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Chronic Administration of Cannabidiol to Healthy Volunteers and Epileptic Patients
Abstract
In phase 1 of the study, 3 mg/kg daily of cannabidiol (CBD) was given for 30 days to 8 health human volunteers. Another 8 volunteers received the same number of identical capsules containing glucose as placebo in a double-blind setting. Neurological and physical examinations, blood and urine analysis, ECG and EEG were performed at weekly intervals. In phase 2 of the study, 15 patients suffering from secondary generalized epilepsy with temporal focus were randomly divided into two groups. Each patient received, in a double-blind procedure, 200-300 mg daily of CBD or placebo. The drugs were administered for along as 4 1/2 months. Clinical and laboratory examinations, EEG and ECG were performed at 15- or 30-day intervals. Throughout the experiment the patients continued to take the antiepileptic drugs prescribed before the experiment, although these drugs no longer controlled the signs of the disease. All patients and volunteers tolerated CBD very well and no signs of toxicity or serious side effects were detected on examination. 4 of the 8 CBD subjects remained almost free of convulsive crises throughout the experiment and 3 other patients demonstrated partial improvement in their clinical condition. CBD was ineffective in 1 patient. The clinical condition of 7 placebo patients remained unchanged whereas the condition of 1 patient clearly improved. The potential use of CBD as an antiepileptic drug and its possible potentiating effect on other antiepileptic drugs are discussed.
... CBD has proven to be an effective medicinal therapy in several animal and human studies. Cunha et al. (1980) first reported that a CBD dose of 200 mg/day was effective in the treatment of seizures in humans [51]. A double-blinded, placebo-controlled trial was conducted among 120 children and young adults to study the efficacy of CBD against drug-resistant epilepsy in Dravet syndrome [52]. ...
... CBD has proven to be an effective medicinal therapy in several animal and human studies. Cunha et al. (1980) first reported that a CBD dose of 200 mg/day was effective in the treatment of seizures in humans [51]. A double-blinded, placebo-controlled trial was conducted among 120 children and young adults to study the efficacy of CBD against drug-resistant epilepsy in Dravet syndrome [52]. ...
Background: Post-treatment side effects of chemotherapy can include cognitive deficits commonly known as Chemo-brain. The treatment of patients with Doxorubicin (DOX), one of the most widely used chemotherapeutic drugs in the treatment of cancer, can induce depression, anxiety, and impaired cognitive function. Cannabidiol (CBD) is a non-psychoactive component of Cannabis sativa that has been identified as a possible therapeutic agent against many neurodegenerative disorders, including traumatic brain injury, spinal cord injury, Tau-protein-induced neurodegeneration, and neuropathic pain. Therefore, this study aimed to assess whether oral CBD administration could reduce DOX-induced anxiety and depression-like behaviors and alter the expression of mRNA associated with neuroinflammation. Methods: Female Long Evans Hooded rats received intraperitoneal injections of DOX (6 mg/kg) or the vehicle (0.9% saline) once a week for four weeks, followed by oral administration of CBD (10 mg/kg) three times a week for the same period. Results: CBD was significantly protective against DOX-induced anxiety and depression-like behaviors, as measured by several behavioral tests. Furthermore, CBD improved DOX-induced alterations in the gene expression of biomarkers of neuroinflammation in the hippocampus and prefrontal cortex. Conclusions: This provides insights into future studies on possible mechanisms by which DOX-induced cognitive dysfunction could be alleviated by CBD.
... No final da década de 70, um estudo duplo cego, foi conduzido por um grupo de cientistas brasileiros, utilizando doses diárias de 200mg a 300mg de canabidiol ou placebo para 16 pacientes com estado de mal epiléptico (EME) por até 4 meses e meio. Apenas 1 dos 8 pacientes recebendo canabidiol não mostrou melhora no quadro (CUNHA et al., 1980). Em um estudo do Imperial College London, pesquisadores da instituição acompanharam 10 jovens com até 18 anos de idade e descobriram que a cannabis tem o potencial de reduzir em até 86% a frequência de crises epilépticas em jovens com episódios refratários sem nenhum efeito adverso significativo (ZAFAR et al., 2021 Art. 26. ...
