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The proposed mechanisms of action of CBD in epilepsy

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Abstract

Highly purified cannabidiol (CBD) (approved as Epidiolex® in the United States and as EPIDYOLEX from the EU agency) has demonstrated efficacy with an acceptable safety profile in patients with Lennox-Gastaut or Dravet syndrome in four randomized controlled trials. While the mechanism of action of CBD underlying the reduction of seizures in humans is unknown, CBD possesses affinity for multiple targets, across a range of target classes, resulting in functional modulation of neuronal excitability, relevant to the pathophysiology of many disease types, including epilepsy. Here we present the pharmacological data supporting the role of three such targets, namely Transient receptor potential vanilloid-1 (TRPV1), the orphan G protein-coupled receptor-55 (GPR55) and the equilibrative nucleoside transporter 1 (ENT-1).

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... CBD exhibits greater binding affinity for several noncannabinoid targets, including the transient receptor potential vanilloid 1 (TRPV1) channel, G protein-coupled receptor 55 (GPR55), equilibrative nucleoside transporter 1 (ENT1), serotonin 1A receptor, voltage-gated sodium channels, and T-and L-type VGCCs [20,57]. There is greater research supporting CBD's actions on TRPV1 channels, GPR55, and ENT1 in the treatment of epilepsy [57,58] (Fig. 4). ...
... When activated by vanilloids, such as capsaicin, these channels permit the influx of calcium and sodium, enhancing neuronal depolarization [60]. TRPV1 expression is elevated in epilepsy [58,59]. CBD initially activates TRPV1, but then quickly desensitizes it, thereby limiting calcium influx [58,61] (Fig. 4). ...
... TRPV1 expression is elevated in epilepsy [58,59]. CBD initially activates TRPV1, but then quickly desensitizes it, thereby limiting calcium influx [58,61] (Fig. 4). This reduces presynaptic glutamate exocytosis and neuronal hyperexcitability [20,58] (Fig. 4). ...
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Exosomes, which are membrane-enclosed extracellular vesicles (30 - 200 nm) secreted by cells, may be responsible for the therapeutic benefits associated with the implantation of mesenchymal stem cells. Currently, ultracentrifugation is commonly used to isolate extracellular vesicles and characterize the exosome fraction. In some studies, a second ultracentrifugation step for “washing” is included in the isolation process to increase purity by removing contaminating proteins. This study attempted to investigate the validity of using an additional step to increase the purity of samples as well as examine the effect on recovery by comparing a single ultracentrifugation step to when a second ultracentrifugation step is added to the isolation procedure. The results obtained indicated that the additional step increased the purity of the isolated exosomes by removing contaminating proteins, however, the total yield was lower. The reduced yield is likely the result of misplacing exosomes during the extra step because it is difficult to ensure all exosomes are pelleted and re-suspended after ultracentrifugation. Therefore, the inclusion of an additional ultracentrifugation step in research is dependent on the application. For example, higher purity is a priority in therapeutic applications, while a higher yield is often preferred in diagnostic applications.
... The author also summarized a list of targets and actions reported for CBD. CBD may be an efficient agonist or antagonist of neurotransmitter transporters, of multiple noncannabinoid and transmembrane receptors, as well as of ion channels [59]. According to Klein et al. [58], CBD can show a positive impact on a broad spectrum of seizures. ...
... Ongoing clinical trials also indicate that therapeutic doses of purified CBD can be applied to patients suffering from epilepsy [5,45,60]. CBD is considered to have a great affinity for the treatment of multiple disorders, resulting in the modulation of neuronal excitability and synaptic transmission [59]. ...
... In turn, during the GPR55 activation [61], CBD as an antagonist may increase intracellular calcium via inositol 1,4,5-triphosphate (IP3) signaling. Furthermore, CBD can act on the NCX, reducing or elevating cytosolic calcium [59,62]. ...
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As the major nonpsychotropic constituent of Cannabis sativa, cannabidiol (CBD) is regarded as one of the most promising therapeutic agents due to its proven effectiveness in clinical trials for many human diseases. Due to the urgent need for more efficient pharmacological treatments for several chronic diseases, in this review, we discuss the potential beneficial effects of CBD for Alzheimer’s disease, epilepsy, multiple sclerosis, and neurological cancers. Due to its wide range of pharmacological activities (e.g., antioxidant, anti-inflammatory, and neuroprotective properties), CBD is considered a multimodal drug for the treatment of a range of neurodegenerative disorders, and various cancer types, including neoplasms of the neural system. The different mechanisms of action of CBD are here disclosed, together with recent progress in the use of this cannabis-derived constituent as a new therapeutic approach.
... 105 Different targets that might be relevant for antiseizure effects of CBD include modulation of the G-protein coupled receptor 55 (GPR55), agonistic effects on the transient receptor potential vanilloid 1 (TRPV1) coupled to calcium concentration influx, and adenosine reuptake. 107 In addition, changes in intracellular calcium may in turn affect gene expression patterns, with an impact on the cellular functional state, and adenosine serves as an endogenous anticonvulsant. In experiments in acute seizure models, genetic deficiency of TRPV1 or GPR55 limited the antiseizure effects of CBD. ...
... In experiments in acute seizure models, genetic deficiency of TRPV1 or GPR55 limited the antiseizure effects of CBD. 13,107 CBD has a challenging pharmacokinetic profile, with low and variable bioavailability (<6%), also affected by fat-rich food, 99% protein binding, and metabolism through CYP2C19 and 3A4. 13,108 CBD has shown efficacy in placebo-controlled, randomized trials in DS, LGS, and tuberous sclerosis in doses of 10-25 mg/kg. ...
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Developmental and epileptic encephalopathies (DEEs) are among the most challenging of all epilepsies to manage, given the exceedingly frequent and often severe seizure types, pharmacoresistance to conventional antiseizure medications, and numerous comorbidities. During the past decade, efforts have focused on development of new treatment options for DEEs, with several recently approved in the United States or Europe, including cannabidiol as an orphan drug in Dravet and Lennox-Gastaut syndromes and everolimus as a possible antiepileptogenic and precision drug for tuberous sclerosis complex, with its impact on the mammalian target of rapamycin pathway. Furthermore, fenfluramine, an old drug, was repurposed as a novel therapy in the treatment of Dravet syndrome. The evolution of new insights into pathophysiological processes of various DEEs provides possibilities to investigate novel and repurposed drugs and to place them into the context of their role in future management of these patients. The purpose of this review is to provide an overview of these new medical treatment options for the DEEs and to discuss the clinical implications of these results for improved treatment.
... Cannabidiol (CBD), a nonpsychoactive phytocannabinoid present in marijuana (Mechoulam et al., 1970), has been developed as an antiepileptic agent (Epidiolex) and shown to be effective in treating Dravet syndrome (Devinsky et al., 2017(Devinsky et al., , 2018bMiller et al., 2020) and Lennox-Gastaut syndrome (Devinsky et al., 2018a;Thiele et al., 2019) epilepsies. The molecular mechanism of action of CBD in epilepsy is still unclear (Jones et al., 2010;Rosenberg et al., 2015Rosenberg et al., , 2017Franco and Perucca, 2019;Gray and Whalley, 2020). Unlike D(9)-tetrahydrocannabinol, the other major phytocannabinoid in marijuana, CBD does not act as a direct primary ligand at CB1 or CB2 receptors, the G-protein-coupled receptors activated by endocannabinoids (Pertwee, 2005). ...
... Similar to other antiepileptic drugs like phenytoin and carbamazepine, CBD inhibits not only sodium channels but also voltage-dependent potassium channels and calcium channels (Ross et al., 2008;Hill et al., 2014;Patel et al., 2016;Ghovanloo et al., 2018;Le Marois et al., 2020;Orvos et al., 2020), and has effects on a wide variety of other signaling molecules (Gray and Whalley, 2020;Watkins, 2019;Senn et al., 2020), including TRPV1 (Iannotti et al., 2014), TRPV2 (Qin et al., 2008;Neumann-Raizel et al., 2019), and various G-protein-coupled receptors (de Almeida and Devi, 2020). Although CBD affects many channels and receptors, the fact that well defined binding sites can be seen in structures of CBD-bound proteins (Pumroy et al., 2019;Sait et al., 2020), along with the dramatic state dependence of binding, suggests that its effects are mediated by specific effects on the operation of particular channels and receptors and not by completely nonspecific effects on membranes and membrane proteins. ...
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Cannabidiol (CBD), a chemical found in the Cannabis sativa plant, is a clinically effective antiepileptic drug whose mechanism of action is unknown. Using a fluorescence-based thallium flux assay, we performed a large-scale screen and found enhancement of flux through heterologously-expressed human Kv7.2/7.3 channels by CBD. Using patch clamp recordings, we found that CBD at low concentrations activates Kv7.2/7.3 channels at subthreshold voltages, with 100 nM CBD producing a doubling of current at -50 mV. CBD shifted the voltage-dependence of channels in the hyperpolarizing direction, producing a shift in the midpoint of activation by about ~-14 mV at 300 nM. CBD also effectively enhanced native M-current in both mouse superior cervical ganglion neurons and rat hippocampal neurons. The potent enhancement of Kv2/7.3 channels by CBD seems likely to contribute to its effectiveness as an antiepileptic drug by reducing neuronal hyperexcitability.
... While the precise mechanism of action of CBD in humans remains unknown, there are several plausible targets engaged by CBD. The preclinical evidence strongly implicates three main molecular targets in CBD anticonvulsive properties [7]. In particular, CBD reduces neuronal excitability through functional antagonism of GPR55 receptors, desensitization of TRPV1 receptors, and inhibition of adenosine transport [7], even if other receptors and channels possibly involved in its activity cannot be excluded [8]. ...
... The preclinical evidence strongly implicates three main molecular targets in CBD anticonvulsive properties [7]. In particular, CBD reduces neuronal excitability through functional antagonism of GPR55 receptors, desensitization of TRPV1 receptors, and inhibition of adenosine transport [7], even if other receptors and channels possibly involved in its activity cannot be excluded [8]. A pharmaceutical-grade formulation of purified CBD, derived from C. sativa, was evaluated in several randomized placebo-controlled adjunctive-therapy trials, which resulted in its regulatory approval for the treatment of seizures associated with Dravet syndrome, Lennox-Gastaut syndrome, and tuberous sclerosis complex [6]. ...
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Compounds present in Cannabis sativa L. preparations have recently attracted much attention in the treatment of drug-resistant epilepsy. Here, we screened two olive oil extracts from a non-psychoactive C. sativa variety, fully characterized by high-performance liquid chromatography and gas chromatography. Particularly, hemp oils with different concentrations of terpenes were administered at the same dose of cannabidiol (25 mg/kg/day orally), 1 h before the 6-Hz corneal stimulation test (44 mA). Mice were stimulated once a day for 5 days and evaluated by videoelectrocorticographic recordings and behavioral analysis. Neuronal activation was assessed by FosB/deltaFosB immunoreactivity. Both oils significantly reduced the percentage of mice experiencing convulsive seizures in comparison to olive oil-treated mice (p < 0.050; Fisher’s exact test), but only the oil enriched with terpenes (K2) significantly accelerated full recovery from the seizure. These effects occurred in the presence of reduced power of delta rhythm, and, instead, increased power of theta rhythm, along with a lower FosB/DFosB expression in the subiculum (p < 0.050; Duncan’s method). The overall findings suggest that both cannabinoids and terpenes in oil extracts should be considered as potential therapeutic agents against epileptic seizures and epilepsy.
