Tobacco and cannabis co-use : toxicity, dependence and cessation management.

Volume 7, Issue 2, April 2023     |     PP. 25-45      |     PDF (232 K)    |     Pub. Date: November 13, 2023
DOI: 10.54647/pmh330309    74 Downloads     112893 Views  

Author(s)

Jean PERRIOT M.D., Dispensaire Emile Roux ; Centre de lutte contre la tuberculose et d’aide à l’arrêt du tabac. Université Clermont Auvergne, 63100 Clermont-Ferrand, France.
Michel UNDERNER M.D., Centre Henri Laborit ; Unité de recherche clinique. Université de Poitiers, F - 86021 Poitiers, France.
Elsa CHAPOT M.D., Dispensaire Emile Roux ; Centre de lutte contre la tuberculose et d’aide à l’arrêt du tabac. Université Clermont Auvergne, 63100 Clermont-Ferrand, France.
Gérard PEIFFER M.D., Centre Hospitalier Régional de Metz-Thionville, Service de Pneumologie et Tabacologie. F -57038 Metz, France.

Abstract
Objectives: Tobacco and cannabis are the most used inhaled drugs worldwide. This review looked at the effects of their combined use, the dependence induced, and the ways of helping people to quit.
Method: Medline was searched using the keywords « tobacco smoking » or « cannabis use » or « tobacco marijuana co-use » and « health effects » or « dependence » or ' « smoking cessation intervention » with « Title/Abstract » limits and search period from 1980 to 2023. A selection of articles in English or in French was analyzed.
Results: Combustion smoke from tobacco and cannabis is more toxic than of tobacco or cannabis, induced dependence is more elevated, tobacco and cannabis cessation is more difficult than quitting tobacco or cannabis alone.
Conclusion: The marketing of cannabis with a high active ingredient content, the availability of synthetic forms and the increasing legalization of recreational use, against a backdrop of a slow decline in the prevalence of smoking, is leading to the danger of an increase in the combined use of tobacco and cannabis ; this risk should be a concern for all health authorities and professionnals.

Keywords
Tobacco smoking ; Cannabis use ; Marijuana tobacco co-use ; Dependence ; Treatment.

Cite this paper
Jean PERRIOT M.D., Michel UNDERNER M.D., Elsa CHAPOT M.D., Gérard PEIFFER M.D., Tobacco and cannabis co-use : toxicity, dependence and cessation management. , SCIREA Journal of Health. Volume 7, Issue 2, April 2023 | PP. 25-45. 10.54647/pmh330309

References

[ 1 ] World Health Organization 2021. WHO global report on trends in prevalence of tobacco use 2000–2025.Fourth edition. Access on : https://iris.who.int/bitstream/handle/10665/348537/9789240039322-eng.pdf?sequence=1
[ 2 ] World Drug Report 2019. Access on : https://wdr.unodc.org/wdr2019/field/b5_F.pdf
[ 3 ] Mura P, Underner M, Brunet B. Cannabis : Similarities and differences with tobacco. Rev Mal Respir. 2020 ;37(6) :479-487.
[ 4 ] Perriot J, Peiffer G, Underner M. Tobacco and cannabis consumption : toxicity and management of quitting. Rev Med Liege. 2021 ;76(1) :31-35.
[ 5 ] Expertise collective. Tabac : comprendre la dépendance pour agir. Paris : INSERM, 2004, p473.
[ 6 ] Reynaud M, Benyamina A. Addiction au cannabis. Paris : Flammarion, 2009, p149.
[ 7 ] Arvers P, Mathern G, Dautzenberg B. Old and new tobacco products. Rev Pneumol Clin. 2018 ;74(3) :145-153.
[ 8 ] Aldington S, Williams M, Nowitz M, Weatherall M, Prichard A, McNaugton A, et al. Effects of cannabis on pulmonary structure, function and symptoms Thorax. 2007 ; 62(12) : 1058-1063.
[ 9 ] Moir D, Ricker WS, Levasseur G, Larose Y, Maertens R, White P, et al. A comparison of mainstream and sidestream marijuana and tobacco cigarette smoke produced under two machine smoking conditions Chem Res Toxicol. 2008 ; 21(2) : 494-502.
[ 10 ] Dervaux A., Laqueille X. Cannabis : use and dependence. Presse Med. 2012 ;41(12-Pt1) :1233-40.
