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Cannabidiol as a potential medicine

Cannabidiol (CBD) is one of more than 60 oxygen-containing hydrocarbon constituents of cannabis that are collectively known as plant cannabinoids or phytocannabinoids 1,2 . It was first isolated in 1940, by Roger Adams from Mexican marijuana and by Alexander Todd from Indian charas 3 . However, the correct structure of CBD was not determined until 1963 and its absolute stereochemistry until 1967 4 . The CBD molecule is chiral and it is only the 3K,4K-(-)-enantiomer of this molecule that is found in cannabis. This enan-tiomer is referred to throughout this review as CBD. The chemical nomenclature of CBD differs from that of 6aR,10aR-(-)-A9-tetrahydrocannabinol (A9-THC), the main psychoactive constituent of cannabis. Thus, as shown in Figure 1, whereas A9-THC has a pyran ring which determines its numbering, CBD has no heterocyclic ring and its numbering is based on that of the ter-pene ring. Much of the A9-THC and CBD that is extracted from harvested cannabis derives from the C-2 and...

Other Actions of Cannabidiol

Results from in vitro experiments suggest that cannabidiol has a number of CB1 CB2 receptor-independent actions through which it may affect neurotransmission (reviewed in Pertwee 1988, 2004b). For example, there is evidence that at concentrations in the nanomolar or low micromolar range, this cannabinoid enhances spontaneous or evoked release of certain transmitters, antagonizes R-(+)-WIN55212- and CP55940-induced inhibition of electrically evoked contractile transmitter release in the mouse isolated vas deferens through a CB1-independent mechanism and inhibits the uptake of calcium, 5-HT, noradrenaline and dopamine by rat or mouse synaptosomes. Higher concentrations of cannabidiol inhibit anandamide uptake by rat basophilic leukaemia cells, the metabolism of this endo-cannabinoid by fatty acid amide hydrolase and the synaptosomal uptake of GABA. There is also evidence that cannabidiol is a TRPV1 receptor agonist, a ligand for the putative abnormal-cannabidiol receptor (Sect. 4.1.5)...

Isomerizing the cannabidiol with sulfuric acid

One drop of 100 sulfuric acid was added to a mixture of 1.94 gm of crystalline cannabidiol in 35 cc of cyclohexane. After refluxing for one hour, the alkaline beam test was negative. The solution was decanted from the sulfuric acid, then was washed twice with aqueous 5 bicarbonate

Pharmacokinetics and Metabolism of the Plant Cannabinoids Tetrahydrocannabinol Cannabidiol and Cannabinol

3 Pharmacokinetics of Abstract Increasing interest in the biology, chemistry, pharmacology, and toxicology of cannabinoids and in the development of cannabinoid medications necessitates an understanding of cannabinoid pharmacokinetics and disposition into biological fluids and tissues. A drug's pharmacokinetics determines the onset, magnitude, and duration of its pharmacodynamic effects. This review of cannabinoid pharmacokinetics encompasses absorption following diverse routes of administration and from different drug formulations, distribution of analytes throughout the body, metabolism by different tissues and organs, elimination from the body in the feces, urine, sweat, oral fluid, and hair, and how these processes change over time. Cannabinoid pharmacokinetic research has been especially challenging due to low analyte concentrations, rapid and extensive metabolism, and physicochem-ical characteristics that hinder the separation of drugs of interest from biological matrices and...

Pharmacokinetics of Cannabidiol

Cannabidiol (CBD) is a natural constituent of Cannabis sativa that is not psychoactive (Benowitz et al. 1980 Perez-Reyes et al. 1973b Pertwee 2004), but possesses pharmacological activity that is being explored for therapeutic applications (Pertwee 2004). CBD has been reported to be neuroprotective (Hampson et al. 1998), analgesic (Holdcroft 1984 Karst et al. 2003 Vaughan and Christie 1984), sedating (Holdcroft 1984 Melamede 1984 Plasse 1984 Vaughan and Christie 1984), antiemetic (Plasse 1984), anti-spasmodic (Baker et al. 2000), and anti-inflammatory (Malfait et al. 2000). In addition, it has been reported that CBD blocks the anxiety produced by THC (Zuardi et al. 1982) and is useful in the treatment of autoimmune diseases (Melamede 1984). These potential therapeutic applications alone warrant investigation of CBD pharmacokinetics, but also, the controversy over whether CBD alters the pharmacokinetics of THC in a clinically significant manner needs to be resolved (Agurell et al. 1984...

Isolation of pure cannabidiol

If completely clear THC (a clear, thin, colorless oil) is desired, it is necessary first to isolate pure cannabidiol from the chromatographed oil by converting it to cannabidiol-bis-3,5-dinitrobenzoate. This is then converted back into pure cannabidiol which is now in the form of white crystalline prisms. The process for this operation is found on pages 456 and 457 of the Lloydia volume previously mentioned, and a description of it follows. Pure cannabidiol is made by adding 220 ml of liquid ammonia to a solution of 288 gm cannabidiol-bis-3,5-dinitrobenzoate in anhydrous toluene (400 ml) at -70 C. in a Parr bomb. 1'he sealed apparatus was mechanically stirred. During five hours the pressure built to 110 psi and the temperature rose to 20 C. The ammonia fumes were released overnight. The product was dissolved in heptane (400 ml) and insoluble 3,5-dinitrobenza-mide was removed by filtration. The precipitate was washed twice with 150 ml heptane. The heptane solutions were combined and...

Cannabinoid Receptor Mediated Regulation of Ion Channels

Studies of the effects of cannabinoid drugs on neurophysiological responses in the years prior to the elucidation of the existence of a cannabinoid receptor were targeted at investigating a mechanism for the anticonvulsant properties of cannabidiol and mixed excitatory properties of A9-THC (for a description and other original references see Karler and Turkanis 1981 Turkanis and Karler 1981). The laboratory of Karler and Turkanis used an in vivo model of cat spinal motor neurons to observe changes in amplitude of excitatory post-synaptic potentials evoked by these cannabinoid compounds (Turkanis and Karler 1983,1986). These researchers also used cultured neuroblastoma cells to identify A9-THC and 11-OH-A9-THC-induced depression of inward Na+ currents, suggesting a possible mechanism for CNS depression by these compounds (Turkanis et al. 1991).

Advances in Medical Cannabis Research

Both recreational and medical Cannabis typically originate from either seeded plants used primarily for traditional hashish production or seedless plants grown primarily for sinsemilla marijuana and occasionally for modern hashish production. THC, A9-tetrahydrocannabinol CBD, cannabidiol. Fig. 5. Both recreational and medical Cannabis typically originate from either seeded plants used primarily for traditional hashish production or seedless plants grown primarily for sinsemilla marijuana and occasionally for modern hashish production. THC, A9-tetrahydrocannabinol CBD, cannabidiol.

CB1 Cannabinoid Receptors Participate in the Control of Cardiovascular Responses

Interestingly, abnormal cannabidiol , a neurobiologically inactive cannabi-noid, causes hypotension and mesenteric vasodilation in mice lacking CB1 and CB2 receptors that can be blocked by SR141716A (Jarai et al. 1999). These findings suggest the existence of a yet unidentified endothelial cannabinoid receptor. A further line of evidence was obtained when endotoxin lipopolysaccharide (LPS)-induced hypotension was studied in cannabinoid receptor-deficient animals. Intravenous injection of 100 g kg LPS caused a similar hypotension in phenobarbital anaesthetised wild-type animals and in mice deficient in CB1 or both CB1 and CB2 receptors (Batkai et al. 2001). This hypotensive effect was also blocked by pre-treatment with SR141716A (Batkai et al. 2004), again indicating that this compound exerts some of its effects through non-CB1 receptors.

Epilepsy Animal studies

There are many studies which show that A9-THC can induce seizures at high doses. This literature has been reviewed by Consroe and Snider (1986). A9-THC, A8-THC, A9-THC acids, cannabinol, and CBD raise electroshock induced seizure thresholds in mice (Consroe and Snider, 1986). Further, metabolites of A9-THC, also reduce seizure thresholds (11-hydroxy-A9-THC, 8-hydroxy-A9-THC and 8-dihydroxy-A9-THC). Synthetic analogs also reduce thresholds (9-nor- A8-THC, 1,2 dimethylheptyl isomers of 6-10THC, 9-nor-9 hydroxy-hexahydro-cannabinol and 9-nor-9 hydroxy-hexahydro-cannabinol. Several CBD analogs are also active, i.e., those with a 1,2 dimethylheptyl side chain of the resorcinal moiety and the + isomer of CBD. These later CBD analogs have somewhat greater potency than the parent homologs. Further, CBD analogs have the greatest protective index PI (Toxic Dose50 Effective Dose50). Interestingly, CBD has a PI comparable to classic anti-epileptic drugs (Phenytoin, phenobarbital and carbamazpine)...

