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PubMed1978

Stability of tetrahydrocannabinols II.

The biphasic degradation of delta9-tetrahydrocannabinol (I), as monitored by flame-ionization GLC, produced delta8-tetrahydrocannabinol (II), cannabidiol (X), 9-hydroxyhexahydrocannabinol (VI), 9,10-dihydro-9-hydroxyisocannabidiol (VI), and and 6,12-dihydro-6-hydroxycannabidiol (VIII) in acidic solutions. Further identification was made by GLC, mass spectrometry, and comparison with authentic samples. Only II and IV were produced above pH 4 in the neutral region by first-order kinetics. The acidic degradation of cannabidiol (X) gave I and the products of the acidic degradation of I. The initial phase of acidic I degradation was assigned to the development of solvolytic equilibria among I, VIII, X, and, possibly, isocannabidiol (IX), with the concomitant production of II and IV. Compounds VIII, IX, and X did not appear in the neutral region since ether cleavage occurred only in strong mineral acids. Hydration of the delta9-double bond resulted only in acid-catalyzed equilibria of cleaved ethers with the delta8-configurations and characterized the second phase of acid degradation of I. Cannabinol and hexahydrocannabinol were found together in several cases due to the disproportionation of I as catalyzed by silicic acid, silica gel, and chloroform.

Chemical Phenomena↗
PubMedDate not supplied

Flavonoid glycosides and cannabinoids from the pollen of Cannabis sativa L.

Chemical investigation of the pollen grain collected from male plants of Cannabis sativa L. resulted in the isolation for the first time of two flavonol glycosides from the methanol extract, and the identification of 16 cannabinoids in the hexane extract. The two glycosides were identified as kaempferol 3-O-sophoroside and quercetin 3-O-sophoroside by spectroscopic methods including high-field two-dimensional NMR experiments. The characterisation of each cannabinoid was performed by GC-FID and GC-MS analyses and by comparison with both available reference cannabinoids and reported data. The identified cannabinoids were delta9-tetrahydrocannabiorcol, cannabidivarin, cannabicitran, delta9-tetrahydrocannabivarin, cannabicyclol, cannabidiol, cannabichromene, delta9-tetrahydrocannabinol, cannabigerol, cannabinol, dihydrocannabinol, cannabielsoin, 6a, 7, 10a-trihydroxytetrahydrocannabinol, 9, 10-epoxycannabitriol, 10-O-ethylcannabitriol, and 7, 8-dehydro-10-O-ethylcannabitriol.

Cannabinoids↗
PubMed2005

Pharmacological actions of cannabinoids.

Mammalian tissues express at least two types of cannabinoid receptor, CB1 and CB2, both G protein coupled. CB1 receptors are expressed predominantly at nerve terminals where they mediate inhibition of transmitter release. CB2 receptors are found mainly on immune cells, one of their roles being to modulate cytokine release. Endogenous ligands for these receptors (endocannabinoids) also exist. These are all eicosanoids; prominent examples include arachidonoylethanolamide (anandamide) and 2-arachidonoyl glycerol. These discoveries have led to the development of CB1- and CB2-selective agonists and antagonists and of bioassays for characterizing such ligands. Cannabinoid receptor antagonists include the CB1-selective SR141716A, AM251, AM281 and LY320135, and the CB2-selective SR144528 and AM630. These all behave as inverse agonists, one indication that CB1 and CB2 receptors can exist in a constitutively active state. Neutral cannabinoid receptor antagonists that seem to lack inverse agonist properties have recently also been developed. As well as acting on CB1 and CB2 receptors, there is convincing evidence that anandamide can activate transient receptor potential vanilloid type 1 (TRPV1) receptors. Certain cannabinoids also appear to have non-CB1, non-CB2, non-TRPV1 targets, for example CB2-like receptors that can mediate antinociception and "abnormal-cannabidiol" receptors that mediate vasorelaxation and promote microglial cell migration. There is evidence too for TRPV1-like receptors on glutamatergic neurons, for alpha2-adrenoceptor-like (imidazoline) receptors at sympathetic nerve terminals, for novel G protein-coupled receptors for R-(+)-WIN55212 and anandamide in the brain and spinal cord, for novel receptors for delta9-tetrahydrocannabinol and cannabinol on perivascular sensory nerves and for novel anandamide receptors in the gastro-intestinal tract. The presence of allosteric sites for cannabinoids on various ion channels and non-cannabinoid receptors has also been proposed. In addition, more information is beginning to emerge about the pharmacological actions of the non-psychoactive plant cannabinoid, cannabidiol. These recent advances in cannabinoid pharmacology are all discussed in this review.

