To Whom it may concern
On behalf of Drug Free Australia and our coalition of drug prevention researchers, we wish to commend to you, research that could well be a game-changer in informing and preventing a large proportion of Australia’s substance use issues.
The research is in various stages of development and a synopsis of current and emerging research, being done by Dr Stuart Reece and Professor Gary Hulse should be of genuine interest for all Australian Health Professionals. However, it appears that, to date, too many of the world’s researchers have placed this important research in the ‘too hard’ basket, similar to the way the NHS in the United Kingdom did with research into Pandemics.
At present the COVID-19 pandemic and how it is being addressed, should be a ‘wakeup call’ to Australian health authorities that prevention is the single most important goal. A ‘Harm Minimisation’ only approach, fails to achieve best-practice primary prevention outcomes. The passive discounting of the primary pillar of the National Drug Strategy – Demand Reduction over the last 30 years (and particularly the last 10) has seen a very large increase in illegal drug use in this nation.
The only exception to this has been seen in the correct and full use of both demand and supply reduction on the drug Tobacco. There has been little or no use of harm reduction mechanisms and a relentless and unified approach to abstinent/cessation modelling and it has worked spectacularly well, seeing Australia with, arguably, the lowest daily tobacco use in the world.
The research, that we now summarise, should not be placed in Australia’s ‘too hard’ basket. Rather, it warrants recognition by all Australian Health authorities for the world break-through that it is. Such evidence-based data offers timely insights that should promote and resource primary prevention and demand reduction.
Synopsis of the research:
1. Canadian Cannabis Consumption and Patterns of Congenital Anomalies: An Ecological Geospatial Analysis Albert Stuart Reece, MBBS(Hons), FRCS(Ed), FRCS(Glas), FRACGP, MD(UNSW), and Gary Kenneth Hulse, BBSc(Hons), MBSc, PhD
https://journals.lww.com/journaladdictionmedicine/Abstract/publishahead/Canadian_Cannabis_Consumption_and_Patterns_of.99248.aspx
Status
Mapping showed cannabis use was more common in the northern Territories of Canada in the Second National Survey of Cannabis Use 2018. Total congenital anomalies, all cardiovascular defects, orofacial clefts, Downs syndrome and gastroschisis were all found to be more common in these same regions and rose as a function of cannabis exposure.
When Canada was dichotomized into high and low cannabis use zones by Provinces v Territories the Territories had a higher rate of total congenital anomalies 450.026 v 390.413 (O.R.=1.16 95%C.I. 1.08-1.25, P=0.000058; attributable fraction in exposed 13.25%, 95%C.I. 7.04–19.04%). In geospatial analysis in a spreml spatial error model cannabis was significant both alone as a main effect (P<2.0×10-16) and in all its first and second order interactions with both tobacco and opioids from P<2.0×10-16.
Conclusion:
These results show that the northern Territories of Canada share a higher rate of cannabis use together with elevated rates of total congenital anomalies, all cardiovascular defects, Down’s syndrome and gastroschisis. This is the second report of a significant association between cannabis use and both total defects and all cardiovascular anomalies and the fourth published report of a link with Downs syndrome and thereby direct major genotoxicity.
The correlative relationships described in this paper are confounded by many features of social disadvantage in Canada’s northern territories. However, in the context of a similar broad spectrum of defects described both in animals and in epidemiological reports from Hawaii, Colorado, USA and Australia they are cause for particular concern and indicate further research.
139 References – click on this link to access.
https://journals.lww.com/journaladdictionmedicine/Abstract/publishahead/Canadian_Cannabis_Consumption_and_Patterns_of.99248.aspx
2. Cannabis Consumption Patterns Parallel the East-West Gradient in Canadian Neural Tube Defect Incidence – An Ecological Study
https://www.researchgate.net/publication/337911618_Cannabis_Consumption_Patterns_Explain_the_East-West_Gradient_in_Canadian_Neural_Tube_Defect_Incidence_An_Ecological_Study
Status:
Whilst a known link between prenatal cannabis exposure (PCE) and anencephaly exists, the relationship of PCE with neural tube defects (NTD’s) generally has not been defined. Published data from Canada Health and Statistics Canada was used to assess this relationship. Both cannabis use and NTDs were shown to follow an east-west and north-south gradient. Last year cannabis consumption was significantly associated (P<0.0001; Cannabis use: time interaction P<0.0001). These results were confirmed when estimates of termination for anomaly were used. Canada Health population data allowed the calculation of an NTD O.R.=1.27 (95%C.I. 1.19-1.37; P<10-11) for high risk provinces v. the remainder with an attributable fraction in exposed populations of 16.52% (95%C.I. 12.22-20.62). Data show a robust positive statistical association between cannabis consumption as both a qualitative and quantitative variable and NTDs on a background of declining NTD incidence. In the context of multiple mechanistic pathways these strong statistical findings implicate causal mechanisms.