Forms Of Cannabis The Plant And The Preparations

Cannabis preparations are primarily derived from the female plant of Cannabis sativa. The plant contains dozens of different cannabinoids (ElSohly, 2002 Iversen, 2007), but the primary psychoactive constituent in cannabis products is delta-9-tetrahydrocannabinol (THC) (Iversen, 2007 Pertwee, 2008). Administration of THC in pure form produces psychological and physical effects that are similar to those users report when they are smoking cannabis (Wachtel et al., 2002), and drugs that block the effects of THC on brain receptors also block the effects of cannabis in animals (Pertwee, 2008) and humans (Heustis et al., 2001). The effects of THC may also be modulated by cannabidiol (CBD), a nonpsychoactive compound that is found in varying amounts in most cannabis products (Iversen, 2007).

Cannabinoid effects on endogenous CNS opioid systems Effects on endogenous CNS opioid receptors

A full 15 years ago, the present author's research group reported that cannabinoids alter in vitro opioid receptor binding in both membrane-bound and solubilized partially purified preparations of rat CNS opioid receptors (Vaysse et al., 1985, 1987). We found that A9-THC produces a dose dependent inhibition of mu and delta opioid receptor binding, but does not alter kappa opioid, sigma, DA, or mus-carinic acetylcholine receptors (Vaysse et al., 1985, 1987 Gardner and Lowinson, 1991 Gardner, 1992). When subjected to Scatchard analyses, the mu opioid receptor binding data indicated that A9-THC produces a significant decrease in receptor density with no change in receptor affinity, consistent with a noncompetitive mechanism for cannabinoid inhibition of mu opioid receptors. Studies of A9-THC on solubilized, partially purified opioid receptors revealed similar findings (Vaysse et al., 1987 Gardner and Lowinson, 1991 Gardner, 1992). On the basis of these findings, we suggested as early as...

Animal and in vitro toxicology

Some authors have reported neuroprotective actions of cannabinoids. WIN55,212-2 reduced cerebral damage in rat hippocampus or cerebral cortex after global ischemia or focal ischemia in vivo (24). The endocannabinoid 2AG protected against damage elicited by closed head injury in mouse brain, and the protective effects were blocked by rimonabant (25). THC had a similar effect in vivo in protecting against damage elicited by ouabain (26). Rat hippocampal neurons in tissue culture were protected against glutamate-mediated damage by low concentrations of WIN55,212-2 or CP-55940, and these effects were mediated through CB1 receptors (27). But not all of these effects seem to require mediation by cannabinoid receptors. The protective effects of WIN55,212-2 did not require either CB1 or CB2 cannabinoid receptors in cortical neurons exposed to hypoxia (24), and there were similar findings for the protective actions of anandamide and 2-AG in cortical neuronal cultures (28). Both THC and...

Novel and As Yet Uncharacterized NonCEI NonCB2 Receptors in the Endothelium

Strong pharmacological and biochemical evidence exists also for non-CB non-CB2 AEA receptors in vascular endothelium (Jarai et al., 1999 Wagner et al., 1999). Jarai and co-workers showed that AEA can induce an endothelium-dependent relaxation of rat and mouse mesenteric arteries via novel endothelial sites of action activated by the nonpsychotropic cannabinoid abnormal cannabidiol, as well as by some of its analogs, and antagonized by the natural cannabinoid, cannabidiol (Jarai et al., 1999) (Figure 6.1). Interestingly, the endothelium-dependent action of both AEA and abnormal cannabidiol on the mesenteric artery was partly antagonized by a rather selective concentration (0.5 M) of the CE antagonist SR141716A. More recent observations showed that the novel endothelial sites of action of AEA are (1) coupled to G-proteins, as they are blocked by pertussis toxin pretreatment of the rat mesenteric artery, (2) coupled to BK(Ca) calcium channels and to the PI3 kinase Akt signaling pathway,...

Endocannabinoids And Their Formation In The Brain

Cannabinoid receptor type-II (CB2 receptor) is mainly present on immune cells (91). Furthermore, microglial cells, as well as macrophages, express CB2 receptors upon stimulation (96), especially at the leading edge of migrating microglial cells (97), which also express the so-called abnormal cannabidiol-sensitive receptor (CBabn receptor) (97). The CBabn receptor was first demonstrated on endothelial cells, where it could be activated by a cannabidiol derivative (abnormal cannabidiol) as well as anandamide (98). In these cells, 2-AG behaves as a full agonist and anandamide as a partial agonist on CBabn receptors (97). It is, therefore, accepted that anandamide is a partial agonist on all three types of cannabinoid receptors, whereas 2-AG provides a full agonist response on the receptors. By contrast, anandamide activates the vanilloid VR1 receptor as a full agonist (99-101), whereas 2-AG has no stimulatory activity (99). The VR1 receptor is a nonselective cation channel primarily...

Calcium Mobilization And Activation Of The Phospholipase Cinositol Phosphate System And Other Pathways

Many studies have addressed whether the cannabinoid ligands can mobilize intracellular calcium via activation of phospholipase C (PLC). Most studies have concluded that while the cannabinoid ligands can activate PLC, this effect is not receptor mediated. Early studies demonstrated that A9-THC did not activate phosphoinositide-specific PLC in guinea-pig cerebral cortical slices (Reichman et al., 1991). Studies in rat hippocampal cultured cells demonstrated that A9-THC inhibited carbachol-induced formation of labelled inositol phosphates, however, this effect was pertussis toxin-insensitive, and cannabidiol, which is not a canna-binoid receptor agonist, produced the same effect with a slightly greater potency than A9-THC. Further evidence that this effect was not cannabinoid receptor mediated came from Felder et al. (1992) who demonstrated that HU-210 had no detectable stimulatory effect on inositol phosphate production at concentrations up

Adle Thomas and Roger G Pertwee

The mouse isolated vas deferens is a nerve-smooth muscle preparation that serves as a highly sensitive and quantitative functional in vitro bioassay for cannabinoid CB1 receptor agonists. Additionally, it is commonly used as a bioassay for competitive surmountable CB1 receptor antagonists, and also provides a means for distinguishing neutral CB1 antagonists from CB1 inverse agonists. The bioassay of CB1 receptor agonists relies on the ability of these ligands to produce concentration-related decreases in the amplitude of electrically evoked contractions of the vas deferens. This they do by acting on naturally expressed prejunctional neuronal CB1 receptors to inhibit release of the contractile neurotransmitters, noradrenaline and ATP, that is provoked by the electrical stimulation. The bioassay of competitive surmountable CB1 receptor antagonists involves determining the ability of these compounds to produce parallel dextral shifts in CB1 receptor agonist log concentration-response...

Some Interpretational Difficulties

Although there is good evidence that cannabinoids can act via neuronal cannabinoid CB1 receptors to inhibit electrically evoked contractions of the mouse isolated vas deferens (Subheading 1.), there is also evidence that this tissue contains additional pharmacological targets with which some cannabi-noids can interact to produce this inhibitory response. Thus, the endocannabi-noid anandamide appears to inhibit electrically evoked contractions of the vas deferens by acting not only on CB1 receptors but also on neuronal vanilloid (TRPV1) receptors (Subheading 1.). There is also evidence that anandamide and several other established CB1 CB2 receptor agonists can act though a CB2-like cannabinoid receptor to inhibit electrically evoked contractions of this tissue preparation (17). In addition, other as yet uncharacterized neuronal and non neuronal targets for cannabinoids may be present in the mouse vas deferens (11,12). A further complication is that some cannabinoids, including the...

