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Trends and Characteristics of Manufactured Cannabis Product and Cannabis Plant Product Exposures Reported to US Poison Control Centers, 2017-2019

Trends and Characteristics of Manufactured Cannabis Product and Cannabis Plant Product Exposures... Research Letter | Substance Use and Addiction Trends and Characteristics of Manufactured Cannabis Product and Cannabis Plant Product Exposures Reported to US Poison Control Centers, 2017-2019 Julia A. Dilley, PhD; Janessa M. Graves, PhD; Ashley Brooks-Russell, PhD; Jennifer M. Whitehill, PhD; Erica L. Liebelt, MD Introduction Supplemental content Author affiliations and article information are Legalization of adult use cannabis products has led to a consumer-driven marketplace. A growing listed at the end of this article. share of retail cannabis sales are manufactured cannabis products, which may contain higher levels of tetrahydrocannabinol (THC) than unprocessed cannabis plant materials, resulting in greater short-term effects (eg, cognitive and psychomotor impairment). Public health concerns are emerging about these risks. Our study objective was to assess recent patterns in reports of cannabis-related exposures by product type. Methods For this cross-sectional study, we accessed National Poison Data System data on cannabis exposures reported to US poison centers for January 2017 through December 2019. Cannabis product type codes were added to the system in 2016. We compared trends and characteristics of exposures for manufactured products that require processing of plant materials (eg, concentrates, edibles, vaporized liquids) and unprocessed plant materials (eg, flower) (eMethods in the Supplement). Two-sided P values <.05 were considered statistically significant. This study followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline for cross-sectional studies. The institutional review board at Washington State University determined this study was exempt from review because it used deidentified data. Results Among the total 28 630 exposures, plant materials were the most commonly involved (18 763 exposures [65.5%]), followed by edibles (5537 [19.3%]), concentrates (2734 [9.6%]), vaporized liquids (1075 [3.8%]), and other manufactured products (521 [1.8%]) (Table). Manufactured product exposure cases more often involved children: 2505 cases (27.0%) involved patients under 10 years old, compared with 1490 plant-based exposures (8.4%). Exposures to edibles had the greatest proportion of children (1905 exposures [36.6%]). More than half of all calls were made from a health care facility; manufactured product calls came from a residence nearly twice as often as plant-based exposure calls (3927 [39.8%] vs 3817 [20.3%]; P < .001). Most manufactured cannabis product exposures were for those products alone (8040 exposures [81.5%]). In contrast, most plant exposures (11 556 [61.6%]) also involved other agents (eg, alcohol, other drugs). Among exposures where only cannabis was involved, a slightly smaller percentage of manufactured product exposures overall (2918 [36.3%]) were associated with serious medical outcomes compared with plant-based exposures (2803 [38.9%]). Vaporized liquid exposures were most likely to have serious medical outcomes (268 [42.3%]). During 2019, population-based rates for manufactured cannabis product exposures overall and for most specific products were greater where adult cannabis use was legal. One exception was vaping: exposure calls per 100 000 population were 0.29 in nonlegal states (692 total exposures) and 0.21 in legal states (195 total exposures). Open Access. This is an open access article distributed under the terms of the CC-BY License. JAMA Network Open. 2021;4(5):e2110925. doi:10.1001/jamanetworkopen.2021.10925 (Reprinted) May 24, 2021 1/4 JAMA Network Open | Substance Use and Addiction Trends in Cannabis Product Exposures Reported to US Poison Control Centers Table. Characteristics of Cannabis-Related Exposures Reported to US Poison Centers by Cannabis Product Type, January 2017 to December 2019 Exposures, No. (%) Specific manufactured products General product categories Concentrates Vaporized liquids Edibles Other Total manufactured Plant materials Characteristic (n = 2734) (n = 1075) (n = 5537) (n = 521) (n = 9867) (n = 18 763) P value Total 2017 275 (10.1) 33 (3.1) 697 (12.6) 89 (17.1) 1094 (11.1) 7146 (38.1) <.001 2018 1002 (36.7) 151 (14.1) 1943 (35.1) 174 (33.4) 