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

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==Introduction==
==Introduction==
[[wikipedia:Cannabinoid#Phytocannabinoids|Phytocannabinoids]] have garnered global attention recently due to the therapeutic potentials in Parkinson’s disease<ref name="ChagasEffects14">{{cite journal |title=Effects of cannabidiol in the treatment of patients with Parkinson's disease: an exploratory double-blind trial |journal=Journal of Psychopharmacology |author=Chagas, M.H.N.; Zuardi, A.W.; Tumas, V. et al. |volume=28 |issue=11 |pages=1088–98 |year=2014 |doi=10.1177/0269881114550355 |pmid=25237116}}</ref>, schizophrenia<ref name="McGuireCanna18">{{cite journal |title=Cannabidiol (CBD) as an Adjunctive Therapy in Schizophrenia: A Multicenter Randomized Controlled Trial |journal=American Journal of Psychiatry |author=McGuire, P.; Robson, P.; Cubala, W.J. et al. |volume=175 |issue=3 |pages=225–31 |year=2018 |doi=10.1176/appi.ajp.2017.17030325 |pmid=29241357}}</ref>, cancers<ref name="JeongCanna19">{{cite journal |title=Cannabidiol-induced apoptosis is mediated by activation of Noxa in human colorectal cancer cells |journal=Cancer Letters |author=Jeong, S.; Yun, H.K.; Jeong, Y.A. et al. |volume=447 |pages=12–23 |year=2019 |doi=10.1016/j.canlet.2019.01.011 |pmid=30660647}}</ref><ref name="ShafariPotent19">{{cite journal |title=Potential Use of Cannabinoids for the Treatment of Pancreatic Cancer |journal=Journal of Pancreatic Cancer |author=Sharafi, G.; He, H.; Nikfarjam, M. |volume=5 |issue=1 |pages=1–7 |year=2019 |doi=10.1089/pancan.2018.0019 |pmid=30706048 |pmc=PMC6352507}}</ref>, pain, anxiety, depression, and other neurological disorders<ref name="MarchettiRole13">{{cite journal |title=Role of calcium channels in heavy metal toxicity |journal=ISRN Toxicology |author=Marchetti, C. |volume=2013 |at=184360 |year=2013 |doi=10.1155/2013/184360 |pmid=23724297 |pmc=PMC3658387}}</ref>, as well as the [[Food and Drug Administration]] (FDA) approval of Epidiolex for Dravet syndrome<ref name="KaplanCanna17">{{cite journal |title=Cannabidiol attenuates seizures and social deficits in a mouse model of Dravet syndrome |journal=Proceedings of the National Academy of Sciences of the United States of America |author=Kaplan, J.S.; Stella, N.; Catterall, W.A. et al. |volume=114 |issue=42 |pages=11229–234 |year=2017 |doi=10.1073/pnas.1711351114 |pmid=28973916 |pmc=PMC5651774}}</ref> and Lennox-Gauss Syndrome.<ref name="PauliCanna20">{{cite journal |title=Cannabidiol Drugs Clinical Trial Outcomes and Adverse Effects |journal=Frontiers in Pharmacology |author=Pauli, C.S.; Conroy, M.; Heuvel, B.D.V.. et al. |volume=11 |at=63 |year=2020 |doi=10.3389/fphar.2020.00063 |pmid=32161538 |pmc=PMC7053164}}</ref> As of 2019, a total of 33 states, the District of Columbia, Guam, Puerto Rico, and the U.S Virgin Islands have approved [[wikipedia:Cannabis|cannabis]] for medicinal purposes, and 21 states are considering bills that would [[wikipedia:Legality of cannabis|decriminalize]] it under legislative action. With recent legalization in Canada in 2019, more countries are beginning to question the rationale behind criminalizing cannabis.<ref name="HabibiLegal18">{{cite journal |title=Legalizing cannabis violates the UN drug control treaties, but progressive countries like Canada have options |journal=Ottawa Law Review |author=Habibi, R.; Hoffman, S.J. |volume=49 |issue=2 |pages=427–60 |year=2018 |url=https://rdo-olr.org/en/2018/legalizing-cannabis-violates-the-un-drug-control-treaties-but-progressive-countries-like-canada-have-options/}}</ref> As interest in cannabis expands around the globe, many issues have arisen concerning the lack of [[wikipedia:Cannabis cultivation|cultivation]] standards and overall [[quality control]] of cannabis products. Recently the [[wikipedia:United States Pharmacopeia|United States Pharmacopeia]] (USP) formed a Cannabis Expert Panel, which has evaluated specifications necessary to define key cannabis quality attributes, including limits for [[wikipedia:Contamination|contaminants]] such as [[wikipedia:Pesticide|pesticide]] residues, microbial [[wikipedia:Pathogen|pathogen]] levels, [[wikipedia:Mycotoxin|mycotoxins]], and [[wikipedia:Heavy metals|elemental contaminants]], based on toxicological considerations and aligned with the existing USP procedures for general tests and assays.