Journal:Cannabis contaminants limit pharmacological use of cannabidiol - Revision history

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	\|download = [https://www.frontiersin.org/articles/10.3389/fphar.2020.571832/pdf https://www.frontiersin.org/articles/10.3389/fphar.2020.571832/pdf] (PDF)		\|download = [https://www.frontiersin.org/articles/10.3389/fphar.2020.571832/pdf https://www.frontiersin.org/articles/10.3389/fphar.2020.571832/pdf] (PDF)
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	~~\| text = This article should be considered a work in progress and incomplete. Consider this article incomplete until this notice is removed.~~
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	==Abstract==		==Abstract==
	For nearly a century, [[wikipedia:Cannabis\|cannabis]] has been stigmatized and [[wikipedia:Legality of cannabis\|criminalized]] across the globe, but in recent years, there has been a growing interest in cannabis due to the therapeutic potential of [[wikipedia:Cannabinoid#Phytocannabinoids\|phytocannabinoids]]. With this emerging interest in cannabis, concerns have arisen about the possible [[wikipedia:Contamination\|contaminations]] of [[wikipedia:Hemp\|hemp]] with [[wikipedia:Pesticide\|pesticides]], [[wikipedia:Heavy metals\|heavy metals]], microbial [[wikipedia:Pathogen\|pathogens]], and [[wikipedia:Carcinogen\|carcinogenic]] compounds during the [[wikipedia:Cannabis cultivation\|cultivation]], manufacturing, and packaging processes. This is of particular concern for those turning to cannabis for [[wikipedia:Cannabis (drug)\|medicinal purposes]], especially those with compromised immune systems. This review aims to provide types of contaminants and examples of cannabis contamination using case studies that elucidate the medical consequences consumers risk when using adulterated cannabis products. Thus, it is imperative to develop universal standards for cultivation and [[LII:Past, Present, and Future of Cannabis Laboratory Testing and Regulation in the United States\|testing]] of products to protect those who consume cannabis.		For nearly a century, [[wikipedia:Cannabis\|cannabis]] has been stigmatized and [[wikipedia:Legality of cannabis\|criminalized]] across the globe, but in recent years, there has been a growing interest in cannabis due to the therapeutic potential of [[wikipedia:Cannabinoid#Phytocannabinoids\|phytocannabinoids]]. With this emerging interest in cannabis, concerns have arisen about the possible [[wikipedia:Contamination\|contaminations]] of [[wikipedia:Hemp\|hemp]] with [[wikipedia:Pesticide\|pesticides]], [[wikipedia:Heavy metals\|heavy metals]], microbial [[wikipedia:Pathogen\|pathogens]], and [[wikipedia:Carcinogen\|carcinogenic]] compounds during the [[wikipedia:Cannabis cultivation\|cultivation]], manufacturing, and packaging processes. This is of particular concern for those turning to cannabis for [[wikipedia:Cannabis (drug)\|medicinal purposes]], especially those with compromised immune systems. This review aims to provide types of contaminants and examples of cannabis contamination using case studies that elucidate the medical consequences consumers risk when using adulterated cannabis products. Thus, it is imperative to develop universal standards for cultivation and [[LII:Past, Present, and Future of Cannabis Laboratory Testing and Regulation in the United States\|testing]] of products to protect those who consume cannabis.
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	[[wikipedia:Polycyclic aromatic hydrocarbon\|Polycyclic aromatic hydrocarbons]] (PAHs) are ubiquitous environmental pollutants usually generated by the incomplete combustion of organic materials (e.g., oil, coal, and wood).<ref name="Abdel-ShafyARev16">{{cite journal \|title=A review on polycyclic aromatic hydrocarbons: Source, environmental impact, effect on human health and remediation \|journal=Egyptian Journal of Petroleum \|author=Abdel-Shafy, H.I.; Mansour, M.S.M. \|volume=25 \|issue=1 \|pages=107–23 \|year=2016 \|doi=10.1016/j.ejpe.2015.03.011}}</ref> 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.<ref name="VečerkaWarn18">{{cite web \|url=https://www.icci.science/en/article/news/warning-for-consumers-of-cbd-and-cannabis-oils-sold-on-the-eu-market/ \|title=Warning for consumers of CBD and cannabis oils sold on the EU market \|author=Večerka, J. \|publisher=International Cannabis and Cannabinoids Institute \|date=16 February 2018 \|accessdate=22 January 2020}}</ref> Excessive PAH content in CBD oils can be attributed to the smoke from nearby forest fires or from drying cannabis with propane heaters.<ref name="ZelinkovaTheOcc15">{{cite journal \|title=The Occurrence of 16 EPA PAHs in Food - A Review \|journal=Polycyclic Aromatic Compounds \|author=Zelinkova, Z.; Wenzl, T. \|volume=35 \|issue=2–4 \|pages=248–84 \|year=2015 \|doi=10.1080/10406638.2014.918550 \|pmid=26681897 \|pmc=PMC4673601}}</ref> 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 carcinogens, and can found in cannabis products worldwide. In the E.U., 20 out of 29 tested CBD oil brands were shown to have PAH levels higher than the legislative limits of 20 mg/kg.<ref name="WhiteARev19">{{cite journal \|title=A Review of Human Studies Assessing Cannabidiol's (CBD) Therapeutic Actions and Potential \|journal=Journal of Clinical Pharmacology \|author=White, C.M. \|volume=59 \|issue=7 \|pages=923–34 \|year=2019 \|doi=10.1002/jcph.1387 \|pmid=30730563}}</ref> 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.<ref name="Abdel-ShafyARev16" /> 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.<ref name="Abdel-ShafyARev16" /> The extent to how any given PAH is eliminated is highly dependent on its unique physical and chemical properties.<ref name="Abdel-ShafyARev16" /> 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.<ref name="JettCanna18">{{cite journal \|title=Cannabis Use, Lung Cancer, and Related Issues \|journal=Journal of Thoracic Oncology \|author=Jett, J.; Stone, E.; Warren, G. et al. \|volume=13 \|issue=4 \|pages=480–487 \|year=2018 \|doi=10.1016/j.jtho.2017.12.013 \|pmid=29374567}}</ref>		[[wikipedia:Polycyclic aromatic hydrocarbon\|Polycyclic aromatic hydrocarbons]] (PAHs) are ubiquitous environmental pollutants usually generated by the incomplete combustion of organic materials (e.g., oil, coal, and wood).<ref name="Abdel-ShafyARev16">{{cite journal \|title=A review on polycyclic aromatic hydrocarbons: Source, environmental impact, effect on human health and remediation \|journal=Egyptian Journal of Petroleum \|author=Abdel-Shafy, H.I.; Mansour, M.S.M. \|volume=25 \|issue=1 \|pages=107–23 \|year=2016 \|doi=10.1016/j.ejpe.2015.03.011}}</ref> 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.<ref name="VečerkaWarn18">{{cite web \|url=https://www.icci.science/en/article/news/warning-for-consumers-of-cbd-and-cannabis-oils-sold-on-the-eu-market/ \|title=Warning for consumers of CBD and cannabis oils sold on the EU market \|author=Večerka, J. \|publisher=International Cannabis and Cannabinoids Institute \|date=16 February 2018 \|accessdate=22 January 2020}}</ref> Excessive PAH content in CBD oils can be attributed to the smoke from nearby forest fires or from drying cannabis with propane heaters.<ref name="ZelinkovaTheOcc15">{{cite journal \|title=The Occurrence of 16 EPA PAHs in Food - A Review \|journal=Polycyclic Aromatic Compounds \|author=Zelinkova, Z.; Wenzl, T. \|volume=35 \|issue=2–4 \|pages=248–84 \|year=2015 \|doi=10.1080/10406638.2014.918550 \|pmid=26681897 \|pmc=PMC4673601}}</ref> 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 carcinogens, and can found in cannabis products worldwide. In the E.U., 20 out of 29 tested CBD oil brands were shown to have PAH levels higher than the legislative limits of 20 mg/kg.<ref name="WhiteARev19">{{cite journal \|title=A Review of Human Studies Assessing Cannabidiol's (CBD) Therapeutic Actions and Potential \|journal=Journal of Clinical Pharmacology \|author=White, C.M. \|volume=59 \|issue=7 \|pages=923–34 \|year=2019 \|doi=10.1002/jcph.1387 \|pmid=30730563}}</ref> 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.<ref name="Abdel-ShafyARev16" /> 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.<ref name="Abdel-ShafyARev16" /> The extent to how any given PAH is eliminated is highly dependent on its unique physical and chemical properties.<ref name="Abdel-ShafyARev16" /> 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.<ref name="JettCanna18">{{cite journal \|title=Cannabis Use, Lung Cancer, and Related Issues \|journal=Journal of Thoracic Oncology \|author=Jett, J.; Stone, E.; Warren, G. et al. \|volume=13 \|issue=4 \|pages=480–487 \|year=2018 \|doi=10.1016/j.jtho.2017.12.013 \|pmid=29374567}}</ref>

			==Other foreign matter==
			Other debris such as metal fragments, hairs, dusts, machine oils, or insect parts can be found in some CBD oil products, as can be seen in other foods or food products.<ref name="DryburghCanna18" /> 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.

			==Discussion==
			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 the cannabinoid profile. However, cannabis 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—developed by the American Herbal Products Association—called ''Recommendations for Regulators — Cannabis Operations'' that provides a detailed set of recommended instructions on cultivation, packaging, testing, and dispensing of cannabis products (both THC and CBD products), which has proven invaluable for ensuring the safe cultivation of cannabis.<ref name="AHPARecomm16">{{cite web \|url=http://www.ahpa.org/Portals/0/PDFs/Committee/CC/Cannabis_Operations_Recommendations_Regulators.pdf \|format=PDF \|title=Recommendations for Regulators - Cannabis Operations \|author=American Herbal Products Association \|publisher=American Herbal Products Association \|date=02 February 2020}}</ref> 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 [[wikipedia:Controlled Substances Act#Schedules of controlled substances\|Schedule I]] 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.

			==Acknowledgements==
			===Author contributions===
			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.

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

			===Conflict of interest===
			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.