3270 (33.1) 6011 (32.0) 2019 1457 (53.3) 891 (82.9) 2897 (52.3) 258 (49.5) 5503 (55.8) 5606 (29.9) Age group Children (<10 y) 423 (16.6) 77 (7.5) 1905 (36.6) 100 (20.3) 2505 (27.0) 1490 (8.4) <.001 Youth (10-20 y) 999 (39.1) 551 (53.6) 1561 (30.0) 95 (19.3) 3206 (34.5) 7.369 (41.3) Adults (≥21 y) 1134 (44.4) 400 (38.9) 1746 (33.5) 297 (60.4) 3577 (38.5) 8.984 (50.4) Caller site Health care facility 1375 (50.3) 644 (59.9) 2676 (48.3) 248 (47.6) 4943 (50.1) 13 624 (72.6) Residence 1100 (40.2) 373 (34.7) 2230 (40.3) 224 (43.0) 3927 (39.8) 3817 (20.3) <.001 Other 243 (8.9) 52 (4.8) 570 (10.3) 47 (9.0) 912 (9.2) 1206 (6.4) Unknown 16 (0.6) 6 (0.6) 61 (1.1) 2 (0.4) 85 (0.9) 115 (0.6) Coingestants Cannabis only 2138 (78.2) 633 (58.9) 4898 (88.5) 371 (71.2) 8040 (81.5) 7207 (38.4) <.001 Polysubstances 596 (21.8) 442 (41.1) 639 (11.5) 150 (28.8) 1827 (18.5) 11 556 (61.6) Medical outcome Minor or less 1369 (64.0) 365 (57.7) 3114 (63.6) 274 (73.9) 5122 (63.7) 4404 (61.1) Moderate or greater 769 (36.0) 268 (42.3) 1784 (36.4) 97 (26.2) 2918 (36.3) 2803 (38.9) Legal status of state (2019 exposures only) Not legal 946 (65.4) 692 (78.0) 1328 (46.5) 153 (59.3) 3119 (57.3) 3806 (68.7) <.001 Rate per 100 000 0.40 0.29 0.56 0.07 1.33 1.62 Adult use legal 501 (34.6) 195 (22.0) 1528 (53.5) 105 (40.7) 2329 (42.8) 1735 (31.3) Rate per 100 000 0.54 0.21 1.64 0.11 2.50 1.86 Quarterly slope coefficients 35.2 (22.5 to 27.8 (13.1 to 67.8 (58.8 to 4.7 (1.7 to 33.9 (17.7 to −45.3 (−67.1 to <.001 (95% CI) 47.8) 42.4) 76.8) 7.7) 50.0) −23.6) a c Excludes cases with coingestants (ie, only includes cannabis exposures alone). Quarterly slope coefficients are from a linear regression of counts per quarter. b d States with legal adult use in 2019 included: Alaska, California, Colorado, Illinois, P value is for an interaction term between time and manufactured products group Massachusetts, Maine, Michigan, Nevada, Oregon, Vermont, Washington State, and in a difference-in-difference model. Washington, DC. Figure. Quarterly Number of Cannabis-Related Poison Center Calls by Product Type, January 2017 to December 2019 Product type Total cannabis exposures Other Plant Edibles 1000 materials Vaporized liquid Manufactured products Concentrates 2017 Q1 2017 Q2 2017 Q3 2017 Q4 2018 Q1 2018 Q2 2018 Q3 2018 Q4 2019 Q1 2019 Q2 2019 Q3 2019 Q4 JAMA Network Open. 2021;4(5):e2110925. doi:10.1001/jamanetworkopen.2021.10925 (Reprinted) May 24, 2021 2/4 Cases per quarter, No. JAMA Network Open | Substance Use and Addiction Trends in Cannabis Product Exposures Reported to US Poison Control Centers Total cannabis exposures increased between 2017 and 2019. However, quarterly plant-related exposure reports declined over time, while manufactured product exposure reports increased overall and for each specific product (Figure). Discussion Our findings document that US poison centers are increasingly receiving calls about adverse events associated with exposures to manufactured cannabis products. Higher rates in legal states suggest that continued increases may be expected with adult cannabis use legalization in more states. Children may be at particular risk for exposure to edible products, such as cookies or candy. Although we did not see more serious health outcomes for manufactured product exposures compared with plant products overall, most cannabis plant exposures involved polysubstance use, whereas most cases for manufactured products were for those products alone, suggesting that exposure to manufactured products alone may be relatively more likely to generate adverse events. This is consistent with studies of acute health effects. Manufactured products may present risks both because of THC levels and other processing ingredients. For example, vaporized liquid additive ingredients were implicated in a 2019 national lung injury (e-cigarette or vaping use–associated lung injury [EVALI]) outbreak. Market factors may drive the industry to continue developing novel products, which could present additional health risks. Applying regulatory controls to market-driven innovations in potency and additives is key. Novice cannabis users are often advised to “start low, go slow”; this guidance may be equally applicable to regulating new retail cannabis markets and products. This study was limited by its data source. Poison centers provide useful information about specific product exposures and medical outcomes; however, data are self-reported and may underestimate the