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The three main cannabinoids--cannabidiol (CBD), tetrahydrocannabinol (THC) and cannabinol (CBN)-can be isolated from purified extract of cannabis by preparative gas chromatography in satisfactory amounts and with a degree of purity similar to that of the sample substances provided by the United Nations Narcotics Laboratory.
A capillary GC method for the simultaneous determination of cannabidiol (CBD), tetrahydrocannabinol (THC), and cannabinol (CBN) in cannabis is described. The major components in cannabis were extracted with chloroform. After being concentrated by evaporation, the residue was dissolved in methanol. The resulting solution was used for analysis. The conditions for determination were: FID detector, HP-5 capillary column, 10 m x 0.53 mm x 2.65 microns film, column temperature 220 degrees C. The recoveries of the three major components were 97.3%-104.0%(CBD), 97.3%-106.6%(THC) and 95.3%-102.4% (CBN). The coefficients of variation are less than 3%. The limit of detection for the three components was 0.2 mg/L, and their linearity was in the range of 20-120 mg/L. Identification of each component was achieved by comparison of retention times with the standards. This method has the advantages of simplicity, rapidity, sensitivity and accuracy.
The effects of four cannabinoids on the physical properties of brain synaptic plasma membranes (SPM), lipid extracts of SPM and phospholipid vesicles were evaluated using fluorescence probes. In vitro, the psychoactive cannabinoids, delta 9-tetrahydrocannabinol (delta 9-THC) and 11-hydroxyl-delta 9-tetrahydrocannabinol (11-OH-delta 9-THC) at concentrations of 1 and 3 microM decreased polarization of the fluorescence emission of 1,6-diphenyl-1,3,5-hexatriene (DPH) in SPM. At the same concentrations, cannabidiol (CBD) and cannabinol, cannabinoids devoid of marijuana-like psychoactivity, had no effect on DPH polarization. The effects of 11-OH-delta 9-THC and CBD on vesicles made from lipids extracted from SPM were identical to their effects on intact SPM. These changes in DPH polarization were not due to changes in fluorescence lifetime and indicate that, at low concentrations, the psychoactive cannabinoids increase the rotational mobility of DPH in the membrane core. In contrast, in SPM-extracted lipids, both 11-OH-delta 9-THC and CBD decreased the mobility of stearic acid with an anthroyloxy label at both the second (2-AS) and twelfth (12-AS) carbon atoms. Studies of DPH polarization in various phosphatidylcholines (PC) demonstrated that the actions of the cannabinoids were dependent on initial bilayer fluidity. 11-OH-delta 9-THC was less effective at decreasing polarization of trimethylammonium DPH (TMA-DPH), a probe of the bilayer surface, than of DPH whereas CBD affected mobility of the two probes equally. Neither CBD nor 11-OH-delta 9-THC altered DPH mobility in phosphatidylethanolamine, phosphatidylserine vesicles. These findings indicate that the psychoactive cannabinoids increase fluidity in the hydrophobic core of brain membranes and support a membrane perturbant hypothesis of the mechanism of delta 9-THC action.
The cytogenetic effects of delta 9-tetrahydrocannabinol (THC) and cannabinol (CBN) (10 mg/kg) were investigated in hybrid mice of genotype (C57BL x C3H)F1. Mice were treated for 5 consecutive days with the specific cannabinoid; 16 days after the last treatment the meiotic cells were evaluated. Analysis of the spermatocyte bivalents at the first meiotic metaphase failed to reveal any numerical or structural abnormality. Contrary to previous reports we failed to find any major meiotic abnormalities associated with THC and CBN treatments. There was no evidence of ring or chain figures. The centromeric banding procedure (C banding) was used to support observations of Giemsa stained cells. It has previously been reported that cannabinoids suppress the incorporation of 3H-uridine into pachytene spermatocytes and round spermatids; the absence of chromosome aberrations in the present study suggests that an adverse effect appears to be present, but may be at a level other than cytogenetic.
The combined use of high-pressure liquid chromatography (HPLC) and high-resolution gas-liquid chromatography (GLC) afforded a means of isolating three substances in samples of cannabis, of determining their retention times in HPLC and in GLC with and without derivation, and of identifying them, by comparison with the data in the literature, with the three major constituents of cannabis: cannabidiol (CBD), delta-9-tetrahydrocannabinol (delta-9-THC) and cannabinol (CBN), without using either control substances or a mass spectrometer. Furthermore, calculation of the peak area ratios (formula: see text); for the different sample varieties can serve as a criterion for the differentiation of resinous cannabis and textile cannabis.
