Category Archives: THC (Delta-9-Tetrahydrocannabinol)

A randomised phase II trial of temozolomide with or without cannabinoids in patients with recurrent glioblastoma (ARISTOCRAT): protocol for a multi-centre, double-blind, placebo-controlled trial

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“Background: Glioblastoma (GBM) is the most common adult malignant brain tumour, with an incidence of 5 per 100,000 per year in England. Patients with tumours showing O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation represent around 40% of newly diagnosed GBM. Relapse/tumour recurrence is inevitable. There is no agreed standard treatment for patients with GBM, therefore, it is aimed at delaying further tumour progression and maintaining health-related quality of life (HRQoL). Limited clinical trial data exist using cannabinoids in combination with temozolomide (TMZ) in this setting, but early phase data demonstrate prolonged overall survival compared to TMZ alone, with few additional side effects.

Jazz Pharmaceuticals (previously GW Pharma Ltd.) have developed nabiximols (trade name Sativex®), an oromucosal spray containing a blend of cannabis plant extracts, that we aim to assess for preliminary efficacy in patients with recurrent GBM.

Methods: ARISTOCRAT is a phase II, multi-centre, double-blind, placebo-controlled, randomised trial to assess cannabinoids in patients with recurrent MGMT methylated GBM who are suitable for treatment with TMZ. Patients who have relapsed ≥ 3 months after completion of initial first-line treatment will be randomised 2:1 to receive either nabiximols or placebo in combination with TMZ. The primary outcome is overall survival time defined as the time in whole days from the date of randomisation to the date of death from any cause. Secondary outcomes include overall survival at 12 months, progression-free survival time, HRQoL (using patient reported outcomes from QLQ-C30, QLQ-BN20 and EQ-5D-5L questionnaires), and adverse events.

Discussion: Patients with recurrent MGMT promoter methylated GBM represent a relatively good prognosis sub-group of patients with GBM. However, their median survival remains poor and, therefore, more effective treatments are needed. The phase II design of this trial was chosen, rather than phase III, due to the lack of data currently available on cannabinoid efficacy in this setting. A randomised, double-blind, placebo-controlled trial will ensure an unbiased robust evaluation of the treatment and will allow potential expansion of recruitment into a phase III trial should the emerging phase II results warrant this development.”

https://pubmed.ncbi.nlm.nih.gov/38225549/

“Phytocannabinoids occur naturally in cannabis plants and have been used medicinally for centuries for a variety of purposes . Δ9-tetrahydrocannabinol (THC) is the major psychoactive constituent in cannabis, and cannabidiol (CBD) the major non-psychoactive constituent.

In vivo studies have found that the administration of CBD and THC reduced tumour growth in animal models of glioma.

Jazz Pharmaceuticals (previously GW Pharma Ltd.) have developed nabiximols (trade name Sativex®), an oromucosal spray of a complex botanical mixture containing THC and CBD as the principal cannabinoids, with additional cannabinoid constituents and non-cannabinoid components.”

https://bmccancer.biomedcentral.com/articles/10.1186/s12885-023-11792-4

“Sativex is a standardized medication containing 2.5 mg/actuation CBD and 2.7 mg/ actuation THC.”

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3836266/

Cannabinoids and the Endocannabinoid System in Early SARS-CoV-2 Infection and Long COVID-19-A Scoping Review

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“Coronavirus disease-19 (COVID-19) is a highly contagious illness caused by the SARS-CoV-2 virus.

The clinical presentation of COVID-19 is variable, often including symptoms such as fever, cough, headache, fatigue, and an altered sense of smell and taste. Recently, post-acute “long” COVID-19 has emerged as a concern, with symptoms persisting beyond the acute infection. Vaccinations remain one of the most effective preventative methods against severe COVID-19 outcomes and the development of long-term COVID-19. However, individuals with underlying health conditions may not mount an adequate protective response to COVID-19 vaccines, increasing the likelihood of severe symptoms, hospitalization, and the development of long-term COVID-19 in high-risk populations.

This review explores the potential therapeutic role of cannabinoids in limiting the susceptibility and severity of infection, both pre- and post-SARS-CoV-19 infection.

Early in the SARS-CoV-19 infection, cannabinoids have been shown to prevent viral entry, mitigate oxidative stress, and alleviate the associated cytokine storm.

Post-SARS-CoV-2 infection, cannabinoids have shown promise in treating symptoms associated with post-acute long COVID-19, including depression, anxiety, post-traumatic stress injury, insomnia, pain, and decreased appetite.