<ref name="SarmaCanna20">{{cite journal |title=Cannabis Inflorescence for Medical Purposes: USP Considerations for Quality Attributes |journal=Journal of Natural Products |author=Sarma, N.D.; Waye, A.; ElSholy, M.A. et al. |volume=83 |issue=4 |at=1334–51 |year=2020 |doi=10.1021/acs.jnatprod.9b01200 |pmid=32281793}}</ref> Aside from inaccuracy in labeling phytocannabinoid content, it has been reported that cannabis and derived products are often contaminated by microbes, heavy metals, pesticides, [[wikipedia:Carcinogen|carcinogens]], and debris, which must be addressed to ensure the safety of consumers (Table 1).<ref name="McPartlandContam17">{{cite book |chapter=Contaminants of Concern in Cannabis: Microbes, Heavy Metals and Pesticides |title=Cannabis sativa L. - Botany and Biotechnology |author=McPartland, J.M.; McKernan, K.J. |editor=Chandra, S.; Lata, H.; ElSohly, M.A. |publisher=Springer International Publishing |pages=457–74 |year=2017 |isbn=9783319545646 |doi=10.1007/978-3-319-54564-6}}</ref><ref name="DryburghCanna18">{{cite journal |title=Cannabis contaminants: Sources, distribution, human toxicity and pharmacologic effects |journal=British Journal of Clinical Pharmacology |author=Dryburgh, L.M.; Bolan, N.S.; Grof, C.P.L. et al. |volume=84 |issue=11 |pages=2468-2476 |year=2018 |doi=10.1111/bcp.13695 |pmid=29953631 |pmc=PMC6177718}}</ref>
[[wikipedia:Cannabinoid#Phytocannabinoids|Phytocannabinoids]] have garnered global attention recently due to the therapeutic potentials in Parkinson’s disease<ref name="ChagasEffects14">{{cite journal |title=Effects of cannabidiol in the treatment of patients with Parkinson's disease: an exploratory double-blind trial |journal=Journal of Psychopharmacology |author=Chagas, M.H.N.; Zuardi, A.W.; Tumas, V. et al. |volume=28 |issue=11 |pages=1088–98 |year=2014 |doi=10.1177/0269881114550355 |pmid=25237116}}</ref>, schizophrenia<ref name="McGuireCanna18">{{cite journal |title=Cannabidiol (CBD) as an Adjunctive Therapy in Schizophrenia: A Multicenter Randomized Controlled Trial |journal=American Journal of Psychiatry |author=McGuire, P.; Robson, P.; Cubala, W.J. et al. |volume=175 |issue=3 |pages=225–31 |year=2018 |doi=10.1176/appi.ajp.2017.17030325 |pmid=29241357}}</ref>, cancers<ref name="JeongCanna19">{{cite journal |title=Cannabidiol-induced apoptosis is mediated by activation of Noxa in human colorectal cancer cells |journal=Cancer Letters |author=Jeong, S.; Yun, H.K.; Jeong, Y.A. et al. |volume=447 |pages=12–23 |year=2019 |doi=10.1016/j.canlet.2019.01.011 |pmid=30660647}}</ref><ref name="ShafariPotent19">{{cite journal |title=Potential Use of Cannabinoids for the Treatment of Pancreatic Cancer |journal=Journal of Pancreatic Cancer |author=Sharafi, G.; He, H.; Nikfarjam, M. |volume=5 |issue=1 |pages=1–7 |year=2019 |doi=10.1089/pancan.2018.0019 |pmid=30706048 |pmc=PMC6352507}}</ref>, pain, anxiety, depression, and other neurological disorders<ref name="MarchettiRole13">{{cite journal |title=Role of calcium channels in heavy metal toxicity |journal=ISRN Toxicology |author=Marchetti, C. |volume=2013 |at=184360 |year=2013 |doi=10.1155/2013/184360 |pmid=23724297 |pmc=PMC3658387}}</ref>, as well as the [[Food and Drug Administration]] (FDA) approval of Epidiolex for Dravet syndrome<ref name="KaplanCanna17">{{cite journal |title=Cannabidiol attenuates seizures and social deficits in a mouse model of Dravet syndrome |journal=Proceedings of the National Academy of Sciences of the United States of America |author=Kaplan, J.S.; Stella, N.; Catterall, W.A. et al. |volume=114 |issue=42 |pages=11229–234 |year=2017 |doi=10.1073/pnas.1711351114 |pmid=28973916 |pmc=PMC5651774}}</ref> and Lennox-Gauss Syndrome.