Cannabis-derived Compounds Research Articles

Evaluation of the Efficacy of a Full-Spectrum Low-THC Cannabis Plant Extract Using In Vitro Models of Inflammation and Excitotoxicity

Evidence has accumulated that Cannabis-derived compounds have the potential to treat neuroinflammatory changes present in neurodevelopmental conditions such as autism spectrum disorder. However, research is needed on the specific brain health benefits of strains of whole Cannabis extract that are ready for commercial production. Here, we explore the anti-inflammatory and neuroprotective effects of NTI-164, a genetically unique high-cannabidiol (CBD), low-Δ9-tetrahydrocannabinol extract, and also CBD alone on BV-2 microglia and SHSY-5Y neurons. Inflammation-induced up-regulation of microglial inflammatory markers was significantly attenuated by NTI-164, but not by CBD. NTI-164 promoted undifferentiated neuron proliferation and differentiated neuron survival under excitotoxic conditions. These effects suggest the potential for NTI-164 as a treatment for neuropathologies.

Investigation of the anti-inflammatory and antioxidant properties of cannabis in cosmeceuticals

Biotechnology, as an interdisciplinary scientific field, is crucial in identifying the valuable active ingredients of plants. Their application extends beyond medical and pharmaceutical formulations to encompass cosmetics, in which these natural substances play a significant role. This article aimed to investigate the potential advantages of integrating cannabis-derived compounds into skincare cosmetic formulations. Their therapeutic efficacy on diverse dermatoses was emphasised. The diverse applications of cannabinoids and terpenes in cosmetic formulations were also examined. Scientific report analysis confirms the beneficial effects of cannabis-derived compounds, including cannabidiol and seed oil, in enhancing skin health and addressing inflammation and dermatological issues. The potential of cannabis-derived compounds in creating novel and effective cosmeceutical products was emphasised.

Effect of cannabidiol and hemp extract on viability and function of hepatocytes derived from human induced pluripotent stem cells

Since the passage of the 2018 Agriculture Improvement Act (2018 Farm Bill), the number of products containing cannabis-derived compounds available to consumers have rapidly increased. Potential effects on liver function as a result from consumption of products containing cannabidiol (CBD), including hemp extracts, have been observed but the mechanisms for the effects are not fully understood. In this study, hepatocytes derived from human induced pluripotent stem cells (iPSCs) were used to evaluate potential hepatic effects of CBD and hemp extract at exposure concentrations ranging from 0.1 to 30 μM. Despite that a significant reduction in cell viability occurred only in the 30 μM group for both CBD and hemp extract, significant changes to cytochrome P450 activity, mitochondrial membrane potential, and lipid accumulation occurred within the concentration range of 0.1–3 μM for both CBD and hemp extract. Albumin and urea production, caspase 3/7 activity, and intracellular glutathione were significantly affected within the concentration range of 3–30 μM by CBD or hemp extract. These findings indicate that CBD and hemp extract can alter hepatic function and metabolism. The current study contributes data to help inform the evaluation of potential hepatotoxic effects of products containing cannabis-derived compounds.

The Elusive Truth of Cannabinoids for Rheumatic Pain.

Medical cannabis (MC) has entered mainstream medicine by a unique route. Regulatory acceptance as a medical product in many jurisdictions has bypassed the traditional evidence-based pathway required for therapies. Easier access to MC, especially related to recreational legalization of cannabis, has led to widespread use by patients for symptom relief of a variety of medical conditions and often without medical oversight. Musculoskeletal pain remains the most common reason for MC use. This review examines real-world issues pertaining to MC and offers some guidance for clinical care of patients with rheumatic diseases being treated with MC. Controlled clinical studies of cannabis products in patients with rheumatic diseases have been small and tested a range of compounds, routes of administration, and clinical populations, limiting our ability to generate conclusions on MC's effectiveness in this population. Observational cohort studies and surveys suggest that use of MC and related products in patients with rheumatic diseases improves pain and associated symptoms but is commonly accompanied by mild to moderate side effects. Conflicting evidence contributes to practitioner and patient uncertainty regarding the use of MC for rheumatic disease-related pain. Despite promising preclinical and observational evidence that MC and cannabis-derived compounds are useful in the management of rheumatic disease-related pain, there remains limited high-quality clinical evidence to substantiate these findings. There are a significant number of clinical trials on this topic currently planned or underway, however, suggesting the next decade may yield more clarity. Nevertheless, given that many people with rheumatic diseases are using cannabis products, healthcare professionals must remain apprised of the evidence pertaining to cannabinoids, communicate such evidence to patients in a meaningful way that is free from personal bias and stigma, and maintain strong collaborative clinical care pertaining to MC.

