Using In Silico Molecular Docking to Explain Differences in Receptor Binding Behavior of HHC and THCV Isomers: Revealing New Binding Modes.

Even slight structural differences between phytocannabinoid isomers are usually enough to cause a change in their biological properties. In this study, we used in vitro CB1 agonism/antagonism assays to compare the receptor binding functionality of THCV (tetrahydrocannabivarin) and HHC (hexahydrocannabinol) isomers and applied molecular docking to provide an explanation for the difference in the activities. No CB1 agonism was observed for ∆9- and ∆8-THCV. Instead, both isomers antagonized CP 55940, with ∆9-THCV being approximately two times more potent than the ∆8 counterpart (IC50 = 52.4 nM and 119.6 nM for ∆9- and ∆8-THCV, respectively). Docking simulations found two binding poses for THCV isomers, one very similar to ∆9-THC and one newly discovered pose involving the occupation of side pocket 1 of the CB1 receptor by the alkyl chain of the ligand. We suggested the latter as a potential antagonist pose. In addition, our results established 9R-HHC and 9S-HHC among partial agonists of the CB1 receptor. The 9R-HHC (EC50 = 53.4 nM) isomer was a significantly more potent agonist than 9S (EC50 = 624.3 nM). ∆9-THC and 9R-HHC showed comparable binding poses inside the receptor pocket, whereas 9S-HHC adopted a new and different binding posture that can explain its weak agonist activity.

Non-Psychoactive Phytocannabinoids Inhibit Inflammation-Related Changes of Human Coronary Artery Smooth Muscle and Endothelial Cells.

Atherosclerosis is associated with vascular smooth muscle cell proliferation, chronic vascular inflammation, and leukocyte adhesion. In view of the cardioprotective effects of cannabinoids described in recent years, the present study investigated the impact of the non-psychoactive phytocannabinoids cannabidiol (CBD) and tetrahydrocannabivarin (THCV) on proliferation and migration of human coronary artery smooth muscle cells (HCASMC) and on inflammatory markers in human coronary artery endothelial cells (HCAEC). In HCASMC, CBD and THCV at nontoxic concentrations exhibited inhibitory effects on platelet-derived growth factor-triggered proliferation (CBD) and migration (CBD, THCV). When interleukin (IL)-1ß- and lipopolysaccharide (LPS)-stimulated HCAEC were examined, both cannabinoids showed a concentration-dependent decrease in the expression of vascular cell adhesion molecule-1 (VCAM-1), which was mediated independently of classical cannabinoid receptors and was not accompanied by a comparable inhibition of intercellular adhesion molecule-1. Further inhibitor experiments demonstrated that reactive oxygen species, p38 mitogen-activated protein kinase activation, histone deacetylase, and nuclear factor κB (NF-κB) underlie IL-1ß- and LPS-induced expression of VCAM-1. In this context, CBD and THCV were shown to inhibit phosphorylation of NF-κB regulators in LPS- but not IL-1ß-stimulated HCAEC. Stimulation of HCAEC with IL-1ß and LPS was associated with increased adhesion of monocytes, which, however, could not be significantly abolished by CBD and THCV. In summary, the results highlight the potential of the non-psychoactive cannabinoids CBD and THCV to regulate inflammation-related changes in HCASMC and HCAEC. Considering their effect on both cell types studied, further preclinical studies could address the use of CBD and THCV in drug-eluting stents for coronary interventions.

Pharmacokinetics of Oral Minor Cannabinoids in Blood and Brain.