In order to detect hashish intake, urine, blood and serum were analysed for the main components of hashish, i.e., tetrahydrocannabinol (THC), cannabidiol, cannabinol and the decomposition product of THC, THC-carboxylic acid. After extraction and silylation, the samples were analysed by gas chromatography-mass spectrometry with multiple ion detection. The Emit-st-system is used as a pretest for urine.
In order to gain information about the topology of the brain cannabinoid receptor (CB1), a Receptor Steric (RS) Map for cannabinoids at this receptor was calculated. The classical cannabinoids (-)-11-hydroxy-delta-9-tetrahydrocannabinol (K1 = 210 +/- 56 nM), (-)-9-nor-9-beta-hydroxy-hexahydrocannabinol (K1 = 124 +/- 17 nM), nabilone (K1 = 120 +/- 13 nM), and the non-classical cannabinoid, CP-55,244 (K1 = 1.4 +/- .3 nM) were used as template molecules. The RS map was obtained as the union of the van der Waals' volumes of only those accessible conformers identified by MMP2 calculations that were able to clear a region of steric interference at the CB1 receptor previously characterized by us [Reggio, P.H., Panu, A.M. and Miles, S. (1993), J. Med. Chem., 36, 1761-1771]. The utility of the RS Map was explored by screening the accessible conformers of the classical cannabinoid, cannabinol (CBN), (K1 = 3200 +/- 450 nM), for its ability to fit within the RS map. Only the global minimum energy conformer of CBN (53.2% abundance at 298K) was able to fit within the RS map. These results imply that one reason for the reduced affinity of CBN may be that only 53.2% of CBN molecules are shaped properly to fit in the binding pocket for cannabinoids at the CB1 receptor.
Glucuronide conjugates of cannabidiol (CBD), 7-hydroxy-CBD, propyl-CBD, cannabinol (CBN), 7-hydroxy-CBN, CBN-7-oic acid, propyl CBN and cannabichromene have been identified as major metabolites of CBD, CBN and their propyl homologues and of cannabichromene in mouse liver. Trace amounts of the glucuronide conjugates of delta1- and delta1(6)-tetrahydrocannabinol (THC) were also detected. Identification was made by combined gas-liquid chromatographic and mass spectrometric studies of the trimethylsilyl (TMS), d9-TMS and methyl ester-TMS derivatives of the glucuronides and the TMS derivatives of the product of the reduction of the metabolites with lithium aluminium deuteride.
The 11-oic acid metabolites of delta-9-tetrahydrocannabinol (THC), cannabinol (CBN), and cannabidiol (CBD) can be identified presumptively in human urine using standard thin layer chromatographic procedures. Other acidic metabolites are also excreted but these are not yet identified. These acidic metabolites appear in urine soon after exposure but persist for at least 48 to 72 hours. Such long persistence does not permit their detection to be used for forensic purposes. Using only simple chemical methods, we have been able to identify presumptively the 11-oic acids of THC, CBN and CBD in the urine of persons taking these materials. A sequential thin-layer chromatography system we have devised provided the basis for this first report of such isolation without the use of labeled drug or mass spectrometric methods.
Pigeons, trained to discriminate the effects of i.m. injections of delta9-tetrahydrocannabinol (delta9-THC, 0.25 mg/kg) from the effects of the vehicle in a drug discrimination paradigm, were tested for generalization with the isomeric delta8-THC, cannabidiol (CBD) and cannabinol (CBN). When given in sufficient doses, delta8-THC and CBN were found to substitute for delta9-THC whereas CBD did not. CBD and CBN did not antagonize the stimulus effect of delta9-THC. The combination of CBN and delta9-THC rather appeared to accentuate the drug response.
Systemic administration of cannabinoids decreases intraocular pressure (IOP). To determine whether the mechanism of action originates in the central nervous system, we administered various cannabinoids into the cerebral ventricles of conscious New Zealand albino rabbits. When delta 9-tetrahydrocannabinol (delta 9-THC), delta 8-tetrahydrocannabinol, cannabinol, and cannabidiol were given intravenously, only delta 9-THC produced dose-dependent ocular hypotension and miosis. Bolus administration into the cerebral ventricles or ventriculocisternal perfusion of delta 9-THC did not change IOP or pupil size. In urethane-anesthetized rabbits, IOP and blood pressure were lowered by intravenous administration of delta 9-THC but not by bolus cerebral administration. These observations indicate that the action of cannabinoids on IOP does not originate in the central nervous system. Alteration of blood pressure may be involved in the mechanism of ocular hypotension induced by delta 9-THC.
