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The co-administration of cannabinol with delta1-tetrahydrocannabinol accelerates the rate of clearance of delta1-tetrahydrocannabinol from rat blood. This increased rate of clearance appears to follow that of cannabinol. The implications of these findings are discussed.
The in vivo liver metabolism of cannabinol has been studied in the mouse and rat by combined gas chromatography and mass spectrometry. Cannabinol glucuronide was the major metabolite of cannabinol in the mouse and was accompanied by relatively large amounts of 7-hydroxycannabinol, cannabinol-7-oic acid and their corresponding glucuronide conjugates. Lower concentrations of glucuronides were found in the rat. Two series of disubstituted metabolites were found containing either a 7-hydroxyl or a 7-carboxylic acid group and a second hydroxyl group in the 1 inch-4 inch positions of the sidechain. These were of low concentration in the mouse but higher in the rat; 1 inch-hydroxy metabolites were particularly abundant in the latter species. Also found in the rat livers were small amounts of sidechain monohydroxy metabolites and larger quantities of 4 inches, 5 inches-bisnorcannabinol-3 inches-oic acid; these were absent in the mouse. The metabolites were identified using the trimethylsilyl (TMS), [2H9] TMS and methyl ester-TMS derivatives, and by reduction of acid metabolites with lithium aluminium deuteride to the corresponding alcohols.
Elfazepam (7-chloro-1-[2-(ethylsulfonyl)ethyl]-5-(2-fluorophenyl)-1,3-dihydro-2H-1,4benzodiazepin-2-one) and-9-aza-cannabinol )10 hydroxy-beta-(3-methyl-2-octyl)-5',5-dimethyl-5H-1 benzopyranol 3,4-d pyridine, HC1) were administered IV to study their effects on feed intake and acid secretion in abomasal Pavlov pouches in sheep. Elfazepam and 9-aza-cannabinol increased 3-fold 3 hr postinjection feed intake and decreased abomasal acid secretion compared to saline and DMSO (dimethyl sulfoxide) control treatments. At doses which elicit feeding, 9-aza-cannabinol was a much more potent inhibitor of acid secretion than elfazepam. These results are consistent with the theory of localized hypothalamic nuclei which have roles in the control of both feed intake and gastric acid secretion. However, in contrast to feeding associated with normal hunger, the benzodiazepine and cannabinol stimulated feeding is associated with decreased gastric acid secretion.
The ability of cannabinol and delta-8-tetrahydrocannabinol (delta-8-THC), two cannabinoid marihuana components, to modify delayed-type hypersensitivity (DTH) to sheep red blood cells (SRBC) was investigated in mice. Reduction of DTH reactivity by cannabinol required multiple, daily, postimmunization drug administration. Neither multiple preimmunization dosings nor a single postimmunization dosing was effective. Delta-8-THC produced moderate (13-33%) suppression of DTH reactivity only upon multiple, preimmunization treatments, whereas postimmunization administration only delayed peak DTH reactivity 24 hours without altering the absolute response level. These results indicate that delta-8-THC and cannabinol possess slight to moderate activity in the suppression of DTH.
The butyl homologues of delta1-tetrahydrocannabinol, delta1-tetrahydrocannabinolic acid, cannabinol and cannabidiol have been identified in several samples of cannabis. 8 samples contained delta1-tetrahydrocannabinolic acid, one sample contained cannabinol and one sample contained both cannabinol and cannabidiol. Separation by gas chromatography and identification by gas chromotography-mass spectrometry was achieved by the preparation of trimethylsilyl, d9-trimethylsilyl, triethylsilyl and tri-n-propylsilyl derivatives.
Stable cyclic methyl- and n-butylboronates were prepared from the cannabinolic acids and used as derivatives for the characterization of these compounds by combined gas chromatography mass spectrometry. Retention times of the methylboronates were comparable with those of the trimethylsilyl derivatives. The mass spectra of these derivatives were more characteristic of the cannabinoid skeleton than were the spectra of the trimethylsilyl derivatives where fragmentation was associated with the trimethylsilyl groups. Molecular weights were lower and abundant molecular ions were obtained. These derivatives also offered the possibility of distinguishing between isomeric cannabinolic acids where only isomers possessing adjacent phenolic and carboxylic functions form cyclic boronates.