Animals↗
PubMed1975

Comparative analgesic activity of various naturally occurring cannabinoids in mice and rats.

The analgesic effectiveness of delta-9-tetrahydrocannabinol (THC), a crude marihuana extract (CME), cannabinol (CBN), cannabidiol (CBD), morphine SO-4 and aspirin following oral administration was directly compared in mice using the acetic-induced writhing and hot plate tests and the Randall-Selitto paw pressure test in rats. THC and morphine were equipotent in all tests except that morphine was significantly more potent in elevating pain threshold in the uninflamed rat hind paw. In terms of THC content, CME was nearly equipotent in the hot plate and Randall-Selitto tests, but was 3 times more potent in the acetic acid writhing test. On the other hand, CBN, like aspirin, was only effective in reducing writhing frequency in mice (3 times more potent than aspirin) and raising pain threshold of the inflamed hind paw of the rat (equipotent with aspirin). CBD did not display a significantly analgesic effect in any of the test systems used. The results of this investigation seem to suggest that both THC and CME possess narcotic-like analgesic activity similar to morphine, while CBN appears to be a non-narcotic type analgesic like aspirin.

Acetates↗
PubMed1985

Hashish extract impairs retention of defeat-induced submissive behavior in mice.

The effects of hashish extract on adaptive behavior of male mice were studied in a paradigm which allows the investigation of learning mechanisms in a social context. Mice of the C3H strain, which were not submissive in a confrontation with a nonaggressive DBA mouse on day 1, were defeated on day 2 over 3 min by aggressive, isolated DBA mice, and showed conditioned submissive behavior upon mere contact with a nonaggressive DBA mouse on day 3. A hashish extract containing 38.6-39.4% delta 9-tetrahydrocannabinol (delta 9-THC), 11.6-12.0% cannabinol and 47.7-48.5% cannabidiol was administered orally in all experiments. Hashish extract given 90 min before defeat on day 2, in dosages corresponding to 1, 5, and 10 mg delta 9-THC/kg, impaired retention of defensive upright, defensive sideways and immobility on day 3 (experiment 1). Experiment 2 showed that the drug (5, and 10 mg delta 9-THC/kg) had no antinociceptive potency in mice and did not modify defeat-induced analgesia. Experiment 3, with drug (5 mg delta 9-THC/kg) or solvent administration on day 2 and day 3, showed that the retention deficit was neither due to state-dependent learning, nor to impaired retrieval. It is suggested that hashish extract administered before learning may interfere with memory processing.

Aggression↗
PubMed1979

Interactions among the cannabinoids in the antagonism of the abdominal constriction response in the mouse.

The ability of delta 9-tetrahydrocannabinol (THC), cannabinol (CBN), cannabidiol (CBD), 11-OH THC and 8 alpha, 11-diOH THC to antagonise the abdominal constriction response in the mouse induced by formic acid, phenylquinone, 5-hydroxytryptamine, prostaglandin E1 (PGE1) and bradykinin was tested. THC was an effective antagonist against all nociceptive agents with an ED50 in all cases between 1.0 and 2.6 mg/kg. CBN, while also effective against all nociceptive agents, was less potent than THC, with an ED50 range between 46.2 and 112.5 mg/kg. CBD in doses as high as 200 mg/kg was without effect. Using PGE1 as the nociceptive agent, 11-OH THC was equipotent to THC while 8 alpha, 11-diOH THC was inactive. Naloxone, while able to antagonise the antinociceptive effect of morphine against formic acid-induced writhing, did not reverse the antinociceptive effects of THC. There were no pharmacological interactions between THC, CBD and CBN.

