Difference between revisions of "Journal:Cannabis contaminants limit pharmacological use of cannabidiol"

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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.




Revision as of 23:11, 14 September 2020

Full article title Cannabis contaminants limit pharmacological use of cannabidiol
Journal Frontiers in Pharmacology
Author(s) Montoya, Zackary; Conroy, Matthieu; Vanden Heuvel, Brian D.; Pauli, Christopher S.; Park, Sang-Hyuck
Author affiliation(s) Colorado State University–Pueblo
Primary contact Email: sanghyuck dot park at csupueblo dot edu
Editors Khan, Tanveer A.
Year published 2020
Volume and issue 11
Article # 571832
DOI 10.3389/fphar.2020.571832
ISSN 1663-9812
Distribution license Creative Commons Attribution 4.0 International
Website https://www.frontiersin.org/articles/10.3389/fphar.2020.571832/full
Download https://www.frontiersin.org/articles/10.3389/fphar.2020.571832/pdf (PDF)
Emblem-important-yellow.svg This article should be considered a work in progress and incomplete. Consider this article incomplete until this notice is removed.

Abstract

For nearly a century, cannabis has been stigmatized and criminalized across the globe, but in recent years, there has been a growing interest in cannabis due to the therapeutic potential of phytocannabinoids. With this emerging interest in cannabis, concerns have arisen about the possible contaminations of hemp with pesticides, heavy metals, microbial pathogens, and carcinogenic compounds during the cultivation, manufacturing, and packaging processes. This is of particular concern for those turning to cannabis for 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 testing of products to protect those who consume cannabis.

Keywords: cannabis, cannabidiol, cannabis contaminants, hemp, phytocannabinoids

Introduction

Phytocannabinoids have garnered global attention recently due to the therapeutic potentials in Parkinson’s disease[1], schizophrenia[2], cancers[3][4], pain, anxiety, depression, and other neurological disorders[5], as well as the Food and Drug Administration (FDA) approval of Epidiolex for Dravet syndrome[6] and Lennox-Gauss Syndrome.[7] As of 2019, a total of 33 states, the District of Columbia, Guam, Puerto Rico, and the U.S Virgin Islands have approved cannabis for medicinal purposes, and 21 states are considering bills that would decriminalize it under legislative action. With recent legalization in Canada in 2019, more countries are beginning to question the rationale behind criminalizing cannabis.[8] As interest in cannabis expands around the globe, many issues have arisen concerning the lack of cultivation standards and overall quality control of cannabis products. Recently the United States Pharmacopeia (USP) formed a Cannabis Expert Panel, which has evaluated specifications necessary to define key cannabis quality attributes, including limits for contaminants such as pesticide residues, microbial pathogen levels, mycotoxins, and elemental contaminants, based on toxicological considerations and aligned with the existing USP procedures for general tests and assays.[9] Aside from inaccuracy in labeling phytocannabinoid content, it has been reported that cannabis and derived products are often contaminated by microbes, heavy metals, pesticides, carcinogens, and debris, which must be addressed to ensure the safety of consumers (Table 1).[10][11]


Tab1 Montoya FrontPharm2020 11.jpg

Table 1 List of cannabis contaminants and sources, target/mechanism, and its respective risks to human health. GABA = γ-amino butyric acid.

These contaminants are imminent threats that directly impact public health and wellness, particularly to the immunocompromised and pediatric patients who take cannabis products as a treatment for numerous human disorders, including cancer patients and those suffering from epileptic seizures.[12] To increase public awareness, we provide examples of contamination, its medical consequences reported in clinical research, and then suggest that each risk category be analyzed for best practices to limit exposure of contaminants to the consumer. We recommend hemp producers, manufacturers, medical professionals, and legislators recognize this risk and establish regulatory measures to educate the public and lessen the adverse effects caused by the contaminants in cannabis, particularly in cannabidiol (CBD)-based products.

