[Design and application of special solid phase extraction column for three cannabinol compounds in hemp].

Cannabidiol (CBD), cannabinol (CBN), and Δ9-tetrahydrocannabinol (THC) are the most important components of hemp, whose concentrations determine the properties and applications of hemp. Hemp contains a large number of impurities, which must be removed from the extracting solution before determining the cannabinol contents by ultra-high performance liquid chromatography (UHPLC). Neutral alumina, magnesium silicate, and graphitized carbon black have different surface characteristics when used as adsorbents. The removal rates of pigments, total sugar, total fatty acid glyceride, and metal ions as well as the recoveries of the three cannabinols in the extraction solution were evaluated. The amounts of neutral alumina, magnesium silicate, and graphitized carbon black were 1.80 g, 0.15 g, and 0.05 g, respectively. The three adsorbents were mixed well and packed into a polypropylene pipe to prepare a special 2 g/6 mL solid phase extraction (SPE) column for determining the three cannabinol compounds in hemp. The chemical components of the hemp flowers and leaves were extracted with an ethyl acetate/methanol (9∶1, v/v) mixture. After the extracting solution was allowed to pass through the SPE column, the recoveries of CBD, CBN, and Δ9-THC were 98.9%, 95.7%, and 99.2%, respectively. The removal rates of xanthophyll, chlorophyll a, and chlorophyll were 96.3%, 99.2%, and 95.5%, respectively. The removal rates of total sugar, total fatty glyceride, and metal ions were 98.5%, 96.9%, and 85.4%, respectively. In this study, the chromatographic conditions for analyzing the three cannabinol compounds were optimized. The cannabinol compounds were separated within 10 min on an Eclipse Plus C18 column (50 mm×2.1 mm, 1.8 µm) using a mobile phase consisting of 1% (v/v) acetic acid and acetonitrile (30∶70, v/v) at a flow rate of 0.5 mL/min. The detection wavelength was set at 210 nm with a diode array detector, and the sample injection volume was 1 µL. Good linear relationships were observed between the mass peak areas and mass concentrations of CBD, CBN, and Δ9-THC in the range of 0.5-50 mg/L. The corresponding correlation coefficients (R2) were 0.9983, 0.9995, and 0.9981, while the detection limits were 0.45 µg/L, 0.53 µg/L, and 0.38 µg/L. The recoveries of CBD, CBN, and Δ9-THC were 90.3%-96.9%, 93.7%-95.6%, and 90.8%-96.1%, with relative standard deviations (RSDs) of 2.2%-6.1%, 4.1%-8.0%, and 2.4%-4.8%, respectively. The results were satisfactory, demonstrating that the special SPE column made of neutral alumina, magnesium silicate, and graphitized carbon black was well suited for the determination of the three cannabinol compounds in hemp.

Formulation of Cannabidiol in Colloidal Lipid Carriers.

In this study, the general processability of cannabidiol (CBD) in colloidal lipid carriers was investigated. Due to its many pharmacological effects, the pharmaceutical use of this poorly water-soluble drug is currently under intensive research and colloidal lipid emulsions are a well-established formulation option for such lipophilic substances. To obtain a better understanding of the formulability of CBD in lipid emulsions, different aspects of CBD loading and its interaction with the emulsion droplets were investigated. Very high drug loads (>40% related to lipid content) could be achieved in emulsions of medium chain triglycerides, rapeseed oil, soybean oil and trimyristin. The maximum CBD load depended on the type of lipid matrix. CBD loading increased the particle size and the density of the lipid matrix. The loading capacity of a trimyristin emulsion for CBD was superior to that of a suspension of solid lipid nanoparticles based on trimyristin (69% vs. 30% related to the lipid matrix). In addition to its localization within the lipid core of the emulsion droplets, cannabidiol was associated with the droplet interface to a remarkable extent. According to a stress test, CBD destabilized the emulsions, with phospholipid-stabilized emulsions being more stable than poloxamer-stabilized ones. Furthermore, it was possible to produce emulsions with pure CBD as the dispersed phase, since CBD demonstrated such a pronounced supercooling tendency that it did not recrystallize, even if cooled to -60 °C.

