No full-text available
To read the full-text of this research,
you can request a copy directly from the authors.
Cannabidiol for neurodegenerative disorders: Important new clinical applications for this phytocannabinoid?
Abstract
Cannabidiol (CBD) is a phytocannabinoid with therapeutic properties for numerous disorders exerted through molecular mechanisms that are yet to be completely identified. CBD acts in some experimental models as an anti-inflammatory, anticonvulsant, antioxidant, antiemetic, anxiolytic and antipsychotic agent, and is therefore a potential medicine for the treatment of neuroinflammation, epilepsy, oxidative injury, vomiting and nausea, anxiety and schizophrenia, respectively. The neuroprotective potential of CBD, based on the combination of its anti-inflammatory and antioxidant properties, is of particular interest and is presently under intense preclinical research in numerous neurodegenerative disorders. In fact, CBD combined with Δ(9) -tetrahydrocannabinol is already under clinical evaluation in patients with Huntington's disease to determine its potential as a disease-modifying therapy. The neuroprotective properties of CBD do not appear to be exerted by the activation of key targets within the endocannabinoid system for plant-derived cannabinoids like Δ(9) -tetrahydrocannabinol, i.e. CB(1) and CB(2) receptors, as CBD has negligible activity at these cannabinoid receptors, although certain activity at the CB(2) receptor has been documented in specific pathological conditions (i.e. damage of immature brain). Within the endocannabinoid system, CBD has been shown to have an inhibitory effect on the inactivation of endocannabinoids (i.e. inhibition of FAAH enzyme), thereby enhancing the action of these endogenous molecules on cannabinoid receptors, which is also noted in certain pathological conditions. CBD acts not only through the endocannabinoid system, but also causes direct or indirect activation of metabotropic receptors for serotonin or adenosine, and can target nuclear receptors of the PPAR family and also ion channels. © 2012 The Authors. British Journal of Clinical Pharmacology © 2012 The British Pharmacological Society.
... 183 Through the 5-HT1A receptor, CBD is associated with antiepileptic, anticataleptic, neu-J Explor Res Pharmacol roprotective, antiemetic, anxiolytic, antidepressant, antipsychotic, and analgesic effects. 86,[191][192][193][194][195] Others have also indicated that CBD acts via a negative allosteric mechanism in DRN somatodentritic 5-HT 1A receptors that does not require CB1, 5-HT 2A , or GABA A receptors. 86,186 ...
... 17,221 CBD is known to be neuroprotective in Parkinson's disease, where dopaminergic neurons of the substantia nigra pars compacta are shown to degenerate. 78,194,229 Conversely, in animal models, dopaminergic pathways are attenuated by CBD, resulting in decreased motor functions. 24 While data indicate that for some, the benefits of CBD may outweigh the risks, it is clearly necessary to continue researching optimal treatment levels related to disease improvement. ...
... In addition, pure THC has been described as a potentially dangerous drug. Efforts have been made to circumvent these The therapeutic potential of CBD has been evaluated in cardiovascular, neurodegenerative, and metabolic conditions, as well as for cancer [1,2,[21][22][23][24][25]. These pathologies are usually associated with oxidative stress and inflammation [1]. ...
... Its effects are thought to be associated with the antagonism of GPR55 and the consequent inhibition of intracellular calcium release, reducing neuronal hyperexcitability, which could be seen as an antiepileptic feature [4]. Nevertheless, more evidence is needed to support this mechanism of action [25,120,126]. CBD is also a partial agonist of serotonin 1A and 2A (5-HT1A and 5-HT2A) receptors, with some authors speculating that this affinity sustains its anticonvulsant effect [126]. As such, targeting these receptors could be a valid therapeutic option due to their regulatory action on neuronal depolarization, although their role in epilepsy is still unclear [125,127]. ...
The phytocannabinoid cannabidiol (CBD) is receiving increasing attention due to its pharmacological properties. Although CBD is extracted from Cannabis sativa, it lacks the psychoactive effects of Δ9-tetrahydrocannabinol (THC) and has become an attractive compound for pharmacological uses due to its anti-inflammatory, antioxidant, anticonvulsant, and anxiolytic potential. The molecular mechanisms involved in CBD’s biological effects are not limited to its interaction with classical cannabinoid receptors, exerting anti-inflammatory or pain-relief effects. Several pieces of evidence demonstrate that CBD interacts with other receptors and cellular signaling cascades, which further support CBD’s therapeutic potential beyond pain management. In this review, we take a closer look at the molecular mechanisms of CBD and its potential therapeutic application in the context of cancer, neurodegeneration, and autoimmune diseases.
... Cannabinoids are mostly used as anxiolytic, relaxing and anti-inflammatory natural agents with adjuvant properties for the treatment of epilepsy, schizophrenia, multiple sclerosis, depression or chronic pain [38,46,[50][51][52][53][54][55]. In the case of epilepsy, it has been shown that the brain tissue of these patients shows an overexpression of proinflammatory cytokine IL-1β and IL-6 genes together with nuclear transcription factor kappa B (NFKB) [56]. ...
... In the case of epilepsy, it has been shown that the brain tissue of these patients shows an overexpression of proinflammatory cytokine IL-1β and IL-6 genes together with nuclear transcription factor kappa B (NFKB) [56]. Cannabinol can inhibit the G protein-coupled orphan receptor (GRP55) and decrease NFKB signaling, the latter probably by binding to nuclear PPAR-g receptors, thus reducing the expression of proinflammatory enzymes such as iNOS (nitric oxide synthase) and COX-2 (cyclooxygenase type 2) and metalloprotease and proinflammatory cytokine production [10,43,53,57,58]. ...
Cannabis sativa is one of the first medicinal plants used by humans. Its medical use remains controversial because it is a psychotropic drug whose use has been banned. Recently, however, some countries have approved its use, including for recreational and medical purposes, and have allowed the scientific study of its compounds. Cannabis is characterized by the production of special types of natural products called phytocannabinoids that are synthesized exclusively by this genus. Phytocannabinoids and endocannabinoids are chemically different, but both pharmacologically modulate CB1, CB2, GRP55, GRP119 and TRPV1 receptor activities, involving activities such as memory, sleep, mood, appetite and motor regulation, pain sensation, neuroinflammation, neurogenesis and apoptosis. Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD) are phytocannabinoids with greater pharmacological potential, including anti-inflammatory, neuroprotective and anticonvulsant activities. Cannabidiol is showing promising results for the treatment of COVID-19, due to its capability of acting on the unleashed cytokine storm, on the proteins necessary for both virus entry and replication and on the neurological consequences of patients who have been infected by the virus. Here, we summarize the latest knowledge regarding the advantages of using cannabinoids in the treatment of COVID-19.
... Recently, cannabidiol (CBD), a component of Cannabis Sativa, has shown potential as a new antipsychotic drug [202][203][204][205]. CBD may act as a neuroprotective agent through various mechanisms, including reduction of oxidative stress, anti-inflammatory activity, attenuation of the activation of glial cells, and stabilization of glutamate homeostasis [204][205][206][207]. Furthermore, CBD antagonizes CB 1 receptors, potentially through negative allosteric modulation, reducing dopaminergic neurotransmission [202,[204][205][206][207][208]. ...
... Recently, cannabidiol (CBD), a component of Cannabis Sativa, has shown potential as a new antipsychotic drug [202][203][204][205]. CBD may act as a neuroprotective agent through various mechanisms, including reduction of oxidative stress, anti-inflammatory activity, attenuation of the activation of glial cells, and stabilization of glutamate homeostasis [204][205][206][207]. Furthermore, CBD antagonizes CB 1 receptors, potentially through negative allosteric modulation, reducing dopaminergic neurotransmission [202,[204][205][206][207][208]. In animal models of psychosis, the stereotyped behavior and hyperlocomotion induced by dopaminergic drugs have been attenuated with CBD [209,210]. ...
Background: Parkinson’s disease (PD) is the second most common neurodegenerative disorder worldwide. The symptoms of PD are characterized not only by motor alterations but also by a spectrum of nonmotor symptoms. Some of these are psychiatric manifestations such as sleep disorders; depression; cognitive difficulties that can evolve into dementia; and symptoms of psychosis, which include hallucinations, illusions, and delusions. Parkinson’s disease psychosis (PDP) occurs in 18%–50% of patients with PD. Treating PDP is challenging because antipsychotic drugs tend to be inefficient or may even worsen the motor symptoms of the disease.
Methods: This is a narrative review in which an extensive literature search was performed on the Scopus, EMBASE, PubMed, ISI Web of Science, and Google Scholar databases, from inception to August 2021. The terms “Parkinson’s disease psychosis,” “Parkinson psychosis,” “neurodegenerative psychosis,” and “dopamine psychosis” were among the keywords used in the search.
Objective: This review aims to summarize the current understanding of the molecular mechanisms involved in PDP, as well as recent innovative alternatives for its treatment.
Results: Recently, views on the etiology of hallucinations and illusions have evolved remarkably. PDP has been cemented as a multifactorial entity that is dependent not only on extrinsic mechanisms but also novel intrinsic mechanisms including genetic factors, neurostructural alterations, functional disruptions, visual processing disturbances, and sleep disorders. Consequently, innovative pharmacological and biological treatments have been proposed. Pimavanserin, a selective 5-HT2A inverse agonist, stands out after its approval for the treatment of PDP-associated hallucinations and illusions.
Conclusion: Future results from upcoming clinical trials should further characterize the role of this drug in the management of PDP as well as other treatment options with novel mechanisms of action, such as saracatinib, SEP-363856, cannabidiol, electroconvulsive therapy, and transcranial magnetic stimulation.
... The chemistry and pharmacology of CBD, as well as various molecular targets including CBD receptors and other CBD-interactive components of the endocannabinoid system, have been reviewed extensively [4][5][6][7]. The preliminary results of many studies have prompted the exploration of the therapeutic potential of CBD in relation to various diseases, particularly cancer and drug-resistant epilepsy [7][8][9][10][11][12]. ...
The COVID-19 pandemic provoked a global health crisis and highlighted the need for new therapeutic strategies. In this study, we explore the potential of the molecular consortia of cannabidiol (CBD) and non-steroidal anti-inflammatory drugs (NSAIDs) as novel antiviral dual-target agents against SARS-CoV-2/COVID-19. CBD is a natural compound with a wide range of therapeutic activities, including antiviral and anti-inflammatory properties, while NSAIDs are commonly used to mitigate the symptoms of viral infections. Chemical modifications of CBD with NSAIDs were performed to obtain dual-target agents with enhanced activity against SARS-CoV-2. The synthesised compounds were characterised using spectroscopic techniques. The biological activity of three molecular consortia (CBD–ibuprofen, CBD–ketoprofen, and CBD–naproxen) was evaluated in cell lines transduced with vesicular stomatitis virus-based pseudotypes bearing the SARS-CoV-1 or SARS-CoV-2 spike proteins or infected with influenza virus A/Puerto Rico/8/34. The results showed that some CBD–NSAID molecular consortia have superior antiviral activity against SARS-CoV-1 and SARS-CoV-2, but not against the influenza A virus. This may suggest a potential therapeutic role for these compounds in the treatment of emerging coronavirus infections. Further studies are needed to investigate the efficacy of these compounds in vivo, and their potential use in clinical settings. Our findings provide a promising new approach to combatting current and future viral emergencies.
... There are a lot of studies that describe cannabinoids impact on pain management, Parkinson's disease, spasticity due to multiple sclerosis or paraplegia, epilepsy, ophthalmological diseases, or different kinds of psychiatric disorders [8][9][10][11][12][13][14][15][16]. In recent years, interest in the potential therapeutic properties of CBD in the treatment of cardiovascular [17], cancer [18], metabolic [19], and neurodegenerative [20] diseases has increased. ...
Cannabis-derived therapies are gaining popularity in the medical world. More and more perfect forms of cannabinoids are sought, which could be used in the treatment of many common diseases, including metabolic syndrome, whose occurrence is also increasing. The purpose of this review was to investigate the usefulness of cannabinoids, mainly cannabidiol (CBD), in individuals with obesity, impaired glucose and lipid metabolism, high blood pressure, and non-alcoholic fatty liver disease (NAFLD). We summarised the most recent research on the broad topic of cannabis-derived influence on metabolic syndrome components. Since there is a lot of work on the effects of Δ9-THC (Δ9-tetrahydrocannabinol) on metabolism and far less on cannabidiol, we felt it needed to be sorted out and summarised in this review. The research results on the use of cannabidiol in obesity are contraindicatory. When it comes to glucose homeostasis, it appears that CBD maintains it, sensitises adipose tissue to insulin, and reduces fasting glucose levels, so it seems to be a potential target in this kind of metabolic disorder, but some research results are inconclusive. CBD shows some promising results in the treatment of various lipid disorders. Some studies have proven its positive effect by decreasing LDL and increasing HDL as well. Despite their probable efficacy, CBD and its derivatives will likely remain an adjunctive treatment rather than a mainstay of therapy. Studies have also shown that CBD in patients with hypertension has positive effects, even though the hypotensive properties of cannabidiol are small. However, CBD can be used to prevent blood pressure surges, stabilise them, and have a protective effect on blood vessels. Results from preclinical studies have shown that the effect of cannabidiol on NAFLD may be potentially beneficial in the treatment of the metabolic syndrome and its components. Nevertheless, there is limited data on CBD and NAFLD in human studies. Because of the numerous confounding factors, the conclusions are unclear, and more research in this field is required.
... Cannabidiol inhibits the progression of disorders such as Parkinson's and Alzheimer's. 16 CBD acts as an inhibitor of anandamide reuptake, an inverse agonist of the CB2 receptor, as well as a non-competitive negative allosteric modifier of the CB1 receptor. DELTA.8-Tetrahydrocannabinol ...