Labeling inaccuracy

Mislabeling of phytocannabinoid profiles in CBD products is one of the major concerns to consumers.[13] Inaccurate reporting of the cannabinoid content risks exposing medicinal users to phytocannabinoids of which they have no intent to consume, namely Δ-9-tetrahydracannabinol (THC).[14] This is of particular concern within pediatric patients, as THC intoxication has been shown to alter development of white matter in the brain[15], affect cognitive functioning[16][17], and affect learning and memory within adolescents.[18]

Despite some U.S. states like Colorado having a 15% allowable reporting variance of the phytocannabinoid content on CBD product labels[19], measured contents often exceed this range. For example, a recent study shows that 69% of 84 CBD products purchased from 31 American online retailers were inaccurately labeled for CBD: 26% were overlabeled, whereas 42% were underlabeled for CBD concentration.[20] Additionally, 64% of 14 CBD products sold in the European Union (EU) market presented different cannabinoid profiles from the declared amount.[21] Inaccuracies are also found on labels of hemp-type cannabis sold in the Netherlands, with measured THC and CBD deviating from label claims by 8%–99% in CBD oil samples obtained from patients.[13] In Germany, an analysis of 67 CBD product samples found that 25% of samples were contaminated with residual THC above the lowest level of observable effects, or the lowest level that is known to cause physiological effects in humans (2.5 mg/day).[22] In a recent analysis of 25 CBD oil products purchased in Mississippi, only three of the 25 were within ±20% of label claim, 15 were below the stated claim for CBD, two exceed these claims by more than 50%, and THC content for three products exceeded the 0.3% legal limit.[23]

There are also concerns for edible cannabis products (e.g., gummies, cookies, etc.) containing under- and overreported phytocannabinoid content, specifically THC.[24] In states where cannabis is legal for recreation, these edible products are tested for overall THC potency in addition to dose-specific potency of THC to be sure these products stay under 100 mg total THC with no more than 10 mg of THC per dose.[25] However, in hemp, there is no regulating body overseeing this testing, therefore the responsibility to test CBD edibles is left to each product manufacturer to ensure compliance of cannabinoid content limits, which is often neglected.[25] While currently CBD and THC are the only cannabinoids required to be labeled, it may be beneficial to include the profile of acidic forms of THC and CBD, as well as some representative minor cannabinoids such as cannabigerol (CBG), cannabichromene (CBC), or possibly some of the short chain versions of these referred to as "-varin cannabinoids" (e.g., tetrahydrocannabivarin [THCV] and cannabidivarin [CBDV]) on these labels. These minor cannabinoids are shown to have some therapeutic effects that could be enhanced in combination with other major cannabinoids.[26]

Microbial contamination

Cannabis is associated with various types of microbes, including molds that have been shown to harm immunocompromised patients, as well as bacteria and viruses that have the potential of causing harm to humans. A recent metagenomics study on 15 medicinal Cannabis plants shows that cannabis is associated with a wide range of epiphytic and endophytic microbial communities, including several toxigenic bacterial and fungal species.[27] While most of the microbes found to be in association with cannabis are likely beneficial to the plant in some way or are phytopathogens, several bacterial species have been identified that could be opportunistic pathogens in humans.[27] While there are currently no reports of bacterial infection caused by contaminated cannabis, several examples of fungal contamination, namely the Aspergillus species, are found in the literature and pose a threat to human health.[27] In this section, the authors will introduce some of the possible human pathogenic microbial species and their relevant case studies.

Fungal contaminants

Previous studies have identified several fungal organisms in dispensary-produced cannabis, including species of Penicillium (P. paxilli, P. citrinum, P. commune, P. chrysogenum, P. corylophilum, P. citrinum, and P. steckii), Aspergillus (A. terreus, A. niger, A. flavus, A. versicolor, A. ostianus, and A. sydowii), and Fusarium (F. oxysporum).[27][28] Both Penicillium and Aspergillus species have been known to produce aflatoxins (e.g., aflatoxin B1), while Fusarium species produce other mycotoxins such as fumonisin.[29][30] Cannabis infected with Aspergillus, Penicilium, or Fusarium can severely affect human health as these toxins can all be carcinogenic, hepatotoxic, neurotoxic or nephrotoxic.[31][32][33] The toxicological action depends on various factors, including the mode of exposure and the susceptibility of the infected individual, with immunocompromised patients having the highest risk of infection.[31] In general, these toxins are carcinogenic as they commonly interact with guanine moieties in DNA forming a variety of DNA adducts, which often leads to deterioration of the liver.[31]