<ref name="PauliCanna20">{{cite journal |title=Cannabidiol Drugs Clinical Trial Outcomes and Adverse Effects |journal=Frontiers in Pharmacology |author=Pauli, C.S.; Conroy, M.; Heuvel, B.D.V.. et al. |volume=11 |at=63 |year=2020 |doi=10.3389/fphar.2020.00063 |pmid=32161538 |pmc=PMC7053164}}</ref> As of 2019, a total of 33 states, the District of Columbia, Guam, Puerto Rico, and the U.S Virgin Islands have approved [[wikipedia:Cannabis|cannabis]] for medicinal purposes, and 21 states are considering bills that would [[wikipedia:Legality of cannabis|decriminalize]] it under legislative action. With recent legalization in Canada in 2019, more countries are beginning to question the rationale behind criminalizing cannabis.<ref name="HabibiLegal18">{{cite journal |title=Legalizing cannabis violates the UN drug control treaties, but progressive countries like Canada have options |journal=Ottawa Law Review |author=Habibi, R.; Hoffman, S.J. |volume=49 |issue=2 |pages=427–60 |year=2018 |url=https://rdo-olr.org/en/2018/legalizing-cannabis-violates-the-un-drug-control-treaties-but-progressive-countries-like-canada-have-options/}}</ref> As interest in cannabis expands around the globe, many issues have arisen concerning the lack of [[wikipedia:Cannabis cultivation|cultivation]] standards and overall [[quality control]] of cannabis products. Recently the [[wikipedia:United States Pharmacopeia|United States Pharmacopeia]] (USP) formed a Cannabis Expert Panel, which has evaluated specifications necessary to define key cannabis quality attributes, including limits for [[wikipedia:Contamination|contaminants]] such as [[wikipedia:Pesticide|pesticide]] residues, microbial [[wikipedia:Pathogen|pathogen]] levels, [[wikipedia:Mycotoxin|mycotoxins]], and [[wikipedia:Heavy metals|elemental contaminants]], based on toxicological considerations and aligned with the existing USP procedures for general tests and assays.<ref name="SarmaCanna20">{{cite journal |title=Cannabis Inflorescence for Medical Purposes: USP Considerations for Quality Attributes |journal=Journal of Natural Products |author=Sarma, N.D.; Waye, A.; ElSholy, M.A. et al. |volume=83 |issue=4 |at=1334–51 |year=2020 |doi=10.1021/acs.jnatprod.9b01200 |pmid=32281793}}</ref> Aside from inaccuracy in labeling phytocannabinoid content, it has been reported that cannabis and derived products are often contaminated by microbes, heavy metals, pesticides, [[wikipedia:Carcinogen|carcinogens]], and debris, which must be addressed to ensure the safety of consumers (Table 1).<ref name="McPartlandContam17">{{cite book |chapter=Contaminants of Concern in Cannabis: Microbes, Heavy Metals and Pesticides |title=Cannabis sativa L. - Botany and Biotechnology |author=McPartland, J.M.; McKernan, K.J. |editor=Chandra, S.; Lata, H.; ElSohly, M.A. |publisher=Springer International Publishing |pages=457–74 |year=2017 |isbn=9783319545646 |doi=10.1007/978-3-319-54564-6}}</ref><ref name="DryburghCanna18">{{cite journal |title=Cannabis contaminants: Sources, distribution, human toxicity and pharmacologic effects |journal=British Journal of Clinical Pharmacology |author=Dryburgh, L.M.; Bolan, N.S.; Grof, C.P.L. et al. |volume=84 |issue=11 |pages=2468-2476 |year=2018 |doi=10.1111/bcp.13695 |pmid=29953631 |pmc=PMC6177718}}</ref>
[[File:Tab1 Montoya FrontPharm2020 11.jpg|1100px]]
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{| border="0" cellpadding="5" cellspacing="0" width="1100px"
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  | style="background-color:white; padding-left:10px; padding-right:10px;"| <blockquote>'''Table 1''' List of cannabis contaminants and sources, target/mechanism, and its respective risks to human health. GABA = γ-amino butyric acid.</blockquote>
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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.<ref name="RuchlemerInhaled15">{{cite journal |title=Inhaled medicinal cannabis and the immunocompromised patient |journal=Supportive Care in Cancer |author=Ruchlemer, R.; Amit-Kohn, M.; Raveh, D. et al. |volume=23 |issue=3 |pages=819-22 |year=2015 |doi=10.1007/s00520-014-2429-3 |pmid=25216851}}</ref> 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 [[wikipedia:Hemp|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 [[wikipedia:Cannabidiol|cannabidiol]] (CBD)-based products.