... This approval occurred after a period of 5 years having orphan designation, which allowed the development of clinical trials that demonstrated its efficacy and good tolerability as a symptom-alleviating agent for the treatment of seizures associated with DS (Devinsky et al., 2017;Miller et al., 2020) and Lennox-Gastaut syndrome (Devinsky et al., 2018;Thiele et al., 2018), as well as epilepsy associated with tuberous sclerosis syndrome (Thiele et al., 2021), then confirming previous anecdotal findings (Devinsky et al., 2016;Franco and Perucca, 2019;Franco et al., 2021). Despite these recent advances, an effective therapy against long-term comorbidities in DS, beyond the control of seizure activity, is still lacking, although such benefits may be reached with CBD and/or other cannabinoids (Sagredo et al., 2018), given its well-demonstrated anti-inflammatory, antioxidant and cytoprotective properties (Fernández-Ruiz et al., 2013;Fernández-Ruiz, 2019). Such profile may be particularly useful for long-term comorbidities found in DS patients (Villas et al., 2017;Lagae et al., 2018;Scheffer et al., 2021), an objective recently investigated in Scn1a +/− mice, in which CBD attenuated associated comorbidities (e.g., autism-like social deficits) through effects that appeared to be mediated, at least in part, by GPR55 (Kaplan et al., 2017). ...
Cannabidiol (CBD) has been recently approved as an antiseizure agent in Dravet Syndrome (DS), a pediatric epileptic encephalopathy, but CBD could also be active against associated comorbidities. Such associated comorbidities were also attenuated by the sesquiterpene β-caryophyllene (BCP). Here, we have compared the efficacy of both compounds and further initiated the analysis of a possible additive effect between both compounds in relation with these comorbidities using two experimental approaches. The first experiment was aimed at comparing the benefits of CBD and BCP, including their combination in conditional knock-in Scn1a-A1783V mice, an experimental model of DS, treated since the postnatal day 10th to 24th. As expected, DS mice showed impairment in limb clasping, delay in the appearance of hindlimb grasp reflex and additional behavioural disturbances (e.g., hyperactivity, cognitive deterioration, social interaction deficits). This behavioural impairment was associated with marked astroglial and microglial reactivities in the prefrontal cortex and the hippocampal dentate gyrus. BCP and CBD administered alone were both able to partially attenuate the behavioural disturbances and the glial reactivities, with apparently greater efficacy against glial reactivities obtained with BCP, whereas superior effects in a few specific parameters were obtained when both compounds were combined. In the second experiment, we investigated this additive effect in cultured BV2 cells treated with BCP and/or CBD and stimulated with LPS. As expected, addition of LPS induced a marked increase in several inflammation-related markers (e.g., TLR4, COX-2, iNOS, catalase, TNF-α, IL-1β), as well as elevated Iba-1 immunostaining. Treatment with BCP or CBD attenuated these elevations, but, again and in general, superior results were obtained when both cannabinoids were combined. In conclusion, our results support the interest to continue investigating the combination of BCP and CBD to improve the therapeutic management of DS in relation with their disease-modifying properties.
... CBD treatment is effective for neuroinflammatory-derived conditions such as epilepsy and anxiety. 184 The pathological functions of the CB-2 receptor in inflammatory conditions (e.g., Alzheimer's disease, Parkinson's disease, multiple sclerosis, stress response, and depression) are under active investigation. 185,186 Inflammation is a driving factor of depression and could counter the effects of antidepressant therapies. ...
Neuropsychiatric disorders are multifactorial disorders with diverse aetiological factors. Identifying treatment targets is challenging because the diseases are resulting from heterogeneous biological, genetic, and environmental factors. Nevertheless, the increasing understanding of G protein-coupled receptor (GPCR) opens a new possibility in drug discovery. Harnessing our knowledge of molecular mechanisms and structural information of GPCRs will be advantageous for developing effective drugs. This review provides an overview of the role of GPCRs in various neurodegenerative and psychiatric diseases. Besides, we highlight the emerging opportunities of novel GPCR targets and address recent progress in GPCR drug development.
... Despite analogous chemical structures, these components exert distinct pharmacological impacts (De Petrocellis et al., 2011;Pattnaik et al., 2022). CBD, the second most common ingredient in cannabis, has attracted particular attention for its neuroprotective, antidepressant, and antipsychotic properties (Blessing et al., 2015;Fernández-Ruiz et al., 2013;Leweke et al., 2012). CBD has shown some therapeutic potential toward drug-associated rewarding effects (Chesworth and Karl, 2020;Chye et al., 2019). ...
Cannabidiol (CBD) is a potential treatment to decrease the rewarding properties of psychostimulants. However, the exact mechanism and distinct neuroanatomical areas responsible for the CBD's effects remain unclear. Indicatively, the D1-like dopamine receptors (D1R) in the hippocampus (HIP) are essential for expressing and acquiring drug-associated conditioned place preference (CPP). Therefore, given that involving D1Rs in reward-related behaviors and the encouraging results of CBD in attenuating the psychostimulant's rewarding effects, the present study sought to investigate the role of D1Rs of the hippocampal dentate gyrus (DG) in the inhibitory effects of CBD on the acquisition and expression of METH-induced CPP. To this end, over a 5-day conditioning period by METH (1 mg/kg; sc), different groups of rats were given intra-DG SCH23390 (0.25, 1, or 4 μg/0.5 μl, saline) as a D1Rs antagonist before ICV administration of CBD (10 μg/5 μl, DMSO12%). In addition, a different set of animals, after the conditioning period, received a single dose of SCH23390 (0.25, 1, or 4 μg/0.5 μl) before CBD (50 μg/5 μl) administration on the expression day. The results showed that SCH23390 (1 and 4 μg) significantly reduced the suppressive effects of CBD on the acquisition of METH place preference (P < 0.05 and P < 0.001, respectively). Furthermore, the highest dose of SCH23390 (4 μg) in the expression phase remarkably abolished the preventive effects of CBD on the expression of METH-seeking behavior (P < 0.001). In conclusion, the current study revealed that CBD's inhibitory effect on rewarding properties of METH partially acts through D1Rs in the DG area of the HIP.
... Since hemp seeds are rich in important fatty acids, such as α-linolenic acid [145], hemp oil can be used to help with inflammatory diseases like arthritis, as well as to reduce blood pressure and cholesterol levels in the arteries [147]. Hemp oil, when applied topically, is used to treat open wounds, scalding injuries, and irritations of the skin including psoriasis and neurodermatosis [148]. In addition, hemp contains gamma-linolenic acid, a popular substance with many health advantages. ...
Currently, there are increased interests in growing grain and fiber hemp (Cannabis sativa L.) as well as in large-scale hemp products. Cannabis has been grown/utilized for thousands of years as a fiber, grain, and drug/medicinal plant. However, the strict control of cannabis cultivation to combat illegal use, the spread of new yarns and oilseeds, and the advent of cheap synthetic fibers caused a decreased/eliminated hemp production. Hemp has been banned in most of the world for more than seven decades; it missed out on the Green Revolution and the adoption of new technologies and varieties, creating a knowledge gap. After the 2014 and 2018 Farm Bill in the USA, hemp became legal and the land grand universities launched research programs. The ability to utilize the entire plant for multiple purposes creates opportunity for the market to value hemp products. Hemp production technology varies depending on the type of hemp cultivated (grain, fiber, or cannabinoids), soil characteristics, and environmental factors. Hemp has the potential to be a very sustainable and ecologically benign crop. Hemp roots have a significant potential for absorbing and storing heavy metals such as lead, nickel, cadmium, and other harmful substances. In addition, hemp has been proven to be an excellent carbon trap and biofuel crop. Hemp has the ability to successfully suppress weeds, and it is generally regarded a pesticide-free crop. The purpose of this paper is to examine historic and recent industrial hemp (grain and fiber) literature, with a focus on hemp agronomy and utilization.
... In contrast, 2-AG shows a moderate affinity for both receptors and acts as a complete agonist [35]. The exogenous THC is a partial CB1 and CB2 agonist, whereas the affinity of phytocannabinoid CBD to both CB1 and CB2 receptors is low [36,37]. ...
Since legalization, cannabis/marijuana has been gaining considerable attention as a functional ingredient in food. ∆-9 tetrahydrocannabinol (THC), cannabidiol (CBD), and other cannabinoids are key bioactive compounds with health benefits. The oral consumption of cannabis transports much less hazardous chemicals than smoking. Nevertheless, the response to cannabis is biphasically dose-dependent (hormesis; a low-dose stimulation and a high-dose inhibition) with wide individuality in responses. Thus, the exact same dose and preparation of cannabis may be beneficial for some but toxic to others. The purpose of this review is to highlight the concept of individual variations in response to cannabinoids, which leads to the challenge of establishing standard safe doses of cannabis products for the general population. The mechanisms of actions, acute and chronic toxicities, and factors affecting responses to cannabis products are updated. Based on the literature review, we found that the response to cannabis products depends on exposure factors (delivery route, duration, frequency, and interactions with food and drugs), individual factors (age, sex), and susceptibility factors (genetic polymorphisms of cannabinoid receptor gene, N-acylethanolamine-hydrolyzing enzymes, THC-metabolizing enzymes, and epigenetic regulations). Owing to the individuality of responses, the safest way to use cannabis-containing food products is to start low, go slow, and stay low.
... Despite the therapeutic efficacy, the specific mechanisms underlying the anti-inflammatory/ neuroprotective effects of CBD and CBD-THC products are not yet fully understood and most likely involve receptor-independent mechanisms, such as nuclear factors (see review [285]). To date, no in vivo evidence exists about anti-inflammatory CBD effects in neuropsychiatric disorders, such as schizophrenia, or in wild-type (animals) or healthy conditions (humans). ...
Cannabis is the most used drug of abuse worldwide. It is well established that the most abundant phytocannabinoids in this plant are Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD). These two compounds have remarkably similar chemical structures yet vastly different effects in the brain. By binding to the same receptors, THC is psychoactive, while CBD has anxiolytic and antipsychotic properties. Lately, a variety of hemp-based products, including CBD and THC, have become widely available in the food and health industry, and medical and recreational use of cannabis has been legalized in many states/countries. As a result, people, including youths, are consuming CBD because it is considered “safe”. An extensive literature exists evaluating the harmful effects of THC in both adults and adolescents, but little is known about the long-term effects of CBD exposure, especially in adolescence. The aim of this review is to collect preclinical and clinical evidence about the effects of cannabidiol.
... Additionally, the inhibitory control of NF-κB can be achieved by reducing the phosphorylation of kinases involved in the transcription of this factor such as p38 mitogen-activated protein kinase (p38 MAPK) [137]. Additionally, in the same category of mechanisms with neuroprotective potential are included 5-HT 1A receptors, adenosine reuptake inhibition, and the WNT/β-catenin signaling pathway, which has an important role in β-amyloid (Aβ)-induced glycogen synthase kinase-3 beta activation (GSK-3β) and tau hyperphosphorylation [141,142]. ...
The literature provides scientific evidence for the beneficial effects of cannabidiol (CBD), and these effects extend beyond epilepsy treatment (e.g., Lennox–Gastaut and Dravet syndromes), notably the influence on oxidative status, neurodegeneration, cellular protection, cognitive function, and physical performance. However, products containing CBD are not allowed to be marketed everywhere in the world, which may ultimately have a negative effect on health as a result of the uncontrolled CBD market. After the isolation of CBD follows the discovery of CB1 and CB2 receptors and the main enzymatic components (diacylglycerol lipase (DAG lipase), monoacyl glycerol lipase (MAGL), fatty acid amino hydrolase (FAAH)). At the same time, the antioxidant potential of CBD is due not only to the molecular structure but also to the fact that this compound increases the expression of the main endogenous antioxidant systems, superoxide dismutase (SOD), and glutathione peroxidase (GPx), through the nuclear complex erythroid 2-related factor (Nrf2)/Keep1. Regarding the role in the control of inflammation, this function is exercised by inhibiting (nuclear factor kappa B) NF-κB, and also the genes that encode the expression of molecules with a pro-inflammatory role (cytokines and metalloproteinases). The other effects of CBD on cognitive function and physical performance should not be excluded. In conclusion, the CBD market needs to be regulated more thoroughly, given the previously listed properties, with the mention that the safety profile is a very good one.
... CBD (40-160 mg/day) elevated cumulative sleep latency and minimised the rate of awakenings in patients with insomnia (Sieradzan et al. 2001;Jung and Louis 2016;Crippa et al. 2011;Carlini and Cunha 1981;Chagas et al. 2013;Babson et al. 2017). CBDs were investigated in a limited number of PD patients, although the tests were only conducted for a limited duration, there was a diminution in the prevalence of symptoms, but longer research is needed to validate its therapeutic safety (Chung et al. 2012 Apr;Lastres-Becker et al. 2001 Dec;García et al. 2011;Sagredo et al. 2007;Esposito et al. 2011;Ashton and Glass 2007;Abellanas and Aymerich 2020;Tagliaferro et al. 2006;Esposito et al. 2001;Chung et al. 2016Chung et al. , 2002Chung et al. , 2011Chung et al. , 2017Cassano et al. 2017;Bisogno et al. 2016;Sánchez et al. 2001;Fagan and Campbell 2014;Gao et al. 2008;Zhang et al. 2021;Tilleux and Hermans 2007;Dantzer and Walker 2014;Beal 1992;Beal et al. 1993;Giráldez-Pérez et al. 2014;Sánchez-Blázquez et al. 2013;Miguelez et al. 2008;Colín-González et al. 2016;Naidoo et al. 2011;Farizatto et al. 2017;Han et al. 2020Han et al. , 2016Bisogno and Marzo 2010;Guzmán et al. 2002;Van der Stelt et al. 2001;Hampson et al. 1998;Rubio et al. 2011;Shefa et al. 2006;Villanueva et al. 2015;Moghaddam et al. 2007;Little et al. 2011;Booz 2011;Rajesh et al. 2006;Moris et al. 2015;Paloczi et al. 2018;Geranmayeh et al. 2017;Maya-López et al. 2017;Aguilera-Portillo et al. 2019;Fernández-Ruiz et al. 2013;Carrera and Cacabelos 2019;Oliveira et al. 2019;Xapelli et al. 2013;Reisenberg et al. 2012;Kaur et al. 2019;Kelly et al. 2020;Shin et al. 2017;Goncalves et al. 2008;Oddi et al. 2020;Onaivi et al. 2006;Grote and Hannan 2007;Xia and Mao 2012;Balestrino and Schapira 2020;Brotchie 2003;Lastres-Becker and Fernandez-Ruiz 2006;Segovia et al. 2003;Sieradzan et al. 2001;Sañudo-Peña et al. 1998;Fox and Brotchie 2010;Marzo et al. 2000;González et al. 2005;Pfeiffer 2016;Crippa et al. 2019Crippa et al. , 2011Murueta-Goyena et al. 2019;Ryan et al. 2019;Ferreira-Junior et al. 2019;Gonzalez-Latapi et al. 2020;Bhattacharyya et al. 2010;Bergamaschi et al. 2011;Campos et al. 2013;Vallée et al. 2021;Leweke et al. 2012a, b;Schier et al. 2012;Rajan et al. 2016;Fénelon and Alves 2010;Zhen and Chu 2020;Friedman and Factor 2000;Iffland and Grotenhermen 2017;Davies and Bhattacharyya 2019;Gururajan and Malone 2016;Chagas et al. 2014Chagas et al. , 2013Murillo-Rodríguez et al. 2018;Bliwise 2004;Jung and Louis 2016;Carlini and Cunha 1981;Babson et al. 2017). CBD operates by modulating the circadian cycle, as evidenced by research suggesting that perhaps the CB1 receptor being distributed with in the brain and consequently regulates the sleeping pattern and anandamide stimulation prolongs REM sleep while minimising wakefulness. ...
