The Δ9 -THC-induced suppression of conditioned nausea could be reversed by a CB1 receptor antagonist/reverse agonist , implicating the CB1 receptor in this effect . Limebeer et al. demonstrated that, unlike OND, Δ9 -THC also interfered with the expression of conditioned gaping elicited by the LiCl paired contextual cues in rats. This finding was consistent with the demonstration that Δ9 -THC, unlike OND, also suppressed the expression of conditioned retching in shrews when returned to a LiCl-paired context . The primary non-psychoactive compound found in marijuana, cannabidiol , has also been shown to suppress nausea and vomiting. In shrews, vomiting elicited by LiCl is suppressed by low doses of CBD, while higher doses were found to facilitate vomiting, rather than reducing its expression . Additionally, CBD reduced conditioned retching in shrews elicited by a lithium-paired context . In rats, a dose of 5 mg/kg CBD interfered with the establishment of conditioned gaping elicited by a LiCl paired flavor, as well as its expression . Because CBD has not been shown to bind with known CB receptors, this suppression of nausea and vomiting does not appear to be linked to activity of the CB1 or CB2 receptors . These results suggest that the primary nonpsychoac tive compound found in marijuana may be a useful treatment for conditioned nausea. Arachidonylethanolamide or anandamide is an endogenous agonist for cannabinoid receptors which is rapidly degraded by the fatty acid amide hydrolase that is distributed throughout the brain and periphery . The action of AEA can be prolonged by inhibiting its degradation, through the use of URB597 , an FAAH enzyme inhibitor, that can increase basal levels ofAEA in the rat brain . URB adminis tration has been shown to reduce the establishment of conditioned gaping elicited by LiCl-paired saccharin solu tion in rats . Thus, prolonging the action of AEA with the FAAH inhibitor URB has been shown to suppress the establishment of conditioned nausea in rats. The experiments described below evaluated the potential of the non-psychoactive component of marijuana, CBD,hydroponic system for cannabis and the FAAH inhibitor, URB, to interfere with conditioned gaping elicited by a LiCl-paired chamber in rats.
On each of four conditioning trials, rats were injected with LiCl-paired immediately before placement in a distinctive context laced with the odor of vanilla extract. After the conditioning trials, the rats were injected with CBD or URB before placement in the distinctive CS context. Additionally, experiment 2 evaluated the potential of the CB1 antagonist/ inverse agonist, SR141716A , to reverse the suppres sion of conditioned gaping produced by URB. Finally, in experiment 3, the ability of URB to interfere with the establishment of conditioned gaping was also assessed. In each experiment, to ensure that the suppression of conditioned gaping was not merely an artefact of drug-induced suppression of general activity, the number of seconds that the rats remained immobile was recorded as a measure of activity. The doses of CBD were selected on the basis of our previous work demonstrating that these lower doses suppressed lithium induced vomiting in the shrew, but higher doses potentiated vomiting. Furthermore, a dose of 5 mg/kg of CBD interfered with the establishment and the expression of conditioned gaping elicited by a lithium paired flavour . The doses of URB were chosen based upon results showing that in vivo FAAH activity is blocked with a half-maximal inhibitory dose of 0.15 mg/kg ip with concurrent increase in brain AEA . Additionally, a dose of 0.3 mg/kg has been shown to attenuate the establishment of conditioned gaping elicited by a flavored stimulus .When re-introduced to a context previously paired with LiCl, rats display conditioned gaping ,a measure of conditioned nausea. The expression of this gaping reaction is not reduced by pre-treatment with a classic anti-emetic agent, OND, as has been reported by human chemotherapy patients; however, the psychoactive component in marijuana, Δ9 -THC, did suppress conditioned gaping elicited by a LiCl-paired chamber . In agreement with the gaping data with rats, Parker et al. reported that shrews display a conditioned retching reaction when re-introduced to a chamber previously paired with LiCl and this conditioned retching reaction was sup pressed by pre-treatment with Δ9 -THC or CBD, but not OND. The present findings provide additional support for the potential of cannabinoid treatments to suppress AN on the basis of results with the rat gaping model. Experiment 1 demonstrated that low doses of CBD that suppressed LiCl-induced vomiting and conditioned retching in the shrew as well as the establishment and the expression of gaping elicited by a LiCl-paired flavor in the rat , also suppressed the expression of gaping elicited by LiCl-paired context in the rat.