Origin of Δ9-Tetrahydrocannabinol Impurity in Synthetic Cannabidiol.

Introduction: Cannabidiol (CBD), the nonintoxicating constituent of cannabis, is largely employed for pharmaceutical and cosmetic purposes. CBD can be extracted from the plant or chemically synthesized. Impurities of psychotropic cannabinoids Δ9-tetrahydrocannabinol (Δ9-THC) and Δ8-THC have been found in extracted CBD, thus hypothesizing a possible contamination from the plant. Materials and Methods: In this study, synthetic and extracted CBD samples were analyzed by ultrahigh-performance liquid chromatography coupled to high-resolution mass spectrometry and the parameters that can be responsible of the conversion of CBD into THC were evaluated by an accelerated stability test. Results: In synthetic and extracted CBD no trace of THC species was detected. In contrast, CBD samples stored in the dark at room temperature on the benchtop for 3 months showed the presence of such impurities. Experiments carried out under inert atmosphere in the absence of humidity or carbon dioxide led to no trace of THC over time even at high temperature. Conclusions: The results suggested that the copresence of carbon dioxide and water from the air could be the key for creating the acidic environment responsible for the cyclization of CBD. These findings suggest that it might be appropriate to review the storage conditions indicated on the label of commercially available CBD.

Purified Cannabidiol isolate does not inhibit active caspase-1 release in NLRP inflammasome-mediated UVB or ATP-activated keratinocytes or appear to reduce key inflammatory cytokines in UVB-irradiate keratinocytes.

BACKGROUND: Cannabidiol is a plant-derived cannabinoid that has been suggested to have several human health benefits including potential anti-inflammatory effects. It is now common to find various forms of Cannabidiol, most often referred to as CBD, in nutritional supplements and topical treatments. The mechanisms by which CBD can influence inflammatory pathways in the body, and more particularly in the skin, are presently still unclear. It is known that CBD will bind to cannabinoid receptors, CB1 and CB2, in the body and recent work has shown that in keratinocytes, CBD can regulate inflammation through transcriptional regulation involving the NFÆ™ß nuclear pathways. The fact that CBD operates through the NFÆ™ß pathways suggests that, perhaps, the molecule may influence the expression of active caspase-1 through NLRP inflammasome-mediated pathways. METHODS: Recently, work has published demonstrating that Normal Human Epidermal Keratinocytes (NHEKs) can be activated by UVB and ATP to express active caspase-1 via NLRP inflammasome-mediated pathways. There was a strong interest to see whether highly purified Cannabidiol Isolate (>99% purity) might function to control release of active caspase-1 by testing of NHEKs using the previously described models. In addition, NHEKs expression of non-NLRP inflammasome-induced inflammation markers including IL-6, IL-8 and PGE2 was examined in UVB-activated NHEKs. RESULTS: It was found that purified Cannabidiol Isolate did not influence active caspase-1 release in either UVB or ATP-activated NHEKs suggesting the molecule does not influence the NLRP inflammasome pathways. In addition, it was surprisingly found that the Cannabidiol Isolate did not impact the expression of additional UVB-activated non-NLRP inflammatory markers. CONCLUSIONS: Data presented suggest that if Cannabidiol functions as an anti-inflammatory, it does so through pathways not associated with either the NLRP inflammasome-mediated expression of caspase-1 or through the more commonly known expression of interleukin or prostaglandin inflammatory pathways.

