Is It Time to Test the Antiseizure Potential of Palmitoylethanolamide in Human Studies? A Systematic Review of Preclinical Evidence

Antiseizure medications are the cornerstone pharmacotherapy for epilepsy. They are not devoid of side effects. In search for better-tolerated antiseizure agents, cannabinoid compounds and other N-acylethanolamines not directly binding cannabinoid receptors have drawn significant attention. Among these, palmitoylethanolamide (PEA) has shown neuroprotective, anti-inflammatory, and analgesic properties. All studies examining PEA’s role in epilepsy and acute seizures were systematically reviewed. Preclinical studies indicated a systematically reduced PEA tone accompanied by alterations of endocannabinoid levels. PEA supplementation reduced seizure frequency and severity in animal models of epilepsy and acute seizures, in some cases, similarly to available antiseizure medications but with a better safety profile. The peripheral-brain immune system seemed to be more effectively modulated by subchronic pretreatment with PEA, with positive consequences in terms of better responding to subsequent epileptogenic insults. PEA treatment restored the endocannabinoid level changes that occur in a seizure episode, with potential preventive implications in terms of neural damage. Neurobiological mechanisms for PEA antiseizure effect seemed to include the activation of the endocannabinoid system and the modulation of neuroinflammation and excitotoxicity. Although no human study was identified, there is ground for testing the antiseizure potential of PEA and its safety profile in human studies of epilepsy.

Tribute to Professor Raphael Mechoulam, The Founder of Cannabinoid and Endocannabinoid Research

During the last 60 years the relevance for human health and disease of cannabis (Cannabis sativa or Cannabis indica) ingredients, like the psychoactive compound Δ9-tetrahydrocannabinol (THC), cannabidiol, 120+ cannabinoids and 440+ non-cannabinoid compounds, has become apparent [...]

Genotype screening of Cannabis sativa L. based on the specifics of minor cannabinoids manifestation

Analysis of hemp collection samples based on the content of minor (rare) non-psychotropic cannabinoids, such as cannabichromene (CBC), cannabidivarin (CBDV), and cannabinol (CBN); determination of correlation relationships between them and common compounds; selection of valuable breeding genotypes. Methods. Field, biochemical (gas chromatography of cannabinoid compounds), and statistical (pair, partial, and multiple linear correlations). Results. Quantitative analysis of 210 samp­les of various ecological-geographical and genetic origin (local and wild forms, self-filing lines, hybrids, varieties, synthetic populations, polyploids) with a tetrahydrocannabinol (THC) content of less than 0.08% in dried plants showed the level of manifestation of the trait from its absence within the sensitivity of the gas chromatograph up to 0.6838% CBC, 0.1719% CBC and 0.3274% CBN. In the studied hemp samples, a medium negative relationship was found between the signs of the CBC and cannabidiol (CBD) contents (r = –0.53), a weak negative relationship between CBC and CBDV contents (r = –0.35), medium positive relationships between the signs of CBC and THC contents (r = 0.57) and CBC and CBN contents (r = 0.59). A medium positive correlation (r = 0.57) was found between the signs of CBDV and CBD contents, while CBN had a strong positive relationship with THC (r = 0.82). There is almost no correlation between cannabigerol (CBG) and the minor cannabinoids under study. The biosynthesis of minor cannabinoid compounds is quite complex. Signs manifestation is affected by many genetic and external factors. Partial correlation coefficients (given that one of the three signs is eliminated) and multiple correlation coefficients (given that the relationship of one sign is determined and two other signs are combined) give grounds to state that the gene for CBCA-synthase affects the production of CBD and, in particular THC. Conclusions. The closeness of the linear relationships between minor cannabinoids and common components allows selecting valuable hemp samples with a high content of one or several compounds under the absence or low content of psychotropic THC.

The Therapeutic Potential of Cannabis in Counteracting Oxidative Stress and Inflammation

Significant growth of interest in cannabis (Cannabis sativa L.), especially its natural anti-inflammatory and antioxidative properties, has been observed recently. This narrative review aimed to present the state of the art of research concerning the anti-inflammatory activity of all classes of cannabinoids published in the last five years. Multimodal properties of cannabinoids include their involvement in immunological processes, anti-inflammatory, and antioxidative effects. Cannabinoids and non-cannabinoid compounds of cannabis proved their anti-inflammatory effects in numerous animal models. The research in humans is missing, and the results are unconvincing. Although preclinical evidence suggests cannabinoids are of value in treating chronic inflammatory diseases, the clinical evidence is scarce, and further well-designed clinical trials are essential to determine the prospects for using cannabinoids in inflammatory conditions.

