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The use of the plant species Cannabis sativa and Cannabis indica, popularly known as marijuana, has gained popularity in recent years for the management of a wide variety of medical conditions as a wave of legalization in North America has changed public and medical opinion on its use. Consequently, an expanding body of evidence has begun to emerge that has demonstrated its potential usefulness in the management of conditions such as chronic pain, spasticity, inflammation, epilepsy, and chemotherapy-induced nausea and vomiting among many others. This area of research is controversial and has been heavily debated, however, due to concerns over risks of addiction, long-term health effects, and Cannabis' association with schizophrenia. From a pharmacological perspective, Cannabis' diverse receptor profile explains its potential application for such a wide variety of medical conditions. Cannabis contains more than 400 different chemical compounds, of which 61 are considered cannabinoids, a class of compounds that act upon cannabinoid receptors of the body . Tetrahydrocannabinol (THC) and Cannabidiol (CBD) are two types of cannabinoids found naturally in the resin of the marijuana plant, both of which interact with the cannabinoid receptors that are found throughout the body. Although THC and CBD have been the most studied cannabinoids, there are many others identified to date including cannabinol (CBN), cannabigerol (CBG), Cannabidivarin (CBDV), and Tetrahydrocannabivarin (THCV) that have been shown to modify the physiological effects of cannabis . While both CBD and THC are used for medicinal purposes, they have different receptor activity, function, and physiological effects. THC and CBD are converted from their precursors, tetrahydrocannabinolic acid-A (THCA-A) and cannabidiolic acid (CBDA), through decarboxylation when unfertilized female cannabis flowers are activated either through heating, smoking, vaporization, or baking. While cannabis in its natural plant form is currently used "off-label" for the management of many medical conditions, THC is currently commercially available in synthetic form as Nabilone, as purified isomer as Dronabinol, or in a 1:1 formulation with CBD from purified plant extract as Nabiximols. Cannabinoid receptors are utilized endogenously by the body through the endocannabinoid system, which includes a group of lipid proteins, enzymes, and receptors that are involved in many physiological processes. Through its modulation of neurotransmitter release, the endocannabinoid system regulates cognition, pain sensation, appetite, memory, sleep, immune function, and mood among many others. These effects are largely mediated through two members of the G-protein coupled receptor family, cannabinoid receptors 1 and 2 (CB1 and CB2). CB1 receptors are found in both the central and peripheral nervous systems, with the majority of receptors localized to the hippocampus and amygdala of the brain. Physiological effects of using cannabis make sense in the context of its receptor activity as the hippocampus and amygdala are primarily involved with regulation of memory, fear, and emotion. In contrast, CB2 receptors are mainly found peripherally in immune cells, lymphoid tissue, and peripheral nerve terminals . The primary psychoactive component of Cannabis, delta 9-tetrahydrocannabinol (Δ9-THC), demonstrates its effects through weak partial agonist activity at Cannabinoid-1 (CB1R) and Cannabinoid-2 (CB2R) receptors. This activity results in the well-known effects of smoking cannabis such as increased appetite, reduced pain, and changes in emotional and cognitive processes. In contrast to THC's weak agonist activity, CBD has been shown to act as a negative allosteric modulator of the cannabinoid CB1 receptor, the most abundant G-Protein Coupled Receptor (GPCR) in the body . Allosteric regulation is achieved through the modulation of receptor activity on a functionally distinct site from the agonist or antagonist binding site, which is therapeutically important as direct agonists are limited by their psychomimetic effects while direct antagonists are limited by their depressant effects . There is further evidence that CBD also activates 5-HT1A serotonergic and TRPV1–2 vanilloid receptors, antagonizes alpha-1 adrenergic and µ-opioid receptors, inhibits synaptosomal uptake of noradrenaline, dopamine, serotonin and gaminobutyric acid and cellular uptake of anandamide, acts on mitochondria Ca2 stores, blocks low-voltage-activated (T-type) Ca2 channels, stimulates activity of the inhibitory glycine-receptor, and inhibits activity of fatty amide hydrolase (FAAH) . Due to the differences in receptor profile between CBD and THC, these cannabinoids are understandably used to treat different conditions. Furthermore, when combined with THC, CBD has been shown to modulate THC's activity, resulting in differences in pharmacological effect between "strains", or chemovars, of the Cannabis plant which are bred to contain different concentrations of CBD and THC. For example, strains containing a high proportion of CBD have been shown to reduce the psychosis- and anxiety-inducing effects of THC . Reliably studying the effects of Cannabis is complicated by the large variety of available strains and by the numerous other compounds that Cannabis contains such as terpenes, flavonoids, phenols, amino acids, and fatty acids among many others that have shown potential to modulate the plant's pharmacological effect .
