Cannabinoids and schizophrenia: therapeutic prospects.

Approximately one third of patients diagnosed with schizophrenia do not achieve adequate symptom control with standard antipsychotic drugs (APs). Some of these may prove responsive to clozapine, but non-response to APs remains an important clinical problem and cause of increased health care costs. In a significant proportion of patients, schizophrenia is associated with natural and iatrogenic metabolic abnormalities (obesity, dyslipidaemia, impaired glucose tolerance or type 2 diabetes mellitus), hyperadrenalism and an exaggerated HPA response to stress, and chronic systemic inflammation. The endocannabinoid system (ECS) in the brain plays an important role in maintaining normal mental health. ECS modulates emotion, reward processing, sleep regulation, aversive memory extinction and HPA axis regulation. ECS overactivity contributes to visceral fat accumulation, insulin resistance and impaired energy expenditure. The cannabis plant synthesises a large number of pharmacologically active compounds unique to it known as phytocannabinoids. In contrast to the euphoric and pro-psychotic effects of delta-9-tetrahydrocannabinol (THC), certain non-intoxicating phytocannabinoids have emerged in pre-clinical and clinical models as potential APs. Since the likely mechanism of action does not rely upon dopamine D2 receptor antagonism, synergistic combinations with existing APs are plausible. The anti-inflammatory and immunomodulatory effects of the non-intoxicating phytocannabinoid cannabidiol (CBD) are well established and are summarised below. Preliminary data reviewed in this paper suggest that CBD in combination with a CB1 receptor neutral antagonist could not only augment the effects of standard APs but also target the metabolic, inflammatory and stress-related components of the schizophrenia phenotype.

The cannabinoid Δ(9)-tetrahydrocannabivarin (THCV) ameliorates insulin sensitivity in two mouse models of obesity.

BACKGROUND: Cannabinoid type-1 (CB1) receptor inverse agonists improve type 2 diabetes and dyslipidaemia but were discontinued due to adverse psychiatric effects. Δ(9)-Tetrahydrocannabivarin (THCV) is a neutral CB1 antagonist producing hypophagia and body weight reduction in lean mice. We investigated its effects in dietary-induced (DIO) and genetically (ob/ob) obese mice. METHODS: We performed two dose-ranging studies in DIO mice; study 1: 0.3, 1, 2.5, 5 and 12.5 mg kg(-1), oral twice daily for 30 days and study 2: 0.1, 0.5, 2.5 and 12.5 mg kg(-1), oral, once daily for 45 days. One pilot (study 3: 0.3 and 3 mg kg(-1), oral, once daily) and one full dose-ranging (study 4: 0.1, 0.5, 2.5 and 12.5 mg kg(-1), oral, once daily) studies in ob/ob mice for 30 days. The CB1 inverse agonist, AM251, oral, 10 mg kg(-1) once daily or 5 mg kg(-1) twice daily was used as the positive control. Cumulative food and water intake, body weight gain, energy expenditure, glucose and insulin levels (fasting or during oral glucose tolerance tests), plasma high-density lipoprotein and total cholesterol, and liver triglycerides were measured. HL-5 hepatocytes or C2C12 myotubes made insulin-resistant with chronic insulin or palmitic acid were treated with 0, 1, 3 and 10 µM THCV or AM251. RESULTS: THCV did not significantly affect food intake or body weight gain in any of the studies, but produced an early and transient increase in energy expenditure. It dose-dependently reduced glucose intolerance in ob/ob mice and improved glucose tolerance and increased insulin sensitivity in DIO mice, without consistently affecting plasma lipids. THCV also restored insulin signalling in insulin-resistant hepatocytes and myotubes. CONCLUSIONS: THCV is a new potential treatment against obesity-associated glucose intolerance with pharmacology different from that of CB1 inverse agonists/antagonists.

A phase I study to assess the single and multiple dose pharmacokinetics of THC/CBD oromucosal spray.

PURPOSE: A Phase I study to assess the single and multipledose pharmacokinetics (PKs) and safety and tolerability of oromucosally administered Δ(9)-tetrahydrocannabinol (THC)/cannabidiol (CBD) spray, an endocannabinoid system modulator, in healthy male subjects. METHODS: Subjects received either single doses of THC/CBD spray as multiple sprays [2 (5.4 mg THC and 5.0 mg CBD), 4 (10.8 mg THC and 10.0 mg CBD) or 8 (21.6 mg THC and 20.0 mg CBD) daily sprays] or multiple doses of THC/CBD spray (2, 4 or 8 sprays once daily) for nine consecutive days, following fasting for a minimum of 10 h overnight prior to each dosing. Plasma samples were analyzed by gas chromatography-mass spectrometry for CBD, THC, and its primary metabolite 11-hydroxy-THC, and various PK parameters were investigated. RESULTS: Δ(9)-Tetrahydrocannabinol and CBD were rapidly absorbed following single-dose administration. With increasing single and multiple doses of THC/CBD spray, the mean peak plasma concentration (Cmax) increased for all analytes. There was evidence of dose-proportionality in the single but not the multiple dosing data sets. The bioavailability of THC was greater than CBD at single and multiple doses, and there was no evidence of accumulation for any analyte with multiple dosing. Inter-subject variability ranged from moderate to high for all PK parameters in this study. The time to peak plasma concentration (Tmax) was longest for all analytes in the eight spray group, but was similar in the two and four spray groups. THC/CBD spray was well-tolerated in this study and no serious adverse events were reported. CONCLUSIONS: The mean Cmax values (<12 ng/mL) recorded in this study were well below those reported in patients who smoked/inhaled cannabis, which is reassuring since elevated Cmax values are linked to significant psychoactivity. There was also no evidence of accumulation on repeated dosing.