Introduction: Minor cannabinoids are increasingly being consumed in oral formulations (i.e., edibles, tinctures) for medical and nonmedical purposes. This study examined the pharmacokinetics (PKs) of cannabinoids tetrahydrocannabivarin (THCV), cannabichromene (CBC), cannabinol (CBN), and delta-8-tetrahydrocannabinol (D8-THC) after the first and last oral dose during a 14-day administration period. Materials and Methods: Sprague-Dawley rats (N=6 animals/dose, 50% female) were given an assigned dose of one of four cannabinoids (THCV=3.2-100 mg/kg, CBC=3.2-100 mg/kg, CBN=1-100 mg/kg, or D8-THC=0.32-10 mg/kg) or vehicle (medium-chain triglyceride oil) through oral gavage once daily for 14 days. Blood was collected 45 min and 1.5, 3, and 24 h following the first dose (day 1) and the last dose (day 14) of repeated oral cannabinoid treatment for PK analysis. Outcomes of interest included time to maximum concentration (Tmax), maximum concentration (Cmax), and area under the concentration versus time curve (AUClast). Dose-normalized (DN) Cmax and DN AUClast were also calculated. Brain tissue was collected 24 h post-administration of the first (day 1) and the last (day 14) dose of each cannabinoid to determine concentrations in brain. Results: All cannabinoids tested were detectable in plasma after single and 14-day repeated dosing. DN Cmax and DN AUClast were highest for D8-THC, followed by CBC, CBN, and THCV. There was no sex difference observed in cannabinoid kinetics. Accumulation of D8-THC in plasma was observed after 14 days of administration. THCV levels in plasma were lower on day 14 compared to day 1, indicating potential adaptation of metabolic pathways and increased drug elimination. Cannabinoids were detected in brain tissue 24 h post-administration of the first and the last dose of 17-100 mg/kg THCV, 3.2-100 mg/kg CBC, 10-100 mg/kg CBN, and 10 mg/kg D8-THC. Conclusions: THCV, CBC, CBN, and D8-THC produced detectable levels in plasma and translocated to brain tissue after the first dose (day 1) and the last dose (day 14) of repeated oral dosing. Examination of PKs of these minor cannabinoids in blood and brain provides a critical step for informing target dose ranges and dosing schedules in future studies that evaluate the potential effects of these compounds.

A Two-Phase, Dose-Ranging, Placebo-Controlled Study of the Safety and Preliminary Test of Acute Effects of Oral Δ8-Tetrahydrocannabivarin in Healthy Participants.

Introduction: Tetrahydrocannabivarin (THCV) is an understudied cannabinoid that appears to have effects that vary as a function of dose. No human study has evaluated the safety and nature of effects in a wide range of THCV doses. Methods: This was a two-phase, dose-ranging, placebo-controlled trial of the Δ8 isomer of oral THCV in healthy adults. Phase 1 utilized an unblinded, single-ascending dose design (n=3). Phase 2 used a double-blind, randomized, within-participant crossover design (n=18). Participants received single acute doses of placebo and 12.5, 25, 50, 100, and 200 mg of THCV. Safety measures and subjective and cognitive effects were assessed predose and up to 8 h postdose. Results: Most adverse events (AEs; 55/60) were mild. Euphoric mood was the most common AE. The 12.5, 25, and 200 mg doses produced significantly lower minimum times to complete the digit vigilance test (ps=0.01). The 25 mg dose showed elevations on mean ratings of "energetic" at 1-, 2-, and 4-h postdose, but the maximum postdose rating for this dose did not achieve statistical significance relative to placebo ([95% confidence interval]=3.2 [-0.5 to 6.9], p=0.116). The 100 and 200 mg doses showed elevations on ratings of "feel a drug effect" and "like the drug effect." Almost all urine drug screens (78/79) at 8 h postdose in the active THCV conditions tested positive for tetrahydrocannabinol (THC). Conclusion: All THCV doses displayed a favorable safety profile. Several THCV doses showed a preliminary signal for improved sustained attention, but the effect was not dose dependent. Though mild and not associated with impairment, THC-like effects were observed at higher THCV doses. Oral THCV-containing products could lead to positive urine drug screens for THC. ClinicalTrials.gov ID: NCT05210634.

Hair Regrowth with Novel Hemp Extract: A Case Series.

