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Cannabidiol - antiepileptic drug comparisons and interactions in experimentally induced seizures in rats
Abstract
A comparison of the anticonvulsant and neurotoxic effects of cannabidiol (CBD), delta 9tetrahydrocannabinol, cannabinol and antiepileptic drugs (phenytoin, phenobarbital, carbamazepine, chlordiazepoxide, clonazepam, ethosuximide and trimethadione) was made in rats. Median effective potencies (ED 50 values) for maximal electroshock, audiogenic seizures and TD50 values for a rotor rod neurotoxicity test were calculated. Additionally, the interactive effects of CBD and the antiepileptic drugs against maximal electroshock and audiogenic seizures were studied. Each drug was given orally at peak effect time. CBD was an effective and relatively potent anticonvulsant in both maximal electroshock and audiogenic seizure tests. The anticonvulsant potency of phenytoin was significantly increased when combined with phenobarbital, CBD and phenobarbital plus CBD. Additionally, CBD reliably reduced the anticonvulsant potencies of chlordiazepoxide, clonazepam, trimethadione and ethosuximide. These data indicate that CBD is an effective anticonvulsant with a specificity more comparable to drugs clinically effective in major than minor seizures. Furthermore, it appears that CBD enhances the anticonvulsant effects of the former and reduces the effects of the latter types of antiepileptic drugs.
... The anticonvulsant effects of CBD have been demonstrated across numerous animal models of epilepsy in recent decades. In rats for example, across both MES and AS models, CBD anticonvulsant capability has been demonstrated at varying doses (12 and 17 mg/kg) [81] (Table 1). As well as sole efficacy, CBD was also compared with other AEDs in separate experiments still utilising the MES model. ...
... It was observed that CBD was as potent as the AED phenytoin and had slightly less efficacy compared to another AED, phenobarbital. CBD in this instance was also found to be more effective than both AEDs trimethadione and ethosuximide [81]. ...
... CBDV efficacy has been investigated across numerous animal models of epilepsy. It has anticonvulsant effects across the MES, AS, PTZ and Pilocarpine models of epilepsy [81,90] ( Table 1). Work in the MES model has shown that animals who received 100 or 200 mg/kg demonstrated significantly less hindlimb extension (a key phenotypic marker of seizure severity in animals) after seizure induction. ...
Epilepsy is a neurological disorder mainly characterised by recurrent seizures that affect the entire population diagnosed with the condition. Currently, there is no cure for the disease and a significant proportion of patients have been deemed to have treatment-resistant epilepsy (TRE). A patient is deemed to have TRE if two or more antiepileptic drugs (AEDs) fail to bring about seizure remission. This inefficacy of traditional AEDs, coupled with their undesirable side effect profile, has led to researchers considering alternative forms of treatment. Phytocannabinoids have long served as therapeutics with delta-9-THC (Δ9-THC) receiving extensive focus to determine its therapeutic potential. This focus on Δ9-THC has been to the detriment of analysing the plethora of other phytocannabinoids found in the cannabis plant. The overall aim of this review is to explore other novel phytocannabinoids and their place in epilepsy treatment. The current review intends to achieve this aim via an exploration of the molecular targets underlying the anticonvulsant capabilities of cannabidiol (CBD), cannabidavarin (CBDV), delta-9-tetrahydrocannabivarin (Δ9-THCV) and cannabigerol (CBG). Further, this review will provide an exploration of current pre-clinical and clinical data as it relates to the aforementioned phytocannabinoids and the treatment of epilepsy symptoms. With specific reference to epilepsy in young adult and adolescent populations, the exploration of CBD, CBDV, Δ9-THCV and CBG in both preclinical and clinical environments can guide future research and aid in the further understanding of the role of phytocannabinoids in epilepsy treatment. Currently, much more research is warranted in this area to be conclusive.
... of simultaneous consumption of both. CBD has been reported to interact with several anticonvulsants, including diazepam, lamotrigine, and phenytoin 28,29 ; sedative drugs including barbiturates such as phenobarbital and hexobarbital 30 ; and narcotics such as codeine and morphine. ...
... A pharmacodynamic animal study using maximal electroshock and audiogenic seizure models showed that CBD potentiated the anticonvulsant effects of phenytoin by twofold and discreetly potentiated the effect of phenobarbital. CBD also reduced the anticonvulsant properties of chlordiazepoxide, clonazepam, and ethosuximide 29,38,39 . A pharmacokinetic interaction between CBD and clobazam was reported with decreased clobazam serum levels noted after increasing CBD doses 40 . ...
Cannabidiol, a non-intoxicating phytocannabinoid,
has potential therapeutic effects over a broad range
of disorders. Recently, there has been increased interest
in CBD, as several studies showed promising
anticonvulsant efficacy with few side effects. In 2018,
a CBD-based oral solution, Epidiolex®, was approved
by the FDA to treat two severe forms of pediatric
epilepsy, Dravet syndrome, and Lennox-Gastaut syndrome.
Although only these two syndromes are recognized
indications for CBD, it has been consumed
in an unregulated fashion for a variety of indications
including chronic pain, muscle stiffness, inflammation,
anxiety, smoking cessation, and even cancer.
While CBD legislation in the USA is confusing due
to the differences in state and federal laws, CBD has
proliferated in the US market in several forms such
as CBD oil or capsules, hemp oil/extract, and also
as an ingredient in several dietary supplements,
syrups, teas, and creams. With the ever-increasing
use of CBD and its widespread availability to the
general public, it is important to examine and report
on possible drug–drug interactions between CBD and
other therapeutic agents as well as addictive substances
such as alcohol and tobacco. A detailed literature
search for CBD’s possible interactions was
conducted using online databases. As expected,
CBD has been reported to interact with antiepileptic
drugs, antidepressants, opioid analgesics,
and THC, but surprisingly, it interacts with several
other common medications, e.g. acetaminophen, and
substances including alcohol. This review provides a
comprehensive list of interacting drugs. The possible
mechanisms for these drug-drug interactions are
presented in table format. Given the growing popularity
of CBD as medication and the dearth of
available information on CBD drug-drug interactions,
it is critical to be aware of current drug-drug
interactions and it will be important to investigate
the impact of CBD upon concomitant medication
use in future randomized, controlled trials.
... In previous studies involving conventional rodent seizure models, Δ 9 -THC exhibited anticonvulsant effects (Chesher & Jackson, 1974;Colasanti, Lindamood, & Craig, 1982;Consroe & Wolkin, 1977;Lindamood & Colasanti, 1980;Sofia, Solomon, & Barry, 1976;Wallace, Wiley, Martin, & DeLorenzo, 2001). However, Δ 9 -THC has also exhibited proconvulsant effects in mice and rats in some studies (Chan, Sills, Braun, Haseman, & Bucher, 1996;Sofia et al., 1976;Whalley et al., 2019). ...
... The anticonvulsant effect of Δ 9 -THC in Scn1a +/− mice is consistent with other studies showing anticonvulsant properties of Δ 9 -THC in conventional seizure models, such as the maximal electroshock (MES) and audiogenic seizure models (Chesher & Jackson, 1974;Colasanti et al., 1982;Consroe & Wolkin, 1977;Lindamood & Colasanti, 1980;Sofia et al., 1976;Wallace et al., 2001). However, in contrast to the low anticonvulsant doses of Δ 9 -THC reported here, higher doses of Δ 9 -THC were typically required in these other seizure models (ED 50 values: 7-43.8 mgÁkg −1 ). ...
Background and Purpose
Extracts from the cannabis plant can dramatically improve the health of children suffering from refractory epilepsies such as Dravet syndrome. These extracts typically contain cannabidiol (CBD), a phytocannabinoid with well‐documented anticonvulsant effects, but may also contain Δ⁹‐tetrahydrocannabinol (Δ⁹‐THC). It is unclear whether the presence of Δ⁹‐THC modulates the anticonvulsant efficacy of CBD. Here, we utilized the Scn1a+/− mouse model of Dravet syndrome to examine this question.
Experimental Approach
Scn1a+/− mice recapitulate core features of Dravet syndrome, including hyperthermia‐induced seizures, early onset spontaneous seizures and sudden death. We assessed the effects on CBD and Δ⁹‐THC alone, and in combination on hyperthermia‐induced seizures, spontaneous seizures and premature mortality.
Key Results
Administered alone, CBD (100 mg·kg⁻¹ i.p.) was anticonvulsant against hyperthermia‐induced seizures as were low (0.1 and 0.3 mg·kg⁻¹ i.p.) but not higher doses of Δ⁹‐THC. A subthreshold dose of CBD (12 mg·kg⁻¹) enhanced the anticonvulsant effects of Δ⁹‐THC (0.1 mg·kg⁻¹). Sub‐chronic oral administration of Δ⁹‐THC or CBD alone did not affect spontaneous seizure frequency or mortality while, surprisingly, their co‐administration increased the severity of spontaneous seizures and overall mortality.
Conclusion and Implications
Low doses of Δ⁹‐THC are anticonvulsant against hyperthermia‐induced seizures in Scn1a+/− mice, effects that are enhanced by a sub‐anticonvulsant dose of CBD. However, proconvulsant effects and increased premature mortality are observed when CBD and Δ⁹‐THC are sub‐chronically dosed in combination. The possible explanations and implications of this are discussed.
... On the other hand, CBD has been reported to modulate several CYP enzymes, including the inhibition of CYP1A1, CYP2B6, CYP2C9, CYP2C19, and CYP2D6 (Bornheim et al. 1993;Yamaori et al. 2010Yamaori et al. , 2011bJiang et al. 2013) and the CYP3A family (Bornheim et al. 1993;Yamaori et al. 2011a;Welty et al. 2014;Geffrey et al. 2015). Such modulations could have implications for pharmacokinetic interactions with other drugs particularly antiepileptic drugs (AEDs) (Consroe and Wolkin 1977;Bornheim et al. 1993;Geffrey et al. 2015;Iffland 2016;. ...
