Paul Consroe

Controlled clinical trial of cannabidiol in Huntington's disease

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 Huntingtons 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.

Open label evaluation of cannabidiol in dystonic movement disorders.

Cannabidiol (CBD), a nonpsychoactive cannabinoid of Cannabis, was given to 5 patients with dystonic movement disorders in a preliminary open pilot study. Oral doses of CBD rising from 100 to 600 mg/day over a 6 week period were administered along with standard medication. Dose-related improvement in dystonia was observed in all patients and ranged from 20 to 50%. Side-effects of CBD were mild and included hypotension, dry mouth, psychomotor slowing, lightheadedness, and sedation. In 2 patients with coexisting Parkinsonian features, CBD at doses over 300 mg/day exacerbated the hypokinesia and resting tremor. CBD appears to have antidystonic and Parkinsonism-aggravating effects in humans.

Effects of cannabidiol on behavioral seizures caused by convulsant drugs or current in mice

In mice, running, clonic and tonic convulsions and lethality were assessed following transcorneal (electroshock) current or convulsant drugs, each administered alone and after cannabidiol (CBD) pretreatment. CBD prevented tonic convulsions caused by a convulsant current (CC) 99.99, and by the convulsant dose (CD) 99.99 values of gamma-aminobutyric acid (GABA) inhibitors, 3-mercaptoproprionic acid (3MPA), picrotoxin (PIC), isonicotinic acid hydrazine (INH), pentylenetetrazol (PTZ) and bicuculline (BIC). Rankorder potencies, based on the antitonic ED50 of CBD, were: 3MPA greater than PIC = current = PTZ = BIC. Further, CBD prevented 3MPA-induced lethality, but failed to prevent the occurrence of the other behavioral endpoints of the above treatments. CBD also failed to prevent convulsions and lethality caused by the CD 99.99 of strychnine, a glycine antagonist. The differential effects of CBD suggest that the cannabinoid acts to inhibit seizure spread in the CNS by an action on GABA, but not glycine, mechanisms.

Relative efficacies of cannabinoid CB1 receptor agonists in the mouse brain

We measured (-)-5-(1,1-dimethylheptyl)-2-[5-hydroxy-2-(3-hydroxypropyl)cyclohe xyl]-phenol (CP 55,940)-, (-)11-OH-delta8-tetrahydrocannabinol-dimethylheptyl (HU-210)-, anandamide- and delta9-tetrahydrocannabinol-stimulated G protein activation in mouse brain using the [35S]GTPgammaS functional assay. The Ki values for these drugs were determined by agonist competition binding with the cannabinoid CB1 receptor antagonist [3H]N-(piperidin-1-yl-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4- methyl-1H-pyrazole-3-carboxamidehydrochloride ([3H]SR141716A). This information was used to calculate the efficacy for drug stimulation of G protein activity. The rank order of efficacy was CP 55,940 > HU-210 > anandamide > delta9-tetrahydrocannabinol with the latter two drugs being partial agonists. Since efficacy values relate receptor occupancy to functional responses, we believe efficacy values are a better measure of drug-mediated functional responses compared with measurements of drug potency.

Stock differences in the susceptibility of rats to learned helplessness training

Learned helplessness (LH) consists of shock escape deficits evidenced by animals previously exposed to inescapable shock. This phenomenon has shown promise as a behavioral screen for new antidepressant drugs. Unfortunately, some stocks of rats evidence low susceptibility to LH training. Accordingly, male rats from 8 different stocks were tested for susceptibility to LH training. The outbred stocks consisted of Harlan SD, Sasco Holtzman, and Charles River Holtzman. The inbred stocks (i.e. strains) tested were Lewis, Wistar Kyoto, Brown Norway, Fischer F-344, and Buffalo. The Lewis, Brown Norway, Fischer and Sasco Holtzman rats were found to be virtually non-susceptible to LH training. Harlan SD and Buffalo rats evidenced intermediate susceptibilities of 28% and 33%, respectively. Kyoto and Charles River Holtzman rats were the most susceptible at 53% and 55%, respectively. No stock differences between control animals were observed. These results indicate that wide differences in susceptibility to LH training exist in rats from different stocks or suppliers and researchers should be careful to choose subjects from a susceptible stock. Charles River Holtzman and Wistar Kyoto rats appear to be very susceptible to LH training.

