The Effects of Cannabis on the Adolescent Brain and Epigenetic Ageing

全世界约有2亿人使用大麻。随着大麻在美国，加拿大和其他地区合法获得，这一数字将进一步增加。值得注意的是，青少年由于冒险行为和同伴影响的增加，可能会增加吸食大麻的可能性。然而，大麻使用对大脑发育和个体表观遗传学的潜在不利影响仍然知之甚少。因此，这对大麻合法化构成了一个关键的公共卫生问题。有趣的是，研究表明，典型的青少年大脑区域变化在个体之间的幅度不同，因此大脑被认为对环境因素非常敏感。与青少年神经发育相关的大脑区域也被认为与白色物质纤维高度相关，并表达丰富的内源性大麻素受体。由于大麻作用于这些受体，青春期可能标志着对大麻高度脆弱性的关键发育窗口。我们假设大麻可以改变典型的大脑发育和表观遗传衰老的轨迹。为了验证这一假设，我将从MRC资助的一个主要项目中获得神经成像、认知和遗传数据：“大麻的使用如何影响青少年的大脑、认知功能和心理健康？（CannTeen）"。CannTeen研究包括四组（青少年大麻使用者，青少年对照，成年大麻使用者，成年对照），每三个月随访一年。通过访问这些数据，我的目标是检查所有四个组之间的差异，研究大麻使用和年龄组对以下方面的影响：-脑白色物质微结构（胼胝体和镊子小）使用扩散张量成像技术分析大麻在两个收集的时间点（相隔1年）的慢性影响。- 工作记忆功能，使用间隔一年的两次MRI会议收集的fMRI数据的空间N-Back任务结果来分析急性和慢性影响。表观遗传衰老，使用DNA甲基化技术来检查表观遗传时钟以及表观遗传年龄与参与者的实足年龄的差异。为了深入了解大麻对青少年功能的主观影响，并与上面列出的客观结果并列，我还将对青少年大麻使用者进行定性访谈，进行主题分析。我将调查参与者，以探索他们如何认为大麻影响了他们的大脑功能，并探索混淆变量，如社会经济或友谊菌株。重要的是，以前的研究表明，同龄人主导的活动对青少年受众最有效。因此，为了确保最大的研究影响，并鼓励年轻人参与研究，我将联系当地学校，与青少年学生合作，创建一个新的循证药物教育视频资源，以传播我关于大麻如何影响青少年大脑的研究结果。我们的团队将在社交媒体上分享该项目，包括我们的年轻合作者，以产生广泛的国际影响力和影响力。资助该项目的MRC旨在资助科学前沿的研究，以改善人类健康。该项目与这种精神非常一致，因为它是第一个直接比较青少年和成人大脑和表观遗传学对大麻使用的反应的纵向研究。通过这个项目，我将产生世界第一的发现，有可能告知年龄限制销售政策。此外，通过让年轻人参与这项研究，我们的目标是在考虑使用大麻时直接改善他们的知情决策。因此，我们的目标是从这两个角度改善公众健康。

Cannabis is used by approximately 200 million people worldwide. This number is set to increase further as cannabis becomes legally available in the USA, Canada and beyond. Notably, adolescents may have an increased likelihood to sample cannabis due to their increased risk-taking behaviour and peer-influence. However, the potential adverse impact of cannabis use on the developing brain and an individual's epigenetics remain poorly understood. This therefore poses a key public health concern for cannabis legalisation. Interestingly, research has shown that typical adolescent regional brain changes differ in magnitude between individuals, and so the brain is thought to be highly susceptible to environmental factors. Brain regions associated with adolescent neurodevelopment are also known to highly intercorrelate with white matter fibres and express an abundance of endocannabinoid receptors. As cannabis acts on these receptors, adolescence could mark a crucial developmental window of heightened vulnerability to cannabis. We hypothesise that cannabis could alter the trajectory of typical brain development and epigenetic ageing. To test this hypothesis, I will gain access to neuroimaging, cognitive and genetic data from a major MRC-funded project: "How does cannabis use affect teenagers' brains, cognitive functions and psychological wellbeing? (CannTeen)". The CannTeen study consists of four groups (adolescent cannabis users, adolescent controls, adult cannabis users, adult controls) who were followed up every three months for one year. With access to this data, I aim to examine the differences between all four groups, to study the effect of cannabis use and age group on:- Brain white matter microstructure (corpus callosum and forceps minor) using diffusion tensor imaging techniques to analyse the chronic effects of cannabis across the two collected time points (1 year apart. - Working Memory Function, using the spatial N-Back task results from fMRI data collected from the two MRI sessions one year apart to analyse both acute and chronic effects.- Epigenetic Ageing, using DNA methylation techniques to examine epigenetic clocks and how the epigenetic age differs from the chronological age of the participant.To gain insight into the subjective effect of cannabis on adolescent function, and juxtapose with the objective results listed above, I will also conduct qualitative interviews with adolescent cannabis users for a thematic analysis. I will probe participants to explore how they think that cannabis has affected their brain function and explore confounding variables such as socio-economic or friendship strains. Importantly, previous research suggests that peer-led campaigns are most effective for adolescent audiences. So, to ensure greatest research impact and encourage research engagement with young people, I will contact local schools and work collaboratively with teenage students to create a novel evidence-based drugs educational video resource to disseminate my findings on how cannabis effects the teenage brain. It will be shared on social media by our team including our young collaborators, to generate wide international reach and impact.The MRC, who has funded this project, aims to fund research at the forefront of science to improve human health. This project aligns well with this ethos as it is the first longitudinal study to directly compare how adolescent and adult brains and epigenetics differ in response to cannabis use. Through this project, I will generate world-first findings, with the potential to inform age-restriction sales policy. Plus, by engaging young people in this research, we aim to directly improve their informed decision-making when considering using cannabis. Therefore, we aim to improve public health from both angles.