Abdominal Muscles↗
PubMed1980

Behavioral effects of hashish in mice. II. Nursing behavior and development of the sucklings.

Adult mice were treated from parturition to weaning of their first litter with a hashish extract containing 40% delta 9-tetrahydrocannabinol (delta 9-THC), 45% cannabidiol, 9% cannabinol, and 6% other cannabinoids. Oral administrations of 20 mg delta 9-THC/kg three times a week decreased the weight gain of pups from days 3-6 and 6-10 significantly, resulting in about 15% lower body weights on days 6 and 10 compared with control sucklings. Other parameters of development such as the general appearance of the pups were little affected, except for a slight tendency by day 13, when some additional control pups already had both eyes open. The effects of hashish in sucklings might be caused by drug intake with mother's milk, as well as by a decreased lactation of drugged dams. In addition, our pup retrieving tests at the day 3, 1.5-2 h after the second application of hashish extract, showed a decrease in the mother's locomotive and nonsocial activities and pointed to at least transient impairment of the maternal behavior. By day 10, after the fifth administration of hashish extract, a partial tolerance occurred, with normal care for the young, but still decreased nonsocial activities of the drugged dams. Thus our experiments showed distinct effects of cannabis on mice litters when the parents were drugged postnatally during the period of lactation only.

Aggression↗
PubMed1988

Analgesic and antiinflammatory activity of constituents of Cannabis sativa L.

Two extracts of Cannabis sativa herb, one being cannabinoid-free (ethanol) and the other containing the cannabinoids (petroleum), were shown to inhibit PBQ-induced writhing in mouse when given orally and also to antagonize tetradecanoylphorbol acetate (TPA)-induced erythema of mouse skin when applied topically. With the exception of cannabinol (CBN) and delta 1-tetrahydrocannabinol (delta 1-THC), the cannabinoids and olivetol (their biosynthetic precursor) demonstrated activity in the PBQ test exhibiting their maximal effect at doses of about 100 micrograms/kg. delta 1-THC only became maximally effective in doses of 10 mg/kg. This higher dose corresponded to that which induced catalepsy and is indicative of a central action. CNB demonstrated little activity and even at doses in excess of 10 mg/kg could only produce a 40% inhibition of PBQ-induced writhing. Cannabinoid (CBD) was the most effective of the cannabinoids at doses of 100 micrograms/kg. Doses of cannabinoids that were effective in the analgesic test orally were used topically to antagonize TPA-induced erythema of skin. The fact that delta 1-THC and CBN were the least effective in this test suggests a structural relationship between analgesic activity and antiinflammatory activity among the cannabinoids related to their peripheral actions and separate from the central effects of delta 1-THC.

Analgesics↗
PubMed1978

Microbiological oxidation of the pentyl side chain of cannabinoids.

Syncephalastrum racemosum ATCC 18192 and Mycobacterium rhodochrous ATCC 19067 partially degrade the n-pentyl side chain of cannabidiol, cannabinol, delta8-tetrahydrocannabinol and delta9-tetrahydrocannabinol. Carboxylic acid and alcohol side chain derivatives are major metabolites.

Cannabinoids↗
PubMed2005

Antiestrogenic effects of marijuana smoke condensate and cannabinoid compounds.

The antiestrogenic effects of marijuana smoke condensate (MSC) and three major cannabinoids, ie., delta9-tetrahydrocannabinol (THC), cannabidiol (CBD), and cannabinol (CBN), were evaluated using in vitro bioassays, viz., the human breast cancer cell proliferation assay, the recombinant human estrogen receptor (ER) competitive binding assay, and the reporter gene assay. The inhibitory effects on estrogen were also examined using the ethoxyresorufin-O-deethylase (EROD) assay, the aromatase assay, and the 17beta-estradiol (E2) metabolism assay. The results showed that MSC induced the antiestrogenic effect via the ER-mediated pathway, while THC, CBD, and CBN did not have any antiestrogenic activity. This suggests that the combined effects of the marijuana smoke components are responsible for the antiestrogenicity of marijuana use. In addition, MSC induced the CYP1A activity and the E2 metabolism, but inhibited the aromatase activity, suggesting that the antiestrogenic activity of MSC is also related to the indirect ER-dependent pathway, as a result of the depletion of the in situ E2 level available to bind to the ER. In conclusion, pyrogenic products including polycyclic aromatic hydrocarbons (PAHs) in the non-polar fraction, which is the most biologically active fraction among the seven fractions of MSC, might be responsible for the antiestrogenic effect.