Cardiovascular Effects Of Cannabinoids

In 1999, Wagner and colleagues proposed that anandamide acted, in part, via an endothelial anandamide receptor in rat mesenteric arterial vessels. This was based on the observation that relaxation to anandamide was partly sensitive to both removal of the endothelium and the CBj receptor antagonist SR141716A, but when the endothelium was removed, the sensitivity to the antagonist was lost. This led to the proposal that anandamide acted at a cannabinoid receptor that was sensitive to SR141716A but as it was not the CBj receptor, it was termed the anandamide receptor. An additional observation was that the exogenous cannabinoid A9-THC did not cause vasorelaxation. Subsequent work by that group demonstrated that the endothelial cannabinoid receptor was also activated by the neurobehaviorally inactive abnormal cannabidiol (abn-cbd), which caused vasorelaxation (Jarai et al., 1999). One possibility to arise from the identification of the SR141716A-sensitive, endothelium-dependent component...

Cardiovascular Effects of Cannabinoids In Vivo

In humans, the acute effect of smoking cannabis usually manifests as an increase in heart rate with no significant change in blood pressure (Kanakis et al. 1976). However, chronic use of cannabis in man, as well as both acute and prolonged administration of THC to experimental animals, elicit a long-lasting decrease in bloodpressureandheartrate (Rosenkratz 1974 Benowitz and Jones 1975). Because of the well-known effects of cannabinoids on central nervous system function, early studies of their cardiovascular actions concentrated on the ability of these compounds to inhibit sympathetic tone as the underlying mechanism. Indeed, cross-perfusion experiments in dogs have provided some evidence for a centrally mediated sympatho-inhibitory effect of THC, although additional peripheral sites of action could not be ruled out (Vollmer et al. 1974). Already at this early stage, the potential use of these compounds as antihypertensive agents was considered (Archer 1974), in the hope that their...

Neuroprotective Actions

Cannabinoids that contain a phenol group possess anti-oxidant (electron donor) activity that is sufficient to protect neurons against oxidative stress associated, for example, with glutamate-induced excitoxicity. Thus, as discussed in greater detail elsewhere (El-Remessy et al. 2003 Fowler 2003 Hampson et al. 1998, 2000 Marsicano et al. 2002 Mechoulam et al. 2002 Pertwee 2004b Platt and Drysdale 2004 van der Stelt et al. 2002), this anti-oxidant activity is apparently independent of CB1 or CB2 receptors as it is exhibited both by the CB1 CB2 agonists 49-THC, HU-210 and CP55940, and by the non-psychoactive phytocannabinoid cannabidiol (Fig. 1) and the cis (6aS, 10aS) enantiomer of 11-hydroxy-48-THC-dimethylheptyl, HU-211 (Fig. 4), neither of which has significant affinity for CB1 or CB2 receptors (Table 4). Moreover, neurons of CB1- - mice are no less well protected from oxidative stress by phenolic cannabinoids than neurons of CB1+ + mice (Marsicano et al. 2002). The neuroprotective...

Mechanisms of vasorelaxation for endocannabinoids

In rat mesenteric vessels, Wagner et al. (1999) identified a small endothelial component of relaxation to anandamide which was SR 141716A-sensitive but not mediated by CBj-receptors. This led to them to propose that there is a novel endothelial cannabinoid receptor (Figure 20.3). One alternative explanation for this could be that SR141716A was acting to inhibit responses to anandamide via inhibition of gap junctions (Chaytor et al., 1999). Further work in this area has indicated that a neurobehaviorally inactive cannabinoid, abnormal cannabidiol, causes SR141716A-senstive mesenteric vasodilatation which is also blocked by can-nabidiol (Jarai et al., 1999). From these findings it was proposed that cannabidiol was an antagonist of this novel endothelial cannabinoid receptor, which is coupled to EDHF release (Figure 20.3).

Evidence for Additional Cannabinoid Receptor Subtypes

An abnormal cannabidiol receptor has also been characterized. Cannabi-noids, including anandamide, elicit cardiovascular effects via peripherally located CB1 receptors (Ishac et al. 1996 Jarai et al. 1999 Wagner et al. 1999). Abnormal cannabidiol (abn-cbd), a neurobehaviorally inactive cannabinoid that does not bind to CB1 receptors, caused hypotension and mesenteric vasodilation in WT mice and in mice lacking CB1 receptors or both CB1 and CB2 receptors (Jarai et al. 1999). In contrast to the studies described above, these cardiovascular and endothelial effects were SR141716A-sensitive. A stable analog of AEA (methanan-damide) also produced SR141716A-sensitive hypotension in CB1 CB2 knockout mice. These effects were not due to activation of vanilloid receptors, which also interact with AEA (Zygmunt et al. 1999). A selective antagonist, O-1918, has recently been developed it inhibits the vasorelaxant effects of abn-cbd and anandamide (Offertaler et al. 2003).

Enantioselective Cannabinergic Ligands

(-)-Cannabidiol (CBD) is a non-psychotropic component of cannabis with possible therapeutic use as an anti-inflammatory drug. Recent studies on both enan-tiomers of CBD showed enantioselectivity in their interaction with cannabinoid and vanniloid (VR1) receptors as well as on the cellular uptake and enzymatic hydrolysis of anandamide (Bisogno et al. 2001).

Brain Damage From Head Injury Excitotoxins Ischemia Infection And Poison

Oral cannabidiol 200-300 mg day to standard therapy in patients. Oral cannabidiol 3 mg kg day vs. placebo in controls. Treatment for 4.5 months in both patients and controls Oral cannabidiol 200-300 mg day for 4 weeks Oral cannabidiol 300 mg day for 6 months in addition to standard drugs. Oral cannabidiol 900-1200 mg day for 10 months Cannabidiol improved control in 7 of 8 patients 1 of 7 patients improved on placebo. Somnolence reported by 4 patients on cannabidiol. No psychotropic or neurological effects of cannabidiol noted in controls No significant effect of cannabidiol on seizure frequency No effect of cannabidiol on seizure pattern or frequency. Reduction of seizure frequency while on cannabidiol

The Chemistry Of Cannabis

Dibenzopyran

The very large number of cannabinoids (over 60) known to occur in cannabis (Turner et al., 1980) can be divided into a few main structural types as illustrated in Figure 2. These are the cannabigerol (CBG), cannabichromene (CBC), cannabidiol (CBD), A9-tetrahydrocannabinol (A9-THC), A8-tetrahydrocannabinol (A8-THC), cannabicyclol (CBL), cannabielsoin (CBE), cannabinol (CBN), cannabinodiol (CBND) and cannabitriol (CBO) types. Variations on these basic types are fairly standard presence or absence of a carboxyl group on the phenolic ring (at R2 or R4), a methyl, propyl or butyl side chain replacing the pentyl one (at R3), or a methoxy group in place of one of the hydroxyl moieties. Some of the known compounds in each group are listed in Table 1 (from Turner et al., 1980). For each type, the neutral compound with the pentyl side chain is normally referred to by the name and abbreviation listed above. In general, acid analogues have the letter A suffixed to the abbreviation, methyl ethers...

Cannabinoids Pharmacokinetics and Drug Analysis

Metabolic Transformations

Chemical structure of naturally occurring cannabinoids. 21 CFR 862.3870 defines a cannabinoid test system as a device intended to measure any of the cannabinoids, hallucinogenic compounds endogenous to marihuana, in serum, plasma, saliva, and urine. Cannabinoid compounds include A9-tetrahydrocannabinol, cannabidiol, cannabinol, and cannabichromene. Measurements obtained by this device are used in the diagnosis and treatment of cannabinoid use or abuse and in monitoring levels of cannabinoids during clinical investigational use. Fig. 1. Chemical structure of naturally occurring cannabinoids. 21 CFR 862.3870 defines a cannabinoid test system as a device intended to measure any of the cannabinoids, hallucinogenic compounds endogenous to marihuana, in serum, plasma, saliva, and urine. Cannabinoid compounds include A9-tetrahydrocannabinol, cannabidiol, cannabinol, and cannabichromene. Measurements obtained by this device are used in the diagnosis and treatment of cannabinoid use or...