The concentration of delta-9-tetrahydro-cannabinol in marijuana available in the United States has increased by 250% since investigations of the effects of marijuana on short-term memory first appeared in scientific journals. Moreover, previous investigations of short-term memory in long-term marijuana smokers involved adults only. We evaluated the auditory/verbal and visual/spatial memory of 10 cannabis-dependent adolescents and compared the results with performance of 17 subjects in two control groups. The control groups included 8 adolescent drug abusers who had not been long-term users of cannabis and another 9 adolescents who had never abused any drug. All three groups were matched on age, IQ, and absence of previous learning disabilities. Adolescents with a history of frequent alcohol or phencyclidine abuse were excluded from entering the study. A battery of seven neuropsychological tests was administered initially to all subjects and a parallel test battery was administered 6 weeks thereafter. Significant differences between the cannabis-dependent group and the two control groups were obtained initially on the Benton Visual Retention Test (F[2,24] = 6.07) and the Wechsler Memory Scale Prose Passages (F[2,23] = 7.04). After 6 weeks of supervised abstention from intoxicants, subjects in the cannabis-dependent group showed some significant improvement on the Wechsler Memory Prose Passages score and on the Benton Visual Retention Test; however, the improvement failed to achieve statistical significance. We concluded that cannabis-dependent adolescents have selective short-term memory deficits that continue for at least 6 weeks after the last use of marijuana.
A critical review of applications for the period 2000-2003, taken from the Web of Knowledge database, of the techniques high performance liquid chromatography-electrospray ionisation-mass spectrometry (HPLC-ESI-MS) and capillary electrophoresis-electrospray ionisation-mass spectrometry (CE-ESI-MS) to the detection and determination of small molecules of significance in clinical and forensic science is presented. The molecules of mass less than 500 Da are chosen according to selected structural classes in which they give ESI signals primarily as [M+H](+) ions although other ions such as [M-H](-), [M+Na](+) and [M+NH(4)](+) are also reported. The structural classes are drugs with amine-containing side chains, drugs with N-containing saturated ring structures, 1,4-benzodiazepines, carbohydrates, benzimidazoles, other heterocycles, sulphonylureas, anthracyclines, sulphonamides, penicillins, cephalosporins, tetracyclines, nitrocatechols, steroids, flavonoids, oxazaphosphorines, cannabinols, and miscellaneous molecules. Details are given on the fragmentations, where available, that these ionic species exhibit in-source and in ion-trap, triple quadrupole and time-of-flight mass spectrometers. The review then gives a critical evaluation of these recent HPLC-ESI-MS and CE-ESI-MS analytical methods for the detection and determination of small molecules of clinical and forensic significance. Analytical information on, for example, sample concentration techniques, HPLC and CE separation conditions, recoveries from biological media and limits of detection (LODs) are provided.
A critical review of applications for the period 2000-2004, taken from the Web of Knowledge database, of the technique capillary electrophoresis-electrospray ionisation-mass spectrometry (CE-ESI-MS) in drug analysis is presented. The review is concerned with molecules of mass less than 500 Da, chosen according to selected structural classes in which they give ESI signals primarily as [M+H](+) ions although other ions, such as [M-H](-), [M+Na](+), and [M+NH(4)](+), are also reported. These structural classes are drugs with amine-containing side chains, drugs with N-containing saturated ring structures, 1,4-benzodiazepines, other heterocyclic hypnotics, carbohydrates, sulphonylureas, anthracyclines, sulphonamides, penicillins, cephalosporins, tetracyclines, nitrocatechols, steroids, flavonoids/polyphenols, cannabinols, and miscellaneous molecules. Details are given on the fragmentations, where available, that these ionic species exhibit in-source and in ion-trap, triple quadrupole, and time of flight-mass spectrometers. The review gives a critical evaluation of these recent CE-ESI-MS analytical methods in drug analysis. Analytical information on, for example, sample concentration techniques, CE separation conditions, recoveries from biological media and limits of detection (LODs) are provided. Potential applications of CE-MS to particular drugs or drug classes are also briefly discussed in the text.