While current research primarily focuses on potential treatments for the acute phase of COVID-19, there is a gap in research addressing therapeutics for the early and post-infectious phases. This review highlights the potential for future research to bridge this gap by investigating cannabinoids and the endocannabinoid system as a potential treatment strategy for both early and post-SARS-CoV-19 infection.”

https://pubmed.ncbi.nlm.nih.gov/38202234/

https://www.mdpi.com/2077-0383/13/1/227

Cannabinoids in the treatment of cancer anorexia and cachexia: Where have we been, where are we going?

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“Cachexia-anorexia cancer syndrome remains an unmet clinical need with a dearth of treatment and no standard of care.

Acting through the endocannabinoid system, cannabinoids are one potential cancer cachexia treatment.

Herein, the potential mechanisms for cannabinoids for cancer cachexia are discussed as are previous and ongoing clinical trials.”

https://pubmed.ncbi.nlm.nih.gov/38197037/

https://linkinghub.elsevier.com/retrieve/pii/S2347562523001105

A preliminary study evaluating self-reported effects of cannabis and cannabinoids on neuropathic pain and pain medication use in people with spinal cord injury

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“Approximately 60% of individuals with a spinal cord injury (SCI) experience neuropathic pain, which often persists despite the use of various pharmacological treatments. Increasingly, the potential analgesic effects of cannabis and cannabinoid products have been studied; however, little research has been conducted among those with SCI-related neuropathic pain. Therefore, the primary objective of the study was to investigate the perceived effects of cannabis and cannabinoid use on neuropathic pain among those who were currently or had previously used these approaches. Additionally, the study aimed to determine if common pain medications are being substituted by cannabis and cannabinoids. Participants (N = 342) were recruited from existing opt-in listserv sources within the United States. Of those, 227 met the inclusion criteria and were enrolled in the study. The participants took part in an anonymous online survey regarding past and current use of cannabis and their perceived effects on neuropathic pain, including the use of pain medication. Those in the sample reported average neuropathic pain intensity scores over the past week of 6.8 ± 2.1 (0 to 10 scale), reflecting a high moderate to severe level of pain. Additionally, 87.9% noted that cannabis reduced their neuropathic pain intensity by more than 30%, and 92.3% reported that cannabis helped them to better deal with their neuropathic pain symptoms. Most participants (83.3%) also reported substituting their pain medications with cannabis, with the most substituted medication categories being opioids (47.0%), gabapentinoids (42.8%) and over-the-counter pain medications (42.2%). These preliminary results suggest that cannabis and cannabinoids may be effective in reducing neuropathic pain among those with SCI and may help to limit the need for certain pain medications.”

https://pubmed.ncbi.nlm.nih.gov/38188193/

https://www.frontiersin.org/articles/10.3389/fpain.2023.1297223/full

Awareness and interest in cannabis use for cancer management among cancer survivors

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“Background: We examined the awareness, interest, and information sources relating to cannabis use for cancer management (including management of cancer symptoms and treatment-related side effects) and determined factors associated with cancer survivors’ awareness and interest in learning about cannabis use for cancer management.

Methods: This was a cross-sectional study of adult cancer survivors (N = 1886) receiving treatment at a comprehensive cancer center. Weighted prevalence and multivariable logistic regression analyses were conducted.

Results: Among cancer survivors, 88% were aware and 60% were interested in learning about cannabis use for cancer management. Common sources of information to learn about cannabis use for cancer management were cancer doctors/nurses (82%), other patients with cancer (27%), websites/blogs (26%), marijuana stores (20%), and family/friends (18%). The odds of being aware of cannabis use for cancer management was lower among male compared to female survivors (adjusted odds ratio [AOR]: 0.61; 95% confidence interval [CI]: 0.41-0.90), non-Hispanic Blacks compared to non-Hispanic Whites (AOR: 0.36; 95% CI: 0.21-0.62), and survivors who do not support the legalization of cannabis for medical use compared to those who do (AOR: 0.10; 95% CI: 0.04-0.23). On the other hand, the odds of being interested in cannabis use for cancer management was higher among non-Hispanic Blacks compared to non-Hispanic Whites (AOR: 1.65; 95% CI: 1.04-2.62), and among cancer survivors actively undergoing cancer treatment compared to patients on non-active treatment (AOR: 2.25; 95% CI: 1.74-2.91).