6.4 - Fda Regulation of Cannabis and Cannabis-Derived Compounds

6.4 - Fda Regulation of Cannabis and Cannabis-Derived Compounds

Drug-Cannabinoid Interactions in Selected Therapeutics for Symptoms Associated with Epilepsy, Autism Spectrum Disorder, Cancer, Multiple Sclerosis, and Pain.

Clinical practice entails a translation of research that assists in the use of scientific data and therapeutic evidence for the benefit of the patient. This review critically summarizes the potential impact of cannabinoids in conjunction with other drugs when associated with treatments for epilepsy, autism spectrum disorder, cancer, multiple sclerosis, and chronic pain. In these associations, potential drug interactions may occur and alter the predicted clinical results. Therefore, the potential for drug interactions must always be assessed to avoid therapeutic failures and/or increased side effects. Some effects may be additive, synergistic, or antagonistic, but changes in absorption, distribution, metabolism, particularly through cytochrome P450 (CYP) isoenzymes (e.g., CYP2C9 and CYP3A4), and excretion may also occur. For example, the combination of cannabis-derived compounds and the antifungal drug ketoconazole, a CYP3A4 inhibitor, increases the plasma concentration of Δ-9-tetrahydrocannabinol (THC) and cannabidiol (CBD). In contrast, rifampicin, a CYP3A4 inducer, stands out for reducing plasma THC levels by approximately 20-40% and 50% to 60% for CBD. Other CYP3A4 inhibitors and inducers are likely to have a similar effect on plasma concentrations if co-administered. Pharmacokinetic interactions with anticonvulsant medications have also been reported, as have pharmacodynamic interactions between cannabinoids and medications with sympathomimetic effects (e.g., tachycardia, hypertension), central nervous system depressants (e.g., drowsiness, ataxia), and anticholinergics (e.g., tachycardia and somnolence). Although further studies are still pending, there is currently clinical evidence supporting drug interactions with cannabinoids, requiring doctors to evaluate the risk of drug combinations with cannabinoids and vice versa. The tables provided here were designed to facilitate the identification of biorelevant interactions that may compromise therapeutic efficacy and toxicity.

The clinical use of cannabinoids for pain

Cannabis has been used for medicinal purposes more than millennia., further research concerning the potential applications of medicinal cannabis has gained considerable momentum in the medical community. Among the several cannabinoids produced by cannabis leaves, the most notable compounds include Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD), which act on the endocannabinoid system and play significant physiological roles, such as pain regulation. This manuscript reviews the current knowledge and provides medical evidence about the analgesic potential of medicinal cannabis for chronic pain management. The following databases were searched: MEDLINE, COCHRANE, SCIELO and LILACS. Only randomized controlled trials published within six years were selected. Nine articles met the inclusion criteria for the present review. All nine RCTs reported a significant difference in the reduction in pain intensity; however, only five of the studies reported a significant reduction in pain. The presence of mild-to-moderate adverse events was greater in the intervention groups than in the control group, but these adverse events were well tolerated. The difference in opioid use and other analgesic drugs between the intervention group and the placebo group was not statistically significant. Cannabis-derived compounds promote beneficial effects when administered into patients with chronic pain.

The Cannabis-Induced Epigenetic Regulation of Genes Associated with Major Depressive Disorder.