CONTEXTE: Le cannabidiol est un cannabinoïde d'origine végétale considéré comme bénéfique pour la santé humaine et présentant notamment des effets anti-inflammatoires potentiels. Il est désormais courant de trouver diverses formes de cannabidiol dans les suppléments alimentaires et les traitements topiques. Les mécanismes par lesquels le cannabidiol peut influencer les voies inflammatoires dans l'organisme, et plus particulièrement dans la peau sont actuellement encore flous. On sait que le cannabidiol se lie aux récepteurs cannabinoïdes, CB1 et CB2 dans l'organisme et des travaux récents ont montré que dans les kératinocytes, le cannabidiol peut réguler l'inflammation par régulation transcriptionnelle impliquant les voies nucléaires NF-ƙß. Le fait que le cannabidiol fonctionne par le biais des voies NF-Æ™ß laisse à penser que la molécule peut influencer l'expression de la Caspase-1 active à travers les voies médiées par l'inflammasome NLRP. MÉTHODES: Récemment, des travaux ont été publiés démontrant que les kératinocytes épidermiques humains normaux (Normal Human Epidermal Keratinocytes, NHEK) peuvent être activés par les UVB et l'ATP pour exprimer la Caspase-1 active à travers les voies médiées par l'inflammasome NLRP. On cherchait surtout à savoir si l'isolat de cannabidiol hautement purifié (pureté > 99 %) pouvait fonctionner pour contrôler la libération de Caspase-1 active en analysant les NHEK à l'aide des modèles décrits précédemment. En outre, l'expression des NHEK des marqueurs de l'inflammation induits par l'inflammasome non-NLRP, notamment : IL-6, IL-8 et la PGE2 ont été examinées dans des NHEK activées par les UVB. RÉSULTATS: Il a été constaté que l'isolat de cannabidiol purifié n'influençait pas la libération active de Caspase-1 dans les NHEK activées par les UVB ou l'ATP, ce qui suggère que la molécule n'influence pas les voies de l'inflammasome NLRP. En outre, il a été surprenant de constater que l'isolat de cannabidiol n'avait pas d'impact sur l'expression des marqueurs inflammatoires non-NLRP activés par les UVB supplémentaires. CONCLUSIONS: Les données présentées suggèrent que si le cannabidiol fonctionne comme un anti-inflammatoire, il le fait par des voies non associées à l'expression de la Caspase-1 médiée par l'inflammasome NLRP ou par l'expression plus connue des voies inflammatoires de l'interleukine ou de la prostaglandine.

Isolation, Synthesis And Structure Determination Of Cannabidiol Derivatives And Their Cytotoxic Activities.

In a continuing effort to explore the structural diversity and pharmacological activities of natural products based scaffolds, herein, we report the isolation, synthesis, and structure determination of cannabidiol and its derivatives along with their cytotoxic activities. Treatment of cannabidiol (1) with acid catalyst POCl3 afforded a new derivative 6 along with six known molecules 2 - 5, 7 and, 8. The structure of 6 was elucidated by extensive spectroscopic analyses and DFT calculations of the NMR and ECD data. All the compounds (2 - 8) were evaluated for their cytotoxic potential against a panel of eight cancer cell lines. Compounds 4, 5, 7, and 8 showed pronounced in vitro cytotoxic activity with IC50 values ranging from 5.6 to 60 µM. Out of the active molecules, compounds 4, and 7 were found to be comparable to that of the parent molecule 1 on the inhibition of almost all the tested cancer cell lines.

In vitro and in vivo pharmacological activity of minor cannabinoids isolated from Cannabis sativa.

The Cannabis sativa plant contains more than 120 cannabinoids. With the exceptions of ∆9-tetrahydrocannabinol (∆9-THC) and cannabidiol (CBD), comparatively little is known about the pharmacology of the less-abundant plant-derived (phyto) cannabinoids. The best-studied transducers of cannabinoid-dependent effects are type 1 and type 2 cannabinoid receptors (CB1R, CB2R). Partial agonism of CB1R by ∆9-THC is known to bring about the 'high' associated with Cannabis use, as well as the pain-, appetite-, and anxiety-modulating effects that are potentially therapeutic. CB2R activation by certain cannabinoids has been associated with anti-inflammatory activities. We assessed the activity of 8 phytocannabinoids at human CB1R, and CB2R in Chinese hamster ovary (CHO) cells stably expressing these receptors and in C57BL/6 mice in an attempt to better understand their pharmacodynamics. Specifically, ∆9-THC, ∆9-tetrahydrocannabinolic acid (∆9-THCa), ∆9-tetrahydrocannabivarin (THCV), CBD, cannabidiolic acid (CBDa), cannabidivarin (CBDV), cannabigerol (CBG), and cannabichromene (CBC) were evaluated. Compounds were assessed for their affinity to receptors, ability to inhibit cAMP accumulation, ßarrestin2 recruitment, receptor selectivity, and ligand bias in cell culture; and cataleptic, hypothermic, anti-nociceptive, hypolocomotive, and anxiolytic effects in mice. Our data reveal partial agonist activity for many phytocannabinoids tested at CB1R and/or CB2R, as well as in vivo responses often associated with activation of CB1R. These data build on the growing body of literature showing cannabinoid receptor-dependent pharmacology for these less-abundant phytocannabinoids and are critical in understanding the complex and interactive pharmacology of Cannabis-derived molecules.