Pharmacophore-based Virtual Screening From Phytocannabinoids for Anti-obesity Activity

Search for new pharmacological alternatives for obesity is based on the design and development of compounds that can aid in weight loss so that they can be used safely and effectively over a long period while maintaining their function. The endocannabinoid system is related to obesity by increasing orexigenic signals and reducing satiety signals. Cannabis sativa is a medicinal plant of polypharmaceutical potential that has been widely studied for various medicinal purposes. The in silico evaluation of their natural cannabinoids (also called phytocannabinoids) for anti-obesity purpose stems from the existence of synthetic cannabinoid compounds that have already presented this result, but which did not guarantee patient safety. In order to find new molecules from C. sativa phytocannabinoids, with the potential to interact with the pharmacological target cannabinoid receptor 1, a pharmacophore-based virtual screening was performed, including the evaluation of physicochemical, pharmacokinetic, toxicological predictions and molecular docking. The results obtained from the ZINC12 database pointed to Zinc 69 (ZINC33053402) and Zinc 70 (ZINC19084698) molecules as promising anti-obesity agents. Molecular Dynamics (MD) studies discloses that both complexes were stable by analyzing the RMSD (Root Mean Square Deviation) values, and the binding free energy values demonstrate that the selected structures can interact and inhibit their catalytic activity.

In Situ Decarboxylation-Pressurized Hot Water Extraction for Selective Extraction of Cannabinoids from Cannabis sativa. Chemometric Approach

Isolation of the therapeutic cannabinoid compounds from Cannabis Sativa L. (C. Sativa) is important for the development of cannabis-based pharmaceuticals for cancer treatment, among other ailments. The main pharmacological cannabinoids are THC and CBD. However, THC also induces undesirable psychoactive effects. The decarboxylation process converts the naturally occurring acidic forms of cannabinoids, such as cannabidiolic acid (CBDA) and tetrahydrocannabinolic acid (THCA), to their more active neutral forms, known as cannabidiol (CBD) and tetrahydrocannabinol (THC). The purpose of this study was to selectively extract cannabinoids using a novel in situ decarboxylation pressurized hot water extraction (PHWE) system. The decarboxylation step was evaluated at different temperature (80–150 °C) and time (5–60 min) settings to obtain the optimal conditions for the decarboxylation-PHWE system using response surface methodology (RSM). The system was optimized to produce cannabis extracts with high CBD content, while suppressing the THC and CBN content. The identification and quantification of cannabinoid compounds were determined using UHPLC-MS/MS with external calibration. As a result, the RSM has shown good predictive capability with a p-value < 0.05, and the chosen parameters revealed to have a significant effect on the CBD, CBN and THC content. The optimal decarboxylation conditions for an extract richer in CBD than THC were set at 149.9 °C and 42 min as decarboxylation temperature and decarboxylation time, respectively. The extraction recoveries ranged between 96.56 and 103.42%, 95.22 and 99.95%, 99.62 and 99.81% for CBD, CBN and THC, respectively.

A new multiple purposes variety of industrial hemp ‘Artemida’ with a high oil content and fiber quality

Purpose. Creation of industrial hemp variety of multiple purposes with the absence of cannabinoid compounds, high oil content in seeds and fiber quality. Methods. Bree­ding (self-pollination, varietal-linear hybridization in the conditions of a vegetation house, selection), field, laboratory, instrumental-technological assessment of fiber quality, mathematical statistics. Results. The ‘Artemida’ variety was created as a result of hybridization of the ‘Hlesiia’ variety with the self-pollinated line of the sixth generation of the ‘Zolotoniski 15’ variety and selection for stabilization of high productivity traits and improvement of quality trait of hemp production. The variety belongs to the medium-ripe group; the growing season is 94 days before the phase of technological maturity and 118 days before the phase of biological maturity. When grown for fiber, the variety had a higher fiber yield (2.56 t/ha), the yield of all fiber (30.4% and including long fiber 27.6%). When grown for fiber and seeds, the plant is significantly inferior in height, which is positive for harves­ting seeds with a combine harvester, has a significantly higher seed yield (1.29 t/ha), oil content (36.8%) and fiber yield (2.01 t/ha) in comparison with the standard of the varie­ty ‘Hliana’. The analysis of the correspondence between the empirical and theoretical distribution of such a trait as the oil content in the seeds of elite plants of the ‘Artemida’ variety indicates its high stability. A notable feature of the variety is the formation of friendly seedlings and intensive plant growth at the beginning of the growing season, which helps to reduce the weediness of crops. Conclusions. The new variety of hemp ‘Artemida’ of multiple purposes belongs to the Central European ecological and geographical type, although created as a result of varietal-linear hybridization of different types with selection on the basis of productivity, is characte­rized by complete absence of cannabinoid compounds, high oil content and fiber quality. The variety is recommended for growing for fiber and seeds. Due to its high yield potential, it is competitive in the industrial hemp market.