... The antiepileptic drugs used as first-line therapy are valproate, topiramate, and clobazam, but the response to these drugs is often inadequate (patients are usually drug-resistant), and, although it improves when stiripentol is used as an adjuvant (Frampton, 2019), they have limited efficacy and produce adverse effects, so there is an urgent need of new therapies for DS (Bialer et al., 2018;Brigo et al., 2018). Data generated along the last 6 years suggest that a promising therapy for DS may be based on the use of certain cannabinoids, e.g., cannabidiol (CBD) (Franco and Perucca, 2019;Morano et al., 2020), which not only target the so-called endocannabinoid system but also other elements outside this signaling system (Gray and Whalley, 2020). This has been demonstrated in a series of clinical studies conducted in patients affected by DS, Lennox-Gastaut syndrome, or similar pathologies, using CBD, formulated as Epidiolex R , and concentrating on its activity on seizures (Porter and Jacobson, 2013;Devinsky et al., 2016Devinsky et al., , 2018Nabbout and Thiele, 2020). ...
... As mentioned above, neural tissues collected in the second experiment were also used for determining the status of different elements of the endocannabinoid signaling, which may serve as potential targets for a cannabinoid-based therapy in DS (Rubio et al., 2016;Gray and Whalley, 2020). The objective of these FIGURE 9 | Double immunofluorescence analysis of Ki67 and GFAP in the hippocampal dentate gyrus, including representative immunofluorescence images, of Syn-Cre/Scn1a WT/A1783V mice compared with Scn1a WT/W animals at PND25. ...
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Dravet syndrome (DS) is an epileptic syndrome caused by mutations in the Scn1a gene encoding the α1 subunit of the sodium channel Nav1.1, which is associated with febrile seizures that progress to severe tonic-clonic seizures and associated comorbidities. Treatment with cannabidiol has been approved to reduce seizures in DS, but it may also be active against these comorbidities. The aim of this study was to validate a new mouse model of DS having lower mortality than previous models, which may serve to further evaluate therapies for the long-term comorbidities. This new model consists of heterozygous conditional knock-in mice carrying a missense mutation (A1783V) in Scn1a gene expressed exclusively in neurons of the CNS (Syn-Cre/Scn1aWT/A1783V). These mice have been used here to determine the extent and persistence of the behavioral deterioration in different postnatal days (PND), as well as to investigate the alterations that the disease produces in the endocannabinoid system and the contribution of inflammatory events and impaired neurogenesis in the pathology. Syn-Cre/Scn1aWT/A1783V mice showed a strong reduction in hindlimb grasp reflex at PND10, whereas at PND25, they presented spontaneous convulsions and a greater susceptibility to pentylenetetrazole-induced seizures, marked hyperactivity, deficient spatial working memory, lower levels of anxiety, and altered social interaction behavior. These differences disappeared at PND40 and PND60, except the changes in social interaction and anxiety. The analysis of CNS structures associated with these behavioral alterations revealed an elevated glial reactivity in the prefrontal cortex and the dentate gyrus. This was associated in the dentate gyrus with a greater cell proliferation detected with Ki67 immunostaining, whereas double-labeling analyses identified that proliferating cells were GFAP-positive suggesting failed neurogenesis but astrocyte proliferation. The analysis of the endocannabinoid system of Syn-Cre/Scn1aWT/A1783V mice confirmed reductions in CB1 receptors and MAGL and FAAH enzymes, mainly in the cerebellum but also in other areas, whereas CB2 receptors became upregulated in the hippocampus. In conclusion, Syn-Cre/Scn1aWT/A1783V mice showed seizuring susceptibility and several comorbidities (hyperactivity, memory impairment, less anxiety, and altered social behavior), which exhibited a pattern of age expression similar to DS patients. Syn-Cre/Scn1aWT/A1783V mice also exhibited greater glial reactivity and a reactive response in the neurogenic niche, and regional changes in the status of the endocannabinoid signaling, events that could contribute in behavioral impairment.
... Promising results from double-blind, placebo-controlled phase III clinical trials in Dravet Syndrome (Devinsky et al., 2017) Lennox-Gastaut Syndrome (Devinsky et al., 2018a), and Tuberous Sclerosis (Thiele et al., 2021) have contributed to disease-specific FDA approval of highly purified, plant-derived cannabidiol (Epidiolex® in the U.S.) for multiple clinical populations. Preclinical experiments verify that CBD reduces spontaneous recurrent seizures in a chronic epilepsy model (Patra et al., 2019) and suggest that CBD modulates E:I coordination (Kaplan et al., 2017;Khan et al., 2018), but the molecular signaling underlying CBD's anti-seizure actions is not clearly defined (Gray and Whalley, 2020). ...
... ; https://doi.org/10.1101/2022.09.27.509638 doi: bioRxiv preprint 1D) and exerted effects on GABAARs above that of GPR55 knockdown alone (Fig. 5A), suggesting potential direct effects of CBD on GABAARs (Bakas et al., 2017). Further candidates for CBD's anti-seizure effects (Gray and Whalley, 2020;Ibeas Bih et al., 2015) include agonism of transient receptor potential (TRP) channels (TRPV1, TRPV2, TRPA1) (Bisogno et al., 2001;Costa et al., 2004;De Petrocellis et al., 2011;Qin et al., 2008), negative allosteric modulation of CB1Rs (Laprairie et al., 2015;Straiker et al., 2018), as well as inhibition of the ENT-1 transporter of adenosine (Carrier et al., 2006), CaV3.3 channels (Ross et al., 2008), mitochondrial VDAC1 channels (Rimmerman et al., 2013), and regulation of non-neuronal cells (e.g. glia). ...
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Cannabidiol (CBD), a non-euphoric component of cannabis, reduces seizures in multiple forms of pediatric epilepsy, but the mechanism(s) of anti-seizure action remain unclear. In one leading model, CBD acts at glutamatergic axon terminals, blocking pro-excitatory actions of an endogenous membrane phospholipid, lysophosphatidylinositol (LPI), at the G protein-coupled receptor GPR55. However, the impact of LPI-GPR55 signaling at inhibitory synapses and in epileptogenesis remains underexplored. We found that LPI transiently increased hippocampal CA3 to CA1 excitatory presynaptic release probability and evoked synaptic strength in WT mice, while attenuating inhibitory postsynaptic strength by decreasing GABAAR gamma 2 and gephyrin puncta. Effects of LPI at both excitatory and inhibitory synapses were eliminated by CBD pretreatment and absent after GPR55 deletion. Acute pentylenetrazole-induced seizures elevated levels of GPR55 and LPI, and chronic lithium pilocarpine-induced epileptogenesis potentiated the pro-excitatory effects of LPI. We propose that CBD exerts potential therapeutic effect both by blocking synaptic effects of LPI and dampening hyperexcitability.
... Cannabidiol (CBD), a nonpsychoactive phytocannabinoid present in marijuana (Mechoulam et al., 1970), has been developed as an antiepileptic agent (Epidiolex) and shown to be effective in treating Dravet syndrome (Devinsky et al., 2017(Devinsky et al., , 2018bMiller et al., 2020) and Lennox-Gastaut syndrome (Devinsky et al., 2018a;Thiele et al., 2019) epilepsies. The molecular mechanism of action of CBD in epilepsy is still unclear (Jones et al., 2010;Rosenberg et al., 2015Rosenberg et al., , 2017Franco and Perucca, 2019;Gray and Whalley, 2020). Unlike D(9)-tetrahydrocannabinol, the other major phytocannabinoid in marijuana, CBD does not act as a direct primary ligand at CB1 or CB2 receptors, the G-protein-coupled receptors activated by endocannabinoids (Pertwee, 2005). ...
... Similar to other antiepileptic drugs like phenytoin and carbamazepine, CBD inhibits not only sodium channels but also voltage-dependent potassium channels and calcium channels (Ross et al., 2008;Hill et al., 2014;Patel et al., 2016;Ghovanloo et al., 2018;Le Marois et al., 2020;Orvos et al., 2020), and has effects on a wide variety of other signaling molecules (Gray and Whalley, 2020;Watkins, 2019;Senn et al., 2020), including TRPV1 (Iannotti et al., 2014), TRPV2 (Qin et al., 2008;Neumann-Raizel et al., 2019), and various G-protein-coupled receptors (de Almeida and Devi, 2020). Although CBD affects many channels and receptors, the fact that well defined binding sites can be seen in structures of CBD-bound proteins (Pumroy et al., 2019;Sait et al., 2020), along with the dramatic state dependence of binding, suggests that its effects are mediated by specific effects on the operation of particular channels and receptors and not by completely nonspecific effects on membranes and membrane proteins. ...
Article
The nonpsychoactive phytocannabinoid cannabidiol (CBD) has been shown to have analgesic effects in animal studies but little is known about its mechanism of action. We examined the effects of CBD on intrinsic excitability of primary pain-sensing neurons. Studying acutely dissociated capsaicin-sensitive mouse DRG neurons at 37°C, we found that CBD effectively inhibited repetitive action potential firing, from 15-20 action potentials evoked by 1 s current injections in control to 1-3 action potentials with 2 μm CBD. Reduction of repetitive firing was accompanied by a reduction of action potential height, widening of action potentials, reduction of the afterhyperpolarization, and increased propensity to enter depolarization block. Voltage-clamp experiments showed that CBD inhibited both TTX-sensitive and TTX-resistant (TTX-R) sodium currents in a use-dependent manner. CBD showed strong state-dependent inhibition of TTX-R channels, with fast binding to inactivated channels during depolarizations and slow unbinding on repolarization. CBD alteration of channel availability at various voltages suggested that CBD binds especially tightly [K d (dissociation constant), ∼150 nm] to the slow inactivated state of TTX-R channels, which can be substantially occupied at voltages as negative as -40 mV. Remarkably, CBD was more potent in inhibiting TTX-R channels and inhibiting action potential firing than the local anesthetic bupivacaine. We conclude that CBD might produce some of its analgesic effects by direct effects on neuronal excitability, with tight binding to the slow inactivated state of Nav1.8 channels contributing to effective inhibition of repetitive firing by modest depolarizations.SIGNIFICANCE STATEMENT Cannabidiol (CBD) has been shown to inhibit pain in various rodent models, but the mechanism of this effect is unknown. We describe the ability of CBD to inhibit repetitive action potential firing in primary nociceptive neurons from mouse dorsal root ganglia and analyze the effects on voltage-dependent sodium channels. We find that CBD interacts with TTX-resistant sodium channels in a state-dependent manner suggesting particularly tight binding to slow inactivated states of Nav1.8 channels, which dominate the overall inactivation of Nav1.8 channels for small maintained depolarizations from the resting potential. The results suggest that CBD can exert analgesic effects in part by directly inhibiting repetitive firing of primary nociceptors and suggest a strategy of identifying compounds that bind selectively to slow inactivated states of Nav1.8 channels for developing effective analgesics.