Conclusion: Awareness of cannabis use for cancer management is high within the cancer survivor population. Results indicated health care providers are leading information source and should receive continued medical education on cannabis-specific guidelines. Similarly, tailored educational interventions are needed to guide survivors on the benefits and risks of cannabis use for cancer management.”

https://pubmed.ncbi.nlm.nih.gov/38180296/

“In conclusion, most cancer survivors are aware of and interested in cannabis use for medical management. “

https://onlinelibrary.wiley.com/doi/10.1002/cam4.6902

Cannabis Sativa targets mediobasal hypothalamic neurons to stimulate appetite

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“The neurobiological mechanisms that regulate the appetite-stimulatory properties of cannabis sativa are unresolved. This work examined the hypothesis that cannabinoid-1 receptor (CB1R) expressing neurons in the mediobasal hypothalamus (MBH) regulate increased appetite following cannabis vapor inhalation. Here we utilized a paradigm where vaporized cannabis plant matter was administered passively to rodents. Initial studies in rats characterized meal patterns and operant responding for palatable food following exposure to air or vapor cannabis. Studies conducted in mice used a combination of in vivo optical imaging, electrophysiology and chemogenetic manipulations to determine the importance of MBH neurons for cannabis-induced feeding behavior. Our data indicate that cannabis vapor increased meal frequency and food seeking behavior without altering locomotor activity. Importantly, we observed augmented MBH activity within distinct neuronal populations when mice anticipated or consumed food. Mechanistic experiments demonstrated that pharmacological activation of CB1R attenuated inhibitory synaptic tone onto hunger promoting Agouti Related Peptide (AgRP) neurons within the MBH. Lastly, chemogenetic inhibition of AgRP neurons attenuated the appetite promoting effects of cannabis vapor. Based on these results, we conclude that MBH neurons contribute to the appetite stimulatory properties of inhaled cannabis.”

https://pubmed.ncbi.nlm.nih.gov/38151493/

https://www.nature.com/articles/s41598-023-50112-5

Cannabidiol and Tetrahydrocannabinol Antinociceptive Activity is Mediated by Distinct Receptors in Caenorhabditis elegans

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“Cannabis has gained popularity in recent years as a substitute treatment for pain following the risks of typical treatments uncovered by the opioid crisis. The active ingredients frequently associated with pain-relieving effects are the phytocannabinoids Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD), but their effectiveness and mechanisms of action are still under research. In this study, we used Caenorhabditis elegans, an ideal model organism for the study of nociception that expresses mammal ortholog cannabinoid (NPR-19 and NPR-32) and vanilloid (OSM-9 and OCR-2) receptors. Here, we evaluated the antinociceptive activity of THC and CBD, identifying receptor targets and several metabolic pathways activated following exposure to these molecules. The thermal avoidance index was used to phenotype each tested C. elegans experimental group. The data revealed for the first time that THC and CBD decreases the nocifensive response of C. elegans to noxious heat (32-35 °C). The effect was reversed 6 h post- CBD exposure but not for THC. Further investigations using specific mutants revealed CBD and THC are targeting different systems, namely the vanilloid and cannabinoid systems, respectively. Proteomic analysis revealed differences following Reactome pathways and gene ontology biological process database enrichment analyses between CBD or THC-treated nematodes and provided insights into potential targets for future drug development.”

https://pubmed.ncbi.nlm.nih.gov/38141130/

https://link.springer.com/article/10.1007/s11064-023-04069-6

Cannabis Use and Incident Atrial Fibrillation in a Longitudinal Cohort

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“Background: Cannabis use is increasing worldwide. While prior studies have reported an association between cannabis use and a higher risk of atrial fibrillation (AF), most were cross-sectional and generally relied on diagnostic coding to identify cannabis users, which may not be representative of the typical, recreational cannabis user.

Objective: To examine the association between recreational cannabis use and lifetime AF risk.

Methods: We evaluated the AF risk of participants of the UK Biobank cohort who completed the cannabis use lifestyle questionnaire. Cannabis exposure was categorized as “Occasional Use” for less than 100 times used, “Frequent Use” for more than 100 times used, and “Never” users. AF events were identified using International Classification of Diseases (ICD) codes. Cox models were used to estimate the hazard ratios (HR) between cannabis use and incident AF and were subsequently adjusted for age, sex, race, alcohol, coffee, smoking, education, and baseline cardiovascular comorbidities.

Results: A total of 150,554 participants (mean 63.4 ± 7.7 years, 57.4% female, and 22.2% using cannabis at least once) were followed for a mean 6.1 ± 0.6 years. After multivariable adjustment, there were no statistically significant differences in incident AF among occasional users (HR 0.98, 95% CI 0.89 to 1.08) nor frequent users (HR 1.03, 95% CI 0.81 to 1.32) compared to never users.

