Some studies have also analyzed the first and second half of the BART separately, to examine group differences in risky decision-making as the task progresses. A preliminary study of the BART in the current sample used this method and found that heavy drinking adolescents had a greater number of pumps on the second half of the task compared to controls, though after 5 weeks of abstinence, the groups were equivalent . In addition, at baseline, number of pumps on the second half of the task was positively correlated with number of recent alcohol binges and number of drinks per day. Although the lack of group differences in BART task performance within the current study allows for easier interpretation of the fMRI data, it is also important to consider the real-world generalizability of any laboratory measure of an abstract concept like risky decision-making. Another limitation to this study and all fMRI studies is that other variables may have affected the magnitude of the BOLD response other than the construct of interest . For example, heavy drinkers and controls differed in their use of cannabis and nicotine. However, findings remained unchanged after controlling for cannabis use. While tobacco use was not controlled for in this study, the level of use in the heavy drinking group was relatively low, and no participants met criteria for tobacco dependence. Therefore it is unlikely that tobacco use could have accounted for variability in BOLD response. Heavy drinkers and controls also differed in terms of verbal intellectual functioning and level of externalizing problems. However, level of externalizing problems was not controlled for, primarily because the difference observed on this variable was thought to represent a naturally occurring difference between adolescents who use substances and those who do not. Cerebral blood flow was not measured in this study and is known to have some effect on BOLD response. As resting state perfusion can affect the magnitude of the BOLD response , it is possible that differences in cerebral blood flow could explain BOLD response differences between heavy drinkers and controls.

A recent study by Jacobus and colleagues found that for heavy adolescent marijuana users, cerebral blood flow was reduced in four cortical regions and increased in one region at baseline ; however, after four weeks of abstinence, no between-group differences in cerebral blood flow were found. In extrapolating these findings to adolescent heavy alcohol users, it seems possible that cerebral blood flow could have an impact on the baseline between-group differences in BOLD response in this study, but may be less likely to impact BOLD response differences at the +2weeks and +4weeks time points. The issue of test-retest reliability of the BOLD response should be considered. There has been some controversy about this topic in the literature, as some studies have found high test-retest BOLD signal reliability , and others have reported considerable within-subject variation in BOLD signal change across scan sessions . Changes in BOLD signal response across different scan sessions for the same subject can occur for several reasons, such as fluctuating mood/anxiety/alertness states , levels of effort , motion, scanner drift , physiological changes , and developmental maturation. Many of these variables were measured and controlled for in this study. Specifically, acute anxiety and alertness were found to be equivalent between groups and are therefore unlikely to affect results. In addition, subpar effort was controlled for by removing subjects with five or more “Too Slow” outcomes within a given scan session, as it was assumed that subjects with a high degree of “Too Slow” responses were not adequately engaged in the task. Excess motion was controlled for by removing participants with more than 20% repetitions containing excessive head motion. Field maps applied to the fMRI acquisitions also helped to control the BOLD signal stability across scans, as this process minimizes warping and signal dropout, as well as reduces mislocalization errors, especially in frontal regions. Physiological changes and scanner drift were more difficult to control for and thus there is a small probability that these variables could have affected the reliability of the BOLD signal across repeated assessments in this study. Finally, the probability of Type I error in this study is likely higher than desired due to the large number of tests that were run within each hypothesis.

