Comparative Toxicogenomics Database is a powerful tool to identify the potential mechanistic connections between environmental exposure and adverse health outcomes . We identified 22 insecticides in CTD – including 7 pyrethroids, 6 organophosphates, 4 organochlorines, 2 carbamates, 2 neonicotinoids, and fifipronil – and their association with 57 genes, 146 phenotypes, and the outcome of “Seizures”  in 621 computationally generated CGPD‐ tetramer constructs . Chlorpyrifos had the highest number of tetramers , followed by diazinon  and cypermethrin . Only two cannabinoids – cannabidiol and dronabinol – had curated information in CTD. Dronabinol was a synthetic form of Δ‐9‐tetrahydrocannabinol  approved by U.S. Food and Drug Administration  for the treatment of anorexia, nausea, and vomiting associated with AIDS and cancer chemotherapy . It was used as a surrogate to highlight the THC‐related bioactivity in this network analysis. We further generated 53 CGPD‐tetramers with cannabidiol, dronabinol, and seizure and identified 25 genes and 23 phenotypes . Nineteen genes and 9 phenotypes had connections to both cannabinoid and insecticide CGPD‐tetramers. The fifinding of shared genes and phenotypes was consistent with the fact that many anticonvulsant drugs and insecticides either worked through the same mechanism  or belonged to the same chemical class. Fig. 4 shows the 246 chemical‐gene interactions involved in forming the 621 CGPD‐ tetramers related to pesticides and seizure.Medical cannabis, like many pharmaceuticals and herbal medicines, are prone to contamination of metals, fungi, and pesticides during manufacturing and storage processes . While pharmaceutical contaminants are under robust U.S. FDA regulations , there is the lack of drug safety regulation of medical cannabis at the federal level. Thus, medical cannabis represents a potentially dangerous route of contaminant exposure to patients with susceptible conditions. Here, we surveyed the different approaches taken by the state‐level jurisdictions in the U.S. to regulate medical cannabis and pesticide residues. We show that  movement disorders are the most common neurological diseases qualified for medical use;  the number and action levels of regulated pesticides show great variation between jurisdictions; and  exposure to insecticides and cannabinoids affects the same set of signaling pathways that link to seizure.

In the contemporary cultural environment, cannabis is regarded by users and the society more generally as relatively risk free . An earlier study found that the representations of cannabis risks on social media forums were limited to concerns about driving and sleep effects . These “risks” were framed as avoidable and ephemeral drug‐induced impairments deriving from improper usage. No evidence of concerns was found about adulterated products as the social media representations naturalized cannabis as intrinsically medicinal. This unproblematic naturalization essentially mystifies the chemically‐intensive practices used in legal and illegalcultivation as well as the drug safety concerns of cannabis in medical use. The current study reveals a lack of clarity and consistent language in the listing of neurological diseases qualified for medical use. The culture transition of accepting cannabis as a medicinal plant, vertical grow rack together with the ambiguity of regulatory language for medical use, creates a potentially dangerous route of contaminant exposure to populations with existing vulnerability. The observed variation of pesticide action levels is indicative of the legal and scientific challenges in mitigating the human health risk of pesticide exposure in cannabis use. In the U.S., the pesticide residues of crops and vegetables are regulated under FIFRA . Yet, the illegal status of cannabis at the federal level means that individual states have to develop their own guidance and regulation. The published action levels reflect a variety of strategies taken by the regulatory agencies to approach this problem. Some agencies have developed specific sets of action levels to account for the differences in pesticide‐borne health risks due to the concentration effect of the cannabinoid extraction process  and the toxicokinetics of inhalational, dietary, and dermal exposures . Other agencies opt to impose more stringent action levels by applying the precautionary principle to mitigate such complex exposure scenarios with multiple risks and knowledge gaps . Implementing the U.S. EPA tolerances of food commodities in cannabis and cannabis‐derived products has the advantage of covering a large number of pesticide residues with relatively protective action levels. Yet, the U.S. EPA tolerances are not developed for commodities that are consumed in the inhalable form. Additionally, the effect of pyrolysis on pesticide residues – including the possibility of the generation of hydrogen cyanide – is largely unknown . The current study of CGPD‐tetramers highlights several pesticide groups that can disrupt multiple biological pathways. Several of these pathways are implicated in seizure, epilepsy, and other neurotoxic effects. For instance, exposure to organophosphate insecticides, carbamate insecticides, as well as cannabinoids can each be linked to oxidative stress and mitochondrial toxicity . Such oxidative stress and inflammation are linked to temporal lobe epilepsy through the MAPK pathway . Concomitant exposure to organophosphate insecticides and cannabinoids can also cause developmental neurotoxicity .