... Thus, it is postulated that TRPV1 antagonists penetrating the blood-brain barrier may be promising ASD candidates, which adds to their potent central and peripheral antinociceptive properties. It should be emphasized herein that cannabidiol (CBD) which is one of the newest ASDs effective in DRE (i.e., Dravet and Lennox-Gastaut syndromes in children), has a multi-target mechanism of action and causes desensitization of the TRPV1, besides the inhibition of sodium and calcium conductance [27,28]. Therefore, it is suggested that a multimodal mechanism of action underlines a broad spectrum of antiseizure activity of CBD that was demonstrated in preclinical studies [29]. ...
... Nevertheless, it cannot be completely excluded that such a mechanism of action may be beneficial in other seizure models, thus the hypothesis linking epilepsy and TRPV1 requires further and more detailed studies. Consequently, we assume herein that TRPV1 receptors may be interesting targets for new antiseizure drugs, but only as part of a more complex and complementary pharmacodynamic profile (i.e., inhibition of sodium or calcium conductance, etc.), as it was described for CBD [27]. ...
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In the present study, a focused combinatorial chemistry approach was applied to merge structural fragments of well-known TRPV1 antagonists with a potent anticonvulsant lead compound, KA-104, that was previously discovered by our group. Consequently, a series of 22 original compounds has been designed, synthesized, and characterized in the in vivo and in vitro assays. The obtained compounds showed robust in vivo antiseizure activity in the maximal electroshock (MES) test and in the 6 Hz seizure model (using both 32 and 44 mA current intensities). The most potent compounds 53 and 60 displayed the following pharmacological profile: ED50 = 89.7 mg/kg (MES), ED50 = 29.9 mg/kg (6 Hz, 32 mA), ED50 = 68.0 mg/kg (6 Hz, 44 mA), and ED50 = 73.6 mg/kg (MES), ED50 = 24.6 mg/kg (6 Hz, 32 mA), and ED50 = 56.3 mg/kg (6 Hz, 44 mA), respectively. Additionally, 53 and 60 were effective in the ivPTZ seizure threshold and had no influence on the grip strength and body temperature in mice. The in vitro binding and functional assays indicated a multimodal mechanism of action for 53 and 60. These molecules, beyond TRPV1 antagonism, inhibited calcium currents and fast sodium currents in patch-clamp assays. Further studies proved beneficial in vitro ADME-Tox properties for 53 and 60 (i.e., high metabolic stability, weak influence on CYPs, no neurotoxicity, etc.). Overall, 53 and 60 seem to be interesting candidates for future preclinical development in epilepsy and pain indications due to their interaction with the TRPV1 channel.
... CBD interacts with CB1R and CB2R, but with lower affinity relative to THC. CBD is also thought to antagonize cannabinoid-induced effects indirectly through other receptors [25][26][27][28][29] . Additional in vivo data on the signaling pathways of THC and CBD would highlight functionally important mechanisms. ...
... We also acknowledge that pharmacological inhibitors may not completely block the CB1Rs and CB2Rs, or that they may have off-target effects. Finally, it is also possible that other CBD receptors such as GPR55 and TRPV1 are involved 26 , but this needs further investigation. ...
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In light of legislative changes and the widespread use of cannabis as a recreational and medicinal drug, delayed effects of cannabis upon brief exposure during embryonic development are of high interest as early pregnancies often go undetected. Here, zebrafish embryos were exposed to cannabidiol (CBD) and Δ ⁹ -tetrahydrocannabinol (THC) until the end of gastrulation (1–10 h post-fertilization) and analyzed later in development (4–5 days post-fertilization). In order to measure neural activity, we implemented Calcium-Modulated Photoactivatable Ratiometric Integrator (CaMPARI) and optimized the protocol for a 96-well format complemented by locomotor analysis. Our results revealed that neural activity was decreased by CBD more than THC. At higher doses, both cannabinoids could dramatically reduce neural activity and locomotor activity. Interestingly, the decrease was more pronounced when CBD and THC were combined. At the receptor level, CBD-mediated reduction of locomotor activity was partially prevented using cannabinoid type 1 and 2 receptor inhibitors. Overall, we report that CBD toxicity occurs via two cannabinoid receptors and is synergistically enhanced by THC exposure to negatively impact neural activity late in larval development. Future studies are warranted to reveal other cannabinoids and their receptors to understand the implications of cannabis consumption on fetal development.
... Given that cannabidiol is an ENT1 inhibitor [40], its anticonvulsant effects were proposed to be, at least in part, mediated by the increase in adenosine tone and the subsequent activation of A 1 R. Cannabidiol has been approved in the US and European Union for the treatment of seizures associated with Lennox-Gastaut syndrome, Dravet syndrome, or tuberous sclerosis complex [109,216], supporting the idea of ENT1 inhibition for epileptic treatment, even for drug-resistant types. Nevertheless, in addition to the inhibition of ENT1, the molecular target(s) and effects of cannabidiol appear to be complex, including the activation of voltage-gated sodium channels, serotonin receptors, an orphan receptor (G protein-coupled receptor 55), nicotinic acetylcholine receptors, and anandamide transporters [97,116]. ...
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In modern societies, with an increase in the older population, age-related neurodegenerative diseases have progressively become greater socioeconomic burdens. To date, despite the tremendous effort devoted to understanding neurodegenerative diseases in recent decades, treatment to delay disease progression is largely ineffective and is in urgent demand. The development of new strategies targeting these pathological features is a timely topic. It is important to note that most degenerative diseases are associated with the accumulation of specific misfolded proteins, which is facilitated by several common features of neurodegenerative diseases (including poor energy homeostasis and mitochondrial dysfunction). Adenosine is a purine nucleoside and neuromodulator in the brain. It is also an essential component of energy production pathways, cellular metabolism, and gene regulation in brain cells. The levels of intracellular and extracellular adenosine are thus tightly controlled by a handful of proteins (including adenosine metabolic enzymes and transporters) to maintain proper adenosine homeostasis. Notably, disruption of adenosine homeostasis in the brain under various pathophysiological conditions has been documented. In the past two decades, adenosine receptors (particularly A1 and A2A adenosine receptors) have been actively investigated as important drug targets in major degenerative diseases. Unfortunately, except for an A2A antagonist (istradefylline) administered as an adjuvant treatment with levodopa for Parkinson's disease, no effective drug based on adenosine receptors has been developed for neurodegenerative diseases. In this review, we summarize the emerging findings on proteins involved in the control of adenosine homeostasis in the brain and discuss the challenges and future prospects for the development of new therapeutic treatments for neurodegenerative diseases and their associated disorders based on the understanding of adenosine homeostasis.
... A CBD antiepileptikus hatása ugyanakkor független a CB-receptoroktól. A vegyület feltehetőleg az intracelluláris kalciumszint modulálásával csökkenti a neuronok hiperexcitabilitását, és ez a hatás a GPR55 (G-protein-coupled receptor 55) és a TRPV1 (transient receptor potential cation channel subfamily V member 1) ioncsatornákra, valamint az NT1 transzporterre (nukleozidtranszporter-1) kifejtett hatás következménye [31]. A CB-k terápiás felhasználására irányuló kutatások legújabb irányzata az, hogy nem direkt ható CB 1 -vagy CB 2 -receptor-ligandokat fejlesztenek, hanem a bontó enzimek (FAAH vagy MAGL) gátlása révén emelik az endokannabinoidszintet és következésképp a receptoraktivációt. ...
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Összefoglaló. A kender (Cannabis sativa) gyógyhatásainak megítélése napjainkban változóban van, egyúttal igen ellentmondásos. Munkánk célja a kenderrel és készítményeivel kapcsolatos jogszabályi környezet alakulásának a kender gyógyászati alkalmazásának történetével párhuzamos bemutatása. A kenderrel és tartalomanyagaival kapcsolatos, jelenleg hatályos hazai jogszabályok és nemzetközi egyezmények áttekintése mellett bemutatjuk a kender alkalmazásának történetét a szakirodalmi adatok és a gyógyszerkincs átalakulásának tükrében. A kender ipari pályafutása textilipari alapanyagként kezdődött, de már ezt megelőzően is alkalmazták kábítószerként és gyógyászati célokra. A 20. század során a pszichoaktív szerként való felhasználás vált elterjedtebbé, de a növény hatóanyagainak jobb megismerésével a gyógyászati alkalmazás súlya is nőtt. Jelenleg a kender több vegyülete (kannabidiol, tetrahidrokannabinol) van forgalomban gyógyszerként világszerte, de félszintetikus kannabinoidot (nabilon) tartalmazó készítmények és különböző kannabisztermékek is forgalomban vannak gyógyszerként. Napjainkban alkalmazására jellemző, hogy a racionális gyógyászati használat mellett jelentős a túlzó elvárásokon alapuló, szakszerűtlen alkalmazás. Ez részben a kenderrel kapcsolatos jogi szabályozás anomáliáival is magyarázható. Ennek következménye, hogy élelmiszerként elérhetők a kender epilepsziaellenes hatóanyagát tartalmazó termékek, amelyeket számos gyógyhatás reményében használnak orvosi kontroll nélkül. Megállapítható, hogy az új tudományos eredmények, a területen érdekelt vállalkozások céljai, a fogyasztói igények, a piaci realitás és a jogi szabályozás nem minden esetben és szempontból van összhangban. A kannabinoidok hosszabb távú jövőjét a bizonyítékokon alapuló gyógyászatban nagyban befolyásolják azok a kutatások, amelyek segítségével pontosabb kép alkotható haszon-kockázat profiljukról. Orv Hetil. 2021; 162(45): 1808-1817. Summary. The opinion about the medicinal value of cannabis (Cannabis sativa) is changing but still remains controversial. The aim of our work was to present the evolution of the regulatory environment of Cannabis and its preparations in parallel with its history as medicine. We reviewed the current national legislation and international conventions on Cannabis and its constituents along with the historical and contemporary medicinal application of Cannabis. The utilisation of Cannabis started in the textile industry, but it was applied for recreational and medicinal purposes beforehand. During the 20th century, it was best known for its psychoactivity whereas its medicinal importance increased after elucidating the bioactivities of the active compounds of the plant. Currently different phytocannabinoids (cannabidiol, tetrahydrocannabinol) are marketed as medicines, but semisynthetic cannabinoids and different cannabis-based products are also approved as medicines. Today, there is a trend that goes beyond the rational and medicinal application thus results in improper form of utilisation. This phenomenon could partly be explained by the anomalies of legislative regulations. As a result, products containing the antiepileptic component of cannabis are available as food and used for different medicinal purposes without medical supervision. Evidently, there is no harmony between the new scientific discoveries, the goals of companies involved, the demands of consumers, market realities and current laws in several aspects. Ongoing studies will help to clarify the benefit-risk profiles of cannabinoids and provide major influence on the future of these compounds in the evidence-based medicine. Orv Hetil. 2021; 162(45): 1808-1817.
... It was first identified in 1999 (Sawzdargo et al., 1999) and is expressed on immune cells, including monocytes, NK and microglial cells and is present in both the CNS and the GI tract (Ryberg et al., 2009). An accumulating body of evidence implicates GPR55 in neuronal hyperexcitability and epilepsy, corroborated by recent findings indicating that GPR55 expression is elevated in the epileptic hippocampus (Gray and Whalley, 2020;Rosenberg et al., 2018). Ryberg et al., (2007) showed that cannabidiol displayed antagonist properties at GPR55 and that anandamide stimulated GTPγS binding with an EC50 of 18 nM. ...