	==References==		==References==

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	==Plant growth regulators==		==Plant growth regulators==
	Plant growth regulators are also commonly found in cannabis, including carcinogens and compounds that have been shown to be detrimental to mammals. Daminozide and paclobutraxol 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 the EPA.<ref name="NeffReg05">{{cite journal \|title=Regulatory parallels to Daubert: stakeholder influence, "sound science," and the delayed adoption of health-protective standards \|journal=American Journal of Public Health \|author=Neff, R.A.; Goldman, L.R. \|volume=95 \|issue=Suppl. 1 \|pages=S81–91 \|year=2005 \|doi=10.2105/AJPH.2004.044818 \|pmid=16030344}}</ref> 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.<ref name="RademacherGrowth00">{{cite journal \|title=Growth Retardants: Effects on Gibberellin Biosynthesis and Other Metabolic Pathways \|journal=Annual Review of Plant Physiology and Plant Molecular Biology \|author=Rademacher, W. \|volume=51 \|pages=501–31 \|year=2000 \|doi=10.1146/annurev.arplant.51.1.501 \|pmid=15012200}}</ref> Paclobutraxol has been shown to have detrimental effects on development in several aquatic species<ref name="LiExpos12">{{cite journal \|title=Exposure to paclobutrazol disrupts spermatogenesis in male ''Sebastiscus marmoratus'' \|journal=Aquatic Toxicology \|author=Li, J.; Sun, L.; Zuo, Z. et al. \|volume=122–23 \|pages=120–4 \|year=2012 \|doi=10.1016/j.aquatox.2012.06.007 \|pmid=22789407}}</ref>, and also to disrupt neurotransmitter levels in mice.<ref name="XuInteg20">{{cite journal \|title=Integrated gender-related effects of profenofos and paclobutrazol on neurotransmitters in mouse \|journal=Ecotoxicology and Environmental Safety \|author=Xu, M.; Yang, F. \|volume=190 \|at=110085 \|year=2020 \|doi=10.1016/j.ecoenv.2019.110085 \|pmid=31855789}}</ref> 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.		Plant growth regulators are also commonly found in cannabis, including carcinogens and compounds that have been shown to be detrimental to mammals. Daminozide and paclobutraxol 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 the EPA.<ref name="NeffReg05">{{cite journal \|title=Regulatory parallels to Daubert: stakeholder influence, "sound science," and the delayed adoption of health-protective standards \|journal=American Journal of Public Health \|author=Neff, R.A.; Goldman, L.R. \|volume=95 \|issue=Suppl. 1 \|pages=S81–91 \|year=2005 \|doi=10.2105/AJPH.2004.044818 \|pmid=16030344}}</ref> 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.<ref name="RademacherGrowth00">{{cite journal \|title=Growth Retardants: Effects on Gibberellin Biosynthesis and Other Metabolic Pathways \|journal=Annual Review of Plant Physiology and Plant Molecular Biology \|author=Rademacher, W. \|volume=51 \|pages=501–31 \|year=2000 \|doi=10.1146/annurev.arplant.51.1.501 \|pmid=15012200}}</ref> Paclobutraxol has been shown to have detrimental effects on development in several aquatic species<ref name="LiExpos12">{{cite journal \|title=Exposure to paclobutrazol disrupts spermatogenesis in male ''Sebastiscus marmoratus'' \|journal=Aquatic Toxicology \|author=Li, J.; Sun, L.; Zuo, Z. et al. \|volume=122–23 \|pages=120–4 \|year=2012 \|doi=10.1016/j.aquatox.2012.06.007 \|pmid=22789407}}</ref>, and also to disrupt neurotransmitter levels in mice.<ref name="XuInteg20">{{cite journal \|title=Integrated gender-related effects of profenofos and paclobutrazol on neurotransmitters in mouse \|journal=Ecotoxicology and Environmental Safety \|author=Xu, M.; Yang, F. \|volume=190 \|at=110085 \|year=2020 \|doi=10.1016/j.ecoenv.2019.110085 \|pmid=31855789}}</ref> 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==
			[[wikipedia:Polycyclic aromatic hydrocarbon\|Polycyclic aromatic hydrocarbons]] (PAHs) are ubiquitous environmental pollutants usually generated by the incomplete combustion of organic materials (e.g., oil, coal, and wood).<ref name="Abdel-ShafyARev16">{{cite journal \|title=A review on polycyclic aromatic hydrocarbons: Source, environmental impact, effect on human health and remediation \|journal=Egyptian Journal of Petroleum \|author=Abdel-Shafy, H.I.; Mansour, M.S.M. \|volume=25 \|issue=1 \|pages=107–23 \|year=2016 \|doi=10.1016/j.ejpe.2015.03.011}}</ref> 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.<ref name="VečerkaWarn18">{{cite web \|url=https://www.icci.science/en/article/news/warning-for-consumers-of-cbd-and-cannabis-oils-sold-on-the-eu-market/ \|title=Warning for consumers of CBD and cannabis oils sold on the EU market \|author=Večerka, J. \|publisher=International Cannabis and Cannabinoids Institute \|date=16 February 2018 \|accessdate=22 January 2020}}</ref> Excessive PAH content in CBD oils can be attributed to the smoke from nearby forest fires or from drying cannabis with propane heaters.<ref name="ZelinkovaTheOcc15">{{cite journal \|title=The Occurrence of 16 EPA PAHs in Food - A Review \|journal=Polycyclic Aromatic Compounds \|author=Zelinkova, Z.; Wenzl, T. \|volume=35 \|issue=2–4 \|pages=248–84 \|year=2015 \|doi=10.1080/10406638.2014.918550 \|pmid=26681897 \|pmc=PMC4673601}}</ref> 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 carcinogens, and can found in cannabis products worldwide. In the E.U., 20 out of 29 tested CBD oil brands were shown to have PAH levels higher than the legislative limits of 20 mg/kg.<ref name="WhiteARev19">{{cite journal \|title=A Review of Human Studies Assessing Cannabidiol's (CBD) Therapeutic Actions and Potential \|journal=Journal of Clinical Pharmacology \|author=White, C.M. \|volume=59 \|issue=7 \|pages=923–34 \|year=2019 \|doi=10.1002/jcph.1387 \|pmid=30730563}}</ref> 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.<ref name="Abdel-ShafyARev16" /> 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.<ref name="Abdel-ShafyARev16" /> The extent to how any given PAH is eliminated is highly dependent on its unique physical and chemical properties.<ref name="Abdel-ShafyARev16" /> 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.<ref name="JettCanna18">{{cite journal \|title=Cannabis Use, Lung Cancer, and Related Issues \|journal=Journal of Thoracic Oncology \|author=Jett, J.; Stone, E.; Warren, G. et al. \|volume=13 \|issue=4 \|pages=480–487 \|year=2018 \|doi=10.1016/j.jtho.2017.12.013 \|pmid=29374567}}</ref>

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	Imazalil—also known as enilconazole—and myclobutanil have both been used to prevent fungal infection in cannabis.<ref name="McPartlandContam17" /> Imazalil, a systemic fungicide used to control powdery mildew and other mold or fungal infections in crop plants, has been shown to be an androgen receptor agonist and endocrine disruptor in mammals.<ref name="GoetzInhib09">{{cite journal \|title=Inhibition of rat and human steroidogenesis by triazole antifungals \|journal=Systems Biology in Reproductive Medicine \|author=Goetz, A.K.; Rockett, J.C.; Ren, H. et al. \|volume=55 \|issue=5–6 \|pages=214–26 \|year=2009 \|doi=10.3109/19396360903234045 \|pmid=19938956}}</ref> It can cause detrimental mutations in genes controlling cholesterol metabolism and androgen conversion to estrogen that carry on and persist into the following generations in mammals.<ref name="JinChronic18">{{cite journal \|title=Chronic exposure of mice to low doses of imazalil induces hepatotoxicity at the physiological, biochemical, and transcriptomic levels \|journal=Environmental Toxicology \|author=Jin, C.; Luo, T.; Fu, Z. et al. \|volume=33 \|issue=6 \|pages=650-658 \|year=2018 \|doi=10.1002/tox.22550 \|pmid=29451352}}</ref><ref name="JinMatern19">{{cite journal \|title=Maternal exposure to imazalil disrupts the endocrine system in F 1 generation mice \|journal=Molecular and Cellular Endocrinology \|author=Jin, C.; Zhang, R.; Fu, Z. et al. \|volume=486 \|pages=105–12 \|year=2019 \|doi=10.1016/j.mce.2019.03.002 \|pmid=30853599}}</ref> Myclobutanil is an inhibitor of ergosterol production in fungus, which is essential for the formation of fungal cell walls.<ref name="HesterTrans06">{{cite journal \|title=Transcriptional profiles in liver from rats treated with tumorigenic and non-tumorigenic triazole conazole fungicides: Propiconazole, triadimefon, and myclobutanil \|journal=Toxicologic Pathology \|author=Hester, S.D.; Wolf, D.C.; Nesnow, S. et al. \|volume=34 \|issue=7 \|pages=879–94 \|year=2006 \|doi=10.1080/01926230601047824 \|pmid=17178689}}</ref> In addition to being detrimental to fungi, myclobutanil can also inhibit cholesterol synthesis in mammals at high doses.<ref name="HesterTrans06" /><ref name="BerensteinHiman17">{{cite journal \|title=Human and soil exposure during mechanical chlorpyrifos, myclobutanil and copper oxychloride application in a peach orchard in Argentina \|journal=The Science of the Total Environment \|author=Berenstein, G.; Nasello, S.; Beiguel, E. et al. \|volume=586 \|pages=1254–62 \|year=2017 \|doi=10.1016/j.scitotenv.2017.02.129 \|pmid=28237465}}</ref> Neither of these compounds have been extensively studied in humans, but what is known about their effects on mammalian systems is cause for concern. These fungicides should not be considered safe to use for any cannabis cultivation, and their application should be avoided to protect the health of the consumer.		Imazalil—also known as enilconazole—and myclobutanil have both been used to prevent fungal infection in cannabis.<ref name="McPartlandContam17" /> Imazalil, a systemic fungicide used to control powdery mildew and other mold or fungal infections in crop plants, has been shown to be an androgen receptor agonist and endocrine disruptor in mammals.<ref name="GoetzInhib09">{{cite journal \|title=Inhibition of rat and human steroidogenesis by triazole antifungals \|journal=Systems Biology in Reproductive Medicine \|author=Goetz, A.K.; Rockett, J.C.; Ren, H. et al. \|volume=55 \|issue=5–6 \|pages=214–26 \|year=2009 \|doi=10.3109/19396360903234045 \|pmid=19938956}}</ref> It can cause detrimental mutations in genes controlling cholesterol metabolism and androgen conversion to estrogen that carry on and persist into the following generations in mammals.<ref name="JinChronic18">{{cite journal \|title=Chronic exposure of mice to low doses of imazalil induces hepatotoxicity at the physiological, biochemical, and transcriptomic levels \|journal=Environmental Toxicology \|author=Jin, C.; Luo, T.; Fu, Z. et al. \|volume=33 \|issue=6 \|pages=650-658 \|year=2018 \|doi=10.1002/tox.22550 \|pmid=29451352}}</ref><ref name="JinMatern19">{{cite journal \|title=Maternal exposure to imazalil disrupts the endocrine system in F 1 generation mice \|journal=Molecular and Cellular Endocrinology \|author=Jin, C.; Zhang, R.; Fu, Z. et al. \|volume=486 \|pages=105–12 \|year=2019 \|doi=10.1016/j.mce.2019.03.002 \|pmid=30853599}}</ref> Myclobutanil is an inhibitor of ergosterol production in fungus, which is essential for the formation of fungal cell walls.<ref name="HesterTrans06">{{cite journal \|title=Transcriptional profiles in liver from rats treated with tumorigenic and non-tumorigenic triazole conazole fungicides: Propiconazole, triadimefon, and myclobutanil \|journal=Toxicologic Pathology \|author=Hester, S.D.; Wolf, D.C.; Nesnow, S. et al. \|volume=34 \|issue=7 \|pages=879–94 \|year=2006 \|doi=10.1080/01926230601047824 \|pmid=17178689}}</ref> In addition to being detrimental to fungi, myclobutanil can also inhibit cholesterol synthesis in mammals at high doses.<ref name="HesterTrans06" /><ref name="BerensteinHiman17">{{cite journal \|title=Human and soil exposure during mechanical chlorpyrifos, myclobutanil and copper oxychloride application in a peach orchard in Argentina \|journal=The Science of the Total Environment \|author=Berenstein, G.; Nasello, S.; Beiguel, E. et al. \|volume=586 \|pages=1254–62 \|year=2017 \|doi=10.1016/j.scitotenv.2017.02.129 \|pmid=28237465}}</ref> Neither of these compounds have been extensively studied in humans, but what is known about their effects on mammalian systems is cause for concern. These fungicides should not be considered safe to use for any cannabis cultivation, and their application should be avoided to protect the health of the consumer.