The prevalence of depression is increasing worldwide, as is the number of people suffering from treatment-resistant depression; these patients constitute 30% of those treated. Unfortunately, there have not been significant advances in the treatment of this disorder in the past few decades. Exposure to cannabis and cannabis-derived compounds impacts depression symptomatology in different ways, with evidence indicating that cannabidiol has antidepressant effects; there have been mixed results with medical cannabis. Even though the exact molecular mechanisms of the action underlying changes in depression symptomatology upon exposure to cannabis and cannabis-derived compounds are still unknown, there is strong evidence that these agents have a widespread impact on epigenetic regulation. We hypothesized that exposure to cannabis or cannabis-derived compounds changes the DNA methylation levels of genes associated with depression. To test this hypothesis, we first performed a literature search to identify genes that are differentially methylated upon exposure to cannabis and cannabis-derived compounds, as reported in methylome-wide association studies. We next checked whether genes residing in loci associated with depression, as identified in the largest currently available genome-wide association study of depression, were reported to be epigenetically regulated by cannabis or cannabis-related compounds. Multiple genes residing in loci associated with depression were found to be epigenetically regulated by exposure to cannabis or cannabis-derived compounds. This epigenomic regulation of depression-associated genes by cannabis or cannabis-derived compounds was reported across diverse organisms, tissues, and developmental stages and occurred in genes crucial for neuronal development, functioning, survival, and synapse functioning, as well as in genes previously implicated in other mental disorders.

The Antimicrobial Properties of Cannabis and Cannabis-Derived Compounds and Relevance to CB2-Targeted Neurodegenerative Therapeutics.

Cannabinoid receptor 2 (CB2) is of interest as a much-needed target for the treatment or prevention of several neurogenerative diseases. However, CB2 agonists, particularly phytocannabinoids, have been ascribed antimicrobial properties and are associated with the induction of microbiome compositional fluxes. When developing novel CB2 therapeutics, CB2 engagement and antimicrobial functions should both be considered. This review summarizes those cannabinoids and cannabis-informed molecules and preparations (CIMPs) that show promise as microbicidal agents, with a particular focus on the most recent developments. CIMP–microbe interactions and anti-microbial mechanisms are discussed, while the major knowledge gaps and barriers to translation are presented. Further research into CIMPs may proffer novel direct or adjunctive strategies to augment the currently available antimicrobial armory. The clinical promise of CIMPs as antimicrobials, however, remains unrealized. Nevertheless, the microbicidal effects ascribed to several CB2 receptor-agonists should be considered when designing therapeutic approaches for neurocognitive and other disorders, particularly in cases where such regimens are to be long-term. To this end, the potential development of CB2 agonists lacking antimicrobial properties is also discussed.

A Proteomic View of Cellular and Molecular Effects of Cannabis.

Cannabis (Cannabis sativa), popularly known as marijuana, is the most commonly used psychoactive substance and is considered illicit in most countries worldwide. However, a growing body of research has provided evidence of the therapeutic properties of chemical components of cannabis known as cannabinoids against several diseases including Alzheimer’s disease (AD), multiple sclerosis (MS), Parkinson’s disease, schizophrenia and glaucoma; these have prompted changes in medicinal cannabis legislation. The relaxation of legal restrictions and increased socio-cultural acceptance has led to its increase in both medicinal and recreational usage. Several biochemically active components of cannabis have a range of effects on the biological system. There is an urgent need for more research to better understand the molecular and biochemical effects of cannabis at a cellular level, to understand fully its implications as a pharmaceutical drug. Proteomics technology is an efficient tool to rigorously elucidate the mechanistic effects of cannabis on the human body in a cell and tissue-specific manner, drawing conclusions associated with its toxicity as well as therapeutic benefits, safety and efficacy profiles. This review provides a comprehensive overview of both in vitro and in vivo proteomic studies involving the cellular and molecular effects of cannabis and cannabis-derived compounds.