Introduction: The endocannabinoid system (ECS), discovered in the 1990s, is a system involved with maintaining cellular homeostasis by down-regulating the damaging inflammatory responses and upregulating regenerative processes. Cannabidiol (CBD), tetrahydrocannabivarin (THCV), and cannabidivarin (CBDV) are all phytocannabinoids found in varying quantities in hemp extract. These three cannabinoids have novel therapeutic effects on hair regrowth through the ECS. The method of action is different from and synergistic with current hair regrowth therapies. The three cannabinoids are fat-soluble and poorly absorbed past the epidermis, but topical application easily reaches hair follicles where they act as partial or full CB1 antagonist and agonist of transient receptor potential vanilloid-1 (TRPV1) and vanilloid receptor-4 (TRPV4). All these ECS receptors relate to hair follicle function. Blocking the CB1 receptor on the hair follicle has been shown to result in hair shaft elongation; in addition, the hair follicle cycle (anagen, catagen, and telogen phases) is controlled by TRPV1. The effects of CBD on hair growth are dose dependent and higher doses may result in premature entry into the catagen phase through a different receptor known as TRPV4. CBD has also been shown to increase Wnt signaling, which causes dermal progenitor cells to differentiate into new hair follicles and maintains anagen phase of the hair cycle. Objective: This study was conducted on subjects with androgenetic alopecia (AGA), as follow-up to a prior published study using hemp extract high in CBD without CBDV or THCV. That study showed an average 93.5% increase in hair numbers after 6 months of use. This subsequent study is being done to determine if daily topical application of a hemp-oil high in CBD, THCV, and CBDV concentrations would result in improved hair regrowth in the area of the scalp most affected by AGA. Materials and Methods: A case series study was done of 31 (15 men and 16 women, 27 Caucasian, 2 Asian, and 1 mixed race) subjects with AGA. They used a once-daily topical hemp extract formulation, averaging about 33 mg/day for 6 months. A hair count of the greatest area of alopecia was carried out before treatment was started and again after 6 months of treatment. To facilitate consistent hair count analysis, a permanent tattoo was placed at the point for maximum hair loss on the scalp. The subjects were also asked to qualitatively rate their psychosocial perception of "scalp coverage" improvement after the study was completed. The qualitative scale included "very unhappy," "unhappy," "neutral," "happy," and "very happy." The subjects were photographed in a standard manner before and after the study. The photographs were compared for improvements in "scalp coverage" by an independent physician. The qualitative scale included "none," "mild," "moderate," and "extensive" improvement of scalp coverage. Results: The results revealed that all subjects had some regrowth. This ranged from 31.25% (from 16 to 21 hairs) to 2000% (from 1 to 21 hairs). The average increase was statistically significant 246% (15.07 hairs/cm2 increase) in men and 127% (16.06 hairs/cm2) in women. There were no reported adverse effects. All subjects rated their psychosocial perception of the effects of the hair loss, as "happy" or "very happy." Independent review of the photographs revealed evidence of "mild" to "extensive" scalp coverage improvements for all of the subjects. Conclusion: Although the exact mechanism of therapeutic effects is not known, THCV and CBDV are most likely functioning as full CB1 receptor neutral antagonists and CBD is most likely functioning as a partial CB1 receptor antagonist and potentially through Wnt messaging. All three cannabinoids were functioning as TRPV1 agonists. The addition of menthol through the peppermint extract is probably acting through promoting a rapid onset of anagen phase. This topical hemp formulation was superior to oral finasteride, 5% minoxidil once daily foam and CBD topical extract alone. Since this hemp extract works through novel mechanisms entirely different from both finasteride and minoxidil, it can be used in conjunction with these current drugs and would be expected to have synergistic effects. However, safety and efficacy of this combination would be to be evaluated.

Chemical profiling of Cannabis sativa from eleven Tanzanian regions.

The aim of this research was to investigate the chemical profiles of Cannabis sativa from 11 Tanzanian regions using preliminary tests as well as instrumental analyses with GC-MS and LC-MS. Generally, all the seized samples tested positive for the presence of (Δ9-THC. The preliminary test with Duquenois method followed by chloroform addition revealed the presence of Δ9-tetrahydrocannabinol (Δ9-THC) in all the samples. GC-MS analyses of the samples revealed the presence of nine cannabinoids including Δ9-THC, Δ8-THC, cannabidivarol, cannabidiol, Δ9-tetrahydrocannabivarin (Δ9-THCV), cannabichromene, cannabinol, caryophyllene, and cannabicouramaronone, whereas LC-MS chemical profiling revealed the presence 24 chemical substances, including 4 cannabinoids, 15 different types of drugs and 5 amino acids. The Pwani region had the highest percentage composition of Δ9-THC (13.45%), the main psychoactive ingredient of Cannabis sativa, followed by Arusha (10.92%) and Singida (10.08%). The sample from Kilimanjaro had the lowest percentage of Δ9-THC (6.72%). Apart from cannabinoids, the majority of other chemical substances were found in the Dar es Salaam region sample, which could be attributed to the fact that the city is the epicenter of business rather than the cultivation area, implying that the samples were obtained from different sources and blended as a single package.

