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Cannabidiol: An overview of some chemical and pharmacological

aspects. Part I: Chemical aspects

Article  in  Chemistry and Physics of Lipids · January 2003

DOI: 10.1016/S0009-3084(02)00144-5 · Source: PubMed

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 Chemistry and Physics of Lipids 121 (2002) 35 /43
www.elsevier.com/locate/chemphyslip

Review

Cannabidiol: an overview of some chemical and

pharmacological aspects. Part I: chemical aspects
Raphael Mechoulam
, Lumı́r Hanuš
Department of Medicinal Chemistry and Natural Products, Medical Faculty, Hebrew University of Jerusalem, Ein Kerem Campus, 91120
Jerusalem, Israel

Received 15 June 2002; accepted 20 August 2002

Abstract

Over the last few years considerable attention has focused on cannabidiol (CBD), a major non-psychotropic
constituent of Cannabis. In Part I of this review we present a condensed survey of the chemistry of CBD; in Part II, to
be published later, we shall discuss the anti-convulsive, anti-anxiety, anti-psychotic, anti-nausea and anti-rheumatoid
arthritic properties of CBD. CBD does not bind to the known cannabinoid receptors and its mechanism of action is yet
unknown. In Part II we shall also present evidence that it is conceivable that, in part at least, its effects are due to its
recently discovered inhibition of anandamide uptake and hydrolysis and to its anti-oxidative effect.
# 2002 Elsevier Science Ireland Ltd. All rights reserved.

Keywords: Cannabidiol; Chemical and pharmacological aspects; Cannabis

1. Introduction least one constituent, cannabidiol (CBD) was

found to cause a plethora of pharmacological
Since the isolation and elucidation of the effects, some of which may modify the metabolism
structure of the main active constituent of mar- and effects of THC (see for example Jaeger et al.,
ijuana, D9-tetrahydrocannabinol (THC; Gaoni 1996; Karniol et al., 1974).
and Mechoulam, 1964) an enormous number of In the present overview we shall try to cover
published articles have dealt with its chemistry, some aspects of CBD chemistry and its pharma-
biochemistry, pharmacology and clinical effects. cological and clinical effects. It is by no means
However, considerable anecdotal evidence has exhaustive. The effects of CBD in numerous
emerged that the effects of marijuana are not due systems have been investigated and this short
to THC alone (Grinspoon and Bakalar, 1997). At review is not intended to be of encyclopedic
nature, but mostly expresses the areas of interest
of the authors. The known interactions between

Corresponding author. Tel.: /972-2-675-8634; fax: /972-
THC and CBD are not presented. They require a
2-675-7076 thorough, separate critical evaluation of the lit-
E-mail address: mechou@cc.huji.ac.il (R. Mechoulam). erature, mostly of the 1970’s and 1980’s, based on
0009-3084/02/$ - see front matter # 2002 Elsevier Science Ireland Ltd. All rights reserved.
PII: S 0 0 0 9 - 3 0 8 4 ( 0 2 ) 0 0 1 4 4 - 5
36 R. Mechoulam, L. Hanuš / Chemistry and Physics of Lipids 121 (2002) 35 /43