Case study 1

Penicilliosis (today known as talaromycosis), a fungal infection due to Penicillium species, is rare in immunocompetent people but is found in immunocompromised individuals[34], and it is commonly the cause of death for human immunodeficiency virus (HIV) positive and other immunocompromised patients.[35] Currently, no reports of penicilliosis caused by cannabis are found in the literature; however, immunocompromised individuals should be cautious using cannabis products as several species known to cause this condition have been found in cannabis flowers and products.[27][28]

Case study 2

Aspergillus species are the most common fungi to cause invasive infection in the immunocompromised. This is concerning as Aspergillus-infected cannabis has been previously directly linked to human disease.[36] A case study showed that a patient with lung cancer used illicitly obtained cannabis as an antiemetic agent during chemotherapy and developed invasive pulmonary aspergillosis that caused death in 19 days after diagnosis.[37] Many of the recent metagenomic studies of cannabis show that Aspergillus species are still pervasive in cannabis, which may pose a considerable risk to the consumer, especially the immunocompromised.[27]

Case study 3

Fusarium species are common environmental fungi, capable of causing infections in both animals and plants.[33] Humans infected by Fusarium present with a wide range of symptoms, including fever, neutropenia, pneumonia, sinusitis, or, in some immunocompromised patients, disseminated disease.[38] Fusarium can cause a pulmonary infection that could result from the inhalation of conidia[39], a spore produced by these asexual fungi, which is consistent with the following case. A 2019 case study in an immunocompromised patient with acute myeloid leukemia (AML), who developed invasive disseminated fusariosis, has proven infection by this fungus is fatal.[38] The patient initially presented with painless lesions on her arms and legs, that darkened, grew, and spread to her trunk and all extremities. The patient elected to discontinue treatment and passed two weeks after transitioning to hospice care.[38]

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.[28][30] In fact, starting in the late 1970s through the 1980s, F. oxysporum was physically distributed across the United States to combat illegal cannabis farming.[28] 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.[10][40] Several cannabis drying strategies, such as sweat curing, make samples more susceptible to contamination from various types of Aspergillus because of relatively high water activity inside the stacked plant materials.[10] 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.[10] This indicates some current methods of cultivation and curing still leave the plant susceptible to fungal infection.[41] 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.[10][27][42] A study of five cannabis cultivars had shown that most species of bacteria were identified from samples of endorhiza-, rhizosphere-, and 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.[43] 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.[27] 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.[44] 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, E. coli, Salmonella, and Clostridium are a few common potential human pathogenic species shown to be associated with cannabis.[27] Escherichia coli infection has potential to cause a wide range of diseases depending on the strain encountered, including meningitis in infants, enteritis, and diarrhea.[45][46][47] Exposure to Salmonella can cause bacterial infection with symptoms including diarrhea, vomiting, fever, and enteritis.[29] 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.[48]

There are also concerns for the contamination of cannabis food products by potentially harmful bacteria, including Listeria.[49] 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.[50] Though the presence of these bacteria have been reported as highly prevalent in cannabis[10], 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.[51][52] Viruses found to be associated with cannabis are purely plant pathogens, and it is not assumed that these could cause human related diseases.[10] 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 cadmium, lead, mercury, magnesium, and copper.[11][10][53][54][55] 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.[10] 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.[56] 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.[29] 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.