Animals↗
PubMedDate not supplied

Clinical features and management of intoxication due to hallucinogenic drugs.

Hallucinogenic drugs are unique in that they produce the desired hallucinogenic effects at what are considered non-toxic doses. The hallucinogenic drugs can be categorised into 4 basic groups: indole alkaloid derivatives, piperidine derivatives, phenylethylamines and the cannabinols. The drugs reviewed include lysergic acid diethylamide (LSD), phencyclidine (PCP), cocaine, amphetamines, opiates, marijuana, psilocybin, mescaline, and 'designer drugs.' Particularly noteworthy is that each hallucinogen produces characteristic behavioural effects which are related to its serotonergic, dopaminergic or adrenergic activity. Cocaine produces simple hallucinations, PCP can produce complex hallucinations analogous to a paranoid psychosis, while LSD produces a combination of hallucinations, pseudohallucinations and illusions. Dose relationships with changes in the quality of the hallucinatory experience have been described with amphetamines and, to some extent, LSD. Flashbacks have been described with LSD and alcohol. Management of the intoxicated patient is dependent on the specific behavioural manifestation elicited by the drug. The principles involve differentiating the patient's symptoms from organic (medical or toxicological) and psychiatric aetiologies and identifying the symptom complex associated with the particular drug. Panic reactions may require treatment with a benzodiazepine or haloperidol. Patients with LSD psychosis may require an antipsychotic. Patients exhibiting prolonged drug-induced psychosis may require a variety of treatments including ECT, lithium and l-5-hydroxytryptophan.

Hallucinogens↗
PubMed2003

Determination of cannabinoids in hemp food products by use of headspace solid-phase microextraction and gas chromatography-mass spectrometry.

A fully automated procedure using alkaline hydrolysis and headspace solid-phase microextraction (HS-SPME), followed by on-fiber derivatization and gas chromatographic-mass spectrometric (GC-MS) detection has been developed for determination of cannabinoids in hemp food samples. After addition of a deuterated internal standard, the sample was hydrolyzed with sodium hydroxide and submitted to direct HS-SPME. After absorption of analytes for on-fiber derivatization, the fiber was placed directly into the headspace of a second vial containing N-methyl- N-trimethylsilyltrifluoroacetamide (MSTFA), before GC-MS analysis. Linearity was good for Delta(9)-tetrahydrocannabinol (THC), cannabidiol, and cannabinol; regression coefficients were greater than 0.99. Depending on the characteristics of the matrix the detection limits obtained ranged between 0.01 and 0.17 mg kg(-1) and the precision between 0.4 and 11.8%. In comparison with conventional liquid-liquid extraction this automated HS-SPME-GC-MS procedure is substantially faster. It is easy to perform, solvent-free, and sample quantities are minimal, yet it maintains the same sensitivity and reproducibility. The applicability was demonstrated by analysis of 30 hemp food samples. Cannabinoids were detected in all of the samples and it was possible to differentiate between drug-type and fiber-type Cannabis sativa L. In comparison with other studies relatively low THC concentrations between 0.01 and 15.53 mg kg(-1) were determined.

Cannabinoids↗
PubMed1986

Effects of delta 9-tetrahydrocannabinol on glucagon receptor coupling to adenylate cyclase in rat liver plasma membranes.