... There was a recent upsurge of interest in studying the health benefits of medical marijuana, which was driven by legalization of its use in different states in the USA and Canada and in different countries in Europe (de Jong 2009; Karbakhsh et al. 2018;Wang et al. 2018). This spread of medical marijuana Despite these facts, there is still a massive absence of pharmacokinetic studies that would characterize the interaction between CBD and other antiepileptic and anticonvulsant drugs, although potential interactions were reported before (Consroe and Wolkin 1977;. In this study, we chose to characterize the interactions between CBD and CBZ and its major metabolite, CBZE, in vivo in rats. ...
Carbamazepine (CBZ) is mainly metabolized by CYP3A4 into carbamazepine-10,11-epoxide (CBZE). Cannabidiol (CBD) is a potent inhibitor of the CYP3A family. The aim of this study is to determine the effect of acute and chronic administration of CBD on the pharmacokinetics of CBZ and CBZE. Male SD rats were assigned into four acute and four chronic groups: control (CBZ only), positive control (ketoconazole), low-dose cannabidiol (l-CBD), and high-dose cannabidiol (h-CBD). Acute CBD groups were administered a single dose of CBD, while chronic CBD groups were given multiple doses of CBD for 14 days (q.d.) before CBZ administration. Plasma samples had been collected and analyzed for CBZ and CBZE, then their noncompartmental pharmacokinetic parameters before and after CBD administration were determined. The co-administration of a single l-CBD has significantly increased CBZ’s by 53.1%. Furthermore, CBZE kinetics showed a significant decrease in Cmax by 31.8%. Acute h-CBD caused similar effects on CBZ’s with 40.4% significant decrease in CBZE’s Cmax, when compared to the control. Chronic h-CBD caused a significant decrease in CBZ’s Cmax and by 75.3% and 65.7%, respectively. Besides, and Cmax of CBZE significantly decreased by 75.3% and 78.3%, respectively. These results demonstrated that the pharmacokinetics of CBZ and CBZE had been significantly affected by CBD. When CBD has been administered as a single dose, the effect is believed to be mainly caused by the inhibition of CBZ metabolism through CYP3A. The effect of chronic administration of CBD probably includes kinetic pathways other than the inhibition of CYP3A-dependent pathways.
Graphical abstract
... An animal study using maximal electric shock and audiogenic seizure models showed that CBD potentiated the anticonvulsant effects of phenytoin twofold and modestly potentiated the effect of phenobarbital. CBD also reduced the anticonvulsant properties of chlordiazepoxide, clonazepam, and ethosuximide (Consroe P et al, 1977). Combined administration of CBD and low doses of clonazepam in a conditional mouse model of Dravet syndrome achieved seizure control in an additive manner to reduce thermal sensitivity for seizure induction and seizure duration. ...
RESUMEN El objetivo de este trabajo fue revisar la literatura científica sobre el cannabidiol, solo y en combinación con fármacos que se usen en la actualidad. Se realizo una búsqueda en pub med y gogle scholar, utilizando las siguientes palabras claves combinadas en inglés: Cannabidiol más analgésicos, anticonvulsivantes, antibióticos, antipsicóticos, antidepresivos, antineoplásicos, antieméticos y anestésicos. Se seleccionaron artículos con ensayos in vitro, in vivo y ensayos clínicos. Los resultados muestran que la literatura actual es sobre estudios in vitro e in vivo. Se han realizado estudios de cannabidiol combinado con antiepilépticos, analgésicos, antidepresivos, antiinfecciosos y antipsicóticos con resultados prometedores. Aunque los estudios de combinación de cannabidiol con otros fármacos son escasos, estos sugieren que el cannabidiol podría actuar sinérgicamente, aunque se necesitan mas estudios para confirmarlo. El cannabidiol es un potente inhibidor del CYP3A4 y del CYP2C9 por lo que se debe considerar esta posible interacción. ABSTRACT This work aimed to review the literature on the combination de Cannabidiol and current medicinal drugs. A search in PubMed and Google Scholar was performed. We use the following keywords combination: CBD plus, analgesic, anticonvulsants, antibiotics, antipsychotics, antidepressants, antineoplastics, antiemetics, and anesthetics. Original articles with in vitro, in vivo assays, and clinical trials were selected. Current literature reports mainly in vitro and in vivo studies where CBD is evaluated in combination with other medicinal drugs for epilepsy, pain, depression, infections, and psychosis with promising results. There are few studies on the combination of CBD plus medicinal drugs, however, they suggest that CBD seems to act synergically with the studied drugs, and more confirmatory studies are needed. CBD is a potent CYP3A4 and CYP2C19 Inhibitor; therefore, potential interactions should be considered.
... Historically, cannabis was used to treat convulsions and seizures, which likely influenced early research trends focusing on the effects of THC and CBD on epilepsy, which is a type of disorder in the brain that has seizures as symptoms. There are studies from the 1970s using both THC and CBD, testing and comparing their effects on epilepsy [53][54][55], although the number of studies is not large. A search of PubMed using the keywords 'CBD and epilepsy' or 'CBD and therapeutic' shows that the number of studies suddenly increased after around 2010, which suggests that the finding of cannabinoid receptors in the beginning of the 21st century contributed to the increase in studies. ...
Cannabidiol (CBD) is one of the major phytochemical constituents of cannabis, Cannabis sativa, widely recognized for its therapeutic potential. While cannabis has been utilized for medicinal purposes since ancient times, its psychoactive and addictive properties led to its prohibition in 1937, with only the medical use being reauthorized in 1998. Unlike tetrahydrocannabinol (THC), CBD lacks psychoactive and addictive properties, yet the name that suggests its association with cannabis has significantly contributed to its public visibility. CBD exhibits diverse pharmacological properties, most notably anti-inflammatory effects. Additionally, it interacts with key drug-metabolizing enzyme families, including cytochrome P450 (CYP) and uridine 5′-diphospho-glucuronosyltransferase (UGT), which mediate phase I and phase II metabolism, respectively. By binding to these enzymes, CBD can inhibit the metabolism of co-administered drugs, which can potentially enhance their toxicity or therapeutic effects. Mild to moderate adverse events associated with CBD use have been reported. Advances in chemical formulation techniques have recently enabled strategies to minimize these effects. This review provides an overview of CBD, covering its historical background, recent clinical trials, adverse event profiles, and interactions with molecular targets such as receptors, channels, and enzymes. We particularly emphasize the mechanisms underlying its anti-inflammatory effects and interaction with drugs relevant to organ transplantation. Finally, we explore recent progress in the chemical formulation of CBD in order to enhance its bioavailability, which will enable decreasing the dose to use and increase its safety and efficacy.
... 10 In comparison to conventional antiepileptic medications, CBD exhibits greater effectiveness as an anticonvulsant, offering increased specificity and fewer neurotoxic side effects. 11 Additionally, CBD has great selectivity, no excitability in the central nervous system, and can decrease the duration and amplitude of the post-discharge cAMP response element-binding protein (CREB). The intracellular protein CREB controls the expression of genes that are crucial for dopaminergic neurons. ...
Background
Alzheimer's disease (AD) is a prevalent, incurable, and chronic neurodegenerative condition characterized by the accumulation of amyloid-β protein (Aβ), disrupting various bodily systems. Despite the lack of a cure, phenolic compounds like cannabidiol (CBD), a non-psychoactive component of cannabis, have emerged as potential therapeutic agents for AD.
Objective
This systematic review explores the impact of different types of cannabidiol on AD, unveiling their neuroprotective mechanisms.
Methods
The research used PubMed, Scopus, and Web of Science databases with keywords like “Alzheimer's disease” and “Cannabidiol.” Studies were evaluated based on title, abstract, and relevance to treating AD with CBD. No restrictions on research type or publication year. Excluded were hypothesis papers, reviews, books, unavailable articles, etc.
Results
Microsoft Excel identified 551 articles, with 92 included in the study, but only 22 were thoroughly evaluated. In-vivo and in-silico studies indicate that CBD may disrupt Aβ42, reduce pro-inflammatory molecule release, prevent reactive oxygen species formation, inhibit lipid oxidation, and counteract Aβ-induced increases in intracellular calcium, thereby protecting neurons from apoptosis.
Conclusions
In summary, the study indicates that CBD and its analogs reduce the production of Aβ42. Overall, these findings support the potential of CBD in alleviating the underlying pathology and symptoms associated with AD, underscoring the crucial need for further rigorous scientific investigation to elucidate the therapeutic applications and mechanisms of CBD in AD.
... Many epilepsy induction models have been used to study the antiepileptic properties of CBD [100][101][102][103][104]. Broadly, both antiepileptogenic effects with CB1 and CB2 receptor agonists and pro-epileptogenic effects using blockers of these receptors in temporal lobe models of epilepsy have been observed [62, [105][106][107]. ...
Neurodegenerative diseases have complex etiologies, however, neuroinflammation and oxidative stress are important markers in this pathogenesis and, in this sense, cannabinoids, especially CBD, have been identified as potential therapeutics for playing a neuroprotective role. Studies have demonstrated the neuroprotective effect of cannabinoids and derivatives of Cannabis sativa L in diseases of the central nervous system due to their interaction with the endocannabinoid system through receptors and other molecular targets. The aim of this review was to provide an overview of the endocannabinoid system and a summary of the clinical and preclinical findings of the therapeutic use of cannabinoids in epilepsy, multiple sclerosis and Parkinson’s disease, pointing out interactions with molecular targets and the potential for neuroprotection of CBD. Electronic searches were carried out in international databases, including studies that presented consistent data on this subject. Significant therapeutic effects of CBD were shown for epilepsy and Parkinson’s disease, while nabiximols contributed to the reduction of spasticity, being a frequent option for the treatment of multiple sclerosis. Although much has been projected on the therapeutic potential of cannabinoids for neurological disorders, there is a long way to go in the search for strong scientific evidence of their pharmacological effectiveness.