[ 11 ] Underner M, Urban T, Perriot J, PeifferG, Meurice JC. Cannabis use and impairment of respiratory function. Rev Mal Respir. 2013 ; 30(4) : 272-285.
[ 12 ] Lee MH, Hancox RJ. Effects of smoking cannabis on lung function Expert Rev Respir Med. 2011 ; 5(4) : 537-546.
[ 13 ] Wu TC, Tashkin DP, Djahed B, Rose JE. Pulmonary hazards of smoking marijuana as compared with tobacco. N Engl J Med. 1988 ;318(6) :347-51.
[ 14 ] Tashkin DP, Gliederer F, RoseJ, Change P, Hui KK, Yui KK, et al. Effects of varying marijuana smoking profile on deposition of tar and absorption of CO and delta-9-THC. Pharmacol Biochem Behav.1991 ;40(3) :651-6.
[ 15 ] Karila L, Petit A, Zarmdini, Coscas S, Lowenstein W, Reynaud M. Tobacco use and illicit substance use disorders : what should we have to do ? Presse Med. 2013 ;42(5) :795-805.
[ 16 ] Johansson E, Halldin MM, Agurell MM, Hollister LE, Gillespie HK. Terminal elimination plasma half-life of delta 1-tetrahydrocannabinol (delta 1-THC) in heavy users of marijuana. Eur J Clin Pharmacol. 1989 ; 37(3) :273-7
[ 17 ] Le Boisselier R, Alexandre J, Lelong-Boulouard V, Debruyne D. Focus on cannabinoids and synthetic cannabinoids Clin Pharmacol Ther. 2017 ; 101(2) : 220-229.
[ 18 ] Woody GE,Cottler LB, Cacciola B. Severity of dependence: data from the DSM‐IV field trials. Addiction. 1993 ; 88 (11) : 1573-1579.
[ 19 ] American Psychiatric Association : Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. Arlington, VA, American Psychiatric Association, 2013. Access on : https://repository.poltekkeskaltim.ac.id/657/1/Diagnostic%20and%20statistical%20manual%20of%20mental%20disorders%20_%20DSM5%20(%20PDFDrive.com%20).pdf
[ 20 ] Wega WA, Gil AG. Revisiting drug progression : long-range effects of early tobacco use. Addiction. 2005 ;100 (9) : 1358-69.
[ 21 ] Okoli CT, Richardson CG, Ratner PA, Johnson JL. Adolescents’self-defined tobacco use status, marijuana use, and tobacco dependence. Addict Behav. 2008 ; 33 (11) :1491-9.
[ 22 ] Agrawal A, Lynskey MT, Kapoor M, Bucholz KK, Edenberg HJ, Schuckit M, et al. Are Genetic Variants for Tobacco Smoking Associated With Cannabis Involvement ? Drug Alcohol Depend. 2015 ; 150 :183-7.
[ 23 ] Meier E, Vandray R, Rubin N, Pacek LR, Jensen JA, Donny EC, et al. Cigarette Smokers Versus Cousers of Cannabis and Cigarettes : Exposure to Toxicants. Nicotine Tob Res. 2020 ; 22 (8) :1383-89.
[ 24 ] Trosini-Desert V, Germaud P, Dautzenberg B Tobacco smoke and risk of bacterial infection. Rev Mal Respir. 2004 ;21(3 Pt 1) :539-47.
[ 25 ] Morris CV, DiNieri JA, Szutorisz H, Hurd YL. Molecular mechanisms of maternal cannabis and cigarette use on human neurodevelopment. Eur J Neurosci. 2011 ;34(10) :1574-83.
[ 26 ] Kei U Wong KU, Baum CR. Acute Cannabis Toxicity. Pediatr Emerg Care. 2019 ;35(11) :799-804.
[ 27 ] Claudet I., Le Breton M., Brehin C, Franchitto N. A 10-year review of cannabis exposure in children under 3-years of age: do we need a more global approach? Eur J Pediatr. 2017 ; 176(4) : 553-556.
[ 28 ] Dorey A, Scheerlinck P, Nguyen H, Timothy Albertson T.Acute and Chronic Carbon Monoxide Toxicity from Tobacco Smoking.Mil Med. 2020 ;185(1-2) : e61-e67.