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The blood brain barrier (BBB) is central to the neurovascular unit (NVU) where it creates a semi-permeable barrier between neuronal tissue and the vascular networks that feed the brain. In neurodegenerative conditions and ischaemic stroke, the BBB becomes compromised and as a result its permeability increases. This not only exacerbates neuronal damage at the site of injury but also causes unwanted extravasation of peripheral immune cells into the brain, fuelling the overactivation of the immune response. Endocannabinoids and phytocannabinoids have both displayed neuroprotective effects, attenuating damage in a range of models including Parkinson’s, Huntington’s, amyloid lateral sclerosis and ischaemic stroke. The current study aimed to investigate the neuroprotective properties of emerging phytocannabinoids; specifically focusing on the BBB and NVU in the context of ischaemic stroke pathophysiology. A four-cell blood brain barrier model was constructed consisting of; human brain microvascular endothelial cells (HBMECs), astrocytes, pericytes and neurons. Cells were cultured on collagen coated transwell inserts and permeability was assessed using transepithelial resistance (TEER). A systematic review was conducted to examine work on the neuroprotective properties of minor phytocannabinoids, aside from cannabidiol (CBD) and delta 9-tetrahydrocannabinol (Δ9-THC). Following on from this, in vitro experiments were conducted using minor phytocannabinoids with the most neuroprotective potential; cannabidivarin (CBDV), cannabigerol (CBG) and cannabidiolic acid (CBDA). Inserts or monocultures (four cell model and pericyte, HBMECs and neuronal monolayers) were subjected to either a 4 h oxygen-glucose deprivation (OGD) protocol or an 8 h OGD (astrocyte monocultures), to model ischaemic stroke in vitro. Media was analysed for various chemokines and cytokines using enzyme-linked immunoassays or multiplex assays. From the systematic review, emerging phytocannabinoids cannabidivarin (CBDV) and cannabigerol (CBG) were found to display efficacy in various neurogenerative conditions and of the limited available mechanistic data, were found to mediate some of their effects through peroxisome proliferator-activated receptor gamma (PPARy). Data showed CBDV (300 nM-10 µM) attenuated MCP-1 levels in HBMEC monolayers, as well as reducing IL-6 (30 nM, 1 µM and 10 µM; p<0.05) and VEGF (10 nM- 10 µM; p<0.01) levels in astrocyte monocultures post OGD. CBG (10 nM-3 µM; p<0.0001) also reduced levels of IL-6 secreted by astrocytes and decreased levels of DNA damage response proteins including Chk1, Chk2, H2A.X and p53 post OGD. Neither CBG, nor CBDV reduced levels of IL-6, VEG or IL-8 in pericytes compared to the vehicle control post OGD. Cannabidiolic acid (CBDA) was also investigated and was found to decrease IL-6 in pericyte monocultures which was mediated, at least in part, by 5-HT1A activation. In a four-cell model of the BBB, CBDA offset increases in permeability vs the vehicle control and offered direct protection to neurons, as shown by a lack of propidium iodide (PI) staining in CBDA treated cells, indicating live cells are present. Data presented in this thesis show minor phytocannabinoids CBDV, CBG and CBDA provide protection against OGD mediated damage, with CBDA also offering protection against increases in permeability of the BBB post OGD. These novel data warrant further investigation into the neuroprotective properties of phytocannabinoids, particularly in ischaemic stroke.
... The mechanism of its anti-epileptic activity is still not fully understood, however, it seems it is multimodal. The possible effects of CBD may include intracellular Ca2+ modulation and adenosine-mediated signalling regulations [49]. Gofshteyn et al., conducted a study on CBD-therapy in FIRES patients with promising results-in six out of seven patients the quantity of seizures reduced, mostly in chronic phase [50]. ...
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Febrile Infection-Related Epilepsy Syndrome (FIRES) is a catastrophic, extremely rare epileptic encephalopathy. It strikes previously healthy school-aged children and is usually cryptogenic. Its dramatic onset with refractory status epilepticus is always preceded by a nonspecific febrile illness. The seizure activity in FIRES may last for several weeks with little to no response to antiepileptic treatment, usually resulting in the usage of anaesthetics. This acute phase is followed by a chronic, refractory epilepsy and cognitive deficit, that persist for the rest of the patient’s life. Still to this day no definite cause has been described. In this study we review the current finding in FIRES and describe a case of a 4-year-old patient with a dramatic course of the acute phase in FIRES and unusual presentation of the chronic phase, which is dominated by extrapyramidal symptoms such as dystonia. This case highlights that the clinical presentation of FIRES may differ from those frequently described in literature.
... Although CBD's mechanism of action in ameliorating epileptic symptoms in humans remains unknown, one of its proposed pathways involves the TRP ion channels [177,178]. The expression of transient receptor potential cation channel subfamily V member I (TRPV1) is increased in epilepsy, and linked to elevated neuronal hyperexcitability [179,180]. In rat hippocampal brain slices perfused with artificial cerebrospinal fluid, which serves as an in vitro model of epileptiform activity, CBD has been shown to activate and then rapidly desensitize TRPV1 [179]. ...
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Despite the intricate involvement of the endocannabinoid system in various physiological processes, it remains one of the most under-studied biological systems of the human body. The scope of endocannabinoid signalling is widespread, ranging from modulation of immune responses in innate and adaptive immunity to gestational processes in female physiology. Cannabinoid receptors are ubiquitously distributed in reproductive tissues and are thought to play a role in regulating the immune–reproductive interactions required for successful pregnancy, specifically among uterine natural killer cells and placental extravillous trophoblasts. The use of cannabis during pregnancy, however, can perturb endocannabinoid homeostasis through effects mediated by its major constituents, ∆-9-tetrahydrocannabinol and cannabidiol. Decidualization of the endometrium, invasion, and angiogenesis may be impaired as a consequence, leading to clinical complications such as miscarriage and preeclampsia. In this review, the crosstalk between endocannabinoid signalling in uterine natural killer cells and placental extravillous trophoblasts will be examined in healthy and complicated pregnancies. This lays a foundation for discussing the potential of targeting the endocannabinoid system for therapeutic benefit, particularly with regard to the emerging field of synthetic cannabinoids.
... It is a highly purified, plant-derived, CBD oil-based solution that does not contain tetrahydrocannabinol, and as such does not have euphoric or intrusive side effects. Cannabidiol has mechanisms of action that are distinct from other ASMs (Fig. 4): it modulates intracellular calcium via both G-protein-coupled receptor 55 and transient receptor potential vanilloid 1, and also inhibits adenosine cellular uptake via the equilibrative nucleoside transporter 1 [62]. ...
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Dravet syndrome is a severe developmental and epileptic encephalopathy characterised by refractory seizures and cognitive dysfunction. The treatment is challenging, not least because the seizures are highly drug resistant, requiring multiple anti-seizure medications (ASMs), while some ASMs can exacerbate seizures. Initial treatments include the broad-spectrum ASMs valproate (VPA), and clobazam (CLB) in some regions; however, they are generally insufficient to control seizures. With this in mind, three adjunct ASMs have been approved specifically for the treatment of seizures in patients with Dravet syndrome: stiripentol (STP) in 2007 in the European Union and 2018 in the USA, cannabidiol (CBD) in 2018/2019 (in combination with CLB in the European Union) and fenfluramine (FFA) in 2020. These “add-on” therapies (mostly to VPA/CLB) are used as escalation therapies, with the choice dependent on availability in different countries, patient characteristics and caregiver preferences. Topiramate is also frequently used, with evidence of efficacy in Dravet syndrome, and there is anecdotal evidence of efficacy with bromide, which is frequently used in Germany and Japan. With a growing treatment landscape for Dravet syndrome, there can be practical challenges for clinicians, particularly with issues associated with polypharmacy. This practical guide provides an overview of these main ASMs including their indications/contraindications, mechanism of action, efficacy, safety and tolerability profile, dosage requirements, and laboratory and clinical parameters to be evaluated. Standard laboratory and clinical parameters include blood counts, liver function tests, serum concentrations of ASMs, monitoring the growth of children, as well as weight loss and acceleration of behavioural problems. Regular cardiac monitoring is also important with FFA as it has previously been associated with cases of cardiac valve disease when used in adults at high doses (up to 120 mg/day) in combination with phentermine as a therapy for obesity. Importantly, no signs of heart valve disease have been documented to date at the low doses used in patients with developmental and epileptic encephalopathies. In addition, potential drug–drug interactions and their consequences are a key consideration in everyday practice. Interactions that potentially require dosage adjustments to alleviate adverse events include the following: STP + CLB resulting in increased plasma concentrations of CLB and its active metabolite norclobazam may increase somnolence, and an interaction with STP and VPA may increase gastrointestinal adverse events. Cannabidiol has a bi-directional interaction with CLB producing an increase in plasma concentrations of 7-OH-CBD and norclobazam resulting in the potential for increased somnolence and sedation. In addition, CBD is associated with elevations of liver transaminases particularly in patients taking concomitant VPA. The interaction between FFA and STP requires a dose reduction of FFA. Furthermore, concomitant administration of VPA with topiramate has been associated with encephalopathy and/or hyperammonaemia. Finally, we briefly describe other ASMs used in Dravet syndrome, and current key clinical trials.
... However, there is evidence of the anticonvulsive effect of cannabidiol (CBD) (the main non-psychoactive compound from Cannabis sativa) in vitro and in vivo (Gray & Whalley, 2020;Jones et al., 2010). There are several anecdotal reports of the possible efficacy of plantderived cannabis extracts for treatment of refractory epilepsy in humans (Gaston & Szaflarski, 2018). ...
Article
Overcoming refractory epilepsy's resistance to the combination of antiepileptic drugs (AED), mitigating side effects, and preventing sudden unexpected death in epilepsy are critical goals for therapy of this disorder. Current therapeutic strategies are based primarily on neurocentric mechanisms, overlooking the participation of astrocytes and microglia in the pathophysiology of epilepsy. This review is focused on a set of non-selective membrane channels (permeable to ions and small molecules), including channels and ionotropic receptors of neurons, astrocytes, and microglia, such as: the hemichannels formed by Cx43 and Panx1; the purinergic P2X7 receptors; the transient receptor potential vanilloid (TRPV1 and TRPV4) channels; calcium homeostasis modulators (CALHMs); transient receptor potential canonical (TRPC) channels; transient receptor potential melastatin (TRPM) channels; voltage-dependent anion channels (VDACs) and volume-regulated anion channels (VRACs), which all have in common being activated by epileptic activity and the capacity to exacerbate seizure intensity. Specifically, we highlight evidence for the activation of these channels/receptors during epilepsy including neuroinflammation and oxidative stress, discuss signaling pathways and feedback mechanisms, and propose the functions of each of them in acute and chronic epilepsy. Studying the role of these non-selective membrane channels in epilepsy and identifying appropriate blockers for one or more of them could provide complementary therapies to better alleviate the disease.