Determination of Other Cannabinoids in Urine

Although detection of THCA in urine continues to be the primary method for identifying recent use of marijuana, Manno and Manno and their co-investigators have shown that THC and other metabolites of THC are also excreted in urine as glucuronide conjugates that are not, however, as easily hydrolyzed as THCA glucuronide (38,39). THC and its hydroxylated metabolites are excreted in urine primarily as ether-linked glucuronide conjugates that do not undergo hydrolysis under alkaline conditions. Enzymatic hydrolysis using P-glucuronidase from Escherichia coli at a pH of 6.8 is highly effective in cleaving ether-linked glucuronide conjugates. Manno et al. have used this method for quantitative analysis of cannabidiol, cannabinol, THC, and six THC metabolites in plasma and urine. After enzymatic hydrolysis, they extracted the cannabinoids with hexane ethyl acetate (7 1), derivatized them with BSTFA, and analyzed the products by electron ionization GC MS. Analysis of urine samples by this...

Building a safety box in which to convert highrotating THC to its acetate

The principle of the refluxing operation is approximately the same as was used for isomerizing the cannabidiol to THC with the kitchen apparatus. The explosive and noxious nature of the acetic anhydride necessi tates the use of the safety box. Although it is not necessary to use a glove

Cannabinoid chemistry an overview

Cannabinoid Chemistry

A second cannabis constituent, the psychotropically inactive cannabidiol, was also isolated, but its structure was only partially clarified 8 . Synthetic THC derivatives, which showed cannabis-like activity in animal tests, were prepared, but they obviously differed from the active natural product, on the basis of their UV spectrum 9-12 . In a systematic study of the antibacterial substances in hemp KrejCf and Santavy found that an extract containing carboxylic acids was effective against Staphylococcus aureus and other Gram-positive micro-organisms. They isolated cannabidiolic acid and reported a nearly correct structure 13, 14 (Fig. 1). Advances in isolation methods made possible a clarification of the chemistry of cannabis. In 1963 our group reisolated cannabidiol and reported its correct structure and stereochemistry 15 . A year later we finally succeeded in isolating pure THC (A9-THC) we elucidated its structure, obtained a crystalline derivative and achieved a partial synthesis...

Medical Values of Terpenes

Cannabinoid biosynthesis is mediated by enzymes controlled by individual genes 16-1 ). Terpenoid biosynthesis also begins along the same general pathway by utilizing geraniol molecules directly. THCV, A9-tetrahydrocannabivarin CBVD, cannabidivarin CBCV, cannabichromavarin THC, A9-tetrahydrocannabinol CBD, cannabidiol CBC, cannabichromene CBGV, cannabigerovarin CBG, cannabigerol. (Adapted from ref. 1 .)

Endocannabinoids in the modulation of pain

System that is distinct from, but parallel to, that involving opiates (Iversen and Chapman, 2002). Parallel with the remarkable advances in opioid and cannabinoid research, groundbreaking work over the last decade has led to deeper insights about vanilloid-capsaicin receptors and mechanisms associated with the effects of capsaicin when consumed by humans and animals (Szallasi and Blumberg, 1999, Xue et al., 1999). Just as natural cannabinoids (e.g., A9-THC in marijuana) activate CB receptors, capsaicin (the pungent chemical present in hot chili peppers) is a natural agonist of the cloned VRj vanilloid receptor, a heat-activated nonspecific ion channel protein, acting as a molecular integrator of nociceptive stimuli (Caterina et al., 1997). Although this chapter is mainly concerned with the behavioral effects of endocannabinoids, there is also an accumulating body of work indicating the existence of an endovanilloid system, whose interaction with the endocannab-inoid system may have a...

Methods for the Synthesis of Cannabinergic Ligands

The long history of worldwide self-medication by a mixture of cannabinoids present in Cannabis sativa generated the first wave of interest among synthetic and medicinal chemists in conjunction with the co-developments of modern separation, spectroscopic, and synthetic methods during the last half century. The identification of the family of C21 tricyclic cannabinoids led to the chi-rospecific partial syntheses of these classical cannabinoids from more readily available monoterpenes, and to the total syntheses of these plant constituents, as well as an expanding list of cannabimimetic compounds. However, only a few efficacious drugs, which include Marinol (Dronabinol, (-)-A9-THC from Roxane Labs), Cesamet (Nabilone, developed by Eli Lilly) and Sativex (A9-THC and cannabidiol, developed by GW Pharmaceuticals), have resulted. Cannabinoid synthesis has seen a renewed wave of interest with the discovery and cloning of the CB1 and CB2 cannabinoid receptors and the characterizations of the...

Effects on Anxiety and Insomnia

2.7.4 Cannabidiol Animal and human experiments have demonstrated that this compound has only weak anxiolytic properties (approximately one thirtieth to one sixtieth of the activity of diazepam) it is therefore unlikely that cannabidiol will ever be considered for clinical use (Mistry et al., 1985).

Determination of Cannabinoids in Hair

Determination of drugs in hair has continued to grow in importance its advantages over analysis of other matrices are that it is relatively noninvasive, and drugs can be detected in hair for a much longer time period. However, cannabinoids in blood are not taken up in hair nearly as efficiently as most other drugs are. As a result, concentrations of cannabinoids in hair after smoking or ingestion of marijuana are very low and can only be detected with extremely sensitive analytical methods. Furthermore, cannabinoid metabolites such as THCA are normally present in hair at even lower concentrations than parent cannabinoids such as THC, cannabinol, and canna-bidiol. This is a problem in forensic cases because passive exposure to marijuana smoke can result in external adsorption of cannabinoids to hair follicles. Consequently, a hair analysis that detects THCA provides more convincing evidence of intentional smoking or ingestion of marijuana than a hair analysis that detects THC,...

Marijuana Use In Cell Survival Neurogenesis And Apoptosis

Marijuana use and the effects of exogenous synthetic cannabinoid administration, including the activation of endocannabinoids and multiple signaling capabilities, have been shown to control cell survival and death by inhibiting or stimulating cell growth. Thus, cannabinoids induce growth arrest or apoptosis in a number of transformed neural and nonneural cells in culture (Guzman et al., 2002). Cannabinoids of all classes also have the ability to protect neurons from a variety of insults that are believed to underlie delayed neuronal death after traumatic brain injury, including excito-toxicity, calcium influx, free radical formation, neurodegeneration, and neuroinflammation (Biegon, 2004). Specifically, an important physiological role of cannabinoids is neuroprotection, and in animal studies, inhibition of calcium influx into cells, antioxidant properties that reduce damage caused by oxygen radicals, and modulation of vascular tone has been shown (Grotenhermen, 2004). It has been...

Respiratory effects of inhaled cannabis vapor andor smoke

Cannabis Respiratory Effect

PAIN Pain control is possible not only by consuming cannabis flowers, but possibly even the leaves, because, along with THC, cannabidiol (CBD) seems to have a major analgesic (pain lowering) effect. Not all pain responds to cannabinoids, but some of the most troublesome ones do. Neuropathy and neuralgia both respond well, while acute injury pain gets less immediate relief but eventually feels diminished. Cannabis has synergistic effects with opiates and other drugs, so pain patients can reduce their dosages of prescription drugs that have adverse side effects.

Cannabinoids The Active Chemicals of Marijuana

The biosynthetic route of the cannabinoids (the biochemical pathways by which they are synthesized in the living plant) has not been fully worked out, but the most probable routes are given in figure 3. Starting from precursors such as isoprene or mevalonic acid, compounds of the olivetolic acid and geranyl pyrophosphate type are condensed via intermediates such as can-nabigerolic acid to give cannabidiolic acid, which is cyclized to give tetrahydrocannabinolic acid. Time and heat will subsequently cause a certain amount of the THC acid to be dchydrogenated to cannabinolic acid or cannabinol (CBN). At some point, THC and or cannabidiol (CBD) arc extruded through the cell membrane. Whether this happens continually or only after a critical concentration has been reached has not been established polymers of THC may be formed at this time, but their amounts and possible contribution to marijuana activity have not been investigated.

Sublingual and Dermal Administration

Due to the chemical complexity of cannabis plant material as compared to synthetic THC, cannabis extracts are being explored as therapeutic medications. One reproducible extract of the Cannabis sativa plant contains approximately equal amounts of THC and CBD (see Pharmacokinetics of Cannabidiol, Sect. 3). The efficacy of cannabis extracts has been evaluated in clinical trials for analgesia (Holdcroft 1984 Vaughan and Christie 1984), spasticity, and other indications in affected patients (Zajicek et al. 2003). Cannabis extracts can be administered sublingually to avoid first-pass metabolism by the liver.