82 References – click on this link to access.
https://www.researchgate.net/publication/337911618_Cannabis_Consumption_Patterns_Explain_the_East-West_Gradient_in_Canadian_Neural_Tube_Defect_Incidence_An_Ecological_Study
3. Cannabis exposure as an interactive cardiovascular risk factor and accelerant of organismal ageing: a longitudinal study. Response to Lane
https://bmjopen.bmj.com/content/6/11/e011891.responses
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We wish to thank Dr Lane for his interest in our study. We are pleased to see statistical input to the issues of cannabis medicine as we feel that sophisticated statistical methodologies have much to offer this field.
Most of the concerns raised are addressed in our very detailed report. As described our research question was whether, in our sizeable body of evidence (N=13,657 RAPWA studies), we could find evidence for the now well-described cannabis vasculopathy and what such implications might be. As this was the first study of its type to apply formal quantitative measures of vascular stiffness to these questions it was not clear at study outset if there would be any effect, much less an estimate of effect size. In the absence of this information power calculations would be mere guesswork. Nor indeed are they mandatory in an exploratory study of this type. Similarly the primary focus of our work was on whether cannabis exposure was an absolute cardiovascular risk factor in its own right, and how it compared to established risk factors. Hence Table 2 contains our main results. The role of Table 1 is to illustrate the bivariate (uncorrected) comparisons which can be made, show the various groups involved, and compare the matching of the groups. It is not intended to be a springboard for effect-size-power calculations which are of merely esoteric interest.
Calculations detailing the observed effect size are clearly described in our text being 11.84% and 8.35% age advance in males and females respectively.
Mixed-effects models are the canonical way to investigate longitudinal data given a usual random error structure 1. We agree with Lane that unusual error structures can affect significance conclusions. Diagnostic tests run on our models confirm that the residuals had the usual spheroidal error structure so that the application of mixed-effects models in the classical way is quite satisfactory. Another way to investigate this issue is that of incremental model building comparing models with and without cannabis exposure terms. If one considers regression equations from our data with cannabis use treated either as a categorical (RA/CA ~ Days_Post-Cannabis * BMI + * Cannabis_Category) or a continuous (RA/(CA*BMI) ~ Cigs*SP + * Cannabis_Use +Chol+DP+HDL+HR+CRH) variable one notes firstly that terms including cannabis use remain significant in final models (after model reduction) and secondly that models which include cannabis exposure are significantly better than ones without (Categorical: AIC = 1088.56 v. 1090.22, Log.Ratio = 19.62, P = 0.0204; Continuous: AIC = 412.33 v. 419.73, Log.Ratio = 9.37, P = 0.0022). Unfortunately formatting rules for BMJ Rapid Responses do not allow us to include a detailed table of regression results in each model in the present reply. We also note that AIC’s are little used in our report, and simply indicate the direction of the ANOVA results comparing models linear, quadratic and cubic in chronological age. They also appear routinely in the display of mixed-effects model results. Their use in such contexts is methodologically unremarkable. Control groups are also spelled out in fine detail in Table 1, in all our Figures and in the text.
We are aware that various algorithms for vascular age have been reported in the literature. The list proposed by Lane is correct but non-exhaustive. Such algorithms are generally derived from known cardiovascular risk factors. As clearly stated in our report the algorithm for vascular age we employed is derived from the proprietary software used. As such its details have not been publicized and indeed are commercially protected information.
We have however been assured by AtCor on many occasions that it includes measures of chronological age, sex, arterial stiffness and height (which is important as it dictates distance and thus speed parameters for the reflected and augmented central arterial pressure waves) and is very well validated and tested. AtCor recently advised that their algorithm is based on a very large series of studies done with arterial stiffness published in 2005 2. As such it has distinct advantages over algorithms which do not include indices of arterial stiffness. The AtCor website includes a very interesting, informative and educative animated loop which clearly illustrates the complex relationship between chronological and vascular age as a function of arterial stiffness and vascular tone 3
We are keen to see advanced statistical methods applied to such questions. We are becoming interested in geospatial and spacetime analyses and its application to the important questions of cannabis epidemiology 4. We find the very breadth of the organ systems impacted by cannabis to be quite remarkable with effects on the brain, cardiovasculature, liver, lungs, testes, ovaries, gastrointestinal, endocrine, reproductive and immune systems being well described and constituting most of the body’s major systems 5 6. Testicular and several pediatric cancers have also been described as being cannabis-associated 5. Such a multisystem generality of toxicity suggests to us that some basic cellular functions may be deleteriously affected – as implied by its well described mitochondriopathy 7, its heavy epigenetic footprint 8, accelerated aging as described in our present report 9 or some multi-way interaction between these and other processes. Given that the cannabis industry is presently entering a major commercialization growth phase, and given the multigenerational implications of mitochondriopathy-epigenotoxicity (by direct: substrate supply including ATP, NAD+ and acetate; and indirect: RNA transfer and malate-aspartate and glycerol-3-phosphate shuttle; pathways 10) further study and elucidation of these points is becoming an increasingly imperative international research priority.
