SpringerLink
Log in

Δ9-Tetrahydrocannabinol Effects on Respiration and Heart Rate Across Route of Administration in Female and Male Mice

  • Published:
Cardiovascular Toxicology Aims and scope Submit manuscript

Abstract

The physiological impact of cannabinoid receptor agonists is of great public health interest due to their increased use in recreational and therapeutic contexts. However, the body of literature on cannabinoid receptor agonists includes multiple confounding variables that complicate comparisons across studies, including route of administration, timeline across which phenotypes are observed, agonist dose, and sex of the study cohort. In this study, we characterized the impact of sex and route of administration on Δ9-tetrahydrocannabinol (THC)-induced changes in cardiopulmonary phenotypes in mice. Using noninvasive plethysmography and telemetry, we monitored heart rate and respiration in the same cohort of animals across aerosol, oral gavage, subcutaneous, and intraperitoneal administrations of THC (0–30 mg/kg THC for oral gavage, subcutaneous, and intraperitoneal, and 0-300 mg/ml THC for aerosol). All routes of THC administration altered respiratory minute volume and heart rate, with the direction of effects typically being consistent across dependent measures. THC primarily decreased respiration and heart rate, but females given oral gavage THC showed increased heart rate. Intraperitoneal and subcutaneous THC produced the longest-lasting effects, including THC-induced alterations in physiological parameters for up to 10 h, whereas effects of aerosolized THC were short lived. The fastest onset of effects of THC occurred for aerosolized and intraperitoneal THC. Altogether, the work herein establishes the impact of dosing route on THC-induced heart rate and respiratory alteration in male and female mice. This study highlights important differences in the timeline of cardiopulmonary response to THC following the most common preclinical routes of administration.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price includes VAT (Germany)

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Hasin, D. S., Shmulewitz, D., & Sarvet, A. L. (2019). Time trends in US cannabis use and cannabis use disorders overall and by sociodemographic subgroups: A narrative review and new findings. American Journal of Drug and Alcohol Abuse, 45, 623–643. https://doi.org/10.1080/00952990.2019.1569668.

    Article  PubMed  Google Scholar 

  2. ElSohly, M. A., Mehmedic, Z., Foster, S., Gon, C., Chandra, S., & Church, J. C. (2016). Changes in cannabis potency over the last 2 fecades (1995–2014): Analysis of current data in the United States. Biological Psychiatry, 79, 613–619. https://doi.org/10.1016/j.biopsych.2016.01.004.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Cinnamon Bidwell, L., YorkWilliams, S. L., Mueller, R. L., Bryan, A. D., & Hutchison, K. E. (2018). Exploring cannabis concentrates on the legal market: User profiles, product strength, and health-related outcomes. Addictive Behaviors Reports, 8, 102–106. https://doi.org/10.1016/j.abrep.2018.08.004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Smart, R., Caulkins, J. P., Kilmer, B., Davenport, S., & Midgette, G. (2017). Variation in cannabis potency and prices in a newly legal market: Evidence from 30 million cannabis sales in Washington state. Addiction, 112, 2167–2177. https://doi.org/10.1111/add.13886.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Mehmedic, Z., Chandra, S., Slade, D., Denham, H., Foster, S., Patel, A. S., Ross, S. A., Khan, I. A., & ElSohly, M. A. (2010). Potency trends of ∆9-THC and other cannabinoids in confiscated cannabis preparations from 1993 to 2008. Journal of Forensic Sciences, 55, 1209–1217. https://doi.org/10.1111/j.1556-4029.2010.01441.x.

