Phytocannabinoids have garnered global attention recently due to the therapeutic potentials in Parkinson’s disease (Chagas et al., 2014), Schizophrenia (McGuire et al., 2018), cancers (McGuire et al., 2018; Jeong et al., 2019; Sharafi et al., 2019), pain, anxiety, depression other neurological disorders (Marchetti, 2013) as well as the Food and Drug Administration (FDA) approval of Epidiolex for Dravet syndrome (Kaplan et al., 2017) and Lennox-Gauss Syndrome (Pauli et al., 2020). As of 2019, a total of 33 states, District of Columbia, Guam, Puerto Rico, and the U.S Virgin Island have approved Cannabis for medicinal purposes, 21 states are considering bills that would decriminalize it under legislative action. With recent legalization in Canada in 2019, more countries are beginning to question the rationale behind criminalizing Cannabis (Habibi and Hoffman, 2018). As interest in Cannabis expands throughout the globe, many issues have arisen concerning the lack of cultivation standards and overall quality control of Cannabis products. Recently the United States Pharmacopeia (USP) formed a Cannabis Expert Panel, which has evaluated specifications necessary to define key Cannabis quality attributes including limits for contaminants including pesticide residues, microbial levels, mycotoxins, and elemental contaminants based on toxicological considerations and aligned with the existing USP procedures for general tests and assays (Sarma et al., 2020). Aside from inaccuracy in labeling phytocannabinoid content, it has been reported that Cannabis and derived products are often contaminated by microbes, heavy metals, pesticides, carcinogens, and debris, which must be addressed to ensure the safety of consumers ( Table 1 ) (Mcpartland and Mckernan, 2017; Dryburgh et al., 2018).

These contaminants are imminent threats that directly impact public health and wellness, particularly to the immunocompromised and pediatric patients who take Cannabis products as a treatment for numerous human disorders including cancer patients and those suffering from epileptic seizures (Ruchlemer et al., 2015). To increase public awareness, we provide examples of contamination, its medical consequences reported in clinical research, and then suggest that each risk category be analyzed for best practices to limit exposure of contaminants to the consumer. We recommend hemp producers, manufacturers, medical professionals, and legislators recognize this risk and establish regulatory measures to educate the public and lessen the adverse effects caused by the contaminants in Cannabis, particularly in cannabidiol (CBD)-based products.

Mislabeling of phytocannabinoid profiles in CBD products is one of the major concerns to consumers (Hazekamp, 2018). Inaccurate reporting of the cannabinoid content risks exposing medicinal users to phytocannabinoids of which they have no intent to consume, namely Δ-9-tetrahydracannabinol (THC) (Corroon et al., 2020). This is of particular concern within pediatric patients, as THC intoxication has been shown to alter development of white matter in the brain (Gruber et al., 2014), as well as affect cognitive functioning (Crean et al., 2011; Zamberletti et al., 2015), and learning and memory within adolescents (Wang et al., 2013).

Despite a 15% allowable reporting variance of the phytocannabinoid content on CBD product labels (Herod et al., 2018), measured contents often exceed this range. For example, a recent study shows that 69% of 84 CBD products purchased from 31 American online retailers were inaccurately labeled for CBD, 26% were overlabeled whereas 42% were underlabeled for CBD concentration (Bonn-Miller et al., 2017). Additionally, 64% of 14 CBD products sold in the European Union (EU) market presented different cannabinoid profiles from the declared amount (Pavlovic et al., 2018). Inaccuracies are also found on labels of hemp-type Cannabis sold in the Netherlands with measured THC and CBD deviating from label claims by 8%–99% in CBD oil samples obtained from patients (Hazekamp, 2018). In Germany, an analysis of 67 CBD product samples it was found that 25% of samples were contaminated with residual THC above the lowest level of observable effects, or the lowest level that is known to cause physiological effects in humans (2.5 mg/day) (Lachenmeier et al., 2019). A recent analysis of 25 CBD oil products purchased in Mississippi, of the 25 products, only 3 were within ±20% of label claim, 15 were below the stated claim for CBD, 2 exceed these claims by more than 50%, and THC content for 3 products exceeded the 0.3% legal limit (Gurley et al., 2020). There are also concerns for edible Cannabis products (e.g., gummies, cookies, etc.) containing under and over reported phytocannabinoid content, specifically THC (Vandrey et al., 2015). In states where Cannabis is legal for recreation, these edible products are tested for overall THC potency in addition to dose specific potency of THC to be sure these products stays under 100 mg total THC with no more than 10 mg of THC per dose (Blake and Nahtigal, 2019). However, in hemp, there is no regulating body overseeing this testing, therefore the responsibility to test CBD edibles is left to each product manufacturer to ensure compliance of cannabinoid content limits, which is often neglected (Blake and Nahtigal, 2019). While currently CBD and THC are the only cannabinoids required to be labeled, it may be beneficial to include the profile of acidic forms of THC and CBD and some representative minor cannabinoids such as cannabigerol (CBG), cannabichromene (CBC), or possibly some of the short chain versions of these referred to as Varin cannabinoids on these labels. These minor cannabinoids are shown to have some therapeutic effects that could be enhanced in combination with other major cannabinoids (Deiana, 2017).

