Abstract
Cannabis is a widely consumed drug, so studying the effects of its chronic consumption becomes relevant. Regarding chronic consumption, the phenomenon of tolerance has been described in several drugs, including cannabis. Currently, multiple studies have addressed this phenomenon, with high heterogeneity in terms of methodology, evidence, and results. Our goal is to describe and analyze the literature on cannabis tolerance evaluated in physiological, cognitive, behavioral, and subjective responses, incorporating a critical perspective to account for some gaps and controversies in its study. Cannabis tolerance show a disparity between the effects produced after a first administration compared to its chronic use. Each of them incorporates heterogeneity of cannabinoids, doses, and routes of administration. Also, there is diversity in the regularity and temporal extension of consumption, as well as in its effects at the different response levels. Even when the heterogeneity of measurements allows for incorporating different perspectives, this results in poor standardization and a lack of rigor in what is understood as cannabis tolerance. Furthermore, there is no consideration of the stimuli present at drug administration, which have been relevant in the understanding of tolerance to other drugs as a learning process. Cannabis tolerance should be further studied, incorporating rigorous definitions and measurements that allow the phenomenon to be addressed in a global and standardized manner.
References
Amato, L., Minozzi, S., Mitrova, Z., Parmelli, E., Saulle, R., Cruciani, F., Vecchi, S., & Davoli, M. (2017). Systematic review of safeness and therapeutic efficacy of cannabis in patients with multiple sclerosis, neuropathic pain, and in oncological patients treated with chemotherapy. Epidemiologia e Prevenzione, 41(5-6), 279-293. https://doi.org/10.19191/EP17.5-6.AD01.069
American Psychological Association. (2022, December 8). Tolerance. In APA dictionary of psychology. https://dictionary.apa.org/tolerance
Babor, T. F., Mendelson, J. H., Greenberg, I., & Kuehnle, J. C. (1975). Marijuana consumption and tolerance to physiological and subjective effects. Archives of General Psychiatry, 32(12), 1548-1552. https://doi.org/10.1001/archpsyc.1975.01760300086007
Bass, C. E., & Martin, B. R. (2000). Time course for the induction and maintenance of tolerance to Delta(9)-tetrahydrocannabinol in mice. Drug and Alcohol Dependence, 60(2), 113-119. https://doi.org/10.1016/s0376-8716(99)00150-7
Berger, K. H., Heberlein, U., & Moore, M. S. (2004). Rapid and chronic: Two distinct forms of ethanol tolerance in Drosophila. Alcoholism, Clinical and Experimental Research, 28(10), 1469-1480. https://doi.org/10.1097/01.alc.0000141817.15993.98
Bespalov, A., Müller, R., Relo, A. L., & Hudzik, T. (2016). Drug Tolerance: A Known Unknown in Translational Neuroscience. Trends in Pharmacological Sciences, 37(5), 364-378. https://doi.org/10.1016/j.tips.2016.01.008
Betancourt, R., Corada, L., Dominichetti, J. Laborda, M., Martínez, G., & Miguez, G. (2008). Efecto de la extinción en múltiples contextos sobre la renovación de la tolerancia a las drogas. Psicothema, 20, 279.283.