Delta-Tetrahydrocannabinol (delta 9-THC), the principal psychoactive constituent of Cannabis sativa, was found to increase glucagon activation of liver plasma membrane adenylate cyclase. In the presence of 30 microM delta 9-THC, the EC50 for glucagon was decreased by 60% from 7.6nM to 3.1 nM. 11-OH-delta 9-THC, a psychoactive metabolite of delta 9-THC, also increased glucagon activation of adenylate cyclase while two cannabinoids without marihuana-like psychoactive potency, cannabinol and cannabidiol, did not. At 30 microM, delta 9-THC either slightly decreased or had no effect on the activation of adenylate cyclase by GTP, Gpp(NH)p, fluoride ion, forskolin or ATP alone. Delta 9-THC had no effect on the binding of [125I] glucagon to liver plasma membranes. Arrhenius plots demonstrated that delta 9-THC and 11-OH-delta 9-THC, but not CBD, decreased the activation energy above the break temperature. Therefore, delta 9-THC increased the coupling of the glucagon receptor to adenylate cyclase apparently by removing a constraint on receptor-Ns coupling.

Adenylyl Cyclases↗
PubMed1988

Formation of similar species to carbon monoxide during hepatic microsomal metabolism of cannabidiol on the basis of spectral interaction with cytochrome P-450.

Cannabidiol induced a carbon monoxide-like complex with mouse hepatic microsomal cytochrome P-450 during NADPH-dependent metabolism in vitro on a spectral basis. The reduction by dithionite was required for the maximal development of a spectrum. The complex showed a peak at 450 nm which shifted to 419 or 423 nm, respectively, by further addition of hemoglobin or myoglobin. Cannabidiol-induced complex formation required molecular oxygen, and was decreased by the addition of inhibitors of cytochrome P-450-dependent monoxygenase. Pretreatment of mice with phenobarbital (80 or 100 mg/kg, i.p. for 3 days) but not 3-methylcholanthrene (80 mg/kg, i.p.) increased the complex formation. In contrast, pretreatment with cobaltous chloride (40 mg/kg, i.p. for 3 days) decreased the complex formation. 8,9-Dihydro- and 1,2,8,9-tetrahydrocannabidiols also induced the same spectrum as that of above complex, whereas cannabidiol monomethyl- and dimethylethers reduced this ability. In addition, both cannabidivarin and cannabigerol induced the complex formation, although delta 9-tetrahydrocannabinol, cannabinol and cannabielsoin did not. Olivetol but not d-limonene induced the spectrum of the complex to some extent. These results indicate that cannabidiol induces a carbon monoxide-like complex with cytochrome P-450 during hepatic microsomal metabolism, and suggest that phenobarbital-inducible cytochrome P-450s mediate at least one of the metabolic steps of CBD to form the complex, as well as the importance of the resorcinol moiety of CBD for the complex formation.

Animals↗
PubMed1991

Reduction of the fertilizing capacity of sea urchin sperm by cannabinoids derived from marihuana. III. Activation of phospholipase A2 in sperm homogenate by delta 9-tetrahydrocannabinol.

Inhibition of the egg jelly induced acrosome reaction by delta 9-tetrahydrocannabinol (THC) is associated with the localized disruption of the nuclear envelope and the formation of lipid deposits in sea urchin sperm. This suggests that THC may activate phospholipase(s) within the sperm. We now report effects of THC on phospholipase A2 activity in homogenates of sea urchin sperm using 1-stearoyl-2-[1-14C]arachidonyl phosphatidylcholine as substrate. The release of radioactive arachidonic acid was measured after a 30-min incubation with the enzyme. In the absence of exogenous Ca2+, 100 microM THC produced a significant (P less than 0.001) increase in phospholipase A2 activity. THC activated phospholipase A2 in a concentration (1-100 microM) and time-dependent (0-30 min) manner. Exogenous calcium (10 mM) significantly augmented basal (P less than 0.001) and THC-stimulated (P less than 0.005) phospholipase A2 activity. Calcium chelators [ethylene glycol bis(beta-aminoethyl ether)N,N,N',N'-tetraacetic acid (EGTA) and 1,2-bis(O-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA)] inhibited the basal level of phospholipase A2 activity in the sperm homogenate, and prevented the activation of phospholipase A2 by THC. Submicromolar levels of free calcium ions were required for THC stimulation of phospholipase A2. Cannabinol which mimics the effects of THC on the acrosome reaction also activated phospholipase A2 in sperm homogenate. These results suggest that THC may alter lipid metabolism in sperm by activating calcium-dependent phospholipase A2. Putative metabolites derived from this process may inhibit the acrosome reaction and thereby reduce the fertilizing capacity of sea urchin sperm.

