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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.
... In a study conducted by Cunha et al. [101], 210 mg CBD/day (~3 mg/kg bw/day) or placebo was given for 30 days to 16 healthy human volunteers. No influence on heart rate and electrocardiogram (ECG) was observed. ...
... No influence on heart rate and electrocardiogram (ECG) was observed. In a second study conducted by this group, CBD at a dose of 200-300 mg per person (~2.9-4.3 mg/kg bw/day) was administered for 4.5 months to patients with epilepsy [101]. Again, no influence of CBD on heart rate and ECG was observed. ...
Background: Cannabidiol (CBD) is a cannabinoid present in the hemp plant (Cannabis sativa L.). Non-medicinal CBD oils with typically 5–40% CBD are advertised for various alleged positive health effects. While such foodstuffs containing cannabinoids are covered by the Novel Food Regulation in the European Union (EU), none of these products have yet been authorized. Nevertheless, they continue to be available on the European market. Methods: The Permanent Senate Commission on Food Safety (SKLM) of the German Research Foundation (DFG) reviewed the currently available data on adverse and potential beneficial effects of CBD in the dose range relevant for foods. Results: Increased liver enzyme activities were observed in healthy volunteers following administration of 4.3 mg CBD/kg bw/day and higher for 3–4 weeks. As lower doses were not tested, a no observed adverse effect level (NOAEL) could not be derived, and the dose of 4.3 mg/kg bw/day was identified as the lowest observed adverse effect level (LOAEL). Based on the CBD content and dose recommendations of CBD products on the market, the SKLM considered several exposure scenarios and concluded that the LOAEL for liver toxicity may be easily reached, e.g., via consumption of 30 drops of an oil containing 20% CBD, or even exceeded. A critical evaluation of the available data on potential beneficial health effects of CBD in the dose range at or below the LOAEL of 4.3 mg/kg bw/day revealed no scientific evidence that would substantiate health claims, e.g., in relation to physical performance, the cardiovascular, immune, and nervous system, anxiety, relaxation, stress, sleep, pain, or menstrual health. Conclusions: The SKLM concluded that consumption of CBD-containing foods/food supplements may not provide substantiated health benefits and may even pose a health risk to consumers.
... 62% of the caregivers judged their child's overall condition improved in the cannabidiol group, compared with 34% in the placebo group (p = 0.02). In the study by Cunha et al. (1980) 25 ...
... 62% of the caregivers judged their child's overall condition improved in the cannabidiol group, compared with 34% in the placebo group (p = 0.02). In the study by Cunha et al. (1980) 25 ...
Introduction: There are some types of structurally similar cannabinoids, although with different pharmacological actions. Studies demonstrate how cannabidiol has great therapeutic potential against epilepsy. Objectives: This review aimed to assess the use of cannabidiol in the treatment of diseases such as epilepsy. Methods: The review was conducted and based on the search of scientific articles in the PubMed, Scielo, LILACS and Science Direct electronic databases. Were included articles in English, Portuguese, or Spanish, made available in full and for free within the period from 2009 to 2019, allowing only clinical trials. Results: All articles included in the review reported that the experimental groups obtained a favorable result with cannabidiol compared with the placebo during the experimental period. The most common adverse events observed were somnolence, decreased appetite, diarrhea, upper respiratory tract infection and pyrexia. The severe adverse events mentioned were elevated concentrations of aspartate aminotransferase, alanine aminotransferase and gamma-glutamyltransferase. Conclusion: The administration of cannabidiol as a complementary anticonvulsant medication is capable to reduce epileptic seizures, especially when epilepsy is resistant to pharmacological treatment. Thus, more effective and safe guide for development of new anticonvulsant drugs, derived from Cannabis Sativa, will improve the quality of life of patients with epilepsy.
... 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.
RESUMO Introdução: A cannabis é utilizada para fins medicinais há milhares de anos, mas só recentemente tem-se produzido estudos acerca da aplicabilidade médica dos diversos compostos da planta. Objetivo: Determinar a segurança e eficácia do canabidiol (CBD) na redução da frequência das crises epilépticas quando utilizado em monoterapia ou tratamento complementar em pacientes com epilepsia de difícil controle. Métodos: O presente estudo trata-se de uma revisão sistemática elaborada de acordo com o protocolo Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P). Foram realizadas buscas nas bases de dados PubMed, SciELO e Biblioteca Virtual em Saúde (BVS), e os artigos foram selecionados independentemente por dois revisores em três etapas: triagem por título, por resumo e por leitura integral do artigo. Para cada estudo selecionado, foi realizada coleta de dados-alvo acerca dos indivíduos estudados, seus diagnósticos, tipo de crise epiléptica, frequência das crises antes e após tratamento com CBD, métodos aplicados e principais resultados. Todos os artigos foram investigados quanto a sua qualidade metodológica através da escala CONSORT (Consolidated Standard of Reporting Trial). Resultados: Foram incluídos 6 artigos, 3 são ensaios clínicos duplo-cego controlados e 3 estudos experimentais em humanos não controlados. Todos os estudos demonstraram melhora na frequência das crises após uso do CBD, com redução percentual variando entre 43,9% até controle total das crises. Não foi encontrada associação entre o percentual de redução das frequências das crises e tempo de tratamento. Os efeitos adversos mais encontrados foram sonolência, hiporexia, diarreia, vômitos alterações comportamentais e tonturas. Conclusões: O uso terapêutico do canabidiol foi associado a redução na frequência de crises epilépticas, além de melhora global da qualidade de vida em indivíduos com epilepsia refratária. No entanto, novos estudos randomizados duplo-cego são necessários para