... CBD는 비 향정신성 칸나비노이드로, in vitro 및 in vivo에 서 신경보호 (Crippa et al., 2018), 간질에서의 강력한 항경련 효과 (Consroe and Wolkin, 1977), 항불안 (Guimarães et al., 1990), 항정신병 (Chesney et al., 2022), 항염증 (Atalay et al., 2019), 진통 (Urits et al., 2020) 및 항암효과 및 항암 제와의 상승작용을 가지는 것으로 알려져 있다 (Go et al., 2020;Koltai and Shalev, 2022;Tajik et al., 2022). ...
... CBD has shown activity in MES (Consroe and Wolkin, 1977), magnesium-free, 4-aminopyridine, audiogenic and all GABA inhibition-based models at doses from 50 to 400 mg/kg, while most effects occur at dose higher than 100 mg/kg. Based on rodent data reported to date, CBD currently appears to be the cannabinoid with the greatest therapeutic potential for epilepsy. ...
Ethnopharmacological relevance:
Epilepsy is one of the most prevalent neurological human diseases, affecting 1% of the population in all age groups. Despite the availability of over 25 anti-seizure medications (ASMs), which are approved in most industrialized countries, approximately 30% of epilepsy patients still experience seizures that are resistant to these drugs. Since ASMs target only limited number of neurochemical mechanisms, drug-resistant epilepsy (DRE) is not only an unmet medical need, but also a formidable challenge in drug discovery.
Aim:
In this review, we examine recently approved epilepsy drugs based on natural product (NP) such as cannabidiol (CBD) and rapamycin, as well as NP-based epilepsy drug candidates still in clinical development, such as huperzine A. We also critically evaluate the therapeutic potential of botanical drugs as polytherapy or adjunct therapy specifically for DRE.
Methods:
Articles related to ethnopharmacological anti-epileptic medicines and NPs in treating all forms of epilepsy were collected from PubMed and Scopus using keywords related to epilepsy, DRE, herbal medicines, and NPs. The database clinicaltrials.gov was used to find ongoing, terminated and planned clinical trials using herbal medicines or NPs in epilepsy treatment.
Results:
A comprehensive review on antiepileptic herbal drugs and natural products from the ethnomedical literature is provided. We discuss the ethnomedical context of recently approved drugs and drug candidates derived from NPs, including CBD, rapamycin, and huperzine A. Recently published studies on natural products with preclinical efficacy in animal models of DRE are summarized. Moreover, we highlight that natural products capable of pharmacologically activating the vagus nerve (VN), such as CBD, may be therapeutically useful to treat DRE.
Conclusions:
The review highlights that herbal drugs utilized in traditional medicine offer a valuable source of potential anti-epileptic drug candidates with novel mechanisms of action, and with clinical promise for the treatment of drug-resistant epilepsy (DRE). Moreover, recently developed NP-based anti-seizure medications (ASMs) indicate the translational potential of metabolites of plant, microbial, fungal and animal origin.
... The most significant therapeutic application of CBD, and by direct extension hemp Cannabis, is its powerful antiepileptic properties (Consroe and Wolkin 1977;Cunha et al. 1980). The antiepileptic properties of CBD have been known for decades, but a 2014 case report of Charlotte Figi, who had Dravet syndrome, documented the remarkable decrease in the number of daily seizures . ...
Cannabis is the most versatile species. Hemp and marijuana have been used for fibre, oil, medicinal and recreational purposes from millennia. Throughout the last century, the plant has been generally outlawed because of its psychotropic effects in many nations. In recent past, the studies on cannabis revealed the evidence of its high medicinal properties and its uses in treating life threatening diseases, which leads to the relaxation of legislation in many counties. Now, the genetic and genomics as well as the cannabis derived products enjoys renewed attention. In this chapter, the discussion was made on the advent of genomics and breeding strategies to improve various traits of cannabis. This will bring insights on future direction of cannabis breeding.
... Currently, information on the precise mechanisms of action is limited. Thus, to achieve a more accurate understanding of the pharmacological effects of this plant in the body, it might be essential to perform laboratory research the use of animal models [19][20][21]. Consequently, a high-throughput in vivo model to understand the connection between the chemical composition of different strains and their therapeutic potential then ...
Zebrafish is considered an unprecedented animal model in drug discovery. A review of the literature presents highlights and elucidates the biological effects of chemical components found in Cannabis sativa. Particular attention is paid to endocannabinoid system (eCB) and its main receptors (CB1 and CB2). The zebrafish model is a promising one for the study of cannabinoids because of the many similarities to the human system. Despite the recent advances on the eCB system, there is still the need to elucidate some of the interactions and, thus, the zebrafish model can be used for that purpose as it respects the 3Rs concept and reduced time and costs. In view of the relevance of cannabinoids in the treatment and prevention of diseases, as well as the importance of the zebrafish animal model in elucidating the biological effects of new drugs, the aim of this study was to bring to light information on the use of the zebrafish animal model in testing C. sativa- based medicines .
... The most abundant non-psychotropic cannabinoid from Cannabis sativa is cannabidiol (CBD), which has increased interest for medicinal applications because of its broad biological activity spectrum. The first study about the effectiveness of CBD as an anticonvulsant was carried out by Consroe and Wolking in 1977 [5], a starting point for further research that demonstrated preclinical-evidences of CDB such as anticonvulsant, antinausea, and analgesic effects [6]. Currently, CBD, alone (Epidiolex) or in combination with THC (Sativex), is approved in some countries for the treatment of refractory epilepsy in children and spasticity in multiple sclerosis, 2. 1 ...
Anti-inflammatory and antidiabetogenic properties have been ascribed to cannabidiol (CBD). CBD-based medicinal drugs have been approved for over a lustrum, and a boom in the commercialization of CBD products started in parallel. Herein, we explored the efficacy of CBD in streptozotocin (STZ)-induced diabetic mice to prevent diabetic nephropathy at onset. Eight-to-ten-week-old C57BL6J male mice were treated daily intraperitoneally with 10 mg/kg of CBD or vehicle for 14 days. After 8 days of treatment, mice were challenged with STZ or vehicle (healthy-control). At the end of the study, non-fasting blood glucose (FBG) level was 276 ± 42 mg/dL in vehicle-STZ-treated compared to 147 ± 9 mg/dL (p ≤ 0.01) in healthy-control mice. FBG was 114 ± 8 mg/dL in vehicle-STZ-treated compared to 89 ± 4 mg/dL in healthy-control mice (p ≤ 0.05). CBD treatment did not prevent STZ-induced hyperglycemia, and non-FBG and FBG levels were 341 ± 40 and 133 ± 26 mg/dL, respectively. Additionally, treatment with CBD did not avert STZ-induced glucose intolerance or pancreatic beta cell mass loss compared to vehicle-STZ-treated mice. Anatomopathological examination showed that kidneys from vehicle-STZ-treated mice had a 35% increase of glomerular size compared to healthy-control mice (p ≤ 0.001) and presented lesions with a 43% increase in fibrosis and T cell infiltration (p ≤ 0.001). Although treatment with CBD prevented glomerular hypertrophy and reduced T cell infiltration, it significantly worsened overall renal damage (p ≤ 0.05 compared to vehicle-STZ mice), leading to a more severe renal dysfunction than STZ alone. In conclusion, we showed that CBD could be detrimental for patients with type 1 diabetes, particularly those undergoing complications such as diabetic nephropathy.
... Rarely, magnetic resonance imaging (MRI) shows pseudotumoural lesions that produce uncommon symptoms such as epileptic seizures. In such cases, a correct and timely diagnosis is particularly important, the best combination of drugs must be chosen, and other therapeutic strategies, even unconventional ones, should be considered [1,2] . However, combining different drugs can lead to serious side effects. ...
Multiple sclerosis (MS) can sometimes cause uncommon pseudotumoural lesions that produce atypical symptoms, such as motor epileptic seizures which are often pharmacoresistant. In these cases, accurate diagnosis is essential for correct therapy, even if unconventional. We present the case of a brain tumour in a 40-year-old relapsing-remitting MS patient who presented with pharmacoresistant seizures which eventually responded to nabiximols. After various therapeutic approaches, delta-9-tetrahydrocannabinol therapy was introduced with good results. Spasticity improved, pain decreased and we observed a reduction in the number of daily seizures. It is possible that delta-9-tetrahydrocannabinol can enhance the efficacy of anti-epilepsy therapy.
Learning points:
The patient experienced fewer daily focal motor crises after the administration of nabiximols in the morning.The correct combination of symptomatic drugs can optimize a specific multiple sclerosis (MS) therapy even if the real cause of symptoms is a primary brain tumour and not MS.The addition of nabiximols to the therapeutic program allowed anti-epilepsy drug doses to be reduced and improved the patient's cognitive impairment.
... Similar results were described after intravenous CBD 15 mg/kg [52]. Moreover, CBD 17 mg/kg (orally) was more effective than phenytoin to suppress audiogenic seizures in susceptible rats [53]. Our results of brainstem seizures attenuation agree with previous reports and bring critical new findings of CBD protective effects against acute and chronic seizures, assessed by a detailed neuroethological behavioral characterization [46] of CBD anticonvulsant profile in WARs coupled to immunohistochemical analysis of FosB and CB1R. ...
