General Background on Cannabinoids
The term 'cannabinoid' originally referred to the 60
or so C21 terpenes found in the plant Cannabis sativa,
but today the word is used more broadly to refer to "all ligands of the cannabinoid
receptor and related compounds, including endogenous ligands
of the receptors and a large number of synthetic cannabinoid
analogues" (Grotenhermen, 2003, p. 329). The
cannabinoids present in plants can now be referred to
as the phytocannabinoids. There are two known cannabinoid
receptors in humans, CB1 and CB2. Both
belong to the group of receptors known as G-protein
coupled receptors, and through G-proteins are linked to cellular ion
channels. CB1
receptors are located almost exclusively on neurons of the central and
peripheral nervous system, but are also present in small amounts on cells of
the endocrine glands, leucocytes, spleen, heart and parts of the reproductive,
urinary and gastrointestinal tracts (Pertwee, 1997).
Most of the well-known psychotropic effects of cannabis are produced by
activation of CB1
receptors in the brain. CB2
receptors, on the other hand, are present mainly on immune system cells, appear
to be absent on CNS cells (Pertwee, 2002), and
mediate many of the immunomodulatory effects of cannabinoids. There is also some evidence for at least one
other, as-yet-unidentified cannabinoid receptor.
There is a 48% amino acid sequence similarity between CB1 and CB2 receptors (Howlett et al, 2002). Cannabinoid
receptors appear to be present in all vertebrates, and
many invertebrates as well, indicating that the endocannabinoid
system is evolutionarily conserved (Salzet et al,
2000). Cannabinoid receptors appear to be absent in
insects, however (Salzet and Stefano, 2002).
There are several known endocannabinoids, endogenous substances in the body
that activate the same receptors as THC, the most well-studied being anandamide and 2-arachidonoyl-glycerol (Goodman, 2003).
Unsurprisingly in light of the known effects of exogenous cannabinoids,
the endocannabinoid system seems to be involved in
the regulation of many physiological processes, including appetite and lipogenesis, vasoconstriction and dilation, learning and memory,
immunity, and regulation of pain and inflammation (Goodman, 2003).
The most widely used natural source of cannabinoids
is of course the dioecious plant, Cannabis sativa. There are at
least two recognized subspecies of cannabis, sativa and indica
(indica), and numerous hybrid varieties. All
varieties are capable of interbreeding, and thus do not form truly separate
(reproductively isolated) species, yet the species as a whole is characterized
by very high genetic variability (de Meijer et al,
2002). Most of the psychoactive cannabinoids in
Cannabis are present in glandular trichomes covering the flowers of female plants. Trichomes are present on most terrestrial plants, and
appear to serve as a natural defense against herbivorous predators (for
instance, a trichome may burst when touched by an
insect, exuding a sticky substance that immobilizes the insect). The function
of psychoactive cannabioids in trichomes
of natural cannabis may also function as a defense, since they are present in
virtually all animals, including most of the invertebrates tested.
Surprisingly, however, cannabinoid receptors appear
to be absent in insects, e.g. Drosophila (Salzet
and Stefano, 2002). Natural varieties and cultivars can vary
dramatically in terms of their psychoactive potency (% of THC by weight), cannabinoid profile (THC/CBD ratio), and flower yield, with
the highest yields and potencies typically being found in indica
cultivars.
History of Cannabinoid Use
The plant cannabis and products derived from the cannabis plant have been used
continuously by humans for medicinal and recreational purposes for thousands of
years (Abel,
1980; Earleywine, 2002). Cannabis was probably
first used as a fiber source for textiles and rope, with medical applications
being fortuitously discovered much later. Hemp strands adorning clay pots
dating to 8000BCE have been uncovered in Taiwan
(Earlywine, p. 4). The earliest prescription of
cannabis as medicine is attributed to the Chinese emperor Shen
Neng, who lived approximately 2700BCE. In the Indian
text Atharvaveda, which is thought to have been written
between 2000 and 1400BCE, cannabis is described as an anxiolytic.
References to cannabis as a medicine and intoxicant are found in the writings
of many authors of the ancient world, including Pliny the Elder, Herodotus, Dioscorides, and Plutarch. The earliest probable references
to cannabis as medicine in European literature appear in Rabelais' Gargantua and Pantagruel
(1532). The Portugese botanist Garcia da Orta in his work Colloquies
on the Simples and Drugs of India (1563) described to a western audience
the use of cannabis in India, its sleep-inducing, anxiolytic,
and appetite-stimulating effects, as well as its tendency to induce laughter.
Cannabis was a part of the western pharmacopoeia until its removal from the
U.S. Pharmacopeia in 1941 and its rescheduling as a
Schedule 1 controlled substance in1970. However, despite dramatic efforts to
eradicate its use, the recreational use of cannabis in the west has increased
dramatically over the past several decades, and today it is used recreationally
by a significant portion of the global population. Current data from the
National Household Survey on Drug Abuse 2001 indicate that approximately 37%
(83 million) of all Americans 12 years and older have ever tried cannabis,
while approximately 5% (12 million) report use during the past month (SAMHSA, 2002).
Globally, the number of people who have used cannabis in the last year is
estimated to be approximately 163 million, or about 4% of the world population
aged 15 or older (UNODCP,
2003).
Acute Effects of Cannabinoids in Humans
The most well-known of the cannabinoids, the
ingredient of cannabis that produces most of its known effects, is
delta-9-tetrahydrocannabinol (THC). Prominent physiological effects of THC include
(from Grotenhermen, 2003, p. 344) tachycardia,
increased cardiac output, vasodilation, orthostatic
hypotension, hypertension, reddened conjunctivae in the eyes, reduced tear
flow, decrease of intraocular pressure, analgesia, appetite stimulation, bronchodilation, hyposalivation
and dry mouth. THC also produces psychotropic effects, which are discussed
elsewhere. As noted by Breivogel and Childers (1998)
the effects of cannabinoids on the endocrine system,
movement, nociception, memory and other systems
correlate well with the distribution of receptors in the body. Further, there
is a very strong structure/activity relationship, such that the greater the
affinity of a cannabinoid for its receptor, the more
potent it is in producing the characteristic effects in vivo, such as hypomobility, antinociception,
hypothermia, catalepsy, and psychotropic activity, both in humans and in other
animals (Compton et al, 1993; Melvin et al, 1993). Grotenhermen
(2003, p. 345) notes:
Cannabinoids interact with a multitude of neurotransmitters and neuromodulators, among them acetylcholine, dopamine, gamma-aminobutyric acid (GABA), histamine, serotonin, glutamate, norepinephrine, prostaglandins and opioid peptides. A number of pharmacological effects can be explained (at least in part) on the basis of such interactions. For example, tachycardia and hyposalivation with dry mouth are mediated by effects of THC on release and turnover of acetylcholine. In a rat model, cannabinoid agonists inhibited activation of serotonin 5-HT3 receptors, explaining the antiemetic properties of cannabinoids by interactions with serotonin. Therapeutic effects on movement and spastic disorders could be ascribed in part to interactions with GABAergic, glutaminergic and dopaminergic transmitter systems