    Article  CAS  PubMed  Google Scholar 

  6. Modaresi, F., & Talachian, K. (2022). The characteristics of clinical trials on cannabis and cannabinoids: A review of trials for therapeutic or drug development purposes. Pharmaceutical Medicine, 36, 387–400. https://doi.org/10.1007/s40290-022-00447-7

    Article  PubMed  Google Scholar 

  7. Vandrey, R., Herrmann, E. S., Mitchell, J. M., Bigelow, G. E., Flegel, R., LoDico, C., & Cone, E. J. (2017). Pharmacokinetic Profile of oral Cannabis in humans: Blood and oral Fluid Disposition and Relation to Pharmacodynamic Outcomes. Journal of Analytical Toxicology, 41, 83–99. https://doi.org/10.1093/jat/bkx012.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Naef, M., Russmann, S., Petersen-Felix, S., & Brenneisen, R. (2004). Development and pharmacokinetic characterization of pulmonal and intravenous Δ-9-tetrahydrocannabinol (THC) in humans. Journal of Pharmaceutical Sciences, 93, 1176–1184. https://doi.org/10.1002/jps.20037.

    Article  CAS  PubMed  Google Scholar 

  9. Spindle, T. R., Cone, E. J., Goffi, E., Weerts, E. M., Mitchell, J. M., Winecker, R. E., Bigelow, G. E., Flegel, R. R., & Vandrey, R. (2020). Pharmacodynamic effects of vaporized and oral cannabidiol (CBD) and vaporized CBD-dominant cannabis in infrequent cannabis users. Drug and Alcohol Dependence. https://doi.org/10.1016/j.drugalcdep.2020.107937

    Article  PubMed  PubMed Central  Google Scholar 

  10. Sholler, D. J., Zamarripa, C. A., Spindle, T. R., Martin, E. L., Kuntz, D., Vandrey, R., & Grabenauer, M. (2022). Urinary excretion profile of cannabinoid analytes following acute administration of oral and vaporized cannabis in infrequent cannabis users. Journal of Analytical Toxicology, 46, 882–890. https://doi.org/10.1093/jat/bkac042

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Huestis, M. A., Blount, B. C., Milan, D. F., Newmeyer, M. N., Schroeder, J., & Smith, M. L. (2019). Correlation of creatinine- and specific gravity-normalized free and glucuronidated urine cannabinoid concentrations following smoked, vaporized, and oral cannabis in frequent and occasional cannabis users. Drug Testing and Analysis, 11, 968–975. https://doi.org/10.1002/dta.2576.

    Article  CAS  PubMed  Google Scholar 

  12. Rabgay, K., Waranuch, N., Chaiyakunapruk, N., Sawangjit, R., Ingkaninan, K., & Dilokthornsakul, P. (2020). The effects of cannabis, cannabinoids, and their administration routes on pain control efficacy and safety: A systematic review and network meta-analysis. Journal of the American Pharmacists Association, 60, 225–234. https://doi.org/10.1016/j.japh.2019.07.015

    Article  PubMed  Google Scholar 

  13. Swortwood, M. J., Newmeyer, M. N., Andersson, M., Abulseoud, O. A., Scheidweiler, K. B., & Huestis, M. A. (2017). Cannabinoid disposition in oral fluid after controlled smoked, vaporized, and oral cannabis administration. Drug Testing and Analysis, 9, 905–915. https://doi.org/10.1002/dta.2092.

    Article  CAS  PubMed  Google Scholar 

  14. Lemberger, L., Weiss, J. L., Watanabe, A. M., Galanter, I. M., Wyatt, R. J., & Cardon, P. V. (1972). Δ-9-tetrahydrocannabinol. Temporal correlation of the psychologic effects and blood levels after various routes of administration. New England Journal of Medicine, 286, 685–688. https://doi.org/10.1056/nejm197203302861303.

    Article  CAS  PubMed  Google Scholar 

  15. Sinclair, J., Collett, L., Abbott, J., Pate, D. W., Sarris, J., & Armour, M. (2021). Effects of cannabis ingestion on endometriosis-associated pelvic pain and related symptoms. PLoS One, 16, e0258940. https://doi.org/10.1371/journal.pone.0258940.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Wiley, J. L., Taylor, S. I., & Marusich, J. A. (2021). ∆(9)-Tetrahydrocannabinol discrimination: Effects of route of administration in rats. Drug and Alcohol Dependence. https://doi.org/10.1016/j.drugalcdep.2021.108827

    Article  PubMed  PubMed Central  Google Scholar 

  17. Hložek, T., Uttl, L., Kadeřábek, L., Balíková, M., Lhotková, E., Horsley, R. R., Nováková, P., Šíchová, K., Štefková, K., Tylš, F., Kuchař, M., & Páleníček, T. (2017). Pharmacokinetic and behavioural profile of THC, CBD, and THC + CBD combination after pulmonary, oral, and subcutaneous administration in rats and confirmation of conversion in vivo of CBD to THC. European Neuropsychopharmacology, 27, 1223–1237. https://doi.org/10.1016/j.euroneuro.2017.10.037.