References

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  13. ↑ 13.0 13.1 Hazekamp, A. (2018). "The Trouble with CBD Oil". Medical Cannabis and Cannabinoids 1 (1): 65–72. doi:10.1159/000489287. 
  14. ↑ Corroon, J.; MacKay, D.; Dolphin, W. (2020). "Labeling of Cannabidiol Products: A Public Health Perspective". Cannabis and Cannabinoid Research: 1–5. doi:10.1089/can.2019.0101. 
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  17. ↑ Zamberletti, E.; Gabaglio, M.; Prini, P. et al. (2015). "Cortical neuroinflammation contributes to long-term cognitive dysfunctions following adolescent delta-9-tetrahydrocannabinol treatment in female rats". European Nueropsychopharmacology 25 (12): 2404–15. doi:10.1016/j.euroneuro.2015.09.021. PMID 26499171. 
  18. ↑ Wang, G.S.; Roosevelt, G.; Heard, K. (2013). "Pediatric marijuana exposures in a medical marijuana state". JAMA Pediatrics 167 (7): 630–3. doi:10.1001/jamapediatrics.2013.140. PMID 23712626. 
  19. ↑ Herod, L.; Gardner, B. (2018). "House Bill 18-1023" (PDF). State of Colorado. http://leg.colorado.gov/sites/default/files/documents/2018A/bills/2018a_1023_eng.pdf. 
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  21. ↑ Pavlovic, R.; Nenna, G.; Calvi, L. et al. (2018). "Quality Traits of "Cannabidiol Oils": Cannabinoids Content, Terpene Fingerprint and Oxidation Stability of European Commercially Available Preparations". Molecules 23 (5): 1230. doi:10.3390/molecules23051230. PMC PMC6100014. PMID 29783790. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6100014. 
  22. ↑ Lachenmeier, D.W.; Habel, S.; Fischer, B. et al. (2019). "Are side effects of cannabidiol (CBD) products caused by tetrahydrocannabinol (THC) contamination?". F1000Research 8: 1394. doi:10.12688/f1000research.19931.3. PMC PMC7029751. PMID 32117565. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7029751. 
  23. ↑ Gurley, B.J.; Murphy, T.P.; Gul, W. et al. (2020). "Content versus Label Claims in Cannabidiol (CBD)-Containing Products Obtained from Commercial Outlets in the State of Mississippi". Journal of Dietary Supplements 17 (5): 599–607. doi:10.1080/19390211.2020.1766634. PMID 32431186. 
  24. ↑ Vandrey, R.; Raber, J.C.; Raber, M.E. et al. (2015). "Cannabinoid Dose and Label Accuracy in Edible Medical Cannabis Products". JAMA 313 (24): 2491–3. doi:10.1001/jama.2015.6613. PMID 26103034. 
  25. ↑ 25.0 25.1 Blake, A.; Nahtigal, I. (2019). "The evolving landscape of cannabis edibles". Current Opinion in Food Science 28: 25–31. doi:10.1016/j.cofs.2019.03.009. 
  26. ↑ Deiana, S. (2017). "Chapter 99 - Potential Medical Uses of Cannabigerol: A Brief Overview". In Preedy, V.R.. Handbook of Cannabis and Related Pathologies. Academic Press. pp. 958–67. doi:10.1016/B978-0-12-800756-3.00115-0. ISBN 9780128007563. 
  27. ↑ 27.0 27.1 27.2 27.3 27.4 27.5 27.6 27.7 27.8 McKernan, K.; Spangler, J.; Helbert, Y. et al. (2016). "Metagenomic analysis of medicinal Cannabis samples; pathogenic bacteria, toxigenic fungi, and beneficial microbes grow in culture-based yeast and mold tests". F1000Research 5: 2471. doi:10.12688/f1000research.9662.1. PMC PMC5089129. PMID 27853518. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5089129. 
  28. ↑ 28.0 28.1 28.2 28.3 McParltand, J.M.; Hillig, K.W. (2004). "Cannabis clinic Fusarium wilt". Journal of Industrial Hemp 9 (2): 67–77. doi:10.1300/J237v09n02_07. 