... Cannabidiol (CBD) is the non-psychoactive component extracted from Cannabis sativa. The anti-seizure mechanisms of the CBD are complex and not fully elucidated but seem to involve a decrease in intracellular calcium (by blocking T-type calcium channel, antagonizing GPR55 and activating and desensitizing TRPV1) and an increase in extracellular adenosine (by inhibiting adenosine reuptake) [88,89] (Figure 2). CBD also shows a high affinity with serotonin receptors (5-HT 1A and 5-HT 2A ). ...
Article
Introduction: Management of individuals with Dravet Syndrome has evolved significantly over the past 10 years. Progress has been made in understanding the pathophysiology, the long-term outcome and possible consequences of inappropriate therapies, new drugs have been approved by the regulatory authorities and patients and families expressed their needs beyond seizures’ control. Areas covered: The authors aimed at providing an overview of the main antiseizure medications used in Dravet syndrome with a particular focus on safety considerations. As the highly active phase of seizures takes place before the age of 5 years, the characteristics of antiseizure medications in infancy and childhood have also been considered due to their impact on antiseizure medication safety. Expert opinion: Recent treatments, evaluated via randomized clinical trials, are promising in terms of efficacy and safety in individuals with DS. However, the balance between expected benefits and risks taken must be accurately assessed on an individual basis. There is a lack of data to understand the needs of patients and families, a major point particularly in this population, where the evaluation of efficacy and safety beyond seizures is difficult due to cognitive delay and behavioral disorders and where this evaluation is coming almost exclusively from caregivers.
... In addition to this, it has been demonstrated that the PI3K/mTOR pathway, which is linked to numerous neurological disorders, including epilepsy, is involved in the anticonvulsant effects of CBD [12]. Moreover, CBD inhibits adenosine transport type 1 equilibrative nucleoside transporter (ENT-1) activity and lowers neuronal excitability by functionally antagonizing G-protein-coupled receptor 55 (GPR55) and desensitizing transient receptor potential cation channel subfamily V member 1 (TRPV1) receptors [13]. ...
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We evaluated the effects of cannabidiol (CBD) on seizures and peroxisome proliferator activated receptor gamma (PPAR) levels in an animal model of temporal lobe epilepsy (TLE). Adult male Sprague-Dawley rats were continuously monitored by video-electrocorticography up to 10 weeks after an intraperitoneal kainic acid (15 mg/kg) injection. Sixty-seven days after the induction of status epilepticus and the appearance of spontaneous recurrent seizures in all rats, CBD was dissolved in medium-chain triglyceride (MCT) oil and administered subcutaneously at 120 mg/kg (n = 10) or 12 mg/kg (n = 10), twice a day for three days. Similarly, the vehicle was administered to ten epileptic rats. Brain levels of PPARgamma immunoreactivity were compared to those of six healthy controls. CBD at 120 mg/kg abolished the seizures in 50% of rats (p = 0.033 vs. pretreatment, Fisher’s exact test) and reduced total seizure duration (p < 0.05, Tukey Test) and occurrence (p < 0.05). PPARgamma levels increased with CBD in the hippocampal CA1 subfield and subiculum (p < 0.05 vs. controls, Holm–Šidák test), but only the highest dose increased the immunoreactivity in the hippocampal CA3 subfield (p < 0.001), perirhinal cortex, and amygdala (p < 0.05). Overall, these results suggest that the antiseizure effects of CBD are associated with upregulation of PPARgamma in the hippocampal CA3 region.
... Continued research demonstrated the efficiency of Cannabis in the treatment of medical conditions including epilepsy, multiple sclerosis, Tourette's syndrome, and other neurological diseases [13][14][15]. Additionally, research has further characterized the active compounds-tetrahydrocannabinol (THC) and cannabidiol (CBD)-of Cannabis and their psychological and physiological effects on humans [16][17][18][19]. While clinical research has primarily focused on the efficacy of Cannabis against neurological disorders, a current gap in knowledge is the efficacy of Cannabis and its byproducts as antibacterial agents. ...
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Products derived from Cannabis sativa L. have gained increased interest and popularity. As these products become common amongst the public, the health and potential therapeutic values associated with hemp have become a premier focus of research. While the psychoactive and medicinal properties of Cannabis products have been extensively highlighted in the literature, the antibacterial properties of cannabidiol (CBD) have not been explored in depth. This research serves to examine the antibacterial potential of CBD against Salmonella newington and S. typhimurium. In this study, we observed bacterial response to CBD exposure through biological assays, bacterial kinetics, and fluorescence microscopy. Additionally, comparative studies between CBD and ampicillin were conducted against S. typhimurium and S. newington to determine comparative efficacy. Furthermore, we observed potential resistance development of our Salmonella spp. against CBD treatment.
... Among the Dsm5 potential modifier genes, Trpv1 is an intriguing candidate as a proposed target of cannabidiol, an FDA/EMA-approved Dravet syndrome therapeutic (Gray and Whalley 2020). Recently, we reported differential expression of Trpv1 transcript in cortex, with higher expression in F1.Scn1a +/− mice relative to seizure resistant 129.Scn1a +/− mice (Satpute Janve et al. 2021). ...
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Pathogenic variants in SCN1A result in a spectrum of phenotypes ranging from mild febrile seizures to Dravet syndrome, a severe infant-onset epileptic encephalopathy. Individuals with Dravet syndrome have developmental delays, elevated risk for sudden unexpected death in epilepsy (SUDEP), and have multiple seizure types that are often refractory to treatment. Although most Dravet syndrome variants arise de novo, there are cases where an SCN1A variant was inherited from mildly affected parents, as well as some individuals with de novo loss-of-function or truncation mutations that presented with milder phenotypes. This suggests that disease severity is influenced by other factors that modify expressivity of the primary mutation, which likely includes genetic modifiers. Consistent with this, the Scn1a+/− mouse model of Dravet syndrome exhibits strain-dependent variable phenotype severity. Scn1a+/− mice on the 129S6/SvEvTac (129) strain have no overt phenotype and a normal lifespan, while [C57BL/6Jx129]F1.Scn1a+/− mice have severe epilepsy with high rates of premature death. Low resolution genetic mapping identified several Dravet syndrome modifier (Dsm) loci responsible for the strain-dependent difference in survival of Scn1a+/− mice. To confirm the Dsm5 locus and refine its position, we generated interval-specific congenic strains carrying 129-derived chromosome 11 alleles on the C57BL/6J strain and localized Dsm5 to a 5.9 Mb minimal region. We then performed candidate gene analysis in the modifier region. Consideration of brain-expressed genes with expression or coding sequence differences between strains along with gene function suggested numerous strong candidates, including several protein coding genes and two miRNAs that may regulate Scn1a transcript.
... Further, studies from our group have demonstrated that CBD 1 mg/kg i.v. was associated with reduced HI braininduced inflammation-mediated lung damage in piglets (11). The mechanisms of action of CBD are not fully elucidated, but preclinical studies suggest that CBD possesses a diverse polypharmacology including antagonism of G protein-coupled receptor 55, desensitization of transient receptor potential cation channel subfamily V member 1 and activation of 5-HT 1A receptors (12,13). Despite the lipophilic nature of CBD, our group has demonstrated that CBD can be administered by i.v. ...
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Aim To assess the effects of cannabidiol (CBD) on lung damage in a piglet model of meconium aspiration syndrome (MAS). Materials and Methods Meconium aspiration syndrome was modelled in newborn piglets via intratracheal instillation of 20% meconium in saline collected from healthy newborn humans. Piglets were treated i.v. with 5 mg/kg CBD (MAS + CBD) or Vehicle (MAS + VEH) 30 min after MAS induction and monitored for 6 h. Ventilated piglets without meconium instillation served as controls (CTL). Ventilatory and haemodynamic monitoring, histological and biochemical studies assessed the effects of treatment. Results Post-insult administration of CBD reduced MAS-induced deterioration of gas exchange, improving respiratory acidosis (final pH 7.38 ± 0.02, 7.22 ± 0.03 and 7.33 ± 0.03 and final pCO 2 39.8 ± 1.3, 60.4 ± 3.8 and 45.7 ± 3.1 mmHg for CTL, MAS + VEH and MAS + CBD, respectively, p < 0.05). These beneficial effects were obtained despite the less aggressive ventilatory settings required for CBD-treated animals (final minute volume 230 ± 30, 348 ± 33 and 253 ± 24 mL/kg/min and final Oxygenation Index 1.64 ± 0.04, 12.57 ± 3.10 and 7.42 ± 2.07 mmHg for CTL, MAS + VEH and MAS + CBD, respectively, p < 0.05). CBD’s beneficial effects on gas exchange were associated with reduced histological lung damage, reduced leucocyte infiltration and oedema (histopathological score 1.6 ± 0.3, 8.6 ± 1.4 and 4.6 ± 0.7 points for CTL, MAS + VEH and MAS + CBD, respectively, p < 0.05), as well as reduced TNFα production (0.04 ± 0.01, 0.34 ± 0.06 and 0.12 ± 0.02 A.U. for CTL, MAS + VEH and MAS + CBD, respectively, p < 0.05). Moreover, CBD improved blood pressure stability (final mean blood pressure 74.5 ± 0.2, 62.2 ± 6.2, and 78.67 ± 4.1 mmHg for CTL, MAS + VEH and MAS + CBD, respectively, p < 0.05). Conclusion Cannabidiol reduces histologic lung damage and inflammation in a piglet model of MAS. This translates into improved gas exchange and blood pressure stability.
... The mechanism of action of CBD is still not fully understood. However, modulation of intracellular Ca2 + mobilization (by GPR55 and TRPV1) as well as modulation of adenosine-mediated signal pathways seem to play an essential role [9]. ...
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Anecdotal reports addressing the successful seizure treatment of severe epilepsies with cannabidiol (CBD) have increased both public interest and academic research. Placebo-controlled, randomized, controlled trials proved the efficacy of pharmaceutical-grade CBD in epilepsy treatment, thus leading to pharmaceutical-grade CBD approval by the US Food and Drug Administration and the European Medicines Agency for the treatment of seizures in Dravet syndrome and Lennox-Gastaut syndrome as well as for tuberous complex syndrome by the Food and Drug Administration only. However, the CBD market is confusing because an array of products of different origins, purity, and concentration is available. Additionally, the results from the pivotal studies with plant-derived, pharmaceutical-grade CBD cannot simply be transferred to other epilepsy types or CBD of any origin. Because of the high demands and expectations that patients with epilepsy and their caregivers have regarding CBD, information outlining the proven facts and potential risks is essential. The aim of this article is to thoroughly review available research data and practical recommendations to provide the treating physician with the necessary information for counseling patients with epilepsy.
... Mechanism of action of CBD in epilepsy. Created with BioRender.com(Gray & Whalley, 2020). ...