Cannabidiol (CBD) is a marijuana compound implicated in epilepsy treatment in animal models and pharmacoresistant patients. However, little is known about chronic CBD administration’s effects in chronic models of seizures, especially regarding its potential antiepileptogenic effects. In the present study, we combined a genetic model of epilepsy (the Wistar Audiogenic Rat strain - WARs), a chronic protocol of seizures (the audiogenic kindling - AuK), quantitative and sequential behavioral analysis (neuroethology), and microscopy imaging to analyze the effects of chronic CBD administration in a genetic model of epilepsy. The acute audiogenic seizure is characterized by tonic-clonic seizures and intense brainstem activity. However, during the AuK WARs can develop limbic seizures associated with the recruitment of forebrain and limbic structures. Here, chronic CBD administration, twice a day, attenuated brainstem, tonic-clonic seizures, prevented limbic recruitment, and suppressed limbic (kindled) seizures, suggesting CBD antiepileptogenic effects. Additionally, CBD prevented chronic neuronal hyperactivity, suppressing FosB immunostaining in the brainstem (inferior colliculus and periaqueductal gray matter) and forebrain (basolateral amygdala nucleus and piriform cortex), structures associated with tonic-clonic and limbic seizures, respectively. Chronic seizures increased cannabinoid receptors type 1 (CB1R) immunostaining in the hippocampus and the BLA, while CBD administration prevented changes in CB1R expression induced by the AuK. The neuroethological analysis provided details about CBD’s protective effects against brainstem and limbic seizures associated with FosB expression. Our results strongly suggest chronic CBD anticonvulsant and antiepileptogenic effects associated with reduced chronic neuronal activity and modulation of CB1R expression. We also support the chronic use of CBD for epilepsies treatments.
... Studies indicate that CBD enhances the effect of PHT in the maximal electroshock-induced seizures, supporting its efficacy in major seizures [48,49]. In the present study, we found that PHT reduced the prevalence of major seizures, but it did not modify the expression of minor seizures and the prevalence of status epilepticus. ...
Purpose
: To evaluate the effects of cannabidiol alone or in combination with antiseizure drugs in the expression of recurrent generalized seizures in a rat model.
Methods
: Group A: Male Wistar rats received 3-mercaptopropionic acid (MP) every 12 h for 5 days to induce recurrent generalized seizures. Thereafter, the animals were submitted to a crossover protocol to receive different treatments with cannabidiol, phenytoin and phenobarbital, alone and in combination. Group B: Rats were manipulated as group A, but they received cannabidiol during the induction of recurrent seizures.
Results
: Minor and major seizures were induced after each MP administration. Status epilepticus (SE) detected during the last MP administrations was considered a sign of high seizure severity. Cannabidiol did not modify the expression of the MP induced seizures but reduced the prevalence of SE in both experimental groups. Phenytoin decreased the expression of major seizures but did not modify the prevalence of SE (groups A and B). Cannabidiol combined with phenytoin did not modify these effects. Phenobarbital diminished the expression of major seizures, an effect more evident when combined with cannabidiol (groups A and B). The combination of phenobarbital and cannabidiol reduced the expression of SE of group B. The mortality rate of groups A and B at the end of the crossover protocol was 30% and 9%, respectively (p=0.2).
Conclusion
: CBD associated with appropriate antiseizure drugs reduces the severity and prevalence of generalized seizures. In contrast, CBD alone reduces the seizure severity, but does not avoid the expression of generalized seizures.
... Pharmaceutical-grade CBD oral solution is the first product made directly from the cannabis plant rather than created synthetically to be authorized by regulatory agencies, and the first in a new class of antiseizure medications. Experimental data demonstrated that CBD may have antiseizure properties in a broad range of epilepsy syndromes and etiologies [68,69], and open-label studies suggested the effectiveness of purified CBD in the treatment of children and adults presenting with other epilepsy syndromes and seizure types than those addressed by regulatory trials, including CDKL5 deficiency disorder and Aicardi, Dup15q, and Doose syndromes, SYN-GAP1 encephalopathy, and Sturge-Weber syndrome. Of note, results cannot be directly transferred to other cannabisderived products and non-purified forms of medical marijuana or its components. ...
Background
Cannabidiol (CBD), which is one major constituent of the Cannabis sativa plant, has anti-seizure properties and does not produce euphoric or intrusive side effects. A plant-derived, highly purified CBD formulation with a known and constant composition has been approved by the US Food and Drug Administration for the treatment of seizures associated with Dravet syndrome, Lennox–Gastaut syndrome, and tuberous sclerosis complex. In the European Union, the drug has been authorized by the European Medicines Agency for the treatment of seizures associated with Dravet syndrome and Lennox–Gastaut syndrome, in conjunction with clobazam, and is under regulatory review for the treatment of seizures in patients with tuberous sclerosis complex.Objectives
This systematic review aimed to summarize the currently available body of knowledge about the use of this US Food and Drug Administration/European Medicines Agency-approved oral formulation of pharmaceutical-grade CBD in patients with epileptic conditions, especially developmental and epileptic encephalopathies other than Dravet syndrome and Lennox–Gastaut syndrome.Methods
The relevant studies were identified through MEDLINE and the US National Institutes of Health Clinical Trials Registry in October 2020. There were no date limitations or language restrictions. The following types of studies were included: clinical trials, cohorts, case-control, cross-sectional, clinical series, and case reports. Participants had to meet the following criteria: any sex, any ethnicity, any age, diagnosis of epilepsy, receiving plant-derived, highly purified (> 98% w/w) CBD in a sesame oil-based oral solution for the treatment of seizures. Data extracted from selected records included efficacy, tolerability, and safety outcomes.ResultsFive hundred and seventy records were identified by database and trial register searching. Fifty-seven studies were retrieved for detailed assessment, of which 42 were eventually included for the review. The participants of the studies included patients of both pediatric and adult age. Across the trials, purified CBD was administered at dosages up to 50 mg/kg/day. In a randomized double-blind controlled trial in patients with tuberous sclerosis complex, CBD was associated with a significantly greater percent reduction in seizure frequency than placebo over the treatment period. Open-label studies suggested the effectiveness of CBD in the treatment of children and adults presenting with other epilepsy syndromes than those addressed by regulatory trials, including CDKL5 deficiency disorder and Aicardi, Dup15q, and Doose syndromes, SYNGAP1 encephalopathy, and epilepsy with myoclonic absences. The most common adverse events observed during treatment with CBD included somnolence, decreased appetite, diarrhea, and increased serum aminotransferases.Conclusions
The currently available data suggest that response to treatment with a highly purified, plant-derived CBD oil-based solution can be seen in patients across a broad range of epilepsy disorders and etiologies. The existing evidence can provide preliminary support for additional research.
... On the contrary, there are considerable fewer studies that investigated the effects of CBD on AGS models of genetic origin (reviewed in Lazarini-Lopes et al., 2020). In AGS susceptible rats, the median effective dose of CBD that reduced generalized tonic-clonic seizure was 82 mg/kg following acute intraperitoneal administration (Consroe and Wolkin, 1977). In susceptible DBA/2J mice, concomitant intraperitoneal administration of CBD (27 mg/kg) and its analog cannabidivarin (116 mg/kg) was found to attenuate wild-running, clonic, and tonic seizure, whereas isolated CBD administration was able to attenuate only the incidence of clonic seizures (Hill et al., 2013). ...
Despite evidence that supports cannabidiol (CBD) as an anticonvulsant agent, there remains controversy over the antiseizure efficacy, possible adverse effects, and synergistic interactions with classic antiepileptics such as valproate (VPA). The genetic audiogenic seizure hamster from the University of Salamanca (GASH/Sal) is a reliable experimental model of generalized tonic–clonic seizures in response to intense sound stimulation. The present study examines the behavioral and molecular effects of acute and chronic intraperitoneal administrations of VPA (300 mg/kg) and CBD (100 mg/kg) on the GASH/Sal audiogenic seizures, as well as the coadministration of both drugs. The GASH/Sal animals were examined prior to and after the corresponding treatment at 45 min, 7 days, and 14 days for seizure severity and neuroethology, open-field behaviors, body weight variations, and various hematological and biochemical parameters. Furthermore, the brain tissue containing the inferior colliculus (so-called epileptogenic nucleus) was processed for reverse transcription–quantitative polymerase chain reaction analysis to determine the treatment effects on the gene expression of neuronal receptors associated with drug actions and ictogenesis. Our results indicated that single dose of VPA helps prevent the animals from getting convulsions, showing complete elimination of seizures, whereas 7 days of chronic VPA treatment had few effects in seizure behaviors. Acute CBD administration showed subtle attenuation of seizure behaviors, increasing seizure latency and decreasing the duration of the convulsion phase, but without entirely seizure abolition. Chronic CBD treatments had no significant effects on sound-induced seizures, although some animals slightly improved seizure severity. Acute and chronic CBD treatments have no significant adverse effects on body weight, hematological parameters, and liver function, although locomotor activity was reduced. The combination of VPA and CBD did not alter the therapeutic outcome of the VPA monotherapy, showing no apparent synergistic effects. As compared to sham animals, chronic treatments with CBD caused abnormal mRNA expression levels for Trpv1, Adora1, Slc29a1 , and Cnr1 genes, whereas no differences in gene expression were found for Htr1a and Sigmar1 . Our study shed light on the behavioral and molecular effects of CBD and VPA on the GASH/Sal model and constituted the basis to develop further studies on the pharmacological effects of CBD and its interactions with other anticonvulsants.
... mg/kg dose range). 31,32 We found D 9 -THC to be proconvulsant at lower doses (0.5 and 10 mg/kg). This is consistent with a study reporting biphasic effects of D 9 -THC on the severity of MES seizures, with low doses having proconvulsant effects and high doses being anticonvulsant. ...
Introduction: The cannabinoid Δ⁹-tetrahydrocannabinolic acid (Δ⁹-THCA) has long been suggested in review articles and anecdotal reports to be anticonvulsant; yet, there is scant evidence supporting this notion. The objective of this study was to interrogate the anticonvulsant potential of Δ⁹-THCA in various seizure models—the Scn1a+/− mouse model of Dravet syndrome, the 6-Hz model of psychomotor seizures and the maximal electroshock (MES) model of generalized tonic-clonic seizures.
