Tetrahydrocannabinols: potential cannabimimetic agents for cancer therapy

SpringerLink

“Tetrahydrocannabinols (THCs) antagonize the CB1 and CB2 cannabinoid receptors, whose signaling to the endocannabinoid system is essential for controlling cell survival and proliferation as well as psychoactive effects. Most tumor cells express a much higher level of CB1 and CB2; THCs have been investigated as potential cancer therapeutic due to their cannabimimetic properties. To date, THCs have been prescribed as palliative medicine to cancer patients but not as an anticancer modality.

Growing evidence of preclinical research demonstrates that THCs reduce tumor progression by stimulating apoptosis and autophagy and inhibiting two significant hallmarks of cancer pathogenesis: metastasis and angiogenesis.

However, the degree of their anticancer effects depends on the origin of the tumor site, the expression of cannabinoid receptors on tumor cells, and the dosages and types of THC. This review summarizes the current state of knowledge on the molecular processes that THCs target for their anticancer effects. It also emphasizes the substantial knowledge gaps that should be of concern in future studies. We also discuss the therapeutic effects of THCs and the problems that will need to be addressed in the future. Clarifying unanswered queries is a prerequisite to translating the THCs into an effective anticancer regime.”

https://pubmed.ncbi.nlm.nih.gov/36696005/

https://link.springer.com/article/10.1007/s10555-023-10078-2

Molecular insights into the interaction of eighteen different variants of SARS-CoV-2 spike proteins with sixteen therapeutically important phytocompounds: in silico approach

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“SARS-CoV-2 has mutated many times among different populations. We analyzed wild-type spike protein and 18 different variants of SARS-CoV-2 spike protein known until the beginning of 2022 (alpha, beta, B.1.429, B.1.616, B.1.620, B.1.617.3, C.1.2, delta, epsilon, eta, gamma, iota, kappa, lambda, mu, omicron, theta, and zeta) for their interaction with 16 phytocompounds and remdesivir, resulting into 425 combinations. The largest number of mutations has been reported in the omicron followed by delta variant. However, the virulence of the delta variant has been reported higher as compared to omicron. Mutations at a few locations (D215G, K417N, E484K, N501Y, D614G, and P681H) were common in most of the variants.

3 D structures of all the 18 spike proteins were created using SWISS-MODEL to test the binding affinities with caffeine theophylline, emodin, vitexin, berberine, curcumin, piperine, quercetin, artemisinin, carvacrol, capsaicin, tetrahydrocannabinol, cannabidiol, α- pinene, β- pinene and gingerol.

Phytocompounds and mutant variants were prepared using AutoDock 4.2.6 software. Binding affinities of the selected phytocompounds with the different mutant spike proteins were achieved using AutoDock Vina. Out of all combinations investigated, the best binding affinities were observed with 3 variants of SAR-CoV-2 with 5 phytocompounds along with remdesivir. The range of best binding energies varied from -9.1 to -8.0 kcal/mol. Further, MD simulation was done for selected 9 phytocompound-spike mutant complexes for analyzing the stability of interactions for 100 ns.

ADMET studies via ProTox-II and SwissADME displayed that phytocompounds are safe and less toxic in comparison to remdesivir.”

https://pubmed.ncbi.nlm.nih.gov/36690609/

https://www.tandfonline.com/doi/abs/10.1080/07391102.2023.2169761?journalCode=tbsd20

The impact of phyto- and endo-cannabinoids on central nervous system diseases:A review

Journal of Traditional and Complementary Medicine

“Background and aim: Cannabis sativa L. is a medicinal plant with a long history. Phyto-cannabinoids are a class of compounds from C. sativa L. with varieties of structures. Endocannabinoids exist in the human body. This article provides an overview of natural cannabinoids (phyto-cannabinoids and endocannabinoids) with an emphasis on their pharmacology activities.

Experimental procedure: The keywords “Cannabis sativa L″, “cannabinoids”, and “central nervous system (CNS) diseases” were used for searching and collecting pieces of literature from PubMed, ScienceDirect, Web of Science, and Google Scholar. The data were extracted and analyzed to explore the effects of cannabinoids on CNS diseases.