Six acidic metabolites were isolated from rat faeces and identified by gas chromatographymass spectrometry and proton magnetic resonance. Cannabinol-7-oic acid was the most abundant acidic metabolite isolated. Others present in decreasing order of prominence were 1"-hydroxy-, 4"-hydroxy-, 3"-hydroxycannabinol-7-oic acid, cannabinol-3"-one-7-oic acid and 2"-hydroxycannabinol-7-oic acid.
Nabilone is a modified cannabinol derivative with central nervous system activity. Administration of nabilone in single doses of 1 to 5 mg results in dose-related pharmacologic effects in man. One and 2.5 mg doses of nabilone induced relaxant and sedative effects in all subjects. No euphoria, dry mouth, tachycardia, or postural hypotension was seen after 1 mg, minimal effects were seen after 2.5 mg, and marked effects were seen after 5 mg. Effects were evident within 60 to 90 min and persisted for 8 to 12 hr. Nabilone produced no significant tachycardia. There were no changes in supine blood pressure; however, marked postural hypotension occurred after the 5-mg dose. The administration of nabilone at doses of 1 mg or 2 mg two times daily resulted in euphoria and dry mouth during the first two days of drug; thereafter tolerance developed to these effects but there was no apparent decrease in relaxation. Subjects challenged with a single 5-mg dose of nabilone showed a 66% reduction in symptoms and signs after the 7-day drug period compared to that of the same dose after 1 wk of placebo. Comparison of nabilone with other cannabinol derivatives suggests that some of the undesirable pharmacologic effects can be separated within the group.
Fifty-five clinical trials were conducted to determine the cardiovascular combined effects of stressful oral surgery and systemic cannabinols. In a first study, delta9-tetrahydrocannabinol (THC) was given IV as a premedicant and compared with diazepam and with a placebo. A classic dose-related tachycardia followed THC injection. The peak heart rate response of patients premedicated with 0.044 mg/kg THC was 24.1% higher (p less than 0.05) than the peak effect for a nonsurgerized control group, suggesting a synergistic effect between THC and surgical stress. A predisposition to syncopal hypotension followed THC premedication, and antiarrhythmic effects were observed after large doses. The injection of local anesthetic preparations containing epinephrine did not alter THC cardiovascular response. An apparent drug interaction was observed, however, in a second study, in patients given general anesthesia within 72 hours after smoking marijuana. These patients demonstrated sustained abnormal postoperative tachycardia when compared with control nonsmokers, an effect which may have resulted from an interaction between stored cannabinol metabolites and atropine administered as part of the anesthetic technic. It was concluded that THC had no particular advantage over diazepam or placebo as a premedicant. Further, THC altered the patients' adaptivity to stress and interacted undesirably with other anesthetic medications.
An antiserum raised in sheep against a conjugate of tetrahydrocannabinol with bovine serum albumin has been used as the basis of a radioimmunoassay for cannabinoids in the blood of rabbits given tetrahydrocannabinol, 11-hydroxy-tetrahydrocannabinol, cannabinol or cannabidiol by rapid intravenous injection. In the case of both 11-hydroxy-tetrahydrocannabinol and cannabinol plasma cannabinoid concentrations fell exponentially from an initial peak plasma level attained immediately after the completion of intravascular distribution of the injected bolus. In the case of tetrahydrocannabinol itself, however, there was a progressive rise in plasma cannabinoid concentration between five and fifteen minutes after the rapid intravenous injection. The reasons for this rise in plasma cannabinoid concentration are discussed.
Partially purified glucuronyltransferase immobilized on beaded sepharose has been used to synthesize the glucuronide conjugates of cannabinol, cannabidol, delta9-tetrahydrocannabinol and delta8-tetrahydrocannabinol. Trimethylsilylated methyl esters and per(trimethylsilyl) derivatives of these conjugates have been characterized by their gas chromatographic retention times and their electron impact and ammonia chemical ionization mass spectra.