Black, N., Stockings, E., Campbell, G., Tran, L. T., Zagic, D., Hall, W. D., Farrell, M., & Degenhardt, L. (2019). Cannabinoids for the treatment of mental disorders and symptoms of mental disorders: A systematic review and meta-analysis. The Lancet Psychiatry, 6(12), 995-1010. https://doi.org/10.1016/S2215-0366(19)30401-8
Castaño-Pérez, G., Velásquez, E., & Olaya Pelaéz, A. (2017). Aportes al debate de legalización del uso medicinal de la marihuana en Colombia. Revista Facultad Nacional de Salud Pública, 35(1), 16-26. https://doi.org/10.17533/udea.rfnsp.v35n1a03
Castillo, A., Tolón, M. R., Fernández-Ruiz, J., Romero, J., & Martinez-Orgado, J. (2010). The neuroprotective effect of cannabidiol in an in vitro model of newborn hypoxic-ischemic brain damage in mice is mediated by CB(2) and adenosine receptors. Neurobiology of Disease, 37(2), 434-440. https://doi.org/10.1016/j.nbd.2009.10.023
Chopda, G. R., Parge, V., Thakur, G. A., Gatley, S. J., Makriyannis, A., & Paronis, C. A. (2016). Tolerance to the diuretic effects of cannabinoids and cross-tolerance to a κ-opioid agonist in THC-treated mice. The Journal of Pharmacology and Experimental Therapeutics, 358(2), 334-341. https://doi.org/10.1124/jpet.116.232132
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. https://doi.org/10.1097/ADM.0b013e31820c23fa
Crippa, J. A. S., Derenusson, G. N., Ferrari, T. B., Wichert-Ana, L., Duran, F. L., Martin-Santos, R., Simões, M. V., Bhattacharyya, S., Fusar-Poli, P., Atakan, Z., Filho, A. S., Freitas-Ferrari, M. C., McGuire, P. K., Zuardi, A. W., Busatto, G. F., & Hallak, J. E. C. (2011). Neural basis of anxiolytic effects of cannabidiol (CBD) in generalized social anxiety disorder: a preliminary report. Journal of Psychopharmacology, 25(1), 121-130. https://doi.org/10.1177/0269881110379283
Colizzi, M., & Bhattacharyya, S. (2018). Cannabis use and the development of tolerance: A systematic review of human evidence. Neuroscience and Biobehavioral Reviews, 93, 1-25. https://doi.org/10.1016/j.neubiorev.2018.07.014
Comley, R. E., & Dry, M. J. (2020). Acute tolerance to alcohol-induced impairment in cognitive performance. Experimental and Clinical Psychopharmacology, 28(6), 659-668. https://doi.org/10.1037/pha0000352
Da Silva, G. E., Morato, G. S., & Takahashi, R. N. (2001). Rapid tolerance to Delta(9)-tetrahydrocannabinol and cross-tolerance between ethanol and Delta(9)-tetrahydrocannabinol in mice. European Journal of Pharmacology, 431(2), 201-207. https://doi.org/10.1016/s0014-2999(01)01449-2
D'Souza, D. C., Ranganathan, M., Braley, G., Gueorguieva, R., Zimolo, Z., Cooper, T., Perry, E., & Krystal, J. (2008). Blunted psychotomimetic and amnestic effects of delta-9-tetrahydrocannabinol in frequent users of cannabis. Neuropsychopharmacology, 33(10), 2505-2516. https://doi.org/10.1038/sj.npp.1301643
ElSohly, M. A., Radwan, M. M., Gul, W., Chandra, S., & Galal, A. (2017). Phytochemistry of Cannabis sativa L. Progress in the Chemistry of Organic Natural Products, 103, 1-36. https://doi.org/10.1007/978-3-319-45541-9_1
Freeman, T. P., Hindocha, C., Green, S. F., & Bloomfield, M. (2019). Medicinal use of cannabis-based products and cannabinoids. British Medical Journal (Clinical research ed.), 365, l1141. https://doi.org/10.1136/bmj.l1141
Fitzcharles, M. A., Baerwald, C., Ablin, J., & Häuser, W. (2016). Efficacy, tolerability and safety of cannabinoids in chronic pain associated with rheumatic diseases (fibromyalgia syndrome, back pain, osteoarthritis, rheumatoid arthritis): A systematic review of randomized controlled trials. Der Schmerz, 30(1), 47-61. https://doi.org/10.1007/s00482-015-0084-3
Ginsburg, B. C., Hruba, L., Zaki, A., Javors, M. A., & McMahon, L. R. (2014). Blood levels do not predict behavioral or physiological effects of Δ⁹-tetrahydrocannabinol in rhesus monkeys with different patterns of exposure. Drug and Alcohol Dependence, 139, 1-8. https://doi.org/10.1016/j.drugalcdep.2014.02.696
Gomez, D. M., Everett, T. J., Hamilton, L. R., Ranganath, A., Cheer, J. F., & Oleson, E. B. (2021). Chronic cannabinoid exposure produces tolerance to the dopamine releasing effects of WIN 55,212-2 and heroin in adult male rats. Neuropharmacology, 182, 108374. https://doi.org/10.1016/j.neuropharm.2020.108374
González, S., Cebeira, M., & Fernández-Ruiz, J. (2005). Cannabinoid tolerance and dependence: A review of studies in laboratory animals. Pharmacology, Biochemistry and Behavior, 81(2), 300-318. https://doi.org/10.1016/j.pbb.2005.01.028
