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For physicians of any type to prescribe cannabis it is axiomatic that both the safety and efficacy of cannabinoid treatments be well defined and the risk-benefit relationship be favourable. Central to any discussion of the safety of cannabis medicines therefore is an understanding of their recently delineated significant genotoxicity and epigenotoxicity. As mechanisms of biological action are central to any consideration of the safety and risks posed by cannabinoids advances of the latest Science and the mechanistic insights which spring from them are at once central, critical and pivotal. A clear appreciation of the far ranging impacts of the latest advances then takes centre stage in such discussions.
Recent studies clearly demonstrate that in heart development progenitors of cardiomyocytes rely on glycolytic–glutaminolytic metabolism to supply their metabolic demands [1] and that differentiation into adult cardiomyocytes happens together with conversion to oxidative phosphorylation to supply the higher energy demands required for cardiac contraction. Similar changes have been demonstrated in several other tissue beds. Moreover cancer cells are known to be generally de-differentiated and to have a metabolism based around glycolysis and glutaminolysis so that cancer stem cells are considered to be oncogenically transformed stem cells. In cancer this metabolic glycolytic dependency is called the “Warburg effect”.
A metabolism based on lactate and glutamate indicates that the intracellular and intra-mitochondrial milieu maintains a high concentration of lactate. Key rate limiting gatekeeper enzymes of oxidative phosphorylation are inhibited by these high lactate levels which shuts this down this major pathway. This has been demonstrated particularly for the mitochondrial matrix enzyme pyruvate dehydrogenase which controls the flow of pyruvate into the citric acid cycle and for carnitine acyl transferase situated on the inner and outer mitochondrial membranes and in the intermembrane space which controls the influx of fatty acid chains into β-oxidation which is the required principal high energy source of contracting cardiac muscle [2].
It has been understood for several years that the metabolome supplies the energy and metabolic substrates required for the innumerable post-translational modifications of proteins, nucleosomes and nucleic acids which comprise the epigenome.
However it was recently shown in human cardiac progenitors that not only are critical rate-limiting enzymes of oxidative phosphorylation inhibited by the high intracellular lactate concentration, but that they are actually post-translationally modified by lactate in a process referred to as lactylation [2]. This implies that the metabolic state not only influences (and suppresses) oxidative phosphorylation but that it actually – albeit reversibly - locks this inhibition in place.
Since many cannabinoids are known to be potent mitochondrial inhibitors (through many pathways) and also have a heavy epigenomic footprint it necessarily follows that the normal mutually reinforcing metabolic-epigenomic cross-talk is perturbed and that cells are metabolically primed for de-differentiation.
In addition to the many physiological pathways known to be perturbed by cannabinoids including numerous epigenomic and mitochondrial-metabolic mechanisms [3-5] this disruption of the critical coordinated and synchronized metabolic-epigenomic crosstalk incorporating dysregulation of the state of cellular differentiation contributes powerfully to explanations of the broad association of cannabis with many congenital anomalies recently reported in USA and Europe [3 4] particularly affecting cardiovascular development [6-8] and also with diverse cancer types which has similarly been reported from both sides from the Atlantic [9-11].
It is therefore premature to call for widespread prescribing when what is required is a full and proper re-evaluation of classical and modern pathways of genotoxicity and disruption of cellular metabolism generally and their very significant deleterious impacts on public health in the twenty-first century.
References
1. Du J, Zheng L, Gao P, et al. A small-molecule cocktail promotes mammalian cardiomyocyte proliferation and heart regeneration. Cell Stem Cell 2022;29(4):545-58.e13. doi: 10.1016/j.stem.2022.03.009
2. Wickramasinghe NM, Sachs D, Shewale B, et al. PPARdelta activation induces metabolic and contractile maturation of human pluripotent stem cell-derived cardiomyocytes. Cell Stem Cell 2022;29(4):559-76.e7. doi: 10.1016/j.stem.2022.02.011 [published Online First: 20220323]
3. Reece AS, Hulse GK. Geotemporospatial and causal inference epidemiological analysis of US survey and overview of cannabis, cannabidiol and cannabinoid genotoxicity in relation to congenital anomalies 2001–2015. BMC Pediatrics 2022;22(1):47-124. doi: 10.1186/s12887-021-02996-3
4. Reece A.S., Hulse G.K. Cannabinoid- and Substance- Relationships of European Congenital Anomaly Patterns: A Space-Time Panel Regression and Causal Inferential Study. Environmental Epigenetics 2022;8(1):1-40.