Parkinson's disease is a neurodegenerative disorder which is characterised mostly by loss of dopaminergic nerve cells throughout the nigral area mainly as a consequence of oxidative stress. Muscle stiffness, disorganised bodily responses, disturbed sleep, weariness, amnesia, and voice impairment are all symptoms of dopaminergic neuron degeneration and existing symptomatic treatments are important to arrest additional neuronal death. Some cannabinoids have recently been demonstrated as robust antioxidants that might protect the nerve cells from degeneration even when cannabinoid receptors are not triggered. Cannabinoids are likely to have property to slow or presumably cease the steady deterioration of the brain's dopaminergic systems, a condition for which there is now no treatment. The use of cannabinoids in combination with currently available drugs has the potential to introduce a radically new paradigm for treatment of Parkinson's disease, making it immensely useful in the treatment of such a debilitating illness.
... A contribution of neuroprotective and anti-inflammatory therapeutic strategies for these diseases is important since actual conventional treatments do not stop the neurodegenerative progression. The neuroprotective potential of CBD, resulting from its anti-inflammatory and antioxidant properties, is under intense preclinical research for use in numerous neurodegenerative diseases [22]. Thus, CBD, which lacks any unwanted psychotropic effect, may represent a very promising agent [23,24]. ...
This work is a literature review, presenting the current state of the use of cannabinoids on neurodegenerative diseases. The emphasis is on Parkinson’s (PD) and Alzheimer’s (AD) diseases, the two most prevalent neurological diseases. The review goes from Cannabis sativa and its hundreds of bioactive compounds to Δ<sup>9</sup>-tetrahydrocannabinol (THC) and mainly cannabidiol (CBD) and their interactions with the endocannabinoid receptors (CB1 and CB2). CBD molecular targets were also focused on to explain its neuroprotective action mechanism on neurodegenerative diseases. Although THC is the main psychoactive component of C. sativa, and it may induce transient psychosis-like symptoms, growing evidence suggests that CBD may have protective effects against the psychotomimetic effects of THC and therapeutic properties. Furthermore, a great number of recent works on the neuroprotective and anti-inflammatory CBD effects and its molecular targets are also reviewed. We analyzed CBD actions in preclinical and in clinical trials, conducted with PD and AD patients. Although the data on preclinical assays are more convincing, the same is not true with the clinical data. Despite the consensus among researchers on the potential of CBD as a neuroprotective agent, larger and well-designed randomized clinical trials will be necessary to gather conclusive results concerning the use of CBD as a therapeutic strategy for the treatment of diseases such as PD and AD.
... CBD alone has been FDA-approved for treating treatmentresistant pediatric epilepsy in 2018 (Devinsky et al., 2016). In addition, its anticonvulsant, antiemetic, and sleep-inducing properties have been explored to treat epilepsy and sleep disorders, as well as for treating psychiatric disorders such as schizophrenia, anxiety, and depression (Fernández-Ruiz et al., 2013). CBD showed a better safety profile and tolerability in patients (1,500 mg/day) than THC (Bergamaschi et al., 2011). ...
Despite the significant advances in neurology, the cure for neurodegenerative conditions remains a formidable task to date. Among various factors arising from the complex etiology of neurodegenerative diseases, neuroinflammation and oxidative stress play a major role in pathogenesis. To this end, some phytocannabinoids isolated from Cannabis sativa (widely known as marijuana) have attracted significant attention as potential neurotherapeutics. The profound effect of ∆9-tetrahydrocannabinol (THC), the major psychoactive component of cannabis, has led to the discovery of the endocannabinoid system as a molecular target in the central nervous system (CNS). Cannabidiol (CBD), the major non-psychoactive component of cannabis, has recently emerged as a potential prototype for neuroprotective drug development due to its antioxidant and anti-inflammatory properties and its well-tolerated pharmacological behavior. This review briefly discusses the role of inflammation and oxidative stress in neurodegeneration and demonstrates the neuroprotective effect of cannabidiol, highlighting its general mechanism of action and disease-specific pathways in Parkinson’s disease (PD) and Alzheimer’s disease (AD). Furthermore, we have summarized the preclinical and clinical findings on the therapeutic promise of CBD in PD and AD, shed light on the importance of determining its therapeutic window, and provide insights into identifying promising new research directions.
... A similar effect was obtained with CBD, an inverse agonist at CB1, which represents 34% of CSE constituents. The modulation of ECS is not the only mechanism of action of CBD, and several papers reported the antioxidant and anti-inflammatory activity of this cannabinoid by reducing NF-κB translocation, cytokines release, and the activation of ERK and Akt signaling pathways [40][41][42]. Moreover, it can modulate BDNF levels and reduce lipid peroxidation in SH-SY5Y cells, also through peroxisome proliferator-activated receptor gamma (PPARγ) activation [43,44]. ...
The purpose of this study was to evaluate the neuroprotective effect of a cannabidiol-enriched non-psychotropic Cannabis sativa L. extract (CSE) and its main constituents, cannabidiol and β-caryophyllene. An in vitro model of glutamate-induced neuronal excitotoxicity using SH-SY5Y cells was optimized. The impact of CSE on glutamate-impaired cell viability, brain-derived neurotrophic factor release, CB1 protein expression, and ERK levels was evaluated. The involvement of CB1 modulation was verified by the cotreatment with the CB1 antagonist AM4113. CSE was able to significantly protect SH-SY5Y from glutamate-impaired cell viability, and to counteract the changes in brain-derived neurotrophic factor levels, with a mechanism of action involving ERK modulation. Moreover, CSE completely reversed the reduction of CB1 receptor expression induced by glutamate, and the presence of the CB1 antagonist AM4113 reduced CSE effectiveness, suggesting that CBr play a role in the modulation of neuronal excitotoxicity.
This work demonstrated the in vitro effectiveness of CSE as a neuroprotective agent, proposing the whole cannabis phytocomplex as a more effective strategy, compared to its main constituents alone, and suggested further investigations by using more complex cell models before moving to in vivo studies.
... Unlike ∆ 9 -tetrahydrocannabinol (∆ 9 -THC), CBD is non-psychotropic [9,10]. CBD has a wide range of therapeutic potentials, including the treatment of cancer [11], inflammatory diseases [12], neurodegenerative diseases [13,14], and psychiatric diseases [15]. Recently, CBD (Epidiolex/Epidyolex)) received both food and drug administration (FDA) and European Medicines Agency (EMA) approvals for treating epilepsy in children; this is the first time a constituent isolated from cannabis has been FDA approved [16]. ...
Intraocular pressure (IOP) is regulated primarily through aqueous humor production by ciliary body and drainage through uveoscleral and trabecular meshwork (TM) tissues. The goal of this study was to measure the effect of non-psychotropic cannabidiol (CBD) on aqueous humor outflow through TM and assess the effect of CBD on the TM cell signaling pathways that are important for regulating outflow. Perfused porcine eye anterior segment explants were used to investigate the effects of CBD on aqueous humor outflow. Cultured porcine TM cells were used to study the effects of CBD on TM cell contractility, myosin light chain (MLC) and myosin phosphatase targeting subunit 1 (MYPT1) phosphorylation, and RhoA activation. In the anterior segment perfusion experiments, aqueous humor outflow was increased significantly within 1 h after adding 1 µM CBD and the effect was sustained over the 5 h of measurement. Treatment of TM cells with 1 µM CBD significantly decreased TM cell-mediated collagen contraction, inhibited phosphorylation of MLC and MYPT1, and reduced RhoA activation. Our data demonstrate, for the first time, that as a potential therapeutic agent for lowering intraocular pressure, CBD can enhance aqueous humor outflow and modify TM cell signaling.
... The pharmacological pro le of CBD is complex. It has potent antiin ammatory and antioxidant properties [71,72] and exerts its actions throughout both the endocannabinoid system and other neurotransmitter systems. Treatment with CBD increases anandamide levels, in turn further activating cannabinoid CB 1 receptors [73,74]. ...
Evidence for the clinical use of neuroprotective drugs for the treatment of cerebral ischemia (CI) is still greatly limited. Spatial/temporal disorientation and cognitive dysfunction are among the most prominent long-term sequelae of CI. Cannabidiol (CBD) is a non-psychotomimetic constituent of Cannabis sativa that exerts neuroprotective effects against experimental CI. The present study investigated possible neuroprotective mechanisms of action of CBD on spatial memory impairments that are caused by transient global cerebral ischemia (TGCI) in rats. Hippocampal synaptic plasticity is a fundamental mechanism of learning and memory. Thus, we also evaluated the impact of CBD on neuroplastic changes in the hippocampus after TGCI. Wistar rats were trained to learn an eight-arm aversive radial maze (AvRM) task and underwent either sham or TGCI surgery. The animals received vehicle or 10 mg/kg CBD (i.p.) 30 min before surgery, 3 h after surgery, and then once daily for 14 days. On days 7 and 14, we performed a retention memory test. Another group of rats that received the same pharmacological treatment was tested in the object location test (OLT). Brains were removed and processed to assess neuronal degeneration, synaptic protein levels, and dendritic remodeling in the hippocampus. Cannabidiol treatment attenuated ischemia-induced memory deficits. In rats that were subjected to TGCI, CBD attenuated hippocampal CA1 neurodegeneration and increased brain-derived neurotrophic factor levels. Additionally, CBD protected neurons against the deleterious effects of TGCI on dendritic spine number and the length of dendritic arborization. These results suggest that the neuroprotective effects of CBD against TGCI-induced memory impairments involve changes in synaptic plasticity in the hippocampus.
... Over the last years, research has focused on studying the pharmacological effects of the non-psychoactive cannabinoid CBD (Pisanti et al., 2017;Britch et al., 2021). It has been shown that CBD elicits, via 5-HT 1A receptor, antiepileptic (Silvestro et al., 2020), anticataleptic (Gomes et al., 2013), neuroprotective (Fernández-Ruiz et al., 2013;Silvestro et al., 2020), antiemetic (Rock et al., 2012;Bolognini et al., 2013), anxiolytic (Resstel et al., 2009;Marinho et al., 2015;De Gregorio et al., 2019), antidepressant (Zanelati et al., 2010;Linge et al., 2016;Sartim et al., 2016), antipsychotic (Rodrigues da Silva et al., 2020), or analgesic effects (De Gregorio et al., 2019;Jesus et al., 2019;Britch et al., 2021). Furthermore, CBD increased [(35) S]GTPγS binding, reduced cAMP, and displaced [3H]8-OH-DPAT from cloned human 5-HT 1A receptors, suggesting a partial agonism at 5-HT 1A receptors (Russo et al., 2005). ...
Cannabidiol (CBD), the main non-psychoactive cannabinoid found in the cannabis plant, elicits several pharmacological effects via the 5-HT 1A receptor. The dorsal raphe nucleus (DRN) is the main serotonergic cluster in the brain that expresses the 5-HT 1A receptor. To date, the effect of CBD on the neuronal activity of DRN 5-HT cells and its interaction with somatodendritic 5-HT 1A autoreceptors have not been characterized. Our aim was to study the effect of CBD on the firing activity of DRN 5-HT cells and the 5-HT 1A autoreceptor activation by electrophysiological and calcium imaging techniques in male Sprague–Dawley rat brain slices. Perfusion with CBD (30 μM, 10 min) did not significantly change the firing rate of DRN 5-HT cells or the inhibitory effect of 5-HT (50–100 μM, 1 min). However, in the presence of CBD (30 μM, 10 min), the inhibitory effects of 8-OH-DPAT (10 nM) and ipsapirone (100 nM) were reduced by 66% and 53%, respectively. CBD failed to reverse ipsapirone-induced inhibition, whereas perfusion with the 5-HT 1A receptor antagonist WAY100635 (30 nM) completely restored by 97.05 ± 14.63% the firing activity of 5-HT cells. Administration of AM251 (1 µM), MDL100907 (30 nM), or picrotoxin (20 μM) did not change the blockade produced by CBD (30 μM) on ipsapirone-induced inhibition. Our study also shows that CBD failed to modify the KCl (15 mM, 4 min)-evoked increase in [Ca ²⁺ ] i or the inhibitory effect of ipsapirone (1 μM, 4 min) on KCl-evoked [Ca ²⁺ ] i . In conclusion, CBD does not activate 5-HT 1A autoreceptors, but it hindered the inhibitory effect produced by selective 5-HT 1A receptor agonists on the firing activity of DRN 5-HT cells through a mechanism that does not involve CB 1 , 5-HT 2A, or GABA A receptors. Our data support a negative allosteric modulation of DRN somatodendritic 5-HT 1A receptor by CBD.