burden of cases. Ongoing monitoring of manufactured product–specific adverse events is recommended to understand public health concerns and effectiveness of regulations or harm reduction messaging. ARTICLE INFORMATION Accepted for Publication: March 30, 2021. Published: May 24, 2021. doi:10.1001/jamanetworkopen.2021.10925 Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2021 Dilley JA et al. JAMA Network Open. Corresponding Author: Julia A. Dilley, PhD, Program Design and Evaluation Services, Public Health Division, Oregon Health Authority, 800 NE Oregon St, Ste 260, Portland, OR 97232 (julia.dilley@multco.us). Author Affiliations: Oregon Public Health Division, Portland, Oregon (Dilley); Washington State University, Spokane (Graves); University of Colorado Anschutz Medical Campus, Aurora (Brooks-Russell); University of Massachusetts Amherst, Amherst (Whitehill); Washington Poison Center, Seattle, Washington (Liebelt); Now at Department of Pediatrics, Section of Pediatric Emergency Medicine, Pharmacology & Toxicology, College of Medicine, University of Arkansas for Medical Sciences, Little Rock (Liebelt). Author Contributions: Dr Dilley had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Concept and design: Dilley, Graves, Brooks-Russell, Whitehill. Acquisition, analysis, or interpretation of data: Dilley, Graves, Whitehill, Liebelt. Drafting of the manuscript: Dilley. Critical revision of the manuscript for important intellectual content: All authors. Statistical analysis: Dilley. Obtained funding: Graves. Administrative, technical, or material support: Dilley, Graves, Liebelt. Supervision: Graves, Liebelt. JAMA Network Open. 2021;4(5):e2110925. doi:10.1001/jamanetworkopen.2021.10925 (Reprinted) May 24, 2021 3/4 JAMA Network Open | Substance Use and Addiction Trends in Cannabis Product Exposures Reported to US Poison Control Centers Conflict of Interest Disclosures: Dr Graves reported receiving grants from the Alcohol and Drug Abuse Research Program at Washington State University; she reported serving on the board of directors for the Washington Poison Center outside the submitted work. Dr Whitehill reported receiving consulting fees from Washington State University during the conduct of the study. Dr Liebelt reported receiving consulting fees from Washington State University during the conduct of the study and a grant given her organization (Washington Poison Center) from Verdant Health Commission to develop curriculum and education on harmful effects of cannabis. No other disclosures were reported. Funding/Support: This investigation was supported in part by funds provided for medical and biological research by the State of Washington (initiative measure No 171). Support for Dr Dilley was provided in part by the National Institute on Drug Abuse of the National Institutes of Health (award No 1R01DA039293). Role of the Funder/Sponsor: The funder had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. REFERENCES 1. Firth CL, Davenport S, Smart R, Dilley JA. How high: differences in the developments of cannabis markets in two legalized states. Int J Drug Policy. 2020;75:102611. doi:10.1016/j.drugpo.2019.102611 2. Smart R, Caulkins JP, Kilmer B, Davenport S, Midgette G. Variation in cannabis potency and prices in a newly legal market: evidence from 30 million cannabis sales in Washington state. Addiction. 2017;112(12):2167-2177. doi: 10.1111/add.13886 3. Spindle TR, Cone EJ, Schlienz NJ, et al. Acute effects of smoked and vaporized cannabis in healthy adults who infrequently use cannabis: a crossover trial. JAMA Netw Open. 2018;1(7):e184841. doi:10.1001/jamanetworkopen. 2018.4841 4. Matheson, J, Le Foll B. Cannabis legalization and acute harm from high potency cannabis products: a narrative review and recommendations for public health. Front Psychiatry. 2020;11:591979. doi:10.3389/fpsyt. 2020.591979 5. Krishnasamy VP, Hallowell BD, Ko JY, et al; Lung Injury Response Epidemiology/Surveillance Task Force. Update: characteristics of a nationwide outbreak of e-cigarette, or vaping, product use-associated lung injury—United States, August 2019-January 2020. MMWR Morb Mortal Wkly Rep. 2020;69(3):90-94. doi:10.15585/mmwr. mm6903e2 6. US Census. 