O presente artigo tem como objetivo discorrer sobre o uso medicinal da cannabis, assim como analisar os aspectos legais referentes às autorizações de cultivo tanto para pessoa física, como para associações de pacientes que fazem o uso das suas propriedades medicinais, comentar sobre as legislações que permitiram e vêm a permitir a importação de produtos contendo canabinoides, além de abordar a possibilidade de custeio do tratamento pelo SUS. A metodologia utilizada foi de caráter bibliográfico e documental pelo meio qualitativo com o objetivo de fazer um estudo do avanço no que concerne a regulamentação do uso para fins medicinais, bem como se há necessidade de atualização legislativa.
... n vitro studies have shown a neuroprotective effect of CBD, suggesting that it is a powerful antioxidant and a good treatment (Hampson et al., 1998). Human studies have generally shown positive results for seizure control (Cunha et al., 1980;Devinsky et al., 2016;Thiele et al., 2018). ...
Contrary to a prevailing dogma in twentieth-century neuroscience, emerging evidence suggests that the generation of new neurons continues throughout life, contributing significantly to crucial life functions owing to their robust ability to enhance neuroplasticity. Hippocampal neurogenesis occurs in the subgranular layer of the dentate gyrus, a region characterized by a specific microenvironment conducive to the proliferation of neuronal cells. A substantial body of evidence supports the belief that this phenomenon impacts various functions, including learning, emotional responses, and the formation of new memories. Diseases affecting these areas can significantly disrupt cognition and general behavior. For instance, in mesial temporal lobe epilepsy, aberrant neurogenesis has been observed, leading to increased cell proliferation, altered patterns of cellular integration, errors in information processing, and the formation of abnormal synaptic connections and transmissions. These abnormalities have the potential to generate epileptic seizures, underscoring the profound impact of these diseases on cognitive functions. Conversely, the chronic recurrence of seizures, can result in chronic recurrence of seizures, which can lead to a persistent reduction of neurogenesis in the epileptic brain. This reduction directly impacts various learning processes and the formation of hippocampus-dependent declarative memory. The mechanisms behind these processes remain fully elucidated and involve the delicate balance between neuronal excitation and inhibition, directly influencing brain performance and potentially leading to a decline in cognitive functions. In mesial temporal lobe epilepsy, this condition stands out as one of the most severe disorders affecting the well-being of epileptic patients. While memory is highlighted as one of the most affected functions, it is not the sole cognitive function compromised by this comorbidity. The alterations can extend from language to executive and spatial functions.
... THC has shown some promise as an anticonvulsant, but its unwanted psychoactive effects preclude widespread medicinal use (Hill et al., 2012). On the other hand, the non-psychoactive phytocannabinoid, cannabidiol (CBD), has been shown to be a highly effective ASM (Cunha et al., 1980;Devinsky et al., 2016, Thiele et al., 2018 and in its formulation as Epidiolex, CBD is currently licensed for use in epilepsy in many nations including Europe and North America. ...
Cannabidiol is a non-psychoactive phytocannabinoid that has been implicated as a potential therapeutic in numerous neurological diseases. Perhaps the most widespread therapeutic use of CBD has been in the form of Epidiolex, which is used to treat seizures associated with Lennox-Gastaut syndrome, Dravet syndrome and tuberous sclerosis. Whilst the effectiveness of CBD in seizure reduction is clear, its mechanism of action is complex, and reflects the wide range of pharmacodynamic targets that includes receptors, ion channels and enzymes. This study investigated the effects of action of cannabidiol (CBD) on GABAergic transmission in layer II of the medial entorhinal cortex in animals that had previously undergone a period of status epilepticus (SE) . Spontaneous post-synaptic currents were recorded from medial entorhinal cortex layer II pyramidal cells in animals 1-7 after SE and in age matched controls as well as in tissue resected from children with temporal lobe epilepsy (TLE). CBD enhanced GABA A R-mediated inhibition by increasing decay times and inhibitory charge transfer across the postsynaptic membrane in status epilepticus (SE) but did not alter GABAergic transmission in age-matched control rats. The SE-induced effects of CBD were blocked by ligands acting as inverse agonists at the benzodiazepine site of the GABA A R receptor and the effects of CBD were additive to low-doses of benzodiazepine and barbiturate agonists, consistent with allosteric actions on the GABA A R. Similar effects were observed in both SE rat and human layer II neurons. Overall, these data suggest CBD may act as a positive allosteric modulator (PAM) at postsynaptic GABA A Rs and this action appears to develop following SE.