			==Plant growth regulators==
			Plant growth regulators are also commonly found in cannabis, including carcinogens and compounds that have been shown to be detrimental to mammals. Daminozide and paclobutraxol 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 the EPA.<ref name="NeffReg05">{{cite journal \|title=Regulatory parallels to Daubert: stakeholder influence, "sound science," and the delayed adoption of health-protective standards \|journal=American Journal of Public Health \|author=Neff, R.A.; Goldman, L.R. \|volume=95 \|issue=Suppl. 1 \|pages=S81–91 \|year=2005 \|doi=10.2105/AJPH.2004.044818 \|pmid=16030344}}</ref> 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.<ref name="RademacherGrowth00">{{cite journal \|title=Growth Retardants: Effects on Gibberellin Biosynthesis and Other Metabolic Pathways \|journal=Annual Review of Plant Physiology and Plant Molecular Biology \|author=Rademacher, W. \|volume=51 \|pages=501–31 \|year=2000 \|doi=10.1146/annurev.arplant.51.1.501 \|pmid=15012200}}</ref> Paclobutraxol has been shown to have detrimental effects on development in several aquatic species<ref name="LiExpos12">{{cite journal \|title=Exposure to paclobutrazol disrupts spermatogenesis in male ''Sebastiscus marmoratus'' \|journal=Aquatic Toxicology \|author=Li, J.; Sun, L.; Zuo, Z. et al. \|volume=122–23 \|pages=120–4 \|year=2012 \|doi=10.1016/j.aquatox.2012.06.007 \|pmid=22789407}}</ref>, and also to disrupt neurotransmitter levels in mice.<ref name="XuInteg20">{{cite journal \|title=Integrated gender-related effects of profenofos and paclobutrazol on neurotransmitters in mouse \|journal=Ecotoxicology and Environmental Safety \|author=Xu, M.; Yang, F. \|volume=190 \|at=110085 \|year=2020 \|doi=10.1016/j.ecoenv.2019.110085 \|pmid=31855789}}</ref> 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.


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	==Notes==		==Notes==
	This presentation is faithful to the original, with only a few minor changes to presentation. Some grammar and punctuation was cleaned up to improve readability. In some cases important information was missing from the references, and that information was added. The original article lists references in alphabetical order; this version lists them in order of appearance, by design. A citation for Gorai ''et al.'' is found in the original references and in Table 1, but it is not included in-line in the original text; it has been inserted where it should presumably go for this version. The extremely long nomenclatures for bifenazate, abamectin, imazalil, and other pesticides that are included in the original article are omitted for this version for the sake of brevity, as they add little to the overall intent of the article.		This presentation is faithful to the original, with only a few minor changes to presentation. Some grammar and punctuation was cleaned up to improve readability. In some cases important information was missing from the references, and that information was added. The original article lists references in alphabetical order; this version lists them in order of appearance, by design. A citation for Gorai ''et al.'' is found in the original references and in Table 1, but it is not included in-line in the original text; it has been inserted where it should presumably go for this version. The extremely long nomenclatures for bifenazate, abamectin, imazalil, and other pesticides/growth regulators that are included in the original article are omitted for this version for the sake of brevity, as they add little to the overall intent of the article.

	<!--Place all category tags here-->		<!--Place all category tags here-->

Shawndouglas: Saving and adding more.

2020-09-15T18:10:01Z

Saving and adding more.

← Older revision		Revision as of 18:10, 15 September 2020
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	==Pesticide contamination==		==Pesticide contamination==
	While many claim cannabis is naturally a pest-resistant crop<ref name="ParlContrast19">{{cite journal \|title=Contrasting Roles of Cannabidiol as an Insecticide and Rescuing Agent for Ethanol–induced Death in the Tobacco Hornworm ''Manduca sexta'' \|journal=Scientific Reports \|author=Park, S.-H.; Staples, S.K.; Gostin, E.L. et al. \|volume=9 \|at=10481 \|year=2019 \|doi=10.1038/s41598-019-47017-7}}</ref><ref name="McKernanSeq20">{{cite journal \|title=Sequence and annotation of 42 cannabis genomes reveals extensive copy number variation in cannabinoid synthesis and pathogen resistance genes \|journal=bioRxiv \|author=McKernan, K.J.; Helbert, Y.; Kane, L.T. et al. \|year=2020 \|doi=10.1101/2020.01.03.894428}}</ref>, there is still abundant use of various types of [[wikipedia:Pesticide\|pesticides]] to provide protection, including insecticides, fungicides, and plant growth regulators.<ref name="McPartlandContam17" /><ref name="SandlerCannabis19" /> Unlike most crops that are grown in the United States, there are no federal guidelines provided by the Environmental Protection Agency (EPA) as to which pesticides or how much should be used on cannabis.<ref name="SeltenrichInto19">{{cite journal \|title=Into the Weeds: Regulating Pesticides in Cannabis \|journal=Environmental Health Perspectives \|author=Seltenrich, N. \|volume=127 \|issue=4 \|at=042001 \|year=2019 \|doi=10.1289/EHP5265}}</ref> However, with the recent federal legalization of hemp in the U.S. under the 2016 and 2019 Farm Bills, the EPA has approved a limited number of pesticides for use with hemp-producing ''Cannabis'' plants in the U.S.<ref name="EPAPest19">{{cite web \|url=https://www.epa.gov/pesticide-registration/pesticide-products-registered-use-hemp \|title=Pesticide Products Registered for Use on Hemp \|author=U.S. Environmental Protection Agency \|date=December 2019 \|accessdate=29 May 2020}}</ref> 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.<ref name="McPartlandContam17" /> 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.<ref name="RussoCurrent16">{{cite journal \|title=Current Therapeutic Cannabis Controversies and Clinical Trial Design Issues \|journal=Frontiers in Pharmacology \|author=Russo, E.B. \|volume=7 \|at=309 \|year=2016 \|doi=10.3389/fphar.2016.00309 \|pmid=27683558 \|pmc=PMC5022003}}</ref> 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.<ref name="McPartlandContam17" /> In 2016, it was also shown that Guardian pesticides, which were marketed as all-natural and containing only safe-to-consume chemicals like cinnamon oil and citric acid, did in fact contain abamectin.<ref name="McPartlandContam17" /> 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.<ref name="SullivanDeterm13">{{cite journal \|title=Determination of Pesticide Residues in Cannabis Smoke \|journal=Journal of Toxicology \|author=Sullivan, N.; Elzinga, S.; Raber, J.C. \|volume=2013 \|at=378168 \|year=2013 \|doi=10.1155/2013/378168}}</ref>		While many claim cannabis is naturally a pest-resistant crop<ref name="ParlContrast19">{{cite journal \|title=Contrasting Roles of Cannabidiol as an Insecticide and Rescuing Agent for Ethanol–induced Death in the Tobacco Hornworm ''Manduca sexta'' \|journal=Scientific Reports \|author=Park, S.-H.; Staples, S.K.; Gostin, E.L. et al. \|volume=9 \|at=10481 \|year=2019 \|doi=10.1038/s41598-019-47017-7}}</ref><ref name="McKernanSeq20">{{cite journal \|title=Sequence and annotation of 42 cannabis genomes reveals extensive copy number variation in cannabinoid synthesis and pathogen resistance genes \|journal=bioRxiv \|author=McKernan, K.J.; Helbert, Y.; Kane, L.T. et al. \|year=2020 \|doi=10.1101/2020.01.03.894428}}</ref>, there is still abundant use of various types of [[wikipedia:Pesticide\|pesticides]] to provide protection, including insecticides, fungicides, and plant growth regulators.<ref name="McPartlandContam17" /><ref name="SandlerCannabis19" /> Unlike most crops that are grown in the United States, there are no federal guidelines provided by the Environmental Protection Agency (EPA) as to which pesticides or how much should be used on cannabis.<ref name="SeltenrichInto19">{{cite journal \|title=Into the Weeds: Regulating Pesticides in Cannabis \|journal=Environmental Health Perspectives \|author=Seltenrich, N. \|volume=127 \|issue=4 \|at=042001 \|year=2019 \|doi=10.1289/EHP5265}}</ref> However, with the recent federal legalization of hemp in the U.S. under the 2016 and 2019 Farm Bills, the EPA has approved a limited number of pesticides for use with hemp-producing ''Cannabis'' plants in the U.S.<ref name="EPAPest19">{{cite web \|url=https://www.epa.gov/pesticide-registration/pesticide-products-registered-use-hemp \|title=Pesticide Products Registered for Use on Hemp \|author=U.S. Environmental Protection Agency \|date=December 2019 \|accessdate=29 May 2020}}</ref> 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.<ref name="McPartlandContam17" /> 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.<ref name="RussoCurrent16">{{cite journal \|title=Current Therapeutic Cannabis Controversies and Clinical Trial Design Issues \|journal=Frontiers in Pharmacology \|author=Russo, E.B. \|volume=7 \|at=309 \|year=2016 \|doi=10.3389/fphar.2016.00309 \|pmid=27683558 \|pmc=PMC5022003}}</ref> 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.<ref name="McPartlandContam17" /> In 2016, it was also shown that Guardian pesticides, which were marketed as all-natural and containing only safe-to-consume chemicals like cinnamon oil and citric acid, did in fact contain abamectin.<ref name="McPartlandContam17" /> 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.<ref name="SullivanDeterm13">{{cite journal \|title=Determination of Pesticide Residues in Cannabis Smoke \|journal=Journal of Toxicology \|author=Sullivan, N.; Elzinga, S.; Raber, J.C. \|volume=2013 \|at=378168 \|year=2013 \|doi=10.1155/2013/378168}}</ref>

			As many of these pesticides are [[wikipedia:Lipophilicity\|lipophilic]], they are soluble in the [[wikipedia:Solvent\|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 [[wikipedia:Cannabis concentrate\|extract]]. The authors provide examples of a few compounds found in cannabis from each class of pesticide 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 [[LII:Past, Present, and Future of Cannabis Laboratory Testing and Regulation in the United States\|testing]] of pesticides in cannabis.

			===Insecticides===
			Bifenazate and abamectin are two commonly identified insecticides found on cannabis products that are known to be harmful to mammals.<ref name="RadiTheEff20">{{cite journal \|title=The effects of abamectin on oxidative stress and gene expression in rat liver and brain tissues: Modulation by sesame oil and ascorbic acid \|journal=The Science of the Total Environment \|author=Radi, A.M.; Mohammed, E.T.; Abushouk, A.I. et al. \|volume=701 \|at=134882 \|year=2020 \|doi=10.1016/j.scitotenv.2019.134882 \|pmid=31739238}}</ref> Bifenazate, a spider miticide, is not considered to be acutely toxic, though it is considered to be toxic when chronically exposed to mammals.<ref name="EFSAPeer17">{{cite journal \|title=Peer review of the pesticide risk assessment of the active substance bifenazate \|journal=EFSA Journal \|author=European Food Safety Authority \|volume=15 \|issue=1 \|at=e04693 \|year=2017 \|doi=10.2903/j.efsa.2017.4693 \|pmid=32625279 \|pmc=PMC7009907}}</ref> In animal feeding studies, weight gain in males and weight loss in females were reported in response to chronic exposures of bifenazate in their diets.<ref name="ZarnCurrent18">{{cite journal \|title=Current pesticide dietary risk assessment in light of comparable animal study NOAELs after chronic and short-termed exposure durations \|journal=Archives of Toxicology \|author=Zarn, J.A.; O'Brien, C.D. \|volume=92 \|issue=1 \|pages=157-167 \|year=2018 \|doi=10.1007/s00204-017-2052-4 \|pmid=28929275 \|pmc=PMC5773667}}</ref> Furthermore, bifenazate has only been approved for use on ornamental plants in the U.S., so the EPA has not released any information regarding human mutagenicity for this compound. Abamectin, a macrocyclic lactone, is generally considered safe with toxicity arising only after ingestion of large quantities and is approved for edible plants.<ref name="daSilvaTheChron18">{{cite journal \|title=The chronic exposure to abamectin causes spatial memory deficit and depressive behavior in mice \|journal=Chemosphere \|author=da Silva, W.A.M.; Guimarães, A.T.B.; Montalvão, M.F. et al. \|volume=194 \|pages=523–33 \|year=2018 \|doi=10.1016/j.chemosphere.2017.12.028 \|pmid=29241126}}</ref> Although the exact mechanisms remain unclear, there is evidence that macrocyclic lactones in large doses may pass through the blood-brain barrier to produce γ-amino butyric acid -mimetic (GABA) toxicity-like effects.<ref name="daSilvaTheChron18" /> Current gaps in the knowledge of the long-term effects of these compounds still exist, but cell culture and animal studies continue to shed new light on the overall health impacts of these compounds. Until these compounds are shown to be harmless when inhaled or ingested, their application to cannabis should be limited or ceased entirely to best protect the consumer's health.

