Category Archives: THC (Delta-9-Tetrahydrocannabinol)

Cannabinoids and endocannabinoids as therapeutics for nervous system disorders: preclinical models and clinical studies

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“Cannabinoids are lipophilic substances derived from Cannabis sativa that can exert a variety of effects in the human body. They have been studied in cellular and animal models as well as in human clinical trials for their therapeutic benefits in several human diseases.

Some of these include central nervous system (CNS) diseases and dysfunctions such as forms of epilepsy, multiple sclerosis, Parkinson’s disease, pain and neuropsychiatric disorders. In addition, the endogenously produced cannabinoid lipids, endocannabinoids, are critical for normal CNS function, and if controlled or modified, may represent an additional therapeutic avenue for CNS diseases. This review discusses in vitro cellular, ex vivo tissue and in vivo animal model studies on cannabinoids and their utility as therapeutics in multiple CNS pathologies. In addition, the review provides an overview on the use of cannabinoids in human clinical trials for a variety of CNS diseases.

Cannabinoids and endocannabinoids hold promise for use as disease modifiers and therapeutic agents for the prevention or treatment of neurodegenerative diseases and neurological disorders.”

https://pubmed.ncbi.nlm.nih.gov/37843213/

https://journals.lww.com/nrronline/fulltext/2024/04000/cannabinoids_and_endocannabinoids_as_therapeutics.22.aspx

Pharmacohistory of Cannabis Use-A New Possibility in Future Drug Development for Gastrointestinal Diseases

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“Humans have employed cannabis for multiple uses including medicine, recreation, food, and fibre. The various components such as roots, flowers, seeds, and leaves have been utilized to alleviate pain, inflammation, anxiety, and gastrointestinal disorders like nausea, vomiting, diarrhoea, and inflammatory bowel diseases (IBDs). It has occupied a significant space in ethnomedicines across cultures and religions. Despite multi-dimensional uses, the global prohibition of cannabis by the USA through the introduction of the Marijuana Tax Act in 1937 led to prejudice about the perceived risks of cannabis, overshadowing its medicinal potential. Nevertheless, the discovery of tetrahydrocannabinol (THC), the primary psychoactive compound in cannabis, and the endocannabinoid system renewed scientific interest in understanding the role of cannabis in modulating different conditions, including gastrointestinal disorders. Preparations combining cannabidiol and THC have shown promise in mitigating gut symptoms through anti-inflammatory and motility-enhancing effects. This review revisits the ethnomedicinal use of cannabis in gastrointestinal diseases and emphasizes the need for further research to determine optimal dosages, formulations, and safety profiles of cannabis-based medicines. It also underscores the future potential of cannabinoid-based therapies by leveraging the role of the expanded endocannabinoid system, an endocannabinoidome, in the modulation of gastrointestinal ailments.”

https://pubmed.ncbi.nlm.nih.gov/37834122/

“Taken together, the future of cannabis and cannabinoids research for gastrointestinal disorders involves a comprehensive understanding of their mechanisms of action, multi-centred rigorous clinical trials, personalized medicine approaches, and continued exploration of formulation development and safety considerations. These efforts have the potential to yield novel therapeutic options and improve the quality of life for patients with gastrointestinal disorders.”

https://www.mdpi.com/1422-0067/24/19/14677

Phytocannabinoids Reduce Inflammation of Primed Macrophages and Enteric Glial Cells: An In Vitro Study

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“Intestinal inflammation is mediated by a subset of cells populating the intestine, such as enteric glial cells (EGC) and macrophages. Different studies indicate that phytocannabinoids could play a possible role in the treatment of inflammatory bowel disease (IBD) by relieving the symptoms involved in the disease.

Phytocannabinoids act through the endocannabinoid system, which is distributed throughout the mammalian body in the cells of the immune system and in the intestinal cells. Our in vitro study analyzed the putative anti-inflammatory effect of nine selected pure cannabinoids in J774A1 macrophage cells and EGCs triggered to undergo inflammation with lipopolysaccharide (LPS). The anti-inflammatory effect of several phytocannabinoids was measured by their ability to reduce TNFα transcription and translation in J774A1 macrophages and to diminish S100B and GFAP secretion and transcription in EGCs.

Our results demonstrate that THC at the lower concentrations tested exerted the most effective anti-inflammatory effect in both J774A1 macrophages and EGCs compared to the other phytocannabinoids tested herein.