    Article  CAS  PubMed  Google Scholar 

  18. Marshell, R., Kearney-Ramos, T., Brents, L. K., Hyatt, W. S., Tai, S., Prather, P. L., & Fantegrossi, W. E. (2014). In vivo effects of synthetic cannabinoids JWH-018 and JWH-073 and phytocannabinoid ∆9-THC in mice: Inhalation versus intraperitoneal injection. Pharmacology, Biochemistry and Behavior, 124, 40–47.

    Article  CAS  PubMed  Google Scholar 

  19. Baglot, S. L., Hume, C., Petrie, G. N., Aukema, R. J., Lightfoot, S. H. M., Grace, L. M., Zhou, R., Parker, L., Rho, J. M., Borgland, S. L., McLaughlin, R. J., Brechenmacher, L., & Hill, M. N. (2021). Pharmacokinetics and central accumulation of Δ-9-tetrahydrocannabinol (THC) and its bioactive metabolites are influenced by route of administration and sex in rats. Scientific Reports. https://doi.org/10.1038/s41598-021-03242-7

    Article  PubMed  PubMed Central  Google Scholar 

  20. Welch, S. P., Thomas, C., & Patrick, G. S. (1995). Modulation of cannabinoid-induced antinociception after intracerebroventricular versus intrathecal administration to mice: Possible mechanisms for interaction with morphine. Journal of Pharmacology and Experimental Therapeutics, 272, 310–321.

    CAS  PubMed  Google Scholar 

  21. Borgen, L. A., & Davis, W. M. (1973). Vehicle and route of administration as parameters affecting operant behavioral effects of 9 -tetrahydrocannabinol. Journal of Pharmaceutical Sciences, 62, 479–480. https://doi.org/10.1002/jps.2600620327.

    Article  CAS  PubMed  Google Scholar 

  22. Manwell, L. A., Ford, B., Matthews, B. A., Heipel, H., & Mallet, P. E. (2014). A vapourized ∆(9)-tetrahydrocannabinol (∆(9)-THC) delivery system part II: Comparison of behavioural effects of pulmonary versus parenteral cannabinoid exposure in rodents. Journal of Pharmacological and Toxicological Methods, 70, 112–119. https://doi.org/10.1016/j.vascn.2014.06.004.

    Article  CAS  PubMed  Google Scholar 

  23. Lichtman, A. H., Dimen, K. R., & Martin, B. R. (1995). Systemic or intrahippocampal cannabinoid administration impairs spatial memory in rats. Psychopharmacology, 119, 282–290. https://doi.org/10.1007/bf02246292

    Article  CAS  PubMed  Google Scholar 

  24. Lucas, C. J., Galettis, P., & Schneider, J. (2018). The pharmacokinetics and the pharmacodynamics of cannabinoids. British Journal of Clinical Pharmacology, 84, 2477–2482. https://doi.org/10.1111/bcp.13710.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Spindle, T. R., Martin, E. L., Grabenauer, M., Woodward, T., Milburn, M. A., & Vandrey, R. (2021). Assessment of cognitive and psychomotor impairment, subjective effects, and blood THC concentrations following acute administration of oral and vaporized cannabis. Journal of Psychopharmacology (Oxford England), 35, 786–803. https://doi.org/10.1177/02698811211021583.

