Chronic administration of cannabidiol to healthy volunteers and epileptic patients. Controlled clinical trial of cannabidiol in Huntington's disease. A randomised open multicentre comparative trial of lamotrigine and carbamazepine as monotherapy in patients with newly diagnosed or recurrent epilepsy. A preliminary controlled study to determine whether whole-plant cannabis extracts can improve intractable neurogenic symptoms. Pharmacokinetic evaluation of twice-daily extended-release carbamazepine (CBZ) and four-times-daily immediate-release CBZ in patients with epilepsy. Treatment of epilepsy in mentally retarded patients with a slow-release carbamazepine preparation. Adjuvant vigabatrin in refractory epilepsy: a ceiling to effective dosage in individual patients? Double-blind, placebo-controlled trial of topiramate (600 mg daily) for the treatment of refractory partial epilepsy. Safety, tolerability, and efficacy of orally administered cannabinoids in MS.
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. 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 efficacy and safety of lamotrigine and carbamazepine as monotherapy in patients with untreated, newly diagnosed or recurrent partial and/or generalised tonic-clonic seizures, were compared in a randomised, open, multicentre study. Patients received 24 weeks' treatment with oral lamotrigine 100 mg (LTG 100, n = 115) or 200 mg (LTG 200, n = 111) or carbamazepine 600 mg (CBZ 600, n = 117). Efficacy measurements were comparable between the three treatment groups, although the higher lamotrigine dose was possibly most effective, with 60.4% completing seizure free compared with 51.3% (LTG 100) and 54.7% (CBZ 600). Both dosage regimens of lamotrigine were well tolerated. More patients on CBZ 600 reported adverse experiences, 66% versus 53% (LTG 100) and 58% (LTG 200), and of these a greater proportion were attributed to CBZ 600 treatment, 53% versus 23% (LTG 100) and 28% (LTG 200). Similarly, a greater proportion of the CBZ 600 group required a change in dose, 47% versus 20% (LTG 100) and 17% (LTG 200) or withdrew completely due to adverse experiences, 10.3% versus 4.3% (LTG 100) and 4.5% (LTG 200). The most common adverse experience leading to withdrawal was rash, with approximately double the proportion of reports occurring in patients on CBZ 600 (5.1%) compared with lamotrigine (1.7% on LTG 100 and 2.7% on LTG 200). Overall lamotrigine appeared equally effective but better tolerated compared with carbamazepine. 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 new capsule dosage form of carbamazepine (CBZ) has been developed, consisting of three different types of beads (immediate-release, extended-release, and enteric-release) that may be taken sprinkled on food or swallowed for easy administration. We compared the pharmacokinetics of the extended-release dosage form of CBZ (Carbatrol capsules) twice daily with the conventional immediate-release formulation of CBZ four times daily.
                The randomized, double-blind, two-way, cross-over study was conducted at two sites, with a planned sample size of 24 adult patients with epilepsy. Each treatment was administered for 2 weeks. At the end of the 2-week period, blood samples were obtained hourly for a 24-h period.
                The 90% confidence intervals (CI) of the ratio of the means of the extended-release formulation twice daily to the immediate-release formulation four times daily were within the range of 0.80-1.25 for each of the pharmacokinetic parameters for CBZ and for the summation of CBZ and CBZ-epoxide (CBZ-E). There was no difference in the frequency of seizures between treatment (p = 0.103).