==Labeling inaccuracy==
Mislabeling of phytocannabinoid profiles in CBD products is one of the major concerns to consumers.<ref name="HazekampTheTrouble18">{{cite journal |title=The Trouble with CBD Oil |journal=Medical Cannabis and Cannabinoids |author=Hazekamp, A. |volume=1 |issue=1 |pages=65–72 |year=2018 |doi=10.1159/000489287}}</ref> Inaccurate reporting of the [[wikipedia:Cannabinoid|cannabinoid]] content risks exposing medicinal users to phytocannabinoids of which they have no intent to consume, namely [[wikipedia:Tetrahydrocannabinol|Δ-9-tetrahydracannabinol]] (THC).ref name="CorroonLabeling20">{{cite journal |title=Labeling of Cannabidiol Products: A Public Health Perspective |journal=Cannabis and Cannabinoid Research |author=Corroon, J.; MacKay, D.; Dolphin, W. |pages=1–5 |year=2020 |doi=10.1089/can.2019.0101}}</ref> This is of particular concern within pediatric patients, as THC intoxication has been shown to alter development of white matter in the brain<ref name="GruberWorth14">{{cite journal |title=Worth the wait: Effects of age of onset of marijuana use on white matter and impulsivity |journal=Psychopharmacology |author=Gruber, S.A.; Dahlgren, M.K.; Sagar, K.A. et al. |volume=231 |issue=8 |pages=1455-65 |year=2014 |doi=10.1007/s00213-013-3326-z |pmid=24190588 |pmc=PMC3967072}}</ref>, affect cognitive functioning<ref name="CreanAnEvid11">{{cite journal |title=An evidence based review of acute and long-term effects of cannabis use on executive cognitive functions |journal=Journal of Addiction Medicine |author=Crean, R.D.; Crane, N.A.; Mason, B.J. |volume=5 |issue=1 |pages=1–8 |year=2011 |doi=10.1097/ADM.0b013e31820c23fa |pmid=21321675 |pmc=PMC3037578}}</ref><ref name="ZamberlettiCortical15">{{cite journal |title=Cortical neuroinflammation contributes to long-term cognitive dysfunctions following adolescent delta-9-tetrahydrocannabinol treatment in female rats |journal=European Nueropsychopharmacology |author=Zamberletti, E.; Gabaglio, M.; Prini, P. et al. |volume=25 |issue=12 |pages=2404–15 |year=2015 |doi=10.1016/j.euroneuro.2015.09.021 |pmid=26499171}}</ref>, and affect learning and memory within adolescents.<ref name="WangPedia13">{{cite journal |title=Pediatric marijuana exposures in a medical marijuana state |journal=JAMA Pediatrics |author=Wang, G.S.; Roosevelt, G.; Heard, K. |volume=167 |issue=7 |pages=630–3 |year=2013 |doi=10.1001/jamapediatrics.2013.140 |pmid=23712626}}</ref>


==References==
==References==
Line 37: Line 55:


==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.
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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Revision as of 16:39, 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).ref name="CorroonLabeling20">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.  </ref> This is of particular concern within pediatric patients, as THC intoxication has been shown to alter development of white matter in the brain[14], affect cognitive functioning[15][16], and affect learning and memory within adolescents.[17]


References

  1. ↑ Chagas, M.H.N.; Zuardi, A.W.; Tumas, V. et al. (2014). "Effects of cannabidiol in the treatment of patients with Parkinson's disease: an exploratory double-blind trial". Journal of Psychopharmacology 28 (11): 1088–98. doi:10.1177/0269881114550355. PMID 25237116. 
  2. ↑ McGuire, P.; Robson, P.; Cubala, W.J. et al. (2018). "Cannabidiol (CBD) as an Adjunctive Therapy in Schizophrenia: A Multicenter Randomized Controlled Trial". American Journal of Psychiatry 175 (3): 225–31. doi:10.1176/appi.ajp.2017.17030325. PMID 29241357. 