Apropos of the recent Covid-19 pandemic emergency it is also worth noting that since cannabis is immunosuppressive, is known to be damaging to lungs and airways and often carries chemical, microbial and fungal contaminants cannabis use and cannabis vaping is also likely to have a deleterious effect on the coronavirus epidemic. Such data implies an untoward convergence of two public health epidemics. Appropriate controls on cannabis use imply improved public health management of SARS-CoV-2.
10 References – click on this link to access. https://bmjopen.bmj.com/content/6/11/e011891.responses
4. Cannabis Teratology Explains Current Patterns of Coloradan Congenital Defects: The Contribution of Increased Cannabinoid Exposure to Rising Teratological Trends.
https://www.researchgate.net/publication/334368364_Cannabis_Teratology_Explains_Current_Patterns_of_Coloradan_Congenital_Defects_The_Contribution_of_Increased_Cannabinoid_Exposure_to_Rising_Teratological_Trends/link/5d2d4d39a6fdcc2462e3097c/download
Status
Rising Δ9-tetrahydrocannabinol concentrations in modern cannabis invites investigation of the teratological implications of prenatal cannabis exposure.
Data from Colorado Responds to Children with Special Needs (CRCSN), National Survey of Drug Use and Health, and Drug Enforcement Agency was analyzed. Seven, 40, and 2 defects were rising, flat, and falling, respectively, and 10/12 summary indices rose. Atrial septal defect, spina bifida, microcephalus, Down’s syndrome, ventricular septal defect, and patent ductus arteriosus rose, and along with central nervous system, cardiovascular, genitourinary, respiratory, chromosomal, and musculoskeletal defects rose 5 to 37 times faster than the birth rate (3.3%) to generate an excess of 11 753 (22%) major anomalies. Cannabis was the only drug whose use grew from 2000 to 2014 while pain relievers, cocaine, alcohol, and tobacco did not. The correlation of cannabis use with major defects in 2014 (2019 dataset) was R = .77, P = .0011. Multiple cannabinoids were linked with summary measures of congenital anomalies and were robust to multivariate adjustment.
66 References – click on this link to access
https://www.researchgate.net/publication/334368364_Cannabis_Teratology_Explains_Current_Patterns_of_Coloradan_Congenital_Defects_The_Contribution_of_Increased_Cannabinoid_Exposure_to_Rising_Teratological_Trends/link/5d2d4d39a6fdcc2462e3097c/download
5. 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.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6773386/pdf/kepi-14-11-1633868.pdf
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ABSTRACT Recent data from the Kollins lab (‘Cannabinoid exposure and altered DNA methylation in rat and human sperm’ Epigenetics 2018; 13: 1208–1221) indicated epigenetic effects of cannabis use on sperm in man parallel those in rats and showed substantial shifts in both hypo- and hyper-DNA methylation with the latter predominating. This provides one likely mechanism for the transgenerational transmission of epigenomic instability with sperm as the vector. It therefore contributes important pathophysiological insights into the probable mechanisms underlying the epidemiology of prenatal cannabis exposure potentially explaining diverse features of cannabis-related teratology including effects on the neuraxis, cardiovasculature, immune stimulation, secondary genomic instability and carcinogenesis related to both adult and pediatric cancers. The potentially inheritable and therefore multigenerational nature of these defects needs to be carefully considered in the light of recent teratological and neurobehavioural trends in diverse jurisdictions such as the USA nationally, Hawaii, Colorado, Canada, France and Australia, particularly relating to mental retardation, age-related morbidity and oncogenesis including inheritable cancerogenesis.
Increasing demonstrations that the epigenome can respond directly and in real time and retain memories of environmental exposures of many kinds implies that the genome-epigenome is much more sensitive to environmental toxicants than has been generally realized. Issues of long-term multigenerational inheritance amplify these concerns. Further research particularly on the epigenomic toxicology of many cannabinoids is also required.