Although Hypotheses 1 and 2 included corrections for multiple comparisons within each ROI , there was no comparable correction for the number of comparisons examined across ROIs . Hypothesis 3 also did not employ any multiple comparison corrections, and these analyses should be considered exploratory. Taken together, the results of this study suggest that heavy drinkers display abnormalities in neural functioning during risky decision-making compared to their non-drinking peers, particularly in the right insula during anticipation and the ventromedial prefrontal cortex during evaluation of negative outcomes. Abnormalities in these regions appear to resolve after two to three weeks of abstinence. In addition, heavy drinkers showed some changes in BOLD response across repeated assessments , which provide further support for a neural recovery hypothesis. However, after five weeks of abstinence, heavy drinkers and controls show some differences in neural functioning that persist across time. This suggests that other regions of the brain may take longer to fully recover, or, that there are pre-existing differences in these regions,indoor weed growing accessories which could represent vulnerabilities for future substance use. In addition, this study suggests that differences in neural functioning in reward-related regions can effectively predict real-world report of risk-taking behavior. These findings are important as they suggest that neural functioning may be used as a potential biomarker for risk-taking vulnerability in the future. Future directions for this study should first include replication within a larger sample, to increase confidence in the findings. Second, an examination of the effect of length of abstinence from alcohol prior to study entry on BOLD response in the heavy drinking group will be necessary to determine whether variability in length of abstinence may have contributed to the between-group differences observed in this study. It would also be informative to analyze the first and second half of the BART task separately, as Hansen and colleagues did with the non-fMRI BART task. In addition, an examination of gender differences could be important, given results from previous studies suggesting that females may be especially susceptible to the effects of heavy alcohol use. Measures of hangover severity and withdrawal effects could also be investigated as possible moderating factors of group differences in BOLD response to risky decision-making, as these have been implicated as significantly related to performance on cognitive tasks in heavy alcohol users. The ultimate goal of this study and others like it should be to disseminate findings to youth and families, and to provide psycho education through the creation of prevention materials and public service campaigns. By understanding how the brain responds to risky decision-making after recent alcohol use, and how the brain’s circuitry may “repair” itself with sustained abstinence, adolescents could become motivated to remain abstinent from alcohol, which ultimately, would reduce the rates of accidents and deaths in this age group as a result of risky behavior. This work is being prepared for submission for publication as “fMRI Correlates of Risky Decision-Making in Adolescent Alcohol Users: The Role of Abstinence.” The dissertation author will be the primary author of this material along with co-authors Alan Simmons, Ph.D., Carmen Pulido, Ph.D., Susan Tapert, Ph.D., and Sandra Brown, Ph.D.

Two endogenous agonists of cannabinoid receptors have been well characterized and are now widely used in research: anandamide , and 2-arachidonoylglycerol . Both molecules derive chemically from the polyunsaturated fatty acid, arachidonic acid, which is used in nature as the starting material for other important signaling compounds, such as the eicosanoids. Additional endocannabinoid-related compounds present in the body include virodhamine, which may act as an endogenous antagonist of CB1 receptors, and arachidonoylserine, which may engage an as-yet-uncharacterized cannabinoid-like receptor expressed in the vasculature. As is well-known, the Cannabis plant contains more than 60 cannabinoids, which include -D9 -tetrahydrocannabinol , cannabigerol, cannabidiol, cannabinol, cannabichromene and cannabicyclol. Attention has been mostly focused on D9 -THC, because of its multiple biological properties. Nevertheless, less studied compounds such as cannabidiol may also be important, although we do not yet know at which receptors they may act to achieve their effects. D9 -THC is the only natural cannabinoid presently used in the clinic. In addition to these plant-derived cannabinoids, an extensive set of synthetic cannabinergic agonists has been developed over the last 30 years. Products of these efforts include CP-55940 , created by opening one of the rings of the tricyclic D9 -THC structure and introducing other small changes in its structure; HU-210 , a very potent cannabinoid agonist resembling some D9 -THC metabolites; and WIN55212-2 , which belongs to an altogether different class of chemicals, the aminoalkylindoles. Additionally, the metabolically stable synthetic analog of anandamideR-methanandamide is routinely used as a pharmacological probe to circumvent the short half life of the natural substance. Two important new additions to this armamentarium under discussion at the workshop include a peripherally acting cannabinoid agonist in preclinical development by Novartis for the treatment of neuropathic and inflammatory pain , andBAY-387271 , a centrally acting cannabinoid agonist in Phase II clinical studies for the treatment of stroke. The interest of the pharmaceutical industry in the application of cannabinoid agonists to the treatment of pain conditions is not recent. Indeed, most of the compounds now in experimental use derive from such an interest. Historically however cannabinoid agonist development has not proved clinically fruitful, largely because of the profound psychotropic side effects of centrally active cannabinoid agonists, hence the attention given to peripherally acting cannabinoids, which exhibit significant analgesic efficacy and low central activity in animal models. Neuroprotection is a relatively new area for cannabinoid agonists, but one that appears to be already well advanced. Preclinical studies have made a convincing case for the efficacy of cannabinoid agents not only in experimental brain ischemia, but also in models of Parkinson’s disease and other forms of degenerative brain disorders.