Introduction Of Experimental Pharmacology

Cannabis sativa contains over 421 different chemical compounds, including over 60 cannabinoids (Claussen and Korte 1968 ElSohly et al. 1984 Turner et al. 1980). Cannabinoid plant chemistry is far more complex than pure A9-tetrahydrocannabinol (THC), and different effects maybe expected due to the presence of additional cannabinoids and other chemicals. In all, 18 different classes of chemicals, including nitrogenous compounds, amino acids, hydrocarbons, sugars, terpenes, and simple and fatty acids, contribute to cannabis' known pharmacological and toxicological properties. THC is usually present in cannabis plant material as a mixture of monocarboxylic acids that readily and efficiently decarboxylate upon heating. THC decomposes when exposed to air, heat, or light exposure to acid can oxidize the compound to cannabinol, a much less potent cannabinoid. In addition, cannabis plants dried in the sun release variable amounts of THC through decarboxylation. During smoking, more than 2,000...

Cannabinoid Test System

The Cannabis plant contains more than 400 chemical compounds belonging to 18 different classes, including more than 60 phytocannabinoids that contain a typical C21 structure with pyran and phenolic rings (53-60). Most of the phytocannabinoids belong to several subclass types, including the tetrahydrocannabinol (A9-THC and A8-THC), cannabinol (CBN), cannabidiol (CBD), cannabichromene (CBC), and cannabigerol types (Fig. 1). The main active constituent of cannabis, and the primary psychoactive cannabinoid is A9-THC (55-59). The nomenclature A9-THC is based on the dibenzopyran numbering system the same compound can also be called A1-THC according to the monoterpene numbering system (54). Immunoassays for detecting cannabis abuse in urine have been designed to detect THC metabolites and are generally referred to as the cannabinoid assay or THC assay.

Assays Using Electrically Stimulated Tissues

Analysis of the recorded data involves measuring the height of the last six contractions produced during each 2-min stimulation period. This includes the period immediately before the first addition of agonist, antagonist, or vehicle is made. For experiments with antagonists (Subheading 3.3.2.), any change in contraction height produced by the antagonist is monitored to establish whether the antagonist itself has any direct effect on the amplitude of electrically evoked contractions. SR141716A and cannabidiol are both lig-ands that can significantly enhance the height of electrically evoked contractions in the mouse vas deferens (9,12). The contraction amplitudes measured just prior to the addition of the first (lowest) dose of agonist serve as the baseline amplitudes with which each subsequent set of contraction heights is compared when calculating the percentage change in contraction height produced by the agonist.

Decreased resistance to infection with viruses

Guinea pigs and mice have been used extensively to document the effects of cannabinoids on resistance to infectious agents and to define elements of the immune system targeted by these compounds. Morahan et al. (1979) demonstrated that THC administered intraperitoneally to BALB c mice decreased resistance to Listeria monocytogenes or herpes simplex virus type 2 (HSV-2), pathogens infectious also in humans. Animals inoculated intravenously with Listeria exhibited a significant dose-dependent increase in mortalities following administration of THC at doses as low as 38mg kg. However, doses of 150 to 200mg kg were required to effect maximal suppression of host resistance to Listeria. The decreased resistance produced by THC was similar to that produced by flumethazone, a known immunosuppressive steroid. Furthermore, sodium pentobarbitol, which causes CNS depression and anesthesia, had only a slight effect indicating that the decrease in host resistance was apparently due to the...

Cannabinoids and anxiety

Musty 2 found that cannabidiol (CBD) inhibited the development of stress-induced ulcers in rats as compared with diazepam, which produced an equivalent reduction in the number of stress-induced ulcers. Guimaraes et al. 3 tested rats in the elevated-plus maze. In the test, rats are placed in a plus-shaped maze which is elevated above the floor. Two of the maze arms are enclosed with walls and two are not. Time spent in the enclosed arms is taken as a measure of anxiety or fear. Both CBD and diazepam decreased the amount of time spent in the enclosed arms. Since these studies were conducted, Petitet et al. 4 and Thomas et al. 5 have reported CBD is an antagonist of the CB1 receptor in the micromolar range, suggesting that CBD may have pharmacological effects an antagonist of the CB1 receptor. Musty et al. 6 found that CBD increased licking for water in the lick-suppression test, which reliably discriminates between anxiolytic drugs and those that are non-anxiolytic. Equivalent effects...

Field Crop Production

Thc Cbd 1970s

Medical Cannabis cultivars grown in the United Kingdom by GW Pharmaceuticals, which form the basis for GW's development of prescription medicines. The larger inflorescence (A) is a cannabidiol (CBD)-rich cultivar containing only traces of A9-tetrahydrocannabinol (THC), and the smaller inflorescence (B) is a THC-rich cultivar containing only traces of CBD. Fig. 1. Medical Cannabis cultivars grown in the United Kingdom by GW Pharmaceuticals, which form the basis for GW's development of prescription medicines. The larger inflorescence (A) is a cannabidiol (CBD)-rich cultivar containing only traces of A9-tetrahydrocannabinol (THC), and the smaller inflorescence (B) is a THC-rich cultivar containing only traces of CBD.

Cannabinoid Receptor Ligands

R(+)Methanandamide is a synthetic analogue of anandamide more resistant to hydrolysis than anandamide. Other synthetic cannabinoid receptor agonists can be categorised into 3 chemical drug groups. 1) Classical 2) Nonclassical and 3) aminoalkylindoles. Classical cannab-inoids include plant-derived compounds such as cannabinol and cannabidiol, and their synthetic analogues. The best known is A9THC, however other cannabinoids in this group include the synthetic analogue 11-hydroxy A8-dimethylheptyl (HU210). Nonclassical cannabinoids consist of bicyclic and tricyclic analogues of A9THC but lack the pyran ring CP55,940 is perhaps the most widely used. The aminoalkylindoles are structurally different from the classical and nonclassical cannabinoids, resulting in binding differences. WIN55,212-2 is a member of this class of cannabinoids. Receptor agonists differ in their affinities and efficacies for the cannabinoid receptors.85 A9THC binds equally to CB1 and CB2 in the nanomolar range,...

Pharmacological Actions of Cannabinoids

4.1.5 Receptors for Abnormal-Cannabidiol 4.3 Some CB1- and CB2-Independent Actions of Cannabidiol, HU-211 4.3.2 Other Actions of 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 CBi- and CB2-selective agonists and antagonists and of bioassays for characterizing such ligands. Cannabinoid receptor antagonists include the CBi-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...

General Structure and Distribution

Cb1 Structure

Two cannabinoid receptors have been identified to date the CB1 receptor is localized predominantly in the central nervous system (CNS), whereas the CB2 receptor is located primarily in the immune system. The CB1 receptor cDNA was isolated from a rat brain library by a homology screen for GPCRs and its identity confirmed by transfectingthe clone into CHO cells and demonstrating cannabinoid-mediated inhibition of adenylyl cyclase (Matsuda et al. 1990). Initial identification of the lig-and for this orphan receptor involved the screening of many candidate ligands, including opioids, neurotensin, angiotensin, substance P, and neuropeptide Y, among others, until cannabinoids were found to act via this molecule. In cells transfected with the clone, CP 55,940,49-THC and other psychoactive cannabinoids, but not cannabidiol (which lacks CNS activity) were found to inhibit adenylyl cyclase, whereas in untransfected cells no such response was found. Furthermore, the rank order of potency for...

Effects of longterm exposure to cannabis

Some authors have reported neuroprotective actions of cannabinoids. WIN55,212-2 reduced cerebral damage in rat hippocampus or cerebral cortex after global ischemia or focal ischemia in vivo (57E). The endocannabinoid 2AG protected against damage elicited by closed head injury in mouse brain, and the protective effects were blocked by rimonabant (58E). THC had a similar effect in vivo in protecting against damage elicited by ouabain (59E). Rat hippocampal neurons in tissue culture were protected against glutamate-mediated damage by low concentrations of WIN55,212-2 or CP-55,940, and these effects were mediated through CB1 receptors (60E). But not all of these effects seem to require mediation by cannabinoid receptors. The protective effects of WIN55,212-2 did not require either CB1 or CB2 cannabinoid receptors in cortical neurons exposed to hypoxia (57E ), and there were similar findings for the protective actions of anandamide and 2-AG in cortical neuronal cultures (61E). Both THC and...