A Critical Review of the Role of the Cannabinoid Compounds Δ9-Tetrahydrocannabinol (Δ9-THC) and Cannabidiol (CBD) and their Combination in Multiple Sclerosis Treatment

Many people with MS (pwMS) use unregulated cannabis or cannabis products to treat the symptoms associated with the disease. In line with this, Sativex, a synthetic combination of cannabidiol (CBD) and Δ9-tetrahydrocannabinol (Δ9-THC) has been approved to treat symptoms of spasticity. In animals, CBD is effective in reducing the amounts of T-cell infiltrates in the spinal cord, suggesting CBD has anti-inflammatory properties. By doing this, CBD has shown to delay symptom onset in animal models of multiple sclerosis and slow disease progression. Importantly, combinations of CBD and Δ9-THC appear more effective in treating animal models of multiple sclerosis. While CBD reduces the amounts of cell infiltrates in the spinal cord, Δ9-THC reduces scores of spasticity. In human studies, the results are less encouraging and conflict with the findings in animals. Drugs which deliver a combination of Δ9-THC and CBD in a 1:1 ratio appear to be only moderately effective in reducing spasticity scores, but appear to be almost as effective as current front-line treatments and cause less severe side effects than other treatments, such as baclofen (a GABA-B receptor agonist) and tizanidine (an α2 adrenergic receptor agonist). The findings of the studies reviewed suggest that cannabinoids may help treat neuropathic pain in pwMS as an add-on therapy to already established pain treatments. It is important to note that treatment with cannabinoid compounds may cause significant cognitive dysfunction. Long term double-blind placebo studies are greatly needed to further our understanding of the role of cannabinoids in multiple sclerosis treatment.

Analgesic efficacy of cannabinoids for acute pain management after surgery: a systematic review and meta-analysis

BackgroundEvidence regarding the role of cannabinoids in managing acute postoperative pain is conflicting. The purpose of this systematic review and meta-analysis was to determine the analgesic efficacy of perioperative cannabinoid compounds for acute pain management after surgery.MethodsOriginal research articles evaluating the addition of cannabinoids to standard opioid-based systemic analgesia (Control) in the postoperative period were sought. Our primary outcomes were cumulative oral morphine equivalent consumption and rest pain severity at 24 hours postoperatively. We also assessed analgesic consumption in the postanesthesia care unit (PACU), pain scores in PACU, 6 and 12 hours postoperatively, and opioid-related and cannabinoid-related side effects, patient satisfaction, and quality of recovery as secondary outcomes.ResultsEight randomized controlled trials (924 patients) and four observational studies (4259 patients) were analyzed and included. There were insufficient data to pool for quantification of differences in cumulative oral morphine equivalent consumption and rest pain severity at 24 hours postoperatively with the addition of cannabinoids in comparison to Control. Qualitative synthesis revealed no differences in cumulative oral opioid consumption or pain at rest 24 hours postoperatively with the addition of cannabinoids in comparison to Control. Patients receiving cannabinoids appeared to have an increased weighted mean difference 95% CI of pain at 12 hours by 0.83 cm (0.04 to 1.63) (p=0.04). Patients receiving cannabinoids also appeared to have 3.24 times increased odds of developing hypotension postoperatively (95% CI 1.12 to 9.36) (p=0.03). Qualitative and quantitative synthesis revealed no differences in any other secondary outcomes.ConclusionsOur quantitative and qualitative review of the literature suggests that the analgesic role of perioperative cannabinoid compounds is limited, with no clinically important benefits detected when cannabinoids are added to traditional systemic analgesics compared with traditional systemic analgesics alone. Notably, there appears to be a signal towards increased postoperative pain and hypotension associated with the addition of perioperative cannabinoids to traditional systemic analgesics. These results do not support the routine use of cannabinoids to manage acute postoperative pain at the present time.