Background A growing body of research suggests the therapeutic use of cannabis may affect the use of other substances, including reducing the use of alcohol, tobacco and prescription drugs such as opioid analgesics. However, most of the evidence stems from small, cross-sectional surveys or population-level studies, both of which have significant limitations, including the inability to conclusively determine causality for behavioural changes. Furthermore, very little detail has been gathered on the factors that potentially impact substitution, including patient characteristics and patterns of cannabis use (e.g., X, Y, Z). Additionally, despite consistent calls by physicians, academics, patients and policy-makers around the globe citing the need for high quality studies to identify the risks and benefits of cannabis in both medical and non-medical applications, there are many pre-existing and ongoing challenges to conducting such research. These include shifting regulatory policies that may be impacting access to cannabis for both medical and non-medical use, and that could ultimately be affecting patient retention in prospective medical cannabis studies. In the interest of learning more about how the use of cannabis effects the use of alcohol, tobacco and other substances, and to better understand factors that may be impacting retention in prospective cannabis research, I designed and conducted two studies: 1. The Canadian Cannabis Patient Survey 2019 (CCPS 2019) was a national cross-sectional survey of 2102 Canadian medical cannabis patients that examined demographics, patient patterns of cannabis use, and self-reported changes in the use of alcohol, tobacco, prescription drugs and illicit substances following medical cannabis initiation. 2. The Tilray Observational Patient Survey (TOPS) was a prospective, multi-site, observational study examining the impact of medical cannabis products on quality of life and the use of prescription drugs of 1145 patients over a 6 month period, which provided an opportunity to conduct a survival analysis and other analyses to assess variables potentially impacting retention in longitudinal cannabis studies. Methods This dissertation includes three analyses of the data resulting from these studies in the form of one published and two submitted manuscripts. The first paper provides an overview of research to date examining the impact of cannabis and cannabinoids on alcohol use, followed by an analysis of the 973 CCPS 2019 participants who either previously or currently use alcohol. The questionnaire gathered a detailed inventory of alcohol use prior and post medical cannabis initiation using two separate but related measures: drinking days per month, and standard drinks per week. The analyses used descriptive statistics as well as univariate and multivariate regression analyses to explore patient characteristics and other variables potentially associated with changes in alcohol use post medical cannabis, including assessing the impact of “intent” to use medical cannabis to reduce alcohol use, as well as participation in other substance use treatment modalities. Findings suggest that medical cannabis initiation is associated with significant reductions in alcohol use, and that younger age (<55 years of age), specific intent to use medical cannabis to reduce alcohol use, and greater patterns of alcohol use prior to medical cannabis initiation were associated with greater odds of reducing alcohol. The second paper follows a similar methodology and format as the first paper, but with a focus on tobacco/nicotine (T/N) use. In this case, 650 survey participants reported past or current T/N use, and the analysis focused on assessing patient characteristics and other variables associated with changes in T/N uses per day, with the primary outcome of interest being no use in the 30 days prior to the survey, which was considered to be complete cessation of T/N use. The findings suggest that odds of T/N cessation were greater amongst those who were age 55 or older or that reported >25 T/N uses per day prior to initiating medical cannabis use, and that specific intent to use medical cannabis in T/N reduction/cessation efforts resulted in significantly greater odds of reducing T/N use, while involvement with traditional T/N cessation treatments (pharmacological or psychobehavioral) was negatively associated with T/N cessation. The third paper addresses the challenge of retaining patients in prospective observational medical cannabis studies at a time when there are major policy changes disrupting the legal supply while also increasing access options for adults who use cannabis. The Tilray Observational Patient Study (TOPS) was one of the largest national prospective medical cannabis studies ever conducted, taking place at 21 medical clinics in five provinces. The study was designed to assess the impact of medical cannabis on quality of life and prescription drug use over a six month period. However, initial data analysis on 1145 patients enrolled at/before Oct 15, 2018 that had completed at least one post baseline visit highlighted a significant rate of patients that were lost to follow up (LTFU). This high drop out rate, coupled with a compensation scheme that provided credits to help cover the cost of medical cannabis led to concerns of potential retention bias limited the conclusions that could be drawn from this data. However, the study and resulting data provided a unique opportunity to examine baseline patient characteristics that may have been protective of LTFU, so a survival analysis was conducted on this cohort. Additionally, since the study took place during the official launch of the legalization of adult non-medical use of cannabis in Canada on Oct. 17th, 2018, the potential impact of this significant increase in legal access options on the odds of study retention was the subject of additional analyses. The survival analysis found that baseline use of antidepressants or antiseizure medications, citing no preference for either THC or CBD, and inhalation as a primary method of use were associated with increased probability of survival/retention in the study at six months. Additionally, while the legalization of non-medical adult cannabis use in October 2018 resulted in more than three times the odds of participants being LTFU at six months, being under 55 years old, having a preference for THC, or citing inhalation as a primary method of use was partially protective of LTFU following legalization. Discussion The studies in this dissertation presented an opportunity to gather subjective and objective data on naturalistic patterns of medical cannabis use from large, heterogeneous cohorts of patients, and to explore associated impacts on the use of alcohol, tobacco and other substances. The results of these studies provide a more comprehensive understanding of the public health risks and benefits associated with the medical use of cannabis, and could subsequently inform policy decisions affecting access to cannabis vis-à-vis other drugs, private and public payer considerations related to cost-coverage for medical cannabis, and potentially lead to the development of novel alcohol and tobacco cessation strategies. Additionally, the survival analysis conducted on TOPS participants highlights some of the challenges of conducting medical cannabis research at a time when patients have a multitude of cannabis access options, including legal adult dispensaries and a still robust illicit market. Future longitudinal medical cannabis studies should consider the potential impact of policy changes effecting cannabis access on study retention/survival, and may want to focus on patient populations with characteristics associated with lower odds of LTFU. / Graduate / 2022-03-09