... As CBD does not directly activate the cannabinoid receptor type 1 (CB 1 ), it is, thus, devoid of the psychoactive side effects exhibited by THC and is also considered a safe drug (Pisanti et al., 2017). Given its action as a pleiotropic molecule and its targeting of various proteins of the cannabinoid system, CBD can be described as a neuromodulator, with an increasing amount of data evidencing its neuromodulatory properties in different neurological and neuropsychiatric disorders (Fernández-Ruiz et al., 2013;Campos et al., 2017;Patricio et al., 2020;Xiong and Lim, 2021). Moreover, cannabinoid-related receptors, such as the G-protein coupled receptor 55 (GPR55), may play an important role in the effects exerted by CBD in the central nervous system (CNS) (Ryberg et al., 2007;Ligresti et al., 2016;Kaplan et al., 2017). ...
Cannabidiol (CBD) presents antiparkinsonian properties and neuromodulatory effects, possibly due to the pleiotropic activity caused at multiple molecular targets. Recently, the GPR55 receptor has emerged as a molecular target of CBD. Interestingly, GPR55 mRNA is expressed in the external globus pallidus (GPe) and striatum, hence, it has been suggested that its activity is linked to motor dysfunction in Parkinson’s disease (PD). The present study aimed to evaluate the effect of the intrapallidal injection of both CBD and a selective GPR55 antagonist (CID16020046) on motor asymmetry, fine motor skills, and GAD-67 expression in hemiparkinsonian rats. The hemiparkinsonian animal model applied involved the induction of a lesion in male Wistar rats via the infusion of the neurotoxin 6-hydroxydopamine (6-OHDA) into the medial forebrain bundle via stereotaxic surgery. After a period of twenty days, a second surgical procedure was performed to implant a guide cannula into the GPe. Seven days later, lysophosphatidylinositol (LPI), CBD, or CID16020046 were injected once a day for three consecutive days (from the 28th to the 30th day post-lesion). Amphetamine-induced turning behavior was evaluated on the 14th and 30th days post-injury. The staircase test and fine motor skills were evaluated as follows: the rats were subject to a ten-day training period prior to the 6-OHDA injury; from the 15th to the 19th days post-lesion, the motor skills alterations were evaluated under basal conditions; and, from the 28th to the 30th day post-lesion, the pharmacological effects of the drugs administered were evaluated. The results obtained show that the administration of LPI or CBD generated lower levels of motor asymmetry in the turning behavior of hemiparkinsonian rats. It was also found that the injection of CBD or CID16020046, but not LPI, in the hemiparkinsonian rats generated significantly superior performance in the staircase test, in terms of the use of the forelimb contralateral to the 6-OHDA-induced lesion, when evaluated from the 28th to the 30th day post-lesion. Similar results were also observed for superior fine motor skills performance for pronation, grasp, and supination. Finally, the immunoreactivity levels were found to decrease for the GAD-67 enzyme in the striatum and the ipsilateral GPe of the rats injected with CBD and CID16020046, in contrast with those lesioned with 6-OHDA. The results obtained suggest that the inhibitory effects of CBD and CID16020046 on GPR55 in the GPe could be related to GABAergic overactivation in hemiparkinsonism, thus opening new perspectives to explain, at a cellular level, the reversal of the motor impairment observed in PD models.
... GLT1 has been suggested as a pharmacological target (Soni et al., 2014) with its upregulation having been observed to attenuate HD phenotypes (Miller et al., 2008(Miller et al., , 2012. Cannabidiol is also being explored as a clinical intervention for neurodegenerative disorders (Fernández-Ruiz et al., 2012). Due to the complex interaction between excitatory and inhibitory input and subsequent production and release of eCB, our modeling results suggest that therapeutics that target CB1R specifically on glutamatergic terminals may be needed, because given an overall decrease in the excitatory/inhibitory balance, increasing eCB signaling, in general, may counterproductively increase inhibitory tone. ...
Dysregulated endocannabinoid (eCB) signaling and the loss of cannabinoid receptors (CB1Rs) are important phenotypes of Huntington's disease (HD) but the precise contribution that eCB signaling has at the circuit level is unknown. Using a computational model of spiking neurons, synapses, and eCB signaling, we demonstrate that eCB signaling functions as a homeostatic control mechanism, minimizing excess glutamate. Furthermore, our model demonstrates that metabolic risk, quantified by excess glutamate, increases with cortico-striatal long-term depression (LTD) and/or increased cortico-striatal activity, and replicates a progressive loss of cannabinoid receptors on inhibitory terminals as a function of the excitatory/inhibitory ratio.
... In fact, myriad papers have reported cannabinoid effects on AD using experimental in vitro and in vivo models. For instance, cannabinoid treatment attenuates Aβ and neurofibrillary tau accumulation, as well as memory deficits in AD transgenic mouse models [34,35]; blocks Aβ neuronal proteolysis and prevents Aβ aggregation [36]; mitigates Aβ-induced neuroinflammation and oxidative stress [37]; whereas favoring neurogenesis factors [that is, brain-derived neurotrophic factor (BDNF)] and antiinflammatory cytokine release, as well as presynaptic and axonal proteins upregulation [10,34,[37][38][39][40][41][42][43][44][45]. Thus, we are also hypothesizing that the long-term positive effects of the cannabinoid extract may be due to reduction in AD-related neuroinflammation. ...
Background
Cannabinoid-based therapy has been shown to be promising and is emerging as crucial for the treatment of cognitive deficits, mental illnesses, and many diseases considered incurable. There is a need to find an appropriate therapy for Alzheimer’s disease, and cannabinoid-based therapy appears to be a feasible possibility.
Case presentation
This report addresses the beneficial effect of cannabinoids in microdoses on improving memory and brain functions of a patient with mild-stage Alzheimer’s disease. The patient is a 75-year-old white man presenting with main symptoms of memory deficit, spatial and temporal disorientation, and limited daily activity. The experimental therapeutic intervention was carried out for 22 months with microdoses of a cannabis extract containing cannabinoids. Clinical evaluations using Mini-Mental State Examination and Alzheimer’s Disease Assessment Scale-Cognitive Subscale were performed.
Conclusions
Here we provide original evidence that cannabinoid microdosing could be effective as an Alzheimer’s disease treatment while preventing major side effects. This is an important step toward dissociating cannabinoids’ health-improving effects from potential narcotic-related limitations.
... Phytocannabinoids, which can be extracted from hemp plants, have been used for therapeutic purposes [1][2][3]. ∆9-tetrahydrocannabinol (THC) and cannabidiol (CBD) have been metabolically synthesized from cannabigerol (CBG) via the acid form (THCA or CBDA) with the catalytic action of THCA synthase (EC 1.21.3.7) or CBDA synthase (EC 1.21.3.8) [4]. ...
Extracts of phytocannabinoids from Cannabis sativa have been studied for therapeutic purposes. Although nonpsychoactive CBD has been studied as a promising anticancer drug because it induces apoptosis in many cancer cells, it is also known to induce several physiological changes. In this study, we clarify the functional role it plays in the morphological characteristics of intracellular vesicle formation as well as apoptosis in A549 human lung cancer cells. CBD treatment shows growth inhibition at concentrations above 20 μM, but FACS analysis shows low efficacy in terms of cell death. Microscopic observations suggest that multiple vesicles were detected in the cytoplasmic region of CBD-treated A549 cells. CBD treatment upregulates apoptosis-related proteins, such as p53, PARP, RIP1, RIP3, Atg12, and Beclin, indicating that CBD regulates several types of cell death. CBD treatment also induced E-cadherin, PPARγ, clathrin, β-adaptin, and Tsg101, also known to be cellular-differentiation inducers or vesicle-formation components. Treatment combining CBD with GW9662, a PPARγ inhibitor, reduced CBD-induced cytoplasmic vesicle formation. This indicates that PPARγ regulates the vesicle-formation mechanism. However, CBD-treated E-cad KO clones did not show this regulatory mechanism. These results elucidate the pharmacological and molecular networks associated with CBD in PPARγ-dependent vesicle formation and the induction of apoptosis.
... The constituents of C.sativa are the psychoactive tetrahydrocannabinol (THC), non-psychoactive cannabidiol (CBD), mildly psychoactive cannabinol (CBN), followed by the parent molecule cannabigerol (CBG), cannabichrom (CBC) and in low amounts psychoactive cannabinodiol (CBND) [8]. Especially, CBD has drawn extensive interest because of its various therapeutic and pharmacological attributes [9,10]. A challenge is it has low solubility in aqueous media and a relatively low bioavailability, enabling it to be utilized as single compound or dissolved with polar solvents [11]. ...
Due to its limited treatment options, multi-drug resistant bacteria such as Gram-positive methicillin-resistant Staphylococcus aureus (MRSA) still remains a serious public health threat. The creation of new compelling antimicrobial materials , antibiotics and optional methodologies, which are successful against resistant microbes, is earnestly required. The le-galization of cannabis in Canada has provided a new opportunity to investigate the antimicrobial studies of both extracts and individual cannabinoids. This study investigates pure cannabidiol (CBD) isolated from Cannabis sativa by using a methodology of extraction, purification , characterization, and quantification of CBD. The shredded plant material was dissolved in ethanol, with the extract further purified using supercritical fluid chromatography (SFC) to obtain purified CBD. Product purity was confirmed by HPLC and NMR spectroscopy. CBD's antibacterial activity on MRSA strain USA300 bacteria was studied using dilution series in liquid culture and disk diffusion assays to provide the minimum inhibitory concentration (MIC) and minimal bactericidal concentrations (MBC). We have also performed statical analysis between CBD concentration groups with no CBD (control) and found a significant difference in cell counts of these groups. Past papers had not shown any MBC values-we have obtained a novel MBC value for CBD industrially extracted from Cana-dian grown C. Sativa plants. The results showed that CBD exhibited a significant bacteri-cidal effect on MRSA with the MIC value of 2.5 µg/mL and MBC of 10 µg/mL. CBD powder form gave a higher antimicro-bial activity than its oil form in terms of the inhibition zone. This study shows that CBD exhibits good antimicrobial impact against the MRSA strain showing its utility for enabling a new antibiotic-free method for treating MRSA infections.
... ere have been some complementary options reported for the PD pharmacological treatment [11,16]. Currently, cannabidiol (CBD) is one of the main interesting options for PD because of the identification of its multiple potential targets of action in the central nervous system (CNS) and its therapeutic properties for a range of neurodegenerative diseases [17][18][19]. CBD, a nonpsychotomimetic phytocannabinoid derived from the Cannabis sativa, was found to widely suppress inflammatory signaling and oxidative stress. It has antiparkinsonian potential, as it can alleviate the progression of nigrostriatal damage and protect dopaminergic neurons [20][21][22]. ...
Parkinson’s disease (PD) is a common neurodegenerative disease characterized by a disorder of the dopaminergic system in the midbrain, causing classical PD motor symptoms. The therapeutic effect of cannabidiol (CBD) on PD has been a research frontier in recent years. However, the pathogenesis of PD and the therapeutic mechanism of cannabinoid remain unclear. To further study the causes of PD and the effect of CBD on PD, we exposed the PD transgenic mouse model to CBD and then estimated the motorial and postural coordination through a modified swim test. Afterwards, the mechanism was investigated via the histopathology of substantia nigra and the gut-brain metabolic analysis in the approach of UHPLC-TOF-MS. The results showed that CBD significantly improved motor deficits of PD model and protected the substantia nigra area. The metabolic function of fatty acid biosynthesis, arginine biosynthesis/metabolism, butanoate (ketone body) metabolism, β-alanine metabolism, and pantothenate/CoA biosynthesis was highlighted in the pathological and therapeutic process along the gut-brain axis. In conclusion, CBD could attenuate PD via the neuroprotective effect on the midbrain. The attenuation of the central nervous system in turn improved motor performance of PD, which might be partially induced by the metabolic interaction between the gut-brain. In view of gut-brain metabolomics, the mechanism of PD pathogenesis and the effect of CBD on PD are highly related to the biosynthesis and metabolism of energy and essential substance.
Os canabinoides, compostos derivados da planta de cannabis, têm sido objeto de crescente interesse devido ao seu potencial terapêutico em doenças neurológicas. Este artigo explora as descobertas recentes sobre o uso de canabinoides como tratamento para condições neurológicas, examinando suas propriedades neuroprotetoras, efeitos na neuroinflamação, alívio da dor neuropática e possíveis aplicações em distúrbios neuropsiquiátricos. Às evidências sugerem que os canabinoides podem desempenhar um papel significativo na modulação da neuroinflamação, reduzindo respostas inflamatórias prejudiciais que estão implicadas em doenças neurológicas. Além disso, eles têm demonstrado potencial neuroprotetor, promovendo a sobrevivência e a saúde das células neurais em situações de estresse. Isso abre caminho para possíveis aplicações no tratamento de doenças neurodegenerativas. A capacidade dos canabinoides de aliviar a dor neuropática é outra área de destaque, oferecendo uma alternativa potencial aos tratamentos convencionais. Estudos têm demonstrado que canabinoides, como o CBD, podem interagir com vias de sinalização da dor, proporcionando alívio aos pacientes que sofrem de dor crônica. Além disso, a pesquisa sugere que os canabinoides podem ter benefícios no tratamento de distúrbios neuropsiquiátricos, como ansiedade e depressão. A interação dos canabinoides com os sistemas de neurotransmissão pode contribuir para o equilíbrio das funções cerebrais, influenciando positivamente o estado mental dos pacientes. Embora as descobertas sejam promissoras, é importante notar que a pesquisa sobre canabinoides em doenças neurológicas está em andamento e muitos aspectos ainda precisam ser elucidados. Considerações éticas, regulatórias e de segurança também devem ser cuidadosamente avaliadas à medida que os canabinoides se tornam uma opção terapêutica mais amplamente explorada. Em suma, este artigo apresenta uma visão abrangente do potencial terapêutico dos canabinoides em doenças neurológicas. Enquanto mais pesquisas são necessárias para compreender completamente seus mecanismos de ação e benefícios clínicos, os canabinoides emergem como uma área empolgante de estudo que pode oferecer esperança e novas opções terapêuticas para pacientes com doenças neurológicas.
