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.

Chronic Administration of Cannabidiol to Healthy Volunteers and Epileptic Patients

In 52 studies, performance data were obtained the next day following bedtime ingestion of a sedative-hypnotic or a placebo. Only eight of these studies used insomniac patients. Most studies used young adult males. Benzodiazepine hypnotics were most frequently administered and psychomotor performance was most often measured. Little consistent data are available on cognitive functioning and more complex behavior. Durg-related improvement in performance was not found, and, in comparing active drug to placebo, it is clear that all hypnotics, at some doses, produce decrements in performance the next day. Higher doses consistently showed a decrement, and this decrement was usually persistent over the entire day. Although long-acting drugs generally showed more performance decrement, half-life data were not consistent.

Sedative-hypnotics and human performance.

The basic facts of alcohol absorption, distribution, metabolism, and excretion were described clearly many years ago by Nicloux (1900) and Grehant (1907), among others. They showed that alcohol could be absorbed from the stomach or by inhalation in the lungs, distributed throughout the body fluids and tissues via the blood, eliminated only slowly via the lungs, kidneys, and skin, and removed chiefly by slow metabolic oxidation. Later work by a multitude of investigators has clarified the mechanisms, the quantitative relationships, and the influence of various physiological, pathological, and pharmacological factors upon these processes. Many excellent reviews and major studies were written at various stages in the development of knowledge in this field, including those by Mellanby (1919), Kochmann (1923), Miles (1924), Carpenter (1929), LeBreton (1934), Newman (1941), Goldberg (1943), Casier and Delaunois (1947), Elbel and Schleyer (1956), Himwich (1956), Harger and Forney (1963), and Mardones (1963).

Absorption, Diffusion, Distribution, and Elimination of Ethanol: Effects on Biological Membranes

1. Cannabis extract prolonged sleeping time in mice in a thermally neutral environment (30-32 degrees C) in which hypothermia does not occur. The prolongation was dose related, just detectable at 50 mg/kg, and 4-fold at 500 mg/kg.2. Under these conditions, ether sleeping time was not prolonged.3. Cannabis extract inhibited the aerobic metabolism of phenazone by a microsome-rich 9,000 g supernatant of mouse liver homogenate capable of nicotinamide adenine dinucleotide phosphate (NADPH) generation.4. Delta(1)-Tetrahydrocannabinol (Delta(1)-THC) prolonged pentobarbitone sleep and inhibited phenazone metabolism, but its action was limited, and could not account for the effect of the extract. The carotenes and water-soluble fractions of the extract were inactive on pentobarbitone sleep.5. Cannabidiol was strongly active by both tests; in vivo 39.8 muM/kg (12.5 mg/kg) prolonged sleep by 190%, and in vitro 12.7 muM inhibited phenazone metabolism 20%. These actions were dose related, and could account for the effect of the extract.6. The prolongation of pentobarbitone sleep by cannabis extract in a dose of 200 mg/kg, intraperitoneally, was maximal when given 30 min before the pentobarbitone, still present at 3 h, but undetectable at 24 hours. No phase of enhanced metabolism at 24 or 48 h after single cannabis injection was detected.7. It is concluded that cannabis extract inhibits microsomal activity of mouse liver, chiefly by virtue of its cannabidiol content. It is probable that cannabis consumption by man could lead to altered disposal of many other drugs, used in medicine or otherwise.

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Effect of cannabis and certain of its constituents on pentobarbitone sleeping time and phenazone metabolism

The natural Cannabis sativa compounds, cannabidiol, cannabinol, δ
9- and δ
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.

Hughes Fw

Papers

Pharmacologic properties of some cannabis related compounds.

Gas chromatographic assay of glycol-ethanol combinations in biological materials.

Acute ethanol toxicity in the dog.

Evaluation of anti-motion sickness drugs by component measurements of nystagmus in guinea pigs.

Comparative effects in human subjects of three hypnotics and placebo on mental and motor performance.