BACKGROUND: Medicinal cannabinoids, including medicinal cannabis and pharmaceutical cannabinoids and their synthetic derivatives, such as tetrahydrocannabinol (THC) and cannabidiol (CBD), have been suggested to have a therapeutic role in certain mental disorders. We analysed the available evidence to ascertain the effectiveness and safety of all types of medicinal cannabinoids in treating symptoms of various mental disorders.
METHODS: For this systematic review and meta-analysis we searched MEDLINE, Embase, PsycINFO, the Cochrane Central Register of Controlled Clinical Trials, and the Cochrane Database of Systematic Reviews for studies published between Jan 1, 1980, and April 30, 2018. We also searched for unpublished or ongoing studies on ClinicalTrials.gov, the EU Clinical Trials Register, and the Australian and New Zealand Clinical Trials Registry. We considered all studies examining any type and formulation of a medicinal cannabinoid in adults (≥18 years) for treating depression, anxiety, attention-deficit hyperactivity disorder (ADHD), Tourette syndrome, post-traumatic stress disorder, or psychosis, either as the primary condition or secondary to other medical conditions. We placed no restrictions on language, publication status, or study type (ie, both experimental and observational study designs were included). Primary outcomes were remission from and changes in symptoms of these mental disorders. The safety of medicinal cannabinoids for these mental disorders was also examined. Evidence from randomised controlled trials was synthesised as odds ratios (ORs) for disorder remission, adverse events, and withdrawals and as standardised mean differences (SMDs) for change in symptoms, via random-effects meta-analyses. The quality of the evidence was assessed with the Cochrane risk of bias tool and Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach. This study is registered with PROSPERO (CRD42017059372, CRD42017059373, CRD42017059376, CRD42017064996, and CRD42018102977).
FINDINGS: 83 eligible studies (40 randomised controlled trials, n=3067) were included: 42 for depression (23 randomised controlled trials; n=2551), 31 for anxiety (17 randomised controlled trials; n=605), eight for Tourette syndrome (two randomised controlled trials; n=36), three for ADHD (one randomised controlled trial; n=30), 12 for post-traumatic stress disorder (one randomised controlled trial; n=10), and 11 for psychosis (six randomised controlled trials; n=281). Pharmaceutical THC (with or without CBD) improved anxiety symptoms among individuals with other medical conditions (primarily chronic non-cancer pain and multiple sclerosis; SMD -0·25 [95% CI -0·49 to -0·01]; seven studies; n=252), although the evidence GRADE was very low. Pharmaceutical THC (with or without CBD) worsened negative symptoms of psychosis in a single study (SMD 0·36 [95% CI 0·10 to 0·62]; n=24). Pharmaceutical THC (with or without CBD) did not significantly affect any other primary outcomes for the mental disorders examined but did increase the number of people who had adverse events (OR 1·99 [95% CI 1·20 to 3·29]; ten studies; n=1495) and withdrawals due to adverse events (2·78 [1·59 to 4·86]; 11 studies; n=1621) compared with placebo across all mental disorders examined. Few randomised controlled trials examined the role of pharmaceutical CBD or medicinal cannabis.
INTERPRETATION: There is scarce evidence to suggest that cannabinoids improve depressive disorders and symptoms, anxiety disorders, attention-deficit hyperactivity disorder, Tourette syndrome, post-traumatic stress disorder, or psychosis. There is very low quality evidence that pharmaceutical THC (with or without CBD) leads to a small improvement in symptoms of anxiety among individuals with other medical conditions. There remains insufficient evidence to provide guidance on the use of cannabinoids for treating mental disorders within a regulatory framework. Further high-quality studies directly examining the effect of cannabinoids on treating mental disorders are needed.
FUNDING: Therapeutic Goods Administration, Australia; Commonwealth Department of Health, Australia; Australian National Health and Medical Research Council; and US National Institutes of Health.
AIMS: Cannabidiol is a cannabis-derived medicinal product with potential application in a wide-variety of contexts, however its effective dose in different disease states remains unclear. This review aimed to investigate what doses have been applied in clinical populations, in order to understand the active range of cannabidiol in a variety of medical contexts.
METHODS: Publications involving administration of cannabidiol alone were collected by searching PubMed, EMBASE and ClinicalTrials.gov.
