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Cannabis and its natural derivatives have emerged as promising therapeutics for multiple pathological and nonpathological medical conditions. For example, cannabinoids, the most popular and biologically active chemicals in cannabis, aid in many clinical ailments, including pain, inflammation, epilepsy, sleep disturbances or insomnia, multiple sclerosis, anorexia, schizophrenia, neurodegenerative diseases, anti­nausea, and most importantly, cancer. Despite the comprehensive benefits, certain aspects of cannabis present unique challenges in the medical cannabis landscape. Recent studies have highlighted the inherent challenges associated with cannabinoids' formulation like low solubility, rapid metabolism, poor bioavailability, and erratic pharmacokinetics - all of which contribute to the limited efficacy of cannabinoids. Several efforts are underway to address the bottlenecks and modify the formulations along with the delivery systems to achieve greater solubility/bioavailability, potency, and efficacy in treatment settings while minding the necessary standards for purity associated with the pharmaceutical industry. The current article presents a perspective on (1) a working knowledge of cannabinoids and their mechanisms of action, (2) the landscape of using medicinal cannabis for cancer-related medical conditions along with adversities, (3) current approaches, formulations, and challenges in medicinal cannabis delivery systems (oral, transdermal, pulmonary, and transmucosal), and lastly, (4) emerging approaches to improve delivery systems. Keywords: Cannabis, Cannabinoids, Cancer, Pain, Nanomedicine, Drug delivery systems, Author(s): Manikandan Palrasu; Lillianne Wright; Manish Patel; Lindsey Leech; Scotty Branch; Shea Harrelson; Saeed Khan Introduction: What Are Cannabinoids and How Do They Work? Cannabis and the bioactive derivatives come [...]

This study investigates motilin effects on the proximal stomach in patients with functional dyspepsia (FD) and healthy volunteers. Eight healthy volunteers and 12 patients with FD were infused with synthetic motilin or placebo. Proximal gastric volume was measured with a barostat at constant pressure and during isobaric distensions. Abdominal symptoms were scored by visual analog scales. Plasma motilin concentrations were measured by radioimmunoassay. Motilin concentrations and baseline gastric volumes were similar for patients and healthy volunteers. Motilin, compared with placebo, reduced gastric volume by 112 ml [F(29,195); confidence interval (CI) 95%] in patients and by 96 ml [F(-7,200); CI 95%] in healthy volunteers. In patients, motilin decreased compliance by 76 mi/ mmHg [F(9,143); CI 95%] compared with placebo, which was similar in volunteers [66 mi/mmHg; F(11,120); CI 95%]. Patients were more nauseous during motilin compared with placebo (P = 0.04), whereas healthy volunteers did not experience nausea. We conclude that in a fasted condition, FD patients have a similar proximal gastric motor response to motilin as healthy volunteers, but experience an exaggerated sensation of nausea. barostat; gastric volume; gastric volume waves

Our previous studies suggested that the cytokine tumor necrosis factor-[alpha] (TNF-[alpha]) may act within the neural circuitry of the medullary dorsal vagal complex (DVC) to affect changes in gastric function, such as gastric stasis, loss of appetite, nausea, and vomiting. The definitive demonstration that endogenously generated TNF-[alpha] is capable of affecting gastric function via the DVC circuitry has been impeded by the lack of an antagonist for TNF-[alpha]. The present' studies used localized central nervous system applications of the TNF-adsorbant construct (TNFR:Fc; TNF-receptor linked to the Fc portion of the human immunoglobulin IgG1) to attempt to neutralize the suppressive effects of endogenously produced TNF-[alpha]. Gastric motility of thiobutabarbital-anesthetized rats was monitored after systemic administration of lipopolysaccharide (LPS) to induce TNF-[alpha] production. Continuous perfusion of the floor of the fourth ventricle with TNFR:Fc reversed the potent gastroinhibition induced by LPS, i.e., central thyrotropin-releasing hormone-induced increases in motility were not inhibited. This disinhibition of gastric stasis was not seen after intravenous administration of similar doses of TNFR:Fc nor ventricular application of the Fc fragment of human immunoglobulin. These results validate our previous studies that suggest that circulating TNF-[alpha] may act directly within the DVC to affect gastric function in a variety of pathophysiological states. tumor necrosis factor-ex; gastric stasis; nausea

Physiology and Pathophysiology of the Interstitial Cells of Cajal: From Bench To Bedside. VI. Pathogenesis and therapeutic approaches to human gastric dysrhythmias. Am J Physiol Gastrointest Liver Physiol 283: G8-G15, 2002; 10.1152/ajpgi.00095. 2002.--This review describes recent advances in our knowledge about the pathogenesis and therapeutic approaches to human gastric dysrhythmias. A number of clinical conditions has been found to be associated with gastric slow-wave rhythm disturbances that may relate to the induction of nausea and vomiting. Human and animal studies indicate that multiple neurohumoral factors are involved in the generation of gastric dysrhythmias. Antral distension and increased intestinal delivery of lipids may cause slow-wave disruption and development of nausea. This may be mediated by cholinergic and serotonergic pathways. Similarly, progesterone and estrogen may also disrupt gastric slow-wave rhythm in susceptible individuals. Prostaglandin overproduction in gastric smooth muscle appears to mediate slow wave disruption in diabetes and with tobacco smoking. On the other hand, central cholinergic pathways play an important role in the genesis of gastric dysrhythmias associated with motion sickness. This may be mediated by vasopressin released from the pituitary. Although it is difficult to ascribe with certainty a causative role of slow-wave rhythm disturbances in the genesis of nausea and vomiting, the search has begun for novel antiemetic therapies based on their abilities to ablate or prevent gastric dysrhythmia formation. This includes the use of prostaglandin synthesis inhibitors, central muscarinic receptor antagonists, and dopamine receptor antagonists. Finally direct gastric electrical stimulation using a surgically implanted neurostimulator has shown promise in reducing emesis in patients with gastroparesis and gastric dysrhythmias. nausea; tachygastrias; gastroparesis; prostaglandin; glucose; gastric pacing