We then performed RNA-seq analysis of EGCs exposed to LPS in the presence or absence of THC or THC-COOH. Transcriptomic analysis of these EGCs revealed 23 differentially expressed genes (DEG) compared to the treatment with only LPS. Pretreatment with THC resulted in 26 DEG, and pretreatment with THC-COOH resulted in 25 DEG. To evaluate which biological pathways were affected by the different phytocannabinoid treatments, we used the Ingenuity platform. We show that THC treatment affects the mTOR and RAR signaling pathway, while THC-COOH mainly affects the IL6 signaling pathway.”

https://pubmed.ncbi.nlm.nih.gov/37834076/

https://www.mdpi.com/1422-0067/24/19/14628

Cell death induction and intracellular vesicle formation in human colorectal cancer cells treated with Δ9-Tetrahydrocannabinol

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“Background: Δ9-Tetrahydrocannabinol (Δ9-THC) is a principal psychoactive extract of Cannabis sativa and has been traditionally used as palliative medicine for neuropathic pain. Cannabidiol (CBD), an extract of hemp species, has recently attracted increased attention as a cancer treatment, but Δ9-THC is also requiring explored pharmacological application.

Objective: This study evaluated the pharmacological effects of Δ9-THC in two human colorectal cancer cell lines. We investigated whether Δ9-THC treatment induces cell death in human colorectal cancer cells.

Methods: We performed an MTT assay to determine the pharmacological concentration of Δ9-THC. Annxein V and Western blot analysis confirmed that Δ9-THC induced apoptosis in colorectal cancer cells. Metabolic activity was evaluated using MitoTracker staining and ATP determination. We investigated vesicle formation by Δ9-THC treatment using GW9662, known as a PPARγ inhibitor.

Results: The MTT assay showed that treatment with 40 μM Δ9-THC and above inhibited the proliferation of colorectal cancer cells. Multiple intracytoplasmic vesicles were detected upon microscopic observation, and fluorescence-activated cell sorting analysis showed cell death via G1 arrest. Δ9-THC treatment increased the expression of cell death marker proteins, including p53, cleaved PARP-1, RIP1, and RIP3, suggesting that Δ9-THC induced the death of colorectal cancer cells. Δ9-THC treatment also reduced ATP production via changes in Bax and Bcl-2. Δ9-THC regulated intracytoplasmic vesicle formation by modulating the expression of PPARγ and clathrin, adding that antiproliferative activity of Δ9-THC was also affected.

Conclusion: In conclusion, Δ9-THC regulated two functional mechanisms, intracellular vesicle formation and cell death. These findings can help to determine how cannabinoids can be used most effectively to improve the efficacy of cancer treatment.”

https://pubmed.ncbi.nlm.nih.gov/37837516/

https://link.springer.com/article/10.1007/s13258-023-01466-7

Cannabinol inhibits cell growth and triggers cell cycle arrest and apoptosis in cancer cells

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Biocatalysis and Agricultural Biotechnology

“Cancer is one of the most difficult diseases to treat and cure.”

“Cannabinol (CBN), one of the active ingredients from the cannabis plant, is the breakdown molecule of Δ9-tetrahydrocannabinol (Δ9-THC) which is the most abundant psychoactive cannabinoid.”

“Cannabinol (CBN) is a weak-psychoactive cannabinoid and has been shown to exert several bio-logical activities. At the same time, not much is known about the anti-cancer activities of CBN. In this report, we characterized the anti-tumor effects of CBN on the glioma A172, liver cancer HepG2 and breast cancer HCC1806 cell lines.

We found that CBN reduces the proliferation of the analyzed cancer cells and modulates the level of cannabinoid receptors, including GPR18, CB2 and GPR55. Furthermore, CBN inhibits the ERK1/2 pathway in A172 and HepG2 cells, while suppressing the AKT pathway in HCC1086 cells. Moreover, CBN may cause apoptosis through downregulation of p21 and p27 as well as a cell cycle arrest at G1 or S-phase via decreasing the CDK1, CDK2, and cyclin E1 levels.

Taken together, these results offer new insights into the anti-cancer properties of CBN.”

“CBN, one of the weak-psychoactive cannabinoids, have demonstrated various medicinal properties, including anti-inflammatory, antibacterial, analgesic and even anti-tumor.”