  3. ↑ Jeong, S.; Yun, H.K.; Jeong, Y.A. et al. (2019). "Cannabidiol-induced apoptosis is mediated by activation of Noxa in human colorectal cancer cells". Cancer Letters 447: 12–23. doi:10.1016/j.canlet.2019.01.011. PMID 30660647. 
  4. ↑ Sharafi, G.; He, H.; Nikfarjam, M. (2019). "Potential Use of Cannabinoids for the Treatment of Pancreatic Cancer". Journal of Pancreatic Cancer 5 (1): 1–7. doi:10.1089/pancan.2018.0019. PMC PMC6352507. PMID 30706048. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6352507. 
  5. ↑ Marchetti, C. (2013). "Role of calcium channels in heavy metal toxicity". ISRN Toxicology 2013: 184360. doi:10.1155/2013/184360. PMC PMC3658387. PMID 23724297. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3658387. 
  6. ↑ Kaplan, J.S.; Stella, N.; Catterall, W.A. et al. (2017). "Cannabidiol attenuates seizures and social deficits in a mouse model of Dravet syndrome". Proceedings of the National Academy of Sciences of the United States of America 114 (42): 11229–234. doi:10.1073/pnas.1711351114. PMC PMC5651774. PMID 28973916. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5651774. 
  7. ↑ Pauli, C.S.; Conroy, M.; Heuvel, B.D.V.. et al. (2020). "Cannabidiol Drugs Clinical Trial Outcomes and Adverse Effects". Frontiers in Pharmacology 11: 63. doi:10.3389/fphar.2020.00063. PMC PMC7053164. PMID 32161538. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7053164. 
  8. ↑ Habibi, R.; Hoffman, S.J. (2018). "Legalizing cannabis violates the UN drug control treaties, but progressive countries like Canada have options". Ottawa Law Review 49 (2): 427–60. https://rdo-olr.org/en/2018/legalizing-cannabis-violates-the-un-drug-control-treaties-but-progressive-countries-like-canada-have-options/. 
  9. ↑ Sarma, N.D.; Waye, A.; ElSholy, M.A. et al. (2020). "Cannabis Inflorescence for Medical Purposes: USP Considerations for Quality Attributes". Journal of Natural Products 83 (4): 1334–51. doi:10.1021/acs.jnatprod.9b01200. PMID 32281793. 
  10. ↑ McPartland, J.M.; McKernan, K.J. (2017). "Contaminants of Concern in Cannabis: Microbes, Heavy Metals and Pesticides". In Chandra, S.; Lata, H.; ElSohly, M.A.. Cannabis sativa L. - Botany and Biotechnology. Springer International Publishing. pp. 457–74. doi:10.1007/978-3-319-54564-6. ISBN 9783319545646. 
  11. ↑ Dryburgh, L.M.; Bolan, N.S.; Grof, C.P.L. et al. (2018). "Cannabis contaminants: Sources, distribution, human toxicity and pharmacologic effects". British Journal of Clinical Pharmacology 84 (11): 2468-2476. doi:10.1111/bcp.13695. PMC PMC6177718. PMID 29953631. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6177718. 
  12. ↑ Ruchlemer, R.; Amit-Kohn, M.; Raveh, D. et al. (2015). "Inhaled medicinal cannabis and the immunocompromised patient". Supportive Care in Cancer 23 (3): 819-22. doi:10.1007/s00520-014-2429-3. PMID 25216851. 
  13. ↑ Hazekamp, A. (2018). "The Trouble with CBD Oil". Medical Cannabis and Cannabinoids 1 (1): 65–72. doi:10.1159/000489287. 
  14. ↑ Gruber, S.A.; Dahlgren, M.K.; Sagar, K.A. et al. (2014). "Worth the wait: Effects of age of onset of marijuana use on white matter and impulsivity". Psychopharmacology 231 (8): 1455-65. doi:10.1007/s00213-013-3326-z. PMC PMC3967072. PMID 24190588. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3967072. 
  15. ↑ Crean, R.D.; Crane, N.A.; Mason, B.J. (2011). "An evidence based review of acute and long-term effects of cannabis use on executive cognitive functions". Journal of Addiction Medicine 5 (1): 1–8. doi:10.1097/ADM.0b013e31820c23fa. PMC PMC3037578. PMID 21321675. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3037578. 
  16. ↑ 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. 
  17. ↑ 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. 

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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