González, V. V., Miguez, G., Quezada, V. E., Mallea, J., & Laborda, M. A. (2019). Ethanol tolerance from a Pavlovian perspective. Psychology & Neuroscience, 12(4), 495-509. https://doi.org/10.1037/pne0000181
Gorelick, D. A., Goodwin, R. S., Schwilke, E., Schwope, D. M., Darwin, W. D., Kelly, D. L., McMahon, R. P., Liu, F., Ortemann-Renon, C., Bonnet, D., & Huestis, M. A. (2013). Tolerance to effects of high-dose oral Δ9-tetrahydrocannabinol and plasma cannabinoid concentrations in male daily cannabis smokers. Journal of Analytical Toxicology, 37(1), 11-16. https://doi.org/10.1093/jat/bks081
Greene, N. Z., Wiley, J. L., Yu, Z., Clowers, B. H., & Craft, R. M. (2018). Cannabidiol modulation of antinociceptive tolerance to Δ9-tetrahydrocannabinol. Psychopharmacology, 235(11), 3289-3302. https://doi.org/10.1007/s00213-018-5036-z
Gruber, S. A., Smith, R. T., Dahlgren, M. K., Lambros, A. M., & Sagar, K. A. (2021). No pain, all gain? Interim analyses from a longitudinal, observational study examining the impact of medical cannabis treatment on chronic pain and related symptoms. Experimental and Clinical Psychopharmacology, 29(2), 147-156. https://doi.org/10.1037/pha0000435
Hampson, R. E., Simeral, J. D., Kelly, E. J., & Deadwyler, S. A. (2003). Tolerance to the memory disruptive effects of cannabinoids involves adaptation by hippocampal neurons. Hippocampus, 13(5), 543-556. https://doi.org/10.1002/hipo.10081
Hart, C. L., Ilan, A. B., Gevins, A., Gunderson, E. W., Role, K., Colley, J., & Foltin, R. W. (2010). Neurophysiological and cognitive effects of smoked marijuana in frequent users. Pharmacology, Biochemistry, and Behavior, 96(3), 333-341. https://doi.org/10.1016/j.pbb.2010.06.003
Hart, C. L., van Gorp, W., Haney, M., Foltin, R. W., & Fischman, M. W. (2001). Effects of acute smoked marijuana on complex cognitive performance. Neuropsychopharmacology, 25(5), 757-765. https://doi.org/10.1016/S0893-133X(01)00273-1
Hayakawa, K., Mishima, K., Hazekawa, M., Sano, K., Irie, K., Orito, K., Egawa, T., Kitamura, Y., Uchida, N., Nishimura, R., Egashira, N., Iwasaki, K. & Fujiwara, M. (2008). Cannabidiol potentiates pharmacological effects of Δ9-tetrahydrocannabinol via CB1 receptor-dependent mechanism. Brain Research, 1188, 157-164. https://doi.org/10.1016/j.brainres.2007.09.090
Hayakawa, K., Mishima, K., Nozako, M., Ogata, A., Hazekawa, M., Liu, A. X., Fujioka, M., Abe, K., Hasebe, N., Egashira, N., Iwasaki, K., & Fujiwara, M. (2007). Repeated treatment with cannabidiol but not Delta9-tetrahydrocannabinol has a neuroprotective effect without the development of tolerance. Neuropharmacology, 52(4), 1079-1087. https://doi.org/10.1016/j.neuropharm.2006.11.005
Hayakawa, K., Mishima, K., & Fujiwara, M. (2010). Therapeutic potential of non-psychotropic cannabidiol in ischemic stroke. Pharmaceuticals, 3(7), 2197-2212. https://doi.org/10.3390/ph3072197
Henderson-Redmond, A. N., Crawford, L. C., Sepulveda, D. E., Hale, D. E., Lesperance, J. J., & Morgan, D. J. (2021). Sex differences in tolerance to Delta-9-Tetrahydrocannabinol in mice with cisplatin-evoked chronic neuropathic pain. Frontiers in Molecular Biosciences, 8, 684115. https://doi.org/10.3389/fmolb.2021.684115
Henderson-Redmond, A. N., Nealon, C. M., Davis, B. J., Yuill, M. B., Sepulveda, D. E., Blanton, H. L., Piscura, M. K., Zee, M. L., Haskins, C. P., Marcus, D. J., Mackie, K., Guindon, J., & Morgan, D. J. (2020). c-Jun N terminal kinase signaling pathways mediate cannabinoid tolerance in an agonist-specific manner. Neuropharmacology, 164, 107847. https://doi.org/10.1016/j.neuropharm.2019.107847
Hill, M. N., Gorzalka, B. B., & Choi, J. W. (2004). Augmentation of the development of behavioral tolerance to cannabinoid administration through Pavlovian conditioning. Neuropsychobiology, 49(2), 94-100. https://doi.org/10.1159/000076417
Kayser, R. R., Haney, M., Raskin, M., Arout, C., & Simpson, H. B. (2020). Acute effects of cannabinoids on symptoms of obsessive-compulsive disorder: A human laboratory study. Depression and Anxiety, 37(8), 801-811. https://doi.org/10.1002/da.23032
Lefkof, J. D., Hill, R., & Sarantopoulos, K. (2022). Opioid analgesics, tolerance, dependence and addiction. In R. K. Banik (Ed.), Anesthesiology In-Training Exam Review (pp. 367-374). Springer, Cham.