Another list which appears to include possible allies was found in tobacco industry documents that was handwritten on a copy of the Clean Environment Committee’s donation information sheet, but it is not known who wrote this list. This list included the “NE Tax Research Council, Chamber [of Commerce], Farm Bureau, Solid Waste – Retail Merchants, Smokers, Retail Grocers, University [of Nebraska], Cancer Research, Every Group That Is Currently Recieving Funding.”While the Clean Environment Committee was just getting their petition off the ground, the tobacco industry had their hands full with several other initiatives. Similar tax initiatives were further along in Massachusetts, Colorado and Oregon, and new ones were beginning in Arkansas and Oklahoma as well.The tobacco industry was already focused on these other initiatives and they did not take the threat posed by the Francis Moul and his group very seriously. As a result, the initial response by the tobacco industry was to simply monitor the progress of the Nebraska Clean Environment Committee. As Robert McAdam, Tobacco Institute Vice President of State Affairs for Initiatives, Referendums, and Special Projects, and Daniel Wahby, Director of Special Projects for the Tobacco Institute, stated in a memo to the Tobacco Institute Coordinating Committee, “It has been consistently believed that the proponents of this issue were not politically sophisticated enough to qualify this issue for the ballot. Now that they have filed this issue for circulation, we will be monitoring their activity closely to determine their progress.”Both McAdam and Wahby would lead the tobacco industry’s opposition to the Nebraska Clean Environment Act. Through the middle of May, the tobacco industry mainly focused on monitoring the progress of signature-gathering. A memo from McAdam to the Tobacco Institute Coordinating Committee on May 19, 1992 stated, “There is still little evidence that the proponents of this initiative have organized sufficiently to qualify this issue for the ballot. While they did have some petition gatherers located at polling places during this state’s primary election, they did not have the coverage necessary to obtain sufficient signatures.”At the same time, however, the tobacco industry started to spend money to fight the petition. On May 20, McAdam wrote to the Tobacco Institute Management Committee saying, “In an attempt to pay for some preparatory legal work and for a possible survey should the petition gatherers appear to be reaching their goal, I believe we need to allocate $40,000 for this campaign at this time.”By the middle of June, McAdam was beginning to take the initiative campaign in Nebraska more seriously.

His memo to the Tobacco Institute Coordinating Committee on June 15 stated, “While the proponents of the tax increase initiative in this state continue to appear somewhat disorganized, they have recently hired a professional consulting firm to help them gather signatures throughout the state. They have indicated to reporters that they plan to pay signature gatherers on an hourly basis. While it is still too early to determine if they will be successful, we have organized our legal approach to challenging certain aspects of the initiative, as well as the individual signatures that the proponents may submit.”By June 17, the first assessment for funds to combat the Nebraska initiative was prepared and sent to senior executives within Philip Morris, R.J. Reynolds, Lorillard and American Tobacco with the total amount being the $40,000 requested by McAdam, divided between the companies on the basis of market share.This money was to be sent to the Nebraska Executive Committee c/o Bill Peters,vertical grow system who was the Tobacco Institute’s lobbyist for Nebraska.These “Executive Committees” and other front groups with neutral to positive-sounding names, were led by the Tobacco Institute lobbyist in states where an initiative was underway.For example, money from the tobacco industry to defeat the initiative in Arizona was sent to the Arizona Executive Committee and in New Jersey, the checks were mailed to John O’Conner in the Tobacco Institute’s office in Albany, New York, but the checks were to be made payable to Citizens for Representative Democracy in West Trenton, New Jersey.In July, the Nebraska Clean Environment Committee submitted an estimated 48,000 signatures to the Secretary of State for certification.The total number of signatures that was needed to be placed on the ballot was.By then, the tobacco industry was actively attempting to recruit new allies to help in its fight against this environmental initiative. In addition to the “traditional” tobacco industry allies, which included business and tax groups,the Tobacco Institute was attempting to enlist the aid of WIFE, which stands for Women Involved in Farm Economics. WIFE is a national organization whose president in 1992 was Elaine Stuhr, who was elected a Nebraska state senator from Bradshaw in 1994 and remained in the Legislature as of 2003 . In a letter to Stuhr, Daniel Wahby, the Director of Special Projects for the Tobacco Institute, wrote, “First of all, I would like to take this opportunity to thank you and your organization for your interest in assisting our efforts in defeating the proposed 25 cents per pack excise tax on tobacco products.”Wahby tells Stuhr that he has asked Bill Peters to get in touch with her to give her more information. He states, “I apologize for not having specific information in writing as it relates to the farm community in Nebraska but I trust your conversation with Mr. Peters will give you some information to go on.”Bill Peters, the Tobacco Institute’s lobbyist, told reporters that the true number of signatures that needed to be obtained was more than 61,000 and not the 41,058 that the secretary of state said was necessary.The conflict came over whether language in the Nebraska Constitution required the number of signatures to exceed a percentage of the citizens that were registered to vote in the last election for governor or a percentage of citizens that actually voted in the last election for governor. While Nebraska was filing suit, a team of attorneys general were negotiating with the tobacco industry to create a new settlement to replace the Global Settlement Agreement.

