As communities across the globe are increasingly experiencing a rising influx of cannabis products of many types a pleasant confluence of many events suggests that this is a suitable opportunity to re-investigate the important issue of the extent, impact and implications of cannabis-related carcinogenesis.

It has been known for several years that cannabis is linked with testicular cancer rates and indeed all four studies to have investigated the issue have made positive findings [1–4], with a relative risk of 2.59-fold (95%C.I. 1.60–4.19) [5]. Beyond a simple disease linkage this datum is highly impactful for our understanding of disease mechanisms for two reasons both of which are deserving of close attention. It is well described in the testicular cancer literature that the pathogenesis of testicular cancer begins in utero and is activated by the hormonal surge of puberty so that the preclinical phase of the disease takes place over several decades [6–8]. Patients who smoke cannabis and later contract testicular cancer, whose mean age of incidence is around 34 years, have obviously greatly contracted the preclinical disease course. That is to say that cannabis has aggressively accelerated malignant oncogenic processes from several decades to just a few years. Further the testis houses the male germ cell epithelium so that mutation there necessarily implies heritable mutagenesis potentially transmissible to following generations. This combination of powerful carcinogenesis and transgenerational transmissibility is a most concerning confluence. Similarly several pediatric cancers, including acute myeloid leukaemia (AML), have also been linked with parental cannabis use again demonstrating transgenerational transmissibility of oncogenesis [9–15].

It was recently reported in a geospatial and causal inference study that cannabis is a major driver of the significantly rising US total pediatric cancer rates which have risen 49% 1970–2017 [16]. This is important because what is implied is transgenerational transmission of oncogenesis, exactly as suggested above. Furthermore five major chromosomal anomalies and five major cancers were recently linked with cannabis exposure across USA [17].

Moreover cannabis-related oncogenesis is part of a larger overall story of cannabis-related genotoxicity. Warnings are found on the registered product information and prescribing information for both Epidiolex and Sativex indicating that genotoxicity is an activity of cannabinoids which is widely recognized and accepted by regulators, marketers, distributors and many scientists [18, 19]. It is well established that genotoxicity can be expected to be manifested primarily in increased rates of congenital malformations and cancer incidence [20]. Several cardiac malformations were described by the American Heart Association and American Academy of Pediatrics in a major review in 2007 [21]. However it was recently shown, again in a geospatial and causal inference study, that another common congenital heart defect, atrial septal defect secundum type is also being driven sharply upwards by increased cannabis exposure, which is not occurring uniformly across USA [22]. Description of a new cannabis-related congenital anomaly necessarily implies that our understanding of cannabis teratogenesis is as yet incomplete and indeed we have more to learn in this field. Many congenital anomalies were recently described as being more common in the highest quintile of cannabis using US states [23].

Patterns of cannabinoid consumption are changing rapidly. Cannabis legalization has resulted in not only more children and adults exposed to cannabis [24, 25] but also more people using it more intensely so that the number of people smoking daily or near daily has doubled in USA [26]. And it is well established that the concentration of most cannabinoids has risen dramatically in recent decades [27–29]. Hence more people are smoking stronger cannabis with greater intensity than previously creating a triple convergence of cannabinoid exposure especially in habitual smokers. High concentration “dabs”, highly concentrated oils and waxes and solid cannabinoid “shatter” are widely available in many parts of USA. This very new pattern clearly heralds a new era in cannabis epidemiology so that it is only appropriate that we well understand our recent history and epidemiology in this area. Indeed leading authorities have called for a complete revision of cannabis epidemiology in this new high dose – high intensity – high use paradigm [30]. Of note one widely quoted paper with a null finding on the cannabis cancer link actually omitted high dose cannabis smokers from its analysis by protocol likely amputating the most intriguing and important analytical signal [31].

One of the pillars of the epidemiological link between tobacco and lung cancer is the high odds ratio for smokers who experience a nine-fold elevation in lung cancer risk [32]. The E-Value or expected value is a measure on the relative risk scale of the strength of an association which some unmeasured confounder would require with both the exposure of interest and the outcome of concern to explain away the observed association. It can be calculated from the relative risk ratio or from the output from many common regression models. E-Values have both a point estimate and a 95% lower confidence interval bound [33–35]. The applicable lower E-Value for tobacco-lung cancer is 9.0. Our analysis makes extensive use of E-Values on linear regression equations and rate ratio count data for multiple outcomes [35] as was recently recommended by leading public health authorities [36]. We also considered that it would be useful to explore the formal techniques of causal inference and geotemporospatial regression for selected cancers as appropriate.

Cannabis is not a pure substance but a mixture of many substances. Prior to combustion it has over 400 unique chemicals in it collectively known as cannabinoids [37, 38]. Cannabis contains most of the major carcinogens of tobacco including benzopyrene, anthracyclines and aromatic polycyclic hydrocarbons [31, 37, 38]. THC is a major cannabinoid but cannabidiol is a well described minor constituent. Although cannabidiol currently enjoys a relatively harmless reputation in the popular press due to its relative lack of psychoactivity it has been known for several decades to be damaging to chromosomes, the bases of DNA, mitochondrial metabolism and energy generation and the epigenome [39]. Given that it is so widely available we were especially concerned to ascertain if this supposedly “safe” reputation was borne out by the observed epidemiological trends.

Companion papers examine these relationships as continuous variables [40], in detail in prostate and ovarian cancer [41], and the epidemiology of congenital teratogenesis from a space-time and causal inference perspective [17, 42, 43]. The present paper addresses these issues with variables categorized by quintiles of exposure which allows the calculation of key epidemiological metrics including rate ratios (R.R.), attributable fractions in the exposed (AFE) and population attributable risks (PAR, also known as attributable fractions in the population, AFP). Calculation of such proportions across different substances allows the oncogenicity of the known carcinogens tobacco and alcohol to be directly compared with that of the cannabinoids which is the principle subject of the present enquiry.