Tetrahydrocannabivarin (THCV) Protects Adipose-Derived Mesenchymal Stem Cells (ASC) against Endoplasmic Reticulum Stress Development and Reduces Inflammation during Adipogenesis.

The endoplasmic reticulum (ER) fulfills essential duties in cell physiology, and impairment of this organelle's functions is associated with a wide number of metabolic diseases. When ER stress is generated in the adipose tissue, it is observed that the metabolism and energy homeostasis of the adipocytes are altered, leading to obesity-associated metabolic disorders such as type 2 diabetes (T2D). In the present work, we aimed to evaluate the protective effects of Δ9-tetrahydrocannabivarin (THCV, a cannabinoid compound isolated from Cannabis sativa L.) against ER stress in adipose-derived mesenchymal stem cells. Our results show that pre-treatment with THCV prevents the subcellular alteration of cell components such as nuclei, F-actin, or mitochondria distribution, and restores cell migration, cell proliferation and colony-forming capacity upon ER stress. In addition, THCV partially reverts the effects that ER stress induces regarding the activation of apoptosis and the altered anti- and pro-inflammatory cytokine profile. This indicates the protective characteristics of this cannabinoid compound in the adipose tissue. Most importantly, our data demonstrate that THCV decreases the expression of genes involved in the unfolded protein response (UPR) pathway, which were upregulated upon induction of ER stress. Altogether, our study shows that the cannabinoid THCV is a promising compound that counters the harmful effects triggered by ER stress in the adipose tissue. This work paves the way for the development of new therapeutic means based on THCV and its regenerative properties to create a favorable environment for the development of healthy mature adipocyte tissue and to reduce the incidence and clinical outcome of metabolic diseases such as diabetes.

Comparative metabolism of THCA and THCV using UHPLC-Q-Exactive Orbitrap-MS.

Delta(9)-tetrahydrocannabinolic acid (THCA) and delta(9)-tetrahydrocannabivarin (THCV) are phytocannabinoids with a similar structure derived from Cannabis sativa and possess a variety of biological activities. However, the relationship between the metabolic characterisation and bioactivity of THCA and THCV remains elusive.To explore the relationship between the metabolism of THCA and THCV and their underlying mechanism of activity, human/mouse liver microsomes and mouse primary hepatocytes were used to compare the metabolic maps between THCA and THCV through comparative metabolomics. A total of 29 metabolites were identified containing 7 previously undescribed THCA metabolites and 10 previously undescribed THCV metabolites. Of these metabolites, THCA was transformed into an active metabolite of delta(9)-tetrahydrocannabinol (THC) in these three systems, while THCV was transformed into THC and CBD.Bioactivity assays indicated that all of these phytocannabinoids exhibited anti-inflammatory activity, but the effects of THCA and THCV were slightly different in macrophages RAW264.7. Prediction of ADMET lab demonstrated that THCV and its metabolites were endowed with the advantage of blood-brain barrier (BBB) penetration compared to THCA.In conclusion, this study highlighted that metabolism plays a critical role in the biological activity of phytocannabinoids.

The role of Cannabidiol and tetrahydrocannabivarin to overcome doxorubicin resistance in MDA-MB-231 xenografts in athymic nude mice.

The significant resistance to currently available chemotherapeutics makes treatment for TNBC a key clinical concern. Herein, we studied the anti-cancer potentials of synthetic cannabidiol (CBD) and Tetrahydrocannabivarin (THCV) when used alone or in combination with doxorubicin (DOX) against MDA-MB-231 resistant cells. Pre-treatment with CBD and THCV significantly increased the cytotoxicity of DOX in MDA-MB-231 2D and 3D cultures that were DOX-resistant. Transcriptomics and Proteomics studies revealed that CBD and THCV, by downregulating PD-L1, TGF-ß, sp1, NLRP3, P38-MAPK, and upregulating AMPK induced apoptosis leading to improved DOX's chemosensitivity against DOX resistant MDA-MB-231 tumors in BALB/c nude mice. CBD/THCV in combination with DOX significantly inhibited H3k4 methylation and H2K5 acetylation as demonstrated by western blotting and RT-PCR. Based on these findings, CBD and THCV appear to counteract histone modifications and their subsequent effects on DOX, resulting in chemo-sensitization against MDA-MB-231 resistant cancers.

