Intended for healthcare professionals

Editor's Choice

Should we legalise cannabis?

BMJ 2019; 366 doi: https://doi.org/10.1136/bmj.l4507 (Published 04 July 2019) Cite this as: BMJ 2019;366:l4507

Re: Should we legalise cannabis?

Cannabis Threatens Oocytes, a Non-Renewable National Genomic Resource – and Implications of Prostacyclin Vasodilation and Anti-thrombogenesis

The classic experiments of Morishima reported by NIDA in 1984 leave very little to the imagination in relation to the genotoxic effects of cannabis on developing oocytes. Morishima showed that 20% of oocytes were lost after just the first cell division following cannabis exposure, and the news got worse in subsequent divisions 1. Apparently the oocytes were not able to cope with the genotoxic stress induced by cannabis exposure. Cannabis is known to induce DNA damage by several mechanisms including damage to chromosomes at the time of cell division, dramatic reductions in histone formation which form the core of the nucleosomes around which DNA is twined and are crucially involved in signalling to the transcription and epigenetic machinery to regulate gene expression, alteration of DNA methylation and many other processes 2-6. And genotoxic stress of many types is known to trigger DNA checkpoints and interfere with the normal process of meiotic and mitotic cell division; and are also known to trigger ageing and cellular senescence pathways.

The implications of stimulated senescence in human gametes have not been clearly thought out.

A momentary consideration of the differing biology of gametic reproduction in the two sexes is pertinent. Every medical student is taught that infant females are born with 1,000,000 oocytes in their ovaries, a number which falls to 400,000 by the time of menarche and she loses 20-50 with each menstrual cycle until ovarian exhaustion some time before menopause. This monotonic decline in the oocyte pool caused by their non-replacement directly implies that any genotoxic damage suffered by the developing oocyte would be FIXED in place, and just as we learned through studying mechanisms of chromothripsis and epigenomics, any cells not fatally damaged – which many would be - could pass on these effects to subsequent cell divisions, and potentially the developing embryo. In males the biology is very different, with 1500 sperm formed each second and an estimated 3 million million over a 60 year reproductive lifetime. Genotoxic damage sustained by males 4 7 would therefore have to be passed on by mechanisms involving cell division – of which there are many including chromosomal fragmentation, oxyradical DNA adduct formation particularly of the base guanine, and extensive DNA methylation and epigenomic damage of many types.

Can oocytes repair DNA damage? The answer to this question is not straightforward. It was classically taught that human oocytes have deficient DNA repair mechanisms related to the dramatically reduced availability of DNA repair proteins in contrast to oocytes of other species such as mice and monkeys 8-11. If so this implies that genomic damage would necessarily be passed along. However more recent studies suggest that oocytes have more DNA repair capacity than previously thought 12. However by analogy with epigenomic and chromothripsis studies it seems most unlikely that human oocytes can completely repair their genomic / epigenomic damage particularly in the context of Morishima’s work demonstrating extensive and severe genotoxicity, chromosomal bridging, chromoplexy and obvious macroscopic chromosomal damage.

Such considerations lead to the appalling conclusion that oocytes suffering the very considerable genotoxic / epigenotoxic damage imposed by cannabinoids – including cannabidiol 7 – can be irreversibly damaged and some of these damaged gametes will pass their genetically scrambled misinformation to subsequent embryos. Similar considerations apply to males albeit by well described mechanistic pathways which include cell division.

In this sense oocytes in particular can be conceptualized as a non-renewable genomic resource, and a key component of our national gene-environmental interactive heritage.

One of the less appreciated findings of the stunning paper on the genotoxic effects of cannabis on mice and human sperm by Murphy et. al. was the finding that cannabis exposure in both species reduces prostacyclin by epigenetic mechanisms 4. The thromboxane – prostacyclin axis has been known for several decades to control the balance between vasoconstriction and platelet adhesiveness on the one hand and vasodilatation and platelet disaggregation on the other. Both are highly potent agents active at the nanomolar level and tightly control vasomotor tone and the coagulation state or “stickiness” of the blood. Prostacyclin is a key vasodilator and regulator of microvascular integrity. It is known to have a powerful and potent effect on maintaining the patency of vessels of sub-millimeter diameter.

