taken twice a day, about an hour before lunch and supper. The person swallows the dronabinol solution with a full glass of water (six to eight ounces). Dronabinol may be habit forming. A potentially serious drug- plant interaction means that people taking dronabinol should not eat grapefruit or drink grapefruit juice (Prescribers Digital Reference [PDR], 2022). Dronabinol oil capsules are also contraindicated in those with sesame-oil sensitivities (PDR, 2022). Medical science is beginning to recognize that the interplay of different cannabinoids in combination (and in different ratios) 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 contain 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 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, challenges the user and healthcare professionals who care for them to be mindful of the person’s unique response to the herb or drug. Although there may be research studies, publications, and clinical guidelines that provide standardized dosing information, 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 medicinal qualities and actions of the plant upon various individuals. In Canada and 28 other countries, Sativex© was the first pharmaceutical-grade marijuana-based prescription medication to come to market, but as of summer of 2022 it was not yet approved for use in the United States (GW Pharmaceuticals, n.d.). 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 been approved Approximately 3.4 million people in the United States have epilepsy (Epilepsy Foundation, n.d.), and nearly 30% of those people are unresponsive to standard medications (Detyniecki & Hirsch, 2015). Symptomatic treatment of epilepsy is the most common strategy; however, antiepileptic drugs often have troubling side effects and fail in the treatment of temporal lobe epilepsy (Soltesz et al., 2015). It is understandable that parents of children who must wear crash helmets because of seizures uncontrolled by current pharmaceutical treatments would consider reaching for marijuana or a marijuana-based drug for their children. It may seem a rational choice when weighing the extensive body of historical (Felter & Lloyd, 1898/1983) and anecdotal (Pierre, 2017) clinical evidence for successful treatment with marijuana against the risk that a child faces every time he or she suffers a seizure. To date, there is a lack of quality clinical research evidence with sufficient sample sizes to support or negate marijuana’s traditional use in the treatment of seizures in people of any age. However, evidence is increasing that physiological states such as stress and pathophysiological conditions such as epilepsy modify the endocannabinoid signaling system (ECS).
by the FDA for treatment of two rare childhood epilepsy syndromes (FDA, 2018; Forster, 2018; Mathias, 2018). The endocannabinoid system 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. In this way, the ECS modulates 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 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. One hypothesis explores the possibility that an “endocannabinoid deficiency” may be responsible for some people’s positive responses when dosed with marijuana’s phytocannabinoids. This theory is based on genetic overlap and comorbidity, patterns of symptomatology that could be mediated by the ECS, and the finding that exogenous cannabinoid treatment frequently provides symptomatic benefit. Although objective support and formal clinical trial data have been lacking, “statistically significant differences in cerebrospinal fluid anandamide levels have been documented in migraineurs,” and imaging studies have demonstrated ECS deficiency in posttraumatic stress disorder (PTSD; Russo, 2016, p. 155). Additional studies have provided a firmer foundation for the notion of ECS deficiency, and clinical data show evidence of decreased pain, improved sleep, and other benefits to cannabinoid treatment and adjunctive lifestyle approaches affecting the ECS (Russo, 2016). In epilepsy, cannabinoid type 1 (CB1) receptors are markedly downregulated throughout the hippocampus in the acute phase shortly after the initiating insult, but they are upregulated in the chronic phase of the disorder (Soltesz et al., 2015). “The concurrent upregulation of CB1 receptors on GABAergic terminals and downregulation of CB1 receptors on glutaminergic axons that takes place in epilepsy may mechanistically contribute to seizures” (Soltesz et al., 2015, p. 272), but the importance of these biological processes is not well understood. Studies have shown that the ECS plays an important role in modulating seizure activity, and deficiency or defect in the ECS is being studied as the possible cause for seizure. For example, one study published in the New England Journal of Medicine (Friedman & Devinsky, 2015) found lower levels of anandamide in cerebrospinal fluid in people with epilepsy than in healthy people serving as study controls. It is well documented that cannabinoids can provoke seizures, depending on the dosage, the content and ratio of the CBD and THC, and the underlying conditions in the patient. However, anti-seizure medications that are already on the market are known also to provoke seizures in some patients and to be associated with clinically significant
COMMON MEDICINAL USES AND EVIDENCE OF EFFECTIVENESS FOR MARIJUANA Epilepsy
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