Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Isradipine augmentation of virtual reality cue exposure therapy for tobacco craving: a triple-blind randomized controlled trial

Abstract

Preclinical research with rodents suggests that the L-type calcium channel blocker isradipine can enhance long-term extinction of conditioned place preference for addictive substances when it is administered in conjunction with extinction training. Although isradipine alone, which is FDA-approved for hypertension, has not shown a direct effect on craving in human drug users, its potential to augment behavioral treatments designed to reduce craving remains unknown. We conducted a triple-blind, randomized placebo-controlled pilot clinical trial of isradipine combined with a novel virtual reality cue exposure therapy (VR-CET) approach with multimodal cues that targeted craving. After 24 hours of abstinence, 78 adults with an ongoing history of daily cigarette use received isradipine (n = 40) or placebo (n = 38) and reported craving levels after each of 10 trials of VR-CET. Consistent with pre-registered hypotheses, the isradipine group had significantly lower mean craving across cue exposure trials at the medication-free 24-hour follow-up (d = −0.42, p = 0.046). There were no serious adverse events; however, side effects such as headache and dizziness occurred more frequently in the isradipine group. The findings of the current study support follow-up clinical trials that specifically test the efficacy of isradipine-augmented VR-CET for reducing smoking relapse rates after an initial quit attempt. clinicaltrials.gov: NCT03083353.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: CONSORT diagram of participant flow.
Fig. 2: Craving ratings during the treatment visit.
Fig. 3: Craving ratings during the follow-up visit.

Similar content being viewed by others

Data availability

The data and associated documentation will be made available to users under a data-sharing agreement that provides for: (1) a commitment to using the data only for research purposes and not to identify any individual participant; (2) a commitment to securing the data using appropriate computer technology; and (3) a commitment to destroying or returning the data after analyses are completed.

References

  1. World Health Organization. Tobacco Fact Sheet. 2020. https://www.who.int/docs/default-source/campaigns-and-initiatives/world-no-tobacco-day-2020/wntd-tobacco-fact-sheet.pdf

  2. Centers for Disease Control and Prevention. Smoking & Tobacco Use: Fast Facts and Fact Sheets. 2023. https://www.cdc.gov/tobacco/data_statistics/fact_sheets/fast_facts/index.htm

  3. Cornelius ME, Loretan CG, Wang TW, Jamal A, Homa DM. Tobacco product use among adults—United States, 2020. MMWR Morb Mortal Wkly Rep. 2022;71:397–405.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Xu X, Bishop EE, Kennedy SM, Simpson SA, Pechacek TF. Annual healthcare spending attributable to cigarette smoking: an update. Am J Prev Med. 2015;48:326–33.

    Article  PubMed  Google Scholar 

  5. Shrestha SS, Ghimire R, Wang X, Trivers KF, Homa DM, Armour BS. Cost of cigarette smoking‒attributable productivity losses, U.S., 2018. Am J Prev Med. 2022;63:478–85.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Max W, Sung H-Y, Shi Y. Deaths from secondhand smoke exposure in the United States: economic implications. Am J Public Health. 2012;102:2173–80.

    Article  PubMed  PubMed Central  Google Scholar 

  7. United States Public Health Service, Office of the Surgeon General, National Center for Chronic Disease Prevention and Health Promotion (U.S.), Office on Smoking and Health. Smoking Cessation: A Report of the Surgeon General. Washington, DC: U.S. Department of Health and Human Services; 2020.

  8. Vandaele Y, Daeppen J-B. From concepts to treatment: a dialog between a preclinical researcher and a clinician in addiction medicine. Transl Psychiatry. 2022;12:401.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Liu X, Yuan K, Lu T, Lin X, Zheng W, Xue Y, et al. Preventing incubation of drug craving to treat drug relapse: from bench to bedside. Mol Psychiatry. 2023;28:1415–29.

    Article  PubMed  Google Scholar 

  10. Ferguson SG, Shiffman S. The relevance and treatment of cue-induced cravings in tobacco dependence. J Subst Abuse Treat. 2009;36:235–43.

    Article  PubMed  Google Scholar 

  11. Laviolette SR, van der Kooy D. The neurobiology of nicotine addiction: bridging the gap from molecules to behaviour. Nat Rev Neurosci. 2004;5:55–65.

    Article  CAS  PubMed  Google Scholar 

  12. Volkow ND, Fowler JS, Wang G-J, Swanson JM. Dopamine in drug abuse and addiction: results from imaging studies and treatment implications. Mol Psychiatry. 2004;9:557–69.