Lucas, C. J., Galettis, P., & Schneider, J. (2018). The pharmacokinetics and the pharmacodynamics of cannabinoids. British Journal of Clinical Pharmacology, 84(11), 2477-2482. https://doi.org/10.1111/bcp.13710
Mason, N. L., Theunissen, E. L., Hutten, N., Tse, D., Toennes, S. W., Jansen, J., Stiers, P., & Ramaekers, J. G. (2021). Reduced responsiveness of the reward system is associated with tolerance to cannabis impairment in chronic users. Addiction Biology, 26(1), e12870. https://doi.org/10.1111/adb.12870
Mauzay, D., LaFrance, E. M., y Cuttler, C. (2021). Acute effects of cannabis on symptoms of obsessive-compulsive disorder. Journal of Affective Disorders, 279, 158-163. https://doi.org/10.1016/j.jad.2020.09.124
McKinney, D. L., Cassidy, M. P., Collier, L. M., Martin, B. R., Wiley, J. L., Selley, D. E., & Sim-Selley, L. J. (2008). Dose-related differences in the regional pattern of cannabinoid receptor adaptation and in vivo tolerance development to delta9-tetrahydrocannabinol. The Journal of Pharmacology and Experimental Therapeutics, 324(2), 664–673. https://doi.org/10.1124/jpet.107.130328
McMahon L. R. (2011). Chronic Δ⁹-tetrahydrocannabinol treatment in rhesus monkeys: Differential tolerance and cross-tolerance among cannabinoids. British Journal of Pharmacology, 162(5), 1060-1073. https://doi.org/10.1111/j.1476-5381.2010.01116.x
Miller, S., Daily, L., Leishman, E., Bradshaw, H., & Straiker, A. (2018). Δ9-Tetrahydrocannabinol and cannabidiol differentially regulate intraocular pressure. Investigative Ophthalmology & Visual Science, 59(15), 5904-5911. https://doi.org/10.1167/iovs.18-24838
Mücke, M., Carter, C., Cuhls, H., Prüß, M., Radbruch, L., & Häuser, W. (2016). Cannabinoids in palliative care: Systematic review and meta-analysis of efficacy, tolerability and safety. Der Schmerz, 30(1), 25-36. https://doi.org/10.1007/s00482-015-0085-2
Nguyen, J. D., Creehan, K. M., Kerr, T. M., & Taffe, M. A. (2020). Lasting effects of repeated ∆9-tetrahydrocannabinol vapour inhalation during adolescence in male and female rats. British Journal of Pharmacology, 177(1), 188-203. https://doi.org/10.1111/bph.14856
Nguyen, J. D., Grant, Y., Kerr, T. M., Gutierrez, A., Cole, M., & Taffe, M. A. (2018). Tolerance to hypothermic and antinociceptive effects of ∆9-tetrahydrocannabinol (THC) vapor inhalation in rats. Pharmacology, Biochemistry and Behavior, 172, 33-38. https://doi.org/10.1016/j.pbb.2018.07.007
Nowlan, R., & Cohen, S. (1977). Tolerance to marijuana: Heart rate and subjective "high". Clinical Pharmacology and Therapeutics, 22, 550-556. https://doi.org/10.1002/cpt1977225part1550
Parks, C., Jones, B. C., Moore, B. M., & Mulligan, M. K. (2020). Sex and strain variation in initial sensitivity and rapid tolerance to Δ9-Tetrahydrocannabinol. Cannabis and Cannabinoid Research, 5(3), 231-245. https://doi.org/10.1089/can.2019.0047
Parsons, L. H., & Hurd, Y. L. (2015). Endocannabinoid signalling in reward and addiction. Nature Reviews Neuroscience, 16(10), 579-594. https://doi.org/10.1038/nrn4004