Biological effects of Cannabidiol on normal human healthy cell populations: Systematic review of the literature.

A systematic review was performed to evaluate the biological effects of Cannabidiol (CBD), one of the major components of Cannabis Sativa, on normal human healthy cell populations in terms of cell viability, proliferation, migration, apoptosis and inflammation. Inclusion criteria were: studies on cell lines and primary cell culture from healthy donors, CBD exposure as variable, no CBD exposure as control and published in English language. Quality assessment was based on ToxR tool, with a score of reliability ranging from 15 to 18.Following the PRISMA statement, three independent reviewers performed both a manual and an electronic search using MEDLINE via PubMed, Scopus, Web of Science and Cochrane. From a total of 9437eligible articles, 29 studies have been selected. The average quality assessment score was 16.48.Theresults showed heterogeneous CBD concentration exposure (0.01-50 µM or 0.1 nmol/mL-15 mg/mL). The definition of a threshold limit would allow the identification of specific effects on expected outcomes. From the data obtained CBD resulted to inhibit cell viability in a dose-dependent manner above 2 µM, while in oral cell populations the inhibitory concentration is higher than 10 µM. Moreover, it was observed a significantly inhibition of cell migration and proliferation. On the contrary, it was highlighted a stimulation of apoptosis only at high doses (from 10 µM).Finally, CBD produced an anti-inflammatory effect, with a reduction of the pro-inflammatory cytokine gene expression and secretion. CBD down-regulated ROS production, although at high concentrations (16 µM) increased ROS-related genes expression. The diffusion of CBD for therapeutic and recreational uses require a precise definition of its potential biological effects. A thorough knowledge of these aspects would allow a safe use of this substance without any possible side effects.

Understanding the basics of cannabidiol from cannabis to apply to therapeutics in epilepsy.

The compounds present in cannabis have been in use for both recreational and medicinal purposes for many centuries. Changes in the legislation in South Africa have led to an increase in the number of people interested in using these compounds for self-medication. Many of them may approach their general practitioner as the first source of information about possible therapeutic effects. It is important that medical professionals are able to give patients the correct information. Cannabidiol (CBD) is one of the main compounds in cannabis plants, and there is evidence that it can successfully treat certain patients with epilepsy. This review looks at the most recent evidence on the use of CBD in the treatment of epilepsy and explores the mechanisms behind these beneficial effects.

The potential of cannabidiol in the COVID-19 pandemic.

Identifying drugs effective in the new coronavirus disease 2019 (COVID-19) is crucial, pending a vaccine against SARS-CoV2. We suggest the hypothesis that cannabidiol (CBD), a non-psychotropic phytocannabinoid, has the potential to limit the severity and progression of the disease for several reasons:- (a) High-cannabidiol Cannabis sativa extracts are able to down-regulate the expression of the two key receptors for SARS-CoV2 in several models of human epithelia, (b) cannabidiol exerts a wide range of immunomodulatory and anti-inflammatory effects and it can mitigate the uncontrolled cytokine production responsible for acute lung injury, (c) being a PPARγ agonist, it can display a direct antiviral activity and (d) PPARγ agonists are regulators of fibroblast/myofibroblast activation and can inhibit the development of pulmonary fibrosis, thus ameliorating lung function in recovered patients. We hope our hypothesis, corroborated by preclinical evidence, will inspire further targeted studies to test cannabidiol as a support drug against the COVID-19 pandemic. LINKED ARTICLES: This article is part of a themed issue on The Pharmacology of COVID-19. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v177.21/issuetoc.

