finalfullthesisdjpotter

Chapter 1 Introduction
extracts also showed a significantly increased antihyperalgesic effects compared to
CBD-alone when tested in a rat model of neuropathic pain (Comelli et al., 2008). The
potential benefits for mankind were supported by the observation that patients taking
synthetic derivative nabilone for neurogenic pain actually preferred cannabis herb and
reported that it relieved not only pain but the associated depression and anxiety
(Williamson and Evans, 2000). Reasons suggested included the more rapid absorption
through the lung than the gut; the presence of other ingredients in plant-derived
cannabis which might give additive or synergistic effects; and the ability of smokers to
self-titrate their dose (Grinspoon and Bakalar, 1995).
The decision to evaluate THC/CBD mixtures as a potential medicine was further
supported by the knowledge that the majority of cannabis used in the UK at the time –
at least for recreational purposes – was in the form of cannabis resin. It was suspected,
but not confirmed, that the majority of anecdotal reports for the efficacy of cannabis in
the UK would be based upon this material. Studies in the USA had shown that
cannabis resin (hashish) typically contained approximately equal quantities of both
cannabinoids, whereas herbal cannabis (marijuana) contained predominantly THC
(ElSohly et al, 1984).
A series of clinical trials was subsequently planned which would require the
propagation chemotypes dominant in cannabinoids other than THC and CBD. Some of
these are also discussed in this thesis.
1.8 Cannabinoid and terpene biosynthesis
The cannabinoids of greatest initial interest in this research, Δ -9 tetrahydrocannabinol
and cannabidiol are referred to as ‘pentyl’ cannabinoids, due the presence of a fivecarbon
chain attached to the aromatic moiety (Figure 1.3). Other pentyl cannabinoids
frequently discussed in this thesis are cannabichromene (CBC) and cannabigerol
(CBG). All four have important propyl analogues. The first step in the synthesis of
pentyl cannabinoids is the condensation reaction of geranylpyrophosphate (GPP) with
olivetolic acid. The resulting product CBGA is the direct precursor for the three major
pentyl cannabinoids tetrahydrocannabinolic acid (THCA) (Fellermeier et al., 2001),
cannabidiolic acid (CBDA) (Taura et al. 1996) and cannabichromenic acid (CBCA)
(Gaoni and Mechoulam, 1966). The enzymes affecting the synthesis of these three
cannabinoids are named THC synthase, CBD synthase and CBC synthase
respectively. The first step in the synthesis of propyl cannabinoids is the condensation
reaction of geranylpyrophosphate (GPP) with diverinic acid. The resultant product
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