A Systematic Review of Medical Cannabinoids Dosing in Human.

PURPOSE: This systematic review assesses currently available clinical information on which cannabinoids and what range of doses have been used to achieve positive effects in a diversity of medical context. METHODS: The data were collected according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses protocol guidelines. Inclusion criteria were articles that assessed administration of any cannabinoid to any clinical population, reported in the ClinicalTrials.gov or PubMed databases, that involved a comparison with other treatment or placebo and a result measurement to assess the effectiveness or ineffectiveness of the cannabinoid. Exclusion criteria were review or letter; articles not in the English language; not full-text articles; not a clinical trial, case report, case series, open-label trial, or pilot study; administration in animals, in vitro, or in healthy participants; cannabinoids administered in combination with other cannabinoids (except for cannabidiol [CBD] or tetrahydrocannabinol [THC]) or as whole cannabis extracts; no stated concentration; inhalation or smoke as a route of administration; and no results described. The articles were assessed by the risk of bias. FINDING: In total, 1668 articles were recovered, of which 55 studies met the inclusion criteria for 21 diseases. Positive effects were reported in clinical studies: 52% with THC (range, 0.01-0.5 mg/kg/d [0.62-31 mg/d]), 74% with CBD (range, 1-50 mg/kg/d [62-3100 mg/d]), 64% with THC-CBD (mean, 1:1.3 mg/kg/d [ratio, 1:1]), and 100% with tetrahydrocannabivarin (THCV) (0.2 mg/kg/d). IMPLICATIONS: THC, CBD, and THCV can regulate activity in several pathologies. New studies of cannabinoids are highly encouraged because each patient is unique and requires a unique cannabinoid medication.

Enhancement of transdermal permeation of cannabinoids and their pharmacodynamic evaluation in rats.

The objective of the present study was to enhance the transdermal permeation of cannabinoids: cannabidiol (CBD), cannabigerol (CBG) and tetrahydrocannabivarin (THCV) using chemical permeation enhancer approach and evaluate them for their anti-inflammatory effect in vivo in a paw edema model in rats. Cannabinoids gel formulations were developed using FDA approved inactive ingredients: lactic acid (LA), polyethylene glycol-400 (PEG-400), N-methyl-2 pyrrolidone (NMP), dimethyl sulfoxide (DMSO). In vitro skin permeation testing (IVPT) showed flux of âˆ¼ 13.25 µg/cm2/h for CBD, ∼9.38 µg/cm2/h for CBG and âˆ¼ 51.74 µg/cm2/h for THCV. Additionally, IVPT study showed cumulative drug permeation of 610.96 ± 88.92 µg/cm2, 432.09 ± 35.59 µg/cm2 and 2384.44 ± 42.22 µg/cm2 from CBD, CBG and THCV gel formulations respectively. Further, effect of excipients on cannabinoid permeation showed that, formulation containing lactic acid, NMP and DMSO showed significantly (p < 0.0001) enhanced flux of cannabinoids as compared to formulation without LA, NMP and DMSO. In vivo studies showed that paw edema was significantly (p < 0.0001) reduced in the groups containing CBD, CBG, THCV as compared to control and placebo formulation. In conclusion, flux of CBD, CBG and THCV was significantly enhanced using chemical permeation enhancers approach which helped in reducing rat paw edema.

Motor-like Tics are Mediated by CB2 Cannabinoid Receptor-dependent and Independent Mechanisms Associated with Age and Sex.