			===Fungicides===
			Several fungicides have been reported in samples of cannabis all over the world, including known endocrine disruptors and hepatoxic compounds like imazalil and myclobutanil, respectively.<ref name="McPartlandContam17" /><ref name="SandlerCannabis19" /> These fungicides are often found in higher concentrations in samples obtained from indoor grow facilities than outdoor operations.<ref name="McPartlandContam17" /> As many medicinal cannabis cultivators are now using indoor facilities to cultivate hemp for CBD products year-round, this is a cause for concern in both the hemp- and drug-type markets.

			Imazalil—also known as enilconazole—and myclobutanil have both been used to prevent fungal infection in cannabis.<ref name="McPartlandContam17" /> Imazalil, a systemic fungicide used to control powdery mildew and other mold or fungal infections in crop plants, has been shown to be an androgen receptor agonist and endocrine disruptor in mammals.<ref name="GoetzInhib09">{{cite journal \|title=Inhibition of rat and human steroidogenesis by triazole antifungals \|journal=Systems Biology in Reproductive Medicine \|author=Goetz, A.K.; Rockett, J.C.; Ren, H. et al. \|volume=55 \|issue=5–6 \|pages=214–26 \|year=2009 \|doi=10.3109/19396360903234045 \|pmid=19938956}}</ref> It can cause detrimental mutations in genes controlling cholesterol metabolism and androgen conversion to estrogen that carry on and persist into the following generations in mammals.<ref name="JinChronic18">{{cite journal \|title=Chronic exposure of mice to low doses of imazalil induces hepatotoxicity at the physiological, biochemical, and transcriptomic levels \|journal=Environmental Toxicology \|author=Jin, C.; Luo, T.; Fu, Z. et al. \|volume=33 \|issue=6 \|pages=650-658 \|year=2018 \|doi=10.1002/tox.22550 \|pmid=29451352}}</ref><ref name="JinMatern19">{{cite journal \|title=Maternal exposure to imazalil disrupts the endocrine system in F 1 generation mice \|journal=Molecular and Cellular Endocrinology \|author=Jin, C.; Zhang, R.; Fu, Z. et al. \|volume=486 \|pages=105–12 \|year=2019 \|doi=10.1016/j.mce.2019.03.002 \|pmid=30853599}}</ref> Myclobutanil is an inhibitor of ergosterol production in fungus, which is essential for the formation of fungal cell walls.<ref name="HesterTrans06">{{cite journal \|title=Transcriptional profiles in liver from rats treated with tumorigenic and non-tumorigenic triazole conazole fungicides: Propiconazole, triadimefon, and myclobutanil \|journal=Toxicologic Pathology \|author=Hester, S.D.; Wolf, D.C.; Nesnow, S. et al. \|volume=34 \|issue=7 \|pages=879–94 \|year=2006 \|doi=10.1080/01926230601047824 \|pmid=17178689}}</ref> In addition to being detrimental to fungi, myclobutanil can also inhibit cholesterol synthesis in mammals at high doses.<ref name="HesterTrans06" /><ref name="BerensteinHiman17">{{cite journal \|title=Human and soil exposure during mechanical chlorpyrifos, myclobutanil and copper oxychloride application in a peach orchard in Argentina \|journal=The Science of the Total Environment \|author=Berenstein, G.; Nasello, S.; Beiguel, E. et al. \|volume=586 \|pages=1254–62 \|year=2017 \|doi=10.1016/j.scitotenv.2017.02.129 \|pmid=28237465}}</ref> Neither of these compounds have been extensively studied in humans, but what is known about their effects on mammalian systems is cause for concern. These fungicides should not be considered safe to use for any cannabis cultivation, and their application should be avoided to protect the health of the consumer.



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	==Notes==		==Notes==
	This presentation is faithful to the original, with only a few minor changes to presentation. Some grammar and punctuation was cleaned up to improve readability. In some cases important information was missing from the references, and that information was added. The original article lists references in alphabetical order; this version lists them in order of appearance, by design. A citation for Gorai ''et al.'' is found in the original references and in Table 1, but it is not included in-line in the original text; it has been inserted where it should presumably go for this version.		This presentation is faithful to the original, with only a few minor changes to presentation. Some grammar and punctuation was cleaned up to improve readability. In some cases important information was missing from the references, and that information was added. The original article lists references in alphabetical order; this version lists them in order of appearance, by design. A citation for Gorai ''et al.'' is found in the original references and in Table 1, but it is not included in-line in the original text; it has been inserted where it should presumably go for this version. The extremely long nomenclatures for bifenazate, abamectin, imazalil, and other pesticides that are included in the original article are omitted for this version for the sake of brevity, as they add little to the overall intent of the article.

	<!--Place all category tags here-->		<!--Place all category tags here-->

Shawndouglas: Saving and adding more.

2020-09-15T17:00:34Z

Saving and adding more.

← Older revision		Revision as of 17:00, 15 September 2020
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	Mercury is another hazardous heavy metal found in cannabis, silver in color, the only liquid metal at standard temperature (0° C or 273.15 K) and pressure (1 atm, 101.3kPa, or 760 mmHg) in its elemental form (Hg); however, it is also frequently found in organomercury compounds such as methylmercury, which is considered highly poisonous and deleterious to humans when ingested.<ref name="HongMeth12">{{cite journal \|title=Methylmercury exposure and health effects \|journal=Journal of Preventive Medicine and Public Health \|author=Hong, Y.-S.; Kim, Y.-M.; Lee, K.-E. \|volume=45 \|issue=6 \|pages=353–63 \|year=2012 \|doi=10.3961/jpmph.2012.45.6.353 \|pmid=23230465 \|pmc=PMC3514465}}</ref> In this organomercury form, methylmercury bioaccumulates in the human body, and has a biological half-life of up to 80 days for methylmercury that does not cross the blood brain barrier.<ref name="JoEstim15">{{cite journal \|title=Estimation of the Biological Half-Life of Methylmercury Using a Population Toxicokinetic Model \|journal=International Journal of Environmental Research and Public Health \|author=Jo, S.; Woo, H.D.; Kwon, H.-J. et al. \|volume=12 \|issue=8 \|pages=9054–67 \|year=2015 \|doi=10.3390/ijerph120809054 \|pmid=26264017 \|pmc=PMC4555264}}</ref> However, after crossing the blood brain barrier, methylmercury persists for decades in the brain after the cessation of exposure.<ref name="BjörkmanMerc07">{{cite journal \|title=Mercury in human brain, blood, muscle and toenails in relation to exposure: an autopsy study \|journal=Environmental Health \|author=Björkman, L.; Lundekvam, B.F.; Laegreid, T. et al. \|volume=6 \|at=30 \|year=2007 \|doi=10.1186/1476-069X-6-30 \|pmid=17931423 \|pmc=PMC2098763}}</ref> Mercury has been found at up to 440 ng/g of dry mass of cannabis grown in volcanic soils in Hawaii.<ref name="McPartlandContam17" /> This is cause for concern as smoking cannabis products greatly increases the risk of heavy metal toxicity, with mercury being absorbed 10 times more efficiently by the lungs than the gut.<ref name="McPartlandContam17" /> Chronic human exposure to mercury vapor results in a variety of symptoms, largely neurological, including forgetfulness, irritability, restricted visual fields, tremors, and paranoia.<ref name="SiegelMerc88" /> Considering the health risks, it is in the interest to all cannabis users that mercury contamination be avoided as it would have detrimental effects on all exposed.		Mercury is another hazardous heavy metal found in cannabis, silver in color, the only liquid metal at standard temperature (0° C or 273.15 K) and pressure (1 atm, 101.3kPa, or 760 mmHg) in its elemental form (Hg); however, it is also frequently found in organomercury compounds such as methylmercury, which is considered highly poisonous and deleterious to humans when ingested.<ref name="HongMeth12">{{cite journal \|title=Methylmercury exposure and health effects \|journal=Journal of Preventive Medicine and Public Health \|author=Hong, Y.-S.; Kim, Y.-M.; Lee, K.-E. \|volume=45 \|issue=6 \|pages=353–63 \|year=2012 \|doi=10.3961/jpmph.2012.45.6.353 \|pmid=23230465 \|pmc=PMC3514465}}</ref> In this organomercury form, methylmercury bioaccumulates in the human body, and has a biological half-life of up to 80 days for methylmercury that does not cross the blood brain barrier.<ref name="JoEstim15">{{cite journal \|title=Estimation of the Biological Half-Life of Methylmercury Using a Population Toxicokinetic Model \|journal=International Journal of Environmental Research and Public Health \|author=Jo, S.; Woo, H.D.; Kwon, H.-J. et al. \|volume=12 \|issue=8 \|pages=9054–67 \|year=2015 \|doi=10.3390/ijerph120809054 \|pmid=26264017 \|pmc=PMC4555264}}</ref> However, after crossing the blood brain barrier, methylmercury persists for decades in the brain after the cessation of exposure.<ref name="BjörkmanMerc07">{{cite journal \|title=Mercury in human brain, blood, muscle and toenails in relation to exposure: an autopsy study \|journal=Environmental Health \|author=Björkman, L.; Lundekvam, B.F.; Laegreid, T. et al. \|volume=6 \|at=30 \|year=2007 \|doi=10.1186/1476-069X-6-30 \|pmid=17931423 \|pmc=PMC2098763}}</ref> Mercury has been found at up to 440 ng/g of dry mass of cannabis grown in volcanic soils in Hawaii.<ref name="McPartlandContam17" /> This is cause for concern as smoking cannabis products greatly increases the risk of heavy metal toxicity, with mercury being absorbed 10 times more efficiently by the lungs than the gut.<ref name="McPartlandContam17" /> Chronic human exposure to mercury vapor results in a variety of symptoms, largely neurological, including forgetfulness, irritability, restricted visual fields, tremors, and paranoia.<ref name="SiegelMerc88" /> Considering the health risks, it is in the interest to all cannabis users that mercury contamination be avoided as it would have detrimental effects on all exposed.