206 References – click on this link to access
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6773386/pdf/kepi-14-11-1633868.pdf
6. Canadian Cannabis Consumption and Patterns of Congenital Anomalies: An Ecological Geospatial Analysis.
https://www.ncbi.nlm.nih.gov/pubmed/32187114
Status:
These results show that the northern Territories of Canada share a higher rate of cannabis use together with elevated rates of total congenital anomalies, all cardiovascular defects, Down’s syndrome and gastroschisis. This is the second report of a significant association between cannabis use and both total defects and all cardiovascular anomalies and the fourth published report of a link with Downs syndrome and thereby direct major genotoxicity. The correlative relationships described in this paper are confounded by many features of social disadvantage in Canada’s northern territories. However, in the context of a similar broad spectrum of defects described both in animals and in epidemiological reports from Hawaii, Colorado, USA and Australia they are cause for particular concern and indicate
further.
139 references – click on this link to access https://www.ncbi.nlm.nih.gov/pubmed/32187114
7. The Potential Association Between Prenatal Cannabis use and Congenital Anomalies
https://journals.lww.com/journaladdictionmedicine/Citation/9000/The_Potential_Association_Between_Prenatal.99243.aspx
Status:
Rates of prenatal cannabis use are likely to rise with legalization, increasing social tolerability, and promotion in social media. Cannabis consumption does not appear to be a benign activity, and there may be significant risk factors to the developing fetus when used in pregnancy. Even as epidemiological data continue to emerge, The American College of Obstetricians and Gynecologists and The Society of Obstetricians and Gynecologists of Canada recommend that women avoid the use of cannabis during pregnancy.14 Whether we will definitively establish the risk of prenatal cannabis use on congenital anomalies using epidemiological approaches remains unclear; however, combing data from ecological and patient-level approaches will be crucial. Patient engagement and increasing awareness of the health implications of cannabis are critical first steps to highlight the potential risks of cannabis use in pregnancy.
14. References – click on this link to access
https://journals.lww.com/journaladdictionmedicine/Citation/9000/The_Potential_Association_Between_Prenatal.99243.aspx
8. America Addresses Two Epidemics – Cannabis and Coronavirus and their Interactions: An Ecological Geospatial Study
Status: Embargoed until publication.
Question: Since cannabis is immunosuppressive and is frequently variously contaminated, is its use associated epidemiologically with coronavirus infection rates?
Findings: Geospatial analytical techniques were used to combine coronavirus incidence, drug and cannabinoid use, population, ethnicity, international flight and income data. Cannabis use and daily cannabis use were associated with coronavirus incidence on both bivariate regression and after multivariable spatial regression with high levels of statistical significance. Cannabis use quintiles and cannabis legal status were also highly significant.
Meaning: Significant geospatial statistical associations were shown between cannabis use and coronavirus infection rates consistent with mechanistic reports and environmental exposure concerns.
Extracts from Abstract:
Results. Significant associations of daily cannabis use quintile with CVIR were identified with the highest quintile having a prevalence ratio 5.11 (95%C.I. 4.90-5.33), an attributable fraction in the exposed (AFE) 80.45% (79.61-81.25%) and an attributable fraction in the population of 77.80% (76.88-78.68%) with Chi-squared-for-trend (14,782, df=4) significant at P<10-500. Similarly when cannabis legalization was considered decriminalization was associated with an elevated CVIR prevalence ratio 4.51 (95%C.I. 4.45-4.58), AFE 77.84% (77.50-78.17%) and Chi-squared-for-trend (56,679, df=2) significant at P<10-500. Monthly and daily use were linked with CVIR in bivariate geospatial regression models (P=0.0027, P=0.0059). In multivariable additive models number of flight origins and population density were significant. In interactive geospatial models adjusted for international travel, ethnicity, income, population, population density and drug use, terms including last month cannabis were significant from P=7.3×10-15, daily cannabis use from P=7.3×10-11 and last month cannabis was independently associated (P=0.0365).
Conclusions and Relevance. Data indicate CVIR demonstrates significant trends across cannabis use intensity quintiles and with relaxed cannabis legislation. Recent cannabis use is independently predictive of CVIR in both bivariate and multivariable adjusted models and intensity of use is significant in several interactions. Cannabis thus joins tobacco as a SARS2-CoV-2 risk factor.
Summary and Conclusions
The above research clearly shows the links with substance use and Mental illness, Autism, Congenital anomalies and Paediatric cancer including testicular cancer with marijuana use and abuse. Drug Free Australia respectfully and urgently requests a Position Statement and proposed actions from your Department regarding this research and how it can be further promoted and supported within Australia. We look forward to your timely response.
You can find a list of list of Ngo’s and Medical Professional who written support for Drug Free Australia’s Response to the commercialization of Cannabis/Marijuana/CBD in Australia
https://drugfree.org.au/images/pdf-files/homepagepdf/DRReeceSupport2020_updated6May2020.pdf.
Yours sincerely
Major Brian Watters AO B.A.
President
Drug Free Australia
PO Box 379
Seaford, SA 516