Nanotechnology to deliver cannabinoids in dermatology

<img src=” https://s3.amazonaws.com/production.scholastica/article/24597/large/prnano_662021g_fig_1_060721.jpg?1623108176”> Cannabis-derived compounds and therapies targeting the endocannabinoid system (ECS) are demonstrating benefit for clinical conditions beyond current indications. As our understanding of the ECS in the skin continues to develop, cannabinoids are rapidly showing promise for treating cutaneous pathology. However, unstable pharmacokinetics, bioavailability and skin permeability have been significant constraints on their utility in dermatology. As cannabinoids shift from commercial herbal preparations to prescription drugs, nanosized drug delivery strategies can tackle these physiochemical limitations and allow well-designed clinical trials to establish safety and efficacy. This review summarizes the latest evidence for cannabinoids for skin disease, details the challenges of formulating cannabinoids, and highlights how the success of nanomedicine across therapeutic fields can translate to novel nanocannabinoid therapeutics in dermatology.

Influences of puff protocols and upper airway anatomy on cannabis pharmacokinetics: A CFPD-PK study

Predicting the optimal administration doses of the inhaled Δ9-tetrahydrocannabinol (THC), i.e., one of the major natural compounds in cannabis, is critical for maximizing the therapeutic outcomes and minimizing the toxic side effects. Thus, it is essential to developing an aerosol dosimetry model to simulate the transport, deposition, and translocation of inhaled THC aerosols from the human respiratory system to the systemic region. In this study, a computational fluid-particle dynamics (CFPD) plus pharmacokinetics (PK) model was developed and validated to quantify the localized vapor and particle uptake rates of THC and the resultant THC-plasma concentrations using two human upper airway geometries. In addition, two different puff protocols (4.0/10.0 s and 1.6/11.4 s as the inhalation/holding time ratios) were employed, associated with two different inhaled THC doses (2.0 mg and 8.82 mg, respectively). The computational results demonstrated that multiple parameters had noticeable influences on THC particle deposition and vapor absorption in the upper airways, as well as the resultant pharmacokinetic behaviors. These factors include anatomical features of the upper airway, puff flow rate, duration, and holding time. The results indicated that puff protocol with 4.0/10.0 s inhalation/holding time ratio would be recommended if the treatment needs THC delivery to the deeper lung. Furthermore, the inhaled THC dose had a dominant effect on the THC-plasma PK profiles, which could override the influences of anatomical variability and puff protocols. The developed CFPD-PK modeling framework has the potential to provide localized lung absorption data and PK profiles for in vitro-in vivo correlation, as well as supporting the development and assessment of drug products containing cannabis or cannabis-derived compounds.

Cannabinoids in Audiogenic Seizures: From Neuronal Networks to Future Perspectives for Epilepsy Treatment.

Cannabinoids and Cannabis-derived compounds have been receiving especial attention in the epilepsy research scenario. Pharmacological modulation of endocannabinoid system's components, like cannabinoid type 1 receptors (CB1R) and their bindings, are associated with seizures in preclinical models. CB1R expression and functionality were altered in humans and preclinical models of seizures. Additionally, Cannabis-derived compounds, like cannabidiol (CBD), present anticonvulsant activity in humans and in a great variety of animal models. Audiogenic seizures (AS) are induced in genetically susceptible animals by high-intensity sound stimulation. Audiogenic strains, like the Genetically Epilepsy Prone Rats, Wistar Audiogenic Rats, and Krushinsky-Molodkina, are useful tools to study epilepsy. In audiogenic susceptible animals, acute acoustic stimulation induces brainstem-dependent wild running and tonic-clonic seizures. However, during the chronic protocol of AS, the audiogenic kindling (AuK), limbic and cortical structures are recruited, and the initially brainstem-dependent seizures give rise to limbic seizures. The present study reviewed the effects of pharmacological modulation of the endocannabinoid system in audiogenic seizure susceptibility and expression. The effects of Cannabis-derived compounds in audiogenic seizures were also reviewed, with especial attention to CBD. CB1R activation, as well Cannabis-derived compounds, induced anticonvulsant effects against audiogenic seizures, but the effects of cannabinoids modulation and Cannabis-derived compounds still need to be verified in chronic audiogenic seizures. The effects of cannabinoids and Cannabis-derived compounds should be further investigated not only in audiogenic seizures, but also in epilepsy related comorbidities present in audiogenic strains, like anxiety, and depression.

