Controlled clinical trial of cannabidiol in Huntington's disease. Safety, tolerability, and efficacy of orally administered cannabinoids in MS. Do cannabis-based medicinal extracts have general or specific effects on symptoms in multiple sclerosis? A double-blind, randomized, placebo-controlled study on 160 patients. Chronic administration of cannabidiol to healthy volunteers and epileptic patients. A preliminary controlled study to determine whether whole-plant cannabis extracts can improve intractable neurogenic symptoms. Effects of dronabinol on anorexia and disturbed behavior in patients with Alzheimer's disease. The effect of cannabis on tremor in patients with multiple sclerosis. Efficacy and tolerability of Ginkgo biloba extract EGb 761 by type of dementia: analyses of a randomised controlled trial. A randomized, double-blind, placebo-controlled trial of two doses of Ginkgo biloba extract in dementia of the Alzheimer's type.
Based on encouraging preliminary findings, cannabidiol (CBD), a major nonpsychotropic constituent of Cannabis, was evaluated for symptomatic efficacy and safety in 15 neuroleptic-free patients with Huntington's Disease (HD). The effects of oral CBD (10 mg/kg/day for 6 weeks) and placebo (sesame oil for 6 weeks) were ascertained weekly under a double-blind, randomized cross-over design. A comparison of the effects of CBD and placebo on chorea severity and other therapeutic outcome variables, and on a Cannabis side effect inventory, clinical lab tests and other safety outcome variables, indicated no significant (p greater than 0.05) or clinically important differences. Correspondingly, plasma levels of CBD were assayed by GC/MS, and the weekly levels (mean range of 5.9 to 11.2 ng/ml) did not differ significantly over the 6 weeks of CBD administration. In summary, CBD, at an average daily dose of about 700 mg/day for 6 weeks, was neither symptomatically effective nor toxic, relative to placebo, in neuroleptic-free patients with HD. The authors conducted a randomized, double-blind, placebo-controlled, twofold crossover study in 16 patients with MS who presented with severe spasticity to investigate safety, tolerability, and efficacy of oral Delta(9)-Tetrahydrocannabinol (THC) and Cannabis sativa plant extract. Both drugs were safe, but adverse events were more common with plant-extract treatment. Compared with placebo, neither THC nor plant-extract treatment reduced spasticity. Both THC and plant-extract treatment worsened the participant's global impression. The objective was to determine whether a cannabis-based medicinal extract (CBME) benefits a range of symptoms due to multiple sclerosis (MS). A parallel group, double-blind, randomized, placebo-controlled study was undertaken in three centres, recruiting 160 outpatients with MS experiencing significant problems from at least one of the following: spasticity, spasms, bladder problems, tremor or pain. The interventions were oromucosal sprays of matched placebo, or whole plant CBME containing equal amounts of delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) at a dose of 2.5-120 mg of each daily, in divided doses. The primary outcome measure was a Visual Analogue Scale (VAS) score for each patient's most troublesome symptom. Additional measures included VAS scores of other symptoms, and measures of disability, cognition, mood, sleep and fatigue. Following CBME the primary symptom score reduced from mean (SE) 74.36 (11.1) to 48.89 (22.0) following CBME and from 74.31 (12.5) to 54.79 (26.3) following placebo [ns]. Spasticity VAS scores were significantly reduced by CBME (Sativex) in comparison with placebo (P =0.001). There were no significant adverse effects on cognition or mood and intoxication was generally mild. 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. To determine whether plant-derived cannabis medicinal extracts (CME) can alleviate neurogenic symptoms unresponsive to standard treatment, and to quantify adverse effects.
                A consecutive series of double-blind, randomized, placebo-controlled single-patient cross-over trials with two-week treatment periods.
                Patients attended as outpatients, but took the CME at home.
                Twenty-four patients with multiple sclerosis (18), spinal cord injury (4), brachial plexus damage (1), and limb amputation due to neurofibromatosis (1).
                Whole-plant extracts of delta-9-tetrahydrocannabinol (THC), cannabidiol (CBD), 1:1 CBD:THC, or matched placebo were self-administered by sublingual spray at doses determined by titration against symptom relief or unwanted effects within the range of 2.5-120 mg/24 hours. Measures used: Patients recorded symptom, well-being and intoxication scores on a daily basis using visual analogue scales. At the end of each two-week period an observer rated severity and frequency of symptoms on numerical rating scales, administered standard measures of disability (Barthel Index), mood and cognition, and recorded adverse events.
                Pain relief associated with both THC and CBD was significantly superior to placebo. Impaired bladder control, muscle spasms and spasticity were improved by CME in some patients with these symptoms. Three patients had transient hypotension and intoxication with rapid initial dosing of THC-containing CME.