Result and conclusion: In this paper, schematic diagrams are used to intuitively show the phyto-cannabinoids skeletons’ mutual conversion and pharmacological activities, with special emphasis on their relevant pharmacological activities on central nervous system (CNS) diseases. It was found that the endocannabinoid system and microglia play a crucial role in the treatment of CNS diseases. In the past few years, pharmacological studies focused on Δ9-THC, CBD, and the endocannabinoids system. It is expected to encourage new studies on a more deep exploration of other types of cannabinoids and the mechanism of their pharmacological activities in the future.”

https://pubmed.ncbi.nlm.nih.gov/36685079/

https://www.sciencedirect.com/science/article/pii/S2225411022000761?via%3Dihub

The Effect of Cannabis Plant Extracts on Head and Neck Squamous Cell Carcinoma and the Quest for Cannabis-Based Personalized Therapy

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“Cannabis sativa plants have a wide diversity in their metabolite composition among their different chemovars, facilitating diverse anti-tumoral effects on cancer cells. This research examined the anti-tumoral effects of 24 cannabis extracts representative of three primary types of chemovars on head and neck squamous cell carcinoma (HNSCC). The chemical composition of the extracts was determined using High-Performance Liquid Chromatography (HPLC) and Mass Spectrometry (MS). The most potent anti-tumoral extracts were type III decarboxylated extracts, with high levels of Cannabidiol (CBD). We identified extract 296 (CAN296) as the most potent in inducing HNSCC cell death via proapoptotic and anti-proliferative effects. Using chemical fractionation of CAN296, we identified the CBD fraction as the primary inducer of the anti-tumoral activity. We succeeded in defining the combination of CBD with cannabichromene (CBC) or tetrahydrocannabinol (THC) present in minute concentrations in the extract, yielding a synergic impact that mimics the extract’s full effect. The cytotoxic effect could be maximized by combining CBD with either CBC or THC in a ratio of 2:1. This research suggests using decarboxylated CBD-type extracts enriched with CBC for future preclinical trials aimed at HNSCC treatment.”

https://pubmed.ncbi.nlm.nih.gov/36672446/

“The survival rate of head and neck cancer has only improved slightly over the last quarter century, raising the need for novel therapies to better treat this disease. This research examined the anti-tumor effects of 24 different types of cannabis extracts on head and neck cancer cells. Type III decarboxylated extracts with high levels of Cannabidiol (CBD) were the most effective in killing cancer cells. From these extracts, the specific active molecules were recognized. Combining CBD with Cannabichromene (CBC) in a 2:1 ratio made the effect even stronger. These findings can help doctors match cannabis extracts to treat head and neck cancer. CBD extracts enriched with the non-psychoactive CBC can offer patients more effective treatment. Further research is needed to develop new topical treatments from such extracts.”

“This research suggests using whole cannabis extracts, which are decarboxylated CBD-rich, to induce cancer cell death. In recent years many cancer patients have been treated with cannabis extracts as a palliative treatment. Based on this research, these chemovars can provide additional anti-cancer properties in addition to the palliative effects that cancer patients can benefit from.”

https://www.mdpi.com/2072-6694/15/2/497

Recreational cannabis and opioid distribution

“Twenty-one U.S. states have passed recreational cannabis laws as of November 2022. Cannabis may be a substitute for prescription opioids in the treatment of chronic pain. Previous studies have assessed recreational cannabis laws’ effects on opioid prescriptions financed by specific private or public payers or dispensed to a unique endpoint.

Our study adds to the literature in three important ways: by (1) examining these laws’ impacts on prescription opioid dispensing across all payers and endpoints, (2) adjusting for important opioid-related policies such as opioid prescribing limits, and (3) modeling opioids separately by type. We implement two-way fixed-effects regressions and leverage variation from eleven U.S. states that adopted a recreational cannabis law (RCL) between 2010 and 2019.

