Cannabis use in the United States has generally increased over the past decade as more States have legalized recreational use. In conjunction with changes to the chemical makeup, which has made available cannabis more potent, the long-term effects experienced by cannabis users may have changed, and more individuals may be effected. The current study replicated the methods used in Schreiner & Dunn (2012) and Grant et al. (2003) to conduct a meta-analysis examining the neurocognitive effects of cannabis after abstinence lasting a period of at least 25 days. Previous research has found mixed results, with some studies finding significant differences between abstinent cannabis users and matched healthy controls, and others finding no evidence of significant differences. Results of the current meta-analytical study found no significant effects within the domains of overall effects, attention, forgetting/retrieval, learning, or verbal/language. Results identified a significant small effect size within the domain of abstraction/executive function. Results continue to add to the growing evidence there are no significant long-term neurocognitive effects associated with cannabis use.

No / Almost 50,000 children and young people are affected by life-limiting conditions in the United Kingdom, around a third of which use children's hospices. Anecdotal evidence suggests that cannabinoid-based medicines (CBMs), specifically cannabis oil (CO), are being used by families with increasing frequency to manage distressing symptoms. The use of most nonprescription CBMs in the United Kingdom remains illegal. The objective of the study was to identify the prevalence of CO use by families who use children's hospices in the United Kingdom, and the approaches taken by those services to manage it. Design: An electronic survey was sent to each of the 54 children's hospices in the United Kingdom between May and July 2018, comprising 10 questions. Results: Forty children's hospices from across the four countries of the United Kingdom responded to the survey, representing 74% of British children's hospices. About 87.5% of hospices knew of children who use CO therapeutically. Sixty-nine percent of those hospices have received requests to administer CO during an episode of care. Approaches by organizations around CO management varied across the sectors, including arrangements for storage, administration, and recording of its use. Hospices highlighted how the lack of available guidance made decision making more challenging. Only a third of responding organizations routinely questioned families about the use of cannabis when prescribing medicines. Conclusion: CO is used extensively by children who use children's hospices. Despite recognizing the use of CO, many hospices are unable to support it. There is a need for clear guidelines on how hospices should approach the care needs of children, allowing hospices to meet the needs of children who use CO, and families in a safe, consistent, and relevant way, safeguarding all children, families, and professionals within the organization.

Le cannabis (*Cannabis sativa* L.), plante domestiquée depuis des millénaires, possède une importance économique et sociétale considérable. Utilisée pour ses fibres, son huile, ses graines et ses propriétés médicinales et psychoactives, elle est aujourd'hui au cœur d'une industrie en pleine expansion. Malgré son importance croissante, la culture du cannabis souffre d'un manque de connaissances fondamentales. La production de plants uniformes et de qualité constante est un défi majeur, influencé par des interactions entre différents facteurs génétiques et environnementaux. La culture *in vitro* se présente comme une solution prometteuse pour la production de clones uniformes. Cependant, les variations somaclonales - les variations entre clones induites par des modifications génétiques ou épigénétiques - peuvent altérer la fidélité génétique et épigénétique des clones. Les facteurs épigénétiques, tels que la méthylation de l'ADN, jouent un rôle crucial dans la régulation de l'expression des gènes et peuvent être à l'origine de la variation somaclonale. Comprendre la méthylation de l'ADN au sein des clones de cannabis cultivés *in vitro* est donc essentiel pour garantir la stabilité et l'uniformité à long terme de la production de molécules d'intérêt chez le cannabis. Ce mémoire vise à évaluer la variabilité du méthylome chez une population de clones de cannabis *in vitro*. Pour ce faire, nous avons développé une méthode abordable, appelée CREAM (Comparative Restriction Enzyme Analysis of Methylation), permettant d'analyser les profils de méthylation de l'ADN chez plusieurs individus. Le premier chapitre de ce mémoire présente une revue de littérature approfondie sur les sujets suivants : le cannabis, son importance et les défis liés à sa production; la culture *in vitro* et les paramètres affectant l'uniformité des clones; les facteurs épigénétiques et la méthylation de l'ADN; les approches de séquençage et d'analyse de la méthylation de l'ADN à l'échelle du génome. Le deuxième chapitre, sous forme d'article intégré au mémoire, décrit le développement et la validation de la méthode CREAM, ainsi que son application à l'étude d'une population de 78 clones de cannabis. Les résultats obtenus révèlent une variabilité