Selective recovery of terpenes, polyphenols and cannabinoids from Cannabis sativa L. inflorescences under microwaves

In recent years, hemps health and nutritional properties recognition has led to an impressive growth of Cannabis research, industrial processing, and the related market. Moreover, the demand for natural Cannabis-derived compounds (i.e. terpenes, polyphenols, and cannabinoids) is constantly growing. In spite of the strict regulation of some countries, the global market needs suitable technologies for the smart recovery of bioactive Cannabis metabolites. Conventional extraction procedures can show drawbacks, in terms of environmental impact and their high energy consumption. Microwaves (MW), a mature technique for extraction-process intensification, is attracting great amounts of attention in academic-research and industrial-application fields for its technological advantages. This work aims to design a fast and cost-efficient MW-assisted cascade protocol for bioactive Cannabis compounds recovery in a pilot-scale reactor. Microwave-assisted hydrodistillation (MAHD) can provide a volatile hydrodistillate that is rich in monoterpenes, sesquiterpenes, and a small amount of phytocannabinoids. Using non-canonical protocol of hydrodistillation, the definition of “volatile fraction” is generally considered more appropriate than “essential oil”.The health-promoting activity of this combination has been proposed in literature, and can constitute matter of further investigations. The optimized MAHD procedure yielded 0.35 ± 0.02 % w/w of hydrodistillate, while conventional hydrodistillation gave only 0.12 ± 0.01 %, w/w (in relation to dry inflorescence mass). The water resulting in the vessel after MAHD showed a high total polyphenolic content (5.35 ± 0.23 %, w/w). Two flavones known for their beneficial effects to health, namely luteolin-7-O-glucoside and apigenin-7-O-glucoside, were detected and quantified. An attempt to recover phytocannabinoid using the MW-assisted hydrodiffusion and gravity method (MAHG) was also carried out. Cannabinoids (CBD and THC) content was determined in fresh Cannabis and in production streams. During MAHD, phytocannabinoid decarboxylation inside the residual matrix was around 70 % (69.01 ± 0.98 % and 74.32 ± 1.02 % for THC and CBD respectively). Furthermore, the overall content of these metabolites was not affected by the hydrodistillation, preserving the processed plant material for subsequent ethanolic extraction.

Cannabis-Derived Compounds Cannabichromene and Δ9-Tetrahydrocannabinol Interact and Exhibit Cytotoxic Activity against Urothelial Cell Carcinoma Correlated with Inhibition of Cell Migration and Cytoskeleton Organization.

Cannabis sativa contains more than 500 constituents, yet the anticancer properties of the vast majority of cannabis compounds remains unknown. We aimed to identify cannabis compounds and their combinations presenting cytotoxicity against bladder urothelial carcinoma (UC), the most common urinary system cancer. An XTT assay was used to determine cytotoxic activity of C. sativa extracts on T24 and HBT-9 cell lines. Extract chemical content was identified by high-performance liquid chromatography (HPLC). Fluorescence-activated cell sorting (FACS) was used to determine apoptosis and cell cycle, using stained F-actin and nuclei. Scratch and transwell assays were used to determine cell migration and invasion, respectively. Gene expression was determined by quantitative Polymerase chain reaction (PCR). The most active decarboxylated extract fraction (F7) of high-cannabidiol (CBD) C. sativa was found to contain cannabichromene (CBC) and Δ9-tetrahydrocannabinol (THC). Synergistic interaction was demonstrated between CBC + THC whereas cannabinoid receptor (CB) type 1 and type 2 inverse agonists reduced cytotoxic activity. Treatments with CBC + THC or CBD led to cell cycle arrest and cell apoptosis. CBC + THC or CBD treatments inhibited cell migration and affected F-actin integrity. Identification of active plant ingredients (API) from cannabis that induce apoptosis and affect cell migration in UC cell lines forms a basis for pre-clinical trials for UC treatment.

In Silico and In Vitro Analysis of Major Cannabis-Derived Compounds as Fatty Acid Amide Hydrolase Inhibitors

In Silico and In Vitro Analysis of Major Cannabis-Derived Compounds as Fatty Acid Amide Hydrolase Inhibitors

In Silico and In Vitro Analysis of Major Cannabis-Derived Compounds as Fatty Acid Amide Hydrolase Inhibitors.