Conclusions: Among a large, prospective cohort, there was no evidence that cannabis use was associated with a higher risk of incident AF. An evaluation of cannabis ingestion methods and quantification was not possible using the current dataset.”

https://pubmed.ncbi.nlm.nih.gov/38142832/

https://www.heartrhythmjournal.com/article/S1547-5271(23)03058-8/fulltext

Impacts of delta 9-tetrahydrocannabinol against myocardial ischemia/reperfusion injury in diabetic rats: Role of PTEN/PI3K/Akt signaling pathway

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“Despite the current optimal therapy, patients with myocardial ischemia/reperfusion (IR) injury still experience a high mortality rate, especially when diabetes mellitus is present as a comorbidity. Investigating potential treatments aimed at improving the outcomes of myocardial IR injury in diabetic patients is necessary. Our objective was to ascertain the cardioprotective effect of delta 9-tetrahydrocannabinol (THC) against myocardial IR injury in diabetic rats and examine the role of phosphatase and tensin homolog (PTEN)/phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) signaling pathway in mediating this effect. Diabetes was induced in male Wistar rats (8-10 weeks old, 200-250 g; n = 60) by a single injection of streptozotocin. The duration of the diabetic period was 10 weeks. During the last 4 weeks of diabetic period, rats were treated with THC (1.5 mg/kg/day; intraperitoneally), either alone or in combination with LY294002, and then underwent IR intervention. After 24 h of reperfusion, infarct size, cardiac function, lactate dehydrogenase (LDH) and cardiac-specific isoform of troponin-I (cTn-I) levels, myocardial apoptosis, oxidative stress markers, and expression of PTEN, PI3K, and Akt proteins were evaluated. THC pretreatment resulted in significant improvements in infarct size and cardiac function and decreases in LDH and cTn-I levels (P < 0.05). It also reduced myocardial apoptosis and oxidative stress, accompanied by the downregulation of PTEN expression and activation of the PI3K/Akt signaling pathway (P < 0.05). LY294002 pretreatment abolished the cardioprotective action of THC. This study revealed the cardioprotective effects of THC against IR-induced myocardial injury in diabetic rats and also suggested that the mechanism may be associated with enhanced activity of the PI3K/Akt signaling pathway through the reduction of PTEN phosphorylation.”

https://pubmed.ncbi.nlm.nih.gov/38149557/

“Delta 9-tetrahydrocannabinol (THC) is the main psychoactive component of cannabis and has been shown to have potential therapeutic effects in various medical conditions. THC has been shown to have anti-inflammatory and antioxidant properties, which may reduce the inflammation and oxidative stress associated with myocardial IR injury.[ Recent studies have suggested that THC improves glucose metabolism and insulin sensitivity and reduces blood glucose concentrations, oxidative stress, and inflammation associated with diabetic cardiomyopathy.”

https://www.cjphysiology.org/article.asp?issn=0304-4920;year=2023;volume=66;issue=6;spage=446;epage=455;aulast=Zhao

Targeting Nrf2 Signaling Pathway in Cancer Prevention and Treatment: The Role of Cannabis Compounds

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“The development and progression of cancer are associated with the dysregulation of multiple pathways involved in cell proliferation and survival, as well as dysfunction in redox balance, immune response, and inflammation. The master antioxidant pathway, known as the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway, regulates the cellular defense against oxidative stress and inflammation, making it a promising cancer prevention and treatment target.

Cannabinoids have demonstrated anti-tumor and anti-inflammatory properties, affecting signaling pathways, including Nrf2.

Increased oxidative stress following exposure to anti-cancer therapy prompts cancer cells to activate antioxidant mechanisms. This indicates the dual effect of Nrf2 in cancer cells-influencing proliferation and apoptotic processes and protecting against the toxicity of anti-cancer therapy. Therefore, understanding the complex role of cannabinoids in modulating Nrf2 might shed light on its potential implementation as an anti-cancer support.

In this review, we aim to highlight the impact of cannabinoids on Nrf2-related factors, with a focus on cancer prevention and treatment. Additionally, we have presented the results of several research studies that combined cannabidiol (CBD) with other compounds targeting Nrf2. Further studies should be directed toward exploring the anti-inflammatory effects of cannabinoids in the context of cancer prevention and therapy.”

https://pubmed.ncbi.nlm.nih.gov/38136172/

https://www.mdpi.com/2076-3921/12/12/2052