    Article  CAS  PubMed  Google Scholar 

  26. Spindle, T. R., Cone, E. J., Herrmann, E. S., Mitchell, J. M., Flegel, R., LoDico, C., Bigelow, G. E., & Vandrey, R. (2020). Pharmacokinetics of cannabis brownies: A controlled examination of ∆9-tetrahydrocannabinol and metabolites in blood and oral fluid of healthy adult males and females. Journal of Analytical Toxicology, 44, 661–671. https://doi.org/10.1093/jat/bkaa067

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Sholler, D. J., Strickland, J. C., Spindle, T. R., Weerts, E. M., & Vandrey, R. (2021). Sex differences in the acute effects of oral and vaporized cannabis among healthy adults. Addiction Biology, 26, e12968. https://doi.org/10.1111/adb.12968

    Article  CAS  PubMed  Google Scholar 

  28. Samudre, S. S., Schneider, J. L., Oltmanns, M. H., Hosseini, A., Pratap, K., Loose-Thurman, P., Allen, R. C., Williams, P. B., Lattanzio, F. A. Jr., & Sheppard, J. D. Jr. (2008). Comparison of topical and intravenous administration of WIN 55-212-2 in normotensive rabbits. Current Eye Research, 33, 857–863. https://doi.org/10.1080/02713680802419724.

    Article  CAS  PubMed  Google Scholar 

  29. Chaperon, F., Soubrié, P., Puech, A. J., & Thiébot, M. H. (1998). Involvement of central cannabinoid (CB1) receptors in the establishment of place conditioning in rats. Psychopharmacology, 135, 324–332. https://doi.org/10.1007/s002130050518

    Article  CAS  PubMed  Google Scholar 

  30. Gardner, E. L., Paredes, W., Smith, D., Donner, A., Milling, C., Cohen, D., & Morrison, D. (1988). Facilitation of brain stimulation reward by delta 9-tetrahydrocannabinol. Psychopharmacology, 96, 142–144. https://doi.org/10.1007/bf02431546

    Article  CAS  PubMed  Google Scholar 

  31. Lefever, T. W., Marusich, J. A., Antonazzo, K. R., & Wiley, J. L. (2014). Evaluation of WIN 55,212-2 self-administration in rats as a potential cannabinoid abuse liability model. Pharmacology, Biochemistry and Behavior, 118, 30–35. https://doi.org/10.1016/j.pbb.2014.01.002.

    Article  CAS  PubMed  Google Scholar 

  32. Valjent, E., & Maldonado, R. (2000). A behavioural model to reveal place preference to Δ 9-tetrahydrocannabinol in mice. Psychopharmacology, 147, 436–438. https://doi.org/10.1007/s002130050013

    Article  CAS  PubMed  Google Scholar 

  33. Vlachou, S., Nomikos, G. G., Stephens, D. N., & Panagis, G. (2007). Lack of evidence for appetitive effects of Δ9-tetrahydrocannabinol in the intracranial self-stimulation and conditioned place preference procedures in rodents. Behavioural Pharmacology, 18, 311–319. https://doi.org/10.1097/FBP.0b013e3282186cf2

    Article  CAS  PubMed  Google Scholar 

  34. Balster, R. L., & Prescott, W. R. (1992). Δ 9-tetrahydrocannabinol discrimination in rats as a model for cannabis intoxication. Neuroscience and Biobehavioral Reviews, 16, 55–62.

    Article  CAS  PubMed  Google Scholar 

  35. Wiley, J. L., Lowe, J. A., Balster, R. L., & Martin, B. R. (1995). Antagonism of the discriminative stimulus effects of Δ 9-tetrahydrocannabinol in rats and rhesus monkeys. Journal of Pharmacology and Experimental Therapeutics, 275, 1–6.

    CAS  PubMed  Google Scholar 

  36. Aceto, M. D., Scates, S. M., Lowe, J. A., & Martin, B. R. (1996). Dependence on Δ 9-tetrahydrocannabinol: Studies on precipitated and abrupt withdrawal. Journal of Pharmacology and Experimental Therapeutics, 278, 1290–1295.