Cannabis is associated with various types of microbes including molds that have been shown to harm immunocompromised patients, as well as bacteria and viruses that have the potential of causing harm to humans. A recent metagenomics study on 15 medicinal Cannabis plants shows that Cannabis is associated with a wide range of epiphytic and endophytic microbial communities including several toxigenic bacterial and fungal species (Mckernan et al., 2016). While most of the microbes found to be in association with Cannabis are likely beneficial to the plant in some way or phytopathogens, several bacterial species have been identified that could be opportunistic pathogens in humans (Mckernan et al., 2016). While there are currently no reports of bacterial infection caused by contaminated Cannabis, several examples of fungal contamination, namely Aspergillus sp., are found in the literature and pose a threat to human health (Mckernan et al., 2016). In this section, the authors will introduce some of the possible human pathogenic microbial species and their relevant case studies.

A variety of heavy metals have been found in Cannabis plants and products made with Cannabis (e.g. tinctures and oils), including cadmium, lead, magnesium, copper, and mercury (Siegel et al., 1988; Busse et al., 2008; Mcpartland and Mckernan, 2017; Dryburgh et al., 2018; Gauvin et al., 2018). Cannabis plants have been shown to hyperaccumulate and incorporate these metals into tissues throughout the plant and have been previously explored for their ability to bioremediate contaminated soils (Mcpartland and Mckernan, 2017). Most heavy metals have low biodegradability, which allows them to bioaccumulate up the food chain and persist in the body long-term causing a wide range of health problems (Vardhan et al., 2019). Furthermore, many heavy metals have been shown to have fatal effects in humans when exposed both acutely or chronically, causing a plethora of diseases, such as, cancers and neurological disorders (Daley et al., 2013). While Colorado and California do require heavy metal testing in Cannabis, without similar requirements in place to test for such heavy metal contamination in hemp and CBD products, many people are at risk of exposure to toxic levels of heavy metals. At the greatest risk for detrimental effects from heavy metal contamination are those using CBD as a medical treatment including children suffering from pediatric epilepsy, and the various conditions leading to compromised immune systems. Thus, the authors aim to identify medical consequences of exposure to three major heavy metal contaminants found in Cannabis (i.e., cadmium, lead, and mercury) with a corresponding case study for each.

While many claim Cannabis is naturally a pest resistant crop (Park et al., 2019; Mckernan et al., 2020), there is still abundant use of various types of pesticides to provide protection, including insecticides, fungicides, and plant growth regulators (Mcpartland and Mckernan, 2017; Sandler et al., 2019). Unlike most crops that are grown in the United States, there are no federal guidelines provided by the Environmental Protection Agency (United States Environmental Protection Agency, 2019) as to which pesticides or how much should be used on Cannabis (Seltenrich, 2019). With the recent federal legalization of hemp in the U.S. under the 2016 and 2019 Farm Bills, a limited number of pesticides have been approved for use with hemp or Cannabis plants in the U.S. (United States Environmental Protection Agency, 2019). Previous to the release of this list, a lack of regulation led to the widespread use of hazardous pesticides including bifenazate, myclobutanil, and daminozide, as well as several others intended for ornamental plants and which are not approved for human consumption (Mcpartland and Mckernan, 2017). For example, the pesticide contents of 26 Cannabis samples obtained from Washington dispensaries were investigated, and 84% of the Cannabis samples analyzed were found to contain up to 24 agents of insecticides, miticides, fungicides, insecticidal synergists, and plant growth regulators (Russo, 2016). Also in 2016, it was found that 49% of Cannabis samples obtained from California dispensaries contained pesticides that are purely for ornamental plants including abamectin and bifenazate (Mcpartland and Mckernan, 2017). In 2016, it was also shown that Guardian pesticides, which were marketed as all natural containing only safe to consume chemicals like cinnamon oil and citric acid, did in fact contain abamectin (Mcpartland and Mckernan, 2017). Furthermore, it has been shown that 69% of the pesticides used in cultivation stay in Cannabis during smoking and can create toxic pyrolytic side products, suggesting that pesticide contaminated Cannabis may pose a significant toxicological threat to its users (Sullivan et al., 2013).

As many of these pesticides are lipophilic, they are soluble in the solvents used for extraction of cannabinoids, including CBD oils and other products using extracted cannabinoids. Naturally, this leads to concerns about contamination of Cannabis with pesticides and the potential health risks that would accompany concentrating these pesticides in an extract. The authors provide examples of a few compounds found in Cannabis from each class of pesticides and the potential health risks posed by each. While it is well beyond the scope of this paper to review all types of pesticides used to treat Cannabis, it is clear that pesticides associated with Cannabis and their individual health risks should be considered as important to growers and user alike. For the health of consumers, particularly those with compromised immune systems utilizing Cannabis for its therapeutic properties, it is imperative that a standard protocol continue to be developed for the safe use and testing of pesticides in Cannabis.