AM630 IS A COMPETITIVE CANNABINOID RECEPTOR ANTAGONIST IN THE GUINEA PIG BRAIN

AM630 has been demonstrated to be a cannabinoid receptor antagonist in the mouse brain and vas deferens. Conversely, it was recently reported that AM630 acts as a cannabinoid agonist in the guinea pig ileum. This research was designed to determine whether the difference in the action of AM630 is species specific. Studies conducted in guinea pig brain reveal that AM630 antagonizes the stimulatory effect of the cannabinoid agonist WIN 55,212-2 on [35S]GTPgammaS binding suggesting that difference in AM630 activity in different tissues is not due to species variation.

Assay of plasma cannabidiol by capillary gas chromatography/ion trap mass spectroscopy following high-dose repeated daily oral administration in humans

Plasma levels of cannabidiol (CBD) were ascertained weekly in 14 Huntingtons disease patients undergoing a double-blind, placebo-controlled, crossover trial of oral CBD (10 mg/kg/day = about 700 mg/day) for 6 weeks. The assay procedure involved trimethylsilyl (TMS) derivatization of CBD and the internal standard delta-6-tetrahydrocannabinol (THC), capillary column gas chromatography, ion trap mass spectroscopy in positive ion chemical ionization mode using isobutane, and calculations of CBD levels based on peak ion intensity of the 387 M + H peak of delta-6-THC-TMS and the 459 M + H peak of CBD-2TMS. The sensitivity of the assay was about 500 pg/ml, and the precision was about 10-15%. Mean plasma levels of CBD ranged from 5.9-11.2 ng/ml over the 6 weeks of CBD administration. CBD levels averaged 1.5 ng/ml one week after CBD was discontinued, and were virtually undetectable thereafter. The elimination half-life of CBD was estimated to be about 2-5 days, and there were no differences between genders for half-life or CBD levels. Additionally, no plasma delta-1-THC, the major psychoactive cannabinoid of marijuana, was detected in any subject.

AM630 IS AN INVERSE AGONIST AT THE HUMAN CANNABINOID CB1 RECEPTOR

The present investigation examines WIN 55,212-2 and AM630 at the cloned human cannabinoid CB1 receptor stably expressed in Chinese hamster ovary (CHO) cells. The effect of various concentrations of WIN 55,212-2 and AM630 on basal [35S]GTPgammaS binding to cell membranes was determined. WIN 55,212-2 (100 microM) stimulated basal [35S]GTPgammaS binding 77.9% with an EC50 value of 0.36 microM. Conversely, AM630 (100 microM) inhibited basal [35S]GTPgammaS binding by 20.9% with an EC50 value of 0.90 microM. These results show that WIN 55,212-2 is an agonist and AM630 is an inverse agonist in this system.

Effects of Δ8- and Δ9-Tetrahydrocannabinol on experimentally induced seizures

Abstract Effects of Δ 8 - and Δ 9 -tetrahydrocannabinol ( Δ 8 - and Δ 9 -THC) on three experimentally induced seizure models, i.e., audiogenic seizure (AS) test, maximal electroshock seizure (MES) test and pentylenetetrazol (PTZ)-induced seizure test were determined in the audiogenic rat. Both tetrahydrocannabinols possess a dose-related anticonvulsant effect against AS, MES and PTZ-induced maximal seizure. Although anticonvulsant potencies do not significantly differ, Δ 8 THC is three times more neurotoxic than Δ 9 THC. In addition, both THCs are without effect on minimal seizure and lethality induced by PTZ. Furthermore, the low protective indexes (TD50/ED50) determined in this study suggest that Δ 8 and Δ 9 THC may have poor therapeutic potentials as antiepileptic drugs.

Δ9-Tetrahydrocannabinol, EEG and behavior: The importance of adaptation to the testing milieu

Delta-9-Tetrahydrocannabinol (delta-9-THC) in doses of 0.01, 0.05, 0.1, 0.5, and 1.0 mg/kg, i.v. was administered to adult rabbits previously adapted to the testing chamber. Additionally, a group of rabbits not adapted to any part of the testing regimen was administered 1.0 mg/kg delta-9-THC. Cortical and hippocampal electroencephalographs as well as postural and activity behaviors of the unrestrained animals were recorded. In the adapted rabbits, there were dose-related increased in cortical voltage output, disruption of hippocampal theta rhythm and cortical polyspike bursts. Behaviorally, there was a dose-related tendency for standing and exploration to decrease, and at 0.5 and 1.0 mg/lh, delta-9-THC produced sprawling. In the nonadapted rabbits, administration of 1.0 mg/kh of the drug caused EEG and behavioral stimulation followed by depression of both, The results suggest that the bahavioral actions of cannabinols are largely dependent upon the animals existing state of arousal.