    CAS  PubMed  Google Scholar 

  37. Lichtman, A. H., Fisher, J., & Martin, B. R. (2001). Precipitated cannabinoid withdrawal is reversed by Δ(9)-tetrahydrocannabinol or clonidine. Pharmacology, Biochemistry and Behavior, 69, 181–188. https://doi.org/10.1016/s0091-3057(01)00514-7

    Article  CAS  PubMed  Google Scholar 

  38. Trexler, K. R., Eckard, M. L., & Kinsey, S. G. (2019). CB(1) positive allosteric modulation attenuates ∆(9)-THC withdrawal and NSAID-induced gastric inflammation. Pharmacology, Biochemistry and Behavior, 177, 27–33. https://doi.org/10.1016/j.pbb.2018.12.009.

    Article  CAS  PubMed  Google Scholar 

  39. Tsou, K., Patrick, S. L., & Walker, J. M. (1995). Physical withdrawal in rats tolerant to Δ 9-tetrahydrocannabinol precipitated by a cannabinoid receptor antagonist. European Journal of Pharmacology, 280(15), R13. https://doi.org/10.1016/0014-2999(95)00360-w.

    Article  CAS  PubMed  Google Scholar 

  40. Delaunois, A., Dedoncker, P., Hanon, E., & Guyaux, M. (2009). Repeated assessment of cardiovascular and respiratory functions using combined telemetry and whole-body plethysmography in the rat. Journal of Pharmacological and Toxicological Methods, 60, 117–129. https://doi.org/10.1016/j.vascn.2009.07.003.

    Article  CAS  PubMed  Google Scholar 

  41. National Research Council. (2011). Guide for the care and use of laboratory animals National. Academies Press.

    Google Scholar 

  42. Wiley, J. L., Lefever, T. W., Glass, M., & Thomas, B. F. (2019). Do you feel it now? Route of administration and Δ(9)-tetrahydrocannabinol-like discriminative stimulus effects of synthetic cannabinoids in mice. Neurotoxicology, 73, 161–167. https://doi.org/10.1016/j.neuro.2019.04.002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Kitdumrongthum, S., & Trachootham, D. (2023). An individuality of response to cannabinoids: challenges in safety and efficacy of cannabis products. Molecules. https://doi.org/10.3390/molecules28062791

    Article  PubMed  PubMed Central  Google Scholar 

  44. Wiese, B. M., Alvarez Reyes, A., Vanderah, T. W., & Largent-Milnes, T. M. (2023). The endocannabinoid system and breathing. Frontiers in Neuroscience. https://doi.org/10.3389/fnins.2023.1126004

    Article  PubMed  PubMed Central  Google Scholar 

  45. Glass, M., Dragunow, M., & Faull, R. L. (1997). Cannabinoid receptors in the human brain: A detailed anatomical and quantitative autoradiographic study in the fetal, neonatal and adult human brain. Neuroscience, 77, 299–318. https://doi.org/10.1016/s0306-4522(96)00428-9.

    Article  CAS  PubMed  Google Scholar 

  46. Wiese, B. M., Liktor-Busa, E., Levine, A., Couture, S. A., Nikas, S. P., Ji, L., Liu, Y., Mackie, K., Makriyannis, A., Largent-Milnes, T. M., & Vanderah, T. W. (2021). Cannabinoid-2 agonism with AM2301 mitigates morphine-induced respiratory depression. Cannabis and Cannabinoid Research, 6, 401–412. https://doi.org/10.1089/can.2020.0076

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Del Negro, C. A., Funk, G. D., & Feldman, J. L. (2018). Breathing matters. Nature Reviews Neuroscience, 19, 351–367. https://doi.org/10.1038/s41583-018-0003-6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Calignano, A., Kátona, I., Désarnaud, F., Giuffrida, A., La Rana, G., Mackie, K., Freund, T. F., & Piomelli, D. (2000). Bidirectional control of airway responsiveness by endogenous cannabinoids. Nature, 408, 96–101. https://doi.org/10.1038/35040576.

