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PubMedDate not supplied

Testing human hair for Cannabis. III. rapid screening procedure for the simultaneous identification of delta 9-tetrahydrocannabinol, cannabinol, and cannabidiol.

delta 9-Tetrahydrocannabinol (THC), cannabidiol (CBD), and cannabinol (CBN) are three constituents of the 16 that can be currently isolated from some Cannabis spp plants. Their identification in decontaminated hair can indicate exposure to cannabis. In this study, we propose a rapid, simple, and direct (without derivatization) screening procedure for the simultaneous identification and quantitation of CBD, CBN, and THC in hair of chronic cannabis abusers. Hair samples were washed with methylene chloride, hydrolyzed with sodium hydroxide, extracted with n-hexane-ethyl acetate (9:1, v/v), evaporated to dryness, and injected directly on a gas chromatographic-mass spectrometric system operating in electron-impact mode. THC-d3 was used as the internal standard. Thirty hair samples were tested. CBD was detected 23 times, CBN was detected 22 times, and THC was detected five times. Concentrations ranged from 0.03 to 3.00 ng/mg (mean, 0.44 ng/mg), from 0.01 to 1.07 ng/mg (mean, 0.13 ng/mg), and from 0.1 to 0.29 ng/mg hair (mean, 0.15 ng/mg) for CBD, CBN, and THC, respectively. These results show that this new screening procedure is suitable for the detection of CBD and CBN in the hair of cannabis abusers.

Adolescent↗
PubMed1977

Dihydroxylated metabolites of cannabinol formed by rat liver in vitro.

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''.

Animals↗
PubMed1977

Neutral in vivo metabolites of cannabinol isolated from rat faeces.

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.

Animals↗
PubMed1980

Identification of in vivo liver metabolites of delta 1-tetra-hydrocannabinol, cannabidiol, and cannabinol produced by the guninea-pig.

The metabolites of delta 1-tetrahydroannabinol (delta 1-THC), cannabidiol (CBD), and cannabinol (CBN) produced in vivo by the guinea-pig have been studed by combined gas-liquid chromatography-mass spectrometry, 45 metabolites of delta 1-THC were identified of which 12 have not been reported before. Several other metabolites were detected but not identified. The major metabolic routes involved allylic and aliphatic hydroxylations, oxidations to ketones and acids, oxidative degradation of the side-chain presumably by the beta-oxidation pathway, and formation of glucuronide conjugates. Di- and tri-substituted metabolites were abundant. The metabolism differed considerably from that observed in mouse and rat in that 1''- and 6 beta-hydroxylation and oxidation degradation of the side-chain were major metabolic pathways. 1''-Hydroxy-delta 1-THC was found as a pair of diasteroisomers. Similar metabolic pathways were observed with CBD; twenty metabolites were identified of which two were new. Only 6 metabolites of CBN were identified. These mainly mono-substituted in the same positions as were observed with delta 1-THC and CBD.

Animals↗
PubMed2002

Cannabinol enhancement of interleukin-2 (IL-2) expression by T cells is associated with an increase in IL-2 distal nuclear factor of activated T cell activity.

It has been demonstrated previously that cannabinol (CBN) differentially modulates interleukin-2 (IL-2) protein secretion by T cells with a corresponding change in extracellular signal-regulated kinase activity. The objective of the present studies was to further investigate the molecular mechanism by which CBN enhances IL-2 gene expression using the EL4 T cell line. We demonstrate here that steady-state IL-2 mRNA expression was significantly enhanced by CBN in a concentration-dependent manner in EL4 cells activated with suboptimal concentrations of phorbol-12-myristate-13-acetate (2-10 nM). Concordantly, a marked increase was observed in nuclear factor of activated T cells (NF-AT) DNA binding activity to the IL-2 distal NF-AT site, but not to nuclear factor for immunoglobulin kappa chain in B cells or activator protein 1 motifs. Transient transfection of EL4 cells with a reporter gene under the control of multiple IL-2 distal NF-AT motifs exhibited increased transcriptional activity by CBN in suboptimally activated cells. In addition, the CBN-mediated enhancement of IL-2 protein secretion and the transcriptional activity of the IL-2 distal NF-AT reporter gene was abrogated by the calcium/calmodulin-dependent protein kinase inhibitor KN93, but not by the CB2 receptor antagonist SR144528. Enhancement of IL-2 was also demonstrated with CP55940, Delta(9)-tetrahydrocannabinol, and cannabidiol, thus suggesting that the phenomenon is not unique to CBN. Collectively, these results suggest that increased IL-2 secretion by CBN is mediated through the enhancement of IL-2 gene transcription by activation of NF-AT in a CB1/CB2-independent manner.

Amino Acid Motifs↗
PubMed1990

Effects of delta-9-tetrahydrocannabinol, cannabinol and cannabidiol, alone and in combinations, on luteinizing hormone and prolactin release and on hypothalamic neurotransmitters in the male rat.