2019 national and state population estimates—population for non-legal states. Updated December 30, 2019. Accessed April 9, 2021. https://www.census.gov/newsroom/press-kits/2019/national-state- estimates.html SUPPLEMENT. eMethods. JAMA Network Open. 2021;4(5):e2110925. doi:10.1001/jamanetworkopen.2021.10925 (Reprinted) May 24, 2021 4/4 Supplemental Online Content Dilley JA, Graves JM, Brooks-Russell A, Whitehill JM, Liebelt EL. Trends and characteristics of manufactured cannabis product and cannabis plant product exposures reported to US poison control centers, 2017-2019. JAMA Netw Open. 2021;4(5):e2110925. doi:10.1001/jamanetworkopen.2021.10925 eMethods. This supplemental material has been provided by the authors to give readers additional information about their work. © 2021 Dilley JA et al. JAMA Network Open. eMethods. Case definitions and exclusions. Cannabis-related exposures were identified from the National Poison Data System (NPDS) using the following generic codes (i.e., codes with no reported manufacturer): “plant materials” include dried plant 0083000 (n=18,437) and undried plant (0310123, n=326); “manufactured products” include concentrates (0310124, n=2,734), vape liquids (vaporizer liquid/unknown if flavored 0310096 [n=779], vaporizer liquid with flavoring 0310034 [n=42], vaporizer liquor without flavoring 0310033 [n=38], marijuana liquid flavor unknown 0310097 [n=160], marijuana liquid with flavor 0310036 [n=32], marijuana liquid without flavor 0310035 [n=24]), edibles (0310121, n=5,537), and other cannabis products (capsule/pill 0310122 [n=139], pharmaceutical 0200618 [n=321], topical 0310125 [n=61]). We excluded codes for cannabidiol (CBD, 0310146, n=1,139), unknown preparation (0310126, n=2,421), and synthetic cannabinoids (0200617, n=5,117). We also excluded duplicated exposures (i.e., if more than one cannabis type involved the second product exposure was dropped, n=221), and exposures with final Medical Outcomes of “Confirmed nonexposure” (n=64) or "Unrelated effect, the exposure was probably not responsible for the effect(s)" (n=839). Analyses. We examined patterns of cannabis-related exposures for specific types of manufactured cannabis products, for all manufactured cannabis products combined, and for plant-based cannabis products. We used descriptive statistics to assess patterns by year, age of person exposed, location that the exposure was reported from, and whether other substances than cannabis were involved in the exposure. © 2021 Dilley JA et al. JAMA Network Open. We characterized the final Medical Outcome for cases with no coingestants (i.e., cannabis exposures alone) in order to isolate effects of cannabis products. We characterized the following NPDS-assigned outcomes as “Moderate or greater”: Moderate; Major; Death; and Unable to follow, judged as a potentially toxic exposure. Effects of this level would usually require some form of medical treatment. “Minor or less” outcomes included: minor effect; no effect; not followed, judged as nontoxic exposure (clinical effects not expected); and not followed, minimal clinical effects possible (no more than minor effect possible). For 2019, we compared the combined number of cases in states with legal adult cannabis use to cases in states that had not legalized adult use (this included states with legal medical cannabis). One of the states characterized as legal (Illinois) passed legalization mid-year by legislation, but no other state made substantive changes to their cannabis legalization status during this year. We excluded 126 exposures from the state analysis because state was unknown (n=34) or refused to give (n=35), or exposure occurred outside of states and D.C. For descriptive purposes, cases were also reported as rates per 100,000 population, using 2019 U.S. state population estimates. We used chi-squared tests to assess associations between manufactured cannabis products combined or plant-based cannabis exposures and exposure characteristics. We used linear regression to evaluate trends in exposure counts per quarter, and a difference-in-differences model approach to formally test for differences between slopes for manufactured and plant-based cannabis products. All statistical analyses were conducted with Stata version 14.1 (StataCorp LP, College Station, TX) using the .05 level of significance. © 2021 Dilley JA et al. JAMA Network Open. U.S. Census. Accessed at https://www.census.gov/newsroom/press-kits/2019/national-state- estimates.html NST-EST2019-01, Table 1: population for non-legal states =235,099,102; population for legal states and Washington DC =93,140,421. © 2021 Dilley JA et al. JAMA Network Open. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png JAMA Network Open American Medical Association