Reports suggesting that delta 9-tetrahydrocannabinol (THC) had a potent antiemetic effect in patients treated with cancer chemotherapeutic agents led to the synthesis of other cannabinol derivatives with possibly less side effects. We report here our initial observations with the antiemetic levonantradol in 12 patients with advanced solid tumors receiving cytotoxic polychemotherapy. All patients had a history of vomiting and nausea without successful treatment with standard antiemetic drugs in previous, identical chemotherapy cycles. No other antiemetic or psychoactive drugs were given. Patients received 1 mg levonantradol i.m. 2 hours before as well as 2 and 6 hours after cytotoxic treatment. When compared to the last course of chemotherapy with alternate antiemetic drugs, we found that 11/12 patients had less nausea and vomiting when treated with levonantradol. 8/12 Patients considered the antiemetic treatment with levonantradol better than the one given before. The following side effects were observed: 4 patients complained of pain and local irritation after injection. 2 patients showed a fall in blood pressure, especially orthostatic hypotension. 8 patients complained of sedation and drowsiness. 7 patients experienced psychic side effects, such as decrease of vigilance and reaction, altered sense of timing, body image distortions and even depersonalization. Levonantradol is a potent antiemetic drug but its applicability, especially in outpatients, may be complicated by a high incidence of side effects.
Cannabinoids (or presumed synonyms such as cannabinols or cannabis-like agents) have been variously defined in botanical, chemical, or pharmacological terms, with unfortunate consequences. Botanical definitions include inactive substances such as cannabigerol, as well as alkaloids and other secondary constituents of Cannabis sativa, but exclude synthetics such as levonantradol and nabilone. Chemical definitions include inactive close analogs of THC but exclude a growing number of substances structurally remote from THC that share its actions. Pharmacological definitions have depended on relatively nonspecific or vague behavioral endpoints. However, animal testing methodology has recently been developed that can identify and quantify agents that share THC's unique subjective effects. To avoid preexisting ambiquity in the word cannabinoids, the term cannabimimetics has been coined to include all such agents, regardless of origin or structure. Such a classification emphasizes research toward improved biological selectivity and therapeutic advance. While no totally noncannabimimetic agents with potent analgesic effects have yet been identified among derivatives of THC, selectivity has been uncovered for levonantradol, HHC (racemic-9-nor, 9-beta-OH-hexahydrocannabinol) and several structurally related compounds.
What is currently needed for optimal use of medicinal cannabinoids is a feasible, nonsmoked, rapid-onset delivery system. Cannabis "vaporization" is a technique aimed at suppressing irritating respiratory toxins by heating cannabis to a temperature where active cannabinoid vapors form, but below the point of combustion where smoke and associated toxins are produced. The goal of this study was to evaluate the performance of the Volcano vaporizer in terms of reproducible delivery of the bioactive cannabinoid tetrahydrocannabinol (THC) by using pure cannabinoid preparations, so that it could be used in a clinical trial. By changing parameters such as temperature setting, type of evaporation sample and balloon volume, the vaporization of THC was systematically improved to its maximum, while preventing the formation of breakdown products of THC, such as cannabinol or delta-8-THC. Inter- and intra-device variability was tested as well as relationship between loaded- and delivered dose. It was found that an average of about 54% of loaded THC was delivered into the balloon of the vaporizer, in a reproducible manner. When the vaporizer was used for clinical administration of inhaled THC, it was found that on average 35% of inhaled THC was directly exhaled again. Our results show that with the Volcano a safe and effective cannabinoid delivery system seems to be available to patients. The final pulmonal uptake of THC is comparable to the smoking of cannabis, while avoiding the respiratory disadvantages of smoking.
The mechanism of fragmentation of cannabinoids to fragments m/e 314, 299, 271, 258, 246, 243, and 231 is given. Cannabidiol cannabinoidiol, cannabinol, delta6- and delta1-tetrahydrocannabinol, cannabichromene, cannabicyclol, derivatives with pentyl, propyl, and methyl side chains, their methyl ethers, and cis-trans and ortho-para isomers were analyzed by GLC-mass spectrometry using different energies for fragmentation during GLC elution. The following mechanism was distinguished: loss of a methyl radical, ring closure and rotation, McLafferty rearrangement, retro Diels-Alder, internal protonation, isomerization and internal bond formation, and one-step fragmentation to m/e 231.