			==Pesticide contamination==
			While many claim cannabis is naturally a pest-resistant crop<ref name="ParlContrast19">{{cite journal \|title=Contrasting Roles of Cannabidiol as an Insecticide and Rescuing Agent for Ethanol–induced Death in the Tobacco Hornworm ''Manduca sexta'' \|journal=Scientific Reports \|author=Park, S.-H.; Staples, S.K.; Gostin, E.L. et al. \|volume=9 \|at=10481 \|year=2019 \|doi=10.1038/s41598-019-47017-7}}</ref><ref name="McKernanSeq20">{{cite journal \|title=Sequence and annotation of 42 cannabis genomes reveals extensive copy number variation in cannabinoid synthesis and pathogen resistance genes \|journal=bioRxiv \|author=McKernan, K.J.; Helbert, Y.; Kane, L.T. et al. \|year=2020 \|doi=10.1101/2020.01.03.894428}}</ref>, there is still abundant use of various types of [[wikipedia:Pesticide\|pesticides]] to provide protection, including insecticides, fungicides, and plant growth regulators.<ref name="McPartlandContam17" /><ref name="SandlerCannabis19" /> Unlike most crops that are grown in the United States, there are no federal guidelines provided by the Environmental Protection Agency (EPA) as to which pesticides or how much should be used on cannabis.<ref name="SeltenrichInto19">{{cite journal \|title=Into the Weeds: Regulating Pesticides in Cannabis \|journal=Environmental Health Perspectives \|author=Seltenrich, N. \|volume=127 \|issue=4 \|at=042001 \|year=2019 \|doi=10.1289/EHP5265}}</ref> However, with the recent federal legalization of hemp in the U.S. under the 2016 and 2019 Farm Bills, the EPA has approved a limited number of pesticides for use with hemp-producing ''Cannabis'' plants in the U.S.<ref name="EPAPest19">{{cite web \|url=https://www.epa.gov/pesticide-registration/pesticide-products-registered-use-hemp \|title=Pesticide Products Registered for Use on Hemp \|author=U.S. Environmental Protection Agency \|date=December 2019 \|accessdate=29 May 2020}}</ref> 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.<ref name="McPartlandContam17" /> 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.<ref name="RussoCurrent16">{{cite journal \|title=Current Therapeutic Cannabis Controversies and Clinical Trial Design Issues \|journal=Frontiers in Pharmacology \|author=Russo, E.B. \|volume=7 \|at=309 \|year=2016 \|doi=10.3389/fphar.2016.00309 \|pmid=27683558 \|pmc=PMC5022003}}</ref> 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.<ref name="McPartlandContam17" /> In 2016, it was also shown that Guardian pesticides, which were marketed as all-natural and containing only safe-to-consume chemicals like cinnamon oil and citric acid, did in fact contain abamectin.<ref name="McPartlandContam17" /> 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.<ref name="SullivanDeterm13">{{cite journal \|title=Determination of Pesticide Residues in Cannabis Smoke \|journal=Journal of Toxicology \|author=Sullivan, N.; Elzinga, S.; Raber, J.C. \|volume=2013 \|at=378168 \|year=2013 \|doi=10.1155/2013/378168}}</ref>

Shawndouglas: Saving and adding more.

2020-09-15T16:14:44Z

Saving and adding more.

← Older revision		Revision as of 16:14, 15 September 2020
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	===Cadmium===		===Cadmium===
	Cadmium is a soft, bluish-white heavy metal that is mainly obtained from zinc ore processing. It has a long biological half-life of 14 to 24 years, and bioaccumulates in the human body when chronically exposed.<ref name="PappasToxic11">{{cite journal \|title=Toxic elements in tobacco and in cigarette smoke: Inflammation and sensitization \|journal=Metallomics \|author=Pappas, R.S. \|volume=3 \|issue=11 \|pages=1181-98 \|year=2011 \|doi=10.1039/c1mt00066g \|pmid=21799956 \|pmc=PMC4542087}}</ref> The impact of exposure to cadmium-containing products and cadmium-containing fertilizers on humans remains a major concern.<ref name="Tellez-PlazaCadm13">{{cite journal \|title=Cadmium exposure and clinical cardiovascular disease: A systematic review \|journal=Current Atherosclerosis Reports \|author=Tellez-Plaza, M.; Jones, M.R.; Dominguez-Lucas, A. et al. \|volume=15 \|issue=10 \|at=356 \|year=2013 \|doi=10.1007/s11883-013-0356-2 \|pmid=23955722 \|pmc=PMC3858820}}</ref> Leafy and root vegetables, grains, and tobacco bioconcentrate cadmium from the soil, resulting in exposure through diet and smoking.<ref name="Tellez-PlazaCadm13" /> Cadmium is generally found in higher levels in urine, blood, fat, and lung tissues of tobacco smokers, which correlates with length of time as a smoker.<ref name="PappasToxic11" /> It has also been shown that application of phosphate fertilizers targeted for cannabis growth increases the uptake of cadmium by cannabis when grown in cadmium-contaminated soils, though the mechanism is not yet clear.<ref name="SinganiManure12">{{cite journal \|title=Manure Application and Cannabis Cultivation Influence on Speciation of Lead and Cadmium by Selective Sequential Extraction \|journal=Soil and Sediment Contamintation \|author=Singani, A.A.S.; Ahmadi, P. \|volume=21 \|issue=3 \|pages=305–21 \|year=2012 \|doi=10.1080/15320383.2012.664186}}</ref> Currently, no cases of cadmium-contaminated cannabis causing health problems are found in the literature; however, there are several diseases that have been associated with exposure to cadmium through smoking and diet, including periodontal disease<ref name="BrowarCadm18">{{cite journal \|title=Cadmium Exposure Disrupts Periodontal Bone in Experimental Animals: Implications for Periodontal Disease in Humans \|journal=Toxics \|author=Browar, A.W.; Koufos, E.B.; Wei, Y. et al. \|volume=6 \|issue=2 \|at=32 \|year=2018 \|doi=10.3390/toxics6020032 \|pmid=29899258 \|pmc=PMC6027471}}</ref>, pancreatic cancer<ref name="BuhaCadm17">{{cite journal \|title=Cadmium Exposure as a Putative Risk Factor for the Development of Pancreatic Cancer: Three Different Lines of Evidence \|journal=Biomedical Research International \|author=Buha, A.; Wallace, D.; Matovic, V. et al. \|volume=2017 \|at=1981837 \|year=2017 \|doi=10.1155/2017/1981837 \|pmid=29349066 \|pmc=PMC5733953}}</ref>, and diabetes.<ref name="TinkovTheRole17">{{cite journal \|title=The role of cadmium in obesity and diabetes \|journal=The Science of the Total Environment \|author=Tinkov, A.A.; Filippini, T.; Ajsuvakova, O.P. et al. \|volume=601–602 \|pages=741–55 \|year=2017 \|doi=10.1016/j.scitotenv.2017.05.224 \|pmid=28577409}}</ref> Most severely, chronic exposure causes Itai-Itai disease, which is characterized by intense bone pain, a disrupted gait, and numbness in all extremities.<ref name="KasuyaWater92">{{cite journal \|title=Water Pollution by Cadmium and the Onset of Itai-itai Disease \|journal=Water Science & Technology \|author=Kasuya, M.; Teranishi, H.; Aishima, K. et al. \|volume=25 \|issue=11 \|pages=149–56 \|year=1992 \|doi=10.2166/wst.1992.0286}}</ref> Cannabis products are not likely to be contaminated enough to cause disease as severe as Itai-Itai disease, but because cannabis can hyperaccumulate cadmium, it should still be considered hazardous and tested for in cannabis products.		Cadmium is a soft, bluish-white heavy metal that is mainly obtained from zinc ore processing. It has a long biological half-life of 14 to 24 years, and bioaccumulates in the human body when chronically exposed.<ref name="PappasToxic11">{{cite journal \|title=Toxic elements in tobacco and in cigarette smoke: Inflammation and sensitization \|journal=Metallomics \|author=Pappas, R.S. \|volume=3 \|issue=11 \|pages=1181-98 \|year=2011 \|doi=10.1039/c1mt00066g \|pmid=21799956 \|pmc=PMC4542087}}</ref> The impact of exposure to cadmium-containing products and cadmium-containing fertilizers on humans remains a major concern.<ref name="Tellez-PlazaCadm13">{{cite journal \|title=Cadmium exposure and clinical cardiovascular disease: A systematic review \|journal=Current Atherosclerosis Reports \|author=Tellez-Plaza, M.; Jones, M.R.; Dominguez-Lucas, A. et al. \|volume=15 \|issue=10 \|at=356 \|year=2013 \|doi=10.1007/s11883-013-0356-2 \|pmid=23955722 \|pmc=PMC3858820}}</ref> Leafy and root vegetables, grains, and tobacco bioconcentrate cadmium from the soil, resulting in exposure through diet and smoking.<ref name="Tellez-PlazaCadm13" /> Cadmium is generally found in higher levels in urine, blood, fat, and lung tissues of tobacco smokers, which correlates with length of time as a smoker.<ref name="PappasToxic11" /> It has also been shown that application of phosphate fertilizers targeted for cannabis growth increases the uptake of cadmium by cannabis when grown in cadmium-contaminated soils, though the mechanism is not yet clear.<ref name="SinganiManure12">{{cite journal \|title=Manure Application and Cannabis Cultivation Influence on Speciation of Lead and Cadmium by Selective Sequential Extraction \|journal=Soil and Sediment Contamintation \|author=Singani, A.A.S.; Ahmadi, P. \|volume=21 \|issue=3 \|pages=305–21 \|year=2012 \|doi=10.1080/15320383.2012.664186}}</ref> Currently, no cases of cadmium-contaminated cannabis causing health problems are found in the literature; however, there are several diseases that have been associated with exposure to cadmium through smoking and diet, including periodontal disease<ref name="BrowarCadm18">{{cite journal \|title=Cadmium Exposure Disrupts Periodontal Bone in Experimental Animals: Implications for Periodontal Disease in Humans \|journal=Toxics \|author=Browar, A.W.; Koufos, E.B.; Wei, Y. et al. \|volume=6 \|issue=2 \|at=32 \|year=2018 \|doi=10.3390/toxics6020032 \|pmid=29899258 \|pmc=PMC6027471}}</ref>, pancreatic cancer<ref name="BuhaCadm17">{{cite journal \|title=Cadmium Exposure as a Putative Risk Factor for the Development of Pancreatic Cancer: Three Different Lines of Evidence \|journal=Biomedical Research International \|author=Buha, A.; Wallace, D.; Matovic, V. et al. \|volume=2017 \|at=1981837 \|year=2017 \|doi=10.1155/2017/1981837 \|pmid=29349066 \|pmc=PMC5733953}}</ref>, and diabetes.<ref name="TinkovTheRole17">{{cite journal \|title=The role of cadmium in obesity and diabetes \|journal=The Science of the Total Environment \|author=Tinkov, A.A.; Filippini, T.; Ajsuvakova, O.P. et al. \|volume=601–602 \|pages=741–55 \|year=2017 \|doi=10.1016/j.scitotenv.2017.05.224 \|pmid=28577409}}</ref> Most severely, chronic exposure causes Itai-Itai disease, which is characterized by intense bone pain, a disrupted gait, and numbness in all extremities.<ref name="KasuyaWater92">{{cite journal \|title=Water Pollution by Cadmium and the Onset of Itai-itai Disease \|journal=Water Science & Technology \|author=Kasuya, M.; Teranishi, H.; Aishima, K. et al. \|volume=25 \|issue=11 \|pages=149–56 \|year=1992 \|doi=10.2166/wst.1992.0286}}</ref> Cannabis products are not likely to be contaminated enough to cause disease as severe as Itai-Itai disease, but because cannabis can hyperaccumulate cadmium, it should still be considered hazardous and tested for in cannabis products.