Ramaekers, J. G., Kauert, G., Theunissen, E., Toennes, S. W., & Moeller, M. R. (2009). Neurocognitive performance during acute THC intoxication in heavy and occasional cannabis users. Journal of Psychopharmacology, 23(3), 266-277. https://doi.org/10.1177/0269881108092393
Ramaekers, J. G., Theunissen, E. L., de Brouwer, M., Toennes, S. W., Moeller, M. R., & Kauert, G. (2011). Tolerance and cross-tolerance to neurocognitive effects of THC and alcohol in heavy cannabis users. Psychopharmacology, 214(2), 391-401. https://doi.org/10.1007/s00213-010-2042-1
Ramaekers, J. G., van Wel, J. H., Spronk, D. B., Toennes, S. W., Kuypers, K. P., Theunissen, E. L., & Verkes, R. J. (2016). Cannabis and tolerance: Acute drug impairment as a function of cannabis use history. Scientific Reports, 6, 26843. https://doi.org/10.1038/srep26843
Ritchie, H., & Roser, M. (2019). Drug use. In Our World in Data. https://ourworldindata.org/drug-use#definitions
Romero-Sandoval, E. A., Fincham, J. E., Kolano, A. L., Sharpe, B. N., & Alvarado-Vázquez, P. A. (2018). Cannabis for chronic pain: Challenges and considerations. Pharmacotherapy, 38(6), 651-662. https://doi.org/10.1002/phar.2115
Rutkowska, M., Jamontt, J., & Gliniak, H. (2006). Effects of cannabinoids on the anxiety-like response in mice. Pharmacological Reports, 58(2), 200.
Sal, F., Prados, J., & Urcelay, G. P. (2021). Nicotine chronic tolerance development and withdrawal in the planaria (Schmidtea mediterranea). Pharmacology, Biochemistry and Behavior, 200, 173075. https://doi.org/10.1016/j.pbb.2020.173075
San Martín, C., Cañete, A., Quezada, V., & Miguez, G. (2017). Tolerance. In J. Vonk y T. Shackelford (Eds.), Encyclopedia of Animal Cognition and Behavior. Springer, Cham. https://doi.org/10.1007/978-3-319-47829-6_1101-1
Siegel, S. (1975). Evidence from rats that morphine tolerance is a learned response. Journal of Comparative y Physiological Psychology, 89(5), 498-506.
Siegel, S. (1977). Morphine tolerance acquisition as an associative process. Journal of Experimental Psychology: Animal Behavior Processes, 3(1), 1-13. https://doi.org/10.1037/0097-7403.3.1.1
Siegel, S. (2001). Pavlovian conditioning and drug overdose: When tolerance fails. Addiction Research y Theory, 9(5), 503-513.
Siegel, S. (2005). Drug tolerance, drug addiction, and drug anticipation. Current Directions in Psychological Science, 14(6), 296-300.
Siegel, S. (2008). Learning and the wisdom of the body. Learning & Behavior, 36(3), 242-252.
Siegel, S. (2011). The Four-Loko effect. Perspectives in Psychological Science, 6(4), 357-362.
Siegel, S. (2016). The heroin overdose mystery. Current Directions in Psychological Science, 25(6), 375-379.
Siegel, S., Baptista, M. A. S., Kim, J. A., McDonald, R. V., & Weise-Kelly, L. (2000). Pavlovian psychopharmacology the associative basis of tolerance. Experimental and Clinical Psychopharmacology, 8(3), 276-293.