validação interna e externa. Palavras-chave: Canabidiol; Epilepsia; Crises epilépticas. ABSTRACT Introduction: Cannabis has been used for medicinal purposes for thousands of years, but studies have only recently been made on the medical applicability of the various compounds in the plant. Objective: To establish the safety and efficacy of cannabidiol (CBD) in reducing the frequency of epileptic seizures when used as monotherapy or in combination therapy in patients with difficult to control epilepsy. Methods: The present study is a systematic review elaborated according to the Preferred Reporting Items for Systematic Review and Meta-analysis protocol (PRISMA-P). We searched the PubMed, SciELO and Biblioteca Virtual em Saúde databases, and the articles were independently selected by two reviewers in three stages: triage by title, by abstract and by reading the article in full. We collected objective data about the individuals studied, their diagnoses, type of seizure, frequency of seizures before and after treatment with CBD, methods applied and main results. All articles were examined for their methodological quality through the Consolidated Standard of Reporting Trial scale (CONSORT). Results: Six articles were included in this review. 3 were double-blind controlled clinical trials and 3 were experimental uncontrolled studies in humans. All studies showed an improvement in the frequency of seizures following CBD, with a percentage reduction ranging from 43.9% to total seizure control. The most common adverse effects were somnolence, decreased appetite, diarrhea, vomiting, behavioral changes, and dizziness. Conclusions: The therapeutic use of cannabidiol has been associated with a reduction in the frequency of epileptic seizures, as well as an overall improvement in the quality of life in individuals with
As more and more countries legalize medicinal cannabis, and more and more people start using this therapy, it is absolutely necessary that there should be identified some research priorities regarding therapeutic cannabis, using the pioneering research results from various countries from all over the world. It is also required an accurate preventive or curative professional information for the medical staff of any specialty. The present paper brings an overall image on the research in this field, which, despite of its novelty, already proves to have a great potential in medical research and practice.
Cannabidiol (CBD), the major non-psychotropic compound of Cannabis sp., is an effective treatment for inflammatory and autoimmune diseases and produces various anti-tumor effects but the mechanisms of its long-term actions in vivo remain unclear. We have previously shown that CBD administration (5 mg/kg) in healthy rats significantly decreased lymphocyte numbers in peripheral blood, involving B, T CD4+ and T CD8+ lymphocyte subsets, but not natural killer (NK) cells. To examine the effects of CBD on lymphocyte subsets in the spleen and NK cellular cytotoxicity (NKCC), adult male Wistar rats (n = 63) were administered intraperitoneal injections of CBD (2.5 or 5 mg/kg/day) for 14 consecutive days and lymphocyte counts were obtained using flow cytometry. NKCC in the peripheral blood and spleen was quantified using a Chromium-51 release assay. Furthermore, CB2 receptors were blocked using selective receptor antagonist AM630 (1 mg/kg). The results indicate that repeated administration of CBD at a dose of 5 mg/kg/day resulted in a decrease in splenic lymphocyte number, involving T and B lymphocytes but not NK cells. The decrease in lymphocyte number was partially blocked by pretreatment with CB2 receptor antagonist while no changes in NKCC were observed following CBD administration. These results reveal that in healthy rats, CBD produces similar lymphopenic effects in the spleen as it does in peripheral blood and that the effects of CBD on lymphocyte numbers in vivo are at least partially mediated by CB2 receptors.
Background
The effect of oral Cannabidiol (CBD) on interference during learning and memory (L&M) in healthy human volunteers has not been studied.
Method
A two-arm crossover, randomized, double-blind, placebo-controlled trial was conducted at Colorado State University Pueblo (CSU Pueblo) to evaluate the effects of 246 mg oral CBD on L&M in healthy adults. Among 57 healthy volunteers enrolled, 35 were included in the analyses. For assessment of L&M, Montreal Cognitive Assessment (MOCA) was used to evaluate verbal baseline cognitive function; RAVLT-R tests (List A and List B recalls, Proactive and Retroactive Interference ratios, and Forgetting Speed ratio) were used to evaluate verbal declarative memory; and total prose recall was used to evaluate verbal logical memory. Linear Mixed Models with Bonferroni Corrections were used to compare L&M results between primary outcomes (CBD vs. placebo) and secondary demographic outcomes, with a two-tailed statistical significance of P < 0.05.
Results
CBD administration did not affect any of the dependent variables measured compared to the placebo group. There were no effects of THC, history of CBD use, or sex on CBD’s modulation of L&M. However, a highly significant interaction effect between treatment groups (CBD vs. placebo) and age of subjects was observed for the PI ratio ( P = 0.008; n = 35).
Conclusions
The results of this study suggest that administration of oral CBD alone does not significantly impair L&M in healthy adults. However, age might influence CBD related modulation of proactive interference during human L&M. Future research involving a larger group of older adults is needed to confirm this potential effect.
Trial registration
The study was approved by the CSU Pueblo IRB, conducted in accordance with the Declaration of Helsinki, and registered with ClinicalTrials.gov (NCT06074172).
Drug dependence is of two types. Psychic dependence is a psychic drive to use a drug periodically or continuously, i.e., addiction. Physical dependence is an adaptive state in which cessation of drug use or administration of an antagonist produces physical withdrawal signs. Psychic and physical dependence can exist together or independently. Tolerance refers to the need to take an ever-increasing dose of a drug to achieve the desired effect or to prevent craving or physical withdrawal (1).
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.