			===Lead===
			Lead is a silver to dark gray, soft, malleable, corrosion-resistant heavy metal and is one of the earliest metals discovered.<ref name="FloraToxic12">{{cite journal \|title=Toxicity of lead: A review with recent updates \|journal=Interdisciplinary Toxicology \|author=Flora, G.; Gupta, D.; Tiwari, A. \|volume=5 \|issue=2 \|pages=47–58 \|year=2012 \|doi=10.2478/v10102-012-0009-2 \|pmid=23118587 \|pmc=PMC3485653}}</ref> Lead has been used in automobile, paint, ceramic, and plastic manufacturing, and because lead is nonbiodegradable, it persists in the environment.<ref name="FloraToxic12" /> Lead can have a variable biological half-life from 30 days for lead in the blood and up to 30 years for lead deposited into bone, which is usually a sign of chronic exposure.<ref name="MasonPb14">{{cite journal \|title=Pb neurotoxicity: Neuropsychological effects of lead toxicity \|journal=BioMed Research International \|author=Mason, L.H.; Harp, J.P.; Han, D.Y. \|volume=2014 \|at=840547 \|year=2014 \|doi=10.1155/2014/840547 \|pmid=24516855 \|pmc=PMC3909981}}</ref> Not only has lead been found in cannabis, but also the uptake of lead has been shown to increase in cannabis grown in contaminated soils<ref name="SinganiManure12" />, especially in contaminated urban environments.<ref name="EntwistleAnApp19">{{cite journal \|title=An apple a day? Assessing gardeners' lead exposure in urban agriculture sites to improve the derivation of soil assessment criteria \|journal=Environment International \|author=Entwistle, J.A.; Amaibi, P.M.; Dean, J.R. et al. \|volume=122 \|pages=130–41 \|year=2019 \|doi=10.1016/j.envint.2018.10.054 \|pmid=30449630}}</ref> Once lead enters the body, it can interact with almost every organ; however, its effects on the central nervous system are the most severe.<ref name="MasonPb14" /> Lead acts as a calcium analog interfering with ion channels of mammalian neurons.<ref name="MarchettiRole13" /> It has also been observed that lead is a potent reversible and selective blocker of voltage-dependent calcium channels even at low concentrations in human neurons.<ref name="MarchettiRole13" /><ref name="MasonPb14" /> Lead contamination of cannabis products sold in legal markets will likely be due to the cultivation of cannabis in contaminated soils, but lead has been deliberately added to cannabis as well. This is highlighted by an incident of massive lead poisoning in Leipzig, Germany where lead was intentionally added to cannabis attempting to increase its mass and in turn its street value, which caused 35 people to be treated for blood lead levels up to 1,063 µg/L.<ref name="BusseLead08" /> Symptoms experienced by these patients included nausea, acute colic, formation of a lead seam along the dental margin, peripheral neuropathy, loss of appetite and weight, as well as chronic fatigue and exhaustion.<ref name="BusseLead08" /> An additional 597 cannabis users in the area of Leipzig reported for a screening program initiated by the local health office, of which 27% of patients were found to have levels exceeding human biomonitoring values (above 250 µg/L for men and 150 µg/L for premenopausal/fertile women), also necessitating treatment.<ref name="BusseLead08" /> Lead contamination of cannabis products should be avoided and considered a major health risk to all users.

			===Mercury===
			Mercury is another hazardous heavy metal found in cannabis, silver in color, the only liquid metal at standard temperature (0° C or 273.15 K) and pressure (1 atm, 101.3kPa, or 760 mmHg) in its elemental form (Hg); however, it is also frequently found in organomercury compounds such as methylmercury, which is considered highly poisonous and deleterious to humans when ingested.<ref name="HongMeth12">{{cite journal \|title=Methylmercury exposure and health effects \|journal=Journal of Preventive Medicine and Public Health \|author=Hong, Y.-S.; Kim, Y.-M.; Lee, K.-E. \|volume=45 \|issue=6 \|pages=353–63 \|year=2012 \|doi=10.3961/jpmph.2012.45.6.353 \|pmid=23230465 \|pmc=PMC3514465}}</ref> In this organomercury form, methylmercury bioaccumulates in the human body, and has a biological half-life of up to 80 days for methylmercury that does not cross the blood brain barrier.<ref name="JoEstim15">{{cite journal \|title=Estimation of the Biological Half-Life of Methylmercury Using a Population Toxicokinetic Model \|journal=International Journal of Environmental Research and Public Health \|author=Jo, S.; Woo, H.D.; Kwon, H.-J. et al. \|volume=12 \|issue=8 \|pages=9054–67 \|year=2015 \|doi=10.3390/ijerph120809054 \|pmid=26264017 \|pmc=PMC4555264}}</ref> However, after crossing the blood brain barrier, methylmercury persists for decades in the brain after the cessation of exposure.<ref name="BjörkmanMerc07">{{cite journal \|title=Mercury in human brain, blood, muscle and toenails in relation to exposure: an autopsy study \|journal=Environmental Health \|author=Björkman, L.; Lundekvam, B.F.; Laegreid, T. et al. \|volume=6 \|at=30 \|year=2007 \|doi=10.1186/1476-069X-6-30 \|pmid=17931423 \|pmc=PMC2098763}}</ref> Mercury has been found at up to 440 ng/g of dry mass of cannabis grown in volcanic soils in Hawaii.<ref name="McPartlandContam17" /> This is cause for concern as smoking cannabis products greatly increases the risk of heavy metal toxicity, with mercury being absorbed 10 times more efficiently by the lungs than the gut.<ref name="McPartlandContam17" /> Chronic human exposure to mercury vapor results in a variety of symptoms, largely neurological, including forgetfulness, irritability, restricted visual fields, tremors, and paranoia.<ref name="SiegelMerc88" /> Considering the health risks, it is in the interest to all cannabis users that mercury contamination be avoided as it would have detrimental effects on all exposed.

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	==Heavy metal contamination==		==Heavy metal contamination==
	A variety of heavy metals have been found in ''Cannabis'' plants and products made with cannabis (e.g., tinctures and oils), including [[wikipedia:Cadmium\|cadmium]], [[wikipedia:Lead\|lead]], [[wikipedia:Mercury\|mercury]], magnesium, and copper.<ref name="~~DryburghCanna18~~" /><ref name="~~McPartlandContam17~~" /><ref name="SiegelMerc88">{{cite journal \|title=Mercury in Marijuana: Some of the problems arising from marijuana use might result from the intake of bioaccumulated mercury \|journal=BioScience \|author=Siegel, B.Z.; Garnier, L.; Siegel, S.M. \|volume=38 \|issue=9 \|pages=619–23 \|year=1988 \|doi=10.2307/1310827}}</ref><ref name="BusseLead08">{{cite journal \|title=Lead poisoning due to adulterated marijuana in Leipzig \|journal=Deutsches Arzteblatt International \|author=Busse, F.P.; Fiedler, G.M.; Leichtle, A. et al. \|volume=105 \|issue=44 \|pages=757-62 \|year=2008 \|doi=10.3238/arztebl.2008.0757 \|pmid=19623274 \|pmc=PMC2696942}}</ref><ref name="GauvinMarij18">{{cite journal \|title= Marijuana toxicity: Heavy metal exposure through state-sponsored access to “la Fee Verte” \|journal=Pharmaceutical Regulatory Affairs \|author=Gauvin, D.V.; Zimmermann, Z.J.; Yoder, J. et al. \|volume=7 \|issue=1 \|at=1000202 \|year=2018 \|doi=10.4172/2167-7689.1000202}}</ref> 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.<ref name="McPartlandContam17" /> 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.<ref name="VardhanARev19">{{cite journal \|title=A review on heavy metal pollution, toxicity and remedial measures: Current trends and future perspectives \|journal=Journal of Molecular Liquids \|author=Vardhan, K.H.; Kumar, P.S.; Panda, R.C. \|volume=290 \|at=111197 \|year=2019 \|doi=10.1016/j.molliq.2019.111197}}</ref> 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.<ref name="DaleyTesting13" /> 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.		A variety of heavy metals have been found in ''Cannabis'' plants and products made with cannabis (e.g., tinctures and oils), including [[wikipedia:Cadmium\|cadmium]], [[wikipedia:Lead\|lead]], [[wikipedia:Mercury\|mercury]], magnesium, and copper.<ref name="McPartlandContam17" /><ref name="DryburghCanna18" /><ref name="SiegelMerc88">{{cite journal \|title=Mercury in Marijuana: Some of the problems arising from marijuana use might result from the intake of bioaccumulated mercury \|journal=BioScience \|author=Siegel, B.Z.; Garnier, L.; Siegel, S.M. \|volume=38 \|issue=9 \|pages=619–23 \|year=1988 \|doi=10.2307/1310827}}</ref><ref name="BusseLead08">{{cite journal \|title=Lead poisoning due to adulterated marijuana in Leipzig \|journal=Deutsches Arzteblatt International \|author=Busse, F.P.; Fiedler, G.M.; Leichtle, A. et al. \|volume=105 \|issue=44 \|pages=757-62 \|year=2008 \|doi=10.3238/arztebl.2008.0757 \|pmid=19623274 \|pmc=PMC2696942}}</ref><ref name="GauvinMarij18">{{cite journal \|title= Marijuana toxicity: Heavy metal exposure through state-sponsored access to “la Fee Verte” \|journal=Pharmaceutical Regulatory Affairs \|author=Gauvin, D.V.; Zimmermann, Z.J.; Yoder, J. et al. \|volume=7 \|issue=1 \|at=1000202 \|year=2018 \|doi=10.4172/2167-7689.1000202}}</ref> 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.<ref name="McPartlandContam17" /> 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.<ref name="VardhanARev19">{{cite journal \|title=A review on heavy metal pollution, toxicity and remedial measures: Current trends and future perspectives \|journal=Journal of Molecular Liquids \|author=Vardhan, K.H.; Kumar, P.S.; Panda, R.C. \|volume=290 \|at=111197 \|year=2019 \|doi=10.1016/j.molliq.2019.111197}}</ref> 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.<ref name="DaleyTesting13" /> 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.

			===Cadmium===
			Cadmium is a soft, bluish-white heavy metal that is mainly obtained from zinc ore processing. It has a long biological half-life of 14 to 24 years, and bioaccumulates in the human body when chronically exposed.<ref name="PappasToxic11">{{cite journal \|title=Toxic elements in tobacco and in cigarette smoke: Inflammation and sensitization \|journal=Metallomics \|author=Pappas, R.S. \|volume=3 \|issue=11 \|pages=1181-98 \|year=2011 \|doi=10.1039/c1mt00066g \|pmid=21799956 \|pmc=PMC4542087}}</ref> The impact of exposure to cadmium-containing products and cadmium-containing fertilizers on humans remains a major concern.<ref name="Tellez-PlazaCadm13">{{cite journal \|title=Cadmium exposure and clinical cardiovascular disease: A systematic review \|journal=Current Atherosclerosis Reports \|author=Tellez-Plaza, M.; Jones, M.R.; Dominguez-Lucas, A. et al. \|volume=15 \|issue=10 \|at=356 \|year=2013 \|doi=10.1007/s11883-013-0356-2 \|pmid=23955722 \|pmc=PMC3858820}}</ref> Leafy and root vegetables, grains, and tobacco bioconcentrate cadmium from the soil, resulting in exposure through diet and smoking.<ref name="Tellez-PlazaCadm13" /> Cadmium is generally found in higher levels in urine, blood, fat, and lung tissues of tobacco smokers, which correlates with length of time as a smoker.<ref name="PappasToxic11" /> It has also been shown that application of phosphate fertilizers targeted for cannabis growth increases the uptake of cadmium by cannabis when grown in cadmium-contaminated soils, though the mechanism is not yet clear.<ref name="SinganiManure12">{{cite journal \|title=Manure Application and Cannabis Cultivation Influence on Speciation of Lead and Cadmium by Selective Sequential Extraction \|journal=Soil and Sediment Contamintation \|author=Singani, A.A.S.; Ahmadi, P. \|volume=21 \|issue=3 \|pages=305–21 \|year=2012 \|doi=10.1080/15320383.2012.664186}}</ref> Currently, no cases of cadmium-contaminated cannabis causing health problems are found in the literature; however, there are several diseases that have been associated with exposure to cadmium through smoking and diet, including periodontal disease<ref name="BrowarCadm18">{{cite journal \|title=Cadmium Exposure Disrupts Periodontal Bone in Experimental Animals: Implications for Periodontal Disease in Humans \|journal=Toxics \|author=Browar, A.W.; Koufos, E.B.; Wei, Y. et al. \|volume=6 \|issue=2 \|at=32 \|year=2018 \|doi=10.3390/toxics6020032 \|pmid=29899258 \|pmc=PMC6027471}}</ref>, pancreatic cancer<ref name="BuhaCadm17">{{cite journal \|title=Cadmium Exposure as a Putative Risk Factor for the Development of Pancreatic Cancer: Three Different Lines of Evidence \|journal=Biomedical Research International \|author=Buha, A.; Wallace, D.; Matovic, V. et al. \|volume=2017 \|at=1981837 \|year=2017 \|doi=10.1155/2017/1981837 \|pmid=29349066 \|pmc=PMC5733953}}</ref>, and diabetes.<ref name="TinkovTheRole17">{{cite journal \|title=The role of cadmium in obesity and diabetes \|journal=The Science of the Total Environment \|author=Tinkov, A.A.; Filippini, T.; Ajsuvakova, O.P. et al. \|volume=601–602 \|pages=741–55 \|year=2017 \|doi=10.1016/j.scitotenv.2017.05.224 \|pmid=28577409}}</ref> Most severely, chronic exposure causes Itai-Itai disease, which is characterized by intense bone pain, a disrupted gait, and numbness in all extremities.<ref name="KasuyaWater92">{{cite journal \|title=Water Pollution by Cadmium and the Onset of Itai-itai Disease \|journal=Water Science & Technology \|author=Kasuya, M.; Teranishi, H.; Aishima, K. et al. \|volume=25 \|issue=11 \|pages=149–56 \|year=1992 \|doi=10.2166/wst.1992.0286}}</ref> Cannabis products are not likely to be contaminated enough to cause disease as severe as Itai-Itai disease, but because cannabis can hyperaccumulate cadmium, it should still be considered hazardous and tested for in cannabis products.