du méthylome au sein de la population, soulignant l'importance de la surveillance épigénétique pour la production de cannabis de qualité constante. En somme, ce mémoire apporte des contributions importantes à la compréhension de la méthylation de l'ADN dans les clones de cannabis cultivés *in vitro*. Nos résultats permettront d'améliorer les pratiques de culture et de sélection pour la production de plants uniformes et de qualité supérieure chez une variété d'espèces. / Cannabis (*Cannabis sativa* L.), a plant that has been domesticated for thousands of years, is of considerable economic and social importance. Used for its fibers, oil, seeds and medicinal and psychoactive properties, it is now at the heart of a booming industry. Despite its growing importance, cannabis cultivation suffers from a lack of fundamental knowledge. Producing uniform plants of consistent quality is a major challenge, influenced by interactions between different genetic and environmental factors. Tissue culture offers a promising solution for the production of uniform clones. However, somaclonal variations - variations between clones induced by genetic or epigenetic modifications - can alter the genetic and epigenetic fidelity of clones. Epigenetic factors, such as DNA methylation, play a crucial role in regulating gene expression and may be at the origin of somaclonal variation. Understanding DNA methylation in cannabis clones produced in tissue culture is therefore essential to ensure long-term stability and consistency in the production of molecules of interest in cannabis. This memoir aims to assess methylome variability in a population of *in vitro* cannabis clones. To this end, we have developed an affordable method, called CREAM (Comparative Restriction Enzyme Analysis of Methylation), to analyze DNA methylation profiles in several individuals. The first chapter of this memoir presents an in-depth literature review on the following topics: cannabis, its importance and the challenges associated with its production; tissue culture and parameters affecting clone uniformity; epigenetic factors and DNA methylation; genome-wide approaches to DNA methylation sequencing and analysis. The second chapter, in the form of a scientific article, describes the development and validation of the CREAM method, and its application to the study of a population of 78 cannabis clones. The results obtained reveal methylome variability within the population, underlining the importance of epigenetic monitoring for the production of cannabis of consistent quality. In sum, this memoir makes an important contribution to the understanding of DNA methylation in tissue culture-grown cannabis clones. Our results will help improve cultivation and breeding practices for the production of uniform, high-quality plants in a variety of species.

AN ABSTRACT OF THE THESIS OFSpencer Schuchman, for the Master of Science degree in Plant, Soil, and Agricultural Systems presented on October 18th, 2024, at Southern Illinois University Carbondale. TITLE: THE ROLE OF METHYL JASMONATE IN MODULATING TRICHOME DENSITY, GROWTH, YIELD, AND CANNABINOID ACCUMULATION IN CANNABIS SATIVA L.MAJOR PROFESSOR: Dr. Jose LemeThe relaxation of laws surrounding the cultivation of hemp (Cannabis sativa L.) in recent years has sparked the revitalization of hemp’s use for fiber, food, medicine, as well as recreational purposes. Although the cultivation of hemp is now legal with proper documentation, growers face challenges associated with decades of prohibition, creating an evident gap in knowledge and the need for novel cultivation techniques to improve production standards. A significant determinant of yield quality in high cannabinoid hemp is the density of glandular trichomes and the concentration of cannabinoids these structures contain. Techniques that could manipulate these properties would be inherently valuable to cultivation outcomes. A collection of outdoor and indoor studies revealed that the exogenous application of methyl jasmonate (MeJa) yielded significant increases in trichome density. However, counterintuitively, no increases in cannabinoid concentration were observed to accompany this increase in glandular trichome density. These results contradict similar works where increases in cannabinoid content were observed but not increases in trichome density. This raises the question of how genetic predisposition influences the activity of the plant mechanisms enacted upon by MeJa that ultimately modulate the upregulation of associated genes that determine trichome induction and secondary metabolite synthesis. Unexpected interactions between MeJa and insecticide, as well as ammonium bicarbonate, further illuminate the need for further research to determine the genetic factors involved in modulating the plant’s response to MeJa. The current research sheds light on the importance of genotype in concern to hemp cultivation, where cultivar selection strongly determines cultivation outcomes. Although the current research outlines the promising potential of the stimulatory effects of methyl jasmonate, further research should be conducted to reveal the complexities of its effects on important hemp attributes and how its addition into a production system interacts with other important management strategies and final yield/quality.