the new knowledge of cannabinoid receptors and istry was determined by conversion of CBD into
of CBD effects. menthane carboxylic acid of well established
In Part I of this review we present a condensed absolute stereochemistry (Mechoulam and Gaoni,
survey of the chemistry of CBD; in Part II, to be 1967; Fig. 1). These early results were of consider-
published later, we shall discuss the anti-convul- able importance for the later elucidation of the
sive, anti-anxiety, anti-psychotic, anti-nausea and structure and stereochemisty of D9-THC, the
anti-rheumatoid arthritic properties of CBD. psychoactive component of Cannabis (Gaoni and
Mechoulam, 1964).
The crystal structure of CBD was determined by
2. Isolation, structure and absolute stereochemistry Jones et al. (1977). Two independent forms of this
molecule were noted, which differ mainly in the
CBD was first isolated from Mexican marijuana conformation of the pentyl side chain. The aro-
by Roger Adams and from Indian charas by matic ring and the terpene ring are almost
Alexander Todd, both in 1940. For reviews of perpendicular to each other. The two conformers
the early work see Adams (1941), Todd (1946). On are linked by hydrogen bonding of the hydroxyl
the basis of chemical degradation and correlation moieties.
with cannabinol, a general structure was proposed. The chemical nomenclature of CBD differs from
However, quite surprisingly, for almost 25 years that of THC. While the latter has a pyran ring,
no further work was reported. In 1963 our group which determines its numbering (see Fig. 1), CBD
isolated CBD from Lebanese hashish and estab- has no heterocyclic ring and its numbering stems
lished its structure and relative stereochemistry, at from that of the terpene ring. This, somewhat
positions 3 and 4, mostly on the basis of NMR unfortunate, technicality leads to the same carbon
measurements (Fig. 1; Mechoulam and Shvo, atom being numbered differently in CBD and
1963). A few years later its absolute stereochem- THC.

Fig. 1. Conversion of cannabidiol into D6-cannabidiol and degradation to menthane carboxylic acid.
 R. Mechoulam, L. Hanuš / Chemistry and Physics of Lipids 121 (2002) 35 /43 37

3. Acid cyclizations of CBD the major, or essentially the sole psychoactive

Cannabis constituent, the iso-THC’s and its deri-
Acid catalyzed cyclizations within the CBD vatives have received almost no attention.
molecule take place leading to D9-THC and to
iso-THC (Fig. 2) formed from the respective
carbocations on C-8 and C-1 of the CBD skeleton, 4. Reactions of CBD under basic conditions
respectively (Gaoni and Mechoulam, 1966a, 1968).
The double bond of THC may further isomerize, The double bond in CBD on heating with t -
leading to D8-THC (Gaoni and Mechoulam, pentyl potassium in toluene-hexamethyl-phospho-
1966b). ric triamide undergoes isomerization to the D6
While the THC’s, in particular D9-THC, have position, leading to D6-CBD (Srebnik et al., 1984;
been thoroughly explored, with thousands of Fig. 1). Contrary to natural CBD, the D6-isomer
publications appearing since its establishment as showed THC-like activity in rhesus monkeys

Fig. 2. Cyclizations of CBD and related compounds under acidic conditions.

38 R. Mechoulam, L. Hanuš / Chemistry and Physics of Lipids 121 (2002) 35 /43

(unpublished observations). It should be of con- bubbling of oxygen, which presumably reactivated

siderable interest to compare the conformations of the manganese dioxide (Fig. 5).
the two CBD isomers, in order to establish The same reaction took place without manga-
whether the unexpected difference in activity is nese dioxide by oxidative cyclization in the pre-
due to a steric change. Recently, Wiley et al. (2002) sence of air under irradiation (Fig. 5, Shani and
prepared and evaluated the binding and some in Mechoulam, 1970, 1974).
vivo effects of a series of bicyclic resorcinols that Most of these CBD derivatives were prepared
resemble CBD. Unlike CBD, most of these before the biological properties of CBD were
resorcinol derivatives had good activity in binding discovered and their evaluation may lead to novel
to CB1 and/or CB2. The lack of activity of CBD therapeutic leads.
remains an enigma.

