109
7
THC, the principal active ingredient of cannabis, was only isolated in 1964 (Gaoni and
Mechoulam 1964). By now it is known that plants of the Cannabis genus contain over 100
compounds that are characterized as cannabinoids based on their structure (AizpuruaOlaizola et al. 2016); however, CBD and THC are the two cannabinoids usually produced
in greatest abundance. Of these two, only THC has psychoactive properties. The ratio of
CBD:THC varies in different species of Cannabis but does not change much throughout
the life of a plant. Most other known phytocannabinoids do not have psychoactive properties but some can enhance the effect of THC, while other such as CBD can even counteract
it. Indeed, also THC is normally present in the cannabis plant as its acidic precursor THCA
(tetrahydrocannabinolic acid) that has no psychoactive properties. In order to work on the
cannabinoid receptors, it needs to be decarboxylated to THC by heat or acidification,
which explains the usual intake form for the drug by smoking or digestion. Some cannabinoids can also bind to other receptors, i.e. cannabigerol, which is a potent α2-adrenoreceptor
agonist and a moderate 5-HT1A receptor antagonist (Cascio et al. 2010).
The Cannabis plant is dioecious, and cannabinoids are produced mainly in the bud of
female plants, where they are concentrated in a viscous resin that is secreted by glandular
trichomes. Very little substantial evidence has so far been obtained that would shed light
onto the function of cannabinoids in the female bud. As with many secondary metabolites, it is believed that it plays a role in self-defence, e.g. against herbivores. Cannabinoids
also seem to have antibacterial properties, but these have mainly been investigated with
the idea for use as new antibiotics (Appendino et al. 2008; Radwan et al. 2009). For THC,
high UV-B absorption properties have been described, and it could thus act as a sunscreen
to protect the plant from UV damage (Pate 1983; Lydon et al. 1987).
Novel phytocannabinoids that bind to the CBS2 receptor but are not psychoactive have
been identified in recent years in other plants (Gertsch et al. 2010). These include
N- alkylamides such as N-isobutylamide from Echinacea spp., which bind peripheral CB2
receptors (Gertsch et al. 2006). The CB2 receptor is also targeted by the dietary cannabinoid β-caryophyllene, a bicyclic sesquiterpene commonly found in plant such as cloves,
rosemary or hops but also in cannabis (Gertsch et al. 2008). Its presence could contribute
to the described anti-inflammatory and analgesic effects of clove oil. As for the plants, it
was also shown that β-caryophyllene is part of the root exudate emitted by certain maize
plants when attacked by larvae of coleopteran pests such as the Western corn rootworm
(Diabrotica virgifera). Here it acts as an attractant for the entomopathogenic nematode
Heterorhabditis megidis, a natural enemy of the rootworm, which helps the plants to fend
of the attack (Rasmann et al. 2005). While this system is present in the maize ancestor line
as well as European breeding varieties, it was outbred in American maize lines resulting in
their higher susceptibility to D. virgifera infection (Kollner et al. 2008). ß-caryophyllene is
also found in the volatiles released by maize leafs in response to attack by lepidopteran
larvae like Spodoptera littoralis, where it helps to attract parasitic wasps.
Catechins are phenylpropanoids ubiquitously present in vascular plants, and selected
tea catechins were found to have weak affinity for CB2 and moderated affinities for CB1
receptors (Korte et al. 2010). Falcarinol, a polyacetylene from plants of the Apiaceae family
such as carrots, acts selectively on CB1 (Leonti et al. 2010). Other secondary metabolites do not bind CB-receptors but interfere with signalling indirectly. These include
fatty acid derivatives such as the N-acylethanolamines, N-linoleoylethanolamide and
N-oleoylethanolamide found in chocolate (Theobroma cacao L.) and many other plants
or palmitoylethanolamide that inhibits anandamide breakdown (Di Marzo et al. 1998;
Maurelli et al. 1995; Di Tomaso et al. 1996).