    Article  CAS  PubMed  Google Scholar 

  13. Hiroi N, Scott D. Constitutional mechanisms of vulnerability and resilience to nicotine dependence. Mol Psychiatry. 2009;14:653–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Hyman SE, Malenka RC, Nestler EJ. Neural mechanisms of addiction: the role of reward-related learning and memory. Annu Rev Neurosci. 2006;29:565–98.

    Article  CAS  PubMed  Google Scholar 

  15. Koob GF, Volkow ND. Neurobiology of addiction: a neurocircuitry analysis. Lancet Psychiatry. 2016;3:760–73.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Conklin CA, Robin N, Perkins KA, Salkeld RP, McClernon FJ. Proximal versus distal cues to smoke: the effects of environments on smokers’ cue-reactivity. Exp Clin Psychopharmacol. 2008;16:207–14.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Lazev AB, Herzog TA, Brandon TH. Classical conditions of environmental cues to cigarette smoking. Exp Clin Psychopharmacol. 1999;7:56–63.

    Article  CAS  PubMed  Google Scholar 

  18. Bagot KS, Heishman SJ, Moolchan ET. Tobacco craving predicts lapse to smoking among adolescent smokers in cessation treatment. Nicotine Tob Res. 2007;9:647–52.

    Article  PubMed  Google Scholar 

  19. Janes AC, Pizzagalli DA, Richardt S, deB Frederick B, Chuzi S, Pachas G, et al. Brain reactivity to smoking cues prior to smoking cessation predicts ability to maintain tobacco abstinence. Biol Psychiatry. 2010;67:722–9.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Carter BL, Tiffany ST. Meta-analysis of cue-reactivity in addiction research. Addiction. 1999;94:327–40.

    Article  CAS  PubMed  Google Scholar 

  21. Owens MM, MacKillop J, Gray JC, Beach SRH, Stein MD, Niaura RS, et al. Neural correlates of tobacco cue reactivity predict duration to lapse and continuous abstinence in smoking cessation treatment. Addict Biol. 2018;23:1189–99.

    Article  CAS  PubMed  Google Scholar 

  22. Vafaie N, Kober H. Association of drug cues and craving with drug use and relapse: a systematic review and meta-analysis. JAMA Psychiatry. 2022;79:641–50.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Papini S, Young CC, Gebhardt CS, Perrone A, Morikawa H, Otto MW, et al. Isradipine enhancement of virtual reality cue exposure for smoking cessation: rationale and study protocol for a double-blind randomized controlled trial. Contemp Clin Trials. 2020;94:106013.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Little HJ. L-type calcium channel blockers: a potential novel therapeutic approach to drug dependence. Pharmacol Rev. 2021;73:127–54.

    Article  CAS  PubMed  Google Scholar 

  25. Gonzales PM, Boswell KJ, Hubbell CL, Reid LD. Isradipine blocks cocaine’s ability to facilitate pressing for intracranial stimulation. Pharmacol Biochem Behav. 1997;58:1117–22.

    Article  CAS  PubMed  Google Scholar 

  26. Martellotta MC, Kuzmin A, Muglia P, Gessa GL, Fratta W. Effects of the calcium antagonist isradipine on cocaine intravenous self-administration in rats. Psychopharmacology. 1994;113:378–80.

    Article  CAS  PubMed  Google Scholar 

  27. Mills K, Ansah TA, Ali SF, Shockley DC. Calcium Channel Antagonist Isradipine Attenuates Cocaine-Induced Motor Activity in Rats: Correlation with Brain Monoamine Levelsa. Ann N Y Acad Sci. 1998;844:201–7.

    Article  CAS  PubMed  Google Scholar 

  28. Addy NA, Nunes EJ, Hughley SM, Small KM, Baracz SJ, Haight JL, et al. The L-type calcium channel blocker, isradipine, attenuates cue-induced cocaine-seeking by enhancing dopaminergic activity in the ventral tegmental area to nucleus accumbens pathway. Neuropsychopharmacology. 2018;43:2361–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Pucilowski O, Płaźnik A, Overstreet DH. Isradipine suppresses amphetamine-induced conditioned place preference and locomotor stimulation in the rat. Neuropsychopharmacology. 1995;12:239–44.

    Article  CAS  PubMed  Google Scholar 

  30. Degoulet M, Stelly CE, Ahn K-C, Morikawa H. L-type Ca2+ channel blockade with antihypertensive medication disrupts VTA synaptic plasticity and drug-associated contextual memory. Mol Psychiatry. 2016;21:394–402.