Δ9-Tetrahydrocannabinol (Δ9-THC) inhibits tics in individuals with Tourette syndrome (TS). Δ9-THC has similar affinities for CB1/CB2 cannabinoid receptors. However, the effect of HU-308, a selective CB2 receptor agonist, on repetitive behaviors has not been investigated. The effects of 2,5-dimethoxy-4-iodoamphetamine (DOI)-induced motor-like tics and Δ9-THC were studied with gene analysis. The effects of HU-308 on head twitch response (HTR), ear scratch response (ESR), and grooming behavior were compared between wildtype and CB2 receptor knockout (CB2-/-) mice, and in the presence/absence of DOI or SR141716A, a CB1 receptor antagonist/inverse agonist. The frequency of DOI-induced repetitive behaviors was higher in CB2-/- than in wildtype mice. HU-308 increased DOI-induced ESR and grooming behavior in adult CB2-/- mice. In juveniles, HU-308 inhibited HTR and ESR in the presence of DOI and SR141716A. HU-308 and beta-caryophyllene significantly increased HTR. In the left prefrontal cortex, DOI increased transcript expression of the CB2 receptor and GPR55, but reduced fatty acid amide hydrolase (FAAH) and α/ß-hydrolase domain-containing 6 (ABHD6) expression levels. CB2 receptors are required to reduce 5-HT2A/2C-induced tics in adults. HU-308 has an off-target effect which increases 5-HT2A/2C-induced motor-like tics in adult female mice. The increased HTR in juveniles induced by selective CB2 receptor agonists suggests that stimulation of the CB2 receptor may generate motor tics in children. Sex differences suggest that the CB2 receptor may contribute to the prevalence of TS in boys. The 5-HT2A/2C-induced reduction in endocannabinoid catabolic enzyme expression level may explain the increased endocannabinoids' levels in patients with TS.

Role of Cannabidiol and Tetrahydrocannabivarin on Paclitaxel-induced neuropathic pain in rodents.

The purpose of this study was to evaluate if phytocannabinoids, synthetic cannabidiol (CBD), and tetrahydrocannabivarin (THCV), and their combination, could protect mice from Paclitaxel-induced peripheral neuropathy (PIPN). Six groups of C57BL/6J mice (n = 6) were used in this study. The mice were given paclitaxel (PTX) (8 mg/kg/day, i.p.) on days 1, 3, 5, and 7 to induce neuropathy. Mice were evaluated for behavioral parameters, and dorsal root ganglions (DRG) were collected from the animals and subjected to RNA sequencing and westernblot analysis at the end of the study. On cultured DRGs derived from adult male rats, immunocytochemistry and mitochondrial functional assays were also performed. When compared to individual treatments, the combination of CBD and THCV improved thermal and mechanical neurobehavioral symptoms in mice by twofold. Targets for CBD and THCV therapy were identified by KEGG (RNA sequencing). PTX reduced the expression of p-AMPK, SIRT1, NRF2, HO1, SOD2, and catalase while increasing the expression of PI3K, p-AKT, p-P38 MAP kinase, BAX, TGF-ß, NLRP3 inflammasome, and caspase 3 in DRG homogenates of mice. Combination therapy outperformed monotherapy in reversing these protein expressions. The addition of CBD and THCV to DRG primary cultures reduced mitochondrial superoxides while increasing mitochondrial membrane potentials. WAY100135 and rimonabant altered the neuroprotective effects of CBD and THCV respectively by blocking 5-HT1A and CB1 receptors in mice and DRG primary cultures. The entourage effect of CBD and THCV against PIPN appears to protect neurons in mice via 5HT1A and CB1 receptors respectively.

Cannabis sativa as a Treatment for Obesity: From Anti-Inflammatory Indirect Support to a Promising Metabolic Re-Establishment Target.

Introduction: Obesity is defined as an excess of accumulation of fat that can be harmful to health. Storage of excess fat in the adipose tissue triggers an inflammatory process, which makes obesity a low-grade chronic inflammatory disease. Obesity is considered a complex and multifactorial disease; hence, no intervention strategy appears to be an ideal treatment for all individuals. Therefore, new therapeutic alternatives are often studied for the treatment of this disease. Currently, herbal medicines are gaining ground in the treatment of obesity and its comorbidities. In this context, much attention is being paid to Cannabis sativa derivatives, and their therapeutic functions are being widely studied, including in treating obesity. Objective: Highlight the pharmacological properties of Δ9-tetrahydrocannabivarin (THCV), Δ9-tetrahydrocannabidinol (THC), and cannabidiol (CBD), the predominant isolated components of Cannabis sativa, as well as its therapeutic potential in the treatment of obesity. Methods: This is a narrative review that shows the existing scientific evidence on the clinical application of Cannabis sativa as a possible treatment for obesity. Data collection was performed in the PubMed electronic database. The following word combinations were used: Cannabis and obesity, Cannabis sativa and obesity, THCV and obesity, THC and obesity, CBD and obesity, and Cannabis sativa and inflammation. Results: Evidence shows that Cannabis sativa derivatives have therapeutic potential due to their anti-inflammatory properties. In addition, people who use cannabis have a lower body mass index than those who do not, making the plant an option to reduce and reverse inflammation and comorbidities in obesity. Conclusion: It is concluded that phytocannabinoids derived from Cannabis sativa have therapeutic potential due to its anti-inflammatory, antioxidant, and neuroprotective properties, making the plant a study option to reduce and reverse inflammation and comorbidities associated with obesity.

