No description available.

Indiana University-Purdue University Indianapolis (IUPUI) / Environmental exposure to lead (Pb) and cannabis use are two of the largest public health issues facing modern society in the United States and around the world. Exposure to Pb in early life has been unequivocally shown to have negative impacts on development, and recent research is mounting showing that it may also predispose individuals for risk of developing substance use disorders (SUD). At the same time, societal and legal attitudes towards cannabis (main psychoactive component delta-9-tetrahydrocannabinol) have been shifting, and many American states have legalized the recreational use of cannabis. It is also the 3rd most widely used drug of abuse in the US, and rates of cannabis use disorder are on the rise. This thesis sets out to establish whether there is a link between early life Pb exposure and later THC-related behavior in C57BL6/J mice, as has been demonstrated for other drugs of abuse. The first aim seeks to answer whether Pb exposure affects physiological THC sensitivity (as measured by the cannabinoid-induced tetrad). The second aim seeks to answer whether Pb exposure affects edible THC self-administration and the development of THC tolerance (also measured by the tetrad). It was hypothesized that Pb exposure would decrease THC sensitivity (Aim 1), would enhance THC self-administration (Aim 2), enhance the development of THC tolerance (Aim 2), and finally that sex-dependent effects of Pb-exposure and THC would be observed (Aims 1 & 2). These hypotheses ended up not being supported, but Aim 1 produced findings indicating that THC sensitivity was increased by Pb exposure, but only in female mice. Future research will hopefully be able to fully explore the implications of these findings.

Thesis (Ph. D.)--Virginia Commonwealth University, 2007. / Prepared for: Dept. of Microbiology and Immunology. Bibliography: leaves 92-108. Also available online via the Internet.

Thesis (Ph. D.)--Virginia Commonwealth University, 2009. / Prepared for: Dept. of Microbiology and Immunology . Bibliography: leaves 118-133 . Also available online via the Internet.

The etiology of many gestational disorders is still unknown. However, insufficient trans-placental passage of nutrients and wastes due to poor placentation is characteristic of several pathologies and may be due, in part, to altered function of placental mitochondria. Mitochondrial activity is essential in pregnancy because it sustains the metabolic activity of the placenta throughout gestation. Exposure to stressors that perturb processes governing placentation, including maternal drug use, can negatively impact fetal development. Cannabis use is prevalent during pregnancy. The psychoactive constituent, delta-9-tetrahydrocannbinol (THC), can cross the placenta to affect placental and fetal physiology. Importantly, cannabinoid receptors have been reported on trophoblast cells, and on mitochondria which are abundant in placentae. It has been reported that THC may target the mitochondria in various tissue types, including placental tissue, and alter its function. However, few studies have addressed the physiological control of mitochondria within the placenta, an organ that is critical for fetal growth and pregnancy maintenance. I investigated the role of mitochondria in trophoblast differentiation and syncytialization using rotenone, a complex I inhibitor. Subsequently, I investigated the role of THC on two important aspects of placentation – invasion and syncytialization – using placental trophoblast cells HTR8/SVneo and BeWo, respectively. In response to rotenone and THC, there was increased ROS production, oxidative stress, and altered transcriptional markers favouring mitochondrial fragmentation. Treatment with 20µM THC for 48 hours led to reduced mitochondrial respiration, ATP production and loss of mitochondrial membrane polarity. Critically, these THC-induced mitochondrial changes occurred concomitant with evidence of reduced trophoblast invasion and syncytialization. Furthermore, THC exposure reduced levels of human chorionic gonadotropin, human placental lactogen and insulin-like growth factor 2, which are growth factors necessary for fetal development. Placental mitochondrial dysfunction, particularly when THC-induced, may be critical in a range of gestational disorders which have important implications for maternal and fetal/offspring health. / Dissertation / Doctor of Philosophy (Medical Science) / Cannabis is commonly used by pregnant women. Fetal exposure to cannabis and its components can impair fetal growth and neurological development. These negative fetal outcomes may be the result of poor placental formation, due to placental cell exposure to cannabis and its psychoactive component, delta-9-tetrahydrocannabinol (THC). Importantly, THC can also target intracellular organelles, like the mitochondria which are known as the “powerhouses” of the cell. Few studies have investigated the direct effects of THC on placental development. The purpose of this study was to determine how THC exposure to placental cells may alter their function. We found that THC impaired processes that allow placental attachment to the uterus and form a protective barrier, and compromised mitochondrial function, which are important for placental formation. These findings serve to inform scientists and doctors, thus stimulating the creation of new ideas and methods to further explore the impact of THC on pregnancy outcomes.