The occurrence of weed species with hemp significantly affects the development and yield of hemp (Cannabis sativa L.). Three experimental studies were conducted to examine whether weed species like Amaranthus tuberculatus L., Eleusine indica L., Ipomoea spp. L. suppress the growth of hemp. The results show that the presence of these weed species was responsible for the reduced growth of hemp in terms of height, stem diameter number of leaves except when some weed densities were reduced with a grass-specific herbicide, but the weed species did not have any association with the N (nitrogen) and C (carbon) assimilation of hemp. Additionally, utilizing a de Wit replacement series design, a greenhouse study investigated the competitiveness of the two hemp cultivars ‘Jin Ma’ and ‘NWG’ and three weed species i.e., A. tuberculatus, Glycine max L., and Setaria faberi L. to see how they affect each other through both intra- and interspecific competition. The outcome demonstrated that the weed species were responsible for the loss of yield as well as suppressing the growth of hemp. However, there were some mixtures where the plants were overyielding as well as the effects of two different hemp cultivars varied in response to the three weed species. Moreover, the effect of the three weed species was different based on hemp cultivars and mixture. These two studies suggest that controlling the weedy species in hemp fields is important to reduce the loss of hemp yield. Additionally, another separate greenhouse study looked at the accumulation of Trigonelline (TRG) in the leaves of two hemp cultivars ‘Jin Ma’ and ‘NWG’. The finding of this experiment demonstrates that the amount of TRG varies between when the plants grow under control and drought stress treatment. However, the two cultivars did not vary in terms of TRG accumulation. The three experimental studies showed that weeds have a significant effect on hemp growth parameters, and the accumulation of trigonelline varies based on drought conditions.

Objective: To determine whether use of cannabis in adolescence increases the risk for psychotic outcomes by affecting the incidence and persistence of subclinical expression of psychosis in the general population (that is, expression of psychosis below the level required for a clinical diagnosis). Design: Analysis of data from a prospective population based cohort study in Germany (early developmental stages of psychopathology study). Setting: Population based cohort study in Germany. Participants: 1923 individuals from the general population, aged 14-24 at baseline. Main outcome measure: Incidence and persistence of subthreshold psychotic symptoms after use of cannabis in adolescence. Cannabis use and psychotic symptoms were assessed at three time points (baseline, T2 (3.5 years), T3 (8.4 years)) over a 10 year follow-up period with the Munich version of the composite international diagnostic interview (M-CIDI). Results: In individuals who had no reported lifetime psychotic symptoms and no reported lifetime cannabis use at baseline, incident cannabis use over the period from baseline to T2 increased the risk of later incident psychotic symptoms over the period from T2 to T3 (adjusted odds ratio 1.9, 95% confidence interval 1.1 to 3.1; P=0.021). Furthermore, continued use of cannabis increased the risk of persistent psychotic symptoms over the period from T2 to T3 (2.2, 1.2 to 4.2; P=0.016). The incidence rate of psychotic symptoms over the period from baseline to T2 was 31% (152) in exposed individuals versus 20% (284) in non-exposed individuals; over the period from T2 to T3 these rates were 14% (108) and 8% (49), respectively. Conclusion: Cannabis use is a risk factor for the development of incident psychotic symptoms. Continued cannabis use might increase the risk for psychotic disorder by impacting on the persistence of symptoms.