    Article  CAS  PubMed  Google Scholar 

  49. Bozkurt, T. E. (2019). Endocannabinoid System in the Airways. Molecules. https://doi.org/10.3390/molecules24244626

    Article  PubMed  PubMed Central  Google Scholar 

  50. Tetrault, J. M., Crothers, K., Moore, B. A., Mehra, R., Concato, J., & Fiellin, D. A. (2007). Effects of marijuana smoking on pulmonary function and respiratory complications: A systematic review. Archives of Internal Medicine, 167, 221–228. https://doi.org/10.1001/archinte.167.3.221.

    Article  PubMed  PubMed Central  Google Scholar 

  51. Zwillich, C. W., Doekel, R., Hammill, S., & Weil, J. V. (1978). The effects of smoked marijuana on metabolism and respiratory control. The American Review of Respiratory Disease, 118, 885–891. https://doi.org/10.1164/arrd.1978.118.5.885.

    Article  CAS  PubMed  Google Scholar 

  52. Alon, M. H., & Saint-Fleur, M. O. (2017). Synthetic cannabinoid induced acute respiratory depression: Case series and literature review. Respiratory Medicine Case Reports, 22, 137–141. https://doi.org/10.1016/j.rmcr.2017.07.011

    Article  PubMed  PubMed Central  Google Scholar 

  53. **wala, F. N., & Gupta, M. (2012). Synthetic cannabis and respiratory depression. Journal of Child and Adolescent Psychopharmacology, 22, 459–462. https://doi.org/10.1089/cap.2011.0122.

    Article  CAS  PubMed  Google Scholar 

  54. Wong, K. U., & Baum, C. R. (2019). Acute cannabis toxicity. Pediatric Emergency Care, 35, 799–804. https://doi.org/10.1097/pec.0000000000001970

    Article  PubMed  Google Scholar 

  55. Jones, R. T. (2002). Cardiovascular system effects of marijuana. The Journal of Clinical Pharmacology, 42, 58s–63s. https://doi.org/10.1002/j.1552-4604.2002.tb06004.x

    Article  CAS  PubMed  Google Scholar 

  56. Malit, L. A., Johnstone, R. E., Bourke, D. I., Kulp, R. A., Klein, V., & Smith, T. C. (1975). Intravenous Δ9-tetrahydrocannabinol: Effects of ventilatory control and cardiovascular dynamics. Anesthesiology, 42, 666–673.

    Article  CAS  PubMed  Google Scholar 

  57. DeFilippis, E. M., Bajaj, N. S., Singh, A., Malloy, R., Givertz, M. M., Blankstein, R., Bhatt, D. L., & Vaduganathan, M. (2020). Marijuana use in patients with cardiovascular disease: JACC review topic of the week. Journal of the American College of Cardiology, 75, 320–332. https://doi.org/10.1016/j.jacc.2019.11.025

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Pacher, P., Steffens, S., Haskó, G., Schindler, T. H., & Kunos, G. (2018). Cardiovascular effects of marijuana and synthetic cannabinoids: The good, the bad, and the ugly. Nature Reviews. Cardiology, 15, 151–166. https://doi.org/10.1038/nrcardio.2017.130.

    Article  CAS  PubMed  Google Scholar 

  59. Rezkalla, S., & Kloner, R. A. (2019). Cardiovascular effects of marijuana. Trends in Cardiovascular Medicine, 29, 403–407. https://doi.org/10.1016/j.tcm.2018.11.004.

    Article  CAS  PubMed  Google Scholar 

  60. Page, R. L., II., Allen, L. A., Kloner, R. A., Carriker, C. R., Martel, C., Morris, A. A., Piano, M. R., Rana, J. S., & Saucedo, J. F. (2020). Medical marijuana, recreational cannabis, and cardiovascular health: A scientific statement from the american heart association. Circulation, 142, e131–e152. https://doi.org/10.1161/cir.0000000000000883

    Article  PubMed  Google Scholar 

  61. Farra, Y. M., Eden, M. J., Coleman, J. R., Kulkarni, P., Ferris, C. F., Oakes, J. M., & Bellini, C. (2020). Acute neuroradiological, behavioral, and physiological effects of nose-only exposure to vaporized cannabis in C57BL/6 mice. Inhal Toxicol, 32, 200–217. https://doi.org/10.1080/08958378.2020.1767237.