7.4 · Cannabinoid Receptors: Phytocannabinoids
7
THC, the principal active ingredient of cannabis, was only isolated in 1964 (Gaoni and
Mechoulam 1964). By now it is known that plants of the Cannabis genus contain over 100
compounds that are characterized as cannabinoids based on their structure (AizpuruaOlaizola et al. 2016); however, CBD and THC are the two cannabinoids usually produced
in greatest abundance. Of these two, only THC has psychoactive properties. The ratio of
CBD:THC varies in different species of Cannabis but does not change much throughout
the life of a plant. Most other known phytocannabinoids do not have psychoactive properties but some can enhance the effect of THC, while other such as CBD can even counteract
it. Indeed, also THC is normally present in the cannabis plant as its acidic precursor THCA
(tetrahydrocannabinolic acid) that has no psychoactive properties. In order to work on the
cannabinoid receptors, it needs to be decarboxylated to THC by heat or acidification,
which explains the usual intake form for the drug by smoking or digestion. Some cannabinoids can also bind to other receptors, i.e. cannabigerol, which is a potent α2-adrenoreceptor
agonist and a moderate 5-HT1A receptor antagonist (Cascio et al. 2010).
The Cannabis plant is dioecious, and cannabinoids are produced mainly in the bud of
female plants, where they are concentrated in a viscous resin that is secreted by glandular
trichomes. Very little substantial evidence has so far been obtained that would shed light
onto the function of cannabinoids in the female bud. As with many secondary metabolites, it is believed that it plays a role in self-defence, e.g. against herbivores. Cannabinoids
also seem to have antibacterial properties, but these have mainly been investigated with
the idea for use as new antibiotics (Appendino et al. 2008; Radwan et al. 2009). For THC,
high UV-B absorption properties have been described, and it could thus act as a sunscreen
to protect the plant from UV damage (Pate 1983; Lydon et al. 1987).
Novel phytocannabinoids that bind to the CBS2 receptor but are not psychoactive have
been identified in recent years in other plants (Gertsch et al. 2010). These include
N- alkylamides such as N-isobutylamide from Echinacea spp., which bind peripheral CB2
receptors (Gertsch et al. 2006). The CB2 receptor is also targeted by the dietary cannabinoid β-caryophyllene, a bicyclic sesquiterpene commonly found in plant such as cloves,
rosemary or hops but also in cannabis (Gertsch et al. 2008). Its presence could contribute
to the described anti-inflammatory and analgesic effects of clove oil. As for the plants, it
was also shown that β-caryophyllene is part of the root exudate emitted by certain maize
plants when attacked by larvae of coleopteran pests such as the Western corn rootworm
(Diabrotica virgifera). Here it acts as an attractant for the entomopathogenic nematode
Heterorhabditis megidis, a natural enemy of the rootworm, which helps the plants to fend
of the attack (Rasmann et al. 2005). While this system is present in the maize ancestor line
as well as European breeding varieties, it was outbred in American maize lines resulting in
their higher susceptibility to D. virgifera infection (Kollner et al. 2008). ß-caryophyllene is
also found in the volatiles released by maize leafs in response to attack by lepidopteran
larvae like Spodoptera littoralis, where it helps to attract parasitic wasps.
Catechins are phenylpropanoids ubiquitously present in vascular plants, and selected
tea catechins were found to have weak affinity for CB2 and moderated affinities for CB1
receptors (Korte et al. 2010). Falcarinol, a polyacetylene from plants of the Apiaceae family
such as carrots, acts selectively on CB1 (Leonti et al. 2010). Other secondary metabolites do not bind CB-receptors but interfere with signalling indirectly. These include
fatty acid derivatives such as the N-acylethanolamines, N-linoleoylethanolamide and
N-oleoylethanolamide found in chocolate (Theobroma cacao L.) and many other plants
or palmitoylethanolamide that inhibits anandamide breakdown (Di Marzo et al. 1998;
Maurelli et al. 1995; Di Tomaso et al. 1996).
7.4 · Cannabinoid Receptors: Phytocannabinoids