    Article  CAS  PubMed  Google Scholar 

  31. Natal S, Young CC, Kaur K, Gebhardt ES, Perrone A, Morikawa H, et al. Applications of isradipine in human addiction studies: a systematic literature review. Exp Clin Psychopharmacol. 2023;31:507–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Conklin CA, Tiffany ST. Applying extinction research and theory to cue exposure addiction treatments. Addiction. 2002;97:155–67.

    Article  PubMed  Google Scholar 

  33. Malbos E, Borwell B, Einig-Iscain M, Korchia T, Cantalupi R, Boyer L, et al. Virtual reality cue exposure therapy for tobacco relapse prevention: a comparative study with standard intervention. Psychol Med. 2023;53:5070–80.

    Article  PubMed  Google Scholar 

  34. Segawa T, Baudry T, Bourla A, Blanc JV, Peretti CS, Mouchabac S, et al. Virtual reality (VR) in assessment and treatment of addictive disorders: A systematic review. Front Neurosci. 2020;13:1–14.

    Article  Google Scholar 

  35. Sheehan DV, Lecrubier Y, Sheehan KH, Amorim P, Janavs J, Weiller E, et al. The Mini-International Neuropsychiatric Interview (M.I.N.I.): the development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10. J Clin Psychiatry. 1998;59:22–33.

    PubMed  Google Scholar 

  36. Diagnostic and Statistical Manual of Mental Disorders: DSM-5. Washington, DC: American Psychiatric Association; 2013.

  37. Posner K, Brown GK, Stanley B, Brent DA, Yershova KV, Oquendo MA, et al. The Columbia-Suicide Severity Rating Scale: initial validity and internal consistency findings from three multisite studies with adolescents and adults. Am J Psychiatry. 2011;168:1266–77.

    Article  PubMed  PubMed Central  Google Scholar 

  38. Conti AA, Tolomeo S, Steele JD, Baldacchino AM. Severity of negative mood and anxiety symptoms occurring during acute abstinence from tobacco: a systematic review and meta-analysis. Neurosci Biobehav Rev. 2020;115:48–63.

    Article  CAS  PubMed  Google Scholar 

  39. Perkins KA, Karelitz JL, Jao NC. Optimal carbon monoxide criteria to confirm 24-hr smoking abstinence. Nicotine Tob Res. 2013;15:978–82.

    Article  CAS  PubMed  Google Scholar 

  40. Johnson BA, Ait-Daoud N, Wells LT. Effects of isradipine, a dihydropyridine-class calcium channel antagonist, on D-methamphetamine-induced cognitive and physiological changes in humans. Neuropsychopharmacology. 2000;22:504–12.

    Article  CAS  PubMed  Google Scholar 

  41. Johnson BA, Roache JD, Ait-Daoud N, Wells LT, Mauldin JB. Effects of isradipine on cocaine-induced subjective mood. J Clin Psychopharmacol. 2004;24:180–91.

    Article  CAS  PubMed  Google Scholar 

  42. Johnson BA, Roache JD, Bordnick PS, Ait-Daoud N. Isradipine, a dihydropyridine-class calcium channel antagonist, attenuates some of d-methamphetamine’s positive subjective effects: a preliminary study. Psychopharmacology. 1999;144:295–300.

    Article  CAS  PubMed  Google Scholar 

  43. Johnson BA, Roache JD, Ait-Daoud N, Wallace CL, Wells LT, Wang Y, et al. Effects of isradipine on cocaine-induced changes in cognitive performance in recently abstinent cocaine-dependent individuals. Int J Neuropsychopharmacol. 2005;8:549–56.

    Article  CAS  PubMed  Google Scholar 

  44. Johnson BA, Wells LT, Roache JD, Wallace C, Ait-Daoud N, Wang Y. Isradipine decreases the hemodynamic response of cocaine and methamphetamine: results from two human laboratory studies. Am J Hypertens. 2005;18:813–22.

    Article  CAS  PubMed  Google Scholar 

  45. Roache JD, Johnson BA, Ait-Daoud N, Mauldin JB, Thornton JE, Wells LT, et al. Effects of repeated-dose isradipine on the abuse liability of cocaine. Exp Clin Psychopharmacol. 2005;13:319–26.

    Article  CAS  PubMed  Google Scholar 

  46. Torregrossa MM, Taylor JR. Learning to forget: manipulating extinction and reconsolidation processes to treat addiction. Psychopharmacology. 2013;226:659–72.

    Article  CAS  PubMed  Google Scholar 

  47. Luo M, Gan Q, Fu Y, Chen Z. Cue-reactivity targeted smoking cessation intervention in individuals with tobacco use disorder: a scoping review. Front Psychiatry. 2023;14:1167283.