[ 29 ] Underner M, Perriot J, Peiffer G, Dewitte JD, Jaafari N. Carbon monoxide poisoning in active or passive shisha smokers. Rev Mal Respir. 2020 ;37(5) :376-388.
[ 30 ] Benowitz NL, Liakoni E. Tobacco use disorder and cardiovascular health. Addiction. 2022 ;117(4) :1128-1138.
[ 31 ] Bonaldi C, Pasquereau A, Hill C, Thomas D, Moutengou E, Thanh VN, et al. Hospitalizations for cardiovascular diseases attributable to tobacco smoking in France in 2015. Eur J Prev Cardiol. 2021 ;28(12) :1327-1333.
[ 32 ] Franz C.A., Frishman W.H. Marijuana use and cardiovascular disease. Cardiol Rev. 2016 ; 24(4) : 158-162.
[ 33 ] Goyal H., Awad H.H., Ghali J.K. Role of cannabis in cardiovascular disorders J Thorac Dis. 2017 ; 9(7) : 2079-2092.
[ 34 ] Patel RS, Kamil SH, Bachu R, Adikey A, Ravat V, et al. Marijuana use and acute myocardiac infarction: A systematic review of published cases in the literature. Trends Cardiovasc Med. 2020 ;30(5) :298-307.
[ 35 ] Mittleman MA, Lewis RA, Maclure M, Sherwood JB, Muller JE. Triggering myocardial infarction by marijuana Circulation. 2001 ; 103(23) : 2805-28
[ 36 ] Aryana A, Williams MA. Marijuana as a trigger of cardiovascular events: speculation or scientific certainty? Int J Cardiol. 2007 ; 118(2) : 141-144.
[ 37 ] Herning RI, Better WE, Tate K, Cadet JL. Marijuana abusers are at increased risk for stroke. Preliminary evidence from cerebrovascular perfusion data. Ann N Y Acad Sci. 2001 ;939 :413-415.
[ 38 ] Rumalla K., Reddy AY, Mittal MK. Recreational marijuana use and acute ischemic stroke : a population-based analysis of hospitalized patients in the United States J Neurol Sci. 2016 ; 364 : 191-196.
[ 39 ] Santos RP, Resende Cl, Vieira AP, Brito C. Cannabis arteritis: ever more important to consider BMJ Case Rep. 2017 ;3;2017:bcr2016219111.
[ 40 ] Jayes L, Haslam PL, Gratziou CG, Powell P, Britton J, Vardavas C, et al. Systematic reviews and meta-analyses of the effects of smoking on respiratory health. Chest. 2016 ;150(1) :164-79.
[ 41 ] Godoy P, Castilla J, Soldevila N, Mayoral JM, Toledo D, et al. Smoking may increase the risk of influenza hospitalization and reduce influenza vaccine effectiveness in the elderly. Eur J Public Health. 2018 ;28(1) :150-155.
[ 42 ] Gallus S, Scala M, Possenti I, Jarach CM, Clancy L, Fernandez E, et al. The Role of Smoking in COVID-19 Progression : A Comprehensive Meta-Analysis. Eur Respir Rev. 2023 ; 32(17) : 220191.
[ 43 ] Arcavi L, Benowitz NL. Cigarette smoking and infection. Arch Intern Med. 2004 ;164(20) :2206-16.
[ 44 ] Peiffer G, Underner M, Perriot J. The respiratory effects of smoking. Rev Pneumol Clin. 2018 ; 74(3) :133-144.
[ 45 ] Shaw B, Borchers M, Zander D, et al. Pulmonary Langerhans cell histiocytosis. Semin Respir Crit Care Med. 2020 ; 41(2) : 269-279.
[ 46 ] Hedevang-Olesen W, Katballe N, Sindby JE, Titlestad IL, Andersen PE, Ekholm O, et al. Cannabis increased the risk of primary spontaneous pneumothorax in tobacco smokers: a case-control study. Eur J Cardiothorac Surg. 2017 ;52(4) :679-85.
[ 47 ] Gracie K, Hancox RJ. Cannabis use disorder and the lungs. Addiction. 2021 ;116(1) :182-190.
[ 48 ] Ruppert AM, Perrin J, Khalil A, Vieira T, Abou-Chedid D, Masmoudi H, et al. Diagn Interv Imaging. 2018 ;99(7-8) :465-471.