La polyconsommation d’alcool et de cannabis est rapportée par un grand nombre de jeunes adultes canadiens (Flight, 2007). Les recherches épidémiologiques suggèrent que le statut de polyconsommateur est associé à certains comportements à risque, dont la consommation excessive d’alcool et la conduite d’un véhicule automobile sous l’influence de l’alcool (Jones et al. 2001; Mohler-Kuo, et al. 2003; Shillington & Clapp, 2006). Les études qui soutiennent le risque accru de comportements à risque pour les polyconsommateurs se focalisent sur l’effet des substances. En rupture avec cette approche, ce mémoire présente une étude situationnelle de la polyconsommation en examinant l’effet du statut de polyconsommateur et, pour ceux-ci l’effet de la consommation simultanée d’alcool et de cannabis, en situant l’action dans son contexte de survenu et en examinant la contribution du contexte. La probabilité d’avoir conduit une voiture sous l’influence de l’alcool et d’avoir consommé excessivement de l’alcool sera examinée auprès d’étudiants universitaires. La contribution respective des substances, des situations et de l’expérience de la vie universitaire sera examinée. La méthodologie employée repose sur la construction de modèles de régression logistique multiniveaux, à la fois chez l’ensemble des buveurs (10 747 occasions, nichées dans 4396 buveurs) et dans le sous-échantillon des polyconsommateurs (2311 occasions de consommation d’alcool, nichées dans 880 polyconsommateurs). Les données sont issues de l’Enquête sur les campus canadiens (2004), menée auprès d’un échantillon représentatif de 6282 étudiants issus de 40 universités. Le statut de polyconsommateur est associé à la consommation excessive d’alcool, mais pas à la conduite d’une voiture suite à la consommation. Cependant, la consommation simultanée d’alcool et de cannabis n’est pas associée à un risque plus élevé de consommer excessivement de l’alcool, et est négativement associée à la conduite d’une voiture après la consommation. Plusieurs caractéristiques situationnelles sont associées aux deux comportements à l’étude et diminuent la force d’association entre ces comportements et le statut de polyconsommateur. / Alcohol and cannabis polydrug use is a common consumption pattern among Canadian young adults (Flight, 2007). Moreover, epidemiological studies suggest that alcohol and cannabis use is associated with other risky behaviours such as binge drinking and driving a vehicle under the influence of both substances (Jones et al. 2001; Mohler-Kuo et al. 2003; Shillington & Clapp, 2006). Studies which have reported an increased risk for polydrug users focus on substance use. The present study propose a situational approach, in which the effect of poly drug use, as well as the effect of simultaneous use on these risky behaviours are investigated while considering the context in which the consumption takes place. The probability of driving under the influence of alcohol, and the probability of binge drinking are examined among a sample of university students. The respective contribution of substance use, university life experience and drinking situations is examined. The methodology used to perform this study is based on multilevel logistic regression models, among drinkers (10 747 occasions, nested within 4396 drinkers) as well as among the polydrug users subsample (2311 drinking occasions, nested within 880 individuals). The data are drawn from the Canadian Campus Survey conducted in 2004 with a random nationally representative sample of 6282 students from 40 universities. Polydrug status is positively associated with episodic binge drinking, but not with driving under the influence of alcohol. However, cannabis use is not associated with binge drinking, among polydrug users. Moreover, for this specific population, cannabis smoking is negatively associated with driving under the influence of alcohol. Several situational characteristics are associated with either one or both studied behaviours and partially explain the relationship between those behaviours and polydrug use.

