The (Poly)Pharmacology of Cannabidiol in Neurological and Neuropsychiatric Disorders: Molecular Mechanisms and Targets

Cannabidiol (CBD), the major nonpsychoactive Cannabis constituent, has been proposed for the treatment of a wide panel of neurological and neuropsychiatric disorders, including anxiety, schizophrenia, epilepsy and drug addiction due to the ability of its versatile scaffold to interact with diverse molecular targets that are not restricted to the endocannabinoid system. Albeit the molecular mechanisms responsible for the therapeutic effects of CBD have yet to be fully elucidated, many efforts have been devoted in the last decades to shed light on its complex pharmacological profile. In particular, an ever-increasing number of molecular targets linked to those disorders have been identified for this phytocannabinoid, along with the modulatory effects of CBD on their cascade signaling. In this view, here we will try to provide a comprehensive and up-to-date overview of the molecular basis underlying the therapeutic effects of CBD involved in the treatment of neurological and neuropsychiatric disorders.     

Opportunities,Challenges and Pitfalls of Using Cannabidiol as an Adjuvant Drug in COVID-19 †

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection may lead to coronavirus disease 2019 (COVID-19) which, in turn, may be associated with multiple organ dysfunction. In this review, we present advantages and disadvantages of cannabidiol (CBD), a non-intoxicating phytocannabinoid from the cannabis plant, as a potential agent for the treatment of COVID-19. CBD has been shown to downregulate proteins responsible for viral entry and to inhibit SARS-CoV-2 replication. Preclinical studies have demonstrated its effectiveness against diseases of the respiratory system as well as its cardioprotective, nephroprotective, hepatoprotective, neuroprotective and anti-convulsant properties, that is, effects that may be beneficial for COVID-19. Only the latter two properties have been demonstrated in clinical studies, which also revealed anxiolytic and antinociceptive effects of CBD (given alone or together with Δ⁹-tetrahydrocannabinol), which may be important for an adjuvant treatment to improve the quality of life in patients with COVID-19 and to limit post-traumatic stress symptoms. However, one should be aware of side effects of CBD (which are rarely serious), drug interactions (also extending to drugs acting against COVID-19) and the proper route of its administration (vaping may be dangerous). Clearly, further clinical studies are necessary to prove the suitability of CBD for the treatment of COVID-19.     

Possible Receptor Mechanisms Underlying Cannabidiol Effects on Addictive-like Behaviors in Experimental Animals

Substance use disorder (SUD) is a serious public health problem worldwide for which available treatments show limited effectiveness. Since the legalization of cannabis and the approval of cannabidiol (CBD) by the US Food and Drug Administration, therapeutic potential of CBD for the treatment of SUDs and other diseases has been widely explored. In this mini-review article, we first review the history and evidence supporting CBD as a potential pharmacotherapeutic. We then focus on recent progress in preclinical research regarding the pharmacological efficacy of CBD and the underlying receptor mechanisms on addictive-like behavior. Growing evidence indicates that CBD has therapeutic potential in reducing drug reward, as assessed in intravenous drug self-administration, conditioned place preference and intracranial brain-stimulation reward paradigms. In addition, CBD is effective in reducing relapse in experimental animals. Both in vivo and in vitro receptor mechanism studies indicate that CBD may act as a negative allosteric modulator of type 1 cannabinoid (CB1) receptor and an agonist of type 2 cannabinoid (CB2), transient receptor potential vanilloid 1 (TRPV1), and serotonin 5-HT_1A receptors. Through these multiple-receptor mechanisms, CBD is believed to modulate brain dopamine in response to drugs of abuse, leading to attenuation of drug-taking and drug-seeking behavior. While these findings suggest that CBD is a promising therapeutic candidate, further investigation is required to verify its safety, pharmacological efficacy and the underlying receptor mechanisms in both experimental animals and humans.     

Fabrication and characterization of a cannabidiol-loaded emulsion stabilized by a whey protein-maltodextrin conjugate and rosmarinic acid complex

A cannabidiol (CBD)-loaded oil-in-water emulsion stabilized by a whey protein (WP)-maltodextrin (MD) conjugate and rosmarinic acid (RA) complex was fabricated, and its stability characteristics were investigated under various environmental conditions. The WP-MD conjugates were formed via dry-heating. The interaction between WP and MD was assessed by browning intensity, reduced amount of free amino groups, the formation of high molecular weight components in sodium dodecyl sulfate-PAGE, and changes in secondary structure of whey proteins. The WP-MD-RA noncovalent complex was prepared and confirmed by fluorescence quenching and Fourier-transform infrared spectroscopy spectra. Emulsions stabilized by WP, WP-MD, and WP-RA were used as references to evaluate the effect of WP-MD-RA as a novel emulsifier. Results showed that WP-MD-RA was an effective emulsifier to produce fine droplets for a CBD-loaded emulsion and remarkably improved the pH and salt stabilities of emulsions in comparison with WP. An emulsion prepared with WP-MD-RA showed the highest protection of CBD against UV and heat-induced degradation among all emulsions. The ternary complex kept emulsions in small particle size during storage at 4°C. Data from the current study may offer useful information for designing emulsion-based delivery systems which can protect active substance against environmental stresses.     