Key points
CBD increases inhibition only post status epilepticus .
This effect is blocked by benzodiazepine site inverse agonists
CBD is additive to low-dose zolpidem, suggesting an allosteric effect on the GABA A R
CBD was similarly effective in ex vivo human epileptic tissue
These results suggest CBD is a positive allosteric modulator at the GABA A R
... CBD is a high-potency cannabinoid receptor-1 (CB 1 ) and cannabinoid receptor-2 (CB 2 ) inverse agonist that antagonizes the effects of full CB 1 and CB 2 agonists such as THC. Unlike THC, CBD has no intoxicating effects [16,17], and little abuse liability among cannabis users [18]. CBD also increases availability of the endocannabinoid anandamide (AEA), potentially through inhibition of the AEA-hydrolyzing enzyme fatty acid amide hydrolase (FAAH) [19], and acts at a variety of other potentially relevant molecular targets, including the orphan Gprotein-coupled receptor GPR55 and the 5-HT 1A receptor [20]. ...
Background
As cannabis legalization continues to spread across the United States, average Δ⁹-tetrahydrocannabinol concentrations in recreational products have significantly increased, and no prior study has evaluated effective treatments to reduce cannabis use among high potency cannabis users. Some research has found that the non-intoxicating cannabinoid cannabidiol reduces cannabis use and cannabis use disorder-related symptoms, such as affective disturbance and withdrawal. Results of these studies are promising but limited to synthetic or isolated forms of cannabidiol.
Objective
Conduct a placebo-controlled randomized control trial comparing the effects of hemp-derived cannabidiol on reducing Δ⁹-tetrahydrocannabinol use in concentrate users with cannabis use disorder.
Methods
Design. Double-blind, three-arm randomized placebo-controlled trial.
Setting. University in the Denver-Boulder, CO, USA area.
Study population. Community members who are heavy, stable cannabis concentrate users that meet criteria for at least moderate cannabis use disorder and are seeking to decrease or stop cannabis use.
Data. Self-report demographics, substance use, and mental health characteristics, blood and urine based biomarkers and anthropometrics.
Outcomes. Affective, physiological, and physical withdrawal symptoms, Δ⁹-tetrahydrocannabinol use.
Analysis. Three-group ANOVAs and χ² tests will be used to compare baseline variables between groups. Characteristics that differ between groups will be evaluated as potential covariates in subsequent analyses. A multilevel modeling framework will be used for primary outcome analysis to account for the repeated observations nested within participants over time. Pairwise post-hoc simple effects tests will be conducted to confirm patterns of differences.
Trial registration
ClinicalTrials.gov NCT06107062.
... These two associated constituents, through the typical committal effect of herbal medicines, can produce a synergy regarding the treatment of pain, inflammatory processes, depression, anxiety, epilepsy, cancer, fungal and bacterial infections (Russo, 2011). The main phytocannabinoids found in Cannabis sativa are Δ9-tetrahydrocannabinol (THC), responsible for the hallucinogenic and psychoactive effect of the plant, followed by cannabidiol (CBD), cannabinoid free of this psychotropic activity and which has several pharmacological properties, including anticonvulsant action (Cunha et al, 1980;Rektor et al, 2015;Reddy & Golub, 2016); antiinflammatory action (Honorio, 2006;Pernoncini, 2014), neuroprotective effect (Hampson, Grimaldi, & Axelroad, 1998;Gontijo, 2016), anxiolytic and antipsychotic (Zuardi, 2006). ...