The article analyzes the use of medicinal plants in the treatment of depression. Depression is a disease that affects a large part of the population, known as "evil of the century", characterized by changes in mood, decreased libido, low self-esteem, social isolation, affecting cognitive capacity and the regulation of instincts as well as losses of other emotions. functions. Depressive episodes are classified into three levels: mild, moderate and severe. The objective of our work is to investigate how medicinal plants can be a powerful ally for the treatment of depression, at lower levels, for patients who used conventional antidepressants and were not responded, due to side effects and other issues. We will analyze how cannabidiol, saffron, melissa, Damiana, chamomile, Hypericum perforatum and Crocus sativus in which they have proven action and are compared to the effects of fluoxetine, directly affect the human nervous system. Antidepressants derived from medicinal plants can be used to treat this disease and its intensity. The use of these drugs (plants) has become routine, as it reduces the risk of adverse reactions compared to conventional drugs, making treatment adherence much easier.
Primary cell cultures and cell lines are part of the fundamental tools for the evaluation of the efficacy and cytotoxicity of drugs, protein expression, vaccine production, evaluation of the pathogen-host relationship, among other versatile applications. Cellular study models are used to simulate dental, periodontal, and craniofacial diseases. However, the optimization and standardization can result in multiple errors that can lead to inappropriate interpretations of the results obtained in drug evaluation. This article has detailed the basic aspects of cell cultures, reagent quality control measures and good practices, the most frequent mistakes committed when culturing cells and the applicable prevention methods to reduce the risk of error. Likewise, a pilot study of the biological impact of cannabidiol (CBD) in culture with human stem cells (hDPSC) is detailed, highlighting it’s potential therapeutic effect in dentistry.
The human endocannabinoid system regulates a myriad of physiological processes through a complex lipid signaling network involving cannabinoids and their respective receptors, cannabinoid receptor 1 (hCB1R) and cannabinoid receptor 2 (hCB2R). Anandamide (AEA) and cannabidiol (CBD) are classical examples of cannabinoids that elicit a variety of effects, both beneficial and detrimental, through these receptors. Mounting evidence suggested the presence of other potential cannabinoid targets that may be responsible for other observable effects. However, prior pharmacological studies on these cannabinoid compounds provided scant evidence of direct engagement to these proposed targets. Moreover, to the best of our knowledge, no chemoproteomics studies nor any protein profiling studies have been demonstrated on CBD. Here we showed that, by taking advantage of the recently developed 'label-free' 2D-TPP (2 Dimensional-Thermal Protein Profiling) approach, we have identified several new putative targets of both AEA and CBD. Comparison of these interaction landscapes with those obtained from the well-established affinity-based protein profiling (AfBPP) platforms led to the discovery of both shared and unique protein targets. Subsequent target validation studies of selected proteins led us to conclude that this 2D-TPP strategy complements well with the AfBPP approach.
Medicinal plants have been one of the most important sources of medicine since the dawn of human civilization. Indigenous communities have used products from this plant in different conditions throughout documented history. Cannabis sativa L. is one of the most widely employed herbaceous medicinal plants for textiles and fibers, in medicine, as a source of food, animal food, animal bedding, and agriculture for seeds. This paper highlights the traditional applications, botany, phytochemistry, and pharmacological properties of Cannabis sativa L. Extensive database retrieval, such as Google Scholar, Semantic Scholar, ResearchGate, Academia.edu, PubMed, SciFinder, ChemSpider, CNKI, PubFacts, etc., was performed by using the keywords "Hemp," "Cannabis," as well as the scientific name of this plant species (Cannabis sativa L). Besides, reviews of relevant textbooks, documents, and patents were also employed to collect sufficient information. This study revealed numerous pharmacological activities of Cannabis sativa L. that could help with several medical diseases. Besides that, more than 565 bioactive constituents have been isolated and identified from diverse parts of Cannabis sativa L. This could help discover potential therapeutic effects and develop new medications to benefit human health.
Background: Major deaths due to colorectal cancer (CRC) arise from the metastatic dissemination of primary tumors, which is related to molecules contributing to metastatic phenotype, the pathways they control, and the genes they regulate.
Purpose: To evaluate the effect of eugenol (EUG) and beta-caryophyllene (BCP) in combination with 5-fluorouracil in-vitro cytotoxic activity and in-silico method.
Methods: We tested the compounds on human colorectal cancer cell line HCT116 for the combined effect of 5-FU with EUG and BCP in in-vitro MTT assay. The pharmacokinetic assessment was carried out through in-silico ADMET analysis. Compound-Disease-Target (C-D-T) network were constructed against metastatic Colorectal cancer (mCRC) from which the hub proteins were selected for molecular docking studies. Enrichment analysis for the key targets was explored for gene ontology (GO) and Kyoto Encyclopaedia of Genes and Genomes (KEGG) pathways involved in mCRC to explore their functional role in human body for EUG, BCP and 5-FU.
Results: ADMET analysis showed that both the compounds follow the rule of five with good bioavailability thus, the compounds were found to be in the acceptable range by following drug-likeness properties. MTT assay revealed in-vitrocytotoxic effects of all three compounds and a significant reduction in IC50 values (p < 0.05) when treated the cells in combination thereby giving synergistic effects (CI < 1) represented by the Fa-CI plot. C-D-T network showed that EUG, BCP, and 5-FU target 58, 24, and 49 proteins of metastatic CRC, out of which 11 target proteins were intersected in the Venn diagram. The merged C-D-T network of these three compounds showed 84 target proteins of CRC from which 16 were selected based on their edge count which includes HSP90AA1, IGF-1R, ESR1, and CASP3. These were further screened in molecular docking which depicted that EUG, BCP, and 5-FU inhibited the C-D-T network’s core target protein HSP90AA1 (Heat shock protein-90 alpha) more effectively than any other proteins.
Conclusion: Our data revealed multitarget strategy to increase the effectiveness of the drug 5-FU by reducing its dosage when combined with natural phytocomponents EUG and BCP. Here, the synergism also proved effective against mCRC.
Medical marijuana or cannabis is a psychedelic drug composed of highly lipophilic tetrahydrocannabinol (THC) and cannabidiol (CBD) components derived from the plant C. sativa and C. indica. Parkinson's disease (PD), in which interactivity of biochemical and cellular signaling pathways induces endogenous cannabinoid system, a neuromodulatory system, transmits specific physiological effects when coupled with G-protein-coupled receptor (GPCR) via type 1 cannabinoid receptor (CB1) and type 2 cannabinoid receptor (CB2). Much recent research indicates that interactions between the cannabis system and dopamine in the basal ganglia area diminish levodopa-induced dyskinesia (LID) and other symptoms. Due to the limited number of pharmacological treatment options presently available for PD, in-depth research with clinical trials are crucial in the search for molecules with therapeutic potential studies in a wide range of epidemiological work for PD to increase neural transmission. This chapter reviews the mode of action of cannabinoids in PD.
Practical guide about endocannabinoid medicine and its clinical applications.
Guia prático sobre medicina endocanabinoide e suas aplicações clínicas.
#medicalcannabis #endocannabinology
Como parte de las terapias alternativas para el control de síntomas refractarios en enfermedades avanzadas destaca el uso de cannabidiol. Este se ha estudiado en patologías como enfermedad de Alzheimer, Parkinson y trastornos convulsivos. Los síndromes convulsivos están presentes en todos los grupos etarios. Dentro de este, la epilepsia es refractaria hasta en un 40 % de los pacientes, quienes han demostrado disminución en la frecuencia de convulsiones con el uso concomitante de cannabidiol y antiepilépticos convencionales, con efectos secundarios leves, como diarrea y somnolencia. Con el objetivo de determinar el uso del cannabidiol para el control de síntomas neurológicos refractarios en pacientes con síndromes convulsivos y enfermedades neurodegenerativas, se realizó una búsqueda bibliográfica en Pubmed, Scopus y Embase.Se incluyeron metaanálisis, artículos originales, revisiones sistemáticas y bibliográficas, y documentos de la Organización Panamericana de la Salud, publicados entre 2017 y 2022. Los efectos del cannabidiol lo convierten en una alternativa, adicional a la terapéutica convencional, para el control de síntomas en trastornos neurológicos, disminuyendo de forma sostenida el número total de episodios con un perfil de seguridad aceptable. Existe limitada información respecto al uso de cannabidiol en enfermedades neurodegenerativas, por lo que no se ha evidenciado su efectividad.
Historically, cannabis has always constituted a component of the civilized world; archaeological discoveries indicate that it is one of the oldest crops, while, up until the 19th century, cannabis fibers were extensively used in a variety of applications, and its seeds comprised a part of human and livestock nutrition. Additional evidence supports its exploitation for medicinal purposes in the ancient world. The cultivation of cannabis gradually declined as hemp fibers gave way to synthetic fibers, while the intoxicating ability of THC eventually overshadowed the extensive potential of cannabis. Nevertheless, the proven value of certain non-intoxicating cannabinoids, such as CBD and CBN, has recently given rise to an entire market which promotes cannabis-based products. An increase in the research for recovery and exploitation of beneficial cannabinoids has also been observed, with more than 10 000 peer-reviewed research articles published annually. In the present review, a brief overview of the history of cannabis is given. A look into the classification approaches of cannabis plants/species as well as the associated nomenclature is provided, followed by a description of their chemical characteristics and their medically valuable components. The application areas could not be absent from the present review. Still, the main focus of the review is the discussion of work conducted in the field of extraction of valuable bioactive compounds from cannabis. We conclude with a summary of the current status and outlook on the topics that future research should address.
The cover image is based on the Original Article Phytocannabinoids regulate inflammation in IL‐1β‐stimulated human gingival fibroblasts by Ammaar H. Abidi et al., https://doi.org/10.1111/jre.13050
Cannabis plant has been used from ancient times with therapeutic purposes for treating human pathologies, but the identification of the cellular and molecular mechanisms underlying the therapeutic properties of the phytocannabinoids, the active compounds in this plant, occurred in the last years of the past century. In the late 1980s and early 1990s, seminal studies demonstrated the existence of cannabinoid receptors and other elements of the so-called endocannabinoid system. These G protein-coupled receptors (GPCRs) are a key element in the functions assigned to endocannabinoids and appear to serve as promising pharmacological targets. They include CB1, CB2, and GPR55, but also non-GPCRs can be activated by endocannabinoids, like ionotropic receptor TRPV1 and even nuclear receptors of the PPAR family. Their activation, inhibition, or simply modulation have been associated with numerous physiological effects at both central and peripheral levels, which may have therapeutic value in different human pathologies, then providing a solid experimental explanation for both the ancient medicinal uses of Cannabis plant and the recent advances in the development of cannabinoid-based specific therapies. This chapter will review the scientific knowledge generated in the last years around the research on the different endocannabinoid-binding receptors and their signaling mechanisms. Our intention is that this knowledge may help readers to understand the relevance of these receptors in health and disease conditions, as well as it may serve as the theoretical basis for the different experimental protocols to investigate these receptors and their signaling mechanisms that will be described in the following chapters.Key wordsCannabinoidsEndocannabinoid systemCB1 receptorCB2 receptorGPR55TRPV1 receptorPPARsCannabinoid-based therapies
Background
Almost 90% of patients with dementia suffer from some type of neurobehavioral symptom, and there are no approved medications to address these symptoms.
Objective
To evaluate the safety and efficacy of the medical cannabis oil “Avidekel” for the reduction of behavioral disturbances among patients with dementia.
Materials and methods
In this randomized, double-blind, single-cite, placebo-controlled trial conducted in Israel ( ClinicalTrials.gov : NCT03328676), patients aged at least 60, with a diagnosis of major neurocognitive disorder and associated behavioral disturbances were randomized 2:1 to receive either “Avidekel,” a broad-spectrum cannabis oil (30% cannabidiol and 1% tetrahydrocannabinol: 295 mg and 12.5 mg per ml, respectively; n = 40) or a placebo oil ( n = 20) three times a day for 16 weeks. The primary outcome was a decrease, as compared to baseline, of four or more points on the Cohen-Mansfield Agitation Inventory score by week 16.
Results
From 60 randomized patients [mean age, 79.4 years; 36 women (60.0%)], 52 (86.7%) completed the trial (all eight patients who discontinued treatment were from the investigational group). There was a statistically significant difference in the proportion of subjects who had a Cohen-Mansfield Agitation Inventory score reduction of ≥ 4 points at week 16: 24/40 (60.0%) and 6/20 (30.0%) for investigational and control groups, respectively (χ ² = 4.80, P = 0.03). There was a statistically significant difference in the proportion of subjects who had a Cohen-Mansfield Agitation Inventory score reduction of ≥ 8 points at week 16: 20/40 (50%) and 3/20 (15%), respectively (χ ² = 6.42, P = 0.011). The ANOVA repeated measures analysis demonstrated significantly more improvement in the investigational group compared to the control group at weeks 14 and 16 ( F = 3.18, P = 0.02). Treatment was mostly safe, with no significant differences in the occurrence of adverse events between the two groups.
Conclusion
In this randomized controlled trial, ‘Avidekel’ oil significantly reduced agitation over placebo in patients suffering from behavioral disturbances related to dementia, with non-serious side-effects. Further research is required with a larger sample size.
The excessive consumption of ultra-processed foods and the development of obesity has been associated with several comorbidities, including psychiatric disorders. Excess fat tissue promotes a low-intensity inflammatory state, mainly in the white tissue, which is essential in developing metabolic alterations and influences brain homeostasis. In this scenario, Cannabidiol (CBD), a compound from Cannabis sativa, has presented anxiolytic and anti-inflammatory effects in murine models. This study verified whether CBD treatment would ameliorate the compulsive-like and anxiety-like behaviors observed after mice’s chronic consumption of a high-refined carbohydrate (HC) diet. BALB/c male mice received a control or HC diet for 12 weeks followed by vehicle and CBD (30 mg/Kg, i.p.) administration, and their behavior was evaluated in the Marble Burying test (MB) and Novel Suppressing Feeding test (NSF). The sub-chronic, but not acute, treatment with CBD attenuated the compulsive-like and anxiogenic-like behavior induced by the HC diet. Our data reinforced the harmful effects of the HC diet’s chronic consumption on compulsive and anxious behaviors and the potential of CBD as a drug treatment for psychiatric disorders associated with obesity.