A phase I study to assess the effect of food on the single dose bioavailability of the THC/CBD oromucosal spray.

PURPOSE: To assess the effect of food on the single-dose bioavailability of delta-9-tetrahydrocannabinol (THC)/cannabidiol (CBD) spray, an endocannabinoid system modulator, when administered to healthy male subjects. METHODS: Twelve subjects took part in this fed-fasted cross-over study and received a single dose of THC/CBD spray (4 sprays = 10.8 mg THC + 10 mg CBD) in the fasted then fed state (or vice versa) with a 3-day wash-out period between treatments. Plasma samples were collected at designated time-points for analysis of CBD, THC, and its active metabolite, 11-hydroxy delta-9-tetrahydrocannabinol (11-OH-THC). RESULTS: Statistically significant increases in the mean area under the curve (AUC) and mean maximum plasma drug concentration (Cmax) were observed in subjects during fed conditions. Mean AUC and Cmax were one to three-fold higher for THC and 11-OH-THC, and five and three-fold higher for CBD respectively during fed conditions. A large inter-subject variability in exposure from the same dose was observed, particularly for THC. The Cmax for THC in fed versus fasted subjects was higher in 7 subjects (4.80-14.91 ng/ml) and lower in 5 subjects (2.81-3.51 ng/ml) compared with the mean Cmax of 3.98 ng/ml (range 0.97-9.34 ng/ml) observed in the fasted state. Increases in mean AUC(0-t), AUC(0-inf), and Cmax for THC, CBD, and 11-OH-THC in the fed state were within the range of inter-subject variability, which was considerable. Food also appeared to delay the time to peak concentration (Tmax) of all analytes by approximately 2-2.5 h. Only mild adverse events were reported. CONCLUSIONS: The THC/CBD spray was well tolerated in male subjects at a single dose of four sprays. The large inter-subject variability in exposure suggests that the changes observed are unlikely to be clinically relevant.

The medicinal use of cannabis in the UK: results of a nationwide survey.

The use of cannabis for medical purposes is a controversial but an important topic of public and scientific interest. We report on the results of a self-administered questionnaire study conducted in the United Kingdom between 1998 and 2002. The questionnaire consisted of 34 items and included demographic data, disease and medication use patterns and cannabis use profiles. Subjects were self-selected; 3663 questionnaires were distributed and 2969 were returned [1805 (60.9%) women, mean age 52.7 years (SD 12.7)]. Medicinal cannabis use was reported by patients with chronic pain (25%), multiple sclerosis and depression (22% each), arthritis (21%) and neuropathy (19%). Medicinal cannabis use was associated with younger age, male gender and previous recreational use (p < 0.001). While caution must be exercised in interpreting these data, they point to the need for clinical studies of cannabis and cannabinoids with standardised and quality-controlled products.

Vertebral bone mineral density, content and area in 8789 normal women aged 33-73 years who have never had hormone replacement therapy.

The vertebral bone mineral density (BMD), bone mineral content (BMC) and bone area of the lumbar spine were measured using a bone densitometer in 8789 women aged 33-73 years who had had no previous hormone replacement therapy (HRT). The overall relationship between BMD and age was analyzed on a year-by-year basis, and comprised three separate regions that could each be described by a straight line: 33-46 years (gradient = 0.00166 g cm(-2)/year), 47-63 years (gradient = 0.0121 g cm(-2)/year) and 64-73 years (gradient = 0.0045 g cm(-2)/year). Above the age of 50 years our results were higher than the BMD in most previous reports. In those 3198 women who knew the time of their last menstrual period (mean age 49.25 years, SD 4. 83) bone loss was most rapid in the first 10 menopausal years. In the whole group, the relationship between BMC and age was found to be similar to that of BMD, with three distinct regions, including a rapid drop between the ages of 47 and 63 years (gradient 0.781 g/year). Bone area showed a much more gradual (though significant) decrease with age. Based on WHO definitions and using BMD as an indicator, the percentage of women with osteoporosis varied from zero in the younger age group to about 30% of women aged over 70 years; in contrast, where BMC was used, although the trend with age had a similar shape, the percentages at each year were about half those derived from the corresponding BMD values. Osteopenia derived in the same way occurred in about 50% of women over 70 years using either BMD or BMC. The results presented here provide a reliable local reference range for lumbar spine bone densitometry measurements. They also show that for this site BMD and BMC cannot be used interchangeably to define osteoporosis.