Article
Due to the multiple health benefits associated with the consumption of cannabinoids, there is a current trend on continuing to explore their biological properties. Cannabidiol (CBD) is likely to be the most investigated endocannabinoid from the cannabis plant. Unfortunately, the purification of CBD from its natural source and psychotropic analogue (tetrahydrocannabinol, THC) is timely challenging for the research community based on the similar physiochemical properties of both molecules. This latter fact becomes relevant for the final application of CBD in edibles as a bioactive compound. Therefore, this paper comprehensively reviews the latest development works (over the last 2–3 years) aiming at the extraction of cannabinoids and purification of CBD using traditional, emerging, and synergistic extraction techniques and strategies. Particular emphasis and discussion have been focused on the innovative extraction techniques and the relevant outcomes with detailed strategies to meet such high extraction rates. Biological properties (at lab-scale and clinical case studies), current practices, progress in legislation and commercialization of CBD are also overviewed. Finally, according to the findings of this review, the future trends and research gaps are also given.
... CBDA is similar to CBD in its overall actions at neurological targets such as the glycine receptor, transient receptor potential villinoid and ankyrin receptors (TRPV, TRPA) and 5-hydroxytrapamine 1A receptors (5HT1A) with less known about CBDA's ability to interact with the equilibrative nucleoside transporter activity (19,20). In humans, the pharmacokinetics of CBDA appear to be superior to CBD and have been examined in human clinical trials. ...
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The use of cannabidiol (CBD) in childhood refractory seizures has become a common therapeutic approach for specific seizure disorders in human medicine. Similarly, there is an interest in using CBD, cannabidiolic acid (CBDA) or cannabinoid-rich hemp products in the treatment of idiopathic epilepsy in dogs. We aimed to examine a small cohort in a pilot investigation using a CBD and CBDA-rich hemp product for the treatment of refractory epileptic seizures in dogs. Fourteen dogs were examined in a 24-week randomized cross-over study being provided placebo or CBD/CBDA-rich hemp extract treatment at 2 mg/kg orally every 12 h for each 12-week arm of the study. Serum chemistry, complete blood counts, serum anti-seizure medication (ASM) concentrations and epileptic seizure frequency were followed over both arms of the cross-over trial. Results demonstrated that besides a mild increase in alkaline phosphatase, there were no alterations observed on routine bloodwork at 2, 6, and 12 weeks during either arm of the study. Epileptic seizure frequency decreased across the population from a mean of 8.0 ± 4.8 during placebo treatment to 5.0 ± 3.6 with CBD/CBDA-rich hemp extract ( P = 0.02). In addition, epileptic seizure event days over the 12 weeks of CBD/CBDA-rich hemp treatment were 4.1 ± 3.4, which was significantly different than during the 12 weeks of placebo treatment (5.8 ± 3.1; P =0.02). The number of dogs with a 50% reduction in epileptic activity while on treatment were 6/14, whereas 0/14 had reductions of 50% or greater while on the placebo ( P = 0.02). No differences were observed in serum zonisamide, phenobarbital or bromide concentrations while on the treatment across groups. Adverse events were minimal, but included somnolence (3/14) and transient increases in ataxia (4/14) during CBD/CBDA-rich hemp extract treatment; this was not significantly different from placebo. This further indicates that providing CBD/CBDA-rich hemp extract during refractory epilepsy (only partially responsive to ASM), in conjunction with other ASM appears safe. Based on this information, the use of 2 mg/kg every 12 h of a CBD/CBDA-rich hemp extract can have benefits in reducing the incidence of epileptic seizures, when used concurrently with other ASMs.
... Stiripentol affects the metabolism of other antiseizure medications such as clobazam by enhancing central γ-aminobutyric acid transmission and inhibiting several P450 cytochromes (Devi et al., 2021). Cannabidiol reduces neuronal excitability through inhibition of adenosine transport and modulation of intracellular Ca2 + (Gray and Whalley, 2020). Fenfluramine enhances the effects of 5-hydroxytryptamine to exerts antiepileptic activity (Sourbron et al., 2017). ...
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Purpose: Recently, the U.S. Food and Drug Administration (FDA) approved stiripentol, cannabidiol, and fenfluramine to treat patients with Dravet syndrome (DS). Moreover, soticlestat was determined as a promising new drug for the treatment of DS as it has good efficacy and safety. However, the efficacy and safety of these drugs have not yet been evaluated in “head-to-head” trials. This study aimed to compare and evaluate the efficacy and safety of these adjunctive antiseizure medications in the treatment of DS. Methods: We searched in PubMed, Embase, Cochrane Library, and Web of Science databases for randomized controlled trials (RCTs) and open-label extension (OLE) studies in patients with DS. We performed a random-effect meta-analysis of OLE studies and a network meta-analysis for RCTs to evaluate the efficacy and safety of antiseizure medications in the treatment of DS. Primary efficacy outcomes were defined as a ≥50% reduction in seizure frequency compared with baseline. Furthermore, safety evaluation indicators were defined as the incidence of adverse events (AEs) and serious adverse events (SAEs) during treatment. Relative ranking was assessed using the surface under the cumulative ranking curve (SUCRA) probabilities. Results: Seven RCTs involving four antiseizure medications (stiripentol, cannabidiol, fenfluramine, and soticlestat) and a total of 634 patients were included in the analysis. According to the SUCRA results, all four drugs significantly reduced the frequency of seizures compared with the placebo. Soticlestat was the most likely to reduce seizure frequency by ≥50% compared to the baseline [risk ratio (RR): 19.32; 95% confidence interval (CI): 1.20–311.40], followed by stiripentol and fenfluramine. Stiripentol was ranked highest for the near percentage reduction in the seizure rate from baseline [RR: 12.33; 95% CI: 1.71–89.17] and the occurrence of any treatment-emergent adverse events [RR: 3.73; 95% CI: 1.65–8.43] and serious adverse events [RR: 4.76; 95% CI: 0.61–37.28]. A total of ten OLE studies containing 1,121 patients were included in our study. According to the results of the meta-analysis, the order of probability of reducing seizure frequency by ≥50% was fenfluramine (0.715, 95% CI: 0.621–0.808), stiripentol (0.604, 95% CI: 0.502–0.706), cannabidiol (0.448, 95% CI: 0.403–0.493). And the probability of occurrence of AEs is ranked as fenfluramine(0.832, 95% CI: 0.795–0.869), cannabidiol (0.825, 95% CI:0.701–0.950), stiripentol (0.823, 95% CI: 0.707–0.938), soticlestat (0.688, 95% CI: 0.413–0.890). Conclusion: According to the results of indirect comparison of efficacy and safety, cannabidiol is slightly inferior to the other three antiseizure medications in terms of efficacy and safety. Soticlestat, fenfluramine, and stripentol may have little difference in efficacy, but soticlestat and fenfluramine are safer. Soticlestat is probably the best adjunctive antiseizure medication, followed by fenfluramine. This conclusion is consistent with the comparison of long-term efficacy and safety.
... The full mechanisms of action by which cannabidiol exerts its anti-seizure effects are still being explored, although it is known that it possesses affinity for diverse targets that decrease the neuronal excitability related to the pathogenesis of the disease; cannabidiol targets include the G proteincoupled receptor 55 (GPR55) and transient receptor potential vanilloid 1 (TRPV-1) channels that modulate intracellular calcium, and the equilibrative nucleoside transporter 1 (ENT-1) involved in adenosine-mediated signalling [82,83]. The anticonvulsant effect does not work via cannabinoid receptors, and this lack of appreciable affinity or activity at these receptors means that it is not associated with the psychoactivity of the archetypal cannabinoid, tetrahydrocannabinol [84]. ...
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Lennox-Gastaut syndrome (LGS), a childhood-onset severe developmental and epileptic encephalopathy (DEE), is an entity that encompasses a heterogenous group of aetiologies, with no single genetic cause. It is characterised by multiple seizure types, an abnormal EEG with generalised slow spike and wave discharges and cognitive impairment, associated with high morbidity and profound effects on the quality of life of patients and their families. Drug-refractory seizures are a hallmark and treatment is further complicated by its multiple morbidities, which evolve over the patient’s lifetime. This review provides a comprehensive overview of the current and future options for the treatment of seizures associated with LGS. Six treatments are specifically indicated as adjunct therapies for the treatment of seizures associated with LGS in the US: lamotrigine, clobazam, rufinamide, topiramate, felbamate and most recently cannabidiol. These therapies have demonstrated reductions in drop seizures in 15%–68% of patients across trials, with responder rates (≥ 50% reduction in drop seizures) of 37%–78%. Valproate is still the preferred first-line treatment, generally in combination with lamotrigine or clobazam. Other treatments frequently used off-label include the broad spectrum anti-epileptic drugs (AED) levetiracetam, zonisamide and perampanel, while recent evidence from observational studies has indicated that a newer AED, the levetiracetam analogue brivaracetam, may be effective and well tolerated in LGS patients. Other treatments in clinical development include fenfluramine in late phase III, perampanel, soticlestat–OV953/TAK-953, carisbamate and ganaxolone. Non-pharmacologic interventions include the ketogenic diet, vagus nerve stimulation and surgical interventions; these are also expanding, with the potential for less invasive techniques for corpus callosotomy that have promise for reducing complications. However, despite these advancements, patients continue to experience a significant burden. Because LGS is not a single entity, tailoring of treatment is needed as opposed to a ‘one size fits all’ approach. Further research is needed into the underlying aetiologies and pathophysiology of LGS, together with advancements in treatments that encompass the spectrum of seizures associated with this complex syndrome.
... Currently C. sativa and its byproducts have been shown to be efficacious against several neurological diseases including Tourette's syndrome, epilepsy, and multiple sclerosis [6][7][8]. The characterization of C. sativa's two active compounds tetrahydrocannabinol (THC) and cannabidiol (CBD) has significantly progressed our understanding of the physiological and psychological effects of C. sativa on humans [9][10][11][12]. ...
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New generation antibiotics are needed to combat the development of resistance to anti-microbials. One of the most promising new classes of antibiotics is cannabidiol (CBD). It is a non-toxic and low-resistance chemical that can be used to treat bacterial infections. The antibacterial activity of Cannabis sativa L. byproducts, specifically CBD, has been of growing interest in the field of novel therapeutics. As research continues to define and characterize the antibacterial activity that CBD possesses against a wide variety of bacterial species it is important to examine potential interaction between CBD and common therapeutics such as broad-spectrum antibiotics. Here, we show that CBD-antibiotic co-therapy can effectively fight S. typhimurium via membrane integrity disruption. This research serves to examine the potential synergy between CBD and three broad-spectrum antibiotics for potential antibiotic-CBD co-therapy. In this study, we reveal that Salmonella typhimurium (S. typhimurium) growth is inhibited at very low dosages of CBD-antibiotic. This interesting finding demonstrates that CBD and CBD-antibiotic co-therapies are viable novel alternatives to combating Salmonella typhimurium.