We find that RCLs lead to a reduction in codeine dispensed at retail pharmacies. Among prescription opioids, codeine is particularly likely to be used non-medically. Thus, the finding that RCLs appear to reduce codeine dispensing is potentially promising from a public health perspective.”

https://pubmed.ncbi.nlm.nih.gov/36653623/

https://onlinelibrary.wiley.com/doi/10.1002/hec.4652

“When recreational cannabis is legal, codeine demand drops”

https://news.cornell.edu/stories/2023/01/when-recreational-cannabis-legal-codeine-demand-drops

Oral THC: CBD cannabis extract in main symptoms of Alzheimer disease: agitation and weight loss

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“Objectives: Ten million new cases of dementia are recorded annually worldwide, with agitation and idiopathic weight loss being the most common symptoms. Several pharmacological therapies have emerged in recent years, but the clinical use of cannabis extracts in older patients with AD is constantly growing. This retrospective, analytical, observational, spontaneous trial aimed to enhance the clinical action of THC: CBD cannabis extract administration in AD patients with severe symptoms such as agitation, weight loss, cognitive impairment, and sleep disturbance.

Methods: Thirty patients (9 men and 21 women) diagnosed with mild, moderate, or severe AD, aged 65-90 years, appealing to our Second Opinion Medical Consultation (Modena, Italy), were enrolled and required to use oil-diluted cannabis extract, Bedrocan® (22% THC, 0.5% CBD, Olive Oil 50 ml), twice a day for 12 weeks. The efficacy of cannabinoid therapy was evaluated at baseline and 12 weeks after therapy, employing three self-administered questionnaires completed by the parents of the enrolled patients: NPI-Q, CMAI, and MMSE.

Key findings: The NPI-Q demonstrated a reduction (p<0.0001) in agitation, apathy, irritability, sleep disturbances, and eating disturbances, consequently improving caregiver distress. Levels of physically and verbally aggressive behaviours, measured using the CMAI questionnaire, were lower (p<0.0001) in all patients. The MMSSE questionnaire confirmed a significant decrease (p<0.0001) in cognitive impairment in 45% of the patients.

Conclusion: Our anecdotical, spontaneous, and observational study demonstrated the efficacy and safety of oil-diluted cannabis extract in patients with AD. The limitations of our study are: 1) small patient cohort, 2) absence of control group, 3) self-administered questionnaires that are the most practical but not objective instruments to assess the neurologic functions of AD patients.”

https://pubmed.ncbi.nlm.nih.gov/36655645/

Efficacy and Safety of Medical Marijuana in Migraine Headache: A Systematic Review

“Medical marijuana treatment for migraine is becoming more common, although the legality and societal acceptance of marijuana for medical purposes in the United States have been challenged by the stigma attached to it as a recreational drug.

These substances function to reduce nociception and decrease the frequency of migraine by having an impact on the endocannabinoid system.

Our study reviewed the clinical response, dosing, and side effects of marijuana in migraine management. Using Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we conducted a literature search in PubMed, Google Scholar, and Science Direct, and nine studies were included in the systematic review.

The studies demonstrated that medical marijuana has a significant clinical response by reducing the length and frequency of migraines. No severe adverse effects were noted. Due to its effectiveness and convenience, medical marijuana therapy may be helpful for patients suffering from migraines. However, additional clinical trials and observational studies with longer follow-ups are required to study the efficacy and safety of the drug.”

https://pubmed.ncbi.nlm.nih.gov/36660507/

“The main objective of this article is to assess the efficacy and safety of medical marijuana for the treatment of migraine headaches. All the studies showed encouraging findings on the therapeutic effects of medicinal marijuana in migraine treatment. Additionally, medical marijuana is well-tolerated with fewer side effects and is safe to use in migraine patients.”

https://www.cureus.com/articles/118190-efficacy-and-safety-of-medical-marijuana-in-migraine-headache-a-systematic-review

The effects of cannabidiol and Δ9-tetrahydrocannabinol, alone and in combination, in the maximal electroshock seizure model

Epilepsy Research

“In the present study, cannabidiol (CBD), Δ9-tetrahydrocannabinol (THC), and combinations of CBD and THC, were evaluated in the mouse maximal electroshock (MES) seizure test – an animal model of generalized-onset seizures. Male CF-1 mice were injected intraperitoneally (i.p.) with either CBD, THC or a combination of CBD and THC. The MES test was conducted 2 h after the injection of CBD and 1 h after the injection of THC. A wide range of doses was tested to allow the construction of dose-response curves. Toxicity was assessed using a behavioral rating scale.

