabinoids, the primary active ingredient in marijuana, in multiple human systems.

Research found that cannabinoids play roles in regulating immune system function and have therapeutic potential in immune system-related diseases.

However, the use of cannabinoids still poses certain hazards. For instance, the abuse of cannabinoids by pregnant women can exert certain impacts on fetal nervous system development; cannabinoids use can lead to adverse reactions such as dizziness, nausea, and dry mouth. Moreover, there are still numerous contradictions in current research on the effects of cannabinoids, and the mechanisms by which cannabinoids exert protective effects in certain diseases remain unelucidated.

In this review, we systematically discuss the endocannabinoid system and summarize the molecular and cellular bases of cannabinoid function in the immune system, and elucidate the effects of cannabinoids on immune system-related diseases.”

https://pubmed.ncbi.nlm.nih.gov/41146433/

“These findings collectively demonstrate the protective roles of CB1 agonists in immune system-related diseases.”

“These findings underscore the broad therapeutic efficacy of CB2 agonists in immune system-related diseases.”

“Cannabinoids exert immunoregulatory effects by inducing the apoptosis of immune cells, inhibiting immune cell proliferation, suppressing the production of proinflammatory cytokines, and regulating the functions of immune cells such as B cells, NK cells, and Treg cells.”

https://journals.lww.com/cmj/fulltext/9900/cannabinoids_in_immune_system_related_diseases_.1774.aspx

Evaluation of the Effects of Tetrahydrocannabinol (THC) and Cannabidiol (CBD) on Gingival and Skin Keratinocyte Growth, Migration, Metabolic Activity, and Pro-Inflammatory Cytokine Secretion

Posted on by
Reply
pubmed logo

“Background: Cannabinoids, such as tetrahydrocannabinol (∆-9-THC) and cannabidiol (CBD) have been proposed for topical medicinal use as a treatment for tissue inflammation. In this context, keratinocytes are the first cells that encounter cannabinoids. The present study evaluated the dose-response relationship between different concentrations of THC and CBD and their effects on human skin and gingival keratinocyte growth and migration, to identify suitable non-toxic concentrations of cannabinoids. 

Methods: Human gingival and skin keratinocytes were exposed to CBD or THC at different concentrations for 24 h, and then cell adhesion, morphology, and growth/viability were assessed. The effects of cannabinoids on keratinocyte migration were evaluated at 6, 12, and 24 h. Cytotoxicity of CBD and THC against keratinocyte cells was assessed using an LHD cytotoxicity test. Cell metabolic profiles were evaluated using Mito and Glyco Stress Assays. The anti-inflammatory effects of cannabis derivatives were assessed against LPS-stimulated keratinocytes. Data analysis was performed by one-way ANOVA. 

Results: Only high concentrations (10 and 20 μg/mL) of CBD and THC were cytotoxic to gingival and skin keratinocytes, reduced cell adhesion and growth, and were associated with a delay in cell migration after wounding. Cells exposed to high concentrations (20 μg/mL) of cannabinoids displayed high levels of lactate dehydrogenase (LDH) activity and changes in mitochondrial activities. CBD induced a metabolic shift in skin keratinocyte cells toward glycolysis, while reducing mitochondrial oxidative phosphorylation. In contrast, THC did not alter the metabolic profile of skin keratinocytes. Interestingly, both CBD and THC significantly reduced the LPS-induced inflammatory response by decreasing secretion of IL-6 and IL-8 by gingival and skin keratinocytes. 

Conclusions: Gingival and skin keratinocytes interact differently with cannabinoids. Only high concentrations of cannabinoids were cytotoxic, suggesting that the use of low concentrations of CBD and THC for topical medicinal applications may help control tissue inflammation.”

https://pubmed.ncbi.nlm.nih.gov/41153821/

“Overall, results from this study suggest that CBD and THC may be used in different formulations (e.g., as a moisturizing lotion or spray) in order to manage tissue inflammation caused by pathological conditions, such as lichen planus, dermatitis, and psoriasis.”

https://www.mdpi.com/2227-9059/13/10/2541