Epigenetic Effects of Cannabis Exposure

Henrietta Szutorisz and Yasmin L. Hurd

Biological Psychiatry, 2016, 79, 7,  586–594.

doi:10.1016/j.biopsych.2015.09.014.

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 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 : Cannabinoids; epigenetics; DNA methylation; addiction; CB1 receptor; neurodevelopment

 

Introduction

Extensive political and societal debates are currently being waged at state and federal levels regarding the legalization of marijuana (Cannabis sativa), which remains today the most commonly used illicit substance in the United States and in many countries worldwide. As evident in Figure 1, there has been a dramatic exponential increase of cannabis studies over the past two decades in response to the transformative implications resulting from the growing discussions and laws passed regarding legalization of recreational and medical marijuana use. Of the published studies to date, about 13% relate to the neurobiological effects of cannabis and approximately 27% is directed towards obtaining behavioral insights. Despite the perceived low health risk of cannabis use by the general public, there is growing clinical awareness about the spectrum of behavioral and neurobiological disturbances associated with cannabis exposure such as anxiety, depression, psychosis, cognitive deficits, social impairments, and addiction (1–7). The acute intoxication induced by cannabis consumption is strongly linked with concerns about its direct effects on cognition and motor function, but a central issue relates to its long-term impact especially when exposure occurs during critical periods of brain development. Key gaps of scientific knowledge pertain to the biological mechanisms that maintain persistent phenotypic and molecular alterations long after its acute use.

The major psychoactive cannabinoid within cannabis, Δ9-tetrahydrocannabinol (THC), targets the endocannabinoid (eCB) system, which plays a key role in the development of the brain and several other organs. In recent years, various human and experimental animal studies have evaluated the long-term impact of cannabis and cannabinoids on neurodevelopment, behavior and several biological systems such as immunological mechanisms and reproductive processes (reviewed in (7–10)). Moreover, behavioral abnormalities and molecular impairments in the brain have also been demonstrated to extend even into subsequent generations of offspring whose parents were exposed to cannabinoids before mating (11–15).

The epigenome provides a cellular fingerprint of environmental experiences, including drug exposure history, and thus is a highly relevant biological candidate expected to maintain persistent abnormalities and aberrant neuronal processing over time. The role of epigenetics in psychiatric disorders has been a major scientific focus during the past few years. According to the classic definition, “an epigenetic trait is a stably heritable phenotype resulting from changes in a chromosome without alterations in the DNA sequence” (as proposed by Conrad Waddington in the 1950s); this view implies heritability resulting in a phenotype. In the molecular biological era of recent years, “epigenetic” typically has been used to refer to mechanisms that modulate gene expression without altering the genetic code. Our article provides an overview of research endeavors relevant to cannabis-related epigenetic mechanisms that could shed light about the biological processes that establish the molecular platform that maintains marijuana’s protracted effects on gene expression and ultimately behavior.

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