The effect of Marinol, which contains the antiemetic tetrahydrocannabinol (THC), was evaluated in five cancer patients undergoing chemotherapy. Subjects rated their nausea and vomiting, food intake, appetite and mood status three times daily. Drug therapy (THC) or no drug was administered for an average of four months during the course of their chemotherapy regimen. Subjects began taking THC the first day of chemotherapy and continued (5mg/three times a day) for an average of two weeks. Subjects reported their nausea and vomiting to be increased while receiving THC which coincided with their period of chemotherapy treatment. Subjective ratings for food intake and appetite varied in each case and did not always correlate with actual caloric intake from food. Food intake in most subjects was approximately the same, or greater with THC even though the period when THC was given coincided with chemotherapy treatment, and the use of emetigenic drugs. This resulted in weight maintenance or minor weight loss in most subjects. The absence of THC during chemotherapy treatment resulted in decreased food intake. Some of the moods reported most frequently by subjects while receiving THC were activity, interaction, and relaxation. Depression, social withdrawal, and anxiety were reported less frequently and usually occurred around the time of chemotherapy. The majority of the moods reported indicated that subjects had positive feelings associated with THC therapy. The results of this study indicated that THC benefitted cancer patients by increasing food intake during chemotherapy regimens without causing adverse behavioral changes. / Master of Science

Thesis (Ph. D.)--West Virginia University, 2004. / Title from document title page. Document formatted into pages; contains xi, 124 p. : ill. (some col.). Vita. Includes abstract. Includes bibliographical references (p. 111-121).