The medicinal use of Cannabis sativa has been highlighted as an alternative in the treatment of neurological diseases, due to the cannabidiol (CBD), with anticonvulsant properties. This study evaluated the microbiological quality and antibacterial activity of Cannabis extracts used by patients with refractory epilepsy in order to bring more safety in their use and prescription. Around of 70 samples of Cannabis extracts were evaluated, 10 of them used for antibacterial activity tests. Microbiological quality was measured by observing the growth of bacteria, after the inoculation of the Cannabis extract into BHI Agar, BEM Agar, MacConkey Agar and Mueller-Hinton Agar culture media. For antimicrobial activity, a modified Kirby-Bauer method was performed with 11 bacterial isolates considered potentially pathogenic. Of the analyzed samples, 70 showed no bacterial contamination during its preparation, distribution and storage process, making them safe from a microbiological perspective for human consumption. Regarding antimicrobial activity, the 10 samples tested showed no inhibitory activity against the listed bacteria. The product may not interfere with the microbiota of users being treated, as some of the isolates are part of the human microbiota. Analysis of the microbiological quality and antibacterial activity of cannabis used in patients with severe neurological disorder is of fundamental importance to ensure better safety in its use. Therefore, all Cannabis extracts tested are free of microbial contamination that may compromise product quality, and none of the extracts used in this study inhibited the in vitro growth of the tested bacteria.
... Además, el abuso de Cannabis se ha propuesto como un precipitante de episodios psicóticos en personas con esquizofrenia. [13][14][15][16][17][18] Los cannabinoides son diversos compuestos químicos que pueden unirse a los receptores de sistema endocannabinoide. Estos pueden ser los endocannabinoides, fi tocannabinoides y cannabinoides sintéticos. ...
Introduction: Schizophrenia is a chronic and degenerative mental disorder. There is evidence of neuroinfl ammation in schizophrenia. A9-THC modulates the Th-1/Th-2 balance, inhibits the production of cytokines, chymosins, and the migration of infl ammatory cells. Objective: To evaluate and compare the immunological response of patients with schizophrenia with and without Cannabis use through PANSS, FACT-Sz and lymphocyte populations. Material and methods: Patients who attended the INPRFM from April to November 2016. The sample consisted of 23 patients with schizophrenia divided into those with and without Cannabis use. Results: The average age was 33.7 years; 100% were single, on treatment with risperidone or olanzapine, with an average treatment of 26.96 weeks; the mean dose was 145.65 mg equivalent of chlorpromazine; there was an average of 18.26 hrs from their last consumption; their total time of consumption was 169.57 weeks. The patients had a mean of the total PANSS score of 103.4, and a FACT-Sz, of 65.2, with no signifi cant differences. Signifi cant differences were observed in lymphocyte counts in CD3 + CD8 + T lymphocytes and NK cells. Conclusions: Patients present a decrease in CD4 + CD8 + T lymphocytes and an increase in NK cells; the use other substances, psychiatric and medical co-morbidities are common.
Background: Emerging evidence supports cannabidiol (CBD) as a promising therapeutic compound for various health conditions, despite its approval as a medication (product for medical purposes) remaining restricted to a limited range of clinical indications. Simultaneously, the regulation of cannabis-derived products for medicinal and recreational use has expanded their global market availability to meet local community demands. This scenario presents a complex challenge for clinicians, researchers, and industry, as the global appeal of therapeutic uses of CBD is growing more rapidly than the scientific evidence supporting its safety and effectiveness. Outcomes: A narrative review was conducted to discuss the best evidence regarding the pharmacological profile of CBD, its efficacy, and safety within the context of regulation and perspectives on the development of new cannabinoid-based drugs. Key articles addressing the various facets of this issue were selected for comprehensive analysis. Conclusions: Clinicians and researchers may face unique challenges in understanding the pharmacological profile of CBD and the prospects for developing its clinical indications, given the heterogeneity of clinical terminologies and the quality and composition of cannabis-based medical products available on the market. More basic and clinical research that complies with regulatory agencies’ testing guidelines, such as good manufacturing practices (GMPs), good laboratory practices (GLPs), and good clinical practices (GCPs), is needed to obtain approval for CBD or any other cannabinoid as a therapeutic for broader clinical indications.