Animals↗
PubMed1993

A cytochrome P450 isozyme having aldehyde oxygenase activity plays a major role in metabolizing cannabinoids by mouse hepatic microsomes.

A cytochrome P450 (designated P450 MUT-2) which catalyses the oxidation of 11-oxo-delta 8-tetrahydrocannabinol (11-oxo-delta 8-THC) to delta 8-THC-11-oic acid has been purified from hepatic microsomes of untreated male mice. Analysis of NH2-terminal sequence suggests that the isozyme is a member of the P450 2C gene subfamily. P450 MUT-2 exhibited aldehyde oxygenase activity for 11-oxo-delta 8-TH, 11-oxo-delta 9-THC, 11-oxo-cannabinol (11-oxo-CBN) and 9-anthraldehyde together with high activity for the hydroxylation of cannabinoids at the 11-position. Antibody against P450 MUT-2 significantly inhibited the microsomal formation of delta 8-THC-11-oic acid from 11-oxo-delta 8-THC, but not that of 9-anthracene carboxylic acid from 9-anthraldehyde. Major metabolic reactions of delta 8-THC, delta 9-THC and CBN with mouse hepatic microsomes were the 11-hydroxylation (all cannabinoids), 7 alpha-(delta 8-THC) or 8 alpha-hydroxylation (delta 9-THC) and epoxide formation (delta 8- and delta 9-THC). All these reactions except for 7 alpha-hydroxylation of delta 8-THC and alpha-epoxide formation from delta 9-THC were also markedly inhibited by the antibody. These results indicate that P450 MUT-2 is a major enzyme for metabolizing cannabinoids by mouse hepatic microsomes.

Animals↗
PubMed1996

Tetrahydrocannabinol inhibition of macrophage nitric oxide production.

delta 9-Tetrahydrocannabinol (THC) inhibited nitric oxide (NO) production by mouse peritoneal macrophages activated by bacterial endotoxin lipopolysaccharide (LPS) and interferon-gamma (IFN)-gamma). Inhibition of NO production was noted at THC concentrations as low as 0.5 microgram/mL, and was nearly total at 7 micrograms/mL. Inhibition was greatest if THC was added 1-4 hr before induction of nitric oxide synthase (NOS) by LPS and IFN-gamma, and declined with time after addition of the inducing agents. This suggested that an early step such as NOS gene transcription or NOS synthesis, rather than NOS activity, was affected by THC. Steady-state levels of mRNA for NOS were not affected by THC. In contrast, protein synthesis was inhibited as indicated by immunoblotting. NOS activity was also decreased in the cytosol of cells pretreated with THC. Addition of excess cofactors did not restore activity. Inhibition of NO production was greater at low levels of IFN-gamma, indicating the ability of the cytokine to overcome inhibition. The effectiveness of various THC analogues, in decreasing order of potency, was delta 8-THC > delta 9-THC > cannabidiol > or = 11-OH-THC > cannabinol. The presumably inactive stereoisomer, (+)delta 9-THC, and the endogenous ligand for cannabinoid receptors, anandamide, were weakly inhibitory. Inhibition may be mediated by a process that depends partly on stereoselective receptors and partly on a nonselective process. LPS, IFN-gamma, hormone receptor agonists, and forskolin increased macrophage cyclic AMP levels. THC inhibited this increase, indicating functional cannabinoid receptors. Addition of 8-bromocyclic AMP increased NO 2-fold, and partially restored NO production that had been inhibited by THC. This occurred only under conditions of limited NOS induction, suggesting that the effect of THC on cyclic AMP was responsible for only a small portion of the inhibition of NO.

Animals↗