terminal half-life of 25 to 30 hours (Abrams, 2016). When THC is ingested, it is initially metabolized in the liver to a psychoactive substance called 11-hydroxy-THC , explaining why people eating marijuana-baked products or capsules may report a more significant psychoactive effect compared with those who inhale it (Abrams, 2016). Original research leading to successful isolation of THC helped bring about the discovery and cloning of cannabinoid receptors (CB1 receptors) in 1990. THC acts on CB1 receptors, which also receive chemicals involved in normal brain function and development, and which share a common signaling pathway with opioids, promoting, and reinforcing each other’s properties. These CB1 receptors are located at presynaptic junctions, where they are involved in the regulation of ion channels and modulation of the release of dopaminergic, gamma- aminobutyric acid (GABA), glutamatergic, serotoninergic, adrenergic, and cholinergic neurotransmitters (Howlett, 1995). Working backward, if the human brain has specific cannabinoid receptors, it is unlikely that, from an evolutionary standpoint, humans would have developed them in response to chemicals found in plants. More likely, humans would only have evolved CB1 receptors in response to the existence of an endogenous ligand (an ion, atom, or molecule that binds to a protein) for the CB1 receptor. Based on this understanding, research ultimately led to the discovery of arachidonic acid ethanolamide, or anandamide, a naturally occurring human cannabinoid chemical. For differentiation, the term phytocannabinoid refers to constituents that occur naturally in the marijuana plant, as opposed to endocannabinoids, which occur naturally in lipid- The endocannabinoid system and drug development The study of drug development from a single plant such as marijuana, with its extensive cultural history, takes time, resources, and innovation. Because the marijuana drug market still includes massive amounts of whole-plant material, the trajectory for drug development involves people and professionals from many different societal and scientific paths. Agricultural scientists working where marijuana may be grown legally can develop plant cultivars, but vendors looking for plants with higher THC levels are working in the field as well. High- THC-level marijuana is what is being sold on the recreational market. More than 700 cultivars have been identified for Cannabis sativa and C. indica (Hazekamp & Fishedick, 2012). People with expertise in pharmacognosy, pharmaceutical and natural product development, study plants and their constituents to discover mechanisms of action for observed effects in humans that might be replicated in synthetic drug development. One of the primary foci of this work with marijuana has been to find ways to achieve therapeutic benefits from the plant without its psychoactive effects. Two major neuroactive phytocannabinoids (plant constituents) responsible for actions in the Cannabis plant are cannabidiol (CBD) and THC (Volkow, 2016). Much pharmaceutical drug development has been focused on separating and studying these two constituents from marijuana. The psychoactive effect attributed to THC is the primary concern of people involved in crude plant development for recreational use. Marijuana contains more than 500 identified phytochemical constituents, of which at least 104 are cannabinoids (Fasinu et al., 2016). Marijuana’s “phytocannabinoid” compounds have potential central nervous system action, with heterogeneous psychoactive effects and neuropharmacological actions. Research on the endocannabinoid system (ECS) is an emerging field attempting to answer public demand for greater scientific understanding of the marijuana plant at the center of the ongoing sociopolitical controversy over self-medication with marijuana. Healthcare professionals, parental advocates, and end users pose the questions that drive demand for drug development (Kendall & Alexander, 2017). The data most often utilized for forensic, legislative, and medicinal purposes are examination for the presence of
derived neurotransmitters found in the human body. In 1993, a second type of cannabinoid receptor was discovered and cloned, and while CB1 receptors are located predominantly in the central nervous system, these other receptors are expressed in peripheral tissues and are known as CB2 receptors (Turcotte et al., 2016). The cannabinoid THC attaches to C1 on neurons in various brain regions and activates them, causing disruption in mental and physical functions (NIDA, 2021c). People feel effects other than a “high.” These effects can include changes in mood, impaired movement, altered sense of time, sensory alterations, difficulty thinking and problem solving, and impaired memory (NIDA, 2021c). In higher doses of C. sativa or C. indica , people can also experience hallucinations, delusions, and psychosis (NIDA, 2021c). Chronic users of marijuana can generally distinguish between the highs produced by smoking Cannabis sativa versus the effects of C. indica . The C. sativa high is characterized as uplifting and energetic, felt in the head and described as spacey or hallucinogenic. C. sativa gives a feeling of optimism and well- being, along with pain relief, and it is used for daytime smoking. Cannabis indica provides an effect described as a “body high” that promotes relaxation, stress relief, and an overall sense of calm. Cannabis indicas are supposedly effective for insomnia and are therefore used in the late evening (Hazekamp & Fishedick, 2012). Stimulation of CB2 receptors in the periphery may contribute to other medicinal effects, such as counteracting inflammation (Thomas et al., 2007; Vučković et al., 2018). THC and tests that distinguish hemp (fiber) from marijuana (medicinal). However, the most widely studied and preferred medicinal constituent is CBD. Whereas THC exerts its pharmacologic effects by mimicking the body’s own cannabinoid neurotransmitters and binds to the two G-protein-coupled cell membrane receptors CB1 and CB2, CBD has little binding affinity for either of the two cannabinoid receptors. Instead, CBD binds to fatty acid-binding proteins (FABPs), which may explain its lack of psychoactive activity. These receptors are involved in the sensations of pain and cold and sensitivity to heat (Bisogno et al., 2001). Cannabidiol is seeing utility as a treatment of epilepsy, particularly in young patients (Klotz et al., 2018). So, while THC is responsible for the euphoric and psychotomimetic effects of marijuana, CBD demonstrates other medicinal effects, including analgesic, anti-inflammatory, and anxiolytic activity, without the psychoactive effects of THC (Fasinu et al., 2016; Ligresti et al., 2016). To date, the FDA has approved only two oral cannabinoid medications for cancer-related, chemotherapy-induced nausea and vomiting: dronabinol (Marinol, Syndros) and the synthetic cannabinoid nabilone (Cesamet; FDA, 2019; MedlinePlus, 2022). Although one meta-analysis of controlled trials has found these drugs to be helpful when compared with placebo, unfortunately neither of these medications represents a first- line therapy and they each exhibit variable success (Badowski, 2017; National Cancer Institute, 2022). Dronabinol is pure THC in an oil-filled, soft gelatin capsule. Nabilone is a synthetic analogue of THC. Designs for synthetic drugs are often derived from the chemical structures of original plants or constituents. Nabilone comes as a capsule and as a solution (liquid) to take by mouth. Dronabinol capsules and solution are used to treat nausea and vomiting caused by chemotherapy and are usually taken one to three hours before chemotherapy and then every two to four hours after chemotherapy, for a total of four to six doses a day. The first dose of the solution is usually taken on an empty stomach at least 30 minutes before eating, but the following doses can be taken with or without food. When dronabinol capsules and solution are prescribed to increase appetite, they are usually
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