Dr Nora Volkow, Director of NIDA has expounded on the links between cannabis use and the cardiovascular disorders of myocardial infarction and stroke in adults 13 14. Cannabinoids acting via type 1 cannabinoid receptors (CB1R’s), the dominant cannabinoid receptor in the body, have been shown to strongly induce proinflammatory including arteritic states 15 16. Cannabis has also been shown to upregulate thromboxane at the proteomic level 17. The recent demonstration that cannabis epigenetically suppresses prostacyclin production offers a further major mechanistic basis for cannabinoid vasotoxicity. It also establishes a major point of cross-talk between cannabinoid and prostaglandin proinflammatory signalling which is clinically relevant.

This becomes of clinical significance when the association of cannabis with gastroschisis and multiple other cardiovascular disorders is considered 6 18-22. The links between maternal cannabis use and gastroschisis have been described elsewhere 6 20-22. Fascinatingly geographical microclusters of gastroschisis in Canada, California and Australia have also been described 23-26 suggesting that some environmental exposure is occurring within a tight geographical radius which is damaging foetal development.

If cannabis is linked with both vasospasm and a thrombogenic state then the fate of embryonic anterior abdominal wall closure, which normally occurs about the tenth or twelfth week of foetal development, would seem to be inevitably imperiled.

Were cannabis to be linked just with mental illness, just with autistic spectrum disorder, just with 28 congenital defects or just with a 50% rise in TOTAL pediatric cancers then there should be no debate on any measures which increase its use, access or availability. That it has been linked with all four areas, in the context of its many other known harms – respiratory, driving, impaired developmental trajectory, reduction in IQ, hippocampal shrinkage, brain disconnection and immunopathies - implies directly that the cannabis legalization debate itself is non-viable and profoundly and inherently misleading.

What is required is improved public education to dispel the widespread myths, and set the truth at liberty and give it legs to set the world’s people free wherever they reside in the beautiful way the truth has always done. Can we rise to the challenge??

