Cannabidiol Cannabinoids

Group of compounds which naturally occur in the hemp plant, Cannabis saiiva. Most of them are unsoluble in water. The most abundant cannabinoids are A9--tetrahydrocannabinol (THC), its precursor cannabidiol and cannabinol, which is formed spontaneously from THC. Cannabinoids exert their effects through G-protein coupled cannabinoid receptors (CBi/CB2). 

The lUPAC name of cannabidiol is 2-[(lS, 6iI)-3-methyl-6-prop-l-en-2-yl-l-cyclohex-2-enyl]-5-pentyl-benzene-1,3-diol. Cannabidiol (CBD, 2.9) in its acidic form cannabidiolic acid (CBDA, 2.10) is the second major cannabinoid in C. sativa besides A9-THC. As already mentioned for A9-THC, variations in the length of the side chain are also possible for CBD. Important in this context are the propyl side chain-substituted CBD, named cannabidivarin (CBDV, 2.11), and CBD-C4 (2.12), the homologous compound with a butyl side chain. Related to the synthesis starting from CBD to A9-THC as described in Sect. 3.1, it was accepted that CBDA serves as a precursor for THCA in the biosynthesis. Recent publications indicate that CBDA and THCA are formed from the same precursor, cannabigerolic acid (CBGA), and that it is unlikely that the biosynthesis of THCA from CBDA takes place in C. sativa. 

Before the discovery of specific cannabinoid receptors, the term cannabinoid was used to describe the biologically active constituents of the Cannabis sativa plant, including A -THC (67), cannabidiol (68) and their analogues and derivatives, many of which have characteristic pharmacological effects. 

A -THC, the main psychoactive component of cannabis, is a moderately potent partial agonist of the CBi and CB2 receptors, while cannabidiol has little affinity for either receptor (Table 6.7). The term classical cannabinoids is used to describe cannabinoid receptor modulators structurally related to (67), which have a tricyclic dibenzopyran core. While several other structural types of cannabinoid receptor modulators have been discovered in recent years, the classical cannabinoids are still by far the most extensively studied group in terms of SAR and pharmacology. 

The term non-classical cannabinoids is applied to a group of bicyclic compounds identified by researchers at Pfizer in the 1980s [129], These compounds lack the pyran ring of the classical cannabinoids and the second phenolic hydroxyl group of the cannabidiols, resulting in a simplified substructure represented by CP 47,497 (192) [130, 131], The non-classical cannabinoids still retain the three main pharmacophoric elements described above for the classical cannabinoids and the SAR in these regions parallels that of the classical cannabinoids [132]. 

There are over 400 constituent compounds in marijuana. More than 60 of these are pharmacologically active cannabinoids, of which 4 are the most important. The most psychoactive is delta-9-tetrahydrocannabinol (A-9-THC). The other three important natural cannabinoids are A-8-THC, cannabinol and cannabidiol (Kumar et al., 2001). In addition, some of the metabolites of THC, such as 11-hydroxy-A-9-THC, are also psychoactive. As a consequence and contrary to many other drugs, the metabolism of THC in the liver does not decrease intoxication, rather it prolongs it. 

Cannabinoids appear to have a very complex interaction with seizure activity, exerting both anticonvulsant and proconvulsant effects. Anecdotal testimonies abound (Grinspoon and Bakalar, 1993), but there has been very little controlled human research. In single-case studies both use and withdrawal of marijuana have been linked to the resumption of seizures (Keeler and Reifler, 1967 Consroe et al., 1975). In a randomised placebo-controlled blind study, patients who responded poorly to standard treatments experienced improved seizure control in response to cannabidiol administration. Cannabidiol does not interact with cannabinoid receptors, and animal studies indicate that it has different anticonvulsant effects to other cannabinoids (Cunha et al., 1980). As such it may prove to have useful therapeutic properties. 

Cannabinoids Chemicals synthesised from precursor terpenes in Cannabis sativa including cannabidiol, cannibinol and THC. 

HHC) (Tripathi 1987). Unless stated otherwise, THC will be used to refer to A9-THC throughout the remainder of this chapter. Other cannabinoids that are not psychoactive include cannabinol and cannabidiol. More recently, endogenous substances have been identified that activate these receptors, and are referred to collectively as endocannabinoids (table 10.2). 

Route of administration alters the effectiveness of cannabinoids. Orally administered THC has a slower and more erratic absorption. THC was found to be 45 times more effective for analgesia after intravenous than after subcutaneous administration (Martin 1985). The pharmacokinetics of different chemical constituents of cannabis vary (Consroe et al. 1991). The elimination half-life of cannabidiol is estimated to be about 2-5 days, with no differences between genders. Comparably, the elimination half-life of Al-THC is approximately 4 days, and may be prolonged in chronic users (Johansson et al. 1988, 1989). 

Electrophysiological responses to cannabinoids are complex. THC produces both CNS excitation and depression in several electrophysiological paradigms (Turkanis and Karler 1981). The effect produced depended on the cannabinoid dosage and paradigm used. In contrast to THC, cannabidiol generated no CNS excitation, and produced either depressant effects or no effects at all. 

Cannabidiol and THC reduced neurotoxicty induced by glutamate in cortical neurons (Hampson et al. 1998). This result was effective for toxicity induced at both NMDA and AMPA/kainate receptors, and was independent of cannabinoid receptor activity. The mechanism of neuroprotection appears to be by their potent antioxidant activity. They were even more protective against glutamate neurotoxicity than either ascorbate or o-tocopherol. 