It was found that: 1) the ED50 for THC alone was 52 mg/kg and its therapeutic index (TI) was 1.7; 2) the ED50 for CBD alone was 190 mg/kg and its TI was 2.4; and 3) the ED50 for a 15:1 combination of CBD+THC was 130 mg/kg + 8.6 mg/kg (CBD + THC). Thus, CBD and THC were both effective in the MES model, and CBD was somewhat more effective in the presence of low (non-therapeutic) doses of THC.

The improvement in CBD’s effect, however, was less dramatic than that seen in past experiments with the amygdala-kindling model (Fallah et al., 2021). Both CBD alone and CBD+THC in combination might be useful in the treatment of generalized-onset seizures. The advantage of adding THC to CBD, however, might be less than in the treatment of focal-onset seizures.”

https://pubmed.ncbi.nlm.nih.gov/36646020/

https://www.sciencedirect.com/science/article/abs/pii/S0920121123000128?via%3Dihub

Cannabis as antivirals

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“Cannabis is a plant notorious for its psychoactive effect, but when used correctly, it provides a plethora of medicinal benefits. With more than 400 active compounds that have therapeutic properties, cannabis has been accepted widely as a medical treatment and for recreational purposes in several countries.

The compounds exhibit various clinical benefits, which include, but are not limited to, anticancer, antimicrobial, and antioxidant properties.

Among the vast range of compounds, multiple research papers have shown that cannabinoids, such as cannabidiol and delta-9-tetrahydrocannabinol, have antiviral effects. Recently, scientists found that both compounds can reduce severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) viral infection by downregulating ACE2 transcript levels and by exerting anti-inflammatory properties. These compounds also act as the SARS-CoV-2 main protease inhibitors that block viral replication.

Apart from cannabinoids, terpenes in cannabis plants have also been widely explored for their antiviral properties. With particular emphasis on four different viruses, SARS-CoV-2, human immunodeficiency virus, hepatitis C virus, and herpes simplex virus-1, this review discussed the role of cannabis compounds in combating viral infections and the potential of both cannabinoids and terpenes as novel antiviral therapeutics.”

https://pubmed.ncbi.nlm.nih.gov/36626776/

Selected Seeds as Sources of Bioactive Compounds with Diverse Biological Activities

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“Seeds contain a variety of phytochemicals that exhibit a wide range of biological activities. Plant-derived compounds are often investigated for their antioxidant, anti-inflammatory, immunomodulatory, hypoglycemic, anti-hypercholesterolemic, anti-hypertensive, anti-platelet, anti-apoptotic, anti-nociceptive, antibacterial, antiviral, anticancer, hepatoprotective, or neuroprotective properties.

In this review, we have described the chemical content and biological activity of seeds from eight selected plant species-blackberry (Rubus fruticosus L.), black raspberry (Rubus coreanus Miq.), grape (Vitis vinifera L.), Moringa oleifera Lam., sea buckthorn (Hippophae rhamnoides L.), Gac (Momordica cochinchinensis Sprenger), hemp (Cannabis sativa L.), and sacha inchi (Plukenetia volubilis L). This review is based on studies identified in electronic databases, including PubMed, ScienceDirect, and SCOPUS.

Numerous preclinical, and some clinical studies have found that extracts, fractions, oil, flour, proteins, polysaccharides, or purified chemical compounds isolated from the seeds of these plants display promising, health-promoting effects, and could be utilized in drug development, or to make nutraceuticals and functional foods. Despite that, many of these properties have been studied only in vitro, and it’s unsure if their effects would be relevant in vivo as well, so there is a need for more animal studies and clinical trials that would help determine if they could be applied in disease prevention or treatment.”

https://pubmed.ncbi.nlm.nih.gov/36615843/

“In conclusion, seeds are a source of many promising compounds that have the potential to be implemented in the prevention or treatment of diseases in the future, but the process of introducing them in conventional medicine must be preceded by a thorough in vivo investigation of their effectiveness and safety.”

https://www.mdpi.com/2072-6643/15/1/187