6. Photochemical reactions of CBD

5. Oxidation of CBD and CBD acid
In a review of the pharmacological work of his
CBD in base in the presence of oxygen is group Loewe mentions that ‘‘. . . unwirksamen
oxidized to monomeric and dimeric hydroxy- Cannabidiol wurde nach Ultraviolet-bestrahlung
quinones (Fig. 3). The anions of the oxidized ein wirkstoffgehalt nachgewiesen . . .’’, but this
compounds have a deep violet color (Mechoulam work was never reported in detail (Loewe, 1950).
et al., 1968). This is the basis of the Beam reaction We have found that irradiation of CBD in
used for identification of Cannabis. methanol with a 450 W lamp in a Corex vessel
Oxidation of CBD diacetate with selenium gave a mixture from which mainly isomeric 1-
dioxide leads mainly to the aldehyde on the C-10 methoxy dihydro CBD’s were obtained (Shani and
position (Fig. 4), with no oxidation of the C-7 Mechoulam, 1971). However, irradiation in cyclo-
position as seen with THC (Lander et al., 1976). hexane led to the formation of some THC, in
However, oxidation with sodium chromate takes addition to iso-THC, reduced CBD and the
place on the C-6 position (Lander et al., 1976). addition product of cyclohexane to CBD, giving
An alternative entry to substitution at C-10 of cyclohexyl CBD (Fig. 6). These reactions indicate
CBD was reported (Jorapur et al., 1985), using the that CBD is photoreactive and should be guarded
10-bromo-CBD acetate obtained by treatment of from light when stored.
CBD diacetate with N -bromosuccinimide (Jora-
pur et al., 1984).
Cannabidiolic acid methyl ester on oxidation 7. Synthesis of CBD
with manganese dioxide gave mainly the epimers
of the methyl esters of the naturally occurring Several syntheses of CBD have been reported.
cannabielsoic acid (Shani and Mechoulam, 1970). The most efficient one apparently is the acid
This reaction could be significantly improved on condensation of p-mentha-2,8-dien-1-ol with oli-

Fig. 3. Quinone formation from CBD.

 R. Mechoulam, L. Hanuš / Chemistry and Physics of Lipids 121 (2002) 35 /43 39

Fig. 4. Oxidations of CBD diacetate.

vetol, as originally proposed by Petrzilka et al. hydroxylation, mostly on C-7, leading to 7-hy-
(1967) and later improved by Baek et al., (1985) droxy-CBD, followed by further oxidations, lead-
(Fig. 7). The yield reported (41% of crystalline ing to CBD-7-oic acid, and numerous
material) in this one step reaction makes CBD hydroxylated derivatives of this acid (Fig. 8,
readily available. Harvey and Mechoulam, 1990; Harvey et al.,
1991). Glucuronides of these oxidized metabolites
are also formed (for a review see Agurell et al.,
8. Metabolism of CBD 1986).
The syntheses of both 7-hydroxy-CBD (Tchili-
The metabolism of CBD is well established. In bon and Mechoulam, 2000) and of CBD-7-oic acid
numerous species, including man, the first step is (unpublished) have recently been achieved (Fig. 9).

Fig. 5. Formation of cannabelsoic acid-type compounds from CBD.

40 R. Mechoulam, L. Hanuš / Chemistry and Physics of Lipids 121 (2002) 35 /43

Fig. 6. Photochemical reactions of CBD.

Fig. 7. Synthesis of CBD.

 R. Mechoulam, L. Hanuš / Chemistry and Physics of Lipids 121 (2002) 35 /43 41

Fig. 8. Metabolites of CBD.

9. CBD chemistry: a summary potentially therapeutic, effects caused by CBD, it

seems plausible that novel synthetic approaches
The chemistry of CBD has been well explored will be developed in the future to lead to new types
over the last 35 years. In view of the various, of derivatives.
42 R. Mechoulam, L. Hanuš / Chemistry and Physics of Lipids 121 (2002) 35 /43

Fig. 9. Synthesis of 7-OH-CBD and CBD-7-oic acid. (a) CH3I, K2CO3 in DMF; (b) 3-chloro-perbenzoic acid in CH2CK2; (c)
methylmagnesium bromide, N-cyclohexylisopropylamine in toluene; (d) acetic anhydride in pyridine; (e) t-butyl-dimethyl-silyl bromide
in CH2Cl2; (f) tetrabutylammonium acetate in acetone; (g) NaOH aq; (h) CH3MgI at 2008C; (i) blocking of phenolic groups; (j)
oxidation of allylic alcohol to acid.

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