Department of Biomedicine, Aarhus University, 8000 Aarhus, Denmark.
Department of BioMolecular Sciences, School of Pharmaceutical Sciences of Ribeirao Preto, University of Sao Paulo (USP), Ribeirão Preto 14040-903, Brazil.
Genes (Basel). 2022 Aug 12;13(8):1435. doi: 10.3390/genes13081435.
The prevalence of depression is increasing worldwide, as is the number of people suffering from treatment-resistant depression; these patients constitute 30% of those treated. Unfortunately, there have not been significant advances in the treatment of this disorder in the past few decades. Exposure to cannabis and cannabis-derived compounds impacts depression symptomatology in different ways, with evidence indicating that cannabidiol has antidepressant effects; there have been mixed results with medical cannabis. Even though the exact molecular mechanisms of the action underlying changes in depression symptomatology upon exposure to cannabis and cannabis-derived compounds are still unknown, there is strong evidence that these agents have a widespread impact on epigenetic regulation. We hypothesized that exposure to cannabis or cannabis-derived compounds changes the DNA methylation levels of genes associated with depression. To test this hypothesis, we first performed a literature search to identify genes that are differentially methylated upon exposure to cannabis and cannabis-derived compounds, as reported in methylome-wide association studies. We next checked whether genes residing in loci associated with depression, as identified in the largest currently available genome-wide association study of depression, were reported to be epigenetically regulated by cannabis or cannabis-related compounds. Multiple genes residing in loci associated with depression were found to be epigenetically regulated by exposure to cannabis or cannabis-derived compounds. This epigenomic regulation of depression-associated genes by cannabis or cannabis-derived compounds was reported across diverse organisms, tissues, and developmental stages and occurred in genes crucial for neuronal development, functioning, survival, and synapse functioning, as well as in genes previously implicated in other mental disorders.
全球范围内抑郁症的患病率正在上升，同时治疗抵抗性抑郁症患者的数量也在增加；这些患者占治疗人群的 30%。不幸的是，在过去几十年中，这种疾病的治疗并没有取得重大进展。接触大麻和大麻衍生化合物会以不同的方式影响抑郁症的症状，有证据表明大麻二酚具有抗抑郁作用；而医用大麻的效果则喜忧参半。尽管接触大麻和大麻衍生化合物引起的抑郁症症状变化的具体分子机制尚不清楚，但有强有力的证据表明，这些药物对表观遗传调控有广泛的影响。我们假设接触大麻或大麻衍生化合物会改变与抑郁症相关的基因的 DNA 甲基化水平。为了验证这一假设，我们首先进行了文献检索，以确定在甲基组全关联研究中报告的与接触大麻和大麻衍生化合物相关的基因中，哪些基因的甲基化水平存在差异。接下来，我们检查了在目前最大的抑郁症全基因组关联研究中确定的与抑郁症相关的基因座中，是否有报告称这些基因受到大麻或与大麻相关的化合物的表观遗传调控。研究发现，多个与抑郁症相关的基因座中的基因受到接触大麻或大麻衍生化合物的表观遗传调控。大麻或大麻衍生化合物对抑郁症相关基因的这种表观基因组调控在不同的生物体、组织和发育阶段都有报道，并且发生在对神经元发育、功能、存活和突触功能至关重要的基因中，以及先前与其他精神障碍有关的基因中。