References

1. Morishima A. Effects of cannabis and natural cannabinoids on chromosomes and ova. NIDA Res Monogr 1984;44:25-45.
2. Tahir SK, Zimmerman AM. Influence of marihuana on cellular structures and biochemical activities. Pharmacology, biochemistry, and behavior 1991;40(3):617-23.
3. Tilak SK, Zimmerman AM. Effects of cannabinoids on macromolecular synthesis in isolated spermatogenic cells. Pharmacology 1984;29(6):343-50. [published Online First: 1984/01/01]
4. Murphy SK, Itchon-Ramos N, Visco Z, et al. Cannabinoid exposure and altered DNA methylation in rat and human sperm. Epigenetics 2018 doi: 10.1080/15592294.2018.1554521
5. Reece A. S., Husle G.K. Cannabis Teratology Explains Current Patterns of Coloradan Congenital Defects: The Contribution of Increased Cannabinoid Exposure to Rising Teratological Trends Clinical Pediatrics 2019;In Press
6. 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
7. Russo C, Ferk F, Misik M, et al. Low doses of widely consumed cannabinoids (cannabidiol and cannabidivarin) cause DNA damage and chromosomal aberrations in human-derived cells. Archives of toxicology 2018 doi: 10.1007/s00204-018-2322-9
8. Mihalas BP, Redgrove KA, McLaughlin EA, et al. Molecular Mechanisms Responsible for Increased Vulnerability of the Ageing Oocyte to Oxidative Damage. Oxid Med Cell Longev 2017;2017:4015874. doi: 10.1155/2017/4015874
9. Feng R, Sang Q, Kuang Y, et al. Mutations in TUBB8 and Human Oocyte Meiotic Arrest. New England Journal of Medicine 2016;374(3):223-32. doi: doi:10.1056/NEJMoa1510791
10. Pfender S, Kuznetsov V, Pasternak M, et al. Live imaging RNAi screen reveals genes essential for meiosis in mammalian oocytes. Nature 2015;524(7564):239-42. doi: 10.1038/nature14568
11. Wang X, Liu D, He D, et al. Transcriptome analyses of rhesus monkey preimplantation embryos reveal a reduced capacity for DNA double-strand break repair in primate oocytes and early embryos. Genome Res 2017;27(4):567-79. doi: 10.1101/gr.198044.115
12. Stringer JM, Winship A, Liew SH, et al. The capacity of oocytes for DNA repair. Cell Mol Life Sci 2018;75(15):2777-92. doi: 10.1007/s00018-018-2833-9
13. Volkow ND, Baler RD, Compton WM, et al. Adverse Health Effects of Marijuana Use. New England Journal of Medicine 2014;370(23):2219-27. doi: doi:10.1056/NEJMra1402309
14. Volkow ND, Compton WM, Weiss SR. Adverse health effects of marijuana use. N Engl J Med 2014;371(9):879. doi: 10.1056/NEJMc1407928
15. Menahem S. Cardiovascular Effects of Cannabis Usage. In: V.R. P, ed. Handbook of Cannabis and Related Pathologies: Biology, Pharmacology and Treatment. New York: Academic Press 2017:481-85.
16. Pacher P, Steffens S, Hasko G, et al. Cardiovascular effects of marijuana and synthetic cannabinoids: the good, the bad, and the ugly. Nat Rev Cardiol 2018;15(3):151-66. doi: 10.1038/nrcardio.2017.130
17. Wang J, Yuan W, Li MD. Genes and pathways co-associated with the exposure to multiple drugs of abuse, including alcohol, amphetamine/methamphetamine, cocaine, marijuana, morphine, and/or nicotine: a review of proteomics analyses. Molecular neurobiology 2011;44(3):269-86. doi: 10.1007/s12035-011-8202-4
18. Reece A. S., Hulse G.K. Cannabis Teratology Explains Current Patterns of Coloradan Congenital Defects: The Contribution of Increased Cannabinoid Exposure to Rising Teratological Trends Clinical Pediatrics 2019;In Press
19. Reece AS, Hulse G.K. Impacts of Cannabinoid Epigenetics on Human Development: Reflections on Murphy et. al. “Cannabinoid Exposure and Altered DNA Methylation in Rat and Human Sperm” Epigenetics 2018; 13: 1208-1221. Epigenetics 2019;In Press
20. Reece A.S. Chronic Toxicology of Cannabis. Clinical Toxicology 2009;In Press(Accepted 28/05/09.)
21. Reece AS. Known Cannabis Teratogenicity Needs to be Carefully Considered. British Medical Journal 2018;362:k3357. [published Online First: 4th August 2018]
22. Reece AS, Norman A, Hulse GK. Cannabis exposure as an interactive cardiovascular risk factor and accelerant of organismal ageing: a longitudinal study. BMJ Open 2016;6(11):e011891. doi: 10.1136/bmjopen-2016-011891
23. Anderson JE, Cheng Y, Stephenson JT, et al. Incidence of gastroschisis in california. JAMA Surgery 2018 doi: 10.1001/jamasurg.2018.1744
24. Bassil KL, Yang J, Arbour L, et al. Spatial variability of gastroschisis in Canada, 2006-2011: An exploratory analysis. Canadian journal of public health 2016;107(1):e62-7. doi: 10.17269/cjph.107.5084
25. McMillan M. Birth Defects Exceed NSW Average. Northern Star Newspaper, 3rd June 2011. Lismore: Northern Star, 2011.
26. Expert Review Panel Appointed to New South Wales Health. Review of Gastroschisis on the NSW North Coast. In: From New South Wales Health Department Center for Record Linkage DC, Dr Lee Taylor, ltayl@doh.health.nsw.gov.au ,, ed. Sydney: New South Wales Health Department,
, 2011:1-11.

Competing interests: No competing interests

18 July 2019
Albert S Reece
Physician
University of Western Australia
35 Stirling Hwy, Crawley