[ 49 ] Pradère A, Ruppert AM, Peiffer G, Perriot J, Adler M, Underner M. Inhaled marijuana and the lung, a toxic cocktail ? Rev Mal Respir. 2022 ;39(8) :708-718.
[ 50 ] Underner M, Urban T, Perriot J, de Chazeron I, Meurice JC. Cannabis smoking and lung cancer. Rev Mal Respir. 2014 ;31(6) :488-98.
[ 51 ] Aldington S, Harwood M, Cox B, Weatherall M, Beckert L, Hansell A, et al. Cannabis use and risk of lung cancer : a case-control study. Eur Respir J. 2008 ; 31(2) : 280-286. 51 - Aldington S, Harwood M, Cox B, Weatherall M, Beckert L, Hansell A, et al. Cannabis use and risk of lung cancer : a case-control study. Eur Respir J. 2008 ; 31(2) : 280-286.
[ 52 ] Benedict K, Thompson GR, Jackson BR. Cannabis Use and Fungal Infections in a Commercially Insured Population, United States, 2016. Emerg Infect Dis. 2020 ;26(6) :1308-1310.
[ 53 ] Nguyen LT, Picard-Bernard V, Perriot J, Legionnaires Disease in Cannabis Smokers, Chest. 2010 ;138(4) :989-991.
[ 54 ] Underner M, Perriot J, Peiffer J, Urban T, Jaafari N. Acute eosinophilic pneumonia and illicit psychoactive substance use. Rev Mal Respir. 2020 ;37(1) :34-44.
[ 55 ] Underner M, Perriot J, Peiffer G, Urban T, Jaafari N. Diffuse alveolar hemorrhage in cannabis smokers. Systematic literature review. Rev Mal Respir. 2023 ;40(6) :506-519.
[ 56 ] Werner AK, Koumans EH, Chatham-Stephens K, Salvatore PP, Armatas C, Byers P, et al. Hospitalizations and Deaths Associated with EVALI. N Engl J Med. 2020 ;382(17) :1589-1598.
[ 57 ] Minichino A, Bersani FS, Calò WK, Spagnoli F, Francesconi M, Vicinanza R, Delle Chiaie R, Biondi M. Smoking behaviour and mental health disorders--mutual influences and implications for therapy. Int J Environ Res Pub. 2013 ;10(10) :4790-811.
[ 58 ] Dervaux A, Laqueille X. Smoking and schizophrenia : epidemiological and clinical features. Encephale. 2008 ;34(3) :299-305.
[ 59 ] Nigg JT. Attention-deficit/hyperactivity disorder and adverse health outcomes. Clin Psychol Rev. 2013 ;33(2) :215-28.
[ 60 ] Moylan S, Jacka FN, Pasco JA, Berk M. Cigarette smoking, nicotine dependence and anxiety disorders: a systematic review of population-based, epidemiological studies. BMC Med. 2012 ;10 :123.
[ 61 ] Hitsman B., Borrelli B., McChargue D.E., Spring B., Niaura R. History of depression and smoking cessation outcome: A meta-analysis. J. Consult. Clin. Psychol. 2003 ;71 :657–663
[ 62 ] Li XH, An FR, Ungvari GS, Ng CH, Chiu HFK, Wu PP, et al. Prevalence of smoking in patients with bipolar disorder, major depressive disorder and schizophrenia and their relationships with quality of life. Sci Rep. 2017 ;7(1) :8430.
[ 63 ] Li D, Yang X, Ge Z, Hao Y, Wang Q, Liu F, et al. Cigarette smoking and risk of completed suicide : a meta-analysis of prospective cohort studies. J Psychiatr Res. 2012 ;46(10) :1257-1266.
[ 64 ] Expertise collective. Cannabis : quels effets sur le comportement et la santé. Paris : INSERM, 2001, p429.
[ 65 ] Bartholomew J, Holroyd S, Heffernan TM. Does cannabis use affect prospective memory in young adults? J Psychopharmacol. 2010 ; 24(2) : 241-246.
[ 66 ] Shelton SK, Mills E, Saben JL, Devivo M, Williamson K, Abbott D, et al. Why do patients come to the emergency department after using cannabis? Clin Toxicol (Phila). 2020 ;58 (6) :453-459.