L’utilisation du cannabis peut précipiter la schizophrénie, en particulier chez les individus qui présentent une vulnérabilité génétique aux désordres mentaux. Des recherches humaines et animales indiquent que la neuréguline 1 (Nrg1) est un gène de susceptibilité à la schizophrénie. L’objectif de cette thèse est d’examiner si une modification du gène Nrg1 chez des souris mutante module les effets neuronaux et comportementaux des cannabinoïdes après traitement aiguë et chronique. De plus cette thèse examine les effets d'un pré-traitement au delta9-tétrahydrocannabinol, le principal composant psychotropique du cannabis, sur un modèle de flexibilité cognitive chez la souris. / Cannabis use may precipitate schizophrenia, especially in individuals who have a genetic vulnerability to the disorder. Human and animal researches indicate that neuregulin 1 (Nrg1) is a susceptibility gene for schizophrenia. This thesis aim at investigating if partial deletion of Nrg1 in mutant mice modulate the neuronal and behavioural effects cannabinoids after acute or chronic treatment. In addition, this thesis examine the effects of a pre-treatment with delta9-tetrahydrocannabinol, the main psychoactive constituent of cannabis, in a model of cognitive flexibility in the mice.

Syftet med denna studie är att utröna varför personer väljer att använda syntetiska cannabinoider. Vidare ämnade studien undersöka om personer som använder syntetiska cannabinoider också använder andra droger. Samtidigt har studien målet att ta reda på i vilken utsträckning drogens laglighet inverkar vid valet att använda drogen. Studien är kvantitativ. Undersökningen utfördes genom en webbenkät som besvarades av totalt 356 respondenter. Av dessa hade 171 personer använt syntetiska cannabinoider. I resultatet framkom att anledningarna till att använda drogen är flera, men de främsta visade sig vara laglighet, nyfikenhet, tillgänglighet, ruset samt att det ej visar sig vid urinprov. Personer som använder syntetiska cannabinoider har en tendens att också använda flera andra droger. Drogens laglighet visade sig ha en relativt stor inverkan på valet att använda den. Det visade sig också att män i större utsträckning använder syntetiska cannabinoider i jämförelse med kvinnor. / The purpose of this study is to examine why people choose to use synthetic cannabinoids. Furthermore, the study intended to investigate whether people who use synthetic cannabinoids also using other drugs. Meanwhile the study has the objective to find out to what extent the drug affects the legality of the choice to use the drug. The study is quantitative. The survey was conducted through an online survey and was answered by a total of 356 respondents. Of these, 171 people used synthetic cannabinoids. The result showed that the reason for using the drug are several, but the main proved were legality, curiosity, availability, intoxication and that it is not revealed by urine testing. People using synthetic cannabinoids have a tendency to also use several other drugs. The legacy of the drug was found to have a relatively large impact on the decision to use it. It was also found that men in greater occurrence use synthetic cannabinoids compared to women.

The overall purpose of this paper was to critically analyze the legal prerequisites for using medical cannabis in Sweden. The legal method and the legal analysis method have been the basis for the analysis of current law, regarding medical use of cannabis and drug abuse. Current law has been analyzed led by a medical approach to clarify the legal and medical meaning of drug abuse. The Narcotic Drugs Punishment Act makes no distinction between drug abuse and medical use, which means that all forms of use ending up in a drug offence. It ́s not obvious what constitutes narcotics because the cannabis plant is divided into different species and it ́s also available in various forms of preparations. Against this background, the medical usage of cannabis seems to have ended up in a legal grey zone. The cannabis preparation called Bediol includes whole plant parts of cannabis and is treated as drug abuse according to the law, but regarding the legal view of CBD-extract the position is more unclear. The prevailing opinion in law cases of today is that CBD-extracts do not constitute drugs. The question of cannabis for self-medication has been pointed in NJA 2017 s. 872, the Supreme Court considers that the medical motive mitigates the crime classification and that a medical purpose can cause a situation of emer- gency. It ́s still unclear how the