RESULTS: A total of 1038 articles were retrieved, of which 35 studies met inclusion criteria covering 13 medical contexts. 23 studies reported a significant improvement in primary outcomes (e.g. psychotic symptoms, anxiety, seizures), with doses ranging between <1 - 50 mg/Kg/day. Plasma concentrations were not provided in any publication. Cannabidiol was reported as well tolerated and epilepsy was the most frequently studied medical condition, with all 11 studies demonstrating positive effects of cannabidiol on reducing seizure frequency or severity (average 15 mg/Kg/day within randomised controlled trials). There was no signal of positive activity of CBD in small randomised controlled trials (range n=6-62) assessing diabetes, Crohn's disease, ocular hypertension, fatty liver disease or chronic pain. However, low doses (average 2.4 mg/Kg/day) were used in these studies.
CONCLUSION: This review highlights cannabidiol has a potential wide range of activity in several pathologies. Pharmacokinetic studies as well as conclusive phase III trials to elucidate effective plasma concentrations within medical contexts are severely lacking and highly encouraged.
We performed a systematic review of the scientific literature assessing the use of exogenous cannabinoids in the treatment of movement disorders including Huntington's disease, Parkinson's disease, Tourette's syndrome, tics, essential tremor, tremor associated with multiple sclerosis, Wilson's disease, dystonia, and myoclonus. Databases searched for articles published in English include: Pubmed, Web of Science, PsycINFO, and Clinicaltrials.gov. A total of 21 case series and clinical trials evaluating the use of cannabinoids in the treatment of movement disorders were identified. All studies either consisted of small sample sizes, or the primary outcome was not the effect of exogenous cannabinoid treatment on a specific movement. None of the studies reviewed were powered to detect a difference with the treatment of a cannabinoid agonist. Therefore, currently no conclusions can be made on the efficacy of cannabinoids in the treatment of movement disorders.
La medicina en su continuo desarrollo se ha interesado por descubrir y utilizar substancias útiles para el cuerpo humano y el tratamiento de enfermedades. Desde hace años existe un debate en el campo de la ciencia en relación a la marihuana, el debate se sitúa entre quienes la consideran una planta con potenciales utilidades terapéuticas y quienes la consideran una droga de abuso. Método: Se revisaron 10 bases de datos con el fin de encontrar estudios clínicos con humanos, sobre los efectos de los aannabinoides, fitocannabinoides y cannabinoides sintéticos en distintas condiciones médicas. Resultados: 37 estudios fueron descritos, los estudios fueron analizados de acuerdo al país donde se realizaron, participantes, componentes y condición médica.
A pesar de un amplio estudio en las últimas décadas, los tratamientos disponibles para la esquizofrenia son sólo moderadamente eficaces y causan metabólica grave y efectos secundarios neurológicos. Por lo tanto, existe una necesidad urgente de nuevas dianas terapéuticas para el tratamiento de la esquizofrenia. Una nueva diana farmacológica muy prometedor en el contexto de la esquizofrenia es el sistema endocannabinoide. Modulación de este sistema por el principal componente psicoactivo de la marihuana, Δ9-tetrahidrocannabinol (THC), induce efectos psicóticos agudos y el deterioro cognitivo. Sin embargo, el, cannabidiol agente cannabinoide derivado de plantas no psicoactivo (CDB) puede tener propiedades antipsicóticas, y por lo tanto puede ser un nuevo agente prometedor en el tratamiento de la esquizofrenia. En este artículo revisamos los estudios que investigaron las propiedades antipsicóticas de CDB en sujetos humanos. Los resultados muestran la capacidad de CDB para contrarrestar los síntomas psicóticos y deterioro cognitivo asociado con el uso de cannabis, así como con la administración de THC aguda. Además, el CDB puede disminuir el riesgo de desarrollar psicosis que se relaciona con el consumo de cannabis. Estos efectos son posiblemente mediadas por efectos opuestos del CDB y el THC en los patrones de la actividad cerebral en regiones clave implicados en la fisiopatología de la esquizofrenia, tales como el cuerpo estriado, el hipocampo y la corteza prefrontal. Los primeros estudios clínicos a pequeña escala con el tratamiento CDB los pacientes con síntomas psicóticos confirman aún más el potencial de la CDB como un compuesto antipsicótico efectivo, seguro y bien tolerado, aunque se necesitarán grandes ensayos clínicos aleatorios antes de que esta nueva terapia puede ser introducido en clínica práctica.