    Article  PubMed  PubMed Central  Google Scholar 

  48. Pericot-Valverde I, Germeroth LJ, Tiffany ST. The use of virtual reality in the production of cue-specific craving for cigarettes: a meta-analysis. Nicotine Tob Res. 2016;18:538–46.

    Article  PubMed  Google Scholar 

  49. Betts JM, Dowd AN, Forney M, Hetelekides E, Tiffany ST. A meta-analysis of cue reactivity in tobacco cigarette smokers. Nicotine Tob Res. 2021;23:249–58.

    Article  PubMed  Google Scholar 

  50. R Core Team R. R: A Language and Environment for Statistical Computing. Vienna, Austria: R Foundation for Statistical Computing; 2013.

  51. van Buuren S, Groothuis-Oudshoorn K. Mice: multivariate imputation by chained equations in R. J Stat Softw. 2011;45:1–67.

    Article  Google Scholar 

  52. Schröder B, Kroczek A, Kroczek LOH. Cigarette craving in virtual reality cue exposure in abstainers and relapsed smokers. Sci Rep. 2024;14:7538.

    Article  PubMed  PubMed Central  Google Scholar 

  53. Shiffman S, Scharf DM, Shadel WG, Gwaltney CJ, Dang Q, Paton SM, et al. Analyzing milestones in smoking cessation: illustration in a nicotine patch trial in adult smokers. J Consult Clin Psychol. 2006;74:276–85.

    Article  PubMed  Google Scholar 

  54. Tiffany ST, Cox LS, Elash CA. Effects of transdermal nicotine patches on abstinence-induced and cue-elicited craving in cigarette smokers. J Consult Clin Psychol. 2000;68:233–40.

    Article  CAS  PubMed  Google Scholar 

  55. Waters AJ, Shiffman S, Sayette MA, Paty JA, Gwaltney CJ, Balabanis MH. Cue-provoked craving and nicotine replacement therapy in smoking cessation. J Consult Clin Psychol. 2004;72:1136–43.

    Article  PubMed  Google Scholar 

  56. Bavley CC, Fetcho RN, Burgdorf CE, Walsh AP, Fischer DK, Hall BS, et al. Cocaine- and stress-primed reinstatement of drug-associated memories elicit differential behavioral and frontostriatal circuit activity patterns via recruitment of L-type Ca2+ channels. Mol Psychiatry. 2020;25:2373–91.

    Article  CAS  PubMed  Google Scholar 

  57. Biala G, Budzynska B. Reinstatement of nicotine-conditioned place preference by drug priming: effects of calcium channel antagonists. Eur J Pharmacol. 2006;537:85–93.

    Article  CAS  PubMed  Google Scholar 

  58. Morikawa H, Young CC, Smits J. Usage of L-type calcium channel blockers to suppress drug reward, memory and addiction: past, present, and future. Neuropharm. 2022;221:109290.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We would like to acknowledge the substantial contributions of the following individuals to successful completion of this project: Alejandra Gonzalez-Badia, Eli Gebhardt, Alexander Perrone, Annabelle DiVita, Samanta Natal, Karamveer Kaur, and Dr. Stephen Blair and Dr. Stephanie Morgan.

Funding

This research was supported by a grant from The National Institutes of Health, National Institute of Drug Abuse (1R21DA049539-01; MPI: Young & Smits).

Author information

Authors and Affiliations

Authors

Contributions

Drs. Young, Papini, and Smits made substantial contributions to the conception or design of the work; the acquisition, analysis, or interpretation of data for the work; Drafting the work or revising it critically for important intellectual content; Final approval of the version to be published; and Agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. Drs. Minami, Morikawa, Roache and Otto made substantial contributions to the conception or design of the work; the analysis, or interpretation of data for the work; Revising the work critically for important intellectual content; and Final approval of the version to be published.

Corresponding author

Correspondence to Cara C. Young.

Ethics declarations

Competing interests

MO: No conflicts in relation to the topic of this manuscript, but he is compensated for his role as an advisor for Big Health and also receives grant funding from Big Health. JS reports receiving grants from the NIH and DOD and personal fees from Big Health, Elsevier, American Psychological Association, Oxford University Press, and Springer. He also has equity ownership in Earkick, Inc. Earkick does not develop products that are related to the current study. HM receives current funding from NIH/NIDA [R01DA054274]. The other authors declare no competing interests.

Additional information

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

Supplementary information

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

Young, C.C., Papini, S., Minami, H. et al. Isradipine augmentation of virtual reality cue exposure therapy for tobacco craving: a triple-blind randomized controlled trial. Neuropsychopharmacol. (2024). https://doi.org/10.1038/s41386-024-01872-9

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1038/s41386-024-01872-9

Search

Quick links