Accumulated evidence suggests that enhancing the endocannabinoid (eCB) tone, in particular of anandamide (N-arachidonoylethanolamine, AEA), has therapeutic potential in many human diseases. Fatty acid amide hydrolase (FAAH) is a membrane-bound enzyme principally responsible for the degradation of AEA, and thus it represents a relevant target to increase signaling thereof. In recent years, different synthetic and natural compounds have been developed and tested on rat FAAH, but little is known of their effect on the human enzyme. Here, we sought to investigate six major cannabis-derived compounds to compare their action on rat and human FAAHs. To this aim, we combined an in silico analysis of their binding mode and affinity, with in vitro assays of their effect on enzyme activity. This integrated approach allowed to disclose differences in efficacy towards rat and human FAAHs, and to highlight the role of key residues involved in the inhibition of both enzymes. This study suggests that the therapeutic efficacy of compounds targeted towards FAAH should be always tested in vitro on both rat and human enzymes.

Development of cannabidiol as a treatment for severe childhood epilepsies.

In recent years, there has been a growing appreciation by regulatory authorities that cannabis-based medicines can play a useful role in disease therapy. Although often conflagrated by proponents of recreational use, the legislative rescheduling of cannabis-derived compounds, such as cannabidiol (CBD), has been associated with the steady increase in the pursuit of use of medicinal cannabis. One key driver in this interest has been the scientific demonstration of efficacy and safety of CBD in randomised, placebo-controlled clinical trials in children and young adults with difficult-to-treat epilepsies, which has encouraged increasing numbers of human trials of CBD for other indications and in other populations. The introduction of CBD as the medicine Epidiolex in the United States (in 2018) and as Epidyolex in the European Union (in 2019) as the first cannabis-derived therapeutic for the treatment of seizures was underpinned by preclinical research performed at the University of Reading. This work was awarded the British Pharmacological Society Sir James Black Award for Contributions to Drug Discovery 2019 and is discussed in the following review article.

Cannabis-derived compounds: What you need to know

Cannabis-derived compounds: What you need to know

Cannabis constituents reduce seizure behavior in chemically-induced and scn1a-mutant zebrafish

Current antiepileptic drugs (AEDs) are undesirable for many reasons including the inability to reduce seizures in certain types of epilepsy, such as Dravet syndrome (DS) where in one-third of patients does not respond to current AEDs, and severe adverse effects that are frequently experienced by patients. Epidiolex, a cannabidiol (CBD)-based drug, was recently approved for treatment of DS. While Epidiolex shows great promise in reducing seizures in patients with DS, it is used in conjunction with other AEDs and can cause liver toxicity. To investigate whether other cannabis-derived compounds could also reduce seizures, the antiepileptic effects of CBD, Δ9-tetrahydrocannabinol (THC), cannabidivarin (CBDV), cannabinol (CBN), and linalool (LN) were compared in both a chemically-induced (pentylenetetrazole, PTZ) and a DS (scn1Lab−/−) seizure models. Zebrafish (Danio rerio) that were either wild-type (Tupfel longfin) or scn1Lab−/− (DS) were exposed to CBD, THC, CBDV, CBN, or LN for 24 h from 5 to 6 days postfertilization. Following exposure, total distance traveled was measured in a ViewPoint Zebrabox to determine if these compounds reduced seizure-like activity. Cannabidiol (0.6 and 1 μM) and THC (1 and 4 μM) significantly reduced PTZ-induced total distance moved. At the highest THC concentration, the significant reduction in PTZ-induced behavior was likely the result of sedation as opposed to antiseizure activity. In the DS model, CBD (0.6 μM), THC (1 μM), CBN (0.6 and 1 μM), and LN (4 μM) significantly reduced total distance traveled. Cannabinol was the most effective at reducing total distance relative to controls. In addition to CBD, other cannabis-derived compounds showed promise in reducing seizure-like activity in zebrafish. Specifically, four of the five compounds were effective in the DS model, whereas in the PTZ model, only CBD and THC were, suggesting a divergence in the mode of action among the cannabis constituents.