Advanced Refinement Techniques

The translucent amber oil produced by charcoal-filtering the ether phase of the extraction and isomerizing the cannabidiol present to THC contains, in most cases, between thirty and sixty per cent THC. Utilizing rather complex and exacting techniques of modern chemistry, it is possible to further refine this oil. Fractional distillation of the oil will yield a product which is up to twice as strong as the ether phase, and can be converted into nearly pure THC. Totally pure THC, a thin transparent oil, can be produced by chemically isolating the pure cannabidiol and then isomerizing it to THC. This is a very complex chemical operation and requires much sophisticated equipment and chemicals. One who is not skilled and practiced in the art of chemistry should not attempt these operations before familiarizing himself with the developments of cannabis chemistry and learning proper safety and laboratory techniques from an expert chemist. If completely clear THC (a clear, thin, colorless...

Ligand Ligand Studies CoMFA Pharmacophores for Classical Nonclassical CBs

Mutagen Effect

One of the molecular regions of the classical non-classical CBs that has been the focus of recent interest is the C-3 alkyl side chain. Several groups have looked at the effect of the introduction of unsaturation or functionality in the alkyl side chain of classical CBs. 1',1'-Cyclopropyl side chain substituents were found to enhance the affinities of (- -tetrahydrocannabinol (48-THC) and respective cannabidiol analogs for the CBi and CB2 cannabinoid receptors (Papahatjis et al. 2002). For novel analogs of 48-THC (9) in which the conformation of the side chain was restricted by incorporating the first one or two carbons into a six-membered ring fused with the aromatic phenolic ring, results indicated that the southbound chain conformer retained the highest affinity for both receptors (Khanolkar et al. 1999). Papahatjis and co-workers (1998) published a study involving side chain-constrained analogs of48-THC, including a 3-(1-heptynyl) analog synthesized in a -11-HHC (10) series and a...

Endocannabinoid Molecular Targets Beyond CB1 and CB2 Receptors

- AEA abnormal-cannabidiol receptors another possible GPCR for AEA and for the non-psychotropic cannabinoid, abnormal-cannabidiol (abn-cbd), has been detected in vascular endothelial cells. This putative receptor mediates the local vasodilator (but not the systemic hypotensive) effects of AEA, and is blocked by both cannabidiol and a synthetic analogue, O-1918 (Jarai et al. 1999 Offertaler et al. 2003). It is coupled to guanylyl cyclase and p42 44 mitogen-activated protein kinase and protein kinase B Akt. Interestingly, this novel endothelial receptor seems to be activated also by NADA (O'Sullivan et al. 2004). A receptor sensitive to abn-cbd has been proposed to mediate microglial cell migration (Walter et al. 2003), but this site of action, unlike the one in endothelial cells, was also activated by 2-AG.

Cannabinoid and Terpenoid Biosynthesis

Our basic understanding of the biosynthesis of the major cannabinoids comes largely from the research of Yukihiro Shoyama and colleagues at Kyushu University in Japan (16,17). Cannabinoid biosynthesis begins with the incorporation of geranyl pyrophosphate (a terpenoid compound) with either a C10 polyketide for the propyl (C3 side chain) or a C12 polyketide for the pentyl (C5 side chain) cannabinoid series into either cannabigerovarin (CBGV) or cannabigerol (CBG), respectively. Research by Etienne de Meijer at HortaPharm B.V. in the Netherlands shows that there is a single allele (Pr) controlling the propyl pathway to CBGV and another allele (Pe) controlling the pentyl pathway to CBG. The biosyntheses of THC, cannabidiol (CBD), and cannabichromene (CBC) (or tetrahydrocannabivarin THCV , cannabidivarin CBDV , or cannabichromavarin CBCV ) are controlled by a suite of three enzymes, each controlled by a single allele T, D, and C, respectively. The three enzymes can likely use either...

Neuronal NonCB1 NonCB2 NonTRPV1 Receptors

Evidence for the presence of a G protein-coupled non-CB1, non-CB2 receptor for anandamide and R-(+)-WIN55212 has come from experiments in which it was found that 35S GTPyS binding to whole-brain membranes from CB1- - C57BL 6 mice or to cerebellar homogenates from CB1- - CD1 mice could be enhanced by these two cannabinoids (Breivogel et al. 2001 Di Marzo et al. 2000 Monory et al. 2002). Near maximal concentrations of anandamide and R-(+)-WIN55212 were not fully additive in their effects on 35S GTPyS binding to CBr - C57BL 6 brain membranes, supporting the hypothesis that these two agents were acting through a common mechanism (Breivogel et al. 2001). This putative receptor for anandamide and R-(+)-WIN55212 appears not tobe aTRPV1 receptor (Sect. 4.1.1) or to resemble the proposed abnormal-cannabidiol receptor (Sect. 4.1.5) as neither of these pharmacological targets is R-(+)-WIN55212-sensitive and as the TRPV1 receptor is not G protein coupled. However, the possibility does remain that...

Novel Endothelial Endocannabinoid Receptor

Abn-cbd is a synthetic analog of the behaviorally inactive plant-derived cannabinoid, cannabidiol. Several years ago, abn-cbd was reported to be inactive in two, rather non-specific, behavioral paradigms used to screen cannabinoids in mice, but to cause profound hypotension in dogs (Adams et al. 1977). This prompted us to speculate that abn-cbd may be a selective agonist of the putative vascular endothelial cannabinoid receptor. A detailed study of the pharmacology of abn-cbd supported this possibility (Jarai et al. 1999). Abn-cbd does not bind to CB1 receptors in the rat brain or to the human CB2 receptor at concentrations up to 100 M (Of-fertaler et al. 2003), and is inactive in the Martin behavioral tetrad in mice at doses up to 60 mg kg (Jarai et al. 1999). Yet, abn-cbd (20 mg kg i.v.) causes SR141716-sensitive hypotension in both wild-type and CB1 receptor knockout mice. Furthermore, abn-cbd causes endothelium-dependent vasodilation in the buffer-perfused mesenteric vascular bed...

Cannabinoids effects on vomiting and nausea in animal models

Smoking marijuana may represent a more efficient and rapid route of administration. However, it is also possible that as marijuana contains over 60 other compounds, some of these additional consitutents may contribute to the anti-emetic anti-nausea effect. Another major cannabinoid found in marijuana is cannabidiol (CBD) however, unlike A9-THC, CBD does not produce psy-chomimetic effects 61 . CBD, unlike A9-THC, does not bind to the known cannabinoid receptors. It may act by blocking the reuptake of anandamide (an endogenous cannabinoid), or by inhibiting enzymatic hydrolysis of anan-damide, or bind with some as-yet-unknown cannabinoid receptor 61-63 . In mice, CBD is a highly effective anti-inflammatory agent 63 , as well as a neu-roprotective antioxidant 64 . In shrews, CBD inhibits cisplatin-induced 32 and lithium-induced 31 emesis and in rats CBD inhibits nausea 38 . These effects are described more fully below.

Second Edition

Reviewing the work on the botany and chemistry of marijuana which has appeared in the twelve years since the publication of the first edition of this work is both gratifying and dismaying. It is gratifying in that the conclusions reached earlier are in need of no significant revision and dismaying in that they have been largely ignored. It is amazing that so little work has been done on such a fundamental issue as the effect of cannabidiol on the high and other actions of THC and that when studies on the high finally appeared they were done by Brazilians Probably the red tape involved in doing research on humans with psychedelics is a major barrier. I am reminded of the failure of nearly thirty years of research to determine the influence of iso-LSD on the LSD experience. Likewise, only a few of the hundreds of THC and LSD homologs and analogs have been adequately tested for psy-choactivity. Only a trickle of work has appeared on the promising marijuana clones. Also, no attempt seems...

Future Directions

Expressed in cultured cells but also when expressed naturally. The existence of such constitutive activity is reflected in the pharmacological properties of established cannabinoid receptor antagonists, all of which appear to be inverse agonists rather than neutral antagonists. Ligands that behave as neutral cannabinoid receptor antagonists are beginning to be described in the literature. These now need to be characterized more fully, as such antagonists would serve as important additional pharmacological tools and might also possess advantages over inverse agonists in the clinic. Evidence for the presence of non-CB1, non-CB2 pharmacological targets for at least some cannabinoid receptor agonists is emerging, prompting a need to establish the extent to which these proposed additional targets contribute to the pharmacology of these agonists. For some of these targets, ligands that do not also interact with CB1 or CB2 receptors have already been identified, and it will now be important...