    Article  CAS  PubMed  Google Scholar 

  62. Iring, A., Ruisanchez, É., Leszl-Ishiguro, M., Horváth, B., Benkő, R., Lacza, Z., Járai, Z., Sándor, P., Di Marzo, V., Pacher, P., & Benyó, Z. (2013). Role of endocannabinoids and cannabinoid-1 receptors in cerebrocortical blood flow regulation. PLoS One, 8, e53390. https://doi.org/10.1371/journal.pone.0053390.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Schmid, K., Niederhoffer, N., & Szabo, B. (2003). Analysis of the respiratory effects of cannabinoids in rats. Naunyn-Schmiedeberg’S Archives of Pharmacology, 368, 301–308. https://doi.org/10.1007/s00210-003-0787-3.

    Article  CAS  PubMed  Google Scholar 

  64. Padley, J. R., Li, Q., Pilowsky, P. M., & Goodchild, A. K. (2003). Cannabinoid receptor activation in the rostral ventrolateral medulla oblongata evokes cardiorespiratory effects in anaesthetised rats. British Journal of Pharmacology, 140, 384–394. https://doi.org/10.1038/sj.bjp.0705422.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Pfitzer, T., Niederhoffer, N., & Szabo, B. (2004). Central effects of the cannabinoid receptor agonist WIN55212-2 on respiratory and cardiovascular regulation in anaesthetised rats. British Journal of Pharmacology, 142, 943–952. https://doi.org/10.1038/sj.bjp.0705874.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Vivian, J. A., Kishioka, S., Butelman, E. R., Broadbear, J., Lee, K. O., & Woods, J. H. (1998). Analgesic, respiratory and heart rate effects of cannabinoid and opioid agonists in rhesus monkeys: Antagonist effects of SR 141716A. Journal of Pharmacology and Experimental Therapeutics, 286, 697–703.

    CAS  PubMed  Google Scholar 

  67. Weed, P. F., Gerak, L. R., & France, C. P. (2018). Ventilatory-depressant effects of opioids alone and in combination with cannabinoids in rhesus monkeys. European Journal of Pharmacology, 833, 94–99. https://doi.org/10.1016/j.ejphar.2018.05.041.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Doherty, P. A., McCarthy, L. E., & Borison, H. L. (1983). Respiratory and cardiovascular depressant effects of nabilone, N-methyllevonantradol and Δ 9-tetrahydrocannabinol in anesthetized cats. Journal of Pharmacology and Experimental Therapeutics, 227, 508–516.

    CAS  PubMed  Google Scholar 

  69. Graham, J. D., & Li, D. M. (1973). Cardiovascular and respiratory effects of cannabis in cat and rat. British Journal of Pharmacology, 49, 1–10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Moss, I. R., & Friedman, E. (1976). Δ9-tetrahydrocannabinol: Depression of ventilatory regulation; other respiratory and cardiovascular effects. Life Sciences, 19, 99–104. https://doi.org/10.1016/0024-3205(76)90379-9.

    Article  CAS  PubMed  Google Scholar 

  71. Niederhoffer, N., & Szabo, B. (1999). Effect of the cannabinoid receptor agonist WIN55212-2 on sympathetic cardiovascular regulation. British Journal of Pharmacology, 126, 457–466. https://doi.org/10.1038/sj.bjp.0702337.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Marchetti, B., Bilel, S., Tirri, M., Arfè, R., Corli, G., Roda, E., Locatelli, C. A., Cavarretta, E., De Giorgio, F., & Marti, M. (2023). The old and the new: Cardiovascular and respiratory alterations induced by acute JWH-018 administration compared to ∆(9)-THC-A preclinical study in mice. International Journal of Molecular Sciences. https://doi.org/10.3390/ijms24021631

    Article  PubMed  PubMed Central  Google Scholar 

  73. Richards, J. R. (2020). Mechanisms for the risk of acute coronary syndrome and arrhythmia associated with phytogenic and synthetic cannabinoid use. Journal of Cardiovascular Pharmacology and Therapeutics, 25, 508–522. https://doi.org/10.1177/1074248420935743