Highly selective 5-hydroxytryptamine3 (5-HT3) receptors agonist, ondansetron, was utilized to determine the activity of 5-HT3 receptors during gastric distension and intraduodenal lipid infusion. Lipid infusion in the small intestines causes proximal gastric distensions that lead to nausea and vomiting in humans. The activation of 5-HT3 receptors by intraduodenal 5-HT3 leads to nausea. However, administration of ondansetron inhibited nausea and vomiting by blocking the activation of 5-HT3 receptors.

Vection-evoked dysrhythmias are mediated by central cholinergic pathways, and there is added regulation by alpha-adrenergic pathways. Roles of central cholinergic and alpha-adrenergic pathways in circular vection-evoked gastric dysrhythmias and nausea were studied on 8 volunteers with motion sickness histories, using vection (60 degrees/s) and electrogastrographic parameters.

Nausea occurs in up to half of all pregnant women, and if severe, may require hospitalization for weight loss and dehydration. The mechanisms underlying this nausea are not understood. In other conditions with nausea, dysrhythmias of the slow waves, which make up the basic electrical rhythm controlling the stomach muscle, have been found. To determine if slow-wave dysrhythmias are associated with the nausea of pregnancy as well, slow waves were studied in 26 pregnant women with nausea, 6 pregnant women without nausea, 6 postpartum women without nausea, and 16 healthy, nonpregnant women. Women who had nausea had faster, slower, or no slow waves, and this relationship was statistically significant. The study provides the first evidence that electrical-muscular abnormalities of stomach muscle contraction are present in pregnant women with nausea. Further study may be useful to relate the presence of regulatory hormones to the alterations in stomach muscle contraction. (Consumer Summary produced by Reliance Medical Information, Inc.)

Relationship between increasing duodenal lipid doses, gastric perception, and plasma hormone levels in humans. Am J Physiol Regulatory Integrative Comp Physiol 278: R1217-R1223, 2000.--Duodenal lipid causes gastric relaxation, CCK secretion, and nausea. Vasopressin has been implicated in motion sickness-related nausea. We hypothesized that increasing doses of lipid enhance gastric relaxation and CCK-vasopressin secretion, resulting in a dose-related exacerbation of nausea. Nine healthy subjects received isotonic saline or lipid (1, 2, or 3 kcal/min, L1, L2, L3) duodenally. Changes in gastric volume, sensations, and plasma hormone levels were assessed during infusions and isobaric gastric distensions. Lipid infusions increased gastric volume, plasma CCK (but not vasopressin) levels, and gastric compliance during distensions, compared with saline. Plasma CCK levels were related to the dose of lipid administered [CCK levels at 30 min (pmol/l), saline: 1.1 [+ or -] 0.2, L1: 1.8 [+ or -] 0.2, L2: 3.0 [+ or -] 0.2, L3:4.3 [+ or -] 0.6]. During distensions, nausea increased in intensity with increasing doses of lipid [score (where 0 is no sensation and 100 is strongest sensation), saline: 7 [+ or -] 4, L1: 19 [+ or -] 7, L2: 44 [+ or -] 7, L3: 66 [+ or -] 8]; however, no further rise in plasma CCK occurred. Because neither lipid nor distension alone induced significant nausea, we conclude that the interaction between these stimuli together with a modulation by CCK is responsible for the effects observed. Vasopressin is not involved in lipid- and distension-induced nausea. cholecystokinin; gastric distension; nausea; vasopressin; dose-response relationship

Jednak, Michelle A., Elizabeth M. Shadigian, Michael S. Kim, Michelle L. Woods, Forrest G. Hooper, Chung Owyang, and William L. Hasler. Protein meals reduce nausea and gastric slow wave dysrhythmic activity in first trimester pregnancy. Am. J. Physiol. 277 (Gastrointest. Liver Physiol. 40): G855-G861, 1999.--First trimester nausea is associated with gastric slow wave dysrhythmias (tachygastria, bradygastria). We tested the roles of meal composition and caloric content on nausea and slow wave rhythm in 14 nauseated pregnant women. Electrogastrography quantified dysrhythmic activity and signal power responses to meals. Symptomatic women reported mild to moderate nausea and exhibited increased dysrhythmias during fasting (P [is less than] 0.05). Protein-predominant meals reduced nausea and dysrhythmic activity to greater degrees than equicaloric carbohydrate and fat meals and noncaloric meals (P [is less than] 0.05). Meal consistency did not affect symptom responses, although liquid meals decreased dysrhythmias more than solids (P [is less than] 0.05). Carbohydrates and fats increased electrogastrographic power to similar degrees as proteins, whereas responses to noncaloric meals were less. In conclusion, protein meals selectively reduce nausea and gastric slow wave dysrhythmias in first trimester pregnancy. Meal consistency is a limited factor in the favorable effects of protein. Electrogastrographic power changes do not explain the symptom response to protein. Thus dietary modulation of gastric myoelectric rhythm with protein supplementation may provide symptomatic benefit in nausea of pregnancy. electrophysiology; gastrointestinal motility; electrogastrography; gastric emptying