5. Reece AS, Hulse GK. Chromothripsis and epigenomics complete causality criteria for cannabis- and addiction-connected carcinogenicity, congenital toxicity and heritable genotoxicity. Mutat Res 2016;789:15-25. doi: 10.1016/j.mrfmmm.2016.05.002
6. Jenkins KJ, Correa A, Feinstein JA, et al. Noninherited risk factors and congenital cardiovascular defects: current knowledge: a scientific statement from the American Heart Association Council on Cardiovascular Disease in the Young: endorsed by the American Academy of Pediatrics. Circulation 2007;115(23):2995-3014. doi: 10.1161/CIRCULATIONAHA.106.183216
7. Reece AS, Hulse GK. Contemporary epidemiology of rising atrial septal defect trends across USA 1991-2016: a combined ecological geospatiotemporal and causal inferential study. BMC Pediatr 2020;20(1):539-50. doi: 10.1186/s12887-020-02431-z [published Online First: 2020/12/01]
8. Reece A.S., Hulse G.K. European Epidemiological Patterns of Cannabis- and Substance- Related Congenital Cardiovascular Anomalies: Geospatiotemporal and Causal Inferential Study. Environmental Epigenetics 2022;In Press
9. Reece A.S., Hulse G.K. Geotemporospatial and Causal Inferential Epidemiological Overview and Survey of USA Cannabis, Cannabidiol and Cannabinoid Genotoxicity Expressed in Cancer Incidence 2003–2017: Part 1 – Continuous Bivariate Analysis. Archives of Public Health 2022;80:99-133. doi: doi.org/10.1186/s13690-022-00811-8
10. Reece A.S., Hulse G.K. Epidemiological Overview of Multidimensional Chromosomal and Genome Toxicity of Cannabis Exposure in Congenital Anomalies and Cancer Development Scientific Reports 2021;11(1):13892-912. doi: 10.10389/s41598-021-93411-5
11. Reece A.S., Hulse G.K. Epidemiological Overview of Cannabis- and Substance- Carcinogenesis in Europe: A Lagged Causal Inferential Panel Regression Modelling and Marginal Effects Study. Manuscript submitted 2022
Competing interests:
No competing interests
06 July 2022
Albert S Reece
Professor & Physician
University of Western Australia
35 Stirling Hwy, Crawley, Perth, Western Australia, Australia, 6009.,
Disruption of Interlocking Synchrony Between Metabolome and Epigenome Key to Understanding Widespread Embyrotoxicity and Carcinogenicity of Diverse Cannabinoids
Dear Editor
For physicians of any type to prescribe cannabis it is axiomatic that both the safety and efficacy of cannabinoid treatments be well defined and the risk-benefit relationship be favourable. Central to any discussion of the safety of cannabis medicines therefore is an understanding of their recently delineated significant genotoxicity and epigenotoxicity. As mechanisms of biological action are central to any consideration of the safety and risks posed by cannabinoids advances of the latest Science and the mechanistic insights which spring from them are at once central, critical and pivotal. A clear appreciation of the far ranging impacts of the latest advances then takes centre stage in such discussions.
Recent studies clearly demonstrate that in heart development progenitors of cardiomyocytes rely on glycolytic–glutaminolytic metabolism to supply their metabolic demands [1] and that differentiation into adult cardiomyocytes happens together with conversion to oxidative phosphorylation to supply the higher energy demands required for cardiac contraction. Similar changes have been demonstrated in several other tissue beds. Moreover cancer cells are known to be generally de-differentiated and to have a metabolism based around glycolysis and glutaminolysis so that cancer stem cells are considered to be oncogenically transformed stem cells. In cancer this metabolic glycolytic dependency is called the “Warburg effect”.
A metabolism based on lactate and glutamate indicates that the intracellular and intra-mitochondrial milieu maintains a high concentration of lactate. Key rate limiting gatekeeper enzymes of oxidative phosphorylation are inhibited by these high lactate levels which shuts this down this major pathway. This has been demonstrated particularly for the mitochondrial matrix enzyme pyruvate dehydrogenase which controls the flow of pyruvate into the citric acid cycle and for carnitine acyl transferase situated on the inner and outer mitochondrial membranes and in the intermembrane space which controls the influx of fatty acid chains into β-oxidation which is the required principal high energy source of contracting cardiac muscle [2].
It has been understood for several years that the metabolome supplies the energy and metabolic substrates required for the innumerable post-translational modifications of proteins, nucleosomes and nucleic acids which comprise the epigenome.