Singh, H., Schulze, D. R., & McMahon, L. R. (2011). Tolerance and cross-tolerance to cannabinoids in mice: Schedule-controlled responding and hypothermia. Psychopharmacology, 215(4), 665-675. https://doi.org/10.1007/s00213-010-2162-7
Tai, S., Hyatt, W. S., Gu, C., Franks, L. N., Vasiljevik, T., Brents, L. K., Prather, P. L., & Fantegrossi, W. E. (2015). Repeated administration of phytocannabinoid Δ(9)-THC or synthetic cannabinoids JWH-018 and JWH-073 induces tolerance to hypothermia but not locomotor suppression in mice, and reduces CB1 receptor expression and function in a brain region-specific manner. Pharmacological Research, 102, 22-32. https://doi.org/10.1016/j.phrs.2015.09.006
Uliel-Sibony, S., Hausman-Kedem, M., Fattal-Valevski, A., & Kramer, U. (2021). Cannabidiol-enriched oil in children and adults with treatment-resistant epilepsy-does tolerance exist? Brain and Development, 43(1), 89-96. https://doi.org/10.1016/j.braindev.2020.06.018
United Nations Office on Drugs and Crime. (2022). World Drug Report 2022. Executive Summary, Policy Implications. United Nations publication. https://www.unodc.org/res/wdr2022/MS/WDR22_Booklet_1.pdf
Uran, B., Tulunay, F. C., Ayhan, I. H., Ulkü, E., & Kaymakçalan, S. (1980). Correlation between the dose and development of acute tolerance to the hypothermic effect of THC. Pharmacology, 21(6), 391-395. https://doi.org/10.1159/000137458
Verrico, C. D., Mathai, D. S., Gu, H., Sampson, A. R., & Lewis, D. A. (2020). Recovery from impaired working memory performance during chronic Δ-9-tetrahydrocannabinol administration to adolescent rhesus monkeys. Journal of Psychopharmacology, 34(2), 211-220. https://doi.org/10.1177/0269881119882857
Wang, T., Collet, J. P., Shapiro, S., & Ware, M. A. (2008). Adverse effects of medical cannabinoids: a systematic review. CMAJ: Canadian Medical Association Journal, 178(13), 1669-1678. https://doi.org/10.1503/cmaj.071178
Whiting, P. F., Wolff, R. F., Deshpande, S., Di Nisio, M., Duffy, S., Hernandez, A. V., Keurentjes, J. C., Lang, S., Misso, K., Ryder, S., Schmidlkofer, S., Westwood, M., & Kleijnen, J. (2015). Cannabinoids for medical use: A systematic review and meta-analysis. JAMA: Journal of the American Medical Association, 313(24), 2456-2473. https://doi.org/10.1001/jama.2015.6358
Wilkerson, J. L., Schulze, D. R., & McMahon, L. R. (2019). Tolerance and dependence to Δ9-tetrahydrocannabinol in rhesus monkeys: Activity assessments. PloS One, 14(3), e0209947. https://doi.org/10.1371/journal.pone.0209947
Winsauer, P. J., Molina, P. E., Amedee, A. M., Filipeanu, C. M., McGoey, R. R., Troxclair, D. A., Walker, E. M., Birke, L. L., Stouwe, C. V., Howard, J. M., Leonard, S. T., Moerschbaecher, J. M., & Lewis, P. B. (2011). Tolerance to chronic delta-9-tetrahydrocannabinol (Δ⁹-THC) in rhesus macaques infected with simian immunodeficiency virus. Experimental and Clinical Psychopharmacology, 19(2), 154-172. https://doi.org/10.1037/a0023000
Withey, S. L., Kangas, B. D., Charles, S., Gumbert, A. B., Eisold, J. E., George, S. R., Bergman, J. & Madras, B. K. (2021). Effects of daily Δ9-Tetrahydrocannabinol (THC) alone or combined with cannabidiol (CBD) on cognition-based behavior and activity in adolescent nonhuman primates. Drug and Alcohol Dependence, 221, 108629. https://doi.org/10.1016/j.drugalcdep.2021.108629
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
Copyright (c) 2023 Esperanza Ibáñez-Jiménez, Gonzalo Miguez, Vanetza Quezada-Scholz, Felipe Alfaro, Francisca Bertin, Camila Aguilar, Simón Ramírez, Mario Arturo Laborda Rojas