AN ABSTRACT OF THE DISSERTATION OFBrett Lacey, for the Doctor of Philosophy degree in Criminology and Criminal Justice, presented on March 26, 2021, at Southern Illinois University Carbondale. TITLE: LEGALIZATION EFFECTS ON ILLEGAL MULTI-STATE CANNABIS DISTRIBUTION NETWORKS MAJOR PROFESSOR: Dr. Christopher W. Mullins Although a broad and detailed history of illegal cannabis trafficking networks exist, it remains a relatively understudied group in the current legal context. Prior research has been limited in three crucial aspects: it has been geographically limited to single states or jurisdictions, studies have been limited to examining one role while mentioning others only peripherally, and the majority of earlier similar studies were conducted from the 1980s through 2000s. It is unclear whether these findings represent current black market actors in the cannabis industry. This study will attempt to address these temporal, legal, and geographical gaps in empirical research through conducting in depth semi-structured interviews with 36 active illicit cannabis traffickers from California, Colorado, Illinois, and Oregon. Overall, it addresses how illegal cannabis distribution networks operate across varying roles, their decision making processes regarding legality, the processes involved in shipping or mailing cannabis, and the corresponding monetary system involved with conducting transactions without physical interaction. Overall findings mirrored prior research in that the black market of cannabis will persist and continue to flourish in the current legalization context. However, findings also indicated that black market actors are highly adept to adapting to policy, possess considerable business acumen, and detailed an entire system of trafficking and associated monetary system rarely mentioned previously. To theoretically contextualize this research, this study utilized institutional anomie theory, organizational adaptation theory, and rational choice theory.