The acute effects of low oral doses of delta 9-tetrahydrocannabinol (THC), cannabinol (CBN) and cannabidiol (CBD) administered alone or in combinations on LH and prolactin (PRL) secretion and on hypothalamic norepinephrine (NE), dopamine (DA) and serotonin (5-HT) dynamics were examined in adult male rats. Plasma LH levels were significantly reduced 60 min after administration of 0.5 mg THC/kg body weight and 30, 60 and 120 min after administration of THC + CBN or THC + CBD. There were no changes in plasma PRL in response to cannabinoid treatments. The turnover of NE in both the median eminence (ME) and medial basal hypothalamus (MBH) was dramatically affected by all the cannabinoid treatments. Complete suppression of NE turnover occurred 30 min post-THC and 120 min post-THC + CBN in the ME and 120 min post-THC + CBD in the MBH. Cannabinoids did not significantly affect DA turnover in the MBH or the content of NE, DA, 5-HT or 5-hydroxyindole-3-acetic acid in either the ME or MBH. These data demonstrate that treatment of adult male rats with a low dose of THC suppresses LH secretion and that CBN and CBD potentiate this action of THC. Although the mechanisms responsible for the inhibition of LH release by cannabinoids cannot be positively identified from these experiments, the results suggest that alterations in hypothalamic noradrenergic activity may be involved in this effect.

Animals↗
PubMed1977

delta1-tetrahydrocannabinol, cannabidiol and cannabinol effects on the immune response of mice.

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.

Animals↗
PubMed1983

Effects of delta 9-tetrahydrocannabinol, cannabinol and cannabidiol on the immune system in mice. II. In vitro investigation using cultured mouse splenocytes.

The effects of the cannabinoids, delta 9-tetrahydrocannabinol (THC), cannabinol (CBN) and cannabidiol (CBD), on the primary-like immune response were investigated in primary cultures of mouse splenocytes. Splenocyte cultures were stimulated with sheep erythrocytes in vitro and incubated with cannabinoids for the first 24 h after antigenic stimulation (prior to initiation of DNA synthesis), from 24 h to 6 days after antigenic stimulation, and for the entire 5-day period. THC (1 and 5 microM) and CBD (5 microM) depressed the primary-like immune response of stimulated mouse splenocytes when incubated for the first 24 h after antigenic stimulation and the entire 6-day culture period. CBN did not show any measurable suppression of the primary-like immune response. Treatment of splenocyte cultures with cannabinoids after the first 24 h after antigenic stimulation showed no impairment of the in vitro primary-like immune response.

Animals↗
PubMed2004

Human skin permeation of Delta8-tetrahydrocannabinol, cannabidiol and cannabinol.

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.

Abdomen↗
PubMed1995

Synthesis and pharmacological effects in mice of halogenated cannabinol derivatives.

Eight halogenated derivatives of cannabinol (CBN) substituted on the aromatic ring at the 2 and/or 4 position were synthesized and their pharmacological effects were evaluated by intracerebroventricular injection (50 micrograms/mouse) in mice, using hypothermia, pentobarbital-induced sleep prolongation, catalepsy and anticonvulsant effect as indices. The hypothermic effects of monohalogenated derivatives of CBN were comparable to that of CBN, whereas the effects of dihalogenated derivatives of CBN except for the fluorinated derivative were attenuated. In the interaction with pentobarbital, two monochlorinated derivatives exhibited a significant prolongation of sleeping time, although other derivatives did not significantly affect the sleeping time. The cataleptogenic effects of monofluoro- and 4-bromo-CBN were stronger than that of CBN. 4-Bromo-CBN exhibited a significant prolongation of seizure latency induced by pentylenetetrazol. These data suggest that halogenation of CBN modifies the pharmacological profile of the cannabinoid.

Animals↗
PubMed1999

Cannabinol-mediated inhibition of nuclear factor-kappaB, cAMP response element-binding protein, and interleukin-2 secretion by activated thymocytes.

Cannabinol (CBN), an immunosuppressive cannabinoid and ligand for the peripheral cannabinoid receptor CB2, inhibits the cAMP signaling cascade in forskolin-stimulated thymocytes. The objective of the present studies was to further characterize the mechanism of CBN immune modulation by investigating its effects on interleukin-2 (IL-2) secretion, cAMP response element (CRE), and kappaB DNA binding activity in phorbol ester (phorbol-12-myristate-13-acetate, PMA) plus calcium ionophore (PMA/Io)-activated thymocytes. PMA/Io treatment induced CRE and kappaB DNA binding activity that was attenuated in the presence of CBN. A concomitant and concentration-related inhibition of IL-2 also was produced by CBN in PMA/Io-activated thymocytes. PMA/Io induced two CRE DNA binding complexes, a major complex consisting of a cAMP response element-binding protein (CREB)-1 homodimer, and a minor CREB-1/activating transcription factor (ATF)-2 complex. Both CRE complexes were inhibited by CBN. Conversely, two kappaB DNA binding complexes were observed, but only one was PMA/Io-inducible. However, the DNA binding activity of both complexes was diminished in the presence of CBN. The PMA/Io-inducible kappaB complex was a p65/c-Rel heterodimer. Analysis of up-stream regulation revealed a decrease in phosphorylated CREB/ATF nuclear proteins in PMA/Io-activated thymocytes after CBN treatment. Similarly, CBN prevented the phosphorylation-dependent degradation of the nuclear factor-kappaB inhibitory protein IkappaB-alpha. These results provide a potential link between the CBN-mediated inhibition of thymocyte function, including IL-2 production, and the inhibition of two critical transcription factor families, CREB/ATF and NF-kappaB/Rel.