A low dose of 5 mg/kg CBD has also been reported to serve as an effective anti-inflammatory agent , as well as a neuroprotective antioxidant . As CBD is a non-psychoactive component in marijuana, the ability of CBD to suppress conditioned gaping is promising for its use in the suppression of AN. The effective anti-nausea range of CBD appears to be narrow because at the highest dose tested , CBD did not suppress the expression of gaping elicited by a LiCl-paired context. Our previous work with the Suncus murinus revealed that although doses of 1–10 mg/kg CBD reversed LiCl-induced vomiting, higher doses potentiated LiCl-induced vomiting. It is possible, that CBD also produces a biphasic effect on the expression of conditioned gaping with lower doses reducing the expression of conditioned gaping, but higher doses enhancing the expression of gaping elicited by a LiCl-paired context. Experiments 2 and 3 demonstrated that the FAAH inhibitor, URB, also suppressed the display of AN as measured by gaping in rats. Presumably, prolonging the action of endogenous AEA produced an anti-nausea effect when rats were re-exposed to the LiCl-paired context. The effect of URB on the expression of conditioned gaping was dose-dependent,cannabis drying rack with 0.3 mg/kg serving as the effective dose. The suppression of gaping by URB was reversed by pre-treatment with the CB1 antagonist/inverse agonist, SR141716A, suggesting a CB1 mechanism of action. URB also interfered with the establishment of conditioned gaping when administrated before each pairing of the contextual stimuli with LiCl. This finding was consistent with that recently reported by Cross-Mellor et al. demonstrating that URB interfered with the estab lishment of conditioned gaping elicited by exposure to a LiCl-paired flavor. Presumably, URB reduced the nausea produced by the LiCl resulting in weaker conditioning. The potential of CBD or URB to suppress the gaping reactions during re-exposure to the context previously paired with LiCl-induced nausea might also be accounted for by interference with memory for the previously established association, rather than by interference with conditioned nausea per se. The design of the present experiments cannot discriminate between these two potential mechanisms; however, a memory deficit explanation is less tenable in light of the finding in experiment 1 that the highest dose of CBD did not modify the expression of gaping. Furthermore, at a dose of 5 mg/kg CBD neither affected the acquisition nor retrieval of a floor-amphetamine association in a conditioned place preference task or of a flavor-lithium association in a conditioned taste avoidance task .
Finally, Varvel et al. reported that mice pre-treated with the FAAH inhibitor, OL-135, as well as FAAH knockout mice with elevated central AEA levels, did not display memory impairment or motor disruption in a spatial memory task ; in fact, the FAAH knockouts displayed a significant increase in acquisition rate. The unpleasant experience of AN reported by chemother apy patients may impact the patient’s resolve to continue treatment. Because classic anti-emetics such as OND have proven ineffective in the alleviation of AN, there is a need to develop effective pharmacotherapies. The current findings, along with past research provide support for the role of the EC system in the suppression of nausea to a context previously paired with illness. Through the use of the FAAH inhibitor URB, the action of AEA is prolonged, interfering with the expression of the conditioned gaping response to a context paired with illness, as a model for anticipatory nausea in rats. As URB administration modulates the EC system, it may be a preferred therapeutic over exogenously adminis tered cannabinoids, in the alleviation of conditioned nausea.Obtaining informed consent for human participation in research is a regulatory obligation; however, it is also an ethical priority. Every effort should be made to ensure all aspects of study participation are clearly presented and easy to understand . Institutional review boards are the administrative bodies that enforce the federal regulations for protection of human research subjects with a goal of evaluating the probability and magnitude of potential risks of harm against potential benefits of knowl edge gained, recommending strategies for managing risks and generally promoting rigorous and ethical research. Although IRBs are responsible for reviewing and approving the information presented about a study, the actual process of obtaining informed consent from a potential research participant can vary both within and across studies. As a result, the informed consent delivery processes can range from simply letting the prospective participants review the informed consent information alone to actively engaging with individuals in a face-to-face discussion to increase the likelihood that study information is understood by the prospective volunteer to make a decision about participation . Whereas informed consent is a cornerstone of behavioral and biomedical research ethics , there are no requirements to assess whether the informed consent process used in a particular study is effective in facilitating authentic informed consent. Research on this topic, however, suggests as many as 50% of participants do not understand some or all components of informed consent across surgical and clinical trials . There are likely several reasons for this: the inclusion of research-oriented language with which many participants may not be familiar ; the inclusion of complex, IRB-required language addressing liability ; and the extensive length of consent documents, which often makes them difficult to navigate and comprehend . Individual IRBs typically require informed consent documents be at or below a certain grade reading level, often ranging from 5th grade to 10th grade reading levels ; however, many informed consent documents have reading levels well above those standards .
For example, one study examined readability of 124 HIV clinical trial consent forms and found median readability of 9.2 grade level, with confidentiality sections at a median of 12.6 grade level and overall document length almost 30 pages on average . Ensuring participants are satisfied with the informed consent process is particularly important at research facilities that have long-term relationships with participants , and/or among vulnerable patient populations that may have particularly strong concerns about privacy protections and data confidentiality. For example, HIV is an acquired and potentially transmissible disease that is stigmatized in both social and medical settings . Although the body of research on people living with HIV is vast, there is only one study that specifically evaluated the thoughts of PWH on the informed consent process . This study, conducted 25 years ago, assessed the informed consent process for an HIV drug trial and found approximately 56% of participants reported understanding all information on informed consent forms and 21% thought too much information was included. Unfortunately, the authors did not evaluate participant thoughts about what information was the most or least helpful, which is necessary for improving the informed consent process. The lack of informed consent research among PWH highlights the need for greater understanding of how PWH perceive the informed consent process. This research on the consent process is essential if we are to improve the likelihood that consent is truly “informed,” and, moreover, ensure individuals have the information needed to provide their voluntary agreement to participate in research. There are validated assessment tools used to evaluate informed consent comprehension , Miller et al.. These tools have been useful particularly with populations with diminished cognitive capacity . While knowledge assessment tools can provide some indication that relevant information has been conveyed and, potentially understood, more research is needed to identify what influences meaningful and authentic informed consent. The purpose of this study was to evaluate the informed consent process used at a large U.S. HIV research center among participants with and without HIV. An overarching goal was to better understand participant perceptions to inform improvements of the informed consent content and process.