Trends and Characteristics of Manufactured Cannabis Product and Cannabis Plant Product Exposures Reported to US Poison Control Centers, 2017-2019

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Research Letter | Substance Use and Addiction Trends and Characteristics of Manufactured Cannabis Product and Cannabis Plant Product Exposures Reported to US Poison Control Centers, 2017-2019 Julia A. Dilley, PhD; Janessa M. Graves, PhD; Ashley Brooks-Russell, PhD; Jennifer M. Whitehill, PhD; Erica L. Liebelt, MD Introduction Supplemental content Author affiliations and article information are Legalization of adult use cannabis products has led to a consumer-driven marketplace. A growing listed at the end of this article. share of retail cannabis sales are manufactured cannabis products, which may contain higher levels of tetrahydrocannabinol (THC) than unprocessed cannabis plant materials, resulting in greater short-term effects (eg, cognitive and psychomotor impairment). Public health concerns are emerging about these risks. Our study objective was to assess recent patterns in reports of cannabis-related exposures by product type. Methods For this cross-sectional study, we accessed National Poison Data System data on cannabis exposures reported to US poison centers for January 2017 through December 2019. Cannabis product type codes were added to the system in 2016. We compared trends and characteristics of exposures for manufactured products that require processing of plant materials (eg, concentrates, edibles, vaporized liquids) and unprocessed plant materials (eg, flower) (eMethods in the Supplement). Two-sided P values <.05 were considered statistically significant. This study followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline for cross-sectional studies. The institutional review board at Washington State University determined this study was exempt from review because it used deidentified data. Results Among the total 28 630 exposures, plant materials were the most commonly involved (18 763 exposures [65.5%]), followed by edibles (5537 [19.3%]), concentrates (2734 [9.6%]), vaporized liquids (1075 [3.8%]), and other manufactured products (521 [1.8%]) (Table). Manufactured product exposure cases more often involved children: 2505 cases (27.0%) involved patients under 10 years old, compared with 1490 plant-based exposures (8.4%). Exposures to edibles had the greatest proportion of children (1905 exposures [36.6%]). More than half of all calls were made from a health care facility; manufactured product calls came from a residence nearly twice as often as plant-based exposure calls (3927 [39.8%] vs 3817 [20.3%]; P < .001). Most manufactured cannabis product exposures were for those products alone (8040 exposures [81.5%]). In contrast, most plant exposures (11 556 [61.6%]) also involved other agents (eg, alcohol, other drugs). Among exposures where only cannabis was involved, a slightly smaller percentage of manufactured product exposures overall (2918 [36.3%]) were associated with serious medical outcomes compared with plant-based exposures (2803 [38.9%]). Vaporized liquid exposures were most likely to have serious medical outcomes (268 [42.3%]). During 2019, population-based rates for manufactured cannabis product exposures overall and for most specific products were greater where adult cannabis use was legal. One exception was vaping: exposure calls per 100 000 population were 0.29 in nonlegal states (692 total exposures) and 0.21 in legal states (195 total exposures). Open Access. This is an open access article distributed under the terms of the CC-BY License. JAMA Network Open. 2021;4(5):e2110925. doi:10.1001/jamanetworkopen.2021.10925 (Reprinted) May 24, 2021 1/4 JAMA Network Open | Substance Use and Addiction Trends in Cannabis Product Exposures Reported to US Poison Control Centers Table. Characteristics of Cannabis-Related Exposures Reported to US Poison Centers by Cannabis Product Type, January 2017 to December 2019 Exposures, No. (%) Specific manufactured products General product categories Concentrates Vaporized liquids Edibles Other Total manufactured Plant materials Characteristic (n = 2734) (n = 1075) (n = 5537) (n = 521) (n = 9867) (n = 18 763) P value Total 2017 275 (10.1) 33 (3.1) 697 (12.6) 89 (17.1) 1094 (11.1) 7146 (38.1) <.001 2018 1002 (36.7) 151 (14.1) 1943 (35.1) 174 (33.4) 3270 (33.1) 6011 (32.0) 2019 1457 (53.3) 891 (82.9) 2897 (52.3) 258 (49.5) 5503 (55.8) 5606 (29.9) Age group Children (<10 y) 423 (16.6) 77 (7.5) 1905 (36.6) 100 (20.3) 2505 (27.0) 1490 (8.4) <.001 Youth (10-20 y) 999 (39.1) 551 (53.6) 1561 (30.0) 95 (19.3) 3206 (34.5) 7.369 (41.3) Adults (≥21 y) 1134 (44.4) 400 (38.9) 1746 (33.5) 297 (60.4) 3577 (38.5) 8.984 (50.4) Caller site Health care facility 1375 (50.3) 644 (59.9) 2676 (48.3) 248 (47.6) 4943 (50.1) 13 624 (72.6) Residence 1100 (40.2) 373 (34.7) 2230 (40.3) 224 (43.0) 3927 (39.8) 3817 (20.3) <.001 Other 243 (8.9) 52 (4.8) 570 (10.3) 47 (9.0) 912 (9.2) 1206 (6.4) Unknown 16 (0.6) 6 (0.6) 61 (1.1) 2 (0.4) 85 (0.9) 115 (0.6) Coingestants Cannabis only 2138 (78.2) 633 (58.9) 4898 (88.5) 371 (71.2) 8040 (81.5) 7207 (38.4) <.001 Polysubstances 596 (21.8) 442 (41.1) 639 (11.5) 150 (28.8) 1827 (18.5) 11 556 (61.6) Medical outcome Minor or less 1369 (64.0) 365 (57.7) 3114 (63.6) 274 (73.9) 5122 (63.7) 4404 (61.1) Moderate or greater 769 (36.0) 268 (42.3) 1784 (36.4) 97 (26.2) 2918 (36.3) 2803 (38.9) Legal status of state (2019 exposures only) Not legal 946 (65.4) 692 (78.0) 1328 (46.5) 153 (59.3) 3119 (57.3) 3806 (68.7) <.001 Rate per 100 000 0.40 0.29 0.56 0.07 1.33 1.62 Adult use legal 501 (34.6) 195 (22.0) 1528 (53.5) 105 (40.7) 2329 (42.8) 1735 (31.3) Rate per 100 000 0.54 0.21 1.64 0.11 2.50 1.86 Quarterly slope coefficients 35.2 (22.5 to 27.8 (13.1 to 67.8 (58.8 to 4.7 (1.7 to 33.9 (17.7 to −45.3 (−67.1 to <.001 (95% CI) 47.8) 42.4) 76.8) 7.7) 50.0) −23.6) a c Excludes cases with coingestants (ie, only includes cannabis exposures alone). Quarterly slope coefficients are from a linear regression of counts per quarter. b d States with legal adult use in 2019 included: Alaska, California, Colorado, Illinois, P value is for an interaction term between time and manufactured products group Massachusetts, Maine, Michigan, Nevada, Oregon, Vermont, Washington State, and in a difference-in-difference model. Washington, DC. Figure. Quarterly Number of Cannabis-Related Poison Center Calls by Product Type, January 2017 to December 2019 Product type Total cannabis exposures Other Plant Edibles 1000 materials Vaporized liquid Manufactured products Concentrates 2017 Q1 2017 Q2 2017 Q3 2017 Q4 2018 Q1 2018 Q2 2018 Q3 2018 Q4 2019 Q1 2019 Q2 2019 Q3 2019 Q4 JAMA Network Open. 2021;4(5):e2110925. doi:10.1001/jamanetworkopen.2021.10925 (Reprinted) May 24, 2021 2/4 Cases per quarter, No. JAMA Network Open | Substance Use and Addiction Trends in Cannabis Product Exposures Reported to US Poison Control Centers Total cannabis exposures increased between 2017 and 2019. However, quarterly plant-related exposure reports declined over time, while manufactured product exposure reports increased overall and for each specific product (Figure). Discussion Our findings document that US poison centers are increasingly receiving calls about adverse events associated with exposures to manufactured cannabis products. Higher rates in legal states suggest that continued increases may be expected with adult cannabis use legalization in more states. Children may be at particular risk for exposure to edible products, such as cookies or candy. Although we did not see more serious health outcomes for manufactured product exposures compared with plant products overall, most cannabis plant exposures involved polysubstance use, whereas most cases for manufactured products were for those products alone, suggesting that exposure to manufactured products alone may be relatively more likely to generate adverse events. This is consistent with studies of acute health effects. Manufactured products may present risks both because of THC levels and other processing ingredients. For example, vaporized liquid additive ingredients were implicated in a 2019 national lung injury (e-cigarette or vaping use–associated lung injury [EVALI]) outbreak. Market factors may drive the industry to continue developing novel products, which could present additional health risks. Applying regulatory controls to market-driven innovations in potency and additives is key. Novice cannabis users are often advised to “start low, go slow”; this guidance may be equally applicable to regulating new retail cannabis markets and products. This study was limited by its data source. Poison centers provide useful information about specific product exposures and medical outcomes; however, data are self-reported and may underestimate the burden of cases. Ongoing monitoring of manufactured product–specific