                Cannabis medicinal extracts can improve neurogenic symptoms unresponsive to standard treatments. Unwanted effects are predictable and generally well tolerated. Larger scale studies are warranted to confirm these findings. A placebo-controlled crossover design, with each treatment period lasting 6 weeks, was used to investigate effects of dronabinol in 15 patients with a diagnosis of probable Alzhemer's disease who were refusing food. Eleven patients completed both study periods; one patient who died of a heart attack 2 weeks before the end of the study was also included in the analysis. The study was terminated in 3 patients: one developed a grand mal seizure and 2 developed serious intercurrent infections. Body weight of study subjects increased more during the dronabinol treatment than during the placebo periods. Dronabinol treatment decreased severity of disturbed behavior and this effect persisted during the placebo period in patients who received dronabinol first. Adverse reactions observed more commonly during the dronabinol treatment than during placebo periods included euphoria, somnolence and tiredness, but did not require discontinuation of therapy. These results indicate that dronabinol is a promising novel therapeutic agent which may be useful not only for treatment of anorexia but also to improve disturbed behavior in patients with Alzheimer's disease. Disabling tremor is common in patients with multiple sclerosis (MS). Data from animal model experiments and subjective and small objective studies involving patients suggest that cannabis may be an effective treatment for tremor associated with MS. To our knowledge, there are no published double-blind randomized controlled trials of cannabis as a treatment for tremor in MS patients.
                The authors conducted a randomized double-blind placebo-controlled crossover trial to examine the effect of oral cannador (cannabis extract) on 14 patients with MS with upper limb tremors. There were eight women and six men, with a mean age of 45 years and mean Expanded Disability Status Scale score of 6.25. Patients were randomly assigned to receive each treatment and the doses escalated over a 2-week period before each assessment. The primary outcome was change on a tremor index, measured using a validated tremor rating scale. The study was powered to detect a functionally significant 50% improvement in the tremor index. Secondary outcomes included accelerometry, an ataxia scale, spiral drawing, finger tapping, and nine-hole pegboard test performance.
                Analysis of the data showed no significant improvement in any of the objective measures of upper limb tremor with cannabis extract compared to placebo. Finger tapping was faster on placebo compared to cannabis extract (p < 0.02). However, there was a nonsignificant trend for patients to experience more subjective relief from their tremors while on cannabis extract compared to placebo.
                Cannabis extract does not produce a functionally significant improvement in MS-associated tremor. Secondary analyses of a randomised controlled trial were performed to find out whether treatment effects of Ginkgo biloba extract EGb 761 differed by type of dementia. Three hundred ninety-five patients aged 50 years or above, with dementia with neuropsychiatric features were treated with EGb 761 (240 mg/day) or placebo for 22 weeks. Patients scored between 9 and 23 on the Short Syndrome Test (SKT), a cross-culturally validated cognitive test battery. Their total score on the Neuropsychiatric Inventory (NPI) was at least 5. Efficacy was assessed by the SKT test battery (primary outcome measure), the Verbal Fluency Test, the Clock-Drawing Test, the NPI, the Hamilton Rating Scale for Depression (HAMD), and the Gottfries-Bråne-Steen Scale (GBS). Applying standard research diagnostic criteria 214 patients were diagnosed with Alzheimer's disease (probable AD or possible AD with cerebrovascular disease) and 181 with probable vascular dementia (VaD). Under EGb 761 treatment the SKT total score improved by -3.0+/-2.3 and -3.4+/-2.3 points in patients with AD and VaD, respectively, whereas the patients on placebo deteriorated by +1.2+/-2.5 and +1.5+/-2.2 points, respectively (p<0.01 for both drug-placebo differences). Significant drug-placebo differences were found for all secondary outcome variables with no major differences between AD and VaD subgroups. The rate of adverse events tended to be higher for the placebo group. Previous studies of Ginkgo biloba extract (GbE) in patients with various forms of cognitive impairment or dementia have shown promising results.
                To determine the clinical efficacy of GbE in mild to moderate dementia of the Alzheimer type.
                Randomized, placebo-controlled, double-blind, parallel-group, multicenter trial.
                Outpatient clinics of universities and private research centers specialized in dementia.
                513 outpatients with uncomplicated dementia of the Alzheimer's type scoring 10 to 24 on the Mini-Mental State Examination and less than 4 on the modified Hachinski Ischemic Score, free of other serious illnesses and not requiring continuous treatment with any psychoactive drug.
                26-week treatment with GbE at daily doses of 120 mg or 240 mg or placebo.
                Cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog), Alzheimer's Disease Cooperative Study Clinical Global Impression of Change (ADCS-CGIC).
                There were no significant between-group differences for the whole sample. There was little cognitive and functional decline of the placebo-treated patients, however. For a subgroup of patients with neuropsychiatric symptoms there was a greater decline of placebo-treated patients and significantly better cognitive performance and global assessment scores for the patients on GbE.
                The trial did not show efficacy of GbE, however, the lack of decline of the placebo patients may have compromised the sensitivity of the trial to detect a treatment effect. Thus, the study remains inconclusive with respect to the efficacy of GbE.
This review finds no evidence that cannabinoids are effective in the improvement of disturbed behaviour in dementia or in the treatment of other symptoms of dementia. More randomized double-blind placebo controlled trials are needed to determine whether cannabinoids are clinically effective in the treatment of dementia.