The co-abuse of alcohol and marijuana is widespread, although the mechanisms underlying this behavior are unclear. There is some evidence of a relationship between the neural processes that mediate the effects of ethanol and marijuana. For example, research has shown that exposure to marijuana increases responding for, and intake of, ethanol. The alcohol deprivation effect is an anima l model of alcoholism that suggests that the reinforcing efficacy of ethanol, as measured by intake, increases following a period of deprivation. Recent research indicates that rats chronically exposed to marijuana during periods of alcohol deprivation consume ethanol above and beyond deprivation alone. It is unclear, however, whether the marijuana exposure or the repeated deprivations increased motivation to consume ethanol. In the present experiment, rats were trained to self-administer ethanol on a progressive ratio schedule and subjected to two separate periods of deprivation during which either drug or saline was chronically administered for 7 days. Breakpoint (i.e., last ratio completed) was recorded as a measure of the reinforcing efficacy of ethanol. Following deprivations, breakpoint was initially lower than baseline, regardless of whether the drug or saline was administered. Breakpoint recovered to, but did not exceed, baseline levels following both deprivations, indicating a lack of increased reinforcing efficacy of ethanol after repeated deprivation or chronic exposure to marijuana. The lack of an expression of an alcohol deprivation effect following deprivation may have been due to the length and number of deprivations employed. Furthermore, lowered breakpoint recorded following chronic drug administration during deprivation may have been due to the dose administered or stress generated by chronic injections . Further investigation is necessary to separate and clarify the variables responsible for the present results.

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Objective: To examine associations between in utero marijuana exposure and birth outcomes. Study design: In two separate cohorts (Appalachian, Rocky Mountain), data were collected from medical records. Marijuana exposure was positive based on urine drug screening at delivery, with nonexposed controls matched on multiple factors including other substance exposure. Result: Marijuana-exposed newborns (n = 531) had significantly worse birth outcomes than controls (n = 531), weighing 218 g less, 82%, 79%, and 43% more likely to be low birth weight, preterm, or admitted to the NICU, respectively, and significantly lower Apgar scores. Conclusion: Marijuana exposure in utero predicted newborn factors linked to longer-term health and development issues. Effects were not attributable to other comorbidities in this study due to rigorous matching and biochemical verification of marijuana and other drug use. Findings add to growing evidence linking marijuana exposure to adverse birth and longer-term outcomes. Women should be encouraged to avoid marijuana use during pregnancy.

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Adult marijuana users seeking treatment (N = 291) were randomly assigned to 3 treatment conditions: 1) a cognitive-behavioral relapse prevention support group (RPSG), 2) individualized assessment and advice group, and 3) delayed treatment control group. The purpose of this study was to examine the relationship between psychological distress, self-efficacy, and marijuana use. Measures of marijuana use, psychological distress, situational self-efficacy, coping self-efficacy, temptation to use, and frequency of encountering situations were used. Only a portion of the hypotheses were supported. Psychologically distressed individuals had lower self-efficacy for psychologically distressing (PD) situations as opposed to non-psychologically distressing (NPD) situations. Participants had lower self-efficacy for NPD situations than PD situations. The RPSG condition did not have the hypothesized effect on self-efficacy for PD situations. / Master of Science

The purpose of this study is to investigate the temporal order in the association between marijuana use and depression. There are two possible hypothesis examined, and for each of them is conducted a separate set of analyses. The dependent variable in the first hypothesis is current depression, predicted by previous and current marijuana use, abuse, and dependence. In the second hypothesis the dependent variables are current marijuana use, abuse, and dependence, predicted by previous and current depression. To conduct the analyses this study uses data from the National Comorbidity Survey (NCS). The NCS is an epidemiological research study of the prevalence, causes, and consequences of psychiatric disorders and comorbodity, analyzing data from a national sample of 8098 participants covering an age range from 15 to 54 years old. Results show that prior depression is the main predictor of current depression while marijuana use has a weak effect on current depression. Marijuana users are slightly more depressed than never users, but the lag of the effect is short. There is a strong association between marijuana use and abuse and other drug use and abuse. Findings show that prior marijuana and other drug use and abuse predict current marijuana use and abuse. There is a weak association between current depression and current marijuana use, and when controlled for prior marijuana use this association disappears. The results of this study provide no support for the coping theory. There is a clear pattern of comorbidity of both, mental disorders, and substance use and abuse. / Master of Science