“In this study, we revealed the antitumor activity of CBN in three different tumor cell lines, glioma A172, liver cancer HepG2 and breast cancer HCC1806 cell lines. We report that cannabinol inhibits proliferation of several cancer cell lines by regulation of the signaling pathways involving ERK and AKT as well as by altering the expression of cannabinoid receptors. Moreover, we also found that CBN induces apoptosis and cell cycle arrest and partially uncovered underlying molecular mechanisms. Our findings provide novel information about the anti-cancer properties of CBN and justify further research to investigate the role of CBN as cancer therapeutic.”

https://www.sciencedirect.com/science/article/abs/pii/S1878818123000282

Stigma-related barriers to medical cannabis as harm reduction for substance use disorder: Obstacles and opportunities for improvement

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“Emerging evidence on substituting cannabis for more harmful drugs has led to cannabis becoming a novel harm-reduction strategy for combating the current drug poisoning crisis. However, the authorization of medical cannabis as part of a harm-reduction approach and recovery strategy has significant implementation barriers rooted in longstanding stigma towards cannabis. Through a multi-discipline collaboration of Canadian clinicians and academic researchers, we highlighted stigma barriers and opportunities to address these barriers to elicit improved delivery of medical cannabis as a harm-reduction therapy within existing therapeutic frameworks. Evidence from existing literature and real-world experiences converged on three key themes related to stigma barriers: (1) Lack of medical cannabis education within the healthcare community, (2) lack of consensus and coordination among harm-reduction services and (3) access to medical cannabis. We highlight potential solutions to these issues, including improved healthcare education, better coordination between care teams and suggestions for improving access. Through this discussion, we hope to contribute to reducing the stigma around using medical cannabis as a harm-reduction strategy for individuals with a substance use disorder and consider new perspectives in policy development surrounding recovery services.”

https://pubmed.ncbi.nlm.nih.gov/37767954/

https://onlinelibrary.wiley.com/doi/10.1111/inm.13231

An Individual’s Lived Experiences of Taking Cannabis-Based Medicinal Products (CBMPs) to Treat Anxiety

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“This report documents the case of a patient (the author) participating in a clinical trial of medical cannabis (Cannabis sativa L.)-the Sapphire Access Scheme, run by the Sapphire Medical Clinic as part of the UK Medical Cannabis Registry-to explore the impacts of cannabis-based medicinal products (CBMPs) on anxiety. For most of my life, I have experienced often very serious bouts of poor mental health arising, in part, from childhood abuse, and have been diagnosed with several mental health conditions which constitute disabilities. I have received various conventional treatments and multiple alternative therapies. However, none of these have enabled me to consistently manage my conditions long-term, and I often suffer relapses. As part of the Sapphire Access Scheme, I complete regular quantitative questionnaires regarding the impacts of the CBMPs on my anxiety and have also obtained the clinic’s permission to qualitatively document and write up the impacts of CBMPs on my mental health. Here, I present a preliminary autoethnographic exploration of my lived experiences of CBMP use over the first four months of the trial, which show that even within such a short space of time, CBMPs have had a positive impact on treating what had previously been treatment-refractive chronic anxiety.”

https://pubmed.ncbi.nlm.nih.gov/37754635/

https://www.mdpi.com/1660-4601/20/18/6776

The Use of Dispensary-Obtained Tetrahydrocannabinol as a Treatment for Neuropsychiatric Symptoms of Dementia

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“Objective: Neuropsychiatric symptoms (NPS) of dementia represent a large driver of health care costs, caregiver burden, and institutionalization of people with dementia. Management options are limited, and antipsychotics are often used, although they carry a significant side effect profile. One novel option is tetrahydrocannabinol (THC); however, in the US, to obtain THC for patients with dementia, caregivers have to go to a commercial dispensary. We evaluated the effectiveness of dispensary-obtained THC for patients with dementia and NPS.

Methods: Two independent reviewers reviewed charts of patients with diagnosed dementia (N = 50) seen in geriatric psychiatry between 2017 and 2021 for whom dispensary-obtained THC was recommended. The primary outcome was effectiveness in treating NPS; secondary outcomes were the proportion of caregivers who obtained and administered THC (uptake), post-THC antipsychotic use, and adverse reactions leading to treatment discontinuation.

