Low doses of widely consumed cannabinoids (cannabidiol and cannabidivarin) cause DNA damage and chromosomal aberrations in human-derived cells

Abstract

Cannabidiol (CBD) and cannabidivarin (CBDV) are natural cannabinoids which are consumed in increasing amounts worldwide in cannabis extracts, as they prevent epilepsy, anxiety, and seizures. It was claimed that they may be useful in cancer therapy and have anti-inflammatory properties. Adverse long-term effects of these drugs (induction of cancer and infertility) which are related to damage of the genetic material have not been investigated. Therefore, we studied their DNA-damaging properties in human-derived cell lines under conditions which reflect the exposure of consumers. Both compounds induced DNA damage in single cell gel electrophoresis (SCGE) experiments in a human liver cell line (HepG2) and in buccal-derived cells (TR146) at low levels (≥ 0.2 µM). Results of micronucleus (MN) cytome assays showed that the damage leads to formation of MNi which reflect chromosomal aberrations and leads to nuclear buds and bridges which are a consequence of gene amplifications and dicentric chromosomes. Additional experiments indicate that these effects are caused by oxidative base damage and that liver enzymes (S9) increase the genotoxic activity of both compounds. Our findings show that low concentrations of CBD and CBDV cause damage of the genetic material in human-derived cells. Furthermore, earlier studies showed that they cause chromosomal aberrations and MN in bone marrow of mice. Fixation of damage of the DNA in the form of chromosomal damage is generally considered to be essential in the multistep process of malignancy, therefore the currently available data are indicative for potential carcinogenic properties of the cannabinoids.Electronic supplementary materialThe online version of this article (10.1007/s00204-018-2322-9) contains supplementary material, which is available to authorized users.

Canadian Cannabis Consumption and Patterns of Congenital Anomalies: An Ecological Geospatial Analysis

“…Cannabis has been shown to work on developing organisms by a number of complex pathways which have been summarized elsewhere ( Reece et al, 2016 ; Reece and Hulse, 2016 ; Reece, 2018 ; Reece and Hulse, 2019b, 2020b, 2020c ). Briefly stated cannabinoids have been shown to work via: interference with synapse formation by interruption of neurexin / neuroligin scaffolding ( Foldy et al, 2013 ; Anderson et al, 2015 ; Wang, 2016 ); impeding notch signaling ( Lu et al, 2006 ; Newton et al, 2009 ; Tanveer et al, 2012 ; Kim et al, 2014 ) an important morphogen for cardiac, vascular, brain, and hemopoietic tissues ( Carlson, 2014 ); impeding robo/slit signaling with effects on human neocortical exuberant outgrowth, nerve and blood vessel guidance, tissue development in kidney, breast, lung and muscle ( Alpar et al, 2014 ; Blockus and Chedotal, 2016 ), spinal cord midline guidance, several neurodevelopmental disorders including dyslexia ( Galaburda et al, 2006 ) and psychopathy ( Viding et al, 2010 ); impeding axonal guidance by interference with stathmin signaling ( Tortoriello et al, 2014 ); cytoskeletal impairment affecting the actin cytoskeleton ( Wang et al, 2011 ; Miller et al, 2019 ) and microtubule structure and function ( Wang et al, 2011 ; Miller et al, 2019 ); defects on egg and sperm development including gross sperm deformities involving head and tail malformations ( Morishima, 1984 ; Hembree et al, 1999 ; Szutorisz and Hurd, 2016 ; Johnson et al, 2017 ; Murphy et al, 2018 ); impairment of mitochondrial function ( Sarafian et al, 2003 ; Sarafian et al, 2006 ); impairment of sperm mitochondrial function ( Rossato et al, 2005 ); impairment of replacement of sperm histones by protamines ( Chioccarelli et al, 2010 ); epigenetic effects ( Yang et al, 2014 ) and micronucleus effects ( Van Went, 1978 ; Piatti et al, 1989 ; Parolini and Binelli, 2014 ; Reece and Hulse, 2016 ) including cytoplasmic bridges and nuclear blebbing ( Morishima, 1984 ; Huang et al, 1999 ; Russo et al, 2018 ).…”

Epidemiological Associations of Various Substances and Multiple Cannabinoids with Autism in USA

“…However cannabidiol is known to be both directly genotoxic [14,[89][90][91] and to be toxic to mitochondria whose energy and normal metabolism is required for normal genome maintenance [38,39,92,93]. Proper expression of the protein complexes of the mitochondria is known to require coordinated transcription of the nuclear and genomic genomes.…”

“…Many reports of cannabinoid toxicology and genotoxicity suggest an asymptotic (steeply rising) pseudo-exponential (mimicking an exponential rise) dose-response relationship [14][15][16][17][18]. The implications of this on neurobehavioural neurotoxicology and general toxicology may prove to be most profound as the population moves into a higher cannabis use paradigm.…”

Challenges and Opportunities in Preclinical Research of Synthetic Cannabinoids for Pain Therapy

“…Both phytocannabinoids and SCs have been assessed in several studies by means of the COMET method, and the available data indicate that CBD and cannabidivarin can cause DNA damage and chromosomal aberrations in human hepatoma and buccal epithelial cells at concentrations similar to those seen in recreational users of cannabis [57]. The assessment of XLR-11 and RCS4, as well as frequently used SCs, yielded similar results for human lymphocytes and buccal-and lung-derived human cell lines, generating the hypothesis that long-term consumption of these SCs might lead to respiratory tract tumours [58].…”