An Evaluation of Understudied Phytocannabinoids and Their Effects in Two Neuronal Models.

Cannabis contains more than 100 phytocannabinoids. Most of these remain poorly characterized, particularly in neurons. We tested a panel of five phytocannabinoids-cannabichromene (CBC), cannabidiolic acid (CBDA), cannabidivarin (CBDV), cannabidivarinic acid (CBDVA), and Δ9-tetrahydrocannabivarin (THCV) in two neuronal models, autaptic hippocampal neurons and dorsal root ganglion (DRG) neurons. Autaptic neurons expressed a form of CB1-dependent retrograde plasticity while DRGs expressed a variety of transient receptor potential (TRP) channels. CBC, CBDA, and CBDVA had little or no effect on neuronal cannabinoid signaling. CBDV and THCV differentially inhibited cannabinoid signaling. THCV inhibited CB1 receptors presynaptically while CBDV acted post-synaptically, perhaps by inhibiting 2-AG production. None of the compounds elicited a consistent DRG response. In summary, we find that two of five 'minor' phytocannabinoids tested antagonized CB1-based signaling in a neuronal model, but with very different mechanisms. Our findings highlight the diversity of potential actions of phytocannabinoids and the importance of fully evaluating these compounds in neuronal models.

Efficacy of Phytocannabinoids in Epilepsy Treatment: Novel Approaches and Recent Advances.

Epilepsy is a neurological disorder mainly characterised by recurrent seizures that affect the entire population diagnosed with the condition. Currently, there is no cure for the disease and a significant proportion of patients have been deemed to have treatment-resistant epilepsy (TRE). A patient is deemed to have TRE if two or more antiepileptic drugs (AEDs) fail to bring about seizure remission. This inefficacy of traditional AEDs, coupled with their undesirable side effect profile, has led to researchers considering alternative forms of treatment. Phytocannabinoids have long served as therapeutics with delta-9-THC (Δ9-THC) receiving extensive focus to determine its therapeutic potential. This focus on Δ9-THC has been to the detriment of analysing the plethora of other phytocannabinoids found in the cannabis plant. The overall aim of this review is to explore other novel phytocannabinoids and their place in epilepsy treatment. The current review intends to achieve this aim via an exploration of the molecular targets underlying the anticonvulsant capabilities of cannabidiol (CBD), cannabidavarin (CBDV), delta-9-tetrahydrocannabivarin (Δ9-THCV) and cannabigerol (CBG). Further, this review will provide an exploration of current pre-clinical and clinical data as it relates to the aforementioned phytocannabinoids and the treatment of epilepsy symptoms. With specific reference to epilepsy in young adult and adolescent populations, the exploration of CBD, CBDV, Δ9-THCV and CBG in both preclinical and clinical environments can guide future research and aid in the further understanding of the role of phytocannabinoids in epilepsy treatment. Currently, much more research is warranted in this area to be conclusive.

Δ9-Tetrahydrocannabivarin (THCV): a commentary on potential therapeutic benefit for the management of obesity and diabetes.

Δ9-Tetrahydrocannabivarin (THCV) is a cannabis-derived compound with unique properties that set it apart from the more common cannabinoids, such as Δ9-tetrahydrocannabinol (THC). The main advantage of THCV over THC is the lack of psychoactive effects. In rodent studies, THCV decreases appetite, increases satiety, and up-regulates energy metabolism, making it a clinically useful remedy for weight loss and management of obesity and type 2 diabetic patients. The distinctions between THCV and THC in terms of glycemic control, glucose metabolism, and energy regulation have been demonstrated in previous studies. Also, the effect of THCV on dyslipidemia and glycemic control in type 2 diabetics showed reduced fasting plasma glucose concentration when compared to a placebo group. In contrast, THC is indicated in individuals with cachexia. However, the uniquely diverse properties of THCV provide neuroprotection, appetite suppression, glycemic control, and reduced side effects, etc.; therefore, making it a potential priority candidate for the development of clinically useful therapies in the future. Hopefully, THCV could provide an optional platform for the treatment of life-threatening diseases.