However it was recently shown in human cardiac progenitors that not only are critical rate-limiting enzymes of oxidative phosphorylation inhibited by the high intracellular lactate concentration, but that they are actually post-translationally modified by lactate in a process referred to as lactylation [2]. This implies that the metabolic state not only influences (and suppresses) oxidative phosphorylation but that it actually – albeit reversibly - locks this inhibition in place.
Since many cannabinoids are known to be potent mitochondrial inhibitors (through many pathways) and also have a heavy epigenomic footprint it necessarily follows that the normal mutually reinforcing metabolic-epigenomic cross-talk is perturbed and that cells are metabolically primed for de-differentiation.
In addition to the many physiological pathways known to be perturbed by cannabinoids including numerous epigenomic and mitochondrial-metabolic mechanisms [3-5] this disruption of the critical coordinated and synchronized metabolic-epigenomic crosstalk incorporating dysregulation of the state of cellular differentiation contributes powerfully to explanations of the broad association of cannabis with many congenital anomalies recently reported in USA and Europe [3 4] particularly affecting cardiovascular development [6-8] and also with diverse cancer types which has similarly been reported from both sides from the Atlantic [9-11].
It is therefore premature to call for widespread prescribing when what is required is a full and proper re-evaluation of classical and modern pathways of genotoxicity and disruption of cellular metabolism generally and their very significant deleterious impacts on public health in the twenty-first century.
References
1. Du J, Zheng L, Gao P, et al. A small-molecule cocktail promotes mammalian cardiomyocyte proliferation and heart regeneration. Cell Stem Cell 2022;29(4):545-58.e13. doi: 10.1016/j.stem.2022.03.009
2. Wickramasinghe NM, Sachs D, Shewale B, et al. PPARdelta activation induces metabolic and contractile maturation of human pluripotent stem cell-derived cardiomyocytes. Cell Stem Cell 2022;29(4):559-76.e7. doi: 10.1016/j.stem.2022.02.011 [published Online First: 20220323]
3. Reece AS, Hulse GK. Geotemporospatial and causal inference epidemiological analysis of US survey and overview of cannabis, cannabidiol and cannabinoid genotoxicity in relation to congenital anomalies 2001–2015. BMC Pediatrics 2022;22(1):47-124. doi: 10.1186/s12887-021-02996-3
4. Reece A.S., Hulse G.K. Cannabinoid- and Substance- Relationships of European Congenital Anomaly Patterns: A Space-Time Panel Regression and Causal Inferential Study. Environmental Epigenetics 2022;8(1):1-40.
5. Reece AS, Hulse GK. Chromothripsis and epigenomics complete causality criteria for cannabis- and addiction-connected carcinogenicity, congenital toxicity and heritable genotoxicity. Mutat Res 2016;789:15-25. doi: 10.1016/j.mrfmmm.2016.05.002
6. Jenkins KJ, Correa A, Feinstein JA, et al. Noninherited risk factors and congenital cardiovascular defects: current knowledge: a scientific statement from the American Heart Association Council on Cardiovascular Disease in the Young: endorsed by the American Academy of Pediatrics. Circulation 2007;115(23):2995-3014. doi: 10.1161/CIRCULATIONAHA.106.183216
7. Reece AS, Hulse GK. Contemporary epidemiology of rising atrial septal defect trends across USA 1991-2016: a combined ecological geospatiotemporal and causal inferential study. BMC Pediatr 2020;20(1):539-50. doi: 10.1186/s12887-020-02431-z [published Online First: 2020/12/01]
8. Reece A.S., Hulse G.K. European Epidemiological Patterns of Cannabis- and Substance- Related Congenital Cardiovascular Anomalies: Geospatiotemporal and Causal Inferential Study. Environmental Epigenetics 2022;In Press
9. Reece A.S., Hulse G.K. Geotemporospatial and Causal Inferential Epidemiological Overview and Survey of USA Cannabis, Cannabidiol and Cannabinoid Genotoxicity Expressed in Cancer Incidence 2003–2017: Part 1 – Continuous Bivariate Analysis. Archives of Public Health 2022;80:99-133. doi: doi.org/10.1186/s13690-022-00811-8
10. Reece A.S., Hulse G.K. Epidemiological Overview of Multidimensional Chromosomal and Genome Toxicity of Cannabis Exposure in Congenital Anomalies and Cancer Development Scientific Reports 2021;11(1):13892-912. doi: 10.10389/s41598-021-93411-5
11. Reece A.S., Hulse G.K. Epidemiological Overview of Cannabis- and Substance- Carcinogenesis in Europe: A Lagged Causal Inferential Panel Regression Modelling and Marginal Effects Study. Manuscript submitted 2022
Competing interests: No competing interests