Having learned from the failure of the Global Settlement, the attorneys general decided to limit their settlement negotiations with the tobacco industry to issues that they had the full authority to settle directly, rather than including legislative proposals. The deal that they brokered became the Master Settlement Agreement.In exchange for payments to the states determined by a complex formula related to cigarette consumption and inflation that extended indefinitely , public access to tobacco industry documents, limitations on advertising and promotions and disbanding the Council for Tobacco Research, the Council for Indoor Air Research and the Tobacco Institute, the states agreed to drop their lawsuits.In addition, the tobacco industry, having learned that a lengthy debate on the merits did not serve its interests, insisted that the individual states had to decide whether they would participate within seven days following announcement of the Settlement.This last component of the Master Settlement Agreement raised some concern with tobacco control advocates in Nebraska. Before the deal had been finalized between the attorneys general and the tobacco industry, the members of SmokeLess Nebraska and Mark Welsch of GASP were publicly worrying that seven days would not permit the State of Nebraska, particularly Attorney General Stenberg, to closely examine the details of the settlement before deciding whether or not to sign the agreement.Dave Holmquist of the American Cancer Society stated, “We just think seven days is an awfully short time to make a decision on something that will affect the American people for a long time to come.”When the Master Settlement Agreement was formally announced on Saturday November 14, 1998, it seemed highly likely that Nebraska would participate. By Monday Attorney General Stenberg and Governor Nelson came out in favor the settlement.Stenberg, who had final say on whether to sign the Master Settlement Agreement, said that he wanted to consult State Senator Roger Wehrbein , Chairperson of the Appropriations Committee, and State Senator Don Wesely , Chairperson of the Health and Human Services Committee, before making his final decision.Stenberg explained his rationale for favoring the settlement, saying, “It is unlikely that Nebraska would obtain a judgement of more than $1 billion [the estimated value of the MSA to the state over the first 25 years] if we refuse this settlement and continue our own lawsuit.”Early Tuesday November 17, 1998, Attorney General Stenberg announced that he had decided to accept the Master Settlement Agreement.Once again, Stenberg reiterated his position that he felt Nebraska would not receive as much in its own lawsuit as it would receive by participating in the Master Settlement Agreement. Governor Nelson stated that he felt that the settlement was not perfect but that it was acceptable; he said “I’ve never been one to let my desire for the perfect get in the way of the good.”By signing the Master Settlement Agreement, Nebraska’s share of the settlement over the first 25 years was estimated to be $1.17 billion.Annual MSA payments for Nebraska are between $38.1 and $49.9 million.In 1998, Nebraska established trust funds for the tobacco settlement money that the state was expecting to receive from the Global Settlement Agreement and which it eventually received under the Master Settlement Agreement. While the Legislature, responding to pressure from Governor Nelson, decided early on that the settlement money would be used for improvements to the state’s health infrastructure, the Legislature was less committed using the money received as a result of the state’s Medicaid expenditures due to smoking to actually reduce the harm done by smoking through tobacco prevention and control efforts. During the 1998 legislative session, when Nebraska was anticipating receiving money from the Global Settlement Agreement, Governor Nelson and state legislators, such as Don Wesely of Lincoln, the Chairperson of the Health and Human Services Committee, and Jim Jensen of Omaha stated their desire to ensure that the settlement money be applied to improving the healthcare system of the state.