Changes in Phospholipid/Ceramide Profiles and Eicosanoid Levels in the Plasma of Rats Irradiated with UV Rays and Treated Topically with Cannabidiol

Chronic UV radiation causes oxidative stress and inflammation of skin and blood cells. Therefore, in this study, we assessed the effects of cannabidiol (CBD), a natural phytocannabinoid with antioxidant and anti-inflammatory properties, on the phospholipid (PL) and ceramide (CER) profiles in the plasma of nude rats irradiated with UVA/UVB and treated topically with CBD. The results obtained showed that UVA/UVB radiation increased the levels of phosphatidylcholines, lysophospholipids, and eicosanoids (PGE2, TxB2), while downregulation of sphingomyelins led to an increase in CER[NS] and CER[NDS]. Topical application of CBD to the skin of control rats significantly upregulated plasma ether-linked phosphatidylethanolamines (PEo) and ceramides. However, CBD administered to rats irradiated with UVA/UVB promoted further upregulation of CER and PEo and led to significant downregulation of lysophospholipids. This was accompanied by the anti-inflammatory effect of CBD, manifested by a reduction in the levels of proinflammatory PGE2 and TxB2 and a dramatic increase in the level of anti-inflammatory LPXA4. It can therefore be suggested that topical application of CBD to the skin of rats exposed to UVA/UVB radiation prevents changes in plasma phospholipid profile resulting in a reduction of inflammation by reducing the level of LPE and LPC species and increasing antioxidant capacity due to upregulation of PEo species.     

Plant-Origin Stabilizer as an Alternative of Natural Additive to Polymers Used in Packaging Materials

Over the past 25 years, cannabis plants have gained major popularity in the research community. This study aimed to evaluate the antioxidant capacity and stabilization efficiency of cannabidiol (CBD) extract in two different polymers: polylactide (PLA) and ethylene–norbornene copolymer (Topas) that are used in packaging materials more often. The research technology included weathering in a special chamber, surface free energy and color change measurements, surface morphology and Fourier-transform infrared spectroscopy (FTIR) analysis, thermogravimetry, and determination of the oxidation induction time or temperature (OIT) values, based on which the effectiveness of the cannabidiol extract could be estimated. Obtained results showed that the addition of CBD to polymer mixtures significantly increased their resistance to oxidation, and it can be used as a natural stabilizer for polymeric products. Moreover, samples with cannabidiol changed their coloration as a result of weathering. Therefore, this natural additive can also be considered as a colorimetric indicator of aging that informs about the changes in polymeric materials during their lifetime. On the other hand, surface properties of samples with cannabidiol content did not alter much compared to pure Topas and PLA.     

Monocyclic Quinone Structure-Activity Patterns: Synthesis of Catalytic Inhibitors of Topoisomerase II with Potent Antiproliferative Activity

The monocyclic 1,4-benzoquinone, HU-331, the direct oxidation product of cannabidiol, inhibits the catalytic activity of topoisomerase II but without inducing DNA strand breaks or generating free radicals, and unlike many fused-ring quinones exhibits minimal cardiotoxicity. Thus, monocyclic quinones have potential as anticancer agents, and investigation of the structural origins of their biological activity is warranted. New syntheses of cannabidiol and (±)-HU-331 are here reported. Integrated synthetic protocols afforded a wide range of polysubstituted resorcinol derivatives; many of the corresponding novel 2-hydroxy-1,4-benzoquinone derivatives are potent inhibitors of the catalytic activity of topoisomerase II, some more so than HU-331, whose monoterpene unit replaced by a 3-cycloalkyl unit conferred increased antiproliferative properties in cell lines with IC₅₀ values extending below 1 mM, and greater stability in solution than HU-331. The principal pharmacophore of quinones related to HU-331 was identified. Selected monocyclic quinones show potential for the development of new anticancer agents.     

酶辅助溶剂法提取火麻叶中大麻二酚工艺条件的优化

为了研究从火麻的植物叶中利用酶辅助以及溶剂萃取方法制备富含大麻二酚的浸膏,考察了加热预处理方式、酶的种类、酶解的时间、酶量、料液比以及萃取时间等因素对浸膏得率的影响,并利用气相色谱方法对浸膏中的大麻二酚含量进行了表征。确定了最佳的工艺条件：火麻叶在100 ℃的烘箱中加热处理2 h;采用的复合植物水解酶（Viscozyme L）和酸性蛋白酶的复合物进行酶解,用量分别为物料的0.5%,酶解时间1 h;料液比1∶20（g∶mL）,萃取时间3 h。在此工艺条件下,浸膏得率达到5.40%,大麻二酚含量为56.11 mg/g。     

Tamoxifen Sensitizes Acute Lymphoblastic Leukemia Cells to Cannabidiol by Targeting Cyclophilin-D and Altering Mitochondrial Ca2+ Homeostasis

Cytotoxic effects of cannabidiol (CBD) and tamoxifen (TAM) have been observed in several cancer types. We have recently shown that CBD primarily targets mitochondria, inducing a stable mitochondrial permeability transition pore (mPTP) and, consequently, the death of acute lymphoblastic leukemia (T-ALL) cells. Mitochondria have also been documented among cellular targets for the TAM action. In the present study we have demonstrated a synergistic cytotoxic effect of TAM and CBD against T-ALL cells. By measuring the mitochondrial membrane potential (ΔΨm), mitochondrial calcium ([Ca²⁺]_m) and protein-ligand docking analysis we determined that TAM targets cyclophilin D (CypD) to inhibit mPTP formation. This results in a sustained [Ca²⁺]_m overload upon the consequent CBD administration. Thus, TAM acting on CypD sensitizes T-ALL to mitocans such as CBD by altering the mitochondrial Ca²⁺ homeostasis.