Results: Caregiver uptake of dispensary-obtained THC was high (38/50, 76%). The majority of patients (30/38, 79%) who took THC had an improvement in NPS according to their caregivers. THC was recommended most often for the NPS of agitation, aggression, irritability, lability, anxiety, and insomnia. Among the 20 patients who were taking antipsychotics at baseline and took THC, over half (12/20, 60%) were able to decrease or discontinue the antipsychotic. Adverse reactions to THC included dizziness, worsening of agitation, and worsening of paranoia; two caregivers of patients who took THC reported adverse reactions that led to treatment discontinuation.

Conclusions: Our results suggest that dispensary-obtained THC can be effective in managing a subset of NPS in patients with dementia and may decrease the requirement for antipsychotics.”

https://pubmed.ncbi.nlm.nih.gov/37728481/

https://www.psychiatrist.com/jcp/neurologic/dementia/dispensary-obtained-tetrahydrocannabinol-treatment-neuropsychiatric-symptoms-dementia/

Transcriptomic Profiling after In Vitro Δ8-THC Exposure Shows Cytoskeletal Remodeling in Trauma-Injured NSC-34 Cell Line

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“Neuronal cell death is a physiological process that, when uncontrollable, leads to neurodegenerative disorders like spinal cord injury (SCI). SCI represents one of the major causes of trauma and disabilities worldwide for which no effective pharmacological intervention exists. Herein, we observed the beneficial effects of Δ8-Tetrahydrocannabinol (Δ8-THC) during neuronal cell death recovery. We cultured NSC-34 motoneuron cell line performing three different experiments. A traumatic scratch injury was caused in two experiments. One of the scratched was pretreated with Δ8-THC to observe the role of the cannabinoid following the trauma. An experimental control group was neither scratched nor pretreated. All the experiments underwent RNA-seq analysis. The effects of traumatic injury were observed in scratch against control comparison. Comparison of scratch models with or without pretreatment highlighted how Δ8-THC counteracts the traumatic event. Our results shown that Δ8-THC triggers the cytoskeletal remodeling probably due to the activation of the Janus Kinase Signal Transducer and Activator of Transcription (JAK/STAT) signaling pathway and the signaling cascade operated by the Mitogen-Activated Protein (MAP) Kinase signaling pathway. In light of this evidence, Δ8-THC could be a valid pharmacological approach in the treatment of abnormal neuronal cell death occurring in motoneuron cells.”

https://pubmed.ncbi.nlm.nih.gov/37765076/

https://www.mdpi.com/1424-8247/16/9/1268

The Effect of Orally Administered Δ9-Tetrahydrocannabinol (THC) and Cannabidiol (CBD) on Obesity Parameters in Mice

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“Prolonged cannabis users show a lower prevalence of obesity and associated comorbidities. In rodent models, Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD) from the plant Cannabis sativa L. have shown anti-obesity properties, suggesting a link between the endocannabinoid system (ECS) and obesity. However, the oral administration route has rarely been studied in this context. The aim of this study was to investigate the effect of prolonged oral administration of pure THC and CBD on obesity-related parameters and peripheral endocannabinoids. C57BL/6 male mice were fed with either a high-fat or standard diet and then received oral treatment in ramping doses, namely 10 mg/kg of THC or CBD for 5 weeks followed by 30 mg/kg for an additional 5 weeks. Mice treated with THC had attenuated weight gain and improved glucose tolerance, followed by improvement in steatosis markers and decreased hypertrophic cells in adipose epididymal tissue. Mice treated with CBD had improved glucose tolerance and increased markers of lipid metabolism in adipose and liver tissues, but in contrast to THC, CBD had no effect on weight gain and steatosis markers. CBD exclusively decreased the level of the endocannabinoid 2-arachidonoylglycerol in the liver. These data suggest that the prolonged oral consumption of THC, but not of CBD, ameliorates diet-induced obesity and metabolic parameters, possibly through a mechanism of adipose tissue adaptation.”

https://pubmed.ncbi.nlm.nih.gov/37762099/

“In conclusion, the present findings provide evidence for the ability of THC to improve obesity-related metabolic complications when administered orally in ramping doses. The limited effect of CBD demonstrated in our study suggests that the low prevalence of obesity and metabolic diseases seen in cannabis users is mainly attributed to the presence of THC.”

https://www.mdpi.com/1422-0067/24/18/13797