Therapeutic potential of cannabinoid medicines
Philip J. Robson
Drug and Testing Analysis, 2014
Doi : 10.1002/dta.1529
Cannabis was extensively used as amedicine throughout the developed world in the nineteenth century but went into decline early in the twentieth century ahead of its emergence as the most widely used illicit recreational drug later that century. Recent advances in cannabinoid pharmacology alongside the discovery of the endocannabinoid system (ECS) have re-ignited interest in cannabis-based medicines. The ECS has emerged as an important physiological system and plausible target for new medicines. Its receptors and endogenous ligands play a vital modulatory role in diverse functions including immune response, food intake, cognition, emotion, perception, behavioural reinforcement,motor co-ordination, body temperature, wake/sleep cycle, bone formation and resorption, and various aspects of hormonal control. In disease itmay act as part of the physiological response or as a component of the underlying pathology. In the forefront of clinical research are the cannabinoids delta-9-tetrahydrocannabinol and cannabidiol, and their contrasting pharmacology will be briefly outlined. The therapeutic potential and possible risks of drugs that inhibit the ECS will also be considered. This paper will then go on to review clinical research exploring the potential of cannabinoid medicines in the following indications: symptomatic relief in multiple sclerosis, chronic neuropathic pain, intractable nausea and vomiting, loss of appetite and weight in the context of cancer or AIDS, psychosis, epilepsy, addiction, and metabolic disorders.
Keywords : cannabinoids; endocannabinoid system; medicinal cannabis; tetrahydrocannabinol; cannabidiol
Cannabis in the twenty-first century is perceived primarily as the most widely used illegal recreational drug, but this relatively recent notoriety obscures its extensive utilization as a medicine throughout the world for several thousand years. Evidence of its use in treating malaria, constipation, pain, and dysmenorrhoea appear from oral tradition as early as 2600 B.C.E. in China and in following centuries
it crops up in pharmacopoeias from Asia, the Middle East, Southern Africa and South America.[1,2] First named Cannabis sativa by Leonhardt Fuchs in 1542, it was introduced to British medical practice in the nineteenth century by W.B. O’Shaughnessy as an analgesic, anti-spasmodic, anti-emetic and hypnotic. It entered the United States (US) Dispensatory in 1854 and reached its zenith in Western medicine late in the nineteenth century.
The decline of medicinal cannabis began early in the twentieth century as a result of the growing availability of potent synthetic medicines alongside variable potency of these herbal preparations and unreliable sources of supply. This decline was hastened by increasing concerns about recreational use in some countries, particularly Egypt, South Africa, and the USA. These found political expression at the 1923 League of Nations meeting, and an international convention held in Geneva in 1925 required signatory nations to limit the use of cannabis strictly for medical purposes. Fuelled by lurid propaganda emanating from the newly formed US Bureau of Narcotics (which evolved into the present day Drug Enforcement Administration), cannabis entered the pariah status that remains its lot today. Despite this, the medicinal potential of the plant still induces millions of otherwise law-abiding citizens to use it to relieve their symptoms. This has given rise to many legal anomalies: at the time of writing, 18 US states have decriminalized ‘medical marijuana’ even though it remains illegal under federal law.
Although there is increasing evidence of the efficacy of smoked or vaporized marijuana in the treatment of a variety of intractable conditions, it is unlikely that any such material will ever obtain regulatory approval for use as a conventional medicine. This paper will therefore focus on pharmaceutical preparations derived from components of cannabis, whether synthetic or plant-derived. Preclinical research has indicated a wide range of potential therapeutic applications for cannabinoid medicines, but only those with at least preliminary evidence of utility in humans will be described in this paper.
The endocannabinoid system (ECS)
The principal psychoactive ingredient of cannabis, delta-9-tetrahydrocannabinol (THC – also known as dronabinol), was identified in 1964. Early attempts to understand its mechanism of action centred largely on electrophysiological data which suggested that euphoria might be due to a depression of inhibitory activity in the septum, cerebellum, and thalamus. Enlightenment came with the discovery in 1988 and subsequent cloning of a specific protein receptor (cannabinoid receptor-1; CB1R) for THC and its analogues located on nerve cells. The presence of a receptor implies the existence of endogenous ligands and the first of these ‘endocannabinoids’, N-arachidonoylethanolamine (anandamide), was identified (again by Raphael Mechoulam et al.) in 1992. A second ligand, 2-arachidonoylglycerol (2 AG), came to light soon after. At about the same time a second cannabinoid receptor (cannabinoid receptor-2; CB2R), this time on blood cells and immune tissue, was discovered and cloned. The development of specific antagonists for these two receptors permitted detailed evaluation of their physiological roles, and in time the mechanisms for the synthesis, transport, and catabolism of these ligands were ascertained. For a more detailed review of the endocannabinoid system see Di Marzo et al.
The CB1R is the most abundant G protein coupled receptor in the central nervous system (CNS), and is particularly highly expressed in the neocortex, hippocampus, basal ganglia, and cerebellum. Significant densities are also found in certain areas of the brainstem (but not the medullary respiratory centres), spinal cord, and peripheral nerves. This distribution matches quite closely the known pharmacology of THC, which acts as a partial agonist at CB1Rs. Neurotransmitter release and postsynaptic depolarisation triggers on-demand synthesis of endocannabinoids from arachidonic acid. These travel in a retrograde direction across the synapse to activate presynaptic CB1Rs which then inhibit further neurotransmitter release through inhibition of adenylate cyclase, mitogen-activated
protein kinases, and voltage-activated Ca2+ channels, and stimulation of inwardly rectifying K+ channels. By modulating both excitatory and inhibitory neurotransmitters, this negative feedback
system permits fine control of a wide range of physiological functions. Taking into account the additional influence of CB2Rs, these include immune response, learning, food intake, pain transduction, emotion, perception, behavioural reinforcement, motor co-ordination, body temperature, wake/sleep cycle, hormonal function, bone formation and destruction, and apoptosis.
There is growing evidence that the ECS is deranged in a wide range of medical and psychiatric conditions, either as part of the physiological response or as a component of the underlying pathology. The ECS is thus a plausible target for a novel pharmacological approach to many currently intractable disorders, either by targeting the receptors directly with agonists or antagonists, or by augmenting the endocannabinoids themselves.[9,11]