adverse events is recommended to understand public health concerns and effectiveness of regulations or harm reduction messaging. ARTICLE INFORMATION Accepted for Publication: March 30, 2021. Published: May 24, 2021. doi:10.1001/jamanetworkopen.2021.10925 Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2021 Dilley JA et al. JAMA Network Open. Corresponding Author: Julia A. Dilley, PhD, Program Design and Evaluation Services, Public Health Division, Oregon Health Authority, 800 NE Oregon St, Ste 260, Portland, OR 97232 (julia.dilley@multco.us). Author Affiliations: Oregon Public Health Division, Portland, Oregon (Dilley); Washington State University, Spokane (Graves); University of Colorado Anschutz Medical Campus, Aurora (Brooks-Russell); University of Massachusetts Amherst, Amherst (Whitehill); Washington Poison Center, Seattle, Washington (Liebelt); Now at Department of Pediatrics, Section of Pediatric Emergency Medicine, Pharmacology & Toxicology, College of Medicine, University of Arkansas for Medical Sciences, Little Rock (Liebelt). Author Contributions: Dr Dilley had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Concept and design: Dilley, Graves, Brooks-Russell, Whitehill. Acquisition, analysis, or interpretation of data: Dilley, Graves, Whitehill, Liebelt. Drafting of the manuscript: Dilley. Critical revision of the manuscript for important intellectual content: All authors. Statistical analysis: Dilley. Obtained funding: Graves. Administrative, technical, or material support: Dilley, Graves, Liebelt. Supervision: Graves, Liebelt. JAMA Network Open. 2021;4(5):e2110925. doi:10.1001/jamanetworkopen.2021.10925 (Reprinted) May 24, 2021 3/4 JAMA Network Open | Substance Use and Addiction Trends in Cannabis Product Exposures Reported to US Poison Control Centers Conflict of Interest Disclosures: Dr Graves reported receiving grants from the Alcohol and Drug Abuse Research Program at Washington State University; she reported serving on the board of directors for the Washington Poison Center outside the submitted work. Dr Whitehill reported receiving consulting fees from Washington State University during the conduct of the study. Dr Liebelt reported receiving consulting fees from Washington State University during the conduct of the study and a grant given her organization (Washington Poison Center) from Verdant Health Commission to develop curriculum and education on harmful effects of cannabis. No other disclosures were reported. Funding/Support: This investigation was supported in part by funds provided for medical and biological research by the State of Washington (initiative measure No 171). Support for Dr Dilley was provided in part by the National Institute on Drug Abuse of the National Institutes of Health (award No 1R01DA039293). Role of the Funder/Sponsor: The funder had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. REFERENCES 1. Firth CL, Davenport S, Smart R, Dilley JA. How high: differences in the developments of cannabis markets in two legalized states. Int J Drug Policy. 2020;75:102611. doi:10.1016/j.drugpo.2019.102611 2. Smart R, Caulkins JP, Kilmer B, Davenport S, Midgette G. Variation in cannabis potency and prices in a newly legal market: evidence from 30 million cannabis sales in Washington state. Addiction. 2017;112(12):2167-2177. doi: 10.1111/add.13886 3. Spindle TR, Cone EJ, Schlienz NJ, et al. Acute effects of smoked and vaporized cannabis in healthy adults who infrequently use cannabis: a crossover trial. JAMA Netw Open. 2018;1(7):e184841. doi:10.1001/jamanetworkopen. 2018.4841 4. Matheson, J, Le Foll B. Cannabis legalization and acute harm from high potency cannabis products: a narrative review and recommendations for public health. Front Psychiatry. 2020;11:591979. doi:10.3389/fpsyt. 2020.591979 5. Krishnasamy VP, Hallowell BD, Ko JY, et al; Lung Injury Response Epidemiology/Surveillance Task Force. Update: characteristics of a nationwide outbreak of e-cigarette, or vaping, product use-associated lung injury—United States, August 2019-January 2020. MMWR Morb Mortal Wkly Rep. 2020;69(3):90-94. doi:10.15585/mmwr. mm6903e2 6. US Census. 