Isolation, Purification, and Antimicrobial Characterization of Cannabidiolic Acid and Cannabidiol from Cannabis sativa L.

The emergence of multi-drug resistant bacteria such as methicillin-resistant Staphylococcus aureus (MRSA) causes a major threat to public health due to its limited therapeutic options. There is an urgent need for the development of new effective antimicrobial agents and alternative strategies that are effective against resistant bacteria. The parallel legalization of cannabis and its products has fueled research into its many therapeutic avenues in many countries around the world. This study aimed at the development of a reliable method for the extraction, purification, characterization, and quantification of cannabidiolic acid (CBDA) and its decarboxylated form cannabidiol (CBD) present in the fiber type Cannabis sativa L. The two compounds were extracted by ethanol, purified on a C18 sep-pack column, and the extracts were analyzed by high performance liquid chromatography coupled with ultraviolet (UV)-vis and ESI-MS (electrospray ionization mass spectrometry) detection. The antimicrobial effect of CBDA and CBD was also evaluated. CBD displayed a substantial inhibitory effect on Gram-positive bacteria with minimal inhibitory concentrations ranging from 1 to 2 µg/mL. Time kill analysis and minimal bactericidal concentration revealed potential bactericidal activity of CBDA and CBD. While cannabinoids showed a significant antimicrobial effect on the Gram-positive S. aureus and Staphylococcus epidermidis, no activity was noticed on Gram-negative Escherichia coli and Pseudomonas aeruginosa. CBDA presented a two-fold lower antimicrobial activity than its decarboxylated form, suggesting that the antimicrobial pharmacophore of the analyzed cannabinoids falls in the ability for permeabilizing the bacterial cell membrane and acting as a detergent-like agent. A synergy test performed on MRSA with CBD and a range of antibiotics did not indicate a synergetic effect, but noteworthy no antagonist influence either. CBD and CBDA manifested low hemolytic activity on human red blood cells. Likewise, the safety of CBD toward human keratinocyte cells presents no toxicity at a concentration of up to seven-fold higher than the antibacterial minimal inhibitory concentration. Similarly, both CBD and CBDA are well tolerated by mammals, including humans, and conserve a safe value limits for blood-contacting drug development. Overall, CBD exhibited a strong antimicrobial effect against Gram-positive strains and could serve as an alternative drug for tackling MRSA.

Differentiating Full-Spectrum Hemp Extracts from CBD Isolates: Implications for Policy, Safety and Science.

The passage of the 2018 United States Agriculture Improvement Act removed industrial hemp, defined as Cannabis sativa L. containing less than 0.3% THC content by dry weight, from Schedule I of the Controlled Substances Act and made it an agricultural commodity. Following these changes, the popularity of hemp-derived cannabidiol (CBD) dietary supplements by consumers has greatly exceeded the scientific understanding of purported benefits, safety and composition of these botanical extracts. Further complicating CBD hemp supplement regulation, Food and Drug Administration (FDA) considers CBD to be an approved drug (Epidiolex) in the treatment of severe epilepsy disorders, Dravet and Lennox-Gastaut syndromes. At the same time, hemp-derived CBD supplements can contain a complex phytochemical matrix from the hemp plant, distinguishing the composition of these products from isolated CBD preparations. This work aims to provide clarity on differentiating botanical full-spectrum hemp extracts containing CBD from isolates, from a phytochemical, toxicological and regulatory perspective.

Terpenoids, Cannabimimetic Ligands, beyond the Cannabis Plant.