                Our results demonstrate that extended-release CBZ twice daily was bioequivalent to immediate-release CBZ four times daily, with regard to CBZ levels and summation of CBZ and CBZ-E levels, based on the pharmacokinetic parameters evaluated. Substituting one formulation for the other did not cause patients to have a significant change in seizure frequency. Pharmacokinetic properties and efficacy of a conventional (C) carbamazepine (CBZ) preparation divided into three daily doses and a slow-release CBZ preparation (SR) divided into two daily doses were evaluated in a randomized, double-blind, cross-over study. The trial started with a 8-week baseline period followed by the two treatment periods each 10 weeks long. At the end of each period, a 24-h blood sample series for determination of serum CBZ and carbamazepine-10,11-epoxide (CBZE) was collected. The occurrence of seizures was monitored day and night during the whole study period by experienced nurses. The mean age of the 20 evaluable patients was 24.9 and the duration of epilepsy 19.2 and carbamazepine treatment 7.0 years. The bioavailability of CBZ from the two preparations was similar. The mean fluctuation of serum CBZ concentration (Cmax-Cmin/Css) was 16% smaller during SR. The mean serum CBZ concentration in the morning samples was significantly (P less than 0.001) higher during SR treatment. The mean total number of seizures was approximately four per week and did not differ between the two treatments, but during the last 2 weeks of the study period the occurrence of seizures was significantly smaller during SR (P = 0.02). A double-blind, randomized, cross-over study of additional vigabatrin (gamma-vinyl-GABA, VGB, 1.0 g twice daily for 6 weeks, followed by 1.5 g twice daily for 6 weeks) and matched placebo was undertaken in 24 patients with refractory epilepsy. Nineteen completed the trial satisfactorily. Fewer seizure days were reported during VGB treatment [placebo 41, VGB 23, p < 0.05, 95% confidence interval (CI) -1.5 to -14]. An overall reduction in median seizure numbers failed to reach statistical significance (n = 19; placebo 52, VGB 32, NS, 95% CI -18 to +24). Subgroup analysis, however, showed a significant reduction in partial seizures (n = 17) with 2 g VGB daily (placebo 22, VGB 13, p < 0.05, 95% CI -0.5 to -16.5), but not with higher dosage (placebo 28, VGB 22, NS, 95% CI -18 to +11). A deterioration in control of partial seizures as compared with the equivalent placebo phase was observed when patients were changed from 2 to 3 g/day VGB (2 g VGB 13, 3 g VGB 22, p = 0.05, 95% CI 0 to +20). Loss of efficacy was noted in 3 patients, and seizure control worsened slightly in 5 others. One previously resistant patient developed a therapeutic response, and 2 other patients reported an additional useful reduction in seizures. In the remaining 8 patients, seizure frequency did not change. VGB did not appear to benefit tonic-clonic seizures. Serum VGB concentrations were higher during treatment with 3 g (15.5 +/- 8.9 mg/L) daily than with 2 g (13.5 +/- 11.2 mg/L). No important alterations were noted in the concentrations of concomitantly administered antiepileptic drugs (AEDs) throughout the trial. VGB is useful adjuvant therapy for treatment of partial seizures. There may be a ceiling to effective dosage. This demands individual dose titration for each patient. We wished to evaluate adjunctive therapy for partial-onset seizures with topiramate (TPM) for efficacy and safety in a double-blind, placebo-controlled, randomized, parallel-group study.
                Sixty outpatients with epilepsy (47 men and 13 women, mean age 32.9 years) were studied. All had a documented history of partial-onset seizures with or without secondarily generalized seizures. After an 8-week baseline during which patients had at least one seizure per week, 30 patients each were randomized to TPM 300 mg twice daily (b.i.d.) or placebo for 12 weeks.
                TPM was significantly superior to placebo, as indicated by all efficacy assessments: greater median percent reduction from baseline in the average monthly seizure rate (46 vs. -12%, p = 0.004); greater number of treatment responders (patients with > or = 50% reduction in seizure rate) (47 vs. 10%, p = 0.001), and better investigator (p = 0.002) and patient (p = 0.010) global assessments of treatment. Among TPM-treated patients, the most commonly reported adverse events (AE) were headache, somnolence, fatigue, dizziness, and abnormal thinking. Most AE were mild or moderate in severity.
                The results of the present trial indicate that TPM 600 mg/day is effective in the treatment of refractory partial-onset seizures with or without secondarily generalized seizures. 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.
No reliable conclusions can be drawn at present regarding the efficacy of cannabinoids as a treatment for epilepsy. The dose of 200 to 300 mg daily of cannabidiol was safely administered to small numbers of patients, for generally short periods of time, and so the safety of long term cannabidiol treatment cannot be reliably assessed.