cannabidiol and delta-8-tetrahydrocannabinol

Plasma levels of cannabidiol (CBD) were ascertained weekly in 14 Huntington's 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.

Topics: Administration, Oral; Adolescent; Adult; Aged; Cannabidiol; Dronabinol; Female; Gas Chromatography-Mass Spectrometry; Half-Life; Humans; Huntington Disease; Male; Middle Aged

The antidepressant action of cannabis as well as the interaction between antidepressants and the endocannabinoid system has been reported. This study was conducted to assess the antidepressant-like activity of Delta(9)-THC and other cannabinoids. Cannabinoids were initially evaluated in the mouse tetrad assay to determine doses that do not induce hypothermia or catalepsy. The automated mouse forced swim (FST) and tail suspension (TST) tests were used to determine antidepressant action. At doses lacking hypothermic and cataleptic effects (1.25, 2.5, and 5 mg/kg, i.p.), both Delta(9)-THC and Delta(8)-THC showed a U-shaped dose response with only Delta(9)-THC showing significant antidepressant-like effects at 2.5 mg/kg (p<0.05) in the FST. The cannabinoids cannabigerol (CBG) and cannabinol (CBN) did not produce antidepressant-like actions up to 80 mg/kg in the mouse FST, while cannabichromene (CBC) and cannabidiol (CBD) exhibited significant effect at 20 and 200mg/kg, respectively (p<0.01). The antidepressant-like action of Delta(9)-THC and CBC was further confirmed in the TST. Delta(9)-THC exhibited the same U-shaped dose response with significant antidepressant-like action at 2.5 mg/kg (p<0.05) while CBC resulted in a significant dose-dependent decrease in immobility at 40 and 80 mg/kg doses (p<0.01). Results of this study show that Delta(9)-THC and other cannabinoids exert antidepressant-like actions, and thus may contribute to the overall mood-elevating properties of cannabis.

Topics: Animals; Antidepressive Agents; Cannabidiol; Cannabinoids; Cannabis; Catalepsy; Depression; Dose-Response Relationship, Drug; Dronabinol; Hindlimb Suspension; Hypothermia; Immobility Response, Tonic; Male; Mice; Random Allocation; Swimming

The purpose of this study was to quantify the in-vitro human skin transdermal flux of Delta8-tetrahydrocannabinol (Delta8-THC), cannabidiol (CBD) and cannabinol (CBN). These cannabinoids are of interest because they are likely candidates for transdermal combination therapy. Differential thermal analysis and in-vitro diffusion studies with human tissue were completed for the compounds. Heats of fusion, melting points and relative thermodynamic activities were determined for the crystalline compounds, CBD and CBN. Flux, permeability, tissue concentration and lag times were measured in the diffusion experiments. CBN had a lower heat of fusion and corresponding higher calculated relative thermodynamic activity than CBD. Ethanol concentrations of 30 to 33% significantly increased the transdermal flux of Delta8-THC and CBD. Tissue concentrations of Delta8-THC were significantly higher than for CBN. Lag times for CBD were significantly smaller than for CBN. The permeabilities of CBD and CBN were 10-fold higher than for Delta8-THC. Combinations of these cannabinoids with ethanol will be further studied in transdermal patch formulations in vitro and in vivo, as significant flux levels of all the drugs were obtained. CBD, the most polar of the three drugs, and other more polar cannabinoids will also be the focus of future drug design studies for improved transdermal delivery rates.

Topics: Abdomen; Cannabidiol; Cannabinol; Diffusion Chambers, Culture; Dronabinol; Humans; In Vitro Techniques; Permeability; Skin; Tissue and Organ Harvesting

One aspect of cannabinoid structure-activity relationships (SARs) that has not been thoroughly investigated is the aromatic (A) ring. Although halogenation of the side chain enhances potency, our recent observation that iodination of the A ring also enhanced activity was surprising. The purpose of this investigation was to establish the steric and electrostatic requirements at these sites of the cannabinoid molecule via molecular modeling, while determining pharmacological activity. Molecular modeling was performed using the Tripos molecular mechanics force field and the semiempirical quantum mechanical package AM1. The Ki values for novel cannabinoids were determined in a [3H]CP-55,940 binding assay and ED50 values generated from four different evaluations in a mouse model. The present studies underscore the increase in potency produced by a dimethylheptyl (DMH) side chain. Trifluoro substitutions on the pentyl side chain, or bromination of the DMH side chain, had little effect on the pharmacological activity. Any substitution at the C4 position of the aryl ring resulted in a loss of activity, which appears to be due to steric hindrances. Nitro, but not iodo, substitution at the C2 position essentially produces an inactive analog, and the drastic alteration of the electrostatic potential appears to be responsible. The altered pharmacological profile of the 2-iodo analog seems to be related to an alteration in the highest occupied molecular orbital because there is no alteration in the electron density map compared to delta 8-tetrahydrocannibinol.

Topics: Analgesics; Animals; Body Temperature; Cannabidiol; Cannabinoids; Cyclohexanols; Dronabinol; Male; Mice; Mice, Inbred ICR; Models, Molecular; Molecular Conformation; Motor Activity; Receptors, Cannabinoid; Receptors, Drug; Structure-Activity Relationship

Albumin is a major carrier of drugs and fatty acids in biological fluids. These protein-drug complexes serve to solubilize, transport these compounds to sites of action, and have been associated with increased half-life for these compounds. The authors are interested in the pH and temperature effects of the binding of delta-9-tetrahydrocannabinol to albumin. Ultrafiltration techniques were used in the separation of free to bound compounds. Cannabinoids bind to bovine serum albumin rapidly. The cannabinoid binding sites are more sensitive to temperature changes (37-47 degrees C) than changes in pH with 37 degrees C and pH 7.4 resulting in optimal binding. These conditions would result in the greatest viability in the cells, while allowing for the use of a variety of compounds in in vitro studies for the administration of compounds to isolated cells and cell lines.

Topics: Binding Sites; Cannabidiol; Cannabinoids; Cannabinol; Carrier Proteins; Chromatography, High Pressure Liquid; Dronabinol; Hydrogen-Ion Concentration; Kinetics; Serum Albumin, Bovine; Temperature; Ultrafiltration