Animal studies

Bicher and Mechoulam (1968) found A9-THC and A8-THC (i.p.) were about 1 2 as effective as morphine (s.c.). On three tests of analgesia the hot plate test, the acetic-acid writhing test and the tail flick test, Sofia and colleagues (1975) conducted a comparison of the pain relieving effects of A9-THC, a crude marijuana extract (CME), cannabinol (CBN), cannabidiol (CBD), morphine SO-4 and aspirin (all p.o). They used acetic-induced writhing, hot plate tests and the Randall-Selitto paw pressure tests in rats. A9-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 A9-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...

Receptor Subtypes

In another set of studies, cannabinoids including AEA were found to elicit cardiovascular effects via peripherally located CB1 receptors (Ishac et al., 1996 Jarai et al., 1999 Wagner et al., 1999). Abnormal cannabidiol (abn-cbd), a neurobehaviorally inactive cannabinoid, which does not bind to CBj receptors, caused hypotension and mesenteric vasodilation in wild-type mice and in mice lacking either CBj receptors only or both CBj and CB2 receptors (Jarai et al., 1999). In contrast to the studies described earlier, these cardiovascular and endothelial effects were SR141716A sensitive. A stable analog of AEA, methanandamide, also produced SR141716A-sensitive hypotension in CB1 CB2 knockout mice. These effects were not due to activation of vanilloid receptors, which also interact with AEA (Zygmunt et al., 1999). This subtype is referred to as the abnormal cannabidiol receptor (Walter et al., 2003). A selective antagonist, O-1918, has recently been developed it inhibits the vasorelaxant...

Presynaptic Neuron

Cannabidiol is a plant-derived cannabinoid that presents an interesting pharmacological profile, comparable to that previously mentioned for HU-211 (see above). CBD is non-psychoactive, because does not bind significantly to CB1 receptors. However, it exhibits an antioxidant potency comparable, and, even superior, to that of classic dietary antioxidants such as ascorbate and a-toco-pherol 56 . CBD was equivalent to A9-THC as an antioxidant compound, but it would be more advantageous than A9-THC for a potential clinical use because it can be used at higher doses and for longer times than those possible with A9-THC, due to its lack of psychoactivity. An additional advantage for CBD is that its use in prolonged treatment does not induce tolerance 60 , a phenomenon often observed with A9-THC 61 . On the other hand, it should be mentioned that recent evidence suggests that CBD might also act by blocking endocannabinoid uptake, thus increasing endocannabinoid levels 62 , or by binding to...

Spirituality

The drawbacks of these insomnia drugs led a woman with multiple sclerosis to smoke marijuana before bed. She reported successful, restful sleep as a result (Grinspoon & Bakalar, 1997). Although THC causes many of marijuana's effects, cannabidiol appears to have the biggest impact on sleep. A sample of 15 insomniacs who received cannabidiol improved their sleep dramatically (Carlini & Cunha, 1981). Despite these encouraging data for cannabidiol, some of the best treatments for insomnia require changing behaviors rather than taking drugs. These interventions include multiple steps. People with sleep problems often benefit from retiring at the same time each night, avoiding stimulants like caffeine, and using their beds only for sleep and sex rather than other activities. This sort of good sleep hygiene may provide better rest than any medications. Nevertheless, further research on smoked marijuana and isolated cannabidiol can provide intriguing information on the role of the...

Avoidance Tasks

Similarly, an acquisition impairment was reported for rats tested in an active avoidance paradigm (Izquierdo and Nasello 1973). The weak CBi receptor ligand cannabidiol (3.5 mg kg) reduced conditioned responding, but was not effective when administered immediately post-training. This result is in agreement with more recent active avoidance training in CB1-null mutant mice, which showed increased conditioned responding consistent with memory enhancement (Martin et al. 2002). At odds with these results is the finding that rats chronically treated with A9 THC (20 mg kg) for 3 months and subsequently left untreated for 30 or 118 days before training in a shuttle box outperformed controls (Stiglick et al. 1984). Animals that had been exposed to A9THC attained asymptotic performance levels faster than controls. It remains to be shown whether this effect is mediated by the cannabi-noid system. An interesting comparison can be made with hippocampally lesioned animals. Such rats also show...

Anti Tumour Activity

Anti-cancer chemotherapy in reducing tumour growth in mice innoculated with a murine lung cancer strain cannabidiol was ineffective (Harris, 1976). Inhibition of tumour growth and improved animal survival following treatment with THC may be in part due to the ability of cannabinoids to inhibit macromolecular synthesis (Harris et al., 1976). In another study, cannabinol accelerated tumour growth in tissue culture (White et al., 1976).

The Last 40 Years

The proposition that cannabidiol (CBD), a nonpsychoactive component of the cannabis plant, possesses considerable antipsychotic activity (Zuardi and Guimaraes, 1997) is supportive of the self-medication role of cannabis in the disorder, but this action is not via the cannabinoid CBj receptor.

Seizures

Approximately 30 million people suffer from epilepsy, one of the most common seizure disorders. Current medical control for seizures remains ineffective for 20 to 30 of people (Petro, 1997b). The potential promise of cannabinoids in controlling seizures remains unclear. Many case studies suggest that marijuana controls seizures (British Medical Association, 1997 Grinspoon & Bakalar, 1997). Seizures caused by epilepsy may decrease in response to cannabinoids, particularly cannabidiol (Petro, 1997b). A study of 8 epileptics found improvement in seizure symptoms when they took 200 to 300 mg of cannabidiol (Cunha et al., 1980). In another study, 15 epileptics who did not respond well to standard treatment received cannabidiol or placebo in addition to their usual medications. The cannabidiol group showed greater improvement, but the response was quite variable (Carlini & Cunha, 1981). Another study of 12 epileptics using a comparable design failed to...

Emesis

Finally, it should be noted that cannabidiol, a natural cannabinoid that does not activate cannabinoid receptors, suppresses lithium-induced conditioned rejection reactions in a rat model of nausea (Parker et al. 2002) and also potentiates the antiemetic effect of ondansetron and A9-THC in the musk shrew (Kwiatkowska et al. 2004).

Antitumoural Effect

A number of plant-derived for example, -tetrahydrocannabinol (THC) and cannabidiol , synthetic (for example, WIN 55,212-2 and HU-210) and endogenous cannabinoids (for example, anandamide and 2-arachidonoylglycerol) have been shown to exert antiproliferative actions on a wide spectrum of tumour cells in culture (Guzm n 2003 Jones and Howl 2003). More importantly, cannabinoid administration to nude mice curbs the growth of various types of tumour xenografts, including lung carcinoma (Munson et al. 1975), glioma (Galve-Roperh et al. 2000), thyroid epithelioma (Bifulco et al. 2001), lymphoma (McKallip et al. 2002a) and skin carcinoma (Casanova et al. 2003). The antitumoural action of cannabinoids may be exemplified by gliomas. Initial experiments in cultured glioma cells showed that incubation with cannabinoids induces cell death by an apoptotic mechanism (S nchez et al. 1998a). Further studies with animal models showed that local administration of THC or WIN 55,212-2 reduced the size of...

Pyrolysis products

The phenolic cracking products of cannabidiol were isolated and tested for COX-1 inhibition (Spronck et al., 1978). Several of the products showed activity, the most potent being 2-methylolivetol which was about 12 times more potent than cannabid-iol but five times less active than indomethacin. Since cannabidiol is usually the most abundant cannabinoid in the plant, these pyrolysis products may add to the analgesic anti-inflammatory effects of smoked Cannabis. It is probably safe to assume that THC also gives rise to bioactive products when subjected to pyrolysis conditions thus making the pharmacology of marijuana smoke a rather complex subject.

In Vivo Studies 321

Reduced the passage of a charcoal meal in mice. A8-THC and A9-THC were shown to be equipotent, while cannabidiol was inactive (Chesher et al. 1973). In a more complete study, Shook and Burks (1989) showed that A9-THC and cannabinol slowed small intestinal transit when injected intravenously in mice and rats, with A9-THC being equipotent to morphine.