Effects of Δ8- and Δ9-tetrahydrocannabinol (Δ8- and Δ9-THC) on three experimentally induced seizure models, i.e., audiogenic seizure (AS) test, maximal electroshock seizure (MES) test and pentylenetetrazol (PTZ)-induced seizure test were determined in the audiogenic rat. Both tetrahydrocannabinols possess a dose-related anticonvulsant effect against AS, MES and PTZ-induced maximal seizure. Although anticonvulsant potencies do not significantly differ, Δ8THC is three times more neurotoxic than Δ9THC. In addition, both THC's are without effect on minimal seizure and lethality induced by PTZ. Furthermore, the low protective indexes (TD50/ED50) determined in this study suggest that Δ8 and Δ9 THC may have poor therapeutic potentials as antiepileptic drugs.
Le cannabidiol administr dose de 100 mg par os et de 30 mg par injection i.v. fut inactif dans les sujets d'tude. Le cannabinol, dose orale de 400 mg, le fut aussi. Ces constituants du cannabis ne contribuent donc pas l'effet pharmacologique.
Se hizo un estudio comparativo de la actividad del
9-tetrahidrocannabinol, cannabinol, y cannabidiol en producir efectos similares a la marihuana cuando son inyectados i.v. a humanos. Estas substancias son los componentes predominantes de la marihuana o del hashish. Se encontro que a las dosis inyectados cannabidiol no tiene ninguna potencia, y que cannabinol es capaz de producir efectos tipicos de la marihuana, aunque a dosis varias veces mas grandes que las del
9-tetrahidrocannabinol.
Based on previous observations that cannabidiol (CBD) blocks some effects of Δ9-tetrahydrocannabinol (Δ9-THC) in laboratory animals, the present work was carried out to study possible interaction between CBD and Δ9-THC in human beings. In a double blind procedure, 40 healthy male volunteers were assigned to 1 of 8 experimental groups, receiving per oral route, placebe, 30 mg Δ9-THC, 15 30 or 60 mg of CBD, and mixtures of 30 mg of Δ9-THC plus either 15, 30 or 60 mg of CBD respectively. Pulse rate, time production tasks and psychological logical reactions were measured at several time intervals after drug ingestion. 30 mg Δ9-THC alone increased pulse rate, disturbed time tasks and induced strong psychological reactions in the subjects. 15–60 mg of CBD alone provoked no effects. On the other hand, CBD was efficient in blocking most of the effects of Δ9-THC when both drugs were given together. CBD also decreased the anxiety component of Δ9-THC effects, in such a way that the subjects reported more pleasurable effects.
The natural Cannabis sativa compounds, cannabidiol, cannabinol,
9- and
8-tetrahydrocannabinol, in that order of potency, decreased the susceptibility of rat dorsal hippocampus to seizure discharges caused by afferent stimulation. The drugs were effective following both intraperitoneal injection and topical application. They were more active, on a dose basis, than the well-known antiepileptic agents mysoline and diphenylhidantoin. Within the dose range effective in depressing hippocampal seizures, they had no effect on hippocampal evoked responses. This suggested that they might act by interfering with K+ release from hippocampal cells, which is known to be the causative factor in hippocampal seizures. This point was investigated using cannabidiol, which was found to effectively block the release of K+ from the hippocampus caused by afferent stimulation.
Six male and four female healthy volunteers were given oral placebo (glucose capsule and orange juice), cannabidiol (CBD 200 mg capsule and orange juice), alcohol (1 g/kg in orange juice and glucose capsule), and CBD (200 mg capsule) plus alcohol (1 g/kg in orange juice) in a double-blind, crossover, randomized design. Treatments were spaced one week apart. Parameters measured were a finger tap test (motor performance), cancellation and differential aptitude tests (psychomotor performance), a 1-min time production task, subjective effects (66 item adjective-pair semantic differential), and breathalyzer estimations of blood alcohol levels. Compared to placebo, alcohol and alcohol plus CBD, but not CBD alone, produced significant impairments of motor and psychomotor performances, overestimations of time production and subjective responses indicating an accurate self-perception of their intoxication and deficits. The combination of alcohol plus CBD resulted in significantly lower blood alcohol levels compared to alcohol given alone, however, there were few differences observed between the pharmacological effects of the two alcohol conditions. Thus, the inactivity of CBD, a major marijuana constituent, on motor and mental performance and effects also extends to its interaction with alcohol.