The feed intake stimulants elfazepam (E), a benzodiazepine, and 9-aza-cannabinol (9-AC) decrease rumen contractions and abomasal acid content in sheep and E increases rumen fluid volume, digestibility and overall nutrient availability. E has been hypothesized to decrease the propulsive activity of the entire GI tract. To further examine the effects of E and 9-AC on gastric function, 4 ewes were prepared with abomasal cannulas and 3 silver/silver chloride monopolar electrodes alternated with 2 strain gauges on the distal one-third of the abomasal serosa. Electromyographical (slow waves and action potentials) and contractile (rates and forces) activities and abomasal pH were measured. Treatment of 8 and 16 mg E had no effect on slow wave frequency, action potential rate, contraction rate, or contraction force. Abomasal content pH was decreased with 8 mg E. Treatments of 125 and 250 microgram 9-AC depressed action potential and contraction rates and contraction force but had no effect on slow wave frequency or pH.
Cannabinol (CBN) was metabolized in vitro by a 10,000 g supernatant from rat liver. After removal of unchanged CBN and its monohydroxylated metabolites four dihydroxylated metabolites were isolated. By nuclear magnetic resonance and mass spectrometry the compounds were identified as 1'',7-dihydroxy-CBN. Side chain hydroxylation occurred predominantly at C-4'' anc C-3''.
The in vivo transformation of cannabinol (CBN) in the rat has been studied. Unchanged CBN and nine neutral mono-oxygenated and dioxygenated CBN metabolites have been identified. In the mono-oxygenated series the metabolites occurred in decreasing order of prominence as follows: 7-hydroxy-CBN, 4''-hydroxy-CBN, 1''-hydroxy-CBN, 2''-hydroxy-CBN, 3''-hydroxy-CBN, 5''-hydroxy-CBN and CBN-7-al. In the dihydroxylated metabolite series only 1'',7-dihydroxy-CBN and 4'',7-dihydroxy-CBN were found with the former as the more prominent metabolite.
delta1-tetrahydrocannabinol (THC) elicited a dose-dependent (1, 5, 10 mg/kg) depression of the immune response, of immature mice, stimulated with sheep red blood cells. The impairment of humoral immunity was specific for THC but not for cannabidiol at 25 mg/kg or cannabinol at 25 mg/kg. The mice were given four daily doses (i.p.) of either drug or vehicle (Tween 80-propylene glycol in 1% saline) or a single injection (i.p.) of sheep red blood cells in addition to four daily doses (i.p.) of drug or vehicle. Suppression of the antigenic response by THC was reflected as a reduction of splenic weight, reduction in the number of splenic antibody-forming cells, lowered hemagglutination titer and reduction in the percentage of splenic white pulp of total spleen volume.
Oral doses of delta-9-tetrahydrocannabinol (THC) 20 mg, combined with placebo or with 40 mg dses of cannabinol (CBN) and cannabidiol (CBD), were given to volunteers. The combination of THC with CBN produced no detectable changes in the quality, intensity, or duration of the effects of THC alone. The THC-CBD combination tended to delay onset and prolong effects of THC, while making them somewhat more intense. Even this interactive effect was slight, providing no reason to abandon the current practice of basing doses of marihuana for clinical studies solely on THC content.
Marijuana, long used for the euphoria which results, recently has been found to stimulate hunger in humans but in several laboratory animals cannabinoids decrease food intake. Sheep, relatively more sensitive to chemicals that affect food intake, were injected IV with the d-and l-isomers of tetrahydrocannabinol and with a 9-aza-cannabinol) 9-AC) (8-(1,2-dimethylheptyl)-5,5-dimethyl-5H-[1]benzopyranol[3,4]pyridin-10-01, HCL) and feeding behavior was monitored. In the first 30 min, food intake was increased by the l-isomer and by 9-AC but not affected by d-delta 9-THC. After 24 h, feed intake was decreased by at least one dose of d-and l-delta 9-THC and 9-AC. The l-but not d-isomer was active at very low doses compared with doses used in many laboratory animals.
The pharmacological activities of delta9-THC [(minus)-delta9-trans-tetrahydrocannabinol], CBN (Cannabinol) and mixtures of delta9-THC + CBN were studied in rabbits, rats and mice. CBN, although in general less active, mimicked the effects of delta9-THC in several pharmacological tests: corneal arreflexia in rabbits; climbing rope, open-field, irritability and aggressiveness after REM sleep deprivation in rats; catatonia, analgesia and sleeping time in mice. When the mixture delta9-THC + CBN was used, a synergistic effect occurred on most of the depressant effects. On the other hand CBN did not interfere with or slightly inhibited the excitatory effects of delta9-THC. In the one peripheral test used, CBN did not alter the delta9-THC effect.