2019 national and state population estimates—population for non-legal states. Updated December 30, 2019. Accessed April 9, 2021. https://www.census.gov/newsroom/press-kits/2019/national-state- estimates.html SUPPLEMENT. eMethods. JAMA Network Open. 2021;4(5):e2110925. doi:10.1001/jamanetworkopen.2021.10925 (Reprinted) May 24, 2021 4/4 Supplemental Online Content Dilley JA, Graves JM, Brooks-Russell A, Whitehill JM, Liebelt EL. Trends and characteristics of manufactured cannabis product and cannabis plant product exposures reported to US poison control centers, 2017-2019. JAMA Netw Open. 2021;4(5):e2110925. doi:10.1001/jamanetworkopen.2021.10925 eMethods. This supplemental material has been provided by the authors to give readers additional information about their work. © 2021 Dilley JA et al. JAMA Network Open. eMethods. Case definitions and exclusions. Cannabis-related exposures were identified from the National Poison Data System (NPDS) using the following generic codes (i.e., codes with no reported manufacturer): “plant materials” include dried plant 0083000 (n=18,437) and undried plant (0310123, n=326); “manufactured products” include concentrates (0310124, n=2,734), vape liquids (vaporizer liquid/unknown if flavored 0310096 [n=779], vaporizer liquid with flavoring 0310034 [n=42], vaporizer liquor without flavoring 0310033 [n=38], marijuana liquid flavor unknown 0310097 [n=160], marijuana liquid with flavor 0310036 [n=32], marijuana liquid without flavor 0310035 [n=24]), edibles (0310121, n=5,537), and other cannabis products (capsule/pill 0310122 [n=139], pharmaceutical 0200618 [n=321], topical 0310125 [n=61]). We excluded codes for cannabidiol (CBD, 0310146, n=1,139), unknown preparation (0310126, n=2,421), and synthetic cannabinoids (0200617, n=5,117). We also excluded duplicated exposures (i.e., if more than one cannabis type involved the second product exposure was dropped, n=221), and exposures with final Medical Outcomes of “Confirmed nonexposure” (n=64) or "Unrelated effect, the exposure was probably not responsible for the effect(s)" (n=839). Analyses. We examined patterns of cannabis-related exposures for specific types of manufactured cannabis products, for all manufactured cannabis products combined, and for plant-based cannabis products. We used descriptive statistics to assess patterns by year, age of person exposed, location that the exposure was reported from, and whether other substances than cannabis were involved in the exposure. © 2021 Dilley JA et al. JAMA Network Open. We characterized the final Medical Outcome for cases with no coingestants (i.e., cannabis exposures alone) in order to isolate effects of cannabis products. We characterized the following NPDS-assigned outcomes as “Moderate or greater”: Moderate; Major; Death; and Unable to follow, judged as a potentially toxic exposure. Effects of this level would usually require some form of medical treatment. “Minor or less” outcomes included: minor effect; no effect; not followed, judged as nontoxic exposure (clinical effects not expected); and not followed, minimal clinical effects possible (no more than minor effect possible). For 2019, we compared the combined number of cases in states with legal adult cannabis use to cases in states that had not legalized adult use (this included states with legal medical cannabis). One of the states characterized as legal (Illinois) passed legalization mid-year by legislation, but no other state made substantive changes to their cannabis legalization status during this year. We excluded 126 exposures from the state analysis because state was unknown (n=34) or refused to give (n=35), or exposure occurred outside of states and D.C. For descriptive purposes, cases were also reported as rates per 100,000 population, using 2019 U.S. state population estimates. We used chi-squared tests to assess associations between manufactured cannabis products combined or plant-based cannabis exposures and exposure characteristics. We used linear regression to evaluate trends in exposure counts per quarter, and a difference-in-differences model approach to formally test for differences between slopes for manufactured and plant-based cannabis products. All statistical analyses were conducted with Stata version 14.1 (StataCorp LP, College Station, TX) using the .05 level of significance. © 2021 Dilley JA et al. JAMA Network Open. U.S. Census. Accessed at https://www.census.gov/newsroom/press-kits/2019/national-state- estimates.html NST-EST2019-01, Table 1: population for non-legal states =235,099,102; population for legal states and Washington DC =93,140,421. © 2021 Dilley JA et al. JAMA Network Open.

Journal

JAMA Network Open – American Medical Association

Published: May 24, 2021

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