These pesticide groups may individually, or additively, produce neurotoxic effects though common mechanisms. For example, exposure to chlorpyrifos, diazinon, and dichlorvos all promotes seizure through cholinergic overstimulation. These organophosphate insecticides have been evaluated by the U.S. EPA as a common mechanism group.The present study is the first to examine the potential human health hazards of pesticidal contaminants on medical cannabis users. While previous studies have surveyed different classes of prevalent contaminants in cannabis, this study provides a proof of concept that  medical use of cannabis may unintentionally expose susceptible patients to harmful pesticides and  pesticidal contaminants, cannabinoids, and gene variants may disrupt the same set of biological functions that link to seizure disorders. A number of knowledge gaps remains to be addressed in order to mitigate pesticide‐borne health risks in medical cannabis, including  the exposure level of insecticide residues in medical patients;  the potential interaction of insecticides and cannabinoids and their adverse effects to human health; and  the health risk of cannabis use attributed to pesticide exposure and genetic variation. Such exposure and hazard information is crucial to our understanding of human health risk of cannabinoids and pesticides, which will support a health‐ protective national standard for cannabis pesticide regulations.With increasing medical cannabis use and rapidly changing cannabis laws, driving under the influence of cannabis  is a major public safety concern . Experimental studies show that acute cannabis intoxication can impair simulator and on-road driving performance as well as outcomes on a range of driving-related cognitive tasks. Recent cannabis use is also associated with a modest increase in crash risk and crash culpability. However, the focus of the literature to date has been on non-medical  cannabis and its acute effects in healthy volunteers. It is unclear whether these findings can be applied to patients who are using cannabis therapeutically. While the intention of medical cannabis use is to alleviate the symptoms associated with various chronic health conditions, rather than to produce intoxication, this doesn’t obviate the legitimate concerns that medical cannabis patients may be at a high risk of DUIC due to their cannabis use. In Australia, however, legal medical cannabis products are dominated by orally delivered oils, sprays and capsules, many of which contain only low or negligible amounts of THC and high amounts of CBD and are therefore unlikely to produce clinically relevant driving impairment.

Given that many medical conditions  can themselves impair driving, it is also conceivable that treating such conditions effectively will have a positive, or at least neutral, effect on driving performance. In a recent review of studies that assessed driving ability in patients with multiple sclerosis-related spasticity who were being treated with nabiximols , most patients reported an improvement in driving ability, most likely due to a reduction in spasticity and/or improved cognitive function. A number of studies to date have investigated the relationship between the introduction of medical cannabis laws in various U.S. states and traffic safety outcomes using data from the Fatality Analysis Reporting System. In most cases, medical cannabis laws had little effect on the prevalence of cannabis-positive driving and, in some cases, were associated with a reduction in traffic fatalities, possibly due to a decrease in the prevalence of driving under the influence of alcohol . This effect has not been entirely uniform, however, with one study reporting an increase in the prevalence of cannabis-positive drivers involved in fatal crashes in 3 out of the 12 U.S. states that were examined. Another study found an increase in cannabis-positive driving in Colorado, specifically following the commercial expansion of their medical cannabis industry in 2009. These data, while inconclusive, best trimming trays suggest that states with less restrictive cannabis laws and greater ease of access may be more susceptible to increases in DUIC prevalence. Given that many jurisdictions have only recently legalised medical cannabis, it may take more time for the impact of such changes on the prevalence of DUIC and cannabis-related crashes to become clear. There are some concerns that increased cannabis availability and changing social attitudes toward its use may affect perceptions of the risks associated with DUIC. A recent study found that >70% of medical cannabis patients in Michigan were driving while a “little high” or “very high”, with over half driving within two hours of using cannabis. The amount of cannabis used was positively associated with DUIC behaviour: respondents using more cannabis were more likely to drive within 2 hours of cannabis use and to self-report driving while intoxicated. In another survey of older drivers in Colorado, where both medical and non-medical cannabis use is legal, 9.3% reported driving within one hour of cannabis use. However, cannabis users were as likely as non-users to report having had a crash or citation. Recent Canadian government analysis indicated that 13.2% of cannabis users were driving within two hours of cannabis use, a proportion unchanged by the recent legalisation of access to non-medical cannabis. Driving within two hours of cannabis use was five times more likely among drivers who reported daily cannabis use.

These findings indicate a relatively high prevalence of DUIC, particularly among frequent cannabis users. While various U.S. states and Canada have relatively mature medical cannabis markets, other countries have introduced medical cannabis more recently, and with quite different regulatory models. Australia, for example, introduced laws permitting medical cannabis access in late 2016, and the roll out to patients has been relatively slow, despite overwhelming public support for patient access. At the same time, Australian States and Territories have expanded their roadside drug testing programmes, thereby increasing the likelihood that drivers will be randomly tested for the presence of THC in oral fluid. Although a positive test result can often lead to a criminal conviction and a driving ban, these laws do not currently differentiate between medical and non-medical cannabis use. It was therefore of interest to examine the attitudes, perceptions and driving-related behaviours of Australian medical cannabis users within this new and rapidly evolving context. Here, we describe the results of a survey that assessed DUIC behaviours in a convenience sample of medical cannabis users in Australia. These questions formed a sub-section of a larger online survey that examined the use of medical cannabis in the community and assessed consumer perspectives on the implementation of the Australian regulatory framework for prescribed medical cannabis . The term ‘medical cannabis’ as it is used here refers to any legal or illegal cannabis-based product being used to treat or alleviate the symptoms of a self-identified health condition. This does not imply that this treatment was recommended or prescribed by a health professional. Respondents were asked when they first tried cannabis and when they first began using it regularly for  medical reasons and for  any reason. Respondents were also asked how many days in the last 28 days they had used cannabis for medical reasons, how many times a day they typically used it and what percentage of their total cannabis use was considered medical. Additional survey questions asked about respondents’ primary method of cannabis use and type of cannabis used . Respondents were also asked how long it took after using medical cannabis until they felt  any effects,  peak effects and  no effects.In total, 1388 respondents completed and provided valid responses to the larger CAMS-18 survey. Of these, 909  completed the entire survey and 806  reported driving a motor vehicle in the past 12 months.