Activating Transcription Factor 1↗
PubMed1975

Interactions in man of delta-9-tetrahydrocannabinol. II. Cannabinol and cannabidiol.

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.

Adult↗
PubMed1979

Cannabinols and feeding in sheep.

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.

Animals↗
PubMed1975

Pharmacologic interaction between cannabinol and delta9-tetrahydrocannabinol.

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.

Aggression↗
PubMed1977

The effect of delta 9-tetrahydrocannabinol, cannabidiol, and cannabinol on the anaesthesia induced by various anaesthetic agents in mice.

delta 9-Tetrahydrocannabinol (2.5-80.0 mg/kg) significantly prolonged the anaesthesia induced by ketamine, pentobarbitone, thiopentone, propanidid, and Alfathesin in a dose-dependent manner. Cannabinol and cannabidiol (both 5.0-80.0 mg/kg) were essentially inactive, except that cannabidiol prolonged pentobarbitone-induced anaesthesia. The interaction of delta 9-tetrahydrocannabinol with the anaesthetic agents was postulated to be due to a centrally mediated action, whereas the effect of cannabidiol on pentobarbitone-induced anaesthesia probably depended on a metabolic interaction. The interaction between the cannabinoids in influencing anaesthesia induced by the above agents was examined, and the interactions were found to be complex.

Alfaxalone Alfadolone Mixture↗
PubMed1976

Minor components of cannabis resin. VI. Mass spectrometric data and gas chromatographic retention times of components eluted after cannabinol.

Minor components of cannabis resin with longer retention times than that of cannabinol have been analyzed by use of a combined gas chromatograph-mass spectrometer-computer system. The presence of 30 such components has been detected. The data obtained indicate that some of the components are hydroxy derivatives of cannabinoids related to olivetol.

Cannabis↗
PubMed2005

Cannabinol delays symptom onset in SOD1 (G93A) transgenic mice without affecting survival.

Therapeutic options for amyotrophic lateral sclerosis (ALS), the most common adult-onset motor neuron disorder, remain limited. Emerging evidence from clinical studies and transgenic mouse models of ALS suggests that cannabinoids, the bioactive ingredients of marijuana (Cannabis sativa) might have some therapeutic benefit in this disease. However, Delta(9)-tetrahydrocannabinol (Delta(9)-THC), the predominant cannabinoid in marijuana, induces mind-altering effects and is partially addictive, compromising its clinical usefulness. We therefore tested whether cannabinol (CBN), a non-psychotropic cannabinoid, influences disease progression and survival in the SOD1 (G93A) mouse model of ALS. CBN was delivered via subcutaneously implanted osmotic mini-pumps (5 mg/kg/day) over a period of up to 12 weeks. We found that this treatment significantly delays disease onset by more than two weeks while survival was not affected. Further research is necessary to determine whether non-psychotropic cannabinoids might be useful in ameliorating symptoms in ALS.

Age Factors↗
PubMed1975

Effects of delta9-tetrahydrocannabinol and cannabinol in man.

The interaction of delta9-tetrahydrocannabinol (delta9-THC) and cannabinol (CBN) was studied in man. Five male volunteers were given placebo, 50 mg CBN, 25 mg delta9-THC, 12.5 mg delta9-THC + 25 mg CBN, and 25 mg delta9-THC + 50 mg CBN (orally). Administrations were spaced 1 week apart. With physiological measures, delta9-THC produced an increase in heart rate while CBN did not. When combined, no change of the delta9-THC effect occurred. No changes occurred on the electrocardiogram, blood pressure, or body temperature. With psychophysical measures no changes occurred in pain thresholds or skin sensitivity as a function of drug treatment. In time estimates of the passage of 1 minute, delta9-THC alone produced underestimates of the passage of 1 minute and CBN alone had no effect. In combination the two drugs had a tendency to produce significant overestimates and underestimates of the passage of 1 minute. On a 66-item adjective-pair drug reaction scale, the volunteers reported feeling drugged, drunk, dizzy, and drowsy under the delta9-THC condition, but not under the CBN condition. With combined drug treatment, volunteers reported feeling more drugged, drunk, dizzy, and drowsy than under the delta9-THC condition alone. None of the drug treatments produced significant changes on other items which included items on perception, emotion, cognition and sociability. It appears that CBN increases the effect of delta9-THC on some aspects of physiological and psychological processes, but that these effects are small and cannot account for the greater potency which has been reported when plant material is used.

Administration, Oral↗