    Article  PubMed  Google Scholar 

  74. Walker, M. K., Boberg, J. R., Walsh, M. T., Wolf, V., Trujillo, A., Duke, M. S., Palme, R., & Felton, L. A. (2012). A less stressful alternative to oral gavage for pharmacological and toxicological studies in mice. Toxicology and Applied Pharmacology, 260, 65–69. https://doi.org/10.1016/j.taap.2012.01.025

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Lunn, S., Diaz, P., O’Hearn, S., Cahill, S. P., Blake, A., Narine, K., & Dyck, J. R. B. (2019). Human pharmacokinetic parameters of orally administered ∆(9)-Tetrahydrocannabinol capsules are altered by Fed Versus fasted conditions and sex differences. Cannabis and Cannabinoid Research, 4, 255–264. https://doi.org/10.1089/can.2019.0037.

    Article  PubMed  PubMed Central  Google Scholar 

  76. Chaui-Berlinck, J. G., & Bicudo, J. E. (1998). The signal in total-body plethysmography: Errors due to adiabatic-isothermic difference. Respiration Physiology, 113, 259–270. https://doi.org/10.1016/S0034-5687(98)00060-7

    Article  CAS  PubMed  Google Scholar 

  77. Lundblad, L. K., Irvin, C. G., Adler, A., & Bates, J. H. (2002). A reevaluation of the validity of unrestrained plethysmography in mice. Journal of Applied Physiology, 93, 1198–1207. https://doi.org/10.1152/japplphysiol.00080.2002

    Article  PubMed  Google Scholar 

  78. Stucky, F., Cazzaniga, G., Aliverti, A., Kayser, B., & Uva, B. (2020). Automating the correction of flow integration drift during whole-body plethysmography. 2020 42nd Annual International Conference of the IEEE Engineering in Medicine & Biology Society, 2020, 5–8. https://doi.org/10.1109/embc44109.2020.9176170

    Article  Google Scholar 

  79. Marusich, J. A., Gamage, T. F., Zhang, Y., Akinfiresoye, L. R., & Wiley, J. L. (2022). In vitro and in vivo pharmacology of nine novel synthetic cannabinoid receptor agonists. Pharmacology Biochemistry and Behavior. https://doi.org/10.1016/j.pbb.2022.173467

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

The authors thank Shanequa Taylor, Nikita Pulley, and Kimberly Custer for excellent technical assistance. Statements and Declarations: Research was supported by U.S. National Institutes of Health / National Institute on Drug Abuse [grant numbers DA045003 and DA040460]. The funding source had no other role other than financial support. The authors have no relevant financial or non-financial interests to disclose. The datasets for the current study are available from the corresponding author on reasonable request.

Author information

Authors and Affiliations

  1. RTI International, 3040 Cornwallis Road Research Triangle Park, Research Triangle Park, NC, 27709, USA

    Lucas T. Laudermilk, Julie A. Marusich & Jenny L. Wiley

Authors
  1. Lucas T. Laudermilk
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Julie A. Marusich
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jenny L. Wiley
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Conceptualization: JLW, methodology: JAM and JLW formal analysis: JLW resources: JAM and JLW writing—original draft: LTL, JLW and JAM, writing—review and editing: LTL, JAM and JLW visualization: JLW funding acquisition: JAM and JLW.

Corresponding author

Correspondence to Julie A. Marusich.

Ethics declarations

Competing Interests

The authors declare no competing interests.

Additional information

Handling Editor: Matthew Campen.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

THC Effects on Respiration and Heart Rate in Mice Supplement (PDF 1077.2 kb)

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Laudermilk, L.T., Marusich, J.A. & Wiley, J.L. Δ9-Tetrahydrocannabinol Effects on Respiration and Heart Rate Across Route of Administration in Female and Male Mice. Cardiovasc Toxicol 23, 349–363 (2023). https://doi.org/10.1007/s12012-023-09810-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12012-023-09810-9

Keywords

Search

Navigation