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	There are also concerns for the contamination of cannabis food products by potentially harmful bacteria, including ''Listeria''.<ref name="McKernanMicro18">{{cite journal \|title=Microbiological examination of nonsterile Cannabis products: Molecular Microbial Enumeration Tests and the limitation of Colony Forming Units \|journal=OSF Preprints \|author=McKernan, K.; Helbert, Y.; Ebling, H. et al. \|year=2018 \|doi=10.31219/osf.io/vpxe5}}</ref> Species of ''Listeria'' have been shown to be opportunistic pathogens that most commonly cause food poisoning or listeriosis; however, if infecting the central nervous system, these bacterium can induce encephalitis or mimic idiopathic inflammatory demyelinating disease.<ref name="MorgandList18">{{cite journal \|title=Listeria monocytogenes-associated respiratory infections: A study of 38 consecutive cases \|journal=Clinical Microbiology and Infection \|author=Morgand, M.; Leclerq, A.; Maury, M.M. et al. \|volume=24 \|issue=12 \|pages=1339.e1-1339.e5 \|year=2018 \|doi=10.1016/j.cmi.2018.03.003 \|pmid=29549058}}</ref> Though the presence of these bacteria have been reported as highly prevalent in cannabis<ref name="McPartlandContam17" />, current literature does not reflect any opportunistic infection caused by use of bacterial-contaminated cannabis products. Still, the presence of human pathogenic bacteria on cannabis presents a possible risk to the consumer, especially the immunocompromised, and therefore ways to limit bacterial contamination should be explored.		There are also concerns for the contamination of cannabis food products by potentially harmful bacteria, including ''Listeria''.<ref name="McKernanMicro18">{{cite journal \|title=Microbiological examination of nonsterile Cannabis products: Molecular Microbial Enumeration Tests and the limitation of Colony Forming Units \|journal=OSF Preprints \|author=McKernan, K.; Helbert, Y.; Ebling, H. et al. \|year=2018 \|doi=10.31219/osf.io/vpxe5}}</ref> Species of ''Listeria'' have been shown to be opportunistic pathogens that most commonly cause food poisoning or listeriosis; however, if infecting the central nervous system, these bacterium can induce encephalitis or mimic idiopathic inflammatory demyelinating disease.<ref name="MorgandList18">{{cite journal \|title=Listeria monocytogenes-associated respiratory infections: A study of 38 consecutive cases \|journal=Clinical Microbiology and Infection \|author=Morgand, M.; Leclerq, A.; Maury, M.M. et al. \|volume=24 \|issue=12 \|pages=1339.e1-1339.e5 \|year=2018 \|doi=10.1016/j.cmi.2018.03.003 \|pmid=29549058}}</ref> Though the presence of these bacteria have been reported as highly prevalent in cannabis<ref name="McPartlandContam17" />, current literature does not reflect any opportunistic infection caused by use of bacterial-contaminated cannabis products. Still, the presence of human pathogenic bacteria on cannabis presents a possible risk to the consumer, especially the immunocompromised, and therefore ways to limit bacterial contamination should be explored.

			===Viral contaminants===
			Our literature searches yielded no reports of human pathogenic viral contamination of cannabis, but other crops have shown contamination by various noroviruses, rotaviruses, and enteroviruses, causing enteric diseases in humans.<ref name="BouwknegtQuant15">{{cite journal \|title=Quantitative farm-to-fork risk assessment model for norovirus and hepatitis A virus in European leafy green vegetable and berry fruit supply chains \|journal=International Journal of Food Microbiology \|author=Bouwknegt, M.; Verhaelen, K.; Rzeżutka, A. et al. \|volume=198 \|pages=50–8 \|year=2015 \|doi=10.1016/j.ijfoodmicro.2014.12.013 \|pmid=25598201}}</ref><ref name="Pérez-MorenoCanna19">{{cite journal \|title=Cannabis resin in the region of Madrid: Adulteration and contamination \|journal=Forensic Science International \|author=Pérez-Moreno, M.; Pérez-Lloret, P.; González-Soriano, J. et al. \|volume=298 \|pages=34–8 \|year=2019 \|doi=10.1016/j.forsciint.2019.02.049 \|pmid=30878463}}</ref> Viruses found to be associated with cannabis are purely plant pathogens, and it is not assumed that these could cause human related diseases.<ref name="McPartlandContam17" /> However, human handling in this industry is frequent, and it is possible that the product could be contaminated with a human pathogen through contact. While no reported cases of viral infection caused by cannabis use are found in the literature, this is not a largely explored area of research and should be considered in future studies. It is possible that human viral pathogens will be identified through further metagenomic studies of cannabis, and until the risk of disease can be ruled out, viral contamination should be considered possible.

			==Heavy metal contamination==
			A variety of heavy metals have been found in ''Cannabis'' plants and products made with cannabis (e.g., tinctures and oils), including [[wikipedia:Cadmium\|cadmium]], [[wikipedia:Lead\|lead]], [[wikipedia:Mercury\|mercury]], magnesium, and copper.<ref name="DryburghCanna18" /><ref name="McPartlandContam17" /><ref name="SiegelMerc88">{{cite journal \|title=Mercury in Marijuana: Some of the problems arising from marijuana use might result from the intake of bioaccumulated mercury \|journal=BioScience \|author=Siegel, B.Z.; Garnier, L.; Siegel, S.M. \|volume=38 \|issue=9 \|pages=619–23 \|year=1988 \|doi=10.2307/1310827}}</ref><ref name="BusseLead08">{{cite journal \|title=Lead poisoning due to adulterated marijuana in Leipzig \|journal=Deutsches Arzteblatt International \|author=Busse, F.P.; Fiedler, G.M.; Leichtle, A. et al. \|volume=105 \|issue=44 \|pages=757-62 \|year=2008 \|doi=10.3238/arztebl.2008.0757 \|pmid=19623274 \|pmc=PMC2696942}}</ref><ref name="GauvinMarij18">{{cite journal \|title= Marijuana toxicity: Heavy metal exposure through state-sponsored access to “la Fee Verte” \|journal=Pharmaceutical Regulatory Affairs \|author=Gauvin, D.V.; Zimmermann, Z.J.; Yoder, J. et al. \|volume=7 \|issue=1 \|at=1000202 \|year=2018 \|doi=10.4172/2167-7689.1000202}}</ref> 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.<ref name="McPartlandContam17" /> 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.<ref name="VardhanARev19">{{cite journal \|title=A review on heavy metal pollution, toxicity and remedial measures: Current trends and future perspectives \|journal=Journal of Molecular Liquids \|author=Vardhan, K.H.; Kumar, P.S.; Panda, R.C. \|volume=290 \|at=111197 \|year=2019 \|doi=10.1016/j.molliq.2019.111197}}</ref> 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.<ref name="DaleyTesting13" /> 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.

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	===Bacterial contaminants===		===Bacterial contaminants===
	Bacterial contamination is less of a direct health threat to cannabis users than fungus and molds, but there have been potentially pathogenic species identified in a few recent studies.<ref name="McPartlandContam17" /><ref name="McKernanMetagen16" />(Sandler et al., 2019) A study of five cannabis cultivars had shown that most species of bacteria were identified from samples of endorhiza-, [[wikipedia:Rhizosphere\|rhizosphere]]-, and [[wikipedia:Bulk soil\|bulk soil]]-associated microbiomes more so than from other regions of the plant. These bacteria contaminates include various species of ''Pseudomonas'', ''Cellvibrio'', ''Oxalobacteraceae'', ''Xanthomonadaceae'', ''Actinomycetales'', and ''Sphingobacteriales'' in the examined microbiomes.<ref name="WinstonUnderstand14">{{cite journal \|title=Understanding cultivar-specificity and soil determinants of the cannabis microbiome \|journal=PLoS One \|author=Winston, M.E.; Hampton-Marcell, J.; Zarraonaindia, I. et al. \|volume=9 \|issue=6 \|at=e99641 \|year=2014 \|doi=10.1371/journal.pone.0099641 \|pmid=24932479 \|pmc=PMC4059704}}</ref> Another study shows a variety of potential human pathogens, including ''Acinetobacter baumannii'', ''Escherichia coli'', ''Pseudomonas aeruginosa'', ''Ralstonia pickettii'', ''Salmonella enterica'', ''Stenotrophomonas maltophilia'', and ''Clostridium botulinum'', in the flowers of medicinal cannabis plants grown at indoor facilities in Massachusetts, Maine, and Rhode Island.<ref name="McKernanMetagen16" /> Endophytic bacterial taxa have also been identified that may provide fungal resistance and other fitness-related traits to cannabis through secondary metabolite production, some of which could be used in growth promotion and/or in biological control designed experiments.<ref name="ScottEndophytes18">{{cite journal \|title=Endophytes of industrial hemp (''Cannabis sativa'' L.) cultivars: identification of culturable bacteria and fungi in leaves, petioles, and seeds \|journal=Canadian Journal of Microbiology \|author=Scott, M.; Rani, M.; Samsatly, J. et al. \|volume=64 \|issue=10 \|pages=664-680 \|year=2018 \|doi=10.1139/cjm-2018-0108 \|pmid=29911410}}</ref> Although some bacteria have been shown to be beneficial to cultivation, the possible pathogenic species that have been associated with cannabis are of greater concern, specifically the risk these species pose to consumers.		Bacterial contamination is less of a direct health threat to cannabis users than fungus and molds, but there have been potentially pathogenic species identified in a few recent studies.<ref name="McPartlandContam17" /><ref name="McKernanMetagen16" /><ref name="SandlerCannabis19">{{cite journal \|title=Cannabis as conundrum \|journal=Crop Protection \|author=Sandler, L.N.; Beckerman, J.L.; Whitford, F. et al. \|volume=117 \|pages=37–44 \|year=2019 \|doi=10.1016/j.cropro.2018.11.003}}</ref> A study of five cannabis cultivars had shown that most species of bacteria were identified from samples of endorhiza-, [[wikipedia:Rhizosphere\|rhizosphere]]-, and [[wikipedia:Bulk soil\|bulk soil]]-associated microbiomes more so than from other regions of the plant. These bacteria contaminates include various species of ''Pseudomonas'', ''Cellvibrio'', ''Oxalobacteraceae'', ''Xanthomonadaceae'', ''Actinomycetales'', and ''Sphingobacteriales'' in the examined microbiomes.<ref name="WinstonUnderstand14">{{cite journal \|title=Understanding cultivar-specificity and soil determinants of the cannabis microbiome \|journal=PLoS One \|author=Winston, M.E.; Hampton-Marcell, J.; Zarraonaindia, I. et al. \|volume=9 \|issue=6 \|at=e99641 \|year=2014 \|doi=10.1371/journal.pone.0099641 \|pmid=24932479 \|pmc=PMC4059704}}</ref> Another study shows a variety of potential human pathogens, including ''Acinetobacter baumannii'', ''Escherichia coli'', ''Pseudomonas aeruginosa'', ''Ralstonia pickettii'', ''Salmonella enterica'', ''Stenotrophomonas maltophilia'', and ''Clostridium botulinum'', in the flowers of medicinal cannabis plants grown at indoor facilities in Massachusetts, Maine, and Rhode Island.<ref name="McKernanMetagen16" /> Endophytic bacterial taxa have also been identified that may provide fungal resistance and other fitness-related traits to cannabis through secondary metabolite production, some of which could be used in growth promotion and/or in biological control designed experiments.<ref name="ScottEndophytes18">{{cite journal \|title=Endophytes of industrial hemp (''Cannabis sativa'' L.) cultivars: identification of culturable bacteria and fungi in leaves, petioles, and seeds \|journal=Canadian Journal of Microbiology \|author=Scott, M.; Rani, M.; Samsatly, J. et al. \|volume=64 \|issue=10 \|pages=664-680 \|year=2018 \|doi=10.1139/cjm-2018-0108 \|pmid=29911410}}</ref> Although some bacteria have been shown to be beneficial to cultivation, the possible pathogenic species that have been associated with cannabis are of greater concern, specifically the risk these species pose to consumers.