Road fatalities related to marijuana intoxication have steadily increased over the last 10 years (Drummer, 1994; Drummer, 1998; Drummer & Gerostamoulos, 1999). This has led to the introduction of sobriety testing in Victoria, Australia to test for driving impairment caused by marijuana and other psychotropic drugs. Surveys have reported an increase in community concern in Australia over the use of marijuana and an increase in the prevalence and use of marijuana (National Campaign Against Drug Abuse Survey; 1985, 1988, 1991, 1993; National Drug Household Survey; 1995, 1998). Commensurate with the increase in the use of marijuana in society, road statistics indicated that the number of road accidents and deaths involving the presence of THC (the active ingredient in marijuana) in driver specimens has also increased (Drummer & Gerostamoulos, 1999). Consistent with these mortality statistics, past research examining the effects of THC on driving ability indicate that THC impairs both car control (Moskowitz, 1985), and the maintenance of the lateral position of a vehicle (Ramaekers et al., 2000). Intoxication by THC is more likely to result in the crashing into obstacles on a driving course than when not intoxicated (Hansteen et al., 1976). These findings indicate that marijuana impairs driving ability and since the prevalence of marijuana use is increasing this poses a significant risk on our roads. It is essential therefore, that a tool that detects levels of THC in drivers, similar to breath analysis instruments used for the detection of alcohol in drivers, is introduced. To date, there is no such reliable instrument, that could be used on the roadside, and that accurately measures the level of THC in humans. For this reason, some government departments have considered the use of sobriety tests to detect impaired driving. In particular, the Standardised Field Sobriety test (SFSTs) that comprises the Horizontal Gaze Nystagmus test (HGN), Walk and Turn test (WAT) and the One Leg Stand test (OLS) were implemented in Victoria, Australia from December 1st 2000. The validity of these tests have been previously examined by other researchers and their conclusions suggest that sobriety tests have a varied accuracy in detecting impairment caused by drugs, ranging from 44% to 94% (Heishman et al., 1996; Compton, 1986). The present study examines the efficiency of sobriety tests to detect impairment in driving caused by marijuana. The SFSTs were examined, as well as the Romberg Balance test (RB) and the Finger to Nose test (FTN) taken from the Drug Evaluation and Classification Program (DECP) (Los Angeles Police Department, USA). The present study was conducted by Swinburne University, Victoria, Australia. The National Institute on Drug Abuse in the USA (NIDA) provided the marijuana cigarettes. The major objectives of the study were to examine the influence of cannabis on driving performance and on performance on the sobriety tests. The relationship between simulated driving performance and sobriety test performance was then examined to establish the accuracy of sobriety tests to predict driving ability. The present study also examined whether any differences in performance either on the driving tests or on the sobriety tests exist between regular cannabis users and non-regular cannabis users. Driving stress was an additional variable assessed to establish whether individuals with low, normal or high driver stress perform differently on the driving task after the consumption of a low and high dose of cannabis. We tested 40 participants comprising 14 females and 26 males. All participants completed a medical examination questionnaire, demographics questionnaire, Frequency of Cannabis Use Questionnaire and Intoxication Rating Questionnaire. All participants completed 3 marijuana sessions involving the administration of a placebo cigarette (0% THC, weight 702mg, .000gm ∆-9-THC; 0.0mg/kg THC), the administration of a low THC cigarette (1.74% THC, weight 779mg, .813gm ∆-9-THC; 0.2mg/kg THC) and the administration of a high THC marijuana cigarette (2.93% THC, weight 790mg, 1.776gm ∆-9-THC; 0.73mg/kg THC). All sessions were randomised (using Latin-square design), counter-balanced and double-blind. In each session, participants completed 3 sobriety tests and 2 driving simulator tests. Sobriety tests were scored by allocating a score of 1 for each sign (error, e.g., hopping during test performance to maintain balance) observed by the administrator. Generally, a score of 2 or more constituted impairment to a degree equivalent to a blood alcohol concentration (BAC) above 0.10%. The driving simulator test comprised 36 variables. Each time the participant performed an error, a loading factor was added to the corresponding variable (e.g., collision (variable) loading factor is 10, if a collision occurred twice a score of 20 was allocated to this variable). The sum of all 36 variables constituted the level of overall driving impairment. Blood samples were taken throughout each session approximately 20 minutes apart. Intoxication Rating Questionnaires revealed that participants reported that the subjective effect of placebo cigarettes was much weaker than the cigarettes that they usually smoke and that no psychological (such as time distortion) and physiological (such as increased heart rate) changes were experienced. For the low THC cigarettes most participants described the strength, and the effects, as similar to cannabis that they usually smoke. The high THC cigarette was described by most participants as being much stronger, and having some different symptoms, when compared to cannabis that they usually smoked. There were however, some differences in the description of the low THC and the high THC cannabis cigarettes between regular and non-regular cannabis users. Regular users reported that the high THC cigarette was more similar to the cannabis that they usually smoke, whereas non-regular users stated that this was more likely to be the case for the low THC cigarette. Results from the driving simulator task revealed that THC impaired the driving variables: �straddling the solid line� and �straddling the barrier line�. The results indicated that increasing levels of THC increasingly impaired the ability to maintain the steady position of a vehicle within the correct traffic lane. The consumption of low and high doses of THC resulted in two or more wheels of the vehicle moving over a solid line marked out for traffic moving in the opposite direction. Low and high doses of THC also resulted in two or more wheels of the vehicle moving over a broken/barrier line marked out for traffic moving in the same direction. Increasing levels of THC appear to impair both balance and attention required to control