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Epigenetic Effects of Cannabis Exposure

The past decade has witnessed a number of societal and political changes that have raised critical questions about the long-term impact of marijuana (Cannabis sativa) that are especially important given the prevalence of its abuse and that potential long-term effects still largely lack scientific data. Disturbances of the epigenome have generally been hypothesized as the molecular machinery underlying the persistent, often tissue-specific transcriptional and behavioral effects of cannabinoids…

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. 2016 Apr 1;79(7):586-94.

doi: 10.1016/j.biopsych.2015.09.014. Epub 2015 Nov 3.

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Henrietta Szutorisz et al. Biol Psychiatry. .

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Abstract

The past decade has witnessed a number of societal and political changes that have raised critical questions about the long-term impact of marijuana (Cannabis sativa) that are especially important given the prevalence of its abuse and that potential long-term effects still largely lack scientific data. Disturbances of the epigenome have generally been hypothesized as the molecular machinery underlying the persistent, often tissue-specific transcriptional and behavioral effects of cannabinoids that have been observed within one’s lifetime and even into the subsequent generation. Here, we provide an overview of the current published scientific literature that has examined epigenetic effects of cannabinoids. Though mechanistic insights about the epigenome remain sparse, accumulating data in humans and animal models have begun to reveal aberrant epigenetic modifications in brain and the periphery linked to cannabis exposure. Expansion of such knowledge and causal molecular relationships could help provide novel targets for future therapeutic interventions.

Keywords: Addiction; CB(1) receptor; Cannabinoids; DNA methylation; Epigenetics; Neurodevelopment.

Figures

Figure 1

Figure 1

Number of publications in PubMed between 1960 and 2014 related to ‘cannabis’ research. The data shows the exponential increase in research studies over recent decades that coincides with changes in the legalization status (starting ~1996) and debates of recreational and medical marijuana use. The drop in publications in the 1970s marks changes in state laws and local regulations banning possession or sale of cannabis and cannabis becoming a Schedule I drug (*).

Figure 2

Figure 2

Several epigenetic mechanisms relevant to the effects of exogenous cannabinoids. (A) Gene expression is regulated by a network of DNA elements (e.g. promoters) and trans-acting factors (proteins that bind to the DNA) that interact physically and functionally to generate appropriate mRNA transcript levels from a gene. The resulting balance can be disrupted by drug exposure. Regulatory mechanisms include DNA methylation (Me), positioning and post-translational modifications of nucleosomes (small blue balls), recruitment of sequence-specific and basal transcription factors and RNA polymerase II, and non-coding RNAs. The DNA-protein structure forms three-dimensional structures (represented by the chromatin loop) that influence the expression of associated genes. (B) DNA methyltranserases (DNMT) generate 5-methylcytosine (pink stars) at CpG sites, facilitated by methyl-CpG binding domain (MBD)-containing proteins. Ten-eleven translocation (TET) proteins mediate the oxidation of 5-methylcytosine to 5-hydroxymethylcytosine (green stars), leading to demethylation of the DNA. (C) Modifications of nucleosomal histone tails such as methylation (Me) and acetylation (Ac) are mediated by histone methyltransferases (HMT) and histone acetyltransferases (HAT), respectively. Depending on modified amino acid residue, methylation can have either permissive (e.g. on lysine4, K4) or repressive (e.g. on lysine 9, K9) effects on transcription. Permissive modifications facilitate gene activation via the recruitment of the RNA polymerase II machinery. Acetylation is removed by histone deacetylases (HDAC) and can lead to transcriptional repression. (D) MicroRNAs are produced from specific genes and target protein-coding messenger RNAs (mRNA) for degradation, thereby prevention protein production.

Figure 3

Figure 3

Biological processes affected by cannabinoid exposure. (A) The active compounds of cannabis target cannabinoid receptors (CB1R and CB2R; expression pattern in the body is indicated by green dots in the human figure). (B) Cannabinoid receptors are trans-membrane receptors of the G protein-coupled family. The CB1R (shown in red), the primary target of THC, is expressed most abundantly in the brain, but also in the lungs, liver, kidneys, immune system, gut, and in germ cells such as the sperm. The CB2R is present mainly in the immune system and in hematopoietic cells with low expression in brain. Cannabinoid receptors can be activated by endocannabinoids (eCBs, green polygons; retrograde signaling), THC, or synthetic cannabinoids (see also Table 1). In the adult brain, activation of the CB1R on the surface of pre-synaptic neurons modulates the release of neurotransmitters (orange dots) that bind to their specific receptors (light blue shapes) in the post-synaptic cell, thereby changing the communication between neurons.

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Source: https://pubmed.ncbi.nlm.nih.gov/26546076/?utm_source=no_user_agent&utm_medium=rss&utm_campaign=pubmed-2&utm_content=1z7zlNEMzQex5jriqkhCblNtckSEpT9xYlxxeymU_73UTETESY&fc=20200804213258&ff=20200811034526&v=2.11.5

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