Materials and Methods: We examined the effect of acute Δ⁹-THCA treatment against hyperthermia-induced seizures, and subchronic treatment on spontaneous seizures and survival in the Scn1a+/− mice. We also studied the effect of acute Δ⁹-THCA treatment on the critical current thresholds in the 6-Hz and MES tests using outbred Swiss mice. Highly purified Δ⁹-THCA was used in the studies or a mixture of Δ⁹-THCA and Δ⁹-THC.
Results: We observed mixed anticonvulsant and proconvulsant effects of Δ⁹-THCA across the seizure models. Highly pure Δ⁹-THCA did not affect hyperthermia-induced seizures in Scn1a+/− mice. A Δ⁹-THCA/Δ⁹-THC mixture was anticonvulsant in the 6-Hz threshold test, but purified Δ⁹-THCA and Δ⁹-THC had no effect. Conversely, both Δ⁹-THCA and Δ⁹-THC administered individually were proconvulsant in the MES threshold test but had no effect when administered as a Δ⁹-THCA/Δ⁹-THC mixture. The Δ⁹-THCA/Δ⁹-THC mixture, however, increased spontaneous seizure severity and increased mortality of Scn1a+/− mice.
Discussion: The anticonvulsant profile of Δ⁹-THCA was variable depending on the seizure model used and presence of Δ⁹-THC. Because of the unstable nature of Δ⁹-THCA, further exploration of Δ⁹-THCA through formal anticonvulsant drug development is problematic without stabilization. Future studies may better focus on determining the mechanisms by which combined Δ⁹-THCA and Δ⁹-THC alters seizure thresholds, as this may uncover novel targets for the control of refractory partial seizures.
... CBD has shown anticonvulsant activity in many acute animal models of seizures, including temporal lobe epilepsy and partial epilepsy (Jones et al., 2012), though limited data are available in animal models of chronic epilepsy and epileptogenesis (dos Santos, Hallak, Leite, Zuardi, & Crippa, 2015), CBD demonstrates variable pharmacokinetic and pharmacodynamic interactions with other AEDs. For example, CBD increases the antiseizure effects of phenytoin and decreases the antiseizure effects of clonazepam and ethosuximide (Consroe & Wolkin, 1977). Drug-drug interactions among AEDs and CBD could be linked to the ability of CBD to inhibit several isoforms of cytochrome P450 (CYP450) resulting in prolonged half-lives of other AEDs and resultant increased therapeutic effectiveness (Zendulka et al., 2016). ...
Refractory epilepsy is a chronic brain network disorder characterized by unresponsiveness to multiple (>2) antiepileptic drugs. Cannabidiol, a non-psychotropic neuroactive substance, is an emerging antiepileptic treatment that was recently approved by the US Food and Drug Administration for the treatment of refractory epilepsy, especially Lennox Gastaut syndrome and Dravet syndrome. Here, we evaluated associations between global brain network dynamics and related changes and responsiveness to cannabidiol therapy using a combination of EEG phase coherence and graph theoretical analyses. Refractory epilepsy patients with Lennox Gastaut syndrome or Dravet syndrome underwent serial EEG testing prior to and during cannabidiol treatment. Patients showing greater than 70% seizure frequency reduction were classified as treatment responders for the purposes of this study. We calculated inter-electrode EEG phase coherence in delta (1-3 Hz), theta (4-7 Hz), alpha (8-12 Hz), and beta (13-30 Hz) frequency bands. Graph theoretical analysis of brain network dynamics were extracted from phase coherence to evaluate measures of network integration (i.e. characteristic path length, global efficiency, and degree) and segregation (i.e. modularity and transitivity). We found that responders, relative to non-responders, showed increased network integration – as indexed by relatively higher global efficiency and lower degree – and increased network segregation – as indexed by relatively higher modularity – exclusively in the beta frequency band. We also found that larger cannabidiol dosages were associated with increased network integration – as indexed by higher global efficiency with increasing dose – and increased network segregation – as indexed by lower transitivity with increasing dose – in the delta, theta, and alpha frequency bands. In summary, we demonstrate novel effects of cannabidiol on brain network dynamics with important implications for the treatment of refractory epilepsy and, possibly, across broader research applications in future.
... Iv an Izquierdo et al. [40] found that CBD downregulated the susceptibility of rat seizures caused by afferent stimuli. Compared with traditional antiepileptics, CBD is an effective anticonvulsant with a higher specificity but fewer neurotoxic effects [41]. In addition, CBD can reduce the post-discharge duration and amplitude, with high selectivity and no excitability to the central nervous system (CREB) [42]. ...
... Studies focusing mainly on purified cannabidiol (CBD) in epilepsy management in drug-resistant patients were published. [5][6][7][8][9][10] The above clinical studies were assessed in a 2012 Cochrane review stating that the trials were based on small samples with inconsistent products, dosages, dose frequencies, and treatment durations. These deficiencies led the Cochrane reviewers to conclude that CBD efficacy in the treatment of epilepsy could not be confirmed, but that a dosage within the range 200-300 mg daily was safe enough to be given over a short time period. ...
In recent years, cannabis has been gaining increasing interest in both the medical research and clinical fields, with regard to its therapeutic effects in various disorders. One of the major fields of interest is its role as an anticonvulsant for refractory epilepsy, especially in the pediatric population. This paper presents and discusses the current accumulated knowledge regarding artisanal cannabis and Epidiolex®, a United States Food and Drug Administration (FDA)-approved pure cannabidiol (CBD), in epilepsy management in pediatrics, by reviewing the literature and raising debate regarding further research directions.
... Data on the potential interactions between cannabidiol and currently used anticonvulsants are quite limited. In an animal study, cannabidiol potentiated the anticonvulsant activity of phenytoin and phenobarbital but it reduced the potency of chlordiazepoxide, clonazepam, trimethadione, and ethosuximide (Consroe and Wolkin, 1977). A pharmacokinetic drug-drug interaction between cannabidiol and clobazam was reported in a group of 13 pediatric patients (Geffrey et al., 2015). ...
... Starting in the 1970s, investigators identified CBD's anticonvulsant properties in rats (Consroe and Wolkin 1977) and conducted an initial testing in humans in small groups (Carlini and Cunha 1981). This was followed by a larger human study using 900-1200 mg/kg daily which showed that CBD was effective in treating seizure states (Trumbly 1990). ...
The use of cannabis for animal species is an area of growing interest, largely due to the therapeutic benefits being observed for humans and animals in the era of cannabis legalization. The close relationship humans have with their pets and other veterinary species has led to a renewed interest in the possibility and promise of cannabis to treat similar health issues in the animal community. This chapter explores the literature available on cannabis, its interactions with the endocannabinoid system, and how animal species interact with various formulations and cannabis treatments. A brief overview of the biology, chemistry, and history of cannabis is discussed with the relevance to veterinary species in mind. The pharmacologically active components are discussed with both anecdotal and objective, evidence-based, and clinical data.
... In preclinical studies, CBD was useful in a variety of seizure models. [4][5][6][7][8][9][10][11] In the following paragraphs, we review the legal status of cannabis, clinical pharmacology, clinical studies on epilepsy, and future directions related to the use of medical cannabis. ...
Several new antiepileptic medicines became available for clinical use in the last two decades. However, the prognosis of epilepsy remains unchanged, with approximately one-third of patients continuing to have drug-resistant seizures. Because many of these patients are not candidates for curative epilepsy surgery, there is a need for new seizure medicines with better efficacy and safety profile. Recently, social media and public pressure sparked a renewed interest in cannabinoids, which had been used for epilepsy since ancient times. However, physicians have significant difficulty prescribing cannabinoids freely because of the paucity of sound scientific studies. Among the two most common cannabinoids, cannabidiol has better antiepileptic potential than tetrahydrocannabinol. The exact antiepileptic mechanism of cannabidiol is currently not known, but it modulates a number of endogenous systems and may have a novel anticonvulsant effect. However, it has broad drug-drug interactions with several agents, including inducer and inhibitor of CYP3A4 or CYP2C19. Cannabidiol can cause liver enzyme elevation, especially when co-administered with valproate. The US Food and Drug Administration (FDA) has approved pharmaceutical-grade cannabidiol oil for two childhood-onset catastrophic epilepsies: Dravet syndrome and Lennox-Gastaut syndrome. The Drug Enforcement Agency also reclassified this product as a schedule V agent. However, other cannabidiol products remain as a schedule I substance and are primarily used without regulation. Additionally, the FDA-approved pharmaceutical-grade cannabidiol oil is expensive, and insurance companies might approve this only for the designated indications. In despair, many individuals may resort to unregulated medical cannabis products in an attempt to control seizures. Rather than spontaneous treatment without medical supervision, adequate medical oversight is indicated to monitor and manage the proper dose, side effects, validity of the product, and drug-drug interactions.
Studies have demonstrated the neuroprotective effect of cannabidiol (CBD) and other Cannabis sativa L. derivatives on diseases of the central nervous system caused by their direct or indirect interaction with endocannabinoid system‐related receptors and other molecular targets, such as the 5‐HT 1A receptor, which is a potential pharmacological target of CBD. Interestingly, CBD binding with the 5‐HT 1A receptor may be suitable for the treatment of epilepsies, parkinsonian syndromes and amyotrophic lateral sclerosis, in which the 5‐HT 1A serotonergic receptor plays a key role. The aim of this review was to provide an overview of cannabinoid effects on neurological disorders, such as epilepsy, multiple sclerosis and Parkinson's diseases, and discuss their possible mechanism of action, highlighting interactions with molecular targets and the potential neuroprotective effects of phytocannabinoids. CBD has been shown to have significant therapeutic effects on epilepsy and Parkinson's disease, while nabiximols contribute to a reduction in spasticity and are a frequent option for the treatment of multiple sclerosis. Although there are multiple theories on the therapeutic potential of cannabinoids for neurological disorders, substantially greater progress in the search for strong scientific evidence of their pharmacological effectiveness is needed.