Background: Cannabidiol (CBD) is a phytocannabinoid with potential in one of the most prevalent syndromes occurring at birth, the hypoxia of the neonate. CBD targets a variety of proteins, cannabinoid CB2 and serotonin 5HT1A receptors included. These two receptors may interact to form heteromers (CB2–5HT1A-Hets) that are also a target of CBD. Aims: We aimed to assess whether the expression and function of CB2–5HT1A-Hets is affected by CBD in animal models of hypoxia of the neonate and in glucose- and oxygen-deprived neurons. Methods: We developed a quantitation of signal transduction events in a heterologous system and in glucose/oxygen-deprived neurons. The expression of receptors was assessed by immuno-cyto and -histochemistry and, also, by using the only existing technique to visualize CB2–5HT1A-Hets fixed cultured cells and tissue sections (in situ proximity ligation PLA assay). Results: CBD and cannabigerol, which were used for comparative purposes, affected the structure of the heteromer, but in a qualitatively different way; CBD but not CBG increased the affinity of the CB2 and 5HT1A receptor–receptor interaction. Both cannabinoids regulated the effects of CB2 and 5HT1A receptor agonists. CBD was able to revert the upregulation of heteromers occurring when neurons were deprived of oxygen and glucose. CBD significantly reduced the increased expression of the CB2–5HT1A-Het in glucose/oxygen-deprived neurons. Importantly, in brain sections of a hypoxia/ischemia animal model, administration of CBD led to a significant reduction in the expression of CB2–5HT1A-Hets. Conclusions: Benefits of CBD in the hypoxia of the neonate are mediated by acting on CB2–5HT1A-Hets and by reducing the aberrant expression of the receptor–receptor complex in hypoxic-ischemic conditions. These results reinforce the potential of CBD for the therapy of the hypoxia of the neonate.
Supplementation with cannabidiol (CBD) may expedite recovery when consumed after exercise. The purpose of this study was to determine if supplementation with CBD reduces inflammation and enhances performance following strenuous eccentric exercise in collegiate athletes. Twenty-four well-trained females (age = 21.2 ± 1.8 years, height = 166.4 ± 8 cm, weight = 64.9 ± 9.1 kg) completed 100 repetitions of unilateral eccentric leg extension to induce muscle damage. In this crossover design, participants were randomized to receive 5 mg/kg of CBD in pill form or a placebo 2 h prior to, immediately following, and 10 h following muscle damage. Blood was collected, and performance and fatigue were measured prior to, and 4 h, 24 h, and 48 h following the muscle damage. Approximately 28 days separated treatment administration to control for the menstrual cycle. No significant differences were observed between the treatments for inflammation, muscle damage, or subjective fatigue. Peak torque at 60°/s (p = 0.001) and peak isometric torque (p = 0.02) were significantly lower 24 h following muscle damage, but no difference in performance was observed between treatments at any timepoint. Cannabidiol supplementation was unable to reduce fatigue, limit inflammation, or restore performance in well-trained female athletes.
Following injury, the endocannabinoid system is activated in the brain suggesting a strategic role in the self-repair mechanisms. Indeed endocannabinoid system manipulation ameliorates traumatic brain injury (TBI) symptoms. Cannabidiol (CBD), together with △⁹-tetrahydrocannabinol (THC), is the main phytocannabinoid extracted from the plant Cannabis sativa, and it plays anti-inflammatory, antioxidant, neuroprotective, anticonvulsant, hypnotic, and antiemetic effects and has proven to be useful in neuropsychiatric, neurodegenerative, post-traumatic stress, and ischemic disorders. Unlike THC, CBD is not psychoactive and enhances the beneficial and reduces the side effects of THC. CBD has negligible action on cannabinoid receptors and modulates the endocannabinoid system throughout the inhibition of endocannabinoid degradation and reuptake. It also stimulates serotonin 1A (5-HT1A), adenosine 2A (A2A), transient receptor potential vanilloid subtype 1 (TRPV1), and nuclear peroxisome proliferator-activated receptor γ (PPARγ). We collect in this chapter all the preclinical and clinical evidence on the beneficial effects of CBD in the TBI considering it important for two main reasons: the lack of effective therapy for the TBI and the good tolerability of the CBD.
There is a long history of informal use of Cannabis sativa (commonly called cannabis) for many purposes, including treating various ailments worldwide. However, the legalization of cannabis in multiple countries, specifically for medical purposes, has grabbed the researchers' attention to discover the scientific evidence of cannabis’s beneficial effects. Among over 500 identified compounds (cannabinoids), Δ9-Tetrahydrocannabinol (THC) and cannabidiol (CBD) are two major active cannabinoids derived from cannabis. Cannabinoids exert their effects through cannabinoid receptors (CB1R and CB2R). In the recent past, clinical trials have shown the efficacy of cannabis and cannabinoids for various human ailments such as cancer, neurological disorders, inflammatory bowel disease, chronic pain, and metabolic disorders. The commonly used constituents and derivatives of cannabis include CBD, THC, THCV, dronabinol, nabilone, and nabiximol. The cannabis constituents have also been used in combination with other agents such as megestrol acetate in some clinical trials. The common routes for the administration of cannabis are oral, sublingual, or topical. Cannabis has also been consumed through smoking, inhalation, or with food and tea. As high as 572 patients and as low as nine patients have participated in a single clinical trial. Cannabis is legalized in some countries with restrictions, such as Belize, Canada, Colombia, Costa Rica, The Czech Republic, Jamaica, Netherlands, South Africa, Spain, and Uruguay. This article provides a compilation of published studies focusing on clinal trials on the therapeutic effects of cannabis. The adverse effects of cannabis and its constituents are also discussed.
Introdução: O objetivo deste trabalho é realizar uma revisão sistemática da literatura sobre o canabidiol para analisar as evidências experimentais de seus efeitos em pacientes com epilepsia refratária. Para a pesquisa contamos com o auxílio da ferramenta de pesquisa Medical Subject Headings (MeSH) (www.ncbi.nlm.nih.gov) e BVS/Bireme (Biblioteca Virtual de Saúde) www.Bvsalud.org onde foram selecionados artigos científicos publicados em inglês entre os anos de 2007 e 2021. A coleta eletrônica na base de dados BVS/Bireme (Biblioteca Virtual de Saúde) foi realizada utilizando os seguintes descritores: cannabidiol AND epilepsy AND (fulltext:("1") AND db:("MEDLINE" OR "LILACS") AND mj:("Cannabidiol" OR "Anticonvulsants" OR "Epilepsy" OR "Drug Resistant Epilepsy") AND type_of_study: ("clinical_trials") AND la:("en")) AND (year_cluster:[2015 TO 2021]).Os artigos de interesse foram estudos que possuíam texto completo disponíveis na íntegra, gratuito e ensaios clínicos publicados entre 2007 a 2021. Foram excluídos teses, dissertações, monografias, artigos de revisão, estudos com animais ou que disponibilizavam apenas o resumo para consulta, ano da publicação não estabelecido. Dessa forma fora selecionados 15 artigos envolvendo pacientes com epilepsia. Os resultados clínicos sugerem que o canabidiol reduz a frequência das crises e pode ser adequadamente seguro em crianças e adultos jovens com altamente resistente ao tratamento. Os eventos adversos mais frequentes incluíram diarreia, vômito, fadiga, pirexia e sonolência.
Introduction:
In the last two decades, our understanding of the therapeutic utility and medicinal properties of cannabis has greatly changed. This change has been accompanied by widespread cannabis use in various communities and different age groups, especially within the United States. With this increase, we should consider the potential effects of cannabis-hemp on general public health and how they could alter therapeutic outcomes.
Material and methods:
The present investigation examined cannabis use for recreational and therapeutic use and a review of pertinent indexed literature was performed. The focused question evaluates "how cannabis or hemp products impact health parameters and do they provide potential therapeutic value in dentistry, and how do they interact with conventional medicines (drugs)." Indexed databases (PubMed/Medline, EMBASE) were searched without any time restrictions but language was restricted to English.
Results:
The review highlights dental concerns of cannabis usage, the need to understand the endocannabinoid system (ECS), cannabinoid receptor system, its endogenous ligands, pharmacology, metabolism, current oral health, and medical dilemma to ascertain the detrimental or beneficial effects of using cannabis-hemp products. The pharmacological effects of pure cannabidiol (CBD) have been studied extensively while cannabis extracts can vary significantly and lack empirical studies. Several metabolic pathways are affected by cannabis use and could pose a potential drug interaction. The chronic use of cannabis is associated with health issues, but the therapeutic potential is multifold since there is a regulatory role of ECS in many pathologies.
Conclusion:
Current shortcomings in understanding the benefits of cannabis or hemp products are limited due to pharmacological and clinical effects not being predictable, while marketed products vary greatly in phytocompounds warrant further empirical investigation. Given the healthcare challenges to manage acute and chronic pain, this review highlights both cannabis and CBD-hemp extracts to help identify the therapeutic application for patient populations suffering from anxiety, inflammation, and dental pain.
In glaucoma, the increased release of glutamate is the major cause of retinal ganglion cell death. Cannabinoids have been demonstrated to protect neuron cultures from glutamate-induced death. In this study, we test the hypothesis that glutamate causes apoptosis of retinal neurons via the excessive formation of peroxynitrite, and that the neuroprotective effect of the psychotropic Delta9-tetrahydroxycannabinol (THC) or nonpsychotropic cannabidiol (CBD) is via the attenuation of this formation. Excitotoxicity of the retina was induced by intravitreal injection of N-methyl-D-aspartate (NMDA) in rats, which also received 4-hydroxy-2,2,6,6-tetramethylpiperidine-n-oxyl (TEMPOL,a superoxide dismutase-mimetic), N-omega-nitro-L-arginine methyl ester (L-NAME, a nitric oxide synthase inhibitor), THC, or CBD. Retinal neuron loss was determined by TDT-mediated dUTP nick-end labeling assay, inner retinal thickness, and quantification of the mRNAs of ganglion cell markers. NMDA induced a dose- and time-dependent accumulation of nitrite/nitrate, lipid peroxidation, and nitrotyrosine (foot print of peroxynitrite), and a dose-dependent apoptosis and loss of inner retinal neurons. Treatment with L-NAME or TEMPOL protected retinal neurons and confirmed the involvement of peroxynitrite in retinal neurotoxicity. The neuroprotection by THC and CBD was because of attenuation of peroxynitrite. The effect of THC was in part mediated by the cannabinoid receptor CB1. These results suggest the potential use of CBD as a novel topical therapy for the treatment of glaucoma.
Cannabidiol is a component of marijuana that does not activate cannabinoid receptors, but moderately inhibits the degradation of the endocannabinoid anandamide. We previously reported that an elevation of anandamide levels in cerebrospinal fluid inversely correlated to psychotic symptoms. Furthermore, enhanced anandamide signaling let to a lower transition rate from initial prodromal states into frank psychosis as well as postponed transition. In our translational approach, we performed a double-blind, randomized clinical trial of cannabidiol vs amisulpride, a potent antipsychotic, in acute schizophrenia to evaluate the clinical relevance of our initial findings. Either treatment was safe and led to significant clinical improvement, but cannabidiol displayed a markedly superior side-effect profile. Moreover, cannabidiol treatment was accompanied by a significant increase in serum anandamide levels, which was significantly associated with clinical improvement. The results suggest that inhibition of anandamide deactivation may contribute to the antipsychotic effects of cannabidiol potentially representing a completely new mechanism in the treatment of schizophrenia.
The inhibitory effects of three major cannabinoids [ 9 -tetrahydrocannabinol (THC), cannabidiol (CBD), cannabinol (CBN)] contained in marijuana, an abused drug, on progesterone 17-hydroxylase activity in rat testis microsomes were investigated. Microsomal progesterone 17-hydroxylase activity was significantly inhibited in the presence of more than 50 M of 9 -THC and CBN compared with control activity, and the IC 50 values for 9 -THC and CBN were estimated to be 42.8 and 32.9 M, respectively. CBD showed less but significant inhibitory effects on 17-hydroxylase activity at concentrations greater than 100 M, and the IC 50 value for the cannabinoid was estimated to be 290.9 M. Kinetic analysis using double reciprocal plots showed that the type of inhibition by CBN was competitive, whereas that of 9 -THC and CBD was the mixed type. These results suggest that the inhibition may be due to metabolic interactions between each cannabinoid and 17-hydroxylase.
Peroxisome proliferator-activated receptor-γ (PPARγ) has been reported to be involved in the etiology of pathological features of Alzheimer's disease (AD). Cannabidiol (CBD), a Cannabis derivative devoid of psychomimetic effects, has attracted much attention because of its promising neuroprotective properties in rat AD models, even though the mechanism responsible for such actions remains unknown. This study was aimed at exploring whether CBD effects could be subordinate to its activity at PPARγ, which has been recently indicated as its putative binding site. CBD actions on β-amyloid-induced neurotoxicity in rat AD models, either in presence or absence of PPAR antagonists were investigated. Results showed that the blockade of PPARγ was able to significantly blunt CBD effects on reactive gliosis and subsequently on neuronal damage. Moreover, due to its interaction at PPARγ, CBD was observed to stimulate hippocampal neurogenesis. All these findings report the inescapable role of this receptor in mediating CBD actions, here reported.
The Cannabis sativa herb contains over 100 phytocannabinoid (pCB) compounds and has been used for thousands of years for both recreational and medicinal purposes. In the past two decades, characterisation of the body's endogenous cannabinoid (CB) (endocannabinoid, eCB) system (ECS) has highlighted activation of central CB(1) receptors by the major pCB, Δ(9)-tetrahydrocannabinol (Δ(9)-THC) as the primary mediator of the psychoactive, hyperphagic and some of the potentially therapeutic properties of ingested cannabis. Whilst Δ(9)-THC is the most prevalent and widely studied pCB, it is also the predominant psychotropic component of cannabis, a property that likely limits its widespread therapeutic use as an isolated agent. In this regard, research focus has recently widened to include other pCBs including cannabidiol (CBD), cannabigerol (CBG), Δ(9)tetrahydrocannabivarin (Δ(9)-THCV) and cannabidivarin (CBDV), some of which show potential as therapeutic agents in preclinical models of CNS disease. Moreover, it is becoming evident that these non-Δ(9)-THC pCBs act at a wide range of pharmacological targets, not solely limited to CB receptors. Disorders that could be targeted include epilepsy, neurodegenerative diseases, affective disorders and the central modulation of feeding behaviour. Here, we review pCB effects in preclinical models of CNS disease and, where available, clinical trial data that support therapeutic effects. Such developments may soon yield the first non-Δ(9)-THC pCB-based medicines.