Plant growth regulators are also commonly found in Cannabis, including carcinogens and compounds that have been shown to be detrimental to mammals. Daminozide (4-(2,2-dimethylhydrazinyl)-4-oxobutanoic acid) and paclobutraxol ((2R,3R)-1-(4-chlorophenyl)-4,4-dimethyl-2-(1,2,4-triazol-1-yl)pentan-3-ol) are two plant growth regulators pervasively found in Cannabis. Daminozide is used to delay the ripening of fruits and is considered relatively nontoxic unless consumed at very high doses; however, it is still considered a human carcinogen by EPA (Neff and Goldman, 2005). This may be a greater concern to the farmers and cultivators than the end user, although little is known about the chronic exposure to daminozide over long periods of time. Paclobutraxol is a plant growth retardant that inhibits the biosynthesis of the plant hormone gibberellin which is responsible for shoot elongation (Rademacher, 2000). Paclobutraxol has been shown to have detrimental effects on development in several aquatic species (Li et al., 2012), and also to disrupt neurotransmitter levels in mice (Xu and Yang, 2020). Considering little is known about the human health consequences of chronic exposure to plant growth regulators, the use of these compounds in Cannabis cultivation should be regulated with the health of the consumer in mind.

Polycyclic aromatic hydrocarbons (PAH) are ubiquitous environmental pollutants usually generated by the incomplete combustion of organic materials (e.g. oil, coal, and wood) (Abdel-Shafy and Mansour, 2016). They are found in some CBD oils and may come either from uptake by the plant during growth or from contaminated carrier oils during product preparation (Večerka, 2018). Excessive PAH content in CBD oils can be attributed to the smoke from nearby forest fires or from drying Cannabis with propane heaters (Zelinkova and Wenzl, 2015). Over 100 types of PAHs exist and some of the most studied and well characterized (i.e., benzo anthracene, chrysene, benzo fluoranthene, benzo pyrene) are known to be hazardous, deemed as carcinogens, and can found in Cannabis products worldwide. In EU, 20 out of 29 tested CBD oil brands were shown to have PAH levels higher than the legislative limits of 20 mg/kg (White, 2019). High levels of PAHs in CBD oil are likely to cause DNA methylation, DNA adducts, and alteration of histone methylation which can lead to immunosuppression (Abdel-Shafy and Mansour, 2016). The elimination of PAHs in the environment is most studied in biological systems through multi-step metabolic pathways, primarily mixed-function oxidase systems, but they can degrade through oxidation reactions in the environment (Abdel-Shafy and Mansour, 2016). The extent to how any given PAH is eliminated is highly dependent on its unique physical and chemical properties (Abdel-Shafy and Mansour, 2016). While it may be impossible to eliminate PAHs in Cannabis products due to the ubiquitous nature of PAHs in the environment and the risk of producing these compounds when smoking Cannabis, consumer exposure can be reduced by addressing the sources of contamination and avoiding growing Cannabis in heavily industrialized areas (Jett et al., 2018).

Other debris such as metal fragments, hairs, dusts, machine oils, or insect parts can be found in some CBD oil products as is seen in other foods or food products (Dryburgh et al., 2018). The FDA considers these foreign contaminants a negligible health hazard but clearly this needs to be addressed by manufactures to develop high-quality control standards required to limit and minimize any foreign matter contamination.

With the recent legalization of Cannabis in many states of the U.S., there have been several state regulatory commissions put into place that address the issue of quality control in terms of contaminants and cannabinoid profile. However, the testing requirements do vary from state to state in terms of the minimum number of contaminants that must be tested for, and only 15 states currently have a regulatory commission in place. For the safety and welfare of all users, both medicinal and recreational, there is a necessity for a standardized set of guidelines for cultivation and testing of Cannabis products. There is currently only one set of guidelines called Recommendations for Regulators — Cannabis Operations that provides detailed set of recommended instructions on cultivation, packaging, testing and dispensing of Cannabis products including both THC and CBD products, which has proven invaluable for ensuring the safe cultivation of Cannabis (American Herbal Products Association, 2016). While these are a great set of guidelines, a more comprehensive understanding of the contamination of Cannabis products is necessary to appropriately eliminate the possible deleterious health effects contaminates may cause. Unfortunately, the classification of Cannabis as a schedule 1 drug federally makes the development and implementation of nationwide standards impossible at the moment, which if left unchanged, could lead to significant health complications in those turning to Cannabis for its medicinal properties.

S-HP and BVH conceived the review idea. MC and ZM wrote the initial draft. S-HP and CP reviewed and edited the manuscript. All authors contributed to the article and approved the submitted version.

This study was funded by the Institute of Cannabis Research (ICR).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.