Medicinal use of Cannabis sativa L. has an extensive history and it was essential in the discovery of phytocannabinoids, including the Cannabis major psychoactive compound-Δ9-tetrahydrocannabinol (Δ9-THC)-as well as the G-protein-coupled cannabinoid receptors (CBR), named cannabinoid receptor type-1 (CB1R) and cannabinoid receptor type-2 (CB2R), both part of the now known endocannabinoid system (ECS). Cannabinoids is a vast term that defines several compounds that have been characterized in three categories: (i) endogenous, (ii) synthetic, and (iii) phytocannabinoids, and are able to modulate the CBR and ECS. Particularly, phytocannabinoids are natural terpenoids or phenolic compounds derived from Cannabis sativa. However, these terpenoids and phenolic compounds can also be derived from other plants (non-cannabinoids) and still induce cannabinoid-like properties. Cannabimimetic ligands, beyond the Cannabis plant, can act as CBR agonists or antagonists, or ECS enzyme inhibitors, besides being able of playing a role in immune-mediated inflammatory and infectious diseases, neuroinflammatory, neurological, and neurodegenerative diseases, as well as in cancer, and autoimmunity by itself. In this review, we summarize and critically highlight past, present, and future progress on the understanding of the role of cannabinoid-like molecules, mainly terpenes, as prospective therapeutics for different pathological conditions.

Is cannabidiol a scheduled controlled substance? Origin makes the difference.

Cannabidiol (CBD) is the main cannabinoid naturally occurring in hemp. It has recently attracted the attention of the scientific community because of its numerous pharmacological activities. However, its legal status changes depending on whether it is chemically synthesized or extracted from the plant: extracted CBD is a scheduled controlled substance, whereas synthetic CBD is not under control. In Europe, extracted CBD is excluded from the cosmetic ingredients of the CosIng database. Given the confusion surrounding these different forms of CBD, there is an urgent need for clarity to shed light from both a regulatory and a chemical point of view. The impurity profiles of synthetic and natural CBD are different and could currently represent the only means to distinguish the origin of this substance.

Validation of a liquid chromatography tandem mass spectrometry (LC-MS/MS) method to detect cannabinoids in whole blood and breath.

Background The widespread availability of cannabis raises concerns regarding its effect on driving performance and operation of complex equipment. Currently, there are no established safe driving limits regarding ∆9-tetrahydrocannabinol (THC) concentrations in blood or breath. Daily cannabis users build up a large body burden of THC with residual excretion for days or weeks after the start of abstinence. Therefore, it is critical to have a sensitive and specific analytical assay that quantifies THC, the main psychoactive component of cannabis, and multiple metabolites to improve interpretation of cannabinoids in blood; some analytes may indicate recent use. Methods A liquid chromatography tandem mass spectrometry (LC-MS/MS) method was developed to quantify THC, cannabinol (CBN), cannabidiol (CBD), 11-hydroxy-THC (11-OH-THC), (±)-11-nor-9-carboxy-Δ9-THC (THCCOOH), (+)-11-nor-Δ9-THC-9-carboxylic acid glucuronide (THCCOOH-gluc), cannabigerol (CBG), and tetrahydrocannabivarin (THCV) in whole blood (WB). WB samples were prepared by solid-phase extraction (SPE) and quantified by LC-MS/MS. A rapid and simple method involving methanol elution of THC in breath collected in SensAbues® devices was optimized. Results Lower limits of quantification ranged from 0.5 to 2 µg/L in WB. An LLOQ of 80 pg/pad was achieved for THC concentrations in breath. Calibration curves were linear (R2>0.995) with calibrator concentrations within ±15% of their target and quality control (QC) bias and imprecision ≤15%. No major matrix effects or drug interferences were observed. Conclusions The methods were robust and adequately quantified cannabinoids in biological blood and breath samples. These methods will be used to identify cannabinoid concentrations in an upcoming study of the effects of cannabis on driving.

Cannabis y los sistemas exocannabinoide y endocannabinoide. Su uso y controversias.

Cannabis (marijuana) is one of the most consumed psychoactive substances in the world. The term marijuana is of Mexican origin. The primary cannabinoids that have been studied to date include cannabidiol and delta-9-tetrahydrocannabinol, which is responsible for most cannabis physical and psychotropic effects. Recently, the endocannabinoid system was discovered, which is made up of receptors, ligands and enzymes that are widely expressed in the brain and its periphery, where they act to maintain balance in several homeostatic processes. Exogenous cannabinoids or naturally-occurring phytocannabinoids interact with the endocannabinoid system. Marijuana must be processed in a laboratory to extract tetrahydrocannabinol and leave cannabidiol, which is the product that can be marketed. Some studies suggest cannabidiol has great potential for therapeutic use as an agent with antiepileptic, analgesic, anxiolytic, antipsychotic, anti-inflammatory and neuroprotective properties; however, the findings on cannabinoids efficacy and cannabis-based medications tolerability-safety for some conditions are inconsistent. More scientific evidence is required in order to generate recommendations on the use of medicinal cannabis.