Different cannabinoids have different effects on seizures. Cannabidiol may have the most therapeutic potential of the cannibinoids (Turkanis et al. 1979). Unlike THC, cannabidiol does not have excitatory effects and instead elevates the afterdischarge threshold. Similar to ethosuximide, it decreased the duration and amplitude of afterdischarges. Cannabidiol also lacks the CNS excitatory effects that THC produces. Lesser tolerance is observed with cannabidiol than other cannabinoids (Karler and Turkanis 1981). 

Turkanis SA, Smiley KA, Borys FIK, Olsen DM, Karler R. (1979). An electrophysiological analysis of the anticonvulsant action of cannabidiol on limbic seizures in conscious rats. Epilepsia. 20(4) 351-63. Tyrey L. (1984). Endocrine aspects of cannabinoid action in female subprimates search for sites of action. NIDA Res Monogr. 44 65-81. 

As shown in Table 2, cocaine concentrations are detected in almost all the studies targeting psychoactive substances or drugs of abuse in the literature, with the exception of Algiers and Serbia, where cannabinoids were found whilst cocaine was not (Tables 3 and 4). In the literature, cannabinoid concentrations are either expressed as A -tetrahydrocannbinol (THC) or as the sum of cannabinol, cannabidiol and THC (known as CBs). 

Fig. 3 Mean, maximum and minimum airborne concentrations of THC and cannabinoids (CBs) at urban and rural locations around the world. CBs sum of cannabinol, cannabidiol and THC...

Until the mid 1960 s the only plant cannabinoid whose structure was fully elucidated was cannabinol (CBN) — a constituent which actually may represent an oxidation artifact. However, on the basis of CBN, the main cannabinoid structure skeleton became known. Thus, cannabidiol (CBD), which had been independently isolated in pure form by Adams and by Todd, was correctly assumed to be, like CBN, a terpenoid derivative attached to olivetol. But its exact structure was not elucidated. The psychoactive components of cannabis were assumed to be related tricyclic derivatives. On the basis of the tentatively elucidated constituents, Todd suggested that the cannabinoids may be formed initially in the plant by condensation of a menthatriene with olivetol. 

Stromberg, L. Minor components of Cannabis resin V. Mass spectrometric data and gas chromatographic retention times of cannabinoid components with retention times shorter than that of cannabidiol. J Chromatogr 1974 96 179. 

At least 60 bioactive compounds are contained in herbal cannabis. A9-Tetrahydrocannabinol (A9-THC) (Mechoulam and Gaoni, 1967), cannabidiol and cannabinol are the major psychoactive or adjuvant ingredients. Cannabinoids act through at least two different G-protein coupled receptors named CBi and CB2 receptors. 

Figure 30-29 Structures of the active components of cannabis, tetrahydrocannabinol, and cannabidiol, and structures of endogenous cannabinoids and of the vanilloid lipid capsaicin.

Among the long list of diverse structures reported to possess central antitussive activity is Ahtetrahydrocannabinol (THC) [1972-08-3] (68), the principal psychoactive component of marijuana (see PSYCHOPHARMACOLOGICALAGENTS). This compound was found to be comparable to codeine against electrically induced cough in the anesthetized cat (90). Two other naturally occurring cannabinoids, cannabidiol and cannabinol, are inactive. 

Method. The derivatives are formed by shaking the sample (dissolved in acetone) for 1 h at 45 °C with a 3-5 molar excess of recrystallized DNS-C1. The reaction is buffered at pH 10.8.0.25 ml of 1N sodium hydroxide is then added in order to hydrolyze the unchanged DNS-C1. The derivatives are extracted with 3 ml of ethyl acetate after addition of 1 ml of a saturated aqueous solution of sodium chloride to the reaction mixture. The organic phase is used for TLC on activated layers of silica gel G. The cannabinoids yield mono-DNS derivatives with the exception of cannabidiol which forms a bis-DNS derivative. The following solvent systems are satisfactory for separation of cannabinoids on silica gel A, benzene-acetone (9 1) B, cyclohexane-ethyl acetate (5 1) C, cyclohexane-acetone-diethylamine (20 4 1) and D, cyclohexane-acetone-triethylamine (20 4 1). The R f values of nine cannabinoids in the above solvent systems are given in Table 4.25. 

More than 400 chemical compounds have been identified in marijuana. Approximately 60 of these are unique to the cannabis plant, substances called cannabinoids. Of the cannabinoids, a group of isomers (chemically similar substances) called tetrahydro-cannabinols (THC) are thought to be the most psychoactive. These are Ai-THC (also called A9-THC) and A6-THC (also called A8-THC). Other cannabinoids include cannabidiolic acid (CBDA), cannabidiol (CBD), and cannabinol (CBN). Their role in marijuana intoxication is less well understood. The amount of THC produced depends on the strain of cannabis and on environmental factors such as growth, harvest, and storage conditions. 

The psychoactive and medicinal chemical compounds found in the resin of the marijuana plant are known as cannabinoids. The cannabis plant contains more than 460 known compounds over 60 of these have a cannabinoid structure. The only cannabinoid that is highly psychoactive and present in large amounts in the resin of the cannabis plant is tetrahydrocannabinol, or THC. The other two major cannabinoids are the cannabidiols and the cannabinols. It appears that the cannabis plant first produces the mildly active cannabidiols, which are converted to the more psychoactive THCs and then broken down to relatively inactive... 

Cannabinoids (cannabigerol, cannabidiol, cannabinol, A-9-tetrahydrocannabinol, A-8-tetrahydrocannabinol, cannabichromene, A-9-tetra-hydrocannabinolic acid)... 

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