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Objective The effects of individual cannabinoids on white matter integrity are unclear. Human studies have shown white matter maturation alterations in regular recreational cannabis users with the magnitude of these effects dependent on the age of exposure. However, studies have yet to determine which phytocannabinoids are most responsible for these changes. In the current study, we analyzed the effects of pharmaceutical grade cannabidiol oral solution (CBD; Epidiolex® in the U.S.; Epidyolex® in the EU; 100 mg/mL oral solution) on white matter integrity using diffusion MRI in patients with treatment resistant epilepsy (TRE). Methods 15 patients with TRE underwent 3 T diffusion MRI prior to receiving CBD and then again approximately 12 weeks later while on a stable dose of CBD for at least two weeks. DTI analyzes were conducted using DSI Studio and tract-based spatial statistics (TBSS). Results DTI analysis using DSI Studio showed significant increases in fractional anisotropy (FA) in the right medial lemniscus (p = 0.03), right superior cerebellar peduncle (p = 0.03) and the pontine crossing tract (p = 0.04); decreased mean diffusivity (MD) in the left uncinate fasciculus (p = 0.02) and the middle cerebellar peduncle (p = 0.04); decreased axial diffusivity (AD) in the left superior cerebellar peduncle (p = 0.05), right anterior limb of the internal capsule (p = 0.03), and right posterior limb of the internal capsule (p = 0.02); and decreased radial diffusivity (RD) in the middle cerebellar peduncle (p = 0.03) and left uncinate fasiculus (p = 0.01). The follow-up ANCOVA also yielded significant results when controlling for covariates of CBD dosage, age, sex, change in seizure frequency, and scanner type: FA increased in the pontine crossing tract (p = 0.03); RD decreased in the middle cerebellar peduncle (p = 0.04) and left uncinate fasciculus (p = 0.04). Subsequent TBSS analysis controlling for the same variables yielded no significant white matter differences between groups. Conclusion These findings indicate relatively minor short-term effects of highly-purified plant-derived CBD on white matter structural integrity in patients with TRE.
Article
Purpose : Although cannabidiol and fenfluramine have been recently approved by the US Food and Drug Administration (FDA) for seizures in children with Dravet syndrome (DS), the comparative efficacy and safety of these and stiripentol as an add-on therapy for DS has not been evaluated in head-to-head trials. The current study aimed to assess the comparative efficacy and safety of add-on anti-seizure medications in DS. Methods : PubMed and EMBASE database search and a manual search was done using keywords; “antiepileptic”, “Dravet syndrome” and “antiseizure”. The primary efficacy outcome was ≥50% reduction in convulsive seizure frequency from baseline while the safety outcome was treatment-emergent adverse events (TEAEs). Frequentist approach were used for combining direct and indirect evidence and network plots prepared. The drugs were ranked based on p-scores obtained using the surface under the cumulative ranking (SUCRA). Heterogeneity across studies was calculated by I² statistic and Q test. Results : Five randomized controlled trials (RCTs) with 565 patients with DS (2-20 years) who received placebo or any of the three active interventions (stiripentol, cannabidiol, and fenfluramine) were included. Compared with placebo, all the three drugs were associated with a significant reduction in convulsive seizure frequency from baseline. Stiripentol had the highest probability ranking for ≥50% reduction in convulsive seizure frequency from baseline [OR: 20.2; 95% CI: 2.1-198.0] and for occurrence of any treatment emergent adverse events (TEAEs) [OR:53.9; 95% CI: 1.4 to 2079.8] followed by fenfluramine and cannabidiol. However, for serious TEAEs, the ranking order was stiripentol followed by cannabidiol and fenfluramine. The trial on stiripentol had limited sample size explaining the wide confidence intervals for the comparative outcomes. Conclusion : In this indirect comparison, fenfluramine and stiripentol have comparable efficacy but fenfluramine appears to be safer in terms of less frequent serious TEAEs. Cannabidiol has relatively lower efficacy and is associated with serious TEAEs. A head-to-head trial between stiripentol, cannabidiol and fenfluramine is the need of the hour.
Article
The therapeutic potential of cannabidiol (CBD) in seizure disorders has been known for many years, but it is only in the last decade that major progress has been made in characterizing its preclinical and clinical properties as an antiseizure medication. The mechanisms responsible for protection against seizures are not fully understood, but they are likely to be multifactorial and to include, among others, antagonism of G protein-coupled receptor, desensitization of transient receptor potential vanilloid type 1 channels, potentiation of adenosine-mediated signaling, and enhancement of GABAergic transmission. CBD has a low and highly variable oral bioavailability, and can be a victim and perpetrator of many drug-drug interactions. A pharmaceutical-grade formulation of purified CBD derived from Cannabis sativa has been evaluated in several randomized placebo-controlled adjunctive-therapy trials, which resulted in its regulatory approval for the treatment of seizures associated with Dravet syndrome, Lennox-Gastaut syndrome and tuberous sclerosis complex. Interpretation of results of these trials, however, has been complicated by the occurrence of an interaction with clobazam, which leads to a prominent increase in the plasma concentration of the active metabolite N-desmethylclobazam in CBD-treated patients. Despite impressive advances, significant gaps in knowledge still remain. Areas that require further investigation include the mechanisms underlying the antiseizure activity of CBD in different syndromes, its pharmacokinetic profile in infants and children, potential relationships between plasma drug concentration and clinical response, interactions with other co-administered medications, potential efficacy in other epilepsy syndromes, and magnitude of antiseizure effects independent from interactions with clobazam. This article is part of the special issue on ‘Cannabinoids’.
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Background and purpose: Cannabis has been used to treat epilepsy for millennia, with such use validated by regulatory approval of cannabidiol (CBD) for the treatment of Dravet syndrome. Unregulated artisanal cannabis-based products used to treat children with intractable epilepsies often contain relatively low doses of CBD but are enriched in other phytocannabinoids. This raises the possibility that other cannabis constituents might have anticonvulsant properties. Experimental approach: We used the Scn1a+/- mouse model of Dravet syndrome to interrogate the cannabis plant for phytocannabinoids with anticonvulsant effects against hyperthermia-induced seizures. The most promising, cannabigerolic acid (CBGA), was further examined against spontaneous seizures and survival in Scn1a+/- mice. CBGA was also examined in conventional electroshock seizure models. In addition, we surveyed the pharmacological effects of CBGA across multiple drug targets. Key results: The initial screen identified three phytocannabinoids with novel anticonvulsant properties: CBGA, cannabidivarinic acid (CBDVA) and cannabigerovarinic acid (CBGVA). CBGA was the most potent and potentiated the anticonvulsant effects of clobazam against hyperthermia-induced and spontaneous seizures, and was anticonvulsant in the MES threshold test. However, CBGA was proconvulsant in the 6-Hz threshold test and a high dose increased spontaneous seizure frequency in Scn1a+/- mice. CBGA was found to interact with numerous epilepsy-relevant targets including GPR55, TRPV1 channels and GABAA receptors. Conclusion: These results suggest CBGA, CBDVA and CBGVA may contribute to the effects of cannabis-based products in childhood epilepsy. While these phytocannabinoids have anticonvulsant potential and could be lead compounds for drug development programs, several liabilities would need to be overcome before CBD is superseded by another in this class.
Article
The developmental and epileptic encephalopathies encompass a group of rare syndromes characterised by severe drug-resistant epilepsy with onset in childhood and significant neurodevelopmental comorbidities. The latter include intellectual disability, developmental delay, behavioural problems including attention-deficit hyperactivity disorder and autism spectrum disorder, psychiatric problems including anxiety and depression, speech impairment and sleep problems. Classical examples of developmental and epileptic encephalopathies include Dravet syndrome, Lennox–Gastaut syndrome and tuberous sclerosis complex. The mainstay of treatment is with multiple anti-seizure medications (ASMs); however, the ASMs themselves can be associated with psychobehavioural adverse events, and effects (negative or positive) on cognition and sleep. We have performed a targeted literature review of ASMs commonly used in the treatment of developmental and epileptic encephalopathies to discuss the latest evidence on their effects on behaviour, mood, cognition, sedation and sleep. The ASMs include valproate (VPA), clobazam, topiramate (TPM), cannabidiol (CBD), fenfluramine (FFA), levetiracetam (LEV), brivaracetam (BRV), zonisamide (ZNS), perampanel (PER), ethosuximide, stiripentol, lamotrigine (LTG), rufinamide, vigabatrin, lacosamide (LCM) and everolimus. Bromide, felbamate and other sodium channel ASMs are discussed briefly. Overall, the current evidence suggest that LEV, PER and to a lesser extent BRV are associated with psychobehavioural adverse events including aggressiveness and irritability; TPM and to a lesser extent ZNS are associated with language impairment and cognitive dulling/memory problems. Patients with a history of behavioural and psychiatric comorbidities may be more at risk of developing psychobehavioural adverse events. Topiramate and ZNS may be associated with negative effects in some aspects of cognition; CBD, FFA, LEV, BRV and LTG may have some positive effects, while the remaining ASMs do not appear to have a detrimental effect. All the ASMs are associated with sedation to a certain extent, which is pronounced during uptitration. Cannabidiol, PER and pregabalin may be associated with improvements in sleep, LTG is associated with insomnia, while VPA, TPM, LEV, ZNS and LCM do not appear to have detrimental effects. There was variability in the extent of evidence for each ASM: for many first-generation and some second-generation ASMs, there is scant documented evidence; however, their extensive use suggests favourable tolerability and safety (e.g. VPA); second-generation and some third-generation ASMs tend to have the most robust evidence documented over several years of use (TPM, LEV, PER, ZNS, BRV), while evidence is still being generated for newer ASMs such as CBD and FFA. Finally, we discuss how a variety of factors can affect mood, behaviour and cognition, and untangling the associations between the effects of the underlying syndrome and those of the ASMs can be challenging. In particular, there is enormous heterogeneity in cognitive, behavioural and developmental impairments that is complex and can change naturally over time; there is a lack of standardised instruments for evaluating these outcomes in developmental and epileptic encephalopathies, with a reliance on subjective evaluations by proxy (caregivers); and treatment regimes are complex involving multiple ASMs as well as other drugs.Graphical Abstract
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Objective: Cannabigerolic acid (CBGA), a precursor cannabinoid in Cannabis sativa, has recently been found to have anticonvulsant properties in the Scn1a+/- mouse model of Dravet syndrome. Poor brain penetration and chemical instability of CBGA limits its potential as an anticonvulsant therapy. Here, we examined whether CBGA methyl ester, a more stable analogue of CBGA, might have superior pharmacokinetic and anticonvulsant properties. In addition, we examined whether olivetolic acid, the biosynthetic precursor to CBGA with a truncated (des-geranyl) form, might possess minimum structural requirements for anticonvulsant activity. We also examined whether olivetolic acid and CBGA methyl ester retain activity at the epilepsy-relevant drug targets of CBGA: G-protein-coupled receptor 55 (GPR55) and T-type calcium channels. Methods: The brain and plasma pharmacokinetic profiles of CBGA methyl ester and olivetolic acid were examined following 10 mg/kg intraperitoneal (i.p.) administration in mice (n = 4). The anticonvulsant potential of each was examined in male and female Scn1a+/- mice (n = 17-19) against hyperthermia-induced seizures (10-100 mg/kg, i.p.). CBGA methyl ester and olivetolic acid were also screened in vitro against T-type calcium channels and GPR55 using intracellular calcium and ERK phosphorylation assays, respectively. Results: CBGA methyl ester exhibited relatively limited brain penetration (13%), although somewhat superior to that of 2% for CBGA. No anticonvulsant effects were observed against thermally induced seizures in Scn1a+/- mice. Olivetolic acid also showed poor brain penetration (1%) but had a modest anticonvulsant effect in Scn1a+/- mice increasing the thermally induced seizure temperature threshold by approximately 0.4°C at a dose of 100 mg/kg. Neither CBGA methyl ester nor olivetolic acid displayed pharmacological activity at GPR55 or T-type calcium channels. Conclusions: Olivetolic acid displayed modest anticonvulsant activity against hyperthermia-induced seizures in the Scn1a+/- mouse model of Dravet syndrome despite poor brain penetration. The effect was, however, comparable to the known anticonvulsant cannabinoid cannabidiol in this model. Future studies could explore the anticonvulsant mechanism(s) of action of olivetolic acid and examine whether its anticonvulsant effect extends to other seizure types.