El cannabis (marihuana) es una de las sustancias psicoactivas más consumidas en el mundo. El término marihuana es de origen mexicano. Los cannabinoides primarios estudiados hasta la fecha incluyen el cannabidiol y el delta-9-tetrahidrocannabinol (Δ9-THC), responsable de la mayoría de los efectos físicos y psicotrópicos del cannabis. Recientemente se descubrió el sistema endocannabinoide formado por receptores, ligandos y enzimas expresados ampliamente en el cerebro y su periferia, donde actúan para mantener el equilibrio en varios procesos homeostáticos. Los cannabinoides exógenos o fitocannabinoides de origen natural interactúan con el sistema endocannabinoide. La marihuana debe ser procesada en un laboratorio para extraer el tetrahidrocannabinol y dejar el cannabidiol, el producto que se puede comercializar. Algunos estudios otorgan al cannabidiol un gran potencial para el uso terapéutico como antiepiléptico, analgésico, ansiolítico, antipsicótico, antiinflamatorio y neuroprotector, sin embargo, son inconsistentes los hallazgos sobre la eficacia de los cannabinoides y la ­tolerabilidad-seguridad de los medicamentos con base en cannabis para cualquier padecimiento. Se requiere más evidencia científica para generar recomendaciones sobre el uso del cannabis medicinal.

Cannabis and the exocannabinoid and endocannabinoid systems. Their use and controversies

Cannabis (marijuana) is one of the most consumed psychoactive substances in the world. The term marijuana is of Mexican origin. The primary cannabinoids that have been studied to date include cannabidiol and delta-9-tetrahydrocannabinol, which is responsible for most cannabis physical and psychotropic effects. Recently, the endocannabinoid system was discovered, which is made up of receptors, ligands and enzymes that are widely expressed in the brain and its periphery, where they act to maintain balance in several homeostatic processes. Exogenous cannabinoids or naturally-occurring phytocannabinoids interact with the endocannabinoid system. Marijuana must be processed in a laboratory to extract tetrahydrocannabinol and leave cannabidiol, which is the product that can be marketed. Some studies suggest cannabidiol has great potential for therapeutic use as an agent with antiepileptic, analgesic, anxiolytic, antipsychotic, anti-inflammatory and neuroprotective properties; however, the findings on cannabinoids efficacy and cannabis-based medications tolerability-safety for some conditions are inconsistent. More scientific evidence is required in order to generate recommendations on the use of medicinal cannabis.

Aplicaciones terapéuticas por acción de los cannabinoides.

The interest on cannabinoids became evident between the 1940 and 1950 decades. Although the active substance of the plant was not known, a series of compounds with cannabinomimetic activity were synthesized, which were investigated in animals and clinically. The most widely tested was Δ6a, 10a-THC hexyl. Δ6a, 10a-THC dimethylheptyl (DMHP) antiepileptic effects were studied in several children, with positive results being obtained in some cases. DMHP differs from sinhexyl in that its side chain is DMHP instead of n-hexyl. The first cannabinoid isolated from Cannabis sativa was cannabinol, although its structure was correctly characterized several years later. Cannabidiol was isolated some years later and was subsequently characterized by Mechoulam and Shvo. In 2013, the National Academy of Medicine and the Faculty of Medicine of the National Autonomous University of Mexico, through the Seminar of Studies on Entirety, decided to carry out a systematic review on a subject that is both complex and controversial: the relationship between marijuana and health. In recent years, studies have been conducted with cannabis in several diseases: controlled clinical trials on spasticity in multiple sclerosis and spinal cord injury, chronic, essentially neuropathic, pain, movement disorders (Gilles de Latourette, dystonia, levodopa dyskinesia), asthma and glaucoma, as well as non-controlled clinical trials on Alzheimer's disease, neuroprotection, intractable hiccups, epilepsy, alcohol and opioid dependence and inflammatory processes.