Δ(9)-Tetrahydrocannabinol, cannabidiol (CBD), and cannabinol are the three major cannabinoids contained in marijuana, which are devoid of nitrogen atoms in their structures. In this study, we investigated the inhibitory effects of the major phytocannabinoids on the catalytic activity of human CYP2D6. These major cannabinoids inhibited the 3-[2-(N,N-diethyl-N-methylammonium)ethyl]-7-methoxy-4-methylcoumarin (AMMC) and dextromethorphan O-demethylase activities of recombinant CYP2D6 and pooled human liver microsomes in a concentration-dependent manner (IC(50) = 4.01-24.9 μM), indicating the strongest inhibitory potency of CBD. However, these cannabinoids showed no or weak metabolism-dependent inhibition. CBD competitively inhibited the CYP2D6 activities with the apparent K(i) values of 1.16 to 2.69 μM. To clarify the structural requirement for CBD-mediated CYP2D6 inhibition, effects of CBD-related compounds on the AMMC O-demethylase activity of recombinant CYP2D6 were examined. Olivetol (IC(50) = 7.21 μM) inhibited CYP2D6 activity as potently as CBD did (IC(50) = 6.52 μM), whereas d-limonene did not show any inhibitory effect. Pentylbenzene failed to inhibit CYP2D6 activity. Furthermore, neither monomethyl nor dimethyl ethers of CBD inhibited the activity. Cannabidivarin having a propyl side chain inhibited CYP2D6 activity; its inhibitory effect (IC(50) = 10.2 μM) was less potent than that of CBD. On the other hand, orcinol and resorcinol showed lack of inhibition. The inhibitory effect of CBD on CYP2D6 activity was more potent than those of 16 compounds without nitrogen atoms tested, such as progesterone. These results indicated that CBD caused potent direct CYP2D6 inhibition, in which two phenolic hydroxyl groups and the pentyl side chain of CBD may play important roles.
Microglial activation is an invariant feature of Alzheimer's disease (AD). It is noteworthy that cannabinoids are neuroprotective by preventing β-amyloid (Aβ)-induced microglial activation both in vitro and in vivo. On the other hand, the phytocannabinoid cannabidiol (CBD) has shown anti-inflammatory properties in different paradigms. In the present study, we compared the effects of CBD with those of other cannabinoids on microglial cell functions in vitro and on learning behavior and cytokine expression after Aβ intraventricular administration to mice. CBD, (R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl) pyrrolo-[1,2,3-d,e]-1,4-benzoxazin-6-yl]-1-naphthalenyl-methanone [WIN 55,212-2 (WIN)], a mixed CB(1)/CB(2) agonist, and 1,1-dimethylbutyl-1-deoxy-Δ(9)-tetrahydrocannabinol [JWH-133 (JWH)], a CB(2)-selective agonist, concentration-dependently decreased ATP-induced (400 μM) increase in intracellular calcium ([Ca(2+)](i)) in cultured N13 microglial cells and in rat primary microglia. In contrast, 4-[4-(1,1-dimethylheptyl)-2,6-dimethoxyphenyl]-6,6-dimethyl-bicyclo[3.1.1]hept-2-ene-2-methanol [HU-308 (HU)], another CB(2) agonist, was without effect. Cannabinoid and adenosine A(2A) receptors may be involved in the CBD action. CBD- and WIN-promoted primary microglia migration was blocked by CB(1) and/or CB(2) antagonists. JWH and HU-induced migration was blocked by a CB(2) antagonist only. All of the cannabinoids decreased lipopolysaccharide-induced nitrite generation, which was insensitive to cannabinoid antagonism. Finally, both CBD and WIN, after subchronic administration for 3 weeks, were able to prevent learning of a spatial navigation task and cytokine gene expression in β-amyloid-injected mice. In summary, CBD is able to modulate microglial cell function in vitro and induce beneficial effects in an in vivo model of AD. Given that CBD lacks psychoactivity, it may represent a novel therapeutic approach for this neurological disease.
Generalized Social Anxiety Disorder (SAD) is one of the most common anxiety conditions with impairment in social life. Cannabidiol (CBD), one major non-psychotomimetic compound of the cannabis sativa plant, has shown anxiolytic effects both in humans and in animals. This preliminary study aimed to compare the effects of a simulation public speaking test (SPST) on healthy control (HC) patients and treatment-naïve SAD patients who received a single dose of CBD or placebo. A total of 24 never-treated patients with SAD were allocated to receive either CBD (600 mg; n=12) or placebo (placebo; n=12) in a double-blind randomized design 1 h and a half before the test. The same number of HC (n=12) performed the SPST without receiving any medication. Each volunteer participated in only one experimental session in a double-blind procedure. Subjective ratings on the Visual Analogue Mood Scale (VAMS) and Negative Self-Statement scale (SSPS-N) and physiological measures (blood pressure, heart rate, and skin conductance) were measured at six different time points during the SPST. The results were submitted to a repeated-measures analysis of variance. Pretreatment with CBD significantly reduced anxiety, cognitive impairment and discomfort in their speech performance, and significantly decreased alert in their anticipatory speech. The placebo group presented higher anxiety, cognitive impairment, discomfort, and alert levels when compared with the control group as assessed with the VAMS. The SSPS-N scores evidenced significant increases during the testing of placebo group that was almost abolished in the CBD group. No significant differences were observed between CBD and HC in SSPS-N scores or in the cognitive impairment, discomfort, and alert factors of VAMS. The increase in anxiety induced by the SPST on subjects with SAD was reduced with the use of CBD, resulting in a similar response as the HC.
The phytocannabinoid cannabidiol (CBD) exhibits antioxidant and antiinflammatory properties. The present study was designed to explore its effects in a mouse model of sepsis-related encephalitis by intravenous administration of lipopolysaccharide (LPS).
Vascular responses of pial vessels were analyzed by intravital microscopy and inflammatory parameters measured by qRT-PCR.
CBD prevented LPS-induced arteriolar and venular vasodilation as well as leukocyte margination. In addition, CBD abolished LPS-induced increases in tumor necrosis factor-alpha and cyclooxygenase-2 expression as measured by quantitative real time PCR. The expression of the inducible-nitric oxide synthase was also reduced by CBD. Finally, preservation of Blood Brain Barrier integrity was also associated to the treatment with CBD.
These data highlight the antiinflammatory and vascular-stabilizing effects of CBD in endotoxic shock and suggest a possible beneficial effect of this natural cannabinoid.
There are at least two types of cannabinoid receptors (CB(1) and CB(2)). Ligands activating these G protein-coupled receptors (GPCRs) include the phytocannabinoid Δ(9)-tetrahydrocannabinol, numerous synthetic compounds, and endogenous compounds known as endocannabinoids. Cannabinoid receptor antagonists have also been developed. Some of these ligands activate or block one type of cannabinoid receptor more potently than the other type. This review summarizes current data indicating the extent to which cannabinoid receptor ligands undergo orthosteric or allosteric interactions with non-CB(1), non-CB(2) established GPCRs, deorphanized receptors such as GPR55, ligand-gated ion channels, transient receptor potential (TRP) channels, and other ion channels or peroxisome proliferator-activated nuclear receptors. From these data, it is clear that some ligands that interact similarly with CB(1) and/or CB(2) receptors are likely to display significantly different pharmacological profiles. The review also lists some criteria that any novel "CB(3)" cannabinoid receptor or channel should fulfil and concludes that these criteria are not currently met by any non-CB(1), non-CB(2) pharmacological receptor or channel. However, it does identify certain pharmacological targets that should be investigated further as potential CB(3) receptors or channels. These include TRP vanilloid 1, which possibly functions as an ionotropic cannabinoid receptor under physiological and/or pathological conditions, and some deorphanized GPCRs. Also discussed are 1) the ability of CB(1) receptors to form heteromeric complexes with certain other GPCRs, 2) phylogenetic relationships that exist between CB(1)/CB(2) receptors and other GPCRs, 3) evidence for the existence of several as-yet-uncharacterized non-CB(1), non-CB(2) cannabinoid receptors; and 4) current cannabinoid receptor nomenclature.
Two non-psychoactive cannabinoids, cannabidiol (CBD) and cannabichromene (CBC), are known to modulate in vitro the activity of proteins involved in nociceptive mechanisms, including transient receptor potential (TRP) channels of vanilloid type-1 (TRPV1) and of ankyrin type-1 (TRPA1), the equilibrative nucleoside transporter and proteins facilitating endocannabinoid inactivation. Here we have tested these two cannabinoids on the activity of the descending pathway of antinociception.
Electrical activity of ON and OFF neurons of the rostral ventromedial medulla in anaesthetized rats was recorded extracellularly and tail flick latencies to thermal stimuli were measured. CBD or CBC along with various antagonists were injected into the ventrolateral periaqueductal grey.
Cannabidiol and CBC dose-dependently reduced the ongoing activity of ON and OFF neurons in anaesthetized rats, whilst inducing antinociceptive responses in the tail flick-test. These effects were maximal with 3 nmol CBD and 6 nmol CBC, and were antagonized by selective antagonists of cannabinoid CB(1) adenosine A(1) and TRPA1, but not of TRPV1, receptors. Both CBC and CBD also significantly elevated endocannabinoid levels in the ventrolateral periaqueductal grey. A specific agonist at TRPA1 channels and a synthetic inhibitor of endocannabinoid cellular reuptake exerted effects similar to those of CBC and CBD.
CBD and CBC stimulated descending pathways of antinociception and caused analgesia by interacting with several target proteins involved in nociceptive control. These compounds might represent useful therapeutic agents with multiple mechanisms of action.
Endocannabinoids act as neuromodulatory and neuroprotective cues by engaging type 1 cannabinoid receptors. These receptors are highly abundant in the basal ganglia and play a pivotal role in the control of motor behaviour. An early downregulation of type 1 cannabinoid receptors has been documented in the basal ganglia of patients with Huntington's disease and animal models. However, the pathophysiological impact of this loss of receptors in Huntington's disease is as yet unknown. Here, we generated a double-mutant mouse model that expresses human mutant huntingtin exon 1 in a type 1 cannabinoid receptor-null background, and found that receptor deletion aggravates the symptoms, neuropathology and molecular pathology of the disease. Moreover, pharmacological administration of the cannabinoid Δ(9)-tetrahydrocannabinol to mice expressing human mutant huntingtin exon 1 exerted a therapeutic effect and ameliorated those parameters. Experiments conducted in striatal cells show that the mutant huntingtin-dependent downregulation of the receptors involves the control of the type 1 cannabinoid receptor gene promoter by repressor element 1 silencing transcription factor and sensitizes cells to excitotoxic damage. We also provide in vitro and in vivo evidence that supports type 1 cannabinoid receptor control of striatal brain-derived neurotrophic factor expression and the decrease in brain-derived neurotrophic factor levels concomitant with type 1 cannabinoid receptor loss, which may contribute significantly to striatal damage in Huntington's disease. Altogether, these results support the notion that downregulation of type 1 cannabinoid receptors is a key pathogenic event in Huntington's disease, and suggest that activation of these receptors in patients with Huntington's disease may attenuate disease progression.
The two main constituents of cannabis, cannabidiol and Δ(9)-tetrahydrocannabinol (THC), have opposing effects both pharmacologically and behaviourally when administered in the laboratory. Street cannabis is known to contain varying levels of each cannabinoid.
To study how the varying levels of cannabidiol and THC have an impact on the acute effects of the drug in naturalistic settings.
Cannabis users (n = 134) were tested 7 days apart on measures of memory and psychotomimetic symptoms, once while they were drug free and once while acutely intoxicated by their own chosen smoked cannabis. Using an unprecedented methodology, a sample of cannabis (as well as saliva) was collected from each user and analysed for levels of cannabinoids. On the basis of highest and lowest cannabidiol content of cannabis, two groups of individuals were directly compared.
Groups did not differ in the THC content of the cannabis they smoked. Unlike the marked impairment in prose recall of individuals who smoked cannabis low in cannabidiol, participants smoking cannabis high in cannabidiol showed no memory impairment. Cannabidiol content did not affect psychotomimetic symptoms, which were elevated in both groups when intoxicated.
The antagonistic effects of cannabidiol at the CB(1) receptor are probably responsible for its profile in smoked cannabis, attenuating the memory-impairing effects of THC. In terms of harm reduction, users should be made aware of the higher risk of memory impairment associated with smoking low-cannabidiol strains of cannabis like 'skunk' and encouraged to use strains containing higher levels of cannabidiol.
Cannabis contains the psychoactive component delta9-tetrahydrocannabinol (delta9-THC), and the non-psychoactive components cannabidiol (CBD), cannabinol, and cannabigerol. It is well-known that delta9-THC and other cannabinoid CB1 receptor agonists are neuroprotective during global and focal ischemic injury. Additionally, delta9-THC also mediates psychological effects through the activation of the CB1 receptor in the central nervous system. In addition to the CB1 receptor agonists, cannabis also contains therapeutically active components which are CB1 receptor independent. Of the CB1 receptor-independent cannabis, the most important is CBD. In the past five years, an increasing number of publications have focused on the discovery of the anti-inflammatory, anti-oxidant, and neuroprotective effects of CBD. In particular, CBD exerts positive pharmacological effects in ischemic stroke and other chronic diseases, including Parkinson’s disease, Alzheimer’s disease, and rheumatoid arthritis. The cerebroprotective action of CBD is CB1 receptor-independent, long-lasting, and has potent anti-oxidant activity. Importantly, CBD use does not lead to tolerance. In this review, we will discuss the therapeutic possibility of CBD as a cerebroprotective agent, highlighting recent pharmacological advances, novel mechanisms, and therapeutic time window of CBD in ischemic stroke.