Human Research

There is much that remains unknown about the various interrelationships between exogenous ingested cannabinoids and the endogenous cannabinoid system and indeed other neuromodulator systems. Despite the evidence for neurotoxicity from animal studies and the human evidence that long-term or heavy use of marijuana adversely affects cognitive and brain function, cannabinoids such as THC and cannabidiol have also, intriguingly, been shown to have neuroprotective antioxidant properties (e.g. Hampson et al., 1998b) - they are capable of protecting neurons from damage. The potential for therapeutic application to a variety of neurological conditions is promising and research clearly suggests other beneficial effects that cannabinoids can have on CNS function, including analgesia, reduction of intra-cranial pressure following head trauma, anticonvulsant and antispasticity effects (see Pertwee, 2000). Cannabidiol or synthetic cannabinoids, such as dexanabinol (HU-211), are better suited for...

The Cannabinoids

Psychoactivity appears to be somewhat less than that of THC. THCV is usually associated with extremely potent grass. CBD (cannabidiol) also occurs in almost all cannabis varieties in quantities that range from trace amounts to 95 percent of all the cannabinoids present. In its pure form it is not psychoactive, but does have sedative, analgesic, and antibiotic properties. CBD contributes to the high by interacting with THC to potentiate or antagonize certain qualities of the high. It appears to potentiate the depressant effects and to antagonize the euphoric effects. It also delays

N 168 r 0919

Clinical trials are evaluating the efficacy of THC, cannabidiol, and other cannab-inoids in the treatment of nausea after cancer chemotherapy, appetite loss, multiple sclerosis, and neuropathic pain (16). A common clinical question might be How will monitoring plasma cannabinoid concentrations aid clinical management of these patients As with any new pharmaceutical preparation, it is necessary to study the drug's pharmacokinetics to more clearly understand required doses, frequency of dosing, contributions of metabolites to effects or toxicity, elimination profiles, and metabolism and excretion in different populations, including newborns, children, ethnic groups, diseased individuals, and the elderly. For example, one must determine the median effective dose, ED50, for these populations to assist clinicians who must prescribe doses that will be efficacious but avoid toxicity.

Elimination

Separating the analgesic activity of the cannabinoids from their significant side effects has been long sought. In the 1970s, Wilson and May suggested that separation was possible which spurred plenty of interest (Wilson and May, 1975). Unfortunately the only separation achieved so far is to produce derivatives that still maintain the psychopharmacological effects but have no analgesic properties. (Reggio et al., 1991) It is known that THC has an analgesic effect, but there are many other cannabinoids in cannabis that can contribute to its pain relieving effects. Cannabidiol, which is devoid of cannabimimetic effects is a potent cyclo-oxygenase inhibitor and analgesic but has been overlooked as studies have concentrated on THC and its derivatives. Metabolites of the cannabinoids may be contributing to the analgesia by an indirect route, e.g. by increasing the permeability of the blood brain barrier to other mediators. Narimatsu, S., Watanabe, K., Matsunaga, T., Yamamoto, I., Imaoka,...

Glaucoma

Attempts to develop other cannabinoid derivatives for glaucoma have not met with great success. A water soluble extract of cannabis with no demonstrable central effects, had an additive effect when administered with timolol, a beta adrenoreceptor blocking agent, in patients with refractory raised intraocular pressure (West and Lockhart, 1978) but the active ingredient(s) in this cocktail were not identified. Green et al. (1978) were unable to show that cannabidiol had any effect on raised intraocular pressure. This has been confirmed by Waller et al. (1984) in both rabbit and unanaesthetised monkey models.

Other Paradigms

A different but highly complex learning protocol was used by Brodkin and Moerschbacher.6 For up to 14 weeks, animals were trained to respond to a sequence oflights by pressing appropriate keys in a modified conditioning box. Once asymptotic performance criteria were met, drugs like cannabidiol and anandamide were injected, but had no effect on performance. By contrast, A9THC and R-methanandamide, a more stable anandamide analogue impaired performance in a dose-related manner. This impairment was reversed by SR141716A, but the antagonist had no effect on its own.6

Active Avoidance

Few reports are available on active avoidance procedures, in which the animals have to escape in a predetermined time window in order to avoid a mild footshock. In rats cannabidiol, a weak CB1 receptor agonist, given i.p. resulted in an acquisition impairment, but had no effect on consolidation of the conditioned responding.48 In agreement with the idea that the effect is mediated via CB1 receptors, CB1 null mutants showed an increase in active avoidance responses67 consistent with memory enhancement. Enhanced acquisition of the active avoidance paradigm was reported for rats that had been chronically treated with A9THC for 3 months, but were left untreated for 30 or 118 days before exposure to the shuttle box. Previously drug-treated animals outperformed controls during initial training and were faster to reach asymptotic levels.98 Such a result is reminiscent of hippocampal lesions, which also facilitated active avoidance learning46 suggesting that systemically administered A9THC...

Involuntary Movement

Cannabidiol, motivating an experiment on 15 Huntington's patients given this cannabinoid or placebo. The treatment did not improve symptoms, but cannabidiol does not activate the CB1 receptor (Consroe et al., 1991 Sandyk & Awerbuch, 1988). Further work with THC or smoked marijuana would provide a better test of the efficacy of cannabinoids in treating Huntington's disease. Dystonias, a heterogeneous group of neurological disorders that typically include involuntary muscle contractions, also may benefit from cannabis. A CB1 receptor agonist decreases dystonia in hamsters (Richter & Loscher, 1994). Cannabidiol, which does not activate this receptor, improved symptoms in 5 dystonic patients (Consroe, Sandyk, & Snider, 1986). The positive effects of both of these drugs suggests a combination therapy that supplies multiple cannabinoids may prove superior to the simple administration of oral THC.

Deyo And Musty 2003

A., and Cunha, J. M. (1991) Effects of cannabidiol in animal models predictive of antipsychotic activity. Psychopharmacology 104, 260-264. 41. Zuardi, A. W., Morais, S. L., Guimaraes, F. S., and Mechoulam, R. (1995) Antipsychotic effect of cannabidiol. J. Clin. Psychiatry 56, 485-486. 42. Musty, R.E. (1984) Possible anxiolytic effects of cannabidiol, in The Cannabinoids (Agurell, S., Dewey, W., and Willette, R., eds.), Academic Press, New York, pp. 829-844.

Ethanol

This work appears to conflict with the earlier work of Benowitz and Jones (1977), who demonstrated that administration of oral THC at a dose of 60-180mg per day for 10-17 days caused only a slight decrease in the rate of metabolism of ethanol. However, it may be that the metabolic effects of the whole cannabis plant, as studied by Lukas' group, differ from THC alone as studied by Benowitz and Jones. But a research group headed by Bird in 1980 reported that none of the major individual cannabinoids THC, cannabinol and cannabidiol affected blood ethanol levels when given prior to drinking. The amount of THC given by Benowitz and Jones was significantly greater than that used by Lukas the cannabis was also given orally as opposed to being smoked, and theirs was not an acute, single dose study. All of these factors may have influenced the different results obtained by the two groups.

Barbiturates

Administration of both THC and cannabidiol results in inhibition of the metabolism of barbiturates in man and in experimental animals. In an investigation of the subjective effects of giving the combination, intravenous THC (27-134 g per kg body weight) was given to seven volunteers who had already received a single dose of intravenous pentobarbitone (100mg per 70kg body weight). Five of the volunteers experienced intense psychotropic side effects such as hallucinations and anxiety as a result four of them could not participate in the study further (Johnstone et al., 1975). Similar additive effects were observed when secobarbitone was co-administered with THC (Lemberger et al., 1976). The combination of the barbiturate and THC was found not to affect ventilation tidal volume and plasma carbon dioxide levels remained unaltered (Johnstone et al., 1975). These additive psychotropic effects of barbiturates and cannabis can be exacerbated by cannabinoid inhibition of barbiturate...

Oleamide Pada Gcms

Bisogno, T., Hanus, L., De Petrocellis, L., Tchilibon, S., Ponde, D.E., Brandi, I., Schiano Moriello A., Davis, J.B., Mechoulam, R., and Di Marzo, V. (2001) Molecular targets for cannabidiol and its synthetic analogues effect on vanilloid VR1 receptors and on the cellular uptake and enzymatic hydrolysis of anandamide, Br. J. Pharmacol., 134 845-52. Ho, W. S. and Hiley, C.R. (2003a) Vasodilator actions of abnormal-cannabidiol in rat isolated small mesenteric artery. Br. J. Pharmacol., 138 1320-32.

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