[ 67 ] Gobbi G, Atkin T, Zytynski T, Wang S, Askari S, Boruff J, et al. Association of Cannabis Use in Adolescence and Risk of Depression, Anxiety, and Suicidality in Young Adulthood : A Systematic Review and Meta-analysis. JAMA Psychiatry. 2019 ;76(4) :426-434.
[ 68 ] Rentero D, Arias F, Sánchez-Romero S, Rubio G, Rodríguez-Jiménez R.Cannabis-induced psychosis: clinical characteristics and its differentiation from schizophrenia with and without cannabis use. Adicciones. 2021 ;33(2) :95-108.
[ 69 ] Stilo SA, Murray RM. Non-Genetic Factors in Schizophrenia. Curr Psychiatry Rep. 2019 ; 21(10) :100.
[ 70 ] Urits I, Gress K, Charipova K, Li N, Berger AA, Cornett EM, Hasoon J, Kassem H, Kaye AD, Viswanath O. Cannabis Use and its Association with Psychological Disorders. Psychopharmacol Bull. 2020 ;50(2) :56-67.
[ 71 ] Manrique-Garcia E, Zammit S, Dalman C, Hemmingsson T, Andreasson S, Allebeck P. Prognosis of schizophrenia in persons with and without a history of cannabis use. Psychol Med. 2014 ;44(12) :2513-21.
[ 72 ] Simmons SM, Caird JK, Sterzer F, Asbridge M. The effects of cannabis and alcohol on driving performance and driver behaviour: a systematic review and meta-analysis. Addiction. 2022 ;117(7) :1843-1856.
[ 73 ] Myran DT, Adrienne Gaudreault, Pugliese M, Manuel DG, Tanuseputro P, Cannabis-Involved Traffic Injury Emergency Department Visits After Cannabis Legalization and Commercialization. JAMA Netw Open. 2023 ;6(9) : e2331551.
[ 74 ] Veitz-Keenan A, Spivakovsky S. Cannabis use and oral diseases Evid Based Dent. 2011 ;12(2) : 38.
[ 75 ] Underner M, Hadjadj S,Beauchant M, Bridoux F, Debiais F, Meurice JC. Effects of smoking on the thyroid gland, digestive system, kidney and bone. Rev Mal Respi. 2008 ; 25(10) :1261-78.
[ 76 ] Underner M, Perriot J, Cosnes J, Beau P, Peiffer G, Meurice JC. Smoking, smoking cessation and Crohn's disease. Presse Med. 2016 ;45(4 Pt 1) :390-402.
[ 77 ] Senderovich H, Patel P, Jimenez Lopez B, Waicus S. A Systematic Review on Cannabis Hyperemesis Syndrome and Its Management Options. Med Princ Pract. 2022 ;31(1) :29-38.  78 - Lo JO, Hedges JC, Girardi G.Impact of cannabinoids on pregnancy, reproductive health, and offspring outcomes. Am J Obstet Gynecol. 2022 ;227(4) :571-581.
[ 78 ] Sharma R, Harlev A, Agarwal A, Esteves SC. Cigarette Smoking and Semen Quality: A New Meta-analysis Examining the Effect of the 2010 World Health Organization Laboratory Methods for the Examination of Human Semen. Eur Urol. 2016 ;70(4) :635-645.
[ 79 ] Wen LM, Rissel C, Cheng Y, Richters J, de Visser RO. Tobacco smoking and sexual difficulties among Australian adults: a cross-sectional study. Sex Health. 2017 ;14(4) :313-319.
[ 80 ] Shiff B, Blankstein U, Hussaen J, Jarvi K, Grober E, Lo K, et al. The impact of cannabis use on male sexual function: A 10-year, single-center experience. Can Urol Assoc J. 2021 ;15(12) : E652-E657.
[ 81 ] Ling PM, Glantz SA. Tobacco company strategies to identify and promote the benefits of nicotine. Tob Control. 2019 ;28(3) :289-296
[ 82 ] Clarke E, Thompson K, Weaver S, Thompson J, O'Connell. Snus : a compelling harm reduction alternative to cigarettes. Harm Reduct J. 2019 ;16(1) :62.