The effect of the plant-derived nonpsychotropic cannabinoid, cannabidiol (CBD), on the function of hydroxytryptamine (5-HT)3A receptors expressed in Xenopus laevis oocytes was investigated using two-electrode voltage-clamp techniques. CBD reversibly inhibited 5-HT (1 microM)-evoked currents in a concentration-dependent manner (IC50 = 0.6 microM). CBD (1 microM) did not alter specific binding of the 5-HT3A antagonist [3H]3-(5-methyl-1H-imidazol-4-yl)-1-(1-methylindol-3-yl)propan-1-one (GR65630), in oocytes expressing 5-HT3A receptors. In the presence of 1 microM CBD, the maximal 5-HT-induced currents were also inhibited. The EC50 values were 1.2 and 1.4 microM, in the absence and presence of CBD, indicating that CBD acts as a noncompetitive antagonist of 5-HT3 receptors. Neither intracellular BAPTA injection nor pertussis toxin pretreatment (5 microg/ml) altered the CBD-evoked inhibition of 5-HT-induced currents. CBD inhibition was inversely correlated with 5-HT3A expression levels and mean 5-HT3 receptor current density. Pretreatment with actinomycin D, which inhibits protein transcription, decreased the mean 5-HT3 receptor current density and increased the magnitude of CBD inhibition. These data demonstrate that CBD is an allosteric inhibitor of 5-HT3 receptors expressed in X. laevis oocytes. They further suggest that allosteric inhibition of 5-HT3 receptors by CBD may contribute to its physiological roles in the modulation of nociception and emesis.
Cannabinoids could provide neuroprotection in neurodegenerative disorders. In this study, we examined whether a treatment with Δ9-tetrahydrocannabinol, a non-selective cannabinoid receptor agonist, or with SR141716, a selective antagonist for the cannabinoid CB1 receptor subtype, could affect the toxicity of the complex II reversible inhibitor malonate injected into the striatum, which replicates the mitochondrial complex II deficiency seen in Huntington's disease patients. As expected, malonate injection produced a significant reduction in cytochrome oxidase activity in the striatum consistent with the expected neurodegeneration caused by this toxin. The administration of Δ9-tetrahydrocannabinol increased malonate-induced striatal lesions compared to vehicle and, surprisingly, SR141716, far from producing effects opposite to those of Δ9-tetrahydrocannabinol, also enhanced malonate effects, and to an even greater extent. In summary, our results are compatible with the idea that manipulating the endocannabinoid system can modify neurodegeneration in Huntington's disease, and suggest that highly selective CB1 receptor agonists might be necessary to produce neuroprotective effects against indirect excitotoxicity.
We have investigated whether a 1:1 combination of botanical extracts enriched in either Δ(9)-tetrahydrocannabinol (Δ(9)-THC) or cannabidiol (CBD), which are the main constituents of the cannabis-based medicine Sativex, is neuroprotective in Huntington's disease (HD), using an experimental model of this disease generated by unilateral lesions of the striatum with the mitochondrial complex II inhibitor malonate. This toxin damages striatal neurons by mechanisms that primarily involve apoptosis and microglial activation. We monitored the extent of this damage and the possible preservation of the striatal parenchyma by treatment with a Sativex-like combination of phytocannabinoids using different histological and biochemical markers. Results were as follows: (i) malonate increased the volume of edema measured by in vivo NMR imaging and the Sativex-like combination of phytocannabinoids partially reduced this increase; (ii) malonate reduced the number of Nissl-stained cells, while enhancing the number of degenerating cells stained with FluoroJade-B, and the Sativex-like combination of phytocannabinoids reversed both effects; (iii) malonate caused a strong glial activation (i.e., reactive microglia labeled with Iba-1, and astrogliosis labeled with GFAP) and the Sativex-like combination of phytocannabinoids attenuated both responses; and (iv) malonate increased the expression of inducible nitric oxide synthase and the neurotrophin IGF-1, and both responses were attenuated after the treatment with the Sativex-like combination of phytocannabinoids. We also wanted to establish whether targets within the endocannabinoid system (i.e., CB(1) and CB(2) receptors) are involved in the beneficial effects induced in this model by the Sativex-like combination of phytocannabinoids. This we did using selective antagonists for both receptor types (i.e., SR141716 and AM630) combined with the Sativex-like phytocannabinoid combination. Our results indicated that the effects of this combination are blocked by these antagonists and hence that they do result from an activation of both CB(1) and CB(2) receptors. In summary, this study provides preclinical evidence in support of a beneficial effect of the cannabis-based medicine Sativex as a neuroprotective agent capable of delaying signs of disease progression in a proinflammatory model of HD, which adds to previous data obtained in models priming oxidative mechanisms of striatal injury. However, the interest here is that, in contrast with these previous data, we have now obtained evidence that both CB(1) and CB(2) receptors appear to be involved in the effects produced by a Sativex-like phytocannabinoid combination, thus stressing the broad-spectrum properties of Sativex that may combine activity at the CB(1) and/or CB(2) receptors with cannabinoid receptor-independent actions.
Background and purpose:
Cannabis extracts and several cannabinoids have been shown to exert broad anti-inflammatory activities in experimental models of inflammatory CNS degenerative diseases. Clinical use of many cannabinoids is limited by their psychotropic effects. However, phytocannabinoids like cannabidiol (CBD), devoid of psychoactive activity, are, potentially, safe and effective alternatives for alleviating neuroinflammation and neurodegeneration.
Experimental approach:
We used experimental autoimmune encephalomyelitis (EAE) induced by myelin oligodendrocyte glycoprotein (MOG) in C57BL/6 mice, as a model of multiple sclerosis. Using immunocytochemistry and cell proliferation assays we evaluated the effects of CBD on microglial activation in MOG-immunized animals and on MOG-specific T-cell proliferation.
Key results:
Treatment with CBD during disease onset ameliorated the severity of the clinical signs of EAE. This effect of CBD was accompanied by diminished axonal damage and inflammation as well as microglial activation and T-cell recruitment in the spinal cord of MOG-injected mice. Moreover, CBD inhibited MOG-induced T-cell proliferation in vitro at both low and high concentrations of the myelin antigen. This effect was not mediated via the known cannabinoid CB(1) and CB(2) receptors.
Conclusions and implications:
CBD, a non-psychoactive cannabinoid, ameliorates clinical signs of EAE in mice, immunized against MOG. Suppression of microglial activity and T-cell proliferation by CBD appeared to contribute to these beneficial effects.
Cannabidiol and other cannabinoids were examined as neuroprotectants in rat cortical neuron cultures exposed to toxic levels of the neurotransmitter, glutamate. The psychotropic cannabinoid receptor agonist Δ9-tetrahydrocannabinol (THC) and cannabidiol, (a non-psychoactive constituent of marijuana), both reduced NMDA, AMPA and kainate receptor mediated neurotoxicities. Neuroprotection was not affected by cannabinoid receptor antagonist, indicating a (cannabinoid) receptor-independent mechanism of action. Glutamate toxicity can be reduced by antioxidants. Using cyclic voltametry and a fenton reaction based system, it was demonstrated that Cannabidiol, THC and other cannabinoids are potent antioxidants. As evidence that cannabinoids can act as an antioxidants in neuronal cultures, cannabidiol was demonstrated to reduce hydroperoxide toxicity in neurons. In a head to head trial of the abilities of various antioxidants to prevent glutamate toxicity, cannabidiol was superior to both a-tocopherol and ascorbate in protective capacity. Recent preliminary studies in a rat model of focal cerebral ischemia suggest that cannabidiol may be at least as effective in vivo as seen in these in vitro studies.
(−)-Cannabidiol (CBD) is a non-psychotropic component of Cannabis with possible therapeutic use as an anti-inflammatory drug. Little is known on the possible molecular targets of this compound. We investigated whether CBD and some of its derivatives interact with vanilloid receptor type 1 (VR1), the receptor for capsaicin, or with proteins that inactivate the endogenous cannabinoid, anandamide (AEA).
CBD and its enantiomer, (+)-CBD, together with seven analogues, obtained by exchanging the C-7 methyl group of CBD with a hydroxy-methyl or a carboxyl function and/or the C-5′ pentyl group with a di-methyl-heptyl (DMH) group, were tested on: (a) VR1-mediated increase in cytosolic Ca2+ concentrations in cells over-expressing human VR1; (b) [14C]-AEA uptake by RBL-2H3 cells, which is facilitated by a selective membrane transporter; and (c) [14C]-AEA hydrolysis by rat brain membranes, which is catalysed by the fatty acid amide hydrolase.
Both CBD and (+)-CBD, but not the other analogues, stimulated VR1 with EC50=3.2 – 3.5 μM, and with a maximal effect similar in efficacy to that of capsaicin, i.e. 67 – 70% of the effect obtained with ionomycin (4 μM). CBD (10 μM) desensitized VR1 to the action of capsaicin. The effects of maximal doses of the two compounds were not additive.
(+)-5′-DMH-CBD and (+)-7-hydroxy-5′-DMH-CBD inhibited [14C]-AEA uptake (IC50=10.0 and 7.0 μM); the (−)-enantiomers were slightly less active (IC50=14.0 and 12.5 μM). CBD and (+)-CBD were also active (IC50=22.0 and 17.0 μM).
CBD (IC50=27.5 μM), (+)-CBD (IC50=63.5 μM) and (−)-7-hydroxy-CBD (IC50=34 μM), but not the other analogues (IC50>100 μM), weakly inhibited [14C]-AEA hydrolysis.
Only the (+)-isomers exhibited high affinity for CB1 and/or CB2 cannabinoid receptors.
These findings suggest that VR1 receptors, or increased levels of endogenous AEA, might mediate some of the pharmacological effects of CBD and its analogues. In view of the facile high yield synthesis, and the weak affinity for CB1 and CB2 receptors, (−)-5′-DMH-CBD represents a valuable candidate for further investigation as inhibitor of AEA uptake and a possible new therapeutic agent.
British Journal of Pharmacology (2001) 134, 845–852; doi:10.1038/sj.bjp.0704327
Biochemical studies on postmortem brains of patients with Parkinson’s disease (PD) have greatly contributed to our understanding
of the molecular pathogenesis of this disease. The discovery by 1960 of a dopamine deficiency in the nigro-striatal dopamine
region of the PD brain was a landmark in research on PD. At that time we collaborated with Hirotaro Narabayashi and his colleagues
in Japan and with Peter Riederer in Germany on the biochemistry of PD by using postmortem brain samples in their brain banks.
We found that the activity, mRNA level, and protein content of tyrosine hydroxylase (TH), as well as the levels of the tetrahydrobiopterin
(BH4) cofactor of TH and the activity of the BH4-synthesizing enzyme, GTP cyclohydrolase I (GCH1), were markedly decreased
in the substantia nigra and striatum in the PD brain. In contrast, the molecular activity (enzyme activity/enzyme protein)
of TH was increased, suggesting a compensatory increase in the enzyme activity. The mRNA levels of all four isoforms of human
TH (hTHl-hTH4), produced by alternative mRNA splicing, were also markedly decreased. This finding is in contrast to a completely
parallel decrease in the activity and protein content of dopamine β-hydroxylase (DBH) without changes in its molecular activity
in cerebrospinal fluid (CSF) in PD. We also found that the activities and/or the levels of the mRNA and protein of aromatic
L-amino acid decarboxylase (AADC, DOPA decarboxylase), DBH, phenylethanolamine N-methyltransferase (PNMT), which synthesize
dopamine, noradrenaline, and adrenaline, respectively, were also decreased in PD brains, indicating that all catecholamine
systems were widely impaired in PD brains.
Inhibitory effects of Δ9-tetrahydrocannabinol (Δ9-THC), cannabidiol (CBD), and cannabinol (CBN) on the catalytic activities of human recombinant cytochrome P450 (CYP) 2A6
and CYP2B6 were investigated. Δ9-THC, CBD, and CBN noncompetitively inhibited coumarin 7-hydroxylase activity of recombinant CYP2A6 with the apparent K
i values of 28.9, 55.0, and 39.8μM, respectively. On the other hand, Δ9-THC, CBD, and CBN inhibited 7-benzoxyresorufin O-debenzylase activity of recombinant CYP2B6 in a mixed fashion with the K
i values of 2.81, 0.694, and 2.55μM, respectively. Because the inhibition of CYP2B6 by CBD was the most potent, investigation
was conducted to determine which moiety of the CBD structure was responsible for the inhibition. Olivetol and d-limonene, the partial structure of CBD, inhibited the CYP2B6 activity to some extent. Inhibitory effects of CBD-2′-monomethyl
ether and CBD-2′,6′-dimethyl ether attenuated with the number of methylations on the phenolic hydroxyl groups in the resorcinol
moiety of CBD. Cannabidivarin, a CBD analogue having a propyl side chain, inhibited the CYP2B6 activity less potently than
CBD possessing a pentyl side chain. Therefore, both structures of pentylresorcinol and terpene moieties of CBD were suggested
to play important roles in the CYP2B6 inhibition. Δ9-THC, CBD, and CBN showed metabolism-dependent inhibition for CYP2A6 but not for CYP2B6. Furthermore, Δ9-THC and CBN were characterized as mechanism-based inhibitors for CYP2A6. The k
inact and K
I values of Δ9-THC were 0.0169min−1 and 0.862μM, respectively; the k
inact and K
I values of CBN were 0.00909min−1 and 1.01μM, respectively. These results indicated that Δ9-THC, CBD, and CBN showed differential inhibition against CYP2A6 and CYP2B6.
KeywordsMarijuana–Nicotine–Cannabinoid–CYP2A6–CYP2B6–Differential inhibition
Huntington’s disease (HD) is one of the most frequently found neurodegenerative disorders. Its main clinical manifestations
arc chorea, cognitive impairment and psychiatric disorders. It is an autosomal-dominant disorder with almost complete penetrance.
The mutation responsible for HD, unstable expansion of a CAG repcat, is located in the 5′ tcrminal section of the gene (ITJS) that encodes huntingtin protein (Htt). The pathophysiology of HD is not entirely clear. One intriguing characteristic of
HD is the special vulnerability of the striatum tomutated Htt, despite similar expression of the mutated protcin in other
brain regions. Aggregation of mutated Htt, transcriptional dysregulation, altered energy metabolism, excitotoxicity, impaired
axonal transport and altered synaptic transmission culminate in neuronal dysfianction and death. There is currently no way
ofpreventing or slowing down the disease progression and death usually occurs at about 20 years after dia