  29. ↑ 29.0 29.1 29.2 Daley, P.; Lampach, D.; Sguerra, S. (12 September 2013). "Testing Cannabis for Contaminants" (PDF). BOTEC Analysis Corporation. https://lcb.wa.gov/publications/Marijuana/BOTEC%20reports/1a-Testing-for-Contaminants-Final-Revised.pdf. 
  30. ↑ 30.0 30.1 Punja, Z.K.; Collyer, D.; Scott, C. et al. (2019). "Pathogens and Molds Affecting Production and Quality of Cannabis sativa L". Frontiers in Plant Science 10: 1120. doi:10.3389/fpls.2019.01120. PMC PMC6811654. PMID 31681341. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6811654. 
  31. ↑ 31.0 31.1 31.2 Pitt, J.I.; Basílico, J.C.; Abarca, M.L. et al. (2000). "Mycotoxins and toxigenic fungi". Medical Mycology 38 (Suppl. 1): 41–6. doi:10.1080/mmy.38.s1.41.46. PMID 11204163. 
  32. ↑ Marasas, W.F.O.; Riley, R.T.; Hendricks, K.A. et al. (2004). "Fumonisins disrupt sphingolipid metabolism, folate transport, and neural tube development in embryo culture and in vivo: A potential risk factor for human neural tube defects among populations consuming fumonisin-contaminated maize". Journal of Nutrition 134 (4): 711–6. doi:10.1093/jn/134.4.711. PMID 15051815. 
  33. ↑ 33.0 33.1 Kamle, M.; Mahato, D.K.; Devi, S. et al. (2019). "Fumonisins: Impact on Agriculture, Food, and Human Health and their Management Strategies". Toxins 11 (6): 328. doi:10.3390/toxins11060328. PMC PMC6628439. PMID 31181628. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6628439. 
  34. ↑ Gorai, S.; Saha, M.; Madhab, V. et al. (2019). "Talaromycosis (Penicilliosis): A Rare, Opportunistic Systemic Fungal Infection". Indian Journal of Dermatology 64 (4): 331–33. doi:10.4103/ijd.IJD_70_17. PMC PMC6714180. PMID 31516150. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6714180. 
  35. ↑ Le, T.; Thanh, N.T.; Thwaites, G.E. (2020). "Talaromycosis (Penicilliosis)". In Ryan, E.T.; Hill, D.R.; Solomon, T. et al.. Hunter's Tropical Medicine and Emerging Infectious Diseases (10th ed.). Elsevier. pp. 682–5. ISBN 9780323555128. 
  36. ↑ Gargani, Y.; Bishop, P.; Denning, D.W. (2011). "Too many mouldy joints - Marijuana and chronic pulmonary aspergillosis". Mediterranean Journal of Hematology and Infectious Diseases 3 (1): e2011005. doi:10.4084/MJHID.2011.005. PMC PMC3103256. PMID 21625309. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3103256. 
  37. ↑ Sutton, S.; Lum, B.L.; Torti, F.M. (1986). "Possible risk of invasive pulmonary aspergillosis with marijuana use during chemotherapy for small cell lung cancer". Drug Intelligence and Clinical Pharmacy 20 (4): 289-91. doi:10.1177/106002808602000416. PMID 3009125. 
  38. ↑ 38.0 38.1 38.2 Dehal, N.; Quimby, D. (2019). "Disseminated Fusariosis in a Patient With Acute Myeloid Leukemia: A Case Report". Cureus 11 (10): e5922. doi:10.7759/cureus.5922. PMC PMC6857921. PMID 31788380. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6857921. 
  39. ↑ Sreeram, S.; Lobo, F.D.; Acharya, V. et al. (2017). "A Fortuitous Turn of Evidence in an Elderly Female - A Case of Pulmonary Fusariosis". Journal of Clinical and Diagnostic Research 11 (2): ED04–ED05. doi:10.7860/JCDR/2017/24736.9191. PMC PMC5376773. PMID 28384871. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5376773. 
  40. ↑ McPartland, J.M.; Cubeta, M.A. (1997). "New species, combinations, host associations and location records of fungi associated with hemp (Cannabis sativa)". Mycological research 101 (7): 853-857. doi:10.1017/S0953756297003584. 
