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 delta-9-tetrahydrocannabinol (THC) levels are working in the field as well. High-THC-level marijuana is what is being sold on the recreational market. Currently, more than 700 cultivars have been identified for Cannabis sativa and C. indica (Hazekamp & Fishedick, 2012).
Another group exists with expertise in pharmacognosy, pharmaceutical and natural product development. They 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 elucidate how to achieve therapeutic benefits from the plant without its psychoactive effects. Plant science has determined that there are two major neuroactive phytocannabinoids (plant constituents) responsible for some of the actions in the Cannabis plant, cannabidiol (CBD) and THC (NIDA, 2017c). 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, Phillips, ElSohly, & Walker, 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 THC and tests that distinguish hemp (fiber) from marijuana (medicinal). However, the most widely studied and preferred medicinal constituent is CBD. Where 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 is thought to explain why it lacks psychoactive activity. These receptor are involved in the sensation of pain, cold, and sensitivity to heat (Bisogno et al., 2001). More recently cannibidiol 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 and Ligresti, De Petrocellis, & Di Marzo, 2016).
To date, the U.S. Food and Drug Administration (FDA) has only approved two oral cannabinoid medications for cancer-related, chemotherapy-induced nausea and vomiting: dronabinol (Marinol©) and the synthetic cannabinoid nabilone (Cesamet©) (Marinol, 2017 and Cesamet, 2013). While one meta-analyses of controlled trials have found these drugs to be helpful when compared with placebo, unfortunately neither of these medications represents a first line therapy and they each have variable success, primarily because they have a single active ingredient (NCI, 2017).
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 1 to 3 hours before chemotherapy and then every 2 to 4 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 used to increase appetite, they are usually taken twice a day, about an hour before lunch and supper. The person swallows the dronabinol solution with a full glass of water (6 to 8 ounces). Dronabinol may be habit forming. People on dronabinol should not eat grapefruit or drink grapefruit juice due to a potentially serious drug-plant interaction (Prescribers Digital Reference [PDR], 2018). Dronabinol oil capsules are also contraindicated in those with sesame-oil sensitivities (PDR, 2018).
Medical science is beginning to recognize that it is the interplay of different cannabinoids in combination (and in different ratios) which may be the key to more effective pharmaceutical products in the future. Determination of the best plant sources of medicinal-grade marijuana typically involves analysis of 28 compounds, using a system such as principle component analysis. Different cultivars and marijuana extracts have variable amounts of THC depending upon the plant variety used in the preparation. Higher THC-to-CBD ratios are associated with more prominent psychoactivity (euphoric, relaxant, and anxiogenic effects), whereas low ratios of THC-to-CBD are more sedating (Fasinu et al., 2016). Cannabis indica has a higher CBD-to-THC ratio. Standardization of constituents in medicinal plants – including marijuana – that are so easily subject to environmental changes is challenging for manufacturers and researchers alike.
Dosing with a marijuana constituent such as THC or CBD, or for that matter with an FDA-approved drug such as dronabinol or nabilone, really challenges the user and healthcare professionals who care for them to be mindful of the person’s unique response to the herb or drug. There may be research studies, publications, and clinical guidelines that provide standardized dosing information, however, the psychoactive nature of THC still requires that it be considered for titration based on a user’s response. The ambiguity inherent in plant medicine practice generally is evidenced when partnering with marijuana. That ambiguity resolves over time as users and healthcare professionals become more knowledgeable concerning the qualities and actions of the plant as medicine upon various individuals.
In Canada and 28 other countries, Sativex© was the first pharmaceutical grade marijuana-based prescription medication to come to market, and it is currently being considered for release in the United States (Sativex, 2015, and Kendall & Alexander, 2017). Sativex© is a dimer of delta-9-tetrahydrocannabinol and cannabidiol and is indicated for use in adult patients with multiple sclerosis neuropathic pain or for cancer pain. Patients self-administer this buccal spray as a cannabinoid analgesic. In the United States, Epidiolex© (cannabidiol) has “cleared the last hurdle after the Drug Enforcement Administration labeled the drug as having a low abuse potential.” (Epidiolex, 2018) The company now plans to bring this treatment for childhood epilepsy to the U.S. market by the end of 2018 (Mathias, 2018).
The endocannabinoid system (ECS) is affected by stress, food intake, and behavioral change. Endocannabinoids act like dopamine in that they bind to specific receptor proteins located on the surface of some cells. A presynaptic dopamine neuron can produce endocannabinoid molecules that bind to cannabinoid receptors on adjacent GABA neurons, thereby reducing the amount of GABA being released (Fasinu et al., 2016). Inhibiting GABA neurons boosts the dopamine signal. The ECS functionally impacts synaptic communication with direct modulatory effects on pain perception, eating, anxiety, learning, memory, and growth and development in the central nervous system, as well as motor control, immune competency, tumor cell proliferation, and inflammation. The endocannabinoids may also “exert effects via non-CB receptors through certain serotonin or vanilloid receptor subtypes” (Fasinu et al., 2016, p. 784). Cannabinoids and their receptors are involved in basic physiology and pathophysiology, including roles in gene expression and possibly in mediating complex disease processes such as schizophrenia, cancer, neurodegeneration, and chronic pain. In addition to the brain, the ECS is found in many parts of the body. For example, the activation of cannabinoid receptors by endocannabinoids on epidermal cells regulates normal function of the skin as a barrier. Engaged CB1 and CB2 receptors can modify the proliferation, differentiation, and apoptosis of epidermal cells. Endocannabinoids also suppress inflammation in the epidermis.
Russo and others are exploring the hypothesis of “endocannabinoid deficiency” and its relationship to people’s positive responses to diseases when dosed with marijuana’s phytocannabinoids. First posed in 2001, this hypothesis was based on genetic overlap and comorbidity, patterns of symptomatology that could be mediated by the ECS, and the finding that exogenous cannabinoid treatment frequently provided symptomatic benefit. However, objective support and formal clinical trial data have been lacking. Currently, however, “statistically significant differences in cerebrospinal fluid anandamide levels have been documented in migraineurs,” and imaging studies have demonstrated ECS deficiency in posttraumatic stress disorder (Russo, 2016, p. 155). Additional studies have provided a firmer foundation for the notion of ECS deficiency, and clinical data shows evidence of decreased pain, improved sleep, and other benefits to cannabinoid treatment and adjunctive lifestyle approaches affecting the ECS (Russo, 2016).
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