Varias líneas de evidencia apuntan experimental y clínica a una estrecha relación entre el cannabis, el sistema cannabinoide endógeno, y la esquizofrenia. Una variedad de estudios en animales y humanos encontró una desregulación de la señalización endocannabinoide en la psicosis. Niveles de anandamida elevados en los pacientes con esquizofrenia que se correlacionan negativamente con sintomatología psicótica indican un papel protector, mientras que 2-araquidonoilglicerol parece contrarrestar los deterioros cognitivos relacionados con la psicosis. Por lo tanto, la manipulación farmacológica del sistema cannabinoide endógeno podría estar asociado con potenciales propiedades antipsicóticas. En la presente revisión sistemática, ambos estudios preclínicos utilizando diferentes modelos animales de la psicosis, así como ensayos clínicos que investigan los efectos antipsicóticos tanto cannabidiol y rimonabant se presentan junto con los posibles mecanismos subyacentes de la acción. Los resultados confirman predominantemente la hipótesis de una actividad antipsicótica de ambos cannabinoides. En comparación, el cannabidiol parece ser superior a rimonabant con un perfil farmacológico similar a los fármacos antipsicóticos atípicos.
Medicinal cannabinoids, including medicinal cannabis and pharmaceutical cannabinoids and their synthetic derivatives, such as tetrahydrocannabinol (THC) and cannabidiol (CBD), have been suggested to have a therapeutic role in certain mental disorders. We analysed the available evidence to ascertain the effectiveness and safety of all types of medicinal cannabinoids in treating symptoms of various mental disorders.
METHODS:
For this systematic review and meta-analysis we searched MEDLINE, Embase, PsycINFO, the Cochrane Central Register of Controlled Clinical Trials, and the Cochrane Database of Systematic Reviews for studies published between Jan 1, 1980, and April 30, 2018. We also searched for unpublished or ongoing studies on ClinicalTrials.gov, the EU Clinical Trials Register, and the Australian and New Zealand Clinical Trials Registry. We considered all studies examining any type and formulation of a medicinal cannabinoid in adults (≥18 years) for treating depression, anxiety, attention-deficit hyperactivity disorder (ADHD), Tourette syndrome, post-traumatic stress disorder, or psychosis, either as the primary condition or secondary to other medical conditions. We placed no restrictions on language, publication status, or study type (ie, both experimental and observational study designs were included). Primary outcomes were remission from and changes in symptoms of these mental disorders. The safety of medicinal cannabinoids for these mental disorders was also examined. Evidence from randomised controlled trials was synthesised as odds ratios (ORs) for disorder remission, adverse events, and withdrawals and as standardised mean differences (SMDs) for change in symptoms, via random-effects meta-analyses. The quality of the evidence was assessed with the Cochrane risk of bias tool and Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach. This study is registered with PROSPERO (CRD42017059372, CRD42017059373, CRD42017059376, CRD42017064996, and CRD42018102977).
FINDINGS:
83 eligible studies (40 randomised controlled trials, n=3067) were included: 42 for depression (23 randomised controlled trials; n=2551), 31 for anxiety (17 randomised controlled trials; n=605), eight for Tourette syndrome (two randomised controlled trials; n=36), three for ADHD (one randomised controlled trial; n=30), 12 for post-traumatic stress disorder (one randomised controlled trial; n=10), and 11 for psychosis (six randomised controlled trials; n=281). Pharmaceutical THC (with or without CBD) improved anxiety symptoms among individuals with other medical conditions (primarily chronic non-cancer pain and multiple sclerosis; SMD -0·25 [95% CI -0·49 to -0·01]; seven studies; n=252), although the evidence GRADE was very low. Pharmaceutical THC (with or without CBD) worsened negative symptoms of psychosis in a single study (SMD 0·36 [95% CI 0·10 to 0·62]; n=24). Pharmaceutical THC (with or without CBD) did not significantly affect any other primary outcomes for the mental disorders examined but did increase the number of people who had adverse events (OR 1·99 [95% CI 1·20 to 3·29]; ten studies; n=1495) and withdrawals due to adverse events (2·78 [1·59 to 4·86]; 11 studies; n=1621) compared with placebo across all mental disorders examined. Few randomised controlled trials examined the role of pharmaceutical CBD or medicinal cannabis.
INTERPRETATION:
There is scarce evidence to suggest that cannabinoids improve depressive disorders and symptoms, anxiety disorders, attention-deficit hyperactivity disorder, Tourette syndrome, post-traumatic stress disorder, or psychosis. There is very low quality evidence that pharmaceutical THC (with or without CBD) leads to a small improvement in symptoms of anxiety among individuals with other medical conditions. There remains insufficient evidence to provide guidance on the use of cannabinoids for treating mental disorders within a regulatory framework. Further high-quality studies directly examining the effect of cannabinoids on treating mental disorders are needed.
FUNDING:
Therapeutic Goods Administration, Australia; Commonwealth Department of Health, Australia; Australian National Health and Medical Research Council; and US National Institutes of Health.