Cannabidiol (CBD) is one of the most interesting constituents of cannabis, garnering significant attention in the medical community in recent years due to its proven benefit for reducing refractory seizures in pediatric patients. Recent legislative changes in the United States have made CBD readily available to the general public, with up to 14% of adults in the United States having tried it in 2019. CBD is used to manage a myriad of symptoms, including anxiety, pain, and sleep disturbances, although rigorous evidence for these indications is lacking. A significant advantage of CBD over the other more well-known cannabinoid delta-9-tetrahydroncannabinol (THC) is that CBD does not produce a “high.” As patients increasingly self-report its use to manage their medical conditions, and as the opioid epidemic continues to drive the quest for alternative pain management approaches, the aims of this narrative review are to provide a broad overview of the discovery, pharmacology, and molecular targets of CBD, its purported and approved neurologic indications, evidence for its analgesic potential, regulatory implications for patients and providers, and future research needs.
Importance:
Products containing cannabidiol(CBD) are easily accessible. CBD is reported to inhibit the drug-metabolizing proteins(DMP) Cytochrome P450(CYP)3A4/5, CYP2C9, CYP2B6, CYP2D6, CYP2E1, CYP1A2, CYP2C19, carboxylesterase 1(CES1), uridine 5'diphospho-glucoronosyltransferase(UGT)1A9, UGT2B7, P-glycoprotein(P-gp) and Breast Cancer Resistance Protein(BCRP). The relevance of CBD-drug interactions is largely unknown. Aim of the study was to identify drugs, potentially interacting with orally ingested CBD, to assess whether CBD-drug interactions have been reported, and if substrates of DMP are frequently prescribed drugs.
Observations:
Identified were 403 drugs as substrates of DMP. CBD-drug interactions were reported for 53/403 substrates in humans (n = 25), in vivo (n = 13) or in vitro (n = 15). In 31/53 substrates, CBD induced an increase, in 1/53 a decrease, in 4/53 no change in the substrate level. For 5/53 substrates, the results were controversial, and in 12/53 no substrate levels were reported. Among the 30 most frequently prescribed drugs in Germany were 67% substrates of DMP and among the 50 most frequently prescribed drugs in the USA 68%.
Relevance and conclusions:
There is an urgent need for pharmacologic studies on CBD-drug interactions. Patients should be educated on the potential risk and awareness should be increased among physicians. Regulatory authorities should become aware of the problem and start an initiative on an international level to increase the safety of CBD.
Cannabis sativa is widely used as a folk medicine in many parts of the globe and has been reported to be a treasure trove of phytoconstituents, including cannabinoids, terpenoids, and flavonoids. Accumulating evidence from various pre-clinical and clinical studies revealed the therapeutic potential of these constituents in various pathological conditions, including chronic pain, inflammation, neurological disorders, and cancer. However, the psychoactive effect and addiction potential associated with cannabis use limited its clinical application. In the past two decades, extensive research on cannabis has led to a resurgence of interest in the clinical application of its constituents, particularly cannabinoids. This review summarizes the therapeutic effect and molecular mechanism of various phytoconstituents of cannabis. Furthermore, recently developed nanoformulations of cannabis constituents have also been reviewed. Since cannabis is often associated with illicit use, regulatory aspects are of vital importance and this review therefore also documented the regulatory aspects of cannabis use along with clinical data and commercial products of cannabis.
Δ9-tetrahydrocannabinol (THC) and its sibling, cannabidiol (CBD), are produced by the same Cannabis plant and have similar chemical structures but differ dramatically in their mechanisms of action and effects on brain functions. Both THC and CBD exhibit promising therapeutic properties; however, impairments and increased incidence of mental health diseases are associated with acute and chronic THC use, respectively, and significant side effects are associated with chronic use of high-dose CBD. This review covers recent molecular and preclinical discoveries concerning the distinct mechanisms of action and bioactivities of THC and CBD and their impact on human behavior and diseases. These discoveries provide a foundation for the development of cannabinoid-based therapeutics for multiple devastating diseases and to assure their safe use in the growing legal market of Cannabis-based products.
Over 30 antiseizure medicines (ASMs) have been uncovered in a diversity of preclinical seizure and epilepsy models, with several critical inflection points in the 20th century fundamentally transforming ASM discovery. This commentary aims to review the historical relevance of cannabidiol's (CBD; Epidiolex) approval for epilepsy in the context of other ASMs brought to market. Further, we highlight how CBD may represent an inflection point for 21st century ASM discovery. CBD is one of the main phytocannabinoids of Cannabis sativa. Unlike its related phytocannabinoid, Δ9-tetrahydrocannabinol, CBD does not exert any euphorigenic, tolerance, or withdrawal effects at anticonvulsant doses. CBD also possess marked anti-inflammatory effects, offering the tantalizing potential of a new pharmacological approach in epilepsy. For decades, hints of the anticonvulsant profile of CBD had been suggested with a small handful of studies in rodent seizure models, yet difficulties in formulation, compounded by the social and regulatory pressures related to medical use of cannabis plant-derived agents constrained any clinical implementation. Nonetheless, CBD possesses a broad antiseizure profile in preclinical seizure and epilepsy models, but the transformative impact of CBD's approval came because of studies in a rodent model of the orphan disease Dravet syndrome (DS). DS is a pediatric developmental epileptic encephalopathy with high mortality, frequent spontaneous recurrent seizures, and marked resistance to conventional ASMs, such as phenytoin and carbamazepine. CBD was approved for DS by the US Food and Drug Administration in 2018 after convincing efficacy was established in randomized, placebo-controlled trials in children. Because of the clinical approval of CBD as a novel, cannabis plant derived ASM for DS, CBD has revealed a new strategy in ASM discovery to reignite 21st century therapeutic development for epilepsy. In this commentary, we review the major preclinical and clinical milestones of the late 20th century that made CBD, a compound historically subjected to regulatory restrictions, a key driver of a new discovery strategy for epilepsy in the 21st century.
Endocannabinoid system (ECS) and its agonist/antagonists are emerging drug target in different pathophysiological conditions, and its role as an anticancer agent has been extensively explored recently. Psychotropic effects of cannabinoid, a century-old ingredient of Cannabis sativa, are widely used as a palliative care for cancer patients apart from its recreational uses. This chapter outlines briefly the overall ECS system which is further extended to exploration of this system in various diseases and cancer. Recent reports have suggested implications of ECS system components as an anticancer agent through different signaling pathways. Important pathways like MAPK and mTOR-AKT contribute to tumor development, angiogenesis, metastasis, and chemotherapy resistance in different cancer types. Interestingly, cannabinoids are found to reverse their effects, through the induction of apoptosis, autophagy, and immune system modulating pathways. We have elaborated the pathways through which ECS system mediates cancer cell death, inhibits the angiogenesis pathway, and negates the chemotherapy resistance in different cancer types. We have also explored how ECS system modulators may regulate diverse signaling mechanisms in tumor microenvironment and whether they impart a therapeutic effect. Finally, we highlighted recent and ongoing clinical trials that include cannabinoids as a therapeutic strategy and several combined approaches toward novel therapeutic avenues in treatment of cancer.
Although humans have used the hemp Cannabis sativa plant for thousands of years, recently there has been a shift in the availability of hemp products that are high in secondary metabolites while maintaining low levels of the intoxicating phytocannabinoid Δ9-tetrahydrocannabinol (Δ9-THC). Historically, there have been many therapeutic applications of hemp in ethnobotanical formulations for a range of conditions. The primary compound of interest is cannabidiol (CBD), which demonstrates powerful antiepileptic properties and is the rationale behind the change in legal status enabling further production and research of hemp. The plant also contains additional phytocannabinoids, as well as other bioactive molecules including terpenes and flavonoids. There is sufficient preliminary evidence for a molecular mechanism through both the endocannabinoid system and the serotonin system; additionally, there may be non-specific interactions that occur when combinations of complex formulations are administered. The interconnected nature of the endocannabinoid system with other signaling systems in the central nervous system, immune system, and other essential peripheral functions complicates the discrete identification of specific molecular mechanisms. When evaluating the potential pharmaceutical applications of the hemp Cannabis sativa plant as a whole, it is found to be well-tolerated in human clinical settings and have vast therapeutic applications across a wide range of symptoms.KeywordsEndocannabinoid systemCannabidiol (CBD)TerpenesFlavonoidsPhytocannabinoidsCannabigerol (CBG)Pharmacology
Objective:
To assess drug-drug interactions between cannabidiol (CBD) and phenobarbital (PB) when simultaneously administered to healthy dogs.
Animals:
9 healthy, purpose bred Beagles.
Procedures:
A 3-phase prospective, randomized pharmacokinetic (PK) interaction study of CBD and PB was performed as follows: phase 1, CBD PK determination and evaluation of CBD tolerability by 3 single-dose CBD (5 mg/kg, 10 mg/kg, and 20 mg/kg) protocols followed by 2-week CBD dosing; phase 2, a single-dose, 3-way, crossover PK study of CBD (10 mg/kg), PB (4 mg/kg), or CBD (10 mg/kg) administration plus PB (4 mg/kg); and phase 3, evaluation of chronic PB (4 mg/kg, q 30 d) administration followed by single-dose CBD (10 mg/kg) PK study.
Results:
Although there were variations in CBD PK variables in dogs receiving CBD alone or in conjunction with PB, significance differences in CBD PK variables were not found. No significant difference was observed in PB PK variables of dogs receiving PB alone or with CBD. During chronic CBD administration, mild gastrointestinal signs were observed in 5 dogs. At daily CBD doses of 10 to 20 mg/kg/d, hypoxia was observed in 5 dogs and increased serum alkaline phosphatase (ALP) activities (range, 301 to 978 U/L) was observed in 4 dogs. A significant increase in ALP activity was observed with chronic administration of CBD during phase 1 between day 0 and day 14.