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The Cannabis plant commonly is known for its viable psychoactive substance. In India it is served in religious functions. Cannabinoids in the cannabis plant include delta-9-tetrahydrocannabinol (THC), Cannabidiol (CBD), and cannabinol (CBN). THC is the primary psychoactive compound, with CBD, and it is a non-psychoactive compound. Despite of being an psychoactive compounds it has many medicinal effect, such as, treatment of various diseases and other health problem such as HIV/AIDS, glaucoma, treatment of pain, eye problem, muscle spasticity, convulsion, asthma, insomnia, hypertension, depression etc. The current studied was undertaken for phytochemical analysis, estimation of protein, and evaluation of Antioxidant and Antimicrobial activity of the studied plant against S.aureus and E.coli. Standard protocol had followed for analyzing phytochemicals. And from the result it was concluded that there are many bioactive phytochemicals present in the extracted plant. The reported phytochemicals are phenol, terpenoids, steroids, saponin, tannin, glycosides, carbohydrate and proteins. Various extract were prepared out of which protein concentration was evaluated for methanol and chloroform and was compared. The antimicrobial activity were evaluated and a recommendable zone of inhibition was seen in methanol extract.
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Research suggests that cannabis-derived delta-9- tetrahydrocannabinol (THC) can be linked to the worsening of psychosis and/or other symptoms of schizophrenia. However, studies have shown that another major cannabinoid found in cannabis, cannabidiol (CBD), may be a potential alternative or adjunctive treatment for psychosis and schizophrenia. As such, herein we review the relevant literature relating to the safety and efficacy of CBD treatment in patients with schizophrenia, including the effects of CBD in treating the positive, negative, and cognitive symptoms of the disorder, as well as the molecular mechanisms by which CBD can reduce schizophrenic symptoms. The potential utility of CBD for mitigating cannabis cravings and cannabis withdrawal in this patient population will also be reviewed. Lastly, the dosing, method of drug delivery, length of treatment, and adverse effects of CBD in patients with schizophrenia are also discussed. Thus, the goal of this narrative review is to help clinicians and researchers better understand the risks and benefits of this potential therapy for this patient population.
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One of the most important characteristics of the brain compared to other organs is its elevated metabolic demand. Consequently, neurons consume high quantities of oxygen, generating significant amounts of reactive oxygen species (ROS) as a by-product. These potentially toxic molecules cause oxidative stress (OS) and are associated with many disorders of the nervous system, where pathological processes such as aberrant protein oxidation can ultimately lead to cellular dysfunction and death. Epilepsy, characterized by a long-term predisposition to epileptic seizures, is one of the most common of the neurological disorders associated with OS. Evidence shows that increased neuronal excitability—the hallmark of epilepsy—is accompanied by neuroinflammation and an excessive production of ROS; together, these factors are likely key features of seizure initiation and propagation. This review discusses the role of OS in epilepsy, its connection to neuroinflammation and the impact on synaptic function. Considering that the pharmacological treatment options for epilepsy are limited by the heterogeneity of these disorders, we also introduce the latest advances in anti-epileptic drugs (AEDs) and how they interact with OS. We conclude that OS is intertwined with numerous physiological and molecular mechanisms in epilepsy, although a causal relationship is yet to be established.
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Despite the ever-increasing number of available options for the treatment of epilepsies and the remarkable advances on the understanding of their pathophysiology, the proportion of refractory patients has remained approximately unmodified during the last 100 years. How efficient are we translating positive outcomes from basic research to clinical trials and/or the clinical scenario? It is possible that fresh thinking and exploration of new paradigms is required to arrive at truly novel therapeutic solutions, as seemingly proven by recently approved first-in-class antiseizure medications and drug candidates undergoing late clinical trials. Here, the author discusses some approximations in line with the network pharmacology philosophy, which may result in highly innovative (and, hopefully, safer and/or more efficacious) medications for the control of seizures, as embodied with some recent examples in the field, namely tailored multi-target agents and low-affinity ligands.
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Products derived from Cannabis sativa have gained increased interest and popularity. As these products become common amongst the public, the heath and potential therapeutic values associated with hemp have become a premier focus of research. While the psychoactive and medicinal properties of Cannabis products have been extensively highlighted in literature, the antibacterial properties of CBD have not been explored in depth. This research serves to examine the antibacterial potential of CBD against Salmonella newington and Salmonella typhimurium. In this study we observed bacterial response to CBD exposure through biological assays, bacterial kinetics, and fluorescence microscopy. Additionally, comparative studies between CBD and ampicillin were conducted against Salmonella typhimurium and Salmonella newington to determine comparative efficacy. Furthermore, we observed potential resistance development of our Salmonella spp. against CBD treatment.
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Background Purified cannabidiol (CBD), a non-psychoactive phytocannabinoid, has gained regulatory approval to treat intractable childhood epilepsies. Despite this, artisanal and commercial CBD-dominant hemp-based products continue to be used by epilepsy patients. Notably, the CBD doses used in these latter products are much lower than that found to be effective in reducing seizures in clinical trials with purified CBD. This might be because these CBD-dominant hemp products contain other bioactive compounds, including phytocannabinoids and terpenes, which may exert unique effects on epilepsy-relevant drug targets. Voltage-gated sodium (Na V ) channels are vital for initiation of neuronal action potential propagation and genetic mutations in these channels result in epilepsy phenotypes. Recent studies suggest that Na V channels are inhibited by purified CBD. However, the effect of cannabis-based products on the function of Na V channels is unknown. Methods Using automated-planar patch-clamp technology, we profile a hemp-derived nutraceutical product (NP) against human Na V 1.1–Na V 1.8 expressed in mammalian cells to examine effects on the biophysical properties of channel conductance, steady-state fast inactivation and recovery from fast inactivation. Results NP modifies peak current amplitude of the Na V 1.1–Na V 1.7 subtypes and has variable effects on the biophysical properties for all channel subtypes tested. NP potently inhibits Na V channels revealing half-maximal inhibitory concentration (IC 50 ) values of between 1.6 and 4.2 μg NP/mL. Purified CBD inhibits Na V 1.1, Na V 1.2, Na V 1.6 and Na V 1.7 to reveal IC 50 values in the micromolar range. The CBD content of the product equates to IC 50 values (93–245 nM), which are at least an order of magnitude lower than purified CBD. Unlike NP, hemp seed oil vehicle alone did not inhibit Na V channels, suggesting that the inhibitory effects of NP are independent of hemp seed oil. Conclusions This CBD-dominant NP potently inhibits Na V channels. Future study of the individual elements of NP, including phytocannabinoids and terpenes, may reveal a potent individual component or that its components interact to modulate Na V channels.
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Microglia, the dynamic innate immune cells of the central nervous system, become activated in epilepsy. The process of microglial activation in epilepsy results in the creation of an inflammatory environment around the site of seizure onset, which contributes to the epileptogenic process and epilepsy progression. Cannabidiol (CBD) has been effective for use as an adjunctive treatment for two severe pediatric seizure disorders. Newly recognized as an Food and Drug Administration (FDA)-approved drug treatment in epilepsy, it has gained in popularity primarily for pain management. Although CBD is readily available in stores and online retailers, its mechanism of action and specifically its effects on microglia and their functions are yet fully understood. In this study, we examine the effects of commercially available CBD on microglia inflammatory activation and neurogenic response, in the presence and absence of seizures. We use systemic administration of kainate to elicit seizures in mice, which are assessed behaviorally. Artisanal CBD is given in different modes of administration and timing to dissect its effect on seizure intensity, microglial activation and aberrant seizure-related neurogenesis. CBD significantly dampens microglial migration and accumulation to the hippocampus. While long term artisanal CBD use does not prevent or lessen seizure severity, CBD is a promising adjunctive partner for its ability to depress epileptogenic processes. These studies indicate that artisanal CBD is beneficial as it both decreases inflammation in the CNS and reduces the number of ectopic neurons deposited in the hippocampal area post seizure.
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Delta-9-tetrahydrocannabinol (D9-THC) is the driving cannabinoid within cannabis that produces its psychoactive effects. However, the plant itself contains over 400 individual chemicals, many with unique pharmacological properties. Further complicating the cannabis market, chemical modifications have been identified to convert naturally derived cannabinoids to alternative cannabinoids and the collection of synthetic cannabinoids, manmade chemicals designed to act at cannabinoid receptors, continues to grow. Recent years have seen a rise in popularity of these alternative cannabinoids, and this trend is likely to continue with the continuing legalization of recreational cannabis throughout the United States. It is vital for medical providers to not only be aware of the wide range of available cannabinoid products, but to be conscious of their differing properties. The current work aims to identify commonly used alternative cannabinoids, examine their complicated legality, and summarize the available literature regarding their clinical effects.
Article
Introduction The safety and efficacy of a formulation high in cannabidiol (CBD) and low in ∆9-tetrahydrocannabinol (THC) to treat drug-resistant epilepsy have been examined previously in children, but not in adult population. The aim of this study was to evaluate whether CBD-rich oil, as an add-on treatment to conventional antiepileptic drugs, was effective, safe, and well-tolerated in adults with drug-resistant focal epilepsy (DRFE).Methods An open-label, prospective cohort, single-center in adult patients with DRFE, were receiving stable doses of antiepileptic drugs (AEDs). A cannabis based-magistral formulation (CBMF) (100 mg/ml CBD and THC <1.9 mg/ml) was administrated 0.1 ml sublingually every 12 hours, up-titrated weekly. The primary outcome was to establish a reduction in seizures frequency >50% at 12 weeks. Adverse-drug reactions monitoring was done. p-value <0.05 was statistically significant.ResultsBetween August 2020 and July 2022, 44 (38.6%) patients completed >3 months of follow-up. The median daily dose of CBD was 200 mg, that of THC was 4 mg, and that of CBD per kilogram of weight was 3.7 mg. The median number of seizures per month before CBD treatment was 11, and after CBD treatment was 2.5 (p<0.001). A reduction in seizures >50% at 12 week was achieved in 79.5% of the patients. The median percentage change in seizure frequency per month was 84.1% at 12 weeks. Five patients reported any adverse-drug reactions.Conclusion The CBMF is a highly effective and safety therapy to treat adult patients with DRFE. The reduction in seizures frequency is maintained over time.
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Marijuana has been used to treat medical disease since well before the 1800s. Recently, increased use of cannabinoids, the chemical components of marijuana, have been seen to treat neurologic illness in children and adults. Unfortunately, data are lacking in treating most neurologic illnesses except in the field of epilepsy and pain from spasticity in multiple sclerosis. Therefore, formal conclusions about the potential efficacy, benefit, and adverse effects for most marijuana based products cannot be made at this time. Further research using gold standard scientific methodology should be performed to help address potential uses and safety for cannabinoids to treat neurologic illnesses.
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