prerequisites “addictive properties” and ”euphoric effects” in paragraph 8 in the Narcotic Drugs Punishment Act shall be read regarding the occasion of medical use. As long as cannabis is under extensive international control the uncertainty remains about how the prerequisites in paragraph 8 in the Narcotic Drugs Punishment Act should be treated in relative to the medical motive. Furthermore, the study based on the Swedish Medical Products Agency’s decision regarding Bediol and Epidiolex shows that the Medical Products Agency has a tolerant attitude towards both cannabis preparations. The study of license decisions has also been relevant to clarify the discrepancy between medical use and how it ́s considered according to the Narcotic Drugs Punishment Act. The study demonstrates how the Swedish Medical Products Agency's attitude does not always interact with the view of the law. Since the decisions about licenses can be seen as an exception to the Narcotic Drugs Punishment Act, there should be some sort of consensus in how the preparations should be viewed from an authority and law point of view. This to not affect the predictability of a drug abuse in respect of the Narcotic Drugs Punishment Act. As the Medical Products Agency considers both the medical rudiments and the medical development this should be taken into account in the Narcotic Drugs Punishment Act in a more extensive way, to reach some sort of consensus. The national law can only be changed in a sharpening direction, which means that a future international reclassification of cannabis may be considered as a guide in how much space the medical motives can be applied in the 8 paragraph in the Narcotic Drugs Punishments Act. / Det övergripande syftet med denna uppsats var att kritiskt analysera de legala förutsättningarna för att använda medicinsk cannabis i Sverige. I uppsatsen har den rättsdogmatiska och rättsanalytiska metoden legat till grund för analysen av gällande rätt avseende medicinskt bruk av cannabis samt narkotikamissbruk. Gällande rätt har till viss del analyserats med ledning av en medicinsk infallsvinkel för att tydliggöra den juridiska och medicinska innebörden av narkoti- kamissbruk. Narkotikastrafflagen gör ingen skillnad på narkotikamissbruk och medicinskt bruk, vilket resulterar i att alla former av bruk innebär ett narkotikabrott. Då cannabisplantan är uppdelad i olika arter och att cannabis finns tillgängligt i olika former av preparat, blir det inte helt självklart vad som utgör narkotika. Mot denna bakgrund tycks det medicinska bruket hamnat i en rättslig gråzon. Preparatet Bediol består av hela cannabisväxtdelar och utgör narkotika i lagens mening men vad gäller CBD-extrakt är rättsläget mer oklart. Rådande uppfattning i rättspraxis är dock att CBD-extrakt inte utgör narkotika. Frågan om cannabis i självmedicineringssyfte har behandlats i NJA 2017 s. 872 där Högsta domstolen beaktade det medicinska motivet genom mildare brottsrubricering och att ett medicinskt syfte kan föranleda en nödsituation. Det kvarstår dock oklarhet huruvida rekvisiten ”beroendeframkallande egenskaper” och euforise- rande effekter” i 8 § narkotikastrafflagen ska beaktas i fråga om ett medicinskt bruk. Så länge cannabis står under omfattande internationell kontroll kvarstår oklarheten vilken tyngd de medicinska motiven bör tillmätas vid tolkning och tillämpning av 8 §. Vidare visar den studie som gjorts beträffande Läkemedelsverkets beslut rörande Bediol och Epidiolex att verket har en tolerant inställning gentemot båda preparaten. Studien som gjorts av licensbesluten har även varit relevant för att tydliggöra diskrepansen som råder mellan medicinskt bruk och hur det betraktas enligt narkotikastrafflagen. Studien påvisar således hur verkets inställning inte alltid samverkar med den straffrättsliga synen. Eftersom licensbesluten kan ses som ett undantag från narkotikastrafflagen bör det finnas någon form av samsyn hur preparaten betraktas ur myndighets respektive straffrättslig synvinkel. Detta för att inte påverka förutsebarheten av vad ett missbruk enligt narkotikastrafflagen innebär. Då Läkemedelsverket beaktar den medicinska grunden i takt med den medicinska utvecklingen bör det för samsynens skull vara relevant att den medicinska potentialen beaktas i större utsträckning även vid tillämpning av narkotikastrafflagen. Nationell lag kan enbart utformas i skärpande riktning, vilket medför att en internationell framtida omklassificering av cannabis får anses vägledande för hur stort utrymme de medicinska motiven kan tillmätas vid tillämpning av 8 §.