the position of a vehicle in traffic. These results are consistent with past research that indicates that THC impairs car control (Moskowitz, 1985) and increases the standard deviation of the lateral position of a vehicle (Smiley et al., 1981; Ramaekers et al., 2000). Research into the effects of THC on brain cannabinoid receptors indicate that THC interferes with normal functioning of the cerebellum, the brain region responsible for balance, posture, and the coordination of movement (Childers & Breivogel, 1998). When driving ability was impaired the level of THC in the blood was between 3 and 5 ng/ml. These findings are consistent with previous research that has reported that driving is maximally impaired by THC plasma levels of 13 ng/ml (approximately 8ng/ml in blood, using a multiplication factor of 1.6 (Giroud, et al., 2001) (Berghaus et al., 1995). The results of the present study also indicated that THC impairs performance on sobriety tests with more individuals impaired with increasing levels of THC (e.g., at Time 1; placebo: 2.5%, low THC: 23.1%, and high THC: 46.2%). Performances on the sobriety tests RB and FTN were unrelated to the level of THC. The test most related to the level of THC was the OLS test, where almost all signs of this test were observed, after the consumption of both low and high THC cigarettes. The accuracy of a �new� sign in the scoring procedure of the HGN test: head moves/jerks (HMJ) was also identified. Including HMJ increased the percentage of individuals scored as impaired after the consumption of low and high THC cigarettes (e.g., at Time 1; placebo: 2.5%, low THC: 38.5% and high THC: 56.4%). Including HMJ as a sign significantly improved the accuracy of the SFSTs to detect impairment associated with the level of THC. The mean level of THC in the blood, when the highest number of participants were classified as impaired, was 70 ng/ml. Differences in performance were observed between regular cannabis users and nonregular cannabis users. Non-regular cannabis users were more impaired on the driving simulator task after the consumption of low and high levels of THC when compared to regular users. Non-regular users recorded significantly longer RTs to emergency situations, more collisions, and shorter distances between the vehicle and an object (after an emergency stop) when compared to regular cannabis users. Signs exhibited during sobriety test performance were related to the level of THC more often for nonregular users compared to regular users. The level of THC in the blood was higher in regular users, compared to non-regular users, at all times in both THC conditions. When driving ability was impaired and significantly related to the level of THC, the SFSTs were also related to level of THC. Sobriety test performance was related to driving impairment, because, as driving impairment increased with the level of THC, so did the number of signs present during the performance of the sobriety tests. Since nonregular users performed more poorly on the driving task compared to regular users, it is no surprise that they exhibited a larger number of signs during the sobriety testing. Although there was a positive linear relationship between driving ability and sobriety tests, such as the relationship between straddling barrier lines and the OLS test, the validity of sobriety tests to predict driving impairment in part depends upon the size of this relationship. Using performance on the SFSTs to assess �impairment�, 46.7% of individuals in the high THC condition were impaired. A discriminant analysis was performed to determine whether the remaining 53.3% of participants were also impaired but not classified as impaired, or whether the SFSTs correctly classified them as not impaired. The results indicated that the sobriety tests (SFSTs; HGN, WAT and OLS) correctly assessed 76.3% of participants in the high THC condition as either impaired on driving or not impaired on driving. Specifically, this percentage included the correct identification of 84% of impaired drivers as impaired, but only 61.5% of unimpaired drivers as unimpaired. The best predictor of driving impairment was the OLS test. In the low THC condition the sobriety tests correctly classified 100% of impaired drivers as impaired, but this occurred at the expense of falsely classifying most unimpaired drivers as also impaired. This finding suggests that sobriety tests detect the presence of THC even when driving is not impaired. Examining the utility of including the �new� sign HMJ in the SFSTs indicated that when identifying impairment on the driving task performed at Time 2, in both the low and high THC condition, the SFSTs were a better predictor of driving impairment when HMJ was included than when the sign was not included. This finding suggests that the inclusion of HMJ in SFSTs scoring procedure increases the likelihood of detecting drivers who are impaired by THC. In conclusion, the results suggest that THC impairs driving ability by reducing one�s ability to maintain a safe position in traffic. At this time THC blood levels are between 3 and 5 ng/ml. THC also impairs driving ability differently for non-regular and regular users of cannabis, where non-regular users are more impaired by THC than regular users. When this occurs, THC blood levels in non-regular users are between 2 and 12 ng/ml, and in regular users between 5 and 16 ng/ml. Performance on the sobriety tests is also impaired by increasing levels of THC. The OLS test is the most sensitive test in detecting the presence of THC. In the present study the SFST battery and each individual test that it comprises are moderate predictors of driving impairment but do misclassify 16% of impaired individuals and 38.5% of not impaired individuals. In addition, the results suggest that sobriety tests are more sensitive to the presence of THC than actual driving impairment. This was revealed by the large number of individuals judged as impaired on driving in the low and high THC conditions even when driving was unaffected. It is important to note that when this occurred, the sobriety tests were accurate in detecting 100% of impaired individuals. Finally, the introduction of the �new� sign HMJ is likely to increase the accuracy of the SFSTs to detect individuals impaired by THC and this sign should be considered for inclusion by policing agencies.

Thesis (Ph.d.) - Swinburne University of Technology, 2001. / Submitted for the degree of Doctor of Philosophy, Swinburne University of Technology, 2001. Typescript. Includes bibliographical references (p. 160-169).

Thesis (M.S.)--University of Alabama at Birmingham, 2008. / Description based on contents viewed June 2, 2008; title from title screen. Includes bibliographical references (p. 32).