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  43. ↑ Winston, M.E.; Hampton-Marcell, J.; Zarraonaindia, I. et al. (2014). "Understanding cultivar-specificity and soil determinants of the cannabis microbiome". PLoS One 9 (6): e99641. doi:10.1371/journal.pone.0099641. PMC PMC4059704. PMID 24932479. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4059704. 
  44. ↑ Scott, M.; Rani, M.; Samsatly, J. et al. (2018). "Endophytes of industrial hemp (Cannabis sativa L.) cultivars: identification of culturable bacteria and fungi in leaves, petioles, and seeds". Canadian Journal of Microbiology 64 (10): 664-680. doi:10.1139/cjm-2018-0108. PMID 29911410. 
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  47. ↑ Valilis, E.; Ramsey, A.; Sidiq, S. et al. (2018). "Non-O157 Shiga toxin-producing Escherichia coli-A poorly appreciated enteric pathogen: Systematic review". International Journal of Infectious Diseases 76: 82–87. doi:10.1016/j.ijid.2018.09.002. PMID 30223088. 
  48. ↑ Sobel, J. (2005). "Botulism". Clinical Infectious Diseases 41 (8): 1167–73. doi:10.1086/444507. PMID 16163636. 
  49. ↑ McKernan, K.; Helbert, Y.; Ebling, H. et al. (2018). "Microbiological examination of nonsterile Cannabis products: Molecular Microbial Enumeration Tests and the limitation of Colony Forming Units". OSF Preprints. doi:10.31219/osf.io/vpxe5. 
  50. ↑ Morgand, M.; Leclerq, A.; Maury, M.M. et al. (2018). "Listeria monocytogenes-associated respiratory infections: A study of 38 consecutive cases". Clinical Microbiology and Infection 24 (12): 1339.e1-1339.e5. doi:10.1016/j.cmi.2018.03.003. PMID 29549058. 
  51. ↑ Bouwknegt, M.; Verhaelen, K.; Rzeżutka, A. et al. (2015). "Quantitative farm-to-fork risk assessment model for norovirus and hepatitis A virus in European leafy green vegetable and berry fruit supply chains". International Journal of Food Microbiology 198: 50–8. doi:10.1016/j.ijfoodmicro.2014.12.013. PMID 25598201. 
  52. ↑ Pérez-Moreno, M.; Pérez-Lloret, P.; González-Soriano, J. et al. (2019). "Cannabis resin in the region of Madrid: Adulteration and contamination". Forensic Science International 298: 34–8. doi:10.1016/j.forsciint.2019.02.049. PMID 30878463. 
  53. ↑ Siegel, B.Z.; Garnier, L.; Siegel, S.M. (1988). "Mercury in Marijuana: Some of the problems arising from marijuana use might result from the intake of bioaccumulated mercury". BioScience 38 (9): 619–23. doi:10.2307/1310827. 
  54. ↑ Busse, F.P.; Fiedler, G.M.; Leichtle, A. et al. (2008). "Lead poisoning due to adulterated marijuana in Leipzig". Deutsches Arzteblatt International 105 (44): 757-62. doi:10.3238/arztebl.2008.0757. PMC PMC2696942. PMID 19623274. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2696942. 
  55. ↑ Gauvin, D.V.; Zimmermann, Z.J.; Yoder, J. et al. (2018). "Marijuana toxicity: Heavy metal exposure through state-sponsored access to “la Fee Verte”". Pharmaceutical Regulatory Affairs 7 (1): 1000202. doi:10.4172/2167-7689.1000202. 
  56. ↑ Vardhan, K.H.; Kumar, P.S.; Panda, R.C. (2019). "A review on heavy metal pollution, toxicity and remedial measures: Current trends and future perspectives". Journal of Molecular Liquids 290: 111197. doi:10.1016/j.molliq.2019.111197. 

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.

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