Δ9-tetrahydrocannabivarin impairs epithelial calcium transport through inhibition of TRPV5 and TRPV6.

Compounds extracted from the cannabis plant, including the psychoactive Δ9-tetrahydrocannabinol (THC) and related phytocannabinoids, evoke multiple diverse biological actions as ligands of the G protein-coupled cannabinoid receptors CB1 and CB2. In addition, there is increasing evidence that phytocannabinoids also have non-CB targets, including several ion channels of the transient receptor potential superfamily. We investigated the effects of six non-THC phytocannabinoids on the epithelial calcium channels TRPV5 and TRPV6, and found that one of them, Δ9-tetrahydrocannabivarin (THCV), exerted a strong and concentration-dependent inhibitory effect on mammalian TRPV5 and TRPV6 and on the single zebrafish orthologue drTRPV5/6. Moreover, THCV attenuated the drTRPV5/6-dependent ossification in zebrafish embryos in vivo. Oppositely, 11-hydroxy-THCV (THCV-OH), a product of THCV metabolism in mammals, stimulated drTRPV5/6-mediated Ca2+ uptake and ossification. These results identify the epithelial calcium channels TRPV5 and TRPV6 as novel targets of phytocannabinoids, and suggest that THCV-containing products may modulate TRPV5- and TRPV6-dependent epithelial calcium transport.

Pharmacology of cannabinoids in the treatment of epilepsy.

The use of cannabis products in the treatment of epilepsy has long been of interest to researchers and clinicians alike; however, until recently very little published data were available to support its use. This article summarizes the available scientific data of pharmacology from human and animal studies on the major cannabinoids which have been of interest in the treatment of epilepsy, including ∆9-tetrahydrocannabinol (∆9-THC), cannabidiol (CBD), ∆9-tetrahydrocannabivarin (∆9-THCV), cannabidivarin (CBDV), and ∆9-tetrahydrocannabinolic acid (Δ9-THCA). It has long been known that ∆9-THC has partial agonist activity at the endocannabinoid receptors CB1 and CB2, though it also binds to other targets which may modulate neuronal excitability and neuroinflammation. The actions of Δ9-THCV and Δ9-THCA are less well understood. In contrast to ∆9-THC, CBD has low affinity for CB1 and CB2 receptors and other targets have been investigated to explain its anticonvulsant properties including TRPV1, voltage gated potassium and sodium channels, and GPR55, among others. We describe the absorption, distribution, metabolism, and excretion of each of the above mentioned compounds. Cannabinoids as a whole are very lipophilic, resulting in decreased bioavailability, which presents challenges in optimal drug delivery. Finally, we discuss the limited drug-drug interaction data available on THC and CBD. As cannabinoids and cannabis-based products are studied for efficacy as anticonvulsants, more investigation is needed regarding the specific targets of action, optimal drug delivery, and potential drug-drug interactions. This article is part of a Special Issue titled Cannabinoids and Epilepsy.

Neuroimaging studies towards understanding the central effects of pharmacological cannabis products on patients with epilepsy.

Recent interest for the use of cannabis-derived products as therapeutic agents in the treatment of epilepsies has necessitated a reevaluation of their effects on brain and behavior. Overall, prolonged cannabis use is thought to result in functional and structural brain alterations. These effects may be dependent on a number of factors: e.g., which phytocannabinoid is used (e.g., cannabidiol (CBD) vs. tetrahyrocannabinol (THC)), the frequency of use (occasional vs. heavy), and at what age (prenatal, childhood, adulthood) the use began. However, due to the fact that there are over seven hundred constituents that make up the Cannabis sativa plant, it is difficult to determine which compound or combination of compounds is responsible for specific effects when studying recreational users. Therefore, this review focuses only on the functional MRI studies investigating the effects of specific pharmacological preparations of cannabis compounds, specifically THC, tetrahydrocannabivarin (THCV), and CBD, on brain function in healthy individuals and persons with epilepsy with references to non-epilepsy studies only to underline the gaps in research that need to be filled before cannabis-derived products are considered for a wide use in the treatment of epilepsy. This article is part of a Special Issue entitled "Cannabinoids and Epilepsy".