Conclusions and clinical relevance:
No significant PK interactions were found between CBD and PB. Dose escalation of CBD or adjustment of PB in dogs is not recommended on the basis of findings of this study.
Objective
To assess the longitudinal impact of highly purified cannabidiol (CBD) on the electroencephalogram (EEG) of children and adults.
Methods
Participants received an EEG prior to starting CBD, after approximately 12 weeks of CBD (FU1) and after approximately one year of CBD therapy (FU2). Longitudinal changes in five EEG measures (background frequency, focal slowing, reactivity, frequency of interictal, and ictal discharges) were examined following CBD exposure. Data were compared between pediatric and adult groups at two follow-up time points and within groups over time. Population-averaged models with generalized estimation equations or linear mixed effects models were used to analyze data where appropriate. Correlation analysis was used to assess any association between changes in seizure frequency and changes in EEG interictal discharge (IED) frequency. An alpha level of 5% was used to assess statistical significance.
Results
At FU1, the adult group showed significant decrease in IED/minute (IDR 0.07, 95% CI [0.04, 0.14], P < 0.001); a nonsignificant decrease was observed among children (IDR 0.87, 95% CI [0.47, 0.64], P = 0.67). The difference in changes over time between participant groups was significant after adjusting for last CBD dose (IDR 11.8, 95% CI [4.86, 28.65], P < 0.0001). At FU2 both groups showed significant reduction from baseline after controlling for last CBD dose. This decrease was more pronounced in children (IDR 15.38, 95% CI [4.93, 47.99], P < 0.001). There was no significant correlation between changes in seizure frequency and EEG IED frequency at each timepoint (P = 0.542, 0.917 and 0.989 from baseline to FU1, FU1 to FU2 and baseline to FU2, respectively).
Significance
This longitudinal EEG study shows that highly-purified plant-derived CBD has positive effects on interictal epileptiform discharge frequency but no effects on other EEG measures. The effect of CBD does not appear to be dose or treatment-duration dependent.
Cannabis and its various derivatives continue to have a growing presence for both recreational and medicinal purposes. Due to such widespread use, health-care providers will need to develop a general, clinical understanding of cannabis and cannabinoids. Despite the general dearth of research within this field, this chapter will provide an overview of the routes of administration as well as highlight potential drug interactions that cannabis products may have with particular classes of pharmaceuticals.
CBD wird seit einigen Jahren als Wirkstoff bei pharmakorefraktären Epilepsien erforscht. In natürlich extrahierter Form hat es in mehreren Studien gezeigt, dass es Anfallsfrequenzen senken kann und gut verträglich ist. In der vorliegenden Arbeit sollte überprüft werden, ob synthetisches CBD, das molekular nahezu identisch ist, eine vergleichbare Wirksamkeit und Verträglichkeit besitzt. Die bisher ungeklärte Frage nach einer EEG-Wirksamkeit von CBD wurde ebenfalls untersucht.
Durchgeführt wurde eine Open-Label-Beobachtungsstudie einer dreimonatigen
Add-On-Therapie mit synthetischem CBD bei 16 Erwachsenen und 19 Kindern mit einem breitem Spektrum pharmakorefraktärer Epilepsien. Erfasst wurden Anfallsfrequenzen sowie aufgetretene Nebenwirkungen und Interaktionen. Überdies wurden EEG vor und nach CBD-Therapie analysiert.
Die monatlichen Frequenzen motorischer Anfälle verringerten sich im Median um
40 % (p < 0,001), die Responderrate für motorische Anfälle betrug 43 %. Diese Effektivität entspricht in etwa den Ergebnissen vergleichbarer Studien mit pflanzlichem CBD. Kinder erreichten signifikant höhere Anfallsreduktionen und Responderraten als Erwachsene. Dieser Unterschied wurde bisher nicht näher untersucht und könnte durch Unterschiede in Alter und Erkrankungsdauer begründet sein. Das VEM erwies sich als vielversprechendes Instrument der objektiven Erfolgskontrolle der CBD-Therapie, insbesondere zur Erfassung schwer erkennbarer nächtlicher Anfälle und von Anfällen mit subtiler Semiologie. Als Hinweis auf eine EEG-Wirksamkeit von CBD zeigten sich bei 64,3 % der Patienten verringerte interiktale ETP-Frequenzen, wobei vergleichbare Untersuchungen aktuell kaum vorliegen. Unsere Kohorte zeigte insgesamt eine gute Verträglichkeit von synthetischem CBD, wie sie auch für pflanzliches CBD berichtet wurde. Nebenwirkungen der Therapie traten bei 71,4 % der Patienten auf. Am häufigsten waren Somnolenz, Diarrhoe und Gewichtszunahme.
Da unsere Kohorte eher klein war und keine Randomisierung und Verblindung vorgenommen wurde, wären größere, randomisiert-kontrollierte Studien mit synthetischem CBD zur Bestätigung unserer Ergebnisse wünschenswert. Vor allem die Frage der unterschiedlichen Wirksamkeit von CBD bei Erwachsenen und Kindern sollte weiter untersucht werden. Ebenfalls interessant wären weitere Arbeiten zur Klärung der Frage, ob sich unsere Hinweise auf eine Reduktion von ETP im interiktalen EEG reproduzieren lassen.
Cannabinoids and Cannabis-derived compounds have been receiving especial attention
in the epilepsy research scenario. Pharmacological modulation of endocannabinoid
system’s components, like cannabinoid type 1 receptors (CB1R) and their bindings,
are associated with seizures in preclinical models. CB1R expression and functionality
were altered in humans and preclinicalmodels of seizures. Additionally, Cannabis-derived
compounds, like cannabidiol (CBD), present anticonvulsant activity in humans and in
a great variety of animal models. Audiogenic seizures (AS) are induced in genetically
susceptible animals by high-intensity sound stimulation. Audiogenic strains, like the
Genetically Epilepsy Prone Rats, Wistar Audiogenic Rats, and Krushinsky-Molodkina,
are useful tools to study epilepsy. In audiogenic susceptible animals, acute acoustic
stimulation induces brainstem-dependent wild running and tonic-clonic seizures.
However, during the chronic protocol of AS, the audiogenic kindling (AuK), limbic and
cortical structures are recruited, and the initially brainstem-dependent seizures give
rise to limbic seizures. The present study reviewed the effects of pharmacological
modulation of the endocannabinoid system in audiogenic seizure susceptibility and
expression. The effects of Cannabis-derived compounds in audiogenic seizures were
also reviewed, with especial attention to CBD. CB1R activation, as well Cannabis-derived
compounds, induced anticonvulsant effects against audiogenic seizures, but the effects
of cannabinoids modulation and Cannabis-derived compounds still need to be verified
in chronic audiogenic seizures. The effects of cannabinoids and Cannabis-derived
compounds should be further investigated not only in audiogenic seizures, but also in
epilepsy related comorbidities present in audiogenic strains, like anxiety, and depression.
Cannabis sativa spp. is an exceptional multicomponent natural resource used as nutritional supplements, textiles, building materials, body care products, food, and medicines, to name a few. It has been cultivated for millennia to exploit the plant’s toolbox of useful natural compounds it offers. This chapter explores the chemical constituents responsible for the plant’s therapeutic properties and examines efficacious compounds as nutraceuticals. A qualitative and quantitative look at these components highlights important trends for both fiber-type hemp and medical C. sativa. Key aspects of C. sativa taxonomy, biology, and biochemistry are addressed. Specifically, the convergent biosynthetic pathways used by the plant to produce cannabinoids and terpenes are outlined. The biologically active components are described at a molecular level and the in vitro and in vivo data are compiled to offer quantitative insight into the mechanism of action, as well as their potential for use as nutraceuticals.
Cannabis-based products are increasingly being used to treat refractory childhood epilepsies such as Dravet syndrome. Cannabis contains at least 140 terpenophenolic compounds known as phytocannabinoids. These include the known anticonvulsant compound cannabidiol (CBD) and several molecules showing emergent anticonvulsant properties in animal models. Cannabichromene (CBC) is a phytocannabinoid frequently detected in artisanal cannabis oils used in the community by childhood epilepsy patients. Here we examined the brain and plasma pharmacokinetic profiles of CBC, cannabichromenic acid (CBCA), cannabichromevarin (CBCV), and cannabichromevarinic acid (CBCVA) following intraperitoneal administration in mice. The anticonvulsant potential of each was then tested against hyperthermia-induced seizures in the Scn1a+/- mouse model of Dravet syndrome. All phytocannabinoids within the CBC series were readily absorbed and showed substantial brain penetration (brain-plasma ratios ranging from 0.2 to 5.8). Anticonvulsant efficacy was evident with CBC, CBCA, and CBCVA, each significantly increasing the temperature threshold at which Scn1a+/- mice had a generalized tonic-clonic seizure. We synthesized a fluorinated derivative of CBC (5-fluoro-CBC), which showed improved brain penetration relative to the parent CBC molecule but not any greater anticonvulsant effect. Since CBC and derivatives are anticonvulsant in a model of intractable pediatric epilepsy, they may constitute part of the mechanism through which artisanal cannabis oils are anticonvulsant in patients.