			While dozens of bacterial species have been found to be present in cannabis plants, ''[[wikipedia:Escherichia coli\|E. coli]]'', ''[[wikipedia:Salmonella\|Salmonella]]'', and ''[[wikipedia:Clostridium\|Clostridium]]'' are a few common potential human pathogenic species shown to be associated with cannabis.<ref name="McKernanMetagen16" /> ''Escherichia coli'' infection has potential to cause a wide range of diseases depending on the strain encountered, including meningitis in infants, enteritis, and diarrhea.<ref name="KimHuman16">{{cite journal \|title=Human Meningitis-Associated ''Escherichia coli'' \|journal=EcoSal Plus \|author=Kim, K.S. \|volume=7 \|issue=1 \|year=2015 \|doi=10.1128/ecosalplus.ESP-0015-2015 \|pmid=27223820 \|pmc=PMC4881430}}</ref><ref name="CroftsEntero18">{{cite journal \|title=Enterotoxigenic E. coli virulence gene regulation in human infections \|journal=Proceedings of the National Academy of Sciences of the United States of America \|author=Crofts, A.A.; Giovanetti, S.M.; Rubin, E.J. et al. \|volume=115 \|issue=38 \|pages=E8968-E8976 \|year=2018 \|doi=10.1073/pnas.1808982115 \|pmid=30126994 \|pmc=PMC6156659}}</ref><ref name="ValilisNon18">{{cite journal \|title=Non-O157 Shiga toxin-producing Escherichia coli-A poorly appreciated enteric pathogen: Systematic review \|journal=International Journal of Infectious Diseases \|author=Valilis, E.; Ramsey, A.; Sidiq, S. et al. \|volume=76 \|pages=82–87 \|year=2018 \|doi=10.1016/j.ijid.2018.09.002 \|pmid=30223088}}</ref> Exposure to ''Salmonella'' can cause bacterial infection with symptoms including diarrhea, vomiting, fever, and enteritis.<ref name="DaleyTesting13" /> ''Clostridium'' can cause botulism, a rare disease with symptoms including cranial nerve palsies and flaccid paralysis of voluntary muscles, with potential progression to respiratory illness and death.<ref name="SobelBotul05">{{cite journal \|title=Botulism \|journal=Clinical Infectious Diseases \|author=Sobel, J. \|volume=41 \|issue=8 \|pages=1167–73 \|year=2005 \|doi=10.1086/444507 \|pmid=16163636}}</ref>

			There are also concerns for the contamination of cannabis food products by potentially harmful bacteria, including ''Listeria''.<ref name="McKernanMicro18">{{cite journal \|title=Microbiological examination of nonsterile Cannabis products: Molecular Microbial Enumeration Tests and the limitation of Colony Forming Units \|journal=OSF Preprints \|author=McKernan, K.; Helbert, Y.; Ebling, H. et al. \|year=2018 \|doi=10.31219/osf.io/vpxe5}}</ref> Species of ''Listeria'' have been shown to be opportunistic pathogens that most commonly cause food poisoning or listeriosis; however, if infecting the central nervous system, these bacterium can induce encephalitis or mimic idiopathic inflammatory demyelinating disease.<ref name="MorgandList18">{{cite journal \|title=Listeria monocytogenes-associated respiratory infections: A study of 38 consecutive cases \|journal=Clinical Microbiology and Infection \|author=Morgand, M.; Leclerq, A.; Maury, M.M. et al. \|volume=24 \|issue=12 \|pages=1339.e1-1339.e5 \|year=2018 \|doi=10.1016/j.cmi.2018.03.003 \|pmid=29549058}}</ref> Though the presence of these bacteria have been reported as highly prevalent in cannabis<ref name="McPartlandContam17" />, current literature does not reflect any opportunistic infection caused by use of bacterial-contaminated cannabis products. Still, the presence of human pathogenic bacteria on cannabis presents a possible risk to the consumer, especially the immunocompromised, and therefore ways to limit bacterial contamination should be explored.

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	There are limited case studies demonstrating cannabis causing fusariosis; however, there are a plethora of studies that have found ''Fusarium'' to be in direct relationship with ''Cannabis'' plants.<ref name="McPartlandCanna04" /><ref name="PunjaPatho19" /> In fact, starting in the late 1970s through the 1980s, ''F. oxysporum'' was physically distributed across the United States to combat illegal cannabis farming.<ref name="McPartlandCanna04" /> While this was intended as a short-term biological control, it has inevitably caused this organism to continually infect legal hemp and cannabis farms today, which may negatively impact the quality of cannabis grown in legal markets.		There are limited case studies demonstrating cannabis causing fusariosis; however, there are a plethora of studies that have found ''Fusarium'' to be in direct relationship with ''Cannabis'' plants.<ref name="McPartlandCanna04" /><ref name="PunjaPatho19" /> In fact, starting in the late 1970s through the 1980s, ''F. oxysporum'' was physically distributed across the United States to combat illegal cannabis farming.<ref name="McPartlandCanna04" /> While this was intended as a short-term biological control, it has inevitably caused this organism to continually infect legal hemp and cannabis farms today, which may negatively impact the quality of cannabis grown in legal markets.

			In addition to pathogenesis in humans by these fungi, ''Penicillium'', ''Aspergillus'', and ''Fusarium'' species are known to produce both aflatoxins and mycotoxins that become especially problematic while drying and storing cannabis products in humid environments.<ref name="McPartlandContam17" /><ref name="McPartlandNew97">{{cite journal \|title=New species, combinations, host associations and location records of fungi associated with hemp (''Cannabis sativa'') \|journal=Mycological research \|author=McPartland, J.M.; Cubeta, M.A. \|volume=101 \|issue=7 \|pages=853-857 \|year=1997 \|doi=10.1017/S0953756297003584}}</ref> Several cannabis drying strategies, such as sweat curing, make [[Sample (material)\|samples]] more susceptible to contamination from various types of ''Aspergillus'' because of relatively high [[wikipedia:Water activity\|water activity]] inside the stacked plant materials.<ref name="McPartlandContam17" /> Sweat curing is not as commonly practiced today; however, there have still been recent reports of unacceptable levels of fungal spores in products grown in both indoor and outdoor facilities.<ref name="McPartlandContam17" /> This indicates some current methods of cultivation and curing still leave the plant susceptible to fungal infection.<ref name="MartynyPotent13">{{cite journal \|title=Potential exposures associated with indoor marijuana growing operations \|journal=Journal of Occupational and Environmental Hygiene \|author=Martyny, J.W.; Serrano, K.a.; Schaeffer, J.W. et al. \|volume=10 \|issue=11 \|pages=622–39 \|year=2013 \|doi=10.1080/15459624.2013.831986 \|pmid=24116667}}</ref> As such, standard testing procedures of fungal mycotoxins in cannabis for both the hemp- and drug-type markets must be developed and are imperative to best protect the consumer, especially those with a compromised immune system using cannabis as a therapy.

			===Bacterial contaminants===
			Bacterial contamination is less of a direct health threat to cannabis users than fungus and molds, but there have been potentially pathogenic species identified in a few recent studies.<ref name="McPartlandContam17" /><ref name="McKernanMetagen16" />(Sandler et al., 2019) A study of five cannabis cultivars had shown that most species of bacteria were identified from samples of endorhiza-, [[wikipedia:Rhizosphere\|rhizosphere]]-, and [[wikipedia:Bulk soil\|bulk soil]]-associated microbiomes more so than from other regions of the plant. These bacteria contaminates include various species of ''Pseudomonas'', ''Cellvibrio'', ''Oxalobacteraceae'', ''Xanthomonadaceae'', ''Actinomycetales'', and ''Sphingobacteriales'' in the examined microbiomes.<ref name="WinstonUnderstand14">{{cite journal \|title=Understanding cultivar-specificity and soil determinants of the cannabis microbiome \|journal=PLoS One \|author=Winston, M.E.; Hampton-Marcell, J.; Zarraonaindia, I. et al. \|volume=9 \|issue=6 \|at=e99641 \|year=2014 \|doi=10.1371/journal.pone.0099641 \|pmid=24932479 \|pmc=PMC4059704}}</ref> Another study shows a variety of potential human pathogens, including ''Acinetobacter baumannii'', ''Escherichia coli'', ''Pseudomonas aeruginosa'', ''Ralstonia pickettii'', ''Salmonella enterica'', ''Stenotrophomonas maltophilia'', and ''Clostridium botulinum'', in the flowers of medicinal cannabis plants grown at indoor facilities in Massachusetts, Maine, and Rhode Island.<ref name="McKernanMetagen16" /> Endophytic bacterial taxa have also been identified that may provide fungal resistance and other fitness-related traits to cannabis through secondary metabolite production, some of which could be used in growth promotion and/or in biological control designed experiments.<ref name="ScottEndophytes18">{{cite journal \|title=Endophytes of industrial hemp (''Cannabis sativa'' L.) cultivars: identification of culturable bacteria and fungi in leaves, petioles, and seeds \|journal=Canadian Journal of Microbiology \|author=Scott, M.; Rani, M.; Samsatly, J. et al. \|volume=64 \|issue=10 \|pages=664-680 \|year=2018 \|doi=10.1139/cjm-2018-0108 \|pmid=29911410}}</ref> Although some bacteria have been shown to be beneficial to cultivation, the possible pathogenic species that have been associated with cannabis are of greater concern, specifically the risk these species pose to consumers.