[ 83 ] Newhouse P, Kellar K, Aisen P, White H, Wesnes K, Coderre E, Pfaff A, Wilkins H, Howard D, Levin ED. Nicotine treatment of mild cognitive impairment: a 6-month double-blind pilot clinical trial. Neurology. 2012 ;78(2) :91-101.
[ 84 ] Barreto GE, Iarkov A, Moran VE. Beneficial effects of nicotine, cotinine and its metabolites as potential agents for Parkinson's disease. Front Aging Neurosci. 2015 ;6 :340.
[ 85 ] Sansone L, Milani F, Fabrizi R, Belli M, Cristina M, Zagà V, de Iure A, Cicconi L. Nicotine : From Discovery to Biological Effects. Int J Mol Sci. 2023 ;24(19) :14570.
[ 86 ] Ling PM, Glantz SA. Tobacco company strategies to identify and promote the benefits of nicotine. Tob Control. 2019 ;28(3) :289-296.
[ 87 ] Montero-Oleas N, IngArevalo-Rodriguez I, Nuñez-González S, Viteri-García A, Simancas-Racines DA, Therapeutic use of cannabis and cannabinoids : an evidence mapping and appraisal of systematic reviews. BMC Complement Med Ther. 2020 ;20(1) :12.
[ 88 ] Solmi M, De Toffol M, Kim JY, Choi MJ, Stubbs B, Thompson T,et al. Balancing risks and benefits of cannabis use : umbrella review of meta-analyses of randomised controlled trials and observational studies. BMJ. 2023 ;382 : e072348.
[ 89 ] McClure EA, Tomko RL, Salazar CA, Akbar SA, Squeglia LM, Herrmann E, et al. Tobacco and cannabis co-use: Drug substitution, quit interest, and cessation preferences. Exp Clin Psychopharmacol. 2019 ;27(3) :265-275.
[ 90 ] Heatherton TF, Kozlowski LT, Frecker RC, Fagerström KO. The Fagerström test for nicotine dependence : a revision of the Fagerström tolerance. Br J Addict 1991 ;86(9) :1119-27.
[ 91 ] Legleye S, Kraus L, Piontek D, Phan O, Jouanne C Validation of the Cannabis Abuse Screening Test in a sample of cannabis inpatients.. Eur Addict Res. 2012 ;18(4) :193-200.
[ 92 ] Zigmond, AS, Snaith, RP. The hospital anxiety and depression scale. Acta Psychiatr Scand . 1983 ;67(6) :361-70.
[ 93 ] Beckham JC, Adkisson KA, Hertzberg J, Kimbrel NA, Budney AJ, Stephens RS, et al. Mobile contingency management as an adjunctive treatment for co-morbid cannabis use disorder and cigarette smoking. Addictive Behaviors. 2018 ;79 : 86–92.
[ 94 ] Lindson N, Annika Theodoulou A, Ordóñez-Mena JM, Fanshawe TR, Sutton AJ, Livingstone-Banks J, et al. Pharmacological and electronic cigarette interventions for smoking cessation in adults: component network meta-analyses. Cochrane Database Syst Rev. 2023 ;9(9) :CD015226.
[ 95 ] Nielsen S, Gowing L, Sabioni P, Le Foll B. Pharmacotherapies for cannabis dependence. Cochrane Database Syst Rev. 2019 ; 1(1) :CD008940.
[ 96 ] Adams TR, Arnsten JH, Ning Y, Nahvi S. Feasibility and Preliminary Effectiveness of Varenicline for Treating Co-Occurring Cannabis and Tobacco Use. J Psychoactive Drugs. 2018 ; 50(1) :12-18.
[ 97 ] Schwitzer T, Gillet C, Bisch M, Di Patrio P, Schwan R, Lapeyrote V. Co-occurrent cannabis and tobacco uses : Clinical knowledge and therapeutic prospects. Thérapies.  2016 ; 71(3) : 315-322.
[ 98 ] Abdoul H, Le Faou AL, Bouchez J, Touzeau D, Lagrue G. Cannabis cessation interventions offered to young French users: predictors of follow-up. Encéphale. 2012 ; 38(2) :141-8.
[ 99 ] Haney M, Vallée M, Fabre S, Collins Reed S, Zanese M, Campistron G, et al. Signaling-specific inhibition of the CB1 receptor for cannabis use disorder : phase 1 and phase 2a randomized trials. Nat Med. 2023 ;29(6) :1487-1499.