Cannabis can synthetize more than 400 compounds, including terpenes, flavonoids, and more than 100 phytocannabinoids. The main phytocannabinoids are Δ-9-tetrahydrocannabinol (THC) and cannabidiol (CBD). Cannabis-based products are used as medicines in several countries. In this text, we present an overview of the main neurochemical mechanisms of action of the phytocannabinoids, especially THC and CBD. We also reviewed the indications and adverse effects of the main cannabis-based medicinal products. THC acts as a partial agonist at cannabinoid 1/2 receptors (CB 1/2). It is responsible for the characteristic effects of cannabis, such as euphoria, relaxation, and changes in perceptions. THC can also produce dysphoria, anxiety, and psychotic symptoms. THC is used therapeutically in nausea and vomiting due to chemotherapy, as an appetite stimulant, and in chronic pain. CBD acts as a noncompetitive negative allosteric modulator of the CB 1 receptor, as an inverse agonist of the CB 2 receptor, and as an inhibitor of the reuptake of the endocannabinoid anandamide. Moreover, CBD also activates 5-HT 1A serotonergic receptors and vanilloid receptors. Its use in treatment-resistant epilepsy syndromes is approved in some countries. CBD does not produce the typical effects associated with THC and has anxiolytic and antipsychotic effects. Some of the most common adverse effects of CBD are diarrhea, somnolence, nausea, and transaminase elevations (with concomitant use of antiepileptics). The mechanisms of action involved in both the therapeutic and adverse effects of the phytocannabinoids are not fully understood, involving not only the endocannabinoid system. This "promiscuous" pharmacology could be responsible for their wide therapeutic spectrum.
In resource-limited countries, the availability and cost of antiepileptic drugs (AEDs) are important factors in antiepileptic treatment selection. Phenobarbital and phenytoin are widely available at a lower cost and are used commonly in the treatment of epilepsy. Carbamazepine and sodium valproate are also available in most countries but are more expensive than phenobarbital and phenytoin. The majority (up to 70%) of patients will have good seizure control with one or more of these AEDs [1, 2]. By and large, the newer AEDs have better side effect profiles with efficacy comparable to the old AEDs. However, these medications are either not available or their cost is prohibitive to be in wide use globally.
Background and Objectives
Despite limited evidence, cannabidiol-rich cannabis extracts have been popularly used in pediatrics. With increased use, it is critical to determine basic pharmacokinetic parameters of cannabidiol in these extracts in the pediatric population. The objective of this study was to determine the disposition of oral cannabidiol cannabis extracts and drug interactions in children with pediatric epilepsy.Methods
We conducted a prospective observational study evaluating the disposition of oral cannabidiol in children (< 18 years of age) receiving cannabidiol extracts for epilepsy. Subjects underwent serial blood draws after oral cannabidiol administration. Cannabidiol and metabolites, along with anticonvulsant concentrations were determined.ResultsTwenty-nine patients had sufficient pharmacokinetic data and were included in the analysis. Mean age was 9.7 years (standard deviation 4.3) and 17 patients (59%) were male. Median peak plasma cannabidiol concentrations was 13.1 ng/mL (interquartile range 6.8–39.3 ng mL); median time to peak of 2.0 h (interquartile range 2.0–4.0 h). Mean acute elimination half-life of oral cannabidiol was 6.2 h (standard deviation 1.8 h). There was an observed half-life of degradation of 533 days noted for cannabidiol concentrations when stored for 0.6–3.1 years. There was some impact on cannabidiol pharmacokinetic parameters when cannabidiol was co-administered with zonisamide (elimination rate constant and V1) and levetiracetam (elimination rate constant).Conclusions
In pediatric patients using oral cannabidiol-rich cannabis extract for epilepsy, the time to peak concentration of plasma cannabidiol and average acute elimination half-life were shorter than those reported for adults. Co-administration of zonisamide and levetiracetam had some impact on cannabidiol pharmacokinetic parameters. There was an observed degradation of plasma cannabidiol in long-term storage.Clinical registrationClinicalTrials.gov Identifer no. NCT02447198.
Interest in cannabis and its related cannabinoids THC and CBD for use as anti-convulsant therapy has been progressively increasing. While the destigmatization of cannabis and cannabis related research have progressed in the last few decades, there are still many questions that remain unanswered. This review seeks to summarize the progress made in cannabis research in the past four decades and to identify possible directions for future research that are critical for the development of cannabinoid-based therapy in epilepsy.
Epilepsy is a neurological disorder characterized by the presence of seizures and neuropsychiatric comorbidities. Despite the number of antiepileptic drugs, one-third of patients did not have their seizures under control, leading to pharmacoresistance epilepsy. Cannabis sativa has been used since ancient times in Medicine for the treatment of many diseases, including convulsive seizures. In this context, Cannabidiol (CBD), a non-psychoactive phytocannabinoid present in Cannabis, has been a promising compound for treating epilepsies due to its anticonvulsant properties in animal models and humans, especially in pharmacoresistant patients. In this review, we summarize evidence of the CBD anticonvulsant activities present in a great diversity of animal models. Special attention was given to behavioral CBD effects and its translation to human epilepsies. CBD anticonvulsant effects are associated with a great variety of mechanisms of action such as endocannabinoid and calcium signaling. CBD has shown effectiveness in the clinical scenario for epilepsies, but its effects on epilepsy-related comorbidities are scarce even in basic research. More detailed and complex behavioral evaluation about CBD effects on seizures and epilepsy-related comorbidities are required.
Cannabis sativa (cannabis) is one of the oldest plants cultivated by men. Cannabidiol (CBD) is the major non-psychomimetic compound derived from cannabis. It has been proposed to have a therapeutic potential over a wide range of neuropsychiatric disorders. In this narrative review, we have summarized a selected number of pre-clinical and clinical studies, examining the effects of CBD in neuropsychiatric disorders. In some pre-clinical studies, CBD was demonstrated to potentially exhibit anti-epileptic, anti-oxidant, anti-inflammatory anti-psychotic, anxiolytic and anti-depressant properties. Moreover, CBD was shown to reduce addictive effects of some drugs of abuse. In clinical studies, CBD was shown to be safe, well-tolerated and efficacious in mitigating the symptoms associated with several types of seizure disorders and childhood epilepsies. Given that treatment with CBD alone was insufficient at managing choreic movements in patients with Huntington's disease, other cannabis-derived treatments are currently being investigated. Patients with Parkinson's disease (PD) have reported improvements in sleep and better quality of life with CBD; however, to fully elucidate the therapeutic potential of CBD on the symptoms of PD-associated movement disorders, larger scale, randomized, placebo-controlled studies still need to be conducted in the future. Currently, there are no human studies that investigated the effects of CBD in either Alzheimer's disease or unipolar depression, warranting further investigation in this area, considering that CBD was shown to have effects in pre-clinical studies. Although, anxiolytic properties of CBD were reported in the Social Anxiety Disorder, antipsychotic effects in schizophrenia and anti-addictive qualities in alcohol and drug addictions, here too, larger, randomized, placebo-controlled trials are needed to evaluate the therapeutic potential of CBD.
Cannabidiol (CBD) is a major active component of the Cannabis plant, which, unlike tetrahydrocannabinol (THC), is devoid of euphoria-inducing properties. During the last 10 years, there has been increasing interest in the use of CBD-enriched products for the treatment of epilepsy. In 2018, an oil-based highly purified liquid formulation of CBD (Epidiolex) derived from Cannabis sativa was approved by the US Food and Drug Administration for the treatment of seizures associated with Dravet syndrome (DS) and Lennox-Gastaut syndrome (LGS). The mechanisms underlying the antiseizure effects of CBD are unclear but may involve, among others, antagonism of G protein-coupled receptor 55 (GPR55), desensitization of transient receptor potential of vanilloid type 1 (TRPV1) channels, and inhibition of adenosine reuptake. CBD has complex and variable pharmacokinetics, with a prominent first-pass effect and a low oral bioavailability that increases fourfold when CBD is taken with a high-fat/high-calorie meal. In four randomized, double-blind, parallel-group, adjunctive-therapy trials, CBD given at doses of 10 and 20 mg/kg/day administered in two divided administrations was found to be superior to placebo in reducing the frequency of drop seizures in patients with LGS and convulsive seizures in patients with DS. Preliminary results from a recently completed controlled trial indicate that efficacy also extends to the treatment of seizures associated with the tuberous sclerosis complex. The most common adverse events that differentiated CBD from placebo in controlled trials included somnolence/sedation, decreased appetite, increases in transaminases, and diarrhea, behavioral changes, skin rashes, fatigue, and sleep disturbances. About one-half of the patients included in the DS and LGS trials were receiving concomitant therapy with clobazam, and in these patients a CBD-induced increase in serum levels of the active metabolite norclobazam may have contributed to improved seizure outcomes and to precipitation of some adverse effects, particularly somnolence.
Objective:
To assess the effect of oral cannabidiol (CBD) administration in addition to conventional antiepileptic treatment on seizure frequency in dogs with idiopathic epilepsy.
Design:
Randomized blinded controlled clinical trial.
Animals:
26 client-owned dogs with intractable idiopathic epilepsy.
Procedures:
Dogs were randomly assigned to a CBD (n = 12) or placebo (14) group. The CBD group received CBD-infused oil (2.5 mg/kg [1.1 mg/lb], PO) twice daily for 12 weeks in addition to existing antiepileptic treatments, and the placebo group received noninfused oil under the same conditions. Seizure activity, adverse effects, and plasma CBD concentrations were compared between groups.
Results:
2 dogs in the CBD group developed ataxia and were withdrawn from the study. After other exclusions, 9 dogs in the CBD group and 7 in the placebo group were included in the analysis. Dogs in the CBD group had a significant (median change, 33%) reduction in seizure frequency, compared with the placebo group. However, the proportion of dogs considered responders to treatment (≥ 50% decrease in seizure activity) was similar between groups. Plasma CBD concentrations were correlated with reduction in seizure frequency. Dogs in the CBD group had a significant increase in serum alkaline phosphatase activity. No adverse behavioral effects were reported by owners.
Conclusions and clinical relevance:
Although a significant reduction in seizure frequency was achieved for dogs in the CBD group, the proportion of responders was similar between groups. Given the correlation between plasma CBD concentration and seizure frequency, additional research is warranted to determine whether a higher dosage of CBD would be effective in reducing seizure activity by ≥ 50%.
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