El interés por los cannabinoides se hizo evidente entre las décadas de 1940 y 1950. Aunque no se conocía el principio activo de la planta, se sintetizaron compuestos con actividad cannabinomimética, los cuales fueron investigados en animales y en la clínica. El más probado fue el ∆6a,10a-THC hexilo. Las acciones antiepilépticas del ∆6a,10a-THC dimetilheptil fueron estudiadas en varios niños; en algunos casos se obtuvieron resultados positivos. El ∆6a,10a-THC dimetilheptil se diferencia del sinhexil en que su cadena lateral es dimetilheptilo en vez de n-hexilo. El primer cannabinoide aislado de Cannabis sativa fue el cannabinol, si bien su estructura fue correctamente caracterizada varios años después. El cannabidiol fue aislado algunos años más tarde y caracterizado posteriormente por Mechoulam y Shvo. Durante 2013, la Academia Nacional de Medicina y la Facultad de Medicina de la Universidad Nacional Autónoma de México, a través del Seminario de Estudios sobre la Globalidad, decidieron realizar una revisión sistemática sobre un tema tan complejo como controvertido: la relación entre la marihuana y la salud. En los últimos años se han realizado estudios con cannabis en varias enfermedades: ensayos clínicos controlados sobre espasticidad en esclerosis múltiple y sobre lesiones medulares, dolor crónico fundamentalmente neuropático y trastornos del movimiento (Gilles de Latourette, distonía, discinesia por levodopa), asma y glaucoma, así como ensayos clínicos no controlados sobre Alzheimer, neuroprotección, hipo intratable, epilepsia, dependencia al alcohol y opioides y procesos inflamatorios.

Therapeutic applications based on cannabinoids action / Aplicaciones terapéuticas por acción de los cannabinoides

The interest on cannabinoids became evident between the 1940 and 1950 decades. Although the active substance of the plant was not known, a series of compounds with cannabinomimetic activity were synthesized, which were investigated in animals and clinically. The most widely tested was Δ6α, 10α-THC hexyl. Δ6α, 10α-THC dimethylheptyl (DMHP) antiepileptic effects were studied in several children, with positive results being obtained in some cases. DMHP differs from sinhexyl in that its side chain is DMHP instead of n-hexyl. The first cannabinoid isolated from Cannabis sativa was cannabinol, although its structure was correctly characterized several years later. Cannabidiol was isolated some years later and was subsequently characterized by Mechoulam and Shvo. In 2013, the National Academy of Medicine and the Faculty of Medicine of the National Autonomous University of Mexico, through the Seminar of Studies on Entirety, decided to carry out a systematic review on a subject that is both complex and controversial: the relationship between marijuana and health. In recent years, studies have been conducted with cannabis in several diseases: controlled clinical trials on spasticity in multiple sclerosis and spinal cord injury, chronic, essentially neuropathic, pain, movement disorders (Gilles de Latourette, dystonia, levodopa dyskinesia), asthma and glaucoma, as well as non-controlled clinical trials on Alzheimer’s disease, neuroprotection, intractable hiccups, epilepsy, alcohol and opioid dependence and inflammatory processes.

Promoting cannabis products to pharmaceutical drugs.

Cannabis sativa is widely used for medical purposes. However, to date, aroma, popular strain name or the content of two phytocannabinoids-Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD) are mostly considered for therapeutic activity. This is despite the hundreds of compounds in this plant and their potential synergistic interactions in mixtures. New, specific and effective cannabis-based drugs must be developed to achieve adequate medical standards for the use of cannabis. To do this, the comprehensive molecular profile of cannabis-based drugs must be defined, and mixtures of compounds should be tested for superior therapeutic activity due to synergistic effects compared to individually isolated cannabis compounds. The biological pathways targeted by these new drugs should also be characterized more accurately. For drug development and design, absorption, distribution, metabolism and elimination versus toxicity (ADME/Tox) must be characterized, and therapeutic doses identified. Promoting the quality and therapeutic activity of herbal or synthetic cannabis products to pharma grade is a pressing need worldwide.